Regulation of TP thromboxane receptor expression and activity by selective P2Y12 receptor antagonists:consequences for dual antiplatelet therapy?

Platelets are small anucleate cells which play a fundamental role in haemostasis restricting blood loss following vessel injury. They also play a critical role in arterial thrombus formation in acute coronary syndromes (ACS). Platelets can respond to small molecule agonists leading to an aggregation response forming a clot or thrombus. Two particularly relevant small molecule agonists are thromboxane (TxA2) and ADP which act on different G protein coupled receptors (GPCRs), present on the platelet plasma membrane. ADP acts through P2Y1 and P2Y12 receptors while TxA2 acts through thromboxane (TP) receptors. Current clinical practice to reduce the risk of thrombus formation in ACS patients employs a dual antiplatelet therapy (DAPT) approach. DAPT consists of a P2Y12 receptor antagonist to block the effects of ADP at P2Y12, and aspirin to ablate the synthesis of TxA2. Notably DAPT, although clinically efficacious, can have the significant side-effect of patient bleeding. However, emerging in vivo and in vitro evidence suggests certain P2Y12 receptor antagonists can reduce the activity of TP receptors and modulate their expression. If specific P2Y12 receptor antagonists can reduce thromboxane receptor activity, the use of aspirin in DAPT may be unnecessary with its removal potentially reducing major bleeding risk. In this thesis, the thromboxane and P2Y12 receptors expression is shown to be deeply connected where co-expression of both receptors bilaterally increases surface receptor expression which is increased further by P2Y12 receptor antagonist Ticagrelor. Further, thromboxane receptor reactivity to agonists is reduced by Ticagrelor pre-treatment in human platelets and cells co-expressing P2Y12R. Lastly, through co-immunoprecipitation, this thesis reports a novel physical interaction between the thromboxane receptor and the P2Y12 receptor which appeared to be further stabilised by Ticagrelor. These findings aim to improve our mechanistic understanding of the interplay between P2Y12 receptor antagonists and the thromboxane receptor in order to inform clinical practice and supplement past and ongoing P2Y12 receptor antagonist monotherapy trials, that challenge the paradigm of DAPT. <br/

Nanoscale, Phonon-Coupled Calorimetry with Sub-Attojoule/Kelvin Resolution

We have developed an ultrasensitive nanoscale calorimeter that enables heat capacity measurements upon minute, externally affixed (phonon-coupled) samples at low temperatures. For a 5 s measurement at 2 K, we demonstrate an unprecedented resolution of ΔC ~ 0.5 aJ/K (~36 000 k_B). This sensitivity is sufficient to enable heat capacity measurements upon zeptomole-scale samples or upon adsorbates with sub-monolayer coverage across the minute cross sections of these devices. We describe the fabrication and operation of these devices and demonstrate their sensitivity by measuring an adsorbed ^4He film with optimum resolution of ~3 × 10^(-5) monolayers upon an active surface area of only ~1.2 × 10^(-9) m^2

Online Learning and Mentors: Addressing the Shortage of Rural Special Educators Through Technology and Collaboration

This article describes a promising model in comprehensive special education personnel preparation to support the recruitment and retention of special education teachers in rural areas. The approach draws on several bodies of research to include best practices for teacher education, online service delivery, collaboration among key stakeholders, and the development of strong mentoring and induction programs. The implementation plan, based on evidence-based practice in special education and online learning, is presented. A key element of this plan is developing and maintaining strong relationships among rural districts, the state department of education, and higher education

Randomized and Blinded Study for the Treatment of Glenohumeral Internal Rotation of Motion Restriction: The Prone-­Passive Stretching Technique

