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NIMH during the tenure of Director Herbert Pardes, M.D. (1978-1984): The President's Commission on Mental Health and the reemergence of NIMH's scientific mission.

To summarize these 5-1/2 years, I would offer the following. NIMH--which, like the mental health field in general, has focused principally on services and broad social issues in the 1960s and 1970s--was modified to be a more scientific institute focused on basic biology and behavioral science, major clinical disorders, diagnosis, treatment, and epidemiology. NIMH in its entirety regained a high level of respect in the general NIH community and won increasing support from Congress and the Administration. Increasingly positive perceptions of NIMH may have had a positive effect on the recruitment issue in psychiatry; the numbers of U.S. recruits started to turn back upward. After the early assault by the OMB and the Reagan Administration on the NIMH budget, the year 1982 and 1983 led to a more supportive attitude, and so the threat to the vitality of NIMH and to its overall fiscal support relented. Programs in research training and mental health clinical training and the intramural program were sustained along with the preeminent focus on building extramural support. We recognized that support of the intramural program accounted for an unduly high proportion of overall NIMH research expenditures. In response, we set firm policies designed to build the extramural program while maintaining the strength of the intramural program without expanding it. I might note parenthetically that I had the opportunity to chair an Intramural Research Program Planning Committee convened by NIMH. Without anticipating Dr. Hyman's comments regarding this effort, I will say that we found the intramural research program to be a national resource that, with continued emphasis on scientific quality, should contribute greatly to the nation's mental health and scientific goals in the years ahead. Perhaps in the most global terms the era can be remembered as one in which NIMH shifted toward becoming a predominantly research institute with related education programs. On the one hand, we drew some limits regarding what was considered the purview of NIMH, and we focused much more on illness. On the other hand, we retained much of the richness of NIMH and its focus on the relationships between various disciplines, while catalyzing the extraordinary explosion of the capacity to understand brain and behavior and thereby bring greater promise to the effort to control psychiatric disorders. The excitement of the research and the greater enthusiasm of the government, along with NIMH's encouragement of citizen group activity, contributed to destigmatization and set the groundwork for a much stronger overall advocacy effort on behalf of NIMH, which has continued over the last 10 to 15 years. Simultaneously, attempts were made to secure more data regarding the usefulness of psychiatric treatments and their effectiveness. This too would serve us well in terms of a more favorable attitude toward improving insurance through Medicare and through other areas of mental health care reimbursement. It is an honor to have worked at NIMH. The staff members there are superb, and I want to express my thanks to them. The dedication of outstanding federal leaders is one of the powerful assets of this nation and has been central to the many accomplishments of NIMH.

Administrative Personnel↗

Dietary long-chain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms.

Increasing evidence from animal and in vitro studies indicates that n-3 fatty acids, especially the long-chain polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid, present in fatty fish and fish oils inhibit carcinogenesis. The epidemiologic data on the association between fish consumption, as a surrogate marker for n-3 fatty acid intake, and cancer risk are, however, somewhat less consistent. This review highlights current knowledge of the potential mechanisms of the anticarcinogenic actions of n-3 fatty acids. Moreover, a possible explanation of why some epidemiologic studies failed to find an association between n-3 fatty acid intake and cancer risk is provided. Several molecular mechanisms whereby n-3 fatty acids may modify the carcinogenic process have been proposed. These include suppression of arachidonic acid-derived eicosanoid biosynthesis; influences on transcription factor activity, gene expression, and signal transduction pathways; alteration of estrogen metabolism; increased or decreased production of free radicals and reactive oxygen species; and mechanisms involving insulin sensitivity and membrane fluidity. Further studies are needed to evaluate and verify these mechanisms in humans to gain more understanding of the effects of n-3 fatty acid intake on cancer risk.

Animals↗

Alcohol and breast cancer. Where are we now and where do we go from here?

