Modulation of disease severity of dystrophic epidermolysis bullosa by a splice site mutation in combination with a missense mutation in the COL7A1 gene

Dystrophic epidermolysis bullosa (EBD) is a clinically heterogeneous skin disorder, characterized by abnormal anchoring fibrils (AF) and loss of dermal-epidermal adherence. EBD has been linked to the COL7A1 gene at chromosome 3p21 which encodes collagen VII, the major component of the AF. Here we investigated two unrelated EBD families with different clinical phenotypes and novel combinations of recessive and dominant COL7A1 mutations. Both families shared the same recessive heterozygous 14 bp deletion at the exon-intron 115 boundary of the COL7A1 gene. The deletion caused in-frame skipping of exon 115 and the elimination of 29 amino acid residues from the pro-alpha1(VII) polypeptide chain. As a result, procollagen VII was not converted to collagen VII and the C-terminal NC-2 propeptide which is normally removed from the procollagen VII prior to formation of the anchoring fibrils was retained in the skin. All affected individuals also carried missense mutations in exon 73 of COL7A1 which lead to different glycine- to-arginine substitutions in the triple-helical domain of collagen VII. Combination of the deletion mutation with a G2009R substitution resulted in a mild phenotype. In contrast, combination of the deletion with a G2043R substitution led to a severe phenotype. The G2043R substitution was a de novo mutation which alone caused a mild phenotype. Thus, different combinations of dominant and recessive COL7A1 mutations can modulate disease activity of EBD and alter the clinical presentation of the patients.      

Dustborne and airborne fungal propagules represent a different spectrum of fungi with differing relations to home characteristics

BACKGROUND: Exposure to fungi is often assessed by culturing floor dust or air samples. Our objective was to evaluate the relationships between dustborne and airborne fungi and to identify factors that modify these relationships. METHODS: From November 1994 to September 1996 sequential duplicate 45-l air samples were collected in bedrooms of 496 homes in the Boston area, using a Burkard culture plate sampler. After air sampling, bedroom floors were sampled with a vacuum cleaner that was modified to collect dust in a cellulose extraction thimble. Dust was sieved, and the fine dust was dilution-plated onto DG-18 media. RESULTS: Concentrations of total culturable fungi per gram of bedroom-floor dust were correlated weakly, but significantly, with those of indoor air (r = 0.13, P < 0.05). Concentrations of some individual taxa in the dust and indoor air were also weakly associated. Adjusting for the concentrations of fungi in outdoor air, dustborne fungal concentrations were positively associated with those in indoor air for the taxa Cladosporium and Penicillium, but not for total fungi. The indoor air fungal levels were often predicted by different covariates to those predicting fungal levels in dust. The type of housing (house or apartment) and the presence of carpeting were often predictive factors for dust fungi. In contrast, outdoor fungal levels were often predictive of the indoor air fungal levels. CONCLUSIONS: Because our data do not indicate a strong overall relationship between culturable fungi in dust and indoor air, the results from these two methods (dust and air sampling) likely represent different types of potential fungal exposures to residents. It may be essential to collect both air and dust samples, as well as information on housing characteristics, as indicators for fungal exposure.     

Ultrastructural studies of interactions of B16 melanoma cells and normal mouse skin fibroblasts in the three-dimensional collagen gels in vitro

In the in vivo system, cancer metastasis is a complex multi-step process. We have utilized an in vitro three-dimensional system to study the initial stages of tumour cell invasion. In this communication, the sequence of events in interactions between B16 melanoma cells and normal mouse skin fibroblasts are described. It is proposed that tumour cells produce a "retractive factor" which induces the underlying fibroblasts to retract so as to facilitate invasion and metastasis.     

