New immunosuppressive agents in transplantation

Immunosuppressive agents have enabled the development of allogenic transplantation during the last 40 years, allowing considerable improvement in graft survival. However, several issues remain such as the nephrotoxicity of calcineurin inhibitors, the cornerstone of immunosuppressive regimens and/or the higher risk of opportunistic infections and cancers. Most immunosuppressive agents target T cell activation and may not be efficient enough to prevent allo-immunization in the long term. Finally, antibody mediated rejection due to donor specific antibodies strongly affects allograft survival.Many drugs have been tested in the last decades, but very few have come to clinical use. The most recent one is CTLA4-Ig (belatacept), a costimulation blockade molecule that targets the second signal of T cell activation and is associated with a better long term kidney function than calcineurin inhibitors, despite an increased risk of acute cellular rejection.The research of new maintenance long-term immunosuppressive agents focuses on costimulation blockade. Agents inhibiting CD40-CD40 ligand interaction may enable a good control of both T cells and B cells responses. Anti-CD28 antibodies may promote regulatory T cells. Agents targeting this costimulation pathways are currently evaluated in clinical trials.Immunosuppressive agents for ABMR treatment are scarce since anti-CD20 agent rituximab and proteasome inhibitor bortezomib have failed to demonstrate an interest in ABMR. New drugs focusing on antibodies removal (imlifidase), B cell and plasmablasts (anti-IL-6/IL-6R, anti-CD38…) and complement inhibition are in the pipeline, with the challenge of their evaluation in such a heterogeneous pathology.     

Virtual Crossmatching in Kidney Transplantation: The Wait Is Over

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Aortitis and periaortitis: The puzzling spectrum of inflammatory aortic diseases

Aortitis and periaortitis are inflammatory diseases of the aorta and its main branches; they differ in the extension of inflammation, which is confined to the aortic wall in aortitis, and spreads to the periaortic space in periaortitis. Aortitis is classified as non-infectious or infectious. Non-infectious aortitis represents a common feature of large-vessel vasculitides but can also be isolated or associated with other rheumatologic conditions. Periaortitis can be idiopathic or secondary to a wide array of etiologies such as drugs, infections, malignancies, and other proliferative diseases. Notably, both aortitis and periaortitis may arise in the context of IgG4-related disease, a recently characterised fibro-inflammatory systemic disease. Prompt recognition, correct diagnosis and appropriate treatment are essential in order to avoid life-threatening complications.     

程序性死亡蛋白-1抗体治疗晚期胃癌的临床研究新进展

目前化疗仍为晚期胃癌的标准治疗手段,而多数患者诊断时已接近晚期。近年新兴的免疫治疗手段程序性死亡蛋白-1(PD-1,programmed death l)抗体,通过阻断肿瘤细胞逃避自身免疫机制,重新激活自身免疫对肿瘤的杀伤作用,从而达到肿瘤的治疗作用。针对晚期胃癌的PD-1抗体治疗的临床研究已在国内外开展,大部分均有较好效果。本文对近年免疫治疗中的PD-1抗体在晚期胃癌的重要临床研究进展进行介绍。     

Perceived Discriminatory Factors that Impact Prenatal Care Satisfaction and Attendance Among Adolescent and Young Adult Couples

ObjectiveTo identify possible discriminatory factors that lead to prenatal care dissatisfaction and disengagement from prenatal care among young, expecting couples with a focus on exploring the experiences of Black and Latinx participants.MethodsA total of 296 young adolescent couples were recruited. Each couple consisted of an expecting female (ExpF) and an expecting male (ExpM). Participants were asked to give responses to a survey, and data was collected at 3 different time points.ParticipantsThe sample consisted of 296 expecting young couples.SettingParticipants were recruited from obstetrics and gynecology clinics and ultrasound clinics from 4 university-affiliated hospitals in southern Connecticut.Outcome MeasuresThe main outcome measure was prenatal care satisfaction. The secondary outcome was number of prenatal care visits that were attended by each member of the couple dyad. Both of these outcomes were assessed to evaluate whether discriminatory factors that participants experienced in healthcare had an effect on each outcome.ResultsA total of 51 males (17.5%) and 36 females (12.4%) reported a perception of experiencing discrimination in the healthcare system a few times a year or more. Those who believed that race contributed to discrimination in the healthcare system were 2.45 times more likely to have an unpleasant prenatal visit (P = .018). Those who believed that age contributed to discrimination in the healthcare system were 2.74 times more likely to have an unpleasant prenatal visit (P = .001). Participants who believed that physical appearance contributed to discrimination in the healthcare system were 2.83 times more likely to have an unpleasant prenatal visit (P = .01).ConclusionBlack and Latinx young expecting couples are not exempt from discriminatory experiences during prenatal care. Recommendations for quality improvement in prenatal healthcare settings include implementation of standard evaluative measures specific to personal treatment and supportiveness of the medical team.     

Does obesity put your brain at risk?

