Prion diseases of humans and farm animals: epidemiology, genetics, and pathogenesis

Neuronal vacuolation (spongiosis), neuronal death, and pronounced glial reactions are the hallmarks of transmissible spongiform encephalopathies (TSEs), or prion diseases. A wealth of physical, biochemical, and immunological evidence indicates that the TSE agent, termed prion, does not contain agent-specific nucleic acid encoding its own constituents, as is the case for all other infectious pathogens. Also, no adaptive immune responses are elicited upon infection. A defining feature of TSEs is the deposition, mainly in the brain and lymphoreticular tissues, of an aggregated and structurally abnormal protein, designated PrP(Sc) or PrP-res, which represents a conformational isomer of the ubiquitous surface protein PrP(C). Biochemical and genetic evidence link PrP and its gene to the disease. Although TSEs are by definition transmissible, a growing number of Prnp-associated non-infectious neurodegenerative proteinopathies are now being recognized.     

Complement activation,regulation, and molecular basis for complement‐related diseases

The complement system is an essential element of the innate immune response that becomes activated upon recognition of molecular patterns associated with microorganisms, abnormal host cells, and modified molecules in the extracellular environment. The resulting proteolytic cascade tags the complement activator for elimination and elicits a pro‐inflammatory response leading to recruitment and activation of immune cells from both the innate and adaptive branches of the immune system. Through these activities, complement functions in the first line of defense against pathogens but also contributes significantly to the maintenance of homeostasis and prevention of autoimmunity. Activation of complement and the subsequent biological responses occur primarily in the extracellular environment. However, recent studies have demonstrated autocrine signaling by complement activation in intracellular vesicles, while the presence of a cytoplasmic receptor serves to detect complement‐opsonized intracellular pathogens. Furthermore, breakthroughs in both functional and structural studies now make it possible to describe many of the intricate molecular mechanisms underlying complement activation and the subsequent downstream events, as well as its cross talk with, for example, signaling pathways, the coagulation system, and adaptive immunity. We present an integrated and updated view of complement based on structural and functional data and describe the new roles attributed to complement. Finally, we discuss how the structural and mechanistic understanding of the complement system rationalizes the genetic defects conferring uncontrolled activation or other undesirable effects of complement.     

Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson's disease

We examined the effect of pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist of the thiazolidinedione class, on dopaminergic nerve cell death and glial activation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. The acute intoxication of C57BL/6 mice with MPTP led to nigrostriatal injury, as determined by tyrosine hydroxylase (TH) immunocytochemistry, and HPLC detection of striatal dopamine and metabolites. Damage to the nigrostriatal dopamine system was accompanied by a transient activation of microglia, as determined by macrophage antigen-1 (Mac-1) and inducible nitric oxide synthase (iNOS) immunoreactivity, and a prolonged astrocytic response. Orally administered pioglitazone (approximately 20 mg/kg/day) attenuated the MPTP-induced glial activation and prevented the dopaminergic cell loss in the substantia nigra pars compacta (SNpc). In contrast, there was little reduction of MPTP-induced dopamine depletion, with no detectable effect on loss of TH immunoreactivity and glial response in the striatum of pioglitazone-treated animals. Low levels of PPARgamma expression were detected in the ventral mesencephalon and striatum, and were unaffected by MPTP or pioglitazone treatment. Since pioglitazone affects primarily the SNpc in our model, different PPARgamma-independent mechanisms may regulate glial activation in the dopaminergic terminals compared with the dopaminergic cell bodies after acute MPTP intoxication.     

Non-invasive diagnosis of cutaneous leishmaniasis by the direct boil loop-mediated isothermal amplification method and MinION™ nanopore sequencing

Cutaneous leishmaniasis (CL) is gaining attention as a public health problem. We present two cases of CL imported from Syria and Venezuela in Japan. We diagnosed them as CL non-invasively by the direct boil loop-mediated isothermal amplification method and an innovative sequencing method using the MinION? sequencer. This report demonstrates that our procedure could be useful for the diagnosis of CL in both clinical and epidemiological settings.     

Endotoxemia,vitamin D and premature biological ageing in Arab adults with different metabolic states

There are limited studies on the association of endotoxin, a potent mediator of gut-derived inflammation and telomere length (TL). We investigated (1) the influence of adiposity on endotoxin and TL amongst Saudi adults according to type 2 diabetes mellitus (T2DM) status and (2) the influence vitamin D may have on TL attrition. Anthropometric data and fasting blood samples were taken from 775 Saudi adults visiting different primary care centers in Riyadh [387 T2DM and 388 non-T2DM]. TL, derived from peripheral blood mononuclear cells, was analyzed by Quantitative real-time polymerase chain reaction and circulating endotoxin levels by Limulus Amebocyte Lysate assay. Subjects were stratified based on obesity and T2DM status. A significant lower TL was observed in the non-obese T2DM group as compared with their non-obese, non-T2DM counterparts (p = 0.002). Significant inverse associations between TL, endotoxin and endotoxin activity were observed in the cohort with obesity. Regression analysis showed that endotoxin was a significant predictor for TL in all subjects and even after stratification according to subgroups; with variances perceived in circulating TL stronger among non-T2DM obese (10%; p = 0.003) than non-T2DM non-obese (12%; p = 0.007). Also, in the non-T2DM group, TL and HDL-cholesterol predicted 29% of the variances perceived in 25(OH)D (p < 0.001). Taken together these findings show that circulating endotoxin and 25(OH)D are associated with premature biological ageing influenced by adiposity and metabolic state; suggesting future intervention studies to manipulate gut microbiome and or vitamin D levels may offer ways to mitigate premature TL attrition.     

