Retinal S-antigen in human subretinal fluid

Studies in experimental models of retinal detachment have proposed that the degree of visual recovery following retinal reattachment depends upon the extent of photoreceptor degeneration. A means of assessing this degeneration would help in establishing postoperative prognosis. S-antigen (S-Ag) is a unique retinal protein found in outer segment disc membranes and photoreceptor cells. In 36 cases of human rhegmatogenous retinal detachment, subretinal fluid (SRF) concentrations of S-Ag, measured by radioimmunoassay, ranged from 43 to 170 ng/ml (serum: 1-28 ng/ml). Analysis of variance showed a positive correlation with the duration of detachment (P less than 0.001). There was a two-fold increase in S-Ag concentrations during the first 2 weeks of detachment (P less than 0.005), with constant levels thereafter. These findings reflect progressive photoreceptor degeneration and/or ongoing synthesis of outer segment proteins in the detached retina that stop after the second week of detachment. SRF S-Ag levels may provide a prognostic indicator of visual recovery after reattachment as well as a sensitive measure of retinal metabolic activity during detachment.     

A System-wide Intervention to Improve HIV Testing in the Veterans Health Administration

Background  Although the benefits of identifying and treating asymptomatic HIV-infected individuals are firmly established, health care providers often miss opportunities to offer HIV-testing. Objective  To evaluate whether a multi-component intervention increases the rate of HIV diagnostic testing. Design  Pre- to post-quasi-experiment in 5 Veterans Health Administration facilities. Two facilities received the intervention; the other three facilities were controls. The intervention included a real-time electronic clinical reminder that encourages HIV testing, and feedback reports and a provider activation program. Patients  Persons receiving health care between August 2004 and September 2006 who were at risk but had not been previously tested for HIV infection Measurements  Pre- to post-changes in the rates of HIV testing at the intervention and control facilities Results  At the two intervention sites, the adjusted rate of testing increased from 4.8% to 10.8% and from 5.5% to 12.8% (both comparisons, p < .001). In addition, there were 15 new diagnoses of HIV in the pre-intervention year (0.46% of all tests) versus 30 new diagnoses in the post-intervention year (0.45% of all tests). No changes were observed at the control facilities. Conclusions  Use of clinical reminders and provider feedback, activation, and social marketing increased the frequency of HIV testing and the number of new HIV diagnoses. These findings support a multimodal approach toward achieving the Centers for Disease Control and Prevention’s goal of having every American know their HIV status as a matter of routine clinical practice.     

Reduced helminth burden increases allergen skin sensitization but not clinical allergy: a randomized, double-blind, placebo-controlled trial in Vietnam

Background: Observational evidence suggests that infection with helminths protects against allergic disease and allergen skin sensitization. It is postulated that such effects are mediated by helminth‐induced cytokine responses, in particular IL‐10. Objective: We tested this hypothesis in a rural area of central Vietnam where hookworm infection is endemic. Methods: One thousand five hundred and sixty‐six schoolchildren aged 6–17 were randomly allocated to receive either anti‐helminthic therapy or a placebo at 0, 3, 6, and 9 months. We compared changes in the prevalence of exercise‐induced bronchoconstriction, allergen skin sensitization, flexural eczema on skin examination, questionnaire‐reported allergic disease (wheeze and rhinitis symptoms), and immunological parameters (hookworm‐induced IFN‐γ, IL‐5, IL‐10) between 0 and 12 months. Results: One thousand four hundred and eighty‐seven children (95% of these randomized) completed the study. The most common helminth infections were hookworm (65%) and Ascaris lumbricoides (7%). There was no effect of the therapy on the primary outcome, exercise‐induced bronchoconstriction (within‐participant mean percent fall in peak flow from baseline after anti‐helminthic treatment 2.25 (SD 7.3) vs. placebo 2.19 (SD 7.8, P=0.9), or on the prevalence of questionnaire‐reported wheeze [adjusted odds ratio (OR)=1.16, 95% confidence interval (CI) 0.35–3.82, P=0.8] and rhinitis (adjusted OR=1.39, 0.89–2.15, P=0.1), or flexural dermatitis on skin examination (adjusted OR=1.15, 0.39–3.45, P=0.8). However, anti‐helminthic therapy was associated with a significantly higher allergen skin sensitization risk (adjusted OR=1.31, 1.02–1.67, P=0.03). This effect was particularly strong for children infected with A. lumbricoides at baseline (adjusted OR=4.90, 1.48–16.19, P=0.009). Allergen skin sensitization was inversely related to hookworm‐specific IL‐10 at baseline (adjusted OR=0.76, 0.59–0.99, P=0.04). No cytokine tested, including IL‐10, changed significantly after the anti‐helminthic therapy compared with the placebo. Conclusion: A significant reduction in worm burden over a 12‐month period in helminth‐infected children increases the risk of allergen skin sensitization but not of clinical allergic disease. The effect on skin sensitization could not be fully explained by any of the immunological parameters tested. Cite this as: C. Flohr, L. N. Tuyen, R. J. Quinnell, S. Lewis, T. T. Minh, J. Campbell, C. Simmons, G. Telford, A. Brown, T. T. Hien, J. Farrar, H. Williams, D. I. Pritchard and J. Britton, Clinical & Experimental Allergy, 2010 (40) 131–152.     

