Autosomal dominant chronic mucocutaneous candidiasis (CMC) is a severe immunodeficiency characterized by mucosal infections with fungi. Mutations affecting a particular region of the STAT1 signaling ...protein cause autosomal dominant CMC, probably through denting of the responses of type 1 and type 17 helper T cells.
Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency disorder that is characterized by susceptibility to infection of the skin, nails, and mucous membranes by candida species and dermatophytes.
1
There are several CMC subtypes: autosomal recessive autoimmune polyendocrinopathy candidiasis with ectodermal dystrophy (APECED), autosomal dominant CMC with or without thyroid disease, and autosomal recessive, isolated CMC.
The defect in APECED resides in the autoimmune regulator
AIRE,
which has a key role in immunotolerance.
2
The susceptibility to candida in patients with APECED is attributed to autoantibodies to interleukin-17 and interleukin-22,
3
since type 17 helper T cells (Th17) are crucial for mucosal antifungal . . .
Abstract Serotonergic signaling is involved in many neurobiological processes and disturbed 5-HT homeostasis is implicated in a variety of psychiatric and addictive disorders. Here, we describe the ...functional characterization of the serotonin transporter (SERT) knockout rat model, that is generated by N-ethyl-N-nitrosurea (ENU)-driven target-selected mutagenesis. Biochemical characterization revealed that SERT mRNA and functional protein are completely absent in homozygous knockout (SERT−/− ) rats, and that there is a gene dose-dependent reduction in the expression and function of the SERT in heterozygous knockout rats. As a result, 5-HT homeostasis was found to be severely affected in SERT−/− rats: 5-HT tissue levels and depolarization-induced 5-HT release were significantly reduced, and basal extracellular 5-HT levels in the hippocampus were ninefold increased. Interestingly, we found no compensatory changes in in vitro activity of tryptophan hydroxylase and monoamine oxidase, the primary enzymes involved in 5-HT synthesis and degradation, respectively. Similarly, no major adaptations in non-serotonergic systems were found, as determined by dopamine and noradrenaline transporter binding, monoamine tissue levels, and depolarization-induced release of dopamine, noradrenaline, glutamate and GABA. In conclusion, neurochemical changes in the SERT knockout rat are primarily limited to the serotonergic system, making this novel rat model potentially very useful for studying the behavioral and neurobiological consequences of disturbed 5-HT homeostasis.
Intracellular signaling via the covalent attachment of different ubiquitin linkages to protein substrates is fundamental to many cellular processes. Although linkage-selective ubiquitin interactors ...have been studied on a case-by-case basis, proteome-wide analyses have not been conducted yet. Here, we present ubiquitin interactor affinity enrichment-mass spectrometry (UbIA-MS), a quantitative interaction proteomics method that makes use of chemically synthesized diubiquitin to enrich and identify ubiquitin linkage interactors from crude cell lysates. UbIA-MS reveals linkage-selective diubiquitin interactions in multiple cell types. For example, we identify TAB2 and TAB3 as novel K6 diubiquitin interactors and characterize UCHL3 as a K27-linkage selective interactor that regulates K27 polyubiquitin chain formation in cells. Additionally, we show a class of monoubiquitin and K6 diubiquitin interactors whose binding is induced by DNA damage. We expect that our proteome-wide diubiquitin interaction landscape and established workflows will have broad applications in the ongoing efforts to decipher the complex language of ubiquitin signaling.
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•UbIA-MS enables proteome-wide profiling of ubiquitin signaling interactors•Resource of ubiquitin linkage-selective interactors in multiple cell types•The inter-UIM region determines selective binding to K48 and K63 ubiquitin linkages•Deubiquitinase UCHL3 selectively binds to and regulates K27 ubiquitin linkages
Zhang et al. report UbIA-MS, a mass-spectrometry-based proteomics workflow to comprehensively study interactions between proteins and ubiquitin linkages, based on in vitro pull-downs with chemically synthesized diubiquitins. Their work reports a rich resource of linkage-selective as well as general ubiquitin interactors in different cell types and upon cellular perturbation.
Laparoscopic total mesorectal excision (TME) surgery for rectal cancer has important technical limitations. Robot-assisted and transanal TME (TaTME) may overcome these limitations, potentially ...leading to lower conversion rates and reduced morbidity. However, comparative data between the three approaches are lacking. The aim of this study was to compare short-term outcomes for laparoscopic TME, robot-assisted TME and TaTME in expert centres.
