Angiogenic effects of low molecular weight heparin in patients with stable coronary artery disease: a pilot study.

OBJECTIVES: The study was designed to assess the feasibility of conducting a trial to investigate whether exercise and low molecular weight heparin therapy with dalteparin sodium (Fragmin) would improve collateral function to the ischemic myocardium in patients with coronary artery disease. BACKGROUND: The severity of myocardial ischemia in patients with coronary artery disease is at least partly dependent on the status of the collateral circulation. Therefore, improvement in collateral function would potentially provide a unique way of alleviating myocardial ischemia. Because the combination of ischemia and heparin has previously been demonstrated to enhance collateral growth, we studied the anti-ischemic effects of combined treatment with dalteparin sodium and exercise-induced ischemia in patients with coronary artery disease. METHODS: Twenty-three patients with stable coronary artery disease were randomized to receive either subcutaneous dalteparin sodium or placebo for a 4-week period. Patients received either placebo or 10,000 IU of dalteparin sodium by subcutaneous injection once daily for weeks 1 and 2 and 5,000 IU daily for weeks 3 and 4. During the 1st 2 weeks, patients were exercised to ischemia three times a day. At baseline and 4 weeks after treatment, treadmill exercise testing, exercise radionuclide ventriculography and 48-h ambulatory ST segment monitoring were performed. RESULTS: Eight (80%) of the 10 dalteparin sodium-treated patients compared with 4 (31%) of 13 placebo-treated patients (p < 0.02) had an increased rate-pressure product at the onset of 1 mm of ST segment depression. The duration of exercise to ischemia increased in all patients treated with low molecular weight heparin and in 62% of placebo-treated patients (p < 0.03). The number and duration of episodes of ST segment depression during ambulatory monitoring decreased by 30% and 35%, respectively (p < 0.05), in the dalteparin sodium group but were unchanged in the placebo group. The decrease in left ventricular ejection fraction with exercise was lower in 80% of dalteparin sodium-treated patients compared with 54% of placebo-treated patients (p = 0.06). When all five factors reflecting collateral function were considered together in a multivariate analysis of variance, there was a significant improvement in low molecular weight heparin-treated patients compared with placebo-treated patients (p = 0.014). CONCLUSIONS: This study provides preliminary evidence suggesting that exercise and low molecular weight heparin therapy with dalteparin sodium lessen myocardial ischemia and that the improvement is likely to be mediated by enhanced collateral function.

Three year anatomic, functional and clinical follow-up after successful percutaneous transluminal coronary angioplasty.

Because the long-term anatomic effects of percutaneous transluminal coronary angioplasty are unknown, follow-up evaluations including coronary angiography, treadmill exercise testing and rest and bicycle exercise radionuclide angiography were performed in 46 patients 6.3 +/- 2.0 and 37.6 +/- 3.6 (mean +/- SD) months after they had undergone successful single lesion angioplasty. The severity of the coronary stenosis decreased significantly at each evaluation; the mean diameter stenosis was 66 +/- 13% before angioplasty, 30 +/- 13% immediately after and 26 +/- 16% and 19 +/- 13% at 6 months and 3 years, respectively. Exercise time increased from 9.8 +/- 4.4 minutes before angioplasty to 18.3 +/- 4.5 minutes immediately after the procedure and remained at that level at 6 months (20.3 +/- 4.6 minutes) and 3 years (18.2 +/- 4.5 minutes). Left ventricular ejection fraction during exercise decreased 4 +/- 6% compared with rest before angioplasty, but increased 7 +/- 7% immediately after angioplasty and this increase was maintained at 6 months (+/- 6 +/- 7%) and 3 years (+/- 4 +/- 6%). Before angioplasty, 1 patient was in Canadian Heart Association functional class 0, 15 were in class II, 24 in class III and 6 in class IV. Three years later, 25 were in class 0, 10 in class I, 7 in class II and 4 in class III. These results indicate that the short-term anatomic and functional success of coronary angioplasty is maintained for at least 3 years.

Detection in human serum by radioimmunoassay of histidyl-proline diketopiperazine, a metabolite of thyrotropin-releasing hormone.

Cyclo(His-Pro) is believed to be a metabolite of TRH. A specific antiserum directed against cyclo(His-Pro) was used to detect immunoreactive material in human serum. Gel filtration column chromatography was used to establish that cyclo(His-Pro)-like immunoreactivity was found not only in free form established to be identical to cyclo(His-Pro) by high pressure liquid chromatography analysis on reverse phase and cation exchange columns, but also in a fraction of about 100,000 mol wt. Free cyclo(His-Pro) was released by heating column fractions of 70,000 mol wt that were not immunoreactive before heating. A procedure for estimation of the content of free cyclo(His-Pro) in human serum was developed. Normal levels of cyclo(His-Pro) determined by this procedure were in the range of 11-33 pmol/ml. The level of cyclo(His-Pro) in sera of individuals with hypothyroidism, hyperthyroidism, or alcoholic cirrhosis was in the normal range, while patients with renal failure had approximately 3-fold elevated levels of the peptide. Analysis of human sera drawn at 3-h intervals over a 24-h period suggested a circadian rhythm of cyclo(His-Pro) levels.

