Context: There is a dearth of studies on the risk of gaming addiction (GA) in children and adolescents with disruptive behavior disorders (DBDs) and its comorbidity with attention-deficit ...hyperactivity disorder (ADHD). Methods: Seventy participants aged 6–16 years diagnosed with ADHD and DBD were included in this cross-sectional, observational study and compared with 40 healthy controls. They were assessed for clinical details of gadget type, duration of use, and purpose on a semi-structured questionnaire. The intensity of video gaming was assessed using Game Addiction Scale (GAS). Behavioral symptoms were assessed on Child Behavior Checklist (CBCL). Descriptive statistics with t-test, analysis of variance, and Pearson's correlational analysis were used as applicable. Results: Use of gadgets for video games for ≥ 4 hours was found to be significantly higher (P = 0.001) in cases (61.5%) than in controls (10%). Most of the cases used Internet for communication (69.4%) and entertainment (58.3%). A significantly higher number of cases (37.1%) fulfilled criteria for video game addiction and the numbers were significantly higher in ADHD + DBD groups as compared to only ADHD or only DBD group. Children with GA had significantly higher scores in all domains of CBCL as compared to those without GA. The GAS score had a significant positive correlation with aggressive behavior, social problems, rule breaking, and attention problem domains of CBCL. Conclusions: GA was significantly higher in ADHD and/or DBD than normal children and adolescents. Comorbidity of ADHD and DBD further increases the risk of GA. Therefore, children with these disorders should be screened routinely for GA.
Tuberculosis epidemics have defied constraint despite the availability of effective treatment for the past half-century. Mycobacterium tuberculosis, the causative agent of TB, is continually exposed ...to a number of redox stressors during its pathogenic cycle. The mechanisms used by Mtb to sense redox stress and to maintain redox homeostasis are central to the success of Mtb as a pathogen. Careful analysis of the Mtb genome has revealed that Mtb lacks classical redox sensors such as FNR, FixL, and OxyR. Recent studies, however, have established that Mtb is equipped with various sophisticated redox sensors that can detect diverse types of redox stress, including hypoxia, nitric oxide, carbon monoxide, and the intracellular redox environment. Some of these sensors, such as heme-based DosS and DosT, are unique to mycobacteria, whereas others, such as the WhiB proteins and anti-σ factor RsrA, are unique to actinobacteria. This article provides a comprehensive review of the literature on these redox-sensory modules in the context of TB pathogenesis.
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► The role of redox stress in tuberculosis pathogenesis is reviewed. ► Classical redox sensors and Mycobacterium tuberculosis are discussed. ► We also discuss the mechanism of redox sensing by heme-based redox sensors in Mycobacterium. ► The role of iron–sulfur cluster proteins in the regulation of redox homeostasis is examined. ► Redox sensing by σ factors and serine/threonine kinases is also reviewed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Mesenchymal stromal cells (MSC) from adult bone marrow are the most commonly used cells in clinical trials. MSCs from single donors are the preferred starting material but suffer from a major setback ...of being heterogeneous that results in unpredictable and inconsistent clinical outcomes. To overcome this, we developed a method of pooling MSCs from different donors and created cell banks to cater clinical needs. Initially, the master cell banks (MCBs) were created at passage 1 (P1) from the bone marrow MSCs isolated from of nine different donors. At this stage, MCBs from three different donors were mixed in equal proportion and expanded till P3 to create working cell banks. Further, the pooled cells and individual donor MSCs were expanded till P5 and cryopreserved and extensively characterised. There was a large heterogeneity among the individual donor MSCs in terms of growth kinetics (90% Coefficient of variation (CV) for cell yield and 44% CV for population doubling time at P5), immunosuppressive ability (30% CV at 1:1 and 300% CV at 1:10 ratio), and the angiogenic factor secretion potential (20% CV for VEGF and71% CV for SDF-1). Comparatively, the pooled cells have more stable profiles (60% CV for cell yield and 7% CV for population doubling time at P5) and exhibit better immunosuppressive ability (15% CV at 1:1 and 32% CV at 1:10 ratio ) and consistent secretion of angiogenic factors (16% CV for VEGF and 51% CV for SDF-1). Further pooling does not compromise the trilineage differentiation capacity or phenotypic marker expression of the MSCs. The senescence and in vitro tumourigenicity characteristics of the pooled cells are also similar to those of individual donor MSCs. We conclude that pooling of MSCs from three different donors reduces heterogeneity among individual donors and produces MSCs with a consistent secretion and higher immunosuppressive profile.