Gründung eines Heimatvereins in Londorf

Recent cases of successful control of human immunodeficiency virus (HIV) by bone marrow transplant in combination with suppressive antiretroviral therapy (ART) and very early initiation of ART have provided proof of concept that HIV infection might now be cured. Current efforts focusing on gene therapy, boosting HIV-specific immunity, reducing inflammation and activation of latency have all been the subject of recent excellent reviews. We now propose an additional avenue of research towards a cure for HIV: targeting HIV apoptosis regulatory pathways. The central enigma of HIV disease is that HIV infection kills most of the CD4 T cells that it infects, but those cells that are spared subsequently become a latent reservoir for HIV against which current medications are ineffective. We propose that if strategies could be devised which would favor the death of all cells which HIV infects, or if all latently infected cells that release HIV would succumb to viral-induced cytotoxicity, then these approaches combined with effective ART to prevent spreading infection, would together result in a cure for HIV. This premise is supported by observations in other viral systems where the relationship between productive infection, apoptosis resistance, and the development of latency or persistence has been established. Therefore we propose that research focused at understanding the mechanisms by which HIV induces apoptosis of infected cells, and ways that some cells escape the pro-apoptotic effects of productive HIV infection are critical to devising novel and rational approaches to cure HIV infection

Undiagnosed mood disorders and sleep disturbances in primary care patients with chronic musculoskeletal pain.

Objective. The study aims to determine the prevalence of undiagnosed comorbid mood disorders in patients suffering chronic musculoskeletal pain in a primary care setting and to identify sleep disturbances and other associated factors in these patients, and to compare the use of health services by chronic musculoskeletal pain patients with and without comorbid mood disorders. Design. Cross-sectional study. Subjects. A total of 1,006 patients with chronic musculoskeletal pain from a representative sample of primary care centers were evaluated. Outcome Measures. Pain was measured using a visual analog scale and the Primary Care Evaluation of Mental Disorders questionnaire was used to measure mood disorders. Results. We observed a high prevalence of undiagnosed mood disorders in chronic musculoskeletal pain patients (74.7%, 95% confidence interval [CI] 71.9–77.4%), with greater comorbidity in women (adjusted odds ratio [OR] = 1.91, 95% CI 1.37–2.66%) and widow(er)s (adjusted OR = 1.87, 95% CI 1.19–2.91%). Both sleep disturbances (adjusted OR = 1.60, 95% CI 1.17–2.19%) and pain intensity (adjusted OR = 1.02, 95% CI 1.01–1.02%) displayed a direct relationship with mood disorders. Moreover, we found that chronic musculoskeletal pain patients with comorbid mood disorders availed of health care services more frequently than those without (P < 0.001). Conclusions. The prevalence of undiagnosed mood disorders in patients with chronic musculoskeletal pain is very high in primary care settings. Our findings suggest that greater attention should be paid to this condition in general practice and that sleep disorders should be evaluated in greater detail to achieve accurate diagnoses and select the most appropriate treatment

CD4 T Cells Treated with gp120 Acquire a CD45R0+/CD45RA+ Phenotype

HIV-infected patients exhibit quantitative and qualitative defects in CD4 T cells, including having increased numbers of CD4+CD45R0+/CD45RA+ T cells, although it remains unclear how these cells arise. Here we demonstrate that gp120 treatment of activated but not resting primary human CD4 T cells decreases number of cells with single positive CD45R0+/CD45RA- effector memory phenotype while proportionally increasing the subset of cells with double positive CD45R0+/CD45RA+ mixed phenotype. We found that double positive CD45R0+/CD45RA+CD4 T cells preferentially undergo apoptosis while single positive CD45R0+/CD45RA- and CD45R0-/CD45RA+ do not. Blocking gp120-CD4 interaction with sCD4 or inhibition Lck activity reverses gp120 induced increase in double positive CD45R0+/CD45RA+CD4 T cells and subsequently diminishes the apoptosis of double positive CD45R0+/CD45RA+ cells. Altogether these data indicate that gp120 ligation of the CD4 receptor increases the number of double positive CD45R0+/CD45RA+ CD4 T cells which subsequently undergo apoptosis in a CD4 dependent manner

Return to work and workplace activity limitations following total hip or knee replacement