Energy intake and physical activity in relation to indexes of body fat: the National Heart, Lung, and Blood Institute Growth and Health Study.

The relationship between energy intake, physical activity, and body fat was investigated in the baseline visit of 2379 black and white girls aged 9-10 y enrolled in the National Heart, Lung, and Blood Institute Growth and Health Study. Three-day food records, three-day physical activity diaries, physical-activity-patterns questionnaires, and an assessment of the number of hours of television and video watched were obtained. Multivariate-regression analyses showed that age, the number of hours of television and video watched, the percent of energy from saturated fatty acids, and the activity-patterns score best explained the variation in body mass index and sum of three skin-fold-thickness measurements for black girls. The best model for white girls included age, the number of hours of television and video watched, and the percent of energy from total fat. These results indicate that body fatness is related to energy intake and expenditure in both black and white girls. Longitudinal studies will help assess the value of these variables in predicting changes in body fat.

A familial basis for the heterogeneity in coronary atherosclerotic disease.

Miniature swine fed a high-cholesterol, high-fat diet demonstrated heterogeneity in the extent of coronary artery disease. Plasma cholesterol or lipoprotein concentrations as well as other known risk factors accounted for little of this heterogeneity. However, the majority of the variability could be accounted for by the familial predisposition to develop cardiovascular disease in the individual animal kindreds. This study strongly suggests that the enhanced rate of development of coronary atherosclerotic disease during hypercholesterolemia is more critically modulated by previously unrecognized genetic actors than by absolute plasma cholesterol concentrations.

Degree of left ventricular hypertrophy in patients with hypertrophic cardiomyopathy and chronic atrial fibrillation.

It has been generally assumed that most patients with hypertrophic cardiomyopathy (HC) who develop atrial fibrillation (AF) have marked left ventricular (LV) hypertrophy and subaortic obstruction. The morphologic and functional features of this subset of patients with HC have not been systematically investigated. The LV morphology and functional profile of 46 patients with HC and chronic AF were compared with those of 81 control patients with HC and normal sinus rhythm. Contrary to expectations, LV hypertrophy (assessed with 2-dimensional echocardiography) was substantially less marked in the patients with AF than in the control patients, and prevalence of subaortic obstruction was similar in the 2 groups. Maximal LV wall thickness and wall thickness index were lower in patients with AF (18 +/- 2 and 56 +/- 7 mm, respectively) than in control patients (22 +/- 6 and 67 +/- 16 mm, respectively; p less than 0.001). Furthermore, mild LV hypertrophy (maximal LV wall thickness less than or equal to 17 mm confined to 1 ventricular segment) was almost twice as frequent in patients with AF (63%) than in control patients (36%; p less than 0.005). Subaortic obstruction was present in 9 patients with AF (20%) and in 28 control patients (35%; p greater than 0.05). In a subgroup of 22 patients with AF who were followed for 4 to 10 years, 5 patients had marked LV wall thinning (greater than or equal to 5 mm, range 5 to 14). In conclusion, these results demonstrate that most patients with HC and chronic AF have the nonobstructive form of HC, and relatively mild LV hypertrophy.

Lack of blood pressure effect with calcium and magnesium supplementation in adults with high-normal blood pressure. Results from Phase I of the Trials of Hypertension Prevention (TOHP). Trials of Hypertension Prevention (TOHP) Collaborative Research Group.

Phase I of the Trials of Hypertension Prevention (TOHP) was a randomized, multicenter investigation that included double-blind, placebo-controlled testing of calcium and magnesium supplementation among 698 healthy adults (10.5% blacks and 31% women) aged 30 to 54 years with high-normal diastolic blood pressure (DBP) (80 to 89 mm Hg). Very high compliance (94 to 96% by pill counts) with daily doses of 1 g of calcium (carbonate), 360 mg of magnesium (diglycine), or placebos was corroborated for the active supplements by significant net increases in all urine and serum compliance measures in white men and for urine compliance measures in white women. Overall, neither calcium nor magnesium produced significant changes in blood pressure at 3 and 6 months. Analyses stratified by baseline intakes of calcium, magnesium, sodium, or initial blood pressures also showed no effect of supplementation. These analyses suggested that calcium supplementation may have resulted in a DBP decrease in white women and that response modifiers in this subgroup might have included lower initial urinary calcium levels, urinary sodium levels, or lower body mass index. However, overall analyses indicated that calcium and magnesium supplements are unlikely to lower blood pressure in adults with high-normal DBP. The subgroup analyses, useful to formulate hypotheses, raise the possibility of a benefit to white women, which requires testing in future trials.

