A comparison of the effects of clozapine and its metabolite norclozapine on metabolic dysregulation in rodent models.

RATIONALE: The second generation antipsychotic drug clozapine is a psychotherapeutic agent with superior efficacy for treatment-resistant schizophrenia. Clozapine is associated with a low likelihood of neurological side-effects, but a high propensity to induce weight gain and metabolic dysregulation. The primary metabolite of clozapine is norclozapine (N-Desmethylclozapine), which has psychoactive properties itself, but its effects on metabolic function remains unknown. The goal of the present study was to determine whether directly administered norclozapine could cause metabolic dysregulation, similar to clozapine. METHODS: Adult female rats were treated with a range of doses of clozapine and norclozapine (0.5, 2, 8 & 20 mg/kg, i.p.) and then subjected to the intraperitoneal glucose tolerance test (IGTT), where glucose levels were recorded for 2 h following a glucose challenge. In parallel, rats were tested with two doses of clozapine and norclozapine (2 & 20 mg/kg, i.p.) in the hyperinsulinemic-euglycemic clamp (HIEC), to measure whole body insulin resistance. RESULTS: In the IGTT, clozapine demonstrated dose-dependent effects on fasting glucose levels and total glucose area-under-the-curve following the glucose challenge, with the two highest doses strongly increasing glucose levels. Only the highest dose of norclozapine increased fasting glucose levels, and caused a non-significant increase in glucose levels following the challenge. By contrast, both doses of clozapine and norclozapine caused a potent and long-lasting decrease in the glucose infusion rate in the HIEC, indicating that both compounds cause whole body insulin resistance. ABSTRACT: While not as potent as its parent compound, norclozapine clearly exerts acute metabolic effects, particularly on insulin resistance. This article is part of the issue entitled 'Special Issue on Antipsychotics'.

Sexual function, self-esteem, and general well-being in Chinese adult survivors of childhood cancers: a cross-sectional survey.

INTRODUCTION: This study was conducted to evaluate sexual function in adult survivors of childhood cancers and investigate possible relationships between sexual function and quality of life, as measured by general well-being, self-esteem, body image, and depressive symptoms. METHODS: This cross-sectional survey was performed in our centre from 14 August 2015 to 8 September 2017. Adult patients who had a history of childhood cancers, and who were disease-free for >3 years, were approached for the study during clinical follow-up. Clinical information was collected from medical records. Self-administered questionnaires regarding quality of life and sexual functioning were given to the patients and resulting data were analysed. RESULTS: Two hundred patients agreed to participate in the study. The overall response rate was 64.8%. Ninety-one (45.5%) patients were women, and the mean age was 25.4 ± 5.57 years. The overall sexual functioning score was 28.3 ± 20.09. Forty-eight (24.0%) patients reported at least one sexual problem. Among patients who reported no sexual problems, more had haematological cancers (P=0.009), fewer underwent surgery (P=0.004), fewer underwent surgery with external effects (P=0.032), and fewer were regular social drinkers (P=0.013); additionally, they had a higher mean Rosenberg self-esteem scale score (P=0.010), lower mean body image scale score (P=0.008), and lower mean Patient Health Questionnaire score (P=0.001). CONCLUSION: Aspects of life beyond disease condition and physical function should be considered in adult survivors of childhood cancers. Appropriate referral and intervention should be initiated for these patients when necessary.

Tumor inhibitory effects of intravesical Ganoderma lucidum instillation in the syngeneic orthotopic MB49/C57 bladder cancer mice model.

ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (GL) has been traditionally used in oriental medicine as superior health tonic, and there are numerous scientific evidences of its antitumorigenic activities. AIM OF THE STUDY: To evaluate the intravesical chemopreventive effects of ethanol extract of GL (GLe) on bladder cancer. MATERIALS AND METHODS: Intravesical therapy is defined as the direct instillation of a liquid drug into bladder through a catheter. Bacille Calmette-Guerin(BCG) solution is applied intravesically as a conventional immunotherapy for preventing recurrence of bladder cancer. By adopting the MB49/C57 bladder cancer mice model, an overall 60 MB49-implanted mice were randomized into 3 groups and treated according to 3 treatment arms, including GLe, BCG and PBS. Additionally, wild-type mice without MB49 cell inoculation and treated with PBS were used as the negative control group. Testing agents were instilled intravesically for 2 h and repeated after one week for evaluating the effects on preventing the tumor formation and growth. The treated-mice were closely monitored for major adverse effects. RESULTS: GLe demonstrated more potent cytotoxic effects than BCG on MB49 cells, although both in dose-dependent manner. In the MB49-implanted mice, 80 µg/ml GLe was shown to delay the tumor formation by one week, whereas the averaged tumor volume measured at endpoint was 3.6-fold and 4.6-fold smaller than that of the BCG or PBS, respectively. However, no significant effects were observed on body weight and hematuria. CONCLUSION: Current findings in mice suggested intravesical GLe therapy as an effective and safe chemopreventive strategy for inhibiting bladder tumor formation.

