Syed Mohammad Husain Rizvi

Postconditioning in rats and mice

Objective. For subsequent studies on the molecular mechanisms of postconditioning, we aimed to identify a robust postconditioning protocol in rat and mouse heart. Design. Isolated rat hearts were subjected to different postconditioning protocols (study 1 and 2). The protection was compared to preconditioning. Rats (study 3) in vivo in two different laboratories were postconditioned. Isolated mouse hearts (study 4) and mice in vivo (study 5) were postconditioned. Results. Postconditioning did not protect isolated, perfused rat hearts, however, preconditioning improved function and reduced infarct size. Postconditioning tended to protect rat hearts in vivo in one laboratory (p = 0.10), whereas protection was seen in the other laboratory (infarct size 51±11% vs controls 62±3%, p = 0.01). Postconditioned mouse hearts were protected, both ex vivo (16±9% vs controls 33±18%, p = 0.02) and in vivo (21±5% vs 42±7%, p < 0.001). Conclusions. Rat hearts are less suitable for studies of mechanisms of postconditioning. The results suggest that the signaling pathways differ between pre- and postconditioning. Mouse hearts were strongly protected by postconditioning, and genetically engineered mice may be useful for postconditioning research.

Increased expression of monocarboxylate transporter 1 after acute ischemia of isolated, perfused mouse hearts

AIMS Lactate is transported by stereo-specific, pH-dependent monocarboxylate transporters (MCTs), of which MCT1 is expressed in abundance in rodent and human hearts. This study investigated the expression and functional role of MCT1 in mouse hearts during acute myocardial ischemia. MAIN METHODS Mice hearts were isolated and Langendorff-perfused with induced global ischemia (40 min) and reperfusion with function and infarct size as end-points. Hearts were collected serially for protein extraction and immunoblotting with an MCT1 antibody, and for determining subcellular localization with immunogold EM. Immortalized cardiomyocytes (HL-1 cells) were injured with hydrogen peroxide, and cell death in the presence or absence of the competitive inhibitor of MCT1, d-lactate, was evaluated by Trypan blue exclusion. KEY FINDINGS MCT1 expression increased after 15 min reperfusion (p<0.05), but was not significantly increased after 60 min. MCT1 was localized in mitochondria, plasma membrane, and intercalated disks. At 15 min reperfusion, gold particle count was increased in the intercalated disks (p<0.05). d-lactate administration to isolated hearts either for 5 min before ischemia or at the first 5 min of reperfusion increased infarct size (p<0.01). A significant impairment of left ventricular performance was found when d-lactate was given before ischemia. MCT1 expression was not influenced by d-lactate. When HL-1 cells were treated with d-lactate before injury was induced with hydrogen peroxide, cell death was increased (p<0.05). SIGNIFICANCE Inhibition of MCT1 increases cell death. Increased MCT1 expression after ischemia and reperfusion is likely to restore cardiac pH through lactate export.

Long-term Change in the Risk of Skin Cancer After Organ Transplantation: A Population-Based Nationwide Cohort Study

Importance The high risk of skin cancer after organ transplantation is a major clinical challenge and well documented, but reports on temporal trends in the risk of posttransplant cutaneous squamous cell carcinoma (SCC) are few and appear contradictory. Objective To study temporal trends for the risk of skin cancer, particularly SCC, after organ transplantation. Design, Setting, and Participants Population-based, nationwide, prospective cohort study of 8026 patients receiving a kidney, heart, lung, or liver transplant in Norway from 1968 through 2012 using patient data linked to a national cancer registry. The study was conducted in a large organ transplantation center that serves the entire Norwegian population of approximately 5.2 million. Exposures Receiving a solid organ transplant owing to late-stage organ failure, followed by long-term immunosuppressive treatment according to graft-specific treatment protocols. Main Outcomes and Measures Occurrence of first posttransplant SCC, melanoma, or Kaposi sarcoma of the skin. Risk of skin cancer was analyzed using standardized incidence ratios (SIRs) and, for SCC, multivariable Poisson regression analysis of SIR ratios, adjusting for 5-year time period of transplantation, different follow-up time, age, sex, and type of organ. Results The study cohort included 8026 organ transplant recipients, 5224 men (65.1%), with a mean age at transplantation of 48.5 years. Median follow-up time was 6.7 years per recipient; total follow-up time, 69 590 person-years. The overall SIRs for SCC, melanoma, and Kaposi sarcoma were 51.9 (95% CI, 48.4-55.5), 2.4 (95% CI, 1.9-3.0), and 54.9 (95% CI, 27.4-98.2), respectively. In those who underwent transplantation in the 1983-1987 period, the unadjusted SIR for SCC was 102.7 (95%, 85.8-122.1), declining to 21.6 (95% CI, 16.8-27.0) in those who underwent transplantation in the 2003-2007 period. Adjusting for different follow-up times and background population risks, as well as age, graft organ, and sex, a decline in the SIR for SCC was found, with SIR peaking in patients who underwent transplantation in the 1983-1987 period and later declining to less than half in patients who underwent transplantation in the 1998-2002, 2003-2007, and 2008-2012 periods, with the relative SIRs being 0.42 (95% CI, 0.32-0.55), 0.31 (95% CI, 0.22-0.42), and 0.44 (95% CI, 0.30-0.66), respectively. Conclusions and Relevance The risk of SCC after organ transplantation has declined significantly since the mid-1980s in Norway. Less aggressive and more individualized immunosuppressive treatment and close clinical follow-up may explain the decline. Still, the risk of SCC in organ transplant recipients remains much higher than in the general population and should be of continuous concern for dermatologists, transplant physicians, and patients.

