Risk factors for decreased bone density and effects of HIV on bone in the elderly.

UNLABELLED: Most studies of bone density in HIV-infected individuals focus on young men. This study compares differences in bone density in elderly HIV positive men and women to HIV negative controls. Bone density was lower in the lumbar spine and hip in the HIV-infected group. Antiretrovirals may be associated with decreased bone mineralization. INTRODUCTION: Individuals with human immunodeficiency virus (HIV) may be at increased risk for osteoporosis. Prolonged exposures to HIV and/or antiretroviral therapy are possible causes for this association. This study compares differences in bone mineral density (BMD) in elderly HIV positive men and women to HIV negative controls. METHODS: A cross-sectional study was conducted among 57 HIV-infected and 47 HIV negative subjects over age 55. BMD at the lumbar spine and total hip and markers of bone turnover were compared. RESULTS: BMD was borderline lower in the lumbar spine and significantly lower in the hip in the HIV-infected group. Controlling for age, sex, race and body mass index, differences between the groups were significant at both sites. There was no difference in markers of bone turnover between the groups. Tenofovir use was significantly associated with decreased BMD at the spine while protease inhibitor use was significantly associated with decreased BMD at the hip. CONCLUSION: Elderly men and women with HIV have lower bone mass than HIV negative controls. Decreased body mass index was the most important risk factor associated with decreased BMD. Bone demineralization was observed among HIV-infected subjects receiving either tenofovir or a protease inhibitor.

Relationships of sex hormone levels to dependence in activities of daily living in the frail elderly.

OBJECTIVES: We undertook this nursing home study in order to determine the relationships between dependency in activities of daily living (ADL) and blood levels of estrone, testosterone, androstenedione, and dehydroepiandrosterone (DHEA). Little is known about this issue. METHODS: cross-sectional study of 370 nursing home residents. Hormone levels in blood specimens drawn in 1997 and 1998 were correlated with degree of ADL dependency recorded in medical charts. RESULTS: Because of multiple comparisons associations were deemed significant for P-values < or =0.017 for males and < or =0.0125 for females. In males, the following were inversely related: testosterone levels with dependency in transferring and eating; estrone with eating and a summary ADL index; and androstenedione with toileting and a summary ADL index (in all cases, r=-0.4; P=0.007-0.015). Inverse trends existed between testosterone levels and dependency in mobility and a summary ADL index; and androstenedione and eating (in all cases r=-0.3; P=0.030-0.055). Among females the following were directly related: estrone levels with dependence in mobility, toileting, transferring, and a summary ADL index; and DHEA with transferring and a summary ADL index (r=0.2-0.3, P=0.0001-0.01). Trends existed between estrone and eating, and DHEA and toileting (r=0.1-0.2, P=0.04). CONCLUSION: In male residents, higher sex hormone levels are associated with better ADL performance. Among females the opposite is true. While further studies are needed to elucidate these relationships, our results and recent findings of others suggest sex hormone actions in older women differ from those in younger populations. A possible stress-related mechanism is also presented.

Nonoverlapping clusters: approximate distribution and application to molecular biology.

An approach is developed for the screening of genomic sequence data to identify gene regulatory regions. This approach is based on deciding if putative transcription factor binding sites are clustered together to a greater extent than one would expect by chance. Given n events occurring on an interval of width L (L base pairs), an r:w cluster is defined as r + 1 consecutive events all contained within a window of length wL. Accurate and easily computable approximations are derived for the distribution of the number of nonoverlapping r:w clusters under the model that the positions of the n events have a uniform distribution. Simulations demonstrate that these approximations have greater accuracy than existing methods. The approximation is applied to detect erythroid-specific regulatory regions in genomic DNA sequences, first in an artificial case where r is specified a priori and then as part of an exploratory approach.

Effects of stathmin inhibition on the mitotic spindle.