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Amygdala activity in context of the splenocardiac model has not been investigated in healthy, young adults and has not been compared between nonsmokers, electronic cigarette users, and smokers. The ...purpose of the current study was to determine whether fluorodeoxyglucose positron emission tomography/computer tomography (FDG PET/CT) scans would demonstrate positively correlated metabolic activity in the amygdala, bone marrow, spleen, and aorta, elucidating activation of the splenocardiac axis in otherwise healthy young people who use tobacco products compared to nonusers. Moreover, the study was conducted to evaluate whether electronic cigarette users and tobacco smokers have similar levels of inflammation compared to nonusers. In 45 healthy adults (mean age = 25 years), including nonsmoker (n = 15), electronic cigarette user (n = 16), and smoker (n = 14) groups, metabolic activity in the amygdala, spleen, aorta, bone marrow of thoracic vertebrae, and adjacent erector spinae skeletal muscle was quantified through visualization of radioactive glucose (18FDG) uptake by FDG‐PET/CT. The maximum standardized uptake value for each region was calculated for correlation analyses and comparisons between groups. In correlation analyses, metabolic activity of the amygdala correlated with metabolic activity in the aorta (r = 0.757), bone marrow (r = 0.750), and spleen (r = 0.665), respectively. Metabolic activity in the aorta correlated with 18FDG uptake in the thoracic vertebrae (r = 0.703) and spleen (r = 0.594), respectively. Metabolic activity in the spleen also correlated with 18FDG uptake in the bone marrow (r = 0.620). Metabolic activity in the adjacent erector spinae skeletal muscle (our control tissue) was not positively correlated with any other region of interest. Finally, there were no statistically significant mean differences in metabolic activity between the three groups: nonsmokers, electronic cigarette users, and smokers in any target tissue. Amygdala metabolic activity, as measured by 18FDG uptake in FDG‐PET/CT scans, positively correlated with inflammation in the splenocardiac tissues, including: the aorta, bone marrow, and spleen, underscoring the existence of a neural‐hematopoietic‐inflammatory axis in healthy, young adults.
To our knowledge, this is the first study to probe for the network of the splenocardiac axis in healthy young people, including a cohort who uses tobacco products. We found moderate‐strong correlation between metabolic activity in all regions of interest, including the amygdala, bone marrow, spleen, and aorta, but not control tissue, skeletal muscle. There were no differences in metabolic activity in any target tissue between cohorts. Our findings are consistent with the early establishment of this network of inflammation in otherwise healthy young adults.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
gamma delta T cells producing interleukin-17A ( gamma delta T17) are thought to develop spontaneously in the thymus and to be maintained in the periphery. Previous studies suggested a role for ...T-helper 17 (Th17) cells in the maintenance of gamma delta T17 via the expression of transforming growth factor- beta 1 (TGF beta 1). However, we have previously found that Th17 cells were not required for expansion of gamma delta T17 cells after lung transplant in a mouse model. Using mice deficient in signal transducer and activator of transcription 3 (STAT3) in CD4 super(+) T cells, which are unable to develop Th17 cells, we investigated the requirement for Th17 cells and TGF beta 1 to maintain gamma delta T17 cells in the lung and lymphoid tissues. At steady state, we found no defect in gamma delta T17 cells in the thymus or periphery of these mice. Further, STAT3-deficient CD4 super(+) T cells produced significantly higher levels of TGF beta 1 than wild-type CD4 super(+) T cells under Th17 differentiation conditions in vitro. To determine whether STAT3-deficient CD4 super(+) T cells could expand gamma delta T17 cells in vivo, we used TCR beta super(-/-) mice, which are known to have a defect in gamma delta T17 cells that can be rescued by Th17 cells. However, adoptive transfer of wild-type Th17 cells or bulk CD4 super(+) T cells did not expand gamma delta T17 cells in TCR beta super(-/-) mice. In contrast, interferon- gamma super(+) gamma delta T cells preferentially expanded, particularly in the lungs. Interestingly, we found in vivo and in vitro that TGF beta 1 may negatively regulate the pool of gamma delta T17 cells. Our data suggest that Th17 cells and TGF beta 1 are not required for the maintenance of gamma delta T17 cells.
