Inherited chondrodysplasia punctata due to a deletion of the terminal short arm of an X chromosome

We studied two families with an inherited deletion of the short arm of an X chromosome (Xp) in which affected male offspring have epiphyseal stippling in infancy (chondrodysplasia punctata), nasal hypoplasia, ichthyosis, and mental retardation. The presence of ichthyosis and the apparent pattern of X-linked recessive inheritance prompted investigation of the short arm of the X chromosome through studies of genetic markers and focused cytogenetic analysis. Biochemical studies suggested that there was a deletion of three genes previously mapped to the X-chromosome short arm, including the steroid sulfatase locus, the Xg locus, and the M1C2X locus. Prometaphase chromosomes demonstrated a deletion of Xp at p22.32 in the affected boys, in their obligate-carrier mothers, and in 11 of 25 women at risk as potential carriers. The women carrying the Xp deletion had normal gonadal function and fertility but were shorter than the noncarriers in their families (P less than 0.00001). These findings have implications for the genetic organization of this portion of the human X chromosome and demonstrate that small cytogenetic abnormalities may account for disorders with apparent mendelian patterns of inheritance.     

HLA and Kaposi''s sarcoma in Sardinia

Twelve Sardinian patients affected by histologically defined classic Kaposi's sarcoma (KS) were HLA-A, B, C and DR typed. Compared to 220 age and ethnically matched healthy controls, KS patients showed a significant increase in HLA-DR5 (66.6 vs 23.1%, P less than 0.001) and a considerable decrease in HLA-DR3 (8.3 vs 53.6%, P = 0.0055). No definite association was observed for other HLA antigens. These results confirm the existence of an HLA associated genetic control of KS susceptibility and support the hypothesis that HLA-DR5 plays the role of a predisposition marker while HLA-DR3 bears a genetic resistance to the disease.     

OIM and related animal models of osteogenesis imperfecta

Osteogenesis imperfecta (OI) is characterized by fragile bones, skeletal deformity, and growth retardation. This heritable disorder of connective tissue is the result of mutations affecting the COL1A1 and COL1A2 genes of type I collagen. Progress in OI research has been limited because of dependence on human fibroblast and osteoblast specimens and the absence of a naturally occurring animal model for this genetic disorder. Recent technology in molecular biology has led to the development of transgenic models of OI based on site directed mutagenesis of type I collagen genes. OIM is a naturally occurring model which incorporates both the phenotypic and biochemical defects of moderate to severe osteogenesis imperfecta. This powerful tool permits the development of models based on different type I collagen mutations. The collagen type I mutation in OIM is a C propeptide deletion which impairs the production of normal pro-alpha2(I). Tissues in OIM contain only [pro-alpha1(I)]3 homotrimer. Thus, although several animal models are now available for research in osteogenesis imperfecta few are viable or fully mimic human disease disorders. OIM duplicates the phenotype and biochemistry of human disease and has a normal life span.     

Sleep and daytime sleepiness in retinitis pigmentosa patients

OBJECTIVE: We examined sleep, daytime sleepiness and the ability to stay awake during the day in patients affected with retinitis pigmentosa (RP), to further delineate the role of photoreceptors in the circadian cycle. METHODS: Twelve individuals diagnosed with RP (40 +/- 8 years) And 12 normally sighted healthy individuals (39 +/- 7 years) matched for age, body mass index (BMI) and sex were selected for the study. Participants had their sleep recorded on two consecutive nights and were monitored on the two following days. On the first day, their ability to stay awake and on the second, their sleep propensity were assessed using the Maintenance of Wakefulness Test (MWT) and the Multiple Sleep Latency Test (MSLT), respectively. Self-report measures were obtained using the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), and the Toronto Hospital Alertness Test (THAT). RESULTS: Subjective daytime sleepiness (ESS: 9 +/- 5 vs. 6 +/- 4, P=0.053) and objectively measured sleep propensity (MSLT: 10 +/- 5 vs. 17 +/- 3 min, P < 0.000) were significantly higher in RP patients than controls, whilst their alertness (THAT: 29 +/- 9 vs. 38 +/- 7, P=0.016) and ability to stay awake (MWT: 21 +/- 9 vs. 29 +/- 2 min, P=0.006) were significantly reduced. Retinitis pigmentosa participants had more disturbed nighttime sleep, with significantly more awakenings (arousal index: 14 +/- 8 vs. 8 +/- 6 h, P=0.039), and tended to have less rapid eye movement (REM) sleep (19 +/- 5 vs. 22 +/- 3%, P=0.094). CONCLUSION: Patients with RP have increased daytime sleepiness, reduced alertness and more disturbed nighttime sleep of poorer quality than their normally sighted counterparts, suggesting an influence of photoreceptor degeneration on the circadian cycle.     

