N1, N2, N3 N3 n-3 Fatty Acids National Cancer Institute - Springer Link

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N1, N2, N3 ▶ Non-REM Sleep

N3 ▶ Slow-Wave Sleep

n-3 Fatty Acids ▶ Omega-3 Fatty Acids

National Cancer Institute Jasmin Tiro and Simon J. Craddock Lee Department of Clinical Sciences, The University of Texas Southwestern Medical Center, Dallas, TX, USA

Basic Information The US National Cancer Institute (NCI) The National Cancer Institute is the oldest and largest of the 27 institutes and 6 centers that comprise the US National Institutes of Health (NIH), which are part of the US Department of Health and Human Services (DHHS) Public

Health Service (PHS). First established in 1937 by Congress, NCI’s mission and responsibilities were expanded in the National Cancer Act of 1971. Currently, the NCI’s main responsibility is to coordinate the National Cancer Program, which fosters research, training, and health information dissemination programs with respect to the cause, diagnosis, prevention, and treatment of cancer, rehabilitation from cancer, and survivorship concerns of cancer patients and their families. Through this program, the NCI: • Supports a national network of regional and community cancer centers • Conducts and fosters cancer research through intramural (its own laboratories and clinics) and extramural programs (grants and cooperative agreements with universities, hospitals, research foundations, and businesses) • Reviews, approves, and monitors grants supporting novel research projects on the causes, diagnosis, treatment, and prevention of cancer • Collects, analyzes, and disseminates cancer research findings • Trains health professionals in cancer diagnosis and treatment and researchers in basic, clinical, cancer control, behavioral, and population sciences • Supports collaborative research between US and foreign researchers Unique Budget Process of the NCI Unique among the institutes in the NIH, NCI has the authority to submit an annual budget

M.D. Gellman & J.R. Turner (eds.), Encyclopedia of Behavioral Medicine, DOI 10.1007/978-1-4419-1005-9, # Springer Science+Business Media New York 2013

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National Cancer Institute

National Cancer Institute, Fig. 1 Bypass budget process of the National Cancer Institute (The National Cancer Institute, NIH (Bethesda, MD), http://www.cancer. gov/aboutnci/ servingpeople/nci-budgetinformation/budgetprocess. Accessed date 7/2011)

proposal directly to the president (called the “Bypass Budget” because it circumvents the NIH/DHHS budget process; see Fig. 1). The White House Office of Management and Budget (OMB) reviews and integrates the NCI proposal into the president’s executive branch budget which reflects the administration’s fiscal and management priorities for the next year. Then, Congress reviews the president’s proposal and makes a recommendation, and final appropriations are enacted into law after approval by both houses of Congress and signature by the president. Every year, NCI publishes online the Bypass Budget Proposal for the coming fiscal year and the Annual Fact Book, which summarizes the distribution of budget among the research programs and funding mechanisms for the past fiscal year. In 2009, NCI’s budget was $4.97 billion not including the additional $1.26 billion from the American Recovery and Reinvestment Act (ARRA) funds intended to be distributed in fiscal years 2009 and 2010. Approximately 43% of the total NCI 2009 budget was allocated for 5,461 research project grants, including 543 grants made possible by ARRA funds. The US government has made cancer a national priority and has allocated significant resources to understand the complexity of cancer as a disease process as well as processes of cancer care. Thus, the NCI has become a leading supporter of behavioral, social, and population research in basic, intervention, and applied science related to cancer.

NCI Organizational Structure and Governance The NCI’s organizational structure consists of the Office of the NCI Director, two intramural divisions/centers, and five extramural divisions. The current NCI director is Dr. Harold Varmus, Nobel laureate. The NCI director receives programmatic and scientific advice and counsel from three national bodies of appointed experts. The National Cancer Advisory Board (NCAB) advises the secretary of DHHS and the NCI director with respect to the activities of the Institute. Appointed by the president, members are leading representatives of health and scientific disciplines, including at least two experts in public health and the behavioral or social sciences. NCAB approves research grant award decisions made by NCI program staff who prioritize applications ranked according to scientific merit through independent peer review. The Board of Scientific Advisors (BSA) provides scientific advice and guidance on a wide variety of matters concerning scientific program policy, progress, and future direction of the NCI’s extramural research programs and provides concept review of extramural program initiatives. The BSA charter specifically requires that one or more members have expertise with cancer epidemiology, cancer prevention and control, cancer education, cancer information services, and community outreach. The Board of Scientific Counselors (BSC) provides analogous scientific advice and guidance regarding intramural research programs.

National Cancer Institute

Major Impact on the Field Division of Cancer Control and Population Sciences (DCCPS) The main division charged with fostering behavioral medicine is the extramural Division of Cancer Control and Population Sciences (DCCPS), created in 1997 and currently led by social psychologist, Dr. Robert Croyle. Cancer control science is defined as “basic and applied research in the behavioral, social, and population sciences to create or enhance interventions that, independently or in combination with biomedical approaches, reduce cancer risk, incidence, morbidity and mortality, and improve quality of life” (Cancer Control Program Review Group, 1998modified). For a history of cancer control and commentary on how to advance the science of cancer control, see Hiatt and Rimer (1999). DCCPS conducts and supports integrated research in a wide range of disciplines and fields including anthropology, behavioral sciences, demography, epidemiology, genetics, health communication, health policy, health services research, psychology, public health, sociology, and surveillance. DCCPS funds research on the full continuum of cancer control that spans prevention, detection, diagnosis, treatment, survivorship, and end-of-life care to “understand the causes and distribution of cancer in populations; support the development and delivery of effective interventions; monitor and explain cancer trends in all segments of the population.” As a result of its mission, DCCPS represents one of the largest concentrations of social, behavioral, and population scientists at the NIH. DCCPS is organized around five research program areas: Epidemiology and Genetics, Surveillance, Applied, Behavioral, and Survivorship. The latter three programs are of central interest to researchers in behavioral medicine. The Applied Research Program fosters research to understand how and why cancer care and control activities in the USA influence patterns and trends in cancer outcomes (incidence, morbidity, mortality, and survival). The Behavioral Research Program fosters a wide range of research from basic behavioral research to

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evaluation and dissemination of interventions to promote cancer prevention and control behaviors and informed decision-making. The Office of Cancer Survivorship fosters research on the short- and long-term biopsychosocial effects of cancer and its treatment. An overview of the history and scientific accomplishments of the first 10 years of DCCPS (1997–2007) can be found online at the NCI website (www. cancercontrol.gov). Current Major Programs and Initiatives of DCCPS

DCCPS is a leader in supporting transdisciplinary research in tobacco control, population health disparities, cancer-related energetics (physical activity), cancer screening, and health communication research (Croyle, 2008; Rebbeck, Paskett, & Sellers, 2010; Stokols et al., 2003). DCCPS has led or partnered with other institutes and offices (e.g., National Heart, Lung, and Blood Institute; National Institute on Minority Health and Health Disparities) on large NIH funding mechanisms to establish research centers to leverage transdisciplinary and team science research in these cancer domains. DCCPS also collaborates with the NIH Office of Behavioral and Social Science Research (OBSSR) to jointly fund innovative grants and projects. For example, the Grid-Enabled Measures Database enables researchers to share standardized measures of theory-based constructs through OppNet, a trans-NIH initiative to fund and advance research elucidating mechanisms and processes within and among individuals and groups that affect health-related behaviors. Other key theoretic and methodologic initiatives that engage behavioral medicine include cognitive, affective, and social processes in health, health behavior theory development, measurement of health constructs (e.g., quality of cancer care), questionnaire design and testing, and the integration of behavioral and biomedical scientific approaches (Stefanek et al., 2009). These scientific areas are reflected in networks of individual investigators collaborating with NCI scientific staff, as well as in funding opportunities calling for grant applications to advance these efforts.

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Cancer Centers Program The National Cancer Act of 1971 also established NCI-designated Cancer Centers for clinical research, training, and demonstration of advanced diagnostic and treatment methods for cancer. To be awarded designation, these centers must periodically undergo peer review and meet a national series of competitive standards and demonstrate excellence in cancer research through the operation of formal programs. As of 2010, there are 66 Cancer Centers across the USA that have been awarded NCI designation. Forty of these centers carry Comprehensive Cancer Center status, which reflects integration and collaborative research in clinical trials and patient care, as well as programmatic emphases in epidemiology and cancer control. As such, NCI-designated Comprehensive Cancer Centers are often leading proponents of cancer-related behavioral medicine.

Conclusion The US National Cancer Institute is the largest organization dedicated to supporting cancer research in the world. Through its efforts, it provides vision and leadership to the global cancer community. This is especially true in the area of behavioral oncology and cancer control. The NCI recognizes the importance of transdisciplinary research efforts in addressing the cancer continuum.

References and Readings Croyle, R. T. (2008). The National Cancer Institute’s transdisciplinary centers initiatives and the need for building a science of team science. American Journal of Preventive Medicine, 35(Suppl. 2), s90–s93. Hiatt, R. A., & Rimer, B. K. (1999). A new strategy for cancer control research. Cancer Epidemiology, Biomarkers & Prevention, 8(11), 957–964. NCI Division of Cancer Control & Population Sciences. Available at: http://cancercontrol.cancer.gov/index. html. Accessed April 2011. Niederhuber, J. E. (2007). A look inside the national cancer institute budget process: Implications for 2007 and beyond. Cancer Research, 67, 856–862. Rebbeck, T. R., Paskett, E., & Sellers, T. A. (2010). Fostering transdisciplinary science. Cancer Epidemiology, Biomarkers & Prevention, 19(5), 1149–1150.

National Children’s Study Stefanek, M. E., Andrykowski, M. A., Lerman, C., Manne, S., Glanz, K., & AACR behavioral science task force. (2009). Behavioral oncology and the war on cancer: Partnering with biomedicine. Cancer Research, 69(18), 7151–7156. Stokols D, Fuqua J, Gress J, Harvey R, Phillips K, Baezconde-Garbanati L, Unger J, Palmer P, Clark MA, Colby SM, Morgan G, Trochim W. (2003). Evaluating transdisciplinary science. Nicotine Tobacco Research, 5(S1): S21–39.

National Children’s Study Steven E. Lipshultz1, Tracie L. Miller2, James D. Wilkinson2 and Miriam A. Mestre3 1 Department of Pediatrics, Epidemiology and Public Health, and Medicine (Oncology), Leonard M. Miller School of Medicine University of Miami Holtz Children’s Hospital of the University of Miami-Jackson Memorial Medical Center Batchelor Children’s Research Institute Mailman Center for Child Development University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA 2 Department of Pediatrics and Epidemiology and Public Health Division of Pediatric Clinical Research Department of Pediatrics, Leonard M. Miller School of Medicine University of Miami Holtz Children’s Hospital of the University of Miami-Jackson Memorial Medical Center Batchelor Children’s Research Institute University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA 3 Division of Pediatric Clinical Research Department of Pediatrics, Leonard M. Miller School of Medicine University of Miami, Miami, FL, USA

Synonyms NCS

Definition The National Children’s Study (NCS) will be the largest longitudinal study of children’s health,

National Health and Nutrition Examination Survey (NHANES)

growth, and development ever conducted in the United States. The main study aims to recruit women from randomly selected study locations around the country, and a sample of 100,000 children born to these recruited mothers will be followed from before birth to 21 years of age. “It is the first large birth cohort study in any nation to specifically examine the influence of environmental factors on birth outcomes, child health, and human development and the first designed to systematically examine the influence of geneenvironment interactions on children’s health” (Landrigan et al., 2006). The NCS defines “environment” broadly, such as air, water, soil, noise, stress, and exposure to natural and manufactured products. By studying children through different phases of growth and development, researchers may be better able to understand the role these factors have on health and disease. The National Children’s Study is led by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH) in collaboration with a consortium of federal government partners. Study partners include the National Institute of Environmental Health Sciences of the NIH, the Centers for Disease Control and Prevention, and the Environmental Protection Agency. The NCS will concentrate on collecting data geared toward the following broad outcomes with key public health significance: pregnancy outcome, neurodevelopment and behavior, lung and airway disease, physical growth and body composition, and injury. Analysis of pilot data from field testing at a subgroup of NCS sites has resulted in modifications to the original study design. The NCS main study is currently scheduled to begin in 2013

Cross-References ▶ Body Composition ▶ Centers for Disease Control and Prevention ▶ Gene-Environment Interaction ▶ Longitudinal Research ▶ National Institute of Child Health and Human Development ▶ National Institutes of Health

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References and Readings Landrigan, P. J., Trasande, L., Thorpe, L. E., Gwynn, C., Lioy, P. J., D’Alton, M. E., et al. (2006). The National Children’s Study: A 21-year prospective study of 100 000 American children. Pediatrics, 118, 2173–2186. Retrieved from www.nationalchildrensstudy.gov

National Health and Nutrition Examination Survey, The ▶ National Health and Nutrition Examination Survey (NHANES)

National Health and Nutrition Examination Survey (NHANES) Barbara Resnick School of Nursing, University of Maryland, Baltimore, MD, USA

Synonyms National health and nutrition examination survey, The

Definition The National Health and Nutrition Examination Survey (NHANES) is a program of studies designed to assess the health and nutritional status of adults and children in the United States. The survey is unique in that it combines interviews and physical examinations. NHANES is a major program of the National Center for Health Statistics (NCHS). NCHS is part of the Centers for Disease Control and Prevention (CDC) and has the responsibility for producing vital and health statistics for the nation. The NHANES program began in the early 1960s and has been conducted as a series of surveys focusing on different population groups

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or health topics. In 1999, the survey became a continuous program. The focus of the survey changes based on current health care trends and needs. Each year the survey includes a sample of 5,000 persons representative of the general population. The NHANES interview includes demographic, socioeconomic, dietary, and healthrelated questions. The examination component consists of medical, dental, and physiological measurements, as well as laboratory tests administered by medical personnel. Findings from this survey are used to determine the prevalence of major diseases and risk factors for diseases. Information is available to consider such things as nutritional status and its association with health promotion and disease prevention. NHANES data are also used to set norms for height, weight, and blood pressure and to establish public health policy, to guide health maintenance and prevention program and services and expand what is known about health in our country.

References and Readings The National Health and Nutrition Examination Survey (NHANES). Retrieved from http://www.cdc.gov/ nchs/nhanes/about_nhanes.htm

National Health Interview Survey Donna Miller1, Cristina A. Fernandez2 and David J. Lee2 1 Centers for Disease Control and Prevention, National Center for Health Statistics, Hyattsville, MD, USA 2 Department of Epidemiology and Public Health, Miller School of Medicine, University of Miami, Miami, FL, USA

Synonyms National health survey; NHIS

National Health Interview Survey

Basic Information The National Health Interview Survey (NHIS) is a principal source of information on the health status of the civilian noninstitutionalized population of the United States. The NHIS is one of the major data collection programs of the National Center for Health Statistics (NCHS), a component of the Centers for Disease Control and Prevention (CDC). The NHIS has been in the field continuously since 1957 and is the nation’s largest household health survey. The survey was authorized by Congress in order to obtain national estimates on disease, injury, impairment, disability, and related issues for the US population. The NHIS has evolved over the years, with significant questionnaire redesigns in 1982 and 1997.

Major Impact on the Field Purpose The main objective of the NHIS is to monitor the health of the United States population through the collection and analysis of data on a broad range of health topics. The NHIS provides data for the analysis of health trends, barriers to care, health status, health-care access and utilization, healthrelated behaviors, and risk factors. A major strength of this survey lies in the ability to display these health characteristics by many demographic and socioeconomic characteristics. Survey results have been instrumental in tracking health status and health-care access, and monitoring progress toward achieving national health objectives. The NHIS is a major source of data used for Healthy People, which provides 10-year national health objectives and tracks progress toward achieving them for improving the health of all Americans. Sample Design The NHIS is a cross-sectional household interview survey designed to be representative of the civilian noninstitutionalized population of the United States. The sampling plan follows a multistage area probability design that permits

National Health Interview Survey

the representative sampling of households and noninstitutional group quarters (e.g., college dormitories). The NHIS sample design is reevaluated and modified after every US decennial census. The NHIS sample design oversamples selected minority subgroups including African Americans, Hispanics, and starting in 2006, Asians. Persons aged 65+ in these selected minority groups are also oversampled. Since the last NHIS sample redesign was implemented in 2006, the expected annual interviewed sample size has been about 35,000 households with approximately 87,500 persons, although the sample sizes vary appreciably over time. The NHIS data files contain sample weights based on the unit of analysis (e.g., household, person). The NHIS sample is chosen such that each person in the covered population has a known nonzero probability of selection. These probabilities of selection, along with adjustments for nonresponse and post-stratification to sex, age, and race/ethnicity census population control totals, are reflected in the sample weights provided. It is necessary to utilize the weights provided in analyses of the NHIS data, along with the stratification and primary sampling unit information, for valid statistical inferences. Content of the Questionnaire The NHIS collects basic health and demographic data, which can be used to develop prevalence estimates of a wide variety of health measures. The NHIS questionnaire contains a set of Core questions and Supplemental questions. The Core includes questions about chronic conditions, disability, health behaviors, risk factors, health insurance coverage, and health-care use. Core questions have remained largely unchanged since 1997, which allows for trend analysis and for pooling data from more than one NHIS year, thus increasing the sample size for analytic purposes. The Supplemental questions change from year to year and collect additional data pertaining to current health issues of national importance (e.g., cancer, immunization, diabetes). A 1997 questionnaire redesign separated the Core questions into three main components: the

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Family Core (collects information on all family members), the Sample Adult Core (collects information directly from one randomly selected adult, aged 18 and over, in each family in the household), and the Sample Child Core, which is only administered if a child resides in the family (collects information on one randomly selected child, aged 17 and under, from a knowledgeable adult family member). The Family Core questionnaire includes sections on health status and limitations, injuries and poisoning, health-care access and use, health insurance coverage, and sociodemographic characteristics. The Sample Adult Core questionnaire includes sections on health conditions and health behaviors in addition to more detailed questions on some topics included in the Family Core. The Sample Child Core questionnaire includes questions on health conditions and more detailed questions on some topics included in the family core. Data Collection Procedures The NHIS data are collected by interviewers who are employed and trained by the US Census Bureau in accordance with procedures specified by NCHS, via personal household interviews. Prior to 1997, NHIS interviews were conducted using paper and pencil. After a questionnaire redesign was implemented in 1997, all data were collected by interviewers using computerassisted personal interviewing, allowing interviewers to enter responses directly into the computer during the interviews. Prior to 1997, all adult members of the household aged 18 and over who were at home at the time of the interview were invited to participate and to respond for themselves; however, a proxy respondent often provided responses for all household members. After the 1997 questionnaire redesign, a greater emphasis was placed on self-reporting to improve data quality. Data collection procedures for conducting the household, family, and children interviews remained largely unchanged, but sample adults must respond for themselves (except in rare cases where they are unable to do so).

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Confidentiality All data collected in the NHIS are used for statistical purposes only and are guaranteed by law to be held in the strictest of confidence. Survey participation is voluntary, and the confidentiality of responses is assured under Section 308(d) of the Public Health Service Act, which forbids the disclosure of any information that may compromise the confidentiality promised to its survey respondents. Record Linkages The NHIS data are routinely linked to administrative records enabling researchers to examine factors that influence disability, chronic disease, health-care utilization, morbidity, and mortality. The NHIS is linked to death certificate records from the National Death Index; Medicare and Medicaid enrollment and claims data from the Centers for Medicare and Medicaid Services; and Retirement, Survivor and Disability Insurance and Supplemental Security Income benefit data from the Social Security Administration. Immunization data for children in the 1997– 1999 NHIS are linked to physician medical records in the National Immunization Provider Record Check Study. Starting with the 1996 Medical Expenditure Panel Survey (MEPS), the NHIS data can be linked to the MEPS data which are drawn from a subsample of households that participated in the prior year’s NHIS, allowing users to link, for example, the 1995 NHIS to the 1996 MEPS. The NHIS data are also linked to contextual data including air monitoring data obtained from the Environmental Protection Agency. Data Availability The NHIS data are available via public-use and restricted-use data files. Public-use NHIS data files are released annually and are available for download from the NCHS web site. Restricteduse linked NHIS data files, which contain indirect identifiers such as geographical locations or specific dates, are available for use through the NCHS Research Data Center (RDC). The RDC is a secure environment designed to protect the confidentiality of survey respondents, while also

National Health Survey

allowing researchers the ability to access restricted-use data for research purposes only. Documentation containing detailed information on the public-use and restricted-use NHIS data files is available on the NCHS web site. Reports providing statistics based on data collected from NHIS and detailed documentation on the NHIS design, sampling procedures, and guidance for analyzing the data are also available. Information on the NHIS Early Release Program which provides very timely estimates of key health and health-related indicators is also provided on the NCHS web site. Harmonized NHIS public-use data and documentation going back to the early 1960s are available in the Integrated Health Interview Series, maintained by the University of Minnesota. (See section G for more information on these resources.)

References and Readings For additional information on NHIS, see: http://www.cdc. gov/nchs/nhis/about_nhis.htm For information on NHIS questionnaires by year of survey, see: http://www.cdc.gov/nchs/nhis/nhis_questionnaires. htm For information on NHIS design and estimation, see: http://www.cdc.gov/nchs/nhis/methods.htm For information on NHIS reports and data linked to NHIS, see: http://www.cdc.gov/nchs/nhis/nhis_products.htm For information on the 1997 NHIS questionnaire redesign, see: http://www.cdc.gov/nchs/nhis/nhis_redesign.htm and ftp://ftp.cdc.gov/pub/Health_Statistics/NCHS/ Dataset_Documentation/NHIS/1997/srvydesc.pdf For information on NHIS Supplements, see: http://www. cdc.gov/nchs/nhis/supplements_cosponsors.htm For information on the NHIS Early Release Program, see: http://www.cdc.gov/nchs/nhis/releases.htm For information on accessing restricted-use NHIS data in the NCHS Research Data Center, see: http://www.cdc. gov/rdc/ For information on NHIS data linked to air quality data, see: http://www.cdc.gov/nchs/data_access/data_linkage/ air_quality.htm For information on the Integrated Health Interview Series (IHIS), see: http://www.ihis.us/ihis/

National Health Survey ▶ National Health Interview Survey

National Institute of Child Health and Human Development

National Heart, Lung, and Blood Institute Martica H. Hall Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

Basic Information The National Heart, Lung, and Blood Institute (NHLBI) is one of the National Institutes of Health (NIH). Its mission is the advancement of research on, and the prevention and treatment of, heart, lung, and blood diseases and sleep disorders. The National Heart Institute (NHI) was established in 1948 as one of the National Institutes of Health (NIH). The National Heart Institute’s mission was to advance research and training related to heart disease and functioning. Its functions were broadened in 1969 and 1976 to include lung (National Heart and Lung Institute; NHLI) and blood diseases (National Heart, Lung, and Blood Institute; NHLBI), respectively. The NHLBI is also responsible for the adequacy and safety of the nation’s blood supply.

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education and career development of a diverse workforce. The Intramural Research Program includes a multinational team of NIH investigators and clinicians who conduct basic and clinical research and technology development related to heart, lung, and blood diseases and sleep disorders. In contrast, the Extramural Research Program supports heart, lung, and blood diseases and sleep disorders research, research training, and career development of investigators outside of the NIH. These activities are supported through various extramural award mechanisms including research, program project, and center grants; cooperative agreements and research contracts; research career development awards; and institutional and individual national research service awards. Three divisions (Cardiovascular, Lung, Blood Diseases and Disorders) foster research and training in their related areas.

Cross-References ▶ National Institutes of Health

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Major Impact on the Field Organizationally, the NHLBI includes the Office of the Director, an Intramural Research Program, and an Extramural Research Program. The Office of the Director provides strategic planning, policy guidance, program development and evaluation, and institute coordination. It also liaisons with Federal agencies, professional societies, and the public and is responsible for the dissemination of information regarding the prevention of heart, lung, and blood diseases and sleep disorders. The Office of the Director includes divisions, centers, and branches that support bioinformatics development; epidemiological studies of the etiology of heart, lung, and blood diseases and sleep disorders; the translation of scientific evidence into clinical practice; and the elimination of health disparities through the

NHLBI home page. www.nhlbi.nih.gov

National Institute of Child Health and Human Development Deborah Lee Young-Hyman Department of Pediatrics, Georgia Prevention Institute Georgia Health Sciences Universtiy, Augusta, GA, USA

Basic Information The National Institute of Child Health and Human Development (NICHD) was established by federal law in October 1962. The mission of NICHD encompasses that every person is born healthy

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National Institute of Diabetes and Digestive and Kidney Diseases

and wanted; no harmful effects are suffered by women in the reproductive process; children have the opportunity to live healthy and productive lives; and to ensure the health, productivity, independence, and well-being of people through optimal rehabilitation (http://www.nih.gov/about/ almanac/organization/NICHD.htm).

Major Impact on the Field This mission statement informs the research programs supported by NICHD as follows: Projects funded through NICHD adopt a life course perspective, such that conditions are studied prior to and during pregnancy, as well as during childhood, as they impact the health and well-being of children and adults, including person based and environmental factors and their interaction. The process of growth and development is assumed to be continual and evolving, such that research focuses also include cellular, molecular, and developmental biology. Basic, clinical, and epidemiologic research is conducted regarding reproductive science, with emphasis on safe and effective regulation of fertility, solving problems of infertility, and understanding consequences of reproductive behavior and population change. This last focus is behavioral and social science based. NICHD also supports the research training of clinicians in order to address areas of critical public health concern. A current focus is obesity prevention and treatment throughout the life course, with particular emphasis on the maternalfetal environment. In 2008–2009, the National Children’s Study was launched in concert with the Centers for Disease Control (CDC), a longitudinal study of environmental influences on child health. This study will follow approximately 100,000 subjects across diverse areas the United States, and span over 20 years, mapping multiple environmental influences on children’s health status. As the issues addressed by NICHD span biologic systems, NICHD often partners with NIDDK and NHLBI to fund projects which target disease prevention and intervention during

childhood, particularly the antecedents of diabetes and cardiovascular disease The division of intramural research addresses the biological and neurobiological, medical, and behavioral aspects of normal and abnormal human development. In addition to issues of biology, NICHD supports research that addresses health literacy and numeracy, health maintenance, use of health care and community resources to improve child health, and the interaction between risk behaviors, psychological morbidity, and health outcomes. NICHD supports a systems approach to discovery, whereby the focus of inquiry can range from the maternal-child dyad, to the family-school or family-health care environment. Therefore, besides a strong commitment to developmental biology discovery, there is emphasis on how health prevention attitudes and behavior translate into public health issues.

