The renin-angiotensin aldosterone system and osteoporosis: findings from the Women's Health Initiative.

New users of RAAS inhibitors, including ACE inhibitors and ARBs, have a small increased risk for fracture in the first 3 years of use, with a reduced risk of fracture with longer duration of use. INTRODUCTION: Pharmacological inhibitors of the renin-angiotensin aldosterone system (RAAS) are used to treat hypertension. However, the relationship of these medications to osteoporosis is inconsistent, and no study has included simultaneous measurements of both incident fractures and bone mineral density (BMD). METHODS: The association of RAAS inhibitor use (n = 131,793) with incident fractures in new users of these medications in women in the Women's Health Initiative over a minimum median follow-up of 6.5 years was assessed by Cox proportional hazard models. The association of incident fractures by a cumulative duration of use of these medications (< 3 years.) and (> 3 years.) was also estimated. Subgroup analysis of fracture risk by RAAS inhibitor use confined to women with hypertension was also performed (n = 33,820). The association of RAAS inhibitor use with changes in BMD of the hip was estimated by linear regression in 8940 women with dual energy X-ray absorptiometry measurements. RESULTS: There was no significant association between RAAS inhibitor use and all fractures in the final adjusted multivariable models including hip BMD (HR 0.86 (0.59, 1.24)). However, among users of RAAS inhibitors, including ACE inhibitors and angiotensin receptor blockers (ARBs), hazard ratios for all incident fracture sites in final multivariable models including hip BMD showed dramatic differences by duration of use, with short duration of use (3 years or less) associated with a marked increased risk for fracture (HR 3.28 (1.66, 6.48)) to (HR 6.23 (3.11, 12.46)) and use for more than 3 years associated with a reduced fracture risk (HR 0.40 (0.24, 0.68) to (HR 0.44 (0.20, 0.97)) . Findings were similar in the subgroup of women with a history of hypertension. There was no significant change in BMD of the hip by RAAS inhibitor use. CONCLUSIONS: In postmenopausal women, use of RAAS inhibitors, including ACE inhibitors and ARBs, is associated with an increased risk for fracture among new users of these medications in the first 3 years of use. However, long-term use (> 3 years) is associated with a reduced risk. Consideration for fracture risk may be part of the decision-making process for initiation of these medications for other disease states.

Oral bisphosphonate use and lung cancer incidence among postmenopausal women.

Background: Bisphosphonates are common medications for the treatment of osteoporosis in older populations. Several studies, including the Women's Health Initiative (WHI), have found inverse associations of bisphosphonate use with risk of breast and endometrial cancer, but little is known about its association with other common malignancies. The objective of this study was to evaluate the association of bisphosphonate use on the incidence of lung cancer in the WHI. Patients and methods: The association between oral bisphosphonate use and lung cancer risk was examined in 151 432 postmenopausal women enrolled into the WHI in 1993-1998. At baseline and during follow-up, participants completed an inventory of regularly used medications including bisphosphonates. Results: After a mean follow-up of 13.3 years, 2511 women were diagnosed with incident lung cancer. There was no evidence of a difference in lung cancer incidence between oral bisphosphonate users and never users (adjusted hazard ratio = 0.91; 95% confidence intervals, 0.80-1.04; P = 0.16). However, an inverse association was observed among those who were never smokers (hazard ratio = 0.57, 95% confidence interval, 0.39-0.84; P < 0.01). Conclusion: In this large prospective cohort of postmenopausal women, oral bisphosphonate use was associated with significantly lower lung cancer risk among never smokers, suggesting bisphosphonates may have a protective effect against lung cancer. Additional studies are needed to confirm our findings.

Mode of birth in twins: data and reflections.

