Cause Of Death In Individuals Research Articles

Genetic association of Glutathione peroxidase-1 (GPx-1) and NAD(P)H:Quinone Oxidoreductase 1(NQO1) variants and their association of CAD in patients with type-2 diabetes

Coronary artery disease (CAD) is a major health concern and the leading cause of death in individuals with type-2 diabetes mellitus (T2DM). Glutathione peroxidase-1 (GPx-1) and NAD(P)H: quinone oxidoreductase (NQO1) are known for its broad range of detoxification. The role of functional variants of these genes in the development of various disorders is proven. Hereby, we investigated the possible role of these variants in the development of CAD in T2DM patients of South Indian population. In this case-control study, a total of 539 patients (T2DM = 241; T2DM-CAD = 298) and 285 controls were included. The C198T GPx-1 and C609T NQO1 single-nucleotide polymorphisms were analyzed by PCR-RFLP. Further, these genotypes were correlated with blood lipid profile. Regression analysis showed that GPx1-C/T genotype is associated with a 1.35-fold increase (95% CI = 1.000-1.824; P = 0.048) and GPx1-T/T genotype is associated with a 1.76-fold increase (95% CI = 1.011 to 3.066; P = 0.046) to the T2DM development. Increased odds ratio showed that NQO1-T/T genotype had a higher occurrence of CAD in diabetic patients with CAD (95% CI = 1.003-2.674, P = 0.049) than T2DM patients without CAD. The level of triglycerides alone showed significant increase for GPx-1-C/T and -T/T genotypes in Tukey's Post hoc analysis (177.1 ± 19.2 vs. 184 ± 23.5; P = 0.039 and 177.1 ± 19.2 vs. 190 ± 22.4; P = 0.006) among the patients with T2DM-CAD. Our work concludes that GPx-1 variants might contribute to the development of diabetes and both GPx-1 and NQO1 variants confirm the association of CAD in people with T2DM of South Indian population.

Pathophysiology and Therapy of Cardiac Dysfunction in Duchenne Muscular Dystrophy

Cardiac dysfunction is a frequent manifestation of Duchenne muscular dystrophy (DMD) and a common cause of death for individuals with this condition. Early diastolic dysfunction and focal fibrosis proceed to dilated cardiomyopathy (DCM), complicated by heart failure and arrhythmia in most patients. Improvements in the management of respiratory insufficiency in DMD have improved lifespan and overall prognosis, but heart failure and sudden death continue to impact survival and quality of life for people with DMD. Since the specific mechanisms resulting in heart failure for people with DMD are poorly understood, current treatments are not targeted, but rely on approaches that are considered standard for DCM. These approaches include angiotensin-converting enzyme (ACE) inhibitors and β-adrenoceptor antagonists. Data from one trial in DMD support the use of ACE inhibitors before the onset of left ventricular dysfunction. Angiotensin receptor blockers have shown similar efficacy to ACE inhibitors in numerous studies of dilated cardiomyopathy, and are a good choice for patients who cannot tolerate ACE inhibition. The pathogenesis of DMD-associated cardiomyopathy may be similar to other genetic disorders of the cytoskeletal complex of ventricular myocytes, though unique features offer targeted opportunities to impact treatment. Novel areas of investigation are focused on the regulatory role of dystrophin in relation to neuronal nitric oxide synthase (nNOS) and transient receptor potential canonical channels (TRPC). Inhibition of phosphodiesterase-5 (PDE5) addresses several aspects of regulatory dysfunction induced by dystrophin deficiency, and studies with PDE5-inhibitors have shown benefits in murine models of DMD. PDE5-inhibitors are currently under investigation in at least one study in humans. This article focuses on mechanisms of cardiac dysfunction, as well as potential targets for pharmacologic manipulation to prevent or improve cardiomyopathy in DMD.

