Showing papers in "Journal of Internal Medicine in 2006"

The prevalence of vitamin D inadequacy amongst women with osteoporosis: an international epidemiological investigation.

Abstract: . Introduction. Vitamin D is essential for calcium metabolism as well as for fracture prevention, and a recent review suggested that the optimal serum 25(OH)D lies in the region of 50–80 nmol L−1 (20–32 ng mL−1). A high prevalence of inadequacy has been reported in many studies but the prevalence of inadequacy amongst women with osteoporosis in different regions of the world has not been well characterized. Setting and subjects. A multinational study of 18 countries at various latitudes (range 64N–38S) was conducted in 2004 and 2005 to determine the average levels of serum 25(OH)D and the prevalence of vitamin D inadequacy. A total of 2606 postmenopausal women with osteoporosis (low bone mineral density, history of fragility fracture) seeking routine medical care were enrolled and serum 25(OH)D levels were measured at a single laboratory visit. Results. Mean serum 25(OH)D level was 26.8 ng mL−1 (SE 0.3) and ranged from 7 to 243 ng mL−1. Regional mean values were highest in Latin America (29.6 ng mL−1, SE 0.6) and lowest in the Middle East (20.4 ng mL−1, SE 0.5). Overall, 64% of women had serum levels 35 ng mL−1. In nonequatorial countries, women recruited during the winter months had somewhat lower serum 25(OH)D levels than those recruited during the summer months in some, but not all, countries. Conclusions. Low levels of serum 25(OH)D are common amongst women with osteoporosis. The results underscore the value of assuring vitamin D adequacy in these women.

The apoB/apoA-I ratio: a strong, new risk factor for cardiovascular disease and a target for lipid-lowering therapy--a review of the evidence.

Abstract: During the last several years interest has focused on the importance of the lipid-transporting apolipoproteins--apoB transports all potentially atherogenic very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL particles, and apoA-I transports and acts as the major antiatherogenic protein in the HDL particles. The evidence for the apoB/apoA-I ratio being a strong, new risk factor for cardiovascular (CV) disease and a target for lipid-lowering therapy is reviewed. Results from clinical prospective studies and lipid-lowering trials in healthy subjects and in patients with different clinical manifestations of atherosclerosis are reported. Risk of nonfatal and fatal myocardial infarction and stroke, and manifestations of atherosclerosis documented by angiographic, ultrasound and other techniques has been related to conventional lipids and apolipoproteins (apo). The cholesterol balance determined as the apoB/apoA-I ratio has repeatedly been shown to be a better marker than lipids, lipoproteins and lipid ratios. The results indicate that the apoB/apoA-I ratio is a simple, accurate and new risk factor for CV disease--the lower the apoB/apoA-I ratio, the lower is the risk. Guidelines should be developed in order to recognize the important clinical risk information embedded in the apoB/apoA-I ratio.

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.

Abstract: There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL(-1) in high-risk patients should be reassessed in the light of the new clinical trial results and a new ultra-low target of <80 mg dL(-1) be considered. The evidence also indicates that the apo B/apo A-I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein-related risk of vascular disease.

Molecular mechanisms of the vascular responses to haemodynamic forces.

Abstract: Blood vessels are permanently subjected to mechanical forces in the form of stretch, encompassing cyclic mechanical strain due to the pulsatile nature of blood flow and shear stress. Significant variations in mechanical forces, of physiological or physiopathological nature, occur in vivo. These are accompanied by phenotypical modulation of smooth muscle cells and endothelial cells, producing structural modifications of the arterial wall. In all the cases, vascular remodelling can be allotted to a modification of the tensional strain or shear, and underlie a trend to reestablish baseline mechanical conditions. Vascular cells are equipped with numerous receptors that allow them to detect and respond to the mechanical forces generated by pressure and shear stress. The cytoskeleton and other structural components have an established role in mechanotransduction, being able to transmit and modulate tension within the cell via focal adhesion sites, integrins, cellular junctions and the extracellular matrix. Mechanical forces also initiate complex signal transduction cascades, including nuclear factor-kappaB and mitogen-activated protein kinase pathways, leading to functional changes within the cell.

Mechanotransduction and the glycocalyx.

