PD-1 signaling promotes control of chronic viral infection by restricting type-I-interferon-mediated tissue damage

Immune responses are essential for pathogen elimination but also cause tissue damage, leading to disease or death. However, it is unclear how the host immune system balances control of infection and protection from the collateral tissue damage. Here, we show that PD-1-mediated restriction of immune responses is essential for durable control of chronic LCMV infection in mice. In contrast to responses in the chronic phase, PD-1 blockade in the subacute phase of infection paradoxically results in viral persistence. This effect is associated with damage to lymphoid architecture and subsequently decreases adaptive immune responses. Moreover, this tissue damage is type I interferon dependent, as sequential blockade of the interferon receptor and PD-1 pathways prevents immunopathology and enhances control of infection. We conclude that PD-1-mediated suppression is required as an immunoregulatory mechanism for sustained responses to chronic viral infection by antagonizing type-I interferon-dependent immunopathology

Methylglyoxal reduces molecular responsiveness to 4 weeks of endurance exercise in mouse plantaris muscle

Endurance exercise triggers skeletal muscle adaptations, including enhanced insulin signaling, glucose metabolism, and mitochondrial biogenesis. However, exercise-induced skeletal muscle adaptations may not occur in some cases, a condition known as exercise-resistance. Methylglyoxal (MG) is a highly reactive dicarbonyl metabolite and has detrimental effects on the body such as causing diabetic complications, mitochondrial dysfunction, and inflammation. This study aimed to clarify the effect of methylglyoxal on skeletal muscle molecular adaptations following endurance exercise. Mice were randomly divided into 4 groups (n = 12 per group): sedentary control group, voluntary exercise group, MG-treated group, and MG-treated with voluntary exercise group. Mice in the voluntary exercise group were housed in a cage with a running wheel, while mice in the MG-treated groups received drinking water containing 1% MG. Four weeks of voluntary exercise induced several molecular adaptations in the plantaris muscle, including increased expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α), mitochondria complex proteins, toll-like receptor 4 (TLR4), 72-kDa heat shock protein (HSP72), hexokinase II, and glyoxalase 1; this also enhanced insulin-stimulated Akt Ser473 phosphorylation and citrate synthase activity. However, these adaptations were suppressed with MG treatment. In the soleus muscle, the exercise-induced increases in the expression of TLR4, HSP72, and advanced glycation end products receptor 1 were inhibited with MG treatment. These findings suggest that MG is a factor that inhibits endurance exercise-induced molecular responses including mitochondrial adaptations, insulin signaling activation, and the upregulation of several proteins related to mitochondrial biogenesis, glucose handling, and glycation in primarily fast-twitch skeletal muscle

Glycative stress and skeletal muscle dysfunctions: as an inducer of "Exercise-Resistance."

Skeletal muscle, the largest tissue in the body, is often overlooked for its role as a locomotor organ, however over the past few decades it has been revealed that it also has an important role as a metabolic organ. In recent years, its role as an endocrine organ that controls the homeostatic functions of organs throughout the body mediated by myokine secretion has come under close scrutiny. Skeletal muscle is indispensable for our daily life activities, and in order to maintain its function, it is necessary to understand the factors that deteriorate muscle function and establish a countermeasure. Glycative stress has recently received attention as a factor that impairs skeletal muscle function. Accumulation of advanced glycation end products (AGEs) in skeletal muscle impairs contractile function and myogenic potential. Furthermore, AGEs in the blood elicit inflammatory signals through binding to RAGE (Receptor for AGEs) expressed on muscle cells, resulting in muscle proteolysis. Habitual exercise is important to mitigate the negative effects of such glycative stress on skeletal muscle. On the other hand, it is known that the beneficial effects of exercise vary among individuals. The state in which the effects of exercise are difficult to obtain is called "exercise-resistance, " and we hypothesize that glycative stress may be one of the causes of exercise-resistance. In this paper, we will discuss the possibility of glycative stress as an inducer of exercise resistance and summarize its impacts on skeletal muscle

The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells

Members of the Runx family of transcriptional regulators are required for the appropriate expression of CD4 and CD8 at discrete stages of T cell development. The roles of these factors in other aspects of T cell development are unknown. We used a strategy to conditionally inactivate the genes encoding Runx1 or Runx3 at different stages of thymocyte development, demonstrating that Runx1 regulates the transitions of developing thymocytes from the CD4−CD8− double-negative stage to the CD4+CD8+ double-positive (DP) stage and from the DP stage to the mature single-positive stage. Runx1 and Runx3 deficiencies caused marked reductions in mature thymocytes and T cells of the CD4+ helper and CD8+ cytotoxic T cell lineages, respectively. Runx1-deficient CD4+ T cells had markedly reduced expression of the interleukin 7 receptor and exhibited shorter survival. In addition, inactivation of both Runx1 and Runx3 at the DP stages resulted in a severe block in development of CD8+ mature thymocytes. These results indicate that Runx proteins have important roles at multiple stages of T cell development and in the homeostasis of mature T cells

