A missense mutation in the human connexin50 gene (GJA8) underlies autosomal dominant "zonular pulverulent" cataract, on chromosome 1q

OBJECTIVE: To determine the effect of hemorrhagic shock on spontaneous and endotoxin-induced cytokine release from intestinal mononuclear cells compared with whole portal venous blood and splenic macrophages. DESIGN: Random assignment to either unmanipulated control group, sham operation group, or hemorrhagic shock group. SETTING: University animal laboratory. SUBJECTS: Male Wistar rats, weighing between 300 and 350 g. INTERVENTIONS: Rats were bled to 30 mm Hg for 30 mins by withdrawal/reinfusion of shed blood and Ringer's lactate equivalent to the shed blood volume. MEASUREMENTS: Rats were killed immediately, 4 hrs, or 24 hrs after reperfusion. Portal venous blood, splenic macrophages, and small bowel mononuclear cells were obtained and spontaneous (unstimulated) and endotoxin-induced supernatant tumor necrosis factor (TNF)-alpha (WEHI 164 subclone 13) and interleukin (IL)-6 (B 13-29 clone 9) release was measured by bioassay. MAIN RESULTS: Increased endotoxin-induced TNF release from gut mononuclear cells and portal venous blood was suppressed 4 and 24 hrs after reperfusion compared with sham operated animals (p < .05). TNF release from splenic macrophages could be significantly increased (p < .05) by addition of endotoxin in all groups with no difference between control, sham, and shock animals. In shock animals, endotoxin-stimulated IL-6 release was significantly greater (p < .05) than control and sham operated rats 4 hrs after reperfusion in portal blood and from splenic macrophages. In contrast to splenic macrophages, gut mononuclear cells and portal venous blood demonstrated high spontaneous IL-6 concentrations without further stimulation by endotoxin. CONCLUSIONS: Hemorrhagic shock induced a hyporesponsiveness from gut mononuclear cells and whole portal venous blood 4 and 24 hrs after reperfusion. Spontaneous and endotoxin-induced stimulation of IL-6 indicates a different modulation of cytokines in gut, portal vein and spleen. The differences of gut mononuclear cells and portal blood compared with the splenic macrophages indicate a compartmentalized cytokine response.     

Expression and function of CTLA-4 in Th1 and Th2 cells

CTLA-4 is expressed on T cells after activation and shares homology with the CD28 costimulatory receptor. In contrast to CD28, CTLA-4 is thought to be a negative regulator of T cell activation. Cross-linking of CTLA-4 during activation of peripheral T cells reduces IL-2 production and arrests T cells in G1. Much less is known about the function of CTLA-4 in differentiated T cells. We have investigated the expression and function of CTLA-4 in established Th1 and Th2 clones and in bulk populations of Th1 and Th2 cells freshly derived in vitro from TCR transgenic splenocytes. We found that CTLA-4 was induced under similar conditions and with similar kinetics following activation of both Th1 and Th2 clones. However, CTLA-4 expression was much higher in Th2 than Th1 clones and lines. This was confirmed by flow cytometry, confocal microscopy, and Northern blot analysis. The ratio of surface to intracellular expression of CTLA-4 and its rate of endocytosis were similar in Th1 and Th2 clones. Inhibition of binding of CTLA-4 to its ligands using soluble anti-CTLA-4 mAb during stimulation with Ag increased the production not only of IL-2 by Th1 clones, but also that of IL-3 and IFN-gamma by Th1 clones and of IL-3, IL-4, IL-5, and IL-10 by Th2 clones. In contrast, when anti-CTLA-4 was coimmobilized with anti-CD3 and anti-CD28 mAbs, a decrease in the production of multiple cytokines was observed. We conclude that CTLA-4 can function to suppress the production of cytokines produced by both Th1 and Th2 cells.     

