Loss of function,missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts

Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes.     

Esophageal candidosis in progressive systemic sclerosis: occurrence, significance, and treatment with fluconazole

Esophageal mucosal brushings from 51 consecutive patients with progressive systemic sclerosis (PSS) (group I), 18 PSS patients continuously treated with high-dose ranitidine or omeprazole (group II), 34 controls referred to the outpatient clinic for endoscopy (group III), and 10 patients receiving long-term potent antireflux therapy for idiopathic gastroesophageal reflux (group IV) were cultured for Candida albicans. There were 44%, 89%, 9%, and 0% Candida albicans culture-positive patients in groups I through IV, respectively. Fifteen patients with candida esophagitis from group II were treated with fluconazole systemically. Eleven and 14 patients became culture-negative after 2 and 4 weeks' treatment, respectively. Three months after fluconazole withdrawal the recurrence rate was 100%. It is concluded that esophageal dysmotility predisposes for candidosis. Adding gastric acid inhibitory treatment to dysmotility enhances the risk significantly (p less than 0.01). The efficiency of fluconazole treatment was close to 100%, but so was the recurrence rate within a short period.     

Anterior interosseous nerve palsy following closed fracture of the proximal ulna. A case report and review of the literature

Complete paralysis of the anterior interosseous nerve was seen in 32-year-old army officer 5 weeks after he sustained a minimally displaced fracture of the proximal ulna. The fracture was immobilized in an arm cast. Thirteen weeks after injury, the cast was removed following evidence of bone union. Complete recovery of the flexor pollicis longus was noted 17 weeks after the injury, while recovery of the flexor profundus to the index finger to grade four lasted 10 months. To the best of our knowledge, this is the first case reported in the English language literature in which anterior interosseous nerve palsy follows isolated fracture of the proximal ulna.     

The expression of CEA, CA 19-9 and HMFG antigens in ovarian clear-cell and endometrioid carcinomas.

The tumour antigen expression of ovarian and endometrial endometrioid carcinomas, ovarian clear-cell carcinomas as well as endometrial and cervical clear-cell carcinomas were immunohistochemically compared. Of special interest were potential differences between the endometrioid and clear-cell carcinomas of the ovary. The expression of CEA and CA 19-9 tumour antigens in all these tumour types was heterogeneous, with 10-20% of the cases being positive for CEA and 40-75% being positive for CA 19-9. In contrast, HMFG IIIC 12, a monoclonal antibody originally directed against human milk fat globule (HMFG) membrane antigens, invariably detected a corresponding antigen on every case of these tumour types. Another HMFG antibody, SM IF 3, on the other hand, detected antigenic material on all clear-cell tumour types, but only rarely on endometrioid tumours of the ovary or endometrium. While HMFG IIIC 12 detects an antigen present on all ovarian, endometrial and mammary carcinomas, antibody SM IF 3 thus appears to be more restricted in its staining patterns. Our results with both of these antibodies indicate that ovarian clear-cell carcinomas and ovarian endometrioid carcinomas have antigenic differences, which provides further evidence that they belong to different tumour entities.     

American Society of Nuclear Cardiology review of the ACCF/ASNC appropriateness criteria for single-photon emission computed tomograph myocardial perfusion imaging (SPECT MPI)

Conclusion  The ACCF/ASNC AC for SPECT MPI provides recommendations for the appropriate use of SPECT MPI. After the publication of the AC document in 2005, the AC has been used by nuclear cardiology practices with many clinical studies evaluating the list of indications in routine clinical practice. From these data. ASNC recommends minor but important changes to the indication list, suggesting the addition of 6 new indications and the modification of the definitions for “chest pain syndrome” and “CHD high risk.”. An objective review of existing indications focused on only those indications that had significant variability among the reviewers (n=20). These indications were reviewed in the presence of existing and new evidence-based data, and ASNC recommends that the grades for 6 indications be re-evaluated. The AC for SPECT MPI will require periodic review as new evidence becomes available or as clinical practice evolves. ASNC recognizes the importance of these criteria to improve the quality of patient care, and it will continue to play a key role in assembling the information for this ongoing review. From the current summary of evidence, ASNC consensus opinions, and ASNC recommendations in this document, ASNC strongly recommends that the AC guidelines be reviewed Prepared by the American Society of Nuclear Cardiology Quality Assurance Subcommittee for Quality in Imaging Standards. Reviewed by members of the American Society of Nuclear Cardiology Quality Assurance Committee. Approved by the American Society of Nuclear Cardiology Board of Directors, September 6, 20.