Showing papers in "Journal of Internal Medicine in 2013"

Review of the key results from the Swedish Obese Subjects (SOS) trial – a prospective controlled intervention study of bariatric surgery

Abstract: Obesity is a risk factor for diabetes, cardiovascular disease events, cancer and overall mortality. Weight loss may protect against these conditions, but robust evidence for this has been lacking. The Swedish Obese Subjects (SOS) study is the first long-term, prospective, controlled trial to provide information on the effects of bariatric surgery on the incidence of these objective endpoints. The SOS study involved 2010 obese subjects who underwent bariatric surgery [gastric bypass (13%), banding (19%) and vertical banded gastroplasty (68%)] and 2037 contemporaneously matched obese control subjects receiving usual care. The age of participants was 37-60 years and body mass index (BMI) was ≥34 kg m(-2) in men and ≥38 kg m(-2) in women. Here, we review the key SOS study results published between 2004 and 2012. Follow-up periods varied from 10 to 20 years in different reports. The mean changes in body weight after 2, 10, 15 and 20 years were -23%, -17%, -16% and -18% in the surgery group and 0%, 1%, -1% and -1% in the control group respectively. Compared with usual care, bariatric surgery was associated with a long-term reduction in overall mortality (primary endpoint) [adjusted hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.54-0.92; P = 0.01] and decreased incidences of diabetes (adjusted HR=0.17; P < 0.001), myocardial infarction (adjusted HR = 0.71; P = 0.02), stroke (adjusted HR=0.66; P = 0.008) and cancer (women: adjusted HR = 0.58; P = 0.0008; men: n.s.]. The diabetes remission rate was increased severalfold at 2 years [adjusted odds ratio (OR) = 8.42; P < 0.001] and 10 years (adjusted OR = 3.45; P < 0.001). Whereas high insulin and/or high glucose at baseline predicted favourable treatment effects, high baseline BMI did not, indicating that current selection criteria for bariatric surgery need to be revised.

VEGFA and tumour angiogenesis.

Abstract: In this review we summarize the current understanding of signal transduction downstream of vascular endothelial growth factor A (VEGFA) and its receptor VEGFR2, and the relationship between these signal transduction pathways and the hallmark responses of VEGFA, angiogenesis and vascular permeability. These physiological responses involve a number of effectors, including extracellular signal-regulated kinases (ERKs), Src, phosphoinositide 3 kinase (PI3K)/Akt, focal adhesion kinase (FAK), Rho family GTPases, endothelial NO and p38 mitogen-activated protein kinase (MAPK). Several of these factors are involved in the regulation of both angiogenesis and vascular permeability. Tumour angiogenesis primarily relies on VEGFA-driven responses, which to a large extent result in a dysfunctional vasculature. The reason for this remains unclear, although it appears that certain aspects of the VEGFA-stimulated angiogenic milieu (high level of microvascular density and permeability) promote tumour expansion. The high degree of redundancy and complexity of VEGFA-driven tumour angiogenesis may explain why tumours commonly develop resistance to anti-angiogenic therapy targeting VEGFA signal transduction.

Breast cancer as a systemic disease: a view of metastasis

Abstract: Breast cancer is now the most frequently diagnosed cancer and leading cause of cancer death in women worldwide. Strategies targeting the primary tumour have markedly improved, but systemic treatments to prevent metastasis are less effective; metastatic disease remains the underlying cause of death in the majority of patients with breast cancer who succumb to their disease. The long latency period between initial treatment and eventual recurrence in some patients suggests that a tumour may both alter and respond to the host systemic environment to facilitate and sustain disease progression. Results from studies in animal models suggest that specific subtypes of breast cancer may direct metastasis through recruitment and activation of haematopoietic cells. In this review, we focus on data implicating breast cancer as a systemic disease.

Lipoprotein(a): resurrected by genetics.

Abstract: Plasma lipoprotein(a) [Lp(a)] is a quantitative genetic trait with a very broad and skewed distribution, which is largely controlled by genetic variants at the LPA locus on chromosome 6q27. Based on genetic evidence provided by studies conducted over the last two decades, Lp(a) is currently considered to be the strongest genetic risk factor for coronary heart disease (CHD). The copy number variation of kringle IV in the LPA gene has been strongly associated with both Lp(a) levels in plasma and risk of CHD, thereby fulfilling the main criterion for causality in a Mendelian randomization approach. Alleles with a low kringle IV copy number that together have a population frequency of 25–35% are associated with a doubling of the relative risk for outcomes, which is exceptional in the field of complex genetic phenotypes. The recently identified binding of oxidized phospholipids to Lp(a) is considered as one of the possible mechanisms that may explain the pathogenicity of Lp(a). Drugs that have been shown to lower Lp(a) have pleiotropic effects on other CHD risk factors, and an improvement of cardiovascular endpoints is up to now lacking. However, it has been established in a proof of principle study that lowering of very high Lp(a) by apheresis in high-risk patients with already maximally reduced low-density lipoprotein cholesterol levels can dramatically reduce major coronary events.