Cross-References ▶ National Children’s Study ▶ National Institutes of Health

References and Readings NICHD home page. www.nichd.nih.gov/

National Institute of Diabetes and Digestive and Kidney Diseases Deborah Lee Young-Hyman Department of Pediatrics, Georgia Prevention Institute Georgia Health Sciences Universtiy, Augusta, GA, USA

Basic Information National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) conducts and

National Institute of Diabetes and Digestive and Kidney Diseases

supports research ranging from basic science to translational multidisciplinary studies regarding the endocrine system. This consists of a system of glands, each of which secretes a type of hormone into the bloodstream to regulate the body. In addition, related organs such as the kidney, liver, and gonads are studied as secondary contributors of hormonal input to the endocrine system. An endocrine axis denotes the interrelationship of function between glands and organs caused by reciprocal hormonal and cellular functions, including the brain. Functions regulated by endocrine hormones range from growth and pubertal development to basic metabolism and brainmediated behavior. The endocrine system has systemic effects on the body, and therefore, NIDDK funds and takes a leadership role in studies encompassing the endocrine system, related organ systems, hormonal dysregulation and chronic disease, lifestyle as it relates to prevention and disease course of metabolic diseases, proteinomics, genomics, and gene environment interactions (http://www2.niddk.nih. gov/AboutNIDDK/).

Major Impact on the Field In addition to its broader mission, NIDDK is dedicated to the funding of projects which address health disparities. Minorities are disproportionately affected by endocrine disorders, in particular diabetes and obesity, and have poorer disease outcomes. Diabetes is the single largest cause of end-stage renal disease (ESRD). In order to address these multifactorial illnesses, the NIDDK is a proponent of multidisciplinary research, reflecting the bench to bedside application of basic research findings to clinical care. NIDDK has a history of funding large clinical trials and epidemiologic studies which have addressed issues such as disease development and progression (types 1 and 2 diabetes), primary and secondary prevention (type 2 diabetes), and secondary prevention (preserving the health of neonates in mothers with gestational diabetes).

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Because treatment of endocrine disorders such as autoimmune and weight-related diabetes is based on individual behavior, the NIDDK has an emphasis on behavioral aspects of disease prevention and management and has funding mechanisms (R18, R34) which emphasize the inclusion of behavior change strategies as primary or secondary treatment of disease prevention and management. Clinical trials, in particular the Diabetes Prevention Program (DPP) and Preventing Type II Diabetes (STOPP-T2D), have had major behavioral components and have helped to establish the clinical superiority of behavior/lifestyle change over pharmacologic intervention in lifestyle-based disease development and treatment (http:// www2.niddk.nih.gov/Research/ScientificAreas/ Diabetes/Type2Diabetes/CTT2.htm). NIDDK also maintains a network of biobehavioral researchers who conduct studies regarding the prevention and early treatment of type 1 diabetes (http://www.diabetestrialnet.org/) and is dedicated to providing funding to train clinician-scientists across disciplines to carry out this work. Content areas of current NIDDK-funded behavioral research include hormonal regulation of appetite; associations between inflammation, glycemia, and mood; insulin resistance, exercise, and cognition; psychiatric disorders and risk for diabetes; translation of effective care models to underserved populations; and health-care delivery channels to improve predisease risk factors such as obesity in children and adults. Applications for funding behavioral approaches are likely to be assigned to the Division of Diabetes, Endocrinology and Metabolic Diseases (DEM).

Cross-References ▶ National Institutes of Health

References and Readings NIDDK home page. www.niddk.nih.gov/

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National Institute of Mental Health Jennifer Pellowski Department of Psychology, University of Connecticut, Storrs, CT, USA

Basic Information The National Institute of Mental Health (NIMH) is a part of the National Institutes of Health (NIH) which focuses on clinical research associated with mental illness and behavioral disorders through biological and behavioral perspectives. It focuses on the prevention, recovery, and cures of mental illness and is the nation’s scientific leader in this area. NIMH was conceived on July 3, 1946 when President Truman signed the National Mental Health Act. This act acknowledged the plight of World War II soldiers coming back from war with mental illnesses caused or exacerbated by the environmental stress of war. It also recognized that the incidence rate of mental illness in the general population was higher than originally thought. To address this need for psychiatric care, the National Institute of Mental Health was formally established on April 15, 1949. Since the beginning, NIMH has been at the forefront of mental health research focusing especially on assessing psychiatric needs of the nation, using cutting-edge technologies to determine when, where, and how mental illness occurs and finding treatments to slow or cure these mental illnesses. It commenced this long history of research in the 1950s and 1960s, starting with the Mental Health Study Act of 1955. The purpose of the Mental Health Study Act was to access the mental health issues effecting the American public as well as what resources were available at that time to treat those suffering from illness. This resulted in the report Action for Mental Illness which called for a national program to address individual needs on specific mental health problems. NIMH continued to make strides during the 1970s and 1980s with its focus on the use of

National Institute of Mental Health

cutting-edge biological techniques, technologies, and treatments to aid in attempts to answer the questions of how, when, and why mental illness happens and how to treat those who are suffering. These aims resulted in the creation of the PET scan to measure brain function as well as the use of lithium, a revolutionary treatment for mania. A resolution later signed by President George H. W. Bush declared the 1990s “The Decade of the Brain,” and NIMH continued to focus on the advances in imaging technologies as well as the interaction between brain, behavior, and the environment to gain more knowledge about specific mental health illnesses. Currently, NIMH works to fulfill four objectives aimed at further determining the causes of mental illness, charting the course of mental illness, developing interventions, and the dissemination of knowledge acquired through NIMH-supported research. To fulfill these objectives, NIMH conducts and funds internal and external research studies. With a budget of upwards of $1.5 billion, NIMH provides many grants to independent researchers, as well as contracts through requests for applications (RFAs). It also provides training grants to pre- and postdoctoral students to encourage entry into biomedical and behavior fields of research. In conjunction with the goals of obtaining new knowledge through research, NIMH also acts to disseminate this newly found knowledge. It accomplishes this through conferences and lectures open to the general public in addition to providing booklets, brochures, and fact sheets. It also supplies curriculum and educational tools to primary and secondary schools to aid in the teaching process. National Institute of Mental Health Parklawn Building, 15C-05 5600 Fishers Lane Rockville, Maryland 20857

Major Impact on the Field The National Institute of Mental Health is the nation’s scientific leader in research on the causes, treatment, and prevention of mental illness. The NIMH acts to bridge the gap between

National Institute on Aging

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research and the larger community by providing leadership in the dissemination of information for clinicians, patients, policy makers, and the general public.

influence on genetics research with a focus on bench to bedside, palliative care and symptom management research, end-of-life research, and research in long-term care.

Cross-References

Major Impact on the Field

▶ Depression ▶ Dissemination ▶ National Institutes of Health ▶ Stress, Posttraumatic

The major impact of NINR has been in the development of nurse researchers and nursing science in general.

Cross-References References and Readings ▶ National Institutes of Health National Institute of Mental Health. A participant’s guide to mental health clinical research. U.S. Department of Health and Human Services. National Institutes of Health. (1999, September). National Institute of Mental Health: Important events in NIMH history. Retrieved February 16, 2011, from NIH 1999 Almanac http://www.nih.gov/about/almanac/archive/ 1999/organization/nimh/history.html National Institutes of Health. (2011, February 11). About NIMH. Retrieved February 16, 2011, from National Institute of Mental Health http://www.nimh.nih.gov/ about/index.shtml Walls, T. (2008, July 31). The National Mental Health Act of 1946 and the establishment of NIMH: Ongoing challenges. Retrieved February 16, 2011, from Scattergood Program for the Applied Ethics of Behavioral Health http://www.scattergoodethics.org/?q¼node/1146

National Institute of Nursing Research Barbara Resnick School of Nursing, University of Maryland, Baltimore, MD, USA

Basic Information The development of NINR has had a major impact on building nursing science as delineated by the many successes and the growing number of doctorally prepared nurses engaged in research. Specifically, NINR has had a great

References and Readings National Institute of Nursing Research, Retrieved from www.ninr.nih.gov. Accessed March 2012. National Institute of Nursing Research publication: Bringing science to life. Retrieved from http://www. ninr.nih.gov/NR/rdonlyres?BCDD9E7E-C6A5-4578B5B5-333895F54AA5/0/NINR_History_Book_508.pdf. Accessed March 2012.

National Institute on Aging Natalie E. Bustillo Department of Psychology, University of Miami, Coral Gables, FL, USA

Basic Information The National Institute on Aging (NIA) is one of the institutes of the National Institutes of Health (NIH). The mission of the NIA is to conduct research about the aging process, to promote understanding of aging, and to disseminate advances in aging research to the public. The NIA sponsors aging research through the extramural and intramural research programs (National Institute on Aging [NIA], 2009).

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The extramural research program consists of aging studies conducted at public and private organizations, such as hospitals and universities. The four extramural research programs supported by the NIA are: Division of Aging Biology, Division of Behavioral and Social Research, Division of Neuroscience, and Division of Geriatrics and Clinical Gerontology. Research conducted by the Division of Aging Biology examines the physiological mechanisms involved in the aging process using humans and animals. Examination of the biological processes involved in aging aid in the understanding of how biochemical changes associated with aging may be risk factors for diseases later in life. The Division of Behavioral and Social Research seeks to understand the aging process at the individual and group level. Emphasis is placed on how individuals change over time and the impact it has on greater society. The Division of Neuroscience supports research related to increasing the understanding of how the nervous system is impacted by the effects of aging. Alzheimer’s disease and other dementias are the main research areas in this division. Research studies supported by the Division of Geriatrics and Clinical Gerontology consist of three main areas, which include Geriatrics, Clinical Gerontology, and Clinical Trials. The focus of this division is to examine age-related health concerns and identify risk factors associated with age-related diseases. The four divisions of the extramural research program offer grants and training opportunities to further enhance the aging research field (NIA, 2011). The intramural research program conducts studies in multiple NIH sites in Maryland. The focus of this research program is to examine the physiological age-related changes that occur throughout the lifespan in order to better understand the physiology of age-related diseases, such as Alzheimer’s disease, atherosclerosis, and cancer. In addition to examining the physiology of age-related diseases, the intramural research program also aims to understand the predictors of positive health (NIA, 2010).

National Institute on Aging

Major Impact on the Field The NIA has made many initiatives in the field of behavioral medicine through their ongoing research studies, clinical trials, and published findings. Clinical Trials The NIA supports multiple clinical trials examining multiple age-related conditions. The various medical conditions funded by the NIA-funded clinical trials include atherosclerosis, diabetes mellitus, hypercholesterolemia, hypertension, inflammation, menopause, obesity, and osteoporosis. In addition, the NIA funds clinical research relevant to promoting health behavior and managing psychological stress. For example, the NIA is committed to understanding more about Alzheimer’s disease. One of the clinical trials funded by the NIA tested whether Pioglitazone, a drug traditionally used to treat type 2 diabetes, was effective at slowing the progression of Alzheimer’s disease (Geldmaher, 2009). Similarly, the NIA funded a trial to evaluate the effectiveness of antioxidant treatments for patients diagnosed with Alzheimer’s disease (Galasko, 2009). Additional clinical trials have been funded by the NIA to assess decisionmaking abilities of patients diagnosed with Alzheimer’s disease and to identify Alzheimer’s disease-related brain changes and predictors of memory loss (de Leon, 2009; Karlawish, 2009). Publications The NIA has published various resources available to the public that demonstrate its initiatives in the field of behavioral medicine. Published resources include information about the importance of engaging in positive health behaviors such as eating a healthy diet, quitting smoking, exercising, and sleeping well. The NIA has also published resources for issues related to depression, coping with death, memory loss, and sexuality in adulthood.

Cross-References ▶ Aging

National Institute on Alcohol Abuse and Alcoholism

References and Readings de Leon, M. J. (2009). PET changes in Alzheimer’s disease (AD). Retrieved November 28, 2011, from http:// clinicaltrials.gov/show/NCT00094913 Galasko, D. (2009). Anti-oxidant treatment of Alzheimer’s disease. Retrieved November 28, 2011, from http:// clinicaltrials.gov/show/NCT00117403 Geldmaher, D. (2009). Pioglitazone in Alzheimer disease. Retrieved November 28, 2011, from http:// clinicaltrials.gov/show/NCT00982202 Karlawish, J. (2009). Memory aid for informed consent in Alzheimer’s research. Retrieved November 28, 2011, from http://clinicaltrials.gov/show/NCT00105612 National Institute on Aging. (2009). About NIA. Retrieved November 28, 2011, from http://www.nia. nih.gov/AboutNIA/ National Institute on Aging. (2010). Welcome to the intramural research program. Retrieved November 28, 2011, from http://www.grc.nia.nih.gov/branches/osd/ mission.htm National Institute on Aging. (2011). Research programs (extramural). Retrieved November 28, 2011, from http://www.nia.nih.gov/ResearchInformation/ ExtramuralPrograms/

National Institute on Alcohol Abuse and Alcoholism Jennifer Pellowski Department of Psychology, University of Connecticut, Storrs, CT, USA

Basic Information The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is part of the National Institutes of Health and focuses on research associated with the causes, treatment, and prevention of alcoholism. NIAAA became the leading federal agency to address alcoholism as a public health problem after the passage of the Comprehensive Alcohol Abuse and Alcoholism Prevention, Treatment, and Rehabilitation Act of 1970. Also referred to as the Hughes Act of 1970, this legislation established NIAAA as part of the National Institute of Mental Health (NIMH). Since its conception, NIAAA has been at the forefront of alcohol-related research

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starting with its investigation of fetal alcohol spectrum disorder (FASD) at a time when many scientists and physicians doubted its existence. In 1977, it held the first national FASD research conference which highlighted epidemiological and clinical research and led to the issue of the first FASD government health advisory. Since then their research has expanded to include the genetics of alcoholism, benefits of alcohol consumption, neurological examinations of the impact of alcohol, and improving health care and treatment of those that suffer from alcohol abuse and alcoholism as well as other topics. It conducts and funds internal and external research studies. NIAAA focuses on multidisciplinary efforts including epigenetics, neuroscience, public health, epidemiology, genetics, and public policy. It also acts to relay information to clinicians, patients, policymakers, and the general public in an accessible manner. Notable projects include Project MATCH and Project COMBINE which have developed new ways of approaching treatment and therapy for those suffering from alcoholism. Additional studies have also identified targeted populations, specifically pregnant women and youth, and subsequently focused research efforts to highlight specific needs of these populations to increase prevention. In addition to internal research, NIAAA also provides financial and other forms of support to researchers through requests for applications (RFAs) and program announcements (PAs) as well as through other small grants. In conjunction with the goal of conducting and supporting research, the NIAAA also works to disseminate this newly found information. It accomplishes this goal through Alcohol Alert, which is published quarterly and aimed at professionals and clinicians. Additionally, the NIAAA also provides information to the general public through pamphlets and brochures as well as educational training programs. NIAAA also sponsors several public health programs that range in topics and targeted populations from pregnant women to youth and young adults.

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National Institute on Alcohol Abuse and Alcoholism 5635 Fishers Lane, MSC 9304 Bethesda, MD 20892-9304 URL: http://www.niaaa.nih.gov

Major Impact on the Field The National Institute on Alcohol Abuse and Alcoholism is the largest funder of research concerning alcoholism and alcohol-related problems in the United States. It is a keystone of alcohol abuse and alcoholism research and provides leadership in the dissemination of information for clinicians, patients, and the general public. The NIAAA acts to bridge the gap between research and the community at large through educational programs and changes in public policy.

Cross-References ▶ Alcohol Abuse and Dependence ▶ Alcohol Consumption ▶ Binge Drinking ▶ National Institutes of Health

References and Readings National Institute on Alcohol Abuse and Alcoholism. (2011). About NIAAA. Retrieved February 14, 2011, from National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/AboutNIAAA/ Pages/default.aspx National Institutes of Health Office of the Director. (1998). National Institute on Alcohol Abuse and Alcoholism: Important events in NIAAA history. Retrieved February 14, 2011, from NIH Almanac 1998: http://www.nih.gov/about/almanac/archive/1998/ organization/niaaa/history.html Thomas, J. D., Warren, K. R., & Hewitt, B. G. (2010). Fetal alcohol spectrum disorders: From research to policy. Alcohol Research and Health, 33, 118–126. Warren, K. R., & Hewitt, B. G. (2010). NIAAA: Advancing alcohol research for 40 years. Alcohol Research and Health, 33, 5–17.

National Institutes of Health

National Institutes of Health Vaughn Bryant1 and Anne Frankel2 1 Behavioral and Social Sciences, Brown University, Providence, RI, USA 2 Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, USA

Basic Information Overview The National Institutes of Health (NIH) is an agency of the United States Department of Health and Human Services. It consists of the Office of the Director (OD) and 27 institutes and centers which make up the largest source of medical and scientific funding in the world (United States Department of Health and Human Services & National Institutes of Health, 2010). The main function of the OD is to “plan, manage, and coordinate” the specific policies and procedures laid out for these institutes (United States Department of Health and Human Services, 2010a). The policies and procedures are developed and implemented through extensive collaboration and input from the OD and NIH staff. Other sources of information include the extramural scientific community, patient advocacy and volunteer organizations, Congress, and the Director’s Council of Public Representatives, a federal committee made up of members of the general public. The current director of the NIH is Francis S. Collins. Dr. Collins’ job is to efficiently and effectively integrate the information from his advisors and provide direction for specific “Areas of Research Emphasis,” the future goals and directions that the NIH identifies as beneficial to science and society. Themes that are to be addressed in the coming years include translational medicine, health-care reform, global health, and empowering and energizing the research community (United States Department of Health and Human Services, 2010a).

National Institutes of Health

Application Process Sustained funding is a necessary component for advancing science. In order to facilitate innovative projects that support scientific progress, the NIH funds grants, cooperative agreements, and contracts (United States Department of Health and Human Services, 2010b). The NIH lists several key factors in being awarded funding: (1) the project must be of high scientific caliber, (2) it must be investigator-initiated, and (3) the research must be unique and innovative. In order to provide guidance for funding opportunities, NIH notifies researchers of the availability of funds through Funding Opportunity Announcements (FOAs), which are posted in the NIH Guide for Grants and Contracts and on Grants.gov. Other sources of funding information include Parent Announcements, Program Announcements (PAs), and Requests for Applications (RFAs). The NIH also supports research centers and intramural research (United States Department of Health and Human Services, 2010b; United States Department of Health and Human Services & National Institutes of Health: Office of Extramural Research, 2009). Funding opportunities exist for a variety of research structures, including individuals, domestic institutions, and foreign institutions. Further, the NIH seeks to fund investigators at various points in their scientific careers. For example, special programs and announcements have been created targeting young and early stage investigators in order to help this population establish their career and ultimately flourish in the realm of scientific research. More senior investigators may choose to be mentors for early stage investigators and directors of projects or institutes (United States Department of Health and Human Services, 2010b). Historically, it has been considered difficult to be awarded an NIH grant. However, competition is critical for improving the level of applications and ultimately the caliber of scholarly research. In order to determine which grants are awarded funding, applications typically go through a rigorous process known as peer review. The peer review process involves multiple readings of each application by credentialed peers in the

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relevant field and helps to establish the quality of the grants funded. The NIH lists five major review criteria looked at by reviewers when examining and scoring applications: the significance of the project; investigator background; level of innovation, approach, and methodology; proposed environment for the study; and probability of success (United States Department of Health and Human Services & National Institutes of Health: Office of Extramural Research, 2011). Before reviewers meet, they give each application a preliminary score on a scale from 1 (exceptional) to 9 (poor). Applications which receive a score above a predetermined threshold score progress to a full committee meeting. At this meeting, reviewers discuss the strengths and weaknesses of each application and create an impact/priority score, which determines the percentile ranking that will organize applications for possible funding. Program officers then determine how review scores are translated into funding for a certain number of applications. Often, applications are submitted twice: if an initial application is not granted review, comments are provided to the applicant, and they are encouraged to submit an amendment. Grants are reviewed both by the center for the scientific review and the institutes themselves for special initiatives. Special review processes only allow for one submission (United States Department of Health and Human Services & National Institutes of Health: Office of Extramural Research, 2011). Funding Success Funding success is an important measure of the level of competition. Success rates are reported as the percentage of reviewed grant applications that receive funding, which is determined by dividing the number of competing applications funded by the sum of the total number of competing applications reviewed and the number of funded carry-overs (United States Department of Health and Human Service & National Institutes of Health, 2009). Success rates are computed on a fiscal year basis and include applications that are peer-reviewed and either scored or unscored

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by an Initial Review Group. Applications that have one or more amendments in the same fiscal year are only counted once. Funding success rates are typically between 10% and 20% (United States Department of Health and Human Services & National Institutes of Health: Office of Extramural Research, 2011; United States Department of Health and Human Service & National Institutes of Health, 2009; United States Department of Health and Human Services, 2010c). In 2010, there was an overall success rate of approximately one in five grants, which accounts for both new investigators and established investigators, who may be more likely to get funding based on past awarded grants. Thus, this measure may not be representative of the level of competition for new or less established investigators. After peer review, successful grantees go through the award process in which the grantee is notified of an award and assigned a program officer who manages the distribution and monitoring of the award. Grant awards can range from a few thousand to tens of millions of dollars and depend on numerous factors including the type of grant (known at NIH as the “grant mechanism”), the institution, the structure of the proposal (individual vs. center), the period of time that the award is assigned, and many more. The oldest and most common mechanism applied for is the R01, which cannot exceed $250,000 annually in direct costs, unless a special request is made (United States Department of Health and Human Services & National Institutes of Health, 2010). Other common grant types are K mechanisms, which represent training grants, fellowships, and early stage investigator-initiated research; U mechanisms, which are cooperative agreements; and R21 exploratory grants. Funding and Scientific Accomplishments Funding of the NIH has been integral to the progression of innovative scientific discovery. President Obama recently released his 2012 budget proposal, in which he requested a 745 million dollar increase to the NIH budget. When added to the existing budget, the total request for the NIH is 32 billion dollars. Considering the 3.5% rate of inflation, the proposed amount is roughly equivalent to flat funding (Brown, 2011).

National Institutes of Health

The latest scientific accomplishments of NIHfunded projects were highlighted in a recent status report (United States Department of Health and Human Services, 2011). Many of these accomplishments have been in the area of HIV/AIDS, with the development of antiretrovirals (ARVs) to treat the disease as one of the most notable. One large-scale study involved an ARV microbicide for women and found a 50% protection rate against HIV transmission. Future research focuses for the NIH in the field of HIV/AIDS will be on vaccine development and efficacy. Advances in technology are key to NIH’s research success. For example, because of NIH-sponsored research, high-resolution imaging is becoming a critical part of studying disease and disease progression. Findings of a study conducted by the National Lung Society suggest that lowdose CT screening can decrease lung-cancer deaths by 20% among heavy smokers. Another technological innovation becoming increasingly important in the treatment of disease is stem cells. Researchers recently found that mouse embryonic and induced pluripotent stem cells can be used to generate new hair cells, which has implications for hearing loss and deafness in humans. Finally, influenza vaccines have been improved to protect against multiple strains of the virus, which has helped science progress toward the goal of eradicating the virus worldwide. Future Changes and Directions There are many areas in the health sciences that are under-researched, including pain control, drug delivery, vaccines, medical informatics, and more that may lead to future initiatives and structural changes. The NIH is currently developing translational research initiatives by creating a clinical and translational research institute, which would help facilitate the process of translating clinical findings to practical applications such as drug development and other health improvements. Another example of a structural change to the NIH is the recent vote by the Scientific Management Review Board to merge the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) (Mcmanus, 2010). These proposals indicate that the NIH is

National Institutes of Health

responsive to changes in science and attempts to accommodate these changes through reorganization and constant refinement both at the structural level and the scientific level.

Major Impact on the Field The NIH is the largest source of funding for medical research in the world. Major contributions to various scientific fields linked directly to NIH funding cannot be understated. For example, the increase in lifespan in the United States from 47 to 78 between 1900 and 2009 has been attributed to the long history of NIH funding (United States Department of Health and Human Services & National Institutes of Health, 2010). Diseases such as smallpox, measles, polio, and chronic conditions such as diabetes and cancer, which were once death sentences, are now eradicated, curable, preventable, or treatable. In fact, rates of cancer diagnoses and cancer-related deaths have seen significant drops in recent years (United States Department of Health and Human Services, 2008). The field of mental health has seen advances, including the development of more effective antidepressants as well as improvements in the overall treatment for mental health and substance use disorders. The Human Genome Project, an ambitious campaign that began in 1990 and involved researchers from all over the world dedicated to decoding the mysteries of the human genetic code, resulted in the sequencing of the human genome in 2003. This enormous effort has given researchers unique insight into more than 1,800 disease genes and has played an invaluable role in the development of genetic tests (United States Department of Health and Human Services & National Institutes of Health, 2011). Prevention research has made immense strides due to NIH funding and has resulted in a better understanding of measures that can be taken to reduce the risk of heart disease, stroke, dementia, and many other adverse health conditions. More than 80 Nobel Prizes have been presented to NIH-funded projects. However, scientific advances resulting from NIH-supported projects extend well beyond the ones receiving special

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recognition, and often the true impact of such projects cannot be gauged until long after their completion. Additionally, despite major cuts to NIH funding, the latest advances in comparative effectiveness research offer a better understanding of how to best utilize and distribute funds to maximize the long-term impact that projects will be able to have in their respective fields. Each day, NIH-funded projects address the challenges of a changing health climate facing chronic disease, the resurgence of old diseases, and emergence of new, and progress toward a healthier society both across the United States and worldwide.

Cross-References ▶ National Cancer Institute ▶ National Institute of Diabetes and Digestive and Kidney Diseases

References and Readings Brown, D., (2011). Budget 2012 and CDC. [Updated February 14, 2011; cited April 25, 2011] Available from http://voices.washingtonpost.com/44/2011/02/ budget-2012-nih-and-cdc.html Mcmanus, R. (2010). Board recommends merger of NIDA, NIAAA. NIH Record, 62(20). [Updated October 1, 2010; cited April 22, 2011] Available from http://nihrecord.od.nih.gov/newsletters/2010/ 10_01_2010/story1.htm NIH home page. www.nih.gov/ United States Department of Health and Human Service & National Institutes of Health. (2009). NIH success rate definition. Bethesda, MD. [Updated February, 2009 cited April 27, 2011]. Available from: http://report. nih.gov/UploadDocs/NIH_Success_Rate_Definition.pdf United States Department of Health and Human Services. (2010a). Office of the director, major components. Bethesda, MD: National Institutes of Health. [Updated October 26, 2010; cited February 26, 2011]. Available from http://www.nih.gov/icd/od/offices.htm United States Department of Health and Human Services. (2010b). Grant application basics. Bethesda, MD: National Institutes of Health. [Updated Nov 16, 2010; Cited Feb 26, 2011]. Available from http:// grants.nih.gov/grants/grant_basics.htm United States Department of Health and Human Services. (2010c). National Institutes of Health: Research portfolio online reporting tools. Bethesda, MD. [Updated December 14, 2010; cited April 28, 2011].

