The challenge of acute-stroke management: does telemedicine offer a solution?

<p><b>Background:</b> Several studies have described successful experiences with the use of telemedicine in acute stroke. The objective of this study was to assess the feasibility, acceptability, and treatment delivery reliability, of telemedicine systems for the clinical and radiological assessment, and management of acute-stroke patients.</p> <p><b>Summary of Review:</b> A systematic review of the literature was carried out. Studies were included if they met the following criteria: (1) study population included participants with a diagnosis of suspected acute stroke, (2) intervention included the use of telemedicine systems to aid assessment, diagnosis, or treatment in acute stroke, and (3) outcomes measured related to feasibility in clinical practice, acceptability to patients, carers, and staff, reliability of telemedicine systems, and effectiveness in delivering treatment, especially tissue plasminogen activator (tPA). Overall, 17 relevant non-randomised studies reported that telemedicine systems were feasible and acceptable. Interrater reliability was excellent for global clinical assessments and decisions on radiological exclusion criteria although agreement for individual assessment items was more variable. Telemedicine systems were associated with increased use of tPA.</p> <p><b>Conclusion:</b> Although there is limited reliable evidence, observational studies have indicated that telemedicine systems can be feasible, acceptable, and reliable in acute-stroke management. In addition, telemedicine consultations were associated with improved delivery of tPA.</p&gt

Molecular Modeling Study for Inhibition Mechanism of Human Chymase and Its Application in Inhibitor Design

Human chymase catalyzes the hydrolysis of peptide bonds. Three chymase inhibitors with very similar chemical structures but highly different inhibitory profiles towards the hydrolase function of chymase were selected with the aim of elucidating the origin of disparities in their biological activities. As a substrate (angiotensin-I) bound crystal structure is not available, molecular docking was performed to dock the substrate into the active site. Molecular dynamics simulations of chymasecomplexes with inhibitors and substrate were performed to calculate the binding orientation of inhibitors and substrate as well as to characterize conformational changes in the active site. The results elucidate details of the 3D chymase structure as well as the importance of K40 in hydrolase function. Binding mode analysis showed that substitution of a heavier Cl atom at the phenyl ring of most active inhibitor produced a great deal of variation in its orientation causing the phosphinate group to interact strongly with residue K40. Dynamics simulations revealed the conformational variation in region of V36-F41upon substrate and inhibitor binding induced a shift in the location of K40 thus changing its interactions with them. Chymase complexes with the most activecompound and substrate were used for development of a hybrid pharmacophore model which was applied in databases screening. Finally, hits which bound well at the active site, exhibited key interactions and favorable electronic properties were identified as possible inhibitors for chymase. This study not only elucidates inhibitorymechanism of chymase inhibitors but also provides key structural insights which will aid in the rational design of novel potent inhibitors of the enzyme. In general, the strategy applied in the current study could be a promising computational approach and may be generally applicable to drug design for other enzymes

Effects of MASP-1 of the Complement System on Activation of Coagulation Factors and Plasma Clot Formation

BACKGROUND: Numerous interactions between the coagulation and complement systems have been shown. Recently, links between coagulation and mannan-binding lectin-associated serine protease-1 (MASP-1) of the complement lectin pathway have been proposed. Our aim was to investigate MASP-1 activation of factor XIII (FXIII), fibrinogen, prothrombin, and thrombin-activatable fibrinolysis inhibitor (TAFI) in plasma-based systems, and to analyse effects of MASP-1 on plasma clot formation, structure and lysis. METHODOLOGY/PRINCIPAL FINDINGS: We used a FXIII incorporation assay and specific assays to measure the activation products prothrombin fragment F1+2, fibrinopeptide A (FPA), and activated TAFI (TAFIa). Clot formation and lysis were assessed by turbidimetric assay. Clot structure was studied by scanning electron microscopy. MASP-1 activated FXIII and, contrary to thrombin, induced FXIII activity faster in the Val34 than the Leu34 variant. MASP-1-dependent generation of F1+2, FPA and TAFIa showed a dose-dependent response in normal citrated plasma (NCP), albeit MASP-1 was much less efficient than FXa or thrombin. MASP-1 activation of prothrombin and TAFI cleavage were confirmed in purified systems. No FPA generation was observed in prothrombin-depleted plasma. MASP-1 induced clot formation in NCP, affected clot structure, and prolonged clot lysis. CONCLUSIONS/SIGNIFICANCE: We show that MASP-1 interacts with plasma clot formation on different levels and influences fibrin structure. Although MASP-1-induced fibrin formation is thrombin-dependent, MASP-1 directly activates prothrombin, FXIII and TAFI. We suggest that MASP-1, in concerted action with other complement and coagulation proteins, may play a role in fibrin clot formation

