Noradrenergic cardiac denervation is associated with gait velocity in Parkinson disease: a dual ligand PET study.

PURPOSE: Preliminary data suggest that gait abnormalities in Parkinson disease (PD) may be associated with sympathetic cardiac denervation. No kinematic gait studies were performed to confirm this observation. We aimed to correlate spatiotemporal kinematic gait parameters with cardiac sympathetic denervation as determined by cardiac [11C]HED PET in PD. METHODS: Retrospective database analysis of 27 PD patients with cardiac sympathetic denervation. All patients underwent spatiotemporal kinematic gait assessment (medication 'off' state), cardiac [11C]HED and dopaminergic brain [11C]DTBZ PET scans. We employed a hierarchical regression approach to examine associations between the extent of cardiac denervation, dopaminergic nigrostriatal neurodegeneration, and three gait parameters - velocity, step length and cadence. RESULTS: More extensive cardiac denervation was associated with slower velocity (estimate: -1.034, 95% CI [-1.65, -0.42], p = 0.002), shorter step length (estimate: -0.818, 95% CI [-1.43, -0.21], p = 0.011) and lower cadence (estimate: -0.752, 95% CI [-1.28, -0.23], p = 0.007) explaining alone 30% (Adjusted-R²: 0.297), 20% (Adjusted-R²: 0.202) and 23% (Adjusted-R²: 0.227) of the variability, respecivetly. These associations remained independent of striatal dopaminergic impairment and confounding factors such as age, Hoehn and Yahr (HY) stages, peripheral neuropathy, cognition, and autonomic symptoms. In contrast, striatal dopaminergic denervation was significantly associated with step length (estimate: 0.883, 95% CI [0.29, 1.48], p = 0.005), explaining about 24% of the variability but was dependent of HY stage. CONCLUSIONS: More severe cardiac noradrenergic denervation was associated with lower gait velocity, independent of striatal dopaminergic denervation and HY stage, impacting both step length and cadence. These results suggest independent contributions of the peripheral autonomic system degeneration on gait dynsfunction in PD.

Evaluation Considerations for Secondary Uses of Clinical Data: Principles for an Evidence-based Approach to Policy and Implementation of Secondary Analysis.

Objectives: To set the scientific context and then suggest principles for an evidence-based approach to secondary uses of clinical data, covering both evaluation of the secondary uses of data and evaluation of health systems and services based upon secondary uses of data. Method: Working Group review of selected literature and policy approaches. Results: We present important considerations in the evaluation of secondary uses of clinical data from the angles of governance and trust, theory, semantics, and policy. We make the case for a multi-level and multi-factorial approach to the evaluation of secondary uses of clinical data and describe a methodological framework for best practice. We emphasise the importance of evaluating the governance of secondary uses of health data in maintaining trust, which is essential for such uses. We also offer examples of the re-use of routine health data to demonstrate how it can support evaluation of clinical performance and optimize health IT system design. Conclusions: Great expectations are resting upon "Big Data" and innovative analytics. However, to build and maintain public trust, improve data reliability, and assure the validity of analytic inferences, there must be independent and transparent evaluation. A mature and evidence-based approach needs not merely data science, but must be guided by the broader concerns of applied health informatics.

[(11)C]Ascorbic and [(11)C]dehydroascorbic acid, an endogenous redox pair for sensing reactive oxygen species using positron emission tomography.

Here we report the radiosynthesis of an endogenous redox pair, [(11)C]ascorbic acid ([(11)C]VitC) and [(11)C]dehydroascorbic acid ([(11)C]DHA), the reduced and oxidized forms of vitamin C, and their application to ROS sensing. These results provide the basis for in vivo detection of ROS using positron emission tomography (PET).

Non-Battle Injuries presenting to the Force Medical Rehabilitation Team on Operation GRITROCK.