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Available from http://report.nih.gov/award/success/ Success_ByIC.cfm United States Department of Health and Human Services. (2011). National Institutes of Health overview by institute. [Cited April 25, 2011] Available from http:// officeofbudget.od.nih.gov/pdfs/FY12/COPY%20of%20 NIH%20BIB%20Chapter%202-9-11-%20FINAL.PDF United States Department of Health and Human Services & National Institutes of Health: Office of Extramural Research. (2009). Description of the NIH guide for grants and contracts. Bethesda, MD. [Updated 2009 June 26; cited 2011 April 25]. Available from http:// grants.nih.gov/grants/guide/description.htm United States Department of Health and Human Services, National Institutes of Health, & National Cancer Institute. (2008). NCI Cancer Bulletin, 5(8). [Updated December 2, 2008; cited August 20, 2011] Available from http://www.cancer.gov/aboutnci/ ncicancerbulletin/archive/2008/120208/page10 United States Department of Health and Human Services & National Institutes of Health. (2010). About the National Institutes of Health. Bethesda, MD. [Updated October 27, 2010; cited February 26, 2011]. Available from http://www.nih.gov/about United States Department of Health and Human Services & National Institutes of Health. (2011). NIH fact sheets: Human genome project. [Cited 2011 August 24] Available from http://report.nih.gov/ NIHfactsheets/ViewFactSheet.aspx?csid=45 United States Department of Health and Human Services & National Institutes of Health. Types of grant programs. (2010). [Updated February 18, 2010; cited April 28, 2011]. Available from http://grants.nih.gov/ grants/funding/funding_program.htm United States Department of Health and Human Services & National Institutes of Health: Office of Extramural Research. (2011). Peer review process. Bethesda, MD. [Updated April 14, 2011, cited April 25, 2011]. Available from http://grants.nih.gov/grants/ peer_review_process.htm Wadman, M., (2010, August 12). One year at the helm. Nature, 466. [Cited February 26, 2011]. Available from http://www.nih.gov/about/director/articles/ nature_08122010.pdf

National Occupational Classification ▶ Job Classification

National Statistics Socioeconomic Classification ▶ Job Classification

National Occupational Classification

Natural Killer Cell Activity Riyad Khanfer1, Benjamin I. Felleman2 and G. Alan Marlatt3 1 School of Sport and Exercise Sciences, The University of Birmingham, Edgbaston, Birmingham, UK 2 Seattle Pacific University, Seattle, Washington, USA 3 University of Washington, Seattle, Washington, USA

Definition Natural killer (NK cells) form an important arm of the innate immune system (non specific immunity). They develop in the bone marrow and circulate in the blood. They are called NK cells because they are always active naturally and can kill before they encounter any antigens. They have important roles in eliminating virally infected cells without having specificity against any particular viruses and act as early component of the host response to viral infections. NK cells also play role in fighting cancer cells in the body. NK cells are considered part of the group of lymphocytes; however, they have neither antigen receptor nor antibody receptor, and they are larger in size than T and B lymphocytes. Upon NK cells activation, they produce cytotoxic granules which contain many molecules like perforins, TNF-a, lymphotoxin-b, INF-a, and many granzymes. NK cells kill virally infected cells by secreting these cytotoxic granules after recognizing the infected cells by lacking MHC molecule (major histocompatability complex) class I, which is not present in the virally infected cells. Also, these granules contain other molecules like TNF (tumor necrosis factor) which can activate apoptosis through death domain of TNF receptor of the target cell; also, NK cells kill by apoptosis via Fas ligand – Fas receptor mechanism upon engagement of the NK cell receptor with the target cell receptor. NK cells have a mechanism of checking cells by detecting the amount of MHC I protein on the cell

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surface; cells which express enough amount of MHC I will escape the killing by NK cells, and cells with reduced amount of MHC I will be targeted and killed by NK cells via programmed cell death after targeted by the cytotoxic granules. NK cells can be activated in response to interferons and macrophage-derived cytotoxins. NK cells secrete cytokines such as interferon g and interleukin 12 which help in CD4 T lymphocytes differentiation. NK cells are among the first to encounter cancer cells of the innate immunity components, and they secrete interferon g which recruit other component of the immune system. To control their cytotoxic activities, NK cells have two types of receptors on their surface: the first set are activating receptors that induce killing by NK cells and called KAR (killer activating receptors), while the second set of receptors are inhibitory which inhibit NK cells activation and therefore prevent killing to the normal host cells (killer inhibitory receptors KIR), and the KIRs are specific for MHC class I molecule. Also, NK cells kill cancer cells as well as viral-infected cells by detecting an important specific protein expressed often at the surface of these cells as a result of cellular physiological stresses, such as postneoplastic transformation or viral infection. NK cells express complementary cell surface receptor for the above stress proteins which strongly activate NK cells and the production of the NK cell cytotoxic granules.

References and Readings

Summary: Specific features of NK cells function and killing Part of innate immunity Kill cancer and virus-infected cells Killing without specificity Have two types of receptors: KAR to kill and KIR to avoid killing Secrete some cytokines like IL12 and IF-g Produce cytotoxic molecules to kill target cells by apoptosis Screen target cells by lack of MHC I expression Recognize stress proteins on physiologically stressed cells

Definition

Cross-References ▶ Immune Function ▶ Macrophages

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Delves, P. J., Martin, S. J., Burton, D. R., & Roitt, I. M. (2006). Roitt’s essential immunology (11th ed.). Malden, MA: Blackwell. Janeway, C. A., Travers, P., Walport, M., & Shlomchik, M. J. (2005). Immunobiology (6th ed.). New York: London Garland Science. Levinson, W. (2006). Review of medical microbiology and immunology (9th ed.). New York: McGraw-Hill Medical. Weinberg, R. (2007). The biology of cancer. New York: Garland Science.

NCS ▶ National Children’s Study

Needle Exchange Programs Hansel Tookes Epidemiology and Public Health, Miller School of Medicine, University of Miami, Miami, FL, USA

Synonyms NEPs; SEPs; Syringe exchange programs

In 2006, injection drug users (IDUs) accounted for 12% of the 56,300 new human immunodeficiency virus (HIV) infections in the USA (Hall et al., 2008). In 2007, 15% of the 43,000 new hepatitis B virus (HBV) infections and 44% of the 17,000 new hepatitis C virus (HCV) infections in the USA were among IDUs (Guardino et al., 2010). IDUs are susceptible to infection via sharing injection equipment and high-risk sexual behavior. While the National Institute on Drug Abuse (NIDA) recommends use of a new, sterile syringe each injection, many IDUs contract these viral infections through the sharing of

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contaminated syringes. In response to these viral epidemics, syringe exchange programs (SEPs) have been implemented in many countries including the United States (USA) (Mathers et al., 2010). These programs allow IDUs to exchange contaminated syringes for sterile syringes, with the goal of reducing the likelihood of IDUs’ sharing used syringes. The first SEPs in the USA opened in the late 1980s in Tacoma, Washington, followed shortly by programs in San Francisco, California; Portland, Oregon; and New York, New York (Hagan, Des Jarlais, Purchase, Reid, & Friedman, 1991). The North American Syringe Exchange Network (NASEN) estimates that there are currently 184 SEPs operating in the USA (Guardino et al., 2010). In December of 2009, President Barack Obama signed a bill authorizing the use of federal dollars for SEPs. This signing marked the end of a 21-year-long Congressional ban on SEPs instituted in 1988 at the height of the AIDS epidemic (Kerlikowske & Crowley, 2010). A 1997 Report to Congress by the then Secretary of Health and Human Services Donna Shalala established SEPs as an effective component of a comprehensive strategy to prevent HIV and other blood-borne infectious diseases (Shalala, 1997). Many studies have shown that SEPs help to reduce the sharing of syringes among IDUs, and IDUs have reported no increased unsafe disposal in areas where SEPs were providing more syringe coverage (Bluthenthal, Anderson, Flynn, & Kral, 2007; Neaigus et al., 2008; Watters, Estilo, Cark, & Lorvick, 1994). Further, SEPs provide a range of preventive care services. Most SEPs services include HIV/AIDS counseling and testing, HCV counseling and testing, condom distribution, referral to substance abuse treatment, alcohol swabs, and safe-injection education. Additional services are often available including primary medical care, tuberculosis screening, and comprehensive hepatitis screening services including HAV and HBV vaccination (Guardino et al., 2010). SEPs help refer IDUs to treatment and do not encourage drug use among IDUs or recruit new users (Vlahov & Junge 1998). SEPs also help

Needle Exchange Programs

IDUs use sterile syringes and share less, reducing risk of blood-borne illness (Des Jarlais et al., 1994; Heimer, Khoshnood, Bigg, Guydish, & Junge, 1998). HIV incidence among IDUs has decreased by 80% from before SEPs (1988– 1990) to their maximum coverage (2003–2006) (Hall et al., 2008). These data are of high public health significance because in 2010, the Departments of State and Health and Human Services have issued policy guidance for US and global partners in the President’s Emergency Plan for AIDS Relief (PEPFAR) in the implementation of SEPs, but SEP coverage has yet to increase domestically. Despite the evidence, IDUs have limited coverage with SEPs offered in only 36 states, the District of Colombia, and Puerto Rico (Guardino et al., 2010). However, in 2011, the Centers for Disease Control and Prevention will issue guidance on SEPs to all US Health Departments, which will include recommendations relevant to syringe exchange programs.

Cross-References ▶ Centers for Disease Control and Prevention ▶ HIV Infection ▶ HIV Prevention

References and Readings Bluthenthal, R. N., Anderson, R., Flynn, N. M., & Kral, A. H. (2007). Higher syringe coverage is associated with lower odds of HIV risk and does not increase unsafe disposal among syringe exchange program clients. Drug and Alcohol Dependence, 89(2–3), 214–222. Daniels, D., Grytdal, S., & Wasley, A. (2009). Surveillance for acute viral hepatitis-United States, 2007. MMWR, 58(SS-3), 1. Des Jarlais, D. C., Freidman, S. R., Sotrheran, J. L., Wenston, J., Marmor, M., Yancovitz, S. R., et al. (1994). Continuity and change within an HIV epidemic: Injection drug users in New York City, 1984–1992. JAMA: The Journal of the American Medical Association, 271, 121–127. Guardino, V., Des Jarlais, D. C., Arasteh, K., Johnston, R., Purchase, D., Solberg, A., Lansky, A., & Lentine, D. (2010). Syringe exchange programs—United States, 2008. MMWR 59, 1488–1491. Accessed August 12, 2010, from http://www.cdc.gov/mmwr/preview/ mmwrhtml/mm5945a4.htm

Negative Affect Hagan, H., Des Jarlais, D. C., Purchase, D., Reid, T., & Friedman, S. R. (1991). The Tacoma syringe exchange. Journal of Addictive Diseases, 10(4), 81–88. Hall, H. I., Song, R., Rhodes, P., et al. (2008). Estimation of HIV Incidence in the United States. JAMA: The Journal of the American Medical Association, 300, 520–529. Heimer, R., Khoshnood, K., Bigg, D., Guydish, J., & Junge, B. (1998). Syringe use and reuse: Effect of needle exchange programs in three cities. JAIDS, 18 (Suppl. 1), AS37–AS44. Kerlikowske, G., & Crowley, J. S. (2010). Expanding access to evidence-based services for injection drug users. Accessed July 26, 2010, from www. Whitehouse.gov (Posted 7.16.10). Mathers, B. M., Degenhardt, L., Ali, H., Wiessing, L., Hickman, M., Matick, R. P., et al. (2010). HIV prevention, treatment and care services for people who inject drugs: A systematic review of global, regional and national coverage. Lancet, 375(9719), 1014–1028. Neaigus, A., Zhao, M., Gyarmathy, V. A., Cisek, L., Friedman, S. R., & Baxter, R. C. (2008). Greater drug injecting risk for HIV, HBV and HCV infection in a city where syringe exchange and pharmacy syringe distribution are illegal. Journal of Urban Health, 85(3), 309–322. Shalala, DE. (1997, February 18). Needle exchange programs in America: Review of published studies and ongoing research. Report to the Committee on Appropriations for the Departments of Labor, Health and Human Services, Educations and Related Agencies. Vlahov, D., & Junge, B. (1998). The role of needle exchange programs in HIV prevention. Public Health Reports, 113(Suppl. 1), 75–80. Watters, J. K., Estilo, M. J., Cark, G. L., & Lorvick, J. (1994). Syringe and needle exchange as HIV/AIDS prevention for injection drug users. JAMA: The Journal of the American Medical Association, 271(2), 115–120.

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(Watson, Clark, & Tellegen, 1988); more specifically, it is a construct that is defined by the common variance between anxiety, sadness, fear, anger, guilt and shame, irritability, and other unpleasant emotions. A variety of converging evidence suggests that negative affect is largely statistically independent from positive affect (e.g., Watson, 1988), but it is also clear that there exists a dimension called pleasantnessunpleasantness that has relations to both negative and positive mood terms (e.g., happiness and sadness). Some workers (e.g., Russell & Carroll, 1999) take the existence of the bipolar pleasantness-unpleasantness factor as evidence that negative affect and positive affect form a single dimension. Negative affect and the dispositional tendency toward negative affect (called neuroticism, negative affectivity, or negative emotionality) are a large component of many forms of psychopathology including mood disorders, anxiety disorders, and personality disorders. Negative affect has also been associated with such important areas in behavioral medicine as coping with illness or caregiving, blood pressure and heart rate, perceived stress, drinking motives, tobacco smoking, drug use, disordered eating, self-reported sleep quality, and cardiovascular disease.

Cross-References

Negative Affect Deborah M. Stringer Department of Psychology, University of Iowa, Iowa City, IA, USA

Synonyms

▶ Negative Affectivity ▶ Negative Thoughts ▶ Neuroticism ▶ Positive Affect ▶ Positive Affect Negative Affect Scale (PANAS) ▶ Stress

Emotional distress; Negative emotion

References and Readings Definition Negative affect is a broad concept that can be summarized as feelings of emotional distress

Russell, J. A., & Carroll, J. M. (1999). On the bipolarity of positive and negative affect. Psychological Bulletin, 125, 3–30. doi:10.1037//0033-2909.125.1.3. Watson, D. (1988). The vicissitudes of mood measurement: Effects of varying descriptors, time frames, and

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response formats on measures of positive and negative affect. Journal of Personality and Social Psychology, 55, 128–141. doi:10.1037//0022-3514.55.1.128. Watson, D., Clark, L. A., & Tellegen, A. (1988). Development and validation of brief measures of positive and negative affect: The PANAS scales. Journal of Personality and Social Psychology, 54, 1063–1070. doi:10.1037//0022-3514.54.6.1063.

Negative Affectivity Johan Denollet CoRPS – Center of Research on Psychology in Somatic diseases, Tilburg University, Tilburg, The Netherlands

Synonyms Neuroticism

Definition Negative affectivity (NA) is a broad personality trait that refers to the stable tendency to experience negative emotions (Watson & Clark, 1984). Individuals who are high in NA are more likely to report negative affective mood states across time and regardless of the situation. They also report more somatic symptoms and have an attention bias toward adverse stimuli or potentially threatening situations (Watson & Pennebaker, 1989). NA is closely related to neuroticism (Costa & McCrae, 1987) as one of the broad trait domains in the Five Factor Model of personality. Because NA is centrally defined by the tendency to experience negative affect (Watson & Pennebaker, 1989), the label NA is used here to designate dysphoric individual differences that are relatively stable over time. From a cognitive point of view, individuals who are high in NA may take a gloomy view of things and are inclined to be worrying. From an affective point of view, symptoms of depressed mood are often accompanied by other negative emotions like anxiety and anger (Watson & Clark, 1984).

Negative Affectivity

There are a number of reasons why it is important to account for individual differences in NA in clinical research and practice. First, psychological risk factors tend to cluster together within individuals; clustering of these factors, in turn, elevates the risk for adverse outcomes. NA is a personality trait that predisposes to clustering of negative emotions as a psychological risk factor (Denollet, 2005; Suls & Bunde, 2005). Second, individuals who are high in NA may scan the world for signs of impending trouble and seem to focus their attention on adverse stimuli (Watson & Pennebaker, 1989). This may explain why NA or neuroticism has been associated with more reactivity to stressful events and with more negative appraisals of interpersonal stressors. Third, NA may be related to difficulties in coping with life stress (Depue & Monroe, 1986) and is associated with an increased risk of affective disorder (Watson, Clark, & Harkness, 1994) and symptoms of both emotional and somatic distress (Watson & Pennebaker, 1989). Some have argued that neuroticism or NA is associated with complaints of chest pain but not actual heart disease (Costa & McCrae, 1987). However, one should not overlook potential associations between NA and decrements in physical health. There is a substantial overlap among the various negative affective dispositions (anger, anxiety, and depression) that have been associated with an increased risk of cardiovascular disease. This suggests that a general disposition toward negative emotions – the core of NA – may be important as a potential determinant of adverse health outcomes (Denollet, 2005; Suls & Bunde, 2005). Broad and stable personality traits such as NA may carry with them much potential for scientific and clinical purposes. NA taps into chronic attributes of individuals and has many referent attributes and therefore has much predictive and explanatory power. NA can be reliably assessed with the 7-item NA measure of the DS14 (Denollet, 2005), a scale that was specifically designed to assess this stable tendency to experience negative emotions.

Negative Thoughts

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Cross-References

Negative Relationship ▶ Neuroticism ▶ Type D Personality

▶ Inverse Relationship

References and Readings

Negative Religious Coping Costa, P. T., & McCrae, R. R. (1987). Neuroticism, somatic complaints, and disease: Is the bark worse than the bite? Journal of Personality, 55, 299–316. Denollet, J. (1991). Negative affectivity and repressive coping: Pervasive influence on self-reported mood, health, and coronary-prone behavior. Psychosomatic Medicine, 53, 538–556. Denollet, J. (2005). DS14: Standard assessment of negative affectivity, social inhibition, and type D personality. Psychosomatic Medicine, 67, 89–97. Depue, R. A., & Monroe, S. M. (1986). Conceptualization and measurement of human disorder in life stress research: The problem of chronic disturbance. Psychological Bulletin, 99, 36–51. Suls, J., & Bunde, J. (2005). Anger, anxiety, and depression as risk factors for cardiovascular disease: The problems and implications of overlapping affective dispositions. Psychological Bulletin, 131, 260–300. Watson, D., & Clark, L. A. (1984). Negative affectivity: The disposition to experience aversive emotional states. Psychological Bulletin, 96, 465–490. Watson, D., Clark, L. A., & Harkness, A. R. (1994). Structures of personality and their relevance to psychopathology. Journal of Abnormal Psychology, 103, 18–31. Watson, D., & Pennebaker, J. W. (1989). Health complaints, stress, and distress: Exploring the central role of negative affectivity. Psychological Reviews, 96, 234–254.

▶ Religious Coping

Negative Social Interaction ▶ Social Conflict

Negative Thoughts Louise C. Hawkley Department of Psychology, University of Chicago, Chicago, IL, USA

Synonyms Anger; Anxiety; Avoidance; Catastrophizing/ Catastrophic thinking; Depression; Hostility; Loneliness; Negative affect; Negative cognitions; Neuroticism; Perceived stress; Pessimism; Rumination; Worry

Negative Cognitions ▶ Negative Thoughts

Negative Emotion ▶ Negative Affect

Negative Emotionality ▶ Neuroticism

Definition Negative thoughts are cognitions about the self, others, or the world in general that are characterized by negative perceptions, expectations, and attributions and are associated with unpleasant emotions and adverse behavioral, physiological, and health outcomes. Negative thoughts are cognitive components of negative psychosocial variables such as depressive symptoms, anxiety, loneliness, and hostility. Depressive cognitions, for instance, include thoughts of hopelessness, helplessness,

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and diminished self-worth. Anxiety is a negative affective state or trait that is accompanied and perpetuated by worry and rumination. Loneliness is a negative state or trait that is characterized by perceptions of social threat, negative expectations in social interactions, and lower self-esteem. Hostility is characterized by derogation of others and thoughts of aggression and revenge. Negative thoughts are often intrusive and unwanted and require effort to suppress. Negative thoughts are assumed to play a major role, together with related negative emotions, in the associations of negative psychosocial variables with poorer health behaviors, greater physiological reactivity, poorer health, and higher rates of mortality. Negative thoughts tend to co-occur with each other, and their combined contributions may exceed those of any particular negative thought. Alternatively, specific negative thoughts may exert unique effects on health-related outcomes. The effects of loneliness on systolic blood pressure, for example, are independent of the effects of negative thoughts related to perceived stress, depressive symptoms, poor social support, and hostility (Hawkley, Thisted, Masi, & Cacioppo, 2010). On the other hand, worrying and pessimism tend to be correlated, and each has shown a positive prospective association with risk for coronary heart disease (Kubzansky et al., 1997; Kubzansky, Sparrow, Vokonas, & Kawachi, 2001), but it is not known whether the effects of worrying and pessimism on disease risk are independent of each other or confounded with each other. Mechanistic models of health risk employ negative thoughts as precursors to behaviors that have health consequences. For instance, low self-esteem has been shown to prospectively predict health problems through its effect on the quality of social bonds (Stinson et al., 2008). Neuroticism is a personality trait that is defined as a propensity for negative thoughts and experiences of many kinds and has been associated with mortality (Shipley, Weiss, Der, Taylor, & Deary, 2007). Because neuroticism is associated with a variety of specific negative thoughts, studies sometimes employ neuroticism

Neighborhood-Level Studies

as a covariate to determine the extent to which health effects are attributable to a specific negative psychosocial variable or negative thought as opposed to negativity more generally.

Cross-References ▶ Happiness and Health ▶ Psychological Factors ▶ Psychosocial Predictors ▶ Psychosocial Variables ▶ Unipolar Depression

References and Readings Hawkley, L. C., Thisted, R. A., Masi, C. M., & Cacioppo, J. T. (2010). Loneliness predicts increased blood pressure: Five-year cross-lagged analyses in middle-aged and older adults. Psychology and Aging, 25, 132–141. Kubzansky, L. D., Kawachi, I., Spiro, A., III, Weiss, S. T., Vokonas, P. S., & Sparrow, D. (1997). Is worrying bad for your heart? A prospective study of worry and coronary heart disease in the normative aging study. Circulation, 95, 818–824. Kubzansky, L. D., Sparrow, D., Vokonas, P., & Kawachi, I. (2001). Is the glass half empty or half full? A prospective study of optimism and coronary heart disease in the normative aging study. Psychosomatic Medicine, 63, 910–916. Shipley, B. A., Weiss, A., Der, G., Taylor, M. D., & Deary, I. J. (2007). Neuroticism, extraversion, and mortality in the UK health and lifestyle survey: A 21-year prospective cohort study. Psychosomatic Medicine, 69, 923–931. Stinson, D. A., Logel, C., Zanna, M. P., Holmes, J. G., Cameron, J. J., Wood, J. V., et al. (2008). The cost of lower self-esteem: Testing a self- and social-bonds model of health. Journal of Personality and Social Psychology, 94, 412–428.

Neighborhood-Level Studies ▶ Built Environment

Neoplasm of the Prostate ▶ Cancer, Prostate

Neurocognitive Assessment

NEPs ▶ Needle Exchange Programs

Nerve Cell ▶ Neuron

Nerve Damage ▶ Diabetic Neuropathy

Nested Case-Control Study

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cost of analyzing some biological samples, some of these resources are often not analyzed in detail at the time of collection, but are stored for future use. The nested case-control study is performed using subjects who develop the disease of interest in due course, and control subjects who are selected from those who were disease-free at the time the case subjects (those who developed the disease) were diagnosed. The appropriate data sets and samples are then retrieved and analyzed for these two subsets (cases and controls) of the original cohort recruited into the study. This approach maintains the major advantage of a cohort study in that the exposure data were collected before the development of the disease in the case subjects, while requiring the analysis (and associated costs) for only those who become entered into the nested case-control study (Webb, Bain, & Pirozzo, 2005).

▶ Nested Study

Cross-References

Nested Study J. Rick Turner Cardiovascular Safety, Quintiles, Durham, NC, USA

Synonyms

▶ Case-Control Studies ▶ Cohort Study

References and Readings Webb, P., Bain, C., & Pirozzo, S. (2005). Essential epidemiology: An introduction for students and health professionals. Cambridge, UK: Cambridge University Press.

Nested case-control study

Definition

Neurobehavioral Assessment A nested case-control study is one that is “nested” within a cohort study. In many cohort studies, all subjects provide a wide range of information at the time of recruitment, e.g., results from a physical examination, answers to multiple questionnaires, blood and urine samples, and results from imaging techniques. Because of the large numbers of subjects in these studies and the

▶ Neuropsychology

Neurocognitive Assessment ▶ Neuropsychology

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Neuroendocrine Activation Wiebke Arlt and Ana Vitlic School of Sport & Exercise Sciences, The University of Birmingham, Edgbaston, Birmingham, UK

Synonyms Flight-or-fight response; Stress cascade; Stress response

Definition Neuroendocrine activation is activation of both neuronal and endocrine pathways in situations when either internal or external factors act in a way that disturbs the body’s homeostasis.

