In 2006, a consensus concerning functional gastrointestinal intestinal disorders in infants and toddlers was described. At that time, little evidence regarding epidemiology, pathophysiology, ...diagnostic workup, treatment strategies, and follow-up was available. Consequently, the criteria for the clinical entities were more experience based than evidence based. In the past decade, new insights have been gained about the different functional gastrointestinal intestinal disorders in these age groups. Based on those, further revisions have been made to the criteria. The description of infant colic has been expanded to include criteria for the general pediatrician and specific criteria for researchers. The greatest change was the addition of a paragraph regarding the neurobiology of pain in infants and toddlers, including the understanding of the neurodevelopment of nociception and of the wide array of factors that can impact the pain experience.
Antibodies to the phospholipase A2 receptor 1 (PLA2R1) have been reported in 70% of cases of idiopathic membranous nephropathy (IMN). The genetic susceptibility of IMN has been accounted for by HLA ...DQA1 and PLA2R1 genes. Here we retrospectively quantified PLA2R antibodies by ELISA, and genotyped DQ alleles and PLA2R1 single-nucleotide polymorphisms for association with clinical criteria for disease activity at the time of first sample and with outcome over a median total follow-up of 90 months. In 90 prevalent patients with biopsy-proven IMN, anti-PLA2R antibodies were present in 75% of patients with IMN with active disease and were significantly higher than in patients in partial or complete remission at the time of antibody measurement. There was a differential IgG subclass response (4>2>3>1) at an early stage, i.e., within 6 months of biopsy. Levels of PLA2R antibodies were significantly linked to DQA1*05:01 and DQB1*02:01. Survival analysis of patients with IMN showed that PLA2R antibodies are significantly linked with outcome. Thus, high levels of PLA2R antibodies are linked with active disease and a higher risk of declining renal function during follow-up. Future therapeutic trials in IMN should monitor anti-PLA2R, as patients with a high antibody burden may benefit from earlier therapeutic intervention.
Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem ...cell markers driven by aberrant allele-specific deregulation of
, a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose
to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to
. Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed
allele and association of
with activated hematopoietic progenitor cell
-regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic
expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia. SIGNIFICANCE: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of
driven by diverse structural alterations, including
superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries.
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Sepsis is associated with generalised endothelial injury and capillary leak and has traditionally been treated with large volume fluid resuscitation. Some patients with sepsis will accumulate bodily ...fluids. The aim of this study was to systematically review the association between a positive fluid balance/fluid overload and outcomes in critically ill adults, and to determine whether interventions aimed at reducing fluid balance may be linked with improved outcomes.
We searched MEDLINE, PubMed, EMBASE, Web of Science, The Cochrane Database, clinical trials registries, and bibliographies of included articles. Two authors independently reviewed citations and selected studies examining the association between fluid balance and outcomes or where the intervention was any strategy or protocol that attempted to obtain a negative or neutral cumulative fluid balance after the third day of intensive care compared to usual care. The primary outcomes of interest were the incidence of IAH and mortality.
Among all identified citations, one individual patient meta-analysis, 11 randomised controlled clinical trials, seven interventional studies, 24 observational studies, and four case series met the inclusion criteria. Altogether, 19,902 critically ill patients were studied. The cumulative fluid balance after one week of ICU stay was 4.4 L more positive in non-survivors compared to survivors. A restrictive fluid management strategy resulted in a less positive cumulative fluid balance of 5.6 L compared to controls after one week of ICU stay. A restrictive fluid management was associated with a lower mortality compared to patients treated with a more liberal fluid management strategy (24.7% vs 33.2%; OR, 0.42; 95% CI 0.32-0.55; P < 0.0001). Patients with intra-abdominal hypertension (IAH) had a more positive cumulative fluid balance of 3.4 L after one week of ICU stay. Interventions to decrease fluid balance resulted in a decrease in intra-abdominal pressure (IAP): an average total body fluid removal of 4.9 L resulted in a drop in IAP from 19.3 ± 9.1 mm Hg to 11.5 ± 3.9 mm Hg.
