The prognostic importance of different definitions of worsening renal function in congestive heart failure

BACKGROUND: Worsening renal function in patients hospitalized for heart failure portends a poor prognosis. However, criteria used to define worsening renal function are arbitrary, and the implications of different definitions remain unclear. We therefore compared the prognostic importance of various definitions of worsening renal function in 1,002 patients hospitalized for congestive heart failure (CHF). METHODS AND RESULTS: The patient population was 49% female, aged 67 +/- 15 years. Twenty-three percent had a prior history of renal failure, 73% had known depressed ejection fraction, and 63% had known CHF. On admission to the hospital, 47% were receiving ACE inhibitors, 22% beta-blockers, 70% diuretics and 6% NAID's. 72% developed increased serum creatinine during the hospitalization, with 20% developing an increase of > or = 0.5 mg/dL. Worsening renal function predicted both in-hospital mortality and length of stay > 10 days. Even an increased creatinine of 0.1 mg/dL was associated with worse outcome. Sensitivity for death decreased from 92% to 65% as the threshold for increased creatinine was raised from 0.1 to 0.5 mg/dL, with specificity increasing from 28% to 81%. At a threshold of a 0.3 mg/dL increase, sensitivity was 81% and specificity was 62% for death and 64% and 65% for length of stay >10 days. Adding a requirement of final creatinine of > or = 1.5 mg/dL improved specificity. CONCLUSIONS: This analysis demonstrates that any detectable decrease in renal function is associated with increased mortality and prolonged hospital stay. This suggests that therapeutic interventions which improve renal function might be beneficial.     

Thyrotoxic thyroiditis after radiotherapy for Hodgkin's disease

Exposure of the thyroid gland to ionizing radiation has been associated with a variety of abnormalities. Among these are tardive hypothyroidism and an increased risk of developing thyroid nodules and cancer. Although acute thyroiditis has been known to complicate radioactive iodine 131 therapy, it has rarely been associated with external beam irradiation. Thyrotoxic painless thyroiditis developed in two patients after mantle-field irradiation for Hodgkin's disease.     

Spectrum of coronary arterial spasm. Clinical, angiographic and myocardial metabolic experience in 29 cases

A relationship of coronary arterial spasm to variant angina pectoris, subendocardial ischemia, major ventricular arrhythmias and myocardial infarction has been demonstrated. In 29 patients, spasm was angiographically observed in normal-appearing coronary arteries (7 patients) as well as superimposed on various degrees of coronary atherosclerotic obstruction (22 patients). All patients experienced an atypical anginal syndrome; 16 patients also experienced typical exertional angina. Coronary spasm appeared to be a major contributory factor in eight occurrences of myocardial infarction and in 11 incidents of ventricular tachycardia, ventricular fibrillation and heart block.

Coronary spasm in the 29 cases was distributed in the following fashion: left main trunk, 6 cases; right main trunk, 12 cases; proximal left anterior descending artery, 13 cases; proximal circumflex artery, 1 case; distal left anterior descending artery, 1 case; and distal circumflex artery, 2 cases. In 5 cases coronary spasm was noted at multiple sites.

In contrast to findings in patients manifesting only typical exertional angina, the hemodynamic findings during spasm were those of a hypodynamic state. Left ventricular systolic pressure decreased from 138.9 ± 6.0 (mean ± standard error of the mean) to 113.2 ± 6.2 mm Hg; left ventricular end-diastolic pressure did not change significantly. Myocardial lactate extraction during spasm was invariably markedly reduced: −53.19 percent ± 15.44 (P < 0.001). However, the effect of coronary sinus pacing on myocardial lactate extraction was not significantly abnormal: +15.74 percent ± 6.66.

The respective roles of medical and surgical intervention are uncertain. Only 3 patients had a completely satisfactory pharmacologic response to nitrates alone or in combination with propranolol, and the condition of 5 others was partially improved; the remaining 21 patients were judged intractable to medical management. Coronary bypass surgery was performed as the ultimate recourse in 18 patients. However, short-term results reveal that only nine (50 percent) showed improvement, four (22 percent) had myocardial infarction during or after surgery and four (22 percent) died.

These studies confirm that coronary arterial spasm is a definite pathogenetic factor in a variety of acute myocardial ischemic syndromes. The incidence and full clinical significance of this functional disorder remain to be determined.     

A convenient approximation of life expectancy (the “DEALE”): II. Use in medical decision-making

We show how to use a bedside approximation of life expectancy in quantitative decision-making. This method, the declining exponential approximation of life expectancy (DEALE), enables the physician to collate various survival data with information on morbidity to determine a quality-adjusted expected survival for a potential management plan. The keystone in the DEALE approach is the approximation of survival by a simple exponential function. This approximation makes it possible to translate data from various literature sources (life expectancy tables, five-year survival rates, survival curves, median survival) into a single, unified mortality scale. In this paper, we use the DEALE method to obtain approximations of quality-adjusted life expectancy and illustrate the application of the method in a quantitative analysis of a clinical decision.     