Stathmin is a major cytosolic phosphoprotein that plays an important role in the regulation of microtubule dynamics during cell cycle progression. It has recently been proposed that the major function of stathmin is to promote depolymerization of the microtubules that make up the mitotic spindle. In this report, we tested the prediction that a deficiency in stathmin expression would result in constitutive stabilization of microtubules and lead to abnormalities in the organization of the mitotic spindle. Our studies demonstrate that antisense inhibition of stathmin expression in K562 erythroleukemic cells results in increased ratio of polymerized to depolymerized tubulin. These changes are associated with phenotypic abnormalities of the mitotic spindle and difficulty in completing mitosis. These studies also showed that inhibition of stathmin expression results in increased susceptibility of K562 leukemic cells to the pharmacological agents, like taxol, which are known to stabilize the mitotic spindle. In contrast, stathmin inhibition results in decreased sensitivity to vinblastine, an agent that destabilizes the mitotic spindle. Thus, our experimental findings are supportive of the model that stathmin is a microtubule-destabilizing factor that plays an important role in the regulation of the mitotic spindle. We also suggest a potential therapeutic approach for cancer based on the combination of stathmin inhibition with pharmacologic agents that stabilize the mitotic spindle.

Organochlorine exposures and breast cancer risk in New York City women.

A hospital-based case-control study of breast cancer risk related to organochlorine (OC) exposure was conducted in a multiethnic setting in New York City. We enrolled 175 breast cancer patients and 355 control patients. The overall racial/ethnic distribution was 57% Caucasian, 21% Hispanic, 22% African-American; cases and controls were frequency-matched by age and race/ethnicity. Tumor markers (estrogen and progesterone receptors, p53, erbB-2) were assessed and organochlorines (DDE, DDT, trans-nonachlor, and higher (HPCB) and lower (LPCB) chlorinated biphenyls) were measured in blood serum. Tumors among minority women were of slightly higher stage than among Caucasians, but tumor markers were similar across the racial/ethnic groups. DDE levels were highest among African-American and Hispanic women; DDT was highest among Hispanics; HPCBs were highest among African-Americans; LPCBs were lowest among Hispanics; and trans-nonachlor was highest among African-Americans. However, OC levels were not associated with risk for breast cancer, nor did OCs differ with respect to tumor stage or tumor markers. Higher DDE levels were associated with increasing body mass index (BMI), but with decreasing level of education, frequency of nulliparity, and frequency of family history of breast cancer. HPCB levels decreased with BMI and were not correlated with breast cancer risk factors. These relationships can be attributed to historical patterns of exposure and to metabolic differences in OCs related to BMI.

"We don't carry that"--failure of pharmacies in predominantly nonwhite neighborhoods to stock opioid analgesics.

BACKGROUND: We have observed that many black and Hispanic patients receiving palliative care at a major urban teaching hospital are unable to obtain prescribed opioids from their neighborhood pharmacies. In this study, we investigated the availability of commonly prescribed opioids in New York City pharmacies. METHODS: We surveyed a randomly selected sample of 30 percent of New York City pharmacies to obtain information about their stock of opioids. For each pharmacy, U.S. Census estimates for 1997 were used to determine the racial and ethnic composition of the neighborhood (defined as the area within a 0.4-km [0.25-mile] radius of the pharmacy) and the proportion of residents who were more than 65 years old. Data on robberies, burglaries, and arrests involving illicit drugs in 1997 were obtained for the precinct in which each pharmacy was located. We used a generalized linear model to examine the relation between the racial or ethnic composition of neighborhoods and the opioid supplies of pharmacies, while controlling for the proportion of elderly persons at the census-block level and for crime rates at the precinct level. RESULTS: Pharmacists representing 347 of 431 eligible pharmacies (81 percent) responded to the survey. A total of 176 pharmacies (51 percent) did not have sufficient supplies of opioids to treat patients with severe pain. Only 25 percent of pharmacies in predominantly nonwhite neighborhoods (those in which less than 40 percent of residents were white) had opioid supplies that were sufficient to treat patients in severe pain, as compared with 72 percent of pharmacies in predominantly white neighborhoods (those in which at least 80 percent of residents were white) (P<0.001). CONCLUSIONS: Pharmacies in predominantly nonwhite neighborhoods of New York City do not stock sufficient medications to treat patients with severe pain adequately.