Background and aimsThe negative impact of obesity on the brain is an issue of increasing clinical interest. Hence, this review summarized evidence linking obesity with brain morphology (gray and white matter volume), brain function (functional activation and connectivity), and cognitive function.MethodsA criticals review of the relevant published English articles between 2008 and 2022, using PubMed, Google Scholar and Science Direct. Studies were included if (1) an experimental/intervention study was conducted (2) the experiment/intervention included both high fat diet or body weight, whether it could counteract the negative effect brain morphological or functional change. Critical analysis for a supporting study was also carried out.ResultsBrain dysfunction can be recognized as result from neuroinflammation, oxidative stress, change in gut-brain hormonal functionality decrease regional blood flow or diminished hippocampal size and change in gut-brain hormonal functionality; which collectively translate into a cycle of deranged metabolic control and cognitive deficits, often obesity referred as changes in brain biochemistry and brain function. Recently, a few changes in brain structure and functions could be traced back even to obese children or adult. Evidence here suggested that obesity elicits early neuroinflammation effects, which likely disrupt the normal metabolism in hypothalamus, and hippocampus result from brain insulin resistance. The mechanisms of these robust effects are discussed herein.ConclusionBrain disease is inseparable from obesity itself and requires a better recognition to allow future therapeutic targeting for treatment of obesity. Additional research is needed to identify the best treatment targets and to identify if these changes reversible.     

Hypervariable antigenic region 1 of classical swine fever virus E2 protein impacts antibody neutralization

Envelope glycoprotein E2 of classical swine fever virus (CSFV) is the major antigen that induces neutralizing antibodies and confers protection against CSFV infection. There are three hypervariable antigenic regions (HAR1, HAR2 and HAR3) of E2 that are different between the group 1 vaccine C-strain and group 2 clinical isolates. This study was aimed to characterize the antigenic epitope region recognized by monoclonal antibody 4F4 (mAb-4F4) that is present in the group 2 field isolate HZ1-08, but not in the C-strain, and examine its impact on neutralization titers when antisera from different recombinant viruses were cross-examined. Indirect ELISA with C-strain E2-based chimeric proteins carrying the three HAR regions showed that the mAb-4F4 bound to HAR1 from HZ1-08 E2, but not to HAR2 or HAR3, indicating that the specific epitope is located in the HAR1 region. Of the 6 major residues differences between C-strain and field isolates, Glu713 in the HAR1 region of strain HZ1-08 is critical for mAb-4F4 binding either at the recombinant protein level or using intact recombinant viruses carrying single mutations. C-strain-based recombinant viruses carrying the most antigenic part of E2 or HAR1 from strain HZ1-08 remained non-pathogenic to pigs and induced good antibody responses. By cross-neutralization assay, we observed that the anti-C-strain serum lost most of its neutralization capacity to RecC-HZ-E2 and QZ-14 (subgroup 2.1d field isolate in 2014), and vice versa. More importantly, the RecC-HAR1 virus remained competent in neutralizing ReC-HZ-E2 and QZ-14 strains without compromising the neutralization capability to the recombinant C-strain. Thus, we propose that chimeric C-strain carrying the HAR1 region of field isolates is a good vaccine candidate for classical swine fever.     

Crohn's disease with gastroduodenal involvement: Diagnostic approach

Crohn's disease(CD) is a chronic idiopathic inflammatory disease of gastrointestinal tract characterizedby segmental and transmural involvement of gastrointestinal tract. Ileocolonic and colonic/anorectal is a most common and account for 40% of cases and involvement of small intestine is about 30%. Isolated involvement of stomach is an extremely unusual presentation of the disease accounting for less than 0.07% of all gastrointestinal CD. To date there are only a few documented case reports of adults with isolated gastric CD and no reports in the pediatric population. The diagnosis is difficult to establish in such cases with atypical presentation. In the absence of any other source of disease and in the presence of nonspecific upper gastrointestinal endoscopy and histological findings, serological testing can play a vital role in the diagnosis of atypical CD. Recent studies have suggested that perinuclear anti-neutrophil cytoplasmic antibody and anti-Saccharomycescervisia antibody may be used as additional diagnostic tools. The effectiveness of infliximab in isolated gastric CD is limited to only a few case reports of adult patients and the long-term outcome is unknown.     

重症肌无力患者血清Titin抗体和RyR抗体的临床研究

目的探讨重症肌无力（MG）患者血清Titin抗体和Ryanodine受体（RyR）抗体的临床意义。方法采用ELISA法检测61例MG患者和35例健康体验者（正常对照组）的血清Titin抗体、RyR抗体、AChR抗体。结果MG组Titin抗体和RyR抗体阳性率均显著高于对照组（均P＜0.001）；合并胸腺瘤MG（MGT）组患者Titin抗体阳性率明显高于未合并胸腺瘤MG（NTMG）组（P＜0.01）；MGT组和NTMG组患者RyR抗体阳性率差异无统计学意义（P＞0.05）；晚发型MG患者中Titin抗体和RyR抗体阳性率均明显高于早发型MG患者（均P＜0.05）；全身型或重症型（ⅡA、ⅡB、Ⅲ、Ⅳ型）Titin抗体阳性率显著高于眼肌型（Ⅰ型）（P＜0.01），而两组间RyR抗体阳性率未见统计学差异（P＞0.05）；MG患者Titin抗体和RyR抗体水平与肌无力严重程度相关分析呈正相关（r=0.520、0.487，均P＜0.01）。结论Titin抗体和RyR抗体检测有助于MG的诊断，且Titin抗体有助于鉴别MG患者是否伴随胸腺瘤及进行Osserman分型。Titin抗体与RyR抗体水平还与MG患者病情的严重程度相关，可应用于评估MG患者的病情与预后。