2-Deoxy-glucose ameliorates the peritoneal mesothelial and endothelial barrier function perturbation occurring due to Peritoneal Dialysis fluids exposure.

Peritoneal dialysis (PD) and prolonged exposure to PD fluids (PDF) induce peritoneal membrane (PM) fibrosis and hypervascularity, leading to functional PM degeneration. 2-deoxy-glucose (2-DG) has shown potential as PM antifibrotic by inhibiting hyper-glycolysis induced mesothelial-to-mesenchymal transition (MMT). We investigated whether administration of 2-DG with several PDF affects the permeability of mesothelial and endothelial barrier of the PM. The antifibrotic effect of 2-DG was confirmed by the gel contraction assay with embedded mesothelial (MeT-5A) or endothelial (EA.hy926) cells cultured in Dianeal® 2.5 % (CPDF), BicaVera® 2.3 % (BPDF), Balance® 2.3 % (LPDF) with/without 2-DG addition (0.2 mM), and qPCR for αSMA, CDH2 genes. Moreover, 2-DG effect was tested on the permeability of monolayers of mesothelial and endothelial cells by monitoring the transmembrane resistance (RTM), FITC-dextran (10, 70 kDa) diffusion and mRNA expression levels of CLDN-1 to -5, ZO1, SGLT1, and SGLT2 genes. Contractility of MeT-5A cells in CPDF/2-DG was decreased, accompanied by αSMA (0.17 ± 0.03) and CDH2 (2.92 ± 0.29) gene expression fold changes. Changes in αSMA, CDH2 were found in EA.hy926 cells, though αSMA also decreased under LPDF/2-DG incubation (0.42 ± 0.02). Overall, 2-DG mitigated the PDF-induced alterations in mesothelial and endothelial barrier function as shown by RTM, dextran transport and expression levels of the CLDN-1 to -5, ZO1, and SGLT2. Thus, supplementation of PDF with 2-DG not only reduces MMT but also improves functional permeability characteristics of the PM mesothelial and endothelial barrier.

Prevalence and Determinants of Restless Legs Syndrome (Willis-Ekbom Disease) in an Older Greek Population.

OBJECTIVES: The present study aimed to explore the descriptive and analytic epidemiology of restless legs syndrome (RLS) in the older Greek population, with a specific focus on lifestyle indicators. METHODS: Baseline data from the randomly selected non-demented older participants of the population-based HELIAD cohort were analyzed. Multivariable binary logistic regression with RLS diagnosis as the dichotomous dependent outcome was performed. Demographic, socioeconomic, anthropometric, dietary, sleep-related and psychological parameters, physical activity, use of psychoactive substances and personal medical history were investigated for potential associations. RESULTS: A total of 133 from the eligible sample of 1,838 participants were diagnosed with RLS. The mean age-sex standardized prevalence of RLS among the elderly was estimated at 6.1% (95%CI = 5.0-7.2), with a female (8.0%, 95%CI = 6.4-9.6) to male (3.7%, 95%CI = 2.4-5.1) ratio of 2.1. The prevalence of RLS peaked during the 8th decade of life and diminished thereafter. The positive associations of RLS with female sex [OR = 2.06, 95%CI = (1.19-3.57)], anxiety levels [assessed by the 22-point HADS scale, OR = 1.08, 95%CI = (1.03-1.13)] and traumatic brain injury [OR = 2.22, 95%CI = (1.37-3.62)] were reproduced. Good sleep quality was related to 55% [95%CI~(24-83%)] lower odds of having RLS in comparison with both poor and moderate quality. Adherence to the Mediterranean dietary pattern [assessed by a 55-point scale, OR = 1.06, 95%CI = (1.01-1.11)], and low daily energy intake [low-moderate vs. low: OR = 0.45, 95%CI = (0.26-0.79)]; [moderate-high vs. low: OR = 0.69, 95%CI = (0.40-1.22)]; [high vs. low: OR = 0.31, 95%CI = (0.13-0.69)] were related to RLS for the first time. CONCLUSIONS: More emphasis should be placed on the dietary-nutritional aspects of RLS.