Vitamin D in Norwegian renal transplant recipients: A longitudinal study with repeated measurements in winter and summer

BackgroundOrgan transplant recipients (OTR) have an increased risk of non-melanoma skin cancer (NMSC) and are advised to avoid direct sunlight. OTR living in the Nordic countries are especially vulnerable to hypovitaminosis D as vitamin D production in the skin is restricted to the summer months.ObjectivesTo investigate constitutional and external factors predicting hypovitaminosis and seasonal variation of vitamin D in renal transplant recipients (RTR) living in the vicinity of Oslo (59° N).MethodsNinety-four RTR were included. Interviews covering dietary intake of vitamin D and sun exposure were performed and blood samples were collected in February and August 2013.ResultsMean age of patients was 56.8 years and mean graft age 14.5 years. The mean daily total vitamin D intake was 11.8 μg, and the prevalence of hypovitaminosis D (<75 nmol/L) was 67.0% in winter and 56.4% in summer. Sunscreen users had significantly higher 25(OH)D than nonusers (p = 0.03). Excluding patients having travelled to southern latitudes during the last three months before blood sampling, no statistical difference was found between winter and summer values of vitamin D (p = 0.60). Being male or having red/light blond hair colour increased vitamin D values significantly from winter to summer.ConclusionsHypovitaminosis D is relatively frequent in Norwegian RTR but not as frequent as earlier reported in studies of RTR from lower latitudes. Lack of seasonal variation in vitamin D may be explained by sun protective behaviour and high dietary intake of vitamin D among patients in this study.

High mortality due to cutaneous melanoma in Norway: a study of prognostic factors in a nationwide cancer registry

Purpose The purpose of this study was to examine why Norway has the highest rate of mortality due to cutaneous melanoma (CM) in Europe. The Norwegian Malignant Melanoma Registry (NMMR) enables the study of clinical and histopathological characteristics of patients who die due to CM. Results The NMMR and the Norwegian Cause of Death Registry provided data on the clinical and histopathological factors as well as the date and cause of death, through June 2015 for all first invasive CMs diagnosed in 2008–2012 (n=8087). Cox regression was used to estimate associations between clinical and pathological factors and CM-specific death. Multiple imputation was used to handle missing data. Results The CMs were equally distributed between men (49.9%) and women (50.1%), and the median follow-up was 4.0 years (range: 0.08–7.5 years). Trunk was the most common anatomic site (48%), superficial spreading melanoma was the dominant melanoma subtype (68.2%), median Breslow thickness was 1.0 mm, ulceration was present in 23% of CMs, and 91.8% of cases were in a local clinical stage at diagnosis. Compared to women, men were diagnosed at a higher age, with thicker and more-often-ulcerated tumor, and more often were in advanced clinical stages. During follow-up, 1015 patients died due to CM, representing 52.8% of all deaths. The nodular subtype made up the dominant proportion of fatal CM cases (55.3% in women, 64.6% in men). Sex, age, anatomic site (trunk), T-stage, ulceration, clinical stage, and having a second primary CM were associated with increased risk of CM-specific death. Conclusion Our data suggest that the high rate of mortality due to CM observed in Norway is attributable to the more advanced stage of the disease at diagnosis. Most high-risk cases occurred in male patients ≥70 years of age. Efforts to improve awareness and secondary prevention of CM, including warning signs of all melanoma subtypes, are required urgently and should be targeted toward men in particular.