Bernard E. Kreger

Gram-negative bacteremia: IV. Re-evaluation of clinical features and treatment in 612 patients

Clinical features and specific aspects of treatment were evaluated in 612 patients with gram-negative bacteremia observed over a 10 year period. Coagulation abnormalities or thrombocytopenia were observed in 64 per cent of the patients. Evidence of disseminated intravascular coagulation (DIC) was found in approximately 10 per cent of them but was of sufficient severity to be associated with subcutaneous or visceral bleeding in 3 per cent of them. The frequency of coagulation abnormalities, other than DIC, was greater in patients with more severe underlying disease but DIC occurred with similar frequency irrespective of the severity of underyling host disease. Coagulation abnormalities of all types were associated with increased fatality rates. Hypothermia was noted in 13 per cent of the patients at the onset of bacteremia but was transient and was not associated with increased fatality. Failure to mount a febrile response greater than 99.6 degrees F within the first 24 hours of bacteremia was associated with a significant increase in fatality rates. Prior corticosteroid therapy diminished the febrile response to bacteremia. Age, underlying host disease, granulocytopenia, congestive heart failure, diabetes mellitus, renal insufficiency, nosocomial infections, and antecedent treatment with antibiotics, corticosteroids, and antimetabolites significantly increased fatality rates. Appropriate antibiotic treatment reduced the fatality rate of those with bacteremia by approximately one-half among patients in each category of severity of underlying host disease. In addition, it was shown that early appropriate antibiotic therapy also reduced the frequency with which shock developed by one half. Even after development of shock, appropriate antibiotic therapy significantly reduced fatality rates. The use of combinations of antibiotics could not be demonstrated to significantly improve survival rates. Minimal differences in therapeutic efficacy could be demonstrated between individual antibiotics and various combinations of antimicrobials. Shock occurred in approximately 40 per cent of the patients and its frequency was not influenced by the species of etiologic agent. Contrary to previous reports, corticosteroid therapy in patients with shock did not enhance survival and treatment with an average of 4.0 g/day of hydrocortisone or its equivalents was associated with a significant increase in fatality rates.

Variability of Body Weight and Health Outcomes in the Framingham Population

BACKGROUND Fluctuation in body weight is a common phenomenon, due in part to the high prevalence of dieting. In this study we examined the associations between variability in body weight and health end points in subjects participating in the Framingham Heart Study, which involves follow-up examinations every two years after entry. METHODS The degree of variability of body weight was expressed as the coefficient of variation of each subjects measured body-mass-index values at the first eight biennial examinations during the study and on their recalled weight at 25 years of age. Using the 32-year follow-up data, we analyzed total mortality, mortality from coronary heart disease, and morbidity due to coronary heart disease and cancer in relation to intraindividual variation in body weight, including only end points that occurred after the 10th biennial examination. We used age-adjusted proportional-hazards regression for the data analysis. RESULTS Subjects with highly variable body weights had increased total mortality (P = 0.005 for men, P = 0.01 for women), mortality from coronary heart disease (P = 0.009 for men, P = 0.009 for women), and morbidity due to coronary heart disease (P = 0.0009 for men, P = 0.006 for women). Using a multivariate analysis that also controlled for obesity, trends in weight over time, and five indicators of cardiovascular risk, we found that the positive associations between fluctuations in body weight and end points related to mortality and coronary heart disease could not be attributed to these potential confounding factors. The relative risks of these end points in subjects whose weight varied substantially, as compared with those whose weight was relatively stable, ranged from 1.27 to 1.93. CONCLUSIONS Fluctuations in body weight may have negative health consequences, independent of obesity and the trend of body weight over time.

Regional obesity and risk of cardiovascular disease; the Framingham Study.

Risk of cardiovascular events was determined over 24 years of surveillance in relation to general adiposity reflected by relative weight and by regional obesity estimated by skinfolds and waist girth per inch of height. Upper quintile values of relative weight, subscapular skinfolds and waist girth were each associated with increased risks of cardiovascular disease in both sexes. Risk of total cardiovascular events increased with the degree of regional, central or abdominal obesity. Mortality from cardiovascular disease was also increased. Increased relative weight and central obesity were both associated with increased risk factors including cholesterol, blood pressure, glucose and uric acid. Changes in weight were mirrored by changes in risk factors with linear trends over a 15 lb range of weight fluctuations. Subscapular skinfold and the ratio of subscapular-to-triceps skinfold, measures of central obesity, were in either sex also associated with an increased probability of coronary attacks in particular. The subscapular skinfold contributed to CHD risk independent of body mass index (BMI). Multivariate analyses taking all the risk factors into account indicate an independent effect of abdominal obesity on stroke, cardiac failure and cardiovascular and all-cause mortality in men. In women, only the subscapular-to-triceps skinfold ratio independently contributes to CHD, cardiovascular and all cause mortality. Regional obesity appears to be an independent contributor to cardiovascular disease at a given level of general adiposity, its effect only partially mediated through promotion of other known risk factors. These data suggest that cardiovascular disease is as closely linked to abdominal as to general adiposity.