Routes of Albumin Overload Toxicity in Renal Tubular Epithelial Cells.

Besides being a marker of kidney disease severity, albuminuria exerts a toxic effect on renal proximal tubular epithelial cells (RPTECs). We evaluated whether an unfolded protein response (UPR) or DNA damage response (DDR) is elicited in RPTECs exposed to high albumin concentration. The deleterious outcomes of the above pathways, apoptosis, senescence, or epithelial-to-mesenchymal transition (EMT) were evaluated. Albumin caused reactive oxygen species (ROS) overproduction and protein modification, and a UPR assessed the level of crucial molecules involved in this pathway. ROS also induced a DDR evaluated by critical molecules involved in this pathway. Apoptosis ensued through the extrinsic pathway. Senescence also occurred, and the RPTECs acquired a senescence-associated secretory phenotype since they overproduced IL-1ß and TGF-ß1. The latter may contribute to the observed EMT. Agents against endoplasmic reticulum stress (ERS) only partially alleviated the above changes, while the inhibition of ROS upregulation prevented both UPR and DDR and all the subsequent harmful effects. Briefly, albumin overload causes cellular apoptosis, senescence, and EMT in RPTECs by triggering UPR and DDR. Promising anti-ERS factors are beneficial but cannot eliminate the albumin-induced deleterious effects because DDR also occurs. Factors that suppress ROS overproduction may be more effective since they could halt UPR and DDR.

Interleukin Variants Are Associated with the Development and Progression of IgA Nephropathy: A Candidate-Gene Association Study and Meta-Analysis.

The interleukin-1 gene cluster encodes cytokines, which modulate mesangial cell proliferation and matrix expansion, both constituting central factors in the development and progression of immunoglobulin A nephropathy (IgAN). A candidate-gene study was performed to examine the association of polymorphisms of the interleukin-1 gene cluster with the risk of progressive IgAN. To gain deeper insights into the involvement of interleukin genes in IgAN, a meta-analysis of genetic association studies (GAS) that examine the association between interleukin variants and IgAN was conducted. Association study: The case-control study consisted of 121 unrelated Caucasians with sporadic, histologically diagnosed IgAN and of 246 age- and sex-matched healthy controls. Persistent proteinuria (>2 g/24 h) and/or impaired kidney function (serum creatinine > 1.5 mg/dL) defined progressive (n = 67) vs. non-progressive (n = 54) IgAN cases. Genotypes were assessed for two promoter-region single-nucleotide polymorphisms, C-899T (rs1800587) in IL1A and C-511T (rs16944) in IL1B, and for one penta-allelic variable-length tandem repeat polymorphism (VNTR 86 bp intron 2) in IL1RN. The association of these variants with the susceptibility of IgAN and the development of progressive IgAN (healthy status, IgAN, progressive IgAN) was tested using the generalized odds ratio (ORG) metric. Linkage disequilibrium and haplotype analysis were also performed. Meta-analysis: We included in the meta-analysis 15 studies investigating association between 14 interleukin variants harbored in eight different genes and IgAN. The ORG was used to evaluate the association between interleukin variants and IgAN using random effects models. The present case-control study revealed association of IL1B C-511T (rs16944) with the progression of IgAN (p = 0.041; ORG = 2.11 (1.09-4.07)). On haplotype analysis, significant results were derived for the haplotypes C-C-1 (p = 0.005; OR = 0.456 (0.261~0.797)) and C-T-2 (p = 0.003; OR = 4.208 (1.545-11.50)). Regarding association and meta-analysis results, variants in IL1B (rs1143627 and rs16944), IL1RN (rs928940, rs439154, and rs315951) and IL10 (rs1800871) were associated with IgAN based on either genotype or allele counts. Genetic variants and haplotypes in the IL1B, IL1RN, and IL10 genes might contribute to an increased risk for development and progression of IgAN.

Comparative safety and efficacy of paracetamol versus non-steroidal anti-inflammatory agents in neonates with patent ductus arteriosus: A systematic review and meta-analysis of randomized controlled trials.

