Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207(+) dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E ...mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207(+) DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c(+) and CD14(+) fractions and in bone marrow (BM) CD34(+) hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207(+) DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.
In contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data of metastases of 429 CRC patients ...participating in the pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups characterized by signatures known from primary CRC, signatures associated with received prior treatments, and metastasis-specific signatures. Compared to primary CRC, we identify additional putative (non-coding) driver genes and increased frequencies in driver gene mutations. In addition, we identify specific genes preferentially affected by microsatellite instability. CRC-specific 1kb-10Mb deletions, enriched for common fragile sites, and LINC00672 mutations are associated with response to treatment in general, whereas FBXW7 mutations predict poor response specifically to EGFR-targeted treatment. In conclusion, the genomic landscape of mCRC shows defined changes compared to primary CRC, is affected by prior treatments and contains features with potential clinical relevance.
The aim of the study was to determine the prevalence of New Delhi metallo-β lactamase-1 (NDM-1) producing Enterobacteriaceae in Kuwait over a one year period. Consecutive Enterobacteriaceae isolates ...with reduced susceptibility to carbapenems were collected from four government hospitals in Kuwait from January-December 2014. Their susceptibility to 18 antibiotics was performed by determining the minimum inhibitory concentration. Isolates resistant to carbapenems were tested by PCR for resistant genes. Finger printing of the positive isolates was done by DiversiLab®. Clinical data of patients harboring NDM-1 positive isolates were analyzed. A total of 764 clinically significant Enterobacteriaceae isolates were studied. Of these, 61 (8%) were carbapenem-resistant. Twenty one out of these 61 (34.4%) were NDM-1-producers. All patients positive for NDM-1-carrying bacteria were hospitalized. About half were females (11/21 52.3%), average age was 53.3 years and the majority were Kuwaitis (14/21 66.6%). Six patients (28.5%) gave a history of travel or healthcare contact in an endemic area. Mortality rate was relatively high (28.6%). The predominant organism was Klebsiella pneumoniae (14 66.6%) followed by E. coli (4 19%). All NDM-1-positive isolates were resistant to meropenem, ertapenem, cefotaxime, cefoxitin and ampicillin, while 95.2% were resistant to imipenem, cefepime, and piperacillin-tazobactam. They were multidrug resistant including resistance to tigecycline, but 90% remained susceptible to colistin. About two-thirds of isolates (61.9%) co-produced-extended spectrum β-lactamases. During the study period, an outbreak of NDM-1 positive K. pneumoniae occurred in one hospital involving 3 patients confirmed by DiversiLab® analysis. In conclusion, NDM-1-producing Enterobacteriaceae is a growing healthcare problem with increasing prevalence in Kuwait, especially in hospitalized patients, leaving few therapeutic options. A high prevalence of NDM-1 necessitates the implementation of strict infection control to prevent the spread of these organisms.
Enterohemorrhagic Escherichia coli (EHEC) colonize intestinal epithelium by generating characteristic attaching and effacing (AE) lesions. They are lysogenized by prophage that encode Shiga toxin 2 ...(Stx2), which is responsible for severe clinical manifestations. As a lysogen, prophage genes leading to lytic growth and stx2 expression are repressed, whereas induction of the bacterial SOS response in response to DNA damage leads to lytic phage growth and Stx2 production both in vitro and in germ-free or streptomycin-treated mice. Some commensal bacteria diminish prophage induction and concomitant Stx2 production in vitro, whereas it has been proposed that phage-susceptible commensals may amplify Stx2 production by facilitating successive cycles of infection in vivo. We tested the role of phage induction in both Stx production and lethal disease in microbiome-replete mice, using our mouse model encompassing the murine pathogen Citrobacter rodentium lysogenized with the Stx2-encoding phage Φstx2dact. This strain generates EHEC-like AE lesions on the murine intestine and causes lethal Stx-mediated disease. We found that lethal mouse infection did not require that Φstx2dact infect or lysogenize commensal bacteria. In addition, we detected circularized phage genomes, potentially in the early stage of replication, in feces of infected mice, confirming that prophage induction occurs during infection of microbiota-replete mice. Further, C. rodentium (Φstx2dact) mutants that do not respond to DNA damage or express stx produced neither high levels of Stx2 in vitro or lethal infection in vivo, confirming that SOS induction and concomitant expression of phage-encoded stx genes are required for disease. In contrast, C. rodentium (Φstx2dact) mutants incapable of prophage genome excision or of packaging phage genomes retained the ability to produce Stx in vitro, as well as to cause lethal disease in mice. Thus, in a microbiome-replete EHEC infection model, lytic induction of Stx-encoding prophage is essential for lethal disease, but actual phage production is not.
