ABSTRACT
We present optical and near-infrared data of three Type II supernovae (SNe II), SN 2008bm, SN 2009aj, and SN 2009au. These SNe display the following common characteristics: signs of early ...interaction of the ejecta with circumstellar material (CSM), blue B − V colours, weakness of metal lines, low expansion velocities, and V-band absolute magnitudes 2–3 mag brighter than those expected for normal SNe II based on their expansion velocities. Two more SNe reported in the literature (SN 1983K and LSQ13fn) share properties similar to our sample. Analysing this set of five SNe II, which are luminous for their low expansion velocities (LLEV), we find that their properties can be reproduced assuming ejecta–CSM interaction that lasts between 4 and 11 weeks post-explosion. The contribution of this interaction to the radiation field seems to be the dominant component determining the observed weakness of metal lines in the spectra rather than the progenitor metallicity. Based on hydrodynamic simulations, we find that the interaction of the ejecta with a CSM of ∼3.6 M⊙ can reproduce the light curves and expansion velocities of SN 2009aj. Using data collected by the Chilean Automatic Supernova Search, we estimate an upper limit for the LLEV SNe II fraction to be 2–4 per cent of all normal SNe II. With the current data set, it is not clear whether the LLEV events are a separated class of SNe II with a different progenitor system, or whether they are the extreme of a continuum mediated by CSM interaction with the rest of the normal SN II population.
Treatment strategies for cystic fibrosis (CF) lung disease include antibiotics, mucolytics, and anti-inflammatory therapies. Increasing evidence suggests that macrolide antibiotics might be ...beneficial in patients with CF.
To determine if an association between azithromycin use and pulmonary function exists in patients with CF.
A multicenter, randomized, double-blind, placebo-controlled trial conducted from December 15, 2000, to May 2, 2002, at 23 CF care centers in the United States.
Of the 251 screened participants with a diagnosis of CF, 185 (74%) were randomized. Eligibility criteria included age 6 years or older, infection with Pseudomonas aeruginosa for 1 or more years, and a forced expiratory volume in 1 second (FEV1) of 30% or more. Participants were stratified by FEV1 (> or =60% predicted vs <60% predicted), weight of less than 40 kg vs 40 kg or more, and CF center.
The active group (n = 87) received 250 mg (weight <40 kg) or 500 mg (weight > or =40 kg) of oral azithromycin 3 days a week for 168 days; placebo group (n = 98) received identically packaged tablets.
Change in FEV1 from day 0 to completion of therapy at day 168 and determination of safety. Secondary outcomes included pulmonary exacerbations and weight gain.
The azithromycin group had a mean 0.097-L (SD, 0.26) increase in FEV1 at day 168 compared with 0.003 L (SD, 0.23) in the placebo group (mean difference, 0.094 L; 95% confidence interval CI, 0.023-0.165; P =.009). Nausea occurred in 17% more participants in the azithromycin group (P =.01), diarrhea in 15% more (P =.009), and wheezing in 13% more (P =.007). Participants in the azithromycin group had less risk of experiencing an exacerbation than participants in the placebo group (hazard ratio, 0.65; 95% CI, 0.44-0.95; P =.03) and weighed at the end of the study an average 0.7 kg more than participants receiving placebo (95% CI, 0.1-1.4 kg; P =.02).
Azithromycin treatment was associated with improvement in clinically relevant end points and should be considered for patients with CF who are 6 years or older and chronically infected with P aeruginosa.
Nonadherence to antihypertensive medication is common, especially in those with apparent treatment-resistant hypertension (true treatment-resistant hypertension requires exclusion of nonadherence), ...and its routine detection is supported by clinical guidelines. Chemical adherence testing is a reliable and valid method to detect adherence, yet methods are unstandardized and are not ubiquitous. This article describes the principles of chemical adherence testing for hypertensive patients and provides a set of recommendations for centers wishing to develop the test. We recommend testing should be done in either of two instances: (1) in those who have resistant hypertension or (2) in those on 2 antihypertensives who have a less than 10 mm Hg drop in systolic blood pressure on addition of the second antihypertensive medication. Furthermore, we recommend that verbal consent is secured before undertaking the test, and the results should be discussed with the patient. Based on medications prescribed in United Kingdom, European Union, and United States, we list top 20 to 24 drugs that cover >95% of hypertension prescriptions which may be included in the testing panel. Information required to identify these medications on mass spectrometry platforms is likewise provided. We discuss issues related to ethics, sample collection, transport, stability, urine versus blood samples, qualitative versus quantitative testing, pharmacokinetics, instrumentation, validation, quality assurance, and gaps in knowledge. We consider how to best present, interpret, and discuss chemical adherence test results with the patient. In summary, this guidance should help clinicians and their laboratories in the development of chemical adherence testing of prescribed antihypertensive drugs.
SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase and a nuclease that restricts HIV-1 in noncycling cells. Germ-line mutations in SAMHD1 have been described in patients with ...Aicardi-Goutières syndrome (AGS), a congenital autoimmune disease. In a previous longitudinal whole genome sequencing study of chronic lymphocytic leukemia (CLL), we revealed a SAMHD1 mutation as a potential founding event. Here, we describe an AGS patient carrying a pathogenic germ-line SAMHD1 mutation who developed CLL at 24 years of age. Using clinical trial samples, we show that acquired SAMHD1 mutations are associated with high variant allele frequency and reduced SAMHD1 expression and occur in 11% of relapsed/refractory CLL patients. We provide evidence that SAMHD1 regulates cell proliferation and survival and engages in specific protein interactions in response to DNA damage. We propose that SAMHD1 may have a function in DNA repair and that the presence of SAMHD1 mutations in CLL promotes leukemia development.
•Acquired pathogenic mutations in SAMHD1 are found in up to 11% of relapsed/refractory patients with CLL.•SAMHD1 is mobilized to sites of DNA damage.
Genetic susceptibility to antisocial behavior may increase fetal sensitivity to prenatal exposure to cigarette smoke. Testing putative gene x exposure mechanisms requires precise measurement of ...exposure and outcomes. We tested whether a functional polymorphism in the gene encoding the enzyme monoamine oxidase A (MAOA) interacts with exposure to predict pathways to adolescent antisocial behavior. We assessed both clinical and information-processing outcomes. One hundred seventy-six adolescents and their mothers participated in a follow-up of a pregnancy cohort with well-characterized exposure. A sex-specific pattern of gene x exposure interaction was detected. Exposed boys with the low-activity MAOA 5' uVNTR (untranslated region variable number of tandem repeats) genotype were at increased risk for conduct disorder (CD) symptoms. In contrast, exposed girls with the high-activity MAOA uVNTR genotype were at increased risk for both CD symptoms and hostile attribution bias on a face-processing task. There was no evidence of a gene-environment correlation (rGE). Findings suggest that the MAOA uVNTR genotype, prenatal exposure to cigarettes and sex interact to predict antisocial behavior and related information-processing patterns. Future research to replicate and extend these findings should focus on elucidating how gene x exposure interactions may shape behavior through associated changes in brain function.
Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within ...the distal intestine. Previous studies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not fitting the current knowledge have thus often been ignored. We identify and validate novel HSCR genes using whole exome sequencing (WES), burden tests, in silico prediction, unbiased in vivo analyses of the mutated genes in zebrafish, and expression analyses in zebrafish, mouse, and human.
We performed de novo mutation (DNM) screening on 24 HSCR trios. We identify 28 DNMs in 21 different genes. Eight of the DNMs we identified occur in RET, the main HSCR gene, and the remaining 20 DNMs reside in genes not reported in the ENS. Knockdown of all 12 genes with missense or loss-of-function DNMs showed that the orthologs of four genes (DENND3, NCLN, NUP98, and TBATA) are indispensable for ENS development in zebrafish, and these results were confirmed by CRISPR knockout. These genes are also expressed in human and mouse gut and/or ENS progenitors. Importantly, the encoded proteins are linked to neuronal processes shared by the central nervous system and the ENS.
Our data open new fields of investigation into HSCR pathology and provide novel insights into the development of the ENS. Moreover, the study demonstrates that functional analyses of genes carrying DNMs are warranted to delineate the full genetic architecture of rare complex diseases.
Retrospective, longitudinal analysis of sensory, motor and functional outcomes from individuals with thoracic (T2-T12) sensorimotor complete spinal cord injury (SCI).
To characterize neurological ...changes over the first year after traumatic thoracic sensorimotor complete SCI.
