Microglial TNFR2 signaling regulates the inflammatory response after CNS injury in a sex-specific fashion.

Microglia, the resident immune cells of the central nervous system (CNS), play a major role in damage progression and tissue remodeling after acute CNS injury, including ischemic stroke (IS) and spinal cord injury (SCI). Understanding the molecular mechanisms regulating microglial responses to injury may thus reveal novel therapeutic targets to promote CNS repair. Here, we investigated the role of microglial tumor necrosis factor receptor 2 (TNFR2), a transmembrane receptor previously associated with pro-survival and neuroprotective responses, in shaping the neuroinflammatory environment after CNS injury. By inducing experimental IS and SCI in Cx3cr1CreER:Tnfrsf1bfl/fl mice, selectively lacking TNFR2 in microglia, and corresponding Tnfrsf1bfl/fl littermate controls, we found that ablation of microglial TNFR2 significantly reduces lesion size and pro-inflammatory cytokine levels, and favors infiltration of leukocytes after injury. Interestingly, these effects were paralleled by opposite sex-specific modifications of microglial reactivity, which was found to be limited in female TNFR2-ablated mice compared to controls, whereas it was enhanced in males. In addition, we show that TNFR2 protein levels in the cerebrospinal fluid (CSF) of human subjects affected by IS and SCI, as well as healthy donors, significantly correlate with disease stage and severity, representing a valuable tool to monitor the inflammatory response after acute CNS injury. Hence, these results advance our understanding of the mechanisms regulating microglia reactivity after acute CNS injury, aiding the development of sex- and microglia-specific, personalized neuroregenerative strategies.

A preclinical randomized controlled multi-centre trial of anti-interleukin-17A treatment for acute ischaemic stroke.

Multiple consensus statements have called for preclinical randomized controlled trials to improve translation in stroke research. We investigated the efficacy of an interleukin-17A neutralizing antibody in a multi-centre preclinical randomized controlled trial using a murine ischaemia reperfusion stroke model. Twelve-week-old male C57BL/6 mice were subjected to 45 min of transient middle cerebral artery occlusion in four centres. Mice were randomly assigned (1:1) to receive either an anti-interleukin-17A (500 µg) or isotype antibody (500 µg) intravenously 1 h after reperfusion. The primary endpoint was infarct volume measured by magnetic resonance imaging three days after transient middle cerebral artery occlusion. Secondary analysis included mortality, neurological score, neutrophil infiltration and the impact of the gut microbiome on treatment effects. Out of 136 mice, 109 mice were included in the analysis of the primary endpoint. Mixed model analysis revealed that interleukin-17A neutralization significantly reduced infarct sizes (anti-interleukin-17A: 61.77 ± 31.04 mm3; IgG control: 75.66 ± 34.79 mm3; P = 0.01). Secondary outcome measures showed a decrease in mortality (hazard ratio = 3.43, 95% confidence interval = 1.157-10.18; P = 0.04) and neutrophil invasion into ischaemic cortices (anti-interleukin-17A: 7222 ± 6108 cells; IgG control: 28 153 ± 23 206 cells; P < 0.01). There was no difference in Bederson score. The analysis of the gut microbiome showed significant heterogeneity between centres (R = 0.78, P < 0.001, n = 40). Taken together, neutralization of interleukin-17A in a therapeutic time window resulted in a significant reduction of infarct sizes and mortality compared with isotype control. It suggests interleukin-17A neutralization as a potential therapeutic target in stroke.

The Impact of Negative Mood on Event-Related Potentials When Viewing Pornographic Pictures.

Background: Negative affective states may increase the risk for problematic pornography use. Underlying neurophysiological mechanisms are, however, not completely understood. Previous research suggests that the participants' emotional state may affect neural processing of sexual stimuli. The aim of this study was to investigate neural correlates of negative affect-induced alterations in sexual cue reactivity in healthy men. The moderating effects of habitual porn consumption, trait sexual motivation, and symptoms of cybersex addiction were also considered. Method: Sixty-four healthy men engaged in a sexual cue reactivity task (passive viewing of explicit sexual pictures and neutral pictures depicting scenes of social interaction) during negative (n = 32) vs. neutral affect (n = 32), induced via tailored feedback on a performance task. Self-reported sexual arousal and event-related brain potentials indicated cue reactivity and motivated attention. Symptoms of cybersex addiction and trait sexual motivation were assessed with the help of the short Internet Addiction Test, adapted to online sexual activities, and the Trait Sexual Motivation Questionnaire. Results: Negative feedback increased negative affect after the performance task. While sexual pictures compared to neutral pictures elicited significantly larger P300 and late positive potential (LPP) amplitudes, there was no general effect of negative feedback on sexual stimuli-related P300 and LPP amplitudes. In the negative feedback group, men with higher solitary sexual motivation levels showed higher P300/LPP difference amplitudes for sexual stimuli compared to men with lower levels of solitary sexual motivation. The opposite effect was found in the group with neutral feedback. There was no link to other aspects of trait sexual motivation and symptoms of cybersex addiction. Conclusions: Results suggest that higher levels of solitary sexual motivation may enhance motivated attention toward sexual stimuli among men receiving negative performance feedback. Other characteristics of sexual behaviors and traits provided no exploratory value. Future studies extending onto men suffering from compulsive sexual behavior disorder will have to closer look at the neurophysiological bases of why and when some men develop an addictive pornography consumption.

Profiling Complement System Components in Primary CNS Vasculitis.

