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.
The modern era of drug development for A lzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for A lzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for A lzheimer's disease during the past 30 years, considering the drugs, potential targets, late‐stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late‐stage A lzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta‐analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild‐to‐moderate A lzheimer's disease criteria, recently extending to early or prodromal A lzheimer disease or ‘mild cognitive impairment due to A lzheimer's disease’, for drugs considered to be disease modifying. The duration of trials has remained at 6–12 months for drugs intended to improve symptoms; 18‐ to 24‐month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early‐stage A lzheimer's disease trial samples using biomarkers and phase‐specific outcomes. In conclusion, validated drug targets for A lzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late‐phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.
The construct of mild cognitive impairment ( MCI ) has evolved over the past 10 years since the publication of the new MCI definition at the K ey S ymposium in 2003, but the core criteria have remained unchanged. The construct has been extensively used worldwide, both in clinical and in research settings, to define the grey area between intact cognitive functioning and clinical dementia. A rich set of data regarding occurrence, risk factors and progression of MCI has been generated. Discrepancies between studies can be mostly explained by differences in the operationalization of the criteria, differences in the setting where the criteria have been applied, selection of subjects and length of follow‐up in longitudinal studies. Major controversial issues that remain to be further explored are algorithmic versus clinical classification, reliability of clinical judgment, temporal changes in cognitive performances and predictivity of putative biomarkers. Some suggestions to further develop the MCI construct include the tailoring of the clinical criteria to specific populations and to specific contexts. The addition of biomarkers to the clinical phenotypes is promising but requires deeper investigation. Translation of findings from the specialty clinic to the population setting, although challenging, will enhance uniformity of outcomes. More longitudinal population‐based studies on cognitive ageing and MCI need to be performed to clarify all these issues.
Atherosclerosis is a maladaptive, nonresolving chronic inflammatory disease that occurs at sites of blood flow disturbance. The disease usually remains silent until a breakdown of integrity at the arterial surface triggers the formation of a thrombus. By occluding the lumen, the thrombus or emboli detaching from it elicits ischaemic symptoms that may be life‐threatening. Two types of surface damage can cause atherothrombosis: plaque rupture and endothelial erosion. Plaque rupture is thought to be caused by loss of mechanical stability, often due to reduced tensile strength of the collagen cap surrounding the plaque. Therefore, plaques with reduced collagen content are thought to be more vulnerable than those with a thick collagen cap. Endothelial erosion, on the other hand, may occur after injurious insults to the endothelium instigated by metabolic disturbance or immune insults. This review discusses the molecular mechanisms involved in plaque vulnerability and the development of atherothrombosis.
Dendrimers are discrete nanostructures/nanoparticles with ‘onion skin‐like’ branched layers. Beginning with a core, these nanostructures grow in concentric layers to produce stepwise increases in size that are similar to the dimensions of many in vivo globular proteins. These branched tree‐like concentric layers are referred to as ‘generations’. The outer generation of each dendrimer presents a precise number of functional groups that may act as a monodispersed platform for engineering favourable nanoparticle–drug and nanoparticle–tissue interactions. These features have attracted significant attention in medicine as nanocarriers for traditional small drugs, proteins, DNA / RNA and in some instances as intrinsically active nanoscale drugs. Dendrimer‐based drugs, as well as diagnostic and imaging agents, are emerging as promising candidates for many nanomedicine applications. First, we will provide a brief survey of recent nanomedicines that are either approved or in the clinical approval process. This will be followed by an introduction to a new ‘nanoperiodic’ concept which proposes nanoparticle structure control and the engineering of ‘critical nanoscale design parameters’ ( CNDP s) as a strategy for optimizing pharmocokinetics, pharmocodynamics and site‐specific targeting of disease. This paradigm has led to the emergence of CNDP ‐directed nanoperiodic property patterns relating nanoparticle behaviour to critical in vivo clinical translation issues such as cellular uptake, transport, elimination, biodistribution, accumulation and nanotoxicology. With a focus on dendrimers, these CNDP ‐directed nanoperiodic patterns are used as a strategy for designing and optimizing nanoparticles for a variety of drug delivery and imaging applications, including a recent dendrimer‐based theranostic nanodevice for imaging and treating cancer. Several emerging preclinical dendrimer‐based nanotherapy concepts related to inflammation, neuro‐inflammatory disorders, oncology and infectious and ocular diseases are reviewed. Finally we will consider challenges and opportunities anticipated for future clinical translation, nanotoxicology and the commercialization of nanomedicine.