Non-Battle Injuries (NBI) represent a significant attritional threat to personnel deployed on operations. Operation (Op) GRITROCK involved personnel deployed across both land and maritime environments and was the first deployment of the Primary Casualty Receiving Facility (PCRF) on contingency operations of this type. This article outlines the incidence, demographics and functional outcome of individuals assessed for NBI by the embarked rehabilitation team. A total of 138 injured individuals were assessed over the period Oct 2014 - Mar 2015. ARGUS personnel made up 83.3% (n=115) of the injured population. Most common presentations were low back pain (LBP) (21%) and soft tissue lower limb injuries (14.5%), primarily occurring through individual sport (42.8%) or normal duty (34.8%). The Force Medical Rehabilitation Team (FMRT) effectively retained troops in theatre; although 22.5% (n=31) were considered urgent cases, only one individual required medical evacuation. 53.6% of presentations were exacerbations of a previous injury. Future work will examine the long-term outcome of these injuries.

Musculoskeletal injury patterns associated with military operations.

Musculoskeletal injury represents a significant attritional threat to troops on deployment and comprises a significant proportion of aeromedical evacuations from theatre. Whilst the incidence and outcome of battle injury (BI) is increasingly well understood, the picture regarding non-battle injury (NBI) is less clear despite the significantly higher incidence rate. This paper outlines and compares current evidence regarding the incidence, contributing factors and functional outcome of recent operational BI and NBI and highlights the need for further study into UK specific data and demographics.

A framework for promoting scholarship productivity in occupational therapy curricula.

This paper describes a curricular model to support the production of quality research and development of occupational therapy professional students, prepared to become leaders in the production and utilization of evidence for practice. This model is designed for programs with faculty challenged by the dual mandate of program excellence and expectations for scholarly productivity needed for tenure and promotion: typically programs at research universities. The essence of the model is the paralleling of research and competencies for clinical practice where faculty and students participate as a community of scholars. It is based on the literature that addresses the tensions between achieving excellence in research and scholarly productivity, and excellence in teaching. The experience of one university with this model over a five-year period of time is shared with the student-faculty productivity outcomes. These outcomes include dissemination of 55 collaborative peer reviewed products and faculty has generated support for 25 paid graduate assistantships. The combination of student outcomes and faculty support for their research has strengthened the ability of the faculty to excel in meeting the University mandate of scholarship while providing a high quality professional educational program.

Pre-hospital body surface potential mapping improves early diagnosis of acute coronary artery occlusion in patients with ventricular fibrillation and cardiac arrest.

AIMS: To determine whether 80-lead body surface potential mapping (BSPM) improves detection of acute coronary artery occlusion in patients presenting with out-of-hospital cardiac arrest (OHCA) due to ventricular fibrillation (VF) and who survived to reach hospital. METHODS AND RESULTS: Of 645 consecutive patients with OHCA who were attended by the mobile coronary care unit, VF was the initial rhythm in 168 patients. Eighty patients survived initial resuscitation, 59 of these having had BSPM and 12-lead ECG post-return of spontaneous circulation (ROSC) and in 35 patients (age 69±13 yrs; 60% male) coronary angiography performed within 24 h post-ROSC. Of these, 26 (74%) patients had an acutely occluded coronary artery (TIMI flow grade [TFG] 0/1) at angiography. Twelve-lead ECG criteria showed ST-segment elevation (STE) myocardial infarction (STEMI) using Minnesota 9-2 criteria--sensitivity 19%, specificity 100%; ST-segment depression (STD) ≥0.05 mV in ≥2 contiguous leads--sensitivity 23%, specificity 89%; and, combination of STEMI or STD criteria--sensitivity 46%, specificity 100%. BSPM STE occurred in 23 (66%) patients. For the diagnosis of TFG 0/1 in a main coronary artery, BSPM STE had sensitivity 88% and specificity 100% (c-statistic 0.94), with STE occurring most commonly in either the posterior, right ventricular or high right anterior territories. CONCLUSION: Among OHCA patients presenting with VF and who survived resuscitation to reach hospital, post-resuscitation BSPM STE identifies acute coronary occlusion with sensitivity 88% and specificity 100% (c-statistic 0.94).

A collaborative teaching strategy for enhancing learning of evidence-based clinical decision-making.