Description From its very origin, life has been exposed to a highly dynamic environment. In order to survive, everything, from the simple primordial ribonucleic acid (RNA) molecules to the highly structured organisms that exist in the present world, had to learn how to fight these changes and eventually benefit from them. Nevertheless, no matter how beneficial these changes proved to be in the end, first encountered, they usually provoked a physiological response, commonly known as stress. Often, very hostile environments forced more complex organisms, like vertebrates, to develop a response that Walter Cannon (1914) first introduced as a “fight-or-flight” response, which describes a number of physiological changes involved in regulation of the body’s response to stimuli. This response aims to maintain body homeostasis, the mechanism that keeps internal environment in the body as constant and balanced as possible (Paca´k & Palkovits, 2001). One of the key features in this adaptive response is neuroendocrine activation (Miller & O’Callaghan, 2002), which includes activation of

Neuroendocrine Activation

two systems, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). Neuroendocrine activation can be triggered in two ways: as a feedback signal from peripheral receptors that have recognized the altered homeostasis or by the direct simulation from an activated brain regulatory center (Vigas & Jezova´, 1996). Even though different stressors activate different pathways and circuits within an organism, they will always result in the series of neural and endocrine adaptations known as the stress cascade (Miller & O’Callaghan, 2002). The key site involved in neuroendocrine activation is the hypothalamus (Barrett, 2005). Activation of both HPA axis and SNS starts from this very small but extremely important part of diencephalon. The hypothalamus consists of large number of nuclei and fiber tracts situated in three prominent features: supraoptic (anterior) region, tuberal or middle region, and mammillary or posterior region. From its posterolateral nuclei, the hypothalamus establishes strong, direct connections with autonomic nuclei in the brain stem and spinal cord. In this way, this part of central nervous system (CNS) structure controls SNS functions (Barrett). At the same time, and as a response to stress, the hypothalamus releases a neuropeptide called corticotrophin-releasing hormone (CRH) (Griffin & Ojeda, 2004), which stimulates the anterior pituitary gland to release another hormone, adrenocorticotropic hormone or ACTH, into general circulation. ACTH in turn stimulates the adrenal cortical cells of the adrenal glands to synthesize and release speciesspecific glucocorticoids into blood. The tight control of these glucocorticoids (mainly cortisol in humans) is sustained via negative feedback that controls and, in the end, terminates the release of CRH (Griffin & Ojeda). The necessity for this very subtle regulation of HPA axis at different levels is well represented by adverse health consequences caused by its dysregulation (Tsigos & Chrousos, 2002). For example, increased HPA axis activity and the hyperproduction of cortisol can lead to melancholic depression which can be accompanied by atherosclerosis, suppression of immune cells, infectious diseases, deposition of visceral

Neuroendocrine Activation

fat, and enhanced resistance to autoimmune/ inflammatory disease (Tsigos & Chrousos). Hypo-production of cortisol, on the other hand, will lead to the state of the relative resistance to infectious but increased susceptibility to inflammatory and autoimmune diseases, and, in its more severe form, a serious condition known as Addison’s disease (Griffin & Ojeda, 2004). Clearly, one of the very important consequences of HPA axis activation is immunosuppression (Nance & Meltzer, 2003) that includes changes in leukocyte trafficking and function, decreased production of inflammatory cytokines, and inhibition of their effects on target tissues. However, although glucocorticoids can express variable effects on different systems, resulting sometimes in activation and sometimes in their suppression, their primary goal is always to act as the guardians of body homeostasis (Munck, Guyre, & Holbrook, 1984). Therefore, it is not stress that glucocorticoids fight against, it is altered homeostasis that triggers their secretion and activation. Stress triggers the activation of both pituitary gland and adrenal cortex, as well as specialized “neuroendocrine tissue” in the hypothalamus, but it can also act via sympathetic neurons responsible for presence of the circulating catecholamines, adrenaline, and noradrenaline, (epinephrine and norepinephrine) secreted from adrenal medulla (Barrett, 2005). This is known as the sympatho-adrenal-medullary axis or SAM axis/system. Stress can also cause an integrated response that originates entirely within the central nervous system, where activation of cortical and hypothalamic brain centers acts via postganglionic sympathetic neurons, innervating the smooth muscles of blood vessels, heart, skeletal muscles, kidney, gut, and other organs (Barrett). In other words, both short-term physiological changes (such as acute exercise) and chronic pathophysiological disorders (chronic heart failure) will lead to CNS-mediated SNS activation (Goldstein, 1987). SNS activation involves the release of noradrenaline at the end of the postganglionic neurons, but through its preganglionic fibers of splanchnic nerves, it also regulates hormone secretion from adrenal medulla (Barrett, 2005). The cells of this

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endocrine gland, chromaffin cells, synthesize and secrete adrenaline, and, to a lesser extent, noradrenaline. The presence of these catecholamines in the blood stream (e.g., in response to the exercise-induced stress) will lead to cognitive arousal, cardiac stimulation and vasoconstriction of peripheral blood vessels with preserved skeletal muscle blood flow, and relaxed bronchial smooth muscle, increasing oxygen delivery to the exercising muscle, and it will also affect gastrointestinal, renal, endocrine, and other systems (Barrett). On the other hand, a rise in plasma glucocorticoid levels activates different hormones, prostaglandins and other arachidonic acid metabolites, lymphokines, and bioactive peptides which in turn challenge homeostasis through different physiological mechanisms again affecting endocrine, renal, nervous, as well as the immune systems. However, unlike components of HPA axis, secretion of adrenal medullary hormones is not regulated by endocrine feedback loop, but it is controlled by CNS instead (Barrett). In sum, activation of the autonomic and neuroendocrine system during stress has been developed as a protective mechanism in “flightor-fight” situations where it serves to mobilize the metabolic resources necessary to support the requirements of the organism (Havel & Taborsky, 2003). The problem arises when neuroendocrine activation exceeds the body’s metabolic requirements, typical in situations of chronic psychological stress, large amounts of caffeine uptake, as well as the pathological condition of chronic myocardial infarction. One example of this negative effect of neuroendocrine activation in humans today is stress-induced hyperglycemia (Havel & Taborsky). Clearly, neuroendocrine activation during stress through sympathoadrenomedullary system triggers the release of neuropeptides such as adrenaline and noradrenaline and, via activation of HPA axis, causes an increase in secretion of cortisol and the pancreatic hormone glucagon (Havel & Taborsky), with a simultaneous decrease in insulin production. As the pancreatic hormone glucagon raises blood glucose levels, and insulin acts as its antagonist, this neuroendocrine pattern will

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cause an increase in hepatic glucose production in situations that demand increased muscular activity (Havel & Taborsky). In other words, increased physical activity present in the “flightor-fight” response will increase the demand for the glucose consumption and effectively balance higher glucose production, therefore maintaining glucose plasma level (Havel & Taborsky). Among modern types of stress, exercise-induced stress is the only one that parallels somatic motor activation present during “flight-or-fight” response (Havel & Taborsky). Other common types of stress such as hypoxia, trauma, myocardial infarction, etc., will trigger neuroendocrine activation and secretion of glucosemobilizing hormones without adequate glucose utilization and therefore will lead to the state of hyperglycemia (Havel & Taborsky). Caffeine intake (Lane, Pieper, Phillips-Bute, Bryant, & Kuhn, 2002) can also mimic stress-induced activation of neuroendocrine system and lead to a rise in plasma levels of adrenaline, noradrenaline, as well as glucocorticoids such as cortisol. Similar to stress situations, it not only enhances cardiac output, diastolic blood pressure and heart rate, as well as skeletal muscle blood flow but can also potentiate already stress-induced increases in cardiac output and plasma concentration of adrenaline and cortisol (Lane et al., 2002). One of the important protective roles of neuroendocrine activation is sustaining circulation in vital organs (such as heart, brain, kidney), in the situations of extensive volume loss, e.g., hemorrhage (Swedberg, 2002). In order to sustain its role, neuroendocrine activation causes tachycardia, constriction of peripheral blood vessels, and volume expansion. Unfortunately, what is beneficial in one situation can become detrimental in other pathological conditions such as chronic heart failure (Swedberg). Direct consequences of chronic neuroendocrine activation in this case are sodium and water retention that leads to congestion, vessel constrictions that will increase demand of oxygen, and toxic cellular effects, all of which combined together may cause cardiac dysfunction and higher morbidity and death in chronic heart failure patients (Swedberg).

Neuroendocrine Activation

Hence, neuroendocrine activation is an adaptive response to changing and demanding external and internal environment, and another example of the complex structure of living organisms, so carefully and subtly regulated that exposure to any new phenomenon, can turn this strong protector into a very dangerous enemy.

Cross-References ▶ ACTH ▶ Adrenal Glands ▶ Hypothalamus

References and Readings Barrett, E. J. (2005). The adrenal gland. In W. F. Boron & E. L. Boulpaep (Eds.), Medical physiology: A cellular and molecular approach (pp. 1049–1065). Philadelphia: Elsevier. Becker, K. L. (2001). Principles and practice of endocrinology and metabolism. Philadelphia: Lippincott Williams and Wilkins. Cannon, W. B. (1914). The emergency function of the adrenal medulla in pain and the major emotions. American Journal of Physiology, 33, 356–372. Goldstein, D. S. (1987). Stress-induced activation of the sympathetic nervous system. Baillie`re’s Clinical Endocrinology and Metabolism, 1, 253–278. Griffin, J. E., & Ojeda, S. R. (2004). Textbook of endocrine physiology. New York: Oxford University Press. Havel, P. J., & Taborsky, G. J., Jr. (2003). Stress-induced activation of the neuroendocrine system and its effects on carbohydrate metabolism. In D. Porte, R. S. Sherwin, A. Baron, M. Ellenberg, & H. Rifkin (Eds.), Ellenberg and Rifkin’s diabetes mellitus (pp. 129–150). New York: McGraw-Hill Professional. Lane, J. D., Pieper, K. F., Phillips-Bute, B. G., Bryant, J. E., & Kuhn, C. M. (2002). Caffeine affects cardiovascular and neuroendocrine activation at work and home. Psychosomatic Medicine, 64, 593–603. Miller, D. B., & O’Callaghan, J. P. (2002). Neuroendocrine aspects of the response to stress. Metabolism, 51, 5–10. Munck, A., Guyre, P. M., & Holbrook, N. J. (1984). Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocrine Reviews, 5, 25–44. Nance, D. M., & Meltzer, J. C. (2003). Interactions between the adrenergic and immune systems. In J. Brienenstock, E. J. Goetzel, & M. G. Blennerhassett (Eds.), Autonomic neuroimmunology (pp. 15–34). New York: Taylor & Francis.

Neuroendocrine Theory of Aging Paca´k, K., & Palkovits, M. (2001). Stressor specificity of central neuroendocrine responses: Implications for stress-related disorders. Endocrine Reviews, 22, 502–548. Swedberg, K. (2002). Importance of neuroendocrine activation in chronic heart failure. Impact on treatment strategies. European Journal of Heart Failure, 2, 229–233. Tsigos, C., & Chrousos, G. P. (2002). Hypothalamicpituitary-adrenal axis, neuroendocrine factors and stress. Journal of Psychosomatic Research, 53, 865–871. Vigas, M., & Jezova´, D. (1996). Activation of the neuroendocrine system during changes in homeostasis during stress conditions. Bratislava Medical Journal, 97, 63–71.

Neuroendocrine Theory of Aging Emil C. Toescu Division of Medical Sciences, The University of Birmingham, Edgbaston, Birmingham, UK

Synonyms Hormone theory of aging

Definition The neuroendocrine hypothesis of aging proposes that aging results from the functional perturbations, both in neuronal control and in endocrine output, of the hypothalamic-pituitaryadrenal axis. These perturbations result in dysfunction in the activity of various endocrine glands and their target organs. The other consequence is a developing imbalance in hormonal cross-communication between various endocrine axes.

Description The neuroendocrine system has two central components: the hypothalamus, a structure that is part

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of the central nervous system (CNS), and the pituitary gland, situated in an anatomical bone depression at the base of the skull, just behind the crossing of the optical nerves (optic chiasm). The two components, forming the hypothalamopituitary (HP) axis are extensively linked, though a stalk that contains both vascular and neuronal connections. The activity of the system is regulated both by neurotransmitters and neuropeptides secreted locally in the CNS and by circulating hormones. Together, these factors control the secretion by the hypothalamus of hormonal factors that induce or inhibit the downstream release of hormones from the pituitary gland. In addition to this central role in the control of the endocrine system, the hypothalamus has also an important role in the control and integration of activities in the sympathetic and parasympathetic branches of the autonomic nervous system, thus influencing a wide array of essential physiological functions such as heart beat, blood pressure, and vascular reactivity or glucose metabolism. By changes in neuronal activity in specific discrete nuclei, the hypothalamus also regulates the food intake and the distribution and regulation of fat metabolism, in response to peripheral appetite-inducing, orexigenic (ghrelin), or appetite-reducing, anorexigenic (e.g., leptin) agents. Aging is associated with multiple endocrinological changes, including a decrease in estrogens in women (menopause) and testosterone in men (andropause), dehydroepiandrosterone (DHEA) and DHEA sulfate (adrenopause), as well as decreases in growth hormone (GH) and insulin-like growth factor (IGF-1) (somatopause). The general form of the neuroendocrine hypothesis of aging proposes that aging results from the functional perturbations, both in neuronal control and in endocrine output, of the HP axis, that result in a dysfunction in the activity of the endocrine glands and their target organs, as well as imbalances in the hormonal and signaling cross communication between the various components of the endocrine axes. A relevant feature of the activity of the neuroendocrine system is that the secretion of many of the hormonereleasing factors controlling individual endocrine

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systems is cyclical, integrated mainly in diurnal (24 h), but also in monthly or longer cycles, through activity in the hypothalamic suprachiasmatic nucleus (SCN). Thus, the neuroendocrine hypothesis of aging proposes that with aging, through yet to be defined mechanisms, the activity of the body clock is perturbed resulting in a gradual and progressive dys-synchronization of the hormonal output. Similar disruptions in SCN activity affect other processes showing a diurnal cycle, such as the sleeping. Several examples can illustrate this effect of aging on the endocrine system and the resulting functional effects. Thus, with increasing age, there is a decreased secretion of hypothalamic gonadotrophin-releasing hormone (GnRH) and a significant change in the pulsatile rhythm of its secretion that results in a decreased and more erratic secretion of luteinizing hormone (LH). This desynchronization, together with the decrease in the ovarian secretion of regulatory factors, leads, over a period of time, to the loss of reproductive cycles in females. The associated decrease in number of ovarian follicles contributes also to the decline in estrogen levels in aged women, leading to some of the of age-associated changes in postmenopausal women, such as the atrophy of the secondary reproductive tissues, reductions in bone density, or alterations in various cognitive functions. Decreased secretion of GnRH in males results in changes in LH and consecutive decrease in androgen levels, with corresponding loss of skeletal muscle and reproductive functions. In many instances, the term “neuroendocrine theory of aging” is used in a much more restricted meaning and refers to the consequences of the age-related changes in the hypothalamopituitary-adrenocortical gland (HPA) axis. At the top of this axis, the parvocellular neurons in the paraventricular nucleus of the hypothalamus secrete corticotrophin-releasing hormone (CRH) that stimulates the anterior pituitary secretion of the adrenocorticotropic hormone (ACTH). The target organs for this latter hormone are the adrenal glands (situated above each kidney), where it activates the secretion of the glucocorticoids (GCs; cortisol, in humans, corticosterone, in

Neuroendocrine Theory of Aging

rodents) from specific cortical cells in the cortex of the gland. The GCs have a wide range of effects – some are related to glucose metabolism, inducing through various mechanisms increases in glucose concentration in the blood, while others are related with the immune response, up-regulating overall the expression of antiinflammatory proteins and decreasing the levels of pro-inflammatory proteins. In addition to these effects, and very relevant to the mechanisms linking glucocorticoids with the aging process, the GCs hormones play a vital role in regulating the stress response. Together with other stresssensitive systems (e.g., the sympathetic response mediated by secretions from the medullar part of the same adrenal gland), GCs prepare the body for adaptation by mobilizing energy stores, suppressing nonessential physiological systems (e.g., feeding, reproduction), and generating behavioral responses to stimuli perceived as stressful. In the various target organs, including the brain, GCs act through two types of receptors. The glucocorticoid receptor (GR) is expressed throughout the brain, with relatively higher density in the hippocampus and prefrontal cortex. The mineralocorticoid receptor (MR) has a more restricted distribution, mainly in the hippocampus. The existence of both types of receptors in hippocampus is very relevant since the hippocampus, while being a central node in the networks controlling learning and memory, is also exerting an inhibitory effect on the hypothalamic release of CRH and, thus, can exert significant control on the HPA axis. Two interrelated concepts are important for understanding this formulation of the neuroendocrine theory of aging, particularly in respect to brain aging: (1) chronic stress is associated with increases in circulating GC concentrations and (2) such increases in GCs induce an enhanced vulnerability of neurons to a variety of neuroand excito-toxic agents. Thus, in a simple scheme, the decrease in the number of GRs and MRs observed with increasing age would contribute to an impaired regulation of the HPA axis, enhanced basal levels of circulating GCs, neuronal death and hippocampal atrophy, and cognitive impairment (the glucocorticoid hypothesis of brain aging).

Neuroendocrine Theory of Aging

Experimental evidence indicates that, in fact, the age-dependent changes in HPA axis activity are of a much subtler nature. With age, there are variable changes in the effects of GCs (cortisol) on ACTH secretion or of ACTH on cortisol secretion, while the capacity of the adrenal gland to produce GCs is not affected. Whereas the physiological cortisol circadian rhythmicity is maintained in essence, a significant age-related increase in the peak cortisol levels in physiological aging and an advance shift in the onset of the circadian cortisol rise result in an overall elevated serum GC level. With the important role of the GCs in mediating the stress response, one of the important functional consequences of these changes in the activity of the HPA axis is an increased responsiveness and an impaired ability to terminate stress responses, resulting in prolonged GCs exposures. Further difficulties in tracing a simple causal relationship between dysregulation in the HPA axis, aging, and behavioral and cognitive impairment have been generated by recent data indicating that not all types of cognition are impaired, such that both encoding and consolidation of emotional learning is, in fact, facilitated by GCs or that in certain conditions, such as the caloric restriction model in rodents, increased GCs levels can be present while cognition performance is better than in the aged-matched control groups on a normal diet. Such results led to the recent proposal that the relationship between GCs, aging, and cognition represents a divergent imbalance between an age-dependent increase in GCs efficacy on some cell types, such as neurons in the hippocampus, enhancing the catabolic processes, and a decreased efficacy on other cell types, resulting in a decreased protective, anti-inflammatory response. It is still unknown whether the age-associated reduction in hippocampal volume is the primary event leading to elevated levels of cortisol or the other way around, elevated levels of cortisol causing hippocampal atrophy. It is also possible that both events reflect a broader syndrome, often observed during aging, called the metabolic syndrome, and characterized by reduced glucose tolerance, hypertension, obesity, and elevated

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levels of cortisol. In addition, the actual role of circulating GCs in controlling the aging process is further complicated by the fact that the concentrations of active GC forms (cortisol, in humans, and corticosterone, in rodents) that interact with the intracellular receptors are controlled not only by the circulating levels of GCs but also by powerful pre-receptor mechanisms in the cytosol, such as the enzyme 11b-hydroxysteriod dehydrogenase I (11-HSD I), that is able to convert inactive forms of GCs (cortisone) into active forms (cortisol). Recent experiments indicate that modulation of 11-HSD I expression and activity has effects both on the aging phenotype and on the age-associated cognitive changes. An important line of support for a neuroendocrine theory of aging comes from studies in the last few decades on the powerful effect of caloric restriction (CR) in delaying aging and increasing life span, in species ranging from yeast and worms to mice, rats, and monkeys (the results in humans are promising but not yet conclusive). From an evolutionary viewpoint, the effect of CR appears to be explained by organisms having evolved adaptation mechanisms in their neuroendocrine systems to maximize survival during periods of food shortage. Although CR induces wider endocrine modifications (fall in thyroid hormones (T3), increased circulating corticosterone (in rodents), with little change in the secretion of the central regulator factors on the HPA axis, and decreased gonadal hormones), the proposed central mechanism of action of CR is through insulin signaling. It is known that aging is associated with increases in insulin resistance and adiposity, and it is becoming clear that long-time exposure to insulin resistance accelerates biological aging. For example, in diabetes, there is early onset of certain diseases of aging, such as dementia, as well as signs of general body aging such as frailty. Chronic stress may accelerate these age-related metabolic changes. Stress is related to obesity, especially abdominal obesity, and insulin resistance in both animal and human models. Lifting the veil as to the endocrine mechanisms involved, the positive effects of CR are reproduced, to a large extent, in animal models

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that have spontaneous or genetically engineered reductions in the activity of the GH/IGF-1 axis, starting with the initial reports of antiaging effects of hypophysectomized animals, more than 50 years ago. The nature of the processes involved was discovered by genetic studies, initiated in worms (C. elegans), showing that mutations in some genes in this pathway confer resistance to environmental stress, enhanced resistance to starvation, and, most importantly, extended longevity. Many of these same genes are conserved in humans: the insulin/insulin-like growth factor-I (IGF-I) peptide and daf-2 gene (in worms) are homologs of the human insulin and IGF-I receptor, while age-1 (worms) is related to a conserved phosphoinositol-3-kinase that responds to insulin receptor activation, and daf-16 (worms) is a homolog of a human transcription factor. The endocrine mechanisms of the antiaging effects of CR highlight also some of the subtleties of the complex set of processes that regulate the process of normal aging and the resultant potential pitfalls in designing and offering rejuvenation cures. Insulin/IGF-1 signaling is one of the most crucial cellular pathways regulating protein synthesis, glucose metabolism, and cellular proliferation and differentiation. The somatotropic axis in mammals, having the growth hormone (GH) as the major peripheral hormone, can stimulate the expression and secretion of IGF-1 in the liver and modulate the metabolism of several target tissues directly via different GH receptors. Several endocrine mutants, expressing either elevated or reduced levels of GH/IGF-1 hormones, highlight the significance of this axis in the regulation of growth and body size since the deficiencies in the function of GH/IGF-1 axis invariably lead to decreased anabolic capacity and reduced growth. The fact that the GH circulating levels are reduced with age could thus account for many of the features of the aging phenotype and form one face of the so-called GH/IGF-1 paradox of aging. The other face of it is the demonstration of the significant antiaging effects of reducing IGF/insulin signaling, as exemplified by the CR process. To date, the

Neuroendocrine Theory of Aging

paradox does not have a satisfactory resolution, and it is difficult to decide whether reduced activity in the GH/IGF-1 axis should be viewed as a cause or a simple effect of aging. Furthermore, it can be argued that the decline in GH secretion with age represents a protective mechanism against insulin resistance and/or cancer or even an activation of survival mechanisms rather than simply reflecting a progressive failure of the hypothalamus-somatotrope axis. One way to reduce the conceptual tension generated by this neuroendocrine paradox is to invoke one of the most powerful evolutionary theories of aging, the antagonistic pleiotropy theory, which argues that, from an evolutionary perspective, aging results from the action of a number of physiological and/or homeostatic systems that exert several effects (pleiotropic), some of which being positive and beneficial at early stages of individual development, while others being negative and detrimental at later stages of development. Against this backdrop, opinions about the potential use and benefits of GH or GH secretagogues as antiaging agents differ widely and are highly controversial. Overall, data from well-designed clinical studies reported to date indicate unfavorable risk–benefit ratio for treatment of normal elderly subjects with GH. Prescribing GH to individuals who are not GH deficient in an attempt to slow aging is not supported by the available evidence, is not included among its approved uses, and, in the US, is specifically disallowed. The same cautious view should be taken in respect to the adrenal sex steroid, dehydroepiandrosterone (DHEA) proposed as another antiaging fountain of youth hormone. With age, there is a large and abrupt decrease of estrogens in postmenopausal women and a slower and gradual decrease of testosterone in men. In a similar fashion, DHEA and its sulfate ester also fall progressively with age. The fact that the changes in DHEA correlate well with other age-induced modifications, such as increased fat mass and visceral adiposity, reduced bone mineral density, reduced muscle mass, and increased frailty, led to proposals for DHEA treatments or even sex hormones, in elderly individual otherwise

Neurogenomics

endocrinologically well. However, wellcontrolled clinical trials have repeatedly failed to show significant improvements in either the biological parameters tested or in the overall quality of life reporting.

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Neurogenomics Ornit Chiba-Falek Duke University Medical Center, Durham, NC, USA

Cross-References Synonyms ▶ Hypothalamic-Pituitary-Adrenal Axis ▶ Neuroendocrine Activation

Neurogenetics

References and Readings

Definition

Bartke, A. (2009). The somatotropic axis and aging: Mechanisms and persistent questions about practical implications. Experimental Gerontology, 44(6–7), 372–374. Brown-Borg, H. M. (2009). Hormonal control of aging in rodents: The somatotropic axis. Molecular and Cellular Endocrinology, 299(1), 64–71. Chahal, H. S., & Drake, W. M. (2007). The endocrine system and ageing. The Journal of Pathology, 211(2), 173–180. Dumitriu, D., Rapp, P. R., McEwen, B. S., & Morrison, J. H. (2010). Estrogen and the aging brain: An elixir for the weary cortical network. Annals of the New York Academy of Sciences, 1204, 104–112. Hertoghe, T. (2005). The “multiple hormone deficiency” theory of aging: Is human senescence caused mainly by multiple hormone deficiencies? Annals of the New York Academy of Sciences, 1057, 448–465. Landfield, P. W., Blalock, E. M., Chen, K. C., & Porter, N. M. (2007). A new glucocorticoid hypothesis of brain aging: Implications for Alzheimer’s disease. Current Alzheimer Research, 4(2), 205–212. Levay, E. A., Tammer, A. H., Penman, J., Kent, S., & Paolini, A. G. (2010). Calorie restriction at increasing levels leads to augmented concentrations of corticosterone and decreasing concentrations of testosterone in rats. Nutrition Research, 30(5), 366–373. Stewart, P. M. (2006). Aging and fountain-of-youth hormones. The New England Journal of Medicine, 355(16), 1724–1726. Weinert, B. T., & Timiras, P. S. (2003). Invited review: Theories of aging. Journal of Applied Physiology, 95(4), 1706–1716.

Neurogenomics is the interface of neurobiology and genome sciences. It is the study of how the genome as a whole contributes to the evolution, development, structure, and function of the nervous system. Neurogenomics research employs genetic strategies, including investigations of the genome sequence and products (transcriptomes and proteomes), to identify genes involved in the nervous system and to understand their gene-product function and the biological mechanisms through which they contribute to brain development, function, plasticity, and disease. A major goal in neurogenomics is the isolation of genes linked to neurological diseases such as Alzheimer’s and Parkinson’s diseases. Outcomes of such research programs will improve the ability to diagnose neurological disease even before it strikes and will advance the development of novel therapeutic targets to prevent and/or halt the progression of these diseases.

Neurogenetics ▶ Neurogenomics

Description Trends toward large-scale interdisciplinary research projects advance the neurosciences and provide firm foundation the vigorous exploration of the frontier between neurobiology and genome sciences. Neurogenomics field includes, but is not limited to, research of genes that cause neurological disorders; molecular mechanisms through which disease genes act; animal models

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and in vitro techniques for studying pathways of gene function; genetically based studies of neuronal patterning, migration, connectivity, and cognitive/behavioral function; and the genetic basis of normal neural development and function. These studies promote also the development of preclinical disease biomarkers, gene-based therapeutics for neurological disorders, and pharmaceuticals targeted to specific gene products. Genetic methodologies are having a rapidly increasingly impact on studies of the normal and diseased nervous system. The recent advances in genomic and other high-throughput “omic” technologies have allowed an expansion from single-gene to genome-wide analyses, providing a step forward toward a global understanding of neurological and neuropsychiatric disorders. To date, more than 200 genes have been identified that cause or contribute, in various extents, to neurological disorders. Examples of recent milestone advances are the following: (1) A meta-analysis of genome-wide association studies in Parkinson’s disease identified 11 Parkinson’s risk loci that surpassed the threshold for genome-wide significance. Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BST1, GAK, and LRRK2), and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). (2) Large Alzheimer’s GWAs and replication studies reported genome-wide significant association with the strongest most established genetic risk factor for sporadic late-onset Alzheimer’s disease, the APOE genomic region, and with three novel loci (CLU, CR1, and PICALM). (3) Using comparative genomics approach, it was found that rare structural variants (CNV) disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Furthermore, the development of new model organisms (such as the C. elegance, honeybee, Drosophila, and zebra fish) for neuroscience research is being accelerated by extensive genome sequencing and the application of comparative and functional genomics technologies.

Neurogenomics

These modern technologies also impact the availability of information and data sharing. Resources for neurogenomics research – such as tissue and information registries, gene expression and function atlases of the brain of animal models, human brain transcriptomes, and whole genome genotypes from neurological affected subjects and control – have been rapidly developed and are becoming publicly available for investigators to use.

