Oxidative and nitrosative stress mediated renal cellular damage induced by cyclosporine A: role of sulphated polysaccharides

Oxidative and nitrosative stress are known to exert various adverse effects on biological systems and this seems to be one of the major contributor of nephrotoxicity induced by cyclosporine A (CsA), which is a major clinical challenge, despite its potent immunosuppressive effect. Sulphated polysaccharides of marine origin are well known for its antioxidant properties, among its other biological applications. CsA administration (25 mg/kg body weight, orally, for 21 d) showed increased level of oxidants and xanthine oxidase activity. CsA induced nitrosative stress was evident from a marked elevation in the expression of inducible nitric oxide synthase mRNA in renal tissue and a concomitant increase in plasma nitric oxide level. Augmented levels of malondialdehyde, 8-hydroxy-2-deoxyguanosine and protein carbonyl coupled with diminished protein thiols; hallmarks of lipid peroxidation, DNA damage and protein oxidation were noted in CsA administered rats. Membrane damage was further confirmed by altered ATPase activities in the renal tissue. Simultaneous treatment with sulphated polysaccharides (5 mg/kg body weight, subcutaneously) remarkably prevented the above alterations mediated by oxidative and/or nitrosative stress during CsA induction. Hence, these findings conclude that the use of an antioxidant agent like sulphated polysaccharides could be a useful tool in reducing CsA-induced nephrotoxicity.     

Pancreas transplantation: The Wake Forest experience in the new millennium

AIM: To investigate the Wake Forest experience with pancreas transplantation in the new millennium with attention to surgical techniques and immunosuppression.METHODS: A monocentric, retrospective review of outcomes in simultaneous kidney-pancreas transplant (SKPT) and solitary pancreas transplant (SPT) recipients was performed. All patients underwent pancreas transplantation as intent-to-treat with portal venous and enteric exocrine drainage and received depleting antibody induction; maintenance therapy included tapered steroids or early steroid elimination with mycophenolate and tacrolimus. Recipient selection was based on clinical judgment whether or not the patient exhibited measureable levels of C-peptide.RESULTS: Over an 11.25 year period, 202 pancreas transplants were performed in 192 patients including 162 SKPTs and 40 SPTs. A total of 186 (92%) were primary and 16 (8%) pancreas retransplants; portal-enteric drainage was performed in 179 cases. A total of 39 pancreas transplants were performed in African American (AA) patients; of the 162 SKPTs, 30 were performed in patients with pretransplant C-peptide levels > 2.0 ng/mL. In addition, from 2005-2008, 46 SKPT patients were enrolled in a prospective study of single dose alemtuzumab vs 3-5 doses of rabbit anti-thymocyte globulin induction therapy. With a mean follow-up of 5.7 in SKPT vs 7.7 years in SPT recipients, overall patient (86% SKPT vs 87% SPT) and kidney (74% SKPT vs 80% SPT) graft survival rates as well as insulin-free rates (both 65%) were similar (P = NS). Although mortality rates were nearly identical in SKPT compared to SPT recipients, patterns and timing of death were different as no early mortality occurred in SPT recipients whereas the rates of mortality following SKPT were 4%, 9% and 12%, at 1-, 3- and 5-years follow-up, respectively (P < 0.05). The primary cause of graft loss in SKPT recipients was death with a functioning graft whereas the major cause of graft loss following SPT was acute and chronic rejection. The overall incidence of acute rejection was 29% in SKPT and 27.5% in SPT recipients (P = NS). Lower rates of acute rejection and major infection were evidenced in SKPT patients receiving alemtuzumab induction therapy. Comparable kidney and pancreas graft survival rates were observed in AA and non-AA recipients despite a higher prevalence of a “type 2 diabetes” phenotype in AA. Results comparable to those achieved in insulinopenic diabetics were found in the transplantation of type 2 diabetics with detectable C-peptide levels.CONCLUSION: In the new millennium, acceptable medium-term outcomes can be achieved in SKPT and SPTs as nearly 2/3rds of patients are insulin independent following pancreas transplantation.     