Adherence to antidepressant therapy for major depressive patients in a psychiatric hospital in Thailand

Poor adherence to antidepressant therapy is an important barrier to the effective management of major depressive disorder. This study aims to quantify the adherence rate to antidepressant treatment and to determine the pattern of prescriptions of depressed patients in a psychiatric institute in Thailand.This retrospective study used electronic pharmacy data of outpatients aged 15 or older, with a new diagnosis of major depression who received at least one prescription of antidepressants between August 2005 and September 2008. The medication possession ratio (MPR) was used to measure adherence over a 6 month period.1,058 were eligible for study inclusion. The overall adherence (MPR > 80%) in those attending this facility at least twice was 41% but if we assume that all patients who attended only once were non-adherent, adherence may be as low as 23%. Fluoxetine was the most commonly prescribed drug followed by TCAs. A large proportion of cases received more than one drug during one visit or was switched from one drug to another (39%).Adherence to antidepressant therapy for treatment of major depression in Thailand is rather low compared to results of adherence from elsewhere

Pharmacological Targeting of Native CatSper Channels Reveals a Required Role in Maintenance of Sperm Hyperactivation

The four sperm-specific CatSper ion channel proteins are required for hyperactivated motility and male fertility, and for Ca2+ entry evoked by alkaline depolarization. In the absence of external Ca2+, Na+ carries current through CatSper channels in voltage-clamped sperm. Here we show that CatSper channel activity can be monitored optically with the [Na+]i-reporting probe SBFI in populations of intact sperm. Removal of external Ca2+ increases SBFI signals in wild-type but not CatSper2-null sperm. The rate of the indicated rise of [Na+]i is greater for sperm alkalinized with NH4Cl than for sperm acidified with propionic acid, reflecting the alkaline-promoted signature property of CatSper currents. In contrast, the [Na+]i rise is slowed by candidate CatSper blocker HC-056456 (IC50 ∼3 µM). HC-056456 similarly slows the rise of [Ca2+]i that is evoked by alkaline depolarization and reported by fura-2. HC-056456 also selectively and reversibly decreased CatSper currents recorded from patch-clamped sperm. HC-056456 does not prevent activation of motility by HCO3− but does prevent the development of hyperactivated motility by capacitating incubations, thus producing a phenocopy of the CatSper-null sperm. When applied to hyperactivated sperm, HC-056456 causes a rapid, reversible loss of flagellar waveform asymmetry, similar to the loss that occurs when Ca2+ entry through the CatSper channel is terminated by removal of external Ca2+. Thus, open CatSper channels and entry of external Ca2+ through them sustains hyperactivated motility. These results indicate that pharmacological targeting of the CatSper channel may impose a selective late-stage block to fertility, and that high-throughput screening with an optical reporter of CatSper channel activity may identify additional selective blockers with potential for male-directed contraception

Ferritin immobilization on patterned poly(2-hydroxyethyl methacrylate) brushes on silicon surfaces from colloid system

In this paper, we describe a graft polymerization/solvent immersion method for generating poly(2-hydroxyethyl methacrylate) (PHEMA) brushes in various patterns. We used a novel fabrication process, involving very-large-scale integration and oxygen plasma treatment, to generate well-defined patterns of polymerized PHEMA on patterned Si(100) surfaces. We observed brush- and mushroom-like regions for the PHEMA brushes, with various pattern resolutions, after immersing wafers presenting lines of these polymers in MeOH and n-hexane, respectively. The interaction between PHEMA and ferritin protein sheaths in MeOH and n-hexane (good and poor solvent for PHEMA, respectively) was used to capture and release ferritins from fluidic system. The “tentacles” behaver for PHEMA brushes was found through various solvents in fluidic system. Using high-resolution scanning electron microscopy, we observed patterned ferritin Fe cores on the Si surface after pyrolysis of the patterned PHEMA brushes and ferritin protein sheaths, which verify the “tentacles” behaver for PHEMA brushes

Somatic ‘Soluble’ Adenylyl Cyclase Isoforms Are Unaffected in Sacytm1Lex/Sacytm1Lex ‘Knockout’ Mice