Biofilm formation of microorganisms causes persistent tissue and foreign body infections resistant to treatment with antimicrobial agents. Up to 80% of human bacterial infections are biofilm associated; such infections are most frequently caused by S taphylococcus epidermidis , P seudomonas aeruginosa , S taphylococcus aureus and E nterobacteria such as E scherichia coli . The accurate diagnosis of biofilm infections is often difficult, which prevents the appropriate choice of treatment. As biofilm infections significantly contribute to patient morbidity and substantial healthcare costs, novel strategies to treat these infections are urgently required. Nucleotide second messengers, c‐di‐ GMP , (p)pp G pp and potentially c‐di‐ AMP , are major regulators of biofilm formation and associated antibiotic tolerance. Consequently, different components of these signalling networks might be appropriate targets for antibiofilm therapy in combination with antibiotic treatment strategies. In addition, cyclic di‐nucleotides are microbial‐associated molecular patterns with an almost universal presence. Their conserved structures sensed by the eukaryotic host have a widespread effect on the immune system. Thus, cyclic di‐nucleotides are also potential immunotherapeutic agents to treat antibiotic‐resistant bacterial infections.
Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles ACP, Speight N, Vallings R, Bateman L, Baumgarten‐Austrheim B, Bell DS, Carlo‐Stella N, Chia J, Darragh A, Jo D, Lewis D, Light AR, Marshall‐Gradisbik S, Mena I, Mikovits JA, Murovska M, Pall ML, Stevens S (Independent, Vancouver, BC, Canada; Independent, Calgary, AB, Canada; Department of Physiology and Medicine, Vrije University of Brussels, Himmunitas Foundation, Brussels, Belgium; Department of Medicine,University of Miami Miller School of Medicine and Miami Veterans Affairs Medical Center, Miami, FL, USA; Department of Medicine, University of Alberta, Edmonton, AB, Canada; Honorary Consultant for NHS at Peterborough/Cambridge, Lowestoft, Suffolk, UK; Gold Coast Public Health Unit, Southport, Queensland; Health Sciences and Medicine, Bond University, Robina, Queensland, Australia; Faculty of Health Sciences, McMaster University and St Joseph’s Healthcare Hamilton, Hamilton, ON, Canada; Independent, Durham, UK; Howick Health and Medical Centre, Howick, New Zealand; Fatigue Consultation Clinic, Salt Lake Regional Medical Center; Internal Medicine, Family Practice, University of Utah, Salt Lake City, UT, USA; ME/CFS Center, Oslo University Hospital HF, Norway; Department of Paediatrics, State University of New York, Buffalo, NY; Independent, Pavia, Italy; Harbor‐UCLA Medical Center, University of California, Los Angeles, CA; EV Med Research, Lomita, CA, USA; University of Limerick, Limerick, Ireland; Pain Clinic, Konyang University Hospital, Daejeon, Korea; Donvale Specialist Medical Centre, Donvale, Victoria, Australia; Departments or Anesthesiology, Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah, USA; Health Sciences and Medicine, Bond University, Robina, Queensland, Australia; Department of Medicina Nuclear, Clinica Las Condes, Santiago, Chile; Whittemore Peterson Institute, University of Nevada, Reno, NV, USA; Miwa Naika Clinic, Toyama, Japan; A. Kirchenstein Institute of Microbiology and Virology, Riga Stradins University, Riga, Latvia; Department of Biochemistry & Basic Medical Sciences, Washington State University, Portland, OR; Department of Sports Sciences, University of the Pacific, Stockton, CA USA). Myalgic encephalomyelitis: International Consensus Criteria (Review). J Intern Med 2011; 270 : 327–338. The label ‘chronic fatigue syndrome’ (CFS) has persisted for many years because of the lack of knowledge of the aetiological agents and the disease process. In view of more recent research and clinical experience that strongly point to widespread inflammation and multisystemic neuropathology, it is more appropriate and correct to use the term ‘myalgic encephalomyelitis’ (ME) because it indicates an underlying pathophysiology. It is also consistent with the neurological classification of ME in the World Health Organization’s International Classification of Diseases (ICD G93.3). Consequently, an International Consensus Panel consisting of clinicians, researchers, teaching faculty and an independent patient advocate was formed with the purpose of developing criteria based on current knowledge. Thirteen countries and a wide range of specialties were represented. Collectively, members have approximately 400 years of both clinical and teaching experience, authored hundreds of peer‐reviewed publications, diagnosed or treated approximately 50 000 patients with ME, and several members coauthored previous criteria. The expertise and experience of the panel members as well as PubMed and other medical sources were utilized in a progression of suggestions/drafts/reviews/revisions. The authors, free of any sponsoring organization, achieved 100% consensus through a Delphi‐type process. The scope of this paper is limited to criteria of ME and their application. Accordingly, the criteria reflect the complex symptomatology. Operational notes enhance clarity and specificity by providing guidance in the expression and interpretation of symptoms. Clinical and research application guidelines promote optimal recognition of ME by primary physicians and other healthcare providers, improve the consistency of diagnoses in adult and paediatric patients internationally and facilitate clearer identification of patients for research studies.