Measuring NHS performance 1990–2009 using amenable mortality: interpret with care

The new performance framework for the NHS in England will assess how well health services are preventing people from dying prematurely, based on the concept of mortality amenable to healthcare. We ask how the different parts of the UK would be assessed had this measure been in use over the past two decades, a period that began with somewhat lower levels of health expenditure in England and Wales than in Scotland and Northern Ireland but which, after 1999, saw the gap closing. We assessed the change in age-standardized death rates in England and Wales, Northern Ireland and Scotland in two time periods: 1990-1999 and 1999-2009. Mortality data by five-year age group, sex and cause of death for the years 1990 to 2009 were analysed using age-standardized death rates from causes considered amenable to healthcare. The absolute change was assessed by fitting linear regression and the relative change was estimated as the average annual percent decline for the two periods. United Kingdom. Not applicable. Mortality from causes amenable to healthcare. Between 1990 and 1999 deaths amenable to medical care had been falling more slowly in England and Wales than in Scotland and Northern Ireland. However the rate of decline in England and Wales increased after 1999 when funding of the NHS there increased. Examination of individual causes of death reveals a complex picture, with some improvements, such as in breast cancer deaths, occurring simultaneously across the UK, reflecting changes in diagnosis and treatment that took place in each nation at the same time, while others varied. Amenable mortality is a useful indicator of health system performance but there are many methodological issues that must be taken into account when interpreting it once it is adopted for routine use in England.

Simplified Symptom Pattern Method for verbal autopsy analysis: multisite validation study using clinical diagnostic gold standards

BackgroundVerbal autopsy can be a useful tool for generating cause of death data in data-sparse regions around the world. The Symptom Pattern (SP) Method is one promising approach to analyzing verbal autopsy data, but it has not been tested rigorously with gold standard diagnostic criteria. We propose a simplified version of SP and evaluate its performance using verbal autopsy data with accompanying true cause of death.MethodsWe investigated specific parameters in SP's Bayesian framework that allow for its optimal performance in both assigning individual cause of death and in determining cause-specific mortality fractions. We evaluated these outcomes of the method separately for adult, child, and neonatal verbal autopsies in 500 different population constructs of verbal autopsy data to analyze its ability in various settings.ResultsWe determined that a modified, simpler version of Symptom Pattern (termed Simplified Symptom Pattern, or SSP) performs better than the previously-developed approach. Across 500 samples of verbal autopsy testing data, SSP achieves a median cause-specific mortality fraction accuracy of 0.710 for adults, 0.739 for children, and 0.751 for neonates. In individual cause of death assignment in the same testing environment, SSP achieves 45.8% chance-corrected concordance for adults, 51.5% for children, and 32.5% for neonates.ConclusionsThe Simplified Symptom Pattern Method for verbal autopsy can yield reliable and reasonably accurate results for both individual cause of death assignment and for determining cause-specific mortality fractions. The method demonstrates that verbal autopsies coupled with SSP can be a useful tool for analyzing mortality patterns and determining individual cause of death from verbal autopsy data.

Performance of the Tariff Method: validation of a simple additive algorithm for analysis of verbal autopsies

BackgroundVerbal autopsies provide valuable information for studying mortality patterns in populations that lack reliable vital registration data. Methods for transforming verbal autopsy results into meaningful information for health workers and policymakers, however, are often costly or complicated to use. We present a simple additive algorithm, the Tariff Method (termed Tariff), which can be used for assigning individual cause of death and for determining cause-specific mortality fractions (CSMFs) from verbal autopsy data.MethodsTariff calculates a score, or "tariff," for each cause, for each sign/symptom, across a pool of validated verbal autopsy data. The tariffs are summed for a given response pattern in a verbal autopsy, and this sum (score) provides the basis for predicting the cause of death in a dataset. We implemented this algorithm and evaluated the method's predictive ability, both in terms of chance-corrected concordance at the individual cause assignment level and in terms of CSMF accuracy at the population level. The analysis was conducted separately for adult, child, and neonatal verbal autopsies across 500 pairs of train-test validation verbal autopsy data.ResultsTariff is capable of outperforming physician-certified verbal autopsy in most cases. In terms of chance-corrected concordance, the method achieves 44.5% in adults, 39% in children, and 23.9% in neonates. CSMF accuracy was 0.745 in adults, 0.709 in children, and 0.679 in neonates.ConclusionsVerbal autopsies can be an efficient means of obtaining cause of death data, and Tariff provides an intuitive, reliable method for generating individual cause assignment and CSMFs. The method is transparent and flexible and can be readily implemented by users without training in statistics or computer science.