Abstract: Endothelial cells (ECs) line all blood vessel walls and are exposed to the mechanical forces of blood flow which modulate their function and play a role in vascular regulation, remodelling and disease. The principal mechanical forces sensed by ECs are the shear stress of flowing blood on their apical surface, and the circumferential stress resisting blood pressure, which induces stretch in the cell body. 'Mechanotransduction' refers to the mechanisms by which these forces are transduced into biomolecular responses of the cells. Given the importance of endothelial mechanotransduction in cardiovascular physiology and pathology, numerous research efforts have been dedicated to identifying the mechanosensory component(s) of ECs. This review focuses on mechanotransduction of shear stress by ECs and considers the evidence in support of the surface glycocalyx acting as a mechanotransducer.

Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man.

Abstract: . Lunda˚sen T, Ga¨lman C, Angelin B,Rudling M (Karolinska University Hospital Huddinge,Stockholm, Sweden). Circulating intestinal fibroblastgrowth factor 19 has a pronounced diurnal variationand modulates hepatic bile acid synthesis in man(Rapid Communication). J Intern Med 2006; 260:530–536.Bile acids (BAs) traversing the enterohepatic circu-lationexertseveralimportantmetaboliceffects.Theirhepatic synthesis, controlled by the enzyme choles-terol 7a-hydroxylase (CYP7A1), has a unique diur-nal variation in man. Here we provide evidence thatthe transintestinal flux of BAs regulates serum levelsof intestinal fibroblast growth factor 19 (FGF19) thatin turn modulate BA production in human liver.Basal FGF19 levels varied by 10-fold in normal sub-jects, and were reduced following treatment with aBA-binding resin and increased upon feeding the BAchenodeoxycholic acid. Serum FGF19 levels exhib-ited a pronounced diurnal rhythm with peaksoccurring 90–120 min after the postprandial rise inserum BAs. The FGF19 peaks in turn preceded thedeclining phase of BA synthesis. The diurnal rhythmof serum FGF19 was abolished upon fasting. Weconclude that, in humans, circulating FGF19 has adiurnal rhythm controlled by the transintestinal BAflux, and that FGF19 modulates hepatic BA synthe-sis. Through its systemic effects, circulating FGF19may also mediate other known BA-dependent effectson lipid and carbohydrate metabolism.Keywords: bile acids, cholesterol, diurnal rhythm,enterohepatic circulation, FXR, lipid metabolism.

Does cytomegalovirus play a causative role in the development of various inflammatory diseases and cancer

Abstract: Human cytomegalovirus (HCMV) is a herpes virus that infects and is carried by 70-100% of the world's population During its evolution, this virus has developed mechanisms that allow it to survive in an immunocompetent host For many years, HCMV was not considered to be a major human pathogen, as it appeared to cause only rare cases of HCMV inclusion disease in neonates However, HCMV is poorly adapted for survival in the immunosuppressed host and has emerged as an important human pathogen in AIDS patients and in patients undergoing immunosuppressive therapy following organ or bone marrow transplantation HCMV-mediated disease in such patients has highlighted the possible role of this virus in the development of other diseases, in particular inflammatory diseases such as vascular diseases, autoimmune diseases and, more recently, with certain forms of cancers Current research is focused on determining whether HCMV plays a causative role in these diseases or is merely an epiphenomenon of inflammation Inflammation plays a central role in the pathogenesis of HCMV This virus has developed a number of mechanisms that enable it to hide from the cells of the immune system and, at the same time, reactivation of a latent infection requires immune activation Numerous products of the HCMV genome are devoted to control central functions of the innate and adaptive immune responses By influencing the regulation of various cellular processes including the cell cycle, apoptosis and migration as well as tumour invasiveness and angiogenesis, HCMV may participate in disease development Thus, the various drugs now available for treatment of HCMV disease (eg ganciclovir, acyclovir and foscarnet), may also prove to be useful in the treatment of other, more widespread diseases

Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain

Abstract: A normal brain function requires constant levels of cholesterol, and the need for constancy seems to be higher here than in any other organ. Nature has met this need by isolation of brain cholesterol by a highly efficient blood-brain barrier. As a low synthesis of cholesterol is present in the brain, a mechanism for compensatory elimination is required. A decade ago we made the unexpected finding that the favoured mechanism for this involves conversion into 24S-hydroxycholesterol, followed by diffusion over the blood-brain barrier. Recent studies by us and others on this new pathway have given new insights into the mechanisms by which cholesterol homeostasis is maintained in the brain. We recently demonstrated a flux of another oxygenated product of cholesterol, 27-hydroxycholesterol, in the opposite direction. The latter flux may be important for neurodegeneration, and may be the link between hypercholesterolaemia and Alzheimer's disease. An overview of the above studies is presented and the possibility that the cholesterol 24S-hydroxylase in the brain may be important for memory and learning and that it may be a new drug target is discussed.