AIM: Ibuprofen and indomethacin are the preferred drug treatment for patent ductus arteriosus (PDA) in preterm neonates. The comparative safety and efficacy of paracetamol as an alternative has not yet been well established. The aim of our study was to define the comparative efficacy and safety of paracetamol versus ibuprofen and indomethacin for PDA. METHODS: We performed a systematic literature search in PubMed, Scopus and Cochrane databases on randomized controlled trials comparing the efficacy and/or the safety of paracetamol versus ibuprofen and/or indomethacin and meta-analysed the available data. RESULTS: There were 1718 neonates from 20 eligible studies. Paracetamol did not differ from ibuprofen or indomethacin regarding the primary (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.69-1.26, P-value: 0.650, when compared to ibuprofen, and OR: 0.78; 95% CI: 0.20-3.02, P-value: 0.716, when compared to indomethacin) and overall (OR: 1.17; 95% CI: 0.82-1.66, P-value: 0.394, when compared to ibuprofen, and OR: 1.12; 95% CI: 0.58-2.15, P-value: 0.733, when compared to indomethacin) PDA closure rates. Paracetamol resulted in significantly reduced risk of oliguria and a tendency towards less gastrointestinal bleeding. CONCLUSION: There was no significant difference between paracetamol and ibuprofen or indomethacin in the PDA closure rates. However, paracetamol caused fewer adverse effects.

A systematic review and meta-analysis of interventional studies of bisphosphonates and denosumab in multiple myeloma and future perspectives.

Bisphosphonates (BPs) and denosumab (DENOS), due to their ability to inhibit osteoclast activity, are used to prevent skeletal complications in multiple myeloma (MM) patients. The NCBI PubMed, Web of Science, Scopus and ClinicalTrials.gov databases, were systematically searched for interventional studies, assessing the use of BP and DENOS in MM patients. Overall survival, disease progression, skeletal-related events, bone pain, osteonecrosis of the jaw (ONJ) and renal toxicity were the outcomes of interest. A total of 993 studies were retrieved and 43 were used for qualitative synthesis. Clodronate (CLOD) and zoledronic acid (ZOL) were effective in reducing skeletal complications compared to placebo. Results are mixed regarding the efficacy of pamidronate in reducing skeletal related events. ONJ rates were higher for ZOL, but under 5%, with CLOD having the safest profile. DENOS demonstrated non-inferiority to ZOL, in improving overall survival [pooled Hazard Ratio(HR) 1.02(95% CI 0.72,1.44)], progression free survival [pooled HR 0.92(95% CI 0.76,1.11)] and in reducing skeletal related events [pooled HR 1.03(95% CI 0.92,1.16)], with similar rates of ONJ and better safety profile regarding renal toxicity. Denosumab has comparable efficacy and safety with ZOL and may even replace BPs in the future, in the management of myeloma bone disease.

Key Genetic Components of Fibrosis in Diabetic Nephropathy: An Updated Systematic Review and Meta-Analysis.

Renal fibrosis (RF) constitutes the common end-point of all kinds of chronic kidney disease (CKD), regardless of the initial cause of disease. The aim of the present study was to identify the key players of fibrosis in the context of diabetic nephropathy (DN). A systematic review and meta-analysis of all available genetic association studies regarding the genes that are included in signaling pathways related to RF were performed. The evaluated studies were published in English and they were included in PubMed and the GWAS Catalog. After an extensive literature review and search of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, eight signaling pathways related to RF were selected and all available genetic association studies of these genes were meta-analyzed. ACE, AGT, EDN1, EPO, FLT4, GREM1, IL1B, IL6, IL10, IL12RB1, NOS3, TGFB1, IGF2/INS/TH cluster, and VEGFA were highlighted as the key genetic components driving the fibrosis process in DN. The present systematic review and meta-analysis indicate, as key players of fibrosis in DN, sixteen genes. However, the results should be interpreted with caution because the number of studies was relatively small.

Dapagliflozin Prevents High-Glucose-Induced Cellular Senescence in Renal Tubular Epithelial Cells.

