The Influence of Recombinant Human Erythropoietin on Apoptosis and Cytokine Production of CD4+ lymphocytes from Hemodialyzed Patients

Recombinant human erythropoietin (rhEPO) treatment of hemodialyzed (HD) patients normalizes the altered phenotype of CD4⁺ lymphocytes and restores the balance of Th1/Th2 cytokines. We decided to test how the presence of rhEPO in cell culture modulates cytokine production of CD4⁺ lymphocytes in HD patients with stable hemoglobin level and expression of activation antigens of stimulated CD4⁺ lymphocytes similar to those observed in healthy individuals. We also tested whether the presence of rhEPO in cell culture protects stimulated CD4⁺ lymphocytes of HD patients from apoptosis. Peripheral blood mononuclear cells (PBMC) of HD patients were stimulated with an immobilized anti-CD3 antibody with or without addition of rhEPO. The percentage of apoptotic CD4⁺ lymphocytes and the level of Th1/Th2 cytokines in culture supernatants were measured with flow cytometry. HD patients showed a decrease in the percentage of apoptotic CD4⁺ cells after stimulation with the anti-CD3 antibody combined with rhEPO. The level of IFN-γ and IL-10 was increased while the level of TNF-α was decreased in the presence of rhEPO in cell culture from HD patients. These results confirm the role of rhEPO signaling in T lymphocytes of HD patients.     

Infantile peripheral neuropathy,deafness, and proximal tubulopathy associated with a novel mutation of the RRM2B gene

Mitochondrial DNA depletion syndromes are a group of autosomal recessive hereditary disorders characterized by reduction of the amount of mitochondrial DNA in the affected tissue (muscle, liver, brain, or kidneys). We report a case of an infant with myopathy, deafness, peripheral neuropathy, nephrocalcinosis, proximal renal tubulopathy, moderate lactic acidosis, and a novel mutation of the RRM2B gene.Mitochondrial DNA depletion syndromes are a group of autosomal recessive hereditary disorders characterized by reduction of the mitochondrial DNA amount in the affected tissue (1). Depletion of mitochondrial DNA can affect specific tissues or combination of organs and tissues including muscles, liver, brain, or kidneys (2,3).Different defects of nuclear genes may lead to different clinical manifestations, such as hepatocerebral syndrome, encephalopathy, or myopathy. One of the recently identified genes for mitochondrial DNA depletion syndromes is RRM2B, which encodes an isoform of a small subunit of ribonucleotide reductase. This enzyme plays an essential role in nucleotide synthesis, converting ribonucleotides to deoxyribonucleotides. Since 2008, 14 mutations of RRM2B gene have been reported (3,4). All the reported mutations are unique and there is no mutation that appears in more than one family (1-4).All reported patients had myopathy and primary lactic acidosis. More than a half of them died before the fourth month of age. The oldest patient with RRM2B mutation was a 42 years old woman with clinical findings suggestive of neurogastrointestinal encephalopathy (5). In this report, we review a case of an infant with muscular hypotonia, myopathy, peripheral neuropathy, deafness, nephrocalcinosis, proximal renal tubulopathy, moderate lactic acidosis, and a novel mutation of the RRM2B gene.     

Association Between IL-6 Concentration and Diabetes-Related Variables in DM1 Patients with and without Microvascular Complications

Interleukin 6 (IL-6) plays an important role in the initiation and acceleration of chronic inflammation and could contribute to development of microvascular complications in patients with type 1 diabetes (DM1). Therefore, this study was aimed to investigate the association between concentration of IL-6 in relation to glucose control, lipid profile, and body mass index (BMI) in 69 DM1 patients subdivided according to the absence or presence of microvascular complications. BMI, level of fasting plasma glucose (FPG), and concentrations of total cholesterol (TCH), LDL cholesterol (LDL-C), and IL-6 were higher in DM1 patients compared to the control group. In DM1 patients, IL-6 concentration was positively correlated with level of FPG, LDL-C, TCH concentrations, and BMI. These correlations were stronger in the subgroup of patients with microvascular complications. In addition, BMI independently influences IL-6 concentration in DM1 patients. In conclusion, elevated IL-6 concentration is associated with diabetes-related variables which could accelerate progression of microvascular complications in DM1 patients.     

TNF-α and IL-1β sensitize human MSC for IFN-γ signaling and enhance neutrophil recruitment

During inflammatory processes, tissue environmental cues are influencing the immunoregulatory properties of tissue-resident mesenchymal stem/stromal cells (MSC). In this study, we elucidated one of the molecular and cellular responses of human MSC exposed to combinations of inflammatory cytokines. We showed that during multi-cytokine priming by TNF-α, IL-1β, and IFN-γ, IL-1β further augmented the well-established immunoregulatory activity induced by TNF-α/IFN-γ. On the molecular level, TNF-α and IL-1β enhanced the expression of IFN-γ receptor (IFN-γR) via NF 'kappa-light-chain-enhancer' of activated B-cells (NF-κΒ) signaling. In turn, enhanced responsiveness to IFN-γ stimulation activated STAT5 and p38-MAPK signaling. This molecular feedback resulted in an increased IL-8 release and augmented recruitment of polymorphonuclear granulocytes (PMN). Our study suggests the possibility that responses of MSC to multi-cytokine priming regimens may be exploited therapeutically to fine-tune inflammatory activity in tissues. This study elucidates molecular mechanisms underlying the immunological priming of mesenchymal stromal cells (MSC) and their interaction with neutrophils.     