肺外科手術における術後早期の高次脳機能および術中脳酸素需給バランスに対する麻酔薬の効果 : ランダム化比較試験

PURPOSE: One-lung ventilation (OLV) may impair cerebral oxygen balance and induce postoperative cognitive dysfunction (POCD). It is unclear whether the type of anesthetic influences the incidence of POCD in patients undergoing OLV. This prospective study compared the incidence of POCD and intraoperative cerebral oxygen desaturation in OLV patients anesthetized with propofol vs sevoflurane during lung surgery. METHODS: There were 148 participants enrolled in this study and randomized equally to either the propofol or the sevoflurane group. Anesthesia was maintained with either propofol or sevoflurane combined in both groups with fentanyl and epidural anesthesia. Regional cerebral oxygen saturation (rSO2), jugular bulb venous oxygen saturation (SjO2), and the incidence of cerebral oxygen desaturation (rSO2 or SjO2 < 50% or rSO2 < 80% of baseline) were measured during anesthesia. Cognitive function was assessed using seven neurocognitive tests two days preoperatively, five days postoperatively (primary outcome), and three months postoperatively. Bivariable and multivariable regression analyses were conducted to identify factors associated with POCD. RESULTS: Rates of POCD did not differ statistically between groups five days postoperatively (propofol, 16/72 patients; sevoflurane, 24/72 patients; RR, 0.67; 95% CI, 0.39 to 1.15; P = 0.14) or three months postoperatively (propofol, 9/60 patients; sevoflurane, 12/58 patients; RR, 0.73; 95% CI, 0.33 to 1.59; P = 0.42). Only three subjects per group showed intraoperative cerebral oxygen desaturation. Multivariable regression analysis revealed older age as an independent predictor of POCD. CONCLUSIONS: No statistically significant difference in the incidence of POCD could be detected between the sevoflurane and propofol anesthesia groups. Postoperative cognitive dysfunction was relatively frequent following OLV in both groups. (REGISTRATION NUMBER: UMIN 000002826).博士（医学）・乙第1397号・平成29年3月15日© Canadian Anesthesiologists' Society 2016This is a post-peer-review, pre-copyedit version of an article published in Canadian journal of anaesthesia. The final authenticated version is available online at: http://dx.doi.org/10.1007/s12630-016-0700-4

Case of adult-onset Coats’ disease with epiretinal membrane treated with 25-gauge pars plana vitrectomy

We describe a case of untreated adult-onset Coats’ disease with a proliferative epiretinal membrane (ERM) treated successfully with 25-gauge pars plana vitrectomy (25GPPV). A 26-year-old man presented with a 3-week history of decreased vision in his left eye. At the initial examination, the decimal best-corrected visual acuity (BCVA) was 0.7 in the left eye. Ophthalmoscopy revealed the typical appearance of Stage 2A Coats’ disease but with a proliferative ERM in the posterior pole. The patient received 2 monthly intravitreal injections of 2.5 mg bevacizumab, 5 laser photocoagulations to the area of telangiectasia, and 1 session of cryoretinopexy. Nine months after the initial visit, a traction by the ERM on the parafoveal area developed causing macular edema which reduced the BCVA to 0.3. He underwent 25GPPV with the removal of the ERM. In addition, the peripheral telangiectasia was treated intraoperatively with both laser photocoagulation and cryoretinopexy. Postoperatively, the traction to the parafoveal area was released and the BCVA improved to 0.6 which remained stable during the follow-up period of 13 months.We conclude that 25GPPV combined with ERM peeling, laser photocoagulation, and cryoretinopexy can be effective for adult-onset Coats’ disease associated with an ERM

The transcription factor Foxo1 controls germinal center B cell proliferation in response to T cell help

Germinal center (GC) B cells cycle between two states, the light zone (LZ) and the dark zone (DZ), and in the latter they proliferate and hypermutate their immunoglobulin genes. How this functional transition takes place is still controversial. In this study, we demonstrate that ablation of Foxo1 after GC development led to the loss of the DZ GC B cells and disruption of the GC architecture, which is consistent with recent studies. Mechanistically, even upon provision of adequate T cell help, Foxo1-deficient GC B cells showed less proliferative expansion than controls. Moreover, we found that the transcription factor BATF was transiently induced in LZ GC B cells in a Foxo1-dependent manner and that deletion of BATF similarly led to GC disruption. Thus, our results are consistent with a model where the switch from the LZ to the DZ is triggered after receipt of T cell help, and suggest that Foxo1-mediated BATF up-regulation is at least partly involved in this switch

Quantification of (-)-epigallocatechin-3-gallate Inhibition of Migration and Invasion of Oral Squamous Cell Carcinoma Cell Lines Using Real-time Cell Analysis

Catechins found in green tea, in particular (−)-epigallocatechin-3-gallate (EGCG), have antitumor activity. The primary antitumor actions of catechins are anti-oxidative, anti-angiogenic, and anti-metastatic effects. Cell migration and invasion contribute to the metastatic potential of tumors. Real-time cell analysis (RTCA) measures cell migration and invasion in vitro. In the present study, using RTCA, we investigated whether the cell migration and invasion of oral squamous cell carcinomas (OSCCs) of the tongue and floor of the mouth were inhibited by EGCG. Studies were performed using the human SCC-4 and SAS cell lines, which are poorly differentiated OSCCs of the tongue, and the HO-1-u-1 cell line, an OSCC of the floor of the mouth. SCC-4 cells exhibited high cell migration and invasion compared with the SAS and HO-1-u-1 cells. EGCG was most effective in inhibiting the migration and invasion of SCC-4 cells, and inhibited OSCC cell invasion more strongly than it inhibited cell migration. EGCG inhibited the expression of matrix metalloproteinase (MMP)-2, MMP-9, and integrin α1 and β1 mRNA in the OSCC cell lines, particularly SCC-4 cells. The findings of the present study suggest that EGCG inhibits OSCC cell migration and invasion by inhibiting MMP-2, MMP-9, and integrin α1and β1 expression. Thus, EGCG may be a suitable agent or lead compound for the inhibition of OSCC metastasis