Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective

'Protective autoimmunity' refers to a well-controlled anti-self response that helps the body resist neurodegeneration. The response is mediated by autoimmune T cells, which produce cytokines and growth factors. Using an in vitro assay of hippocampal slices, we show that the cytokines interferon-gamma and (especially) interleukin-4, characteristic of pro-inflammatory and anti-inflammatory T cells, respectively, can make microglia neuroprotective. Aggregated beta-amyloid, like bacterial cell wall-derived lipopolysaccharide, rendered the microglia cytotoxic. Cytotoxicity was correlated with a signal transduction pathway that down-regulates expression of class-II major histocompatibility proteins (MHC-II) through the MHC-II-transactivator and the invariant chain. Protection by interleukin-4 was attributed to down-regulation of tumor necrosis factor-alpha and up-regulation of insulin-like growth factor I. These findings suggest that beneficial or harmful expression of the local immune response in the damaged CNS depends on how microglia interpret the threat, and that a well-regulated T-cell-mediated response enables microglia to alleviate rather than exacerbate stressful situations in the CNS.     

The role of HLA A2 and Cw2 in the pathogenesis of human demodicosis

BACKGROUND: Demodicosis is a chronic skin disease caused by parasitic mites of the genus Demodex. It usually affects the face area causing major esthetical problems. The pathogenesis of demodicosis is not fully understood; however, it is quite apparent that immunological mechanisms mediate its development. OBJECTIVE: The goal of this study was to study the correlation between immunological and immunogenetic data obtained from patients with demodicosis in order to clarify the pathogenesis of Demodex infestation. METHODS: Twenty-five patients with demodicosis and 13 age- and sex-matched healthy subjects participated in the study. The presence of mites was determined by microscopic inspection of sebum gland secretions. The immune response was evaluated by identifying membrane markers of different immune cells using monoclonal antibodies (anti-CD3+, CD4+, CD8+, CD16+, CD20+ and CD95+) while the concentration of IgA, IgM and IgG was measured by simple radial immunodiffusion. The level of circulating immune complexes and total hemolytic complement as well as the preparatory and digestive function of neutrophils and the functional activity of leukocytes were also studied. Patients were typed for HLA A, B, Bw and Cw using the microlymphocytotoxicity method. RESULTS: The comparison between patients with and without the A2 phenotype showed that the latter have lower numbers of CD8+, lower functional activity of leukocytes, higher concentrations of IgA, larger affected skin areas and are more often affected by deep papular and papulopustular forms of demodicosis than those with the A2 phenotype, showing that this allele has a protective role in demodicosis. Patients exhibiting the Cw2 phenotypes were rather susceptible to demodicosis. They showed decreased numbers of CD3+, increased levels of phagocytic activity, higher mite density and severer skin damage as compared to patients lacking Cw2. CONCLUSIONS: The HLA A2 and Cw2 phenotypes have an important diagnostic, prognostic and pathogenetic significance and could play a role in resistance or susceptibility to demodicosis by regulating the end phase of the immune response.     

Preimplantation genetic diagnosis for polycystic kidney disease

OBJECTIVE: To use preimplantation genetic diagnosis for achieving a polycystic kidney disease (PKD)-free pregnancy for a couple in which the female partner was affected by PKD but whose PKD1 or PKD2 carrier status was not established. DESIGN: Case report. SETTING: The IVF program of Reproductive Genetics Institute, Chicago, Illinois. PATIENT(S): An at-risk couple with the female partner affected by PKD, whose PKD1 or PKD2 carrier status was not established. INTERVENTION(S): Removal of PB1 and PB2 and testing for three closely linked markers to PKD1 (Kg8, D16S664, and SM7) and four closely linked markers to PKD2 (D4S2922, D4S2458, D4S423, and D4S1557) after standard IVF. MAIN OUTCOME MEASURE(S): Deoxyribonucleic acid analysis of PB1 and PB2 indicating whether corresponding oocytes were PKD1 or PKD2 allele free, for the purpose of transferring only embryos resulting from mutation-free oocytes. RESULT(S): Of 11 oocytes tested by PB1 and PB2 DNA analysis, 7 were predicted to contain PKD1 or PKD2, with the remaining 4 free of both mutations. Three embryos resulting from these oocytes were transferred, yielding a twin pregnancy and the birth of two unaffected children. CONCLUSION(S): This is the first preimplantation genetic diagnosis for PKD, which resulted in the birth of healthy twins confirmed to be free of PKD1 and PKD2. Preimplantation genetic diagnosis based on linked marker analysis provides an alternative for avoiding the pregnancy and birth of children with PKD, even in at-risk couples without exact PKD1 or PKD2 carrier information.     

The postoperative blood-sparing efficacy of oral versus intravenous tranexamic acid after total knee replacement

To assess the blood-sparing efficacy of tranexamic acid (TA) administered orally or via a variable IV infusion, 80 healthy patients undergoing elective total knee replacement were studied according to a prospective, controlled, randomized, single-blinded study design. Patients were allocated to one of four treatment groups. In group TA-long, 30 min before deflation of the limb tourniquet, an IV bolus dose of TA 15 mg/kg was administered over 30 min. Thereafter, a constant IV infusion of 10 mg . kg(-1) . h(-1) was administered until 12 h after final deflation of the limb tourniquet. In group TA-short, a similar regimen was followed; however, the constant IV infusion was discontinued 2 h after final deflation of the limb tourniquet (time of discharge from the postanesthesia care unit). Thereafter, oral TA 1 g was administered after 6 and 12 h. In group TA-oral, 60 min before surgery an oral dose of TA 1 g was administered. After surgery, a similar dose of TA was administered every 6 h for the next 18 h. In the control group, TA was not administered. At patient discharge, postoperative allogeneic blood administration was significantly more in group Control when compared with each of the three TA treatment groups. Because oral drug administration is simple and does not require specific infusion equipment, the authors suggest that oral TA is a superior blood-sparing strategy compared with IV drug administration.     