Cross-References ▶ Alzheimer’s Disease ▶ Gene ▶ Genetics ▶ Genome-Wide Association Study (GWAS) ▶ Genomics ▶ Parkinson’s Disease: Psychosocial Aspects

References and Readings Boguski, M. S., & Jones, A. R. (2004). Neurogenomics: At the intersection of neurobiology and genome sciences. Nature Neuroscience, 7, 429–433. Gibbs, J. R., van der Brug, M. P., Hernandez, D. G., Traynor, B. J., Nalls, M. A., Lai, S. L., et al. (2010). Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genetics, 6, e1000952. Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., et al. (2009). Genomewide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nature Genetics, 41, 1088–1093. International Parkinson Disease Genomics Consortium. (2011). Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet, 377(9766), 641–649. Lein, E. S., Hawrylycz, M. J., Ao, N., Ayres, M., Bensinger, A., Bernard, A., et al. (2007). Genomewide atlas of gene expression in the adult mouse brain. Nature, 445, 168–176. Walsh, T., McClellan, J. M., McCarthy, S. E., Addington, A. M., Pierce, S. B., Cooper, G. M., et al. (2008). Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science, 320, 539–543. Whitworth, A. J., Wes, P. D., & Pallanck, L. J. (2006). Drosophila models pioneer a new approach to drug discovery for Parkinson’s disease. Drug Discovery Today, 11, 119–126.

Neuroimaging

Neuroimaging Elliott A. Beaton Department of Psychiatry and Behavioral Sciences and the M.I.N.D. Institute, University of California-Davis, Sacramento, CA, USA

Synonyms Brain imaging; Computerized tomography (CT); Diffuse optical imaging (DOI); Event-related optical imaging (EROI); Functional magnetic resonance imaging (fMRI); Imaging; Magnetic resonance imaging (MRI); Positron emission tomography (PET)

Definition Neuroimaging broadly refers to the relatively noninvasive technologies and techniques for localizing, measuring, and visualizing central nervous system function and structure. Common neuroimaging methodologies include magnetic resonance imaging (MRI), positron emissions tomography (PET), and computerized tomography (CAT/CT).

Description Neuroimaging refers to a collection of techniques used to noninvasively view structure and function of living brain tissue. The methods used to visualize brain tissue have evolved significantly over the last several decades from using x-ray technologies to the more recent and increasingly ubiquitous (nuclear) magnetic resonance imaging. Contrast X-Rays and Computerized Axial Tomography (CAT/CT) X-ray photography creates images by passing x-rays through the body and onto a photographic plate by taking advantage of variation in x-ray radiation absorption of different tissues. Certain molecules and denser

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materials absorb more radiation and thus less reaches the photographic plate. This method is excellent for seeing skeletal bones that appear on the photographic plate with a high degree of contrast compared to surrounding tissues. It is less useful for tissues that do not strongly differ in x-ray radiation absorption such as parts of the brain. One method to get around this is to introduce a radiopaque agent to increase contrast by differentially absorbing x-rays. This allows for the visualization of the cerebral ventricular and circulatory systems. Pneumoencephalography involves injecting air into the cerebral ventricular system to briefly displace cerebral spinal fluid (CSF), and cerebral angiography involves injecting a radiopaque dye into a cerebral artery. These methods are limited in the information they produce but can be used to examine general brain atrophy, damage, or displacement of blood vessels. The next step in the evolution of x-ray imaging of the living brain was the introduction of computed tomography (CT) which is sometimes referred to as computerized axial tomography (CAT). However, CT is more appropriate because “axial” merely refers to the plane of image acquisition, and images can just as easily be acquired in the coronal or sagittal planes. CT utilizes an x-ray detector rather than a photographic plate. The x-ray source and detector are mounted opposite one another on a rotating ring inside a tube that encircles the person being scanned. The CT scanner captures numerous images of the brain from several angles as the x-ray source and detector rotate around the head. These images are then reconstructed by a computer to make three-dimensional multislice images of the living brain. The brighter and darker areas of the images are described as “hyperdense” and “hypodense,” respectively, with grayish components of the images as “isodense.” Water and CSF appears almost black, white matter darker than gray matter, and skull as nearly white. Variation in image intensity is more carefully delineated in Hounsfield units (HU) with water having an HU of 0, CSF and HU between 8 and 18, gray matter and white matter HU ¼ 37–41 and 30–34, respectively, and bone

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HU ¼ 600–2,000. CT scans have the benefit of being relatively inexpensive and having very fast acquisition times, making them particularly valuable tools for detecting recent brain trauma and intracranial lesions in emergency situations. Limitations of CT scanning include poorer contrast between brain tissue types, and the number of CT scan any one person can have at a given time is limited because of safety requirements to limit exposure to x-ray radiation. Furthermore, while CT can be used to visualize brain structure, it is not useful for measuring brain function while engaging in a process or activity. Other methods allowing for accurate localization of brain function include positron emissions tomography (PET) and functional magnetic resonance imaging (fMRI). Imaging equipment that combine CT and PET technologies in one package are now commonly available and increase information yield and utility with the practical benefit of taking up less space than dedicated CT and PET scanners. Single-Photon/Positron Emissions Tomography (SPECT/PET) Positron emissions tomography (PET) and singlephoton emission computerized tomography (SPECT) are used to image brain activity. This method also uses radiation and radiation detectors, but rather than shooting an x-ray through the material to be imaged, PET utilizes radiolabeled tracers in the form of chemicals that have specific actions within the brain. For example, fluorine-18labeled 2-fluoro-2-deoxy-D-glucose (18 F-FDG) is a commonly used radiotracer. When 18 F-FDG is injected into the carotid artery, it is rapidly taken up by metabolically active neurons during an experimental task as it very similar to glucose. However, it cannot be metabolized like glucose and thus accumulates in active brain regions where it slowly breaks down. The radioactive label (or ligand) gives off photons (i.e., SPECT) as a result of a nuclear process where a proton in the nucleus is converted into a neutron, neutrino, and a positron (i.e., PET). Both the neutrino and the positron are then ejected from the nucleus. The kinetic energy of the ejected positron both varies and declines at a rate that depends on the nature of

Neuroimaging

the surrounding material. When an ejected positron meets an electron, it creates an annihilation reaction where the electron and the positron turn into two photons that travel in opposite directions (180 ) of each other. These photons are measured as a line by two of a series of scintillation detectors mounted in opposition from one another. The images created by the PET scanner are not images of the brain itself; rather, they are images created from the relative distributions of detected amounts of radioactivity in brain regions of interest. PET is powerful methodology that can be used to study hemodynamics, drug action localization, receptor function, metabolism, and even molecular processes including DNA synthesis. PET is particularly valuable in detecting disease processes that may be evident as metabolic variation but not are yet manifested as anatomical abnormality that could be detected using CT or MRI. However, PET images can be effectively combined with CT or MRI images, providing accurate localization of accumulated radioactivity. PET is also advantageous in that radiation exposure is relatively limited. The primary limitation of PET is the necessity for local access to a cyclotron to produce radiotracers. The radiotracers have a very short half-life and thus must be made in close physical proximity to the PET scanner and utilized quickly. The limitations of PET and CT have led to a significant increase in application of methods that do not utilize hard radiation like x-rays or radiolabels that are expensive to produce. Structural and functional magnetic resonance imaging (sMRI and fMRI, respectively) and the recent emergence of near infrared spectroscopic imaging (NIRSI) allow for detailed analyses of both brain structure and function in the living brain. Magnetic Resonance Imaging (MRI)/ Functional Magnetic Resonance Imaging (fMRI) Magnetic resonance imaging (MRI) methods produce images of the brain and other bodily regions that are high in both contrast and resolution. Although some MRI methods utilize contrast agents, MRI does not expose patients or study participants to ionizing radiation. Rather,

Neuroimaging

this technique utilizes a very powerful homogeneous and stable electromagnetic field. This brief description of how MRI works is limited to “classical”/Newtonian physics, but quantum mechanical descriptions are available elsewhere. Protons are found in all of the nuclei of the atoms that make up the body, but conventional MRI utilizes hydrogen protons. Hydrogen protons spin randomly with their magnetic moments “pointing” in random directions until they are in the influence of the strong magnetic field of the MRI scanner where they all align in parallel with the direction (z-axis) of the external field generated by the electromagnet. Application of a radiofrequency (RF) pulse is applied to the z-axis aligned hydrogen protons with an excitation/receiver coil. As a result of absorbed energy from the RF pulse, the hydrogen protons move or “flip” into a higher energy state that is antiparallel to the z-axis toward the x-y plane. With the removal of the RF pulse, the hydrogen protons “relax” or move back into alignment with the external electromagnetic field along the z-axis and release the absorbed energy form the RF pulse as electromagnetic waves that are detected by the excitation/receiver coil and other magnetic gradient coils in three dimensions. Static contrast methodologies are used to generate anatomical images of the brain. Depending on the type of RF pulse applied, the images highlight different types of tissue or fluids. Static contrast between tissue types is achieved by three properties of protons in tissues: (1) the proton density (i.e., how many hydrogen protons are in the region), (2) proton relaxation times along the z-axis (i.e., the longitudinal relaxation time or T1), and (3) proton relaxation times along the x-y plane (i.e., the transverse relaxation time or T2). Motion contrasts detect dynamic properties of protons in tissues and fluids to generate images of blood flow, capillary irrigation, perfusion, and diffusion of water. Functional MRI (fMRI) refers to MRI methodologies that estimate brain activity. Brain slices are repeatedly imaged over time, allowing for statistical contrast of experimental manipulations. The most common is blood oxygen level-

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dependant (BOLD) fMRI. BOLD fMRI methods exploit changes in levels of oxygen in the blood that result from the metabolic demands of brain tissue during neural activity. Active brain tissue utilizes oxygen, and the change from an oxygenated state to a deoxygenated state can be detected because deoxygenated blood is paramagnetic. Other methods include perfusion or dynamic-contrast MRI, which measures changes in blood volume using an injected paramagnetic contrast agent such as gadolinium, or magnetic resonance spectroscopy (MRS), which measures localized levels of brain metabolites. There is also diffusion MRI that measures diffusion coefficients of water in brain tissue. Diffusion tensor imaging (DTI) examines the water diffusion coefficients in neighboring voxels to estimate the shapes and directions of white matter tracts. MRI possesses advantages over CT and PET including very high-resolution images that can be acquired without ionizing radiation. In most MRI procedures, no contrast agent is needed, and the procedures are completely noninvasive. MRI still requires significant safety procedures though. The magnet is always active, and any objects that are susceptible to magnetism can become dangerous projectiles within the boundaries of the field. Furthermore, patients and study participants must be screened for metallic objects or medical devices such as pacemakers in and on their bodies. Diffuse Optical Imaging or Tomography (DOI/ DOT) and Near Infrared Spectroscopy (NIRS) Diffuse optical imaging (DOI) and near infrared spectroscopy (NIRS) are relatively new applications for measuring relative changes in blood volume and oxygenation via hemoglobin levels as a proxy for cellular metabolism. These methods exploit changes in the properties of near IR light projected through tissue in the absorptive spectra and light scattering properties of water, oxygenated hemoglobin, and deoxygenated hemoglobin. Like BOLD fMRI, DOI measures the hemodynamic response as blood flows to the active tissue supplying oxygen to satisfy the metabolic needs of neurons in the active

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region. Changes in the way that light moves through brain tissue from the IR source to the IR detector can be computationally modeled, and blood flow to particular brain regions can be examined based on the placement of the IR source and detectors. Modeling how light moves through the various tissues of the head is a complex process that contributes to DOI and NIRS limitations. One method of simplifying the model is to assume the brain region being scanned is essentially “flat” and that the tissues do not differ in their optical properties. However, anatomical MRI can be combined with DOI/NIRS to provide a better model of absorption and scattering of light with bone and other head tissues. Advantages of this technology include a high degree of portability, rapid data acquisition, relative low cost, and complete noninvasiveness. The primary disadvantages result from the lack of robust spatial resolution and that imaging is limited to surface and nearsurface brain tissue.

References and Readings Azar, F., & Intes, X. (Eds.). (2008). Translational multimodal optical imaging. Norwood, MA: Artech House. Christian, P. E., & Waterstram-Richm, K. M. (Eds.). (2012). Nuclear medicine and PET/CT technology and techniques (7th ed.). St. Louis, MO: Mosby. Hanson, S. J., & Bunzl, M. (Eds.). (2010). Foundational issues in human brain mapping. Cambridge, MA: The MIT Press. Huttel, S. A., Song, A. W., & McCarthy, G. (2008). Functional magnetic resonance imaging (2nd ed.). Sunderland, MA: Sinauer Associates. Jezzard, P., Mathews, P. M., & Smith, S. S. (2001). Functional MRI: An introduction to methods. New York: Oxford University Press. Jiang, H. (2010). Diffuse optical tomography. Boca Raton, FL: CRC Press/Taylor and Francis LLC. Mettler, F. A., & Guiberteau, M. J. (2006). Essentials of nuclear medicine imaging (5th ed.). Philadelphia: Saunders/Elsevier. Romans, L. (2011). Computed tomography for technologists: A comprehensive text. Baltimore: Wolters Kluwer Health/Lippincot Williams and Wilkins. Wahl, R. L., & Beanlands, R. S. B. (Eds.). (2009). Principles and practice of PET and PET/CT (2nd ed.). Philadelphia: Lippincott Williams and Wilkins/Wolters Kluver.

Neuroimmunology

Neuroimmunology Yori Gidron Faculty of Medicine and Pharmacy, Free University of Brussels (VUB), Jette, Belgium

Definition This term refers to the interdisciplinary field merging neurology, immunology, and aspects of neuroscience. It is a scientific and clinical domain. Scientifically, neuroimmunology tries to understand the bidirectional links between the nervous and immune systems, and their implications to illnesses. Clinically, various “classical” neuroimmune diseases (e.g., multiple sclerosis – MS) and recently more diseases are being recognized for their influence by both the nervous and immune systems, including cancer and coronary heart disease. The biological underpinnings of neuroimmunology include the descending pathways from the brain to the immune system, manifested by innervation of lymph nodes, effects of stress hormones on immunity, and the presence of neurotransmitter receptors on immune cells (Dantzer, Konsman, Bluthe´, & Kelley, 2000). In parallel, ascending pathways include the vagus nerve, expressing receptors for interleukin-1, brain regions lacking the blood–brain barrier (BBB), and a “domino-like” effect of prostaglandins, an end point of inflammation, on both sides of the BBB (Dantzer et al., 2000; Tracey, 2009). MS, for example, represents an inflammatory autoimmune insult on nerves, which eventually leads to the episodic and degenerative characteristic of this disease (Compston & Coles, 2002). Understanding neuroimmune interactions has been pivotal for developing treatments for MS. Another extraordinary example is the work of Schwartz and colleagues who demonstrated that due to the “immune privilege” status of the brain, closed brain injuries may not undergo immune protection, while in contrast, following a homing intervention of T cells to the brain, recovery is accelerated (Schwartz & Moalem, 2001). The relevance of neuroimmune interactions to other diseases has

Neuroimmunomodulation

recently been claimed by researchers in relation to coronary heart disease (Gidron, Kupper, Kwaijtaal, Winter, & Denollet, 2007) and cancer (Gidron, Perry, & Glennie, 2005), based on multiple converging evidence. Ongoing scientific efforts may hopefully reveal the clinical implications of such neuroimmune associations for such and other diseases.

Cross-References ▶ Neuroimmunomodulation

References and Readings Compston, A., & Coles, A. (2002). Multiple sclerosis. The Lancet, 359, 1221–1231. Dantzer, R., Konsman, J. P., Bluthe´, R. M., & Kelley, K. W. (2000). Neural and humoral pathways of communication from the immune system to the brain: Parallel or convergent? Autonomic Neuroscience, 85, 60–65. Gidron, Y., Kupper, N., Kwaijtaal, M., Winter, J., & Denollet, J. (2007). Vagus-brain communication in atherosclerosis-related inflammation: A neuroimmunomodulation perspective of CAD. Atherosclerosis, 195, e1–e9. Gidron, Y., Perry, H., & Glennie, M. (2005). The Vagus may inform the brain about sub-clinical tumours and modulate them: An hypothesis. The Lancet Oncology, 6, 245–248. Schwartz, M., & Moalem, G. (2001). Beneficial immune activity after CNS injury: Prospects for vaccination. Journal of Neuroimmunology, 113, 185–192. Tracey, K. J. (2009). Reflex control of immunity. Nature Reviews Immunology, 9, 418–428.

Neuroimmunomodulation Yori Gidron Faculty of Medicine and Pharmacy, Free University of Brussels (VUB), Jette, Belgium

Definition This term refers to the modulating role of the nervous system in relation to immune functions.

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This modulation reflects part of the bidirectional communication between the nervous system and the immune system. Neuroimmunomodulation is possible due to existence of receptors for neurotransmitters (e.g., norepinephrine, acetylcholine) on immune cells and due to innervation of lymph nodes by sympathetic nervous system (SNS) fibers (Felten et al., 1984). These innervating fibers influence the trafficking and proliferation of immune cells, all evidence for neuroimmunomodulation. Another more recently discovered form of neuroimmunomodulation includes the one by the vagus nerve, where its descending (efferent) branches inhibit cytokine synthesis in peripheral monocytes, via the alpha-7 nicotinic acetylcholine receptor (Tracey, 2009). The neuroimmunomodulating role of the vagus may have clinical implications since the inflammatory response is in the core of the etiology of severe chronic diseases such as cancer and coronary heart disease. Thus, vagal activity is hypothesized to possibly modulate the progress of such diseases (Gidron, Kupper, Waijtaal, Winter, & Denollet, 2007; Gidron, Perry, & Glennie, 2005), a matter under current investigation. Neuroimmunomodulation is also manifested by the differential effects of the cerebral hemispheres on peripheral immunity. Studies have shown that the left hemisphere has immune-potentiating effects while the right hemisphere has immunosuppressive effects (Davidson, Coe, Dolski, & Donzella, 1999; Meador et al., 2004). These effects were found in animals and humans and were found to be mediated by the sympathetic response, since blocking beta-adrenergic receptors abolished differences in immunity between the hemispheres. Here too, the neuroimmunomodulatory effects of the hemispheres may have clinical roles since a shift from left to right hemisphere activity during stressful periods correlated with more reported illness (Lewis, Weekes, & Wang, 2007). Furthermore, in a matched prospective design, people with right hemisphere lateralization were at significantly higher risk of reporting the common cold than those with left hemispheric lateralization, independent of confounders (Gidron, Hall, Wesnes, & Bucks, 2010). Neuroimmunomodulation has

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a central role in behavior medicine, by possibly explaining how psychological factors influence the risk of disease, since the SNS, vagal nerve activity, and hemispheric lateralization are each related to psychological factors as well as to immunity and risk of certain illnesses. Research is only at the beginning of understanding these neuromodulatory links and of possibly utilizing them in the service of preventing or treating diseases.

Cross-References ▶ Immune Responses to Stress ▶ Neuroimmunology ▶ Psychoneuroimmunology

References and Readings Davidson, R. J., Coe, C. C., Dolski, I., & Donzella, B. (1999). Individual differences in prefrontal activation asymmetry predict natural killer cell activity at rest and in response to challenge. Brain, Behavior, and Immunity, 13, 93–108. Felten, D. L., Livnat, S., Felten, S. Y., Carlson, S. L., Bellinger, D. L., & Yeh, P. (1984). Sympathetic innervation of lymph nodes in mice. Brain Research Bulletin, 13, 693–699. Gidron, Y., Hall, P., Wesnes, K. A., & Bucks, R. S. (2010). Does a neuropsychological index of hemispheric lateralization predict onset of upper respiratory tract infectious symptoms? British Journal of Health Psychology, 15, 469–477. Gidron, Y., Kupper, N., Waijtaal, M., Winter, J., & Denollet, J. (2007). Vagus-brain communication in atherosclerosis-related inflammation: A neuroimmunomodulation perspective of CAD. Atherosclerosis, 195, e1–e9. Gidron, Y., Perry, H., & Glennie, M. (2005). The vagus may inform the brain about sub-clinical tumours and modulate them: An hypothesis. The Lancet Oncology, 6, 245–248. Lewis, R. S., Weekes, N. Y., & Wang, T. H. (2007). The effect of a naturalistic stressor on frontal EEG asymmetry, stress, and health. Biological Psychology, 75, 239–247. Meador, K. J., Loring, D. W., Ray, P. G., Helman, S. W., Vazquez, B. R., & Neveu, P. J. (2004). Role of cerebral lateralization in control of immune processes in humans. Annals of Neurology, 55, 840–844. Tracey, K. J. (2009). Reflex control of immunity. Nature Reviews Immunology, 9, 418–428.

Neurological

Neurological Yori Gidron Faculty of Medicine and Pharmacy, Free University of Brussels (VUB), Jette, Belgium

Definition Neurological refers to any process or disorder involving the nervous system or its components. The nervous system includes the central and peripheral nervous systems (CNS, PNS, respectively). These systems are composed of neuronal fibers (axons and dendrites) which transmit neurological information to and from neurons, cell bodies that process neurological information, as well as other types of cells (e.g., astrocytes, microglia). The CNS, the “headquarters” of the body, processes and regulates multiple bodily responses and psychological responses to external and internal stimuli. These numerous neurological processes are carried out by various levels of the CNS including the brain stem (basic vital signs), limbic system (memory, sensory, autonomic, immune, hormonal, and emotional processes), and the cortex (executive function and information processing, overall modulation of multiple systems). Neurological disorders are a heterogeneous group of disorders that involve abnormal functioning of the nervous system, PNS or CNS, or both. These could be manifested motorically (as in Parkinson’s disease and stroke), behaviorally (as in Alzheimer’s disease), or in neurophysiological tests (as in epilepsy or stroke). Neurological diseases caused by genetic mutations are often congenital (e.g., congenital insensitivity to pain with anhydrosis), developmental disorders of the nervous system (e.g., spina bifida), neurodegenerative diseases (e.g., Alzheimer’s disease), diseases due to cerebral ischemia (e.g., stroke), injuries to the PNS or CNS, seizures (e.g., epilepsy), cancers (e.g., glioma), and infections (e.g., meningitis). These disorders are treated by

Neuromuscular Diseases

neurologists, physicians who specialize in neurological disorders, their etiology and treatment. A major consequence of neurological disorders is their psychosocial impact, both on the patient and on his or her social environment. Often, the social stigma associated with certain neurological problems is quite severe (de Boer, 2010) and has the potential to isolate patients. This is of great importance for behavior medicine and includes the assessment of the health-related quality of life affected by such conditions. The accumulating evidence linking neuroimmune processes (e.g., inflammation, vagal nerve modulation) to peripheral and central pathways (Tracey, 2009) and to diseases reveals the importance of the interdisciplinary nature of the neurologist’s work, encompassing basic biology, medicine, and behavioral sciences.

Cross-References ▶ Neuroimaging ▶ Neuron

References and Readings de Boer, H. M. (2010). Epilepsy stigma: Moving from a global problem to global solutions. Seizure, 19, 630–636. Tracey, K. J. (2009). Reflex control of immunity. Nature Reviews Immunology, 9, 418–428.

Neuromuscular Diseases Robert J. Gatchel and Matthew T. Knauf Department of Psychology, College of Science, The University of Texas at Arlington, Arlington, TX, USA

Synonyms Neuromuscular disorders

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Definition Neuromuscular disease is a broad term that encompasses many different specific diseases and ailments that, in general, impair the functioning of the muscles, the neuromuscular junction, and/or the peripheral nervous system (LaDonna, 2011; National Institute of Neurological Disorders and Stroke [NINDS], 2011).

Description Many different specific diseases fall under the broad spectrum of neuromuscular diseases. Because it would be impossible to list each and every disease in this brief section, the most prevalent ones are included here: (1) motor system disorders (e.g., amyotrophic lateral sclerosis, Parkinson’s disease), (2) central nervous system disorders (e.g., multiple sclerosis), (3) muscular dystrophies (e.g., Steinert’s, Duchenne, Becker), (4) autoimmune disorders (e.g., myasthenia gravis), (5) neuropathies (acquired or inherited), and (6) hereditary muscular disorders (e.g., spinal muscular atrophy). There are also numerous other diseases that fall under each of the above categories. For example, muscular dystrophies include a group of more than 30 diseases, but the most common are myotonic (i.e., Steinert’s, which primarily affects adults) and Duchenne (which primarily affects children) [NINDS, 2011]. Neuromuscular diseases may present symptoms at any time during an individual’s lifetime, some may be present while an individual is an infant or child, but others may not be present until mid- to later portions of an individual’s lifetime. Reported overall prevalence rates for all individuals that may be affected by an inherited neuromuscular disease at sometime during their life (infancy to adulthood) are approximately 1 in 3,500 individuals (Emery, 1991). Many of the neuromuscular diseases are chronic and/or inherited, as well as progressive in nature, and individuals with these disorders tend to require specialized care in dealing with them (LaDonna, 2011; Seesing, Drost, van der Wilt, & van Engelen, 2011). In addition,

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adjustment of the current treatment may be required if new symptoms arise at any time or if the existing symptoms begin to aggregate over time (Seesing et al., 2011). Many of the common symptoms of neuromuscular disease may include fatigue, muscle weakness, loss of motor control, and spasticity. Recent studies have shown that chronic pain may also be considered a common symptom of neuromuscular disease (Engel, Kartin, Carter, Jensen, & Jaffe, 2009; Hoffman et al., 2005; Jensen et al., 2005; Tiffreau et al., 2006). It has been reported that the rates for adults with neuromuscular diseases who have chronic pain range from 70% to 96% of those affected (Engel et al., 2009). One interesting point that should be noted is that chronic pain is not only present for adults with neuromuscular disease but is also present in children with neuromuscular diseases (Engel et al., 2009). It has been reported that the rate for children with neuromuscular diseases who have chronic pain is over 70% (Engel et al., 2009). In addition to the physical impact of neuromuscular disease, there may also be a psychosocial impact as well. While individuals with neuromuscular diseases may experience a lower quality of life due to the effects of the disease, there is evidence that there are some activities, such as employment, recreational physical activity, and social outlets (peer support), that may improve quality of life (LaDonna, 2011). Also, the more independence that individuals with neuromuscular diseases are able to maintain, (i.e., the more activities that individuals can do by/for themselves), the better their quality of life (Abresch et al., 1998). Once an individual has been diagnosed with having a neuromuscular disorder, the appropriate treatment plan may begin. While there is currently no “cure” for neuromuscular diseases and current treatments are limited (LaDonna, 2011), various treatments aimed at managing the diseases have included (1) drug therapy, (2) referral to specialists for potential surgical intervention (e.g., stimulator implants), (3) patient and familial education and counseling, (4) massage therapy, (5) acupuncture, (6) biofeedback or relaxation training, (7) chiropractic manipulation, (8) nerve blocks, and (9) hypnosis (Jensen,

Neuromuscular Diseases

Abresch, Carter, & McDonald, 2005). Drug therapies may include giving the patient immunosuppressive drugs, analgesic medication (e.g., nonsteroidal anti-inflammatory, narcotic), muscle relaxants, anticonvulsants, and/or antidepressants. Any one of the treatments listed may be used to manage the neuromuscular disease itself, and they may also be employed to manage the pain that is associated with neuromuscular disease. Patients may go to many different specialists, ranging from occupational/physical therapists to physiatrists to surgeons, depending on the severity of the disease. Patient and familial education may be done individually or with family present, and patients and family members also have the option to go to counselors and support groups. Currently, there is little evidence to suggest that any one treatment provides either significant and/ or permanent reprieve of pain, as patients with neuromuscular disease who reported using any one or combination of pain treatments still report some pain (Jensen et al., 2005). Because there is currently no cure for the diseases, disease management approaches must be employed. It is important to attempt to identify the cause of the neuromuscular disease and any pain associated with the disease in order to provide the best method of management (Jensen et al., 2005). However, research is still needed to examine the etiology of the diseases, and, in addition, more research is needed to examine the underlying mechanisms of the pain that is associated with neuromuscular diseases. If new symptoms arise over the course of the disease, physicians and other specialists may conduct appropriate further testing and adjustment of treatments as warranted.

