Targeted interleukin-10 plasmid DNA therapy in the treatment of osteoarthritis: Toxicology and pain efficacy assessments

Osteoarthritis results in chronic pain and loss of function. Proinflammatory cytokines create both osteoarthritis pathology and pain. Current treatments are poorly effective, have significant side effects, and have not targeted the cytokines central to osteoarthritis development and maintenance. Interleukin-10 is an anti-inflammatory cytokine that potently and broadly suppresses proinflammatory cytokine activity. However, interleukin-10 protein has a short half-life in vivo and poor joint permeability. For sustained IL-10 activity, we developed a plasmid DNA-based therapy that expresses a long-acting human interleukin-10 variant (hIL-10var). Here, we describe the 6-month GLP toxicology study of this therapy. Intra-articular injections of hIL-10var pDNA into canine stifle joints up to 1.5 mg bilaterally were well-tolerated and without pathologic findings. This represents the first long-term toxicologic assessment of intra-articular pDNA therapy. We also report results of a small double-blind, placebo-controlled study of the effect of intra-articular hIL-10var pDNA on pain measures in companion (pet) dogs with naturally occurring osteoarthritis. This human IL-10-based targeted therapy reduced pain measures in the dogs, based on veterinary and owner ratings, without any adverse findings. These results with hIL-10var pDNA therapy, well-tolerated and without toxicologic effects, establish the basis for clinical trials of a new class of safe and effective therapies for OA.     

Does choice of antiretroviral drugs matter for inflammation?

Introduction: The massive implementation of combination antiretroviral therapy (cART) has forever changed the landscape of HIV infection. This unprecedented success has turned HIV infection into a manageable chronic disease. The increased survival of people living with HIV is, however, shadowed by a high burden of aging-related comorbidities. The pathogenic basis underlying this excess of co-morbid conditions is most likely a persistent inflammatory and immune activation state, despite an optimal control of HIV replication, which in turn has largely been attributed to bacterial or bacterial products translocation from the gut.

Area covered: This review is focused on the relationship between cART and the chronic inflammatory and immune activation status in otherwise virologically well-controlled people living with HIV (PLWH). Particular focus will be placed on the differences, if any, between distinct cART modalities, with emphasis on less-drug cART regimens, and especially on dual therapies.

Expert opinion: Research to address the increased inflammatory and immune activation status of cART-treated, HIV-infected patients, should focus on adjuvant means of therapy, rather than on the cART regime itself. With current antiretrovirals, no difference between dual and triple regimens has been demonstrated, provided that virological and immunological outcomes be non-inferior.     

利培酮和齐拉西酮对精神分裂症患者血浆细胞因子的影响

目的:研究抗精神病药对精神分裂症患者细胞因子的影响。方法:符合ICD-10精神分裂症诊断的60名患者,随机分为利培酮组(给予利培酮治疗)和齐拉西酮组(给于齐拉西酮治疗),并以健康对照组比较,对患者在治疗前及治疗8周后测量血浆IL-2、IL-6及TNF-α水平,并对患者进行PANSS量表评定。结果:两组患者治疗前后血浆IL-2、IL-6及TNF-α水平与对照组比较,差异有统计学意义(P0.05)。两组患者治疗后血浆IL-2、IL-6及TNF-α水平较治疗前降低,差异有统计学意义(P0.05)。治疗前IL-2水平与PANSS量表阳性症状评分呈正相关(r=0.54,P0.05)治疗后TNF-α与阴性症状分呈显著正相关(r=0.41,P0.05)。结论:精神分裂症患者存在免疫功能异常,利培酮和齐拉西酮可以降低精神分裂症患者细胞因子水平。细胞因子水平与精神病理存在一定相关性。     

Influence of Statins on Circulating Inflammatory Cytokines in Patients With Abnormal Glucose Homeostasis: A Meta-analysis of Data From Randomized Controlled Trials

PurposeChronic inflammation increases the risks for cardiovascular disease, type 2 diabetes, and cancer. Recently, the antiinflammatory effects of statins, as cholesterol-lowering medications, have been considered. This study systematically reviewed and summarized earlier findings from randomized clinical trials about the effects of statins on serum concentrations of C-reactive protein (CRP) and interleukin (IL)-6 in patients with abnormal glucose homeostasis.MethodsRelevant articles published through October 2019 were searched using suitable key words on the PubMed/MEDLINE, SCOPUS, EMBASE, and Google Scholar databases. RCTs were included if they compared the effects of statins on serum concentrations of CRP and IL-6 in adults with abnormal glucose homeostasis. The effect sizes were represented as weighted mean differences (WMDs) and 95% CI s using a random-effects model. Subgroup analysis was performed to find possible sources of heterogeneity.FindingsOverall, 17 publications with 21 effect sizes and which enrolled 3766 subjects (1895 participants in intervention and 1871 in control groups) were included. Combining 13 effect sizes from 10 studies, a significant reduction in serum CRP concentration following the administration of atorvastatin was found (WMD, −0.35; 95% CI, −0.54 to −0.17; I² = 90.6%). Based on 5 effect sizes from 4 studies, we found a statistically significant reduction in serum IL-6 concentration after atorvastatin therapy (WMD, −0.44; 95% CI, −0.65 to −0.22; I² = 93.9%). Pooling 6 effect sizes from 5 studies revealed a significantly reduced serum concentration of CRP after simvastatin therapy (WMD, −0.66; 95% CI, −0.79 to −0.54; I² = 97.6%).ImplicationsThe administration of atorvastatin or simvastatin in patients with abnormal glucose hemostasis was associated with a reduced serum CRP concentration. Atorvastatin therapy might also help to decrease serum IL-6 concentration in these patients.     