Endothelial mechanotransduction, nitric oxide and vascular inflammation.

Abstract: Numerous aspects of vascular homeostasis are modulated by nitric oxide and reactive oxygen species (ROS). The production of these is dramatically influenced by mechanical forces imposed on the endothelium and vascular smooth muscle. In this review, we will discuss the effects of mechanical forces on the expression of the endothelial cell nitric oxide synthase, production of ROS and modulation of endothelial cell glutathione. We will also review data that exercise training in vivo has a similar effect as laminar shear on endothelial function and discuss the clinical relevance of these basic findings.

Long QT syndrome: reduced repolarization reserve and the genetic link.

Abstract: Marked QT prolongation and torsades de pointes can occur not only in the congenital long QT syndromes (LQTSs) but also as a consequence of environmental stimuli, notably administration of certain drugs. A key feature of this 'acquired' form of the LQTS has been its unpredictable nature. That is, although risk factors have been identified in series of patients, they have not been terribly useful in addressing risk in an individual patient. Normal cardiac repolarization depends critically on the interplay of multiple ion currents, and these provide some redundancy, or 'reserve', to protect against excessive QT prolongation by drugs. We have proposed that lesions in these repolarizing mechanisms can remain subclinical but nevertheless increase risk on drug exposure, and have termed this situation 'reduced repolarization reserve'. The evidence in support of this concept is presented, and the known and potential contributions by genetic variants to risk is examined. Assessing variability in susceptibility to acquired LQTS provides a framework for analysis of other complex gene-environment interactions.

Interpreting trends in cancer patient survival

Abstract: Data on cancer patient survival are an invaluable tool in the evaluation of therapeutic progress against cancer as well as other lethal diseases. As with all quantitative information routinely used in evidence-based clinical management – including diagnostic tests, prognostic markers and comparisons of therapeutic interventions – data on patient survival require evaluation based on an understanding of the underlying statistical methodology, methods of data collection and classification, and, most notably, clinical and biologic insight. This article contains an introduction to the methods used for estimating cancer patient survival, including cause-specific survival, relative survival and period analysis. The methods, and their interpretation, are illustrated through presentation of trends in incidence, mortality and patient survival for a range of different cancers. Our aim was to lay out the strengths and limitations of survival analysis as a tool in the evaluation of progress in the diagnosis and treatment of cancer.

Cardiovascular disease and Alzheimer's disease: common links.

Abstract: Growing evidence supports a strong and likely causal association between cardiovascular disease (CVD), and its risk factors, with incidence of cognitive decline and Alzheimer's disease. Individuals with subclinical CVD are at higher risk for dementia and Alzheimer's. Several cardiovascular risk factors are also risk factors for dementia, including hypertension, high LDL cholesterol, low HDL cholesterol and especially diabetes. Moderate alcohol appears to be protective for both CVD and dementia. In contrast, inflammatory markers predict cardiovascular risk, but not dementia, despite biological plausibility for such a link. The substantial overlap in risk factors points to new avenues for research and prevention.

Acupuncture – a critical analysis

Abstract: Even though widely used in today's clinical practice, acupuncture has remained a controversial subject. Many reviews are currently available but most lack a critical stance and some are overtly promotional. The aim of this overview is to provide a balanced, critical analysis of the existing evidence. Some of the original concepts of traditional acupuncture are not supported by good scientific evidence. Several plausible theories attempt to explain how acupuncture works but none are proved beyond doubt. The clinical effectiveness of acupuncture continues to attract controversy. Many controlled clinical trials and numerous systematic reviews of these studies have been published. Considerable problems are encountered when interpreting these data. Heterogeneity is a significant drawback of both clinical trials and systematic reviews. Some of the controversies may be resolved through the use of the new 'placebo needles' which enable researchers to adequately control for placebo effects of acupuncture. The majority of studies using such devices fails to show effects beyond a placebo response. Acupuncture has been associated with serious adverse events but most large-scale studies suggest that these are probably rare. Nonserious adverse effects occur in 7-11% of all patients. In conclusion, acupuncture remains steeped in controversy. Some findings are encouraging but others suggest that its clinical effects mainly depend on a placebo response.