Absence of IFN-γ accelerates thrombus resolution through enhanced MMP-9 and VEGF expression in mice

Deep vein thrombosis (DVT) is a major cause of pulmonary thromboembolism, a leading cause of death in individuals with DVT. Several lines of evidence indicate proinflammatory cytokines such as TNF-α are involved in thrombus formation and resolution, but the roles of IFN-γ remain unclear. To address this issue, we performed ligation of the inferior vena cava to induce DVT in WT and IFN-γ-deficient (Ifng-/-) mice. In WT mice, intrathrombotic IFN-γ levels were elevated progressively as the postligation interval was extended. Thrombus size was substantially smaller at 10 and 14 days in Ifng-/- mice than in WT mice. Intrathrombotic collagen content was remarkably reduced at more than 10 days after the ligation in Ifng-/- mice compared with WT mice. The expression and activity of MMP-9, but not MMP-2, was higher at the late phase in Ifng-/- mice than in WT mice. Moreover, intrathrombotic recanalization was increased in Ifng-/- mice, with enhanced Vegf gene expression, compared with that in WT mice. Activation of the IFN-γ/Stat1 signal pathway suppressed PMA-induced Mmp9 and Vegf gene expression in peritoneal macrophages. Furthermore, administration of anti-IFN-γ mAbs accelerated thrombus resolution in WT mice. Collectively, these findings indicate that IFN-γ can have detrimental roles in thrombus resolution and may be a good molecular target for the acceleration of thrombus resolution in individuals with DVT.

Peripheral Tissue Trauma Triggers an Inflammatory Response Causing Intestinal Microvascular Serum Leak Which Disrupts Gastrointestinal Motility

Introduction: Combat and civilian trauma is the leading cause of death for individuals in the prime of their life. Gastrointestinal dysfunction plays a key role in the detrimental sequelae of trauma (systemic inflammatory response, feeding intolerance, reflux/aspiration pneumonia and bacterial overgrowth/dissemination through mucosal barrier failure), but the mechanisms through which peripheral tissue injury can induce these responses is unclear. Aims: To investigate the mechanism of trauma-induced gastrointestinal dysfunction in a precisely controllable non-narcotic, tissue-bone matrix (TBX) trauma model, which is known to reproducibly display significant gastrointestinal dysmotility. Methods: A non-narcotic murine tissue trauma model was constructed by the dorsal subcutaneous implantation of minced donor syngeneic tissue-bone matrix (TBX) precisely adjusted to 17.5% body weight and studied after 21 hrs. Inflammatory mediators in serum, fresh TBX and TBX wound fluid at 21hrs were measured by electrochemiluminescence detection and intestinal muscularis microvascular leak was microscopically quantified in whole-mounts after i.v. injection of FITC-dextran (70k MW). Gastrointestinal transit and jejunal circular muscle contractility was assessed after injection of normal mouse serum (i.p. 100μl q1h x 8). Results: Compared to normal serum, TNF α was only acutely elevated in fresh TBX fluid (1.1±0.01, 4.1±0.22 and 1.1±0.01 ng/ml) and IL 1β exhibited increased levels in both fresh TBX fluid and in TBX wound fluid (1.9±0.22, 107.6±1.45 and 92.2±6.12 ng/ml). Whereas, IL-6 (80.4±10.0, 158.5±4.08 and 26851.1±4883.39 ng/ml) and kerotinocyte chemokine (KC; 237.5±47.14, 110.4±1.59 and 9763.2±817.29 ng/ml) were significantly increased in the re-harvested TBX wound fluid after 21 hours of implantation. The systemic response to the implanted TBX resulted in significant serum elevations in IL-6, KC and IL-10 compared to control and sham surgical groups at 21 hrs (N=6 each), as well as causing significant intestinal muscularis microvascular leak. Interestingly, i.p. injections of normal serum into naive mice recapitulated the TBX-induced dysmotility causing delayed gastrointestinal transit (9.8±0.15 vs. 3.4±0.22) and a 49.5% suppression in bethanechol stimulated jejunal muscle strip contractility compared to saline injections (N=6). Conclusion: Peripheral tissue injury and consequent systemic inflammatory response cause intestinal muscularis microvascular leak and dysmotility, which can be recapitulated by intraperitoneal injection of exogenous normal serum. These novel findings demonstrate the key regulatory effect of intestinalmicrovascular leak on gastrointestinal motility in trauma.