Thrombolysis in postinfarction angina

Postinfarction angina carries a poor prognosis, with a 20-70% incidence of recurrent myocardial infarction (MI) or death within the subsequent 3-6 months. The pathophysiologic mechanisms causing postinfarction angina may include thrombus, complex coronary arterial lesions that form a nidus for thrombus formation, inadequate collateral supply following acute MI, or intimal endothelial dysfunction. The role of thrombus has been established in the pathophysiology of Q-wave MI, and thrombolytic treatment of patients presenting with acute transmural MI has been shown to salvage left ventricular function and to reduce mortality. However, thrombolytic therapy for the acute MI does not reduce the incidence of recurrent ischemia or infarction, as is evident from the 18-26% incidence of recurrent ischemia reported in the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) and Thrombolysis in Myocardial Infarction (TIMI) trials. In the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) study the incidence of reinfarction was documented as 4% in the streptokinase group, which was actually significantly greater than in the placebo group (2%). In a randomized placebo-controlled study of thrombolysis for postinfarction angina, 29 patients were randomized to placebo (P group, n = 17) or to thrombolytic therapy (T group, n = 12). Patient groups were similar with respect to age, location of MI, ejection fraction, severity of coronary artery disease, and antianginal therapy. Patients underwent coronary angiography 6 +/- 1 days postinfarction. Filling defects consistent with intracoronary thrombus was seen in 11 of 12 T group patients and in 11 of 17 P group patients prior to treatment. Lysis occurred in 7 of 11 T patients and 1 of 11 P (p less than 0.02). Holter-detected silent ischemia was compared pre- and posttherapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serial changes in markers of disease activity with corticosteroid treatment in sarcoidosis

Serial changes in various markers of disease activity with corticosteroid therapy were assessed in 12 patients with active sarcoidosis. After six weeks of treatment with 40 mg daily of prednisone, all but one patient demonstrated symptomatic and radiographic improvement. For the entire patient group, there were corresponding improvements in forced vital capacity, from 59.2 +/- 5.5 to 70.5 +/- 5.3 percent of the predicted value (p less than 0.001, Student paired t test), serum angiotensin-converting enzyme levels, from 66.0 +/- 12.1 to 28.2 +/- 4.0 U/ml (p = 0.003), 67gallium lung scanning scores, from 3.6 +/- 0.2 to 0.8 +/- 0.3 (p less than 0.001), serum gamma globulin levels, from 2.40 +/- 0.2 to 1.5 +/- 0.1 g/dl (p less than 0.001), and erythrocyte sedimentation rate, from 26.8 +/- 2.7 to 14.8 +/- 3.0 mm per hour (p less than 0.001). Changes in percent of bronchoalveolar lavage fluid lymphocytes were less impressive (from 28.7 +/- 4.9 to 21.2 +/- 5.1, p = 0.034), but the geometric mean number of bronchoalveolar lavage fluid-IgG-secreting cells decreased from 23,861 to 3,830 (p = 0.013). Serial evaluations in five patients treated with decreasing doses of alternate-day prednisone for an additional 10 1/2 months indicated that changes in 67gallium lung scanning scores corresponded most closely to the clinical course in five of five patients. Determination of serum angiotensin-converting enzyme levels also closely paralleled the clinical course in four of five patients, whereas the other parameters measured were more variable markers of clinical response. However, abnormalities of bronchoalveolar lavage fluid-IgG-secreting cells often persisted in the absence of clinically evident disease, and the percentages of bronchoalveolar lavage fluid lymphocytes were frequently normal in patients who responded subsequently to corticosteroids. Larger prospective studies are warranted to more extensively evaluate various measurements of disease activity, especially bronchoalveolar lavage fluid analysis, in sarcoidosis.     

