Showing papers in "Annals of Medicine in 2012"
TL;DR: Pending confirmation from larger RCTs, this analysis shows SGLT2 inhibitors are safe and effective for hyperglycemia treatment in T2DM.
Abstract: Background. Current treatment of hyperglycemia in type 2 diabetes (T2DM) is often ineffective and has unwanted effects. Therefore, novel antidiabetic drugs are under development. Objective. To assess effi cacy and safety of the new antidiabetic drugs sodium glucose co-transport-2 (SGLT2) inhibitors in T2DM. Design and setting. Among 151 articles published on MEDLINE, Cochrane Library, EMBASE, PubMed, International meeting abstracts through December 2010, 13 randomized placebo-controlled trials (RCT) were included. Measurements. Two reviewers retrieved articles and evaluated study quality by appropriate scores. Main outcomes were pooled using random- or fimodels. Results. Dapaglifl ozin signifi cantly reduced HbA1c (weighted mean difference (WMD) ‐0.52%; 95% CI ‐0.46, ‐0.57%; P 0.00001) fasting plasma glucose (WMD ‐18.28 mg/dL; 95% CI ‐20.66, ‐15.89; P 0.00001), body mass index (WMD ‐1.17%; ‐1.41, ‐0.92%; P 0.00001), systolic (WMD ‐4.08 mmHg; ‐4.91, ‐3.24), and diastolic (WMD ‐1.16 mmHg; ‐1.67, ‐0.66) blood pressure, and serum uric acid (WMD ‐41.50 μ mol/L; ‐47.22, ‐35.79). Other SGLT2 inhibitors showed similar results. Dapaglifl ozin treatment increased the risk of urinary (OR 1.34; 1.05 ‐ 1.71) and genital (OR 3.57; 2.59 ‐ 4.93) tract infection; it also mildly increased the risk of hypoglycemia (OR 1.27; 1.05 ‐ 1.53) when co-administered with insulin. Limitations. Limitations of the literature include the small number, size, and duration of RCTs. Conclusions. Pending confi rmation from larger RCTs, this analysis shows SGLT2 inhibitors are safe and effective for hyperglycemia treatment in T2DM.
252 citations
TL;DR: The PVI, mean platelet volume (MPV), is universally available with routine blood counts by automated hemograms and therefore is an attractive index to study in clinical scenarios and is useful in assessing the etiology of thrombocytopenia.
Abstract: Platelet size correlates with platelet activity and can be assessed by platelet volume indices (PVI). The PVI, mean platelet volume (MPV), is universally available with routine blood counts by automated hemograms and therefore is an attractive index to study in clinical scenarios. PVI are useful in assessing the etiology of thrombocytopenia. In addition, a normal platelet distribution width in the setting of thrombocytosis is highly suggestive of a reactive etiology. Higher MPV is also associated with the presence of cardiovascular risk factors, chest pain due to acute coronary syndrome, and adverse outcome after acute coronary syndrome. Results from studies evaluating MPV in patients with peripheral artery disease, unprovoked deep vein thrombosis, and pulmonary embolism further advocate a potential role for MPV in identifying patients at high risk of thrombosis.Nevertheless, most of these data come from retrospective studies some of which have small study populations and confounding factors influ...
238 citations
TL;DR: Both epidemiological and experimental data support associations between disrupted physiological rhythms, a reduction in adequate sleep, and light-at-night-induced suppression of an essential endogenously produced molecule, melatonin.
Abstract: Obesity has become an epidemic in industrialized and developing countries. In 30 years, unless serious changes are made, a majority of adults and many children will be classified as overweight or obese. Whereas fatness alone endangers physiological performance of even simple tasks, the associated co-morbidity of obesity including metabolic syndrome in all its manifestations is a far more critical problem. If the current trend continues as predicted, health care systems may be incapable of handling the myriad of obesity-related diseases. The financial costs, including those due to medical procedures, absenteeism from work, and reduced economic productivity, will jeopardize the financial well-being of industries. The current review summarizes the potential contributions of three processes that may be contributing to humans becoming progressively more overweight: circadian or chronodisruption, sleep deficiency, and melatonin suppression. Based on the information provided in this survey, life-style factors (independent of the availability of abundant calorie-rich foods) may aggravate weight gain. Both epidemiological and experimental data support associations between disrupted physiological rhythms, a reduction in adequate sleep, and light-at-night-induced suppression of an essential endogenously produced molecule, melatonin. The implication is that if these problems were corrected with life-style changes, body-weight could possibly be more easily controlled.
