Pathologic alterations in podocytes lead to failure of an essential component of the glomerular filtration barrier and proteinuria in chronic kidney diseases. Elevated levels of saturated free fatty acid (FFA) are harmful to various tissues, implemented in the progression of diabetes and its complications such as proteinuria in diabetic nephropathy. Here, we investigated the molecular mechanism of palmitate cytotoxicity in cultured mouse podocytes. Incubation with palmitate dose-dependently increased cytosolic and mitochondrial reactive oxygen species, depolarized the mitochondrial membrane potential, impaired ATP synthesis and elicited apoptotic cell death. Palmitate not only evoked mitochondrial fragmentation but also caused marked dilation of the endoplasmic reticulum (ER). Consistently, palmitate upregulated ER stress proteins, oligomerized stromal interaction molecule 1 (STIM1) in the subplasmalemmal ER membrane, abolished the cyclopiazonic acid-induced cytosolic Ca2+ increase due to depletion of luminal ER Ca2+. Palmitate-induced ER Ca2+ depletion and cytotoxicity were blocked by a selective inhibitor of the fatty-acid transporter FAT/CD36. Loss of the ER Ca2+ pool induced by palmitate was reverted by the phospholipase C (PLC) inhibitor edelfosine. Palmitate-dependent activation of PLC was further demonstrated by following cytosolic translocation of the pleckstrin homology domain of PLC in palmitate-treated podocytes. An inhibitor of diacylglycerol (DAG) kinase, which elevates cytosolic DAG, strongly promoted ER Ca2+ depletion by low-dose palmitate. GF109203X, a PKC inhibitor, partially prevented palmitate-induced ER Ca2+ loss. Remarkably, the mitochondrial antioxidant mitoTEMPO inhibited palmitate-induced PLC activation, ER Ca2+ depletion and cytotoxicity. Palmitate elicited cytoskeletal changes in podocytes and increased albumin permeability, which was also blocked by mitoTEMPO. These data suggest that oxidative stress caused by saturated FFA leads to mitochondrial dysfunction and ER Ca2+ depletion through FAT/CD36 and PLC signaling, possibly contributing to podocyte injury.

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To build a risk score (RS) model of fatal intracranial hemorrhage (FICH) in patients with acute leukemia, we retrospectively assessed risk factors in 792 patients newly diagnosed with acute leukemia, 41 of whom had analyzable FICH. We found that female gender (relative risk (RR) ¼ 5.234, Po0.001), acute promyelocytic leukemia (RR ¼ 4.057, P ¼ 0.003), leukocytosis (RR ¼ 3.301, P ¼ 0.004), thrombocytopenia (RR ¼ 3.283, P ¼ 0.005) and prolonged prothrombin time (RR ¼ 3.291, P ¼ 0.016) were significantly associated with occurrence of FICH in multivariate analysis. To calculate RS for FICH, one point was assigned for each risk factor, making the RS between 0 and 5. The RS model segregated patients into three prognostic groups: a low-risk group (LRG) for RS of 0 or 1; an intermediate-risk group (IRG) for RS of 2 or 3; and a high-risk group (HRG) for RS of 4 or 5. Expectation of FICH was well correlated with risk groups (all P-values o0.001). Overall survival was significantly shorter in the HRG compared with the LRG. The RS model we constructed to predict the occurrence of FICH will be verified through prospective studies.

The aim of this study was to assess the efficacies and toxicities of immunosuppressive treatments for lupus nephritis (LN) versus cyclophosphamide (CYC). A meta-analysis was performed to determine treatment efficacy and toxicity outcomes between mycophenolate mofetil (MMF) and CYC induction therapies, between MMF and azathioprine (AZA) as maintenance therapies, and between low-dose intravenous (IV) CYC and high-dose IV CYC therapy. Ten randomized controlled trials (RCTs) were included in the meta-analysis. In terms of induction therapies, MMF did not increase complete remission or partial remission rates as compared with CYC. However, the relative risks (RRs) of amenorrhea and leukopenia tended to be lower in the MMF group than in the CYC group. Meta-analysis of MMF versus AZA as a maintenance therapy showed no difference between the two groups in terms of response rates or the risk of developing end-stage renal disease. Low-dose IV CYC therapy had lower relapse rates than high-dose IV CYC therapy (RR 0.465, 95% confidence interval [CI] 0.261-0.830, p-value 0.010), and was associated with a lower infection risk (RR 0.688, 95% CI 0.523-0.905, p-value 0.008). In conclusion, MMF was found to be as effective as CYC and tended to have a better safety profile as an induction therapy for LN than CYC.