Long term risk of infections in Hodgkin lymphoma long‐term survivors

Background Long-term side effects associated with the treatment of Hodgkin’s lymphoma (HL) have frequently been reported during the last decades. Studies have shown increased mortality in HL survivors. Following Hodgkin’s lymphoma, second malignancies (SM) and cardiovascular disease (CVD) are the most common causes of death in individuals treated for HL. This study investigates the incidence of side effects such as SM, CVD and infections in a cohort diagnosed with HL in Sweden between 1965 and 1995. In addition, this study identifies covariate risk factors for late side effects in order to develop strategies that prevent morbidity and mortality in HL survivors. Methods Using the Swedish Cancer Registry (SCR) at the National Board of Health and Welfare and the Multi-Generation Registry at Statistics (MGR) Sweden, we identified 6946 individuals diagnosed with HL between the years 1965 and 1995, and their first degree relatives (FDR) (n=17 858). In addition we identified the malignancies and inpatient care for CVD and infections for the HL cohort and their FDR. The standard incidence ratio (SIR) was calculated for the risk of SM, CVD and infections. For SM and CVD the risk also was stratified and calculated for family history of disease. The Swedish Hodgkin Intervention and Prevention study (SHIP), a prospective study, invited 702 individuals treated for HL at the age of 45 years or younger and who were treated in the region of Skane, Uppsala or Umea. The participants completed a questionnaire and were invited to an out-patient visit to an oncologist with clinical examination and blood tests. Any pathological findings were referred for further investigation. Results An increased risk for SM in HL long-term survivors was observed and seems to increase with the number of FDRs with cancer. There was also an increased risk for inpatient care due to congestive heart failure (CHF) and coronary artery disease (CAD). A family history of CHF and CAD further increased the risk for these diseases. The risk for inpatient care due to infections was increased and remained increased after 20 years or longer. The risk for infections was associated with splenectomy and hypothyroidism. Radiotherapy was an independent risk factor for cardiovascular disease in the cohort of the prospective study. ConclusionLong-term survivors from HL have an increased risk for developing late side effects such as SM, CVD and infections. Since many HL patients are young and the cure rate from the disease is high, it is of great importance to offer focused surveillance programs to selected individuals who are at high risk, e.g. individuals who received radiotherapy as part of their treatment and who have other known risk factors for cardiovascular disease such as hypertension, hypercholesterolemia, family history and smoking.

Atrial fibrilation in a tetraplegic paralympic athlete

BackgroundIndividuals with Spinal Cord Injury (SCI) experience various types of cardiovascular dysregulation depending on the level of their cord lesion. The recognition and management of cardiovascular dysfunction following SCI represent...

Flexible modeling of the effects of continuous prognostic factors in relative survival

Relative survival methods permit separating the effects of prognostic factors on disease-related 'excess mortality' from their effects on other-causes 'natural mortality', even when individual causes of death are unknown. As in conventional 'crude' survival, accurate assessment of prognostic factors requires testing and possibly modeling of non-proportional effects and, for continuous covariates, of non-linear relationships with the hazard. We propose a flexible extension of the additive-hazards relative survival model, in which the observed all-causes mortality hazard is represented by a sum of disease-related 'excess' and natural mortality hazards. In our flexible model, the three functions representing (i) the baseline hazard for 'excess' mortality, (ii) the time-dependent effects, and (iii) for continuous covariates, non-linear effects, on the logarithm of this hazard, are all modeled by low-dimension cubic regression splines. Non-parametric likelihood ratio tests are proposed to test the time-dependent and non-linear effects. The accuracy of the estimated functions is evaluated in multivariable simulations. To illustrate the new insights offered by the proposed model, we apply it to re-assess the effects of patient age and of secular trends on disease-related mortality in colon cancer.

Suicide rate: Trends and implications in Upper Egypt

Suicide is an important problem, ranking among the top 10 causes of death for individuals in all ages in developed countries. The present study is a retrospective study evaluating suicide cases in Assiut, one of the largest province in Egypt from 2005 to 2009. There were 117 cases of which involved 68 male victims (58.11%) and involved 49 females (48.11%). Suicide rates ranged from (0.6 to 0.8 per 100,000). Age predominance was 20–⩽30years. The method of suicide was different between male and female victims, as male victims tried to use more violent methods than females. Conclusion: the present study showed that suicide rates have increased since 1987, indicating a grave problem that needs to be solved.

