Koilonychia, dome-shaped epiphyses, and vertebral platyspondylia

A 2.5-year-old girl presented with koilonychia since birth and was subsequently found to have dome-shaped femoral epiphyses and platyspondylia with anterior central tongues on a skeletal survey.     

Fine mapping and evaluation of candidate genes for cervical cancer on 11q23

We previously showed that loss of heterozygosity (LOH) at 11q23 is a common genetic alteration in cervical cancer (CC) and that it correlates with extensive invasion of lymph-vascular spaces. In the current study, we looked for allelic loss in paired normal/tumor genomic DNA from 121 cervical tumors by using 20 well-mapped microsatellite markers on 11q. LOH at one or more loci was observed in 81 (66.9%) tumors. The deletion patterns in tumors are complex. However, at least three LOH islands could be defined between D11S614 and D11S4167. We also genotyped 11 CC cell lines and analyzed the results using the homozygosity mapping-of-deletions method. Five of the 11 cell lines showed continuous homozygosity that extended through 11q23.3-11q24.1. We used a candidate-gene approach to screen candidate tumor-suppressor genes (TSGs) that were localized in that region. Intragenic changes in the entire coding sequence of four candidate genes (RNF26, USP2, POU2F3, and TRIM29) in the region and a proposed TSG (PPP2R1B) centromeric to the region were evaluated. The expression status of USP2, POU2F3, TRIM29, and another proposed TSG that is telomeric to the region (BCSC1) also was examined. We identified previously described single-nucleotide polymorphisms (SNPs), several novel variants, and three rare SNPs in the five candidate genes. Decreased expression of POU2F3 and TRIM29 was found in some cervical tumors and CC cell lines. Our results indicate that a major region of LOH in cervical cancer exists within a 3.6-Mb stretch of DNA on 11q23.3-q24.1 and that somatic mutations in RNF26, USP2, TRIM29, POU2F3, or PPP2R1B probably are not important for cervical carcinogenesis.     

Microvessel density in muscles of dogs with golden retriever muscular dystrophy

Due to the abundance of muscle, intravascular administration seems required for efficient gene or cell therapy of muscular dystrophy. Here, we examined the skeletal muscle microvasculature to assess if it is altered with dystrophin deficiency. Image analysis of capillaries was performed in three muscles of one- to ten-month-old golden retriever muscular dystrophy (GRMD) dogs and compared with healthy controls. In the gracilis muscle (and in the biceps brachii muscle) of 4- to 10-month-old GRMD dogs, the microvessel density (445+/-47 microvessels per mm(2)), the capillary to fiber ratio (111+/-26 capillaries per 100 myofibers), and the mean intercapillary distance (49+/-3 microm), were similar in affected and control dogs. The sartorius cranialis muscle in GRMD dogs showed microvessel depletion and increased intercapillary distance, but unaltered capillary to fiber ratio, relative to the controls. The mean diameter of microvessels and the total vascular area were higher in GRMD muscles than in control ones. In severely affected GRMD muscles at 7-10 months of age, fibrosis was associated with decreased microvessel density, increased intercapillary distance and microvessel diameter, but normal capillary to fiber ratio and total vascular area.     

Comparative trial of short-course ofloxacin for uncomplicated typhoid fever in Vietnamese children

An open, randomised comparison of 2 or 3 days of oral ofloxacin (10 mg/kg/day) for uncomplicated typhoid fever was conducted in 235 Vietnamese children. Multi-drug-resistant Salmonella typhi was isolated from 182/202 (90%) children and 5/166 (3%) tested isolates were nalidixic acid-resistant (Na(R)). Eighty-nine of 116 children randomised to 2 days and 107/119 randomised to 3 days were blood culture-positive and eligible for analysis. There were 12 (13.5%) failures in the 2-day group (six clinical failures, four blood culture-positive post treatment, two relapses) compared with eight (7.5%) failures in the 3-day group (four clinical failures, one blood culture-positive post treatment, three relapses) (OR 1.9, 95% CI 0.7-5.5,p = 0.17). There were no significant differences in the mean (95% confidence interval) fever clearance times (h) [92 (82-102) vs 101 (93-110), p = 0.18] or duration of hospitalisation (d) [7.6 (7.2-8.1) vs 8.0 (7.6-8.4), p = 0.19] between the two groups. There was one failure in the four eligible children infected with an Na(R) isolate of S. typhi. No adverse events were attributable to the ofloxacin. These results extend previous observations on the efficacy of short courses of ofloxacin for children with uncomplicated multi-drug-resistant typhoid fever.     