Sofi F, Valecchi D, Bacci D, Abbate R, Gensini GF, Casini A, Macchi C (Centro S. Maria agli Ulivi, Onlus IRCCS; Thrombosis Centre, University of Florence; Azienda Ospedaliero‐Universitaria Careggi, Florence, Italy) Physical activity and risk of cognitive decline: a meta‐analysis of prospective studies. J Intern Med 2011; 269 : 107–117. Objective. The relationship between physical activity and cognitive function is intriguing but controversial. We performed a systematic meta‐analysis of all the available prospective studies that investigated the association between physical activity and risk of cognitive decline in nondemented subjects. Methods. We conducted an electronic literature search through MedLine, Embase, Google Scholar, Web of Science, The Cochrane Library and bibliographies of retrieved articles up to January 2010. Studies were included if they analysed prospectively the association between physical activity and cognitive decline in nondemented subjects. Results. After the review process, 15 prospective studies (12 cohorts) were included in the final analysis. These studies included 33 816 nondemented subjects followed for 1–12 years. A total of 3210 patients showed cognitive decline during the follow‐up. The cumulative analysis for all the studies under a random‐effects model showed that subjects who performed a high level of physical activity were significantly protected (−38%) against cognitive decline during the follow‐up (hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.54–0.70; P < 0.00001). Furthermore, even analysis of low‐to‐moderate level exercise also showed a significant protection (−35%) against cognitive impairment (HR 0.65, 95% CI 0.57–0.75; P < 0.00001). Conclusion. This is the first meta‐analysis to evaluate the role of physical activity on cognitive decline amongst nondemented subjects. The present results suggest a significant and consistent protection for all levels of physical activity against the occurrence of cognitive decline.
Nanotechnology, nanomedicine and nanotoxicology are complementary disciplines aimed at the betterment of human life. However, concerns have been expressed about risks posed by engineered nanomaterials (ENMs), their potential to cause undesirable effects, contaminate the environment and adversely affect susceptible parts of the population. Information about toxicity and biokinetics of nano-enabled products combined with the knowledge of unintentional human and environmental exposure or intentional delivery for medicinal purposes will be necessary to determine real or perceived risks of nanomaterials. Yet, results of toxicological studies using only extraordinarily high experimental doses have to be interpreted with caution. Key concepts of nanotoxicology are addressed, including significance of dose, dose rate, and biokinetics, which are exemplified by specific findings of ENM toxicity, and by discussing the importance of detailed physico-chemical characterization of nanoparticles, specifically surface properties. Thorough evaluation of desirable versus adverse effects is required for safe applications of ENMs, and major challenges lie ahead to answer key questions of nanotoxicology. Foremost are assessment of human and environmental exposure, and biokinetics or pharmacokinetics, identification of potential hazards, and biopersistence in cells and subcellular structures to perform meaningful risk assessments. A specific example of multiwalled carbon nanotubes (MWCNT) illustrates the difficulty of extrapolating toxicological results. MWCNT were found to cause asbestos-like effects of the mesothelium following intracavitary injection of high doses in rodents. The important question of whether inhaled MWCNT will translocate to sensitive mesothelial sites has not been answered yet. Even without being able to perform a quantitative risk assessment for ENMs, due to the lack of sufficient data on exposure, biokinetics and organ toxicity, until we know better it should be made mandatory to prevent exposure by appropriate precautionary measures/regulations and practicing best industrial hygiene to avoid future horror scenarios from environmental or occupational exposures. Similarly, safety assessment for medical applications as key contribution of nanotoxicology to nanomedicine relies heavily on nano-specific toxicological concepts and findings and on a multidisciplinary collaborative approach involving material scientists, physicians and toxicologists.