Complement activation has been implicated in the pathogenesis of many vasculitic syndromes such as anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Using an array-based multiplex system, we simultaneously quantified serum and CSF levels of activated and regulatory complement system proteins in patients with primary CNS vasculitis (PACNS; n = 20) compared to patients with non-inflammatory conditions (n = 16). Compared to non-inflammatory controls, levels of C3a, C5a, and SC5b-9, indicative for general activation of the complement system, of C4a, specific for the activation of the classical pathway, Ba and Bb, reflective for alternative complement activation as well as concentrations of complement-inhibitory proteins factor H and factor I were unchanged in patients with PACNS. Our study does not support the hypothesis that complement activation is systemically increased in patients with PACNS.

Students at Saarland University dental school-A survey on their background and curriculum perception.

INTRODUCTION: With the aim of optimising dental education without overburdening students, new legislation restructuring the undergraduate dental curriculum in German is under way. The goal of this study was to survey the current situation of dental students at one specific university with respect to their socio-economic background, admission to dental school, curriculum perception and work-life balance. MATERIALS AND METHODS: An online questionnaire was presented to all undergraduate students enrolled at Saarland University who had at least completed the first preclinical practical course in dentistry. RESULTS: A response rate of 85% was reached with two-thirds of the student body being females. The profession of 40% of students' parents either was physicians or dentist. Students reported a slight reduction in time spent for leisure activities during their studies, however, with sports activities hardly being affected. With respect to a proper work-life balance, almost 50% of respondents considered their clinical workload as being too high. Students did not express a clear opinion regarding curriculum structure, whilst the content mostly satisfied their expectations (59%). The majority (71%) of students considered their preclinical training as being demanding whilst less than 3% fully agreed that preclinical training provided an optimal background for patient treatment. The learning modules in the first clinical semester were considered as being adequate by 56% of students. Examinations during courses were seen as properly reflecting the students' knowledge by 79% of students. DISCUSSION: The status quo of German dental students is characterised by a high workload affecting the students' work-life balance and by a transition between preclinical and clinical education which only about half the student body perceives as being adequate. Patient-based examinations obviously are not considered as being problematic.

Development of a high-resolution NGS-based HLA-typing and analysis pipeline.

The human leukocyte antigen (HLA) complex contains the most polymorphic genes in the human genome. The classical HLA class I and II genes define the specificity of adaptive immune responses. Genetic variation at the HLA genes is associated with susceptibility to autoimmune and infectious diseases and plays a major role in transplantation medicine and immunology. Currently, the HLA genes are characterized using Sanger- or next-generation sequencing (NGS) of a limited amplicon repertoire or labeled oligonucleotides for allele-specific sequences. High-quality NGS-based methods are in proprietary use and not publicly available. Here, we introduce the first highly automated open-kit/open-source HLA-typing method for NGS. The method employs in-solution targeted capturing of the classical class I (HLA-A, HLA-B, HLA-C) and class II HLA genes (HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, HLA-DPB1). The calling algorithm allows for highly confident allele-calling to three-field resolution (cDNA nucleotide variants). The method was validated on 357 commercially available DNA samples with known HLA alleles obtained by classical typing. Our results showed on average an accurate allele call rate of 0.99 in a fully automated manner, identifying also errors in the reference data. Finally, our method provides the flexibility to add further enrichment target regions.

Trichophyton rubrum-induced Majocchi's Granuloma in a heart transplant recipient. A therapeutic challenge.

BACKGROUND: Solid organ transplant recipients are at an increased risk for infections because of long-term immunosuppression to prevent graft rejection. Fungal infections with dermatophytes are a common cause of cutaneous infections seen in organ transplant recipients and cutaneous dermatophyte infections may progress to Majocchi's granuloma. Itraconazole is an anti-fungal compound used for the treatment of infections of the skin, nails and mucous membranes. MAIN OBSERVATION: We report on a heart transplant recipient who developed widespread Trichophyton rubrum infection presenting as Majocchi's granuloma. Itraconazole treatment was complicated by drug interactions. Tricho-phyton rubrum infection progressed, while itraconazole treatment was varied in dose and delivery form. CONCLUSIONS: In patients with Trichophyton rubrum infections, refractory to itraconazole treatment, altered drug absorption or drug interactions has to be considered. Careful monitoring and adjustment of itraconazole is of vital importance.

[Lesions of the mouth mucosa. An anamnestic and clinical study of 100 consecutive patients with mucosal lesions]. / Veränderungen der Mundschleimhaut. Eine anamnestische und klinische Untersuchung von 100 konsekutiv zugeviesenen Patienten mit Mukosaläsionen.

The present study evaluates and analyzes anamnestic and clinical findings of 100 consecutively referred patients with oral mucosal lesions. The mean age of the cohort was 50.5 years (range 8-91 years) with a female rate of 60 percent. A total of 9 malignant neoplasia were found among the 100 mucosal lesions, including 7 squamous cell carcinomas and 2 mucoepidermoid carcinomas. In addition, 11 cases presented with leukoplakia and 4 cases with lichen planus, both recognized as possible precancerous conditions. These figures support the essential role of the dentist with respect to initial diagnosis and prevention of oral cancer. In addition, stomatologic follow-up examinations are recommended to be performed by each and every general practitioner. In the near future, the dentist will assess oral mucosal lesions more frequently due to the increasing number of elderly patients and to the fact that elderly people present with more lesions compared to younger patients. consistent to literature data, patients with leukoplasia and squamous cell carcinoma had the highest rates of tobacco and alcohol consumption. Therefore, the dentist may also become active in giving preventive information to the patient. the results of the present study showed, that--by employing a standardized examination--a correct clinical diagnosis was identical to the final diagnosis established by laboratory techniques.