Conflicting clinical trials and the uncertainty of treating mild hypertension

Recommendations to treat patients with mild hypertension are based principally on six randomized clinical trials conducted in three countries between 1964 and 1979. To determine whether the methods and results of these randomized clinical trials justify the current therapeutic policy, a clinical epidemiologic analysis of the data was performed focusing on (1) clinical versus statistical significance, (2) clinical heterogeneity of patients' baseline state, (3) suitable management of the untreated control patients, and (4) choice of outcome events. This analysis suggested that the results of available studies are better suited to public health decisions (number of cardiovascular deaths prevented nationwide) than personal health decisions (whether treatment does more good than harm for individual patients), and that current evidence does not justify a uniform policy of treating all asymptomatic patients with mild hypertension.     

Coronary revascularization under age 40 years. Risk factors and results of surgery

Groups of patients such as the elderly, the diabetic and women have been studied to evaluate the effectiveness of coronary revascularization. In this report 77 patients under age 40 years undergoing coronary revascularization were studied. There was a high prevalence rate of predisposing factors. Sixty-eight percent reported a family history of heart disease and 27 percent a history of diabetes; 57 percent were hypertensive, 43 percent were overweight, 91 percent smoked, 5 percent were diabetic and 16 percent had abnormal glucose tolerance curves. Sixty-four percent had hypercholesterolemia (cholesterol 250 mg/100 ml) and 56 percent hyperlipidemia. Forty-four percent had had a previous myocardial infarction; 95 percent had angina pectoris, 12 percent preinfarction angina and 9 percent congestive cardiac failure. There were no operative deaths. The incidence rate of perioperative myocardial infarction (new Q waves in the electrocardiogram) was 4 percent. The mean length of of follow-up was 26 months (range 6 months to 5 years). The late mortality rate was 4 percent. Eight percent had a late myocardial infarction. Overall graft patency was 85 percent. Sixty-seven percent of patients were free of angina, and 17 percent were in improved condition. Seventy-one percent returned to work, while 29 percent remained unemployed. This study shows that in young patients, coronary revascularization is associated with low mortality and morbidity rates and that, despite the wide prevalence of predisposing factors, the prognosis and graft patency rate of these patients are similar to those of other groups.     

Mammographic parenchymal patterns and risk of breast cancer in postmenopausal women

A case-control study was conducted to assess whether certain "high-risk" mammographic parenchymal patterns are associated with the increased occurrence of breast cancer in postmenopausal women. Patients in the case group included 105 women with histologically confirmed breast cancer; subjects in the control group included 104 women with fibrocystic breast disease and 103 women with clinically normal breasts. All mammographic results were evaluated "blindly" by a radiologist who classified the breast parenchyma into "high-risk" and "low-risk" categories according to the criteria proposed by Wolfe. These data showed a similar proportion of allegedly "high-risk" breast parenchymal patterns among patients in all three groups. The finding that breast parenchymal patterns are not associated with an increased risk of breast cancer in women 50 years of age or older is consistent with the results of earlier studies in which the association is present only in younger, premenopausal women, and is absent in older, predominantly postmenopausal women. Consequently, it is concluded that these parenchymal patterns should not be used to select postmenopausal women for breast cancer screening programs, or to guide the evaluation of postmenopausal women with breast lumps or symptoms.     

Clinical spectrum of postpartum renal failure

Four patients in whom renal functional abnormalities developed in the postpartum period are discussed. Two patients had a fulminant, fatal course, typical of most of the previously reported cases of postpartum renal failure. The other two patients, however, had only mild, transient renal abnormalities. Pathologically, all four patients showed changes suggestive of fibrin deposition in the renal vasculature. It is suggested that postpartum renal failure includes a spectrum of disease from fulminant renal failure with extensive fibrin deposition to minor renal dysfunction with minimal fibrin deposition.     

Hepatic disease in erythropoietic protoporphyria.

Two sisters had erythropoietic protoporphyria and a spectrum of liver disease. One (F.B.) died in hepatic failure within 3 months after the development of jaundice. Only 10 months before she died, she had exhibited only bromsulfalein retention and a borderline increase in serum transaminase. Surgical exploration because of the jaundice revealed patency of the bile ducts which was confirmed at autopsy. Wedge biopsy and autopsy specimens of liver showed an active cirrhosis with massive amounts of protoporphyrin in Kupffer cells, portal histiocytes, bile canaliculi and parenchymal cytoplasm. The other sister (L.R.) had never had symptomatic liver disease and only a slight increase in serum transaminase and bromsulfalein retention. On needle biopsy, the liver specimen showed portal inflammation with erosion of limiting plates, occasional bridging between triads and central areas of cell dropout. Protoporphyrin pigment was present in portal histiocytes, areas of central collapse and, more rarely, in parenchymal cytoplasm. These studies demonstrate that significant, progressive hepatic disease may occur insidiously in erythropoietic protoporphyria, and that once jaundice appears it may be followed rapidly by fatal hepatic failure.     