Neoadjuvant treatment of endometrial cancer using anastrozole: A randomised pilot study

Objective

Excessive oestrogenic stimulation is a well-known risk factor for the development and progression of endometrial cancer. Aromatase is the key enzyme which catalyses the conversion of androgens to oestrogens in postmenopausal women. Inhibition of aromatase may therefore be a useful strategy in the management of endometrial cancer. A pilot study was designed to assess the feasibility of a neoadjuvant model and understand the biological effects of anastrozole, an aromatase inhibitor, in the treatment of endometrial cancer.

Methods

Patients with endometrial cancer who consented to participate in the study were randomised to receive anastrozole or placebo for a minimum of 14 days prior to definitive surgery. Endometrial samples were obtained before and after treatment. Immunohistochemistry was performed to ascertain the expression of oestrogen receptor alpha (ERα), progesterone receptor (PR), androgen receptor (AR), ki-67 and Bcl2 before and after treatment in glands and stroma of the endometrium.

Results

A total of 16 patients were randomised to the anastrozole arm and 8 to the placebo arm (2:1 randomisation). A significant decrease in the glandular expression of ERα and AR was observed in the anastrozole arm. There was no significant change in the expression of PR or Bcl2. Expression of ki-67, a proliferation marker, also decreased significantly following treatment with anastrozole.

Conclusions

Treatment with anastrozole caused a significant decrease in proliferation as demonstrated by decreased ki-67 expression. A large randomised controlled trial is warranted to fully assess the role of anastrozole in the neoadjuvant treatment of endometrial cancer.     

The over-expression of survivin enhances the chemotherapeutic efficacy of YM155 in human hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. The inability of chemotherapeutic drugs to selectively target HCC tumor cells because of their predominant resistant phenotype to most conventional anticancer agents bestows a major obstacle for the clinical management of HCC. In this report, we have examined and demonstrated the remarkable heterogeneity of expression of survivin and its phosphorylated active form (p-survivin) in HCC patients'' tissues and cell lines. Furthermore, the expression of survivin and p-survivin in HCC cell lines was found to be associated with response to the small-molecule survivin suppressant YM155. Therefore, in the HCC cell lines that express elevated level of survivin and p-survivin, YM155 efficiently inhibited their proliferation, induced cell cycle arrest and apoptosis resulting in DNA damage through the dysregulation of cell-cycle checkpoint-related regulatory genes. Importantly, YM155 yielded significantly better therapeutic effect than sorafenib when tested in an orthotopic mouse model using patient-derived HCC xenografts with elevated survivin and p-survivin expression. Our results clearly demonstrated that the level of survivin and p-survivin expression could serve as molecular predictive biomarkers to select potential YM155-responsive patients, in a move towards delivering precision medicine for HCC patients.     

Analysis of the UK recommendations on obesity based on a proposed implementation framework

Background  

There is considerable expertise in the obesity field in identifying, appraising, and synthesising evidence to develop guidelines and recommendations for policy and practice. The recommendations, while based on evidence, are not formulated in a way that readily leads to implementation. This paper analyses the recent UK recommendations on obesity using a proposed implementation framework.     

A review of chronic pain after inguinal herniorrhaphy

BACKGROUND: Chronic pain was believed to be a recognized but infrequent complication after inguinal hernia repair. Evidence suggests that patients with chronic pain place a considerable burden on health services. However, few scientific data on chronic pain after this common elective operation are available. OBJECTIVES: To review the frequency of chronic pain and to discuss etiological theories and current treatment options for patients with chronic post herniorrhaphy pain. MATERIALS AND METHODS: All studies of postoperative pain after inguinal hernia repair with a minimum follow-up period of 3 months, published between 1987 and 2000, were critically reviewed. RESULTS AND DISCUSSION: The frequency of chronic pain after inguinal hernia repair was found to be as high as 54%, much more than previously reported. Quality of life of these patients is affected. Chronic pain is reported less often after laparoscopic and mesh repairs. Recurrent hernia repair, preoperative pain, day case surgery, delayed onset of symptoms, and high pain scores in the first week after surgery, however, were identified to be risk factors for the development of chronic pain. Definition of chronic pain was not explicit in the majority of the reviewed studies. Accurate evaluation of the frequency of chronic pain will require standardization of definition and methods of assessment. Prospective studies are required to define the role of risk factors identified in this review.     