Our understanding of the earliest stages of crown bird evolution is hindered by an exceedingly sparse avian fossil record from the Mesozoic era. The most ancient phylogenetic divergences among crown ...birds are known to have occurred in the Cretaceous period
, but stem-lineage representatives of the deepest subclades of crown birds-Palaeognathae (ostriches and kin), Galloanserae (landfowl and waterfowl) and Neoaves (all other extant birds)-are unknown from the Mesozoic era. As a result, key questions related to the ecology
, biogeography
and divergence times
of ancestral crown birds remain unanswered. Here we report a new Mesozoic fossil that occupies a position close to the last common ancestor of Galloanserae and fills a key phylogenetic gap in the early evolutionary history of crown birds
. Asteriornis maastrichtensis, gen. et sp. nov., from the Maastrichtian age of Belgium (66.8-66.7 million years ago), is represented by a nearly complete, three-dimensionally preserved skull and associated postcranial elements. The fossil represents one of the only well-supported crown birds from the Mesozoic era
, and is the first Mesozoic crown bird with well-represented cranial remains. Asteriornis maastrichtensis exhibits a previously undocumented combination of galliform (landfowl)-like and anseriform (waterfowl)-like features, and its presence alongside a previously reported Ichthyornis-like taxon from the same locality
provides direct evidence of the co-occurrence of crown birds and avialan stem birds. Its occurrence in the Northern Hemisphere challenges biogeographical hypotheses of a Gondwanan origin of crown birds
, and its relatively small size and possible littoral ecology may corroborate proposed ecological filters
that influenced the persistence of crown birds through the end-Cretaceous mass extinction.
Acinetobacter baumannii is an opportunistic pathogen of intensive care unit (ICU) patients. A. baumannii colonizes many parts of the body including the gastrointestinal tract. Endemic and epidemic ...strains are polyclonal. There is no clarity on the origin of polyclonality of A. baumannii. The objective of the study was to define the genetic relatedness of serial isolates and the origin of polyclonality. Serial rectal isolates from ICU patients whose rectum was colonized on ≥5 sampling occasions were selected. From a total of 32 eligible colonized patients, isolates from a subgroup of 13 patients (a total of 108 isolates) showing different patterns of colonization as revealed by pulsed-field gel electrophoresis (PFGE) were studied. The isolates were analyzed by PFGE pulsotypes, sequence types (STs) by multi-locus sequence typing (MLST) and clonal complex (CC) by eBURST analysis. Serial isolates constituted a mixture of identical, related and unrelated pulsotypes. Analysis by STs and CCs were less discriminatory. The data suggest a combination of an initial colonizing isolate undergoing mutation as well as colonization by independent isolates. Further clarity on the origin of diversity should be better obtained by whole-genome sequencing.
Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence ...for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥ 1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal.
Ventricular arrhythmias and sudden cardiac death John, Roy M, Dr; Tedrow, Usha B, MD; Koplan, Bruce A, MD ...
The Lancet (British edition),
10/2012, Letnik:
380, Številka:
9852
Journal Article
Recenzirano
Management strategies for ventricular arrhythmias are guided by the risk of sudden death and severity of symptoms. Patients with a substantial risk of sudden death usually need an implantable ...cardioverter defibrillator (ICD). Although ICDs effectively end most episodes of ventricular tachycardia or ventricular fibrillation and decrease mortality in specific populations of patients, they have inherent risks and limitations. Generally, antiarrhythmic drugs do not provide sufficient protection from sudden death, but do have a role in reducing arrhythmias that cause symptoms. Catheter ablation is likewise important for reducing the frequency of spontaneous arrhythmias and is curative for some patients, usually those with idiopathic arrhythmias and no heart disease. Arrhythmia surgery is now infrequent, offered by only a few specialised centres for refractory arrhythmias. Advances in understanding of genetic arrhythmia syndromes and in technology for mapping and ablation of ventricular arrhythmias, and enhanced algorithms in implantable devices for rhythm management, have contributed to improved outcomes.
We describe and analyze the results of the third global energy and water cycle experiment atmospheric boundary layer Study intercomparison and evaluation study for single-column models. Each of the ...nineteen participating models was operated with its own physics package, including land-surface, radiation and turbulent mixing schemes, for a full diurnal cycle selected from the Cabauw observatory archive. By carefully prescribing the temporal evolution of the forcings on the vertical column, the models could be evaluated against observations. We focus on the gross features of the stable boundary layer (SBL), such as the onset of evening momentum decoupling, the 2-m minimum temperature, the evolution of the inertial oscillation and the morning transition. New process diagrams are introduced to interpret the variety of model results and the relative importance of processes in the SBL; the diagrams include the results of a number of sensitivity runs performed with one of the models. The models are characterized in terms of thermal coupling to the soil, longwave radiation and turbulent mixing. It is shown that differences in longwave radiation schemes among the models have only a small effect on the simulations; however, there are significant variations in downward radiation due to different boundary-layer profiles of temperature and humidity. The differences in modelled thermal coupling to the land surface are large and explain most of the variations in 2-m air temperature and longwave incoming radiation among models. Models with strong turbulent mixing overestimate the boundary-layer height, underestimate the wind speed at 200 m, and give a relatively large downward sensible heat flux. The result is that 2-m air temperature is relatively insensitive to turbulent mixing intensity. Evening transition times spread 1.5 h around the observed time of transition, with later transitions for models with coarse resolution. Time of onset in the morning transition spreads 2 h around the observed transition time. With this case, the morning transition appeared to be difficult to study, no relation could be found between the studied processes, and the variation in the time of the morning transition among the models.
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