Cross-References ▶ Chronic Pain Patients ▶ Multiple Sclerosis: Psychosocial Factors

References and Readings Abresch, R. T., Seyden, N. K., & Wineinger, M. A. (1998). Quality of life. Issues for persons with neuromuscular

Neuron diseases. Physical Medicine and Rehabilitation Clinics of North America, 9(1), 233–248. Emery, A. E. H. (1991). Population frequencies of inherited neuromuscular diseases – a world survey. Neuromuscular Disorders, 1(1), 19–29. Engel, J. M., Kartin, D., Carter, G. T., Jensen, M. P., & Jaffe, K. M. (2009). Pain in youths with neuromuscular disease. The American Journal of Hospice & Palliative Care, 26(5), 405–412. Hoffman, A. J., Jensen, M. P., Abresch, R. T., & Carter, G. T. (2005). Chronic pain in persons with neuromuscular disorders. Physical Medicine and Rehabilitation Clinical North America, 16(4), 1099–1112. Jensen, M. P., Abresch, R. T., Carter, G. T., & McDonald, C. M. (2005). Chronic pain in persons with neuromuscular disease. Archives of Physical Medicine and Rehabilitation, 86, 1155–1163. LaDonna, K. A. (2011). A literature review of studies using qualitative research to explore chronic neuromuscular disease. Journal of Neuroscience Nursing, 43(3), 172–182. National Institute of Neurological Disorders and Stroke (NINDS). (2011). Muscular dystrophy: Hope through research. Office of Communications and Public Liaison, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. Seesing, F. M., Drost, G., van der Wilt, G. J., & van Engelen, B. G. (2011). Effects of shared medical appointments on quality of life and cost-effectiveness for patients with a chronic neuromuscular disease. Study protocol of a randomized controlled trial. BMC Neurology, 11, 106. Tiffreau, V., Viet, G., & The´venon, A. (2006). Pain and neuromuscular disease: The results of a survey. American Journal of Physical Medicine & Rehabilitation, 85(9), 756–766.

Neuromuscular Disorders ▶ Neuromuscular Diseases

Neuron Marijke De Couck Free University of Brussels (VUB), Jette, Belgium

Synonyms Nerve cell

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Definition Neurons are the basic building blocks of the nervous system, which includes the brain, the spinal cord, and the peripheral nervous system. These specialized cells are the information-processing units responsible for receiving, processing, and transmitting information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Structure Although the morphology of various types of neurons differs in some respects, they all contain four distinct regions with differing functions in the communication of information: the cell body (soma), the dendrites, the axon, and the axon terminals. Most neurons have multiple dendrites, which receive chemical signals from the axon termini of other neurons. Dendrites convert these signals into small electric impulses and transmit them in the direction of the cell body. The cell body contains the nucleus and is the site of synthesis of virtually all neuronal proteins. Almost every neuron has a single axon, which is specialized for the conduction of a particular type of electric impulse, called an action potential, away from the cell body toward the axon terminus. When an action potential reaches a chemical synapse, a neurotransmitter is released into the synaptic cleft. The axon terminals are the small branches of the axon that form the synapses, or connections, with other cells. A single axon in the central nervous system can synapse with many neurons and induce responses in all of them simultaneously (Lodish, Berk, & Zipursky, 2000). Classification Neurons can be classified by their morphology and function. Functionally, we can distinguish afferent neurons, efferent neurons, and interneurons. Sensory neurons are afferent neurons that convey information from tissues and organs to the central nervous system. Motor neurons are efferent neurons that transmit signals from the central nervous system to the effector cells. The interneurons connect neurons within specific regions of the central nervous system.

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Neurons can also be classified anatomically into unipolar, bipolar, and multipolar neurons. Unipolar neurons are those where the dendrite and axon merge into a single process of the cell body. Bipolar neurons are those where axon and single dendrite are on opposite ends of the soma, while multipolar neurons consist of more than two dendrites. Functions Neurons connect to each other to form networks. Neurotransmitters are used to carry the signal across the synapse to other neurons (Lodish et al., 2000). The shape, structure, and connectivity of nerve cells are important aspects of neuronal function. Genetic and epigenetic factors that alter neuronal morphology or synaptic localization of pre- and postsynaptic proteins contribute significantly to neuronal output and function and may underlie clinical states. Furthermore, neuronal loss is one of the major pathological hallmarks of neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. In daily mental functioning and psychiatric conditions, the pathways and amounts of neurotransmitters crossing between neurons influence and represent at the neuronal level such conditions. Examples include reduced serotonin in depression and aggression. Numerous studies have shown that neuronal stimulation can also influence behavior. For example, a study in rats showed that the stimulation of one single neuron in the somatosensory cortex can change the animal’s detection behavior (Houweling & Brecht, 2008). Thus, the neuron is the basic unit of the nervous system, and understanding its multiple functions is of pivotal significance in health and disease.

References and Readings Houweling, A. R., & Brecht, M. (2008). Behavioural report of single neuron stimulation in somatosensory cortex. Nature, 451, 65–68. Lodish, H., Berk, A., Zipursky, S. L., et al. (2000). Molecular cell biology (4th ed.). New York: WH Freeman.

Neuronal Nitric Oxide Synthase (nNOS)

Neuronal Nitric Oxide Synthase (nNOS) ▶ Nitric Oxide Synthase (NOS)

Neuropeptide Y (NPY) Mustafa al’Absi University of Minnesota Medical School, University of Minnesota, 235 School of Medicine, Duluth, MN, USA

Synonyms Hormones

Definition Neuropeptide Y (NPY) is a 36-amino acid hormone expressed in multiple sensory, cerebral, and autonomic pathways. It is a highly conserved peptide reflecting its important role in the body. In 1982, NPY was isolated from the hypothalamus, and early studies to characterize specific locations and functions of this neuropeptide documented the presence of NPY neurons within the paraventricular nucleus (PVN) of the hypothalamus. Subsequent experiments using a technique called in situ hybridization also found the highest cellular levels of NPY messenger RNA within the arcuate nucleus of the hypothalamus. Research has also demonstrated the presence of NPY in other areas within the brainstem, monoaminergic neurons, and GABAergic neurons in the cortex. Peripherally, NPY is present in sympathetic nerve fibers and innervated organs including the blood vessels, heart, gastrointestinal tract, thyroid gland, and sensory nerves. Several receptors are targeted by NPY and these receptors are widely distributed throughout the body. These include subtypes Y1 and Y5 receptors which mediate effects of NPY on appetite stimulation, and receptors Y2 and Y4 which mediate NPY effects on appetite reduction.

Neuropeptide Y (NPY)

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The wide distribution of these receptors results in various effects on multiple central and peripheral functions. These effects can be a result of direct NPY action or indirect though influencing other neurotransmitters, such as norepinephrine and glutamate.

NPY release are high in obesity animal models. Factors that contribute to obesity, such as glucocorticoids, also increase NPY release. Other hormones that block NPY, such as leptin, have also been found to reduce appetite and reduce risk for obesity.

NPY Functions NPY plays a significant role in a number of physiological and behavioral processes. It is involved in regulating emotions, energy balance, and cognitive functions. NPY increases food intake while also increasing rate and proportion of nutrients storage as fat. It may also interrupt pain processing leading to analgesic effects. Administering NPY by injecting it directly into the PVN leads to increases in the release of corticotropinreleasing hormone (CRH). Because CRH is involved in regulating various psychological and stress-related processes, it is thought that NPY is indirectly involved in these processes.

NPY and Emotion Regulation NPY is involved in the regulation of emotional and affective behaviors. It also influences cognition functions and pain perception. For example, several of the NPY hypothalamic functions have been found to be dysregulated in depression. Hypothalamic-pituitary-adrenal (HPA) axis functions and disruption of appetite regulation in addition to disrupted circadian rhythm occur in depression and have been attributed to certain abnormalities of NPY functions. When NPY is administered into the hypothalamic PVN, it increased ACTH and corticosterone. It is also known that NPY fibers directly innervate CRHproducing neurons within PVN, and injection of NPY increases CRH levels. Patients with depression show decreased levels of NPY in CSF. Similar observation was found in suicide victims. Pharmacological treatment for depression using tricyclic antidepressants and treatment using electroconvulsive shocks were associated with increased NPY in multiple areas of the brain. Research also suggests that depressive symptoms associated with withdrawal from a stimulant like cocaine may be related to reduced levels of NPY caused by chronic drug use. Studies related to anxiety have also shown a negative association between the level of anxiety and NPY levels in cerebrospinal fluid. Observational research using electrophysiological and behavioral approaches in multiple models of anxiety has demonstrated anxiolytic effects of NPY when administered intracerebroventricularly. This research has also been advanced toward pinpointing specific structures that are involved in this effect of NPY and has shown that localized microinjection into the central nucleus of the amygdala was specifically effective in producing NPY anti-anxiety effects. NPY anxiolytic effect in the amygdala appears to be mediated by Y1 receptor. Considering that this

NPY and Appetite Regulation The involvement of NPY in appetite regulation has received significant attention over the last 20 years, with animal research documenting NPY orexigenic effect. Studies on rats and using multiple methodologies, including immunochemical and in situ hybridization techniques, have shown that activation of NPY neurons increases food intake. Injecting the NPY agonist dexamethasone into the third ventricle or the hypothalamus increases appetite. Consistent results were also found when using antagonists that block NPY receptor. The blocking effect led to reduction in NPY neuron activity and reduction in food intake. When the receptors that inhibit the release of NPY (called autoreceptor Y2) were activated in the arcuate nucleus reduction in appetite was noted. Blocking these autoreceptors also led to the reverse effect of increased food intake. Studies that used genetically obese rats have also been conducted to investigate the role of NPY and found that NPY contributes to obesity through direct and indirect pathways. For example, both NPY mRNA and

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location is where multiple stress-response factors and neurochemical pathway also interact suggests that NPY plays a significant role in regulating the stress response. Studies both in humans and in animals indicate the possibility that NPY is directly involved in regulating the stress response and emotional reactivity. In humans, observational studies have indicated that NPY may have anxiolytic effects and may help in coping with stress by facilitating speedy recovery after exposure to intense stressors. Related to this, one study in veterans with posttraumatic stress disorder (PTSD) measured plasma NPY and compared them with veterans with no PTSD. The study found that veterans who did not suffer from PTSD had higher NPY levels than those with PTSD, suggesting that NPY may be a marker of the ability to recover from stress. On the other hand, studies in both mice and monkeys have demonstrated that exposure to repeated stress leads to increased NPY release. This is a similar effect to that seen when the animal ingests a high fat, high sugar diet. It is possible that the increased NPY concentrations contribute to increased fat buildup, especially around the waist and abdomen, and the effects of chronic stress on metabolism function are mediated by NPY.

Cross-References ▶ Anxiety ▶ Appetite ▶ Depression ▶ Leptin ▶ Stress

References and Readings Allen, Y. S., Adrian, T. E., Allen, J. M., Tatemoto, K., Crow, T. J., Bloom, S. R., et al. (1983). Neuropeptide Y distribution in the rat brain. Science, 221, 877–879. Morales-Medina, J. C., Dumont, Y., & Quirion, R. (2010). A possible role of neuropeptide Y in depression and stress. Brain Res, 1314, 194–205. Yehuda, R., Brand, S., & Yang, R. K. (2006). Plasma neuropeptide Y concentrations in combat exposed veterans: Relationship to trauma exposure, recovery from PTSD, and coping. Biol Psychiatry, 59, 660–663.

Neuropsychological Assessment

Neuropsychological Assessment ▶ Neuropsychology

Neuropsychology Richard Hoffman Academic Health Center, School of Medicine-Duluth Campus University of Minnesota, Duluth, MN, USA

Synonyms Brain-behavior relationships; Neurobehavioral assessment; Neurocognitive assessment; Neuropsychological assessment

Definition Neuropsychology is a subdivision of the field of psychology that is concerned with the investigation of brain-behavior relationships. The broad category of neuropsychology can be further divided into experimental neuropsychology and clinical neuropsychology, with this latter specialty definable as an applied science focusing on the behavioral sequelae and manifestations of brain dysfunction.

Description Neuropsychology is currently one of the fastest growing scientific specialty areas in the field of psychology, and the subspecialty area of human clinical neuropsychology is of direct relevance to behavior medicine practitioners as well as physicians in clinical practice, especially neurologists and neurosurgeons. Neuropsychologists in clinical practice use a variety of specially constructed tests and test batteries to assess the functional effects of brain trauma, infection, neoplasias, and structural changes to the brain (including

Neuropsychology Neuropsychology, Table 1 Domains of brainbehavior functioning in neuropsychological assessment Orientation and general mental status Estimation of premorbid status Potential for malingering/symptom validity testing Sensory deficits and paresthesias Motor and gait disturbances Psychomotor activity and speed of information processing Processing efficiency and reaction time Response inhibition Visual search and visuomotor scanning Psychomotor efficiency Speed of information processing Motor speed Grip strength Disorders of perceptual function/apraxias Attention and concentration Mental speed Visual attention Auditory attention Divided attention/visual monitoring and visual sequencing Vigilance and sustained attention Selective attention/freedom from distractibility Working memory Verbal abilities and language skills Disorders of language functions/aphasias Receptive language Expressive language Object naming/anomias Verbal fluency Phonemic fluency Semantic fluency Learning and memory Visual learning and immediate memory Verbal learning and immediate memory Visual delayed memory Verbal delayed memory Long-term declarative memory and remote memory Nondeclarative and procedural memory Implicit memory Incidental memory Semantic and episodic autobiographical memory Recognition and working memory speed Spatial memory Visual perception Spatial cognition Visuospatial skills and construction skills Drawing skills (continued)

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Neuropsychology, Table 1 (continued) Visual discrimination Visuospatial construction Visuospatial integration Facial recognition matching Executive functions and conceptual skills Metacognitive functions Cognitive flexibility Abstract reasoning/concept formation Planning and sequencing ability Judgment Decision making Novel problem solving Overall intellectual abilities Crystallized intelligence Fluid intelligence Academic achievement skills Emotional functioning, personality, and affect Instrumental activities of daily living/competencies Compensatory strategies

vascular abnormalities and strokes) as well as degenerative central nervous system disorders, cortical and subcortical dementias, and progressive disorders of the nervous system, such as multiple sclerosis, Huntington’s disease, and Parkinson’s disease. Specialized neuropsychological test batteries have been constructed to investigate the neurocognitive effects alcohol and drugs of abuse, assess the functional effects of epilepsy and diabetes, and assess the effects of neurotoxins and hypoxia. In the field of neuropsychiatry, the neuropsychology of schizophrenia and the mood and affective disorders has been extensively studied and neuropsychological impairments have been identified that are independent of medication effects or the psychiatric illnesses themselves. Modern clinical neuropsychology is very much a hybrid specialty, with influences from – and ties to – neurology, neurosurgery, neuroimaging (especially functional neuroimaging), neuropsychiatry, cognitive psychology, neuroscience, and clinical psychology as well as the significant advances that have been made in experimental neuropsychology, particularly in the areas of memory and learning. This is

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Neuropsychology

Neuropsychology, Table 2 Common diagnostic questions that neuropsychological assessment can help answer Does the patient have an impaired memory and, if so, what does that mean for that patient and for the treating physicians? Is dementia present and, if so, what kind of dementia and how severe is it? Can the patient understand and follow health-care provider instructions regarding their medical care? What is the patient capable of doing vocationally and can the patient return to work following a neurological injury? What components need to be included in the patient’s rehabilitation plan? Is the patient a candidate for a cognitive rehabilitation program and what should be included in this program? Does the patient have only psychological or psychiatric problems, or do they have brain problems as well? What problems remain for the patient following successful physical recovery from a head injury, stroke, or other brain injury? What is the patient’s capacity in a legal sense (can they drive a car safely, manage their money adequately, participate fully in legal matters such as criminal or civil trials, can they maintain professional licensure)? What are the cognitive and functional effects of progressive illnesses as time progresses (dementias, brain tumors, progressive deteriorating disorders such as Huntington’s, etc.)? What is normal aging versus neurological disease/dementia? Is the temporal lobe epilepsy patient a candidate for resection surgery? Does the patient have specific learning disabilities/attention deficit disorder? What needs to be included in educational programming and follow-up? Is the patient in need of a conservator or guardian? Are there neuropsychological deficits that require supervision, additional support, or placement out of the home (such as nursing home placement)?

reflected in the broad range of functional domains that are examined in neuropsychological assessment, as noted in Table 1. Specialized neuropsychological test batteries have been developed for child and pediatric populations in addition to the adult and aged adult populations, and neuropsychological assessment is great value in the assessment of developmental and learning disorders of childhood. Child and pediatric neuropsychology has close ties to both child neurology and behavioral pediatrics, in addition to child psychiatry and contemporary learning models in child psychology. Neuropsychology is a relatively new area of scientific inquiry. Sir William Osler first used the term “neuropsychology” in 1913, but neuropsychology as an emerging scientific discipline can trace its roots to the contemporary psychology, experimental/cognitive psychology, and neurology of the mid-1930s. In 1935, Ward Halstead at the University of Chicago – in close collaboration with neurologists and neurosurgeons – carefully observed the behavior of brain-damaged patients and constructed a battery of ten functional tests or neuropsychological tests designed to provide a comprehensive assessment of the functional

impairment seen in individuals with known injury to the brain. This was the first true battery of neuropsychological tests, later refined by Ralph Reitan at the University of Indiana (working closely with neurosurgery colleagues), culminating in the Halstead-Reitan neuropsychological test battery, which is still in use today. A contemporary of Halstead’s in Russia, the neurologist and psychoanalyst A.R. Luria, was carefully studying aphasia in the 1930s and later did extensive single-case studies in the 1940s of the effect of brain injury on the behavior of individuals, many who were injured in World War II. The legacy of Luria is reflected in contemporary neuropsychological assessment that emphasizes an individualized, hypothesis-testing approach to neuropsychological assessment, including careful observation of the qualitative responses of the patient examinee. There are currently a wide variety of specialized neuropsychological test batteries that have been constructed to examine specific diseases or disorders, many of which are designed to be administered following one or more cognitive screening tests. There are also dozens of single neuropsychological tests designed to assess very specific areas of brain functioning. Many of the

Neurotensin

newer test batteries are hypothesis driven and symptom specific such that individual patients with the same medical diagnosis or disorder may be given different component subtests depending upon their specific presenting symptoms and performance on the initial tests given (the flexible battery approach). There also remain several fixed neuropsychological test batteries where all patients – or all patients with a given diagnosis or disorder – are given the same tests. Irrespective of whether a fixed or flexible battery approach is employed, the performance of the examinee is customarily compared relative to normative data of individuals without neurological disorder matched by age, gender, and education in order to arrive at reliable and valid conclusions. The earliest neuropsychological test batteries were designed to accurately and efficiently assess the type and extent of specific brain problems and the area or areas of the brain affected and were quite successful in doing so. At the present time, neuropsychological assessment can extend localization information already available from neuroimaging studies and also address in addition many more issues related to treatment planning, educational planning, and the impact of brain problems on a variety of tasks of daily living, some of which are listed in Table 2.

Cross-References ▶ Cognitive Function ▶ Cognitive Impairment ▶ Neurological

References and Readings Armstrong, C., & Morrow, L. (Eds.). (2010). Handbook of medical neuropsychology. New York: Springer. Davis, A. (Ed.). (2010). Handbook of pediatric neuropsychology. New York: Springer. Feinberg, T., & Farah, M. (Eds.). (2003). Behavioral neurology and neuropsychology (2nd ed.). New York: McGraw-Hill. Grant, I., & Adams, K. M. (Eds.). (2009). Neuropsychological assessment of neuropsychiatric and neuromedical disorders. New York: Oxford University Press.

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Kolb, B., & Whishaw, I. Q. (2008). Fundamentals of human neuropsychology (6th ed.). New York: Worth. Kreutzer, J., DeLuca, J., & Caplan, B. (2011). Encyclopedia of clinical neuropsychology. New York: Springer. Lezak, M. D., Howieson, D., & Loring, D. W. (2004). Neuropsychological assessment (4th ed.). New York: Oxford University Press. Marcotte, T. D., & Grant, I. (Eds.). (2010). Neuropsychology of everyday functioning. New York: Guilford Press. McCarthy, R.A., & Warrington, E.K. (in press). Cognitive neuropsychology: a clinical introduction (2nd ed.). London: Elsevier (Academic Press). Strauss, E., Sherman, M. S., & Spreen, O. (2006). A compendium of neuropsychological tests: Administration, norms, and commentary. New York: Oxford University Press.

Neurotensin Yori Gidron Faculty of Medicine and Pharmacy, Free University of Brussels (VUB), Jette, Belgium

Definition Neurotensin (NT) is a multipotent 13-amino acid neuropeptide, originally found in the hypothalamus of cattle. It plays multiple physiological and pathological roles since it affects the nervous, cardiac, immune, and gastrointestinal systems, among others. NT is found in the central nervous system (CNS) and in the gastrointestinal system. It seems to play a role as an endogenous antipsychotic peptide and a role in colorectal cancer (Mustain, Rychahou, & Evers, 2011). In cancer, NT and its receptor neurotensin receptor 1 have been found to play oncogenic roles. They mark prognosis in breast, lung, and head and neck cancers. Furthermore, NT seems to play a role in tumor growth as it acts as a growth factor as well as in metastasis (Dupouy et al., 2011). These have important implications for drug development in the treatment of cancers as well. Dysregulation of NT also plays a role in schizophrenia and in the sensitizing reaction toward drugs, thus playing a possible role in addiction

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as well. Given this knowledge, NT can be a target in the treatment of such diseases (Caceda, Kinkead, & Nemeroff, 2006). NT is closely related to the dopaminergic system and has thus been studied in relation to diseases related to dopamine including Parkinson’s disease. NT is widely distributed in the CNS and is projected in numerous circuits including the mesocorticolimbic circuit, implicated in pain and in the stress response. Given its multipotent roles in regulation of behavior and in onset of diseases, it requires further research in behavior medicine as well.

Cross-References ▶ Addictive Behaviors

References and Readings Ca´ceda, R., Kinkead, B., & Nemeroff, C. B. (2006). Neurotensin: Role in psychiatric and neurological diseases. Peptides, 27, 2385–2404. Dupouy, S., Mourra, N., Doan, V. K., Gompel, A., Alifano, M., & Forgez, P. (2011). The potential use of the neurotensin high affinity receptor 1 as a biomarker for cancer progression and as a component of personalized medicine in selective cancers. Biochimie, 93, 1369–1378. Mustain, W. C., Rychahou, P. G., & Evers, B. M. (2011). The role of neurotensin in physiologic and pathologic processes. Current Opinion in Endocrinology, Diabetes, and Obesity, 18, 75–82.

Neurotic Anger, Subcategory of Anger Yori Gidron Faculty of Medicine and Pharmacy, Free University of Brussels (VUB), Jette, Belgium

Neurotic Anger, Subcategory of Anger

Neurotic anger (or neurotic hostility) is contrasted with antagonistic anger (or antagonistic hostility), which refers mainly to the behavioral component of anger (Dembroski & Costa, 1987). Neurotic anger includes feelings of anger and is associated with the personality dimension of neuroticismemotional stability, with neuroticism being the tendency to attend to, experience, and report negative affect. In contrast, antagonistic anger refers mainly to the agreeable-antagonism dimension of personality and includes disagreeable behavior, argumentativeness, rudeness, being evasive, and lack of cooperation. This distinction is of great importance in behavior medicine because studies have shown that mainly antagonistic, but not neurotic anger/hostility, is the element of anger/hostility predictive of cardiovascular reactivity to stress and of coronary artery disease (Felsten, 1996). Furthermore, some studies even suggest that neuroticism (which includes neurotic anger) may be a factor unrelated to survival (Costa & McCrae, 1987). The latter authors suggested that neuroticism (and neurotic anger) is related mainly to self-reported but not to objective indices of health, primarily because self-reported indices are biased by perceptions and reporting of physical and emotional symptoms, strongly related to neuroticism. These perceptions are thought to involve less physiological overactivity, while antagonistic anger/hostility is thought to involve greater physiological reactivity, explaining its prediction of cardiac disease (Felsten, 1996). It has been suggested that use of objective measures of disease could partly solve this issue as well as use of measures of antagonistic anger/hostility. On the other hand, clinically, while individuals with neurotic anger may not always be more ill on objective measures, they suffer from excessive distress, for which they require psychological assistance.

Cross-References Definition This term refers to a type of anger which mainly reflects the affective component of anger.

▶ Anger-in ▶ Anger-out ▶ Coronary Artery Disease ▶ Neuroticism

Neuroticism

References and Readings Costa, P. T., & McCrae, R. R. (1987). Neuroticism, somatic complaints, and disease: Is the bark worse than the bite? Journal of Personality, 55, 299–316. Dembroski, T. M., & Costa, P. T., Jr. (1987). Coronary prone behavior: Components of the type A pattern and hostility. Journal of Personality, 55, 211–235. Felsten, G. (1996). Five-factor analysis of Buss-Durkee hostility inventory neurotic hostility and expressive hostility factors: Implications for health psychology. Journal of Personality Assessment, 67, 179–194.

Neuroticism Leigh A. Sharma Department of Psychology, University of Iowa, Kenosha, WI, USA

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moderately through adulthood (Roberts & Mroczek, 2008), and evidence demonstrates that females tend to score slightly but significantly higher than males (Costa, Terracciano, & McCrae, 2001). Neuroticism is a dimension of normal personality, though it is linked to several psychological phenomena and behavioral tendencies. Evidence demonstrates neuroticism acts as a nonspecific vulnerability to the internalizing disorders (e.g., anxiety, depression) and that it can account for a portion of the comorbidity among them (Malouff, Thorsteinsson, & Schutte, 2005). Further, after controlling for sociodemographic variables, neuroticism has been linked to higher rates of smoking, drinking alcohol, and using illegal drugs; poor physical health; lower quality of life; and mortality from all causes (Lahey, 2009).