Verbal autopsy interpretation: a comparative analysis of the InterVA model versus physician review in determining causes of death in the Nairobi DSS

BackgroundDeveloping countries generally lack complete vital registration systems that can produce cause of death information for health planning in their populations. As an alternative, verbal autopsy (VA) - the process of interviewing family members or caregivers on the circumstances leading to death - is often used by Demographic Surveillance Systems to generate cause of death data. Physician review (PR) is the most common method of interpreting VA, but this method is a time- and resource-intensive process and is liable to produce inconsistent results. The aim of this paper is to explore how a computer-based probabilistic model, InterVA, performs in comparison with PR in interpreting VA data in the Nairobi Urban Health and Demographic Surveillance System (NUHDSS).MethodsBetween August 2002 and December 2008, a total of 1,823 VA interviews were reviewed by physicians in the NUHDSS. Data on these interviews were entered into the InterVA model for interpretation. Cause-specific mortality fractions were then derived from the cause of death data generated by the physicians and by the model. We then estimated the level of agreement between both methods using Kappa statistics.ResultsThe level of agreement between individual causes of death assigned by both methods was only 35% (κ = 0.27, 95% CI: 0.25 - 0.30). However, the patterns of mortality as determined by both methods showed a high burden of infectious diseases, including HIV/AIDS, tuberculosis, and pneumonia, in the study population. These mortality patterns are consistent with existing knowledge on the burden of disease in underdeveloped communities in Africa.ConclusionsThe InterVA model showed promising results as a community-level tool for generating cause of death data from VAs. We recommend further refinement to the model, its adaptation to suit local contexts, and its continued validation with more extensive data from different settings.

Access to farming pesticides and risk for suicide in Chinese rural young people

Suicide is a leading cause of death in individuals 15–34 years of age in China. Highly lethal pesticides are a common method used for suicide in Chinese rural areas. This case-control study aimed to test hypotheses concerning the suicide risks associated with pesticide access. Subjects included 370 rural completed suicides aged 15–34 years and 370 living controls matched on age, gender and residence (rural/urban location). Data were collected by a psychological autopsy design with proxy respondents. Pesticide access was a significant risk factor for suicide even after controlling for other known risk factors in social and psychiatric domains, such as education level, living situation, marital status, family annual income and mental disorder. Increased risk was accounted for by access to insecticide rather than other types of pesticides. Suicide intervention in China should focus on restricting access to pesticides, especially highly toxic insecticide, improving the resuscitation skills of rural primary-care health providers, promoting psychological and social support networks in rural areas and educating the general public about the suicide risk of having pesticides stored at the households.

HER2-mediated upregulation of MMP-1 is involved in gastric cancer cell invasion

HER2 overexpression is associated with metastasis—the main cause of death in individuals with gastric cancer. In this study, we demonstrated that vector-based shRNA significantly knocked down the expression of HER2 and considerably inhibited both the migration and invasion of gastric cancer cells. HER2 knockdown resulted in the downregulation of the expression of MMP-1, while HER2 overexpression improved the transcription of MMP-1 through the activation of an MMP-1 promoter. The promoter region of MMP-1 between −2500 and −2000 bp was found to be crucial for the upregulation of HER2-mediated transcription. Furthermore, a truncated promoter (−70 to + 63) did not display any transcriptional activity. Cell invasion activity was almost completely inhibited when MMP-1 was knocked down. Conversely, the overexpression of MMP-1 partly rescued the invasion ability of cell strains with knocked-down HER2. These findings help further understanding of the molecular mechanisms through which HER2 promotes malignancy, and suggest that targeting both HER2 and MMP-1 may be required to effectively block HER2 signaling in gastric cancer therapy.

Diabetes, Insulin Use, and Cancer Risk: Are Observational Studies Part of the Solution–or Part of the Problem?

