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The blood–brain barrier (BBB) is confined to the endothelium of brain capillaries and is indispensable for fluid homeostasis and neuronal function. In this study, we show that endothelial Wnt/beta-catenin (beta-cat) signaling regulates induction and maintenance of BBB characteristics during embryonic and postnatal development. Endothelial specific stabilization of beta-cat in vivo enhances barrier maturation, whereas inactivation of beta-cat causes significant down-regulation of claudin3 (Cldn3), up-regulation of plamalemma vesicle-associated protein, and BBB breakdown. Stabilization of beta-cat in primary brain endothelial cells (ECs) in vitro by N-terminal truncation or Wnt3a treatment increases Cldn3 expression, BBB-type tight junction formation, and a BBB characteristic gene signature. Loss of beta-cat or inhibition of its signaling abrogates this effect. Furthermore, stabilization of beta-cat also increased Cldn3 and barrier properties in nonbrain-derived ECs. These findings may open new therapeutic avenues to modulate endothelial barrier function and to limit the devastating effects of BBB breakdown.
The thickness of the cerebral cortex can provide valuable information about normal and abnormal neuroanatomy. High resolution MRI together with powerful image processing techniques has made it possible to perform these measurements automatically over the whole brain. Here we present a method for automatically generating voxel-based cortical thickness (VBCT) maps. This technique results in maps where each voxel in the grey matter is assigned a thickness value. Sub-voxel measurements of thickness are possible using sub-sampling and interpolation of the image information. The method is applied to repeated MRI scans of a single subject from two MRI scanners to demonstrate its robustness and reproducibility. A simulated data set is used to show that small focal differences in thickness between two groups of subjects can be detected. We propose that the analysis of VBCT maps can provide results that are complementary to other anatomical analyses such as voxel-based morphometry.
Background: In Germany, 17% of 59,000 persons living with HIV/AIDS are female. Accordingly, the research focus in clinical studies as well as in cohort analyses has been almost exclusively on HIV-positive men. As a consequence, there is an urgent need to characterize and evaluate the outcome of HAART in HIV-positive women and to identify special requirements of this particular patient population.
Methods: Cross-sectional multicentre (n = 31 centres) evaluation to observe characteristics of 1,557 HIV-positive women receiving medical care in Germany between June 2007 and March 2008. Data acquisition was performed using standardized questionnaires.
Summary of results: Of 1,557 HIV-positive women studied, 1,191 (77%) received HAART. Mean age was 40 years and average time of known HIV-infection was 9 years. Risk of HIV transmission was: 40% heterosexual intercourse in Germany, 36% heterosexual intercourse in a high prevalence country; 17% IDU; 7% other reasons for transmission. 46% of the women had a migration background. Mean time on antiretroviral treatment was 7 years. 53% of the female participants had been treated with >2 HAART-regimens. 47% of the study subjects received a PI-based regimen, 33% a NNRTI-based regimen; 20% were on other combinations. The most commonly used PI and NNRTI were lopinavir/r and nevirapine, respectively. Only 48% of all women under HAART achieved a viral load <40 copies/ml. There was a significant difference between the PI-treated group with 44% patients <40 copies/ml and the NNRTI-treated group with 56% <40 copies/ml (p = 0.003).
Conclusion: We found that HIV-positive women depicted an inferior virological response to HAART compared to those previously published in German cohort analyses dominated by men (response rates >75%). Possible differences in adherence or drug resistance may have impacted these results and are currently being evaluated in ongoing sub-analyses. Of note, the lack of a study arm with male patients is a limitation of this investigation. However, this is partly off-set by the fact that there are good comparative data in the male population found in other cohorts. We conclude that our results are in discordance to the popular assumption that there are no gender specific differences in virological treatment outcome of HAART.
Poster presentation: Purpose of the study To compare the virological, immunological and clinical response to three boosted double protease inhibitor (PI) regimens of saquinavir and ritonavir in combination with lopinavir (LOPSAQ), atazanavir (ATSAQ) or fosamprenavir (FOSAQ) without reverse transcriptase inhibitors (RTI) in HIV-positive patients with limited RTI treatment options. ...
Objective: To develop comprehensive recommendations for the treatment of the various clinical manifestations of psoriatic arthritis (PsA) based on evidence obtained from a systematic review of the literature and from consensus opinion. Methods: Formal literature reviews of treatment for the most significant discrete clinical manifestations of PsA (skin and nails, peripheral arthritis, axial disease, dactylitis and enthesitis) were performed and published by members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Treatment recommendations were drafted for each of the clinical manifestations by rheumatologists, dermatologists and PsA patients based on the literature reviews and consensus opinion. The level of agreement for the individual treatment recommendations among GRAPPA members was assessed with an online questionnaire. Results: Treatment recommendations were developed for peripheral arthritis, axial disease, psoriasis, nail disease, dactylitis and enthesitis in the setting of PsA. In rotal, 19 recommendations were drafted, and over 80% agreement was obtained on 16 of them. In addition, a grid that factors disease severity into each of the different disease manifestations was developed to help the clinician with treatment decisions for the individual patient from an evidenced-based perspective. Conclusions: Treatment recommendations for the cardinal physical manifestations of PsA were developed based on a literature review and consensus between rheumatologists and dermatologists. In addition, a grid was established to assist in therapeutic reasoning and decision making for individual patients. It is anticipated that periodic updates will take place using this framework as new data become available.
