Low serum haemolytic function of the fourth complement component (C4) in insulin dependent diabetes.

Low serum concentrations of the fourth component of complement (C4) are found in insulin dependent diabetes, and may be important in the aetiology of the disease. To ascertain whether function of C4 is also impaired both its haemolytic activity and its concentration were measured in 34 insulin dependent diabetics, 15 non-insulin dependent diabetics, 20 healthy subjects, and 12 pairs of monozygotic twins discordant for insulin dependent diabetes. C4 function was measured by a radial immune haemolytic assay, and C4 concentration by laser nephelometry. Both measurements were significantly lower in insulin dependent diabetics (C4 function: median 47%, range 4-100%; C4 concentration: 0.22 g/l, 0.10-0.38 g/l) than in non-insulin dependent diabetics (67%, 33-138%, p less than 0.01; 0.27 g/l, 0.16-0.50 g/l, p less than 0.02) and controls (74%, 33-138%, p less than 0.01; 0.27 g/l, 0.18-0.40 g/l, p less than 0.03). C4 function and concentration were lower in both diabetic (48%, 12-100%; 0.17 g/l, 0.08-0.31 g/l) and non-diabetic twins (47%, 12-100%; 0.17 g/l, 0.07-0.36 g/l) than controls (p less than 0.01; p less than 0.01). Thirteen (38%) of the insulin dependent diabetics had a reduction in either C4 function or concentration, but in only five were both features reduced. Values of function and concentration were strongly correlated in both diabetic and non-diabetic twins (r = 0.95, p less than 0.001; r = 0.92, p less than 0.001). These results show defects in C4 function and concentration in insulin dependent diabetes, which--being present in the non-diabetic co-twin of diabetics--may represent a genetic predisposition to the disease.     

The changing survival profile of people with Down's syndrome: implications for genetic counselling

Cohort studies have indicated that the survival of individuals with Down's syndrome has dramatically increased over the past 50 years. Early childhood survival in particular has shown major improvement, due largely to advances in cardiac surgery and in general health management. The present study was based on a continuous cohort of 1332 people with Down's syndrome in Western Australia, registered for intellectual disability services between 1953 and 2000. Their life expectancy was 58.6 years, 25% lived to 62.9 years, and the oldest living person is 73 years of age. Life expectancy for males was greater than females by 3.3 years. The substantial increase in survival across the study period means that the life expectancy of people with Down's syndrome is approaching that of the general population, but accompanied by a range of significant mid-life health problems. The findings are of relevance to all developed countries and have considerable implications in terms of the counselling information provided to families at risk of having a child with Down's syndrome.     

Accumulation of p53 in response to adenovirus early region 1A sensitizes human cells to tumor necrosis factor alpha-induced apoptosis

Many tumor cells are resistant to tumor necrosis factor alpha (TNFalpha)-induced apoptosis. Adenovirus early region 1A (AdE1A) sensitizes the otherwise resistant cells to TNFalpha. AdE1A also stabilizes the p53 protein. The present study demonstrates a correlation between AdE1A-induced sensitization and stabilization of p53 in TNFalpha-induced apoptosis since the N-terminal and CR2 regions, the binding sites for CBP/p300, Rb and 26S proteasome regulatory components, are required for both these actions of AdE1A. TNFalpha does not induce apoptosis and AdE1A fails to sensitize TNFalpha cytotoxicity in p53-negative cells. However, introduction of exogenous p53 overcomes the cellular resistance to TNFalpha toxicity and enhances AdE1A sensitization, demonstrating that AdE1A sensitizes TNFalpha-induced apoptosis by its stabilization of p53. A proteasome inhibitor, lactacystin, enhances TNFalpha cytotoxicity in p53-positive and -negative cells, suggesting that accumulation of cellular proteins other than p53 might also regulate the cellular response to TNFalpha signaling.     

Differential effects of complement activation induced by cobra venom factor on pulmonary transvascular fluid and protein exchange

Sheep were prepared with lung lymph fistulas for assessment of the effects of complement activation on pulmonary transvascular fluid and protein exchange in the intact animal. Cobra venom factor (CVF 200 +/- 46 U/kg) was injected intravenously for activation of the complement system. In some animals (n = 6), pulmonary lymph flow (Qlym) and pulmonary arterial pressure (Ppa) increased without a change in the lymph-to-plasma protein concentration ratio (L/P) or in pulmonary blood flow (QL), indicating an increase in pulmonary vascular permeability to proteins. In another group (n = 6), Qlym and the L/P did not change, and there were also no changes in Ppa and QL following a similar injection of CVF. Morphologic evidence showed that leukocytes were trapped in pulmonary vessels and interstitium of both groups. Pulmonary edema was also present in both groups. Complement activation does not uniformly increase pulmonary lymph flow despite pathologic evidence of leukocyte sequestration and pulmonary edema. The lack of change in lymph flow in some animals may be due to lymphatic insufficiency, or lack of generation of humoral mediators, and/or a decrease in pulmonary capillary pressure.     

Dystrophin gene deletions in South Indian Duchenne muscular dystrophy patients

66 unrelated patients from Southern India with Duchenne Muscular Dystrophy (DMD) were studied for intragenic deletion in 18 exons and Pm region of the DMD gene using multiplex PCR. Of these 41 (62.1%) showed intragenic deletions. 78% of the deletions were located at the distal hotspot region (44-55 exons) and 22% of the deletions were located at the proximal region (exon 2-19). Exon 50 is most frequently deleted. Deletions in isolated cases were significantly more compared to familial cases. The lower incidence reported from South India compared to North India, is suggestive of variations in the Southern and Northern population.     

Cytomegalovirus detection by biotinylated DNA probes

Clinical specimens from 317 patients suspected of cytomeglovirus infection were examined by immunofluorescence (IF) using monoclonal antibodies and by a biotinylated DNA probe kit after cell culture isolation. Of the 317 samples, 68 were positive by culture isolation. Of these 67 were IF positive when the cytopathic effect (CPE) was 1⁺ or less, whereas 56 gave positive results with DNA probes when the CPE was 2⁺. A further 83 specimens were examined directly by immunoperoxidase histopathology (IHP), IF and the DNA probe kit: 26 of these were positive by IHP examination, 25 by IF and only 6 by DNA probes. The sensitivity of the DNA probe kit was not satisfactory when the clinical tissue specimens were directly examined. However, the sensitivity improved considerably to 82% if the specimens were propagated first in cell culture. The IF method detected the virus before and after cell culture isolation equally well (96%–98.5%). Compared to the IF method, the DNA probe kit is costly and requires more labor and time.This paper was presented in part at the 88th annual meeting of the American Society for Microbiology, Miami Beach, FL, USA, 1988     

Cytochemical localization of 5'-nucleotidase activity in retinal photoreceptor cells

Further cytochemical studies on the ultrastructural localization of 5'-nucleotidase in the rat retina have revealed activity to be associated with the complex synapses formed by the rod spherules of the receptors and the bipolar and horizontal cell processes. Activity was also seen on the axolemma of receptor fibers. In the rod inner segment strong reaction product is located intracellularly. In the rod outer segment the enzyme appears to be located only on the cytoplasmic side of the disc membrane and not intradiscally . Retinal pigment cells are rich in 5'-nucleotidase. Their microvilli accompany the tips of the receptor cells and show enzyme activity in an ecto position. A role for 5'-nucleotidase is possible in the metabolism of guanylate and adenylate nucleotides both of which are important for visual transduction processes.