Notes

Characterization of a carbapenem-resistant Citrobacter amalonaticus coharbouring bla IMP-4 as well as qnrs1 family genes.
The identification of aichiviruses in several animal hosts is providing hints that will lead to an understanding of their origin and evolutionary patterns.Extremely rare diseases are increasingly recognized due to wide-spread, inexpensive genomic sequencing. Understanding the incidence of rare disease is important for appreciating its health impact and allocating recourses for research. However, estimating incidence of rare disease is challenging because the individual contributory alleles are, themselves, extremely rare. We propose a new method to determine incidence of rare, severe, recessive disease in non-consanguineous populations that use known allele frequencies, estimate the combined allele frequency of observed alleles and estimate the number of causative alleles that are thus far unobserved in a disease cohort. Experiments on simulated and real data show that this approach is a feasible method to estimate the incidence of rare disease in European populations but due to several limitations in our ability to assess the full spectrum of pathogenic mutations serves as a useful tool to provide a lower threshold on disease incidence.The pathogenesis of tuberculosis (TB) remains poorly understood, as no more than 5-10% of individuals infected with Mycobacterium tuberculosis go on developing clinical disease. The contribution of human genetics to TB pathogenesis has been amply documented by means of classic genetics since the turn of the twentieth century. Over the last 20 years, following-up on the study of Mendelian susceptibility to mycobacterial disease (MSMD), monogenic disorders have been found to underlie TB in some patients. Rare inborn errors of immunity, such as autosomal recessive, complete IL-12Rβ1 and TYK2 deficiencies, impairing the IL-12- and IL-23-dependent induction of IFN-γ, were initially identified in a few patients. More recently, homozygosity for a common variant of TYK2 (P1104A) that selectively disrupts cellular responses to IL-23 was found in two cohorts of TB patients. It shows high penetrance in areas endemic for TB and appears to be responsible for about 1% of TB cases in populations of European descent. Both rare and common genetic etiologies of TB affect IFN-γ immunity, providing a rationale for novel preventive and therapeutic approaches for TB control, including the use of recombinant IFN-γ.Identifying genetic risk factors for parasitic infections such as the leishmaniases could provide important leads for improved therapies and vaccines. Until recently most genetic studies of human leishmaniasis were underpowered and/or not replicated. Here, we focus on recent genome-wide association studies of visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL). For VL, analysis across 2287 cases and 2692 controls from three cohorts identified a single major peak of genome-wide significance (Pcombined = 2.76 × 10-17) at HLA-DRB1-HLA-DQA1. HLA-DRB1*1501 and DRB1*1404/DRB1*1301 were the most significant protective versus risk alleles, respectively, with specific residues at amino acid positions 11 and 13 unique to protective alleles. Epitope-binding studies showed higher frequency of basic AAs in DRB1*1404-/*1301-specific epitopes compared to hydrophobic and polar AAs in DRB1*1501-specific epitopes at anchor residues P4 and P6 which interact with residues at DRB1 positions 11 and 13. For CL, genome-wide significance was not achieved in combined analysis of 2066 cases and 2046 controls across 2 cohorts. Rather, multiple top hits at P  less then  5 × 10-5 were observed, amongst which IFNG-AS1 was of specific interest as a non-coding anti-sense RNA known to influence responses to pathogens by increasing IFN-γ secretion. Association at LAMP3 encoding dendritic cell lysosomal associated membrane protein 3 was also interesting. LAMP3 increases markedly upon activation of dendritic cells, localizing to the MHC Class II compartment immediately prior to translocation of Class II to the cell surface. Together these GWAS results provide firm confirmation for the importance of antigen presentation and the regulation of IFNγ in determining the outcome of Leishmania infections.Biallelic variants in TOR1AIP1, encoding the integral nuclear membrane protein LAP1 (lamina-associated polypeptide 1) with two functional isoforms LAP1B and LAP1C, have initially been linked to muscular dystrophies with variable cardiac and neurological impairment. Furthermore, a recurrent homozygous nonsense alteration, resulting in loss of both LAP1 isoforms, was identified in seven likely related individuals affected by multisystem anomalies with progeroid-like appearance and lethality within the 1st decade of life. Here, we have identified compound heterozygosity in TOR1AIP1 affecting both LAP1 isoforms in two unrelated individuals affected by congenital bilateral hearing loss, ventricular septal defect, bilateral cataracts, mild to moderate developmental delay, microcephaly, mandibular hypoplasia, short stature, progressive muscular atrophy, joint contractures and severe chronic heart failure, with much longer survival. Cellular characterization of primary fibroblasts of one affected individual revealed absence of both LAP1B and LAP1C, constitutively low lamin A/C levels, aberrant nuclear morphology including nuclear cytoplasmic channels, and premature senescence, comparable to findings in other progeroid forms of nuclear envelopathies. We additionally observed an abnormal activation of the extracellular signal-regulated kinase 1/2 (ERK 1/2). Ectopic expression of wild-type TOR1AIP1 mitigated these cellular phenotypes, providing further evidence for the causal role of identified genetic variants. Altogether, we thus further expand the TOR1AIP1-associated phenotype by