Treatment predictors are important tools for the management of therapy in patients with chronic hepatitis B and C virus (HBV, HCV) infection. In chronic hepatitis B, several pretreatment parameters have been identified for prediction of virologic response to interferon alfa-based antiviral therapies or treatment with polymerase inhibitors. In interferon alfa and pegylated interferon alfa-treated patients, low baseline HBV DNA concentrations, HBV genotype A (B), and high baseline ALT levels are significantly associated with treatment response. In patients treated with nucleos(t)ide analogues, low baseline HBV DNA but not viral genotype is positively associated with virologic response. During treatment the best predictor of response is HBV DNA kinetics. Early viral suppression is associated with favourable virologic response and reduced risk for subsequent resistance mutations. For the current standard treatment with pegylated interferon alfa and ribavirin in patients with chronic hepatitis C, infection with HCV genotypes 2 and 3, baseline viral load below 400,000–800,000 IU/ml, Asian and Caucasian ethnicity, younger age, low GGT levels, absence of advanced fibrosis/cirrhosis, and absence of steatosis in the liver have been identified as independent pretreatment predictors of a sustained virologic response. After initiation of treatment, initial viral decline with undetectable HCV-RNA at week 4 of therapy (RVR) is the best predictor of sustained virologic response independent of HCV genotype.
The timing of feedback to early visual cortex in the perception of long-range apparent motion
(2008)
When 2 visual stimuli are presented one after another in different locations, they are often perceived as one, but moving object. Feedback from area human motion complex hMT/V5+ to V1 has been hypothesized to play an important role in this illusory perception of motion. We measured event-related responses to illusory motion stimuli of varying apparent motion (AM) content and retinal location using Electroencephalography. Detectable cortical stimulus processing started around 60-ms poststimulus in area V1. This component was insensitive to AM content and sequential stimulus presentation. Sensitivity to AM content was observed starting around 90 ms post the second stimulus of a sequence and most likely originated in area hMT/V5+. This AM sensitive response was insensitive to retinal stimulus position. The stimulus sequence related response started to be sensitive to retinal stimulus position at a longer latency of 110 ms. We interpret our findings as evidence for feedback from area hMT/V5+ or a related motion processing area to early visual cortices (V1, V2, V3).
Objectives To examine the dose-response relationship between cumulative exposure to kneeling and squatting as well as to lifting and carrying of loads and symptomatic knee osteoarthritis (OA) in a population-based case-control study. Methods In five orthopedic clinics and five practices we recruited 295 male patients aged 25 to 70 with radiographically confirmed knee osteoarthritis associated with chronic complaints. A total of 327 male control subjects were recruited. Data were gathered in a structured personal interview. To calculate cumulative exposure, the self-reported duration of kneeling and squatting as well as the duration of lifting and carrying of loads were summed up over the entire working life. Results The results of our study support a dose-response relationship between kneeling/squatting and symptomatic knee osteoarthritis. For a cumulative exposure to kneeling and squatting > 10.800 hours, the risk of having radiographically confirmed knee osteoarthritis as measured by the odds ratio (adjusted for age, region, weight, jogging/athletics, and lifting or carrying of loads) is 2.4 (95% CI 1.1-5.0) compared to unexposed subjects. Lifting and carrying of loads is significantly associated with knee osteoarthritis independent of kneeling or similar activities. Conclusions As the knee osteoarthritis risk is strongly elevated in occupations that involve both kneeling/squatting and heavy lifting/carrying, preventive efforts should particularly focus on these "high-risk occupations".
Poster presentation: Purpose of the study The aim of the Rainbow Cohort is to assess the tolerability and efficacy of initiating treatment with, or switching treatment to saquinavir (SQV) 500 mg film-coated tablet formulation. We present the final 48-week subgroup analysis of antiretroviral therapy (ART)-naïve patients. ...
Dendrite morphology, a neuron's anatomical fingerprint, is a neuroscientist's asset in unveiling organizational principles in the brain. However, the genetic program encoding the morphological identity of a single dendrite remains a mystery. In order to obtain a formal understanding of dendritic branching, we studied distributions of morphological parameters in a group of four individually identifiable neurons of the fly visual system. We found that parameters relating to the branching topology were similar throughout all cells. Only parameters relating to the area covered by the dendrite were cell type specific. With these areas, artificial dendrites were grown based on optimization principles minimizing the amount of wiring and maximizing synaptic democracy. Although the same branching rule was used for all cells, this yielded dendritic structures virtually indistinguishable from their real counterparts. From these principles we derived a fully-automated model-based neuron reconstruction procedure validating the artificial branching rule. In conclusion, we suggest that the genetic program implementing neuronal branching could be constant in all cells whereas the one responsible for the dendrite spanning field should be cell specific.