De novo variants in CNOT3 cause a variable neurodevelopmental disorder.

As a result of exome-based sequencing work performed by the DDD study, de novo variants in CNOT3 have emerged as a newly recognised cause of a developmental disorder. This paper describes molecular and clinical details of 16 probands with developmental disorders and de novo CNOT3 variants. It is the first such description of the developmental phenotype associated with CNOT3 variants. Eight of these cases were discovered as part of the DDD study, while the other eight were found as a result of large-scale sequencing work performed by other groups. A highly specific phenotype was not recognised in these 16 cases. The most consistent phenotypic features seen in subjects with de novo variants in CNOT3 were hypotonia, relatively small stature, developmental delay, behavioural problems and intellectual disability. There is no easily recognisable facial phenotype, but some common dysmorphic features such as anteverted nares, thin upper lip and low set eyebrows were shared among some of the probands. Haploinsufficiency appears to be the most likely mechanism of action, with eight cases found to have protein-truncating variants. Of the other eight cases (all missense variants), three share an amino acid substitution at the same position which may therefore represent an important functional domain.

Methods to detect CNVs in the human genome.

The detection of quantitative changes in genomic DNA, i.e. deletions and duplications or Copy Number Variants (CNVs), has recently gained considerable interest. First, detailed analysis of the human genome showed a surprising amount of CNVs, involving thousands of genes. Second, it was realised that the detection of CNVs as a cause of genetic disease was often neglected, but should be an essential part of a complete screening strategy. In both cases new efficient CNV screening methods, covering the entire range from specific loci to genome-wide, were behind these developments. This paper will briefly review the methods that are available to detect CNVs, discuss their strong and weak points, show some new developments and look ahead. Methods covered include microscopy, fluorescence in situ hybridization (including fiber-FISH), Southern blotting, PCR-based methods (including MLPA), array technology and massive parallel sequencing. In addition, we will show some new developments, including a 1400-plex CNV bead assay, fast-MLPA (from DNA to result in approximately 6 h) and a simple Melting Curve Analysis assay to confirm potential CNVs. Using the 1400-plex CNV bead assay, targeting selected chromosomal regions only, we detected confirmed rearrangements in 9% of 320 mental retardation patients studied.

Ioversol clinical safety summary.

The authors evaluated double-blind comparative and open-label clinical trials in 1,186 patients who received ioversol to evaluate the safety and efficacy of ioversol, a new nonionic low-osmolality contrast medium, at iodine concentrations of 32%, 24%, and 16%. The results indicate that ioversol was well tolerated in all patients and showed fewer adverse effects than conventional ionic agents. The diagnostic efficacy of ioversol was comparable to both conventional and other nonionic agents with respect to diagnostic quality. However, the improved patient tolerance may contribute to higher quality radiographs. The effects on renal function were monitored at 24, 48, 72, and 96 hours and did not reveal any clinically or statistically significant changes.

Pharmacokinetics and urinary excretion of clavulanic acid after oral administration of amoxicillin and potassium clavulanate.

Clavulanic acid is a beta-lactamase inhibitor which prevents microbial lactamase inactivation of beta-lactam antibiotics. The pharmacokinetics and urinary excretion of clavulanic acid were studied in eight healthy adult volunteers after oral administration of 500 mg amoxicillin and 125 mg potassium clavulanate. Serum and urine clavulanic acid concentrations were assayed using high-performance liquid chromatography. Pharmacokinetic parameters were: t 1/2 beta = 1.019 +/- 0.090 hour, t 1/2 alpha = 0.276 +/- 0.031 hour, lag time = 0.321 +/- 0.018 hour, tmax = 1.042 +/- 0.80 hour, Cmax = 2.098 +/- 0.441 micrograms/ml, and AUC = 4.897 +/- 0.979 micrograms X hr/ml. Cumulative urinary excretion of clavulanic acid (as percentage of dose administered) was: 14.05 +/- 2.87 within 2 hours, 25.77 +/- 3.98 within 4 hours, and 27.85 +/- 4.27 within 6 hours after administration.

Treatment of skin and skin structure infections: a comparative study of Augmentin and cefaclor.

Sixty-four patients were entered into a double-blind study of Augmentin and cefaclor. Pathogenic bacteria were recovered from twenty-one patients who received Augmentin and seventeen patients who received cefaclor. The primary diagnoses were pyodermas and impetigo, as well as cellulitis, folliculitis, infected skin structure, and infected surgical sites. Eighty-one percent of the Augmentin-treated patients were classified as successfully treated, based on clinical and bacteriologic criteria, as were eighty-nine percent of the patients treated with cefaclor. Side effects were minimal in both groups; no laboratory abnormalities were found. Both Augmentin and cefaclor are useful oral antimicrobial agents in the treatment of infections of the skin and skin structure.