Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression

Androgens play an important role in prostate cancer (PCa) development and progression. Accordingly, androgen deprivation therapy remains the front-line treatment for locally recurrent or advanced PCa, but patients eventually relapse with the lethal form of the disease termed castration resistant PCa (CRPC). Importantly, castration does not eliminate androgens from the prostate tumor microenvironment which is characterized by elevated tissue androgens that are well within the range capable of activating the androgen receptor (AR). In this mini-review, we discuss emerging data that suggest a role for the enzymes mediating pre-receptor control of dihydrotestosterone (DHT) metabolism, including AKR1C2, HSD17B6, HSD17B10, and the UGT family members UGT2B15 and UGT2B17, in controlling intratumoral androgen levels, and thereby influencing PCa progression. We review the expression of steroidogenic enzymes involved in this pathway in primary PCa and CRPC, the activity and regulation of these enzymes in PCa experimental models, and the impact of genetic variation in genes mediating pre-receptor DHT metabolism on PCa risk. Finally, we discuss recent data that suggests several of these enzymes may also play an unrecognized role in CRPC progression separate from their role in androgen inactivation.     

Evaluation of epigallocatechin gallate and epicatechin gallate effects on acrylamide-induced neurotoxicity in rats and cytotoxicity in PC 12 cells

The neurotoxicity of acrylamide (ACR) monomer occurs through different mechanisms such as oxidative stress. Epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) are green tea catechins which are known as powerful antioxidants. In this study, we examined the possible protective effects of ECG and EGCG on ACR neurotoxicity in both in-vitro and in-vivo models. PC12 cells were exposed to different concentrations of ECG and EGCG. After 24 and 48?hours, ACR was added to the cells (IC₅₀?=?4.85?mM) and cell viability was measured through MTT assay after 24?hours. Male Wistar rats were pretreated with ECG, EGCG (10, 20 and 40?mg/kg, i.p) and vitamin E (200?IU/kg i.p.) for 3?days. Afterwards they were treated with ACR (50?mg/kg, i.p.) for 11?days. After the treatment period, gait score examination was performed and molondialdehyde (MDA) and reduced glutathione (GSH) were measured in cerebral cortex. ACR reduced the cell viability in a concentration-dependent manner. Both ECG and EGCG (20?μM) showed inhibitory effects on ACR cytotoxicity. ACR significantly induced gait abnormalities, decreased GSH level and increased lipid peroxidation in cerebral cortex. ECG and EGCG (20?mg/kg) improved all ACR toxic effects. Although the food intake was increased in pretreated groups compared to the ACR-treated group, intensive weight loss was observed due to the green tea’s different weight loss mechanisms. ECG and EGCG inhibited the cytotoxicity of ACR in PC12 cells and increased GSH level and decreased lipid peroxidation in rat cerebral cortex.     

Penbactam for Helicobacter pylori eradication: A randomised comparison of quadruple and triple treatment schedules in an Iranian population

Background & study aimsSelection of the best drug regimens for eradication of Helicobacter pylori infection especially in patients at risk of peptic ulcer relapses and the development of complications is challenging. This study assessed and compared the efficacy of the two common PPI based triple therapies to a quadruple therapy including PPI, metronidazole, amoxicillin and a bismuth compound in Iranian population.Patients & MethodsThree hundred and thirty patients with peptic ulcer and H. pylori infection were included in the study. Patients were randomly assigned to one of the three treatment protocols all given twice daily: (a) A 14-day quadruple therapy (OMAB group) comprising omeprazole 20 mg, metronicazole 500 mg, amoxicillin 1 g, and bismuth subcitrate 240 mg; (b) A 14-day triple regimen (OCP group) comprising omeprazole 20 mg plus clarithromycine 500 mg and penbactam 750 mg and (c) A 14-day triple regimen (OCA group) comprising omeprazole 20 mg plus clarithromycine 500 mg and amoxicillin 1 g. Cure was defined as a negative urea breath test at least six weeks after treatment.ResultsThe per-protocol eradication rates achieved with both OCP regimen (87.0%) and OCA treatment (90.8%) were significantly higher than the OMAB treatment protocol (56.0%); however, no significant difference emerged in eradication rates between the two triple treatment schedules. No significant differences between the groups were found in most side-effects.ConclusionTwo-week quadruple therapy showed a lower eradication rate compared to common triple treatment schedules when used as first-line eradication treatment for H. pylori infection in Iranian population.     

