Low Muscle Levels of Pyridoxine in McArdle's Syndrome

Pyridoxal phosphate is a covalently bound cofactor of glycogen phosphorylase. Phosphorylase is a major muscle protein and therefore represents a significant pool of pyridoxal phosphate. Muscle pyridoxine content was measured in three patients with myophosphorylase deficiency (McArdle's syndrome) in whom there was a marked diminution or absence of phosphorylase protein as determined by acrylamide gel electrophoresis. Total muscle pyridoxine in the patients with McArdle's syndrome (0.55 ± 0.08 μg/g wet weight, mean ± SD) was markedly reduced compared with 11 human control subjects who had normal levels of muscle phosphorylase (total muscle B₆ = 2.49 ± 0.47). Despite such drastically low levels of muscle pyridoxine, these patients had no evidence of pyridoxine “deficiency.” These results suggest that low muscle B₆ in McArdle's syndrome represents the specific loss of pyridoxal phosphate normally bound to phosphorylase apoenzyme and imply that phosphorylase pyridoxal phosphate accounts for 75 to 80 percent of the total pyridoxine in normal human muscle.     

Prospective randomized trial of glucose-insulin-potassium in acute myocardial infarction. Effects on myocardial hemodynamics, substrates and rhythm.

Fifty consecutive patients admitted within 12 hours of the onset of symptoms of acute myocardial infarction were randomly assigned to treatment with intravenous glucose-insulin-potassium infusion (23 patients) or to a control group (0.5 N sodium chloride infusion) (27 patients). The glucose-insulin-potassium infusion consisted of 30 g glucose, 50 U regular insulin and 80 mEq KCl per liter infused at 1.5 ml/kg per hour for 2 days. Serial measurements were made of pulmonary arterial end-diastolic pressure, cardiac index, daily fluid intake and output, serum glucose, potassium, urea nitrogen, free fatty acids, osmolarity, creatine kinase-MB isoenzyme and cardiac rhythm. Although all patients admitted comatose died (three glucose-insulin-potassium recipients, one control subject), hospital mortality in patients admitted noncomatose was 0 percent (0 of 20) in glucose-insulin-potassium recipients versus 12 percent (3 of 26) in the control group (three deaths secondary to late pump failure). Glucose-insulin-potassium recipients experienced 4.9 ± 1.3 hours of three or more premature ventricular complexes/min compared with 11.1 ± 1.9 hours for control subjects (P < 0.02). Twelve control patients had 60 episodes of ventricular tachycardia compared with seven glucose-insulin-potassium recipients, who had 12 episodes of ventricular tachycardia. During glucose-insulin-potassium infusion, fluid intake and output, serum glucose and potassium were significantly increased compared with values in control subjects, blood urea nitrogen and free fatty acids were decreased, whereas osmolarity, pulmonary arterial end-diastolic pressure and cardiac index did not differ significantly from control values. Creatine kinase-MB infarct size averaged 124 ± 15 IU/liter in glucose-insulinpotassium recipients and 109 ± 14 IU/liter in control subjects (difference not significant).These data demonstrate that, in patients with acute infarction, glucose-insulin-potassium infusion (1) does not adversely alter hemodynamics, (2) reduces free fatty acids, (3) diminishes frequency of ventricular arrhythmias, but (4) has no demonstrable effect on infarct size as assessed with creatine kinase isoenzyme values. In this ongoing randomized clinical trial, the number of patients studied is too small to permit definite conclusions to be reached regarding the effect of glucose-insulin-potassium infusion on hospital survival.     

Is the PARADIGM-HF cohort representative of the real-world heart failure patient population?

Introduction

A new drug with prognostic impact on heart failure, sacubitril/valsartan, has been introduced in current guidelines. However, randomized trial results can be compromised by lack of representativeness. We aimed to assess the representativeness of the PARADIGM-HF trial in a real-world population of patients with heart failure.

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.     

Improved tolerance to successive glucose loads in acromegaly.