Patients undergoing rectal cancer surgery between 2015 and 2017 in expert centres for laparoscopic, robot-assisted or TaTME were included. Outcomes for TME surgery performed by the specialized technique in the expert centres were compared after propensity score matching. The primary outcome was conversion rate. Secondary outcomes were morbidity and pathological outcomes.
A total of 1078 patients were included. In rectal cancer surgery in general, the overall rate of primary anastomosis was 39.4, 61.9 and 61.9 per cent in laparoscopic, robot-assisted and TaTME centres respectively (P < 0.001). For specialized techniques in expert centres excluding abdominoperineal resection (APR), the rate of primary anastomosis was 66.7 per cent in laparoscopic, 89.8 per cent in robot-assisted and 84.3 per cent in TaTME (P < 0.001). Conversion rates were 3.7 , 4.6 and 1.9 per cent in laparoscopic, robot-assisted and TaTME respectively (P = 0.134). The number of incomplete specimens, circumferential resection margin involvement rate and morbidity rates did not differ.
In the minimally invasive treatment of rectal cancer more primary anastomoses are created in robotic and TaTME expert centres.
Background
Intestinal microbiota have been found to be linked to cardiovascular disease via conversion of the dietary compounds choline and carnitine to the atherogenic metabolite TMAO ...(trimethylamine‐N‐oxide). Specifically, a vegan diet was associated with decreased plasma TMAO levels and nearly absent TMAO production on carnitine challenge.
Methods and Results
We performed a double‐blind randomized controlled pilot study in which 20 male metabolic syndrome patients were randomized to single lean vegan‐donor or autologous fecal microbiota transplantation. At baseline and 2 weeks thereafter, we determined the ability to produce TMAO from d6‐choline and d3‐carnitine (eg, labeled and unlabeled TMAO in plasma and 24‐hour urine after oral ingestion of 250 mg of both isotope‐labeled precursor nutrients), and fecal samples were collected for analysis of microbiota composition. 18F‐fluorodeoxyglucose positron emission tomography/computed tomography scans of the abdominal aorta, as well as ex vivo peripheral blood mononuclear cell cytokine production assays, were performed. At baseline, fecal microbiota composition differed significantly between vegans and metabolic syndrome patients. With vegan‐donor fecal microbiota transplantation, intestinal microbiota composition in metabolic syndrome patients, as monitored by global fecal microbial community structure, changed toward a vegan profile in some of the patients; however, no functional effects from vegan‐donor fecal microbiota transplantation were seen on TMAO production, abdominal aortic 18F‐fluorodeoxyglucose uptake, or ex vivo cytokine production from peripheral blood mononuclear cells.
Conclusions
Single lean vegan‐donor fecal microbiota transplantation in metabolic syndrome patients resulted in detectable changes in intestinal microbiota composition but failed to elicit changes in TMAO production capacity or parameters related to vascular inflammation.
Clinical Trial Registration
URL: http://www.trialregister.nl. Unique identifier: NTR 4338.
We obtained the full genome of Middle East respiratory syndrome coronavirus (MERS-CoV) from a camel in Qatar. This virus is highly similar to the human England/Qatar 1 virus isolated in 2012. The ...MERS-CoV from the camel efficiently replicated in human cells, providing further evidence for the zoonotic potential of MERS-CoV from camels.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Thrombocytopenia is a common finding in small for gestational age (SGA) neonates and is thought to result from a unique pathophysiologic mechanism related to chronic intrauterine hypoxia. Our ...objective was to estimate the incidence and severity of early-onset thrombocytopenia in SGA neonates, and to identify risk factors for thrombocytopenia. We performed a retrospective cohort study of all consecutive SGA neonates admitted to our ward and a control group of appropriate for gestational age (AGA) neonates matched for gestational age at birth. Main outcome measures were incidence and severity of thrombocytopenia, hematological and clinical risk factors for thrombocytopenia, and bleeding. A total of 330 SGA and 330 AGA neonates were included, with a mean gestational age at birth of 32.9 ± 4 weeks. Thrombocytopenia (<150x10(9)/L) was found in 53% (176/329) of SGA neonates and 20% (66/330) of AGA neonates (relative risk (RR) 2.7, 95% confidence interval (CI) 2.1, 3.4). Severe thrombocytopenia (21-50x10(9)/L) occurred in 25 neonates (8%) in the SGA and 2 neonates (1%) in the AGA group (RR 12.5, 95% CI 3.0, 52.5). Platelet counts <20x10(9)/L were not recorded. Within the SGA group, lower gestational age at birth (p = <0.01) and erythroblastosis (p<0.01) were independently associated with a decrease in platelet count. Platelet count was positively correlated with birth weight centiles. In conclusion, early-onset thrombocytopenia is present in over 50% of SGA neonates and occurs 2.7 times as often as in AGA neonates. Thrombocytopenia is seldom severe and is independently associated with lower gestational age at birth and erythroblastosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The purpose of this study was to compare performance of children with Developmental Coordination Disorder (DCD) and typically developing (TD) children in a dual task paradigm with a dynamic balance ...task on the Wii Fit as primary task and a concurrent cognitive (counting) or a concurrent bimanual fine motor task as secondary tasks.