CRB-65 predicts death from community-acquired pneumonia.

Abstract: . Objective. The study was performed to validate the CURB, CRB and CRB-65 scores for the prediction of death from community-acquired pneumonia (CAP) in both the hospital and out-patient setting. Design. Data were derived from a large multi-centre prospective study initiated by the German competence network for community-acquired pneumonia (CAPNETZ) which started in March 2003 and were censored for this analysis in October 2004. Setting. Out- and in-hospital patients in 670 private practices and 10 clinical centres. Subjects. Analysis was done for n = 1343 patients (n = 208 out-patients and n = 1135 hospitalized) with all data sets completed for the calculation of CURB and repeated for n = 1967 patients (n = 482 out-patients and n = 1485 hospitalized) with complete data sets for CRB and CRB-65. Intervention. None. 30-day mortality from CAP was determined by personal contacts or a structured interview. Results. Overall 30-day mortality was 4.3% (0.6% in out-patients and 5.5% in hospitalized patients, P < 0.0001). Overall, the CURB, CRB and CRB-65 scores provided comparable predictions for death from CAP as determined by receiver–operator-characteristics (ROC) curves. However, in hospitalized patients, CRB misclassified 26% of deaths as low risk patients. Availability of the CRB-65 score (90%) was far superior to that of CURB (65%), due to missing blood urea nitrogen values (P < 0.001). Conclusions. Both the CURB and CRB-65 scores can be used in the hospital and out-patients setting to assess pneumonia severity and the risk of death. Given that the CRB-65 is easier to handle, we favour the use of CRB-65 where blood urea nitrogen is unavailable.

Associations between apolipoprotein B, apolipoprotein AI, the apolipoprotein B/AI ratio and coronary heart disease: a literature-based meta-analysis of prospective studies.

Abstract: . Objectives. To assess associations of circulating levels of apolipoprotein (apo) AI, apoB and the apoB/AI ratio (apoB/A) with risk of incident coronary heart disease (CHD). Design. Literature-based meta-analysis of prospective studies. Data sources. Prospective studies in essentially general populations that reported on associations between apoAI, apoB or apoB/A and first incident CHD outcomes. Studies were identified by computer-based searches and by manual searches of the relevant literature. Results. Data from 23 relevant studies were identified. For apoAI, with 6333 CHD cases in 21 studies, comparison of individuals in the bottom third with those in the top third of baseline values yielded a combined relative risk of 1.62 (95% confidence interval: 1.43–1.83), i.e. an inverse association. For apoB, a combined analysis of 6320 CHD cases from 19 studies gave a relative risk of 1.99 (1.65–2.39) for a comparison of individuals in the top third versus those in the bottom third of baseline values. For apoB/A, with 3730 CHD cases from seven studies, a comparison of individuals in the top third versus the bottom third of baseline values gave a combined relative risk of 1.86 (1.55–2.22). These associations were somewhat stronger following correction for within-person variations in apolipoprotein levels. There was evidence of heterogeneity amongst the published studies, but it was only partly explained by available study-level characteristics. Conclusions. The present quantitative review suggests the existence of moderately strong associations between baseline levels of each of apoAI, apoB, and apoB/A and risk of CHD. More detailed analysis, perhaps based on individual participant data from prospective studies, could help to overcome several limitations in the present review and to clarify any relevance of these apolipoproteins to disease prediction and aetiology.

Vascular smooth muscle cell phenotypic plasticity and the regulation of vascular calcification

Abstract: Vascular smooth muscle cells (VSMCs) exhibit an extraordinary capacity to undergo phenotypic change during development, in vitro and in association with disease. Unlike other muscle cells they do not terminally differentiate. Development and maintenance of the mature contractile phenotype is regulated by a number of interacting transcription factors. In response to injury contractile VSMCs can be induced to change phenotype, proliferate and migrate to effect repair. On completion of the repair process VSMCs return to a nonproliferating contractile phenotype. In this way, in the context of atherosclerosis, a protective fibrous cap is formed and maintained at sites of injury. However in disease, when modulatory signals are perturbed, this phenotypic transition is dysregulated and VSMCs are induced to undergo inappropriate differentiation into cells with features of other mesenchymal lineages such as osteoblasts, chondrocytes and adipocytes. Moreover, evidence is accumulating that these aberrant phenotypic transitions contribute to the pathogenesis of vascular diseases such as atherosclerosis and Monckeberg's Sclerosis. Indeed, the osteo/chondrocytic conversion of VSMCs and the association of this phenotype with vascular calcification is a paradigm for how inappropriate differentiation can influence disease processes. Understanding of the mechanisms and signalling pathways involved in this particular phenotype change is well advanced offering the possibility for the design of successful therapeutic interventions in the future.