miR‐223: infection, inflammation and cancer

Abstract: Expression of the microRNA miR-223 is deregulated during influenza or hepatitis B infection and in inflammatory bowel disease, type 2 diabetes, leukaemia and lymphoma. Although this may also be the result of the disease per se, increasing evidence suggests a role for miR-223 in limiting inflammation to prevent collateral damage during infection and in preventing oncogenic myeloid transformation. Validated targets for miR-223 that have effects on inflammation and infection include granzyme B, IKKα, Roquin and STAT3. With regard to cancer, validated targets include C/EBPβ, E2F1, FOXO1 and NFI-A. The effect of miR-223 on these targets has been documented individually; however, it is more likely that miR-223 affects multiple targets simultaneously for key processes where the microRNA is important. Such processes include haematopoietic cell differentiation, particularly towards the granulocyte lineage (where miR-223 is abundant) and as cells progress down the myeloid lineage (where miR-223 expression decreases). NF-κB and the NLRP3 inflammasome are important inflammatory mechanisms that are dampened by miR-223 in these cell types. The miRNA can also directly target viruses such as HIV, leading to synergistic effects during infection. Here we review the recent studies of miR-223 function to show how it modulates inflammation, infection and cancer development.

Electronic health records: new opportunities for clinical research

Abstract: Clinical research is on the threshold of a new era in which electronic health records (EHRs) are gaining an important novel supporting role. Whilst EHRs used for routine clinical care have some limitations at present, as discussed in this review, new improved systems and emerging research infrastructures are being developed to ensure that EHRs can be used for secondary purposes such as clinical research, including the design and execution of clinical trials for new medicines. EHR systems should be able to exchange information through the use of recently published international standards for their interoperability and clinically validated information structures (such as archetypes and international health terminologies), to ensure consistent and more complete recording and sharing of data for various patient groups. Such systems will counteract the obstacles of differing clinical languages and styles of documentation as well as the recognized incompleteness of routine records. Here, we discuss some of the legal and ethical concerns of clinical research data reuse and technical security measures that can enable such research while protecting privacy. In the emerging research landscape, cooperation infrastructures are being built where research projects can utilize the availability of patient data from federated EHR systems from many different sites, as well as in international multilingual settings. Amongst several initiatives described, the EHR4CR project offers a promising method for clinical research. One of the first achievements of this project was the development of a protocol feasibility prototype which is used for finding patients eligible for clinical trials from multiple sources.

The role of mitochondrial DNA mutations and free radicals in disease and ageing

Abstract: Considerable efforts have been made to understand the role of oxidative stress in age-related diseases and ageing. The mitochondrial free radical theory of ageing, which proposes that damage to mitochondrial DNA (mtDNA) and other macromolecules caused by the production of reactive oxygen species (ROS) during cellular respiration drives ageing, has for a long time been the central hypothesis in the field. However, in contrast with this theory, evidence from an increasing number of experimental studies has suggested that mtDNA mutations may be generated by replication errors rather than by accumulated oxidative damage. Furthermore, interventions to modulate ROS levels in humans and animal models have not produced consistent results in terms of delaying disease progression and extending lifespan. A number of recent experimental findings strongly question the mitochondrial free radical theory of ageing, leading to the emergence of new theories of how age-associated mitochondrial dysfunction may lead to ageing. These new hypotheses are mainly based on the underlying notion that, despite their deleterious role, ROS are essential signalling molecules that mediate stress responses in general and the stress response to age-dependent damage in particular. This novel view of ROS roles has a clear impact on the interpretation of studies in which antioxidants have been used to treat human age-related diseases commonly linked to oxidative stress.

Atrial fibrillation prevalence revisited.

Abstract: Background The estimate of 0.4–1.0% prevalence of atrial fibrillation in the most recent American guidelines is based mainly on studies including patients with permanent atrial fibrillation (AF), although recent evidence shows that the stroke risk is similar with paroxysmal and persistent AF. Our objective was to determine the prevalence of AF in Sweden, irrespective of type and to what extent patients with AF receive adequate stroke prophylaxis. Method Retrospective study of patients with a clinical diagnosis of atrial fibrillation between 2005 and 2010 in the national Swedish Patient Register matched with data from the National Prescribed Drugs Register. Results We identified 307 476 individuals with a diagnosis of atrial fibrillation. Of these, 209 141 were still alive on the last day of the inclusion period, signifying a prevalence of clinically diagnosed AF in Sweden of 2.9% of the total adult (≥20 years) population. Only 42% of them had purchased an oral anticoagulant within 6 months of the first presentation with AF during the study period. Those at the highest risk of stroke were those least likely to receive anticoagulant treatment. Undertreatment was common amongst women and individuals >80 years, whilst overtreatment was common amongst young men without risk factors. Conclusion The prevalence of atrial fibrillation is at least 2.9% of the Swedish adult population, not counting ‘silent atrial fibrillation’. The official US figures probably underestimate the magnitude of the problem by a factor of 3–5. More than 80% had risk factors motivating anticoagulation therapy.

Effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile and inflammation markers in metabolic syndrome - a randomized study (SYSDIET)

Abstract: Background Different healthy food patterns may modify cardiometabolic risk. We investigated the effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile, blood pressure and inflammatory markers in people with metabolic syndrome. Methods We conducted a randomized dietary study lasting for 18-24weeks in individuals with features of metabolic syndrome (mean age 55years, BMI 31.6kgm-2, 67% women). Altogether 309 individuals were screened, 200 started the intervention after 4-week run-in period, and 96 (proportion of dropouts 7.9%) and 70 individuals (dropouts 27%) completed the study, in the Healthy diet and Control diet groups, respectively. Healthy diet included whole-grain products, berries, fruits and vegetables, rapeseed oil, three fish meals per week and low-fat dairy products. An average Nordic diet served as a Control diet. Compliance was monitored by repeated 4-day food diaries and fatty acid composition of serum phospholipids. Results Body weight remained stable, and no significant changes were observed in insulin sensitivity or blood pressure. Significant changes between the groups were found in non-HDL cholesterol (-0.18, mmolL-1 95% CI -0.35; -0.01, P=0.04), LDL to HDL cholesterol (-0.15, -0.28; -0.00, P=0.046) and apolipoprotein B to apolipoprotein A1 ratios (-0.04, -0.07; -0.00, P=0.025) favouring the Healthy diet. IL-1 Ra increased during the Control diet (difference -84, -133; -37ngL-1, P= 0.00053). Intakes of saturated fats (E%, beta estimate 4.28, 0.02; 8.53, P=0.049) and magnesium (mg, -0.23, -0.41; -0.05, P=0.012) were associated with IL-1 Ra. Conclusions Healthy Nordic diet improved lipid profile and had a beneficial effect on low-grade inflammation.

Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force.

Abstract: Angiogenic endothelial cells and tumour cells can survive under hypoxic conditions and even proliferate and migrate in a low-oxygen environment. In both cell types, high rates of glycolysis (i.e. conversion of glucose to lactate) and glutaminolysis provide most of the required biosynthetic intermediates and energy to support sprouting and cell division without coupling to oxidative phosphorylation. This metabolic preference is observed under hypoxic conditions, but also in situations in which oxygen is present. In the case of tumour cells, this is known as the Warburg effect and is largely governed by oncogenes. In endothelial cells lining tumour blood vessels, the option of respiration-independent metabolism allows the neovasculature to resist the hostile environment of fluctuating oxygen tension (ranging from severe hypoxia to quasi-normal levels of oxygen). In addition, accumulation in tumours of lactate, the end-product of glycolysis, largely contributes to the angiogenic phenotype through inhibition of prolyl hydroxylase 2 and the activation of HIF1α and NFκB. Activation of the latter in a hypoxia-independent manner leads to the increased production of interleukin-8/CXCL8 which drives the autocrine stimulation of endothelial cell proliferation and maturation of neovessels. In conclusion, the addiction of proliferating endothelial cells for glucose and glutamine as fuels and the driving force of lactate to promote angiogenesis provide novel potential treatment options without the disadvantages of conventional anti-angiogenic drugs.

The medical use of oxygen: a time for critical reappraisal.

Abstract: Oxygen treatment has been a cornerstone of acute medical care for numerous pathological states. Initially, this was supported by the assumed need to avoid hypoxaemia and tissue hypoxia. Most acute treatment algorithms, therefore, recommended the liberal use of a high fraction of inspired oxygen, often without first confirming the presence of a hypoxic insult. However, recent physiological research has underlined the vasoconstrictor effects of hyperoxia on normal vasculature and, consequently, the risk of significant blood flow reduction to the at-risk tissue. Positive effects may be claimed simply by relief of an assumed local tissue hypoxia, such as in acute cardiovascular disease, brain ischaemia due to, for example, stroke or shock or carbon monoxide intoxication. However, in most situations, a generalized hypoxia is not the problem and a risk of negative hyperoxaemia-induced local vasoconstriction effects may instead be the reality. In preclinical studies, many important positive anti-inflammatory effects of both normobaric and hyperbaric oxygen have been repeatedly shown, often as surrogate end-points such as increases in gluthatione levels, reduced lipid peroxidation and neutrophil activation thus modifying ischaemia–reperfusion injury and also causing anti-apoptotic effects. However, in parallel, toxic effects of oxygen are also well known, including induced mucosal inflammation, pneumonitis and retrolental fibroplasia. Examining the available ‘strong’ clinical evidence, such as usually claimed for randomized controlled trials, few positive studies stand up to scrutiny and a number of trials have shown no effect or even been terminated early due to worse outcomes in the oxygen treatment arm. Recently, this has led to less aggressive approaches, even to not providing any supplemental oxygen, in several acute care settings, such as resuscitation of asphyxiated newborns, during acute myocardial infarction or after stroke or cardiac arrest. The safety of more advanced attempts to deliver increased oxygen levels to hypoxic or ischaemic tissues, such as with hyperbaric oxygen therapy, is therefore also being questioned. Here, we provide an overview of the present knowledge of the physiological effects of oxygen in relation to its therapeutic potential for different medical conditions, as well as considering the potential for harm. We conclude that the medical use of oxygen needs to be further examined in search of solid evidence of benefit in many of the current clinical settings in which it is routinely used.