Our primary objective was to compare neonatal and maternal outcomes in women with twin pregnancies, beyond 32 weeks, having a planned vaginal birth or a planned caesarean section (CS). This was a retrospective cohort study from a single tertiary centre over nine years. 534 sets of twins ≥32 + 0 weeks of gestation were included. 401 sets were planned vaginally and 133 sets were planned by CS. We compared a composite adverse perinatal outcome (perinatal mortality or serious neonatal morbidity; five minute APGAR score ≤4, neurological abnormality and need for intubation) and a composite maternal adverse outcome (major haemorrhage, trauma or infection) between the groups. There were no significant differences. Given the similarity of these results with several other larger studies of twin birth, we sought to look at reasons why there is still a rising rate of CS for twin births. We further make suggestions for keeping this rate to a sensible minimum. Impact statement What is already known on this subject? The largest randomised controlled study comparing planned vaginal birth with planned CSs for lower risk twins between 32 and 39 weeks of gestation, showed no added safety from planned CS. However, in most of the Western countries this conclusion has failed to increase the number of planned vaginal births for lower risk twins. What do the results of this study add? This observational study from a single tertiary centre provides external validation of the twin trial results in a practical day-to-day setting. It also provides insights as to how planned vaginal birth can be developed and maintained, with a key focus on safety and maternal participation in decision making. It does focus on consent and providing accurate data. What are the implications of these findings for clinical practice and/or further research? There are good grounds to encourage vaginal birth for low-risk twin pregnancies. The trend of rising caesarean rates in low-risk twin pregnancies worldwide will erode important skills for the conduct of vaginal births without any clear benefit for mothers or babies. The current situation demands careful thought about implementing innovative training opportunities for younger obstetricians. Finally, we need intelligent responses to many non-evidence-based factors which can drive clinical practice.

Benefit/risk for adjuvant breast cancer therapy with tamoxifen or aromatase inhibitor use by age, and race/ethnicity.

In early adjuvant breast cancer trial reports, aromatase inhibitors more effectively reduced breast recurrence with lower risk of thromboembolic events and endometrial cancer than tamoxifen, while aromatase inhibitors had higher fracture and cardiovascular disease risk. We used data from updated patient-level meta-analyses of adjuvant trials in analyses to summarize the benefits and risks of these agents in various clinical circumstances. Baseline incidence rates for health outcomes by age and race/ethnicity, absent aromatase inhibitor, or tamoxifen use were estimated from the Women's Health Initiative. Aromatase inhibitor and tamoxifen effects on distant recurrence were obtained from a meta-analysis of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (Big-1-98) clinical trials. Impact on other health outcomes were obtained from meta-analyses of randomized trials comparing aromatase inhibitor to tamoxifen use and from placebo-controlled chemoprevention trials. All health outcomes were given equal weight when modeling net benefit/risk for aromatase inhibitor compared to tamoxifen use by breast cancer recurrence risk, age (decade), race/ethnicity, hysterectomy (yes/no), and by prior myocardial infarction. Over a 10-year period, the benefit/risk index was more favorable for aromatase inhibitor than for tamoxifen as adjuvant breast cancer therapy in almost all circumstances regardless of patient age, race/ethnicity, breast cancer recurrence risk, or presence or absence of a uterus. Only in older women with prior myocardial infarction and low recurrence risk was an advantage for tamoxifen seen. Using a benefit/risk index for endocrine adjuvant breast cancer therapy in postmenopausal women, benefit was higher for aromatase inhibitor use in almost all circumstances.

Erratum to: Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

[This corrects the article DOI: 10.14283/jarlife.2024.1.].

Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

Background: Emerging evidence suggests that a number of factors can influence blood-based biomarker levels for Alzheimer's disease (AD) and Alzheimer's related dementias (ADRD). We examined the associations that demographic and clinical characteristics have with AD/ADRD blood-based biomarker levels in an observational continuation of a clinical trial cohort of older individuals with type 2 diabetes and overweight or obesity. Methods: Participants aged 45-76 years were randomized to a 10-year Intensive Lifestyle Intervention (ILI) or a diabetes support and education (DSE) condition. Stored baseline and end of intervention (8-13 years later) plasma samples were analyzed with the Quanterix Simoa HD-X Analyzer. Changes in Aß42, Aß40, Aß42/Aß40, ptau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were evaluated in relation to randomization status, demographic, and clinical characteristics. Results: In a sample of 779 participants from the Look AHEAD cohort, we found significant associations between blood-based biomarkers for AD/ADRD and 15 of 18 demographic (age, gender, race and ethnicity, education) and clinical characteristics (APOE, depression, alcohol use, smoking, body mass index, HbA1c, diabetes duration, diabetes treatment, estimated glomerular filtration rate, hypertension, and history of cardiovascular disease) . Conclusions: Blood-based biomarkers of AD/ADRD are influenced by common demographic and clinical characteristics. These factors should be considered carefully when interpreting these AD/ADRD blood biomarker values for clinical or research purposes.

