Hypertension: pathophysiology and treatment

Arterial hypertension is a major cause of morbidity and mortalitybecause of its association with coronary heart disease, cerebrovasculardisease and renal disease. The extent of target organ involvement(i.e. heart, brain and kidneys) determines outcome. North Americanstudies have shown that hypertension is a major contributorto 500 000 strokes (250 000 deaths) and 1 000 000 myocardialinfarctions (500 000 deaths) per annum.     

CASK and Dlg form a PDZ protein complex at the mammalian neuromuscular junction

Membrane-associated guanylate kinases (MAGUKs) are modular adapter proteins that serve as scaffolding molecules and anchor channels and receptors via their PDZ (PSD-95, Dlg, Zo-1) domains. Calcium, calmodulin-associated serine/threonine kinase (CASK) is a MAGUK that is critical at synapses in the central nervous system and at cell-cell junctions because of its interactions with channels, receptors, and structural proteins. We show via confocal microscopy that CASK and another MAGUK, Discs Large (Dlg), are present at the mammalian neuromuscular junction in skeletal muscle. Immunoprecipitation data from mouse muscle show that CASK associates with Dlg, providing evidence of a MAGUK protein complex at this synapse. These data indicate that CASK and Dlg may act as a scaffold for organizing receptors and channels at the postsynaptic membrane of the neuromuscular junction.     

Cardiovascular physiology during supine cycle ergometry and dobutamine stress

PURPOSE: This study compared cardiac hemodynamics during supine cycle ergometry and dobutamine stress. METHODS: Thirty-two healthy volunteers (19 female, 13 male, 23.5 +/- 3.5 yr old) completed respective tests on separate days and in random order. Heart rate, blood pressure, and cardiac output were recorded at baseline and peak stress. Echocardiographic measures included left ventricular end-diastolic dimension, fractional shortening, heart rate corrected velocity of circumferential fiber shortening, end-systolic wall stress, and the difference between measured and predicted fiber shortening for measured wall stress. RESULTS: Compared with peak exercise, dobutamine infusion resulted in lower cardiac output (12 +/- 2 vs 16 +/- 4 l x min(-1), P < 0.0001), heart rates (163 +/- 7 vs 175 +/- 12 beats x min(-1), P < 0.0001), and systolic blood pressure (160 +/- 22 vs 185 +/- 20 mm Hg, P < or = 0.0001). Echocardiography demonstrated smaller left ventricular end-diastolic dimension (4.2 +/- 0.7 vs 4.5 +/- 0.7 cm, P = 0.013), higher fractional shortening (0.55 +/- 0.07 vs 0.50 +/- 0.06%, P < 0.001), higher VCFc (2.07 +/- 0.36 vs 1.54 +/- 0.20 circs x s(-1), P < 0.001) higher VCFdiff (0.94 +/- 0.35 vs 0.48 +/- 0.20 circs x s(-1), P < 0.001), and lower end-systolic wall stress (25 +/- 11 vs 42 +/- 16 g x cm(-2), P < 0.001). The stress-velocity relationship during dobutamine demonstrated higher y-intercept and steeper slope, indicating greater load-independent contractility. CONCLUSION: The cardiovascular adaptation to exercise and dobutamine stress differ significantly. Cardiac output during peak exercise is greater than during peak dobutamine secondary to increased heart rate and stroke volume. Despite a greater increase in contractility and decrease in afterload, a smaller increase in cardiac output during dobutamine stress may be secondary to limited ventricular preload.     

Mitochondrial dysfunction in autistic patients with 15q inverted duplication

Two autistic children with a chromosome 15q11-q13 inverted duplication are presented. Both had uneventful perinatal courses, normal electroencephalogram and magnetic resonance imaging scans, moderate motor delay, lethargy, severe hypotonia, and modest lactic acidosis. Both had muscle mitochondrial enzyme assays that showed a pronounced mitochondrial hyperproliferation and a partial respiratory chain block most parsimoniously placed at the level of complex III, suggesting candidate gene loci for autism within the critical region may affect pathways influencing mitochondrial function.     