198 citations
TL;DR: The most recent discovery of a pathological hexanucleotide repeat expansion in the gene C9orf72 as a frequent cause of both FTLD and ALS has eventually confirmed the association of these two at first sight distinct neurodegenerative diseases.
Abstract: There is increasing evidence that frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) represent a continuum of neurodegenerative diseases. FTLD is complicated by ALS in a significant proportion of patients, and neuropsychological studies have demonstrated frontotemporal dysfunction in up to 50% of ALS patients. More recently, advances in neuropathology and molecular genetics have started to disclose the biological basis for the observed clinical concurrence. TDP-43 and FUS have been discovered as key pathological proteins in both FTLD and ALS. The most recent discovery of a pathological hexanucleotide repeat expansion in the gene C9orf72 as a frequent cause of both FTLD and ALS has eventually confirmed the association of these two at first sight distinct neurodegenerative diseases. Mutations in the TARDBP, FUS, and VCP genes had previously been associated with different phenotypes of the FTLD-ALS spectrum, although in these cases one end of the spectrum predominates. Whilst on the one hand providing evidence for overlap, these discoveries have also highlighted that FTLD and ALS are etiologically diverse. In this review, we review the recent advances that support the existence of an FTLD-ALS spectrum, with particular emphasis on the molecular genetic aspect.
173 citations
TL;DR: The present review addresses the putative function of ROS in the pathogenesis of hypertension and focuses on the role of Noxs in ROS generation in vessels and the kidney.
Abstract: Reactive oxygen species (ROS) are signaling molecules that influence many physiological processes. Increased ROS bioavailability and altered redox signaling (oxidative stress) have been implicated in chronic diseases including hypertension. Although oxidative stress may not be the sole cause of hypertension, it amplifies blood pressure elevation in the presence of other prohypertensive factors (salt, renin-angiotensin system, sympathetic hyperactivity). A major source for cardiovascular ROS is a family of non-phagocytic NADPH oxidases (Nox1, Nox2, Nox4, Nox5). Other sources of ROS involve mitochondrial electron transport enzymes, xanthine oxidase, and uncoupled nitric oxide synthase. Although evidence from experimental and animal studies supports a role for oxidative stress in the pathogenesis of hypertension, there is still no convincing proof that oxidative stress is a cause of human hypertension. However, what is clear is that oxidative stress is important in the molecular mechanisms associated with cardiovascular and renal injury in hypertension and that hypertension itself can contribute to oxidative stress. The present review addresses the putative function of ROS in the pathogenesis of hypertension and focuses on the role of Noxs in ROS generation in vessels and the kidney. Implications of oxidative stress in human hypertension are discussed, and clinical uncertainties are highlighted.
167 citations
TL;DR: The main molecular mechanisms of mitochondrial diseases, as presently known, are reviewed and the putative consequences of mitochondrial dysfunction on a cellular level are discussed.
Abstract: Mitochondria are essential organelles with multiple functions, the most well known being the production of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). The mitochondrial diseases are defined by impairment of OXPHOS. They are a diverse group of diseases that can present in virtually any tissue in either adults or children. Here we review the main molecular mechanisms of mitochondrial diseases, as presently known. A number of disease-causing genetic defects, either in the nuclear genome or in the mitochondria's own genome, mitochondrial DNA (mtDNA), have been identified. The most classical genetic defect causing mitochondrial disease is a mutation in a gene encoding a structural OXPHOS subunit. However, mitochondrial diseases can also arise through impaired mtDNA maintenance, defects in mitochondrial translation factors, and various more indirect mechanisms. The putative consequences of mitochondrial dysfunction on a cellular level are discussed.
161 citations
TL;DR: It is summarized how therapeutic interventions may improve the bioavailability of NO and thus prevent/cure endothelial dysfunction and how the role of other endothelium-derived mediators is summarized, with special emphasis on their interaction(s) with the NO pathway.