SummaryObjectiveTotal hip (THR) and knee (TKR) replacements increasingly are performed on younger people making return to work a salient outcome. This research evaluates characteristics of individuals with early and later return to work following THR and TKR. Additionally, at work limitations pre-surgery and upon returning to work, and factors associated with work limitations were evaluated.Methods190 THR and 170 TKR of a total 931 cohort participants were eligible (i.e., working or on short-term disability pre-surgery). They completed questionnaires pre-surgery and 1, 3, 6 and 12 months post-surgery that included demographics, type of occupation, and the Workplace Activity Limitations Scale (WALS).Results166 (87%) and 144 (85%) returned to work by 12 months following THR and TKR, respectively. Early (1 month) return to work was associated with, male gender, university education, working in business, finance or administration, and low physical demand work. People with THR returned to work earlier than those with TKR. For both groups, less pain and every day functional limitations were associated with less workplace activity limitations at the time return to work.ConclusionsThe majority of individuals working prior to surgery return to work following hip or knee replacement for osteoarthritis (OA) and experience fewer limitations at work than pre-surgery. The changing workforce dynamics and trends toward surgery at younger ages mean that these are important outcomes for clinicians to assess. Additionally, this is important information for employers in understanding continued participation in employment for people with OA

HIV Protease Cleavage of Procaspase 8 is Necessary for Death of HIV-Infected Cells

Numerous host and viral factors are capable of causing death of HIV infected cells, uninfected bystander cells, or both. We assessed the relevance of HIV protease in infected cell killing by mutating its obligate substrate for death, procaspase 8. VSV pseudotyped HIV infection of cells expressing WT caspase 8 resulted in apoptotic cell death and generation of the HIV protease specific cleavage product of procaspase 8, casp8p41. Conversely, both cell death and casp8p41 production were inhibited in cells expressing procaspase 8 engineered to be resistant to HIV protease cleavage. Lymph nodes from HIV-infected patients with ongoing viral replication also selectively expressed casp8p41, which colocalized with both infected and apoptotic cells. HIV protease cleavage of procaspase 8 appears to be a necessary event for infected cell killing, which is responsible for infected cell death within lymphoid tissues from HIV-infected patients

TRAIL Dependent Fratricidal Killing of gp120 Primed Hepatocytes by HCV Core Expressing Hepatocytes

The mechanism by which HIV and HCV cooperatively accelerate hepatocyte damage is not clearly understood; however, each virus affects the TRAIL: TRAIL- receptor system. We, therefore, questioned whether the independent effects of HCV and HIV combine to synergistically result in TRAIL dependent hepatocyte killing. We describe that Huh7 hepatocytes treated with HIV gp120 results in both increase TRAIL-R2 expression and an acquired sensitivity to TRAIL mediated killing. Moreover HCV infection and HCV core expression alone in Huh7 cells upregulates TRAIL. Co-incubation of HIV gp120 primed hepatocytes with HCV core expressing hepatocytes results in the selective death of the HIV gp120 primed hepatocytes that is selectively blocked by TRAIL–R2-Fc fusion protein. Liver biopsies from HIV mono-infected patients have increased TRAIL-R2; biopsies from HCV infected patients have increased TRAIL, while co-infected liver biopsies have increased PARP cleavage within hepatocytes indicating enhanced apoptosis. These findings suggest a pathogenic model to understand why HIV/HCV co-infection accelerates liver injury

Structural analysis of the role of the (β)3 subunit of the (α)V(β)3 integrin in IGF-I signaling

The disintegrin echistatin inhibits ligand occupancy of the (α)V(β)3 integrin and reduces Insulin-like growth factor I (IGF-I) stimulated migration, DNA synthesis, and receptor autophosphorylation in smooth muscle cells. This suggests that ligand occupancy of the (α)V(β)3 receptor is required for full activation of the IGF-I receptor. Transfection of the full-length (β)3 subunit into CHO cells that have no endogenous (β)3 and do not migrate in response to IGF-I was sufficient for IGF-I to stimulate migration of these anchorage dependent cells. In contrast, transfection of either of two truncated mutant forms of (β)3 (terminating at W(715) or E(731)) or a mutant with substitutions for Tyr(747) Tyr(759) (YY) into either CHO or into porcine smooth muscle cells did not restore the capacity of these cells to migrate across a surface in response to IGF-I. This effect was not due to loss of IGF-I receptor autophosphorylation since the response of the receptor to IGF-I was similar in cells expressing either the full-length or any of the mutant forms of the (β)3 subunit. Echistatin reduced IGF-I receptor phosphorylation in cells expressing the full-length or the YY mutant forms of (β)3 subunit, but it had no effect in cells expressing either of two truncated forms of (β)3. A cell-permeable peptide homologous to the C-terminal region of the (β)3 subunit (amino acids 747–762) reduced IGF-I stimulated migration and receptor autophosphorylation of non-transfected porcine smooth muscle cells. These results demonstrate that the full-length (β)3 with intact tyrosines at positions 747 and 759 is required for CHO cells to migrate in response to IGF-I. Furthermore, a region of critical amino acids between residues 742–762 is required for echistatin to induce its regulatory effect on receptor phosphorylation. Since the IGF-I receptor does not bind to (α)V(β)3 the results suggest that specific but distinct regions of the (β)3 subunit interact with intermediary proteins to facilitate IGF-I stimulated cell migration and echistatin induced inhibition of IGF-I signal transduction