Potentiation of thrombus instability: a contributory mechanism to the effectiveness of antithrombotic medications

© The Author(s) 2018The stability of an arterial thrombus, determined by its structure and ability to resist endogenous fibrinolysis, is a major determinant of the extent of infarction that results from coronary or cerebrovascular thrombosis. There is ample evidence from both laboratory and clinical studies to suggest that in addition to inhibiting platelet aggregation, antithrombotic medications have shear-dependent effects, potentiating thrombus fragility and/or enhancing endogenous fibrinolysis. Such shear-dependent effects, potentiating the fragility of the growing thrombus and/or enhancing endogenous thrombolytic activity, likely contribute to the clinical effectiveness of such medications. It is not clear how much these effects relate to the measured inhibition of platelet aggregation in response to specific agonists. These effects are observable only with techniques that subject the growing thrombus to arterial flow and shear conditions. The effects of antithrombotic medications on thrombus stability and ways of assessing this are reviewed herein, and it is proposed that thrombus stability could become a new target for pharmacological intervention.Peer reviewedFinal Published versio

The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1

Resveratrol is a cancer preventative agent that is found in red wine. Piceatannol is a closely related stilbene that has antileukaemic activity and is also a tyrosine kinase inhibitor. Piceatannol differs from resveratrol by having an additional aromatic hydroxy group. The enzyme CYP1B1 is overexpressed in a wide variety of human tumours and catalyses aromatic hydroxylation reactions. We report here that the cancer preventative agent resveratrol undergoes metabolism by the cytochrome P450 enzyme CYP1B1 to give a metabolite which has been identified as the known antileukaemic agent piceatannol. The metabolite was identified by high performance liquid chromatography analysis using fluorescence detection and the identity of the metabolite was further confirmed by derivatisation followed by gas chromatography–mass spectrometry studies using authentic piceatannol for comparison. This observation provides a novel explanation for the cancer preventative properties of resveratrol. It demonstrates that a natural dietary cancer preventative agent can be converted to a compound with known anticancer activity by an enzyme that is found in human tumours. Importantly this result gives insight into the functional role of CYP1B1 and provides evidence for the concept that CYP1B1 in tumours may be functioning as a growth suppressor enzyme

The reliability of three-dimensional scapular attitudes in healthy people and people with shoulder impingement syndrome

<p>Abstract</p> <p>Background</p> <p>Abnormal scapular displacements during arm elevation have been observed in people with shoulder impingement syndrome. These abnormal scapular displacements were evaluated using different methods and instruments allowing a 3-dimensional representation of the scapular kinematics. The validity and the intrasession reliability have been shown for the majority of these methods for healthy people. However, the intersession reliability on healthy people and people with impaired shoulders is not well documented. This measurement property needs to be assessed before using such methods in longitudinal comparative studies. The objective of this study is to evaluate the intra and intersession reliability of 3-dimensional scapular attitudes measured at different arm positions in healthy people and to explore the same measurement properties in people with shoulder impingement syndrome using the Optotrak Probing System.</p> <p>Methods</p> <p>Three-dimensional scapular attitudes were measured twice (test and retest interspaced by one week) on fifteen healthy subjects (mean age 37.3 years) and eight subjects with subacromial shoulder impingement syndrome (mean age 46.1 years) in three arm positions (arm at rest, 70° of humerothoracic flexion and 90° of humerothoracic abduction) using the Optotrak Probing System. Two different methods of calculation of 3-dimensional scapular attitudes were used: relative to the position of the scapula at rest and relative to the trunk. Intraclass correlation coefficient (ICC) and standard error of measure (SEM) were used to estimate intra and intersession reliability.</p> <p>Results</p> <p>For both groups, the reliability of the three-dimensional scapular attitudes for elevation positions was very good during the same session (ICCs from 0.84 to 0.99; SEM from 0.6° to 1.9°) and good to very good between sessions (ICCs from 0.62 to 0.97; SEM from 1.2° to 4.2°) when using the method of calculation relative to the trunk. Higher levels of intersession reliability were found for the method of calculation relative to the trunk in anterior-posterior tilting at 70° of flexion compared to the method of calculation relative to the scapula at rest.</p> <p>Conclusion</p> <p>The estimation of three-dimensional scapular attitudes using the method of calculation relative to the trunk is reproducible in the three arm positions evaluated and can be used to document the scapular behavior.</p

Counting the costs: Comparing depot medroxyprogesterone acetate and norethisterone oenanthate utilisation patterns in South Africa