In this review we summarize the current understanding of signal transduction downstream of vascular endothelial growth factor A ( VEGFA ) and its receptor VEGFR 2, 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 ( ERK s), Src, phosphoinositide 3 kinase ( PI 3K)/Akt, focal adhesion kinase ( FAK ), Rho family GTP ases, 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.
The prevalence of carbapenem‐resistant Gram‐negative bacilli is on the rise worldwide, posing a major public health threat. Previously, this was mostly a problem in Pseudomonas and Acinetobacter, but during the last decade, carbapenem resistance has escalated in medically important species such as Klebsiella pneumoniae and Escherichia coli . In particular, the rising trend in E. coli is of concern, as this may lead to almost untreatable community‐acquired infections. Resistance is conferred by carbapenemases, which are beta‐lactamases that can breakdown essentially all beta‐lactams. Moreover, bacteria carrying these resistance determinants are often resistant to other treatment options, due to the frequent co‐acquisition of non‐beta‐lactam resistance genes located on the same mobile genetic elements. The detection of carbapenemase‐producing Enterobacteriaceae ( CPE ) is a challenge, because some carbapenemases produce relatively discrete levels of carbapenem resistance. Current clinical evidence for treatment guidance is limited and based on retrospective observational studies and case reports. Existing data support the use of combination therapy for treatment of severe infections caused by CPE . Combination regimens including colistin, carbapenems, tigecycline, aminoglycosides and fosfomycin have been used. Randomized controlled studies of combination regimens are ongoing and may help to determine the optimal therapy. Novel beta‐lactamase inhibitors may also have a role in future treatment of these infections. Strict infection control measures including isolation or cohort care of affected patients as well as contact tracing and active screening are needed to curb the spread of CPE . In this review, we provide a clinical perspective on the management of patients infected or colonized with CPE .
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.
Background and objectivesIn the past two decades, an increasing number of nationwide, Swedish Healthcare Quality Registries (QRs) focusing on specific disorders have been initiated, mostly by physicians. Here, we describe the purpose, organization, variables, coverage and completeness of 103 Swedish QRs. MethodsFrom March to September 2013, we examined the 2012 applications of 103 QRs to the Swedish Association of Local Authorities and Regions (SALAR) and also studied the annual reports from the same QRs. After initial data abstraction, the coordinator of each QR was contacted at least twice between June and October 2013 and asked to confirm the accuracy of the data retrieved from the applications and reports. ResultsAbout 60% of the QRs covered 80% of their target population (completeness). Data recorded in Swedish QRs include aspects of disease management (diagnosis, clinical characteristics, treatment and lead times). In addition, some QRs retrieve data on self-reported quality of life (EQ5D, SF-36 and disease-specific measures), lifestyle (smoking) and general health status (World Health Organization performance status, body mass index and blood pressure). ConclusionDetailed clinical data available in Swedish QRs complement information from government-administered registries and provide an important source not only for assessment and development of quality of care but also for research.
Primary adrenal insufficiency ( PAI ), or Addison's disease, is a rare, potentially deadly, but treatable disease. Most cases of PAI are caused by autoimmune destruction of the adrenal cortex. Consequently, patients with PAI are at higher risk of developing other autoimmune diseases. The diagnosis of PAI is often delayed by many months, and most patients present with symptoms of acute adrenal insufficiency. Because PAI is rare, even medical specialists in this therapeutic area rarely manage more than a few patients. Currently, the procedures for diagnosis, treatment and follow‐up of this rare disease vary greatly within Europe. The common autoimmune form of PAI is characterized by the presence of 21‐hydroxylase autoantibodies; other causes should be sought if no autoantibodies are detected. Acute adrenal crisis is a life‐threatening condition that requires immediate treatment. Standard replacement therapy consists of multiple daily doses of hydrocortisone or cortisone acetate combined with fludrocortisone. Annual follow‐up by an endocrinologist is recommended with the focus on optimization of replacement therapy and detection of new autoimmune diseases. Patient education to enable self‐adjustment of dosages of replacement therapy and crisis prevention is particularly important in this disease. The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addison's disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortium's investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow‐up.