Ectopic lipid storage and insulin resistance: a harmful relationship

Abstract: Obesity increases the risk of metabolic diseases, including insulin resistance and type 2 diabetes, as well as cardiovascular disease. In addition to lipid accumulation in adipose tissue, obesity is associated with increased lipid storage in ectopic tissues, such as skeletal muscle and liver. Furthermore, lipid accumulation in the heart may result in cardiac dysfunction and heart failure. It has recently been demonstrated that intracellular lipid accumulation in ectopic tissues leads to pathological responses and impaired insulin signalling. Here, we will review the current understanding of how lipid storage and lipid droplet physiology affect the risk of developing metabolic diseases.

Long‐term outcome of enzyme‐replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications

Abstract: Objective The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards ‘hard’ clinical end-points in comparison with the natural course of the disease.

Pathophysiology of heparan sulphate: many diseases, few drugs

Abstract: Heparan sulphate (HS) polysaccharides are covalently attached to the core proteins of various proteoglycans at cell surfaces and in the extracellular matrix. They are composed of alternating units of hexuronic acid and glucosamine, with sulphate substituents in complex and variable yet cell-specific patterns. Whereas HS is produced by virtually all cells in the body, heparin, a highly sulphated HS variant, is confined to connective-tissue-type mast cells. The polysaccharides interact with a multitude of proteins, mainly through ionic binding, and thereby control key processes in development and homoeostasis. Similar interactions also implicate HS in various pathophysiological settings, including cancer, amyloid diseases, infectious diseases, inflammatory conditions and some developmental disorders. Prospects for the development of HS-based drugs, which are still largely unrealized, are discussed.

Cardiovascular disease event rates in patients with severe psoriasis treated with systemic anti-inflammatory drugs: a Danish real-world cohort study.

Abstract: Objectives Psoriasis is a chronic inflammatory disorder associated with cardiovascular morbidity and mortality. Systemic anti-inflammatory drugs, including biological agents, are widely used in the treatment of patients with moderate to severe psoriasis and may attenuate the risk of cardiovascular disease events. We therefore examined the rate of cardiovascular disease events in patients with severe psoriasis treated with systemic anti-inflammatory drugs. Design, setting and participants Individual-level linkage of nationwide administrative databases was used to assess the event rates associated with use of biological agents, methotrexate or other therapies, including retinoids, cyclosporine and phototherapy, in Denmark from 2007 to 2009. Main outcome measure Death, myocardial infarction and stroke. Results A total of 2400 patients with severe psoriasis, including 693 patients treated with biological agents and 799 treated with methotrexate, were identified. Incidence rates per 1000 patient-years and 95% confidence intervals (CIs) for the composite endpoint were 6.0 (95% CI 2.7–13.4), 17.3 (95% CI 12.3–24.3) and 44.5 (95% CI 34.6–57.0) for patients treated with biological agents, methotrexate and other therapies, respectively. Age- and sex-adjusted hazard ratios (HRs) were 0.28 (95% CI 0.12–0.64) and 0.65 (95% CI 0.42–1.00) for patients treated with biological agents and methotrexate, respectively, using other therapies as the reference cohort. Corresponding HRs for a secondary composite endpoint of cardiovascular death, myocardial infarction and stroke were 0.48 (95% CI 0.17–1.38) and 0.50 (95% CI 0.26–0.97). Conclusion In this nationwide study of patients with severe psoriasis, systemic anti-inflammatory treatment with biological agents or methotrexate was associated with lower cardiovascular disease event rates compared to patients treated with other anti-psoriatic therapies.

Environmental stress, ageing and glial cell senescence: a novel mechanistic link to Parkinson's disease?

Abstract: Exposure to environmental toxins is associated with a variety of age-related diseases including cancer and neurodegeneration. For example, in Parkinson's disease (PD), chronic environmental exposure to certain toxins has been linked to the age-related development of neuropathology. Neuronal damage is believed to involve the induction of neuroinflammatory events as a consequence of glial cell activation. Cellular senescence is a potent anti-cancer mechanism that occurs in a number of proliferative cell types and causes the arrest of proliferation of cells at risk of malignant transformation following exposure to potentially oncogenic stimuli. With age, senescent cells accumulate and express a senescence-associated secretory phenotype (SASP; that is the robust secretion of many inflammatory cytokines, growth factors and proteases). Whereas cell senescence in peripheral tissues has been causally linked to a number of age-related pathologies, little is known about the induction of cellular senescence and the SASP in the brain. On the basis of recently reported findings, we propose that environmental stressors associated with PD may act in part by eliciting senescence and the SASP within non neuronal glial cells in the ageing brain, thus contributing to the characteristic decline in neuronal integrity that occurs in this disorder.

Hypoglycaemic episodes and risk of dementia in diabetes mellitus: 7‐year follow‐up study