The cell wall of Mycobacterium tuberculosis is configured of bioactive lipid classes that are essential for virulence and potentially involved in the formation of foamy macrophages (FMs) and ...granulomas. Our recent work established crosstalk between M. tuberculosis cell wall lipids and the host lipid-sensing nuclear receptor TR4. In this study, we have characterized, identified, and adopted a heterologous ligand keto-mycolic acid from among M. tuberculosis lipid repertoire for the host orphan NR TR4. Crosstalk between cell wall lipids and TR4 was analyzed by transactivation and promoter reporter assays. Mycolic acid (MA) was found to transactivate TR4 significantly compared with other cell wall lipids. Among the MA, the oxygenated form, keto-MA, was responsible for transactivation, and the identity was validated by TR4 binding assays followed by TLC and nuclear magnetic resonance. Isothermal titration calorimetry revealed that keto-MA binding to TR4 is energetically favorable. This keto-MA-TR4 axis seems to be essential to this oxygenated MA induction of FMs and granuloma formation as evaluated by in vitro and in vivo model of granuloma formation. TR4 binding with keto-MA features a unique association of host nuclear receptor with a bacterial lipid and adds to the presently known ligand repertoire beyond dietary lipids. Pharmacologic modulation of this heterologous axis may hold promise as an adjunct therapy to frontline tuberculosis drugs.
Context: Melasma is an acquired chronic disorder of hyperpigmentation. Tranexamic acid (TXA) has been shown to be effective in reducing the severity of melasma. Aims: The aim of this study is to ...compare the efficacy of intralesional TXA with topical Kligman's regimen in the treatment of facial melasma and to assess their safety profile. Settings and Design: A double arm open-labeled randomized controlled trial was conducted at a tertiary care center in western India. Materials and Methods: Sixty-eight cases of facial melasma of either sex and age ≥ 18 years were randomized into two groups. Group A received intradermal injections of TXA 4 mg/mL, whereas group B received topical Kligman's therapy. Patients were evaluated at baseline, 4th, 8th, and 12th week semi-objectively using modified melasma area severity index (mMASI) score, physician's global assessment scale, and patient's global assessment scale. Statistical Analysis: Data were analyzed using SPSS v16 software. Mann-Whitney U-test, Friedman's analysis of variance test, and Pearson's χ2 test were used. P-value less than 0.05 was considered as statistically significant. Results: Fifty-nine patients completed the study. The decrease in mean mMASI score was statistically significant at 4th, 8th, and 12th week for both groups. On intergroup comparison, a statistically significant difference was observed between both the groups at 12th week (P < 0.01), with group B showing better response to therapy but no difference at baseline and at 4th and 8th week. Group A showed no significant side effects, whereas group B showed erythema, burning, and hypopigmentation in nine, six, and three patients, respectively. Conclusion: Kligman's regimen remains the gold standard for melasma but with multiple serious adverse effects. Intralesional TXA is a safe and promising modality in the treatment of melasma. It can be used in non-responding cases and in those who develop side effects of Kligman's regimen.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