BACKGROUND: In South Africa, where health care resources are limited, it is important to ensure that drugs provision and use is rational. The Essential Drug List includes depot medroxyprogesterone acetate (DMPA) and norethisterone oenanthate (NET-EN) as injectable progestagen-only contraceptives (IPCs), and both products are extensively used. OBJECTIVES AND METHODS: Utilisation patterns of the injectable contraceptive products DMPA and NET-EN are compared in the context of current knowledge of the safety and efficacy of these agents. Utilisation patterns were analysed by means of a Pareto (ABC) analysis of IPCs issued from 4 South African provincial pharmaceutical depots over 3 financial years. A case study from rural KwaZulu-Natal, South Africa, is used to examine utilisation patterns and self-reported side effects experienced by 187 women using IPCs. RESULTS: IPCs accounted for a substantial share of total state expenditure on drugs. While more DMPA than NET-EN was issued, NET-EN distribution from 2 depots increased over the 3-year period. Since DMPA was cheaper, if all NET-EN clients in the 1999/2000 financial year (annualised) had used DMPA, the 4 depots could have saved 4.95 million South African Rands on product acquisition costs alone. The KZN case study showed slightly more NET-EN (54%) than DMPA (46%) use; no significant differences in self-reported side effects; and that younger women were more likely to use NET-EN than DMPA (p = 0.0001). CONCLUSIONS: Providing IPCs on the basis of age is not appropriate or cost effective. Rational use of these products should include consideration of the cost of prescribing one over another

Deletion of the Chd6 exon 12 affects motor coordination

Members of the CHD protein family play key roles in gene regulation through ATP-dependent chromatin remodeling. This is facilitated by chromodomains that bind histone tails, and by the SWI2/SNF2-like ATPase/helicase domain that remodels chromatin by moving histones. Chd6 is ubiquitously expressed in both mouse and human, with the highest levels of expression in the brain. The Chd6 gene contains 37 exons, of which exons 12-19 encode the highly conserved ATPase domain. To determine the biological role of Chd6, we generated mouse lines with a deletion of exon 12. Chd6 without exon 12 is expressed at normal levels in mice, and Chd6 Exon 12 −/− mice are viable, fertile, and exhibit no obvious morphological or pathological phenotype. Chd6 Exon 12 −/− mice lack coordination as revealed by sensorimotor analysis. Further behavioral testing revealed that the coordination impairment was not due to muscle weakness or bradykinesia. Histological analysis of brain morphology revealed no differences between Chd6 Exon 12 −/− mice and wild-type (WT) controls. The location of CHD6 on human chromosome 20q12 is overlapped by the linkage map regions of several human ataxias, including autosomal recessive infantile cerebellar ataxia (SCAR6), a nonprogressive cerebrospinal ataxia. The genomic location, expression pattern, and ataxic phenotype of Chd6 Exon 12 −/− mice indicate that mutations within CHD6 may be responsible for one of these ataxias

Girls' disruptive behavior and its relationship to family functioning: A review

Although a number of reviews of gender differences in disruptive behavior and parental socialization exist, we extend this literature by addressing the question of differential development among girls and by placing both disruptive behavior and parenting behavior in a developmental framework. Clarifying the heterogeneity of development in girls is important for developing and optimizing gender-specific prevention and treatment programs. In the current review, we describe the unique aspects of the development of disruptive behavior in girls and explore how the gender-specific development of disruptive behavior can be explained by family linked risk and protective processes. Based on this review, we formulate a gender-specific reciprocal model of the influence of social factors on the development of disruptive behavior in girls in order to steer further research and better inform prevention and treatment programs

Health-related quality of life after traumatic brain injury : deriving value sets for the QOLIBRI-OS for Italy, The Netherlands and The United Kingdom

Purpose The Quality of Life after Brain Injury overall scale (QOLIBRI-OS) measures health-related quality of life (HRQoL) after traumatic brain injury (TBI). The aim of this study was to derive value sets for the QOLIBRI-OS in three European countries, which will allow calculation of utility scores for TBI health states. Methods A QOLIBRI-OS value set was derived by using discrete choice experiments (DCEs) and visual analogue scales (VAS) in general population samples from the Netherlands, United Kingdom and Italy. A three-stage procedure was used: (1) A selection of health states, covering the entire spectrum of severity, was defined; (2) General population samples performed the health state valuation task using a web-based survey with three VAS questions and an at random selection of sixteen DCEs; (3) DCEs were analysed using a conditional logistic regression and were then anchored on the VAS data. Utility scores for QOLIBRI-OS health states were generated resulting in estimates for all potential health states. Results The questionnaire was completed by 13,623 respondents. The biggest weight increase for all attributes is seen from "slightly" to "not at all satisfied", resulting in the largest impact on HRQoL. "Not at all satisfied with how brain is working" should receive the greatest weight in utility calculations in all three countries. Conclusion By transforming the QOLIBRI-OS into utility scores, we enabled the application in economic evaluations and in summary measures of population health, which may be used to inform decision-makers on the best interventions and strategies for TBI patients.Peer reviewe