The educational literature cites a lack of student motivation to learn how to use research evidence in clinical decision-making because the students do not observe clinicians using evidence. This lack of motivation presents a challenge to educators as they seek to instill the value of evidence-based clinical decision-making (EBCD) in students. One problem is that students in entry-level programs do not have the experience needed to know what to look for, and secondly, clinical decision-making is contextually based in a patient problem. Our approach offers one solution to bridging the gap between classroom teaching and real-world implementation of EBCD through a three-phase collaborative approach. Occupational and physical therapy students are partnered with clinicians to find and appraise evidence to answer the real-world questions posed by these therapists. This paper describes the implementation of the partnership, teaching/learning outcomes, logistics, and implications for clinicians. We found this approach increased student motivation and greatly enhanced the learning experience. Future directions include implementing a framework which allows for the assessment of the strategy on the facility and creates opportunities to integrate the use of EBCD in all aspects of facility practice.

ST elevation on the exercise ECG in patients presenting with chest pain and no prior history of myocardial infarction.

OBJECTIVE: To assess the aetiology, and prognosis of ST-segment elevation (STE) on the exercise electrocardiogram in patients with chest pain without a prior history of myocardial infarction (MI). METHODS: Between January 1998 and December 2005, 14 941 exercise stress tests were performed to assess chest pain in patients without a prior history of MI. Those who developed STE were identified. RESULTS: STE occurred in 0.78% (116/14 941). Coronary angiography was performed in 108 patients. All patients had at least one severe coronary artery stenosis (>70%). The site of STE on exercise ECG was shown to be 95.4% predictive of a severe stenosis in the coronary artery supplying that area. Lateral STE was rare (1/116). Ninety-eight patients underwent revascularisation; 67 patients had percutaneous coronary intervention (PCI) and 31 underwent coronary artery bypass grafting (CABG). Follow-up included recording of death, MI, cerebrovascular event, heart failure and target vessel revascularisation. The projected 7-year event-free survival probability was 62.1% for those undergoing CABG, 77.1% for those who had PCI and 68.6% for those not undergoing revascularisation (no difference between these three groups, log rank p = 0.802). CONCLUSIONS: STE on the exercise ECG is rare but specific for ischaemic heart disease and is predictive of a severe stenosis in the corresponding coronary artery. Prognosis is favourable following revascularisation.

Outcome after radial forearm, gastro-omental, and jejunal free flaps in oral and oropharyngeal reconstruction.

We undertook a retrospective study of the outcome of radial forearm, gastro-omental, and jejunal free tissue transfer for oral and oropharyngeal reconstruction in 30 patients (10 in each group). No significant differences were found between the type of free flap and the clinical outcome. More long-term difficulties were experienced with swallowing than with speech. The selection of free flap did not correlate with speech function (P=0.44), swallowing (P=0.68), or management of saliva (P=0.59). No significant difference was found between the patients' outcome and the site of resection of the tumour. There were more complications after gastro-omental flaps and this may influence the choice of reconstruction.

Clinically integrated studies in pathology: their contribution to atherosclerosis research.

This article, prepared in honor of Daria Haust, reviews some features of research into atherosclerosis and coronary heart disease over the past 150 years, and beyond. Attention is drawn to problems arising when people of strong personality dominate a particular field of research to the exclusion of pertinent observations that do not fit neatly into their particular paradigm. As the world becomes more complex and, in theory at least, communications between scientists become easier, these dangers are not necessarily diminished. Clinical medicine in its broadest sense must continue to relate in the traditional way to the specialties grouped within pathology. Undergraduates must receive instruction concerning the importance of the historical record and an understanding of the nature of science, its strengths, limitations, and boundaries.

Does the "Thunderbirds syndrome" still exist.