Phosphorylation of mitochondrial elongation factor Tu in ischemic myocardium: basis for chloramphenicol-mediated cardioprotection

The objective of this study was to identify the mitochondrial proteins that undergo changes in phosphorylation during global ischemia and reperfusion in the isolated rabbit heart. We also assessed whether the cardioprotective intervention of ischemic preconditioning affected mitochondrial protein phosphorylation. We established a reconstituted system using isolated mitochondria and cytosol from control or ischemic hearts. We found that phosphorylation of a 46-kDa protein on a serine residue was increased in ischemia and that phosphorylation was reduced in control or preconditioned hearts. Using 2D gel electrophoresis and mass spectrometry, we have identified the 46-kDa protein as mitochondrial translational elongation factor Tu (EF-Tu(mt)). These data reveal that ischemia and preconditioning modulate the phosphorylation of EF-Tu(mt) and suggest that the mitochondrial protein synthesis machinery may be regulated by phosphorylation. Phosphorylation of mitochondrial EF-Tu has not been previously described; however, in prokaryotes, EF-Tu phosphorylation inhibits protein translation. We hypothesized that phosphorylation of mitochondrial EF-Tu would inhibit mitochondrial protein translation and attempted to reproduce the effect with inhibition of mitochondrial protein synthesis by chloramphenicol. We found that chloramphenicol pretreatment significantly reduced infarct size, suggesting that mitochondrial protein synthesis is one determinant of myocardial injury during ischemia and reperfusion.     

Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes

BACKGROUND: Troglitazone promotes adipocyte differentiation in vitro and increases insulin sensitivity in vivo. Therefore, troglitazone may have therapeutic benefit in lipoatrophic diabetes. OBJECTIVE: To determine whether troglitazone ameliorates hyperglycemia and hypertriglyceridemia or increases fat mass in lipoatrophic patients. DESIGN: Open-labeled prospective study. SETTING: United States and Canada. PATIENTS: 20 patients with various syndromes associated with lipoatrophy or lipodystrophy. INTERVENTION: 6 months of therapy with troglitazone, 200 to 600 mg/d. MEASUREMENTS: Levels of hemoglobin A1c triglycerides, free fatty acids, and insulin; respiratory quotient; percentage of body fat; liver volume; and regional fat mass. RESULTS: In the 13 patients with diabetes who completed 6 months of troglitazone therapy, hemoglobin A1c levels decreased by a mean of 2.8% (95% CI, 1.9% to 3.7%; P < 0.001). In all 19 study patients, fasting triglyceride levels decreased by 2.6 mmol/L (230 mg/dL) (CI, 0.7 to 4.5 mmol/L [62 to 398 mg/dL]; P = 0.019) and free fatty acid levels decreased by 325 micromol/L (CI, 135 to 515 micromol/L; P = 0.035). The respiratory quotient decreased by a mean of 0.12 (CI, 0.08 to 0.16; P < 0.001), suggesting that troglitazone promoted oxidation of fat. Body fat increased by a mean of 2.4 percentage points (CI, 1.3 to 4.5 percentage points; P = 0.044). Magnetic resonance imaging showed an increase in subcutaneous adipose tissue but not in visceral fat. In one patient, the serum alanine aminotransferase level increased eightfold during the 10th months of troglitazone treatment but normalized 3 months after discontinuation of treatment Liver biopsy revealed an eosinophilic infiltrate, suggesting hypersensitivity reaction as a cause of hepatotoxicity. CONCLUSION: Troglitazone therapy improved metabolic control and increased body fat in patients with lipoatrophic diabetes. The substantial benefits of troglitazone must be balanced against the risk for hepatotoxicity, which can occur relatively late in the treatment course.     

Use of the day 6 bone marrow to alter remission induction therapy in patients with acute myeloid leukaemia: a leukemia intergroup study

Patients with acute myeloid leukaemia who fail to show substantial bone marrow cytoreduction by day 6 of induction therapy enter complete remission (CR) less frequently than patients with good bone marrow leukaemic cytoreduction. The objective of the current study was to determine whether an increase in the intensity of therapy on days 8, 9 and 10 ('augmentation' of remission induction therapy) for patients with poor bone marrow cytoreduction detected in the day 6 bone marrow could improve the complete remission rate without increasing the number of toxic deaths. Patients from six centres were entered and treated with standard dose ara-C for 7 or 10 d and an anthracycline for the first 3 d. Patients aged less than 60 years and with greater than 30% bone marrow biopsy cellularity or greater than 10% abnormal cells on the aspirate obtained 6 d after the start of therapy were augmented with cytosine arabinoside 3 g/m2 every 12 h on days 8, 9 and 10. Therapy was augmented in 116 of the 252 patients less than 60 years. There was a highly statistically significant difference between augmented and nonaugmented patients (P less than 0.001) for the per cent biopsy cellularity and per cent abnormal cells in the day 6 marrow. The CR rate for augmented patients was 69% and for nonaugmented patients 60% suggesting that augmentation therapy abrogated the prognostic significance of more extensive residual leukaemia in the day 6 bone marrow. The results suggest that augmentation of remission induction for patients with poor bone marrow cytoreduction detected 6 d after initiation of therapy, may salvage patients who are destined to fail remission induction because of resistant disease without producing excessive toxicity.