Tamoxifen versus placebo in the treatment of Peyronie's disease

PURPOSE: We evaluated the effects of oral tamoxifen and placebo in patients with Peyronie's disease. MATERIALS AND METHODS: We selected 25 patients with Peyronie's disease who did not have calcified plaque for treatment in the andrology outpatient clinic. A medical history was obtained, and physical examination, penile x-ray, penile ultrasound and pharmacologically induced erection with prostaglandin E1 were performed. Patients were randomly divided into group 1--those who received 20 mg. tamoxifen twice daily for 3 months and group 2--those who received placebo for the same period. The same evaluations were done 4 months later and results were compared. Qualitative (chi-square test) and quantitative (Student's t test) results were analyzed using the Yates correction factor with p <0.05 considered significant. RESULTS: Pain subsided in 66.6 and 75% of the patients treated with tamoxifen and placebo, respectively (p >0.05). In groups 1 and 2 a reduction in the penile deformity was noticed by 46.1 and 41.7% of the patients (p >0.05), and a decrease in plaque size was noticed by 30.7 and 25%, respectively. On the other hand, objective measurements did not reveal any difference in plaque area or curvature angle. CONCLUSIONS: This study did not show significant improvement in pain, curvature or plaque size in patients with Peyronie's disease who were treated with tamoxifen compared with those treated with placebo.     

Structural isomerization of synephrine influences its uptake and ensuing glutathione depletion in rat-isolated cardiomyocytes

Synephrine is a natural compound, frequently added to ephedra-free dietary supplements for weight-loss, due to its effects as a nonspecific adrenergic agonist. Though only p-synephrine has been documented in plants, the presence of m-synephrine has also been reported in weight-loss products. The use of synephrine in dietary supplements was accompanied by reports of adverse effects, especially at the cardiovascular level. It is well known that the imbalance in cardiac glutathione levels can increase the risk of cardiomyopathy. The present work aimed to study the role of organic cation-mediated transport of m- and p-synephrine and the possibility that p- and m-synephrine induce intracellular changes in glutathione levels in calcium-tolerant freshly isolated cardiomyocytes from adult rat. After a 3 h incubation with 1 mM p- or m-synephrine, the intracellular content of synephrine was measured by gas chromatography/ion trap-mass spectrometry (GC/IT-MS); cell viability and intracellular glutathione levels were also determined. To evaluate the potential protective effects of antioxidants against the adverse effects elicited by m-synephrine, cells were pre-incubated for 30 min with Tiron (100 μM) or N-acetyl-cysteine (NAC) (1 mM). To assess the influence of α₁-adrenoceptors activation in glutathione depletion, a study with prazosin (100 nM) was also performed. The results obtained provide evidence that organic cation transporters OCT3 and OCT1 play a major role in m- and p-synephrine-mediated transport into the cardiomyocytes. The importance of these transporters seems similar for both isomers, although p-synephrine enters more into the cardiomyocytes. Furthermore, only m-synephrine induced intracellular total glutathione (GSHt) and reduced glutathione (GSH) depletion. NAC and Tiron were able to counteract the m-synephrine-induced GSH and GSHt decrease. On the other hand, the incubation with prazosin was not able to change m-synephrine-induced glutathione depletion showing that this effect is independent of α₁-adrenoceptor stimulation. In conclusion, both positional isomers require OCT3 and OCT1-mediated transport to enter into the cardiomyocytes; however, the hydroxyl group in the p-position favours the OCT-mediated transport into cardiomyocytes. Furthermore, the structural isomerization of synephrine influences its toxicological profile since only m-synephrine caused GSH depletion.     

Elimination of antigen-presenting cells and autoreactive T cells by Fas contributes to prevention of autoimmunity

Fas (also known as Apo-1 and CD95) receptor has been suggested to control T cell expansion by triggering T cell-autonomous apoptosis. This paradigm is based on the extensive lymphoproliferation and systemic autoimmunity in mice and humans lacking Fas or its ligand. However, with systemic loss of Fas, it is unclear whether T cell-extrinsic mechanisms contribute to autoimmunity. We found that tissue-specific deletion of Fas in mouse antigen-presenting cells (APCs) was sufficient to cause systemic autoimmunity, implying that normally APCs are destroyed during immune responses via a Fas-mediated mechanism. Fas expression by APCs was increased by exposure to microbial stimuli. Analysis of mice with Fas loss restricted to T cells revealed that Fas indeed controls autoimmune T cells, but not T cells responding to strong antigenic stimulation. Thus, Fas-dependent elimination of APCs is a major regulatory mechanism curbing autoimmune responses and acts in concert with Fas-mediated regulation of chronically activated autoimmune T cells.     

