Effect of soluble guanylyl cyclase activator and stimulator therapy on nitroglycerin-induced nitrate tolerance in rats.

Chronic nitroglycerin (GTN) anti-ischemic therapy induces side effects such as nitrate tolerance and endothelial dysfunction. Both phenomena could be based on a desensitization/oxidation of the soluble guanylyl cyclase (sGC). Therefore, the present study aims at investigating the effects of the therapy with the sGC activator BAY 60-2770 and the sGC stimulator BAY 41-8543 on side effects induced by chronic nitroglycerin treatment. Male Wistar rats were treated with nitroglycerin (100mg/kg/d for 3.5days, s.c. in ethanol) and BAY 60-2770 (0.5 or 2.5mg/kg/d) or BAY 41-8543 (1 and 5mg/kg/d) for 6days. Therapy with BAY 60-2770 but not with BAY 41-8543 improved nitroglycerin-triggered endothelial dysfunction and nitrate tolerance, corrected the decrease in aortic nitric oxide levels, improved the cGMP dependent activation of protein kinase I in aortic tissue and reduced vascular, cardiac and whole blood oxidative stress (fluorescence and chemiluminescence assays; 3-nitrotyrosine staining). In contrast to BAY 41-8543, the vasodilator potency of BAY 60-2770 was not impaired in isolated aortic ring segments from nitrate tolerant rats. sGC activator therapy improves partially the adverse effects of nitroglycerin therapy whereas sGC stimulation has only minor beneficial effects pointing to a nitroglycerin-dependent sGC oxidation/inactivation mechanism contributing to nitrate tolerance.

It is possible to perform a double-blind hyperbaric session: a double-blinded randomized trial performed on healthy volunteers.

In hyperbaric medicine, blinded trials are remarkably few, making results susceptible to criticism. The scopes of the present study are to present a method for a double-blinded randomized clinical study and evaluate the validity of the method in a hyperbaric setting. Twenty-two healthy volunteers with no diving experience were included. The volunteers were randomized either to a "therapeutic pressure" group (15 msw, 253 kPa) or to a "placebo" group (2 msw, 120 kPa). The two profiles were made equal regarding noise, temperature and ventilation. The volunteers were asked whether they had been exposed to placebo or therapeutic pressure. They were asked to present their certainness of the answer on a visual analogue scale (VAS). Fisher's exact test calculates a probability of P = 0,328, which indicates that the volunteers have no valid opinion as to whether they were exposed to 15 msw or to 2 msw. It is found that it is possible to perform a blinded treatment on healthy volunteers with no prior diving experience.

Postural stability before and after hyperbaric oxygen treatment.

OBJECTIVE: The purpose of this study was to determine the effect of hyperbaric oxygenation (HBO) on postural stability in healthy volunteers. The study was performed in accordance with treatment protocols for divers' decompression sickness and carbon monoxide poisoning. METHODS: Twenty-one healthy male divers, aged 31 +/- 6.88 years (mean +/- SD), were tested with quantitative Romberg's test before and after HBO (90 min in a pressure chamber at an ambient pressure of 253 kPa, approximately 15 m of sea water, breathing pure oxygen). The quantitative Romberg's test is a calculation of the average sway for 50 s. RESULTS: No difference was found between sway before and after the HBO (P < 0.05), i.e. we were unable to show that the results of quantitative Romberg's test are affected by HBO. Thus, the quantitative Romberg's test may be a valuable tool in evaluating patients with decompressions sickness, carbon monoxide intoxication and other neurological diseases normally treated with HBO.

Isobutyl-nitrite-induced methemoglobinemia; treatment with an exchange blood transfusion during hyperbaric oxygenation.

A young man was accidentally intoxicated with isobutyl nitrite by a threefold lethal dose. Due to nitrites' ability to change hemoglobine into methemoglobine the patient showed signs of severe hypoxia, which could not be treated by conventional means. Therefore the patient was rapidly transferred to a hyperbaric chamber. The patient was treated with pure oxygen at 283 kPa under which a blood exchange transfusion was performed. The patient fully recovered.

Combined treatment with calcipotriol ointment and low-dose ultraviolet A1 phototherapy in childhood morphea.

