Molecular mechanisms of cardiac pathology in diabetes - Experimental insights.

Diabetic cardiomyopathy is a distinct pathology independent of co-morbidities such as coronary artery disease and hypertension. Diminished glucose uptake due to impaired insulin signaling and decreased expression of glucose transporters is associated with a shift towards increased reliance on fatty acid oxidation and reduced cardiac efficiency in diabetic hearts. The cardiac metabolic profile in diabetes is influenced by disturbances in circulating glucose, insulin and fatty acids, and alterations in cardiomyocyte signaling. In this review, we focus on recent preclinical advances in understanding the molecular mechanisms of diabetic cardiomyopathy. Genetic manipulation of cardiomyocyte insulin signaling intermediates has demonstrated that partial cardiac functional rescue can be achieved by upregulation of the insulin signaling pathway in diabetic hearts. Inconsistent findings have been reported relating to the role of cardiac AMPK and ß-adrenergic signaling in diabetes, and systemic administration of agents targeting these pathways appear to elicit some cardiac benefit, but whether these effects are related to direct cardiac actions is uncertain. Overload of cardiomyocyte fuel storage is evident in the diabetic heart, with accumulation of glycogen and lipid droplets. Cardiac metabolic dysregulation in diabetes has been linked with oxidative stress and autophagy disturbance, which may lead to cell death induction, fibrotic 'backfill' and cardiac dysfunction. This review examines the weight of evidence relating to the molecular mechanisms of diabetic cardiomyopathy, with a particular focus on metabolic and signaling pathways. Areas of uncertainty in the field are highlighted and important knowledge gaps for further investigation are identified. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.

Nationwide bowel cancer screening programme in England: cohort study of lifestyle factors affecting participation and outcomes in women.

BACKGROUND: In 2006, the National Health Service Bowel Cancer Screening Programme in England (NHSBCSP) began offering routine population-based biennial faecal occult blood testing (FOBt) at ages 60-69. There is, however, limited information on how characteristics of individuals affect participation and outcomes of screening, and we studied this association by linking NHSBCSP data to a large prospective cohort of women. METHODS: Electronic linkage of the NHSBCSP and Million Women Study records identified 899 166 women in the study cohort with at least one invitation for screening. NHSBCSP provided information on screening acceptance, FOBt results, screen-detected colorectal cancer and other outcomes. The Million Women Study provided prospectively collected information on personal and lifestyle factors. Multiple regression was used to estimate relative risks (RRs) of factors associated with acceptance and outcomes of screening. RESULTS: Overall, 70% of women (628 976/899 166) accepted their first invitation for bowel cancer screening, of whom 9133 (1.5%) were FOBt-positive, 743 (0.1%) had screen-detected colorectal cancer and 3056 (0.5%) had screen-detected colorectal adenoma. Acceptance was lower in women from the most than the least deprived tertile, in South Asians and in Blacks than in Whites, in current than in never smokers and in obese than in normal weight women: adjusted RRs (95% confidence interval) for acceptance vs not, 0.90 (0.90-0.90); 0.77 (0.75-79); 0.94 (0.92-0.96); 0.78 (0.77-0.78); and 0.88 (0.88-0.89), respectively: P<0.001 for each. These factors were also associated with an increased risk of being FOBt-positive and of having screen-detected adenoma, but were not strongly associated with the risk of screen-detected colorectal cancer. Relative risks for screen-detected adenoma were 1.22 (1.12-1.34), 2.46 (1.75-3.45), 1.61 (1.05-2.48), 1.53 (1.38-1.68) and 1.77 (1.60-1.95), respectively (P<0.001 for all, except for Blacks vs Whites P=0.03). Use of hormone therapy for menopause was associated with reduced risk of screen-detected adenoma, RR ever vs never use, 0.87 (0.81-0.93), P<0.001 and colorectal cancer, 0.78 (0.68-0.91), P=0.001. INTERPRETATION: Among women in England, socioeconomic and lifestyle factors strongly affect participation in routine bowel cancer screening, risk of being FOBt-positive and risk of having screen-detected colorectal adenoma. However, screen-detected colorectal cancer risk is not strongly related to these factors.

Investigating eye movement acquisition and analysis technologies as a causal factor in differential prevalence of crossed and uncrossed fixation disparity during reading and dot scanning.