Contribution of bacterial cells as nucleation centers in microbiologically induced CaCO3 precipitation—A mathematical modeling approach

The microbiologically induced calcite precipitation (MICP) has been extensively studied for geotechnical engineering through simultaneous action of natural phenomena and engineering processes. The focus of bacterial contribution to the MICP has been directed to calcium carbonate productivity, while the additional bacterial role as a crystal nucleation center was not explained especially from a mathematical prediction modeling point of view. Therefore, this study provides explanations and a mathematical modeling approach of bacterial influence on the MICP induced by newly-isolated ureolytic Bacillus strains and Sporosarcina pasteurii DSM 33. Using the obtained results of low-cost, rapid, and simple assays, artificial neural network modeling was applied for cell surface predispositions, pH changes as well as calcium-involved function in biofilm formation during the MICP, for the first time. Based on the obtained contribution of the alkalophilic/alkaloresistant bacteria, calcite precipitation can be significantly directed by the presence, of ureolytic bacterial cells as nucleation centers during CaCO₃ precipitation as well as their morphology, surface characteristics, potential to form a biofilm, and/or generate pH changes.     

Is there a relation between vitamin D,interleukin-17, and bone mineral density in patients with inflammatory bowel disease?

IntroductionIn inflammatory bowel diseases (IBD), osteopenia and osteoporosis constitute a significant medical problem. Cytokines, especially IL-17, play an important role in the pathogenesis of IBD and osteoporosis. Vitamin D is a regulator of bone metabolism, and helps maintain immune system homeostasis.Material and methodsThe research sample consisted of 208 persons: 83 patients (age 35 ±11.99 years) with Crohn’s disease (CD); 86 patients (age 39.58 ±14.74 years) with ulcerative colitis (UC); and 39 persons (age 30.74 ±8.63 years) in the control group (CG). Clinical data on bone mineral density of the lumbar spine (L2-L4), bone mineral density of the femoral neck (FN), and body mass index (BMI) were collected. 25OHD and IL-17 serum concentrations were also measured.ResultsBody mass index (kg/m²) results: in CD, 21.51 ±3.68; in UC, 23.31 ±4.38; and in CG, 24.57 ±3.45 (p < 0.01). Densitometry results for L2–L4 T-score SD: in CD –0.83 ±1.45; in UC –0.47 ±1.15; in CG 0.09 ±0.70. Densitometry results for FN T-score SD: in CD –0.62 ±1.26; in UC –0.29±1.17; in CG 0.41 ±1.03 25OHD (ng/ml) serum concentrations: in CD, 21.33±12.50; in UC, 22.04±9.56; in CG, 21.56±9.11 (ns). IL-17 (pg/ml) serum concentrations: in CD, 8.55±10.99; in UC, 11.67±12.97; in CG, 5.16±9.11 (ns).ConclusionsInflammatory bowel diseases patients and persons from the CG did not differ in vitamin D or IL-17 levels. Patients with a mild course of the disease had a higher vitamin D concentration and bone mineral density. In UC, higher vitamin D concentrations were associated with lower IL-17 concentrations. The IBD patients with a severe course of the disease had a lower body mass than those in the CG and the patients with a mild course of the disease.     

Prognostic value of the PIK3CA,AKT, and PTEN mutations in oral squamous cell carcinoma: literature review

Over 260,000 (2013) new oral squamous cell carcinoma (OSCC) cases are reported annually worldwide. Despite development in OSCC management, the outcome is still unsatisfactory. Identification of new molecular markers may be of use in prevention, prognosis, and choice of an appropriate therapy. The intracellular molecular signalling pathway of phosphatidyl-inositol-3-kinase is involved in the process of cell growth, differentiation, migration, and survival. The main components of this pathway: PIK3CA (phosphatidylinositol-4,5-bisphosphate-3-kinase catalytic subunit α), PTEN (phosphatase and tensin homologue deleted on chromosome 10), and AKT (serine-threonine kinase) are potential objects of research when introducing new therapeutic agents. The aim of this paper is to evaluate the PIK3CA, PTEN, and AKT gene mutations as prognostic factors in OSCC and to describe their role in aggressive disease progression. This is crucial for oral cancer biology understanding and for indicating which direction new clinical treatments should take.     

Dark chocolate reduces endothelial dysfunction after successive breath-hold dives in cool water

Objective

The aim of this study is to observe the effects of dark chocolate on endothelial function after a series of successive apnea dives in non-thermoneutral water.

Methods

Twenty breath-hold divers were divided into two groups: a control group (8 males and 2 females) and a chocolate group (9 males and 1 female). The control group was asked to perform a series of dives to 20 m adding up to 20 min in the quiet diving pool of Conflans-Ste-Honorine (Paris, France), water temperature was 27 °C. The chocolate group performed the dives 1 h after ingestion of 30 g of dark chocolate. Flow-mediated dilatation (FMD), digital photoplethysmography, nitric oxide (NO), and peroxynitrite ONOO^?) levels were measured before and after each series of breath-hold dives.

Results

A significant decrease in FMD was observed in the control group after the dives (95.28 ± 2.9 % of pre-dive values, p < 0.001) while it was increased in the chocolate group (104.1 ± 2.9 % of pre-dive values, p < 0.01). A decrease in the NO level was observed in the control group (86.76 ± 15.57 %, p < 0.05) whereas no difference was shown in the chocolate group (98.44 ± 31.86 %, p > 0.05). No differences in digital photoplethysmography and peroxynitrites were observed between before and after the dives.

Conclusion

Antioxidants contained in dark chocolate scavenge free radicals produced during breath-hold diving. Ingestion of 30 g of dark chocolate 1 h before the dive can thus prevent endothelial dysfunction which can be observed after a series of breath-hold dives.