Upon-admission adrenal steroidogenesis is adapted to the degree of illness in intensive care unit patients

Adrenal function was studied in 2 groups of intensive care unit (ICU) patients with varying degrees of illness, as determined by Acute Physiological and Chronic Health Evaluation (APACHE). The 15 seriously ill patients with high APACHE scores (greater than or equal to 25) had elevated Therapeutic Intervention Scores and increased mortality compared to the 15 ill patients (APACHE, less than or equal to 10; 67% vs. 27%). Plasma cortisol, aldosterone, and androstenedione concentrations were increased in the ICU patients compared to those in normal subjects (n = 23), being greater in the seriously ill patients. Plasma dehydroepiandrosterone sulfate (DHEAS) concentrations were low in both groups of ICU patients. The ratios of aldosterone or androstenedione to cortisol were not altered, whereas the DHEAS to cortisol ratios were reduced in the ICU patients. ACTH injection elicited increases in plasma cortisol, aldosterone, and androstenedione concentrations in both groups of ICU patients, and the ratios of aldosterone and androstenedione to cortisol did not change. In the seriously ill patients, plasma DHEAS increased, so that the DHEAS to cortisol ratio did not change, whereas in less ill patients plasma DHEAS did not increase, so that the DHEAS to cortisol ratio was reduced. In this study of patients admitted to an ICU, impairment of adrenal steroid secretion appears to be specific for DHEAS. Although plasma cortisol was elevated in ill patients proportional to the degree of illness, the contribution of the concomitant decrease in DHEAS to this increase is not clear.     

Population-based frequency of dyslipidemia syndromes in coronary-prone families in Utah

The frequency of familial dyslipidemia syndromes was determined from blood tests in 33 objectively ascertained families with early coronary heart disease (CHD) (two or more siblings with CHD by the age of 55 years). Three fourths of persons with early CHD in these families had 90th percentile lipid abnormalities (cholesterol level at or above the 90th percentile, triglyceride level at or above the 90th percentile, and/or high-density lipoprotein cholesterol (HDL-C) level at or less than the 10th percentile). The HDL-C and triglyceride abnormalities were twice as common as low-density lipoprotein-cholesterol abnormalities. The most common syndromes found were familial combined hyperlipidemia (36% to 48% of families with CHD), familial dyslipidemic hypertension (21% to 54% of families with CHD), and isolated low levels of HDL-C (15%), with overlapping familial dyslipidemic hypertension with familial combined hyperlipidemia and low-level HDL-C. Well-defined monogenic syndromes were uncommon: familial hypercholesterolemia being 3% and familial type III hyperlipidemia, 3%. Another 15% of families with CHD had no lipid abnormalities at the 90th percentile. Physicians should learn to recognize and treat these common familial syndromes before the onset of CHD by evaluating family history and all three standard blood lipid determinations. Failure to recognize and treat them leaves affected family members at high risk of premature CHD.     

Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin

The fruit fly Drosophila melanogaster was used to examine the mode of action of the novel insecticide and acaricide nodulisporic acid. Flies resistant to nodulisporic acid were selected by stepwise increasing the dose of drug in the culture media. The resistant strain, glc(1), is at least 20-fold resistant to nodulisporic acid and 3-fold cross-resistant to the parasiticide ivermectin, and exhibited decreased brood size, decreased locomotion, and bang sensitivity. Binding assays using glc(1) head membranes showed a marked decrease in the affinity for nodulisporic acid and ivermectin. A combination of genetics and sequencing identified a proline to serine mutation (P299S) in the gene coding for the glutamate-gated chloride channel subunit DmGluClalpha. To examine the effect of this mutation on the biophysical properties of DmGluClalpha channels, it was introduced into a recombinant DmGluClalpha, and RNA encoding wild-type and mutant subunits was injected into Xenopus oocytes. Nodulisporic acid directly activated wild-type and mutant DmGluClalpha channels. However, mutant channels were approximately 10-fold less sensitive to activation by nodulisporic acid, as well as ivermectin and the endogenous ligand glutamate, providing direct evidence that nodulisporic acid and ivermectin act on DmGluClalpha channels.     

Is mammography painful? A multicenter patient survey

Anecdotal reports of pain experienced during mammography have been a source of anxiety and concern for some women considering screening. To determine what asymptomatic women actually experience during mammography, a survey of 1847 women was performed at seven breast-imaging centers. Women recorded their experience on a six-point scale ranging from no discomfort to severe pain. Eighty-eight percent of the women experienced no discomfort (49%) or mild discomfort (39%). Only 9% experienced moderate discomfort; 1%, severe discomfort; and 1%, moderate pain. No woman had pain so severe that it would make her reconsider having a mammogram again. The degree of discomfort was slightly greater in women who complained of breast tenderness within three days prior to the mammogram but was not strongly related to age, menstrual status, or week of the menstrual cycle. We conclude that in a vast majority of women mammography causes no or mild physical discomfort and that actual pain is an uncommon occurrence.     

