Role of the liver in regulation of ketone body production during sepsis.

During caloric deprivation, the septic host may fail to develop ketonemia as an adaptation to starvation. Because the plasma ketone body concentration is a function of the ratio of hepatic production and peripheral usage, a pneumococcal sepsis model was used in rats to measure the complex metabolic events that could account for this failure, including the effects of infection on lipolysis and esterification in adipose tissue, fatty acid transport in plasma and the rates of hepatic ketogenesis and whole body oxidation of ketones. Some of the studies were repeated with tularemia as the model infection. From these studies, it was concluded that during pneumococcal sepsis, the failure of rats to become ketonemic during caloric deprivation was the result of reduced ketogenic capacity of the liver and a possibly decreased hepatic supply of fatty acids. The latter appeared to be a secondary consequence of a severe reduction in circulating plasma albumin, the major transport protein for fatty acids, with no effect on the degree of saturation of the albumin with free fatty acids. Also, the infection had no significant effect on the rate of lipolysis or release of fatty acids from adipose tissue. Ketone body usage (oxidation) was either unaffected or reduced during pneumococcal sepsis in rats. Thus, a reduced rate of ketone production in the infected host was primarily responsible for the failure to develop starvation ketonemia under these conditions. The liver of the infected rat host appears to shuttle the fatty acids away from beta-oxidation and ketogenesis and toward triglyceride production, with resulting hepatocellular fatty metamorphosis.

Elevated systolic blood pressure as a predictor of long-term cancer mortality: analysis by site and histologic subtype in 10,000 middle-aged and elderly men.

The association of a casual reading of blood pressure (BP) in 1963 to subsequent 15-year cancer mortality was examined in a cohort of 10,059 middle-aged and elderly men. Systolic BP (SBP), but not diastolic BP, predicted significantly long-term cancer mortality occurring in 369 subjects. The covariate-adjusted relative risk (RR) estimated by Cox's proportional hazard model was 1.10 [95% confidence interval (CI), 1.00-1.21]. In patients aged less than 60 at the beginning of the study, increased cancer mortality was mainly observed in association with SBP of more than 150 mm Hg. In subjects aged 60 or above, the estimated RR was 1.21 (95% CI, 1.03-1.42). Exclusion of 40 men in whom diagnosis made prior to 1963 or death occurred through 1965 did not alter the results. An excess mortality in men who reported pharmacologic treatment for hypertension while under follow-up was fully accountable by their age, BP, and smoking habits. Analysis by site suggested that the association was mainly due to increased mortality from cancer of the digestive and genitourinary organs (estimated RR's, respectively, 1.20 and 1.26; 95% CI's, respectively, 1.03-1.39 and 0.99-1.59). Analysis by histologic subtype suggests an association with adenocarcinoma (RR = 1.19, 95% CI, 1.04-1.37) but not squamous cell or transitional cell carcinomas, myeloma, lymphomas, and leukemias.

Transluminal carbon dioxide-laser catheter angioplasty for dissolution of atherosclerotic plaques.

Carbon dioxide laser energy was used for the dissolution of atheromatous plaques. Flexible, nontoxic infrared optical fibers were used for the transmission of the carbon dioxide laser beam intraarterially. Dissolution of plaques and recanalization of obstructed arteries were achieved both in vitro and in vivo with controllable damage to the vessel walls.

Unusual pericardial calcification in Gaucher's disease.

Gaucher's disease is a hereditary metabolic disorder characterized by the abnormal accumulation of glucocerebrosides in reticuloendothelial cells. A 58-year-old man had Gaucher's disease and suffered from hypersplenism, cirrhosis of the liver, and free-floating calcifications in the pericardial space. The literature of the pericardial involvement in Gaucher's disease is reviewed.

Intrathoracic and abdominal pressure variations as an efficient method for cardiopulmonary resuscitation: studies in dogs compared with computer model results.

