The role of HUCB derived stem cells therapy in repair of renal damage and improvement of renal function in cisplatin induced acute renal failure in rats

Acute renal failure (ARF) is a common clinical problem with increasing incidence, serious consequences, unsatisfactory therapeutic options and enormous financial burden to society. The aim is to investigate the role of human umbilical cord blood (HUCB) derived mesenchymal (MSCs) and CD34+ hematopoietic stem cell therapy in repair of renal damage and improvement of renal function in cisplatin-induced ARF model. Forty four rats were divided into 4 equal groups. ARF was induced in 3 groups using cisplatin and was confirmed by an increase in serum urea and creatinine levels after 5 days. On the same day, 2 groups were injected via the tail vein by either MSCs (1x106 cells/rat) or CD34+ hematopoietic cells (5 x105 cells/rat). The third group received intravenous injection of phosphate buffer saline and served as positive control, while the last group was normal control. Renal functions were followed up every 4 days. Thirty-three days after initiation of cisplantin injection, rats were sacrificed, kidneys were extracted for histopathological and immunohistochemical examination for detection of human specific anti-vimentin monoclonal mouse anti body to investigate homing of HUCB stem cells into the damaged renal tissue. Treatment with MSCs and CD34+ cells significantly decreased both serum urea and creatinine induced by cisplatin administration with concomitant improvement in the degree of necrotic and degenerative changes. There was no significant difference in these parameters between MSCs and CD 34+ stem cells treated groups. There was positive reaction for human specific anti-vimentin in 88.9% of animals in MSCs treated rats versus 87.5% in CD34+ cells treated rats. HUCB derived CD 34+ and MSCs accelerate regeneration of renal tubular epithelial cells and lead to reduction of progressive renal injury in cisplatin-induced acute renal failure rats.Keywords: Acute renal failure; CD 34+ cells; Umbilical cord blood; Mesenchymal stem cell

Prognostic value of FOXP3 and TGF-b expression in both peripheral blood and lymph nodes in patients with B-Non Hodgkin’s lymphoma

Foxp3 has been studied as a biomarker of Treg cells in many solid malignant diseases, although its role as an immunomodulator in B-NHL remain poorly understood and the effect of traditional chemotherapy on its expression remains unclear. In this study the role of circulating and intra-tumoral Treg and TGF-b in patients with B-NHL before and after chemotherapy was evaluated. Enumeration of Treg cells was carried out by flow cytometric staining of their cell surface markers CD4 and CD25 as well as by molecular analysis of its signature transcription factor FoxP3. Expression of FoxP3 was done using quantitative real-time PCR while TGF-b mRNA expression was semi-quantitatively assayed by the conventional reverse transcription-PCR. In addition, spontaneous versus mitogen-induced release of TGF-b by PBMCs was assessed by a short term cell culture followed by ELISA. This was done before and after six cycles of CHOP chemotherapy. The results were evaluated in relation to the clinicopathological data.A significant increase in mRNA transcripts of both Fox P3 and TGF-b as well as the percentage of CD4+/CD25+ in B-NHL patients before receiving the chemotherapy were recorded, when compared either to healthy controls or to patients after completion the treatment regimen. Interestingly 6 cycles of CHOP treatment caused significant reduction in all parameters under study, relative to the situation before treatment. A significant enhancement in spontaneous TGF-b release in B-NHL patient either before or after chemotherapy was obtained. These results strongly confirm the possible involvement of Treg cells and TGF-b in orienting the clinical course of the disease as well as the ability of targeting them in immunotherapeutic approaches. KEYWORDS FOXP3; TGF; Non Hodgkin’s lymphoma; NH

Publisher Correction: A novel two-score system for interferon status segregates autoimmune diseases and correlates with clinical features

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Patients with diffuse idiopathic skeletal hyperostosis have an increased burden of thoracic aortic calcifications

