13 research outputs found
Parental origin and somatic mosaicism of PHOX2B mutations in Congenital Central Hypoventilation Syndrome.
Heterozygous polyalanine repeat expansions of PHOX2B have been associated with Congenital Central Hypoventilation Syndrome, a rare neurocristopathy characterized by absence of adequate control of respiration during sleep. Here we report a PHOX2B mutational screening in 63 CCHS patients, 58 of whom presenting with poly-A expansions or frameshift, missense and nonsense mutations. To assess a somatic or germline occurrence of poly-A length variations, the relative amounts of mutant and wild type alleles have been quantified in 20 selected CCHS patients presenting with an expansion, and in their parents. Somatic mosaicism was shown in four parents, while no mosaic was found among CCHS patients. Moreover, while co-segregation analysis of the PHOX2B poly-A expansions with selected marker alleles in the same 20 CCHS trios has not demonstrated any parent-of-origin effect of the mutations, it has provided further clues to clarify the molecular mechanism underlying the expansion occurrence. Finally, the segregation of PHOX2B poly-A anomalous tracts within family members has allowed us to exclude tendency of polymorphic variations towards expansion. This strengthens the notion that expanded polyalanine tracts, identified as frequent disease-causing mutations also in other human diseases, are mitotically and meiotically stable
The clinical effectiveness of an integrated multidisciplinary evidence-based program to prevent intraoperative pressure injuries in high-risk children undergoing long-duration surgical procedures: a quality improvement study
The prevention of hospital-acquired pressure injuries (HAPIs) in children undergoing long-duration surgical procedures is of critical importance due to the potential for catastrophic sequelae of these generally preventable injuries for the child and their family. Long-duration surgical procedures in children have the potential to result in high rates of HAPI due to physiological factors and the difficulty or impossibility of repositioning these patients intraoperatively. We developed and implemented a multi-modal, multi-disciplinary translational HAPI prevention quality improvement program at a large European Paediatric University Teaching Hospital. The intervention comprised the establishment of wound prevention teams, modified HAPI risk assessment tools, specific education, and the use of prophylactic dressings and fluidized positioners during long-duration surgical procedures. As part of the evaluation of the effectiveness of the program in reducing intraoperative HAPI, we conducted a prospective cohort study of 200 children undergoing long-duration surgical procedures and compared their outcomes with a matched historical cohort of 200 children who had undergone similar surgery the previous year. The findings demonstrated a reduction in HAPI in the intervention cohort of 80% (p < 0.01) compared to the comparator group when controlling for age, pathology, comorbidity, and surgical duration. We believe that the findings demonstrate that it is possible to significantly decrease HAPI incidence in these highly vulnerable children by using an evidence-based, multi-modal, multidisciplinary HAPI prevention strategy
Sarcoglycan heterologous expression.
Mutations in sarcoglycans (SGs) cause autosomal-recessive limb-girdle muscular dystrophy. SGs exist as a complex of four transmembrane proteins (a, b, c, and d). We have recently shown that a-SG is an ecto-ATPase, i.e. an enzyme able to hydrolyze extracellular ATP. The ecto-ATPase activity and assembly of the SG complex was examined in heterologous expression systems. Individual or all four SGs were expressed in HEK 293 and COS-1 cells by using different expression vectors. Our results show that in COS-1 cells localisation to cell membrane of the SG complex requires the contemporary expression of all four isoforms. In contrast, a-SG can be expressed alone in HEK
cells and its localization at cell membrane determines the de novo appearance of ecto-ATPase activity.