Children's Exposure to Environmental Tobacco Smoke in the Home: Comparison of Urine Cotinine and Parental Reports

The authors examined the relationship between parent-reported estimates of children's exposure to environmental tobacco smoke (ETS) in the home and children's urinary cotinine levels. Data were collected from a largely ethnic minority, low-income, urban sample of households in which a child had asthma and at least 1 household member smoked. Information about level of household smoking restriction, parental smoking status, and number of cigarettes smoked per day accounted for approximately 45% of the variance in cotinine concentration. Detailed information about the duration of household smoking or children's ETS exposure added no additional significant information. Questionnaires eliciting detailed information about smoking habits and children's ETS exposure may be no better at predicting children's urinary cotinine levels than simpler surveys that inquire about smoking restrictions in the home, parental smoking status, and number of cigarettes smoked at home per day.     

Efalizumab for severe refractory atopic eczema: retrospective study on 11 cases

Background Efalizumab is a recombinant humanized murine monoclonal antibody against CD11a, approved for the treatment of plaque psoriasis. However, recent reports suggest that it also may be effective in the treatment of severe atopic dermatitis (AD). Objective To evaluate the clinical effect of efalizumab in AD. Methods A systematic retrospective study of the medical files of patients treated with efalizumab for AD in Danish dermatology departments. Positive outcome was defined as improvement of the disease registered in the patient's file over a period exceeding 6 months. Results Two of eleven patients had a positive outcome. Nine patients stopped treatment due to progression of AD or lack of effect. Limitations Retrospective study. Conclusions Only a minority of patients with severe AD responded to efalizumab treatment in a standard dose.     

Spatiotemporal expression patterns of slit and robo genes in the rat brain.

Diffusible chemorepellents play a major role in guiding developing axons toward their correct targets by preventing them from entering or steering them away from certain regions. Genetic studies in Drosophila revealed a repulsive guidance system that prevents inappropriate axons from crossing the central nervous system midline; this repulsive system is mediated by the secreted extracellular matrix protein Slit and its receptors Roundabout (Robo). Three distinct slit genes (slit1, slit2, and slit3) and three distinct robo genes (robo1, robo2, rig-1) have been cloned in mammals. However, to date, only Robo1 and Robo2 have been shown to be receptors for Slits. In rodents, Slits have been shown to function as chemorepellents for several classes of axons and migrating neurons. In addition, Slit can also stimulate the formation of axonal branches by some sensory axons. To identify Slit-responsive neurons and to help analyze Slit function, we have studied, by in situ hybridization, the expression pattern of slits and their receptors robo1 and robo2, in the rat central nervous system from embryonic stages to adult age. We found that their expression patterns are very dynamic: in most regions, slit and robo are expressed in a complementary pattern, and their expression is up-regulated postnatally. Our study confirms the potential role of these molecules in axonal pathfinding and neuronal migration. However, the persistence of robo and slit expression suggests that the couple slit/robo may also have an important function in the adult brain.     

Highly parallel identification of essential genes in cancer cells

More complete knowledge of the molecular mechanisms underlying cancer will improve prevention, diagnosis and treatment. Efforts such as The Cancer Genome Atlas are systematically characterizing the structural basis of cancer, by identifying the genomic mutations associated with each cancer type. A powerful complementary approach is to systematically characterize the functional basis of cancer, by identifying the genes essential for growth and related phenotypes in different cancer cells. Such information would be particularly valuable for identifying potential drug targets. Here, we report the development of an efficient, robust approach to perform genome-scale pooled shRNA screens for both positive and negative selection and its application to systematically identify cell essential genes in 12 cancer cell lines. By integrating these functional data with comprehensive genetic analyses of primary human tumors, we identified known and putative oncogenes such as EGFR, KRAS, MYC, BCR-ABL, MYB, CRKL, and CDK4 that are essential for cancer cell proliferation and also altered in human cancers. We further used this approach to identify genes involved in the response of cancer cells to tumoricidal agents and found 4 genes required for the response of CML cells to imatinib treatment: PTPN1, NF1, SMARCB1, and SMARCE1, and 5 regulators of the response to FAS activation, FAS, FADD, CASP8, ARID1A and CBX1. Broad application of this highly parallel genetic screening strategy will not only facilitate the rapid identification of genes that drive the malignant state and its response to therapeutics but will also enable the discovery of genes that participate in any biological process.     

Involvement of sinoaortic afferents in renal sympathoinhibition and vasodilation induced by acute hypernatremia

Despite the abundance of evidence that supports the important role of aortic and carotid afferents to short‐term regulation of blood pressure and detection of variation in the arterial PO₂, PCO₂ and pH, relatively little is known regarding the role of these afferents during changes in the volume and composition of extracellular compartments. The present study sought to determine the involvement of these afferents in the renal vasodilation and sympathoinhibition induced by hypertonic saline (HS) infusion. Sinoaortic‐denervated and sham male Wistar rats were anaesthetised with intravenous (i.v.) urethane (1.2 g/kg body weight (bw)) prior to the measurement of the mean arterial pressure (MAP), renal vascular conductance (RVC) and renal sympathetic nerve activity (RSNA). In the sham group, the HS infusion (3 mol/L NaCl, 1.8 mL/kg bw, i.v.) induced transient hypertension (12 ± 4 mmHg from baseline, peak at 10 min; P < 0.05), an increase in RVC (127 ± 9% and 150 ± 13% from baseline, at 20 and 60 min respectively; P < 0.05) and a decrease in RSNA (?34 ± 10% and ?29 ± 5% from baseline, at 10 and 60 min respectively; P < 0.05). In sinoaortic‐denervated rats, HS infusion promoted a sustained pressor response (30 ± 5 and 17 ± 6 mmHg of baseline values, at 10 and 30 min respectively; P < 0.05) and abolished the increase in RVC (85 ± 8% from baseline, at 10 min) and decrease in RSNA (?4 ± 3% from baseline, at 10 min). These results suggest that aortic and carotid afferents are involved in cardiovascular and renal sympathoinhibition responses induced by acute hypernatremia.