Background: Prior research has focused on specific interventions to reduce the symptoms of glenohumeral internal rotation deficit (GIRD) and posterior glenohumeral (GH) tightness; however, clinicians often utilize a prone stretching technique instead for which a lack of evidence exists to support the use of. Hypothesis: Improvements in GH Internal rotation (IR) range of motion (ROM) will be greater in a group of overhead athletes using a prone-passive stretching technique than for overhead athletes using a cross-body stretching technique. Design: Randomized and blinded comparative research study Methods: 34 asymptomatic overhead athletes exhibiting ≥ 10˚ of GH IR deficit randomly received either 12 prone-passive (n=17) or cross-body (n=17) stretching treatments for the deficit over a consecutive 28 day period. Measures of IR and externals rotations (ER) for both the dominant and non-dominant shoulders were taken with a modified digital inclinometer before and after participants underwent 12 treatments over a consecutive 28-day period in either the prone-passive or cross-body group. Results: Analysis revealed increased dominant shoulder IR ROM and total motion, whereas IR deficit decreased for both groups, but no group differences. Gain scores for the prone-passive and cross-body respectively: IR ROM (13.23˚ ± 7.78˚, 8.47˚ ± 8.71˚), IR deficit (-12.64˚ ± 11.49˚, -9.13 ± 8.33˚), and total motion (14.81˚ ± 11.27˚, 9.97˚ ± 11.99˚). Conclusion: The prone-passive stretching technique is as effective as the cross-body technique at improving IR ROM, IR deficit, and total motion in the shoulder joint in participants with IR deficit. Clinical Relevance: Accounting for IR deficits in the overhead athlete shoulder is effectively managed through both clinician-assisted and self-stretching techniques. Clinicians treating overhead athletes with greater limitations in IR ROM may find the prone-passive technique advantageous when compared to the cross-body technique

Prevalence, Predictors and Prognosis of Post-Stroke Hyperglycaemia in Acute Stroke Trials: Individual Patient Data Pooled Analysis from the Virtual International Stroke Trials Archive (VISTA)

&lt;br&gt;Background: Post-stroke hyperglycaemia (PSH) is associated with higher mortality and dependence, but further data on predictors of PSH and its evolution over time are required. We examined the prevalence, predictors, and prognosis of acute PSH using data from well-characterised clinical trials in the VISTA database.&lt;/br&gt; &lt;br&gt;Methods: Data were extracted for individual participants enrolled &#60;24 h after stroke with ≥1 blood glucose readings documented. PSH was defined as glucose &#62;7.0 mmol/l. Outcome measures were: (1) prevalence of PSH; (2) predictors of PSH by binary logistic regression; (3) mortality, and (4) favourable functional outcome [modified Rankin Scale (mRS) score &#60;2] at day 90.&lt;/br&gt; &lt;br&gt;Results: For 2,649 subjects treated at a median 5.5 h after admission, PSH was present in 1,126 (42.6%, 95% CI 40.7–44.5) on admission and within the first 48 h in 1,421 (53.7%, 95% CI 51.8–55.6). PSH developed between 24 and 48 h in 19.4% (95% CI 17.5–21.4) of initially normoglycaemic subjects. Admission and 48-hour PSH were predicted predominantly by a history of diabetes (for admission PSH: OR 7.40, 95% CI 5.60–9.79) and less clearly by stroke severity. Favourable outcome (mRS &#60;2) at day 90 was less likely with PSH within the first 48 h, advanced age, and higher NIHSS score, and more likely with recombinant tissue plasminogen activator treatment.&lt;/br&gt; &lt;br&gt;Conclusions: Over 40% of ischaemic stroke patients are hyperglycaemic on admission, and 20% of those who are initially normoglycaemic develop hyperglycaemia within 48 h. Diabetes is the strongest predictor of acute hyperglycaemia. Hyperglycaemia within the first 48 h is independently associated with higher mortality and poorer functional outcome, with an absolute increase of 12.9%.&lt;/br&gt

Resting state connectivity and cognitive performance in adults with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cognitive impairment is an inevitable feature of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), affecting executive function, attention and processing speed from an early stage. Impairment is associated with structural markers such as lacunes, but associations with functional connectivity have not yet been reported. Twenty-two adults with genetically-confirmed CADASIL (11 male; aged 49.8 ± 11.2 years) underwent functional magnetic resonance imaging at rest. Intrinsic attentional/executive networks were identified using group independent components analysis. A linear regression model tested voxel-wise associations between cognitive measures and component spatial maps, and Pearson correlations were performed with mean intra-component connectivity z-scores. Two frontoparietal components were associated with cognitive performance. Voxel-wise analyses showed an association between one component cluster and processing speed (left middle temporal gyrus; peak −48, −18, −14; ZE = 5.65, pFWEcorr = 0.001). Mean connectivity in both components correlated with processing speed (r = 0.45, p = 0.043; r = 0.56, p = 0.008). Mean connectivity in one component correlated with faster Trailmaking B minus A time (r = −0.77, p &lt; 0.001) and better executive performance (r = 0.56, p = 0.011). This preliminary study provides evidence for associations between cognitive performance and attentional network connectivity in CADASIL. Functional connectivity may be a useful biomarker of cognitive performance in this population