Compliance of the fish outflow tract is altered by thermal acclimation through connective tissue remodelling

To protect the gill capillaries from high systolic pulse pressure, the fish heart contains a compliant non-contractile chamber called the bulbus arteriosus which is part of the outflow tract (OFT) which extends from the ventricle to the ventral aorta. Thermal acclimation alters the form and function of the fish atria and ventricle to ensure appropriate cardiac output at different temperatures, but its impact on the OFT is unknown. Here we used ex vivo pressure–volume curves to demonstrate remodelling of passive stiffness in the rainbow trout (Oncorhynchus mykiss) bulbus arteriosus following more than eight weeks of thermal acclimation to 5, 10 and 18°C. We then combined novel, non-biased Fourier transform infrared spectroscopy with classic histological staining to show that changes in compliance were achieved by changes in tissue collagen-to-elastin ratio. In situ gelatin zymography and SDS-PAGE zymography revealed that collagen remodelling was underpinned, at least in part, by changes in activity and abundance of collagen degrading matrix metalloproteinases. Collectively, we provide the first indication of bulbus arteriosus thermal remodelling in a fish and suggest this remodelling ensures optimal blood flow and blood pressure in the OFT during temperature change.     

Effects of methylphenidate on discounting of delayed rewards in attention deficit/hyperactivity disorder.

Impulsivity is a central component of attention deficit/hyperactivity disorder (ADHD). Delay discounting, or a preference for smaller, immediate rewards over larger, delayed rewards, is considered an important aspect of impulsivity, and delay-related impulsivity has been emphasized in etiological models of ADHD. In this study, we examined whether stimulant medication, an effective treatment for ADHD, reduced discounting of delayed experiential and hypothetical rewards among 49 children (ages 9–12 years) with ADHD. After a practice day, participants completed a 3-day double-blind placebo-controlled acute medication assessment. Active doses were long-acting methylphenidate (Concerta), with the nearest equivalents of 0.3 and 0.6 mg/kg TID immediate-release methylphenidate. On each testing day, participants completed experiential (real-world money in real time) and hypothetical discounting tasks. Relative to placebo, methylphenidate reduced discounting of delayed experiential rewards but not hypothetical rewards. Broadly consistent with etiological models that emphasize delay-related impulsivity among children with ADHD, these findings provide initial evidence that stimulant medication reduces delay discounting among those with the disorder. The results also draw attention to task parameters that may influence the sensitivity of various delay discounting measures to medication effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Protecting centrifugal pumps at low flow

Centrifugal pumps which operate under variable flow rates often require protection against prolonged operation at low flow rates. Determining the flow rate at which protection is required and the type of protection required is as important as the actual provision of low flow protection. This discussion deals with the correct application of low flow protection of centrifugal pumps and does not address the determination of the flow rate below which low flow protection is required.     

The inter-rate reliability of a generic measure of severity of illness

BACKGROUND: There has been increasing interest in the development of measures to quantify baseline severity of illness and thus provide a more meaningful interpretation of health outcomes. OBJECTIVE: We aimed to assess the inter-rater reliability of a generic measure of illness severity, the Duke University Severity of Illness (DUSOI) checklist. METHODS: Selected general practices and hospital outpatient departments across Tyneside and Humberside in the UK were used as the setting. Thirty-three clinicians were posted copies of the same set of 14 patient records and asked to rate the severity of illness of each patient using the DUSOI. The subjects were 27 GPs, three consultant chest physicians and three diabetologists. The main outcome measures were: (i) intraclass correlation coefficients used to express clinician agreement upon severity scores; and (ii) a 'gold standard', constructed in order to assess clinician agreement upon the health problems identified in the patient record to be considered as constituents of overall severity. RESULTS: It was found that the degree of inter-rater reliability of severity scoring was satisfactory, with an intraclass correlation coefficient of 0.43. In terms of identification of problems to be rated, there was considerable agreement between raters and a specially compiled 'gold standard' of health problems. CONCLUSION: The DUSOI has potential use in routine clinical practice, but strategies should be developed in order to maximize the reliability of rating illness severity on such a generic measure.     

Isolated diastolic heart failure--what is it?

Epidemiological evidence suggests that 20 to 40% of all patients with heart failure have normal systolic function. Isolated diastolic dysfunction may be the principle pathophysiological mechanism in these patients. The diagnosis of isolated diastolic heart failure is problematic and not merely based on demonstrating normal systolic function. The prognosis in isolated diastolic heart failure is more favourable than in systolic heart failure. At the present time, there is no licensed treatment for isolated diastolic heart failure and treatment is largely empirical.