Multivitamin and mineral use and breast cancer mortality in older women with invasive breast cancer in the women's health initiative.

Multivitamin use is common in the United States. It is not known whether multivitamins with minerals supplements (MVM) used by women already diagnosed with invasive breast cancer would affect their breast cancer mortality risk. To determine prospectively the effects of MVM use on breast cancer mortality in postmenopausal women diagnosed with invasive breast cancer, a prospective cohort study was conducted of 7,728 women aged 50-79 at enrollment in the women's health initiative (WHI) in 40 clinical sites across the United States diagnosed with incident invasive breast cancer during WHI and followed for a mean of 7.1 years after breast cancer diagnosis. Use of MVM supplements was assessed at WHI baseline visit and at visit closest to breast cancer diagnosis, obtained from vitamin pill bottles brought to clinic visit. Outcome was breast cancer mortality. Hazard ratios and 95 % confidence intervals (CIs) for breast cancer mortality comparing MVM users to non-users were estimated using Cox proportional hazard regression models. Analyses using propensity to take MVM were done to adjust for potential differences in characteristics of MVM users versus non-users. At baseline, 37.8 % of women reported MVM use. After mean post-diagnosis follow-up of 7.1 ± 4.1 (SD) years, there were 518 (6.7 %) deaths from breast cancer. In adjusted analyses, breast cancer mortality was 30 % lower in MVM users as compared to non-users (HR = 0.70; 95 % CI 0.55, 0.91). This association was highly robust and persisted after multiple adjustments for potential confounding variables and in propensity score matched analysis (HR = 0.76; 95 % CI 0.60-0.96). Postmenopausal women with invasive breast cancer using MVM had lower breast cancer mortality than non-users. The results suggest a possible role for daily MVM use in attenuating breast cancer mortality in women with invasive breast cancer but the findings require confirmation.

Does withdrawal of antihypertensive medication increase the risk of cardiovascular events? Trial of Nonpharmacologic Interventions in the Elderly (TONE) Cooperative Research Group.

The Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommends that attempts to discontinue antihypertensive drug therapy be considered after blood pressure (BP) has been controlled for 1 year. However, discontinuation of drug therapy could unmask underlying conditions and precipitate clinical cardiovascular events. The Trial of Nonpharmacologic Interventions in the Elderly (TONE) was a clinical trial of the efficacy of weight loss and/or sodium reduction in controlling BP after withdrawal of drug therapy in patients with a BP< 145/85 mm Hg on 1 antihypertensive medication. Of 975 participants, 886 entered the drug withdrawal phase of the trial and 774 were successfully withdrawn from their medications. Thirty-three events (stroke, transient ischemic attack, myocardial infarction, arrhythmia, congestive heart failure, angina, other) occurred between randomization and the onset of drug withdrawal (median time 3.6 months), 57 events occurred either during or after drug withdrawal (14.0 months), and 36 events occurred after resumption of antihypertensive therapy (15.9 months). Event rates per 100 person-years were 5.5, 5.5, and 6.8 for the 3 time periods (p=0.84) in the nonoverweight group and 7.2, 5.2, and 5.6 (p=0.08) in the overweight group. The study shows that antihypertensive medication can be safely withdrawn in older persons without clinical evidence of cardiovascular disease who do not have diastolic pressure > or = 150/90 mm Hg at withdrawal, providing that good BP control can be maintained with nonpharmacologic therapy.

Ah receptor mediating induction of cytochrome P450IA1 in a novel continuous human liver cell line (Mz-Hep-1). Detection by binding with [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin and relationship to the activity of aryl hydrocarbon hydroxylase.