Abstract: The present review first summarizes the complex chain of events, in endothelial and vascular smooth muscle cells, that leads to endothelium-dependent relaxations (vasodilatations) due to the generation of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) and how therapeutic interventions may improve the bioavailability of NO and thus prevent/cure endothelial dysfunction. Then, the role of other endothelium-derived mediators (endothelium-derived hyperpolarizing (EDHF) and contracting (EDCF) factors, endothelin-1) and signals (myoendothelial coupling) is summarized also, with special emphasis on their interaction(s) with the NO pathway, which make the latter not only a major mediator but also a key regulator of endothelium-dependent responses.
154 citations
TL;DR: In this large-scale Japan-wide general population study, an absolute VFA value of about 100 cm2 equated with obesity-related cardiovascular risk factor accumulation, irrespective of gender, age, and BMI.
Abstract: Background. The management of cardiovascular risk factors is important for prevention of atherosclerotic cardiovascular diseases (ACVD). Visceral fat accumulation plays an important role in the clustering of cardiovascular risk factors, leading to ACVD. The present study investigated the gender- and age-specific relationship between obesity-related cardiovascular risk factor accumulation and computed tomography (CT)-measured fat distribution in a large-scale Japanese general population.Methods and results. Fat distribution was measured on CT scans in 12,443 subjects (males/females = 10,080/2,363), who underwent medical health check-up at 9 centers in Japan. The investigated obesity-related cardiovascular risk factors were hyperglycemia, dyslipidemia, and elevated blood pressure. Visceral fat area (VFA) for all males and old females showed almost symmetric distribution, while that of young females showed skewed distribution with a marked left shift. Only a small proportion of young females had larg...
145 citations
TL;DR: All pharmacologic treatments were significantly more effective than inert controls andVarenicline was the only treatment demonstrating effects over other options, and should be considered in the development of clinical practice guidelines.
Abstract: Aim. This review compared the effect of high-dose nicotine replacement therapy (NRT) and combinations of NRT for increasing smoking abstinence rates compared to standard-dose NRT patch, varenicline, and bupropion on smoking abstinence.Methods. Ten electronic databases were searched (up to January 2012) for randomized controlled trials (RCT) of standard-dose (≤ 22 mg) or high-dose nicotine patch therapy (> 22 mg), combination NRT (e.g. nicotine patch + nicotine inhaler), bupropion, and varenicline. Analysis consisted of random-effects pairwise meta-analysis and a Bayesian multiple treatment comparison (MTC).Results. We identified 146 RCTs (65 standard-doses of the nicotine patch (≤ 22 mg); 6 high-dose NRT patch (> 22 mg); 5 high versus standard-dose NRT patch; 5 combination NRT versus inert controls; 6 combination versus single NRT patch; 48 bupropion; and 11 varenicline). The MTC found that all therapies offered treatment benefits at most time points over controls. Combination NRT and higher-dose NRT did ...
135 citations
TL;DR: The present mini-review successively addresses the concept of ‘tissue’ biomarker, applies it to arterial stiffness, describes the methodology of measurement, gives some pathophysiological links in order to explain the occurrence of stroke and myocardial infarction in patients with high arterial stiffening, and raises the issue of whether arterials stiffness is a surrogate marker.
Abstract: Classical risk scores may underestimate the risk of cardiovascular events in specific risk groups suitable for early prevention, such as asymptomatic hypertensive subjects. Arterial stiffness and wave reflection are now well accepted as the most important determinants of increasing systolic and pulse pressures in aging societies, thus affording a major contribution to stroke and myocardial infarction. A major reason for measuring arterial stiffness in hypertensive patients comes from the demonstration that arterial stiffness has a predictive value for cardiovascular events, beyond classical cardiovascular risk factors. Aortic stiffening also gives direct evidence of target organ damage, and improves the determination of the overall cardiovascular risk of asymptomatic hypertensive subjects. In clinical practice, the measurement of aortic stiffness may avoid patients being mistakenly classified as at low or moderate risk, when they actually have an abnormally high aortic stiffness placing them within a high...
97 citations
TL;DR: The most recent epidemiological data on the incidence of both diseases in adolescents, and several aspects linking MetS with NAFLD are summarized, discussing the possible role played by genetics and intrauterine environment.