The mechanism of the Staub-Traugott effect, or facilitated glucose disposal with closely timed successive glucose loads, remains poorly understood. Progressive suppression of growth hormone has been suggested as an explanation. To test this hypothesis, three successive intravenous glucose loads were administered to seven active acromegalic patients and six healthy controls. All subjects showed a clear Staub-Traugott effect despite failure of hyperglycemia to suppress abnormally high growth hormone levels in the acromegalics. Except for higher basal and incremental insulin release in the acromegalic patients, patterns of insulin secretion and suppression of free fatty acids were not substantially different from controls. These studies clearly suggest that hyperglycemia-induced suppression of growth hormone is not the cause of the Staub-Traugott effect.     

Clinical importance of "breakthrough" bacteremia

Fifty-one episodes of bacteremia and a single episode of fungemia occurred during treatment with seemingly adequate doses of appropriate antibiotics. Clinical findings in these "breakthrough" bacteremias and fungemia were compared with those in 448 non-breakthrough episodes. Breakthrough was more likely to be caused by facultative or aerobic gram-negative rods (e.g., Enterobacteriaceae and Pseudomonas species) than by anaerobes. Of the underlying conditions examined, immunosuppressive doses of glucocorticosteroids, diabetes mellitus, and moderate renal failure were significantly more frequent in patients with breakthrough. A significant association was also observed between an intra-abdominal primary focus of infection (abscesses, biliary tract or bowel infections) and the occurrence of breakthrough. Mortality in breakthrough bacteremia was 61 percent compared with 40 percent in non-breakthrough episodes. The phenomenon of breakthrough bacteremia shows the potential limitations of antibiotic therapy alone.     

Plasma cyclic adenosine 3'5'-monophosphate (AMP) levels in acute myocardial infarction

Plasma cyclic adenosine 3′5′-monophosphate (AMP) levels were measured in 44 patients with acute myocardial infarction, 33 patients with other cardiac and noncardiac diseases and 20 normal volunteers. The normal range of cyclic AMP was 4 to 16 picomoles/ml. The 35 surviving patients with acute myocardial infarction tended to have a slightly increased level of plasma cyclic AMP during the first 24 hours with a subsequent return to normal; the 9 nonsurvivors had abnormally high levels of cyclic AMP. An inverse correlation was found between cyclic AMP levels and stroke work index, and plasma cyclic AMP levels were of equal or better prognostic value than stroke work index. Plasma cyclic AMP levels were in the normal range in patients without acute myocardial infarction. Thus, very high levels of plasma cyclic AMP, found in patients with fatal myocardial infarction, appear to have clinical significance.     

Effects of intracoronary streptokinase in acute myocardial infarction

Intracoronary streptokinase (SK) was administered to 11 patients with evolving acute transmural myocardial infarction 5.5 ± 0.4 hours from the onset of symptoms. Ten patients (91%) had total coronary occlusion, and one had subocclusion of the vessel corresponding to the ECG site of infarction. Intracoronary nitroglycerin failed to restore patency of total occlusion in all patients. In 9 of 11 patients (82%), patency was restored or improved with intracoronary SK. Thrombolysis was successful in 8 of 11 patients (73%), and one patient with transient patency developed acute reocclusion. Average time from SK infusion to reperfusion was 24 ± 7 minutes. Patients with successful thrombolysis had patency initially restored at a dosage of 61,000 ± 15,000 IU of SK and received a total dosage of 136,000 ± 17,000 IU. Patency persisted at late study in six of eight patients, and two patients developed late reocclusion. Successful thrombolysis was associated with significant improvement in left ventricular ejection fraction (LVEF) from early to late study, in contrast to deterioration of LVEF in patients with unsuccessful recanalization (p < 0.001). Systemic fibrinolytic activity occurred in 8 of 11 patients at a mean dosage of 125,000 ± 15,000 IU of SK and was unassociated with significant bleeding. Significant decrease in hemoglobin concentration in the early hospital phase occurred in patients receiving SK but did not differ from decreases occurring in a matched control population receiving conventional therapy for infarction. Thus intracoronary thrombolysis with SK was successful in the majority of patients during the early phase of evolving transmural infarction, and successful thrombolysis was associated with significant improvement in LVEF. Systemic fibrinolysis occurs in most patients despite small total doses of SK, and the significant decrease in hemoglobin in these patients may be unrelated to SK, since similar changes occurred in a control population receiving conventional therapy.     

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.