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Unlabelled: The impact of calcium and vitamin D intake on bone density and one-year fracture risk was assessed in 76,507 postmenopausal Caucasian women. Adequate calcium with or without vitamin D significantly reduced the odds of osteoporosis but not the risk of fracture in these Caucasian women., Introduction: Calcium and vitamin D intake may be important for bone health; however, studies have produced mixed results., Methods: The impact of calcium and vitamin D intake on bone mineral density (BMD) and one-year fracture incidence was assessed in 76,507 postmenopausal Caucasian women who completed a dietary questionnaire that included childhood, adult, and current consumption of dairy products. Current vitamin D intake was calculated from milk, fish, supplements and sunlight exposure. BMD was measured at the forearm, finger or heel. Approximately 3 years later, 36,209 participants returned a questionnaire about new fractures. The impact of calcium and vitamin D on risk of osteoporosis and fracture was evaluated by logistic regression adjusted for multiple covariates., Results: Higher lifetime calcium intake was associated with reduced odds of osteoporosis (peripheral BMD T-score < or =-2.5; OR = 0.80; 95% CI 0.72, 0.88), as was a higher current calcium (OR = 0.75; (0.68, 0.82)) or vitamin D intake (OR = 0.73; 95% CI 0.0.66, 0.81). Women reported 2,205 new osteoporosis-related fractures. The 3-year risk of any fracture combined or separately was not associated with intake of calcium or vitamin D., Conclusions: Thus, higher calcium and vitamin D intakes significantly reduced the odds of osteoporosis but not the 3-year risk of fracture in these Caucasian women.

Unlabelled: Women with osteoporosis on raloxifene were randomized to 1-34hPTH + raloxifene or raloxifene alone for one year. In the PTH + raloxifene group, bone turnover increased 125-584%, spine BMD increased 9.6%, hip BMD increased 1.2-3.6% and radius BMD declined 4.3%. During the follow-up year, on continued raloxifene, BMD declined slightly at all sites except the femoral neck., Introduction: The influence of prior antiresorptives on response to 1-34PTH and the ability to maintain BMD gains might differ for antiresorptive agents with different potencies. The objectives were to evaluate biochemical and bone density responses to 1-34PTH in patients on prior and ongoing raloxifene and to determine whether raloxifene maintains bone gains., Methods: Forty-two postmenopausal women with osteoporosis on raloxifene were randomized to raloxifene alone or 1-34PTH daily for 12 months (continuing raloxifene). Women were then followed for 12 months on raloxifene alone. Bone turnover markers and BMD were measured at baseline and at 3, 6, 12, 18 and 24 months., Results: Biochemical indices increased rapidly during PTH treatment with peak increments of 125-584% for the three markers (p<0.001 vs. baseline). After one year of PTH, mean BMD increases were 9.6% for spine, 2.7% for total hip, 3.6% for trochanter (all p<0.005) and 1.2% in femoral neck (NS), while BMD declined 4.3% in the radius (p=0.003). After PTH withdrawal, on continued raloxifene, BMD declined slightly (0.7-2.9% losses; NS) at all sites, except the femoral neck, where BMD increased modestly (p=0.04). At 24 months, spine and femoral neck BMD remained significantly higher than baseline, while radius BMD remained significantly lower (all p<0.04)., Conclusion: Substantial gains in BMD of the spine and hip, but not the radius, are seen with one year of PTH treatment in patients on prior raloxifene. After PTH is discontinued, raloxifene partially maintains PTH-induced BMD gains in the spine and hip.

The determinants of bone mineral density (BMD) at multiple sites were examined in a fit college population. Subjects were 755 males (mean age = 18.7 years) entering the United States Military Academy. A questionnaire assessed exercise frequency and milk, caffeine, and alcohol consumption and tobacco use. Academy staff measured height, weight, and fitness. Calcaneal BMD was measured by peripheral dual-energy x-ray absorptiometry (pDXA). Peripheral-quantitative computed tomography (pQCT) was used to measure tibial mineral content, circumference and cortical thickness. Spine and hip BMD were measured by DXA in a subset (n = 159). Mean BMD at all sites was approximately one standard deviation above young normal (p < 0.05). African Americans had significantly higher hip, spine and heel BMD and greater tibial mineral content and cortical thickness than Caucasians and Asians. In Caucasians (n = 653), weight was a significant determinant of BMD at every skeletal site. Prior exercise levels and milk intake positively related to bone density and size, while caffeine had a negative impact. There was an apparent interaction between milk and exercise in BMD at the heel, spine, hip and tibial mineral content and cortical thickness. Our data confirm the importance of race, body size, milk intake and duration of weekly exercise as determinants of BMD and bone size.