Abstract: Objective We investigated the risk of dementia in patients with type 2 diabetes with or without prior hypoglycaemic episodes. Subjects and Setting One million subjects randomly selected from the National Health Insurance Research Database, Taiwan. Results A total of 15 404 diabetic subjects without prior dementia and a mean age of 64.2 years were enrolled in the study. About 2% (n = 289) of participants had at least one episode of hypoglycaemia in a 3-year period; these subjects were older and more likely to be women and also had higher rates of insulin use and comorbidities compared to those without hypoglycaemia. During a total of 7 years of follow-up (mean and median follow-up, 3.8 and 4.8 years, respectively), 1106 patients with diabetes (7.2%) developed dementia. The incidence rate of dementia was higher in diabetic subjects with [29.9 per 1000 person-years (95% CI 22.1–39.2)] compared to those without [11.1 per 1000 person-years (95% CI 10.3–11.8)] hypoglycaemic episodes. The crude rate ratio (RR) and age- and gender-adjusted RR values for dementia were 2.76 (95% CI 2.06–3.70, P < 0.001) and 1.60 (95% CI 1.19–2.14, P = 0.002), respectively, in diabetic subjects with hypoglycaemia compared to those without hypoglycaemia. Results of Cox proportional hazards analysis revealed that hypoglycaemia, older age, female gender and insulin use were independent predictors of dementia. Conclusion Adult diabetic patients with prior hypoglycaemia had a significantly increased risk of dementia. The influence of hypoglycaemic episodes on brain function warrants further investigation.

Gender differences in cardiovascular disease risk factors, treatments and complications in patients with type 2 diabetes: the RIACE Italian multicentre study

Abstract: Objectives Poorer control of risk factors for cardiovascular disease (CVD) has been reported in diabetic women, as compared with diabetic men. It has been proposed that this finding is due to gender disparities in treatment intensity. We investigated this hypothesis in a large contemporary cohort of subjects with type 2 diabetes. Design Observational, cross-sectional study. Subjects and setting Consecutive patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study (n = 15 773), attending 19 hospital-based diabetes clinics in 2007–2008. Main outcome measures Traditional CVD risk factors, macro- and microvascular complications and current glucose-, lipid- and blood pressure (BP)-lowering treatments were assessed. Results Although CVD was more prevalent in men, women showed a less favourable CVD risk profile and worse performance in achieving treatment targets for haemoglobin A1c, LDL, HDL and non-HDL cholesterol, systolic blood pressure (BP) and in particular obesity [body mass index (BMI) and waist circumference], but not for triglycerides and diastolic BP. However, women were more frequently receiving pharmacological treatment for hypertension and to a lesser extent hyperglycaemia and dyslipidaemia than men, and female gender remained an independent predictor of unmet therapeutic targets after adjustment for confounders such as treatments, BMI, duration of diabetes and, except for the systolic BP goal, age. Conclusions In women with type 2 diabetes from the RIACE cohort, a more adverse CVD risk profile and a higher likelihood of failing treatment targets, compared with men, were not associated with treatment differences. This suggests that factors other than gender disparities in treatment intensity are responsible.

Effects of individual and combined dietary weight loss and exercise interventions in postmenopausal women on adiponectin and leptin levels

Abstract: Background Excess body weight and a sedentary lifestyle are associated with the development of several diseases, including cardiovascular disease, diabetes and cancer in women. One proposed mechanism linking obesity to chronic diseases is an alteration in adipose-derived adiponectin and leptin levels. We investigated the effects of 12-month reduced calorie, weight loss and exercise interventions on adiponectin and leptin concentrations. Methods Overweight/obese postmenopausal women (n = 439) were randomized as follows: (i) a reduced calorie, weight-loss diet (diet; N = 118), (ii) moderate-to-vigorous intensity aerobic exercise (exercise; N = 117), (iii) a combination of a reduced calorie, weight-loss diet and moderate-to-vigorous intensity aerobic exercise (diet + exercise; N = 117), and (iv) control (N = 87). The reduced calorie diet had a 10% weight-loss goal. The exercise intervention consisted of 45 min of moderate-to-vigorous aerobic activity 5 days per week. Adiponectin and leptin levels were measured at baseline and after 12 months of intervention using a radioimmunoassay. Results Adiponectin increased by 9.5% in the diet group and 6.6% in the diet + exercise group (both P ≤ 0.0001 vs. control). Compared with controls, leptin decreased with all interventions (diet + exercise, −40.1%, P < 0.0001; diet, −27.1%, P < 0.0001; exercise, −12.7%, P = 0.005). The results were not influenced by the baseline body mass index (BMI). The degree of weight loss was inversely associated with concentrations of adiponectin (diet, P-trend = 0.0002; diet + exercise, P-trend = 0.0005) and directly associated with leptin (diet, P-trend < 0.0001; diet + exercise, P-trend < 0.0001). Conclusion Weight loss through diet or diet + exercise increased adiponectin concentrations. Leptin concentrations decreased in all of the intervention groups, but the greatest reduction occurred with diet + exercise. Weight loss and exercise exerted some beneficial effects on chronic diseases via effects on adiponectin and leptin.

Syndromes of orthostatic intolerance: a hidden danger.

Abstract: Orthostatic hypotension (OH) is a relatively common heterogenous and multifactorial disorder, traditionally classified as neurogenic (less common but often more severe) or nonneurogenic (more common, with no direct signs of autonomic nervous system disease). The different clinical variants of orthostatic intolerance include initial, classical and delayed OH as well as postural tachycardia syndrome. Orthostatic instability may induce syncopal attacks either alone or in combination with other mechanisms, and is often dismissed as a precipitating factor. Moreover, prevalent OH is an independent risk factor for all-cause mortality and cardiovascular morbidity, and the majority of patients with OH are asymptomatic or have few nonspecific symptoms. Management of symptomatic orthostatic intolerance includes both nonpharmacological and pharmacological methods, but it is not always successful and may lead to complications. Future studies of OH should focus on mechanisms that lead to neurogenic and nonneurogenic OH, novel diagnostic methods and more effective therapeutic modalities.