A positive cumulative fluid balance is associated with IAH and worse outcomes. Interventions to limit the development of a positive cumulative fluid balance are associated with improved outcomes. In patients not transgressing spontaneously from the Ebb to Flow phases of shock, late conservative fluid management and late goal directed fluid removal (de-resuscitation) should be considered.
γ‐secretase processing of amyloid precursor protein (APP) has long been of interest in the pathological progression of Alzheimer's disease (AD) due to its role in the generation of amyloid‐β. The ...catalytic component of the enzyme is the presenilins of which there are two homologues, Presenilin‐1 (PS1) and Presenilin‐2 (PS2). The field has focussed on the PS1 form of this enzyme, as it is typically considered the more active at APP processing. However, much of this work has been completed without appropriate consideration of the specific levels of protein expression of PS1 and PS2. We propose that expression is an important factor in PS1‐ and PS2‐γ‐secretase activity, and that when this is considered, PS1 does not have greater activity than PS2. We developed and validated tools for quantitative assessment of PS1 and PS2 protein expression levels to enable the direct comparison of PS in exogenous and endogenous expression systems, in HEK‐293 PS1 and/or PS2 knockout cells. We show that exogenous expression of Myc‐PS1‐NTF is 5.5‐times higher than Myc‐PS2‐NTF. Quantitating endogenous PS protein levels, using a novel PS1/2 fusion standard we developed, showed similar results. When the marked difference in PS1 and PS2 protein levels is considered, we show that compared to PS1‐γ‐secretase, PS2‐γ‐secretase has equal or more activity on APP and Notch1. This study has implications for understanding the PS1‐ and PS2‐specific contributions to substrate processing, and their potential influence in AD pathogenesis.
γ‐secretase processing of APP plays a vital role in Alzheimer's disease (AD) due to amyloid‐β generation. While presenilin‐1‐γ‐secretase is typically the primary focus, we propose that considering both catalytic homologues, presenilin‐1 (PS1) and presenilin‐2 (PS2), protein expression levels is crucial. Our study quantifies PS1 and PS2 levels and finds PS1 expression is significantly higher in HEK‐293 cells. When accounting for this, PS2‐γ‐secretase shows comparable or greater activity on APP and Notch1, impacting our understanding of their roles in AD pathogenesis.
Transcriptome sequencing has identified multiple subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL) of prognostic significance, but a minority of cases lack a known genetic driver. Here, ...we used integrated whole-genome (WGS) and -transcriptome sequencing (RNA-seq), enhancer mapping, and chromatin topology analysis to identify previously unrecognized genomic drivers in B-ALL. Newly diagnosed (n = 3221) and relapsed (n = 177) B-ALL cases with tumor RNA-seq were studied. WGS was performed to detect mutations, structural variants, and copy number alterations. Integrated analysis of histone 3 lysine 27 acetylation and chromatin looping was performed using HiChIP. We identified a subset of 17 newly diagnosed and 5 relapsed B-ALL cases with a distinct gene expression profile and 2 universal and unique genomic alterations resulting from aberrant recombination-activating gene activation: a focal deletion downstream of PAN3 at 13q12.2 resulting in CDX2 deregulation by the PAN3 enhancer and a focal deletion of exons 18-21 of UBTF at 17q21.31 resulting in a chimeric fusion, UBTF::ATXN7L3. A subset of cases also had rearrangement and increased expression of the PAX5 gene, which is otherwise uncommon in B-ALL. Patients were more commonly female and young adult with median age 35 (range,12-70 years). The immunophenotype was characterized by CD10 negativity and immunoglobulin M positivity. Among 16 patients with known clinical response, 9 (56.3%) had high-risk features including relapse (n = 4) or minimal residual disease >1% at the end of remission induction (n = 5). CDX2-deregulated, UBTF::ATXN7L3 rearranged (CDX2/UBTF) B-ALL is a high-risk subtype of leukemia in young adults for which novel therapeutic approaches are required.
Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between
, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) ...transcription factors. We explored how and when
fusions arise by studying the whole genomes of Ewing sarcomas. In 52 of 124 (42%) of tumors, the fusion gene arises by a sudden burst of complex, loop-like rearrangements, a process called chromoplexy, rather than by simple reciprocal translocations. These loops always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions. Similar loops forming canonical fusions were found in three other sarcoma types. Chromoplexy-generated fusions appear to be associated with an aggressive form of Ewing sarcoma. These loops arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.
Myogenic differentiation proceeds through a highly coordinated cascade of gene activation that necessitates epigenomic changes in chromatin structure. Using a screen of small molecule epigenetic ...probes we identified three compounds which inhibited myogenic differentiation in C2C12 myoblasts; (+)-JQ1, PFI-1, and Bromosporine. These molecules target Bromodomain and Extra Terminal domain (BET) proteins, which are epigenetic readers of acetylated histone lysine tail residues. BETi-mediated anti-myogenic effects were also observed in a model of MYOD1-mediated myogenic conversion of human fibroblasts, and in primary mouse and human myoblasts. All three BET proteins BRD2, BRD3 and BRD4 exhibited distinct and dynamic patterns of protein expression over the course of differentiation without concomitant changes in mRNA levels, suggesting that BET proteins are regulated at the post-transcriptional level. Specific BET protein knockdown by RNA interference revealed that BRD4 was required for myogenic differentiation, whereas BRD3 down-regulation resulted in enhanced myogenic differentiation. ChIP experiments revealed a preferential binding of BRD4 to the Myog promoter during C2C12 myoblast differentiation, co-incident with increased levels of H3K27 acetylation. These results have identified an essential role for BET proteins in the regulation of skeletal myogenesis, and assign distinct functions to BRD3 and BRD4.
Knee pain is one of the most common reasons for outpatient visits in the U.S. The great majority of such cases can be effectively evaluated through physical examination and judicious use of ...radiography. Despite this, an increasing number of magnetic resonance images (MRIs) of the knee are being ordered for patients with incomplete work-ups or for inappropriate indications. We hypothesized that MRIs ordered by orthopaedic providers were more likely to result in changes in diagnoses and/or plans for care than those ordered by non-orthopaedic providers.
We reviewed the charts of all consecutive new patients seen at our orthopaedic outpatient office between January 1, 2010, and December 31, 2011, with International Classification of Diseases, Ninth Revision (ICD-9) codes for meniscal or unspecific sprains and strains of the knee. A total of 1592 patients met our inclusion criteria and were divided into two groups: those initially evaluated and referred by their primary care physician (PCP) (n = 747) and those initially evaluated by one of our staff orthopaedic surgeons (n = 845).
MRI-ordering rates were nearly identical between orthopaedic surgeons and PCPs (25.0% versus 24.8%; p = 0.945). MRIs ordered by orthopaedic surgeons, however, resulted in significantly more arthroscopic interventions than those ordered by PCPs (41.2% versus 31.4%; p = 0.042). Orthopaedic surgeons ordered MRIs for patients who were more likely to benefit from arthroscopic intervention, including patients who were younger (mean age, 45.1 years versus 56.5 years for those with PCP-ordered MRIs; p < 0.001), patients with acute symptoms (39.3% versus 22.2%; p < 0.001), and patients with a history of trauma (49.3% versus 36.2%; p = 0.019). Finally, orthopaedic surgeons were less likely than PCPs to order MRIs for patients with substantial osteoarthritis who subsequently underwent total knee arthroplasty (4.3% versus 9.2%; p = 0.048).
MRI utilization by orthopaedic surgeons results in more appropriate interventions for patients with symptoms and findings most amenable to surgical intervention.
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