Abstract: In the last three decades the incidence of metabolic syndrome (MetS) has been growing worldwide along with an increase of obesity, type 2 diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD). In children and adolescents such epidemics are particularly worrisome, since the metabolic consequences in adulthood will significantly burden the health care system. Although the definition of MetS in childhood is still controversial, there is agreement with respect to NAFLD being the hepatic manifestation of MetS. However, the molecular pathogenesis of MetS and its contribution to NAFLD is complex and closely related to the pre- and postnatal environment as well as to genetic predisposing factors. The analysis of the possible relationships between NAFLD and MetS is particularly interesting, not only from an epidemiological point of view, but also to better understand the genetic and environmental factors contributing to the development of both diseases. We here summarize the most recent epidemiological data on the incidence of both diseases in adolescents, and several aspects linking MetS with NAFLD, discussing the possible role played by genetics and intrauterine environment.
TL;DR: Primary prevention by screening is still the most important intervention to limit the adverse effects of CT on reproductive health and the evidence linking CT and other adverse pregnancy outcomes is weak.
Abstract: Chlamydia trachomatis (CT) is the most common bacterial cause of sexually transmitted infections. CT infections are strongly associated with risk-taking behavior. Recommendations for testing have been implemented in many countries. The effectiveness of the screening programs has been questioned since chlamydia rates have increased. However, the complication rates including pelvic inflammatory disease, tubal factor infertility, and tubal pregnancy have been decreasing, which is good news. The complication rates associated with CT infection have clearly been over-estimated. Genetic predisposition and host immune response play important roles in the pathogenesis of long-term complications. CT plays a co-factor role in the development of cervical neoplasia caused by high-risk human papillomavirus (HPV) types. The evidence linking CT and other adverse pregnancy outcomes is weak. The current nucleic acid amplification tests perform well. A new genetic variant of CT was discovered in Sweden but has only rarely been detected elsewhere. Single-dose azithromycin remains effective against CT. Secondary prevention by screening is still the most important intervention to limit the adverse effects of CT on reproductive health.
TL;DR: Understanding the factors and mechanisms driving vascular calcification will provide novel therapeutic targets for its prevention and perhaps ultimately its regression, and is an independent risk factor for cardiovascular mortality.
Abstract: Vascular calcification is an active and regulated process which is integral to cardiovascular disease and intimately linked to hypertension. Dysfunctional vascular smooth muscle cells, microvesicles, and dysregulated mineralization inhibitors play key roles in the calcification process, which occurs in the vessel intima in association with atherosclerosis as well as in the vessel media during ageing. Historically hypertension was considered a risk factor promoting atherosclerosis and associated intimal calcification. However, it is now recognized that not all vascular calcification occurs with atherosclerosis, and calcification of the vessel media is associated with arterial stiffening and is a major cause of isolated systolic hypertension in the elderly. Importantly, vascular calcification, regardless of its anatomical site, is an independent risk factor for cardiovascular mortality. Therefore, understanding the factors and mechanisms driving these processes will provide novel therapeutic targets for its prevention and perhaps ultimately its regression.
TL;DR: Telomeres are located at the end of chromosomes and are composed of repetitive TTAGGG tandem repeats and associated proteins of crucial importance for telomere function, and are considered a ‘biological clock’ of the cell.
Abstract: Telomeres are located at the end of chromosomes. They are composed of repetitive TTAGGG tandem repeats and associated proteins of crucial importance for telomere function. Telomeric DNA is shortened by each cell division until a critical length is achieved and the cell enters senescence and eventually apoptosis. Telomeres are therefore considered a ‘biological clock’ of the cell. Telomerase adds nucleotides to telomeric DNA thereby contributing to telomere maintenance, genomic stability, functions, and proliferative capacity of the cell. In certain rare forms of progeria, point mutations within the telomere lead to accelerated telomere attrition and premature aging.Endogenous factors causing telomere shortening are aging, inflammation, and oxidative stress. Leukocyte telomere length (LTL) shortening is inhibited by estrogen and endogenous antioxidants. Accelerated telomere attrition is associated with cardiovascular risk factors such as age, gender, obesity, smoking, sedentary life-style, excess alcohol i...
TL;DR: Visceral fat reduction with life-style modification is a potentially useful strategy in the prevention of ACVD in patients with the metabolic syndrome and through health promotion programs using risk factor-oriented approaches may be effective in reducing ACVD events.
Abstract: Atherosclerosis, the underlying cause of atherosclerotic cardiovascular disease (ACVD), develops due not only to a single cardiovascular risk factor but to a variety of complex factors. The concept...