A dataset of 399 thoracic complete SCI subjects from the European Multi-center study about SCI (EMSCI) was examined for neurological level, sensory levels and sensory scores (pin-prick and light touch), lower extremity motor score (LEMS), ASIA Impairment Scale (AIS) grade, and Spinal Cord Independence Measure (SCIM) over the first year after SCI.
AIS grade conversions were limited. Sensory scores exhibited minimal mean change, but high variability in both rostral and caudal directions. Pin-prick and light touch sensory levels, as well as neurological level, exhibited minor changes (improvement or deterioration), but most subjects remained within one segment of their initial injury level after 1 year. Recovery of LEMS occurred predominantly in subjects with low thoracic SCI. The sensory zone of partial preservation (ZPP) had no prognostic value for subsequent recovery of sensory levels or LEMS. However, after mid or low thoracic SCI, ≥3 segments of sensory ZPP correlated with an increased likelihood for AIS grade conversion.
The data suggest that a sustained deterioration of three or more thoracic sensory levels or loss of upper extremity motor function are rare events and may be useful for tracking the safety of a therapeutic intervention in early phase acute SCI clinical trials, if a significant proportion of study subjects exhibit such an ascent.
The Diagnosis and Staging Working Group of the NIH Consensus Development Project on Criteria for Clinical Trials in chronic GVHD (CGVHD) recently proposed criteria for diagnosis and assessment of ...overall CGVHD severity. We retrospectively reviewed 54 consecutive patients diagnosed with CGVHD between January 2002 and December 2005 after sibling donor transplant to assess the applicability of the new criteria in prognosticating survival and transplant-related mortality (TRM). A total of 8 patients (15%) were reclassified as late onset/persistent or recurrent acute GVHD (late aGVHD), 15 (28%) had overlap syndrome and 31 (57%) had classic CGVHD. Three-year overall survival was worse in patients with late aGVHD (3-year probability 25% (95% CI 4-56%)) followed by overlap syndrome (3-year probability 87% (95% CI 56-96%)) and CGVHD (3-year probability 75% (95% CI 54-87%)); P=0.001. Among patients with overlap syndrome and CGVHD, a trend towards worse survival was seen in patients with severe disease (3-year probability 57.3% (95% CI 21-82%)) as compared to mild+moderate disease (3-year probability 85.1% (95% CI 68-94)); P=0.1. This analysis, undertaken in a contemporary cohort of related donor recipients, indicates that the consensus guidelines are applicable to this population of CGVHD patients.
Hirschsprung disease (HSCR) is a complex genetic disorder characterized by the absence of enteric nervous system (ENS) in the distal region of the intestine. Down Syndrome (DS) patients have a ...>50-fold higher risk of developing HSCR than the general population, suggesting that overexpression of human chromosome 21 (Hsa21) genes contribute to HSCR etiology. However, identification of responsible genes remains challenging. Here, we describe a genetic screening of potential candidate genes located on Hsa21, using the zebrafish. Candidate genes were located in the DS-HSCR susceptibility region, expressed in the human intestine, were known potential biomarkers for DS prenatal diagnosis, and were present in the zebrafish genome. With this approach, four genes were selected: RCAN1, ITSN1, ATP5PO and SUMO3. However, only overexpression of ATP5PO, coding for a component of the mitochondrial ATPase, led to significant reduction of ENS cells. Paradoxically, in vitro studies showed that overexpression of ATP5PO led to a reduction of ATP5PO protein levels. Impaired neuronal differentiation and reduced mitochondrial ATP production, were also detected in vitro, after overexpression of ATP5PO in a neuroblastoma cell line. Finally, epistasis was observed between ATP5PO and ret, the most important HSCR gene. Taken together, our results identify ATP5PO as the gene responsible for the increased risk of HSCR in DS patients in particular if RET variants are also present, and show that a balanced expression of ATP5PO is required for normal ENS development.
•Down Syndrome patients have 50-fold higher risk of developing Hirschsprung disease.•ATP5PO located in Chromossome 21, codes for a component of the mitochondrial ATPase.•Overexpression of ATP5PO leads to reduced ATP levels and neuronal differentiation.•ATP5PO and RET, the major Hirchsprung gene, show an epistatic interaction.•Balanced expression of ATP5PO is required for normal ENS development.
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