Mechanisms of Salmonella pathogenesis in animal models

Animal models play an important role in understanding the mechanisms of bacterial pathogenesis. Here we review the recent studies of Salmonella infection in various animal models. Although mice are a classic animal model for Salmonella, mice do not normally get diarrhea, raising the question of how well the model represents normal human infection. However, pre-treatment of mice with oral streptomycin, which apparently reduces the normal microbiota, leads to an inflammatory diarrheal response upon oral infection with Salmonella. This has led to a re-evaluation of the role of various Salmonella virulence factors in colonization of the intestine and induction of diarrhea. Indeed, it is now clear that Salmonella purposefully induces inflammation, which leads to the production of both carbon sources and terminal electron acceptors by the host that allow Salmonella to outgrow the normal intestinal microbiota. Overall use of this modified mouse model provides a more nuanced understanding of Salmonella intestinal infection in the context of the microbiota with implications for the ability to predict human risk.     

TNFα‐induced abnormal activation of TNFR/NF‐κB/FTH1 in endometrium is involved in the pathogenesis of early spontaneous abortion

Early spontaneous abortion (ESA) is one of the most common complications during pregnancy and the inflammation condition in uterine environment such as long‐term exposure to high TNFα plays an essential role in the aetiology. Ferritin heavy chain (FTH1) is considered to be closely associated with inflammation and very important in normal pregnancy, yet the underlying mechanism of how TNFα induced abortion and its relationship with FTH1 remain elusive. In this study, we found that TNFα and FTH1 were positively expressed in decidual stromal cells and increased significantly in the ESA group compared with the normal pregnancy group (NP group). Besides, TNFα expression was positively correlated with FTH1 expression. Furthermore, in vitro cell model demonstrated that high TNFα could induce the abnormal signals of TNFR/NF‐κB/FTH1 and activate apoptosis both in human endometrium stromal cells (hESCs) and in local decidual tissues. Taken together, the present findings suggest that the excessive apoptosis in response to TNFα‐induced upregulation of FTH1 may be responsible for the occurrence of ESA, and thus provide a possible therapeutic target for the treatment of ESA.     

肋间神经阻滞复合全麻联合静脉自控镇痛对胸腔镜肺大疱切除术患者术后镇痛效果及恢复情况的影响

摘要 目的：探讨在胸腔镜肺大疱切除术中应用肋间神经阻滞复合全麻联合静脉自控镇痛的术后镇痛效果及患者恢复情况。方法：研究对象选取进行胸腔镜肺大疱切除术的80例患者,依据简单数字表法分为对照组和观察组,每组各40例。对照组接受全麻联合静脉自控镇痛,观察组在此基础上复合肋间神经阻滞,比较两组术后镇痛效果及恢复情况。结果：与术前比,术后12 h、24 h两组患者的CD4⁺、CD4⁺/CD8⁺均先降低后升高,且观察组各时间点均高于对照组;两组患者的CD8⁺均先升高后降低,且观察组各时间点均低于对照组（P<0.05）。术后24 h、48 h,观察组比对照组在镇痛泵按压次数和输注镇痛药物总量有减少（P<0.05）。与对照组比,观察组患者的术毕到拔管时间、下床活动时间、住院时间均更短（P<0.05）。与对照组（22.50%、20.00%）比,观察组患者的并发症、不良反应总发生率（2.50%、5.00%）更低（P<0.05）。结论：在胸腔镜肺大疱切除术中应用肋间神经阻滞复合全麻联合静脉自控镇痛,取得了显著的镇痛成效,不仅能够减轻患者的术后疼痛,还能减轻机体免疫抑制,同时不增加并发症和不良反应发生风险,临床应用安全性较高。     

小儿肺热咳喘颗粒联合雾化吸入用乙酰半胱氨酸溶液对支气管肺炎患儿肺通气功能、炎症因子和免疫球蛋白的影响

摘要 目的：观察小儿肺热咳喘颗粒联合雾化吸入用乙酰半胱氨酸溶液对支气管肺炎患儿肺通气功能、炎症因子和免疫球蛋白的影响。方法：选择2019年9月-2023年1月期间合肥市第二人民医院收治的100例支气管肺炎患儿,采用双色球法将患儿分为对照组和研究组,各为50例。对照组患儿接受雾化吸入用乙酰半胱氨酸溶液,研究组患儿在对照组的基础上接受小儿肺热咳喘颗粒。对比两组临床症状、炎症因子水平[白细胞介素-6（IL-6）、降钙素原（PCT）、C反应蛋白（CRP）]、免疫球蛋白[免疫球蛋白（Ig）A、IgM、IgG]、肺通气功能指标[吸气时间（TI）、呼气时间（TE）、吸呼比（TI/TE）、达峰时间比（TPF%TE）、达峰容积比（VPF%VE）]和不良反应发生率。结果：与对照组相比,研究组的肺部湿啰音消失时间、咳嗽消失时间、咳痰消失时间、退热时间更短（P<0.05）。研究组治疗10 d后CRP、IL-6、PCT低于对照组（P<0.05）。研究组治疗10 d后IgA、IgM、IgG高于对照组（P<0.05）。研究组治疗10 d后VT、TI、TE、TI/TE、TPF%TE、VPF%VE高于对照组（P<0.05）。两组不良反应发生率对比未见差异（P>0.05）。结论：小儿肺热咳喘颗粒联合雾化吸入用乙酰半胱氨酸溶液治疗支气管肺炎,可有效缩短临床症状缓解时间,改善肺通气功能,降低炎症因子水平,调节免疫球蛋白,且安全性较好。