OBJECTIVES: DISH has been associated with increased coronary artery calcifications and incident ischaemic stroke. The formation of bone along the spine may share pathways with calcium deposition in the aorta. We hypothesized that patients with DISH have increased vascular calcifications. Therefore we aimed to investigate the presence and extent of DISH in relation to thoracic aortic calcification (TAC) severity. METHODS: This cross-sectional study included 4703 patients from the Second Manifestation of ARTerial disease cohort, consisting of patients with cardiovascular events or risk factors for cardiovascular disease. Chest radiographs were scored for DISH using the Resnick criteria. Different severities of TAC were scored arbitrarily from no TAC to mild, moderate or severe TAC. Using multivariate logistic regression, the associations between DISH and TAC were analysed with adjustments for age, sex, BMI, diabetes, smoking status, non-high-density lipoprotein cholesterol, cholesterol lowering drug usage, renal function and blood pressure. RESULTS: A total of 442 patients (9.4%) had evidence of DISH and 1789 (38%) patients had TAC. The prevalence of DISH increased from 6.6% in the no TAC group to 10.8% in the mild, 14.3% in the moderate and 17.1% in the severe TAC group. After adjustments, DISH was significantly associated with the presence of TAC [odds ratio (OR) 1.46 [95% CI 1.17, 1.82)]. In multinomial analyses, DISH was associated with moderate TAC [OR 1.43 (95% CI 1.06, 1.93)] and severe TAC [OR 1.67 (95% CI 1.19, 2.36)]. CONCLUSIONS: Subjects with DISH have increased TACs, providing further evidence that patients with DISH have an increased burden of vascular calcifications

B cell tetherin: a flow‐cytometric cell‐specific assay for response to Type‐I interferon predicts clinical features and flares in SLE

Objective: Type I interferon (IFN-I) responses are broadly associated with autoimmune disease including SLE. Given the cardinal role of autoantibodies in SLE, we investigated whether a B cell-specific IFN assay might correlate with SLE activity. Methods: B cells and PBMCs were stimulated with IFN-I and IFN-II. Gene expression was scrutinized for pathway-related membrane protein expression. A flow-cytometric assay for tetherin (CD317), an IFN-induced protein ubiquitously expressed on leucocytes, was validated in vitro then clinically against SLE diagnosis, plasmablast expansion, and BILAG-2004 score in a discovery cohort (156 SLE; 30 RA; 22 healthy controls). A second longitudinal validation cohort of 80 patients was also evaluated for SLE flare prediction. Results: In vitro, a close cell-specific and dose-responsive relationship between IFN-I responsive genes and cell surface tetherin in all immune subsets existed. Tetherin expression on multiple cell subsets was selectively responsive to stimulation with IFN-I compared to IFN-II and -III. In patient samples from the discovery cohort memory B-cell tetherin was best associated with diagnosis (SLE/HC: effect size=0.11, p=0.003; SLE/RA: effect size=0.17,

Diffuse idiopathic skeletal hyperostosis is associated with incident stroke in patients with increased cardiovascular risk

OBJECTIVES: Earlier retrospective studies have suggested a relation between DISH and cardiovascular disease, including myocardial infarction. The present study assessed the association between DISH and incidence of cardiovascular events and mortality in patients with high cardiovascular risk. METHODS: In this prospective cohort study, we included 4624 patients (mean age 58.4 years, 69.6% male) from the Second Manifestations of ARTerial disease cohort. The main end point was major cardiovascular events (MACE: stroke, myocardial infarction and vascular death). Secondary endpoints included all-cause mortality and separate vascular events. Cause-specific proportional hazard models were used to evaluate the risk of DISH on all outcomes, and subdistribution hazard models were used to evaluate the effect of DISH on the cumulative incidence. All models were adjusted for age, sex, body mass index, blood pressure, diabetes, non-HDL cholesterol, packyears, renal function and C-reactive protein. RESULTS: DISH was present in 435 (9.4%) patients. After a median follow-up of 8.7 (IQR 5.0–12.0) years, 864 patients had died and 728 patients developed a MACE event. DISH was associated with an increased cumulative incidence of ischaemic stroke. After adjustment in cause-specific modelling, DISH remained significantly associated with ischaemic stroke (HR 1.55; 95% CI: 1.01, 2.38), but not with MACE (HR 0.99; 95% CI: 0.79, 1.24), myocardial infarction (HR 0.88; 95% CI: 0.59, 1.31), vascular death (HR 0.94; 95% CI: 0.68, 1.27) or all-cause mortality (HR 0.94; 95% CI: 0.77, 1.16). CONCLUSIONS: The presence of DISH is independently associated with an increased incidence and risk for ischaemic stroke, but not with MACE, myocardial infarction, vascular death or all-cause mortality