The alcohol-breast cancer hypothesis is important because (1) breast cancer is a major source of morbidity and mortality, (2) alcohol consumption is common, and (3) drinking is modifiable. Reports from more than 50 epidemiologic investigations of this hypothesis have now appeared. A recent metaanalysis of these studies indicates both a modest positive association between alcohol and breast cancer (an approximately 25% increase in risk with daily intake of the equivalent of two drinks) and a dose-response relation. Data suggest that risk increases with consumption of alcohol in general, regardless of beverage type. Several factors, including age, weight, and estrogen usage, have been shown to modify this relation in some studies. The authors discuss a series of methodologic issues in the study of alcohol and breast cancer. These include error in alcohol assessment, difficulties in evaluating small relative risks, and the potential for confounding. Several biologic mechanisms could account for an alcohol-breast cancer relation, with increasing attention being paid to a possible mediating effect of reproductive steroid hormones. Animal studies are a relatively recent development in this area; results have been mixed. Incorporation of more refined temporal, quantitative, and qualitative indicators of alcohol exposure in future epidemiologic studies would be valuable, as would further exploration of the endocrine and other metabolic effects of moderate alcohol consumption. The alcohol-breast cancer hypothesis remains intriguing, but causality has not been established.

Age Factors↗

Community and occupational studies of lung cancer and polycyclic organic matter.

Finland is used as a model in attempts to study the possible association of the incidence of lung cancer and exposure of population to fossil fuel combustion products. Unfortunately because of great geographical variation of unknown origin in the incidence of lung cancer in Finland, detailed studies of the possible role of an individual exposure in the lung cancer risk are not possible. This background variation in the incidence is much greater than variation carried by any known etiological factor and does not clearly correlate with the degree of urbanization, industrialization, regional use of fossil fuels, number of motor vehicles or smoking habits. To get more precise information on the possible association of lung cancer incidence with exposure to fossil fuel combustion products, occupational studies serve as powerful tools. The definition of population is more reliable and the measurement of exposures can be done more precisely; moreover the management of confounding and modifying factors is more effective than in community studies. So far the studies carried out among the Finnish working population exposed to PAH compounds reveal an association between the lung cancer risk and exposure to PAHs.

Adult↗

Actual causes of death in the United States, 2000.

CONTEXT: Modifiable behavioral risk factors are leading causes of mortality in the United States. Quantifying these will provide insight into the effects of recent trends and the implications of missed prevention opportunities. OBJECTIVES: To identify and quantify the leading causes of mortality in the United States. DESIGN: Comprehensive MEDLINE search of English-language articles that identified epidemiological, clinical, and laboratory studies linking risk behaviors and mortality. The search was initially restricted to articles published during or after 1990, but we later included relevant articles published in 1980 to December 31, 2002. Prevalence and relative risk were identified during the literature search. We used 2000 mortality data reported to the Centers for Disease Control and Prevention to identify the causes and number of deaths. The estimates of cause of death were computed by multiplying estimates of the cause-attributable fraction of preventable deaths with the total mortality data. MAIN OUTCOME MEASURES: Actual causes of death. RESULTS: The leading causes of death in 2000 were tobacco (435 000 deaths; 18.1% of total US deaths), poor diet and physical inactivity (365 000 deaths; 15.2%) [corrected], and alcohol consumption (85 000 deaths; 3.5%). Other actual causes of death were microbial agents (75 000), toxic agents (55 000), motor vehicle crashes (43 000), incidents involving firearms (29 000), sexual behaviors (20 000), and illicit use of drugs (17 000). CONCLUSIONS: These analyses show that smoking remains the leading cause of mortality. However, poor diet and physical inactivity may soon overtake tobacco as the leading cause of death. These findings, along with escalating health care costs and aging population, argue persuasively that the need to establish a more preventive orientation in the US health care and public health systems has become more urgent.

Accidents, Traffic↗

Insights into different results from different causal contrasts in the presence of effect-measure modification.