The Ah receptor regulates induction of cytochrome P450IA1 and mediates certain toxicities of polyhalogenated aromatics such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). It has been characterized previously in continuous cell lines, notably the mouse hepatoma line Hepa 1, the human squamous cell carcinoma line A431, and the human liver cell line Hep G2. The present work extends our knowledge of the Ah receptor in continuous human liver cell lines. Ah receptor can be detected in Mz-Hep-1, a hepatitis B virus-negative cell line derived from a Thorotrast-induced hepatocellular carcinoma. The mean concentration of Ah receptor in Mz-Hep-1 cells was 341 +/- 22 fmol/mg cytosol protein (mean +/- SEM, nine separate determinations). This is equivalent to approximately 30,000 sites per cell. The concentration of Ah receptor in Mz-Hep-1 cells is similar to that in Hepa 1 cells and approximately three times higher than that in Hep G2 cells. The Mz-Hep-1 Ah receptor sedimented in continuous sucrose gradients at approximately 9 S. Specificity of binding by [3H]TCDD was demonstrated by competitive binding of non-radiolabeled 2,3,7,8-tetrachlorodibenzofuran, 3-methylcholanthrene (MC), and dibenz[a,h]anthracene in 50-fold molar excess. Phenobarbital, which is not a substrate for P450IA1, did not compete with [3H]TCDD for binding to Mz-Hep-1 Ah receptor. Dexamethasone and estradiol also did not compete with [3H]TCDD for binding, suggesting non-identity of Ah receptor with glucocorticoid or estrogen receptor. In separate experiments, glucocorticoid receptor was identified in Mz-Hep-1 cells. By Scatchard plot analysis, the apparent equilibrium dissociation constant (Kd) for binding of [3H]TCDD to Mz-Hep-1 Ah receptor was estimated to be 4.4 nM, compared to 0.8 nM in Hepa 1 cells. By Woolf plot analysis the Kd was 5.4 nM, compared to 1.2 nM in Hepa 1 cells. The [3H]TCDD.Ah receptor complex extracted from nuclei of Mz-Hep-1 cells incubated with [3H]TCDD in culture at 37 degrees sedimented at approximately 6 S under conditions of high ionic strength. Aryl hydrocarbon hydroxylase (AHH) activity was detectable in Mz-Hep-1 cells after pretreatment with inducing chemicals. Mz-Hep-1 cells have the highest concentrations of Ah receptor in any continuous human liver cell line thus far investigated. The Mz-Hep-1 Ah receptor is similar physicochemically to that described in murine systems. AHH activity is inducible in Mz-Hep-1 cells.

Effects on subject response of information brochures and small cash incentives in a mail-based case-control study.

PURPOSE: To investigate the impact on subject response of an information brochure and cash incentives included with mailed questionnaires in case-control studies. METHODS: A randomized trial was carried out within a case-control study investigating cancer in the Province of Ontario. Brochures were included with half of the mailed questionnaires sent to 7487 cases and 2561 controls. Controls were also sent cash incentives of $2, $5, or no money. RESULTS: With the brochure, response changed from 75.0% to 75.8% in cases, and from 70.3% to 71.1% in controls. Adjusting for differences in age, residence, sex, and cancer site/status, the change was 0.2% [95% confidence interval (CI) = -1.7-2.1] in cases, and 0.6% (95% CI = -3.1-4.3) in controls. The $2 and $5 incentives increased overall response in controls from 61.9% to 72.8% and 77.2%, respectively, i.e., by 10.9% (95% CI = 6.1-15.6) and 15.1% (95% CI = 10.4-19.7), after adjustment. This effect was largely confined to urban areas (for $2 and $5, respectively: 5.5% and 14.2% in Toronto, 15.3% and 20.4% in other urban areas vs. 2.7% and 1.0% in rural areas; p = 0.02). Response time showed little or no improvement when the brochure was included, but was markedly reduced for both the $2 and $5 incentives. CONCLUSIONS: Cash incentives can improve subject response in epidemiologic studies, whereas information brochures do not appear to have an effect.

Glycemic control of older adults with type 2 diabetes: findings from the Third National Health and Nutrition Examination Survey, 1988-1994.