Role of adenosine receptor activation in antioxidant enzyme regulation during ischemia-reperfusion in the isolated rat heart

The aim of the present study was to investigate the protective role of pharmacological preconditioning on antioxidant enzymes using A(1) and A(3) adenosine receptor agonists in the recovery of the isolated myocardium after cardioplegic ischemia. Two different modes of preconditioning were studied: isolated rat hearts were perfused with A(1) receptor agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) or A(3) 2-chloro-N(6)-(3-iodobenzyl) adenosine-5'-N-methyluronamide (Cl-IB-MECA) (1 nM), followed by cardioplegic ischemia and reperfusion (30 min each) (perfusion mode), or CCPA or Cl-IB-MECA (100 micro g/kg) were injected intravenously 24 h before the experiment (injection mode). Hearts treated with CCPA improved in terms of mechanical function, infarct size, ATP levels, superoxide dismutase, and catalase (p < 0.005) in both modes of administration. Cl-IB-MECA was beneficial mainly in the injected group. Reduced damage to the mitochondria in the CCPA-treated hearts was observed using electron microscopy evaluation. In the Cl-IB-MECA-injected hearts, mitochondrial damage was moderate. CCPA in both modes of treatment and Cl-IB-MECA in the injected mode were beneficial in protecting the perfused isolated rat heart, subjected to normothermic cardioplegic ischemia. This protection was partially related to the higher myocardial activity of superoxide dismutase and catalase.     

Predictors of self-reported HIV infection among drug injectors in Ukraine

OBJECTIVE: To identify characteristics, including current high-risk drug and sex behaviors, associated with self-reported HIV infection among injection drug users (IDUs) in Ukraine. DESIGN: Targeted sampling of IDUs from Kiev, Odessa, and Makeevka/Donetsk, Ukraine. METHODS: From June through August 2002, 100 IDUs from each site were recruited through street outreach, including 212 who had previously been tested for HIV and knew their serostatus. Subjects were administered a standardized computer-assisted interview assessing HIV-related drug and sex risk behaviors and history of HIV testing. RESULTS: Twenty six percent of the 212 participants reported they were HIV-positive. Univariate followed by multiple logistic regression analyses were used to identify factors associated with HIV infection. In the 30-day period before their interview, HIV-infected IDUs were significantly more likely to have injected with a needle previously used by another injector without disinfecting, frontloaded and/or backloaded, and shared the drug solution from a common container. In addition, they had higher prevalence rates for hepatitis B virus and hepatitis C virus than those not infected with HIV. On the other hand, they were more likely to have reported no sex partners and, if sexually active, more likely to have used a condom. CONCLUSION: The high HIV seroprevalence among IDUs in Ukraine, combined with their continued engagement in needle-related risk behaviors, assures the continuance of the epidemic in this region, a region that is the epicenter of HIV in Europe.     

Mental health, social functioning, and disability in postwar Afghanistan

Context  More than 2 decades of conflict have led to widespread human suffering and population displacement in Afghanistan. In 2002, the Centers for Disease Control and Prevention and other collaborating partners performed a national population-based mental health survey in Afghanistan. Objective  To provide national estimates of mental health status of the disabled (any restriction or lack of ability to perform an activity in the manner considered normal for a human being) and nondisabled Afghan population aged at least 15 years. Design, Setting, and Participants  A national multistage, cluster, population-based mental health survey of 799 adult household members (699 nondisabled and 100 disabled respondents) aged 15 years or older conducted from July to September 2002. Fifty district-level clusters were selected based on probability proportional to size sampling. One village was randomly selected in each cluster and 15 households were randomly selected in each village, yielding 750 households. Main Outcome Measures  Demographics, social functioning as measured by selected questions from the Medical Outcomes Study 36-Item Short-Form Health Survey, depressive symptoms measured by the Hopkins Symptoms Checklist-25, trauma events and symptoms of posttraumatic stress disorder (PTSD) measured by the Harvard Trauma Questionnaire, and culture-specific symptoms of mental illness and coping mechanisms. Results  A total of 407 respondents (62.0%) reported experiencing at least 4 trauma events during the previous 10 years. The most common trauma events experienced by the respondents were lack of food and water (56.1%) for nondisabled persons and lack of shelter (69.7%) for disabled persons. The prevalence of respondents with symptoms of depression was 67.7% (95% confidence interval [CI], 54.6%-80.7%) and 71.7% (95% CI, 65.0%-78.4%), and symptoms of anxiety 72.2% (95% CI, 63.8%-80.7%) and 84.6% (95% CI, 74.1%-95.0%) for nondisabled and disabled respondents, respectively. The prevalence of symptoms of PTSD was similar for both groups (nondisabled, 42.1%; 95% CI, 34.2%-50.1%; and disabled, 42.2%; 95% CI, 29.2%-55.2%). Women had significantly poorer mental health status than men did. Respondents who were disabled had significantly lower social functioning and poorer mental health status than those who were nondisabled. Feelings of hatred were high (84% of nondisabled and 81% of disabled respondents). Coping mechanisms included religious and spiritual practices; focusing on basic needs, such as higher income, better housing, and more food; and seeking medical assistance. Conclusions  In this nationally representative survey of Afghans, prevalence rates of symptoms of depression, anxiety, and PTSD were high. These data underscore the need for donors and health care planners to address the current lack of mental health care resources, facilities, and trained mental health care professionals in Afghanistan.