Gliflozins are a new class of antidiabetic drugs with renoprotective properties. In cultures of primary human renal tubular epithelial cells (RPTECs) subjected to high-glucose conditions in the presence or absence of dapagliflozin, we evaluated cellular senescence pathways. High glucose increased sodium-glucose cotransporter-2 (SGLT-2) expression and glucose consumption, enhancing reactive oxygen species production. The latter induced DNA damage, ataxia telangiectasia mutated kinase (ATM), and p53 phosphorylation. Stabilized p53 increased the cell cycle inhibitor p21, resulting in cell cycle arrest and increasing the cellular senescence marker beta-galactosidase (GLB-1). RPTECs under high glucose acquired a senescence-associated secretory phenotype, which was detected by the production of IL-1ß, IL-8, and TGF-ß1. By decreasing SGLT-2 expression and glucose consumption, dapagliflozin inhibited the above pathway and prevented RPTEC senescence. In addition, dapagliflozin reduced the cell cycle inhibitor p16 independently of the glucose conditions. Neither glucose concentration nor dapagliflozin affected the epithelial-to-mesenchymal transition when assessed with α-smooth muscle actin (α-SMA). Thus, high glucose induces p21-dependent RPTEC senescence, whereas dapagliflozin prevents it. Since cellular senescence contributes to the pathogenesis of diabetic nephropathy, delineating the related molecular mechanisms and the effects of the widely used gliflozins on them is of particular interest and may lead to novel therapeutic approaches.

Association of assisted reproductive technology with autism spectrum disorder in the offspring: an updated systematic review and meta-analysis.

This study aims to provide an up-to-date meta-analysis of data from studies investigating the risk of bearing a child with autism spectrum disorder (ASD) after being conceived by assisted reproductive technology (ART). The study was conducted according to the PRISMA Statement. PubMed and Scopus databases were searched up to August 2, 2020. Observational studies using a type of conception of assisted reproductive technology and examined as outcome offspring with ASD were included. A random effect model was applied due to the heterogeneity of the studies. Statistical analysis was performed with Stata 13 software. The Newcastle-Ottawa scale was used to assess the methodological quality of the included studies. The search strategy identified 587 potentially relevant studies. A total of 15 studies provided adequate data for statistical comparisons and, therefore, were included in the meta-analysis. Analysis of the subset of studies that examined all offspring and controlled for confounder factors revealed that the use of ART is associated with a higher risk of ASD (RR = 1.11, 95% CI = 1.03-1.19, p < 0.009), while in the case of studies that focused on singletons, a statistically significant association between ART and ASD was not observed (RR = 0.96, 95% CI = 0.82-1.13, p = 0.654).Conclusion: The present meta-analysis confirmed the existing positive correlation between ART and ASD in offspring, suggesting that ART is correlated with a higher risk for bearing a child with ASD. In contrast, this relationship is not confirmed in singletons. High quality prospective studies with a larger number of participants are still required. What is Known: • Studies that investigated the association between ART and ASD in offspring have shown conflicting results. • A previous meta-analysis showed that offspring conceived by ART are 1.35 times more likely to develop ASD than offspring spontaneously conceived. What is New: • This investigation separately considered studies with and without adjustment for confounders. • The findings from the two analyses were similar.

Intravenous sodium valproate in status epilepticus: review and Meta-analysis.