Therapeutic Concentrations of Mitoxantrone Elicit Energetic Imbalance in H9c2 Cells as an Earlier Event

Mitoxantrone (MTX) is a chemotherapeutic agent that emerged as an alternative to anthracycline therapy. However, MTX also causes late cardiotoxicity, being oxidative stress and mitochondrial-impaired function proposed as possible mechanisms. This work aimed to investigate the relevance of these mechanisms to the MTX toxicity in H9c2 cells, using therapeutic concentrations. The observed cytotoxicity of MTX was time and concentration dependent in both lactate dehydrogenase leakage assay and MTT reduction assay. Two therapeutic concentrations (100 nM and 1 μM) and three time points were selected (24, 48, and 96 h) for further studies. Both MTX concentrations caused a significant increase in caspase-3 activity, which was not prevented by inhibiting MTX CYP450-metabolism. Significant decreases were observed in the total and reduced glutathione levels only in MTX 100 nM at 96 h; however, neither alterations in oxidized glutathione nor increases in the malondialdehyde levels were observed at any time or concentrations tested. On the other hand, changes in the intracellular ATP levels, mitochondrial membrane potential, and intracellular calcium levels were observed in both concentrations and all time tested. Noteworthy, decreased levels of ATP-synthase expression and activity and increases in the reactive species generation were observed at 96 h in both working concentrations. However, the radical scavenger N-acetylcysteine or the mitochondrial function enhancer L-carnitine did not prevent MTX cytotoxicity. Thus, this work evidenced the early MTX-induced energetic crisis as a possible key factor in the cell injury.     

Sex-specific effects of isolation stress and consumption of palatable diet during the prepubertal period on metabolic parameters

Objectives

Social isolation during the prepubertal period may have long-term effects on metabolism. The exposure to stressful events is associated with increased palatable food intake, constituting reward-based eating. However, palatable food consumption in early life may lead to metabolic alterations later in life. We investigated whether isolation stress during early life can lead to metabolic alterations in male and female rats with or without exposure to a palatable diet.

Methods

Animals were stressed by isolation during one week after weaning, with or without exposure to a palatable diet.

Results

Stress and palatable diet induced increased caloric consumption. In females, there was a potentiation of consumption in animals exposed to stress and palatable diet, reflected by increased weight gain and triacylglycerol levels in juveniles, as well as increased adiponectin levels. Most of the effects had disappeared in the adults. Different effects were observed in males: in juveniles, stress increased unacylated ghrelin levels, and hypothalamic neuropeptide Y (NPY). Subsequently, adult males that were exposed to a palatable diet during prepuberty showed increased body weight and retroperitoneal fat deposition, increased glycemia, and decreased plasma adiponectin and hypothalamic NPY. Exposure to stress during prepuberty led to increased adrenals during adulthood, decreased LDL-cholesterol and increased triacylglycerol levels.

Conclusion

Isolation stress and consumption of palatable diet changes metabolism in a sex-specific manner. Prepuberty female rats were more prone to stress effects on food consumption, while males showed more long-lasting effects, being more susceptible to a metabolic programming after the consumption of a palatable diet.     

Efficacy of UVA1 phototherapy in 230 patients with various skin diseases

OBJECTIVE: Investigation of the efficacy of ultraviolet (UV) A1 phototherapy on atopic eczema, scleroderma, granuloma annulare, urticaria pigmentosa, prurigo nodularis, lichen sclerosus et atrophicus, T-cell lymphoma, keratosis lichenoides chronica, chronic urticaria and some rare, sclerosing skin diseases. METHODS: The data of 230 patients treated with low-dose, medium-dose and high-dose UVA1 therapy during 6 years were retrospectively analysed. The mean single dose (J/cm(2)), the mean number of irradiations and the mean total dose (J/cm(2)) were evaluated. The efficacy of phototherapy was assessed by a grading scale and the number of patients was given in percentage for each group. RESULTS: Good therapeutic effects of UVA1 therapy were shown in patients with atopic eczema, scleroderma, lichen sclerosus et atrophicus, keratosis lichenoides chronica, prurigo nodularis and with cutaneous T-cell lymphoma. Positive effects in some patients were seen in the urticaria pigmentosa and granuloma annulare group, no change to slight improvement was seen in most of the patients with rare, sclerosing skin diseases and no effect was seen in the chronic urticaria group. CONCLUSION: Besides topical and systemic therapy, UVA1 radiation is a good option of treatment in various skin diseases. It is one of the first-line treatments for several sclerotic diseases and it often improves pruritus considerably.