Hitherto, the inhibition of LMP7 has been shown to suppress several autoimmune diseases which correlated with a reduction in the differentiation of pathogenic Th1 and Th17 cells. Since Th1 and especially Th17 cells play a central role in the host defence against C. albicans, we investigated the impact of immunoproteasome inhibition on the immune response against this pathogen. In a first approach, we stimulated naive splenocytes with heat-killed C. albicans yeast in vitro, leading to IL-17A and IFN-γ release into the culture supernatant. Compared to cells treated with DMSO, we observed reduced IL-17A and IFN-γ production by splenocytes pulsed with 200 nM ONX 0914 (Fig. 1A). This effect was LMP7-dependent because ONX 0914 treatment of splenocytes from LMP7−/− mice did not lead to reduced cytokine production (Supplementary Fig. S1). In order to investigate whether LMP7 inhibition has a similar effect on human peripheral blood mononuclear cells (PBMCs), PBMCs from healthy volunteers were stimulated with heat-killed C. albicans in vitro and cytokines were measured in the supernatant by ELISA. Similar to murine splenocytes, ONX 0914 treatment of human PBMCs resulted in reduced IL-17A and IFN-γ production in response to C. albicans (Fig. 1B). Interestingly, the secretion of IL-6, a key cytokine for Th17 differentiation, was reduced in human PBMCs by LMP7 inhibition while it was not affected in murine splenocytes (Fig. 1A). Next, naive murine splenocytes were negatively sorted for CD4+ T cells and either the ‘antigen presenting cells’-containing fraction (splenocytes – CD4+ T cells) or the CD4+ T cell fraction was pulsed with 200 nM ONX 0914. Untreated and treated cell fractions were combined and stimulated with heat-killed C. albicans. IFN-γ and IL-17A production was also strongly reduced by ONX 0914 treatment of only the ‘antigen presenting cells’-containing fraction (splenocytes – CD4+ T cells) (Supplementary Fig. S2A). Similarly, the release of IFN-γ and IL-17A was reduced by treatment of the CD4+ T cell fraction, although not quite significant for IFN-γ (Supplementary Fig. S2B). Moreover, when splenocytes were stimulated with C. albicans in the presence of blocking antibodies to MHC-II, we observed a strong reduction of IL-17A (Supplementary Fig. S2C) indicating that IL-17A production is to a large degree dependent on MHC-II antigen presentation. These results indicate that ONX 0914 is able to block the production of proinflammatory cytokines by directly acting on CD4+ T cells as well as affecting ‘antigen presenting cells’.

To assess the tissue outgrowth of C. albicans, kidneys, brains, and livers of the sacrificed animals were removed aseptically, weighed, and homogenized in sterile distilled water using a tissue homogenizer. The number of viable C. albicans cells in the tissues was determined by plating serial dilutions on YPD plates. The colonies were counted after 24 h of incubation at 30 °C, and the fungal burden was expressed as log10 CFU/g tissue.

Clostridium difficile의 어원은 ‘어려운 박테리아’라는 뜻으로 염증성 장 질환 환자의 50%가 이 균에 감염되며 설사, 복통, 패혈증 등을 유발할 수 있어 위험요소로 작용한다. 미국의 Clostridium difficile 감염 사례는 매년 500,000건 이상이며, 그로 인한 치료 비용은 $32억으로 추산되고, 앞으로 감염률과 치료 비용은 더욱 증가할 것으로 예상되고 있다. 더 심각한 문제는 미국 식품 산업의 70% 이상이 항생제를 사용하고 있으며, 항생제 사용으로 인해 미국 소에서 독성이 강해진 C. difficile(B1 NAP1 strain)이 발견되고 있다는 점이다. C. difficile 포자는 위산과 담즙에 노출돼도 살아남아 소장으로 유입될 수 있으며 대장에서 증식해 장내 미생물의 혼란을 유발한다. C. difficile이 크게 증식하면 면역 기능이 저하되므로 설사와 장염이 발생한다(C.diff Associated Diarrhea-CDAD). 이를 치료하기 위해 또 다시 항생제를 투여해야 하고, 이는 다시 C. difficile 감염 기회 위험을 높이는 악순환이 반복되는 것이다. 특히나 최근의 역학연구 결과들은 C. difficile 감염이 IBD 질환을 악화시키고 사망률을 높이는데 영향을 미치기 때문에 주의 깊은 진단과 관리가 필요하다는 것을 뒷받침한다. C. difficile의 진단을 위해서는 대변 검사를 통한 세포독성 검사 등을 시행해야 하고, 임상적으로 위험도가 높은 환자의 경우 의심이 될 때에는 주저하지 말고 정밀한 검사를 해야 한다. 초기 C. difficile 감염 치료를 위해서는 중증도에 따라 나누어 치료 전략을 도입해야 한다. 일반적으로 중증 감염의 경우 vancomycin 혹은 fidaxomicin이 1차 약제로 적절하고, vancomycin이 metronidazole보다 효과적이며 염증성 장 질환 환자의 대장절제 수술률을 낮출 수 있다. C. difficile 감염이 동반된 염증성 장 질환은 더 높은 대장절제 수술률과 재발률을 보이는데, C. difficile 감염 환자의 1/4은 90일 이내에 재발하고, 1/3은 단기간 내에 재발하며 고령 환자일수록 재발률이 높다. 여러 사례들은 스테로이드제제의 사용을 제한하는 것이 도움이 되며, 급속한 악화(flare) 예방을 위해 TNF 억제제를 투여하는 것이 재발과 감염을 함께 조절할 수 있는 최선의 치료 전략임을 시사했다. 최근 연구되고 있는 Fecal Microbiome Transplant(FMT) 시술도 재발성 C. difficile 감염 치료에 안전하고 효과적인 것으로 결과를 보이고 있다.