PURPOSE: Both propensity score (PS) matching and inverse probability of treatment weighting (IPTW) allow causal contrasts, albeit different ones. In the presence of effect-measure modification, different analytic approaches produce different summary estimates. METHODS: We present a spreadsheet example that assumes a dichotomous exposure, covariate, and outcome. The covariate can be a confounder or not and a modifier of the relative risk (RR) or not. Based on expected cell counts, we calculate RR estimates using five summary estimators: Mantel-Haenszel (MH), maximum likelihood (ML), the standardized mortality ratio (SMR), PS matching, and a common implementation of IPTW. RESULTS: Without effect-measure modification, all approaches produce identical results. In the presence of effect-measure modification and regardless of the presence of confounding, results from the SMR and PS are identical, but IPTW can produce strikingly different results (e.g., RR = 0.83 vs. RR = 1.50). In such settings, MH and ML do not estimate a population parameter and results for those measures fall between PS and IPTW. CONCLUSIONS: Discrepancies between PS and IPTW reflect different weighting of stratum-specific effect estimates. SMR and PS matching assign weights according to the distribution of the effect-measure modifier in the exposed subpopulation, whereas IPTW assigns weights according to the distribution of the entire study population. In pharmacoepidemiology, contraindications to treatment that also modify the effect might be prevalent in the population, but would be rare among the exposed. In such settings, estimating the effect of exposure in the exposed rather than the whole population is preferable.

Bias↗

Manipulation of fecal pH by dietary means.

Epidemiological and animal studies suggest that colonic fermentation and fecal pH may be risk factors for colorectal cancer. To modify these factors, we sought to develop a simple instrument for use in intervention studies. Three 14-day studies with 32, 40, and 30 healthy volunteers maintained on their regular diet were carried out to evaluate the effect of various food supplements on fecal pH. The interventions tested included supplementary lactulose, Metamucil, oat bran, wheat bran, or no supplement. The results showed that it is possible to provide a simple intervention to reduce fecal pH by 0.4 unit with oat bran administered at 75-100 g/day over a 14-day period, using a wheat combination, equivalent in macronutrients and fiber, as a control.

Adult↗

Estrogens in the causation of breast, endometrial and ovarian cancers - evidence and hypotheses from epidemiological findings.

Estrogens along with progesterone/progestins, and other hormones, are important determinants of cancer in the breast, endometrium and ovary. Estrogens may increase the risk of breast cancer through various mechanisms and at various phases of life, with a possible synergistic effect of progesterone/progestins. Exposure to high doses of placental hormones, such as estrogens and/or progesterone, during pregnancy may play a pivotal role in reducing subsequent breast cancer susceptibility. Estrogens cause endometrial cancer, an effect that can be reduced, prevented or reversed by progesterone/progestin - if allowed to act for a sufficiently long period of each cycle. The role of sex hormones seems important for ovarian carcinogenesis. Intake of combined oral contraceptives has a substantial and well-documented protective effect on endometrial and ovarian cancer risks. Epidemiological observations and experimental data from an animal model indicate that estrogens may have an adverse effect, while progesterone/progestins have a risk reducing effect directly on the ovarian epithelium. Thus, estrogens and other sex hormones have potential effects on the three most important female cancers. Research has yet to define how some of the risk factors can be modified or treatment regimens can be improved to reduce these cancer risks.

Age Factors↗

Dietary (n-6) PUFA and intestinal tumorigenesis.

Cancer is the second leading cause of death in the United States, and mortality due to colorectal cancer is only surpassed by lung cancer. Epidemiological studies demonstrate that dietary polyunsaturated fats can have a profound effect on colorectal cancer risk. Experimental data indicate that modulation of cellular (n-6) PUFA metabolism can affect the progression of the disease. This paper discusses the role (n-6) PUFA play in promoting intestinal tumorigenesis and how dietary PUFA from different families interact to modify the neoplastic process. Dietary PUFA that attenuate arachidonic acid metabolism [such as (n-3) PUFA] have antineoplastic properties, whereas those that augment arachidonic acid metabolism, such as linoleic, gamma-linolenic, and arachidonic acids do not appear to enhance tumorigenesis when added to the Western diet but may diminish the beneficial effects of other dietary lipids. It is the relative contributions of the different dietary PUFA that may determine overall risk for and progression of the disease.