Expression of the micro RNA 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, IKK α, Roquin and STAT 3. With regard to cancer, validated targets include C/ EBP β, E2F1, FOXO 1 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 micro RNA 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 NLRP 3 inflammasome are important inflammatory mechanisms that are dampened by miR‐223 in these cell types. The mi RNA 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.
Plasma lipoprotein(a) [ L p(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, L p(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 L p(a) levels in plasma and risk of CHD , thereby fulfilling the main criterion for causality in a M endelian 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 L p(a) is considered as one of the possible mechanisms that may explain the pathogenicity of L p(a). Drugs that have been shown to lower L p(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 L p(a) by apheresis in high‐risk patients with already maximally reduced low‐density lipoprotein cholesterol levels can dramatically reduce major coronary events.
. de Boer RA, van Veldhuisen DJ, Gansevoort RT, Muller Kobold AC, van Gilst WH, Hillege HL, Bakker SJL, van der Harst P (University of Groningen). The fibrosis marker galectin-3 and outcome in the general population. J Intern Med 2012; 272: 5564. Objective. Galectin-3 is involved in fibrosis and inflammation and plays a role in heart failure, renal disease, obesity and cancer. We aimed to establish the relationship between galectin-3 and cardiovascular (CV) risk factors and mortality in the general population. Design and subjects. This study included 7968 subjects from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort, with a median follow-up of approximately 10 years. Plasma galectin-3 was measured in baseline samples. Main outcome measures. We investigated the relationships between galectin-3 levels, demographic characteristics and risk factors of CV disease. We determined the prognostic value for all-cause, CV and cancer mortality. Results. The mean age of the population was 50 +/- 13 years. Mean blood pressure was 129/74 mmHg, mean cholesterol was 5.7 +/- 1.1 mmol L-1 and median galectin-3 was 10.9 ng mL-1 [interquartile range (IQR) 9.013.1]. Galectin-3 levels correlated with a wide range of risk factors of CV disease, including blood pressure, serum lipids, body mass index, renal function and N-terminal pro-B-type natriuretic peptide (P <0.0001). We observed a strong association between galectin-3 and age. Furthermore, we found a gender interaction, with female subjects (n = 4001) having higher median galectin-3 levels (11.0 ng mL-1, IQR 9.113.4 vs. men (n = 3967) 10.7 ng mL-1, IQR 8.912.8; P <0.0001), and galectin-3 levels in women more strongly correlated with risk factors of CV disease. After correction for the classical CV risk factors (smoking, blood pressure, cholesterol and diabetes), galectin-3 levels independently predicted all-cause mortality (hazard ratio per SD galectin-3 1.09, 95% CI 1.011.19; P = 0.036), but not CV and cancer mortality separately. Conclusions. Galectin-3 is associated with age and risk factors of CV disease, with a strong gender interaction for these correlations. Galectin-3 predicts all-cause mortality in the general population.
Ahlehoff O, Gislason GH, Charlot M, Jørgensen CH, Lindhardsen J, Olesen JB, Abildstrøm SZ, Skov L, Torp‐Pedersen C, Hansen PR. (Copenhagen University Hospital Gentofte, Hellerup; Copenhagen University Hospital Bispebjerg, Copenhagen; National Institute of Public Health, University of Southern Denmark, Copenhagen; Copenhagen University Hospital Gentofte, Hellerup; University of Copenhagen, Copenhagen, Denmark) Psoriasis is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study. J Intern Med 2011; 270 : 147–157. Objective. The magnitude of the cardiovascular risk from psoriasis and psoriatic arthritis is debated. We therefore investigated the psoriasis‐related risk of adverse cardiovascular events and mortality. Design, setting and subjects. We conducted a cohort study of the entire Danish population aged ≥18 years followed from 1997 to 2006 by individual‐level linkage of nationwide registers. Psoriasis was defined by prescription claims and classified as severe if patients received hospital‐based treatment. Time‐dependent Poisson regression models were applied to assess cardiovascular risk in patients with psoriasis and psoriatic arthritis. Main outcome measures. All‐cause mortality, cardiovascular mortality and hospitalizations for myocardial infarction (MI), stroke and coronary revascularization were recorded. Results. A total of 34 371 patients with mild psoriasis and 2621 with severe psoriasis, including 607 with psoriatic arthritis, were identified and compared with 4 003 265 controls. The event rates and rate ratios (RRs) of all‐cause mortality, cardiovascular death, MI, coronary revascularization, stroke and a composite of MI, stroke and cardiovascular death were increased in patients with psoriasis. The rate ratio increased with disease severity and decreased with age of onset. The overall RRs for the composite endpoint were 1.20 (95% confidence interval [CI] 1.14–1.25) and 1.58 (95% CI 1.36–1.82) for mild and severe psoriasis, respectively. The corresponding RRs for cardiovascular death were 1.14 (95% CI 1.06–1.22) and 1.57 (95% CI1.27–1.94). The risk was similar in patients with severe skin affection alone and those with psoriatic arthritis. Conclusions. Psoriasis is associated with increased risk of adverse cardiovascular events and all‐cause mortality. Young age, severe skin affection and/or psoriatic arthritis carry the most risk. Patients with psoriasis may be candidates for early cardiovascular risk factor modification.