BACKGROUND: Mammalian Soluble adenylyl cyclase (sAC, Adcy10, or Sacy) represents a source of the second messenger cAMP distinct from the widely studied, G protein-regulated transmembrane adenylyl cyclases. Genetic deletion of the second through fourth coding exons in Sacy(tm1Lex)/Sacy(tm1Lex) knockout mice results in a male sterile phenotype. The absence of any major somatic phenotype is inconsistent with the variety of somatic functions identified for sAC using pharmacological inhibitors and RNA interference. PRINCIPAL FINDINGS: We now use immunological and molecular biological methods to demonstrate that somatic tissues express a previously unknown isoform of sAC, which utilizes a unique start site, and which 'escapes' the design of the Sacy(tm1Lex) knockout allele. CONCLUSIONS/SIGNIFICANCE: These studies reveal increased complexity at the sAC locus, and they suggest that the known isoforms of sAC play a unique function in male germ cells

Evaluating the Influence of Epidemiological Parameters and Host Ecology on the Spread of Phocine Distemper Virus through Populations of Harbour Seals

Catriona Harris was supported by a grant from the UK Natural Environment Research Council. The funders had no role in study design, data collections and analysis, decision to publish, or preparation of the manuscript.Background: Outbreaks of phocine distemper virus (PDV) in Europe during 1988 and 2002 were responsible for the death of around 23,000 and 30,000 harbour seals, respectively. These epidemics, particularly the one in 2002, provided an unusual opportunity to estimate epidemic parameters for a wildlife disease. There were marked regional differences in the values of some parameters both within and between epidemics. Methodology and Principal Findings: We used an individual-based model of seal movement that allowed us to incorporate realistic representations of space, time and animal behaviour into a traditional epidemiological modelling framework. We explored the potential influence of a range of ecological (foraging trip duration, time of epidemic onset, population size) and epidemiological (length of infectious period, contact rate between infectious and susceptible individuals, case mortality) parameters on four readily-measurable epidemic characteristics (number of dead individuals, duration of epidemic, peak mortality date and prevalence) and on the probability that an epidemic would occur in a particular region. We analysed the outputs as if they were the results of a series of virtual experiments, using Generalised Linear Modelling. All six variables had a significant effect on the probability that an epidemic would be recognised as an unusual mortality event by human observers. Conclusions: Regional and temporal variation in contact rate was the most likely cause of the observed differences between the two epidemics. This variation could be a consequence of differences in the way individuals divide their time between land and sea at different times of the year.Publisher PDFPeer reviewe

Using quantile regression to investigate racial disparities in medication non-adherence

<p>Abstract</p> <p>Background</p> <p>Many studies have investigated racial/ethnic disparities in medication non-adherence in patients with type 2 diabetes using common measures such as medication possession ratio (MPR) or gaps between refills. All these measures including MPR are quasi-continuous and bounded and their distribution is usually skewed. Analysis of such measures using traditional regression methods that model mean changes in the dependent variable may fail to provide a full picture about differential patterns in non-adherence between groups.</p> <p>Methods</p> <p>A retrospective cohort of 11,272 veterans with type 2 diabetes was assembled from Veterans Administration datasets from April 1996 to May 2006. The main outcome measure was MPR with quantile cutoffs Q1-Q4 taking values of 0.4, 0.6, 0.8 and 0.9. Quantile-regression (QReg) was used to model the association between MPR and race/ethnicity after adjusting for covariates. Comparison was made with commonly used ordinary-least-squares (OLS) and generalized linear mixed models (GLMM).</p> <p>Results</p> <p>Quantile-regression showed that Non-Hispanic-Black (NHB) had statistically significantly lower MPR compared to Non-Hispanic-White (NHW) holding all other variables constant across all quantiles with estimates and p-values given as -3.4% (p = 0.11), -5.4% (p = 0.01), -3.1% (p = 0.001), and -2.00% (p = 0.001) for Q1 to Q4, respectively. Other racial/ethnic groups had lower adherence than NHW only in the lowest quantile (Q1) of about -6.3% (p = 0.003). In contrast, OLS and GLMM only showed differences in mean MPR between NHB and NHW while the mean MPR difference between other racial groups and NHW was not significant.</p> <p>Conclusion</p> <p>Quantile regression is recommended for analysis of data that are heterogeneous such that the tails and the central location of the conditional distributions vary differently with the covariates. QReg provides a comprehensive view of the relationships between independent and dependent variables (i.e. not just centrally but also in the tails of the conditional distribution of the dependent variable). Indeed, without performing QReg at different quantiles, an investigator would have no way of assessing whether a difference in these relationships might exist.</p