346 research outputs found
Pharmacological basis and clinical evidence of dabigatran therapy
Dabigatran is an emerging oral anticoagulant which is a direct inhibitor of thrombin activity. It has been approved in the European Union and the United States of America for the prevention of thrombosis after major orthopedic surgery. It has also been approved by the American Food and Drug Administration and the European Medicines Agency for the prevention of stroke in chronic atrial fibrillation. Dabigatran provides a stable anticoagulation effect without any need to perform periodical laboratory controls. Of note, there is a growing amount of clinical evidence which shows its safety and efficacy. For these reasons, dabigatran may suppose a revolution in oral anticoagulation. However, two important limitations remain. First, it is contraindicated in patients with end-stage renal disease. Second, there is no evidence of the prevention of thrombosis in mechanical heart valves
Neurobiological Correlates of Decision-Making in Framing Conditions
Human decision-making is a complex process, of which the neurobiological correlates are not well understood. Several theories have been proposed, among others Prospect theory which assumes a different evaluation of gains and losses of the same value. De Martino et al. tested the influence of the âframing effectâ on decision-making and we aimed to replicate their study as some of the findings remained unclear. A general tendency to act in accordance with the frame was shown in a behavioural study. In order to uncover the underlying neural correlates, participants performed the same task in an fMRI scanner. Even though the amygdala could not be linked to framing, increased activity in the ACC when making frame-incongruent decisions was established. This can be related to acting in a more rational manner. Furthermore, activity in the cerebellum was increased when making a choice, indicating the involvement of this brain area in decision-making under uncertainty
Update on anti-coagulation in atrial fibrillation
Atrial fibrillation (AF), the most common clinically relevant arrhythmia, affects 2.2 million individuals in the USA and 4.5 million in Europe, resulting in significant morbidity and mortality. Pharmacotherapy aimed at controlling both heart rate and rhythm is employed to relieve AF symptoms, though debate continues about which approach is preferable. AF prevalence rises with age from 0.4% to 1% in the general population to 11% in those aged >70 years. AF is associated with a pro-thrombotic state and other comorbidities; age, hypertension, heart failure and diabetes mellitus all play a key role in AF pathogenesis. Anti-coagulation is essential for stroke prevention in patients with AF and is recommended for patients with one or more risk factors for stroke. Used within the recommended therapeutic range, warfarin and other vitamin K antagonists decrease the incidence of stroke and mortality in AF patients. Warfarin remains under-used, however, because of the perceived high risk of haemorrhage, narrow therapeutic window and need for regular monitoring. Several novel anti-coagulants show promise in AF-related stroke prevention. In particular, the novel, oral, direct thrombin inhibitor, dabigatran etexilate, recently licensed by the US Food and Drug Administration (FDA) and Health Canada has shown improved efficacy and safety compared with warfarin for stroke prevention in AF, and has the potential to replace warfarin in this indication. The increasing number of new therapeutic options, including improved anti-arrhythmic agents, novel anti-coagulants and more accessible ablation techniques, are likely to deliver better care for AF patients in the near future
The acute angiogenic signalling response to low-load resistance exercise with blood flow restriction
This study investigated protein kinase activation and gene expression of angiogenic factors in response to low-load resistance exercise with or without blood flow restriction (BFR). In a repeated measures cross-over design, six males performed four sets of bilateral knee extension exercise at 20% 1RM (reps per setâ=â30:15:15:continued to fatigue) with BFR (110â
mmHg) and without (CON). Muscle biopsies were obtained from the vastus lateralis before, 2 and 4â
h post-exercise. mRNA expression was determined using real-time RT-PCR. Protein phosphorylation/expression was determined using Western blot. p38MAPK phosphorylation was greater (pâ=â0.05) at 2â
h following BFR (1.3âÂąâ0.8) compared to CON (0.4âÂąâ0.3). AMPK phosphorylation remained unchanged. PGC-1Îą mRNA expression increased at 2â
h (5.9âÂąâ1.3 vs. 2.1âÂąâ0.8; pâ=â0.03) and 4â
h (3.2âÂąâ0.8 vs. 1.5âÂąâ0.4; pâ=â0.03) following BFR exercise with no change in CON. PGC-1Îą protein expression did not change following either exercise. BFR exercise enhanced mRNA expression of vascular endothelial growth factor (VEGF) at 2â
h (5.2âÂąâ2.8 vs 1.7âÂąâ1.1; pâ=â.02) and 4â
h (6.8âÂąâ4.9 vs. 2.5âÂąâ2.7; pâ=â.01) compared to CON. mRNA expression of VEGF-R2 and hypoxia-inducible factor 1Îą increased following BFR exercise but only eNOS were enhanced relative to CON. Matrix metalloproteinase-9 mRNA expression was not altered in response to either exercise. Acute low-load resistance exercise with BFR provides a targeted angiogenic response potentially mediated through enhanced ischaemic and shear stress stimuli
Dabigatran in patients with atrial fibrillation: perioperative and periinterventional management
In any type of invasive surgery, the patientâs individual risk of thromboembolism has to be weighed against the risk of bleeding. Based on various everyday situations in clinical routine, the purpose of the present expert recommendations is to provide appropriate perioperative and periinterventional management for patients with atrial fibrillation undergoing long-term treatment with the thrombin inhibitor dabigatran. As we currently have no routine laboratory test to measure therapeutic levels of the substance or the risk of bleeding, general measures such as a standardized documentation of the patientâs history, a sufficient time interval between the last preoperative dose and the procedure, and careful control of local hemostasis should be given special attention
Cognitive behavioral therapy of socially phobic children focusing on cognition: a randomised wait-list control study
BACKGROUND: Although literature provides support for cognitive behavioral therapy (CBT) as an efficacious intervention for social phobia, more research is needed to improve treatments for children.