BACKGROUND: Although nearly half of all people who have diabetes are aged 65 or older, glycemic control of older adults with diabetes has not been well described. METHODS: We conducted a cross-sectional study of 1,482 participants with self-reported type 2 diabetes in the Third National Health and Nutrition Examination Survey, 1988-1994 (NHANES III), a nationally representative sample of the US noninstitutionalized civilian population. Variables included in this analysis included age, sociodemographic factors, drug treatment, and level of glycemic control. RESULTS: The mean % (+/-SE) HbA1c was 7.78 +/- 0.21, 7.64 +/- 0.18, 7.71 +/- 0.14, and 7.27 +/- 0.14 in persons aged 20 to 54, 55 to 64, 65 to 74 and > or = 75 years, respectively. The mean mg/dL (+/-SE) fasting plasma glucose (FPG) was 175.9 +/- 7.6, 164.5 +/- 6.1, 183.3 +/- 5.3, and 158.5 +/- 5.5 in the four age groups and older, respectively. When controlling for race, gender, education, and duration of diabetes, age was not significantly associated with levels of HbA1c [P (trend) =0.17] or FPG [P (trend) =0.19]. Among NHANES III participants aged 65 or older, ADA guidelines for glycemic control (HbA1c < 7%) were achieved by 71%, 44%, and 27% of persons using no drug therapy, oral hypoglycemic agents, and insulin, respectively. CONCLUSIONS: Although many older adults with type 2 diabetes do not achieve targets for glucose control, there is no evidence to suggest that community-dwelling older adults with diabetes are treated less vigorously than younger persons with diabetes.

Prevalence of undiagnosed non-insulin-dependent diabetes mellitus and impaired glucose tolerance in a cohort of older persons with hypertension.

OBJECTIVE: To determine the prevalence of undiagnosed non-insulin-dependent diabetes mellitus (NIDDM) and impaired glucose tolerance (IGT) in a cohort of older persons with hypertension. To examine the usefulness of screening for NIDDM in this study population. DESIGN: Cross-sectional study. SETTING: University of Tennessee, Memphis and the General Clinical Research Center (GCRC). PATIENTS: Ninety-five participants in the Trial of Nonpharmacologic Interventions in the Elderly (TONE) study who agreed to participate in an ancillary study. MEASUREMENTS: A standard oral glucose tolerance test (OGTT) with insulin and C-peptide levels was performed before the beginning of the TONE intervention. RESULTS: In this cohort, 43 participants (45.3%) had normal glucose tolerance (NGT), 41 (43.2%) had IGT, and 11 (11.6%) had undiagnosed NIDDM. The positive predictive value for NIDDM of a fasting glucose > or = 115 mg/dL in our participants was 57%. Hyperinsulinemia occurred in only one participant, a subject in the IGT group. CONCLUSIONS: Our data demonstrate that undiagnosed NIDDM is common in our cohort of older persons who are being treated for essential hypertension and that impaired glucose tolerance may be more common than in the general population of the same age. Further, our data show that the vast majority of this older, obese, hypertensive cohort did not have fasting hyperinsulinemia. We also infer that a fasting glucose alone has a low positive predictive value for screening of NIDDM in our older cohort. As the prevalence of NIDDM and impaired glucose tolerance in older hypertensive patients in the general population is unknown, we believe that further investigation is needed to characterize the relationship of hypertension, glycemic status, and hyperinsulinemia in the general population.

Does syndrome X exist in hypertensive elderly persons with impaired glycemic control?

BACKGROUND: This report focuses on the glycemic state in relation to insulin and lipid levels of a cohort of elderly hypertensive persons to estimate the prevalence of syndrome X. METHODS: A cross-sectional study was performed at the University of Tennessee, Memphis, and the General Clinical Research Center (GCRC) on 95 participants in the Trial of Nonpharmacologic Interventions in the Elderly (TONE) study who agreed to participate in an ancillary study. A standard oral glucose tolerance test (OGTT) with insulin and C-peptide levels and a fasting lipid profile were obtained. RESULTS: In this sample of healthy elderly participants with hypertension who were taking an antihypertensive medication, 43 (45.3%) had normal glucose tolerance (NGT), 41 (43.2%) had impaired glucose tolerance (IGT), and 11 (11.6%) had undiagnosed non-insulin-dependent diabetes mellitus (NIDDM). Fasting hyperinsulinemia occurred in only one participant, who was in the IGT group. Hypertriglyceridemia and low high density lipoprotein (HDL) occurred in four persons, none of whom had hyperinsulinemia. Persons in the NIDDM and IGT groups had decreased beta cell function compared to persons in the NGT group, but did not have increased peripheral insulin resistance as estimated from the OGTT data. CONCLUSIONS: Our data demonstrated that in this cohort of elderly hypertensive participants with a high prevalence of central obesity, impaired glycemic control was common, but was not associated with fasting hyperinsulinemia or peripheral insulin resistance. Furthermore, we conclude that syndrome X essentially did not occur in these participants and postulate that the primary etiology for their impaired glycemic control is beta cell dysfunction. Further research is needed to elucidate these relationships.