Objective: Status epilepticus (SE) is a common neurologic emergency. The present study constitutes a meta-analysis of published randomized control trials (RCTs) evaluating the use of intravenous sodium valproate (VPA) in SE.Methods: MEDLINE and Cochrane databases were comprehensively searched, while retrieved RCTs and meta-analyses were manually screened. Prespecified outcome measures included seizure-cessation, 24 h-efficacy, constitute (liver enzyme increase, arrhythmias, bone-marrow suppression, hypotension and respiratory depression) and severe (life-threatening) adverse events (AEs). Evidence synthesis was performed when appropriate, using Random-Effects (RE) or Fixed-Effects (FE) model based on heterogeneity between trials (homogeneity assumed when PQ > 0.1 and I2 < 50%). Outcomes were assessed using Odds-Ratios (ORs) and 95%Confidence-Intervals (95% CIs). Every available comparison was investigated in terms of efficacy and tolerability.Results:Thirteen studies were retrieved and five comparisons were available, four of which involved two or more studies. Results were compatible with no significant difference between VPA and Phenytoin both in terms of efficacy and tolerability [seizure-cessation: FE-OR = 1.99, 95% CI = (0.83-4.75), 24 h-efficacy: FE-OR = 1.32, 95% CI = (0.60-2.89), composite AEs: FE-OR = 0.45, 95% CI = (0.17-1.21)]. Phenobarbital proved more commonly associated with composite AEs than VPA [seizure-cessation: RE-OR = 0.68, 95% CI = (0.05-9.44), 24 h-efficacy: RE-OR = 0.88, 95% CI = (0.02-33.9), composite AEs: FE-OR = 0.26, 95% CI = (0.09-0.82), severe AEs: FE-OR = 0.30, 95% CI = (0.04-2.28)]. Diazepam was determined inferior to VPA concerning safety issues [seizure-termination: FE-OR = 0.77, 95% CI = (0.34-1.79), severe respiratory depression: FE-OR = 0.06, 95% CI = (0.01-0.48), severe hypotension: FE-OR = 0.09, 95% CI = (0.01-0.72)]. The combination of Lorazepam (LZP) with VPA and the combination of LZP with Levetiracetam presented no difference in efficacy [24h-efficacy: FE-OR = 0.68, 95% CI = (0.37-1.24)].Conclusions: Although, additional high-quality RCTs are warranted, according to our results, VPA can be considered a safe and effective option in the management of SE.

Meta-Analysis and Bioinformatics Detection of Susceptibility Genes in Diabetic Nephropathy.

The latest meta-analysis of genome-wide linkage studies (GWLS) identified nine cytogenetic locations suggestive of a linkage with diabetic nephropathy (DN) due to type 1 diabetes mellitus (T1DM) and seven locations due to type 2 diabetes mellitus (T2DM). In order to gain biological insight about the functional role of the genes located in these regions and to prioritize the most significant genetic loci for further research, we conducted a gene ontology analysis with an over representation test for the functional annotation of the protein coding genes. Protein analysis through evolutionary relationships (PANTHER) version 16.0 software and Cytoscape with the relevant plugins were used for the gene ontology analysis, and the overrepresentation test and STRING database were used for the construction of the protein network. The findings of the over-representation test highlight the contribution of immune related molecules like immunoglobulins, cytokines, and chemokines with regard to the most overrepresented protein classes, whereas the most enriched signaling pathways include the VEGF signaling pathway, the Cadherin pathway, the Wnt pathway, the angiogenesis pathway, the p38 MAPK pathway, and the EGF receptor signaling pathway. The common section of T1DM and T2DM results include the significant over representation of immune related molecules, and the Cadherin and Wnt signaling pathways that could constitute potential therapeutic targets for the treatment of DN, irrespective of the type of diabetes.

A Role for Human Renal Tubular Epithelial Cells in Direct Allo-Recognition by CD4+ T-Cells and the Effect of Ischemia-Reperfusion.

Direct allorecognition is the earliest and most potent immune response against a kidney allograft. Currently, it is thought that passenger donor professional antigen-presenting cells (APCs) are responsible. Further, many studies support that graft ischemia-reperfusion injury increases the probability of acute rejection. We evaluated the possible role of primary human proximal renal tubular epithelial cells (RPTECs) in direct allorecognition by CD4+ T-cells and the effect of anoxia-reoxygenation. In cell culture, we detected that RPTECs express all the required molecules for CD4+ T-cell activation (HLA-DR, CD80, and ICAM-1). Anoxia-reoxygenation decreased HLA-DR and CD80 but increased ICAM-1. Following this, RPTECs were co-cultured with alloreactive CD4+ T-cells. In T-cells, zeta chain phosphorylation and c-Myc increased, indicating activation of T-cell receptor and co-stimulation signal transduction pathways, respectively. T-cell proliferation assessed with bromodeoxyuridine assay and with the marker Ki-67 increased. Previous culture of RPTECs under anoxia raised all the above parameters in T-cells. FOXP3 remained unaffected in all cases, signifying that proliferating T-cells were not differentiated towards a regulatory phenotype. Our results support that direct allorecognition may be mediated by RPTECs even in the absence of donor-derived professional APCs. Also, ischemia-reperfusion injury of the graft may enhance the above capacity of RPTECs, increasing the possibility of acute rejection.