Previous studies examining binocular coordination during reading have reported conflicting results in terms of the nature of disparity (e.g. Kliegl, Nuthmann, & Engbert (Journal of Experimental Psychology General 135:12-35, 2006); Liversedge, White, Findlay, & Rayner (Vision Research 46:2363-2374, 2006). One potential cause of this inconsistency is differences in acquisition devices and associated analysis technologies. We tested this by directly comparing binocular eye movement recordings made using SR Research EyeLink 1000 and the Fourward Technologies Inc. DPI binocular eye-tracking systems. Participants read sentences or scanned horizontal rows of dot strings; for each participant, half the data were recorded with the EyeLink, and the other half with the DPIs. The viewing conditions in both testing laboratories were set to be very similar. Monocular calibrations were used. The majority of fixations recorded using either system were aligned, although data from the EyeLink system showed greater disparity magnitudes. Critically, for unaligned fixations, the data from both systems showed a majority of uncrossed fixations. These results suggest that variability in previous reports of binocular fixation alignment is attributable to the specific viewing conditions associated with a particular experiment (variables such as luminance and viewing distance), rather than acquisition and analysis software and hardware.

Conjugation of microbial-derived gold nanoparticles to different types of nucleic acids: evaluation of transfection efficiency.

In this study, gold nanoparticles produced by eukaryotic cell waste (AuNP), were analyzed as a transfection tool. AuNP were produced by Fusarium oxysporum and analyzed by spectrophotometry, transmission electron microscopy (TEM), scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy (EDS). Fourier transform infrared spectroscopy (FTIR) and dynamic light scattering (DLS) were used before and after conjugation with different nucleic acid (NA) types. Graphite furnace atomic absorption spectroscopy (GF-AAS) was used to determine the AuNP concentration. Conjugation was detected by electrophoresis. Confocal microscopy and quantitative real-time PCR (qPCR) were used to assess transfection. TEM, SEM, and EDS showed 25 nm AuNP with round shape. The amount of AuNP was 3.75 ± 0.2 µg/µL and FTIR proved conjugation of all NA types to AuNP. All the samples had a negative charge of - 36 to - 46 mV. Confocal microscopy confirmed internalization of the ssRNA-AuNP into eukaryotic cells and qPCR confirmed release and activity of carried RNA.

Cigarette smoking and risk of acoustic neuromas and pituitary tumours in the Million Women Study.

BACKGROUND: The relationship between cigarette smoking and incidence of acoustic neuromas and pituitary tumours is uncertain. METHODS: We examined the relation between smoking and risk of acoustic neuromas and pituitary tumours in a prospective study of 1.2 million middle-aged women in the United Kingdom. RESULTS: Over 10.2 million person years of follow-up, 177 women were diagnosed with acoustic neuromas and 174 with pituitary tumours. Current smokers at recruitment were at significantly reduced risk of incident acoustic neuroma compared with never smokers (adjusted relative risk (RR)=0.41, 95% confidence interval (CI)=0.24-0.70, P=0.001). Past smokers did not have significantly different risk of acoustic neuroma than never smokers (RR=0.87, 95% CI=0.62-1.22, P=0.4). Smoking was not associated with incidence of pituitary tumours (RR in current vs never smokers=0.91, 95% CI=0.60-1.40, P=0.7). CONCLUSION: Women who smoke are at a significantly reduced risk of acoustic neuromas, but not of pituitary tumours, compared with never smokers. Acoustic neuromas are much rarer than the cancers that are increased among smokers.

CD161 receptor participates in both impairing NK cell cytotoxicity and the response to glycans and vimentin in patients with rheumatoid arthritis.

We investigated the role of natural killer (NK) cells and CD161, their primary C-type-lectin-like receptor in rheumatoid arthritis (RA). Samples were compared with healthy donors (HD), dermatomyositic (DM), polymyositic (PM), and osteoarthritic (OA) patients. RA, PM, and DM NK cell cytotoxicities significantly decreased relative to the HD and OA NK cells (p<0.0001). These results correlated with an increased expression of NK cell inhibitory receptor CD161, in active disease RA patients. We demonstrated that NK cells are able to respond to mutated citrullinated vimentin (MCV), an RA-specific autoantigen, leading to increases in both PAD4 enzyme and CD161 mRNA expression. MGAT5 glycosidase involvement was detected in GlcNAc metabolism within the synoviocytes of RA patients. Our findings reveal a functional relationship between CD161 expression and NK cell cytotoxicity as well as reactivity to glycans and MCV, thus providing new insight into the pathogenesis of RA and confirming the involvement of surface glycosylation.