Hepatocyte Isolation From Unused/Rejected Livers for Transplantation: Initial Step Toward Hepatocyte Transplantation,the First Experience From Iran

Background

Hepatocyte transplantation is being used in patients with liver-based metabolic disorders and acute liver failure. Hepatocytes can be isolated from unused/rejected livers under sterile conditions.

Objectives

The quality of the hepatocytes is very important and the main and initial step in hepatocyte transplantation is hepatocyte isolation. In this study we tried to set up the methods of hepatocyte isolation in order to use the high quality cells in acute liver failure or congenital metabolic disorders.

Materials and Methods

In this study, during a year, hepatocytes were isolated from 7 unused/rejected livers among more than 300 harvested livers in Shiraz University of Medical Sciences. The two step collagenase perfusion method was used under GMP (Good manufacturing practice) for hepatocyte isolation.

Results

Highly quality hepatocytes with high viability and low contamination were isolated. The mean viability was 71.8% ± 21.7. In the first 4 cases microbial contamination by Staphylococci, Diphtheroid and Klebsiella was detected, however the last 3 cases were free of any micro organisms. After 5 weeks of cryopreservation in -140°C, the cell viability was still acceptable.

Conclusions

Hepatocyte isolation can be performed as the main and initial step for cell transplantation from unused/rejected liver. It is the first experience in Iran.     

Diagnoses, requests and timing of 503 psychiatric consultations in two general hospitals

The high comorbidity of medical and psychiatric diagnoses in the general hospital population requires collaboration between various medical fields to provide comprehensive health care. This study aims to find the rate of psychiatric consultations, their timing and overall diagnostic trend in comparison to previous studies. Tehran University of Medical Sciences has got an active psychiatric consultation-liaison service which includes services provided by four faculty psychiatrists (two full-time and two part-time). This study was done in two general hospitals by simple sampling in available cases. For each consultation, a board-certified faculty psychiatrist conducted a clinical evaluation based on DSM-IV-TR. Other than psychiatric diagnoses, socio-demographic variables, relative consultation rates, reasons for referral, medical diagnoses and the time stay after admission were assessed. Among 503 patients who were visited by the consultation-liaison service, there were 54.3% female with mean age of 39.8 years. In 90.1% of consultations, at least one DSM-IV-TR diagnosis was made. The most frequent diagnosis groups were mood disorder (43.5%), adjustment disorder (10.9%) and cognitive disorder (7.6%). In about 10.9% of the consultations, multiple psychiatric diagnoses were made. The mean length of hospital stay before the consultation was 12.56 days (range=1-90, SD=13). Based on our findings, the mood and cognitive disorders still remain major foci of consultation-liaison practice in general hospitals; however our findings showed high rate of adjustment disorders diagnosis and ambiguous request for psychiatric consultation which need more interdisciplinary interaction.     

Manifestation of diffuse yellowish keratoderma on the palms and soles in autosomal recessive congenital ichthyosis patients may be indicative of mutations in NIPAL4

Ichthyosis is a heterogeneous disorder characterized by abnormal skin scaling over the whole body. Autosomal recessive congenital ichthyosis (ARCI) comprises various forms, the most important of which are lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). Seven genes have been identified to be causative of ARCI, and these account for disease in 60-80% of the patients. There is notable phenotypic overlap between the major forms of ARCI, and a strong genotype-phenotype correlation has not been found. Here, we initially aimed to identify the causative gene in a large Iranian ARCI pedigree, and subsequently performed genetic analysis on four other affected pedigrees. A genotype-phenotype correlation was sought. Whole genome homozygosity mapping using high-density single nucleotide polymorphism chips was performed on the large pedigree. Linkage to chromosome 5 and a mutation in NIPAL4 causing p.G297R were identified. The same mutation was also identified in two of the remaining four Iranian pedigrees. Two of the NIPAL4 mutation bearing pedigrees were classified as CIE and one as LI. Notably, all NIPAL4 mutation-bearing patients manifested diffuse yellowish keratoderma on the palms and soles. We provide evidence suggesting presentation of this diffuse yellowish keratoderma may be indicative of mutations in NIPAL4, providing an easily assessable genotype-phenotype correlation.