TL;DR: Improving the efficiency of existing aerosolized therapy to direct drug to the appropriate lung regions may improve clinical efficacy and large studies are needed to determine whether better distal lung deposition leads to improvements in small airways function that are translated into clinically significant patient outcomes.
Abstract: Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory disorders of the respiratory tract that are characterized by airflow limitation. They are distinct conditions with different causes, structural changes, and immunopathology. The pathophysiology in asthma and COPD involves not only the proximal large airways, but also the distal small airways, and thus the small airways are an important therapeutic target in the treatment of both diseases. The assessment of diseased distal small airways is challenging. Extensive disease can be present in the small airways with little abnormality in conventional pulmonary function tests. Recent advances in imaging technologies have led to better spatial resolution to assess small airways morphology non-invasively. New physiological tests have been developed to detect disease and response to therapy in regional airways. Improving the efficiency of existing aerosolized therapy to direct drug to the appropriate lung regions may improve clinical efficacy. Approaches to target distal lung regions include developing new drug formulations with smaller aerosol particle size or using inhaler devices that emit aerosolized drug at slow inhalation flows. Large studies are needed to determine whether better distal lung deposition leads to improvements in small airways function that are translated into clinically significant patient outcomes.
TL;DR: In this paper, an intervention group had a larger decrease in the frequency of night-time hot flushes based on phone diary (P for month X group = 0.012), but not on WHQ scale.
Abstract: Background and objective. To estimate whether aerobic training has an effect on frequency of hot flushes or quality of life.
Design. A randomized controlled trial.
Participants and setting. Symptomatic, sedentary women (n = 176), 43–63 years, no current use of hormone therapy.
Intervention. Unsupervised aerobic training for 50 minutes four times per week during 6 months.
Outcomes. Hot flushes as measured with Women's Health Questionnaire (WHQ) and Health-Related Quality of Life (HRQoL, SF-36), daily reported hot flushes on phone-based diary, cardiorespiratory fitness (CRF), and body composition.
Results. Intervention group had larger decrease in the frequency of night-time hot flushes based on phone diary (P for month X group = 0.012), but not on WHQ scale. Intervention group had less depressed mood (P= 0.01) than control women according to change in WHQ score. Changes in WHQ score in depressed mood (P = 0.03) and menstrual symptoms (P=0.01) in the intervention group were significantly dependent on frequency of training sessions. HRQoL was improved among the intervention group women in physical functioning (P= 0.049) and physical role limitation (P= 0.017). CRF improved (P= 0.008), and lean muscle mass increased (P= 0.046) significantly in the intervention group as compared to controls.
Conclusions. Aerobic training may decrease the frequency of hot flushes and improve quality of life among slightly overweight women.
TL;DR: This review highlights recent advances in understanding of how Golgi acidity is maintained and regulated, and how its misregulation contributes to organelle dysfunction and disease.
Abstract: Most organelles within the exocytic and endocytic pathways typically acidify their interiors, a phenomenon that is known to be crucial for their optimal functioning in eukaryotic cells. This review highlights recent advances in our understanding of how Golgi acidity is maintained and regulated, and how its misregulation contributes to organelle dysfunction and disease. Both its biosynthetic products (glycans) and protein-sorting events are highly sensitive to changes in Golgi luminal pH and are affected in certain human disease states such as cancers and cutis laxa. Other potential disease states that are caused by, or are associated with, Golgi pH misregulation will also be discussed.
TL;DR: This review focuses on the stem cell–extracellular matrix interactions by summarizing the observations of the effects of material variables (such as overall architecture, surface topography, charge, ζ-potential, surface energy, and elastic modulus) on thestem cell fate.
Abstract: Regenerative medicine is a multidisciplinary field utilizing the potential of stem cells and the regenerative capability of the body to restore, maintain, or enhance tissue and organ functions. Stem cells are unspecialized cells that can self-renew but also differentiate into several somatic cells when subjected the appropriate environmental cues. The ability to reliably direct stem cell fate would provide tremendous potential for basic research and clinical therapies. Proper tissue function and regeneration rely on the spatial and temporal control of biophysical and biochemical cues, including soluble molecules, cell-cell contacts, cell-extracellular matrix contacts, and physical forces. The mechanisms involved remain poorly understood. This review focuses on the stem cell-extracellular matrix interactions by summarizing the observations of the effects of material variables (such as overall architecture, surface topography, charge, ζ-potential, surface energy, and elastic modulus) on the stem cell fate. It also deals with the mechanisms underlying the effects of these extrinsic, material variables. Insight in the environmental interactions of the stem cells is crucial for the development of new material-based approaches for cell culture experiments and future experimental and clinical regenerative medicine applications.