Bone Mass and the Risk of Breast Cancer among Postmenopausal Women

BACKGROUND Recent studies have shown a direct relation between serum estrogen levels assessed at a single point in time and the risk of breast cancer, but no evidence links estrogen levels assessed repeatedly over an extended interval to the risk of breast cancer. Bone mass has been proposed as a marker of cumulative exposure to estrogen in women. We therefore studied the association between bone mass and the incidence of breast cancer. METHODS Between 1967 and 1970, 1373 women who were 47 to 80 years old and had no history of breast cancer underwent posteroanterior hand radiography in the Framingham Study. We used radiogrametry to measure the cortical width of each womans second metacarpal. Participants were followed until the end of 1993. All incident cases of breast cancer were confirmed by pathological reports. We used a Cox proportional-hazards model to examine the relation of metacarpal bone mass to the risk of postmenopausal breast cancer. RESULTS Postmenopausal breast cancer developed in 91 subjects. Incidence rates per 1000 person-years increased from 2.0 among the women in the lowest age-specific quartile of metacarpal bone mass to 2.6, 2.7, and 7.0 among the women in the second, third, and highest quartiles, respectively. After adjustments for age and other potential confounding factors, the rate ratios for the risk of breast cancer were 1.0, 1.3, 1.3, and 3.5 from the lowest quartile to the highest (P for trend, <0.001). CONCLUSIONS Women in the highest quartile of bone mass are at higher risk for postmenopausal breast cancer than those in the lowest quartile. The mechanisms underlying this relation are not understood, but cumulative exposure to estrogen may play a part.

BMI and waist circumference as predictors of lifetime colon cancer risk in Framingham Study adults

BACKGROUND: It is unclear whether the increased risk of colon cancer associated with obesity differs for men and women, by distribution of body fat, or by location of the tumor. The primary goal of this study was to address these questions.METHODS: Eligible subjects from the Framingham Study cohort were classified according to body mass index (BMI) and waist size during two age periods: 30–54 y (n=3764) and 55–79 y (n=3802). All eligible men and women were cancer-free at baseline and had complete information on the following potential confounders: age, sex, education, height, activity, smoking, and alcohol. There were 157 incident lifetime cases of colon cancer among those followed beginning at 30–54 y of age and 149 lifetime cases among those whose follow up began at 55–79 y. Subjects were stratified further by gender, activity, and tumor location. The Cox Proportional Hazards Models were used to adjust for possible confounding by the above-described factors.RESULTS: A BMI ≥30 led to a 50% increased risk (95% CI: 0.92–2.5) of colon cancer among middle-aged (30–54 y) and a 2.4-fold increased risk (95% CI: 1.5–3.9) among older (55–79 y) adults. The BMI effect was stronger for men than for women and for cases occurring in the proximal colon. These adverse effects generally diminished when waist was added to the multivariable models. A larger waist size (≥99.1 cm (39 in) and 101.6 cm (40 in) for women and men, respectively) was associated with a two-fold increased risk of colon cancer; this risk increased linearly with increasing waist size and was evident for both proximal and distal colon cancer. There was no attenuation of these effects when BMI was added to the multivariable models. A larger waist had a particularly adverse effect among sedentary subjects (relative risk (RR)=4.4 for middle-aged adults; RR=3.0 for older adults).CONCLUSION: These findings suggest that waist circumference is a stronger predictor of colon cancer risk than is BMI, and that central obesity is responsible for an increased risk of cancer of both the proximal and distal colon.

Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study

Objectives To relate cancer since entry into the Framingham Heart Study with the risk of incident Alzheimer’s disease and to estimate the risk of incident cancer among participants with and without Alzheimer’s disease. Design Community based prospective cohort study; nested age and sex matched case-control study. Setting Framingham Heart Study, USA. Participants 1278 participants with and without a history of cancer who were aged 65 or more and free of dementia at baseline (1986-90). Main outcome measures Hazard ratios and 95% confidence intervals for the risks of Alzheimer’s disease and cancer. Results Over a mean follow-up of 10 years, 221 cases of probable Alzheimer’s disease were diagnosed. Cancer survivors had a lower risk of probable Alzheimer’s disease (hazard ratio 0.67, 95% confidence interval 0.47 to 0.97), adjusted for age, sex, and smoking. The risk was lower among survivors of smoking related cancers (0.26, 0.08 to 0.82) than among survivors of non-smoking related cancers (0.82, 0.57 to 1.19). In contrast with their decreased risk of Alzheimer’s disease, survivors of smoking related cancer had a substantially increased risk of stroke (2.18, 1.29 to 3.68). In the nested case-control analysis, participants with probable Alzheimer’s disease had a lower risk of subsequent cancer (0.39, 0.26 to 0.58) than reference participants, as did participants with any Alzheimer’s disease (0.38) and any dementia (0.44). Conclusions Cancer survivors had a lower risk of Alzheimer’s disease than those without cancer, and patients with Alzheimer’s disease had a lower risk of incident cancer. The risk of Alzheimer’s disease was lowest in survivors of smoking related cancers, and was not primarily explained by survival bias. This pattern for cancer is similar to that seen in Parkinson’s disease and suggests an inverse association between cancer and neurodegeneration.

