Blood expression profiles for tuberous sclerosis complex 2, neurofibromatosis type 1, and Down's syndrome

Blood gene expression profiling has been applied to a variety of hematological malignancies, autoimmune disorders, and infectious diseases. This study applies this approach to genetic diseases without obvious blood phenotypes. Three genetic diseases including tuberous sclerosis complex 2, neurofibromatosis type 1, and Down's syndrome were compared with a group of healthy controls. RNA from whole blood was surveyed using Affymetrix U133A arrays. Each disease was associated with a unique gene expression pattern in blood that can be accurately distinguished by a classifier. Genes on chromosome 21 were overexpressed in Down's syndrome, and genes controlling cell cycle and proliferation were associated with tuberous sclerosis complex type 2 or neurofibromatosis type 1. A subset of genes involved in cardiac development or remodeling were overexpressed in patients with Down's syndrome and congenital heart defects. These findings suggest that blood gene expression profiling on a broader basis might be useful for genetic disease screening/diagnosis and might help elucidate mechanisms and pathways that lead to genotype-phenotype differences.     

A Comparative Study of the Effects of Metal Contamination on Collembola in the Field and in the Laboratory

We examined the species diversity and abundance of Collembola at 32 sampling points along a gradient of metal contamination in a rough grassland site (Wolverhampton, England), formerly used for the disposal of metal-rich smelting waste. Differences in the concentrations of Cd, Cu, Pb and Zn between the least and most contaminated part of the 35 metre transect were more than one order of magnitude. A gradient of Zn concentrations from 597 to 9080 microg g(-1) dry soil was found. A comparison between field concentrations of the four metals and previous studies on their relative toxicities to Collembola, suggested that Zn is likely to be responsible for any ecotoxicological effects on springtails at this site. Euedaphic (soil dwelling) Collembola were extracted by placing soil cores into Tullgren funnels and epedaphic (surface dwelling) species were sampled using pitfall traps. There was no obvious relationship between the total abundance, or a range of commonly used diversity indices, and Zn levels in soils. However, individual species showed considerable differences in abundance. Metal "tolerant" (e.g., Ceratophysella denticulata) and metal "sensitive" (e.g., Cryptopygus thermophilus) species could be identified. Epedaphic species appeared to be influenced less by metal contamination than euedaphic species. This difference is probably due to the higher mobility and lower contact with the soil pore water of epedaphic springtails in comparison to euedaphic Collembola. In an experiment exposing the standard test springtail, Folsomia candida, to soils from all 32 sampling points, adult survival and reproduction showed small but significant negative relationships with total Zn concentrations. Nevertheless, juveniles were still produced from eggs laid by females in the most contaminated soils with 9080 microg g(-1) Zn. Folsomia candida is much more sensitive to equivalent concentrations of Zn in the standard OECD soil. Thus, care should be taken in extrapolating the results of laboratory toxicity tests on metals in OECD soil to field soils, in which, the biological availability of contaminants is likely to be lower. Our studies have shown the importance of ecotoxicological effects at the species level. Although there may be no differences in overall abundance, sensitive species that are numerous in contaminated sites, and which may play important roles in decomposition ("keystone species") can be greatly reduced in numbers by pollution.     

GTF2I hemizygosity implicated in mental retardation in Williams syndrome: genotype-phenotype analysis of five families with deletions in the Williams syndrome region

Most individuals with Williams syndrome (WS) have a 1.6 Mb deletion in chromosome 7q11.23 that encompasses the elastin (ELN) gene, while most families with autosomal dominant supravalvar aortic stenosis (SVAS) have point mutations in ELN. The overlap of the clinical phenotypes of the two conditions (cardiovascular disease and connective tissue abnormalities such as hernias) is due to the effect of haploinsufficiency of ELN. SVAS families often have affected individuals with some WS facial features, most commonly in infancy, suggesting that ELN plays a role in WS facial gestalt as well. To find other genes contributing to the WS phenotype, we studied five families with SVAS who have small deletions in the WS region. None of the families had mental retardation, but affected family members had the Williams Syndrome Cognitive Profile (WSCP). All families shared a deletion of LIMK1, which encodes a protein strongly expressed in the brain, supporting the hypothesis that LIMK1 hemizygosity contributes to impairment in visuospatial constructive cognition. While the deletions from the families nearly spanned the WS region, none had a deletion of FKBP6 or GTF2I, suggesting that the mental retardation seen in WS is associated with deletion of either the centromeric and/or telomeric portions of the region. Comparison of these five families with reports of other individuals with partial deletions of the WS region most strongly implicates GTF2I in the mental retardation of WS.     

Upper airway malformation associated with partial trisomy 11q

11q trisomy is associated with a recognizable pattern of multiple malformations. Review of the literature reveals the following recurrent themes common to complex and isolated 11q trisomy: mental retardation, pre- and postnatal growth retardation, hypotonia, a distinct pattern of facial features, congenital heart defects, and limb malformations. We report four patients with partial trisomy 11q, none of which arose from the common 11/22 translocation. Three of the four patients had the previously unreported finding of upper airway obstruction secondary to a malformed epiglottis. The critical region for this malformation appears to be 11q21-23.2.     

RENAL FUNCTION IN CHRONICALLY CATHETERIZED CONSCIOUS DIABETIC RATS USING CONSTANT AND SERVO-CONTROLLED INFUSION

1. Infusion experiments were performed on chronically catheterized conscious rats to assess kidney function before and after the induction of diabetes mellitus with streptozotocin. 2. Two infusion regimens were used, a conventional constant-infusion protocol and a novel computer-driven, servo-controlled fluid replacement technique. The latter enables body fluid status to be maintained throughout a study occasion by servo-controlled replacement of spontaneous urinary fluid losses. 3. The chronically catheterized conscious rat infused using a servo-controlled system appears to be the optimum model for a study of diabetic renal function. The conscious preparation circumvents problems associated with anaesthesia and acute surgery. The servo-controlled infusion protocol maintains the altered fluid status of the diabetic condition. Both hyperfiltration and polyuria, characteristics of human diabetes often absent in anaesthetized and/or constantly infused diabetic rats, were seen in all conscious servo-controlled diabetic animals. 4. The new regimen enables a more accurate assessment of renal function in experimental diabetes than with previous protocols. It should prove useful in future studies, particularly those assessing the role of anti-diabetic drugs on the kidney.     

Effects of continuous distending pressure on lung volumes and lung mechanics in the immediate neonatal period.

The effects of CPAP and CNEP on lung mechanics and lung volumes were investigated in a group of 12 healthy newborn infants. Both resulted in a mild suppression of respiration. The fall in TPR50 was far greater during CPAP than during CNEP. Both led to a one third fall in dynamic compliance. Approximately 50% of the distending pressure was transmitted to the mediastinal structures whether applied as CPAP or CNEP.     

Longitudinal studies of infants with the Wilson-Mikity syndrome. Clinical, radiological and mechanical correlations

Simple clinical measurements were performed on a group of 23 very low birth weight babies (less than 1500 g and less than 32 weeks gestation), and combined with pulmonary function studies in 13 cases. The studied included a special single-breath analysis, or Tidal Resistance Profile, which enabled us to detect air trapping. 2 infants developed classical Wilson-Mikity syndrome and 2 further infants exhibited a milder, shorter form of the same disorder. All 4 survived. Results suggest that all infants in this maturity group are at risk of developing Wilson-Mikity syndrome, and that it comprises a wide spectrum of respiratory dysfunction.