Animals↗

Co-ordination and ecology in practical cancer prevention.

A great deal of information is already available regarding modifiable factors affecting cancer development in a negative or positive fashion. Thus, avoidance of harmful agents like tobacco, vaccination against virus infections, prompt treatment of inflammatory conditions and increased exposure to beneficial influences hold great promise for the achievement of effective prevention. However, this requires a co-ordinated strategy and an integration of efforts in epidemiological and biological research, medical practice and education, and is essential for optimal use of the resources available. In addition, more stress needs to be placed on community approaches. Concentration of particular attention on the 'ecological' interactions among a triad of the major areas of action: (1) information generation; (2) intervention efforts; (3) government policy, appears warranted.

Health Planning↗

Human microsporidiosis: Clinical, diagnostic and therapeutic aspects of an increasing infection.

Human microsporidiosis is a parasitic infection due to species of four different genera: Encephalitozoon; Enterocytozoon; Nosema; and Pleistophora. Although well known as a cause of disease in animals, microsporidiosis was only occasionally reported in humans. Recently, in human immunodeficiency virus (HIV)-infected patients, microsporidia belonging to Encephalitozoon and Enterocytozoon species have proved to be important opportunistic pathogens. Enterocytozoon bieneusi is associated with chronic intermittent diarrhea, cholangiopathy and sinusitis whereas Encephalitozoon intestinalis, Encephalitozoon hellem and Encephalitozoon cuniculi, the three Encephalitozoon species found in humans, are associated with diarrhea, rhinosinusitis, keratoconjunctivitis, nephritis and hepatitis. Diagnosis of microsporidial infections in humans was until recently an invasive, laborious procedure including electron microscopy of small intestine biopsies. However, new simple staining methods using Uvitex 2B or modified trichrome stain for feces and other body fluids have facilitated clinical diagnosis as well as drug evaluation and epidemiological studies. The application of monoclonal antibodies and molecular techniques such as the polymerase chain reaction have further improved microsporidial diagnosis. Treatment of Entero. bieneusi has, until now, been unsuccessful whereas albendazole has proved to be an effective treatment for Encephalitozoon species infection. Identification of effective treatment for Entero. bieneusi infections and further study of the pathogenicity of these microsporidial infections in immunocompetent hosts are important future challenges.

Journal Article↗

Lipoprotein-associated phospholipase A2: a potential therapeutic target for atherosclerosis.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an enzyme that is produced by inflammatory cells, is bound to circulating LDL, and is involved in hydrolyzing polar phospholipids, including those found in oxidized low-density lipoproteins. To date, the biological role of Lp-PLA(2) in atherogenesis has been controversial, with initial reports purporting an atheroprotective effect attributable to the degradation of platelet activating factor and similar molecules. However, more recent studies suggest a proatherogenic role for this enzyme, which is attributed to Lp-PLA(2)-mediated hydrolysis of oxidatively modified low-density lipoproteins that results in the accumulation of proinflammatory products. The liberation of lysophosphatidylcholine and oxidized nonesterified fatty acids from oxidized phospholipids by the action of Lp-PLA(2) results in diverse inflammatory effects on various cell types involved in atherogenesis. This concept is further supported by a number of recently published epidemiology studies suggesting that plasma levels of the enzyme predict future cardiovascular events independent of conventional risk factors. The development of selective inhibitors of Lp-PLA(2) that inhibit enzyme activity in the circulation as well as within human atherosclerotic lesions opens the possibility of therapeutic manipulation of vascular inflammatory processes to reduce residual cardiovascular events in high risk individuals who continue to suffer fatal and nonfatal events despite the current standard of care.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

[Mortality in the area around Massa-Carrara 10 years after ANIC-Agricoltura and Farmoplant chemical plants were shut down].