Summary:The outcomes of patients who experience the failure to reconstitute a trilineage of blood cells after initial neutrophil engraftment were evaluated in 178 patients with hematologic disorders, who underwent allogeneic HCT. Of 165 qualified patients (five with primary engraftment failure; eight deaths before day 60 of HCT), 43 (26%) satisfied the criteria for the initial (n ¼ 22; failure of platelet 420 000/ll or red blood cell transfusion independence/reticulocyte count X1.0% by day 60) or subsequent (n ¼ 21, ANC o500/ll for X3 days, platelet o20 000/ll for X7 days, or red blood cells transfusion/reticulocyte o1.0% after initial trilineage reconstitution) failure. GVHD was the most common clinical condition associated with cytopenia (n ¼ 24). In all, 20 patients (47%) recovered at least partially with a median of 52 days (range 8-323) later, with 12 of those 20 patients recovering completely. The eventual reconstitution failure rate was 14% (23/163 patients). The number of cell lineages involved in the cytopenia was the only independent variable that predicted partial recovery (1 lineage vs 2-3 lineages with odds ratio of 8.69 (95% CI 1.96-38.60), P ¼ 0.004). Five/20 patients with vs 20/23 patients without partial recovery died. Trilineage reconstitution failures after allogeneic HCT need systematic analysis in the future studies.

Programmed cell death 1 (PDCD1 or PD1) polymorphisms have been inconsistently reported to be associated with systemic lupus erythematosus (SLE). The aim of this study was to explore whether the PDCD1 polymorphisms confer a susceptibility to SLE and lupus nephritis (LN). We conducted a meta-analysis on the association of PDCD1 polymorphisms with SLE in overall and specific ethnic populations. A total of 15 separate comparisons were included in this meta-analysis consisting of nine Europeans, two Latin Americans, two Africans, one Asian and one unknown participant. In subgroup analysis, the PD1.3A allele was significantly associated with SLE in Latin Americans (OR = 3.073, 95% CI = 1.416-6.461, P = 0.003), but not in patients of European and African decent. The PD1.3A allele was a risk factor for LN in European descendants (OR = 2.207, 95% CI = 1.488-3.467, P < 0.001). The PD1.5C allele was a risk factor for SLE in Europeans (OR = 1.297, 95% CI = 1.024-1.643, P = 0.031). In conclusion, this meta-analysis demonstrated an association of the PD1.3A allele with LN in European and SLE in Latin-American populations. Furthermore, the PD1.5C allele was associated with SLE susceptibility in Europeans.

Objective We aimed to evaluate the relationship between telomere length and systemic lupus erythematosus (SLE). Methods PUBMED and EMBASE databases were searched; meta-analyses were performed comparing telomere length in SLE patients and healthy controls, and on SLE patients in subgroups based on ethnicity, sample type, assay method and data type. Results Eight studies including 472 SLE patients and 365 controls were ultimately selected which showed that telomere length was significantly shorter in the SLE group than in the control group (standardized mean difference (SMD) = -0.835, 95% confidence interval (CI) = -1.291 to -0.380, p = 3.3 × 10). Stratification by ethnicity showed significantly shortened telomere length in the SLE group in Caucasian, Asian and mixed populations (SMD = -0.455, 95% CI = -0.763 to -0.147, p = 0.004; SMD = -0.887, 95% CI = -1.261 to -0.513, p = 3.4 × 10; SMD = -0.535, 95% CI = -0.923 to -0.147, p = 0.007; respectively). Furthermore, telomere length was significantly shorter in the SLE group than in the control group in whole blood and peripheral blood mononuclear cell groups (SMD = -0.361, 95% CI = -0.553 to -0.169, p = 2.3 × 10; SMD = -1.546, 95% CI = -2.583 to -0.510, p = 0.003; respectively); a similar trend was observed in leukocyte groups (SMD = -0.699, 95% CI = -1.511 to -0.114, p = 0.092). Meta-analyses based on assay method or data type revealed similar associations. Conclusions Our meta-analysis demonstrated that telomere length was significantly shorter in patients with SLE, regardless of ethnicity, sample type or assay method evaluated.

Tacrolimus, at dosages of 1.5-3 mg/day, was found to be effective in DMARD-resistant or -intolerant patients with active RA.