COX-mediated endothelium-dependent contractions: From the past to recent discoveries

Endothelial cells release various substances to control the tone of the underlying vascular smooth muscle. Nitric oxide (NO) is the best defined endothelium-derived relaxing factor (EDRF). Endothelial cells can also increase vascular tone by releasing endothelium-derived contracting factors (EDCF). The over-production of EDCF contributes to the endothelial dysfunctions which accompanies various vascular diseases. The present review summarizes and discusses the mechanisms leading to the release of EDCFs derived from the metabolism of arachidonic acid. This release can be triggered by agonists such as acetylcholine, adenosine nucleotides or by stretch. All these stimuli are able to induce calcium influx into the endothelial cells, an effect which can be mimicked by calcium ionophores. The augmentation in intracellular calcium ion concentration initiates the release of EDCF. Downstream processes include activation of phospholipase A 2 (PLA2), cyclooxygenases (COX) and the production of reactive oxygen species (ROS) and vasoconstrictor prostanoids (endoperoxides, prostacyclin, thromboxane A2 and other prostaglandins) which subsequently diffuse to, and activate thromboxane- prostanoid (TP) receptors on the vascular smooth muscle cells leading to contraction. © 2010 CPS and SIMM All rights reserved.postprin

Optimal design of multiple-objective Lot Quality Assurance Sampling (LQAS) plans.

Lot Quality Assurance Sampling (LQAS) plans are widely used for health monitoring purposes. We propose a systematic approach to design multiple-objective LQAS plans that meet user-specified type 1 and 2 error rates and targets for selected diagnostic accuracy metrics. These metrics may include sensitivity, specificity, positive predictive value, and negative predictive value in high or low anticipated prevalence rate populations. We use Mixed Integer Nonlinear Programming (MINLP) tools to implement our design methodology. Our approach is flexible in that it can directly generate classic LQAS plans that control error rates only and find optimal LQAS plans that meet multiple objectives in terms of diagnostic metrics. We give examples, compare results with the classic LQAS and provide an application using a malaria outcome indicator survey in Mozambique

A comparative study of a flow-cytometry-based assessment of in vitro Plasmodium falciparum drug sensitivity

<p>Abstract</p> <p>Background</p> <p>Recently developed Sybr Green-based <it>in vitro Plasmodium falciparum </it>drug sensitivity assays provide an attractive alternative to current manual and automated methods. The present study evaluated flow cytometry measurement of DNA staining with Sybr Green in comparison with the <it>P. falciparum </it>lactate dehydrogenase assay, the tritiated hypoxanthine incorporation assay, a previously described Sybr Green based plate reader assay and light microscopy.</p> <p>Methods</p> <p>All assays were set up in standardized format in 96-well plates. The 50% inhibitory concentrations (IC₅₀) of chloroquine, mefloquine and dihydroartemisinin against the laboratory adapted <it>P. falciparum </it>strains 3D7, E8B, W2mef and Dd2 were determined using each method.</p> <p>Results</p> <p>The resolution achieved by flow cytometry allowed quantification of the increase in individual cell DNA content after an incubation period of only 24 h. Regression, and Bland and Altman analyses showed that the IC₅₀values determined using the flow cytometry assay after 24 h agreed well with those obtained using the hypoxanthine incorporation assay, the <it>P. falciparum </it>lactate dehydrogenase assay, the Sybr Green plate reader assay and light microscopy. However the values obtained with the flow cytometry assay after 48 h of incubation differed significantly from those obtained with the hypoxanthine incorporation assay, and the <it>P. falciparum </it>lactate dehydrogenase assay at low IC₅₀values, but agreed well with the Sybr Green plate reader assay and light microscopy.</p> <p>Conclusions</p> <p>Although flow cytometric equipment is expensive, the necessary reagents are inexpensive, the procedure is simple and rapid, and the cell volume required is minimal. This should allow field studies using fingerprick sample volumes.</p

Determinants of medication adherence to antihypertensive medications among a Chinese population using Morisky medication adherence scale

&lt;b&gt;Background and objectives&lt;/b&gt; Poor adherence to medications is one of the major public health challenges. Only one-third of the population reported successful control of blood pressure, mostly caused by poor drug adherence. However, there are relatively few reports studying the adherence levels and their associated factors among Chinese patients. This study aimed to study the adherence profiles and the factors associated with antihypertensive drug adherence among Chinese patients.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; A cross-sectional study was conducted in an outpatient clinic located in the New Territories Region of Hong Kong. Adult patients who were currently taking at least one antihypertensive drug were invited to complete a self-administered questionnaire, consisting of basic socio-demographic profile, self-perceived health status, and self-reported medication adherence. The outcome measure was the Morisky Medication Adherence Scale (MMAS-8). Good adherence was defined as MMAS scores greater than 6 points (out of a total score of 8 points).&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt; From 1114 patients, 725 (65.1%) had good adherence to antihypertensive agents. Binary logistic regression analysis was conducted. Younger age, shorter duration of antihypertensive agents used, job status being employed, and poor or very poor self-perceived health status were negatively associated with drug adherence.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusion&lt;/b&gt; This study reported a high proportion of poor medication adherence among hypertensive subjects. Patients with factors associated with poor adherence should be more closely monitored to optimize their drug taking behavior