The congenital long QT syndromes from genotype to phenotype: clinical implications.

Abstract: The long QT syndrome (LQTS) is a genetic disorder responsible for many sudden deaths before age 20. The identification of several LQTS genes, all encoding cardiac ion channels, has had a major impact on the management strategy for both patients and family members. Genotype-guided therapy allows more effective individually tailored therapy. Therapeutic options, including beta-blockers, left cardiac sympathetic denervation, and implantable defibrillators are discussed for patients of known and of unknown genotype. The recent identification of modifier genes which amplify the effect of an LQTS mutation may change the approach to risk stratification.

Fracture risk associated with the use of morphine and opiates

Abstract: Objectives. To study the effect of morphine and opiates on fracture risk. Design. Case-control study. Setting. Nationwide register-based study. Subjects. Cases were all subjects with any fracture sustained during the year 2000 (n = 124 655). For each case, three controls (n = 373 962) matched on age and gender were randomly drawn from the background population. The primary exposure variables were use of morphine and opiates. Morphine and other opiates had been used by 10 015 (8.0%) of the case subjects and 12 108 (3.2%) of the controls. Adjustments were made for several confounders including prior fracture, and use of weak analgesics [nonsteroidal anti-inflammatory drugs, acetylsalicylic acid (ASA) and acetaminophene]. The effect of dose was examined by stratifying for cumulated dose (defined daily dose). Main outcome measure. Fracture. Results. Morphine (1.47, 95% CI 1.37-1.58), fentanyl (2.23, 95% CI 1.89-2.64), methadone (1.39, 95% CI 1.05-1.83), oxycodone (1.36, 95% CI 1.08-1.69), nicomorphine (1.57, 95% CI 1.38-1.78), ketobemidone (1.07, 95% CI 1.02-1.13), tramadol (1.54, 95% CI 1.49-1.58) and codeine (1.16, 95% CI 1.12-1.20) were all associated with an increase in overall fracture risk. No increase was present for buprenorphine (0.86, 95% CI 0.79-0.95), pethidine (0.98, 95% CI 0.89-1.08), dextropropoxiphene (1.02, 95% CI 0.90-1.16), and combinations of ASA and codeine (0.94, 95% CI 0.88-1.01). Conclusions. An increased fracture risk is seen in users of morphine and opiates. The reason for this may be related to the risk of falls due to central nervous system effects such as dizziness. Language: en

Clinical aspects of parvovirus B19 infection

Abstract: Parvovirus B19 is a significant human pathogen that causes a wide spectrum of clinical complications ranging from mild, self-limiting erythema infectiosum in immunocompetent children to lethal cytopenias in immunocompromised patients and intrauterine foetal death in primary infected pregnant women. The infection may also be persistent and can mimic or trigger autoimmune inflammatory disorders. Another important clinical aspect to consider is the risk of infection through B19-contaminated blood products. Recent advances in diagnosis and pathogenesis, new insights in the cellular immune response and newly discovered genotypes of human parvoviruses form a platform for the development of modern therapeutic and prophylactic alternatives.

Clinical implications of hypermucoviscosity phenotype in Klebsiella pneumoniae isolates: association with invasive syndrome in patients with community-acquired bacteraemia.