A survey on the prevalence and utilization characteristics of gua sha in the Hong Kong community.

OBJECTIVE: To conduct a community-based survey to describe the demographics, experience, and utilization variables among the users of gua sha living in Hong Kong. METHOD: A total of 3209 adult respondents were surveyed by using a short Chinese questionnaire. RESULTS: Gua sha was found to have a one-year prevalence of 22.7% and four-week prevalence of 6.6%. The users were seen to be old of age and less educated. The majority believed that gua sha is beneficial to health, practiced in non-regular basis, and mainly employed for treating illnesses. For both male and female, the top two common illnesses to be treated were the respiratory and pain problems, which accounting for 74% of all users. Other illnesses included nervousness, heat stroke, fever, infection, dizziness, diarrhoea and vomiting, oedema, and constipation. As practiced by most respondents, unidirectional pressured stroking was applied repeatedly on the lubricated skin surface at the back region using various smooth-edged tools typically spoons. Almost all users reported the occurrence of skin blemishing and subsequently faded within 7 days after the gua sha treatment. CONCLUSION: The general population of Hong Kong was found to have high prevalence of gua sha usage. The utilization characteristics as reported by the users were generally aligned with the current scientific knowledge, in particular the treatment procedures and response.

The differential immunological activities of Ganoderma lucidum on human pre-cancerous uroepithelial cells.

AIMS OF THE STUDY: Ganoderma lucidum is active to stimulate immunological effector cells, but the effects on uroepithelial cells have never been explored. The present study compared the expression of major cytokines induced by the water (GLw) and ethanol (GLe) extracts of G. lucidum. MATERIALS AND METHODS: The pre-cancerous human uroepithelial cell (HUC-PC) line was employed. A total of 15 cytokines, including major Th1/Th2 cytokines and chemokines, were measured in the complete media after 24h incubation with GLw and GLe. Additionally, the following assays were performed: cytotoxicity, apoptosis, migration of neutrophils, and nuclear factor-kappaB (NF-κB) DNA binding activity. RESULTS: GLe inhibited the growth of HUC-PC cells through apoptosis. Interleukins IL-2, IL-6, and IL-8 were significantly up-regulated by GLe in dose-dependent manners, but not by GLw. However, MCP-1 level was significantly increased by GLw but was oppositely reduced by GLe. Furthermore, the elevation of cytokine expression was correlated with the enhancement of p50/p65 NF-κB activity induced by GLe. The elevated IL-8 levels in GLe-treated cells were also correlated with the migration of neutrophils. CONCLUSIONS: GLe and GLw exhibited different immunological activities on the HUC-PC cells. In particular, the activities of GLe may favor the clearance of high risk urothelial cells, suggesting potent chemopreventive ingredients are extractable by ethanol from G. lucidum.

The dual roles of Ganoderma antioxidants on urothelial cell DNA under carcinogenic attack.

AIMS OF THE STUDY: Ganoderma lucidum possesses significant antioxidant and anti-cancer properties. The effects of Lingzhi antioxidants on oxidative DNA damage and oxidative stress were investigated, in order to understand their roles in bladder chemoprevention. MATERIALS AND METHODS: Antioxidant-enhanced extracts were tested, in terms of ferric reducing antioxidant power (FRAP), 2,2-diphenyl-1-picrylhydrazyl (DPPH.) inhibition, hydrogen peroxide (H(2)O(2)) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentrations, and cytotoxicity, using an in vitro pre-cancerous human uroepithelial cell (HUC-PC) tumorigenic model. RESULTS: Water-soluble extract (GLw) possesses relatively higher antioxidant capacities than the water-insoluble counterpart (GLe); however, under the challenge of carcinogenic 4-aminobiphenyl (ABP), GLw reduced the 8-OHdG concentration in HUC-PC culture, while GLe induced the formation of H(2)O(2) and 8-OHdG in a dose-dependent manner. The modern theory of antioxidant-oxidant balance seems to obey the theory of Yin-Yang in traditional Chinese medicine (TCM). CONCLUSIONS: Water-soluble and water-insoluble components of Ganoderma lucidum exhibited dual roles in oxidative DNA damage. Oxidative DNA damage may be an underlying mechanism of Lingzhi-induced apoptosis in bladder chemoprevention.