An Integrated Agriculture, Atmosphere, and Hydrology Modeling System for Ecosystem Assessments.

We present a regional-scale integrated modeling system (IMS) that includes Environmental Policy Integrated Climate (EPIC), Weather Research and Forecast (WRF), Community Multiscale Air Quality (CMAQ), and Soil and Water Assessment Tool (SWAT) models. The centerpiece of the IMS is the Fertilizer Emission Scenario Tool for CMAQ (FEST-C), which includes a Java-based interface and EPIC adapted to regional applications along with built-in database and tools. The SWAT integration capability is a key enhanced feature in the current release of FEST-C v1.4. For integrated modeling demonstration and evaluation, FEST-C EPIC is simulated over three individual years with WRF/CMAQ weather and N deposition. Simulated yearly changes in water and N budgets along with yields for two major crops (corn grain and soybean) match those inferred from intuitive physical reasoning and survey data given different-year weather conditions. Yearlong air quality simulations with an improved bidirectional ammonia flux modeling approach directly using EPIC-simulated soil properties including NH3 content helps reduce biases of simulated gas-phase NH3 and NH4 + wet deposition over the growing season. Integrated hydrology and water quality simulations applied to the Mississippi River Basin show that estimated monthly streamflow and dissolved N near the outlet to the Gulf of Mexico display similar seasonal patterns as observed. Limitations and issues in different parts of the integrated multimedia simulations are identified and discussed to target areas for future improvements. PLAIN LANGUAGE SUMMARY: Computer modeling tools with land-water-air processes are important for understanding nutrient cycling and its negative impacts on air and water quality. We have developed an integrated modeling system that includes agriculture, atmosphere, and hydrology components. The centerpiece of the system is a computer system that includes an agricultural ecosystem model and tools used to connect different modeling components. The agricultural system can conduct simulations for 42 types of grassland and cropland with the influence of site, soil, and management information along with weather and nitrogen deposition from the atmosphere component. An air quality computer model then uses information from the agricultural model, such as how much ammonia is in the soil, to predict how much ammonia gets in the air. Then, the watershed hydrology and water quality model uses the information from the agricultural and atmospheric models to understand the influence of agriculture and atmosphere on water quality. The paper demonstrates and evaluates the integrated modeling system on issues mainly related to N cycling. The system performs reasonably well in comparison with survey and observation data given the configured modeling constraints. The paper also identifies and discusses the advantages and limitations in each part of the system for future applications and improvements.

Eye-movements reveal attention to social information in autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental condition in which children show reduced attention to social aspects of the environment. However in adults with ASD, evidence for social attentional deficits is equivocal. One problem is that many paradigms present social information in an unrealistic, isolated way. This study presented adults and adolescents, with and without ASD, with a complex social scene alongside another, non-social scene, and measured eye-movements during a 3-s viewing period. Analyses first identified viewing time to different regions and then investigated some more complex issues. These were: the location of the very first fixation in a trial (indicating attentional priority); the effect of a task instruction on scan paths; the extent to which gaze-following was evident; and the degree to which participants' scan paths were influenced by the low-level properties of a scene. Results indicate a superficially normal attentional preference for social information in adults with ASD. However, more sensitive measures show that ASD does entail social attention problems across the lifespan, supporting accounts of the disorder which emphasise lifelong neurodevelopmental atypicalities. These subtle abnormalities may be sufficient to produce serious difficulties in real-life scenarios.

The disengage deficit in hemispatial neglect is restricted to between-object shifts and is abolished by prism adaptation.

We sought to determine the effects of prism adaptation on peripherally cued visual attention shifting in patients with spatial neglect, using a task devised by Egly et al. (J Exp Psychol Gen 123:161-177, 1994) based on the classic Posner paradigm. This task allowed a comparison of "within-object" versus "between-object" attention shifts. A display was presented containing two parallel outline rectangles, and subjects were asked to make rapid responses to a target, which would appear at one end of one of the rectangles. The target location was pre-cued with 75% validity: on invalid trials attention was directed either to the other end of the same rectangle, or to the other rectangle. Healthy subjects and right-hemisphere patients without neglect showed a left-right symmetrical pattern, with a larger validity effect when required to shift attention between rectangles, thus indicating a greater difficulty of attention-shifting between than within the respective shapes. The neglect patients showed the typical leftward "disengage deficit" previously observed in neglect, but only for attention shifts between objects, indicating that the effect is object-based rather than purely spatial. A comparison of vertical and horizontal shift costs showed that this attention-shifting deficit for left-hemifield target stimuli was directional rather than hemifield-based: it was absent for vertical shifts of attention within the left hemifield. Finally, we found that prism adaptation abolished the disengage deficit. We found no effects of prism adaptation in the control subjects. We argue that prism adaptation has a powerful effect on one of the fundamental manifestations of the neglect syndrome.