identifying individuals with biallelic loss-of-function variants who survived beyond the 1st decade of life and reveal novel molecular consequences underlying the TOR1AIP1-associated disorders.OBJECTIVE Observational study to evaluate the long-term motor and non-motor effects of deep brain stimulation (DBS) of the globus pallidus internus (GPi) on medically refractory dystonia. BACKGROUND Dystonia is a chronic disease affecting mainly young patients with a regular life expectancy and lifelong need for therapy. Pallidal DBS is an established treatment for severe isolated dystonia but long-term data are sparse. METHODS We considered 36 consecutive patients with isolated generalized (n = 14) and cervical/segmental (n = 22) dystonia operated at Charité-University Hospital between 2000 and 2007 in a retrospective analysis for long-term outcome of pallidal DBS. In 19 of these patients, we could analyze dystonic symptoms and disability rated by the Burke-Fahn-Marsden Dystonia Rating scale (BFMDRS) at baseline, short-term (ST-FU, range 3-36 months) and long-term follow-up (LT-FU, range 93-197 months). Quality of life and mood were evaluated using the SF36 and Beck Depression Index (BDI) questionnaires. RESULTS Patients reached an improvement in motor symptoms of 63.8 ± 5.7% (mean ± SE) at ST-FU and 67.9 ± 6.1% at LT-FU. Moreover, a significant and stable reduction in disability was shown following DBS (54.2 ± 9.4% at ST-FU and 53.8 ± 9.2% at LT-FU). BDI and SF36 had improved by 40% and 23%, respectively, at LT-FU (n = 14). Stimulation-induced adverse events included swallowing difficulties, dysarthria, and bradykinesia. Pulse generator (n = 3) and electrodes (n = 5) were revised in seven patients due to infection. CONCLUSIONS Pallidal DBS is a safe and efficacious long-term treatment for dystonia with sustained effects on motor impairment and disability, accompanied by a robust improvement in mood and quality of life.BACKGROUND Based on clinical, immunological and histopathological evidence, MOG-IgG-associated encephalomyelitis (MOG-EM) has emerged as a distinct disease entity different from multiple sclerosis (MS) and aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder (NMOSD). MOG-EM is associated with a broader clinical phenotype including optic neuritis, myelitis, brainstem lesions and acute disseminated encephalomyelitis with a substantial clinical and radiological overlap to other demyelinating CNS disorders. OBJECTIVE To evaluate common clinical, MRI and CSF findings, as well as therapy responses in patients with longitudinal extensive transverse myelitis (LETM) as initial clinical presentation of MOG-EM. METHODS After excluding patients with a known diagnosis of MS, we identified 153 patients with myelitis of which 7 fulfilled the inclusion criteria and were investigated for MRI, CSF and clinical parameters. RESULTS Patients with LETM as first clinical presentation of MOG-EM display similar characteristics, namely a lack of gadolinium-enhancement in spinal cord MRI, marked pleocytosis, negative oligoclonal bands, a previous history of infections/vaccinations and response to antibody-depleting treatments for acute attacks and long-term treatment. CONCLUSIONS We identify common pathological findings in patients with LETM as first clinical presentation of MOG-EM which distinguishes it from other forms of LETM and should lead to testing for MOG-IgG in these cases.BACKGROUND To investigate the efficacy of continuous wound infusion (CWI) with local anesthetics for reducing postoperative pain compared with placebo in patients undergoing benign gynecologic laparoscopy. METHODS In this double-blind trial, 66 patients were randomly assigned to receive either ropivacaine or normal saline though a multi-orifice catheter placed into the umbilical surgical wound for 50 h postoperatively. The primary outcome measure was the severity of postoperative pain 1, 6, 12, 24, and 48 h after surgery. The secondary outcome measure was the number of rescue analgesics requested. RESULTS Baseline characteristics did not statistically differ between the ropivacaine and placebo groups. The intensity of postoperative pain was significantly lower in the ropivacaine group than in the placebo group 1, 6, 12, 24, and 48 h after surgery (all P  less then  0.05). The number of rescue analgesics requested was also significantly lower in the ropivacaine group than in the placebo group. There were no significant differences between the two groups regarding other surgical outcomes. CONCLUSION CWI with local anesthetics after laparoscopic surgery provides good analgesia and reduces rescue analgesics consumption.BACKGROUND Although studies of robotic rectal cancer surgery have demonstrated the effects of learning on operation time, comparisons have failed to demonstrate differences in clinicopathological outcomes between unadjusted learning phases. This study aimed to investigate the learning curve of robotic rectal cancer surgery for clinicopathological outcomes and compare surgical outcomes between adjusted learning phases. Study design We enrolled 506 consecutive patients with rectal adenocarcinoma who underwent robotic resection by a single surgeon between 2007 and 2018. Risk-adjusted cumulative sum (RA-CUSUM) for surgical failure was used to analyze the learning curve. Surgical failure was defined as the occurrence of any of the following conversion to open surgery, severe complications (Clavien-Dindo grade ≥ 3a), insufficient number of harvested lymph nodes (LNs), or R1 resection. Comparisons between learning phases analyzed by RA-CUSUM were performed before and after propensity score matching. selleck compound RESULTS In RA-CUSUM analysis, the learning curve was divided into two learning phases phase 1 (1st-177th cases, n = 177) and phase 2 (178th-506th cases, n = 329).
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