Does self-monitoring reduce blood pressure? Meta-analysis with meta-regression of randomized controlled trials

Introduction. Self-monitoring of blood pressure (BP) is an increasingly common part of hypertension management. The objectives of this systematic review were to evaluate the systolic and diastolic BP reduction, and achievement of target BP, associated with self-monitoring. Methods. MEDLINE, Embase, Cochrane database of systematic reviews, database of abstracts of clinical effectiveness, the health technology assessment database, the NHS economic evaluation database, and the TRIP database were searched for studies where the intervention included self-monitoring of BP and the outcome was change in office/ambulatory BP or proportion with controlled BP. Two reviewers independently extracted data. Meta-analysis using a random effects model was combined with meta-regression to investigate heterogeneity in effect sizes. Results. A total of 25 eligible randomized controlled trials (RCTs) (27 comparisons) were identified. Office systolic BP (20 RCTs, 21 comparisons, 5,898 patients) and diastolic BP (23 RCTs, 25 comparisons, 6,038 patients) were significantly reduced in those who self-monitored compared to usual care (weighted mean difference (WMD) systolic −3.82 mmHg (95% confidence interval −5.61 to −2.03), diastolic −1.45 mmHg (−1.95 to −0.94)). Self-monitoring increased the chance of meeting office BP targets (12 RCTs, 13 comparisons, 2,260 patients, relative risk = 1.09 (1.02 to 1.16)). There was significant heterogeneity between studies for all three comparisons, which could be partially accounted for by the use of additional co-interventions. Conclusion. Self-monitoring reduces blood pressure by a small but significant amount. Meta-regression could only account for part of the observed heterogeneity

Utility of Atherosclerosis Imaging in the Evaluation of High-Density Lipoprotein–Raising Therapies

Decreased level of high density-lipoprotein cholesterol (HDL-C) is a rigorous predictor for future cardiovascular events. Much effort is being made to develop HDL-C–raising pharmacotherapies in the attempt to avert the pandemic of atherosclerotic disease. Important properties by which HDL-C–raising compounds are effective involve improvement of cholesterol uptake from macrophages in plaque for transport back to the liver, improvement of endothelial function, and anti-inflammatory effects. Vascular imaging can aid in the determination which HDL-C–raising compounds are effective. Ultrasound and MRI have proved suitable for assessment of structural changes of the vessel wall. Ultrasound can also be used or assessment of endothelial function. 18F-fluordeoxyglucose positron emission tomography has opened up the possibility to assess vessel wall inflammation. In this article we discuss these various imaging techniques and how they can assess efficacy as well as provide pathophysiologic information on the mechanism of action of novel HDL-C–raising drugs

Combinatorial Roles of Heparan Sulfate Proteoglycans and Heparan Sulfates in Caenorhabditis elegans Neural Development

Heparan sulfate proteoglycans (HSPGs) play critical roles in the development and adult physiology of all metazoan organisms. Most of the known molecular interactions of HSPGs are attributed to the structurally highly complex heparan sulfate (HS) glycans. However, whether a specific HSPG (such as syndecan) contains HS modifications that differ from another HSPG (such as glypican) has remained largely unresolved. Here, a neural model in C. elegans is used to demonstrate for the first time the relationship between specific HSPGs and HS modifications in a defined biological process in vivo. HSPGs are critical for the migration of hermaphrodite specific neurons (HSNs) as genetic elimination of multiple HSPGs leads to 80% defect of HSN migration. The effects of genetic elimination of HSPGs are additive, suggesting that multiple HSPGs, present in the migrating neuron and in the matrix, act in parallel to support neuron migration. Genetic analyses suggest that syndecan/sdn-1 and HS 6-O-sulfotransferase, hst-6, function in a linear signaling pathway and glypican/lon-2 and HS 2-O-sulfotransferase, hst-2, function together in a pathway that is parallel to sdn-1 and hst-6. These results suggest core protein specific HS modifications that are critical for HSN migration. In C. elegans, the core protein specificity of distinct HS modifications may be in part regulated at the level of tissue specific expression of genes encoding for HSPGs and HS modifying enzymes. Genetic analysis reveals that there is a delicate balance of HS modifications and eliminating one HS modifying enzyme in a compromised genetic background leads to significant changes in the overall phenotype. These findings are of importance with the view of HS as a critical regulator of cell signaling in normal development and disease