Abstract: . Background. Klebsiella pneumoniae, a Gram-negative bacillus usually forming glistening mucoid colonies with viscid consistency on the culture plate, is a common pathogen causing various clinical infection patterns. However, little is known about the clinical implications of this mucoid character. Objective. The purposes of this study, therefore, were to investigate the frequency of hypermucoviscosity (HV) in bacteraemic isolates of K. pneumoniae, and determine the significance of any association between HV and various clinical manifestations. Design. Retrospective observational study. Patients. Patients diagnosed with K. pneumoniae bacteraemia at a community-based university hospital between June 1999 and June 2001 were enrolled in this analysis. Measurements. Clinical data concerning comorbid diseases and infection patterns was collected. K. pneumoniae bacteraemic isolates were examined for the presence of HV using a modified string test. The clinical impact of HV and risk factors for the invasive syndrome were assessed using statistical analysis. Polymerase chain reaction (PCR) was performed to detect magA, a gene related to HV phenotype. Results. Overall, 200 (64.9%) of the 308 cases of K. pneumoniae bacteraemia were community-acquired infections. Compared with hospital-acquired K. pneumoniae bacteraemia (HA-KpB), community-acquired K. pneumoniae bacteraemia (CA-KpB) was more likely to be monomicrobial in nature (83.5% vs. 64.8%; P < 0.001) and caused by HV strains (41.5% vs. 14.8%; P < 0.001). The prevalence rate of magA among HV phenotypical K. pneumoniae strains was 24.1%. Patients infected with HV-positive strains were more likely to have the distinctive invasive syndrome (i.e. liver abscess, meningitis, pleural empyaema or endophthalmitis) than those infected with HV-negative variants (37.3% vs. 6.8%; P < 0.001). Multivariate logistic regression analysis, adjusted for age, showed that HV phenotype in K. pneumoniae strains (OR 8.86; 95% CI, 3.70–21.25; P < 0.001) was positively associated with the development of the invasive syndrome in CA-KpB cases. Conclusions. The HV phenotype of K. pneumoniae bacteraemic isolates was associated with the development of a distinctive invasive syndrome. Identification of the HV phenotype should prompt clinicians to initiate aggressive investigations for invasive diseases.

Vasculoprotective properties of the endothelial glycocalyx : effects of fluid shear stress

Abstract: The endothelial glycocalyx exerts a wide array of vasculoprotective effects via inhibition of coagulation and leucocyte adhesion, by contributing to the vascular permeability barrier and by mediating shear stress-induced NO release. In this review, we will focus on the relationship between fluid shear stress and the endothelial glycocalyx. We will address the hypothesis that modulation of glycocalyx synthesis by fluid shear stress may contribute to thinner glycocalyces, and therefore more vulnerable endothelium, at lesion-prone sites of arterial bifurcations. Finally, we will discuss the effects of known atherogenic stimuli such as hyperglycaemia on whole body glycocalyx volume in humans and its effect on endothelial function.

Radiographic measure of aorta calcification is a site‐specific predictor of bone loss and fracture risk at the hip

Abstract: . Objective. To investigate whether aorta calcification (AC) – a surrogate marker of atherosclerosis – is an independent indicator of low bone mass density (BMD), accelerated bone loss, and risk of future fractures in postmenopausal women. Design. A prospective epidemiological study. Follow-up period was 7.5 years. Setting. Community-based sample followed by a research institute. Subjects. A total of 2662 generally healthy postmenopausal women with a mean age of 65.0 ± 7.1 years at baseline. Main outcome measures. Annual rate of changes in BMD (DEXA) and AC (X-rays), vertebral fractures (X-rays), hip fractures (questionnaire). Results. Advanced AC at baseline was significantly associated with lower BMD and accelerated bone loss from the proximal femur. In a multivariate logistic regression model, age (OR 1.1, 95% CI 1.0–1.2, P = 0.02), body mass index (BMI; OR 0.9, 95% CI 0.8–1.0, P = 0.03) and the severity of AC (OR 2.3, 95% CI 1.1–4.8, P = 0.03) were independent predictors of hip fractures. Adjusted OR for vertebral fracture was 1.2 (95% CI 1.0–1.5, P = 0.12). Conclusions. Aorta calcification seems to independently contribute to the development of osteoporosis in the proximal femur. Further studies are needed to clarify whether effective atherosclerosis prevention lowers hip fracture risk.

Measurement and meaning of apolipoprotein AI and apolipoprotein B plasma levels

Abstract: Apolipoproteins AI and B are structural components of lipoprotein particles, and also determinants of the metabolic fate of the encapsulated lipid, cholesterol and triglyceride. Development of accurate assays for these apolipoproteins has opened the way for their use as predictors of coronary heart disease risk. Interpretation of AI and apo B levels is best undertaken with background knowledge of the metabolic status of an individual, especially the lipolytic capacity as reflected in the triglyceride concentration. Those with raised triglyceride, in general, not only have an elevated apo B/apo AI ratio, but also apo B-containing lipoproteins with a prolonged residence time and hence ample opportunity for modification and damage. Assessment of apolipoprotein levels is an aid to risk prediction and can be useful in tailoring treatment.

A journey of hope: lessons learned from studies on rare diseases and orphan drugs.