METHODS: Forty four Caucasian children (ages 8-14) meeting diagnostic criteria of social phobia according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; APA, 1994) were randomly allocated to either a newly developed CBT program focusing on cognition according to the model of Clark and Wells (n = 21) or a wait-list control group (n = 23). The primary outcome measure was clinical improvement. Secondary outcomes included improvements in anxiety coping, dysfunctional cognitions, interaction frequency and comorbid symptoms. Outcome measures included child report and clinican completed measures as well as a diagnostic interview.
RESULTS: Significant differences between treatment participants (4 dropouts) and controls (2 dropouts) were observed at post test on the German version of the Social Phobia and Anxiety Inventory for Children. Furthermore, in the treatment group, significantly more children were free of diagnosis than in wait-list group at post-test. Additional child completed and clinician completed measures support the results.
DISCUSSION: The study is a first step towards investigating whether CBT focusing on cognition is efficacious in treating children with social phobia. Future research will need to compare this treatment to an active treatment group. There remain the questions of whether the effect of the treatment is specific to the disorder and whether the underlying theoretical model is adequate.
CONCLUSION: Preliminary support is provided for the efficacy of the cognitive behavioral treatment focusing on cognition in socially phobic children. Active comparators should be established with other evidence-based CBT programs for anxiety disorders, which differ significantly in their dosage and type of cognitive interventions from those of the manual under evaluation (e.g. Coping Cat)
Rational Design and Characterization of D-Phe-Pro-D-Arg-Derived Direct Thrombin Inhibitors
The tremendous social and economic impact of thrombotic disorders, together with the considerable risks associated to the currently available therapies, prompt for the development of more efficient and safer anticoagulants. Novel peptide-based thrombin inhibitors were identified using in silico structure-based design and further validated in vitro. The best candidate compounds contained both l- and d-amino acids, with the general sequence d-Phe(P3)-Pro(P2)-d-Arg(P1)-P1â˛-CONH2. The P1Ⲡposition was scanned with l- and d-isomers of natural or unnatural amino acids, covering the major chemical classes. The most potent non-covalent and proteolysis-resistant inhibitors contain small hydrophobic or polar amino acids (Gly, Ala, Ser, Cys, Thr) at the P1Ⲡposition. The lead tetrapeptide, d-Phe-Pro-d-Arg-d-Thr-CONH2, competitively inhibits Îą-thrombin's cleavage of the S2238 chromogenic substrate with a Ki of 0.92 ÂľM. In order to understand the molecular details of their inhibitory action, the three-dimensional structure of three peptides (with P1Ⲡl-isoleucine (fPrI), l-cysteine (fPrC) or d-threonine (fPrt)) in complex with human Îą-thrombin were determined by X-ray crystallography. All the inhibitors bind in a substrate-like orientation to the active site of the enzyme. The contacts established between the d-Arg residue in position P1 and thrombin are similar to those observed for the l-isomer in other substrates and inhibitors. However, fPrC and fPrt disrupt the active site His57-Ser195 hydrogen bond, while the combination of a P1 d-Arg and a bulkier P1Ⲡresidue in fPrI induce an unfavorable geometry for the nucleophilic attack of the scissile bond by the catalytic serine. The experimental models explain the observed relative potency of the inhibitors, as well as their stability to proteolysis. Moreover, the newly identified direct thrombin inhibitors provide a novel pharmacophore platform for developing antithrombotic agents by exploring the conformational constrains imposed by the d-stereochemistry of the residues at positions P1 and P1â˛
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