Funded by TELETHON ITALY and NIH
Interlead anatomic and electrical distance predict outcome in CRT patients
Background The implantation strategy appears to play a pivotal role in determining response to cardiac resynchronization therapy (CRT). Objective The aim of our study was to determine the association between anatomic and electrical interlead distance and clinical outcome after CRT implantation. Methods We included 216 first-time CRT recipients with left bundle branch block and sinus rhythm. On implantation, the electrical interlead distance (EID), defined as the time interval between spontaneous peak R waves detected at the right ventricular (RV) and left ventricular (LV) pacing sites, was measured. The anatomic distance between the RV and LV lead tips was determined on chest radiographs. Results The mean EID was 74 ± 41 ms, and the mean horizontal corrected interlead distance (HCID) was 125 ± 73 mm. After 12 months, 87 patients (40%) displayed an improvement in their clinical composite score. The cutoff values that best predicted an improved clinical status were as follows: 84 ms for EID (area under the curve 0.59; confidence interval [CI] 0.52-0.66; P =.026) and 90 mm for HCID (area under the curve 0.62; CI 0.55-0.69; P =.004). On multivariate analysis, only EID >84 ms (hazard ratio 0.36; CI 0.14-0.89; P =.028) and HCID >90 mm (hazard ratio 0.45; CI 0.23-0.90; P =.025) were significantly associated with the composite endpoint of death or cardiovascular hospitalization. In particular, the presence of both conditions (EID <84 ms and HCID <90 mm) was associated with the highest rate of events (log-rank test P =.002). Conclusions The interlead anatomic and electrical distance are strongly and independently associated with patient outcome after CRT implantation. The 2 measures show an additive predictive value. (CRT MORE: Cardiac Resynchronization Therapy Modular Registry; www.clinicaltrials.gov, unique identifier: NCT01573091.) © 2015 Heart Rhythm Society
The osmr gene is involved in hirschsprung associated enterocolitis susceptibility through an altered downstream signaling
The OSMR Gene Is Involved in Hirschsprung Associated Enterocolitis Susceptibility through an Altered Downstream Signaling
Hirschsprung (HSCR) Associated Enterocolitis (HAEC) is a common life-threatening complication in HSCR. HAEC is suggested to be due to a loss of gut homeostasis caused by impairment of immune system, barrier defense, and microbiome, likely related to genetic causes. No gene has been claimed to contribute to HAEC occurrence, yet. Genetic investigation of HAEC by Whole-Exome Sequencing (WES) on 24 HSCR patients affected (HAEC) or not affected (HSCR-only) by enterocolitis and replication of results on a larger panel of patients allowed the identification of the HAEC susceptibility variant p.H187Q in the Oncostatin-M receptor (OSMR) gene (14.6% in HAEC and 5.1% in HSCR-only, p = 0.0024). Proteomic analysis on the lymphoblastoid cell lines from one HAEC patient homozygote for this variant and one HAEC patient not carrying the variant revealed two well distinct clusters of proteins significantly up or downregulated upon OSM stimulation. A marked enrichment in immune response pathways (q < 0.0001) was shown in the HAEC H187 cell line, while proteins upregulated in the HAEC Q187 lymphoblasts sustained pathways likely involved in pathogen infection and inflammation. In conclusion, OSMR p.H187Q is an HAEC susceptibility variant and perturbates the downstream signaling cascade necessary for the gut immune response and homeostasis maintenance
Does the CHA2DS2-VASc score reliably predict atrial arrhythmias? Analysis of a nationwide database of remote monitoring data transmitted daily from cardiac implantable electronic devices
Background
CHA2DS2-VASc is a validated score for predicting stroke in patients with atrial fibrillation (AF).
Objective
The purpose of this study was to assess whether the CHA2DS2-VASc score can predict new-onset AF in a cohort of patients with a cardiac implantable electronic device (CIED) followed with remote monitoring.
Methods
Using the database of the Home Monitoring Expert Alliance project, we selected 2410 patients with no documented AF who had received a CIED with diagnostics on atrial high rate episodes (AHREs). The primary endpoint was time to first day with cumulative AHRE burden ≥15 minutes, 5 hours, 24 hours, and ≥7 consecutive days.
Results
During a median duration of 24.1(11.5–42.9) months, the incidence of AHRE increased with increasing CHA2DS2-VASc. At 6 years, occurrence of ≥15-minute AHRE was 80.2% (CHA2DS2-VASc ≤1) vs 93.7% (CHA2DS2-VASc ≥5), whereas ≥5-hour AHRE incidence was 68.4% (CHA2DS2-VASc ≤1) vs 92.5% (CHA2DS2-VASc ≥5). Occurrence of ≥24-hour and ≥7-day AHREs also increased with increasing CHA2DS2-VASc: 9.1% and 3.9% (CHA2DS2-VASc ≤1) vs 40.4% and 28.7% (CHA2DS2-VASc ≥5), respectively. Adjusted hazard ratio for unitary CHA2DS2-VASc increase ranged from 1.09 (confidence interval 1.04–1.14; P <.001) with AHRE burden ≥15 minutes to 1.26 (confidence interval 1.11–1.42; P <.001) with AHRE burden ≥7 days. At receiver operating curve analysis, CHA2DS2-VASc ≥2 was estimated to predict persistent forms of AHREs with 95.8% sensitivity but 11.7% specificity at 3 years. CHA2DS2-VASc ≥5 had 77.0% specificity but 34.6% sensitivity.
Conclusion
In a CIED population with no previous diagnosis of clinical AF, AHRE incidence increased with increasing CHA2DS2-VASc score. The association was stronger with longer AHREs, but the accuracy of CHA2DS2-VASc as AHRE predictor was moderate