Synonyms Cross-References Negative affectivity; Negative emotionality

Definition Neuroticism, broadly defined, refers to an individual’s tendency to experience negative affect or negative emotional states (e.g., anger, anxiety, hostility, sadness); those high in neuroticism react more strongly to negative stimuli (e.g., threat, frustration, loss) than those low in neuroticism. Structural models of personality establish that neuroticism is linked to Digman’s alpha, composed of negative emotionality and disinhibition, in a two-factor model; negative affectivity/negative emotionality splits from disinhibition in three- and fourfactor models and emerges as neuroticism in a five-factor model (Markon, Krueger, & Watson, 2005). Most broad personality measures include a neuroticism scale (e.g., measures of the five-factor model of personality), and as early as 1984, authors were demonstrating the high levels of relations among these scales (Watson & Clark, 1984). Neuroticism scores tend to peak in adolescence and decline

▶ Negative Affect ▶ Negative Thoughts ▶ Personality

References and Readings Costa, P. T., Terraciano, A., & McCrae, R. R. (2001). Gender differences in personality traits across cultures: Robust and surprising findings. Journal of Personality and Social Psychology, 81, 322–331. Lahey, B. B. (2009). Public health significance of neuroticism. American Psychologist, 2009, 241–256. Malouff, J. M., Thorsteinsson, E. B., & Schutte, N. S. (2005). The relationship between the five-factor model of personality and symptoms of clinical disorders: A meta-analysis. Journal of Psychopathology and Behavioral Assessment, 27, 101–114. Markon, K. E., Krueger, R. F., & Watson, D. (2005). Delineating the structure of normal and abnormal personality: An integrative hierarchical approach. Journal of Personality and Social Psychology, 88(1), 139–157. Roberts, B. W., & Mroczek, D. (2008). Personality change in adulthood. Current Directions in Psychological Science, 17, 31–35. Watson, D., & Clark, L. A. (1984). Negative affectivity: The disposition to experience aversive emotional states. Psychological Bulletin, 96(3), 465–490.

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Neurotransmitter

Neurotransmitter

New Drug Development

Susan Dorsey School of Nursing, University of Maryland, Baltimore, MD, USA

▶ Pharmaceutical Development

Definition

NHIS

A neurotransmitter is a naturally occurring (endogenous) chemical messenger that passes a message from one neuron to the next by being released into the synaptic gap from the axon of the presynaptic neuron and then attaching itself to the receptor on the dendrite of the postsynaptic neuron. Neurotransmitters allow neurons to pass on both excitatory and inhibitory messages when they fire. Excitatory messages mean that the next neuron is more likely to fire having received the message, while inhibitory messages mean that the next neuron is less likely to fire. Some chemicals act as both neurotransmitters and hormones. Neurotransmitters can only influence neurons that come into contact with by traveling over the very small gaps at synapses. In contrast, hormones are secreted by endocrine glands into the blood stream, which carries then around the body and enables them to affect cells that are distant from their point of origin. Another major difference is that neurotransmitters exert their influence for a very brief time: reuptake or chemical decomposition takes place very quickly. In contrast, once released into the blood stream, hormones remain present, and hence active, for much longer.

▶ National Health Interview Survey

Cross-References ▶ Central Nervous System ▶ Dopamine ▶ Epinephrine ▶ Serotonin

Industry:

Research

and

Nicotine Motohiro Nakajima and Mustafa al’Absi University of Minnesota Medical School, University of Minnesota, 235 School of Medicine, Duluth, MN, USA

Synonyms Cigarette; Smoking; Tobacco

Definition Nicotine is a psychostimulant alkaloid that is addictive and heavily used in cigarettes and other tobacco-related products. It is primary metabolized by the liver to cotinine, and the average half-life is 2 h.

Description Upon administration, nicotine binds to nicotinic cholinergic receptors (nAChRs), ligand-gated ion channels composed of several subunits, that are located in central and peripheral nervous systems. Stimulation of nAChRs by nicotine leads to the release of various neurotransmitters. Of those, dopamine secreted in the mesolimbic area and the frontal cortex mediates pleasurable experience and rewarding pathways linked

Nicotine Dependence and Nicotine Addiction

to the positive reinforcement of nicotine (Benowitz, 2010). Other neurotransmitters, such as norepinephrine, acetylcholine, glutamate, serotonin, beta-endorphin, and gammaaminobutyric acid (GABA), are also released in response to nicotine and mediate its effects on attention, tension reduction, and appetite suppression. These symptoms are commonly cited motivators of tobacco use by smokers. Nicotine activates the sympathetic nervous system which leads to the release of epinephrine from the adrenal medulla, eventually increasing heart rate, blood pressure, and cardiac output. Nicotine excites paraventricular nucleus in the hypothalamus leading to the release of corticotrophin-releasing factors (CRF), causing the release of adrenocorticotropin (ACTH) from the anterior pituitary, promoting the production of cortisol in the adrenal cortex (i.e., hypothalamic-pituitaryadrenocortical (HPA) axis). Nicotine-induced activation of cardiovascular and HPA functions are very similar to those changes observed during stress. Nicotine modulates pain perception: It induces analgesia via endogenous opioid system. Nicotine may also play a role in stress-induced analgesia through increased activity in the cardiovascular system. Taken together, acute exposure to nicotine activates multiple central nuerochemical regulatory systems that influence psychological and physiological processes and behavior. Pharmacological effects of nicotine play an important role in the development of nicotine dependence and addiction. Repeated exposure to nicotine leads to tolerance or neuroadaptation to the effects of nicotine. Desentization of nAChRs in the central system may contribute to abstinence-related withdrawal symptoms and craving. Nicotine withdrawal is associated with negative affect including anger, tension, depression, difficulty in concentration, impatience, insomnia, and restlessness (Hughes, 2007). Absence of nicotine may also be linked to reduction of cardiovascular and adrenocortical activity. These symptoms typically peak within

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a few days of nicotine abstinence and may last for 2–4 weeks and are powerful determinants of smoking lapse and relapse (al’Absi, Hatsukami, & Davis, 2005). Maintenance of nicotine intake may result from the combination of positive and negative reinforcement. Smokers may take up cigarettes to enhance subjective mood and pleasure (positive reinforcement) but also consume them to maintain levels of nicotine in the body to prevent withdrawal symptoms (negative reinforcement). Certain environmental cues associated with smoking may facilitate subsequent smoking behaviors due to conditioning. Genetic component may also contribute to these processes. Furthermore, chronic nicotine use may be related to structural and functional changes in various stress and emotion-regulations systems as well as endogenous pain modulation mechanisms, which may lead to increased withdrawal symptoms and risk for early smoking relapse.

Cross-References ▶ Cortisol ▶ Dopamine ▶ Heart Disease and Smoking ▶ Smoking Behavior ▶ Stress

References and Readings al’Absi, M., Hatsukami, D., & Davis, G. L. (2005). Attenuated adrenocorticotropic responses to psychological stress are associated with early smoking relapse. Psychopharmacology, 181, 107–117. Benowitz, N. L. (2010). Nicotine addiction. The New England Journal of Medicine, 362, 2295–2303. Hughes, J. R. (2007). Effects of abstinence from tobacco: valid symptoms and time course. Nicotine & Tobacco Research, 9, 315–327.

Nicotine Dependence and Nicotine Addiction ▶ Cessation Intervention (Smoking or Tobacco)

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Nicotine Patch Jed E. Rose Department of Psychiatry, Duke Center for Nicotine & Smoking Cessation Research, Durham, NC, USA

Definition Nicotine skin patches are drug delivery systems that are worn on the skin and provide the user with a controlled dose of nicotine to assist in smoking cessation, by replacing the nicotine previously obtained from cigarettes. The ability of nicotine to permeate intact skin has been known for decades, but the first published study exploring the therapeutic potential of transdermal nicotine to ameliorate tobacco withdrawal symptoms appeared in 1985 (Rose, Herskovic, Trilling, & Jarvik, 1985). Previous work in the 1970s had developed transdermal patches for the delivery of medications such as scopolamine and nitroglycerin. Theoretically, transdermal drug administration has the advantages over oral delivery in providing a more uniform blood level of a therapeutic agent and avoiding first-pass liver metabolism. However, other theoretical considerations initially argued against the efficacy of providing a steady level of nicotine in treating tobacco dependence, since it was widely believed that smokers were addicted to rapid bolus delivery of nicotine from inhaled smoke, which could not be duplicated using a nicotine patch. Nonetheless, transdermal nicotine has been shown to be efficacious in aiding smoking cessation, approximately doubling success rates over placebo. In 1991, nicotine patches were approved for marketing in the United States as a prescription drug, and they have been available over the counter since 1996. Despite wellestablished efficacy (Stead, Perera, Bullen, Mant, & Lancaster, 2008), however, long-term success rates (1 year following treatment) are often only 10–15%.

Nicotine Patch

The standard nicotine patch dose is 21 mg/day, similar to that of a pack of cigarettes; however, the delivery is more uniform than with cigarettes. After 6–8 weeks of wearing 21 mg/day patches, weaning doses are often recommended providing 14 mg/day for 2–4 weeks and 7 mg/day for 2–4 weeks. Combination therapy, entailing adding other forms of nicotine replacement, such as nicotine polacrilex (nicotine chewing gum) or nicotine lozenge, to supplement nicotine patch treatment, increases success rates beyond treatment using the nicotine patch alone. Interestingly, the mechanism of action of nicotine patch therapy has still not been fully elucidated. One hypothesis holds that successful abstinence is facilitated by nicotine replacement due to the alleviation of nicotine withdrawal symptoms. However, while withdrawal alleviation is clearly obtained from nicotine replacement using nicotine patches, other mechanisms may be more important, such as the attenuation of the rewarding effects of cigarette smoking. When a cigarette is smoked after nicotine blood levels have been elevated from wearing nicotine patches, cigarettes are rated less enjoyable (Levin et al., 1994). Moreover, the odds ratio of preventing the first “lapse” following an attempt to quit smoking is only marginally increased by nicotine patch treatment. In contrast, the progression from an initial lapse to a relapse is markedly reduced (Shiffman et al., 2006). These results suggest that nicotine patch treatment helps smokers remain abstinent largely by affecting their reaction to the first cigarette smoked in a way that discourages the subsequent reuptake of smoking. In a similar vein, studies in the last several years have shown that initiating nicotine patch treatment before a target quit date, while smokers temporarily continue to smoke, significantly enhances efficacy (Rose, Herskovic, Behm, & Westman, 2009). Thus, as the rewarding effects of smoking are attenuated, smoking behavior declines, and smokers are better able to succeed in quitting when they reach their target quit date. Although not yet approved in the United States, pre-cessation use of nicotine

Night-Shift Workers and Health

patch has been approved in Australia, Canada, and the United Kingdom.

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Definition

▶ Nicotine ▶ Smoking Behavior

Shift work refers to a job schedule in which employees work hours other than the standard hours of 8 a.m. to 5 p.m. or a schedule other than the standard workweek – Monday through Friday in the USA.

References and Readings

Description

Levin, E. D., Westman, E. C., Stein, R. M., Carnahan, E., Sanchez, M., Herman, S., et al. (1994). Nicotine skin patch treatment increases abstinence, decreases withdrawal symptoms and attenuates rewarding effects of smoking. Journal of Clinical Psychopharmacology, 14, 41–49. Rose, J. E., Herskovic, J. E., Behm, F. M., & Westman, E. C. (2009). Pre-cessation treatment with nicotine patch significantly increases abstinence rates relative to conventional treatment. Nicotine & Tobacco Research, 11(9), 1067–1075. Rose, J. E., Herskovic, J. E., Trilling, Y., & Jarvik, M. E. (1985). Transdermal nicotine reduces cigarette craving and nicotine preference. Clinical Pharmacology and Therapeutics, 38, 450–456. Shiffman, S., Scharf, D. M., Shadel, W. G., Clark, D. B., Gwaltney, C. J., Paton, S. M., et al. (2006). Analyzing milestones in smoking cessation: Illustration in a nicotine patch trial in adult smokers. Journal of Consulting and Clinical Psychology, 74(2), 276–285. Stead, L. F., Perera, R., Bullen, C., Mant, D., & Lancaster, T. (2008) Nicotine replacement therapy for smoking cessation. Cochrane Database of Systematic Reviews 2008 (1), Art. No.: CD000146. DOI:10.1002/14651858. CD000146.pub3.

Human beings are by nature a diurnal species with a natural tendency among adults to sleep at night and be most active during the day. Society is largely structured to facilitate such tendencies, with most social interactions, familial gatherings and work hours during the daylight hours. However, there is often occasion to diverge from these norms especially for work purposes. Today’s society is driven by a 24 h mentality which demands that over 8.6 million people (in the USA) perform shift work (Kryger, Roth & Derent, 2005). Circadian factors are a primary determinant of one’s ability to cope with shift work. Humans are biologically wired to sleep during the night and be most active during the day. Certain biological processes determine the body’s natural sleepwake cycle, particularly the secretion of melatonin in response to the light-dark cycle. Such processes are not easily changed so as to shift the natural cycle. Some evidence indicates that sleep phase adjustment for a night worker, as measured by urine melatonin, can take as long as 5–6 days (90 min phase delay per day) before melatonin onset is readjusted to the new schedule. In addition to endogenous determinants of the sleep cycle, there are other factors known as zeitgebers (time givers) that contribute to one’s perceived normal sleep-wake cycle. Such zeitgebers include social factors like meal times and social gatherings and natural factors like daylight and night. These timing cues help orient the body to a certain time schedule and to encourage humans to be active during the day. However, for a night-shift worker who must be awake during the night, these zeitgebers can work

Cross-References

Night-Shift Workers and Health Alyssa Haney1 and Michele L. Okun2 1 Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA 2 Sleep Medicine Institute and Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

Synonyms Grave yard shift

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against an individual’s inclination to remain awake at night resulting in dysregulated immune, hormonal, and cardiovascular function, thereby contributing to poor health. Domestic factors also play a big role in sleep and subsequent health of the shift worker. For the night worker, social, familial, and societal obligations often impinge on sleep time since they occur in opposition to the night worker’s schedule. Moreover, many shift workers have families and homes to care for that often require significant attention during daylight hours. Not only do these domestic factors inhibit a shift worker from obtaining adequate sleep during the day but they often impact the quality of the sleep he/she does get. Several consequences can arise from poor coping with a shift-work lifestyle, including a predisposition to depression and anxiety (Akerstedt, 2003). Not surprisingly, shifting of one’s sleep to the daytime hours can have negative consequences (Akerstedt, 2003). Not only is shift work (and daytime sleep) in contradiction to most of the biological system’s circadian rhythms, but it is a strong predictor in the development of chronic sleep disorders. For instance, shift workers have been found to have sleep maintenance insomnia as opposed to sleep onset insomnia, which results in a constant state of sleep deprivation. Surveys in Europe and in the USA have found that night workers get approximately 10 h less sleep per week than day workers. Akerstedt and colleagues found that there is a significant loss of Stage 2 and REM sleep among shift workers. Although a night worker’s sleep loss can be partially attenuated by sleeping longer on days off, they are unable to “repay the debt” and still experience chronic sleep deprivation and its consequences. Health consequences of shift work include cardiovascular disease, diabetes, and obesity. There are also associations with stomach problems and ulcers, increased depression, and risk for injury or accidents. Many of these adverse outcomes stem from dysregulation of metabolic, digestive, and immune processes that maintain alignment with the circadian rhythm. While important and often necessary for many people

Nitric Oxide Synthase (NOS)

to perform shift work, it is imperative to understand and appreciate the significant toll that shift work can have on health and social relationships (Akerstedt, 1990).

Cross-References ▶ Cardiovascular Disease ▶ Metabolic Syndrome ▶ Sleep Deprivation

References and Readings Akerstedt, T. (1990). Psychological and psychophysiological effects of shift work. Scandinavian Journal of Work, Environment & Health, 16(Suppl. 1), 67–73. Akerstedt, T. (2003). Shift work and disturbed sleep/ wakefulness. Occupational Medicine, 53(2), 89–94. Kryger, M., Roth, T., & Derent, W. (2005). Principles and practice of sleep medicine. Philadelphia: Elsevier Saunders. van Drongelen, A., Boot, C. R., Merkus, S. L., Smid, T., & van der Beek, A. J. (2011). The effects of shift work on body weight change – A systematic review of longitudinal studies. Scandinavian Journal of Work, Environment & Health, 37(4), 263–275.

Nitric Oxide Synthase (NOS) Sarah Aldred School of Sport and Exercise Sciences, The University of Birmingham, Edgbaston, Birmingham, UK

Synonyms Endothelial nitric oxide synthase (eNOS); Inducible nitric oxide synthase (iNOS); Neuronal nitric oxide synthase (nNOS)

Definition Nitric oxide synthase (NOS) is an enzyme which catalyzes the formation of nitric oxide (NO).

Nitric Oxide Synthase (NOS)

NO is a free radical gas, which acts as a vasodilator, and is formed from the amino acid arginine. NOS comprises a family of enzymes which were first described in 1989. NOS is present in the human body in three distinct isoforms: neuronal NOS (nNOS) found predominantly in neuronal tissue, inducible NOS (iNOS) being inducible in a wide range of cells and tissues, and endothelial NOS (eNOS) which was first found in vascular endothelial cells.

Description Three distinct genes for the human NOS isoforms exist, with 51–57% homology between the human isoforms in primary amino acid sequence. The similarity in genomic structure indicates a common ancestral NOS gene. The isoforms are classified by the tissue in which they were originally found, although it is now known that expression of these enzymes also occurs in other cell types, such as cardiac muscle, skeletal muscle, and blood platelets. The NOS enzymes are dimeric in their active form, and function is facilitated by the cofactors NADPH (nicotinamide adenine dinucleotide phosphate-oxidase) and tetrahydrobiopterin (BH4). Other cofactors are calmodulin/calcium, heme, flavin mononucleotide (FMD), and flavin adenine dinucleotide (FAD). A summary of the reaction catalyzed by NOS can be written as: L  arginine þ 2NADPH þ O2 ¼ L  citrulline þ NO þ 2NAPDþ The enzyme consists of two domains, an oxygenase and a reductase domain, which both have catalytic activities. Binding sites for heme and BH4 reside on the oxygenase domain and are linked to the reductase domain through a binding site for calmodulin. The binding sites for FAD and FMD are also found on the reductase domain. To allow production of NO, the enzyme must be fully coupled through BH4. Deficiencies in any of the cofactors can influence NO biosynthesis. iNOS and nNOS are soluble and found predominantly in the cytosol, while eNOS is

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a membrane-associated protein, docked to regions of the plasma membrane called calveolae. nNOS nNOS was initially identified in neuronal cells, but has since been identified in the many other cells including those of the gastrointestinal tract. It has a role in NO production for sphincter relaxation and blood flow and modulates the response to glutamate. iNOS iNOS as its name suggests is inducible. It is calcium insensitive, in contrast to the calciumsensitive isoforms nNOS and eNOS. iNOS is linked with the immune response. Previous research in this field has identified that iNOS is expressed as a result of inflammation, but its role in inflammatory disease is a complex one. iNOS has also been implicated in attenuation or suppression of inflammatory tissue injury. In addition, NO forms part of the nonspecific immune defense mechanism against invading microorganisms. NO and superoxide ions are produced in response to microorganisms and react together to form the reactive ion peroxynitrite which, with NO, has the ability to react with and kill invading cells. eNOS eNOS is present in the cells of the endothelium, and its main function is to regulate blood flow and blood pressure. eNOS is activated by the pulsatile flow of blood causing a small release of NO with every heart beat. When intracellular levels of calcium increase, eNOS detaches from the plasma membrane and becomes activated. The requirement for calcium is significantly reduced if the enzyme becomes phosphorylated on one of its serine residues, and phosphorylation is now recognized as a common mechanism for activation of eNOS. More details can be found in Packer (1996).

Cross-References ▶ Oxidative Stress

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References and Readings Packer, L. (Ed.). (1996). Nitric oxide, part A: Sources and detection of NO; NO synthase: Sources and detection of NO; NO synthase pt. A (methods in enzymology) (Vol. 268). San Diego: Academic Press.

Nocebo and Nocebo Effect Magne Arve Flaten Department of Psychology, University of Tromsø, Tromsø, Norway

Synonyms Anxiety; Context effect; Expectancy

Definition A nocebo is any inert substance, procedure, apparatus, or similar that alone has no effect in the body. The nocebo effect is the psychological and/ or physiological response to the nocebo when it is administrated with a suggestion that the substance, procedure, apparatus, or similar will increase pain or unpleasantness, or otherwise harm the individual.

Description Placebo comes from the Latin word “nocere” which means “I will harm” and has been used in medicine to describe treatments that worsen or induce symptoms in the patient, without having a specific effect on the symptom. A nocebo effect may occur when a substance, procedure, or other stimulus is administrated to a person together with a suggestion that this will increase pain or unpleasantness, or in some way harm the person. The nocebo effect occurs whether or not the substance or procedure is harmful or painful. Thus, a substance or procedure that induces a placebo effect may, when administrated with the opposite suggestion, induce a nocebo

Nocebo and Nocebo Effect

effect (Flaten, Simonsen, & Olsen, 1999). The nocebo effect may consequently be considered the opposite of the placebo effect. Nocebo effects have mostly been studied in the field of pain. The effect may be observed as an increase in pain report to a painful stimulus after suggestion that the pain will increase, although the stimulus is kept at constant levels. The nocebo effect may also be observed as the induction of pain by a non-painful stimulus that is administrated with information that it will induce pain (Colloca, Sigaudo, & Benedetti, 2008). Nocebo effects have also been observed in asthmatic patients and in nausea, but are not well researched outside the field of pain. Brain imaging studies have shown that nocebo effects are associated with further increases in brain regions activated by painful stimulation, i.e., a painful stimulus activates certain brain regions (often the anterior cingulate cortex and insula), the activation of which have been found to be further increased by expectation that the pain will become more intense. These effects are the opposite of those observed during placebo analgesia. One mechanism underlying nocebo effects is most likely anxiety. Information that a procedure or substance will induce pain or may harm induces anxiety, which in turn increases pain. Administration of an anxiolytic reduces nocebo hyperalgesia. Furthermore, blockade of cholecystokinin, a hormone associated with anxiety, has been found to block completely nocebo hyperalgesia (Benedetti, Lanotte, Lopiano, & Colloca, 2007). Nocebo effects are clinically relevant for diagnostic or therapeutic medical procedures. Injections of anesthetics, e.g., may be made painful, or more painful, if the information provided by health personnel performing these procedures induces nervousness or anxiety in the patient (Varelman, Pancaro, Capiello, & Camann, 2010).

Cross-References ▶ Functional Magnetic Resonance Imaging (fMRI) ▶ Pain

Nonexperimental Designs

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References and Readings

Nonexperimental Designs Benedetti, F., Lanotte, M., Lopiano, L., & Colloca, L. (2007). When words are painful – unraveling the mechanisms of the nocebo effect. Neuroscience, 147(2), 260–271. Colloca, L., Sigaudo, M., & Benedetti, F. (2008). The role of learning in nocebo and placebo effects. Pain, 136 (1–2), 211–218. Flaten, M. A., Simonsen, T., & Olsen, H. (1999). Drugrelated information generates placebo and nocebo responses that modify the drug response. Psychosomatic Medicine, 61(2), 250–255. Varelman, D., Pancaro, C., Capiello, E. C., & Camann, W. R. (2010). Nocebo-induced hyperalgesia during local anesthetic injection. Anesthesia and Analgesia, 110(3), 868–870.

J. Rick Turner Cardiovascular Safety, Quintiles, Durham, NC, USA

Synonyms Observational designs; Observational studies; Observational study

Definition

Noise-Related Hearing Loss ▶ Hearing Impairment (Noise Pollution Related)

Nonadherence ▶ Adherence

Noncoding RNA ▶ RNA

Noncommercial Advertising ▶ Social Marketing

Noncompliance ▶ Adherence ▶ Unintentional Nonadherence

There are two fundamental types of study design: experimental and nonexperimental (Piantadosi, 2005). Experimental designs (discussed in their own entry) involve a series of measurements (observations) made under conditions in which the influences of interest are controlled by the research scientist. Nonexperimental studies are often called observational studies, but this term is inaccurate; it does not definitively distinguish between nonexperimental studies and experimental studies, in which observations are also made. The term “nonexperimental” is not a relative quality judgment compared with experimental. This nomenclature simply distinguishes methodological approaches. In some cases, nonexperimental studies are the only type of medical study that can legitimately be used. If one wishes to examine the potentially negative health impact of a specific influence, such as exposure to nicotine via smoking cigarettes or living close to an environmental toxin, it is not appropriate for the research scientist to exert control over the influence of interest by asking some individuals to smoke or to live in a certain location. Rather, the research scientist makes use of naturally occurring cases of individuals who have and have not smoked and individuals who live close to and far from an environmental toxin to examine a potential relationship between the influence of interest and a specific health outcome. Case-control studies and cohort studies are examples of nonexperimental designs.

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Cross-References

Definition

▶ Case-Control Studies ▶ Cohort Study ▶ Experimental Designs

Sleep can be measured with polysomnography (PSG) (see review, Keenan & Hirshkowitz, 2011). Polysomnographically measured sleep can be classified into distinct behavioral categories. Non-Rapid Eye Movement (NREM) sleep is a distinct sleep behavior classification. NREM sleep is a term used to describe, as the name suggests, sleep stages that are not Rapid Eye Movement (REM) sleep. NREM sleep includes sleep stages N1, N2, and N3 as defined by the 2007 American Academy of Sleep Medicine (AASM) sleep scoring manual (Iber, Ancoli-Israel, Chesson, & Quan, 2007). NREM sleep is otherwise known as the combination of sleep stages 1, 2, 3, and 4 as identified by the Rechtschaffen and Kales “classic criteria” (Rechtschaffen & Kales, 1968). General descriptions of AASM scoring criteria for each NREM sleep stage are briefly stated. N1 is characterized by the expression of slow rolling eye movements, decreased muscle tone, and low-amplitude, mixed-frequency brain activity (4–7 Hz). N2 is characterized by Kcomplexes (a negative vertex sharp brain wave immediately followed by a positive wave that lasts 0.5 s) and sleep spindles (a train of brain waves with high frequency [11–16 Hz] and low amplitude that last 0.5 s). N3 is characterized by slow brain waves that are high amplitude (>75 V), low frequency (0.5–2 Hz), and occur throughout 20% of a given epoch. N3 sleep includes stages 3 and 4 sleep in the Rechtschaffen and Kales’ classification and is also frequently called “delta” or “slow-wave” sleep. NREM sleep has been observed among all mammals (Siegel, 2009). The function of human sleep, and particularly NREM sleep, is complex and unknown (e.g., Rector, Schei, Van Dongen, Belenky, & Krueger, 2009; Siegel, 2009). Theories about the function of each NREM sleep stage are briefly mentioned. N1 serves as the transitional stage from wake to sleep. N2 components (spindles and K-complexes) are thought to integrate new memories and regulate arousal from sleep (Hala´sz, 2005; Tamminen, Payne, Stickgold, Wamsley, Gareth, & Gaskell, 2010). N3, or rather

References and Readings Piantadosi, S. (2005). Clinical trials: A methodologic perspective (2nd ed.). Hoboken, NJ: Wiley. Rothman, K. J., Greenland, S., & Lash, T. L. (2008). Types of epidemiologic studies. In K. J. Rothman, S. Greenland, & T. L. Lash (Eds.), Modern epidemiololgy (3rd ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins.