Leiomyomatosis peritonealis disseminata with endometrium.

A case of leiomyomatosis peritonealis disseminata (LPD) is presented with the unique finding of occasional endometrial glands and stroma within smooth muscle nodules. The possible origins of this tissue are discussed in relation to the histogenesis and prognosis of LPD.

The current practices of internists in prevention of residential fire injury.

Residential fires are a leading cause of unintentional injury in the United States. We completed a cross-sectional study in an urban internal medicine clinic to describe the patients' risk factors for fire injury and internists' current methods for addressing this health problem. We used a physician self-report survey (n = 301), patient interviews (n = 300), and chart reviews (n = 300) in the evaluation. Among physicians returning the questionnaire (70% response rate), more than 85% demonstrated reasonable knowledge of injury as a major health problem and relatively positive attitudes toward incorporating injury prevention into clinical practice. However, 62% of physicians reported "never" and 23% only "seldom" counseling patients about smoke detectors. Among patients attending the clinic, only 63% reported having a smoke detector in their home. Factors associated with not having a smoke detector through multivariate logistic analysis were black race (odds ratio [OR] = 4.3, confidence interval [CI] = 1.7, 10.6) and patient report that physician did not counsel about smoke detectors (OR = 2.38, Cl = 1.15, 4.90). Age younger than 65 (OR = 1.7, Cl = .93, 2.9) and alcohol abuse (OR 1.5, Cl = .92, 2.5) were borderline in their statistical significance. Eighteen percent of the patients reported being counseled by their physician about smoke detectors, although no documentation appeared in any of the charts. In addition, those patients with risk factors for fire injury did not report being counseled more often than their lower risk counterparts.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk factors for male breast cancer in Canada, 1994-1998.

Relatively little attention has been paid to the aetiology of male breast cancer and the current understanding of female breast cancer, primarily related to reproductive events, cannot be readily transferred to understanding the cancer in males. However, since male breast cancer occurs in the absence of factors related to childbearing and menstruation, its aetiology may provide special insights into the causes of breast cancer in women. We examined lifestyle risk factors for male breast cancer as part of a Canadian, multi-site, population-based, case-control study. Eighty-one newly diagnosed, histologically confirmed cases and 1905 male controls aged 42-74 were analysed using unconditional logistic regression. Increased risks were found for men with a mother or sister with breast cancer (adjusted odds ratio (OR) 3.65, 95% confidence interval (95% CI) 1.62-8.19). Higher physical activity levels (moderate, and strenuous recreational plus occupational) were associated with a decreased risk of male breast cancer (highest quartile, adjusted OR 0.48, 95% CI 0.26-0.91). Similarly, higher risks were associated with higher weight 2 years before interview (2.19, 95% CI 1.08-4.43), maximum weight (OR 2.66) and higher body mass index (OR 1.60). Higher vegetable consumption and coffee consumption were associated with decreased risk, whereas higher beta-carotene, vitamin E and calcium supplementation were associated with statistically significant increased risk. The small number of cases and multiple comparisons preclude strong conclusions, but our study is consistent with studies suggesting obesity and family history increase risk, and physical activity decreases risk of breast cancer.

Alcohol, tobacco and coffee consumption and the risk of pancreatic cancer: results from the Canadian Enhanced Surveillance System case-control project. Canadian Cancer Registries Epidemiology Research Group.