Centralized Modularity of N-Linked Glycosylation Pathways in Mammalian Cells

Glycosylation is a highly complex process to produce a diverse repertoire of cellular glycans that are attached to proteins and lipids. Glycans are involved in fundamental biological processes, including protein folding and clearance, cell proliferation and apoptosis, development, immune responses, and pathogenesis. One of the major types of glycans, N-linked glycans, is formed by sequential attachments of monosaccharides to proteins by a limited number of enzymes. Many of these enzymes can accept multiple N-linked glycans as substrates, thereby generating a large number of glycan intermediates and their intermingled pathways. Motivated by the quantitative methods developed in complex network research, we investigated the large-scale organization of such N-linked glycosylation pathways in mammalian cells. The N-linked glycosylation pathways are extremely modular, and are composed of cohesive topological modules that directly branch from a common upstream pathway of glycan synthesis. This unique structural property allows the glycan production between modules to be controlled by the upstream region. Although the enzymes act on multiple glycan substrates, indicating cross-talk between modules, the impact of the cross-talk on the module-specific enhancement of glycan synthesis may be confined within a moderate range by transcription-level control. The findings of the present study provide experimentally-testable predictions for glycosylation processes, and may be applicable to therapeutic glycoprotein engineering

Distinguishing patterns in the dynamics of long-term medication use by Markov analysis: beyond persistence

<p>Abstract</p> <p>Background</p> <p>In order to accurately distinguish gaps of varying length in drug treatment for chronic conditions from discontinuation without resuming therapy, short-term observation does not suffice. Thus, the use of inhalation corticosteroids (ICS) in the long-term, during a ten-year period is investigated. To describe medication use as a continuum, taking into account the timeliness and consistency of refilling, a Markov model is proposed.</p> <p>Methods</p> <p>Patients, that filled at least one prescription in 1993, were selected from the PHARMO medical record linkage system (RLS) containing >95% prescription dispensings per patient originating from community pharmacy records of 6 medium-sized cities in the Netherlands.</p> <p>The probabilities of continuous use, the refilling of at least one ICS prescription in each year of follow-up, and medication free periods were assessed by Markov analysis. Stratified analysis according to new use was performed.</p> <p>Results</p> <p>The transition probabilities of the refilling of at least one ICS prescription in the subsequent year of follow-up, were assessed for each year of follow-up and for the total study period.</p> <p>The change of transition probabilities in time was evaluated, e.g. the probability of continuing ICS use of starters in the first two years (51%) of follow-up increased to more than 70% in the following years. The probabilities of different patterns of medication use were assessed: continuous use (7.7%), cumulative medication gaps (1–8 years 69.1%) and discontinuing (23.2%) during ten-year follow-up for new users. New users had lower probability of continuous use (7.7%) and more variability in ICS refill patterns than previous users (56%).</p> <p>Conclusion</p> <p>In addition to well-established methods in epidemiology to ascertain compliance and persistence, a Markov model could be useful to further specify the variety of possible patterns of medication use within the continuum of adherence. This Markov model describes variation in behaviour and patterns of ICS use and could also be useful to investigate continuous use of other drugs applied in chronic diseases.</p

Intrinsic gain modulation and adaptive neural coding

In many cases, the computation of a neural system can be reduced to a receptive field, or a set of linear filters, and a thresholding function, or gain curve, which determines the firing probability; this is known as a linear/nonlinear model. In some forms of sensory adaptation, these linear filters and gain curve adjust very rapidly to changes in the variance of a randomly varying driving input. An apparently similar but previously unrelated issue is the observation of gain control by background noise in cortical neurons: the slope of the firing rate vs current (f-I) curve changes with the variance of background random input. Here, we show a direct correspondence between these two observations by relating variance-dependent changes in the gain of f-I curves to characteristics of the changing empirical linear/nonlinear model obtained by sampling. In the case that the underlying system is fixed, we derive relationships relating the change of the gain with respect to both mean and variance with the receptive fields derived from reverse correlation on a white noise stimulus. Using two conductance-based model neurons that display distinct gain modulation properties through a simple change in parameters, we show that coding properties of both these models quantitatively satisfy the predicted relationships. Our results describe how both variance-dependent gain modulation and adaptive neural computation result from intrinsic nonlinearity.Comment: 24 pages, 4 figures, 1 supporting informatio

Estimates of Outcomes Up to Ten Years after Stroke: Analysis from the Prospective South London Stroke Register