γδ T cells producing interleukin‐17A (γδT17) are thought to develop spontaneously in the thymus and to be maintained in the periphery. Previous studies suggested a role for T‐helper 17 (Th17) cells ...in the maintenance of γδT17 via the expression of transforming growth factor‐β1 (TGFβ1). However, we have previously found that Th17 cells were not required for expansion of γδT17 cells after lung transplant in a mouse model. Using mice deficient in signal transducer and activator of transcription 3 (STAT3) in CD4+ T cells, which are unable to develop Th17 cells, we investigated the requirement for Th17 cells and TGFβ1 to maintain γδT17 cells in the lung and lymphoid tissues. At steady state, we found no defect in γδT17 cells in the thymus or periphery of these mice. Further, STAT3‐deficient CD4+ T cells produced significantly higher levels of TGFβ1 than wild‐type CD4+ T cells under Th17 differentiation conditions in vitro. To determine whether STAT3‐deficient CD4+ T cells could expand γδT17 cells in vivo, we used TCRβ−/− mice, which are known to have a defect in γδT17 cells that can be rescued by Th17 cells. However, adoptive transfer of wild‐type Th17 cells or bulk CD4+ T cells did not expand γδT17 cells in TCRβ−/− mice. In contrast, interferon‐γ+ γδ T cells preferentially expanded, particularly in the lungs. Interestingly, we found in vivo and in vitro that TGFβ1 may negatively regulate the pool of γδT17 cells. Our data suggest that Th17 cells and TGFβ1 are not required for the maintenance of γδT17 cells.
The phytotherapeutic protein stem bromelain (SBM) is used as an anti-obesity alternative medicine. We show at the cellular level that SBM irreversibly inhibits 3T3-L1 adipocyte differentiation by ...reducing adipogenic gene expression and induces apoptosis and lipolysis in mature adipocytes. At the molecular level, SBM suppressed adipogenesis by downregulating C/EBPα and PPARγ independent of C/EBPβ gene expression. Moreover, mRNA levels of adipocyte fatty acid-binding protein (ap2), fatty acid synthase (FAS), lipoprotein lipase (LPL), CD36, and acetyl-CoA carboxylase (ACC) were also downregulated by SBM. Additionally, SBM reduced adiponectin expression and secretion. SBM's ability to repress PPARγ expression seems to stem from its ability to inhibit Akt and augment the TNFα pathway. The Akt-TSC2-mTORC1 pathway has recently been described for PPARγ expression in adipocytes. In our experiments, TNFα upregulation compromised cell viability of mature adipocytes (via apoptosis) and induced lipolysis. Lipolytic response was evident by downregulation of anti-lipolytic genes perilipin, phosphodiestersae-3B (PDE3B), and GTP binding protein G(i)α(1), as well as sustained expression of hormone sensitive lipase (HSL). These data indicate that SBM, together with all-trans retinoic-acid (atRA), may be a potent modulator of obesity by repressing the PPARγ-regulated adipogenesis pathway at all stages and by augmenting TNFα-induced lipolysis and apoptosis in mature adipocytes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Donor-specific transplantation tolerance that enables weaning from immunosuppressive drugs but retains immune competence to non-graft antigens has been a lasting pursuit since the discovery of ...neonatal tolerance. More recently, efforts have been devoted not only to understanding how transplantation tolerance can be induced but also the mechanisms necessary to maintain it as well as how inflammatory exposure challenges its durability. This review focuses on recent advances regarding key peripheral mechanisms of T cell tolerance, with the underlying hypothesis that a combination of several of these mechanisms may afford a more robust and durable tolerance and that a better understanding of these individual pathways may permit longitudinal tracking of tolerance following clinical transplantation to serve as biomarkers. This review may enable a personalized assessment of the degree of tolerance in individual patients and the opportunity to strengthen the robustness of peripheral tolerance.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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