Intrathoracic pressure variations are currently proposed as the main flow-generation mechanisms in standard and modified cardiopulmonary resuscitation (CPR) techniques. A method of changing pressure within the thorax and abdomen without any degree of heart compression was developed and tested in dogs. Intrathoracic and abdominal pressure waves were induced by cyclic inflation and deflation of the lungs and of perithoracic and periabdominal balloons. Various modes of CPR, depending on the rate of cycling, the use of a periabdominal balloon inflation, and a delay between the abdominal and thoracic pressure waves, were studied during ventricular fibrillation. During artificial systole (high intrathoracic pressure phase), the pressure which developed in the right ventricle (96.7 +/- 20.5 mmHg) was higher than the pressure in the aorta (89.3 +/- 20.5 mmHg, p less than 0.001). In artificial diastole (low intrathoracic pressure phase), the right ventricular pressure (11.7 +/- 2.6 mmHg) was lower than the aortic pressure (17.5 +/- 3.3 mmHg, p less than 0.001). The average flow in the carotid artery was 21.7 +/- 7.8 ml . min-1, which was 18 +/- 6% of the baseline carotid flow before CPR. Three different factors were found to improve the efficiency of CPR: periabdominal balloon inflation simultaneous with the intrathoracic pressure waves; increased frequency of the pressure waves from 60 to 100 cycles per minute; and inflation of the periabdominal balloon 50 to 100 ms before the thoracic balloon. Blood-gas and acid-base balance analysis during CPR revealed well-oxygenated arterial blood with a marked respiratory alkalosis and a slowly developing metabolic acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation between effects of hydralazine on force and on the adenyl cyclase system of ventricular myocardium in dogs and cats.

Hydralazine is a potent arteriolar dilator, which increases cardiac output in patients with heart failure. Previous studies suggested that these beneficial effects might be due in part to a positive inotropic effect. The present study further investigated the effect of hydralazine on myocardial contractility and adenyl cyclase activity. In isolated cat papillary muscles, bath concentrations of hydralazine up to 10(-4) mol X litre-1 did not alter force development, whereas 10(-3) mol X litre-1 hydralazine increased isometric force by 31%. This effect was blocked by 10(-6) mol X litre-1 propranolol and was absent after catecholamine depletion produced by previous reserpine treatment. In canine ventricular myocardium hydralazine in all concentrations used (10(-7) to 10(-3) mol X litre-1) increased control adenyl cyclase activity. This increase was statistically significant in 10(-6) to 10(-3) mol X litre-1 concentrations, reaching a maximum of 69.5% at 10(-4) mol X litre-1. In cat ventricular myocardium 10(-6) to 10(-3) mol X litre-1 hydralazine increased the cyclic AMP production, although to a lesser magnitude than that in canine tissue. Hydralazine 10(-5) mol X litre-1 produced a 37.8% increase, and the maximum effect of 45.2% occurred at 10(-3) mol X litre-1. The positive effects of hydralazine were completely abolished by the addition of propranolol in dogs as well as in cats. Thus the adenyl cyclase stimulation induced by hydralazine is mediated through the beta receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

A probable endocrine basis for the depression of ketone bodies during infectious or inflammatory state in rats.

The effects of infection with Streptococcus pneumoniae, Francisella tularensis, and Venezuelan equine encephalitis virus as well as inflammatory stress induced by the administration of turpentine and endotoxin on plasma ketone bodies and insulin were studied in white rats. All of the infectious/inflammatory stresses caused a significant decrease in the ketonemia of fasting and an elevation of plasma insulin. When a pneumococcal infection was initiated in a diabetic rat, inhibition of fasting ketonemia did not occur. Similarly, pneumococcal infection in the hypophysectomized rat did not result in a noticeable depression of either fasting ketonemia or plasma FFA. The increase in circulating insulin appears to be closely correlated with the inhibition of fasting ketonemia noted in the infectious/inflammatory stress.

Enhanced risk of coronary heart disease mortality in lean hypertensive men.

A recently presented hypothesis contends that the excess coronary heart disease mortality associated with hypertension is more prominent in lean men than in overweight men. This hypothesis was addressed using data collected in the Israeli Ischemic Heart Disease Study (n = 10,059). The ratios of age-adjusted 15-year death rates in hypertensive and normotensive men were 4.7, 2.8, 2.0, and 1.9 in the Quetelet index groups of less than 2.29, 2.29 to 2.56, 2.56 to 2.83 and greater than 2.83 g/cm2, respectively. The corresponding ratios for all-cause mortality were 2.2, 2.1, 2.0, and 1.7, respectively. The group with the highest all-cause age-adjusted mortality, at 33.6%, was that of the leanest (less than 2.29 g/cm2, bottom 20% of the Quetelet index distribution) hypertensive subjects. The same group also displayed the highest coronary heart disease mortality (age-adjusted rate, 18.2%). The findings persisted for both smokers and nonsmokers and after exclusion of men with coronary heart disease or diabetics at intake, men on antihypertensive medication, or those who died in the first 2 years of follow-up (1963-1965). A multivariate risk score for developing myocardial infarction was calculated, based on levels of age, systolic blood pressure, total cholesterol, high density lipoprotein cholesterol, cigarette smoking, diabetes mellitus, and Quetelet index. This score varied little across the four Quetelet index groups in hypertensive men: 5-year mean estimated risks of myocardial infarction were between 70 and 74/1000. In normotensive men the scores increased from 19/1000 in the leanest subjects to 29/1000 in the overweight ones.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of inflammatory and noninflammatory stress on ketone bodies and free fatty acids in rats.