Various therapies for morphea have been used with limited success, including ones with potentially hazardous side effects. When morphea occurs in childhood it may lead to progressive and long-lasting induration of the skin and subcutaneous tissue, growth retardation, and muscle atrophy. We report an open prospective study in which the efficacy of a combined treatment with calcipotriol ointment and low-dose ultraviolet A1 (UVA1) phototherapy in childhood morphea was investigated. Nineteen children (mean age 8.5 years, range 3-13 years) with morphea were exposed to UVA1 (340-400 nm) phototherapy at a dose of 20 J/cm(2) four times a week for 10 weeks. Forty phototherapy sessions resulted in a cumulative dose of 800 J/cm(2) UVA1. In addition, calcipotriol ointment (0.005%) was applied twice a day. After 10 weeks, palpation and inspection showed a remarkable softening and repigmentation of formerly affected skin resulting in a highly significant (p < 0.001) decrease of the mean clinical score from 7.3 +/- 0.9 at the beginning to 2.4 +/- 0.9 (relative reduction 67.1%) at the end of combined therapy. Our results indicate that a combined therapy with calcipotriol ointment and low-dose UVA1 phototherapy is highly effective in childhood morphea. Further controlled studies are necessary to investigate whether this combined therapy is superior to UVA1 phototherapy alone.

Low-dose ultraviolet-A1 phototherapy for lichen sclerosus et atrophicus.

Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory skin disease characterized by white porcelain-like sclerotic skin lesions. It is most commonly seen in adult females and usually affects the genitoanal area. Extragenital LSA appears in 15-20% of cases. We report a 9-year-old Caucasian girl suffering from extragenital LSA that was resistant to conventional treatment. After 40 treatment sessions with low-dose UVA1 phototherapy, all skin lesions were resolved completely. Moreover, the improvement of skin status has been sustained during 6-months of follow-up. Long-wave UVA irradiation has been shown to induce intensively collagenase activity in human dermal fibroblasts. We suggest that UVA1 irradiation could be an effective treatment in patients suffering from extragenital LSA.

Rosacea fulminans triggered by high-dose vitamins B6 and B12.

Rosacea fulminans is a rare variant of rosacea conglobata that occurs almost exclusively in women well past adolescence. The aetiology is unknown, although immunological, hormonal, and vascular factors have been suggested. We report the case of a 17-year-old girl with rosacea fulminans that was temporally associated with daily ingestion of high-dose vitamin B supplements. The onset was sudden and cosmetically disabling. The eruption improved when the vitamin supplement was discontinued and a therapeutic regimen including isotretinoin and methylprednisolone was introduced. It seems appropriate to consider the possibility of such a vitamin B-triggered condition in cases of subjects presenting new or exacerbating facial eruptions.

Advances and perspectives in acne therapy.

Acne is one of the most common diseases in dermatology. It is of considerable esthetic significance, which explains the mental stress in affected patients. Although acne almost always heals spontaneously in early adulthood, treatment measures can shorten the course, reduce the severity of the disease, and avoid complications such as scarring. Treatment has changed substantially in recent years. In accordance with pathogenic principles, effective treatment is possible. In most patients, a combination of drugs aimed at correcting abnormal keratinization and reducing the proliferation of Propionibacterium acnes is sufficient to control the disease. For more severely affected patients with no response to this approach, therapy to suppress sebum production is indicated. Of all therapeutic modalities available, only oral isotretinoin alters the natural course of the disease. In acne inversa, surgical management should be undertaken as early as possible.

Electron transfer from plastocyanin to photosystem I.

Mutant plastocyanins with Leu at position 10, 90 or 83 (Gly, Ala and Tyr respectively in wildtype) were constructed by site-specific mutagenesis of the spinach gene, and expressed in transgenic potato plants under the control of the authentic plastocyanin promoter, as well as in Escherichia coli as truncated precursor intermediates carrying the C-terminal 22 amino acid residues of the transit peptide, i.e. the thylakoid-targeting domain that acts as a bacterial export signal. The identity of the purified plastocyanins was verified by matrix-assisted laser desorption/ionization mass spectrometry. The formation of a complex between authentic or mutant spinach plastocyanin and isolated photosystem I and the electron transfer has been studied from the biphasic reduction kinetics of P700+ after excitation with laser flashes. The formation of the complex was abolished by the bulky hydrophobic group of Leu at the respective position of G10 or A90 which are part of the conserved flat hydrophobic surface around the copper ligand H87. The rate of electron transfer decreased by both mutations to < 20% of that found with wildtype plastocyanin. We conclude that the conserved flat surface of plastocyanin represents one of two crucial structural elements for both the docking at photosystem I and the efficient electron transfer via H87 to P700+. The Y83L mutant exhibited faster electron transfer to P700+ than did authentic plastocyanin. This proves that Y83 is not involved in electron transfer to P700 and suggests that electron transfer from cytochrome f and to P700 follows different routes in the plastocyanin molecule. Plastocyanin (Y83L) expressed in either E. coli or potato exhibited different isoelectric points and binding constants to photosystem I indicative of differences in the folding of the protein. The structure of the binding site at photosystem I and the mechanism of electron transfer are discussed.