Experimental arthritis is dependent on mouse mast cell protease-5

© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. The constitutive heparin+ (HP) mast cells (MCs) in mice express mouseMCprotease (mMCP)-5 and carboxypeptidaseA (mMC-CPA). The amino acid sequence ofmMCP-5is most similar to that of human chymase-1, as are the nucleotide sequences of their genes and transcripts. Using a homologous recombination approach, a C57BL/6 mouse line was created that possessed a disrupted mMCP-5 gene. The resulting mice were fertile and had no obvious developmental abnormality. Lack of mMCP-5 protein did not alter the granulation of the IL-3/IL-9-dependent mMCP-2+ MCs in the jejunal mucosa of Trichinella spiralisinfected mice. In contrast, the constitutive HP+ MCs in the tongues of mMCP-5-null mice were poorly granulated and lacked mMC-CPA protein. Bone marrow-derived MCs were readily developed from the transgenic mice using IL-3. Although these MCs contained high levels of mMC-CPA mRNA, they also lacked the latter exopeptidase. mMCP-5 protein is therefore needed to target translated mMC-CPA to the secretory granule along with HP-containing serglycin proteoglycans. Alternately, mMCP-5 is needed to protect mMC-CPA from autolysis in the cell's granules. Fibronectin was identified as a target of mMCP-5, and the exocytosis ofmMCP-5from theMCs in the mouse's peritoneal cavity resulted in the expression of metalloproteinase protease-9, which has been implicated in arthritis. In support of the latter finding, experimental arthritis was markedly reduced in mMCP-5-null mice relative to wildtype mice in two disease models

Explaining curriculum change: Social studies in Hong Kong

Studies the development of the social studies subject in the curriculum of Hong Kong. Consequences of functional shifts; Reflection of political system in the changing role of teachers; Operation of educational systems by private profitmaking businesses and charitable institutions.published_or_final_versio

Quantitative trait loci for bone traits segregating independently of those for growth in an F-2 broiler X layer cross

An F broiler-layer cross was phenotyped for 18 skeletal traits at 6, 7 and 9 weeks of age and genotyped with 120 microsatellite markers. Interval mapping identified 61 suggestive and significant QTL on 16 of the 25 linkage groups for 16 traits. Thirty-six additional QTL were identified when the assumption that QTL were fixed in the grandparent lines was relaxed. QTL with large effects on the lengths of the tarsometatarsus, tibia and femur, and the weights of the tibia and femur were identified on GGA4 between 217 and 249 cM. Six QTL for skeletal traits were identified that did not co-locate with genome wide significant QTL for body weight and two body weight QTL did not coincide with skeletal trait QTL. Significant evidence of imprinting was found in ten of the QTL and QTL x sex interactions were identified for 22 traits. Six alleles from the broiler line for weight- and size-related skeletal QTL were positive. Negative alleles for bone quality traits such as tibial dyschondroplasia, leg bowing and tibia twisting generally originated from the layer line suggesting that the allele inherited from the broiler is more protective than the allele originating from the layer

Genetic Code Mutations: The Breaking of a Three Billion Year Invariance

The genetic code has been unchanging for some three billion years in its canonical ensemble of encoded amino acids, as indicated by the universal adoption of this ensemble by all known organisms. Code mutations beginning with the encoding of 4-fluoro-Trp by Bacillus subtilis, initially replacing and eventually displacing Trp from the ensemble, first revealed the intrinsic mutability of the code. This has since been confirmed by a spectrum of other experimental code alterations in both prokaryotes and eukaryotes. To shed light on the experimental conversion of a rigidly invariant code to a mutating code, the present study examined code mutations determining the propagation of Bacillus subtilis on Trp and 4-, 5- and 6-fluoro-tryptophans. The results obtained with the mutants with respect to cross-inhibitions between the different indole amino acids, and the growth effects of individual nutrient withdrawals rendering essential their biosynthetic pathways, suggested that oligogenic barriers comprising sensitive proteins which malfunction with amino acid analogues provide effective mechanisms for preserving the invariance of the code through immemorial time, and mutations of these barriers open up the code to continuous change

OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection.

Pathogenic mycobacteria inhibit inflammasome activation to establish infection. Although it is known that potassium efflux is a trigger for inflammasome activation, the interaction between mycobacterial infection, potassium efflux, and inflammasome activation has not been investigated. Here, we use Mycobacterium marinum infection of zebrafish embryos and Mycobacterium tuberculosis infection of THP-1 cells to demonstrate that pathogenic mycobacteria up-regulate the host WNK signalling pathway kinases SPAK and OXSR1 which control intracellular potassium balance. We show that genetic depletion or inhibition of OXSR1 decreases bacterial burden and intracellular potassium levels. The protective effects of OXSR1 depletion are at least partially mediated by NLRP3 inflammasome activation, caspase-mediated release of IL-1β, and downstream activation of protective TNF-α. The elucidation of this druggable pathway to potentiate inflammasome activation provides a new avenue for the development of host-directed therapies against intracellular infections