WT1 expression in peripheral leukocytes of patients with chronic myeloid leukemia serves for the prediction of Imatinib resistance.

The determination of patient's resistance to a particular drug contributes to more efficient therapeutical approach. The aim of this study was to evaluate if the responsiveness of Chronic Myeloid Leukemia (CML) patients to Imatinib therapy was predictable from WT1 gene expression in peripheral blood leukocytes. To examine the resistance we implemented an in vitro cultivation of the primary cells of 48 CML patients with Imatinib. The effect of Imatinib was characterized not only by the expression of WT1 but also by BCR-ABL, and proliferative factor Ki-67.
Our results showed that leukocytes of CML patients, clinically responsive to Imatinib treatment, significantly decreased WT1 expression after in vitro incubation with Imatinib. It was accompanied by an inhibition of expression of Ki-67 but not BCR-ABL. In leukocytes of CML patients clinically resistant to Imatinib, the expression of WT1, Ki-67, and BCR-ABL remained unaffected. The presented results showed that in vitro testing using peripheral blood cells enabled clinicians to predict responsiveness of CML patients to Imatinib.

Lifestyle factors and primary glioma and meningioma tumours in the Million Women Study cohort.

Previous studies have reported inconsistent results on the effect of anthropometric and lifestyle factors on the risk of developing glioma or meningioma tumours. A prospective cohort of 1.3 million middle-aged women was used to examine these relationships. During 7.7 million women-years of follow-up, a total of 1563 women were diagnosed with a primary incident central nervous system tumour: 646 tumours were classified as glioma and 390 as meningioma. Our results show that height is related to the incidence of all central nervous system tumours with a risk of about 20% per 10 cm increase in height (relative risk=1.19, 95% CI=1.10-1.30 per 10 cm increase in height, P<0.001): the risks did not differ significantly between specified glioma and meningioma. Body mass index (BMI) was also related to central nervous system tumour incidence, with a risk of about 20% per 10 kg m(-2) increase in BMI (relative risk=1.17, 95% CI=1.03-1.34 per 10 kg m(-2) increase in BMI, P=0.02). Smoking status, alcohol intake, socioeconomic level, parity, age at first birth, and oral contraceptive use were not associated with the risk of glioma or meningioma tumours. In conclusion, for women in the United Kingdom, the incidence of glioma or meningioma tumours increases with increasing height and increasing BMI.

DNAzymes and cardiovascular disease.

Gene silencing techniques are gaining increasing popularity in the literature, both as a tool for unravelling gene function and to potentially deliver therapeutic benefit, especially in the context of cardiovascular disease. Gene-specific catalytic DNA molecules, or DNAzymes, have shown promise in ameliorating the effects of myocardial ischaemia reperfusion injury and in-stent restenosis in various animal models, demonstrating that these agents may be useful in a clinical setting. A review of the recent advances in the use of DNAzymes in treating cardiovascular disease is therefore essential given the increasing clinical burden of cardiovascular disease worldwide. We have thus sought to firstly provide background into the construct and mechanism of action of DNAzymes, with a discussion of recent improvements in design. Secondly, we have examined the effects of DNAzyme-mediated gene inhibition in in vitro studies of both endothelial and smooth muscle migration and proliferation, as well as in vivo models of acute myocardial infraction and neointima formation. Lastly we compare DNAzymes with other gene silencing tools and discuss issues involved in successfully delivering these drugs in a clinical setting.

Exploring a United States Maize Cellulose Biofuel Scenario Using an Integrated Energy and Agricultural Markets Solution Approach.