Creatine kinase-MB elevation after coronary intervention correlates with diffuse atherosclerosis, and low-to-medium level elevation has a benign clinical course: implications for early discharge after coronary intervention.

OBJECTIVES: The study evaluated the incidence and predictors of creatine kinase-MB isoenzyme (CK-MB) elevation after successful coronary intervention using current devices, and assessed the influence on in-hospital course and midterm survival. BACKGROUND: The CK-MB elevation after coronary intervention predominantly using balloon angioplasty correlates with late cardiac events of myocardial infarction (MI) and death. Whether CK-MB elevation after nonballoon devices is associated with an adverse short and midterm prognosis is unknown. METHODS: The incidence and predictors of CK-MB elevation after coronary intervention were prospectively studied in 1,675 consecutive patients and were followed for in-hospital events and survival. RESULTS: CK-MB elevation was detected in 313 patients (18.7%), with 1-3x in 12.8%, 3-5x in 3.5% and >5x normal in 2.4% of patients. Procedural complications or electrocardiogram changes occurred in only 49% of the CK-MB-elevation cases; CK-MB elevation was more common after nonballoon devices (19.5% vs. 11.5% after percutaneous transluminal coronary angioplasty; p < 0.01). Predictors of CK-MB elevation on multivariate analysis were diffuse coronary disease (p = 0.02), systemic atherosclerosis (p = 0.002), stent use (p = 0.04) and absence of beta-blocker therapy (p = 0.001). Adverse in-hospital cardiac events were more frequent in patients with >5x CK-MB elevation, with no significant difference between 1-5x CK-MB elevation versus normal CK-MB group. During a mean follow-up of 13 +/- 3 months, the incidence of death in the CK-MB-elevation group was 1.6% versus 1.3% in the normal CK-MB group (p = NS). CONCLUSIONS: The CK-MB elevation after coronary intervention was observed even in the absence of discernible procedural complications and was more common in patients with diffuse atherosclerosis. In-hospital clinical events requiring prolonged monitoring were higher in >5x CK-MB-elevation patients only. Midterm survival of CK-MB-elevation patients was similar to those with normal CK-MB. Our prospective analysis shows a lack of adverse in-hospital cardiac events and suggests that early discharge of stable 1-5x normal CK-MB-elevation patients after successful coronary intervention is safe.

Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease.

High levels of fetal hemoglobin (Hb F) protect from many of the complications of sickle cell disease and lead to improved survival. Butyrate and other short chain fatty acids were previously shown to increase Hb F production in erythroid cells in vitro and in animal models in vivo. However, butyrates are also known to inhibit the proliferation of many cell types, including erythroid cells. Experience with the use of butyrate in animal models and in early clinical trials demonstrated that the Hb F response may be lost after prolonged administration of high doses of butyrate. We hypothesized that this loss of response may be a result of the antiproliferative effects of butyrate. We designed a regimen consisting of intermittent or pulse therapy in which butyrate was administered for 4 days followed by 10 to 24 days with no drug exposure. This pulse regimen induced fetal globin gene expression in 9 of 11 patients. The mean Hb F in this group increased from 7.2% to 21.0% (P <.002) after intermittent butyrate therapy for a mean duration of 29.9 weeks. This was associated with a parallel increase in the number of F cells and F reticulocytes. The total hemoglobin levels also increased from a mean of 7.8 g/dL to a mean of 8.8 g/dL (P <.006). The increased levels of Hb F were sustained in all responders, including 1 patient who has been on pulse butyrate therapy for more than 28 months. This regimen, which resulted in a marked and sustained increase in Hb F levels in more than two thirds of the adult sickle cell patients enrolled in this study, was well tolerated without adverse side effects. These encouraging results require confirmation along with an appropriate evaluation of clinical outcomes in a larger number of patients with sickle cell disease.

Quality assurance in molecular genetic testing laboratories.