Charles Wolfe and colleagues collected data from the South London Stroke Register on 3,373 first strokes registered between 1995 and 2006 and showed that between 20% and 30% of survivors have poor outcomes up to 10 years after stroke

Familial aggregation of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia with solid tumors and myeloid malignancies.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.Lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) is a B-cell disorder resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphoplasmacytic cells. LPL/WM is a very rare disease, with an incidence rate of 3-4 cases per million people per year.Currently, the causes of LPL/WM are poorly understood; however, there are emerging data to support a role for immune-related factors in the pathogenesis of LPL/WM. In addition, data show that genetic factors are of importance in the etiology of LPL/WM. In this paper, we will review the current knowledge about familiality of LPL/WM and provide novel data on solid tumors and myeloid malignancies in first-degree relatives of LPL/WM patients.Swedish Cancer Society Stockholm County Council Karolinska Institutet Foundations National Institutes of Health, National Cancer Institute Roch

hMYH and hMTH1 cooperate for survival in mismatch repair defective T-cell acute lymphoblastic leukemia

hMTH1 is an 8-oxodGTPase that prevents mis-incorporation of free oxidized nucleotides into genomic DNA. Base excision and mismatch repair pathways also restrict the accumulation of oxidized lesions in DNA by removing the mis-inserted 8-oxo-7,8-dihydro-2'-deoxyguanosines (8-oxodGs). In this study, we aimed to investigate the interplay between hMYH DNA glycosylase and hMTH1 for cancer cell survival by using mismatch repair defective T-cell acute lymphoblastic leukemia (T-ALL) cells. To this end, MYH and MTH1 were silenced individually or simultaneously using small hairpin RNAs. Increased sub-G1 population and apoptotic cells were observed upon concurrent depletion of both enzymes. Elevated cell death was consistent with cleaved caspase 3 accumulation in double knockdown cells. Importantly, overexpression of the nuclear isoform of hMYH could remove the G1 arrest and partially rescue the toxicity observed in hMTH1-depleted cells. In addition, expression profiles of human DNA glycosylases were generated using quantitative reverse transcriptase–PCR in MTH1 and/or MYH knockdown cells. NEIL1 DNA glycosylase, involved in repair of oxidized nucleosides, was found to be significantly downregulated as a cellular response to MTH1–MYH co-suppression. Overall, the results suggest that hMYH and hMTH1 functionally cooperate for effective repair and survival in mismatch repair defective T-ALL Jurkat A3 cells

The time course of subsequent hospitalizations and associated costs in survivors of an ischemic stroke in Canada

BACKGROUND: Documentation of the hospitalizations rates following a stroke provides the inputs required for planning health services and to evaluate the economic efficiency of any new therapies. METHODS: Hospitalization rates by cause were examined using administrative data on 18,695 patients diagnosed with ischemic stroke (first or subsequent, excluding transient ischemic attack) in Saskatchewan, Canada between 1990 and 1995. Medical history was available retrospectively to January 1980 and follow-up was complete to March 2000. Analyses evaluated the rate and timing of all-cause and cardiovascular hospitalizations within discrete periods in the five years following the index stroke. Cardiovascular hospitalizations included patients with a primary diagnosis of ischemic stroke, transient ischemic attack, myocardial infarction, stable or unstable angina, heart failure or peripheral arterial disease. RESULTS: One-third (36%) of patients were identified by a hospitalized stroke. Mean age was 70.5 years, 48.0% were male, half had a history of stroke or a transient ischemic attack at the time of their index stroke. Three-quarters of the patients (72.7%) were hospitalized at least once during a mean follow-up of 4.6 years, accruing CAD $24 million in the first year alone. Of all hospitalizations, 20.4% were related to cardiovascular disease and 1.6% to bleeds. In the month following index stroke, 12.5% were admitted, an average of 1.04 times per patient hospitalized. Strokes accounted for 33% of all hospitalizations in the first month. The rate diminished steadily throughout the year and stabilized in the second year when approximately one-third of patients required hospitalization, at a rate of about one hospitalization for every two patient-years. Mean lengths of stay ranged from nine days to nearly 40 days. Close-fitting Weibull functions allow highly specific probability estimates. Other cardiovascular risk factors significantly increased hospitalization rates. CONCLUSION: After stroke, there are frequent hospitalizations accounting for substantial additional costs. Though these rates drop after one year, they remain high over time. The number of other cardiovascular causes of hospitalization confirms that stroke is a manifestation of disseminated atherothrombotic disease