OBJECTIVE: To describe mortality of residents in the area of Massa-Carrara for the period 1995-2000 and to compare it with mortality for the years 1990-1994. DESIGN: Geographical descriptive study. SETTING: In the area of Massa-Carrara cause and gender specific standardized mortality ratios (SMR), adjusted for age and municipal deprivation index (reference: Tuscany Region), have been computed for the years 1995-2000 and compared with mortality in the period 1990-1994 calculating ratios between standardized rates by age classes with a direct method (CMF). For those causes showing a statistically significant increase a spatial analysis on a group of municipalities around Massa and Carrara has been carried out. MAIN OUTCOME: Mortality for all causes, and for 30 specific causes. RESULTS: The study results confirm, for the years 1995-2000, the previous observation (1990-1994) of statistically significant excesses for mortality from all causes (SMR 109), all cancers (SMR 112), respiratory diseases (SMR 126), cirrhosis (SMR 226), liver (SMR 161) and lung cancer (SMR 115) in males. A statistically significant excess for larynx (SMR 158) and pleural cancer (SMR 178) is observed in the years 1995-2000, which was not present in 1990-1994. A mortality excess for cirrhosis is confirmed in females (SMR 158) and a new one emerges for liver cancer (SMR 144). The comparison between mortality data for the periods 1995-2000 and 1990-1994 has shown a statistically significant decrease in mortality for all causes and for several specific causes, a significant increase in liver (CMF males 1.35; CMF females 1.78) and blood cancer mortality is also detected (CMF females 1.44). CONCLUSIONS: This study confirms the negative health impact of environmental, occupational exposures in populations living in areas where high-risk factories are located. Adverse health effects are stronger in socially and economically deprived areas, and persist over many years after closing polluting industrial plants. The results of this study point out to the need of health promoting actions aiming at modifying lifestyle risk factors, ameliorating socio-economic conditions, and maintaining a constant control on environment, also through a specific environmental epidemiological surveillance to monitor the impact of reclamation procedures completed or in progress.

Adult↗

Dietary fatty acids and coronary heart disease.

Epidemiological studies have confirmed a strong association between fat intake, especially saturated and trans fatty acids, plasma cholesterol levels and rate of coronary heart disease (CHD) mortality. Meanwhile it is clear, that early atherosclerosis is largely preventable by modifying nutritional behaviour and lifestyle. There is clear evidence that a diet moderate in total fat (25-35 % energy) is superior to extremes in dietary fat. Because fat is energy dense moderation in fat intake is also essential for weight control. Saturated fatty acids are very potent in increasing LDL-cholesterol concentration in plasma a dangerous risk factor for early CHD. Unsaturated fatty acids have numerous beneficial health effects. The results of prospective cohort studies fit well to the experimental experience of the antihypercholesterolemic action of Omega-6 fatty acids and the antithrombotic, vasodilatory and antiarrhythmic properties of Omega-3 fatty acids, while the optimistic rating of Omega-9 fatty acids is less supported by epidemiologic studies. The results of prospective cohort studies are confirmed by intervention trials revealing that saturated fatty acids enhance early development of CHD whereas polyunsaturated fatty acids, especially of the Omega-3 type, significantly preserve from CHD. In context with a prudent diet pattern favourable dietary fatty acid composition offers the best chance for a reduced risk of CHD.

Coronary Disease↗

Control of an outbreak of vancomycin-resistant Enterococcus faecium in an oncology ward in South Africa: effective use of limited resources.