Evaluation of endothelial cell migration with a novel in vitro assay system

In this study we introduce a novel in vitro 'oil-drop' assay system for the measurement of endothelial cell (EC) migration, based on the original concept of the Teflon fence assay (Pratt et al., 1984; Am. J. Pathol. 117: 349–354). An aliquot of 15–20,000 human umbilical vein EC (HUVEC) is pipetted through a layer of mineral oil. The cells readily attach, spread and migrate on the surface of a matrix-coated tissue culture dish as a confluent circular monolayer. Migration is measured as the net increase in the total area covered at 24 hours. We have used this system to quantify EC migration on matrices composed of a mixture of type I collagen and either von Willebrand factor (vWF) or fibronectin (FN) in the presence or absence of tumor necrosis factor (TNF). Plating efficiency on both vWF/collagen and FN/collagen, measured by counting cells after attachment and spreading, is about 80%. With this method, migration on vWF/collagen was about 6.4 mm² and 5.3 mm² for TNF-treated and untreated HUVEC, respectively. HUVEC migration on FN/collagen was slightly greater – 6.4 mm² and 6.5 mm² with and without TNF treatment, respectively. During the 24 hour time period, HUVEC numbers increased 30–40% on vWF/collagen, and 60–80% on FN/collagen, with increased proliferation observed with TNF- treatment. EC proliferation could be completely inhibited by 2 mM hydroxyurea. This assay system has proven useful in our studies to quantify cell migration and proliferation.     

Clinical,hematologic, and immunologic effects of interleukin-10 in humans

We conducted a double-blind, placebo-controlled study to investigate the safety, pharmacokinetics, and immunological properties of interleukin-10 (IL-10) administration in healthy humans. Volunteers received a single intravenous bolus injection of recombinant human IL-10 (1, 10, or 25g/kg) or placebo. Cytokine production in whole blood and peripheral blood mononuclear cells (PBMC) was assessed before and 3, 6, 24, and 48 hr after the injection. Peak serum concentrations of IL-10 (15±1.1, 208±20.1, and 505±22.3 ng/ml) occurred after 2–5 min for 1, 10, and 25g/kg IL-10, respectively. The terminal-phase half-life was 3.18 hr. A transient leukocytosis (24–63% above baseline) was observed 6 hr after injection, which coincided with a dose-dependent decrease (12–24%) in neutrophil superoxide generation. There was a marked inhibition (60–95%) of endotoxin-induced IL-6 production from whole blood in each group receiving IL-10. Production of IL-8 in endotoxin-stimulated blood was reduced in the 10g/kg group. In PBMC stimulated with phytohemagglutinin and phorbol ester, there was a decrease (72–87%) in interferon- (IFN) production 6 hr after IL-10 with a return to pre-IL-10 levels after 24 hr. This reduction was only partially associated with a decrease in the number of CD2-bearing cells. We conclude that IL-10 administration into humans is without significant side effects, and a single injection reducesex vivo production of IL-6, IL-8, and IFN.     

The effects of stress and caffeine on hypertensives

Eighteen male hypertensives on diuretic medication between the ages of 37 and 60 were studied in a double-blind, randomized, crossover design under three conditions: 200 mg of caffeine and mental arithmetic; placebo and mental arithmetic; and 200 mg of caffeine alone. Systolic and diastolic blood pressure, heart rate, and skin conductance were recorded. During rest, caffeine compared to placebo increased blood pressure by 8/6 mm Hg, but had no effect on heart rate or skin conductance. During mental arithmetic, the combined effect of mental stress and caffeine led to a further increase of 17/7 mm Hg, reaching a pressure level of 163/100 mm Hg. Heart rate and skin conductance were increased above their prior caffeine levels. There were no significant differences between the blood pressure response to mental arithmetic with caffeine and that response to mental arithmetic with a placebo, which may have been due to the fact that the hypertensives were already responding at ceiling level during the mental stressor.     

Epidemiology of group C rotavirus infection in Western New York women of childbearing age.

Umbilical cord serum samples (380), an average of 10 per month for 3 years (1990 to 1992), were tested by indirect immunofluorescence assay for group C rotavirus immunoglobulin G. Thirty percent were positive, suggesting that approximately one-third of women of childbearing age in western New York have experienced group C rotavirus infection.     

The risk of myocardial infarction after quitting smoking in men under 55 years of age

We assessed the effect of quitting cigarette smoking on the incidence of nonfatal myocardial infarction in men under the age of 55 in a case-control study of 1873 men with first episodes of myocardial infarction and 2775 controls. For "current" smokers (men who had smoked in the previous year) as compared with those who had never smoked, the estimated relative risk of myocardial infarction, adjusted for age, was 2.9 (95 per cent confidence interval, 2.4 to 3.4). Among exsmokers (those who had last smoked at least one year previously), the relative-risk estimate declined to a value close to unity for those who had abstained for at least two years; the estimate was 2.0 (1.1 to 3.8) for men who had abstained for 12 to 23 months, and the estimates were about 1.0 for men who had abstained for longer intervals. The results were unchanged by allowance for multiple potential confounding factors. A similar pattern was apparent among exsmokers who had smoked heavily for many years; among those predisposed to a myocardial infarction because of family history, hypertension, or other risk factors; and among those with no apparent predisposition. The results suggest that the risk of myocardial infarction in cigarette smokers decreases within a few years of quitting to a level similar to that in men who have never smoked.