Myocardial infarction with normal coronary arteries is common and associated with normal findings on cardiovascular magnetic resonance imaging: results from the Stockholm Myocardial Infarction with Normal Coronaries study

Abstract: Collste O, Sorensson P, Frick M, Agewall S, Daniel M, Henareh L, Ekenback C, Eurenius L, Guiron C, Jernberg T, Hofman-Bang C, Malmqvist K, Nagy E, Arheden H, Tornvall P (Sodersjukhuset, Stockholm; Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden; University of Oslo, Oslo, Norway; Sankt Goran Hospital Capio, Karolinska Institutet, Stockholm; Huddinge, Stockholm; Danderyd Hospital, Karolinska Institutet, Stockholm; and Skane University Hospital, Lund University, Lund, Sweden). Myocardial infarction with normal coronary arteries is common and associated with normal findings on cardiovascular magnetic resonance imaging: results from the Stockholm Myocardial Infarction with Normal Coronaries study. J Intern Med 2013; 273: 189-196. Objectives Myocardial infarction with angiographically normal coronary arteries (MINCA) is an important subtype of myocardial infarction; however, the prevalence, underlying pathophysiology, prognosis and optimal management of this condition are still largely unknown. Cardiovascular magnetic resonance (CMR) imaging has the potential to clarify the underlying pathology in patients with MINCA. The objective of this study was to investigate the diagnostic value of CMR imaging in this group of patients. Design The prospective, multicentre, observational Stockholm Myocardial Infarction with Normal Coronaries (SMINC) study. Setting Coronary care units in the Stockholm metropolitan area. Subjects Patients between 35 and 70 years of age with MINCA were consecutively included in the screening phase of the SMINC study. All patients had a typical clinical presentation, fulfilling the universal definition of myocardial infarction and had normal coronary angiography finding. Patients with known structural or coronary heart disease or other known causes of elevated troponin levels were excluded. Results In total, 176 patients with MINCA were screened from 2007 to 2011. Of these, 152 underwent CMR imaging. The investigation was performed a median of 12 (interquartile range 628) days after hospital admission; 67% of the findings were normal, whereas 19% of patients had signs of myocardial necrosis and 7% had signs of myocarditis. The remaining patients (7%) had either unrecognized hypertrophic cardiomyopathy or could not be classified. Conclusion In this consecutive series of patients with MINCA, CMR imaging may help to differentiate between those with myocarditis, myocardial necrosis and normal myocardium. The incidence of MINCA was higher than previously reported. After excluding cases of myocarditis, MINCA consists of a large group of patients with normal CMR imaging results and a smaller group with myocardial necrosis. The aetiologies of these different imaging findings need to be explored.

The role of dopamine receptors in the neurotoxicity of methamphetamine

Abstract: Methamphetamine is a synthetic drug consumed by millions of users despite its neurotoxic effects in the brain, leading to loss of dopaminergic fibres and cell bodies. Moreover, clinical reports suggest that methamphetamine abusers are predisposed to Parkinson's disease. Therefore, it is important to elucidate the mechanisms involved in methamphetamine-induced neurotoxicity. Dopamine receptors may be a plausible target to prevent this neurotoxicity. Genetic inactivation of dopamine D1 or D2 receptors protects against the loss of dopaminergic fibres in the striatum and loss of dopaminergic neurons in the substantia nigra. Protection by D1 receptor inactivation is due to blockade of hypothermia, reduced dopamine content and turnover and increased stored vesicular dopamine in D1R−/− mice. However, the neuroprotective impact of D2 receptor inactivation is partially dependent on an effect on body temperature, as well as on the blockade of dopamine reuptake by decreased dopamine transporter activity, which results in reduced intracytosolic dopamine levels in D2R−/− mice.

Telomeres and human health.

Abstract: Telomeres are the tips of chromosomes and consist of proteins and hexanucleotide tandem repeats of DNA. The DNA repeats are shortened at each mitotic division of normal cells, and the telomere length chronicles how many divisions the cell has undergone. Thus, telomere length is a marker of fundamental biological pathways. It has been possible to measure telomere length for more than 20 years, and it has been established that telomere length is associated with age, sex and lifestyle factors. Here, the current knowledge of telomere length as a biomarker of disease susceptibility and mortality will be reviewed. In addition, technical difficulties and the reasons why measurement of telomeres has still not been introduced into routine clinical practice will be discussed. Findings from recent studies conducted in many thousands of individuals indicate that telomere length is not–or at best only marginally–independently associated with risk of common disorders such as cardiovascular, pulmonary and neoplastic diseases. However, in sufficiently powered studies, short telomeres are repeatedly and independently found to be associated with increased risk of early death in the general population or in subsets of individuals. This indicates that measurement of telomeres could be a valuable prognostic biomarker in many clinical settings. However, whether short telomeres are a causal factor for or simply a marker of increased risk of early death must be determined. Finally, how Mendelian randomization studies could clarify this issue, and which clinical studies might be carried out to refine this very promising biomarker for routine clinical use will be considered.

Genetically elevated bilirubin and risk of ischaemic heart disease: three Mendelian randomization studies and a meta-analysis.

