Investigation of Dynamic Thiol/Disulfide Homeostasis and Nitrosative Stress in Patients with Wilson Disease

Background: Wilson disease (WD) is an autosomal recessive inherited disorder of copper (Cu²⁺) metabolism, resulting in Cu²⁺ accumulation and liver and central nervous system toxicity. Oxidative stress may have a role in the pathogenesis of Wilson disease, but the roles of thiol/disulfide homeostasis and nitrosative stress have not been examined. The purpose of this study was to evaluate whether there is a modification in thiol/disulfide homeostasis and nitrosative stress in patients with Wilson disease.Methods: A total of 50 patients with Wilson disease (42 under drug treatment and 8 newly diagnosed patients with no drug treatment) and 50 healthy gender- and age-matched controls were enrolled for this study. Serum native thiol and total thiol levels were measured with a spectrophotometric method. The number of disulfide bonds and the related ratios were determined from these measurements. Serum nitric oxide (NO) and 3-nitrotyrosine (3-NT) levels were analyzed using chemiluminescence and ELISA assays, respectively.Results: The average native thiol levels of the patient group under drug treatment were found to be markedly higher than the levels of controls (P < .05). We detected no marked changes in total thiol and disulfide levels, and disulfide/total thiol, disulfide/native thiol, or native thiol/total thiol ratios between groups. We found significant elevations in NO levels in Wilson disease group before drug treatment, and the 3-NT levels in the Wilson disease groups prior to (P < .05) and under drug treatment (P < .01), when compared to controls.Conclusion: Our data are the first to show that nitrosative stress and thiol/disulfide homeostasis can contribute to the pathogenesis of Wilson disease.     

Internalized Stigma in Pediatric Psoriasis: A Comparative Multicenter Study

BackgroundInternalized stigma, adoption of negative attitudes and stereotypes of the society regarding persons'' illness, has not been studied previously in pediatric psoriasis patients.ObjectiveWe aimed to investigate the internalized stigma in pediatric psoriasis patients and to determine differences according to factors affecting internalized stigma compared to adult psoriasis patients.MethodsThis multicenter, cross-sectional, comparative study included 125 pediatric (55 female, 70 male; mean age±standard deviation [SD], 14.59±2.87 years) and 1,235 adult psoriasis patients (577 female, 658 male; mean age±SD, 43.3±13.7 years). Psoriasis Internalized Stigma Scale (PISS), Dermatology Life Quality Index (DLQI), Perceived Health Status (PHS), and the General Health Questionnaire (GHQ)-12 were the scales used in the study.ResultsThe mean PISS was 58.48±14.9 in pediatric group. When PISS subscales of groups were compared, the pediatric group had significantly higher stigma resistance (p=0.01) whereas adult group had higher scores of alienation (p=0.01) and stereotype endorsement (p=0.04). There was a strong correlation between mean values of PISS and DLQI (r=0.423, p=0.001). High internalized stigma scores had no relation to either the severity or localization of disease in pediatric group. However, poor PHS (p=0.007) and low-income levels (p=0.03) in both groups, and body mass index (r=0.181, p=0.04) in the pediatric group were related to high PISS scores.ConclusionInternalized stigma in pediatric patients is as high as adults and is related to poor quality of life, general health, and psychological illnesses. Unlike adults, internalized stigma was mainly determined by psoriasis per se, rather than disease severity or involvement of visible body parts, genitalia or folds.     

Physostigmine and metoclopramide in oesophageal peristaltic spread in man

Simultaneous recordings of electrical and mechanical activities at different levels of the oesophagus were performed in normal men before and after physostigmine and metoclopramide injections. Various parameters of the basal oesophageal peristalsis were significantly modified following drug treatment. In particular, physostigmine injections induced a shortening of electromechanical coupling time and a reduction of the propagation velocities of the electrical and mechanical oesophageal events. Metoclopramide shortened the electromechanical coupling time but increased the electrical and mechanical propagation velocities along the oesophagus.     

Calcineurin inhibitors suppress acute graft-versus-host disease via NFAT-independent inhibition of T cell receptor signaling

Inhibitors of calcineurin phosphatase activity (CNIs) such as cyclosporin A (CsA) are widely used to treat tissue transplant rejection and acute graft-versus-host disease (aGVHD), for which inhibition of gene expression dependent on nuclear factor of activated T cells (NFAT) is the mechanistic paradigm. We recently reported that CNIs inhibit TCR-proximal signaling by preventing calcineurin-mediated dephosphorylation of Lck^S59, an inhibitory modification, raising the possibility of another mechanism by which CNIs suppress immune responses. Here we used T cells from mice that express Lck^S59A, which cannot accept a phosphate at residue 59, to initiate aGVHD. Although CsA inhibited NFAT-dependent gene upregulation in allo-aggressive T cells expressing either Lck^WT or Lck^S59A, it was ineffective in treating disease when the T cells expressed Lck^S59A. Two important NFAT-independent T cell functions were found to be CsA-resistant in Lck^S59A T cells: upregulation of the cytolytic protein perforin in tissue-infiltrating CD8⁺ T cells and antigen-specific T/DC adhesion and clustering in lymph nodes. These results demonstrate that effective treatment of aGVHD by CsA requires NFAT-independent inhibition of TCR signaling. Given that NFATs are widely expressed and off-target effects are a major limitation in CNI use, it is possible that targeting TCR-associated calcineurin directly may provide effective therapies with less toxicity.     