Type-Specific and Cross-Reactive Antibodies in Gram-Negative Bacteremia

Abstract Antibody titers to O-specific and two shared cross-reactive antigens (common entero-bacterial antigen [CA] and a determinant [Re] of rough bacilli) were related to the frequency of shock or a fatal outcome in 175 patients with gram-negative bacteremia. High titers of O antibody did not prevent development of bacteremia and were associated with only a very slight decrease in the frequency of shock and death. The height of antibody titers to CA also did not correlate with the frequency of shock or a fatal outcome. In contrast, both shock and death were 1/3 as frequent among patients with high titers (1:80 or above) of Re antibody. The apparent protective effect of Re antibody was independent of any contribution of O antibody. These observations, coupled with prior animal studies, suggest that enhancement of resistance to enterobacteria might be accomplished by immunization with shared cross-reactive antigens.

A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study

BackgroundBreast and prostate cancer are two commonly diagnosed cancers in the United States. Prior work suggests that cancer causing genes and cancer susceptibility genes can be identified.MethodsWe conducted a genome-wide association study (Affymetrix 100K SNP GeneChip) of cancer in the community-based Framingham Heart Study. We report on 2 cancer traits – prostate cancer and breast cancer – in up to 1335 participants from 330 families (54% women, mean entry age 33 years). Multivariable-adjusted residuals, computed using Cox proportional hazards models, were tested for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate ≥80%, minor allele frequency ≥10%, Hardy-Weinberg test p ≥ 0.001) using generalized estimating equations (GEE) models and family based association tests (FBAT).ResultsThere were 58 women with breast cancer and 59 men with prostate cancer. No SNP associations attained genome-wide significance. The top SNP associations in GEE models for each trait were as follows: breast cancer, rs2075555, p = 8.0 × 10-8 in COL1A1; and prostate cancer, rs9311171, p = 1.75 × 10-6 in CTDSPL. In analysis of selected candidate cancer susceptibility genes, two MSR1 SNPs (rs9325782, GEE p = 0.008 and rs2410373, FBAT p = 0.021) were associated with prostate cancer and three ERBB4 SNPs (rs905883 GEE p = 0.0002, rs7564590 GEE p = 0.003, rs7558615 GEE p = 0.0078) were associated with breast cancer. The previously reported risk SNP for prostate cancer, rs1447295, was not included on the 100K chip. Results of cancer phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.ConclusionAlthough no association attained genome-wide significance, several interesting associations emerged for breast and prostate cancer. These findings can serve as a resource for replication in other populations to identify novel biologic pathways contributing to cancer susceptibility.

Serum cholesterol level, body mass index, and the risk of colon cancer. The Framingham Study.

Background. Some studies have linked low serum cholesterol levels to increased risk of colon cancer, particularly in men. Results have been inconsistent, with pre‐clinical disease frequently offered to explain any apparent association.

Weight Change and the Risk of Late-Onset Breast Cancer in the Original Framingham Cohort

Abstract: Objective: Adult weight gain has been associated with a twofold risk of postmenopausal breast cancer. Data are limited regarding whether weight gain at specific periods of marked changes in estrogen- and insulin-related hormones have different risk associations. This study assesses the relation of adult weight change overall and at specific, hormonally relevant times with diagnosis of a first breast cancer after age 55 (late onset). Methods: Framingham study data were used to assess premenopausal (25-44 yr), perimenopausal (45-55 yr), postmenopausal (after 55 yr), and adult lifetime (from 25 yr) weight change in relation to late-onset breast cancer in 2,873 women followed for up to 48 yr, with 206 late-onset breast cancers. Results: Adult lifetime weight gain was associated with an increased risk of late-onset breast cancer (P trend = 0.046). Weight gain during specific time periods was not associated with breast cancer. Data suggested a possible decreased risk of breast cancer with weight loss from ages 25 to 44 and 45 to 55 yr (relative risk = 0.4 [0.2-1.2] and 0.5 [0.3-0.9], respectively). Conclusion: These data confirm prior reports of an association between adult lifetime weight gain and increased risk of late-onset breast cancer and support current recommendations to avoid adult weight gain.