Using a cross-sectional design, 25 children with DCD and 38 TD children were assessed with the Movement Assessment Battery for Children, 2nd edition (MABC-2) and Divided Attention (DA) task of the KiTAP. Next, the single- and dual-tasks were performed and the level of interference or facilitation of the dual tasks was calculated. Regression analysis determined the predictive value of the DA and MABC-2 component balance outcomes on the dual task performance. On the motor and attentional tasks, the group of children with DCD scored significantly below the level of the TD children. The dual task effect showed similar interference and facilitation of tasks in the different dual-task conditions in both groups.
In the dual task-cognitive condition, the divided attention abilities and the MABC-2 balance score predicted 25% of the Wii Fit dynamic balance task performance, whereas in the dual task-motor condition this was higher (31.6%). In both conditions, DA was a stronger predictor than MABC balance score and appears to be an important factor to consider when developing motor task training for children with DCD.
Although several studies have shown that teaching EBM is effective in improving knowledge, at present, there is no convincing evidence that teaching EBM also changes professional behaviour in ...practice. Therefore, the primary aim of this study was to evaluate the effectiveness of a clinically integrated post-graduate training programme in EBM on evidence-based disability evaluation.
In a cluster randomised controlled trial, fifty-four case-based learning groups consisting of 132 physicians and 1680 patients were randomly assigned to the intervention or control groups. A clinically integrated, post-graduate, 5-day training programme in evidence-based medicine, consisting of (home) assignments, peer teaching, interactive training in searching databases, lectures and brainstorming sessions was provided to the intervention group. The control group received no training. The primary outcome was evidence-based disability evaluation, as indicated by the frequency in use of evidence of sufficient quality in disability evaluation reports. There are no general EBM behaviour outcome measures available. Therefore, we followed general guidelines for constructing performance indicators and defined an a priori cut-off for determination of sufficient quality as recommended for evaluating EB training. Physicians trained in EBM performed more evidence-based disability evaluations compared to physicians in the control group (difference in absolute proportion 9.7%, 95% CI 3.5 to 15.9). The primary outcome differences between groups remained significant after both cluster-adjusted analysis and additional sensitivity analyses accounting for subjects lost to follow-up.
A EBM programme successfully improved the use of evidence in a non-hospital based medical specialty. Our findings support the general recommendations to use multiple educational methods to change physician behaviour. In addition, it appeared important that the professional context of the intervention was very supportive in the sense that searches in databases, using and applying guidelines and other forms of evidence are considered standard practice and are encouraged by colleagues and management.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Surgical removal of the cancerous tissue remains the cornerstone of curative treatment for colorectal cancer and results in an inflammatory response. An exaggerated inflammatory response has ...been implicated in the promotion of tumor proliferation and has shown associations with postoperative complications. Literature on the preferred surgical technique to minimize inflammatory response is inconclusive. Therefore, the aim of this study was to assess the inflammatory response and postoperative incidence of infectious complications following surgery for colorectal cancer.
Methods
Embase, PubMed, and Cochrane databases were searched for RCTs that reported inflammatory parameters as a function of surgical modality only. Data related to CRP or IL-6 levels on postoperative days 1 and 3 and data related to postoperative infections were subject to a pairwise meta-analysis to compare open versus laparoscopic techniques.
Results
The literature search and screening process yielded 4151 studies. Ten studies met criteria, including 568 patients. Only studies on laparoscopic and open surgery were found. Pooled analyses found lower Il-6 and CRP levels on postoperative day 1 and lower CRP levels on postoperative day 3 for laparoscopic surgery compared to open surgery. However, there was no difference in incidence of postoperative infectious complications.
Conclusion
The findings of this study indicate a superior inflammatory profile for laparoscopic surgery compared to an open approach for colorectal cancer surgery. For future research, it would be worthwhile to conduct a randomized controlled trial to compare the postoperative inflammatory response and related clinical outcomes between minimally invasive surgical approaches, including laparoscopic and robot-assisted surgery.
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