CONTEXT: Specific regulation of laboratories performing molecular genetic tests may be needed to ensure standards and quality assurance (QA) and safeguard patient rights to informed consent and confidentiality. However, comprehensive analysis of current practices of such laboratories, important for assessing the need for regulation and its impact on access to testing, has not been conducted. OBJECTIVE: To collect and analyze data regarding availability of clinical molecular genetic testing, including personnel standards and laboratory practices. DESIGN: A mail survey in June 1997 of molecular genetic testing laboratory directors and assignment of a QA score based on responses to genetic testing process items. SETTING: Hospital-based, independent, and research-based molecular genetic testing laboratories in the United States. PARTICIPANTS: Directors of molecular genetic testing laboratories (n = 245; response rate, 74.9%). MAIN OUTCOME MEASURE: Laboratory process QA score, using the American College of Medical Genetics Laboratory Practice Committee standards. RESULTS: The 245 responding laboratories reported availability of testing for 94 disorders. Personnel qualifications varied, although all directors had doctoral degrees. The mean QAscore was 90% (range, 44%-100%) with 36 laboratories (15%) scoring lower than 70%. Higher scores were associated with test menu size of more than 4 tests (P = .01), performance of more than 30 analyses annually (P = .01), director having a PhD vs MD degree (P = .002), director board certification (P = .03), independent (P <.001) and hospital (P = .01) laboratories vs research laboratory, participation in proficiency testing (P<.001), and Clinical Laboratory Improvement Amendment certification (P = .006). Seventy percent of laboratories provided access to genetic counseling, 69% had a confidentiality policy, and 45% required informed consent prior to testing. CONCLUSION: The finding that a number of laboratories had QA scores that may reflect suboptimal laboratory practices suggests that both personnel qualification and laboratory practice standards are most in need of improvement to ensure quality in clinical molecular genetic testing laboratories.

Assessing life expectancies of older nursing home residents.

OBJECTIVE: Care of nursing home (NH) residents is often based on the usual survival of the home's residents. In order to improve our understanding of this population, and, thus, ultimately facilitate individualization of their care, we developed a mathematical model that predicts their survival. SETTING: The Jewish Home and Hospital (JHH), a nursing home. PARTICIPANTS: 1145 older residents who were at the JHH from January 1, 1986, through July 1, 1986. MEASUREMENTS: Information abstracted from medical records and JHH computerized data: clinical, demographic, and dependencies in activities of daily living (ADLs). MAIN OUTCOME MEASURE: survival from July 1, 1986. DESIGN: Retrospective cohort study via medical chart review. The study period covered admission to JHH through January 17, 1996. Accelerated failure time (AFT) models generated the life expectancy model derived from 50% of the study group and were validated on the remaining sample. We computed predicted AFT and proportional hazards (PH) life expectancies. RESULTS: Significant, independent predictors of decreased survival were male gender, increased age, increase in summary ADL index, and impairment of cardiac, respiratory, neurological, and endocrine/metabolic systems. The interaction between gender and respiratory system impairment was significant. The Spearman correlation coefficients between the observed survivals and those predicted by the Phase I model are 0.49 for Phase I residents and 0.42 for Phase II residents. Our sample life table includes NH residents with different risk profiles and their associated survival estimates as well as interquartile ranges. AFT and PH survivals were similar. CONCLUSION: This first comprehensive model that predicts survival of NH residents can help formulate public health policies and identify appropriate NH residents for clinical trials. The model is a promising step toward improving the health care of NH residents.

Effect of tamoxifen on bone fractures in older nursing home residents.

OBJECTIVES: To evaluate the association between tamoxifen (TAM) treatment and rate of bone fractures in older, nursing home residents. PARTICIPANTS: A total of 93,031 women, aged 65 years and older, whose data were part of the 1993 New York State MDS and for whom there was documentation of treatment with at least one medication. SETTING: New York State long-term care facilities. DESIGN: Cross-sectional study via secondary analysis of 1385 matched sets of residents. Each set included one resident who was receiving TAM treatment and up to four residents who were not. MEASUREMENTS: Measurements included age, ethnicity, TAM treatment, hormone replacement therapy, vision impairment, any bone fractures, and, specifically, hip fractures. RESULTS: During the 1.5-year period for which bone fractures are documented in the 1993 MDS, the fracture rates were: 7.62% in women not treated with TAM, 3.20% in women receiving 10 mg TAM daily, and 6.73% in women receiving 20 mg TAM daily. The odds ratio (OR) for bone fractures among women receiving 20 mg TAM daily compared with nontreated women was 0.916 (95% confidence interval (CI): 0.720-1.164; P = .472), and was 0.312 (95% CI: 0.112-0.865; P = .025) for those receiving 10 mg daily. The rates of hip fracture were 4.98%, 2.40%, and 4.57% for controls and women receiving 10 mg and 20 mg TAM daily, respectively. Whereas the hip fracture rate for women receiving 20 mg daily was statistically similar to that of the controls (OR = .963; 95% CI: 0.718-1.291; P = .800), the difference between the controls and those receiving 10 mg daily approached significance (OR: 0.313; 95% CI: 0.096-1.018; P = .054). CONCLUSION: Although standard treatment of 20 mg TAM daily offers no apparent protection against bone fracture in older nursing home residents, a daily 10 mg dose seems to be protective.