TL;DR: These population-based data are consistent with the idea that the beneficial effects of PA on CHD risk are mediated by favorable influences on several risk factors, as judged by independent relations to markers of lipoprotein metabolism, glucose metabolism, and inflammation.
Abstract: Objective. Physical activity (PA) may reduce the risk of coronary heart disease (CHD) by inducing beneficial changes in several risk factors. We studied the associations between PA and a range of risk markers of CHD in young adults.Methods and results. We measured serum lipoproteins, oxidized LDL, adipokines, inflammatory markers, metabolic markers, and arginine metabolites in 2,268 individuals (age 24–39 y). Participants were asked frequency, duration, and intensity of PA in leisure time. In addition, commuting to work was assessed. In both sexes, PA was inversely associated with waist circumference (all P < 0.0001). After controlling for sex, age, and waist circumference, PA was directly associated with HDL-cholesterol and apolipoprotein A1, and inversely with heart rate, smoking, oxidized LDL, apolipoprotein B, insulin, glucose, C-reactive protein, leptin, L-arginine, and phospholipase A2 activity (all P < 0.05).Conclusion. These population-based data are consistent with the idea that the benef...
TL;DR: The results are mixed, and the next objectives should be to combine knowledge and experience obtained in the past from animal models and channel future work to translate this into clinical trials in surgical and interventional reperfusion therapy as well as organ transplantation.
Abstract: Reperfusion of an organ following prolonged ischemia instigates the pro-inflammatory and pro-coagulant response of ischemia / reperfusion (IR) injury. IR injury is a wide-spread pathology, observed in many clinically relevant situations, including myocardial infarction, stroke, organ transplantation, sepsis and shock, and cardiovascular surgery on cardiopulmonary bypass. Activation of the classical, alternative, and lectin complement pathways and the generation of the anaphylatoxins C3a and C5a lead to recruitment of polymorphonuclear leukocytes, generation of radical oxygen species, up-regulation of adhesion molecules on the endothelium and platelets, and induction of cytokine release. Generalized or pathway-specific complement inhibition using protein-based drugs or low-molecular-weight inhibitors has been shown to significantly reduce tissue injury and improve outcome in numerous in-vitro, ex-vivo, and in-vivo models. Despite the obvious benefits in experimental research, only few complement in...
TL;DR: Results from healthy volunteers support the notion that metformin pharmacokinetics can be affected by polymorphisms in genes encoding organic cation transporters, and the likely multifactorial nature of met formin response masks the effects of transporter polymorphisms observed in some clinical studies.
Abstract: Considerable interindividual variability in clinical efficacy is recognized in the treatment of type 2 diabetes mellitus with the biguanide metformin. Metformin is a substrate of organic cation transporters, which play important roles in gastrointestinal absorption, renal and biliary elimination, and distribution to target sites of substrate drugs. This raises the question of whether genetic variations in these transporters affect efficacy and risk of adverse events associated with metformin use. In this review, the pharmacogenetics of metformin is discussed in the light of the most recent literature. Overall, results from healthy volunteers support the notion that metformin pharmacokinetics can be affected by polymorphisms in genes encoding organic cation transporters. When considering the glycemic response to metformin in patients, however, the likely multifactorial nature of metformin response masks the effects of transporter polymorphisms observed in some clinical studies.
TL;DR: The role of the renin-angiotensin-aldosterone system, sympathetic nervous system, and inflammation in relation to the pathophysiology of obesity-related hypertension is reviewed.
Abstract: The advent of the obesity epidemic has highlighted the need to re-assess more closely the pathophysiology of obesity-related hypertension with the aim of identifying new therapies. In this article, we review the role of the renin-angiotensin-aldosterone system, sympathetic nervous system, and inflammation in relation to the pathophysiology of this condition. We also discuss the potential role of the perivascular adipose tissue in the context of obesity-related hypertension.