A Systematic Review and Meta-Analysis of Pharmacogenetic Studies in Patients with Chronic Kidney Disease.

Chronic kidney disease (CKD) is an important global public health problem due to its high prevalence and morbidity. Although the treatment of nephrology patients has changed considerably, ineffectiveness and side effects of medications represent a major issue. In an effort to elucidate the contribution of genetic variants located in several genes in the response to treatment of patients with CKD, we performed a systematic review and meta-analysis of all available pharmacogenetics studies. The association between genotype distribution and response to medication was examined using the dominant, recessive, and additive inheritance models. Subgroup analysis based on ethnicity was also performed. In total, 29 studies were included in the meta-analysis, which examined the association of 11 genes (16 polymorphisms) with the response to treatment regarding CKD. Among the 29 studies, 18 studies included patients with renal transplantation, 8 involved patients with nephrotic syndrome, and 3 studies included patients with lupus nephritis. The present meta-analysis provides strong evidence for the contribution of variants harbored in the ABCB1, IL-10, ITPA, MIF, and TNF genes that creates some genetic predisposition that reduces effectiveness or is associated with adverse events of medications used in CKD.

A SYSTEMATIC REVIEW OF OBSERVATIONAL STUDIES ASSESSING THE IMPACT OF OXIDATIVE STRESS IN COGNITIVE DECLINE.

OBJECTIVE: Introduction: Cognitive functions are defined as the mental processes through which information is received, processed, stored, and retrieved. Oxidation is considered as an important factor that affects negatively the brain function. The aim: To assess the impact of oxidative stress, as it is measured by oxidative markers or by the presence of anti-oxidants, on cognitive decline. PATIENTS AND METHODS: Materials and methods: A systematic review of published observational studies in PubMed and in Scopus was performed. During the review process the keywords were used as follows: ("oxidative stress") AND ("cognitive decline" OR "cognitive dysfunction" OR "cognitive impairment" OR "cognitive deficiency") AND ("observational study" OR "cross sectional study" OR "prospective study" OR "retrospective study" OR "cohort study"). The search was conducted for the years from 2016 to 2020. CONCLUSION: Conclusions: Seventy-four eligible studies were identified. Thirteen studies met the inclusion and quality criteria and were included in the systematic review. The studies conducted in ten different countries. Information about oxidative stress biomarkers is available in eight studies, while information about antioxidant factors is in ten studies. In all the thirteen studies the cognitive function was assessed with specific tools - scales. In the majority of studies, the presence of high scores in oxidative markers was positively associated with cognitive decline, while higher levels of antioxidant markers were associated with better cognitive function. Our results indicate that oxidative stress may be significantly associated with cognitive decline. The presence of the antioxidants glutathione, uric acid, melatonin, cysteine and peroxide dismutase has a positive effect on cognitive function.

Separate and combined effects of cold dialysis and intradialytic exercise on the thermoregulatory responses of hemodialysis patients: a randomized-cross-over study.

BACKGROUND: The separate and combined effects of intradialytic exercise training (IET) and cold dialysis (CD) on patient thermoregulation remain unknown. This study assessed the thermoregulatory responses of hemodialysis patients under four different hemodialysis protocols: a) one typical dialysis (TD) protocol (dialysate temperature at 37 °C), b) one cold dialysis (CD) protocol (dialysate temperature at 35 °C), c) one typical dialysis protocol which included a single exercise bout (TD + E), d) one cold dialysis protocol which included a single exercise bout (CD + E). METHODS: Ten hemodialysis patients (57.2 ± 14.9 years) participated in this randomized, cross-over study. Core and skin temperatures were measured using an ingestible telemetric pill and by four wireless iButtons attached on the skin, respectively. Body heat storage (S) calculated using the thermometric method proposed by Burton. RESULTS: The TD and TD + E protocols were associated with increased S leading to moderate effect size increases in core body temperature (as high as 0.4 °C). The low temperature of the dialysate during the CD and the CD + E protocols prevented the rise in S and core temperature (p > 0.05), even during the period that IET took place. CONCLUSIONS: TD and IET are accompanied by a moderate level of hyperthermia, which can be offset by CD. We recommended that CD or with IET can prevent the excessive rise of S. TRIAL REGISTRATION: Clinical Trial Registry number: NCT03905551 ( clinicaltrials.gov ), DOR: 05/04/2019.