Inherited disorders of 3-methylcrotonyl CoA carboxylation

The clinical course of 4 patients who had reduced activities of 3-methylcrotonyl CoA carboxylase (also called 3-methylcrotonylglycinuria) is described. Two children presented with a metabolic acidosis, one in the neonatal period and the other with episodes of acidosis that started in the second year of life. In the other 2 children neurological symptoms were prominent, one having infantile spasms and the other developmental regression with a skin rash and alopecia. Three of the children responded well to oral biotin and dietary protein restriction but the fourth, despite a biochemical response to biotin, has a severe neurological handicap. The clinical presentation of inborn errors of 3-methylcrotonyl CoA carboxylase is variable. Metabolic acidosis may not be conspicuous and instead neurological features may predominate.     

Suspected poisoning in children. Study of the incidence of true poisoning and poisoning scare in a defined population in North East Bristol

The distinction between true and suspected poisoning in children has not been made clear in previous work on childhood poisoning. A study of suspected poisoning in children under 15 years of age in a defined population of North East Bristol from November 1970 to July 1973 carried out by the Health Education Council Medical Research Division included 53,000 child-years at risk. The number of suspected poisonings was 3-4/1000 population aged under 15 years per year, with a higher incidence in younger age groups. Detailed investigation of the circumstances of the accidents carried out by a multidisciplinary team showed that at least 65%, and possibly as many as 78% were poisoning scares and not true poisoning. The evidence used by the casualty doctor and by the parents to diagnose poisoning was explored, and in many cases was circumstantial. Children with fathers in nonmanual occupations were over-represented. This may reflect differences in patterns of utilization behaviour rather than true differences in incidence.     

The prospects for renal xenotransplantation

Summary: Xenotransplantation of non-human organs into human recipients has long been proposed as a possible strategy to overcome the acute shortage of donor organs. However, vascular organ transplants to humans from phylogenetically disparate species such as the pig are not currently possible due to a rapid rejection process termed hyperacute rejection. This process is initiated by the binding of host pre-formed 'natural antibodies' to the donor vascular endothelium, activation of the host complement system and activation or injury of the donor endothelial cells, leading to intravascular coagulation and loss of the graft due to ischaemic necrosis within minutes to hours of engraftment. Prevention of natural antibody binding and complement activation is viewed as paramount to preventing hyperacute rejection. Even if hyperacute rejection can be prevented, further barriers to successful discordant xenografts such as delayed xenograft rejection and a donor-directed cell-mediated rejection process will still represent major obstacles. This review examines recent advances being made in the various areas of xenograft research and the potential clinical application of pig-to-human xenografts that these strategies may bring.     

Inflammatory bowel disease and predisposition to osteopenia

The prevalence of osteopenia in children with inflammatory bowel disease (IBD) is unknown. The effect of nutritional state, disease activity, and steroid therapy on bone mineral content (BMC) of whole body, lumbar spine, and left femoral neck measured by dual energy x ray absorptiometry in 32 children with IBD was assessed by comparison with 58 healthy local school children. Using the control data, a predicted BMC was calculated taking into account bone area, age, height, weight, and pubertal stage. The measured BMC in children with IBD was expressed as a percentage of this predicted value (% BMC). Mean (SD) % BMC was significantly reduced for the whole body and left femoral neck in the children with IBD (97.0 (4.5)% and 93.1 (12.0)% respectively, p < 0.05). Of the children with IBD, 41% had a % BMC less than 1 SD below the mean for the whole body and 47% at the femoral neck. Reduction in % BMC was associated with steroid usage but not with the magnitude of steroid dose, disease activity, or biochemical markers of bone metabolism. In conclusion, osteopenia is relatively common in childhood IBD and may be partly related to the previous use of steroids.