Introduction: Estrogen therapy (ET), tamoxifen and raloxifene are associated with a two- to three-fold increased risk of venous thrombosis (VT); however, the mechanisms by which each drug increases venous thrombosis propensity are not fully understood. The objectives of this investigation were to compare the effects of these three treatments on hemostasis in a head to head randomized placebo-controlled trial., Patients/methods: Ninety-four postmenopausal women were assigned to receive oral estrogen (conjugated equine estrogen [CEE] 0.625 mg, n=23), tamoxifen 20 mg (n=24), raloxifene 60 mg (n=24) or placebo (n=23) daily for 6 months. Blood samples were analyzed for procoagulant factors (prothrombin, factors VII [fVII], VIII [fVIII], IX [fIX] and XI [fXI], D-dimer and von Willebrand factor [vWf]), anticoagulant factors (antithrombin [AT], total and free protein S, protein C and activated protein C [APC] resistance) and fibrinolytic factors (thrombin activatable fibrinolysis inhibitor [TAFI] and plasminogen activator inhibitor-1 [PAI-1]), at baseline and at 6 months of treatment., Results: Estrogen increased factor VII and D-dimer, and decreased antithrombin, total and free protein S and PAI-1. Changes with tamoxifen were distinct from estrogen with increases in factors VIII, IX, vWf and free protein S, and decreases in AT, total protein S, protein C and plasminogen activator inhibitor-1. Raloxifene produced similar effects as tamoxifen, but did not increase factor IX or decrease protein C., Conclusions: Estrogen, tamoxifen and raloxifene affected hemostasis favoring procoagulation and impairing anticoagulation. The biochemical effects of the selective estrogen receptor modulators (SERMs) were distinct from those of estrogen and differed only subtly from each other.

We previously reported that the abl promoter (Pa) undergoes de novo DNA methylation in the course of chronic myelocytic leukemia (CML). The clinical implications of this finding are the subject of the present study in which samples of CML patients, including a group treated with interferon alpha (IFNalpha) were surveyed. The methylation status of the abl promoter was monitored by polymerase chain reaction (PCR) amplification of the Pa region after digestion with several site-methylation sensitive restriction enzymes. Some 74% of the DNA samples from blood and marrow drawn in the chronic phase were nonmethylated, similar to control samples from non-CML patients. The remaining 26% were partially methylated in the abl Pa region. The latter samples were derived from patients who were indistinguishable from the others on the basis of clinical presentation. Methylated samples were mostly derived from patients known to have a disease of longer duration (26 months v 7.5 months, P = .01). Samples of 30 IFNalpha-treated patients were sequentially analyzed in the course of treatment. Fifteen patients with no evidence of Pa methylation before treatment remained methylation-free. The remainder, who displayed Pa methylation before treatment, reverted to the methylation-free status. The outcome is attributed to IFNalpha therapy, as the Pa methylation status was not reversed in any of the patients treated with hydroxyurea. Methylation of the abl promoter indicates a disease of long-standing, most likely associated with a higher probability of imminent blastic transformation. It appears to predict the outcome of IFNalpha therapy far better than the cytogenetic response.

Unlabelled: OBJECTIVE, DESIGN AND PATIENTS: Between August 1981 and July 1983, 5839 consecutive myocardial infarction patients were hospitalized in 13 coronary care units in Israel. The present study examines 10 year survival among 4037 consecutive patients with a first myocardial infarction with either Q or non-Q waves. Demographic and medical data were collected from hospital records, and 1 year clinical follow-up was complete for 99% of hospital survivors. Mortality follow-up was extended to June 1992 (mean 10 years of follow-up)., Results: Five hundred and eighty patients (14%) had first myocardial infarctions of the non-Q wave type and 3457 of the Q wave type. Hospital mortality was significantly higher in patients with a Q wave (10%) than those with a non-Q wave myocardial infarction (7%) (P < 0.05). One year post-discharge, non-fatal reinfarction and mortality rates were comparable in patients with Q wave (4% and 7%) and non-Q wave myocardial infarctions (4% and 7% respectively). Similarly, 5 to 10 year post-discharge mortality rates were equally high in patients with a non-Q wave (26% and 44%) as in those with a first episode of a Q wave myocardial infarction (22% and 40% respectively)., Conclusions: Patients with a first non-Q wave acute myocardial infarction exhibited relatively better in-hospital survival than counterparts with a first Q wave infarction, but the advantage did not persist after discharge. Patients with a non-Q wave infarction deserve particular attention as their post-discharge mortality risk is similar to counterparts with a first Q wave myocardial infarction.