Human thiopurine S-methyltransferase pharmacogenetics: variant allozyme misfolding and aggresome formation

Thiopurine S-methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs. TPMT genetic polymorphisms represent a striking example of the potential clinical value of pharmacogenetics. Subjects homozygous for TPMT*3A, the most common variant allele for low activity, an allele that encodes a protein with two changes in amino acid sequence, are at greatly increased risk for life-threatening toxicity when treated with standard doses of thiopurines. These subjects have virtually undetectable levels of TPMT protein. In this study, we tested the hypothesis that TPMT*3A might result in protein misfolding and aggregation. We observed that TPMT*3A forms aggresomes in cultured cells and that it aggregates in vitro, functional mechanisms not previously described in pharmacogenetics. Furthermore, there was a correlation among TPMT half-life values in rabbit reticulocyte lysate, aggresome formation in COS-1 cells, and protein aggregation in vitro for the three variant allozymes encoded by alleles that include the two TPMT*3A single-nucleotide polymorphisms. These observations were compatible with a common structural explanation for all of these effects, a conclusion supported by size-exclusion chromatography and CD spectroscopy. The results of these experiments provide insight into a unique pharmacogenetic mechanism by which common polymorphisms affect TPMT protein function and, as a result, therapeutic response to thiopurine drugs.     

Pediatric cortical dysplasia: correlations between neuroimaging, electrophysiology and location of cytomegalic neurons and balloon cells and glutamate/GABA synaptic circuits

Seizures in cortical dysplasia (CD) could be from cytomegalic neurons and balloon cells acting as epileptic 'pacemakers', or abnormal neurotransmission. This study examined these hypotheses using in vitro electrophysiological techniques to determine intrinsic membrane properties and spontaneous glutamatergic and GABAergic synaptic activity for normal-pyramidal neurons, cytomegalic neurons and balloon cells from 67 neocortical sites originating from 43 CD patients (ages 0.2-14 years). Magnetic resonance imaging (MRI), (18)fluoro-2-deoxyglucose positron emission tomography (FDG-PET) and electrocorticography graded cortical sample sites from least to worst CD abnormality. Results found that cytomegalic neurons and balloon cells were observed more frequently in areas of severe CD compared with mild or normal CD regions as assessed by FDG-PET/MRI. Cytomegalic neurons (but not balloon cells) correlated with the worst electrocorticography scores. Electrophysiological recordings demonstrated that cytomegalic and normal-pyramidal neurons displayed similar firing properties without intrinsic bursting. By contrast, balloon cells were electrically silent. Normal-pyramidal and cytomegalic neurons displayed decreased spontaneous glutamatergic synaptic activity in areas of severe FDG-PET/MRI abnormalities compared with normal regions, while GABAergic activity was unaltered. In CD, these findings indicate that cytomegalic neurons (but not balloon cells) might contribute to epileptogenesis, but are not likely to be 'pacemaker' cells capable of spontaneous paroxysmal depolarizations. Furthermore, there was more GABA relative to glutamate synaptic neurotransmission in areas of severe CD. Thus, in CD tissue alternate mechanisms of epileptogenesis should be considered, and we suggest that GABAergic synaptic circuits interacting with cytomegalic and normal-pyramidal neurons with immature receptor properties might contribute to seizure generation.     

The metabolic syndrome: prevalence and risk factors in the urban population of Ho Chi Minh City

The purpose of this study was to determine the prevalence of metabolic syndrome (MeS) and its risk factors in urban population of Ho Chi Minh City. A cross-sectional study was conducted in urban areas of Ho Chi Minh City with 611 participants. The demographic, socio-economic details, anthropometric indexes and blood pressure were recorded. A fasting blood sample was collected for the analyses of glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). MeS was defined by presence of three or more of the following components: abdominal obesity, hypertriglyceridemia, low HDL-cholesterolemia, high blood pressure and high fasting plasma glucose. The crude prevalence of MeS was 18.5% (95% CI: 15.5-21.9). After age, sex standardization, this prevalence was 12.0% (95% CI: 10.9-13.2). The prevalence increased with age and sedentary work. Subjects with MeS had significantly higher body fat percentage than that of normal subjects. Metabolic syndrome showed a positive association with age, body fat percentage and sedentary occupation. This first study on MeS showed that 12% adults in urban areas of Ho Chi Minh City had metabolic syndrome. It suggests that MeS is becoming a noteworthy health problem in Vietnam and to the early detection and appropriate intervention as well as healthy lifestyle education programs need to be established.