The association of LDL receptor activity, LDL cholesterol level, and clinical course in homozygous familial hypercholesterolemia.

Patients with homozygous familial hypercholesterolemia (FH), reveal a marked heterogeneity in plasma cholesterol levels, response to diet as well as drug treatment, and clinical course. Low-density lipoprotein (LDL) receptor activities were assessed by the rate of 14C-oleate cholesteryl ester biosynthesis in fibroblasts from 13 FH homozygotes in tissue culture. The receptor activity of the individual patients was highly correlated with initial pretreatment plasma cholesterol and LDL cholesterol levels (P less than .001, r = -0.89). In addition, the LDL receptor activity was positively correlated with the age of onset of angina based on the Cox model (P less than .035, likelihood ratio = 6.71). An association was also noted between LDL receptor activity and cholesterol reduction with drugs. These data provide direct evidence for the correlation between the heterogeneity of the LDL receptor and the expression of the clinical manifestations of homozygous FH. The determination of pretreatment plasma cholesterol level and LDL receptor activity in patients with homozygous FH provide useful parameters on which to base predictions of the clinical progression of cardiovascular disease. These parameters may also influence the selection of a program for diet and drug therapy. Patients with markedly elevated plasma cholesterol levels and very low LDL receptor activity should be considered to be candidates for multiple drug therapy, and portacaval shunt, and/or periodic plasma exchanges.

Reducing the fat content of ground beef in a school foodservice setting.

OBJECTIVE: The objective was to develop and test the nutrient results of a two-step defatting procedure with ground beef in a school foodservice setting as part of the Eat Smart school lunch component of the Child and Adolescent Trial for Cardiovascular Health (CATCH). SETTING AND DESIGN: The procedure was tested in a school foodservice setting to determine the effect of cooking, draining, and subsequent rinsing with hot water on nutrient composition of ground beef. Samples of raw; cooked and drained; and cooked, drained, and rinsed ground beef were collected and chemically analyzed for total fat, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, cholesterol, iron, and niacin content. RESULTS: The results indicated that the total fat and the saturated, monounsaturated, and polyunsaturated fatty acids were significantly reduced 31% to 35% from cooking and draining (P < .005) and reduced by an additional 25% to 30% from rinsing (P < .0001). Cholesterol content was not affected. Iron content increased after the cooking and rinsing, although not significantly. Niacin content significantly decreased during rinsing by 28% (P < .005), but the mean value of the cooked, drained, and rinsed ground beef still met the criteria of the Food and Drug Administration for a good source of niacin. APPLICATION: The two-step defatting procedure developed for use in a school foodservice setting lowers the total fat and saturated fatty acid content of ground beef without substantially reducing its nutritional quality.

[A case of Lyme carditis]. / Lyme carditis esete.

The authors introduce their patient suffering from Lyme carditis. This causes III. degree AV block, then spontaneous remission, and complete recovery. Depending on the bases of other scientists' works they introduce their experiences in the clinic and therapy of the disease.

Sample size determination in clinical trials with time-dependent rates of losses and noncompliance.

Sample size determination is an important part of planning for clinical trials. During the course of a typical clinical trial, people are lost because of competing risks, noncompliance, and the like. Event rates available to the trial designers usually do not take these losses into consideration so that adjustment of these rates is necessary for sample size calculation. This article presents a method of adjusting such rates in the presence of time-dependent rates of losses, noncompliance, and the like. Lag in the effectiveness of medication is also considered.

Sample sizes based on the log-rank statistic in complex clinical trials.

The log-rank test is frequently used to compare survival curves. While sample size estimation for comparison of binomial proportions has been adapted to typical clinical trial conditions such as noncompliance, lag time, and staggered entry, the estimation of sample size when the log-rank statistic is to be used has not been generalized to these types of clinical trial conditions. This paper presents a method of estimating sample sizes for the comparison of survival curves by the log-rank statistic in the presence of unrestricted rates of noncompliance, lag time, and so forth. The method applies to stratified trials in which the above conditions may vary across the different strata, and does not assume proportional hazards. Power and duration, as well as sample sizes, can be estimated. The method also produces estimates for binomial proportions and the Tarone-Ware class of statistics.

Optimal surgery for papillary thyroid carcinoma.

