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.     

Experience with a metered-dose inhaler with a spacer in the pediatric emergency department

Studies of adults suggest that metered-dose inhalers with spacers are as effective as hand-held nebulizers for bronchodilator delivery. We studied 13 children with acute asthma. They received two puffs every 2 minutes from metered-dose inhalers with spacers (range, 4 to 14 puffs) titrated until improvement stopped. Peak expiratory flow increased 34% for metered-dose inhalers with spacers after the first 2 puffs and increased 87% for metered-dose inhalers with spacers after dose titration. After titration, respiratory rate decreased by 12%, heart rate increased by 2%, and breath sounds improved in 92% of the patients. We concluded that the metered-dose inhalers with spacers are an effective device for the treatment of asthma in the pediatric emergency department and that the use of metered-dose inhalers with spacers with titration can achieve significant bronchodilation in the treatment of patients with acute asthma.     

Preliminary evaluation of vitiligo using in vivo reflectance confocal microscopy

BACKGROUND: Vitiligo is the most common pigmentary disorder with a global incidence from 0.1% to 2% in different geographical areas. Histopathology and histochemistry have shown the reduction of melanocytes in achromic patches, but microscopic changes of lesional and non-lesional skin are still not completely understood. Reflectance confocal microscopy (RCM), based on the different light reflectance index of cutaneous structures, allowed in vivo, en face microscopic evaluation of superficial skin layers with a resolution similar to skin histology. AIM: The purpose of this study was to evaluate RCM features of lesional and non-lesional skin of vitiligo patients. Moreover, re-pigmented areas were taken into consideration in order to evaluate melanocyte response to ultraviolet B (UVB) radiation. SUBJECTS AND METHODS: Sixteen patients of different phototypes affected by active non-segmental vitiligo and 10 controls were enrolled in the study. In vivo skin imaging was done using a commercially available RCM (Lucid, Vivascope 1500. Re-pigmented areas from 6 to 16 patients (after UVB narrow-band therapy) were also examined. RESULTS: Vitiligo lesions showed the disappearance of the bright rings normally seen at the dermo-epidermal junction. Moreover, non-lesional skin of vitiligo patients showed unexpected changes as the presence of half-rings or scalloped border-like features of the bright papillary rings. In re-pigmented areas after UVB narrow band therapy, the presence of activated, dendritic melanocytes was seen. CONCLUSIONS: Considering our results, and following further studies, RCM clinical applications could be used in the therapeutic monitoring and evaluation of the evolution of vitiligo.     

In situ saphenous vein bypass grafts: angiographic evaluation and interventional repair of complications

In situ saphenous vein grafts are being used with increasing frequency for bypass procedures involving the femoral and popliteal arteries. Complications of these procedures include anastomotic stenoses and persistent arteriovenous fistulae that may result in failure of the graft. Balloon angioplasty and embolotherapy with detachable balloons were employed successfully in three or four recent cases of patients with complications from in situ grafts. Tailored angiography is essential for evaluating in situ grafts, and interventional techniques are extremely useful for managing complications.     

Hemorrhagic and nonhemorrhagic brain lesions: evaluation with 0.35-T fast MR imaging

Two fast magnetic resonance (MR) imaging techniques, advanced Fourier and partial-flip imaging, were used at 0.35 T to examine 21 patients with suspected intracranial lesions; the results were quantitatively compared with a conventional spin-echo study. Both of the fast MR techniques yielded a fourfold reduction in imaging time per section. The advanced Fourier sequence showed contrast that was identical to the conventional spin-echo study with signal-to-noise ratios of 58% and 57% for the first and second echoes, respectively. The partial-flip sequence showed a contrast of 109% and 57% for lesions versus substantia alba, and 107% and 78% for substantia grisea versus substantia alba relative to the first and second echoes of the conventional spin-echo study. The partial-flip sequence was particularly sensitive to magnetic susceptibility; this produced artifacts that may undermine the usefulness of partial flip for routine screening in certain parts of the brain. However, this susceptibility significantly improved the detection of intracranial hemorrhage when compared with the spin-echo sequence, particularly when combined with phase mapping of the partial-flip study.