Both bacterial and viral infections prevented or reversed the expected ketogenic response induced in rats by starvation. In contrast, ketogenesis was not inhibited by stresses such as aseptic femoral fracture or immobilization by screen restraint. Infection had no effect on mitochondrial enzymes of terminal respiration and fatty acid oxidation.

Specific metabolic effects imposed by Streptococcus pneumoniae upon the response to femoral fracture in the rat.

The possible potentiation of an infection upon the metabolic consequences of trauma was tested in rats using a 2 X 2 block design which included control, femoral fracture, pneumococcal infection, and fracture plus infection groups. Infection introduced unique metabolic effects different from those of starvation, femoral fracture, or both together. Infection-induced effects included an accelerated conversion of 14C-alanine to glucose, higher serum haptoglobin, alpha2-macrofetoprotein, copper, and ceruloplasmin values, and lower serum iron, zinc, and transferrin concentrations. The first three of these infection-induced effects were diminished in rats with a femoral fracture. No measured effect of infection was increased in traumatized rats.

Systematic analysis of contrast echocardiograms.

Contrast echocardiography was first described in 1968. Since then, many reports have described clinical and experimental uses for the technique. Contrast echocardiography is performed at least occasionally in most echocardiography laboratories, but most physicians use this technique merely to determine the presence of a shunt or, more rarely, for structure identification. Contrast echocardiography can provide much more information. Some different types of information available from contrast echocardiographic records are discussed, including timing of contrast appearance within the cardiac cycle, relative timing of appearance in different cardiac structures, relative intensity of contrast opacification, cyclical changes in contrast opacification, negative contrast effect, slope of contrast trajectories on M-mode contrast echocardiography, and clearance times.

The human coronary microcirculation: an electron microscopic study.

The ultrastructure of the terminal vascular bed of human coronary arteries was studied in the myocardial tissue obtained at surgery from different locations in the heart in five patients. The following vessels were identified: (1) Arterioles; slender and prolonged endothelial cells, flat nuclei and two to three layers of smooth muscle cells. (2) Precapillary sphincters: short endothelial cells, large nuclei bulging into the lumen, close myoendothelial junctions and a single layer of circular smooth muscle. (3) Capillaries: composed of one or more slender endothelial cells. (4) Venules: flat endothelial cells and nuclei, no muscular layer, rich collagen tissue. The function of these structures is believed to be as follows: the arterioles are the smallest blood-distributing arteries in the heart. The precapillary sphincters control blood flow to the capillaries; pressor substances present in the blood are picked up by endothelial cells, pass rapidly through the myoendothelial junctions and cause contractions of the smooth circular muscle layer; the bulging nuclei of endothelial cells then passively obstruct the lumen almost completely. The main exchange of gases and nourishing substances takes place in the capillaries. We postulate that in some pathologic conditions, abnormal constriction of the sphincters may cause diminished flow and be the basis for some well defined or unclear ischemic events.

Segmental study of the terminal coronary vessels in coarctation of the aorta: a natural model for study of the effect of coronary hypertension on human coronary circulation.

An electron microscopic study of the coronary terminal circulation (starting with the small coronary arteries) was carried out on small pieces of myocardium operatively resected from the left ventricle on 11 patients with coarctation of the aorta. The patients were 4 to 20 years of age. Structural modifications were found in the small coronary arteries and arterioles. Two patterns of morphologic alterations were noted in these small resistance vessels. In the first pattern, seen in most of the children, the components of the arterial wall were still distinguishable, and well represented portions of smooth muscle layers were visualized together with muscle cells showing signs of degeneration and more or less widespread collagenous islets. The second pattern, seen in young adults, was characterized by a total collagenous transformation of the arterial wall. In contrast, the smaller microvessels (precapillary sphincter, metarterioles and capillaries) appeared free of pathologic change. It is postulated that the precapillary sphincters play a special protecting and regulating role in the coronary microcirculation in such cases with elevated coronary pressure. It is suggested that surgery should be performed at an early age to prevent further development of structural changes in the microvessels. The microcirculatory damage may contribute to the increased surgical mortality in patients with coarctation of the aorta operated on at a later age. These findings should trigger further research on the small coronary vessels in systemic hypertension.

Subaortic stenosis: an unrecognized problem in transposition of the great arteries.