The purpose of this study was to assess the predictive value of admission heart rate (HR) for in-hospital and 1 year post-discharge mortality in a large cohort of patients hospitalized for acute myocardial infarction (MI). Data were derived from the SPRINT-2 secondary prevention study population, and included 1044 patients (aged 50-79), hospitalized in 14 coronary care units in Israel with acute MI in the years 1985-1986, before the beginning of thrombolytic therapy in acute MI. Demographic, historical and medical data were collected for each patient. All deaths during initial hospitalization and 1 year post-discharge were recorded. In-hospital mortality was 5.2% for 294 patients with HR < 70 beats/min, 9.5% for 532 patients with HR 70-89 beats/min, and 15.1% for 323 patients with HR > or = 90 beats/min (p < 0.01). One year post-discharge mortality was 4.3% for patients with HR < 70 beats/min, 8.7% for patients with HR 70-80 beats/min and 11.8% for patients with HR > or = 90 beats/min (p < 0.01). An increasing trend of mortality with higher HR was confined to patients with mild CHF (p = 0.02) and likely to patients with absent CHF (p = 0.06), but this post hoc observation requires confirmation in larger groups. The combination of high admission HR (> or = 90 beats/min) and a systolic blood pressure < 120 mmHg was a powerful predictor of in-hospital mortality. Multivariate analysis showed that admission HR was an independent risk factor for in-hospital and 1 year post-discharge mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

A prognostic index based on admission characteristics of patients with inferior acute myocardial infarction was developed to predict mortality and other major complications during hospitalization. The study sample included 1841 consecutive patients with a first inferior wall acute myocardial infarction, hospitalized in 13 out of 21 operating coronary care units in Israel. Age, angina in the past, congestive heart failure and blood glucose level > 180 mg/dl were independently associated with higher in-hospital mortality and morbidity. The prognostic weights of these risk factors were determined in a study group which comprised two thirds of the patients (n = 1210) who were randomly selected from the 1841 participants. A prognostic score (range, 0-15) was calculated as the sum of the prognostic weights of the above four risk factors for each patient. These scores were determined in both the study group and in a validation group (the remaining one third of the patients, n = 592). In-hospital mortality in the study group ranged from no death for 102 patients with a prognostic score of 0, to a 37% mortality rate in 106 patients whose prognostic score was > 8. Accordingly, the study group was divided into groups of low-risk (score 0-5), intermediate-risk (score 6-8) and high-risk (score > 8), with in-hospital mortality of 3, 13 and 37%, respectively. In-hospital mortality among patients in the validation group determined to be at low-, intermediate- and high-risk was 3, 13 and 44%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

De novo methylation of CpG islands is a rare event in mammalian cells. It has been observed in the course of developmental processes, such as X chromosome inactivation and genomic imprinting. The methylation of DNA, an important factor in the epigenetic control of gene expression, may also be involved in tumorigenesis. After the t(9;22) chromosomal translocation and generation of the Philadelphia chromosome, the initiating event in chronic myelogenous leukemia (CML), most of the abl coding sequence is fused to the 5' region of the bcr gene. Expression of the hybrid bcr-abl gene is, therefore, regulated by the bcr promoter. In most cases of CML, one of the two abl promoters (Pa) is nested within the bcr-abl transcriptional unit and should be able to transcribe the type Ia 6-kb normal abl mRNA from the Philadelphia chromosome. However, we have found that the 6-kb transcript is present only in CML cell lines containing a normal abl allele and that the apparent inactivation of the nested Pa promoter is associated with allele-specific methylation. Furthermore, we have noticed that the Pa promoter is contained within a CpG island and undergoes progressive de novo methylation in the course of the disease. This is attested to by the fact that DNA samples from CML patients that are methylation-free at the time of diagnosis invariably become methylated in advanced CML. Since tumor progression in CML cannot always be inferred from the clinical presentation, assessment of de novo CpG methylation may prove to be of critical value in management of the disease. It could herald blastic transformation at a stage when bone marrow transplantation, the only potentially curative therapeutic procedure in CML, is still effective.

A unique patient with a painful transient erythematous blotchy eruption of the face, neck, and upper trunk is described. Administration of oral diclofenac sodium resulted in prompt control of the condition. The possible relationship of this syndrome with erythermalgia is reviewed.

Earlier studies have suggested that patients exhibiting late (> 24 h) ventricular fibrillation during acute myocardial infarction had a poorer outcome in comparison to myocardial infarction patients with early (< 24 h) ventricular fibrillation. Between August 1981 and July 1983, 5839 consecutive patients with acute myocardial infarction were hospitalized in 13 out of 21 operating coronary care units in Israel. Demographic and medical data were collected from hospitalization charts and during 1 year of follow-up. Mortality assessment was done for 99% of hospital survivors up to mid-1988 (mean, 5.5 years). The incidence of ventricular fibrillation in the SPRINT Registry was 6% (371/5839). Patients with ventricular fibrillation in the setting of cardiogenic shock (n = 107) were excluded from analysis. Patients with late ventricular fibrillation (n = 109; 41%) were older and had a more complicated hospital course than patients with early ventricular fibrillation (n = 155; 59%). In-hospital and 1-year post-discharge mortality were significantly higher in patients with late ventricular fibrillation (63% and 17%) as compared to patients with early ventricular fibrillation (26% and 4%, respectively; P < 0.05 for each). This difference vanished 5 years after hospital discharge. After multiple logistic regression analysis late occurrence of ventricular fibrillation emerged as an independent predictor of increased in-hospital mortality (Odds ratio, 4.29; 95% confidence interval, 2.11-8.74) but not for subsequent death. Patients with late ventricular fibrillation during the hospital course of acute myocardial infarction had a poorer immediate and subsequent outcome in comparison to patients with early ventricular fibrillation.