An outbreak of vancomycin-resistant enterococci (VRE) occurred in an adult oncology ward of a large teaching hospital in Johannesburg, South Africa. The outbreak strain was identified as an Enterococcus faecium carrying the vanA resistance genotype. Macro-restriction analysis showed that the majority of strains were clonally related. Modified infection control interventions were implemented and control of the outbreak was achieved. Although the epidemiology of VRE is well documented in Europe, North America and Australia, this problem has only recently emerged in South Africa. The epidemiology of the outbreak appears similar to that described for outbreaks elsewhere.

Adult↗

Epidemiology of depressive symptoms in black communities. A comparative analysis.

Data from a community survey of depressive symptoms in a black community in Alabama are analyzed using a binary regression procedure to assess the effects of sociodemographic risk factors. These results are compared to two other studies of depressive symptoms in black communities using the same methods to assess the interaction of risk factors with community/region. Community/region is found to modify the relationship of sex, marital status, and income to rates of depressive symptoms within black populations. It is argued that this interaction is evidence of differential sociocultural processes operating in these communities. Suggestions for more detailed research on depressive symptoms in the black community are offered.

Adolescent↗

Racial and ethnic modifiers of the salt-blood pressure response.

The relation between sodium and blood pressure is a centuries-old question. A substantial body of epidemiological and experimental data has accumulated that strongly implicates NaCl as having a causal role in the genesis of arterial hypertension. Prospective studies that have been performed in diverse populations that have manipulated NaCl exposure by diet or infusion have repeatedly documented an NaCl pressor effect. Further, similar studies in biracial populations have also demonstrated a greater prevalence of "salt sensitivity" in blacks compared with whites. The reasons for this observation are not entirely clear; however, intrinsic or hypertension-induced renal abnormalities that limit natriuretic capacity, reduced Na+,K(+)-ATPase pump activity, other membrane ion transport disturbances, differential exposure to psychological stressors, greater insulin resistance, and dietary factors (reduced Ca+ and K+ intake) have all been suggested as possibly playing a role. Salt sensitivity appears to be a widespread phenomenon. However, it is critically important to determine what factors account for racial differences in salt sensitivity. Moreover, the prevalence of salt sensitivity in the general population is unknown. Current definitions of salt sensitivity are varied and unidirectional. In comparison with bidirectional criteria (blood pressure increase with salt loading and blood pressure decrease with salt restriction), they are probably inadequate to identify salt-sensitive individuals who manifest less extreme blood pressure change after dietary sodium or plasma volume manipulations. More sensitive criteria for diagnosing salt sensitivity will facilitate a better understanding of racial and ethnic differences in the prevalence of salt sensitivity.

Black People↗

Ki-ras mutation modifies the protective effect of dietary monounsaturated fat and calcium on sporadic colorectal cancer.

The geographic differences in the incidence of colorectal cancer have been mostly attributed to variations in diet. The diversity of the Mediterranean diet and the heterogeneity of acquired genetic alterations in colorectal cancer sets the stage for investigating the possible association between dietary factors and mutations in tumor genes known to play a role in the pathogenesis of these neoplasms. With this purpose, we have studied the Ki-ras gene in 108 colorectal cancers using archival tissue and epidemiological data from our previous case-control study. Mutations in exon 1 of the Ki-ras gene were detected by a PCR-single strand conformation polymorphism approach. A polychotomous logistic regression model was used to assess the significance of observed differences between wild-type and mutated tumors with respect to population controls in the different categories of nutrient consumption. Multivariate density models were used to adjust the correlation between nutrients and total energy. Our studies show that high consumption of monounsaturated fats, mostly derived from olive oil, is associated with a statistically significant decrease in the risk of cancer with wild-type Ki-ras genotype but not of Ki-ras mutated cancers. Conversely, we find that high calcium intake is associated with a decreased risk of Ki-ras mutated tumors but not of wild-type tumors. Tumor genotyping can reveal epidemiological associations that are weak or unapparent when cases-control studies are not stratified by tumor genotype.

Aged↗