Piezoelectric or Conventional Osteotomy in Rhinoplasty? A Systematic Review and Meta-Analysis of Clinical Outcomes.

INTRODUCTION: Osteotomy of nasal bones in rhinoplasty is associated with postsurgical morbidities. Recent evidence has suggested that a surgical method applying piezoelectric ultrasound waves for nasal osteotomies in rhinoplasty reduces soft tissue damage and causes less postsurgical morbidities compared to conventional methods. The purpose of this study is to compare clinical outcomes of piezoelectric and conventional lateral nasal osteotomies in rhinoplasty. METHODS: We searched PubMed, CENTRAL, and Web of Science up to 17 August 2019 for studies comparing postoperative outcomes of piezoelectric and conventional lateral osteotomies in rhinoplasty. We included studies comparing results of patients subjected to piezoelectric or conventional lateral nasal osteotomies in rhinoplasty. For outcomes, we considered postoperative pain, eyelid edema, periorbital ecchymosis, and intraoperative mucosal injury. RESULTS: For eyelid edema, a statistically significant difference in favor of piezoelectric osteotomy was documented within the first 3 postoperative days (standardized mean difference [SMD] = -0.65; 95% CI = -1.18, -0.12, p = 0.02; I2 = 69%) and on postoperative day 7 (SMD = -0.69; 95% CI = -1.47, -0.09; p = 0.08; I2 = 85%). This was also the case for periorbital ecchymosis within the first 3 postoperative days (SMD = -0.85; 95% CI = -1.42, -0.28; p = 0.004; I2 = 72%) and on postoperative day 7 (SMD = -0.52; 95% CI = -0.79, -0.24; p = 0.0003; I2 = 71%). Intraoperative mucosal injury (OR = 0.06; 95% CI = 0.01, 0.53; p = 0.01; Ι2 = 0%) and postoperative pain (SMD = -0.99; 95% CI = -1.78, -0.11; p = 0.01; I2 = 49%) were also statistically lower during piezoelectric osteotomies. CONCLUSIONS: This study shows that lateral piezoelectric osteotomy in rhinoplasty decreases postoperative pain, edema, ecchymosis, and intraoperative mucosa injuries compared to the conventional osteotomy technique with a chisel. Piezoelectric osteotomies are especially associated with less postoperative edema and ecchymosis in osteotomies not executed under direct vision.

Histological grading in primary membranous nephropathy is essential for clinical management and predicts outcome of patients.