Protective effect of lipoic acid on oxidative and peroxidative damage in cyclosporine A-induced renal toxicity

Free radical generation, including reactive nitrogen and reactive oxygen species, is known to participate in cell physiology in both a positive and negative manner. Moreover, alterations in their concentrations are implicated in a number of renal diseases. However, there is evidence that high concentration of nitric oxide (NO) occurring as a result of iNOS induction and peroxynitrite formation, is capable of causing lipid peroxidation and protein oxidation in cyclosporine A (CsA) induced cellular damage. The present study was conducted to investigate the possible protective role of Lipoic acid (LA) in nitric oxide mediated cellular abnormalities induced by CsA in rat kidney. Adult male albino rats of Wistar strain were given CsA at a dose of 25 mg/kg body weight, orally for 21 days. An extensive elevation in the activities of xanthine oxidase was noted in the renal tissue of the CsA administered rats. These changes were associated with significant increase in the levels of plasma lipid peroxidation with high protein carbonyl contents and 3-nitrotyrosine formation coupled with diminished protein thiols. In addition, plasma nitrite/nitrate (NO(x)), RT-PCR for inducible NOS (iNOS) mRNA, and immunohistochemically demonstrable iNOS protein were evaluated to assess peroxidative damage. Concomitant treatment with LA (20 mg/kg body weight, orally for 21 days showed that the oxidative stress alteration were significantly decreased in CsA treated renal tissue. While the expression of iNOS and the amounts of NO(x) were decreased simultaneously. These results indicate that the antioxidant LA might have a protective effect against CsA-induced peroxidative changes and cellular damage of the renal tissue of the rat.     

Physical activity attitudes, intentions and behaviour among 18 to 25 year olds: A mixed method study

ABSTRACT: BACKGROUND: Young people (18--25 years) during the adolescence/adulthood transition are vulnerable to weight gain and notoriously hard to reach. Despite increased levels of overweight/obesity in this age group, physical activity behaviour, a major contributor to obesity, is poorly understood. The purpose of this study was to explore physical activity (PA) behaviour among 18--25 year olds with influential factors including attitudes, motivators and barriers. METHODS: An explanatory mixed method study design, based on health Behaviour Change Theories was used. Those at university/college and in the community, including those Not in Education, Employment or Training (NEET) were included. An initial self reported quantitative questionnaire survey underpinned by the Theory of Planned Behaviour and Social Cognitive Theory was conducted. 1313 questionnaires were analysed. Results from this were incorporated into a qualitative phase also grounded in these theories. Seven focus groups were conducted among similar young people, varying in education and socioeconomic status. Exploratory univariate analysis was followed by multi staged modelling to analyse the quantitative data. 'Framework Analysis' was used to analyse the focus groups. RESULTS: Only 28 % of 18--25 year olds achieved recommended levels of PA which decreased with age. Self-reported overweight/obesity prevalence was 22 %, increasing with age, particularly in males. Based on the statistical modelling, positive attitudes toward PA were strong predictors of physical activity associated with being physically active and less sedentary. However, strong intentions to do exercise, was not associated with actual behaviour. Interactive discussions through focus groups unravelled attitudes and barriers influencing PA behaviour. Doing PA to feel good and to enjoy themselves was more important for young people than the common assumptions of 'winning' and 'pleasing others'. Further this age group saw traditional health promotion messages as 'empty' and 'fear of their future health' was not a motivating factor to change current behaviour. CONCLUSION: 18--25 year olds are a difficult group to reach and have low levels of PA. Factors such as, 'enjoyment', 'appearance 'and 'feeling good' were deemed important by this specific age group. A targeted intervention incorporating these crucial elements should be developed to improve and sustain PA levels.