Logistic regression model for analyzing extended haplotype data.

Recently, there has been increased interest in evaluating extended haplotypes in p53 as risk factors for cancer. An allele-specific polymerase chain reaction (PCR) method, confirmed by restriction analysis, has been used to determine absolute extended haplotypes in diploid genomes. We describe statistical analyses for comparing cases and controls, or comparing different ethnic groups with respect to haplotypes composed of several biallelic loci, especially in the presence of other covariates. Tests based on cross-tabulating all possible genotypes by disease state can have limited power due to the large number of possible genotypes. Tests based simply on cross-tabulating all possible haplotypes by disease state cannot be extended to account for other variables measured on the individual. We propose imposing an assumption of additivity upon the haplotype-based analysis. This yields a logistic regression in which the outcome is case or control, and the predictor variables include the number of copies (0, 1, or 2) of each haplotype, as well as other explanatory variables. In a case-control study, the model can be constructed so that each coefficient gives the log odds ratio for disease for an individual with a single copy of the suspect haplotype and another copy of the most common haplotype, relative to an individual with two copies of the most common haplotype. We illustrate the method with published data on p53 and breast cancer. The method can also be applied to any polymorphic system, whether multiple alleles at a single locus or multiple haplotypes over several loci.

A national survey of physician-assisted suicide and euthanasia in the United States.

BACKGROUND: Although there have been many studies of physician-assisted suicide and euthanasia in the United States, national data are lacking. METHODS: In 1996, we mailed questionnaires to a stratified probability sample of 3102 physicians in the 10 specialties in which doctors are most likely to receive requests from patients for assistance with suicide or euthanasia. We weighted the results to obtain nationally representative data. RESULTS: We received 1902 completed questionnaires (response rate, 61 percent). Eleven percent of the physicians said that under current legal constraints, there were circumstances in which they would be willing to hasten a patient's death by prescribing medication, and 7 percent said that they would provide a lethal injection; 36 percent and 24 percent, respectively, said that they would do so if it were legal. Since entering practice, 18.3 percent of the physicians (unweighted number, 320) reported having received a request from a patient for assistance with suicide and 11.1 percent (unweighted number, 196) had received a request for a lethal injection. Sixteen percent of the physicians receiving such requests (unweighted number, 42), or 3.3 percent of the entire sample, reported that they had written at least one prescription to be used to hasten death, and 4.7 percent (unweighted number, 59), said that they had administered at least one lethal injection. CONCLUSIONS: A substantial proportion of physicians in the United States report that they receive requests for physician-assisted suicide and euthanasia, and about 7 percent of those who responded to our survey have complied with such requests at least once.

Higher incidence of diabetes in liver transplant recipients with hepatitis C.