Abstract: Rare diseases are frequently life-threatening or chronically debilitating and the impact on the quality of life of affected patients and their family members is thus significant. However, drug development for these conditions has been limited by a lack of understanding of the underlying mechanisms of disease and the relative unavailability of subjects for clinical trials, as well as the prohibitive cost of investing in a novel pharmaceutical agent with poor market potential. Nevertheless, the introduction of Orphan Drug legislations has provided important incentives for the development of orphan drugs (i.e. drugs that have been abandoned or 'orphaned' by major drug companies). Moreover, recent studies on rare diseases, including inherited immunodeficiencies and metabolic disorders, have served not only to alleviate the plight of patients with rare diseases, but also yielded valuable information on biological processes of relevance for other, more common conditions. These lessons, along with the crucial importance of cooperation between academic institutions, pharmaceutical companies, patient advocacy groups and society in the elucidation of rare diseases, are highlighted in the present review.

Serum lipid levels in relation to serum thyroid-stimulating hormone and the effect of thyroxine treatment on serum lipid levels in subjects with subclinical hypothyroidism: the Tromsø Study

Abstract: . Objective. To evaluate the relation between serum thyroid-stimulating hormone (TSH) and lipids. Design. Cross-sectional epidemiological study, nested case–control study, and a placebo-controlled double-blind intervention study. Methods. In the 5th Tromso study serum TSH, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured. Subjects with subclinical hypothyroidism (SHT) and a matching control group were re-examined and apolipoprotein A1 (Apo A1) and apolipoprotein B (Apo B) were also measured. Subjects with SHT were included in an intervention study with thyroxine supplementation for 1 year. Results. A total of 5143 subjects from the 5th Tromso study were included. A significant and positive correlation between serum TSH levels and serum TC and LDL-C levels were found in both genders. However, in the females this did not reach statistical significance after adjusting for age and BMI. The serum LDL-C were significantly higher and the Apo A1 levels significantly lower in 84 SHT subjects compared with 145 controls, and in the SHT females the TC levels were also significantly elevated. In the intervention study (32 subjects given thyroxine and 32 subjects given placebo), we observed a significant reduction in the Apo B levels after thyroxine medication. In those that at the end of the study had serum TSH levels in the range 0.2–2.0 mIU L−1, the serum TC and LDL-C levels were also significantly reduced. Conclusions. There is a positive association between serum TSH levels and TC and LDL-C levels. These lipid levels are reduced with thyroxine treatment in subjects with SHT.

Low testosterone levels are associated with carotid atherosclerosis in men.

Abstract: . Objective. To study the relationship between endogenous sex hormone levels and intima-media thickness (IMT) of the carotid artery measured by ultrasonography. Design. Population-based cross-sectional study. Methods. Sex hormone levels measured by immunoassay, anthropometric measurements and IMT was studied in 1482 men aged 25–84 years participating in the 1994–1995 Tromso study. The data were analysed with partial correlation, multiple linear regression and logistic regression analysis. Results. Linear regression models showed that total testosterone and sex hormone-binding globulin levels, but not calculated free testosterone, serum oestradiol or dehydroepiandrosterone sulphate levels were inversely associated with the age-adjusted IMT (P = 0.008 and P < 0.001 respectively). These associations were independent of smoking, physical activity, blood pressure and lipid levels, but were not independent of body mass index (BMI). Excluding men with cardiovascular disease (CVD) did not materially change these results. In a logistic regression model adjusted for the confounding effect of CVD risk factors, men with testosterone levels in the lowest quintile (<9.0 nmol L−1) had an independent OR = 1.51 (P = 0.015) of being in the highest IMT quintile. Conclusions. We found an inverse association between total testosterone levels and IMT of the carotid artery in men that was present also after excluding men with CVD, but was not independent of BMI. The clinical relevance of this, however, is uncertain and needs to be investigated in a clinical setting.

Effects of antihypertensive drug treatments on fracture outcomes: a meta-analysis of observational studies.

