In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can ...sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients.
We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients.
Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients.
Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers.
Abstract Objective: This study evaluated the survival benefit of US community-acquired pneumonia (CAP) practice guidelines in the intensive care unit (ICU) setting. Methods: We conducted a ...retrospective cohort study of adult patients with CAP who were admitted to 5 community hospital ICUs between November 1, 1999, and April 30, 2000. The guidelines for antibiotic prescriptions were the 2007 Infectious Diseases Society of America/American Thoracic Society guidelines. Guideline-concordant antimicrobial therapy was defined as a β-lactam plus fluoroquinolone or macrolide, antipseudomonal β-lactam plus fluoroquinolone, or antipseudomonal β-lactam plus aminoglycoside plus fluoroquinolone or macrolide. Patients with a documented β-lactam allergy were considered to have received guideline-concordant therapy if they received a fluoroquinolone with or without clindamycin, or aztreonam plus fluoroquinolone with or without aminoglycoside. All other antibiotic regimens were considered to be guideline discordant. Time to clinical stability, time to oral antibiotics, length of hospital stay, and in-hospital mortality were evaluated with regression models that included the outcome as the dependent variable, guidelineconcordant antibiotic therapy as the independent variable, and the Pneumonia Severity Index (PSI) score and facility as covariates. Results: The median age of the 129 patients included in the study was 71 years (interquartile range, 60–79 years). Sixty-two of 129 patients (48%) were male. Comorbidities included liver dysfunction (7 patients 5%), heart failure (62 48%), renal dysfunction (39 30%), cerebrovascular disease (21 16%), and cancer (14 11%). The median (25th–75th percentile) PSI score was 119 (98–142), and overall mortality was 19% (25 patients). Patient demographics were similar between groups. Fifty-three patients (41%) received guideline-endorsed therapies. Guideline-discordant therapy was associated with an increase in inpatient mortality (25% vs 11%; odds ratio = 2.99 95% CI, 1.08–9.54). Receipt of guideline-concordant antibiotics was not associated with reductions in time to clinical stability, time to oral antibiotics, or length of hospital stay when patients who died were excluded from the analysis. Conclusion: Guideline-concordant empiric antibiotic therapy was associated with improved survival among these patients with CAP who were admitted to 5 ICUs.
Signal transducer and activator of transcription 3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled, and STAT3 impairment contributes to several diseases ...including the monogenic autosomal-dominant hyper-immunoglobulin E (IgE) syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished T helper 17 cell numbers, in absence of
mutations. We identified two distinct homozygous nonsense mutations in
, which encodes a zinc finger transcription factor. Wild-type ZNF341 bound to and activated the
promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in
account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.
Quantification of six herbicide metabolites in human urine Norrgran, Jessica; Bravo, Roberto; Bishop, Amanda M. ...
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences,
01/2006, Letnik:
830, Številka:
2
Journal Article
Recenzirano
We developed a sensitive, selective and precise method for measuring herbicide metabolites in human urine. Our method uses automated liquid delivery of internal standards and acetate buffer and a ...mixed polarity polymeric phase solid phase extraction of a 2
mL urine sample. The concentrated eluate is analyzed using high-performance liquid chromatography–tandem mass spectrometry. Isotope dilution calibration is used for quantification of all analytes. The limits of detection of our method range from 0.036 to 0.075
ng/mL. The within- and between-day variation in pooled quality control samples range from 2.5 to 9.0% and from 3.2 to 16%, respectively, for all analytes at concentrations ranging from 0.6 to 12
ng/mL. Precision was similar with samples fortified with 0.1 and 0.25
ng/mL that were analyzed in each run. We validated our selective method against a less selective method used previously in our laboratory by analyzing human specimens using both methods. The methods produced results that were in agreement, with no significant bias observed.
The South Bronx is a low-income, minority community in New York City. It has one of the highest asthma rates in the country, which community residents feel is related to poor air quality. Community ...residents also feel that the air quality data provided by the New York State Department of Environmental Conservation (DEC) through its network of monitoring stations do not reflect the poor quality of the air they breathe. This is due to the fact that these monitoring stations are located 15m above ground. In the year 2001 this project collected air quality data at three locations in the study area. They were collected close to ground-level at a height of 4m by a mobile laboratory placed in a van as part of the South Bronx Environmental Health and Policy Study. This paper compares data collected by the project with data from DEC's monitoring stations in Bronx County during the same periods. The goal of the comparison is to gain a better understanding of differences in measured air quality concentrations at these different heights. Although there is good agreement in the data among DEC stations there are some important differences between ground-level measurements and DEC data. For PM2.5 the measured concentrations by the van were similar to those recorded by DEC stations. In the case of ozone, the concentrations recorded at ground level were similar or lower than those recorded by DEC stations. For NO2, however, the concentrations recorded at ground level were over twice as high as those recorded by DEC. In the case of SO2, ground level measurements were substantially higher in August but very similar in the other two periods. CO concentrations measured at ground-level tend to be 60–90% higher than those recorded by DEC monitoring stations. Despite these differences, van measurements of SO2 and CO concentrations were well below EPA standards.
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