Abstract: Background Elevated plasma levels of bilirubin, an endogenous antioxidant, have been associated with reduced risk of ischaemic heart disease (IHD) and myocardial infarction (MI). Whether this is a causal relationship remains unclear. Objective We tested the hypothesis that elevated plasma bilirubin is causally related to decreased risk of IHD and MI. Design We used a Mendelian randomization approach and three independent studies from Copenhagen, Denmark. We measured bilirubin in 43 708 white individuals from the general population, and genotyped rs6742078 G>T in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in 67 068 individuals, of whom 11 686 had IHD. Results Third versus first tertile of baseline bilirubin levels was associated with 134% increased bilirubin levels, with sex- and age-adjusted hazard ratios (HRs) of 0.86 [95% confidence interval (CI), 0.76–0.98; P = 0.02] for IHD and 0.81 (95% CI, 0.66–0.99; P = 0.04) for MI, but with corresponding multifactorially adjusted HRs of 0.93 (95% CI, 0.82–1.06; P = 0.29) and 0.90 (95% CI, 0.73–1.12; P = 0.35). UGT1A1 rs6742078 TT versus GG genotype was associated with 95% increased bilirubin levels (P < 0.001); TT versus GG genotype was associated with odds ratios (ORs) of 1.03 (95% CI, 0.96–1.11; P = 0.73) for IHD and 1.01 (95% CI, 0.92–1.12; P = 0.68) for MI. Finally, in a meta-analysis of the present three studies and eight previous studies including a total of 14 711 cases and 60 324 controls, the random effects OR for ischaemic cardiovascular disease for genotypes with approximately 100% increased bilirubin levels versus reference genotypes was 1.01 (95% CI, 0.88–1.16). Conclusion These data suggest that plasma bilirubin is not causally associated with risk of IHD.

Circulating interleukin‐6 concentration and cognitive decline in old age: the PROSPER study

Abstract: BACKGROUND Inflammation is involved in the pathogenesis of cardiovascular disease and cognitive decline. Interleukin-6 (IL-6) has a role in cardiovascular disease, but the association of IL-6 concentration and the functional IL-6 -174 polymorphism with cognitive decline has not been demonstrated unequivocally. The objective of this study was to investigate the associations between both high concentration of IL-6 and the -174 promoter polymorphism, and increased cognitive decline in old age. METHODS Over 5000 participants of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) with a mean age of 75 years and a history of cardiovascular disease or its risk factors were included in this study. We determined baseline concentrations of IL-6 and genotype of the IL-6 -174 polymorphism, of which the C allele was previously shown to be associated with higher circulating concentrations of IL-6. A cognitive test battery was administered at baseline and repeatedly during follow-up (mean 39 months). RESULTS In the cross-sectional analysis of 5653 participants, higher IL-6 concentration was associated with worse executive cognitive function (P 0.14). In the prospective analysis, higher IL-6 concentration was associated with an increased rate of cognitive decline in both executive function (P = 0.002) and memory function (P = 0.002), again independent of cardiovascular disease status and risk factors. Although not associated with IL-6 concentrations, the IL-6 -174 CC genotype was associated with worse performance on the Stroop test (P = 0.045). CONCLUSIONS Higher circulating levels of IL-6 were associated with worse cognitive function and steeper cognitive decline and provide preliminary genetic evidence for a potential causal association. The findings support the importance of the need for further investigation of the IL-6 pathway in cognitive decline.

Manganese toxicity in the central nervous system: the glutamine/glutamate‐γ‐aminobutyric acid cycle

Abstract: Manganese (Mn) is an essential trace element that is required for maintaining proper function and regulation of numerous biochemical and cellular reactions. Despite its essentiality, at excessive levels Mn is toxic to the central nervous system (CNS). Increased accumulation of Mn in specific brain regions, such as the substantia nigra, globus pallidus and striatum, triggers neurotoxicity resulting in a neurological brain disorder, termed manganism. Mn has been also implicated in the pathophysiology of several other neurodegenerative diseases. Its toxicity is associated with disruption of the glutamine (Gln)/glutamate (Glu)-γ-aminobutyric acid (GABA) cycle (GGC) between astrocytes and neurons, thus leading to changes in Glu-ergic and/or GABAergic transmission and Gln metabolism. Here we discuss the common mechanisms underlying Mn-induced neurotoxicity and their relationship to CNS pathology and GGC impairment.

Assessing patients with myocardial infarction and nonobstructed coronary arteries (MINOCA).

Abstract: Over the past 20 years, the management of acute myocardial infarction (AMI) has substantially progressed due to innovations in the assessment of these patients. Firstly, development of the troponin assay has provided a more accurate diagnostic marker of myocardial injury and is now the cornerstone of contemporary AMI definitions [1]. This assay continues to evolve with the recent development of highly sensitive troponin assays, which are likely to further impact on clinical practice. A second important innovation were the studies by DeWood et al., [2] which involved undertaking coronary angiography during AMI. This group demonstrated that ST elevation myocardial infarction (STEMI) was typically associated with an occluded coronary artery, whereas this occurred less frequently in those without ST elevation myocardial infarction [3]. These findings facilitated the development of reperfusion therapies for STEMI, initially involving intravenous thrombolytic therapy and subsequently primary percutaneous coronary interventions, when the former was shown to be less effective in restoring angiographic coronary blood flow and improving clinical outcomes. For non-ST elevation myocardial infarction (NSTEMI), revascularization of the infarct-related vessel is of benefit although not required immediately because total arterial occlusion is less frequently observed at angiography.