There has been a long, unresolved debate regarding the operation of choice for well differentiated carcinoma of the thyroid. We therefore analyzed the feasibility, scope, sample size, and length of follow-up required to determine the optimal operation for papillary thyroid carcinoma. A statistical approach was used to design a randomized prospective trial comparing the endpoints of complications, recurrence, and cause-specific mortality. A complication comparison trial is prohibitive owing to the large population required--approximately 12,000 randomized patients. A recurrence trial appears feasible based on sample size: approximately 360 to 800 patients with a 6 to 10-year follow-up. However, recurrence detection would be severely compromised in the lobectomy arm, and a unilateral lag-time bias would occur. A cause-specific mortality trial proves to be the least objectionable, although a large sample size (n = 3100) would be required. Such a trial is critically dependent on the ability to select an appropriate endpoint. A cause-specific mortality trial proves to be the most objective and statistically valid endpoint.

A simple way to estimate the median time and compare survival distributions in analgesic trials under informative censoring.

We discuss the problem of estimating the median time and comparison of survival curves when data are nonrandomly censored in analgesic trials. In these trials patients experience post-surgical pain at the time of randomization. Time to onset of analgesia is measured by patient-administered stopwatches. An effective analgesic is one for which the median time to onset is "short." The study design allows patients to remedicate if their pain persists, and this remedication prior to pain relief censors the time-to-onset measures. The time to onset for patients who remedicate is nonrandomly censored. Assuming noninformative censoring yields misleading results with the Kaplan-Meier method (for estimation of median time) and the log-rank test (for comparison of survival curves). This assumption can also obscure the superior effect of an effective analgesic over an ineffective one. We propose a simple and intuitive way to handle the nonrandomly censored data in analgesic trials in order to (a) estimate the median time to pain relief and (b) compare the survival distributions between treatments. The method proposed is applied to data collected from an acute pain clinical trial, and the results are discussed.

Hypertension detection, treatment, and control in the United States: not as bad as it seems?

A 1982 report from the National Center for Health Statistics presents rates of awareness, treatment, and control among US adult hypertensives. These rates are age-adjusted by the direct method to permit comparisons among three surveys of US adults conducted over 20 years. The choice of a standard population for the age adjustment, however, results in a systematic decrease in the adjusted rates for awareness, treatment, and control. This decrease leads the casual reader of this often quoted report to conclude that awareness, treatment, and control of hypertension are worse than they actually are. An alternative choice for the standard population is suggested when the inference population is hypertensives rather than the general population.

Surrogate endpoints in clinical trials: cardiovascular diseases.

A surrogate endpoint in a cardiovascular clinical trial is defined as endpoint measured in lieu of some other so-called 'true' endpoint. A surrogate is especially useful if it is easily measured and highly correlated with the true endpoint. Often the 'true' endpoint is one with clinical importance to the patient, for example, mortality or a major clinical outcome, while a surrogate is one biologically closer to the process of disease, for example, ejection fraction. Use of the surrogate can often lead to dramatic reductions in sample size and much shorter studies than use of the true endpoint. We discuss several problems common in trials with surrogate endpoints. Most important is the effect of missing data, especially in the face of informative censoring. Possible solutions are the assignment of scores or formal penalties to missing data.

A comparison of sample size methods for the logrank statistic.

Several methods are available for sample size calculation for clinical trials when survival curves are to be compared using the logrank statistic. We discuss advantages and disadvantages of some of these methods, and present simulation results under exponential, proportional hazards and non-proportional hazard situations.

Selective removal of sickle cells with the IBM 2997 continuous flow blood cell separator.

Partial red cell exchange transfusion is used to manage several complications of sickle cell anemia. Reports have stressed the safety, ease, and speed of red cell exchange procedures performed with blood cell separators, but little information exists concerning operating conditions for the most efficient removal of hemoglobin S (HbS) containing cells. We performed 13 red blood cell exchange transfusions with the IBM 2997 continuous flow blood cell separator on two previously transfused adult homozygous (SS) sickle cell patients. We used both a single stage and a dual stage disposable pathway and varied rotor speed, collection port, and collection interface independently. The patients' baseline percentage HbS ranged from 28 to 64% (mean = 46%); post exchange values ranged from 19.1 to 46% (mean = 32%). Thirty-three of 34 specimens collected from the white cell or platelet port showed a higher percentage of HbS in the collection line compared to simultaneous patient samples. Mean enrichment was 9.4% (range = -4.0 to 35.5%). There was an inverse relationship between the hemoglobin concentration and the percentage of HbS in the collected specimens (p = 0.001; N = 45). Differential separation of sickle cells should decrease the volume of blood required for partial red cell exchange of selected SS patients.