Large-scale sequencing to identify disease causing variants in X-linked mental retardation

A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation
Tarpey et al. (2009)
Nature Genetics 41: 535–543     

High prevalence of vitamin D insufficiency and its association with BMI-for-age among primary school children in Kuala Lumpur,Malaysia

Background  

Deficiencies of micronutrients can affect the growth and development of children. There is increasing evidence of vitamin D deficiency world-wide resulting in nutritional rickets in children and osteoporosis in adulthood. Data on the micronutrient status of children in Malaysia is limited. The aim of this study was to determine the anthropometric and micronutrient status of primary school children in the capital city of Kuala Lumpur.     

The relationship between body mass index,activated protein C resistance and risk of venous thrombosis

Summary. Background: High body mass index (BMI) is associated with an increased risk of venous thrombosis (VT). Clotting factor VIII levels are increased in obese subjects, possibly because of a chronic inflammatory state, which increases activated protein C (APC) resistance. The APC resistance in FV Leiden carriers could be aggravated and further worsened by high FVIII levels in blood group non‐O carriers. We hypothesized that an association exists between BMI and APC resistance, and that this is amplified by the presence of FV Leiden and/or blood group non‐O. Methods: We used the Leiden Thrombophilia Study (LETS) to determine whether an association exists between BMI and APC resistance, and whether the combination of high BMI and APC resistance increases the risk of VT. In a pooled analysis of LETS and a Norwegian case‐cohort study (TROL), we verified whether FV Leiden modified the risk of the occurrence of VT with increasing BMI, and whether this risk was further increased by blood group non‐O. Results: APC resistance increased linearly with increasing BMI, partly because of a concurrent rise in FVIII. A BMI in the median or upper tertile was associated with a 1.9‐fold (95% confidence interval [CI] 1.0–2.5) and 2.2‐fold (95% CI 1.4–3.4) increased risk as compared with the lowest tertile. Both relative risks decreased slightly after FVIII and APC resistance adjustments. The effect of BMI on VT risk was enhanced two‐fold to 10‐fold in FV Leiden or blood group non‐O carriers. Conclusions: The increased risk of VT in individuals with high BMI is partly mediated by FVIII‐related APC resistance. This risk is more pronounced when other causes of increased APC resistance are also present.     

Formulation and evaluation of microsphere based oro dispersible tablets of itopride hcl

Background

The purpose of the present work is to mask the intensely bitter taste of Itopride HCl and to formulate an Oro dispersible tablet (ODT) of the taste-masked drug by incorporation of microspheres in the tablets for use in specific populations viz. pediatrics, geriatrics and patients experiencing difficulty in swallowing.

Methods

With this objective in mind, microspheres loaded with Itopride HCl were prepared by solvent evaporation method using acetone as solvent for pH-sensitive polymer, Eudragit EPO and light liquid paraffin as the encapsulating medium. The prepared microspheres were characterized with regard to yield, drug content, flow properties, particle size and size distribution, surface features, in vitro drug release and taste. The ODTs so prepared from these microspheres were evaluated for hardness, thickness, weight variation, friability, disintegration time, drug content, wetting time, water absorption ratio, moisture uptake, in vitro dispersion, in vitro disintegration, in vitro drug release and stability.

Results

The average size of microspheres was found to be satisfactory in terms of the size and size distribution. Microspheres prepared were of a regular spherical shape. Comparison of the dissolution profiles of microspheres in different pH media showed that microspheres having drug: polymer ratio of 1:2 produced a retarding effect in simulated salivary fluid (pH 6.8) and were further used for formulation into ODTs after addition of suitable amounts of excipients such as superdisintegrant, diluent, sweetener and flavor of directly compressible grade.

Conclusions

Effective taste-masking was achieved for Itopride HCl by way of preparation of microspheres and ODTs of acceptable characteristics.     

Incidence of thrombocytopenia in the neonatal intensive care unit

Background

Thrombocytopenia is the commonest haematological abnormality encountered in the neonatal intensive care unit (NICU). The incidence in neonates varies greatly, depending upon the population studied. The aim of the present study was to study the incidence of thrombocytopenia in the neonates admitted to the NICU.

Method

The study was carried out in 258 consecutive eligible neonates from August 2007 to August 2009. Neonates were placed in two risk groups for thrombocytopenia, viz. high risk and low risk, depending upon the presentation, maternal history and any antenatal/perinatal events. Platelet counts were done on the first, third and fifth day of admission and thereafter every 72 hours till counts were normal. Low counts were collaborated with a peripheral blood smear.

Results and Conclusion

The overall incidence of thrombocytopenia in the study group was 70% (182/258). The incidence in the high-risk group was 93.7% cases (134/143) and in the low-risk group was 41.7% (48/115). This difference was statistically significant. Factors associated with thrombocytopenia were sepsis, extreme low birth weight, intra-uterine growth restriction, birth asphyxia and pre-eclampsia in mothers. The most common severe bleeding manifestation was pulmonary haemorrhage. The overall mortality in babies with thrombocytopenia was 33% despite <90% of these cases having received platelet transfusion. Of these pulmonary haemorrhage was the main cause of death in five cases. It is concluded that thrombocytopenia is very common in the NICU and should be actively looked for so that it can be managed appropriately.     

Bi-directional dideoxy fingerprinting (Bi-ddF): a rapid method for quantitative detection of mutations in genomic regions of 300-600 bp

There is a great need for rapid screening methods that detect essentially all mutations. Dideoxy fingerprinting (ddF) is a highly sensitive screening method that is performed by electrophoresing one lane of a Sanger dideoxy termination reaction through a nondenaturing gel. Mutations may produce an extra segment or eliminate a segment from the termination products (informative dideoxy component). In addition, mutations can be detected by the altered mobility of one or more termination segments (informative SSCP component). To screen larger segments with virtually 100% sensitivity, bi-directional ddF (Bi-ddF) was developed. Bi-ddF is a 'second generation ddF' in which the dideoxy termination reaction is performed simultaneously with two opposing primers. Bi-ddF has two important advantages over ddF: (i) the dideoxy component can detect 10 of the 12 types of possible single-base substitutions; and (ii) the SSCP component is enhanced because alterations of mobility can be detected in either the downstream or upstream direction. As a result, Bi-ddF can screen larger regions of genomic DNA with virtually 100% sensitivity. Bi-ddF detected 100% of 28 single-base substitutions in a 494 bp segment containing exons B and C of the human factor IX gene and 100% of 42 single-base substitutions and one microdeletion present in a 577 bp region containing exon H. In a blinded analysis in which 39 wildtype samples were randomly mixed with 51 mutant samples, all mutations were detected with no false positives. Bi-ddF requires essentially the same effort as ddF, yet twofold more DNA sequence can be screened reliably per unit effort.