Purpose: The aim of the study was to assess the prevalence and the prognostic impact of concomitant peripheral vascular disease (PVD) in patients developing acute myocardial infarction (AMI)., Patients and Methods: Four thousand two hundred fifty-eight consecutive patients with a first AMI hospitalized in 13 of 21 operating coronary care units in Israel were screened. Anamnestic, demographic, and medical data were collected from hospitalization charts, and all patients were followed clinically 1 year after discharge and up to 7 years (mean: 5.5 years) for mortality., Results: The prevalence of clinically diagnosed PVD in patients with a first AMI was 6.3% (269 of 4,258), with no difference between men and women. Patients with PVD were older (66.2 years) and included more hypertensive subjects (47.2%), diabetic persons (26.4%), and individuals with a previous history of cerebrovascular accident (CVA) (11.5%) in comparison to counterparts without PVD (61.7 years; 39.4%, 19.9%, and 3.3%, respectively; p < 0.01 for each). On admission to the coronary care units, 36.5% of patients with PVD were in Killip class II, III, or IV versus only 18.0% in the reference group (p < 0.001). During hospitalization, patients with PVD exhibited a significantly higher rate of paroxysmal atrial fibrillation (17.5%), advanced atrioventricular block (15.2%), and cardiogenic shock (11.9%) in comparison to patients without PVD (11.9%, 10.2%, and 5.3%, respectively; p < 0.01 for each). After adjustment for age, gender, hypertension, history of angina, diabetes mellitus, history of CVA, site of infarction, and congestive heart failure on admission, the odds ratio for in-hospital mortality associated with PVD was 1.37 (90% confidence interval 1.01 to 1.83). There was no independent contribution of PVD to long-term (mean: 5.5 years) postdischarge mortality; the odds ratio was 1.02., Conclusion: PVD in patients with a first AMI independently increases the risk of in-hospital death but does not affect long-term mortality in survivors.

Of 3,981 patients with a first Q-wave acute myocardial infarction (AMI), 1,929 (48%) had an anterior and 1,724 (43%) an inferior wall AMI. These 2 groups were well-matched with respect to age, gender and relevant history. The in-hospital mortality rate was 18%, and the 1- and 5-year post-discharge mortality rates were 9 and 25%, respectively, in patients with anterior wall AMI compared with the corresponding rates of 11, 6 and 19% in those with inferior wall AMI (p < 0.0001 for each category). The frequency of recurrent nonfatal AMI in the year after the index AMI was 8% in the patients with anterior wall AMI compared with 4% in those with inferior wall AMI (p < 0.0001). By multiple logistic regression analysis of events, anterior wall AMI was an independent predictor of in-hospital mortality only. The findings indicate that the anatomic location of a Q-wave AMI influences immediate and short-term survival of patients with a first Q-wave AMI.

This study was undertaken to examine whether clinical factors predict reinfarction within 1 year of a first acute myocardial infarction (AMI) and to quantify the subsequent influence of reinfarction on long-term mortality. Data from 3,695 patients with a first AMI included in the Secondary Prevention Reinfarction Israeli Nifedipine Trial Registry were analyzed. The 1-year reinfarction incidence was 6.0% (220 of 3,695) and in-hospital mortality during reinfarction was 31%. Patients with reinfarction were older (63.0 vs 60.8 years) at entry. The independent clinical predictors for 1-year reinfarction were (adjusted relative odds): peripheral vascular disease (2.12), anterior location of the first AMI (1.62), angina before the first AMI (1.53), congestive heart failure on admission (1.34), diabetes (1.33), systemic hypertension (1.28) and age increment (1.13). One-year reinfarction rate increased from 4.0% in patients with 0 or 1 risk factor to 23.3% in patients with 5 to 6 risk factors (p < 0.0001). Patients with reinfarction had significantly increased 1- and 5-year mortality compared with those who had no reinfarction (11.8 vs 5.3% and 40.1 vs 20.3%, respectively, p < 0.001). Recurrent AMI within 1 year was the most powerful predictor of long-term (mean 5.5 years) total mortality (adjusted relative risk = 4.76).