Complete Pathologic Response after Combined Modality Treatment for Rectal Cancer and Long-Term Survival: A Meta-Analysis

Background

Complete pathologic response (CPR) after neoadjuvant chemoradiotherapy (combined modality treatment, CMT) for rectal cancer seems associated with improved survival compared to partial or no response (NPR). However, previous reports have been limited by small sample size and single-institution design.

Methods

A systematic literature review was conducted to detect studies comparing long-term results of patients with CPR and NPR after CMT for rectal cancer. Variables were pooled only if evaluated by 3 or more studies. Study end points included rates of CPR, local recurrence (LR), distant recurrence (DR), 5-year overall survival (OS), and disease-free survival (DFS).

Results

Twelve studies (1,913 patients) with rectal cancer treated with CMT were included. CPR was observed in 300 patients (15.6%). CPR and NPR patient groups were similar with respect to age, sex, tumor size, distance of tumor from the anus, and stage of disease before treatment. Median follow-up ranged from 23 to 46?months. CPR patients had lower rates of LR [0.7% vs. 2.6%; odds ratio (OR) 0.45, 95% confidence interval (CI) 0.22?C0.90, P?=?0.03], DR (5.3% vs. 24.1%; OR 0.15, 95% CI 0.07?C0.31, P?=?0.0001), and simultaneous LR?+?DR (0.7% vs. 4.8%; OR 0.32, 95% CI 0.13?C0.79, P?=?0.01). OS was 92.9% for CPR versus 73.4% for NPR (OR 3.6, 95% CI 1.84?C7.22, P?=?0.002), and DFS was 86.9% versus 63.9% (OR 3.53, 95% CI 1.62?C7.72, P?=?0.002).

Conclusions

CPR after CMT for rectal cancer is associated with improved local and distal control as well as better OS and DFS.     

Incidence and spatial distribution of adult-onset primary malignant and other central nervous system tumors in Southern Sardinia,Italy

Neurological Sciences - To study for the first time the incidence of adult-onset CNS tumors in Southern Sardinia, Italy. Clinical records of patients &gt; 18&nbsp;years old who...     

Choroidal plasmacytoma in a patient with multiple myeloma. Diagnosis by fine-needle aspiration biopsy

BACKGROUND: To report a case of a secondary plasmacytoma of the choroid. METHODS: Interventional case report with cytopathologic correlation. RESULTS: A 61-year-old male with a breast nodule and a 2-year history of multiple myeloma developed blurred vision and was found to have three confluent, ill-defined areas of choroidal thickening in the left eye. Cytopathology and immunohistochemistry of a transocular fine-needle aspiration biopsy of the largest lesion revealed atypical plasma cells diagnostic of plasmacytoma. Following external beam radiotherapy the choroidal tumors resolved completely. CONCLUSION: Secondary plasmacytoma, despite its rarity, should be included in the differential diagnosis of amelanotic choroidal tumors, particularly in patients with multiple myeloma. Radiotherapy is an effective treatment.     

Effects of low-dose oral contraceptives on sugar metabolism

The effects on carbohydrate metabolism by four low-dose oral contraceptives were evaluated in four low-dose oral contraceptives were evaluated-66 young women randomly divided in four groups. In the various preparations there were a different dosage of estrogen (ethinylestradiol) together different doses and types of progestogen (desogestrel, gestodene, cyproterone acetate). After six months of treatment, in all groups a slight increase of glycemic and insulinemic responses during OGTT was observed; the significance was achieved with the preparation containing cyproterone acetate alone. Glycated hemoglobin did not change. Our results suggest that these new low-dose oral contraceptives induced negligible metabolic side effects.     

Ultrasound monitoring of testis and prostate maturation in hypogonadotropic hypogonadic males during gonadotropin-releasing hormone treatment

The effects of the administration of gonadotropin-releasing hormone (GnRH) on the increase of testis and prostate volume was monitored by ultrasound in six patients affected by idiopathic hypogonadotropic hypogonadism. A significant increase of testis volume was observed after 90 and 180 days (6.65 versus 3.32 mL, 99.1% net increase and 8.47 mL, 176.8% increase, respectively) of pulsatile GnRH treatment. A similar increase of prostate volume was observed at day 90 (12.67 versus 7.78 mL, 70.3% net increase) and day 180 (14.70 mL, 97.7% increase). The ultrasound monitoring of the modifications of testis and prostate volume may represent a biological assay of the effects of GnRH treatment and offer additional data on the response of target organs to the hormonal treatment.     

Evidence of specific benzodiazepine binding to myometrial membrane preparations from human pregnant uterus

The muscle relaxant effect of benzodiazepines (BDZ) is widely held to be mediated at central as well as at peripheral level. In this study we report that crude membrane preparations from the myometrium of pregnant women possess binding sites for [3H]-RO 5-4864, specific ligand for the peripheral type of BDZ receptor. Scatchard analysis shows a high affinity binding site (KD = 3.1 +/- 1.2 nM) and a class of low affinity binding sites (KD greater than 30 nM). Displacement experiments show that various BDZ are differently effective in inhibiting [3H]-RO 5-4864 binding: RO 5-4864 greater than diazepam greater than flunitrazepam greater than lorazepam greater than chlordiazepoxide. In conclusion, these data seem to demonstrate that human myometrium possesses specific binding sites of 'peripheral type' for BDZ. It may be suggested that these binding sites are involved in mediating the myometrial relaxant effect exerted by BDZ. Thus, peripherally active BDZ could be used as tocolytic agents, avoiding BDZ central effects.