Hydrogen peroxide in urine as a potential biomarker of whole body oxidative stress.

The level of hydrogen peroxide (H2O2) in urine has been suggested as a potential biomarker of whole body oxidative stress, but issues of stability, reproducibility and biological variation have not been investigated to date. In this study, we used a refined protocol, which demonstrated improved sensitivity and precision, to determine the stability of H2O2 in urine, and to measure its concentration in apparently healthy subjects. We also investigated intra-individual variation within and between days. Results showed that H2O2 in urine is stable for up to 48 h at 4 degrees C, however, storage of urine at room temperature was associated with up to 50% increase in H2O2 concentration over a few hours. Total H2O2 in freshly voided urine from 55 healthy, fasting subjects ranged from 0.84 to 5.71 microM, or 90-1164 micromol H2O2/mol creatinine. Intra-individual variation was wide. Even when concentration corrected and collected at the same time of day, 2- to 3-fold variation was seen over 4 consecutive days, and over the course of a single day the creatinine-corrected H2O2 also varied significantly. We suggest that this large biological variation limits the usefulness of urine H2O2 as a biomarker of oxidative stress, the exception being when the effects of disease, therapy or diet induce very large changes in its concentration.

Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma.

Von Hippel-Lindau disease (VHL) is an autosomal dominant disorder with inherited susceptibility to various forms of cancer, including hemangioblastomas of the central nervous system, phaeochromocytomas, pancreatic malignancies, and renal cell carcinomas. Renal cell carcinomas constitute a particularly frequent cause of death in this disorder, occurring as bilateral and multifocal tumours, and presenting at an earlier age than in sporadic, non-familial cases of this tumour type. We report here that the VHL gene is linked to the locus encoding the human homologoue of the RAF1 oncogene, which maps to chromosome 3p25 (ref. 4). Crossovers with the VHL locus suggest that the defect responsible for the VHL phenotype is not a mutation in the RAF1 gene itself. An alternative or prior event to oncogene activation in tumour formation may be the inactivation of a putative 'tumour suppressor' which can be associated with both the inherited and sporadic forms of the cancer. Sporadic renal cell carcinomas have previously been associated with the loss of regions on chromosome 3p (refs 5, 6). Consequently, sporadic and VHL-associated forms of renal cell carcinoma might both result from alterations causing loss of function of the same 'tumour suppressor' gene on this chromosome.

Segregation and linkage analyses of von Hippel Lindau disease among 220 descendants from one kindred.

Von Hippel Lindau disease (vHL), an autosomal dominant precancerous condition, had segregated in a large kindred. Fourteen relatives were known to have been affected; record reviews disclosed features of vHL in 15 previously undiagnosed relatives; presymptomatic evaluations detected vHL in 13 additional members of this kindred. Altogether, among 220 descendants of an ancestral couple, 41 had vHL. We screened for HLA haplotypes and for polymorphic gene markers at 31 loci in 102 direct descendants and 16 spouses from this kindred, including 23 with vHL. Linkage analyses failed to reveal a significant lod score with any locus tested, or any HLA linkage disequilibrium. Expression of vHL among the affected relatives was compared with 384 other reported cases of vHL. The age of onset, tissue involvement, and life expectancy in this family were similar to the other reported cases. The sigmoid age-of-onset distribution for vHL most closely matched a square-foot transformation (mean = 26.2(-2) years; variance = 1.224).

Development of the triadic junction in skeletal muscle fibers of fetal and postnatal rats.

Electron microscope examinations of the developing triadic junction in fibers from leg muscles of fetal and postnatal rats reveal a range of complexity from no structural connections across the space between apposed membranes of T and SR to all of the junctional structures visible in adult rat muscle fibers. In triads showing no connections, faintly stained projections from the apposed membranes of T and SR are seen. The simplest form of junctional structure is a series of faintly stained strands that make connections across the space between apposing membranes. Junctional structures stained more intensely show periodic bridges traversing the space plus an intermediate dense line (intermediate density) running parallel to the apposed membranes of T and SR and bisecting the space between apposed membranes. The intermediate density is continuous across the periodic bridges and interbridge spaces and it appears to be connected to the apposed membranes of T and SR. It is suggested that projections from T and SR are precursors of the connections and that the projections interact to form the intermediate density. It is also suggested that bridge and interbridge junctional structures might form compartments isolated from the sarcoplasm and thus enhance the flow of electrical current from T to apposed SR by reducing low-resistance shunting of current flow into the sarcoplasm,