Noncoding deletions reveal a gene that is critical for intestinal function.

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Percutaneous closure of postinfarction ventricular septal defect: in-hospital outcomes and long-term follow-up of UK experience.

Background— Postinfarction ventricular septal defect carries a grim prognosis. Surgical repair offers reasonable outcomes in patients who survive a healing phase. Percutaneous device implantation represents a potentially attractive early alternative. Methods and Results— Postinfarction ventricular septal defect closure was attempted in 53 patients from 11 centers (1997–2012; aged 72±11 years; 42% female). Nineteen percent had previous surgical closure. Myocardial infarction was anterior (66%) or inferior (34%). Time from myocardial infarction to closure procedure was 13 (first and third quartiles, 5–54) days. Devices were successfully implanted in 89% of patients. Major immediate complications included procedural death (3.8%) and emergency cardiac surgery (7.5%). Immediate shunt reduction was graded as complete (23%), partial (62%), or none (15%). Median length of stay after the procedure was 5.0 (2.0–9.0) days. Fifty-eight percent survived to discharge and were followed up for 395 (63–1522) days, during which time 4 additional patients died (7.5%). Factors associated with death after postinfarction ventricular septal defect closure included the following: age (hazard ratio [HR]=1.04; P =0.039), female sex (HR=2.33; P =0.043), New York Heart Association class IV (HR=4.42; P =0.002), cardiogenic shock (HR=3.75; P =0.003), creatinine (HR=1.007; P =0.003), defect size (HR=1.09; P =0.026), inotropes (HR=4.18; P =0.005), and absence of revascularization therapy for presenting myocardial infarction (HR=3.28; P =0.009). Prior surgical closure (HR=0.12; P =0.040) and immediate shunt reduction (HR=0.49; P =0.037) were associated with survival. Conclusions— Percutaneous closure of postinfarction ventricular septal defect is a reasonably effective treatment for these extremely high-risk patients. Mortality remains high, but patients who survive to discharge do well in the longer term. </jats:sec

Understanding of the Hsp90 molecular chaperone reaches new heights

Heat shock protein 90 (Hsp90) was the focus of a recent meeting in the Swiss Alps, where the Hsp90 community met to discuss the operation and functions of this ubiquitous and essential molecular chaperone

Liver Retransplantation in Patients with HIV-1 Infection: An International Multicenter Cohort Study

Liver retransplantation is performed in HIV-infected patients, although its outcome is not well known. In an international cohort study (eight countries), 37 (6%; 32 coinfected with hepatitis C virus [HCV] and five with hepatitis B virus [HBV]) of 600 HIV-infected patients who had undergone liver transplant were retransplanted. The main indications for retransplantation were vascular complications (35%), primary graft nonfunction (22%), rejection (19%), and HCV recurrence (13%). Overall, 19 patients (51%) died after retransplantation. Survival at 1, 3, and 5 years was 56%, 51%, and 51%, respectively. Among patients with HCV coinfection, HCV RNA replication status at retransplantation was the only significant prognostic factor. Patients with undetectable versus detectable HCV RNA had a survival probability of 80% versus 39% at 1 year and 80% versus 30% at 3 and 5 years (p = 0.025). Recurrence of hepatitis C was the main cause of death in the latter. Patients with HBV coinfection had survival of 80% at 1, 3, and 5 years after retransplantation. HIV infection was adequately controlled with antiretroviral therapy. In conclusion, liver retransplantation is an acceptable option for HIV-infected patients with HBV or HCV coinfection but undetectable HCV RNA. Retransplantation in patients with HCV replication should be reassessed prospectively in the era of new direct antiviral agents

Proceedings Of The 23Rd Paediatric Rheumatology European Society Congress: Part Two

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