Waist Circumference as Compared with Body-Mass Index in Predicting Mortality from Specific Causes

Background Whether waist circumference provides clinically meaningful information not delivered by body-mass index regarding prediction of cause-specific death is uncertain. Methods We prospectively examined waist circumference (WC) and body-mass index (BMI) in relation to cause-specific death in 225,712 U.S. women and men. Cox regression was used to estimate relative risks and 95% confidence intervals (CI). Statistical analyses were conducted using SAS version 9.1. Results During follow-up from 1996 through 2005, we documented 20,977 deaths. Increased WC consistently predicted risk of death due to any cause as well as major causes of death, including deaths from cancer, cardiovascular disease, and non-cancer/non-cardiovascular diseases, independent of BMI, age, sex, race/ethnicity, smoking status, and alcohol intake. When WC and BMI were mutually adjusted in a model, WC was related to 1.37 fold increased risk of death from any cancer and 1.82 fold increase risk of death from cardiovascular disease, comparing the highest versus lowest WC categories. Importantly, WC, but not BMI showed statistically significant positive associations with deaths from lung cancer and chronic respiratory disease. Participants in the highest versus lowest WC category had a relative risk of death from lung cancer of 1.77 (95% CI, 1.41 to 2.23) and of death from chronic respiratory disease of 2.77 (95% CI, 1.95 to 3.95). In contrast, subjects in the highest versus lowest BMI category had a relative risk of death from lung cancer of 0.94 (95% CI, 0.75 to 1.17) and of death from chronic respiratory disease of 1.18 (95% CI, 0.89 to 1.56). Conclusions Increased abdominal fat measured by WC was related to a higher risk of deaths from major specific causes, including deaths from lung cancer and chronic respiratory disease, independent of BMI

Isolation and characterisation of human gingival margin-derived STRO-1/MACS+ and MACS− cell populations

Recently, gingival margin-derived stem/progenitor cells isolated via STRO-1/magnetic activated cell sorting (MACS) showed remarkable periodontal regenerative potential in vivo. As a second-stage investigation, the present study's aim was to perform in vitro characterisation and comparison of the stem/progenitor cell characteristics of sorted STRO-1-positive (MACS+) and STRO-1-negative (MACS−) cell populations from the human free gingival margin. Cells were isolated from the free gingiva using a minimally invasive technique and were magnetically sorted using anti-STRO-1 antibodies. Subsequently, the MACS+ and MACS− cell fractions were characterized by flow cytometry for expression of CD14, CD34, CD45, CD73, CD90, CD105, CD146/MUC18 and STRO-1. Colony-forming unit (CFU) and multilineage differentiation potential were assayed for both cell fractions. Mineralisation marker expression was examined using real-time polymerase chain reaction (PCR). MACS+ and MACS− cell fractions showed plastic adherence. MACS+ cells, in contrast to MACS− cells, showed all of the predefined mesenchymal stem/progenitor cell characteristics and a significantly higher number of CFUs (P<0.01). More than 95% of MACS+ cells expressed CD105, CD90 and CD73; lacked the haematopoietic markers CD45, CD34 and CD14, and expressed STRO-1 and CD146/MUC18. MACS− cells showed a different surface marker expression profile, with almost no expression of CD14 or STRO-1, and more than 95% of these cells expressed CD73, CD90 and CD146/MUC18, as well as the haematopoietic markers CD34 and CD45 and CD105. MACS+ cells could be differentiated along osteoblastic, adipocytic and chondroblastic lineages. In contrast, MACS− cells demonstrated slight osteogenic potential. Unstimulated MACS+ cells showed significantly higher expression of collagen I (P<0.05) and collagen III (P<0.01), whereas MACS− cells demonstrated higher expression of osteonectin (P<0.05; Mann–Whitney). The present study is the first to compare gingival MACS+ and MACS− cell populations demonstrating that MACS+ cells, in contrast to MACS− cells, harbour stem/progenitor cell characteristics. This study also validates the effectiveness of the STRO-1/MACS+ technique for the isolation of gingival stem/progenitor cells. Human free gingival margin-derived STRO-1/MACS+ cells are a unique renewable source of multipotent stem/progenitor cells