TL;DR: In older adults living in Finland, DBI was associated with impaired function on previously tested and new outcomes, and this finding supports the use of the DBI as tool, in combination with other assessments, to identify older people at risk of functional impairment.
Abstract: Background. This cross-sectional study aimed to investigate the relationship between exposure to anticholinergic and sedative medications, measured with the Drug Burden Index (DBI), and functional outcomes in community-dwelling older people living in Finland.Methods. The study population consisted of community-dwelling older people (n = 700) enrolled in the Geriatric Multidisciplinary Strategy for the Good Care of the Elderly (GeMS) study. Outcomes included walking speed, chair stands test, grip strength, timed up and go (TUG) test, instrumental activities of daily living (IADL), and Barthel Index.Results. Exposure to DBI drugs was identified in 37% of participants: 24% had a DBI range between >0 <1, and 13% DBI ≥1. After adjusting for confounders, exposure to DBI drugs was associated with slower walking speed (P < 0.0001), poorer performance on chair stands (P = 0.0001) and TUG (P < 0.0001), difficulties in IADL (P < 0.0001), and Barthel Index (P < 0.0001). The mean adjusted walking speed, time t...
TL;DR: Already mildly decreased G FR-Mayo increases the risk of ischemic fatal or non-fatal stroke and severely decreased GFR- Mayo the risk for hemorrhagic stroke in the general population, and in gender-specific analyses isChemic stroke was related to a decreased Gfr-MayO in both genders.
Abstract: Aims. The association between chronic kidney disease (CKD) and different subtypes of stroke is unclear, and previous studies have yielded conflicting results. We aimed to assess the impact of CKD on the risk of fatal or non-fatal ischemic and hemorrhagic stroke in both men and women.Methods. In 539,287 Swedish men and women, mainly undergoing health controls, with mean age 45 years, and no previous stroke or myocardial infarction, hazard ratios for stroke were calculated to assess the association between renal dysfunction and incidence of stroke. We estimated glomerular filtration rates (GFR) using the Mayo (GFR-Mayo) formula. Glomerular filtration rate 60–90, 30–60, and 15–30 mL per minute per 1.73 m2 was defined as mildly, moderately, and severely decreased GFR, respectively.Results. There were 17,678 strokes, of which 72% were ischemic, 15% hemorrhagic, and 12% unspecified, during 12 years of follow-up. Hazard ratios (95% confidence intervals) for ischemic stroke were 1.09 (1.04–1.14) for mildl...
TL;DR: A better understanding of the mechanisms of statin handling will help to minimize adverse effects and interactions, as well as to improve their lipid-lowering efficiency.
Abstract: Statins represent a major advance in the treatment of hypercholesterolemia, a significant risk factor for atherosclerosis. There is, however, notable interindividual variation in the cholesterolemic response to statins, and the origin of this variability is poorly understood; pharmacogenetics has attempted to determine the role of genetic factors. Myopathy, further, has been reported in a considerable percentage of patients, but the mechanisms underlying muscle injury have yet to be fully characterized. Most statins are the substrates of several cytochrome P450s (CYP). CYP polymorphisms may be responsible for variations in hypolipidemic activity; inhibitors of CYPs, e.g. of CYP3A4, can significantly raise plasma concentrations of several statins, but consequences in terms of clinical efficacy are not uniform. Pravastatin and rosuvastatin are not susceptible to CYP inhibition but are substrates of the organic anion-transporting polypeptide (OATP) 1B1, encoded by the SLCO1B1 gene. Essentially all statins are, in fact, substrates of membrane transporters: SLCO1B1 polymorphisms can decrease the liver uptake, as well as the therapeutic potential of these agents, and may be linked to their muscular side-effects. A better understanding of the mechanisms of statin handling will help to minimize adverse effects and interactions, as well as to improve their lipid-lowering efficiency.
TL;DR: Experimental and clinical evidence shows that adaptive transfer of immune cells, rendering mice deficient for a certain subset ofimmune cells, or immunosuppressive treatment affects blood pressure and ameliorates target-organ damage.