Precursors of cardiorespiratory events in infants detected by home memory monitor

In 1,079 infants monitored for >700,000 hr at home for apnea or bradycardia, we found an association between infants having multiple events exceeding conventional or a priori defined more extreme thresholds and less favorable developmental outcome at 1 year of age than infants with few or no events. If it is necessary to prevent such events to minimize risk for developmental morbidity, there is reason to determine whether there are disturbances in advance of the apnea or bradycardia that herald their onset. In the 85 infants with at least 1 extreme event and 1 conventional event, we hypothesized that apnea and bradycardia do not occur de novo but rather are preceded by cardiorespiratory and hemoglobin O2 saturation changes. We compared recorded time intervals preceding these events, and we analyzed three preceding time intervals for each conventional and extreme event, and each non-event recording: Time-2 hr: up to 2 hr before; Time-1 hr: up to 1 hr before; and Time-75 sec: the 75 sec immediately preceding each event. O2 saturation progressively decreased preceding both conventional and extreme events, and progressive increases occurred in heart and breathing rate variability. Duration of respiratory pauses and of periodic breathing progressively increased preceding conventional events, respiratory rate variability increased immediately preceding conventional events and at 1 hr preceding extreme events, and O2 saturation decreased immediately preceding both conventional and extreme events. Thus, conventional and extreme events do not occur de novo but rather are preceded by autonomic instability of the cardiorespiratory system.     

The microcirculation in severe malaria

Severe malaria in humans and animals is initiated by interactions between malaria-infected cells, host blood cells (including monocytes, T cells and platelets) and endothelial cells of the microcirculation. Adhesion to vascular cells, and possible vascular obstruction in severe human disease, involves interaction between host receptors and parasite-derived proteins, such as the variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). Our understanding of how different PfEMP1 variants may target infected erythrocytes to specific sites, such as the placenta, is rapidly increasing. However, in most instances downstream immune-mediated inflammatory processes appear more central than parasite accumulation to development of severe malaria. Using genetically-manipulated animal models of severe malaria, key roles for CD8 T cells and mediators such as lymphotoxin in the pathogenesis of murine disease have been established. Experimental and human studies suggest vascular deposition of activated platelets may have a central role. Here, we review some recent advances in the understanding of severe malaria pathogenesis from human and animal studies, focusing on events at the level of the microcirculation, and highlight the role for activated host cells in initiating the pathology of the disease.     

Cerebral haemostasis and antiphospholipid antibodies

One of the major clinical concerns of the antiphospholipid syndrome (APS) is the propensity of antiphospholipid (aPL) antibodies to cause thrombosis in both the large and small vessels of the brain. In this article, we review the current understanding of haemostasis in cerebral circulation and discuss this in the context of antiphospholipid antibodies. The systemic-defect-local-phenotype paradox is of particular importance in this discussion. In this paradigm, a systemic defect in thrombosis and haemostasis leads to a localized pattern of thrombotic disease because the regional physiological variations in the several prothrombotic and anticoagulant factors and the defect interact so as to favour thrombosis at a particular site. One possible mechanism of initiation of thrombosis in APS is the activation of endothelial cells by aPL that could occur in the cerebral vessels and provoke thrombosis. We review the evidence from gene knockout mice, other animal models and human postmortem examination studies as to which pro- and antithrombotic mechanisms are effecting haemostasis in the cerebral circulation. We conclude that there are large deficits in the understanding of the regulation ofhaemostasis in the human brain. As a consequence there is a lack of knowledge about the effect of aPL on cerebral endothelium and thrombosis. Recent developments in gene expression profiling may have an impact on our understanding of endothelial function in the brain. More research is required.     

Fracture of the femur in old age: A two-centre study of associated clinical factors and the cause of the fall

All patients with fractured neck of the femur admitted to hospitals in two areas (North London and Manchester) in a period of one year have been examined--a total of 384 patients. Compared to control groups of similar age, the older fracture patients showed a higher prevalence of chronic brain syndrome, they were in poorer physical state and their skinfold thickness was less. They also had more unrecognized visual disorders. Those who were younger had a higher prevalence of stroke than comparable controls. The type of fall leading to the fracture varied with age--tripping was the commonest cause in the younger patients the 'drop attacks' in the older. Both stroke and partial sightedness were associated with falls due to loss of balance. The older patients had a very high prevalence of pyramidal tract abnormality associated with chronic brain syndrome--and it appears that these demented patients fall not because of mental confusion but because of associated motor abnormalities. Extra-capsular fractures occur in older patients. They are more likely to have a history of falls but previous fracture is equally common at this age in the fracture and control series.