Abstract: Objective To quantitatively pool findings from observational studies on the risk of fracture outcomes associated with exposure to five antihypertensive drug classes: angiotensin-converting enzyme (ACE) inhibitors, diuretics (in particular thiazide diuretics), β-blockers, calcium-channel blockers and alpha-blockers Design Systematic review and meta-analysis Data sources Publications listed in the MEDLINE, EMBASE and LILACS databases, the ISI proceedings, and bibliographies of retrieved articles Sources were searched from the earliest possible dates through December 2005 Review methods We included case–control and cohort studies presenting relative risks and confidence intervals (CIs) for the association between exposure to antihypertensive agents and fracture outcomes Data were extracted onto a standardized computer worksheet Study quality was assessed using a 10-point questionnaire specific to case–control or cohort study design Results Fifty-four studies were identified Pooled estimates were computed using the software HEpiMA The pooled relative risk (RR) of any fracture with use of thiazide diuretics was 086 (95% CI 081–092) and 114 (95% CI 084–154) with use of nonthiazide diuretics There was a statistically significant reduction of any fracture with use of β-blockers, (RR 086, 95% CI 070–098) The one study with ACE inhibitor data showed protection (RR 081, 95% CI 073–089) No significant associations were found between fractures and exposure to α-blockers or calcium-channel blockers Conclusions Thiazide diuretics and β-blockers appear to lower the risk of fractures in older adults However, these agents cannot be recommended as preventive therapies for fractures until data from randomized controlled trials have established their efficacy Patients who use these inexpensive drugs as treatments for hypertension may also benefit from a reduction in fracture risk

Increased levels of KL-6 and subsequent mortality in patients with interstitial lung diseases.

Abstract: . Objectives. KL-6 is a specific marker in patients with interstitial lung diseases (ILDs); however, the relationship between elevated levels of KL-6 and subsequent mortality is not well defined. To determine if elevated serum levels of KL-6 are associated with increased mortality, and to identify the most suitable cut-off level of KL-6 by which to distinguish between good prognosis and poor prognosis, we evaluated the prognostic significance of serum KL-6 levels in patients with stable-state ILDs. Methods. Two hundred and nineteen patients diagnosed with ILDs (152 with idiopathic interstitial pneumonia and 67 with collagen disease-associated pulmonary fibrosis) at Tsukuba University Hospital from April 1999 to October 2005 were entered in this study. Serum KL-6 levels in patients with ILDs were measured with a commercially available enzyme immunoassay kit, and these patients were then followed up. Results. During the follow-up period, 58 of the 219 patients died of respiratory failure. Patients who died during this period had higher levels of KL-6 than did those who did not (P = 0.0004). The receiver operating characteristic curve analysis showed 1000 U mL−1 as the most suitable cut-off level by which to distinguish between the two groups of patients. The 95% specificity serum KL-6 level with poor outcome was 2750 U mL−1. In univariate and multivariate analysis, elevated serum KL-6 (>1000 U mL−1) in the stable state indicated poor prognosis (P = 0.0005, log-rank test; P = 0.0001, Cox proportional hazard model). Conclusions. Elevated KL-6 level may provide simple, yet valuable information by which to identify patients with ILDs who are at increased risk for subsequent mortality.

Amplification of spatial dispersion of repolarization underlies sudden cardiac death associated with catecholaminergic polymorphic VT, long QT, short QT and Brugada syndromes.

Abstract: This review examines the hypothesis that amplification of spatial dispersion of repolarization in the form of transmural dispersion of repolarization (TDR) underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies including the long QT, short QT and Brugada syndromes as well as catecholaminergic polymorphic ventricular tachycardia. In the long QT syndrome, amplification of TDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells, whereas in the Brugada syndrome, it is thought to be because of selective abbreviation of the APD of right ventricular epicardium. Preferential abbreviation of APD of either endocardium or epicardium appears to be responsible for amplification of TDR in the short QT syndrome. In catecholaminergic polymorphic VT, the reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. In conclusion, the long QT, short QT, Brugada and catecholaminergic VT syndromes are pathologies with very different phenotypes and aetiologies, but which share a common final pathway in causing sudden death.

Calcium and vitamin D in the prevention and treatment of osteoporosis – a clinical update

Abstract: . Combined calcium and vitamin D supplementation is an essential component of the management of osteoporosis, supported by a strong scientific rationale. The types of individuals who should receive calcium and vitamin D supplements are those: (i) patients with documented osteoporosis receiving antiresorptive or anabolic treatment; (ii) patients receiving glucocorticoids; and (iii) individuals with or at high risk of calcium and/or vitamin D insufficiencies, in particular older women and men. This article describes the evidence base that supports targeting these groups. Benefits are most apparent when 800 IU day−1 vitamin D is complemented with a dose of 1000–1200 mg day−1 elemental calcium. Compliance is also key to optimizing clinical efficacy.