Nonidentical Twins ▶ Dizygotic Twins

Non-insulin-Dependent Diabetes Mellitus ▶ Type 2 Diabetes Mellitus

Non-Q Wave Myocardial Infarction ▶ Acute Myocardial Infarction

Non-REM Sleep Salvatore Insana Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA

Synonyms N1, N2, N3; Quiet sleep; Sleep stages 1, 2, 3, and 4

Nonverbal Communication

the amount of N3, is thought to reflect the homeostatic sleep drive, or one’s escalating need for sleep with increasing time awake (Dijk, Brunner, Beersma, & Borbe´ly, 1990). NREM sleep appears central to memory formation; specifically, NREM sleep and REM sleep complement each other to process and consolidate various types of memory (Diekelmann & Born, 2010). Human development: From birth to approximately 6 months post-term, infant sleep patterns are classified into either REM or NREM; during this period, these classifications are also referred to as active sleep and quiet sleep, respectively (Grigg-Damberger et al., 2007). Following 6 months post-term, infant NREM sleep patterns become more complex, and then can be categorized into N1, N2, and N3 sleep stages – in addition to REM sleep. Across the life span, generally, the percentages of N1 and N2 sleep increase, whereas N3 and REM sleep decrease (Ohayon, Carskadon, Guilleminault, & Vitiello, 2004).

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specifications (1st ed.). Westchester, IL: American Academy of Sleep Medicine. Keenan, S., & Hirshkowitz, M. (2011). Monitoring and staging human sleep. In M. H. Kryger, T. Roth, & W. C. Dement (Eds.), Principles and practice of sleep medicine (5th ed., pp. 1602–1609). St. Louis, MO: Elsevier. Ohayon, M. M., Carskadon, M. A., Guilleminault, C., & Vitiello, M. V. (2004). Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: Developing normative sleep values across the human lifespan. Sleep, 27, 1255–1273. Rechtschaffen, A., & Kales, A. (1968). A manual of standardized, techniques and scoring system for sleep stages in human subjects. Washington, DC: NIH Publication No. 204, US Government Printing Office. Rector, D. M., Schei, J. L., Van Dongen, H. P., Belenky, G., & Krueger, J. M. (2009). Physiological markers of local sleep. European Journal of Neuroscience, 29, 1771–1778. Siegel, J. M. (2009). Sleep viewed as a state of adaptive inactivity. Nature Reviews Neuroscience, 10, 747–753. Tamminen, J., Payne, J. D., Stickgold, R., Wamsley, E. J., & Gareth Gaskell, M. (2010). Sleep spindle activity is associated with the integration of new memories and existing knowledge. Journal of Neuroscience, 30, 14356–14360.

Cross-References ▶ Polysomnography ▶ REM Sleep ▶ Sleep ▶ Sleep Architecture

References and Readings Diekelmann, S., & Born, J. (2010). The memory function of sleep. Nature Reviews: Neuroscience, 11, 114–126. Dijk, D. J., Brunner, D. P., Beersma, D. G., & Borbe´ly, A. A. (1990). Electroencephalogram power density and slow wave sleep as a function of prior waking and circadian phase. Sleep, 13, 430–440. Grigg-Damberger, M., Gozal, D., Marcus, C. L., Quan, S. F., Rosen, C. L., Chervin, R. D., et al. (2007). The visual scoring of sleep and arousals in infants and children. Journal of Clinical Sleep Medicine, 3, 201–240. Hala´sz, P. (2005). K-complex, a reactive EEG graphoelement of NREM sleep: An old chap in a new garment. Sleep Medicine Reviews, 9, 391–412. Iber, C., Ancoli-Israel, S., Chesson, A., Quan, S. F., & American Academy of Sleep Medicine. (2007). The AASM manual for the scoring of sleep and associated events: Rules, terminology and technical

Nonseminoma ▶ Cancer, Testicular

Nonsteroidal Anti-inflammatory Medications (NSAIDs) ▶ Anti-inflammatory Medications

Nonverbal Communication Elizabeth Galik School of Nursing, University of Maryland, Baltimore, MD, USA

Synonyms Body language; Kinesics

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Definition

Ekman, P., & Friesen, W. V. (1969). Nonverbal leakage and cues to deception. Psychiatry, 32, 88–105. Ekman, P., & Friesen, W. V. (1975). Unmasking the face. Englewood Cliffs, NJ: Prentice-Hall. Knapp, M. L., & Hall, J. A. (2007). Nonverbal communication in human interaction (5th ed.). Wadsworth: Thomas Learning. Ross, E. (1981). The aprosodias: Functional-anatomic organization of the affective components of language in the right hemisphere. Archives of Neurology, 38, 561–569.

Nonverbal communication is a complex system of communication that involves sending and receiving messages without the use of words. Nonverbal communication consists of a combination of (1) body movement (kinesics), such as gestures, posture, stance, and facial expressions; (2) touch (haptics); (3) eye contact and gaze, (4) bodily use of physical space, position, and proximity (proxemics), and nonverbal vocalizations that convey emotions or attitudes (paralanguage), such as laughing, crying, whistling, speech hesitancy, and tone. Research has indicated that 50–90% of social meaning is transmitted through nonverbal communication (Knapp & Hall, 2007). Functions of nonverbal communication include expression of emotion and attitude, communication of interpersonal relationships, support or contradiction of verbal communication, reflection of personality, and performance of social rituals, such as greetings and farewells (Argyle, 1988; Argyle & Hinde, 1972). Nonverbal communication is particularly influenced by the function of culture (Agliati, Vescovo, & Anolli, 2006). An understanding of nonverbal communication can be applied widely in a variety of fields such as medicine, business, politics, psychology, education, and the criminal justice system.

References and Readings Agliati, A., Vescovo, A., & Anolli, L. (2006). A new methodological approach to nonverbal behavior analysis in cultural perspective. Behavioral Research Methods, 38(3), 364–371. Argyle, M. (1988). Bodily communication (2nd ed.). New York: Methuen. Argyle, M., & Hinde, R. A. (1972). Nonverbal communication. Oxford: Cambridge University Press. Buck, R. (1984). The communication of emotion. New York: Guilford Press. Buck, R., & Duffy, R. (1980). Nonverbal communication of affect in brain damaged patients. Cortex, 16, 351–362. Buck, R., & Van Lear, C. A. (2002). Verbal and nonverbal communication: Distinguishing symbolic, spontaneous, and pseudo-spontaneous nonverbal behavior. Journal of Communication, 52, 522–541.

Norepinephrine/Noradrenaline Sabrina Segal Department of Neurobiology and Behavior, University of California, Irvine, CA, USA

Definition Norepinephrine/noradrenaline is a catecholamine that is released as a stress hormone in the peripheral sympathetic nervous system via the adrenal medulla and initiates the fight or flight response. It is released as a neurotransmitter in the central sympathetic nervous system via noradrenergic neurons. Norepinephrine is synthesized from dopamine by dopamine beta-hydroxylase through a series of enzymatic steps, beginning with tyrosine hydroxylase. This enzyme converts tyrosine to Ldihydroxyphenylalanine (L-DOPA), which in turn is transformed to dopamine by dopa-decarboxylase and packaged into storage vesicles. The membranebound enzyme, beta-hydroxylase, converts dopamine to norepinephrine within storage vesicles.

Cross-References ▶ Catecholamines ▶ Norepinephrine/Noradrenaline ▶ Sympatho-adrenergic Stimulation

References and Readings Cannon, W. B. (1914). The interrelations of emotions as suggested by recent physiological research. The American Journal of Psychology, 25(2), 256–282.

Norms Christensen, N. J. (1982). Catecholamines and essential hypertension. Scandinavian Journal of Clinical and Laboratory Investigation, 42, 211–215. Chrousos, G. P., & Gold, P. W. (1992). The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. Journal of the American Medical Association, 267(9), 1244–1252. Clayton, E., & Williams, C. (2000). Adrenergic activation of the nucleus tractus solitaries potentiates amygdale norepinephrine release and enhances retention performance in emotionally arousing and spatial memory tasks. Behavioral Brain Research, 112, 151–158. Coull, J. T. (1994). Pharmacological manipulations of the alpha2-noradrenergic system: Effects on cognition. Drugs & Aging, 5, 116–126. Kalat, J. W. (1992). Biological psychology (4th ed.). Belmont, CA: Wadsworth Publishing Company. van Stegeren, A. H. (2008). The role of the noradrenergic system in emotional memory. Acta Psychologica, 127(3), 532–541.

Norms Chad Barrett Department of Psychology, University of Colorado Denver, Denver, CO, USA

Synonyms Social norms

Definition In the context of psychological assessment, norms refer to sets of scores from well-defined samples that are used for standardizing and interpreting assessments. Norms are derived from sampling one or more groups of individuals and obtaining the distribution of scores on a particular assessment for each group. These sets of scores make it possible to interpret the scores of individuals who are assessed. The score of individual test takers can be compared to the scores from the group to which they belong. This provides a basis for comparison and makes it possible to interpret a person’s score. For example, if a high school student obtains a certain score on an aptitude test, there is no way to interpret their score without

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comparing it to the scores of other high school students. If only 5% of their peers scored better than them, this would indicate that they demonstrated exceptional aptitude on the test relative to their peers. However, if 95% of their peers scored better than them, this would indicate that they demonstrated a diminished aptitude relative to their peers. Given that norms are essential for interpretation, it is important that norms be based on samples that are sufficiently representative of the populations they represent and large enough to minimize standard error (Kaplan & Saccuzzo, 2008; Kline, 2000). Norms, also called social norms, refer to rules or standards of expected behavior that are shared by members of a certain group. Social norms shape individual group members’ perceptions about the acceptability of certain behaviors (injunctive norms) as well as the type, and frequency, of behaviors that other group members perform (descriptive norms). A person’s perceptions of social norms are often constructed by observing the behavior of other group members, by communicating with other group members, and by exposure to normative messages through media outlets and from explicit or implicit instruction (Dubios, 2003; Hechter & Opp, 2005). Social norms have been found to influence a variety of health-related behaviors, such as eating and exercise habits, alcohol consumption, smoking, drug use, and seeking medical help (Berkman & Glass, 2000; Borsari & Carey, 2003; McNeill, Kreuter, & Subramanian, 2006; Shaikh, Yaroch, Nebeling, Yeh, & Resnicow, 2008; Sorensen et al., 2007). According to the social norms approach, individuals who engage in unhealthy behaviors often overestimate the extent to which others engage in those unhealthy behaviors and underestimate the extent to which others engage in healthy behaviors. Such misperceptions predict the likelihood of engaging in unhealthy or healthy behaviors. Many interventions that focus on correcting such misperceptions by providing normative feedback have been successful in correcting such misperceptions and in promoting healthier behaviors (Berkowitz, 2003, 2004).

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Cross-References

Nosocomial Medical Errors ▶ Assessment ▶ Psychometrics

▶ Iatrogenic Conditions

References and Readings Berkman, L. F., & Glass, T. (2000). Social integration, social networks, social support, and health. In L. F. Berkman & I. Kawachi (Eds.), Social epidemiology (pp. 137–173). New York: Oxford University Press. Berkowitz, A. D. (Ed.). (2003). The social norms resource book. Little Falls, NJ: PaperClip Communications. Berkowitz, A. D. (2004). The social norms approach: Theory, research, and annotated bibliography. Unpublished manuscript. Retrieved November 22, 2011 from http://www.alanberkowitz.com/articles/ social_norms.pdf Borsari, B., & Carey, K. B. (2003). Descriptive and injunctive norms in college drinking: A meta-analytic integration. Journal of Studies on Alcohol, 64, 331–341. Dubios, N. (Ed.). (2003). A sociocognitive approach to social norms. New York: Routledge. Emmons, K. M., Barbeau, E. M., Gutheil, C., Stryker, J. E., & Stoddard, A. M. (2007). Social influences, social context, and health behaviors among working-class, multi-ethnic adults. Health Education & Behaviour, 34, 315–334. Hechter, M., & Opp, K. (Eds.). (2005). Social norms. New York: Russell Sage. Kaplan, R. M., & Saccuzzo, D. P. (2008). Psychological testing: Principles, applications, and issues. Belmont, CA: Cengage Learning. Kline, P. (2000). The handbook of psychological testing (2nd ed.). London: Routledge. McNeill, L. H., Kreuter, M. W., & Subramanian, S. V. (2006). Social environment and physical activity: A review of concepts and evidence. Social Science & Medicine, 63, 1011–1022. Shaikh, A. R., Yaroch, A. L., Nebeling, L., Yeh, M. C., & Resnicow, K. (2008). Psychosocial predictors of fruit and vegetable consumption in adults a review of the literature. American Journal of Preventative Medicine, 34, 535–543. Sorensen, G., Stoddard, A. M., Dubowitz, T., Barbeau, E. M., Bigby, J., Emmons, K. M., et al. (2007). The influence of social context on changes in fruit and vegetable consumption: Results of the healthy directions studies. American Journal of Public Health, 97, 1216–1227.

Nosocomephobia ▶ Hospital Anxiety

NSTEMI ▶ Acute Myocardial Infarction

Null Hypothesis ▶ Hypothesis Testing

Numerical Information ▶ Data

Numerical Representation of (Biological, Psychological, Behavioral) Information ▶ Data

Nurses’ Health Study William Whang Division of Cardiology, Columbia University Medical Center, New York, NY, USA

Definition The Nurses’ Health Study is a long-term cohort study that has collected information about cardiovascular and other disease risk factors, in addition to lifestyle factors, since its beginning in 1976 (Belanger, Hennekens, Rosner, & Speizer, 1978). At the onset, 121,701 female

Nutrition

registered nurses, aged 30–55 years, completed a questionnaire about their medical history and disease risk factors. The cohort has been followed up every 2 years with mailed questionnaires that update exposure information and inquire about newly diagnosed medical illnesses. Numerous analyses involving NHS data have been performed, including investigation of the impact of smoking cessation on longterm risks of coronary artery disease (Kawachi et al., 1994) and relationship between phobic anxiety and coronary heart disease events (Albert, Chae, Rexrode, Manson, & Kawachi, 2005).

References and Readings Albert, C. M., Chae, C. U., Rexrode, K. M., Manson, J. E., & Kawachi, I. (2005). Phobic anxiety and risk of coronary heart disease and sudden cardiac death among women. Circulation, 111, 480–487. Belanger, C. F., Hennekens, C. H., Rosner, B., & Speizer, F. E. (1978). The nurses’ health study. The American Journal of Nursing, 78, 1039–1040. Kawachi, I., Colditz, G. A., Stampfer, M. J., et al. (1994). Smoking cessation and time course of decreased risks of coronary heart disease in middle-aged women. Archives of Internal Medicine, 154, 169–175.

Nutrient Intake ▶ Nutrition

Nutrition Steven Gambert Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD, USA

Synonyms Dietary requirements; Nutrient intake

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Definition Nutrition is the process by which living organisms obtain nutrients and use them for proper growth and development, cellular metabolism, and repair. It is a process that involves the ingestion, digestion, absorption, transport, assimilation, and excretion of essential nutrients.

Description Nutrition is the process by which living organisms obtain nutrients and use them for proper growth and development, cellular metabolism, and repair. It is a process that involves the ingestion, digestion, absorption, transport, assimilation, and excretion of essential nutrients. In order to insure an adequate “nutrition,” there are a variety of macro and micro-nutrients that must be obtained. While the body has the ability to utilize certain nutrients obtained through nutrition to provide the building blocks for cellular growth, maturation, and repair, some are essential and must be part of one’s nutrition. This is illustrated by the fact that although animal and plant protein contain 20 amino acids, 9 are considered “essential” and not able to be produced by the body itself. Recommended Dietary Allowances are established by the Food and Nutrition Board of the National Research Council and represent the nutrient allowances thought to be necessary for the maintenance of good health (National Research Council, NRC, 1989). Malnutrition is the state associated with either an under or over intake of essential components of one’s nutritional requirements including calories and specific nutrients such as protein, fat, minerals, and vitamins. Examples include obesity (an excess intake of calories), marasamus (a deficiency in caloric intake), kwashiorkor (a deficiency in protein intake), among other examples. Certain individuals will require intake above the minimum daily requirement of certain nutrients. One example is calcium. The RDA is 800–1,500 mg of elemental calcium daily. Individuals who are breast-feeding, pregnant, or who have metabolic bone disease should be at the higher range of intake.

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Each individual utilizes nutrients differently based on genetic and environmental factors. Muscle has a higher metabolic utilization than fat and individuals with more muscle have a higher caloric requirement to maintain their body weight. Catecholamines and thyroid hormone play a role in our ability to up and downregulate our metabolism as well as the type of food we consume. For example, individuals who “nibble,” eating multiple meals throughout the day are metabolically different from those who “gorge” (one meal a day) their dietary intake even at the same level of caloric consumption . Eating only one meal a day (gorger) causes the body to function the rest of the day as it is starving and metabolically downregulating metabolism. Not all foods are also handled the same in the body with only 78% of protein utilized by the body due to the increase in metabolic work needed to break down the protein bonds as compared to fat and carbohydrate that are utilized by the body at 99% and 98%, respectively. Nutritional assessment may be done by assessing a variety of measures including body mass index. This is a calculated value that is determined by taking the weight in kilograms divided by the height in meters squared. A value of 19–25 is considered to be normal and values over 30 are considered to be obese. Another measure of nutritional status is pre-albumin with values of 20 or greater indicating adequate protein stores. A questionnaire (mini-nutritional assessment) can provide information to predict who is at risk of malnutrition (Kaiser et al. 2009).

Cross-References ▶ Carbohydrates ▶ Nutrition Data System for Research (NDSR) ▶ Obesity

References and Readings Kaiser, M. J., et al. (2009). Validation of the nutritional assessment short form (MNA8-SF): A practical tool

Nutrition Data System for Research (NDSR) for identification of nutritional status. The Journal of Nutrition, Health & Aging, 3, 782–788. National Research Council (NRC). (1989). Diet and health: Implications for reducing chronic disease risk. Report of the Committee on Diet and health, Food, and Nutrition Board (750 pp). Washington, DC: National Academy Press.

Nutrition Data System for Research (NDSR) Lisa Harnack Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA

Definition Nutrition Data System for Research (NDSR) is a Windows-based dietary analysis program designed for the collection and analyses of 24-h dietary recalls and the analysis of food records, menus, and recipes. The system is developed and maintained by the University of Minnesota Nutrition Coordinating Center (ncc.umn.edu).

Description Overview of NDSR NDSR is a software application that may be used to quantify the food and nutrient intake of individuals, analyze the nutrient composition of menus, and calculate the nutrient composition of food recipes. Consequently, the program has both research and practice applications in the arena of behavioral medicine. Examples of its use include collection and analysis of 24-h dietary recalls from study participants to evaluate the effect of a nutrition intervention on food and nutrient intake. In clinical settings, NDSR is used to analyze food records kept by patients as a behavioral monitoring tool. Institutions such as hospitals, prisons, and colleges use NDSR in planning nutritionally balanced menus. The program is also used to calculate the nutrient content

Nutrition Data System for Research (NDSR)

of recipes for publication in health promotion pamphlets, cook books, etc. Food and Nutrient Database The University of Minnesota Nutrition Coordinating Center (NCC) Food and Nutrient Database serves as the source of food composition information in the software. This database includes over 18,000 foods, including 7,000 brand-name products. Ingredient choices and preparation methods provide more than 160,000 food variants. Values for 162 nutrients, nutrient ratios, and other food components are generated from the database. Also, food group assignments are provided so that intake of food categories such as fruits and vegetables may be calculated. Missing nutrient values are kept to a minimum by obtaining nutrient composition information from a variety of sources and utilizing standardized imputation procedures (Schakel, Sievert, & Buzzard, 1988; Schakel, Buzzard, & Gebhardt, 1997; Westrich, Buzzard, Gatewood, & McGovern, 1994). The database is updated annually to reflect marketplace changes and new analytic data. 24-H Dietary Recall Collection and Analysis Dietary recall data gathered by interview are entered directly into NDSR. The software searches for foods and brand products by name. Sophisticated search algorithms locate the food, and the interview prompts standardize requests for more detail. Dietary intake data gathered by interview are governed by the multiple-pass approach interview methodology. Four distinct passes provide multiple opportunities for the participant to recall and clarify food intake. Dietary supplement use may be assessed in conjunction with collection of 24-h dietary recalls using the Dietary Supplement Assessment Module included in NDSR. Use of all types of dietary supplements and nonprescription antacids is queried in the module. The database linked with the module includes over 2,000 dietary supplement products. A “missing product” feature in the software allows the user to add products to the database. The coding of foods and dietary supplements occurs automatically as data are entered. Calculation of nutrients occurs

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immediately and yields data per ingredient, food, meal, and day in report and analysis file formats. Food Record, Menu, and Recipe Analysis Data entry windows tailored for direct entry of food records, menus, and recipes are provided in NDSR. The coding of foods occurs as data are entered. Calculation of nutrients occurs simultaneously, allowing for generation of reports and analysis files immediately following completion of data entry. Background and History NDSR was developed and is maintained by the University of Minnesota Nutrition Coordinating Center (NCC). NCC was established in 1974 by the National Heart, Lung, and Blood Institute (NHLBI) to support the food-coding and nutrient-analysis needs of two historically significant national collaborative research programs – the Multiple Risk Factor Intervention Trial (MRFIT) and the Lipid Research Clinics (LRC). For these studies, a standardized mainframe computer-based food-coding and nutrient-analysis system was created by NCC in collaboration with NHLBI and outside experts in nutrition, statistics, computer science, and education (Dennis, Ernst, Hjortland, Tillotson, & Grambsch, 1980). This system was designed for in-house use, with NCC staff responsible for using it to code foods for nutrient calculations. By 1977, NCC services were made available to other researchers studying the impact of diet and nutrition on various health conditions, including cardiovascular disease, cancer, hypertension, obesity, diabetes, age-related eye disease, and acquired immune deficiency syndrome (HIV/ AIDS). In 1988, NCC released Nutrition Data System (NDS), a DOS-based software program designed to provide a standardized interview and direct data entry for collection of dietary intake (Feskanich, Sielaff, Chong, & Bartsch, 1989). For the first time, coding of foods and amounts was computerized, providing immediate calculation of nutrient data. The software was developed for distribution to researchers for use on their own computers. A user manual, technical support, and

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training were among the services developed by NCC to support those using NDS. Since 1998, NCC has worked to keep NDSR up-to-date with computer hardware and software advances, and dietary intake assessment methodological improvements. In addition, major expansion to the nutrients and foods in the NCC Food and Nutrient Database has been made to keep the database current, with the ever-expanding food marketplace and the growing number of nutrients and other food components of interest to researchers and of importance to human health.

Dietary supplement; Food supplement; Nutritional supplement

Cross-References

Definition

▶ Fat, Dietary Intake ▶ Nutrition ▶ Nutritional Supplements

A nutritional supplement is a product available in any form that is intended to provide nutrients that are considered to either be lacking or insufficient in the diet. These may contain one of more of the following: vitamins, minerals, fiber, fatty acids, amino acids, and herbs or other botanicals. It is intended for ingestion in pill, capsule, tablet, powder, or liquid form and is not to be used as a conventional food or as a primary form of meal.

References and Readings Dennis, B., Ernst, N., Hjortland, M., Tillotson, J., & Grambsch, V. (1980). The NHLBI nutrition data system. Journal of the American Dietetic Association, 77, 641–647. Feskanich, D., Sielaff, B., Chong, K., & Bartsch, G. (1989). Computerized collection and analysis of dietary intake information. Computer Methods and Programs in Biomedicine, 30, 47–57. Nutrition Data System for Research. http://www.ncc.umn. edu/products/ndsr.html. Schakel, S., Buzzard, M., & Gebhardt, S. (1997). Procedures for estimating nutrient values for food composition databases. Journal of Food Composition and Analysis, 10, 102–114. Schakel, S., Sievert, Y., & Buzzard, M. (1988). Sources of data for developing and maintaining a nutrient database. Journal of the American Dietetic Association, 88, 1268–1271. Westrich, B., Buzzard, M., Gatewood, L., & McGovern, P. (1994). Accuracy and efficiency of estimating nutrient values in commercial food products using mathematical optimization. Journal of Food Composition and Analysis, 77, 223–239.

Nutritional Supplement ▶ Nutritional Supplements

Nutritional Supplements Steven Gambert Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD, USA

Synonyms

Description A nutritional supplement is a product available in any form that is intended to provide nutrients that are considered to either be lacking or insufficient in the diet (US Food and Drug Administration). These may contain one of more of the following: vitamins, minerals, fiber, fatty acids, amino acids, and herbs or other botanicals. It is intended for ingestion in pill, capsule, tablet, powder, or liquid form and is not to be used as a conventional food or as a primary form of meal. While various countries regulate nutritional supplements in different ways, in the United States, nutritional supplements are regulated by the Food and Drug Administration (FDA) as a category of foods, not drugs, and are not regulated by the National Academy of Sciences that provides the Recommended Dietary Allowances (RDA’s) (National Research Council, 1989). Anyone wishing to market a dietary/nutritional supplement that

Nutritional Supplements

contains a “new dietary ingredient” as defined as “a vitamin, mineral, herb or other botanical (Goldman, 2001), amino acid, or dietary substance for use by man to supplement the diet by increasing total dietary intake or a concentrate, metabolite, constituent, extract, or combination of any of these must notify the FDA prior to marketing and receive approval as per the provisions of the Dietary Supplement and Health Education Act of 1994. Nutritional supplements must not be used for diagnosis, treatment, cure, or prevention of any disease. In 2007, the FDA implemented a ‘current good manufacturing practices’ policy to ensure that nutritional supplements are produced in a ‘quality manner,’ do not contain contaminants or impurities, and are accurately labeled.” There are a wealth of products available that are characterized as nutritional supplements with a majority of persons in the USA reporting intake of at least one. While some nutritional supplements may have benefits based on limited studies, many have not been proven to have clinically significant

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benefits (Blendon, DesRoches, Benson, Brodie, & Altman, 2001).

Cross-References ▶ Nutrition

References and Readings Blendon, R. J., DesRoches, C. M., Benson, J. M., Brodie, M., & Altman, D. E. (2001). Americans views on the use and regulation of dietary supplements. Archives of Internal Medicine, 161(6), 805–810. Goldman, P. (2001). Herbal medicines today and the roots of modern pharmacology. Annals of Internal Medicine, 135, 594–600. National Research Council. (1989). Recommended dietary allowances (10th ed.). Washington, DC: National Academy Press. US Food and Drug Administration. (2012). Dietary supplement information. Retrieved from http://www. cfsan.fda.gov/dms/supplmnt.html

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