Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study.

BACKGROUND: In healthy humans, continuous treatment with nitroglycerin (GTN) causes nitric oxide synthase dysfunction, probably through the reduced bioavailability of tetrahydrobiopterin. Recent studies proposed that folic acid is involved in the regeneration of tetrahydrobiopterin in different disease states. Therefore, we investigated whether folic acid administration would prevent this phenomenon. We also sought to determine if folic acid supplementation could prevent the development of tolerance to GTN. METHODS AND RESULTS: On the first visit, 18 healthy male volunteers (aged 19 to 32 years) were randomized to receive either oral folic acid (10 mg once a day) or placebo for 1 week in a double-blind designed study. All subjects also received continuous transdermal GTN (0.6 mg/h). On the second visit, forearm blood flow was measured with venous occlusion strain gauge plethysmography in response to incremental infusions of acetylcholine (7.5, 15, and 30 microgram/min), N-monomethyl-L-arginine (1, 2, and 4 micromol/min), and GTN (11 and 22 nmol/min). Folic acid prevented GTN-induced endothelial dysfunction, as assessed by responses to intraarterial acetylcholine and N-monomethyl-L-arginine (P<0.01). Moreover, in the subjects treated with folic acid plus transdermal GTN, responses to intraarterial GTN were significantly greater than those observed after transdermal GTN plus placebo (P<0.05). CONCLUSION: Our data demonstrate that supplemental folic acid prevents both nitric oxide synthase dysfunction induced by continuous GTN and nitrate tolerance in the arterial circulation of healthy volunteers. We hypothesize that the reduced bioavailability of tetrahydrobiopterin is involved in the pathogenesis of both phenomena. Our results confirm the view that oxidative stress contributes to nitrate tolerance.

Transgene animal model for protein expression and accumulation into forming enamel.

Understanding the cellular and molecular events that regulate the formation of enamel is a major driving force in efforts to characterize critical events during amelogenesis. It is anticipated that through such an understanding, improvements in prevention, diagnosis and treatment-intervention into heritable and acquired diseases of enamel could be achieved. While knowledge of the precise role of an enamel-specific protein in directing the formation of inorganic crystallites remains refractory, progress has been made with other aspects of amelogenesis that can be brought to bear on the subject. One such area of progress has been with the identification of an ameloblast-lineage specific amelogenin gene promoter. This promoter can be used to direct the expression of enamel-specific proteins, as well as the expression of proteins foreign to amelogenesis, into the enamel extracellular matrix where their effect on biomineralization can be ascertained in a prospective manner. The resulting enamel from such animals can be examined by morphologic and biochemical modalities in order to identify the effect of the transgene protein on enamel crystallite formation and subsequent biomineralization. This manuscript outlines such a strategy with the potential for enhancing our understanding of amelogenesis.

Precursors to skin cancer.

Certain cutaneous lesions serve as both precursors of skin cancer and markers for increased risk. The solar or actinic keratosis serves such a role for the nonmelanoma (NMSC) forms of skin cancer (basal cell carcinoma and squamous cell carcinoma). Clinically, these keratoses manifest as rough, scaly, erythematous patches on chronically sun-exposed surfaces. Conversion to squamous cell carcinoma in an individual lesion is uncommon and has been estimated at 1 per 1000 per year. Individuals with actinic keratoses have had sufficient chronic photodamage to produce skin cancer, and regular surveillance is recommended. The second precursor for invasive NMSC is Bowen's disease (squamous cell carcinoma in situ). Invasion of the dermis results in frank squamous cell carcinoma. Some types of viral warts may develop into squamous cell carcinoma. The most important precursor/marker for melanoma is the clinically atypical mole (CAM) or dysplastic nevus. CAMs occur in 5-10% of the U.S. population. CAMs, under photographic follow-up, have been observed to evolve into cutaneous melanoma. The frequency of conversion to melanoma of any single CAM is quite low; however, in melanoma-prone families, prospectively diagnosed melanomas arise in association with a histopathologically observed dysplastic nevus in more than 80% of the cases. Giant congenital melanocytic nevi have an approximately 6% lifetime risk of melanoma development. The risk associated with small congenital nevi is uncertain. Lentigo maligna develop into invasive melanoma with a frequency reported in the literature ranging from 5-50%.

Computerized digital image analysis: an aid for melanoma diagnosis--preliminary investigations and brief review.

Both digital imaging and epiluminescence microscopy hold promise for improved early detection of cutaneous melanoma. Several centers have been actively working in these areas during the past decade. These experiences and preliminary work based on the image capture of 83 pigmented lesions at our center using a prototype digital imaging system (SKINVIEW) are described. This system is based, in part, on the analysis of lesional morphologic features, such as shape, border, and radii. Histopathologic correlation was matched against these features to assess the efficacy of diagnosis. At our center, these parameters alone were not sufficient to discriminate between benign and malignant lesions, in part, because the melanomas were, in general, early lesions and many of the nevi were sufficiently clinically atypical to require removal for discrimination from melanoma. In addition, technical improvements in the image capturing and processing mechanism are needed. Rapid progress in this area is anticipated.

The teaching of occupational health in US medical schools: little improvement in 9 years.

A questionnaire survey of the 127 US medical schools was undertaken to assess the present status of occupational health teaching as a follow-up to two prior similar studies. The present study revealed that 78 (68%) of the 115 responding schools specifically taught occupational health during the 1991/92 academic year, in comparison with 50% in the 1977/78 and 66% in the 1982/83 academic years. The median required curriculum time was 6 hours in 1991/92, as compared with 4 hours in both previous surveys. Despite the increasing recognition of occupational health and growth of information in this field of medicine, occupational health teaching to medical students has not progressed proportionately.