We assessed the clinical and biochemical parameters associated with the development of posttransplantation diabetes (PTDM) in 52 liver transplant recipients followed up for 1 year. Diabetes was present before transplantation in 9.6% (5 of 52) of patients, and PTDM occurred in 23% (11 of 47) of the remaining liver transplant recipients. Of the 13 patients who had hepatitis C as the cause of their liver failure (HC-LD), 8 (62%) developed PTDM; of the 34 patients with other causes of liver failure, 3 (9%) developed PTDM (p < 0.001). Posttransplantation diabetes was also associated with the development of early posttransplantation hyperglycemia, a higher number of liver rejection episodes, and lower serum albumin levels at 6 months. The association of PTDM with HC-LD remained significant in a logistic regression model after adjustment for potential confounding variables. We conclude that PTDM is common in liver transplant recipients. Associated clinical parameters predictive of PTDM include a diagnosis of HC-LD before transplantation, the development of early hyperglycemia after transplantation, multiple episodes of posttransplantation liver rejection and low serum albumin levels at 6 months. The fact that HC-LD remained an independent risk factor for the development of PTDM may suggest a direct or immune-mediated pancreatic effect of the virus.

Severity adjustment for length of stay: is it always necessary?

OBJECTIVE: Severity adjustment is an oft-cited requirement when comparing physicians or medical delivery systems. Each application of severity adjustment, however, has to be tested to validate the need, the method, and its value. We examined the value of severity adjustment for identifying physician outliers when studying length of stay in the hospital. DESIGN: We compared the placement of physicians in an outlier category using a severity-adjusted average length of stay (SLOS) index with their placement using the unadjusted average length of stay (ALOS). Changes in placement of the list were validated by the utilization review coordinators. SETTING: A 614-bed tertiary-care university teaching hospital. SUBJECTS: We analyzed 11,146 discharges from 138 physicians in 1992. RESULTS: The mean ALOS +/- standard deviation was 9.05 + 4.50 days, and the SLOS Index was 7.56 +/- 3.06. There were 120 inliers, 6 high outliers, and 12 low outliers by the ALOS method. Using the SLOS index, 27 of 138 physicians had their categories changed from inlier to outlier or from outlier to inlier. The difference in group changes was more significant for those going from outlier to inlier status (8/120 vs 6/18; P < .001). The patients of the six physicians whose status changed from outlier to inlier status were sicker, as indicated by the comorbidity, complications, and manifestations of disease processes score. The utilization reviewers validated the status changes in 8 of 14 instances. CONCLUSIONS: Severity-adjusted length of stay by the SLOS index appears to provide a more accurate measure than the unadjusted ALOS. The changes, however, were small. It is not clear that the added effort is worthwhile.

Weighted logrank tests to detect a transient improvement in survivorship.

In investigating whether an intervention has an effect on survival, we exploit the flexibility of weighted logrank tests for constructing optimal tests sensitive to specified patterns of changes in the ratios or differences of the hazards as a function of time. The tests presented seem appropriate if either the intervention on trial imposes changes in life style, such as a diet modification or an exercise regimen, or if the effect of therapy itself is limited in duration, such as in the case of drugs for AIDS that may induce drug resistant viruses. For such problems, we postulate no difference between the hazards of the two groups initially, increased discrepancies as time goes on, and an eventual leveling-off of the discrepancies in hazards perhaps due to compliance problems or to adoption of the behavior change under study by individuals in the control group. We suggest a quadratic weight function for such problems and show how to evaluate the power of the proposed tests as well as their efficiency relative to other logrank tests. Other uses of quadratic weight functions, for example for evaluating effects with lag times, and for some parametric procedures are also described. Additive and multiplicative models are presented and both discrete and continuous times are considered.

A non-iterative accurate asymptotic confidence interval for the difference between two proportions.

I propose a new confidence interval for the difference between two binomial probabilities that requires only the solution of a quadratic equation. The procedure is based one estimating the variance of the observed difference at the boundaries of the confidence interval, and uses least squares estimation rather than maximum likelihood as previously suggested. The proposed procedure is non-iterative, agrees with the conventional test of equality of two binomial probabilities, and, even for fairly small sample sizes, appears to yields actual 95 per cent confidence intervals with mean or median probabilities of coverage very close to 0.95. The Yates continuity correction appears to generate confidence intervals with the conditional probability of coverage at least equal to nominal levels.

Correlation of angiographic morphology and clinical presentation in unstable angina.