Biofuel feedstock production in the United States (US) is an emergent environmental nutrient management issue, whose exploration can benefit from a multi-scale and multimedia systems modeling approach that explicitly addresses diverging stakeholder interests. In the present analysis, energy and agricultural markets models and a hybrid process-based agricultural production model are integrated to explore the potential environmental consequences of increased biofuel production from maize grain and stover feedstocks. Yield and cropland reallocation projections are simulated for 20 agricultural crops at a 12km grid resolution across the continental United States. Our results are presented across multiple, spatially expanding domains, and our results for the Upper Mississippi River Basin (UMRB) are compared to previous studies. Our analysis highlights the critical continuing role of agricultural and crop science to provide physically plausible estimates and physical process drivers of yield increases, and suggests that while the UMRB is the target of the greatest agricultural changes under our scenarios, its response does not necessarily reflect the interests of a broad stakeholder community.

Imaging of transfection and intracellular release of intact, non-labeled DNA using fluorescent nanodiamonds.

Efficient delivery of stabilized nucleic acids (NAs) into cells and release of the NA payload are crucial points in the transfection process. Here we report on the fabrication of a nanoscopic cellular delivery carrier that is additionally combined with a label-free intracellular sensor device, based on biocompatible fluorescent nanodiamond particles. The sensing function is engineered into nanodiamonds by using nitrogen-vacancy color centers, providing stable non-blinking luminescence. The device is used for monitoring NA transfection and the payload release in cells. The unpacking of NAs from a poly(ethyleneimine)-terminated nanodiamond surface is monitored using the color shift of nitrogen-vacancy centers in the diamond, which serve as a nanoscopic electric charge sensor. The proposed device innovates the strategies for NA imaging and delivery, by providing detection of the intracellular release of non-labeled NAs without affecting cellular processing of the NAs. Our system highlights the potential of nanodiamonds to act not merely as labels but also as non-toxic and non-photobleachable fluorescent biosensors reporting complex molecular events.

Cholesterol-reduction intervention study (CRIS): a randomized trial to assess effectiveness and costs in clinical practice.

BACKGROUND: The 1988 US National Cholesterol Education Program Expert Panel Report recommended initial treatment with niacin or bile acid sequestrants, followed by other agents if needed, to lower low-density lipoprotein cholesterol (LDL-C) levels in hypercholesterolemic patients who require drug therapy. It is unknown how the effectiveness and costs of such an approach ("stepped care") compare in typical clinical practice to those of initial therapy with lovastatin. PATIENTS AND METHODS: We randomly assigned 612 patients, aged 20 to 70 years, who met 1988 National Cholesterol Education Program guidelines for drug treatment of elevated LDL-C level and had not previously used cholesterol-lowering medication, to either a stepped-care regimen or initial therapy with lovastatin (both n=306). The study, conducted at Southern California Kaiser Permanente, was designed to approximate typical practice: provider compliance with treatment plans was encouraged but not enforced, and patients paid for medication as they customarily would. RESULTS: At 1 year, the decline in mean LDL-C level was significantly greater among patients assigned to initial treatment with lovastatin (22% vs 15% for stepped care; P<.001), as was the number who attained goal LDL-C level (

Dyslipidemia treatment guidelines and management systems in Kaiser Permanente.

Coronary artery disease (CAD) remains the leading cause of morbidity and mortality in the United States. Although risk factors contributing to the development of this disease are well known and effective interventions exist, the majority of patients eligible for pharmacotherapy are inadequately treated or not treated at all. Multiple factors contribute to this treatment gap. With respect to dyslipidemia, 2 of the major challenges facing healthcare organizations are: (1) how to ensure continued monitoring and medication adherence for patients with known atherosclerosis (secondary prevention); and (2) how to select the high-risk patients who will most benefit from treatment from the larger population of individuals who have not had a known coronary event (primary prevention). In Southern California Kaiser Permanente, 2 approaches being used to address these issues are dyslipidemia treatment guidelines and a computerized monitoring system. The guidelines stratify patients based on CAD risk and expected benefit from drug therapy. The computerized monitoring incorporates an "expert system" algorithm that facilitates patient selection in primary prevention and tracking to encourage patient compliance. This article describes these 2 approaches that attempt to maximize the effectiveness and efficiency of dyslipidemia management.

Current estimates from the National Health Interview Survey, 1995.