Endoscopic and histologic activity assessment considering disease extent and prediction of treatment failure in ulcerative colitis

Abstract

Background and Aims

DUBLIN score allows evaluation of disease activity and extent in ulcerative colitis (UC). This study aimed to evaluate DUBLIN score as a predictor of therapeutic failure as well as to associate endoscopic and histological activity scores to assess their joint performance.     

Faecal calprotectin levels after rifaximin treatment in patients with irritable bowel syndrome with diarrhoea: A single-center prospective study

Background and study aimsAlthough unclear, the pathophysiology of irritable bowel syndrome (IBS) is considered to be multifactorial. Recent studies have suggested that IBS is a low-grade inflammatory bowel disease (IBD) with high faecal calprotectin (FC) levels. Rifaximin is a potential therapeutic agent for IBS with diarrhoea (IBS-D) due to its ability to decrease FC levels. This study evaluated the role of FC as a follow-up marker of IBS-D after short-course rifaximin treatment.Patients and methodsNinety-six patients with chronic diarrhoea who fulfilled the Rome IV criteria for IBS-D were enrolled in this study from outpatient clinics. After excluding 18 patients who did not complete the study due to treatment noncompliance or missing follow-up visits, 78 patients (mean age, 39.2 ± 6.9 years) with IBS-D and elevated baseline FC levels were included. An FC level of <50 μg/g was considered normal. Abdominal symptoms were assessed using a Likert scale. All patients received oral rifaximin (550 mg three times daily) for 2 weeks, followed by assessment for abdominal symptoms and FC levels; the treatment was extended to 4 weeks if FC levels remained elevated after 2 weeks of treatment.ResultsFC levels normalised in 66 (84.6%) patients, including 60 and 6 patients treated for 2 and 4 weeks, respectively. The remaining 12 (15.4%) patients with persistently elevated FC levels despite 4 weeks of treatment also showed a significant decline in their final FC levels compared with the baseline, accompanied with a significant improvement in abdominal symptoms (p = 0.001). A cutoff baseline FC value of 148.5 μg/g could predict non-responders with 100% sensitivity and 50% specificity.ConclusionShort-course oral rifaximin treatment results in FC normalisation in IBS-D patients with high baseline FC values. Therefore, FC should be considered as a biomarker of follow-up after rifaximin treatment for IBS-D.     

肥胖与骨质疏松症关系的研究进展

肥胖是许多慢性疾病的危险因素。肥胖与骨之间的病理生理关系是复杂的,最近来自流行病学和动物研究的数据表明:脂肪堆积对骨密度不利。肥胖可能通过多种机制影响骨代谢,由于脂肪细胞和成骨细胞起源于共同的多能间充质干细胞,肥胖能增强脂肪细胞分化并促进脂肪积累,进而减少成骨细胞分化和骨形成。肥胖与慢性炎症有关,在肥胖患者中,循环血液和组织的促炎细胞因子水平增加,从而通过修饰NF-κB(RANK)/RANKL/骨保护通路的受体活性,而增进破骨细胞活性并加速骨吸收。此外,肥胖患者中脂肪细胞分泌瘦素过多和(或)脂联素生成过少可能直接影响骨形成或通过上调促炎细胞因子而间接影响骨吸收。另外,高脂摄入可能干预肠道钙吸收而降低成骨可利用的钙量。本篇叙述了肥胖对骨代谢影响的作用机制,阐明脂肪和骨代谢之间在分子水平的关系,有助于开发预防或治疗肥胖和骨质疏松的治疗性药剂。     

Inflammatory myofibroblastic tumor of the larynx: report of a case and review of the literature

Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm, most commonly seen in children and adolescents. It can occur in nearly every part of the body. Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm mostly seen in the lungs, but also in extrapulmonary sites. But it may rarely be seen in the vical cord. We report a case of a 73-year-old men presented with hoarseness and cough. Laryngoscopy reveals a large non-ulcerated, red subepithelial mass arising from the right vical cord. Magnetic resonance imaging (MRI) scan revealed a mass in the right vical cord, and magnetic resonance imaging (MRI) enhanced scan showed the mass of the right vical cord inhomogeneous enhancement. The patient underwent right cordectomy with KTP laser, and further assessment of the tissue demonstrated a pathologic diagnosis of IMT.