Opioid use for noncancer pain and risk of myocardial infarction amongst adults

Abstract: Backgrounds With increasing use of opioids for chronic noncancer pain comes concern about safety of this class of drugs. Opioid-induced hypogonadism, which could increase the risk for myocardial infarction (MI), has recently come to the attention of clinicians. To evaluate this concern we examined the association between opioid use for noncancer pain and risk of MI amongst adults. Methods We conducted a nested case-control study using the UK General Practice Research Database. Amongst 1.7 million opioid users during 1990–2008, we identified 11 693 incident MI cases aged 18–80 years, and randomly selected up to four controls matched by age, gender, index date (date of onset symptoms or diagnosis of first-ever MI) and general practice via risk-set sampling. Cases and controls were required to have no cancer and no major risk factors for MI before the index date. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from conditional logistic regression. Results Compared with nonuse, current use of opioids was associated with a 1.28-fold (95% CI 1.19–1.37) risk of MI. Cumulative use of opioids with 11–50 (OR = 1.38, 95% CI: 1.28–1.49) or > 50 (OR = 1.25, 95% CI: 1.11–1.40) prescriptions, was also marginally associated with increased risk of MI. The risk was particularly increased in users of morphine (OR = 1.71, 95% CI: 1.09–2.68), meperidine (OR = 2.15, 95% CI: 1.24–3.74) and polytherapy (OR = 1.46, 95% CI: 1.22–1.76). Conclusions Current use of any opioids and cumulative use of 11 or more prescriptions are associated with a small increased risk for MI compared to nonuse and the risk was greater in morphine, meperidine and polytherapy users. Residual confounding, particularly confounding by indication, should be considered in interpreting our results.

Long-lasting neurotoxic effects of exposure to methylmercury during development.

Abstract: Amongst environmental chemical contaminants, methylmercury (MeHg) remains a major concern because of its detrimental effects on developing organisms, which appear to be particularly susceptible to its toxicity. Here, we investigated the effects of low MeHg levels on the development of the nervous system using both in vitro and in vivo experimental models. In neural stem cells (NSCs), MeHg decreased proliferation and neuronal differentiation and induced cellular senescence associated with impairment in mitochondrial function and a concomitant decrease in global DNA methylation. Interestingly, the effects were heritable and could be observed in daughter NSCs never directly exposed to MeHg. By chronically exposing pregnant/lactating mice to MeHg, we found persistent behavioural changes in the male offspring, which exhibited depression-like behaviour that could be reversed by chronic treatment with the antidepressant fluoxetine. The behavioural alterations were associated with a decreased number of proliferating cells and lower expression of brain-derived neurotrophic factor (Bdnf) mRNA in the hippocampal dentate gyrus. MeHg exposure also induced long-lasting DNA hypermethylation, increased histone H3-K27 tri-methylation and decreased H3 acetylation at the Bdnf promoter IV, indicating that epigenetic mechanisms play a critical role in mediating the long-lasting effects of perinatal exposure to MeHg. Fluoxetine treatment restored the Bdnf mRNA expression levels, as well as the number of proliferating cells in the granule cell layer of the dentate gyrus, which further supports the hypothesis that links depression to impaired neurogenesis. Altogether, our findings have shown that low concentrations of MeHg induce long-lasting effects in NSCs that can potentially predispose individuals to depression, which we have reported earlier to occur in experimental animals exposed to MeHg during prenatal and early postnatal development.

Hospitalization for physical illness and risk of subsequent suicide: a population study.

Abstract: Objective To examine suicide risk in relation to physical illness across a broad range of illnesses, including hospitalization history, specific organ or system illness and comorbidity. Design A nested case–control study. Setting Data were retrieved from five Danish national registers. Subjects On the basis of the entire population of Denmark, this study included 27 262 suicide cases, and 468 007 live controls matched for sex and date of birth. Main outcome measures Risk of suicide was assessed using conditional logistic regression. Results In the study population, 63.5% of suicide cases and 44.5% of comparison controls had a history of hospitalization for physical illness. A physical illness significantly increased the risk of subsequent suicide (incidence rate ratios 2.13, 95% CI 2.07–2.18) with a substantially greater effect in women than in men (P < 0.01). The elevated risk increased progressively with frequency and recency of hospitalization and was significant for diseases occurring in all organs or systems of the body. Comorbidity involving several organs or systems increased the risk substantially. The associated estimates were to some extent reduced but remained highly significant after adjustment for psychiatric history and socio-economic status. Taking into account both prevalence and adjusted effect size, physical illness accounted for 24.4%, 21.0% and 32.3% of population attributable risk for suicide in total, male and female populations, respectively. Conclusions Physical illness constitutes a significant risk factor for suicide independent of psychiatric and socio-economic factors. Clinicians treating physically ill patients should be aware of the risk, especially amongst those with multiple or recent hospitalizations, or multiple comorbidities.