Pharmacokinetics of digoxin and digitoxin in patients undergoing hemodialysis

The pharmacokinetics of digoxin and digitoxin in patients undergoing long-term hemodialysis were examined to determine which is the preferred cardiac glycoside in this patient population.Absorption curves from 0 to 24 hours after an oral dose of digitoxin were similar in dlalyzed patients and in control patients. Serum glycoside concentrations after an oral dose of digoxin were higher in dialyzed patients than in control patients, significantly so from 2 to 24 hours, reflecting the absence of the predominantly renal route of excretion of digoxin.When nine dialyzed patients were placed on a maintenance dose of digoxin, 0.125 mg 5 days a week, serum levels plateaued at 30 days at a mean concentration (± SE) of 0.84 ± 0.05 ng/ml. Maintenance therapy with 0.1 mg digitoxin 5 days a week resulted in stabilization of serum levels within 30 days at a mean concentration of 19 ± 1 ng/ml. Variability in the serum glycoside concentrations was determined after stabilization of levels during 2 to 19 week follow-up periods with each drug. Variability in serum levels was somewhat increased during maintenance therapy with digitoxin. On the basis of the pharmacokinetic data obtained in this study, no clear cut preference for one glycoside over the other could be established.     

Methodologic standards and contradictory results in case-control research.

Despite a reversal of the customary direction of the cause → effect reasoning used in prospective (cohort) studies, the retrospective case-control method for the study of disease etiology has become epidemiologically popular and sanctioned by authorities who claim that it rarely produces contradictory results.Nevertheless, we have found at least 17 topics in which conflicts were noted in conclusions that arose either among case-control studies or between case-control and cohort studies of the same topic. The 17 topics include the etiologic relationships of myocardial infarction to coffee-drinking and aspirin, and of various neoplastic diseases to reserpine, estrogens, coffee-drinking, herpesvirus, oral contraceptives, appendectomy, tonsillectomy, prenatal irradiation, benign prostatic hyperplasia, asthma, circumcision, early age of menarche and tuberculosis.The 85 case-control investigations of these topics were each evaluated for the fulfillment of 11 methodologic standards that would enhance scientific quality in the research. The standards include a predetermined method of patient selection, clear specification of the risk agent, unbiased collection of data, efforts to provide anamnestic equivalence, avoidance of constrained selection for cases and controls, equal diagnostic examination, equal prehospital surveillance, equal demographic and clinical susceptibility, and avoidance of protopathic bias in the compared groups. These standards, which were commonly violated in the 85 reviewed investigations, should not be used to provide a general summary score for individual studies, since the impact of each type of violation depends on the topic under investigation and must be appraised separately for that topic.Certain scientific problems of case-control studies are inherent in the research architecture, but others can be eliminated or reduced by better attention to the quality of the conventional research procedures and by special new methods of sampling and analysis. The cited standards can help readers to evaluate the results of casecontrol research and can help designers of future studies to improve their scientific structure and credibility.     

Urinary 3-methylhistidine excretion in juvenile-onset diabetics: Evidence of increased protein catabolism in the absence of ketoacidosis

Urinary 3-methylhistidine excretion (an indicator of protein catabolism) was measured in ten diabetic patients and in age and weight matched control subjects. The diabetic group, while receiving their usual insulin dose, excreted 42% more 3-methylhistidine than the control group (2.7 versus 1.9 μmole/kg body weight/24 hr). When the insulin dose of the diabetic subjects was reduced by 15% or 25%, the concentrations of blood and urinary glucose were significantly increased but the rate of urinary 3-methylhistidine excretion was not increased further. These findings demonstrate augmented protein catabolism in diabetics even in the absence of ketoacidosis. It appears that blood and urine glucose levels are more sensitive to changes in insulin availability than protein catabolism.     

Effect of clinical features on the association of estrogens and breast cancer

In a case-control study using several distinctive control subgroups, no increased risk of breast cancer was found in postmenopausal women who used replacement estrogens. When breast cancer patients and control patients with no breast lesions were assembled from patients who had all received mammography, the overall odds ratio was 0.5, and varied from 0.2 to 1.2 according to the patient's indication for estrogen treatment and the clinical reason for mammography. When a biopsy registry was the source of breast cancer patients and control patients with benign breast disease, the odds ratio was 0.8. In a conventional case-control comparison of breast cancer patients with hospitalized patients having other diagnoses, the odds ratio was 0.9 when specific data about exposure were used to classify patients as estrogen users, but the odds ratio was 3.3 when data about exposure were not recorded equally in the compared groups. These results show that calculations of "risk" depend on important clinical phenomena that have not previously been given suitable attention. The data also provide a possible explanation for the perplexing findings among earlier studies in which the odds ratios varied from "protective" to "causal" values. When the data from the present study are partitioned according to differences in patients' clinical characteristics and reasons for the diagnostic breast procedure, the conflicting results of earlier studies can be reconciled.     