Right ventricular (subaortic) obstruction has only rarely been described in complete transposition of the great arteries. five patients with complete transposition of the great arteries in whom subaortic stenosis was angiocardiographically demonstrated were studied. All had a pressure gradient of 30 to 55 mm Hg across the aortic outflow tract. Two of the patients manifested mild tricuspid insufficiency, and another two had coarctation of the aorta. The etiologic, anatomic, hemodynamic and prognostic aspects of this unusual anomaly are discussed. An angiocardiographically demonstrated series of this anomaly has not been reported on before.

Diagnosing tricuspid regurgitation by direct imaging of the regurgitant flow in the right atrium using contrast echocardiography.

To determine whether tricuspid regurgitation (TR) can be diagnosed by direct imaging of regurgitant flow in the right atrium (RA) using contrast echocardiography, echocardiography was performed in 35 patients using peripheral intravenous injections of 5% dextrose solution. Fifteen patients had TR judged by v-wave synchronous contrast appearance on the inferior vena cava echogram (a previously validated method for diagnosing TR), 5 of whom had clinically obvious TR. Twenty patients had no TR on inferior vena cava contrast echocardiography, 9 of whom were normal volunteers. On subsequent blind review, 13 of the 15 patients with TR were correctly identified on the basis of the regurgitant contrast flow just posterior to the tricuspid valve in the RA. Of the 20 without TR, 19 were correctly identified and there was 1 false-positive result. Using different criteria for the diagnosis (insisting on imaging of flow across the tricuspid valve in systole), another blinded observer correctly diagnosed only 8 of the 15 patients as having TR, but had no false-positive results. To avoid false-positive results, it is important to realize that there are 2 regions where retrograde flow can normally be seen in the RA: (1) briefly at the onset of systole coincident with tricuspid valve closure, and (2) in the posterior RA, as distinct from the anterior RA area just behind the tricuspid valve where TR is diagnosed in this study.(ABSTRACT TRUNCATED AT 250 WORDS)

Two-dimensional echocardiography in discrete subaortic stenosis.

Thirty-seven patients with discrete subaortic stenosis (DSS) underwent 2-dimensional echocardiography (2-D echo) and cardiac catheterization. The peak systolic pressure gradients ranged from 0 to 150 mm Hg. Thirty-two patients had membranous DSS and 5 had fibromuscular DSS. Of 37 patients with DSS, 2-D echo diagnosed the presence and type in 35; in 2, a membrane was demonstrated by angiography. Of the 35 patients accurately diagnosed by 2-D echo, angiography corroborated the diagnosis in 33, but failed to show the membrane in 2. Subsequent cardiac surgery confirmed the accuracy of the echocardiographic diagnosis in these 2 patients. In all patients with membranous DSS, the anterior insertion of the membrane was demonstrated. In 9 of them the posterior insertion was demonstrated by tilt of the transducer but the anterior insertion disappeared. In 4 patients both insertions were demonstrated simultaneously and in 3 patients the membrane was demonstrated as a continuous line. In 4 of the 5 patients with fibromuscular DSS, both insertions of the lesion were demonstrated simultaneously. However, 2-D echo was unsuccessful in assessing the severity of obstruction. In only 1 patient did demonstration of the whole subaortic membrane as a continuous line below the aortic valve correlate with severe obstruction. Thus, the presence and type of DSS, but not the degree and severity, can be accurately and reliably diagnosed by means of 2-D echo.

Exercise-induced left ventricular dysfunction in young men with asymptomatic diabetes mellitus (diabetic cardiomyopathy).

Radionuclide ventriculographic studies were performed at rest and during exercise on 30 consecutive men, aged 21 to 35 years with diabetes mellitus without evidence of coronary artery or any other cardiovascular disease, and in 20 normal age-matched subjects. Sixteen (53%) were treated with insulin and 14 (47%) were treated with either diet (6 patients) or oral antidiabetic therapy (8 patients). All patients from both groups had normal left ventricular (LV) ejection fraction (EF) at rest. In 5 of the 30 diabetic patients (17%), LVEF decreased after exercise, in 8 (27%) it remained unchanged and in 17 it increased normally. Mean LVEF at rest and after exercise in this group was 66 +/- 7% and 72 +/- 7% (+/- standard deviation), respectively. In all normal subjects, LVEF increased after exercise. Mean LVEF at rest and after exercise in the normal group was 66 +/- 7% and 76 +/- 9%, respectively. No patient had evidence of regional dysfunction at rest or after exercise. LV function was not related to serum glucose levels during the test, modality of treatment, insulin dependency or duration of the disease. Three of 4 patients with diabetic microvascular complications showed LV dysfunction. In 4 of 5 patients in whom LVEF decreased after exercise, thallium studies showed normal perfusion. Thus, diabetes mellitus may cause exercise-induced global LV dysfunction in young men with no evidence of cardiovascular disease. This phenomenon apparently does not seem to follow the known course of diabetic microvascular complications.