Abstract: Inflammation and activation of immunity are central features in the pathogenesis of atherosclerosis, ischemic myocardial injury, and hypertension-induced target-organ damage. The renin-angiotensin-aldosterone system can initiate not only innate but also acquired immunity. The latter process includes formation of activating antibodies directed at the angiotensin (Ang) II receptor. Ang II not only regulates vascular tone and sodium balance, but also activates immune cells and promotes cell infiltration into target organs. Studies showed that macrophages and various T cell subtypes play a pivotal role in target-organ damage and even in the regulation of blood pressure and responses to Ang II. Experimental and clinical evidence shows that adaptive transfer of immune cells, rendering mice deficient for a certain subset of immune cells, or immunosuppressive treatment affects blood pressure and ameliorates target-organ damage. Neural mechanisms interact with and regulate these processes. Understanding the mechanisms could direct us to novel therapies.
TL;DR: It is shown that the complement system becomes activated via the alternative pathway in the acute stage of PUUV infection and the level of activation correlates with disease severity, which suggests that complement activation may contribute to the pathogenesis of acute PU UV infection.
Abstract: Introduction. Hantaviruses are important human pathogens that cause clinical diseases characterized by renal and cardiopulmonary manifestations. Their pathogenesis is currently poorly understood. We have studied the role of the complement system in the pathogenesis of Puumala (PUUV) hantavirus infection.Material and methods. We studied the activation of complement by measuring the terminal complement complex SC5b-9 and complement component C3 and C4 levels in patients with acute PUUV infection. Several laboratory parameters and clinical findings reflecting the severity of PUUV-HFRS were evaluated with regard to complement activation. Results.The levels of SC5b-9 were significantly increased and C3 decreased in the acute stage as compared to the levels at full recovery (P < 0.001). We found that SC5b-9 levels were higher in patients with chest X-ray abnormalities than in patients with a normal X-ray during the acute stage (P = 0.028). Furthermore, SC5b-9 and C3 levels showed significant correlation...
TL;DR: Estimating cardiovascular risk goes well beyond the assessment of glycemic control and traditional CVD risk factors, and the estimation of visceral/ectopic fat deposition via readily available imaging techniquesshould be considered.
Abstract: Although excess body fat is a significant health hazard, estimation of body fat content with the body mass index may not adequately reflect the amount of atherogenic adipose tissue (AT), i.e. visceral and ectopic fat. As opposed to subcutaneous AT that supposedly acts as a metabolic sink buffering excess dietary energy, visceral or intra-abdominal AT depots respond to several external stimuli that trigger lipolysis and secretion of free fatty acids (FFAs). Reaching the liver, FFAs accumulate in the liver and, over time, promote a chronic condition known as non-alcoholic fatty liver disease (NAFLD). The liver of the typical NAFLD patient secretes large amounts of very-low-density lipoproteins, the lipid content of which may accumulate in additional organs (skeletal muscle, heart, and pancreas). Here, we review the evidence emerging from functional and population studies that point towards an important role of ectopic fat accumulation in the pathophysiology of type 2 diabetes and cardiovascular disease. We conclude that although patients with impaired glycemic control or type 2 diabetes are at increased cardiovascular disease (CVD) risk, estimating cardiovascular risk goes wellbeyond the assessment of glycemic control and traditional CVD risk factors, and the estimation of visceral/ectopic fat deposition via readily available imaging techniquesshould be considered.
TL;DR: It is demonstrated for the first time it is demonstrated that increased general body mass and particularly waist circumference and intra-abdominal fat are related to thicker and stiffer arteries already early in life.
Abstract: Background. It is unknown at what age overweight starts to takes its toll on the vasculature. We studied the relation between body size measures and vascular characteristics in healthy 5-year-old children. Methods. In 306 5-year-old children from an on-going birth cohort, body size characteristics were measured, including sonographic measurement of abdominal fat. Ultrasonographic measurements of the carotid artery were performed to obtain intima-media thickness (CIMT), arterial wall distensibility, and elastic modulus (EM). Results. Increased body-weight was related to thicker CIMT (linear regression coefficient 2.25 μm/kg; P = 0.003), increased EM (2.73 kPa/kg; P = 0.01), and lower distensibility (−1.23 MPa−1/kg; P = 0.03). Similar relations were found for increased BMI with CIMT and EM. Increased intra-abdominal fat was related to thicker CIMT (9.19 μm/cm; P = 0.02), and increased waist circumference with thicker CIMT (2.17 μm/cm; P = 0.02), lower distensibility (−1.70 MPa−1/cm; P = 0.01), and h...