AIMS: Diagnosis of primary membranous nephropathy (PMN) is mainly based on immunofluorescence/immunohistochemistry findings. However, assessment of specific features on optical microscopy can help to estimate the severity of the disease, guide treatment and predict the response. The aim of this study was to identify, classify and grade the precise histological findings in PMN to predict renal function outcome and guide treatment. METHODS AND RESULTS: Histological parameters, including focal segmental sclerosis (FSGS), tubular atrophy (TA), interstitial fibrosis (IF) and vascular hyalinosis (VH), were re-evaluated in 752 patients with PMN. Their predictive value was estimated separately, and also in a combination score (FSTIV) graded from 0 to 4. Finally, the impact of histology was assessed in the response to immunosuppressive treatment. Mean age of patients was 53.3 (15-85) years and most presented with nephrotic syndrome. FSGS was present in 32% and VH in 51% of the patients, while TA and IF were graded as stage ≥1 in 52% and 51.4%, respectively. The follow-up period was 122.3 (112-376) months. FSGS, TA and IF and VH were associated with impaired renal function at diagnosis (P = 0.02, P < 0.0001, P = 0.001 and P = 0.02, respectively) and at the end of follow-up (P = 0.004, P < 0.0001, P < 0.0001 and P = 0.04, respectively). In multiple regression and binary logistic analysis, the presence of FSGS and degree of TA were the most significant parameters predicting renal function outcome, defined either by eGFR (end), FSGS (r = 0.6, P < 0.0001) and TA (r = 0.6, P < 0.0001), or by the endpoint of >50% eGFR reduction, FSGS (P = 0.001) and TA (P = 0.02). Also, patients presented with FSGS, IF, VH and/or with FSTIV > 1 could benefit from immunosuppression, regardless of clinical presentation. CONCLUSIONS: The presence and degree of four histological indices, FSGS, VH, TA and IF, assessed separately or in combination, and FSTIV score not only predict renal function outcome after long-term follow-up, but can also help in the choice of appropriate treatment. Decisions concerning immunosuppressive treatment can be guided by pathology regardless of clinical findings.

SLC2A1 Tag SNPs in Greek Patients with Diabetic Retinopathy and Nephropathy.

Backround: Genetic variants are implicated in the development of diabetic retinopathy (DR) and nephropathy (DN). The role of solute carrier family 2-facilitated glucose transporter member 1 (SLC2A1), also known as glucose transporter (GLUT1), on DR and DN remain controversial. OBJECTIVE: Examination of the influence of tag SLC2A1 single-nucleotide polymorphisms (SNPs) on the development of DR and DN during the course of type 2 diabetes mellitus (T2DM). METHODS: A total of 169 patients with DR or DN, 107 uncomplicated T2DM patients, and 315 controls were recruited and genotyped for 14 SLC2A1 tag SNPs. SNPs and haplotypes were tested for associations with microvascular diabetes' complications. RESULTS: rs3768029 TT genotype was associated with a lower risk of DR + DN, compared to the CC wild-type (p = 0.0024). Moreover, CT and TT rs841847 genotypes were associated with a higher risk of DR + DN compared to the CC genotype (p = 0.0028). A common haplotype (GGCCCGCATCAAT) was associated with an increased risk of DR, DN, DR ± DN, and DR + DN phenotypes. Mutational loads of rs3768029, rs3729548, rs841853, and rs841847 were found to influence the development of microvascular complications during the T2DM course. CONCLUSIONS: This study provides evidence that SLC2A1 gene variants might be implicated in the development of T2DM microvascular complications.

Correction to: Tryptophan depletion under conditions that imitate insulin resistance enhances fatty acid oxidation and induces endothelial dysfunction through reactive oxygen species-dependent and independent pathways.

In the original publication of the article, last author's name was misspelt. The correct name is given here.

Uric acid increases cellular and humoral alloimmunity in primary human peripheral blood mononuclear cells.

AIM: Hyperuricaemia is common among kidney transplant recipients and has been associated with worse graft outcome. Since episodes of acute cellular rejection and chronic humoral rejection contribute to decreased graft survival, in this study the effect of uric acid on cellular and humoral alloimmunity was evaluated. METHODS: Cellular alloimmunity was assessed by cell proliferation in two-way mixed lymphocyte reaction (MLR) with human peripheral blood mononuclear cells (PBMC). For assessing humoral alloimmunity we developed a method in which humoral alloimmunity was induced in one-way MLR. Then the de novo production of alloantibodies was measured with an antibody-mediated complement-dependent cytotoxicity assay, in which supernatants from the above MRLs were used against resting PBMC similar to the stimulator cells of the above MLRs. RESULTS: Uric acid at a concentration above its crystallization threshold increased cellular proliferation in two-way MLRs. Supernatants from one-way MLRs performed in the presence of uric acid were more cytotoxic against PBMC from individuals that had conferred the stimulator cells for the above MLRs. CONCLUSIONS: Uric acid increases both cellular and humoral alloimmunity in human PBMC. These results offer a possible pathogenetic mechanism for the observed relation between hyperuricaemia and worse kidney allograft survival.