Cancer has overtaken cardiovascular disease as the leading cause of death in individuals under the age of 65 in the general population, but it is still overshadowed by cardiovascular disease in those with diabetes. People with type 2 diabetes are nonetheless more likely to develop cancer—and to die from it—than members of the general population, so cancer should be numbered among the complications of diabetes (1). Furthermore, the number of cancer victims with diabetes will inevitably rise in proportion to our success in combating vascular disease in the diabetic population. How can the increased cancer risk in diabetes be explained? To begin with, it should be noted that obesity, insulin resistance, and/or increased levels of IGF-1 and insulin are strongly associated with most (but not all) of the diabetes-related cancers in the nondiabetic population (1). This suggests that hyperglycemia does not play an essential role in the pathogenesis of these tumors, but does not exclude the possibility that it might have secondary effects such as enhanced tumor growth or resistance to anti-tumor therapy. IGF-1 and insulin offer a more plausible mechanistic explanation for the overlapping risk of cancer in the nondiabetic and diabetic populations. Both hormones are mitogenic (but not mutagenic), both are present at high levels in insulin-resistant states, and their receptors are overexpressed on the surface of cancer cells associated with diabetes. They thus have the potential to act as tumor growth factors in vivo as well as in vitro (2,3). On this argument, which we will refer to as the insulin supply hypothesis, drugs used to treat diabetes might influence the risk of cancer by modulating the insulin/IGF axis (1). There is, however, a possible alternative explanation for the increased risk of cancer in diabetes, which we refer to as the glucose supply hypothesis. …

Ancestry and Pathology in King Tutankhamun's Family

The New Kingdom in ancient Egypt, comprising the 18th, 19th, and 20th dynasties, spanned the mid-16th to the early 11th centuries bc. The late 18th dynasty, which included the reigns of pharaohs Akhenaten and Tutankhamun, was an extraordinary time. The identification of a number of royal mummies from this era, the exact relationships between some members of the royal family, and possible illnesses and causes of death have been matters of debate. To introduce a new approach to molecular and medical Egyptology, to determine familial relationships among 11 royal mummies of the New Kingdom, and to search for pathological features attributable to possible murder, consanguinity, inherited disorders, and infectious diseases. From September 2007 to October 2009, royal mummies underwent detailed anthropological, radiological, and genetic studies as part of the King Tutankhamun Family Project. Mummies distinct from Tutankhamun's immediate lineage served as the genetic and morphological reference. To authenticate DNA results, analytical steps were repeated and independently replicated in a second ancient DNA laboratory staffed by a separate group of personnel. Eleven royal mummies dating from circa 1410-1324 bc and suspected of being kindred of Tutankhamun and 5 royal mummies dating to an earlier period, circa 1550-1479 bc, were examined. Microsatellite-based haplotypes in the mummies, generational segregation of alleles within possible pedigree variants, and correlation of identified diseases with individual age, archeological evidence, and the written historical record. Genetic fingerprinting allowed the construction of a 5-generation pedigree of Tutankhamun's immediate lineage. The KV55 mummy and KV35YL were identified as the parents of Tutankhamun. No signs of gynecomastia and craniosynostoses (eg, Antley-Bixler syndrome) or Marfan syndrome were found, but an accumulation of malformations in Tutankhamun's family was evident. Several pathologies including Köhler disease II were diagnosed in Tutankhamun; none alone would have caused death. Genetic testing for STEVOR, AMA1, or MSP1 genes specific for Plasmodium falciparum revealed indications of malaria tropica in 4 mummies, including Tutankhamun's. These results suggest avascular bone necrosis in conjunction with the malarial infection as the most likely cause of death in Tutankhamun. Walking impairment and malarial disease sustained by Tutankhamun is supported by the discovery of canes and an afterlife pharmacy in his tomb. Using a multidisciplinary scientific approach, we showed the feasibility of gathering data on Pharaonic kinship and diseases and speculated about individual causes of death.