The relationship between alcohol, tobacco and coffee consumption and pancreatic cancer was investigated using population-based case-control data obtained from eight Canadian provinces. Our findings are based on analyses performed on 583 histologically confirmed pancreatic cancer cases and 4813 controls. Questionnaire data were obtained directly from 76% of the cases. Male subjects with 35 or more cigarette pack-years had an increased risk of developing pancreatic cancer relative to never smokers (OR= 1.46, 95% CI 1.00-2.14). Similarly, women reporting at least 23 cigarette pack-years of smoking had an odds ratio of 1.84 (95% CI 1.25-2.69). For the most part, consumption of total alcohol, wine, liquor and beer was not associated with pancreatic cancer. Coffee drinking was not related to pancreatic cancer. More work is needed to clarify the role of these and other potentially modifiable risk factors as a means to reduce the incidence of this disease for which treatment results remain disappointing.

Oral absorption of 21-corticosteroid esters: a function of aqueous stability and intestinal enzyme activity and distribution.

The intestinal absorption of hydrocortisone and prednisolone are compared with three water-soluble derivatives (succinate, phosphate, and lysinate) in experiments at two levels of biological system complexity. Rates of absorption are compared by measuring permeabilities from rat intestinal perfusions of drugs and derivatives in solution. Extents of absorption are compared over a 10-fold dose range of parent steroid and with the steroid derivatives by measuring plasma levels from solid oral dosage in dogs. While the parent steroids are well absorbed over the entire length of the intestinal tract, variability in plasma levels is observed at higher doses. Limited solubility and resultant dissolution rate variability are likely to be playing a role in the early erratic blood level profiles found at higher doses. While the soluble prodrugs have a dissolution rate advantage which results in a greater concentration gradient, their absorption is limited by their aqueous luminal stability, their polarity and resultant passive membrane permeability, and the distribution and activity of enzyme reconversion sites in the intestinal tract. The unstable lysinate ester, targeted for aminopeptidase, has an absorption profile and permeability similar to that of the parent steroid. The absorption of the moderately stable succinate ester is limited by its polarity and the activity of intestinal esterases. The stable phosphate derivative is well absorbed in the upper intestine, where high levels of alkaline phosphatase exist, while the prodrug polarity and drop-off of enzyme activity limit its absorption from the lower gastrointestinal (GI) tract.

Do sweat calcium losses affect bone mass during firefighter training?

Although participation in vigorous exercise is associated with increased bone mass, recent evidence suggests that loss of calcium in sweat may result in a negative calcium balance and, ultimately, a decrease in bone mass. Anthropometric characteristics, habitual physical activity levels, dietary calcium intake, bone mineral content, and bone turnover markers were measured in 42 male recruits before and after 4 months of firefighter training. During two strenuous mid-training sessions, sweat calcium concentrations were measured; they averaged 1.1 mM. Whole body and total hip bone mineral content increased significantly, as did one marker of bone formation, and were not associated with sweat calcium concentration. This study demonstrates that intense physical training sessions that produce high sweat rates do not have an adverse effect on the bone mineral content of healthy young men.

Current physician screening and treatment of hypercholesterolemic patients.

To determine resident physician recognition and treatment of hypercholesterolemia, a retrospective chart audit was performed on 300 systematically selected patients seen in an internal medicine resident's continuity care clinic during the spring of 1992. A self-administered resident survey was given after completion of chart selection. Of the 300 patients, 64 (21%) did not have a cholesterol reading on the chart. The frequency of screening was unaffected by cardiac risk factors, patient race or sex, or resident level of training or specialty. Of the 96 patients who had a total cholesterol greater than 240 mg/dL documented in the chart, 48% received diet therapy, 46% received other nonpharmacologic therapy, 24% received drug therapy, 4% were referred to a lipidologist, and 30% received no treatment. Fasting lipid profiles were ordered for 57% of these patients. The frequency of therapy was unaffected by patient race or sex, resident level of training or specialty, or presence of two or more cardiac risk factors, although patients with a diagnosis of hypercholesterolemia and patients younger than age 65 were treated significantly more often. Resident action primarily involved evaluation rather than therapy. Efforts to improve the aggressiveness of treatment for hypercholesterolemia by resident physicians are necessary.