Correction of tetrad of Fallot with reduced incidence of right bundle branch block.

In 20 patients who underwent a modified surgical repair of tetrad of Fallot complete right bundle branch block developed in only 8 (40 percent). Standard and intraoperative conduction studies indicated that in these patients the right bundle branch block was due to injury of the right bundle branch near the ventricular septal defect (proximal right bundle branch block). The modified operative technique is aimed at minimizing the injury to the right ventricle and it includes a significantly shorter than usual ventriculotomy incision and avoidance of the septal (moderator) band during infundibulectomy. Intra- and postoperative hemodynamic studies of these patients revealed that relief of the right ventricular outflow obstruction was optimal.

Subjective versus objective evaluation of hypnotic efficacy: experience with zolpidem.

There is little published literature on the correlation between subjective and objective efficacy of hypnotics. We wanted to determine whether there was a correlation between the patient's subjective evaluation of the efficacy of the hypnotic with the polysomnographic (PSG) findings. We studied 16 patients with chronic insomnia (sleep latency, greater than or equal to 30 minutes; total sleep time, greater than 240 but less than 420 minutes) for 11 nights who took placebos on nights 1 and 2, zolpidem (imidazopyridine) on nights 3-9 and placebo on nights 10 and 11. Patients completed a questionnaire each morning following PSG, which evaluated subjective sleep quality, sleep latency and total sleep time. These data were compared to PSG findings to answer specific questions about sleep latency reduction, efficacy of the hypnotic after a week's use, sleep quality after discontinuing the drug, and any correlation between subjective and objective measures. PSG findings indicated a shortened sleep latency, increased total sleep time, decreased total wake time and increased sleep efficiency when patients ingested zolpidem 30 minutes before bedtime. We found that after 7 nights (nights 3-9) the drug was still effective in reducing sleep latency and increasing total sleep time. Upon withdrawal (nights 10 and 11) sleep returned to baseline (nights 1 and 2). Subjectively, the patients confirmed those findings on the questionnaire, as well as a subjective reduction in the number of awakenings and, interestingly, a subjective increase in the time spent awake after sleep. Many of the objective variables we examined correlated highly with the subjective variables. While on zolpidem, subjects believed and were objectively shown to have a decreased sleep latency, increased total sleep time and decreased time awake before persistent sleep, although they tended to overestimate sleep latency and time spent awake before persistent sleep and underestimated total sleep time. Although the correlation between objective and subjective measures was high for the group, in individual patients there was an impressive difference between the two, and the highest coefficient of variation between a subjective and objective measures was 0.453. No correlations were found with subjective measures of refreshing quality of sleep, decrease in number of awakenings, how sleepy patients felt in the morning or their ability to concentrate in the morning. Thus, we believe the PSG remains the keystone in the evaluation of hypnotic efficacy.

Using self-reported questionnaire data to prioritize OSA patients for polysomnography.

Many laboratories have large numbers of patients with suspected obstructive sleep apnea (OSA) waiting to be tested. We assessed the use of simple clinical data to detect those patients with an apnea index <20 (low AI) who could be studied less emergently. Using questionnaires completed by patients prior to evaluation, we collected data on 354 consecutive patients (281 males, 73 females; mean age 48.6 years) referred for OSA and assessed with polysomnography (PSG). The questionnaires included the Epworth sleepiness scale (ESS), height, weight, age, and a history of observed apnea. Analysis of receiver operating characteristics curves revealed that both body mass index (BMI) [area under curve = 0.7258, standard error (SE) = 0.03, p < 0.01] and ESS (area under curve = 0.5581, SE = 0.03, p = 0.03) were significantly better than chance alone in detecting people with AI < 20. ESS < or =12 was found in 37.9% of the subjects but 39.6% of those expected to have a low AI using ESS had an AI > or =20. A BMI < or =28 was found in 24.9% of the subjects; 14.8% of those expected to have a low AI using BMI had an AI > or =20. Combining these variables improved accuracy but resulted in smaller groups; a cut-off of ESS < or =12 and BMI < or =28 resulted in a group of 33 (9.3% of subjects), only two (6%) of whom were falsely called low AI. Adding to this the fact that apnea had not been observed resulted in a group of nine patients (2.5% of subjects), none of whom had an AI > or =20. Thus there is a tradeoff; the more variables used, the greater the accuracy but the smaller the percent of cases selected to have low AI. However, in laboratories with hundreds of patients waiting to be tested, any procedure better than chance to help prioritize patients seems worthwhile.