OBJECTIVES: This study sought to correlate angiographically detected complex lesions and intracoronary thrombus with the severity of clinical presentation in unstable angina (UA). BACKGROUND: Unstable angina is usually related to acute thrombosis superimposed on a disrupted plaque. Complex and thrombotic lesions are more prevalent in UA and have been associated with a worse prognosis. The highest levels of the Braunwald classification of UA (III = rest angina within 48 h of presentation; C = postinfarction angina; and c = angina refractory to maximal medical therapy) can be used to assess the severity of clinical presentation, but they have not been directly correlated with thrombotic and complex lesions. METHODS: We conducted a prospective study of 284 patients with UA who underwent cardiac catheterization. A single angiographer with no knowledge of the clinical classifications interpreted all angiograms. Culprit lesions identified in 200 patients were classified as simple or complex. Complex lesions included the categories complex morphology, intracoronary thrombus (ICT) or total occlusion. Lesions were also quantitatively analyzed, and Thrombolysis in Myocardial Infarction (TIMI) flow was assessed. Univariate and multivariate logistic regression analyses of the angiographic findings were performed controlling for all cardiac risk factors, previous angioplasty or bypass surgery and multivessel disease, and we sequentially compared Braunwald classes III, C and c with classes < III, < C and < c, respectively. RESULTS: Class III was associated with complex lesions (p = 0.04) and decreased TIMI flow (p = 0.03). Class C angina correlated with complex lesions (p = 0.04), ICT (p = 0.005) and decreased TIMI flow (p = 0.03). Class c angina was associated with ICT (p = 0.02). The degree of stenosis by quantitative angiography was not associated with any particular Braunwald class. CONCLUSIONS: Recent rest pain and refractory or postinfarction UA, or both, are strongly associated with the general category of complex lesions and specifically with angiographically detected ICT and decreased TIMI flow.

p53 haplotype determination in breast cancer.

Inheritance of certain germ line haplotypes consisting of three biallelic polymorphisms of p53 has been proposed as a risk factor for breast cancer and colorectal cancer [A. Själander et al., Carcinogenesis (Lond.), 17: 1313-1316, 1996, and Carcinogenesis (Lond.), 16: 1461-1464, 1995]. In their studies, pairwise haplotypes of these three polymorphisms were estimated. Extended haplotypes were further projected from the pairwise combinations. To overcome the necessity to estimate pairwise and extended haplotype frequencies, a PCR method has been developed to determine the absolute extended p53 haplotypes in diploid genomes. The method requires allele-specific PCR, confirmed by restriction analysis, and successive amplicon analysis. It has been applied to a nested case-control study of breast cancer (284 subjects; 99 cases and 185 controls; 182 Caucasians, 56 Hispanics, and 46 African-Americans). Evidence is presented that minor variants of the intron 3, codon 72, and intron 6 polymorphisms were moderately elevated in Caucasian breast cancer cases (intron 3, P = 0.03 for genotype and P = 0.01 for allelic frequency; codon 72, P = 0.07 for genotype and P = 0.054 for allelic frequency; and intron 6, P = 0.02 for genotype and P = 0.02 for allele frequency). Accordingly, analysis of haplotype distributions suggested an association of minor p53 haplotypes with breast cancer risk in Caucasians (P = 0.07). The relative allelic frequencies in breast cancer cases compared with controls also differed by age and menopausal status; the 1-2-1 haplotype was overrepresented in postmenopausal cases (P = 0.02) and cases older than 50 years (P = 0.02), whereas the other minor haplotypes (1-1-2 and rare variants) were overrepresented in premenopausal cases (P = 0.003) and cases 50 years of age and younger (P = 0.02). Genotype distributions at each locus and for all control groups were consistent with Hardy-Weinberg equilibria. Differences in haplotype distribution were associated with ethnicity (Caucasians versus African-Americans and Caucasians versus Hispanics, P < 0.001). The new haplotyping method may be useful in the study of gene-environment interactions.

Comparison of ambulatory blood pressure and amounts of left ventricular hypertrophy in men versus women with similar levels of hypertensive clinic blood pressures.

The purpose of this study was to assess several indexes of cardiovascular risk in men and women with moderate to severe hypertension. We found that women with moderate and severe hypertension have lower ambulatory blood pressure and less cardiac hypertrophy than men with similar clinic blood pressure.