Calcium and diabetic vascular dysfunction. Focus on “Elevated Ca2+ sparklet activity during acute hyperglycemia and diabetes in cerebral arterial smooth muscle cells”

DIABETES MELLITUS (DM) is characterized by hyperglycemia associated with either reduced insulin secretion (type I DM) or reduced target-cell insulin sensitivity (type II DM). The incidence of type II diabetes has risen sharply in Western countries in recent years—particularly in children and teenagers—as a result of lifestyle choices that promote obesity. Vascular dysfunction is a key phenotype of diabetes, and the resulting cardiovascular disease is the primary cause of death in individuals with diabetes (2, 9). Vascular dysfunction is responsible not only for increased risk of stroke and heart attack, but also for diabetic end-organ damage, including retinopathy, nephropathy, and neuropathy. Since vascular cells are the first to encounter the elevated levels of plasma glucose in diabetes, it follows that the vasculature is particularly vulnerable to diabetic injury. Hyperglycemia is associated with atherosclerosis, vascular calcification, and increased vascular tone in a variety of vas

PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1

Cardiac complications are a common cause of death in individuals with the inherited multisystemic disease myotonic dystrophy type 1 (DM1). A characteristic molecular feature of DM1 is misregulated alternative splicing due to disrupted functioning of the splicing regulators muscleblind-like 1 (MBNL1) and CUG-binding protein 1 (CUGBP1). CUGBP1 is upregulated in DM1 due to PKC pathway activation and subsequent CUGBP1 protein hyperphosphorylation and stabilization. Here, we blocked PKC activity in a heart-specific DM1 mouse model to determine its pathogenic role in DM1. Animals given PKC inhibitors exhibited substantially increased survival that correlated with reduced phosphorylation and decreased steady-state levels of CUGBP1. Functional studies demonstrated that PKC inhibition ameliorated the cardiac conduction defects and contraction abnormalities found in this mouse model. The inhibitor also reduced misregulation of splicing events regulated by CUGBP1 but not those regulated by MBNL1, suggesting distinct roles for these proteins in DM1 cardiac pathogenesis. The PKC inhibitor did not reduce mortality in transgenic mice with heart-specific CUGBP1 upregulation, indicating that PKC inhibition did not have a general protective effect on PKC-independent CUGBP1 increase. Our results suggest that pharmacological blockade of PKC activity mitigates the DM1 cardiac phenotype and provide strong evidence for a role for the PKC pathway in DM1 pathogenesis.

Overview of Managing Medical Comorbidities in Patients With Severe Mental Illness

Patients with severe mental disorders have increased mortality rates compared with the general population. The leading cause of death for individuals with psychotic illnesses or bipolar disorder is cardiovascular disease (CVD), which is often the result of patients' health problems associated with their psychiatric disorders, including, but not limited to, obesity, metabolic syndrome, and diabetes. Such problems occur more often and have worse outcomes in patients with serious mental illness than the general population because of a combination of factors such as inadequate access to quality care, poor lifestyle choices, and the association between some antipsychotic medications and weight gain. Coordinated somatic and psychiatric treatment, weight-neutral or weight-reducing pharmaceuticals, and behavioral weight management programs may help lessen the burden of CVD in the mental health population.

Assessing the repeatability of verbal autopsy for determining cause of death: two case studies among women of reproductive age in Burkina Faso and Indonesia

BackgroundVerbal autopsy (VA) is an established tool for assessing cause-specific mortality patterns in communities where deaths are not routinely medically certified, and is an important source of data on deaths among the poorer half of the world's population. However, the repeatability of the VA process has never been investigated, even though it is an important factor in its overall validity. This study analyses repeatability in terms of the overall VA process (from interview to cause-specific mortality fractions (CSMF)), as well as specifically for interview material and individual causes of death, using data from Burkina Faso and Indonesia.MethodsTwo series of repeated VA interviews relating to women of reproductive age in Burkina Faso (n = 91) and Indonesia (n = 116) were analysed for repeatability in terms of interview material, individual causes of death and CSMFs. All the VA data were interpreted using the InterVA-M model, which provides 100% intrinsic repeatability for interpretation, and thus eliminated the need to consider variations or repeatability in physician coding.ResultsThe repeatability of the overall VA process from interview to CSMFs was good in both countries. Repeatability was moderate in the interview material, and lower in terms of individual causes of death. Burkinabé data were less repeatable than Indonesian, and repeatability also declined with longer recall periods between the death and interview, particularly after two years.ConclusionWhile these analyses do not address the validity of the VA process in absolute terms, repeatability is a prerequisite for intrinsic validity. This study thus adds new understanding to the quest for reliable cause of death assessment in communities lacking routine medical certification of deaths, and confirms the status of VA as an important and reliable tool at the community level, but perhaps less so at the individual level.