The problem of “protopathic bias” in case-control studies

Among the many sources of bias that can affect the results of casecontrol research, protopathic bias occurs when a pharmaceutical agent is inadvertently prescribed for an early manifestation of a disease that has not yet been diagnostically detected. In a case-control study of estrogens and endometrial cancer, approximately 10 per cent of the patients exposed to estrogens specifically stated that oral estrogens had been prescribed by their physician to treat an episode of uterine bleeding. This result was consistent with another study in which seven of 23 estrogen users were given the medication for the treatment of uterine bleeding before the diagnosis of cancer was made.Protopathic bias, which may account for much of the allegedly protective effect of oral contraceptives on the development of benign breast disease, can also occur in studies of aspirin and myocardial infarction, sex steroids and birth defects, and bronchodilators and death from asthma. This empiric demonstration of protopathic bias helps to indicate the need for careful precautions against its effect.     

Pregnancy and its outcome in women with and without surgical treatment of congenital heart disease

In the state of Connecticut, 233 women with congenital heart defects were prospectively followed up through 482 pregnancies that resulted in 372 infants who were examined frequently during their first 3 years of life. Approximately half of the women had undergone cardiac surgery and they were compared with the women without operation. There was no maternal mortality, and no patient had infective endocarditis, brain abscess or a cerebrovascular accident. The proportion of pregnancies resulting in live births did not differ significantly in mothers with and without cardiac surgery; the average live birth rate was 77 percent in all. However, the number and size of live-born infants was much greater in mothers who had become acyanotic as a result of reparative surgery than in the still cyanotic women, whether or not they had had palliative surgery. In cyanotic women, placental size was abnormally large in relation to birth weight, which was abnormally low.When the mothers were classified according to cardiac function, there was a significant difference between the number of infants born alive to mothers in good to excellent status and the number born to mothers in fair to poor condition. The latter had a significant increase in interrupted pregnancies as well as in cardiovascular complications during pregnancy. The total group had a 16.1 percent incidence rate of infants with congenital heart disease. This rate was corrected to 14.2 percent by removal of seven mothers, two with Noonan's syndrome, one with hypertrophic cardiomyopathy and four with a family history of congenital heart defects.     

Four-valve polymicrobial endocarditis caused by pseudomonas aeruginosa and serratia marcescens

This report describes what is believed to be the first case of mixed Pseudomonas and Serratia endocarditis, of probable nosocomial etiology, with involvement of all four heart valves in a 56 year old nonaddicted patient. Although both organisms were recovered in culture, infection and tissue invasion were documented by light and electron microscopy. The clinical course in this patient differed from more typical patterns of Pseudomonas or Serratia endocarditis that have been observed as complications of narcotic addiction or compromised cardiac status. Our patient had the rare occurrence of endocarditis with two organisms and four-valve involvement. Clinically, however, this presented as a right-sided endocarditis and behaved as though only a single organism were present.     

Enterococcal meningitis: Combined vancomycin and rifampin therapy

Intrathecal vancomycin and oral rifampin have been used together to successfully treat a patient with enterococcal meningitis who was allergic to penicillin and who had failed a course of treatment with chloramphenicol. This therapy was tolerated very well and represents an alternate mode of therapy which should be considered in penicillin allergic patients with enterococcal meningitis.     

Idiopathic thrombocytopenic purpura occurring in a subject previously splenectomized for traumatic splenic rupture: Role of splenosis in the pathogenesis of thrombocytopenia

A 25 year old woman presented with idiopathic thrombocytopenic purpura. She had undergone splenectomy 12 years previously for traumatic splenic rupture. Thrombocytopenia was ultimately resistant to steroid therapy. Howell-Jolly bodies were absent from the peripheral smear and ^99mTC-spleen scan demonstrated foci of increased uptake thought consistent with accessory spleens. However, splenosis alone was demonstrated at laparotomy, and all visible splenotic tissue was surgically removed. The patient responded and adequate platelet counts were maintained after discontinuation of steroid therapy. The functional capacity of splenic implants has been previously demonstrated both in animal and man. However, reports linking splenosis to hematologic disease are rare. In the present case, characteristic splenic function was demonstrated by both the ^99mTc-spleen scan and the absence of the typical peripheral blood findings of asplenia. The hematologic response to the removal of the splenotic tissue attests to its importance in maintaining the thrombocytopenic state. In the setting of prior splenectomy for splenic trauma, splenosis may contribute to hematologic disease. Removal of this splenotic tissue may result in hematologic remission.     

Relations between ventricular refractoriness and regional myocardial blood flow after acute coronary occlusion

Myocardial ischemia has been associated with dispersion of ventricular refractory periods and this dispersion has been related to the ventricular arrhythmias seen with coronary occlusion. This study relates the degree of change in measured ventricular refractory period with the degree of regional myocardial blood flow abnormality after coronary occlusion. When regional myocardial blood flow is less than 70 percent of that of nonischemic areas, refractory periods are significantly (P < 0.001) shortened. The greatest change in refractory periods occurs in areas with a regional myocardial blood flow that is 21 to 40 percent of that of non-ischemic areas. Marked (less than 20 percent) and minimal (61 to 80 percent) reductions in regional myocardial blood flow are associated with less, but still significant, shortening of ventricular refractory periods. Thus dispersion of refractoriness can be related to the inhomogeneity of regional myocardial blood flow after acute coronary occlusion. Interventions designed to salvage ischemic myocardium by increasing regional myocardial blood flow may affect dispersion of ventricular refractory periods in complex and divergent ways.