© 2018 American College of Chest Physicians Background: Acute bronchiolitis is common in young children, and some children develop chronic cough after their bronchiolitis. We thus undertook systematic reviews based on key questions (KQs) using the PICO (Population, Intervention, Comparison, Outcome) format. The KQs were: Among children with chronic cough (> 4 weeks) after acute viral bronchiolitis, how effective are the following interventions in improving the resolution of cough?: (1) Antibiotics. If so what type and for how long? (2) Asthma medications (inhaled steroids, beta2 agonist, montelukast); and (3) Inhaled osmotic agents like hypertonic saline? Methods: We used the CHEST expert cough panel’s protocol and the American College of Chest Physicians (CHEST) methodological guidelines and GRADE framework. Data from the systematic reviews in conjunction with patients¿ values and preferences and the clinical context were used to form these suggestions. Delphi methodology was used to obtain consensus. Results: Several studies and systematic reviews on the efficacy of the three types of interventions listed in the introduction were found but no data were relevant to our KQs. Thus, no recommendations on using the interventions above could be formulated. Conclusions: The panel made several consensus-based suggestions and identified directions for future studies to advance the field of managing chronic cough post-acute bronchiolitis in children.

The aim of this study was to test the impact of RST on biomarkers of acute myocardial necrosis by comparing results to those of traditional MCT. Myocardial dimensions and functions were assessed by transthoracal echocardiograpic (TTE) and electrocardiographic (ECG) investigations following each exercise session. We hypothesized, that despite its short total duration, RST training would significantly increase cTnT and CK-MB, compared to MCT of longer duration. Hypothesis confirming results would elucidate the prevalence of an exercise-induced release of myocardial necrosis biochemical markers complemented by additional information on the dose – response relationship between exercise, biomarker release and myocardial adaptations to high intensity training.

|| Jon66: … How can one argue that ACTUAL hijacking, murder, suicide bombing, indiscriminate rocket attacks, stabbings, etc., are justified because one had ancestors in the area? ||

Middleton, N. et al. Left ventricular function immediately following prolonged exercise: A meta-analysis. Med. Sci. Sports Exerc. 38, 681–687, doi: 10.1249/01.mss.0000210203.10200.12 (2006).

The release makes clear that this blood test is experimental and one can safely assume it is not yet available.

Due to its various pronounced pharmacological effects, VB is widely used in several Asian countries (e.g. Laos, China, Japan, and India)29, and has been used clinically for the therapy of a wide range of diseases. However, the toxicity caused by VB limits its clinical application. Although there are an increasing number of reports drawing attention to the adverse cardiovascular effects associated with VB administraion, there is still little known about the mechanism of cardiotoxicity. Here, the TXNIP/TRX/NF-κB and MAPK/NF-κB pathways were intensively studied to investigate the mechanism of cardiotoxicity induced by VB in rats.

The panel acknowledges uncertainty in these projected estimates, as they were based on modelling and several assumptions in the rates of biopsies and cancers detected in men that were screened and in those who were not. These are likely to vary across clinical contexts and diagnostic strategies. For example, new approaches (including genetic or biomarkers, risk stratification tools, and MRI guided biopsy323334) have the potential for avoiding biopsies in men with non-progressive and slowly progressive cancer, and thus diminish the likelihood of harm from their complications when entering screening through PSA testing. However, the impact of such modalities on patient-important outcomes remains uncertain.

The burden of illness caused by asthma in rural adolescents is poorly defined. We sought to establish knowledge of asthma self-management and various aspects of asthma morbidity i… [more]

Aim: To determine the prevalence of long term (>6 months) oral corticosteroid use and osteoporosis therapy (treatment or prevention) in patients hospitalised with COPD or asthma. Method: All patients admitted to hospital under the care of the respiratory service with a history of COPD or asthma were interviewed to assess their use of OCS, history of osteoporosis and therapy for osteoporosis. Results: 67 patients (mean±SD age 63±17) were enrolled, 48 with COPD and 19 with asthma. 19(28%) were on long term OCS and of these 7(10%) had a previous diagnosis of osteoporosis (5 had had a fracture and all were on osteoporosis therapy; 2 had had no fracture and 1 was on therapy). Of the 12( 18%) patients on long term OCS with no diagnosis of osteoporosis none were on preventative therapy. Of 48 patients not on long term OCS 8 had a previous diagnosis of osteoporosis but only 3 were on therapy. Overall 27 (40%) of 67 patients were on long term OCS or had a previous diagnosis of osteoporosis, 13 (19%) had had a fracture and 11 ( 16%) were on osteoporosis treatment. Conclusion: Amongst patients admitted to hospital with COPD or asthma use of long term OCS or history of osteoporosis is common, while therapy for prevention or treatment of osteoporosis is uncommon.