Administration of ATG according to the absolute T lymphocyte count during therapy for steroid-resistant rejection

In renal transplantation, treatment of steroid-resistant rejection (SRR) with antithymocyte globulin (ATG) has been widely reported but over-immunosuppression remains a common problem. In the first ten patients (group 1) treated for SRR with rabbit ATG, three developed serious viral infections and two deaths occurred due to CMV pneumonitis. ATG was only omitted if thrombocytopenia or neutropenia occurred. In the next 17 patients (group 2) with SRR, ATG was administered according to the absolute T lymphocyte count. T lymphocytes were measured by flow cytometric analysis of CD3-labelled lymphocytes. ATG dosage was adjusted on a daily basis to keep the absolute T lymphocyte count under 50 cells/l. Administration of ATG according to the absolute T lymphocyte count resulted in a significant reduction in the mean dose of ATG given to the group 2 patients (P<0.001). A significant decrease in the incidence of serious viral infections (P=0.04) was achieved without reducing the ability of ATG to reverse the SRR (P=0.29) or increasing the number of grafts lost at 1 year in the group 2 patients (P=0.23).     

Diabetic retinopathy and lipid abnormalities

The relationship of serum lipid levels and diabetic retinopathy has interested clinicians for several decades. Data from both a population-based study of diabetic retinopathy and a controlled, randomized trial of laser photocoagulation and aspirin treatment in diabetic retinopathy have provided further information regarding the importance of the role of serum lipids in patients with elevated serum lipid levels and diabetic retinopathy. Retinal hard exudate, which is accompanied by macular edema, is associated with elevated serum lipid levels. Although the data are observational, visual loss is likely to be associated with retinal hard exudate and serum lipid abnormalities. These relationships are evaluated in the analyses of the data from the Early Treatment Diabetic Retinopathy Study.     

Nutritional supplement use and age-related macular degeneration

Age-related macular degeneration is one of the leading causes of visual loss among people aged 65 years or older. The causes and factors associated with the progression of age-related macular degeneration are unknown presently. Basic research and epidemiologic data support the hypotheses that higher levels of antioxidant vitamins and minerals may protect the eye from the development of age-related macular degeneration. For this reason and also because of the lack of effective treatment for most cases of age-related macular degeneration, nutritional supplements with antioxidants have emerged as possible therapy for age-related macular degeneration. Nutritional supplements are not proven therapy for age-related macular degeneration. The potential beneficial effects and adverse side effects of the nutritional supplements have not yet been fully evaluated in carefully conducted clinical trials. Several randomized placebo-controlled clinical trials are presently underway. Results of these studies will provide important data to clarify the potential beneficial and adverse effects of such treatment. Until these results are available, it would be premature to make recommendations in favor of vitamin or mineral supplements.     

Prospective cohort study of antioxidant vitamin supplement use and the risk of age-related maculopathy

In a prospective cohort study, the authors examined whether self-selection for antioxidant vitamin supplement use affects the incidence of age-related maculopathy. The study population consisted of 21,120 US male physician participants in the Physicians' Health Study I who did not have a diagnosis of age-related maculopathy at baseline (1982). During an average of 12.5 person-years of follow-up, a total of 279 incident cases of age-related maculopathy with vision loss to 20/30 or worse were confirmed by medical record review. In multivariate analysis, as compared with nonusers of supplements, persons who used vitamin E supplements had a possible but nonsignificant 13% reduced risk of age-related maculopathy (relative risk = 0.87, 95 percent confidence interval (CI) 0.53-1.43), while users of multivitamins had a possible but nonsignificant 10% reduced risk (relative risk = 0.90, 95% CI 0.68-1.19). Users of vitamin C supplements had a relative risk of 1.03 (95% CI 0.71-1.50). These observational data suggest that among persons who self-select for supplemental use of antioxidant vitamin C or E or multivitamins, large reductions in the risk of age-related maculopathy are unlikely. Randomized trial data are accumulating to enable reliable detection of the existence of more plausible small-to-moderate benefits of these agents alone and in combination on age-related maculopathy.     

Calcium oxalate urolithiasis in cats

Urolithiasis has long been recognized as a cause of irritative voiding in cats. Before the late 1980s, sterile struvite was the most common urolith; today, however, 40% of feline uroliths are of calcium oxalate. This change may be partly attributable to the change to urine-acidifying, magnesium-restricted diets that were introduced to reduce the formation of struvite. However, it is possible that the diet modifications made by cat food manufacturers simply exposed a population of cats predisposed to calcium oxalate stone formation. Urolithiasis in cats appears to be diet sensitive rather than diet induced. As in humans, water is crucial in the prevention and treatment of feline stones.