OBJECTIVES: This report presents data on national estimates of the incidence of acute conditions, percent of medically attended acute conditions, number of disability days (including restricted activity and bed days, and work- or school-loss days), number of episodes of persons injured and associated activity restriction, prevalence of selected chronic conditions, number of activity limitations due to chronic conditions, number of restricted activity days associated with acute and chronic conditions, respondent-assessed health, number of physician contacts, and short-stay hospitalizations. METHODS: The National Health Interview Survey (NHIS) is a complex, multi-stage, probability sample survey conducted annually by trained interviewers of the U.S. Bureau of the Census for the National Center for Health Statistics. Information is collected during in-home interviews of the civilian noninstitutionalized U.S. population on a variety of health issues. RESULTS: The NHIS estimates that in 1995, there were 174.4 acute conditions per 100 persons. Of these, 67.3 percent were medically attended and this resulted in 674.6 days of restricted activity per 100 persons. Of acute injuries, 91.2 percent were medically attended. The most frequently reported rates for chronic conditions per 1,000 persons included sinusitis (141.3), arthritis (124.7), and deformity and orthopedic impairment (121.4). Some degree of activity limitation due to chronic conditions was reported by 14 percent of persons. There were about six physician contacts per person per year and 7.5 percent of the population had at least one hospitalization in the past year.

Phosphorus losses from grasslands fertilized with broiler litter: EPIC simulations.

Broiler litter, a mixture of poultry excreta and bedding material, is commonly used to fertilize grasslands in the southeastern USA. Previous work has shown that under certain situations, application of broiler (Gallus gallus domesticus) litter to grasslands may lead to elevated levels of phosphorus (P) in surface runoff. The EPIC simulation model may be a useful tool to identify those situations. This work was conducted to evaluate EPIC's ability to simulate event and annual runoff volume and losses of dissolved reactive phosphorus (DRP) from tall fescue (Festuca arundinacea Schreb.)-bermudagrass [Cynodon dactylon (L.) Pers.] paddocks fertilized with broiler litter. The EPIC simulations of event runoff volume showed a trend toward underestimation, particularly for runoff events >30 mm. On an annual basis, EPIC also tended to underestimate runoff, especially at runoff volumes > 100 mm. Both event and annual runoff estimations were strongly associated with observed values, indicating that model calibration could improve the simulation of surface runoff volume. The relationship between simulated and observed values of DRP loss was relatively poor on an event basis (r=0.65), but was stronger (r=0.75) on an annual basis. In general, EPIC tended to underestimate annual DRP losses. This underestimation was apparently caused by the lack of an explicit mechanism to model broiler litter on the soil surface. These results suggested that additional work on the EPIC P submodel would be warranted to improve its simulation of surface application of broiler litter to grasslands.

Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study.

BACKGROUND: Current use of menopausal hormone therapy (HT) increases the risk of venous thromboembolism (VTE) and the formulations used may affect risk. METHODS: A total of 1,058,259 postmenopausal UK women were followed by record linkage to routinely collected National Health Service hospital admission and death records. HT use and risk of VTE was examined using Cox regression to estimate relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: During 3.3 million years of follow-up, 2200 women had an incident VTE, diagnosed, on average, 1.5 years after last reporting HT use. RRs in current vs. never users at last reporting varied by HT formulation: the risk was significantly greater for oral estrogen-progestin than oral estrogen-only therapy (RR = 2.07 [95%CI, 1.86-2.31] vs. 1.42 [1.21-1.66]), with no increased risk with transdermal estrogen-only therapy (0.82 [0.64-1.06]). Among users of oral estrogen-progestin, the risk from HT varied by progestin type, with significantly greater risks for preparations containing medroxyprogesterone acetate than other progestins (2.67 [2.25-3.17] vs. 1.91 [1.69-2.17]; Pheterogeneity = 0.0007). Current users of oral HT at last reporting had twice the risk of VTE in the first 2 years after starting HT than later (Pheterogeneity = 0.0006). Associations were similar for deep vein thrombosis with and without pulmonary embolism. Over 5 years, 1 in 660 who had never used HT were admitted to hospital for (or died from) pulmonary embolism, compared with 1 in 475 current users of oral estrogen-only HT,1 in 390 users of estrogen-progestin HT containing norethisterone/norgestrel, and 1 in 250 users of estrogen-progestin HT containing medroxyprogesterone acetate. CONCLUSIONS: The risk of VTE varied considerably by HT formulation, being greatest in users of oral estrogen-progestin HT, especially formulations containing medroxyprogesterone acetate.