Atherosclerosis is a silent chronic vascular pathology that is the cause of the majority of cardiovascular ischaemic events. The evolution of vascular disease involves a combination of endothelial dysfunction, extensive lipid deposition in the intima, exacerbated innate and adaptive immune responses, proliferation of vascular smooth muscle cells and remodelling of the extracellular matrix, resulting in the formation of an atherosclerotic plaque. High‐risk plaques have a large acellular lipid‐rich necrotic core with an overlying thin fibrous cap infiltrated by inflammatory cells and diffuse calcification. The formation of new fragile and leaky vessels that invade the expanding intima contributes to enlarge the necrotic core increasing the vulnerability of the plaque. In addition, biomechanical, haemodynamic and physical factors contribute to plaque destabilization. Upon erosion or rupture, these high‐risk lipid‐rich vulnerable plaques expose vascular structures or necrotic core components to the circulation, which causes the activation of tissue factor and the subsequent formation of a fibrin monolayer (coagulation cascade) and, concomitantly, the recruitment of circulating platelets and inflammatory cells. The interaction between exposed atherosclerotic plaque components, platelet receptors and coagulation factors eventually leads to platelet activation, aggregation and the subsequent formation of a superimposed thrombus (i.e. atherothrombosis) which may compromise the arterial lumen leading to the presentation of acute ischaemic syndromes. In this review, we will describe the progression of the atherosclerotic lesion along with the main morphological characteristics that predispose to plaque rupture, and discuss the multifaceted mechanisms that drive platelet activation and subsequent thrombus formation. Finally, we will consider the current scientific challenges and future research directions.
ObjectivesRecent metabolomic, experimental and clinical studies have demonstrated that trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite from dietary phosphatidylcholine and carnitine, is a strong predictor of coronary artery disease (CAD). This finding suggests a link between the gut microbiota and atherosclerosis. The potential impact of TMAO in chronic heart failure (HF) is unknown. We hypothesized that TMAO levels would provide prognostic information about adverse outcomes in chronic HF. DesignProspective, observational study including 155 consecutive patients with chronic HF. In addition, 100 patients with stable CAD without HF and 33 matched healthy individuals were included as controls. Plasma levels of TMAO and its precursors choline and betaine were measured, and associations with symptoms, aetiology and transplant-free survival in the patients with HF were explored. ResultsPlasma levels of TMAO (P=0.01), choline (P<0.001) and betaine (P<0.001) were elevated in patients with chronic HF compared to control subjects, with the highest levels in patients with New York Heart Association (NYHA) classes III and IV. Furthermore, TMAO levels were highest in individuals with ischaemic HF, followed by those with stable CAD and nonischaemic HF. TMAO, but not choline or betaine, was associated with reduced transplant-free survival: approximately 50% of patients in the upper tertile of TMAO levels died or received a heart transplant during 5.2years of follow-up (unadjusted Cox-regression: hazard ratio 2.24, 95% confidence interval 1.28-3.92, P=0.005). ConclusionsTMAO levels were elevated in patients with HF and associated with NYHA class, ischaemic aetiology and adverse outcomes. Future studies should focus on gut microbiota, dietary composition and intestinal dysfunction in relation to TMAO levels and clinical outcome in HF.