Rationing of resources within both the private and public health care systems is a fact of life. The Thunderbirds TV series encapsulated an idealistic philosophy that life should be saved independent of the pecuniary cost. Doctors, in particular, are trapped between their role as advocates for the patient within the "Thunderbirds" philosophy and as citizens with a responsibility to use resources wisely. This dichotomy is challenged by point of care rationing, which can conflict with clinical responsibilities, undermines the patient-doctor relationship and is often undertaken in a clandestine manner. This form of controlling health costs is difficult to justify from an ethical perspective, particularly when other forms of health care rationing and expenditure are frequently modulated by political expediency and inadequate economic modelling. Indeed, focusing on improving quality and disease prevention, rather than reducing marginal costs can often control the long-term growth in health expenditure. Doctors have a responsibility to ensure that rationing decisions are made but these should be made as part of a transparent, evidence-based and democratic process away from the point of care. While the resources to implement the "Thunderbirds Syndrome" have never been available, the philosophy must remain at the heart of patient-doctor relationship.

Consensus viewpoint on the treatment of postmenopausal osteoporosis. The Ad Hoc Group on Osteoporosis.

Treatment for postmenopausal osteoporosis should be offered to those with a history of fractures following minimal trauma or with a bone density significantly below the range seen in young normal adults. Underlying diseases contributing to the reduced bone density should be sought and treated appropriately. Lifestyle issues such as smoking, alcohol intake and exercise should be addressed. A calcium intake of at least 1.5 g/day should be achieved. Hormone replacement therapy is the first line pharmacological intervention. The bisphosphonates provide a satisfactory alternative for those unable or unwilling to take hormone replacement therapy.

Effects of catecholamines on isolated human colonic smooth muscle.

1. The effects of catecholamines and some adrenoceptor agonists and antagonists on isolated preparations of human colonic smooth muscle obtained from surgical resections were examined. 2. Strips of circular smooth muscle displayed rhythmic myogenic spontaneous contractions which were inhibited by catecholamines with an order of potency of isoprenaline (1.0) > noradrenaline (0.32) > adrenaline (0.2). Phentolamine (0.7 microM) significantly shifted the noradrenaline concentration-response curve (CRC) to the right but had no significant effect on isoprenaline or adrenaline. Propranolol (1 microM) significantly shifted the isoprenaline to the right but had no significant effect on noradrenaline or adrenaline. 3. Salbutamol (30 microM) had no inhibitory effect on the spontaneous activity and ICI 118,551 (1 microM) had no effect on inhibitory responses to isoprenaline. Betaxolol (1 microM) significantly shifted the CRC to isoprenaline to the right. BRL 37344 had no effect on spontaneous activity. 4. Responsiveness of circular strips to catecholamines was not affected by age of the patient and no consistent differences between males and females were shown. 5. Strips of taenia coli exhibited little or no spontaneous phasic activity. Noradrenaline and isoprenaline relaxed KCl-induced tone. The effects of noradrenaline and isoprenaline were antagonized by propranolol but not by phentolamine. BRL 37344 had no effect on KCl-induced tone. 6. In conclusion, catecholamines relaxed spontaneous activity of human colon circular smooth muscle through an action on both alpha- and beta-adrenoceptors. The alpha-adrenoceptors were of the alpha 1-subtype. The beta-adrenoceptor-mediated relaxation appeared to be primarily beta 1. In taenia coli, catecholamines relaxed KCl-induced tone via beta-adrenoceptors only.

The Effects of Age on the Pharmacokinetics and Pharmacodynamics of Cardiovascular Drugs: Application of Concentration-Effect Modeling. 1. Tolmesoxide.

The effects of age on the disposition and hemodynamic responses to the direct acting vasodilator tolmesoxide were examined in an integrated manner using a combined pharmacokinetic--pharmacodynamic (PKPD) modeling approach. Thirty subjects were studied to represent, as far as was possible, an age continuum. Single doses of tolmesoxide (100 mg) and placebo were administered intravenously and blood was withdrawn and heart rate and blood pressure were measured at frequent intervals up to 10 h post dose. No significant effects of age on the disposition of tolmesoxide and its sulfone metabolite were apparent. Tolmesoxide when compared with placebo produced significant changes in blood pressure and heart rate but PKPD modeling failed to demonstrate any significant effects of age on the blood pressure response to tolmesoxide.

The Effects of Age on the Pharmacokinetics and Pharmacodynamics of Cardiovascular Drugs: Application of Concentration-Effect Modeling. 2. Acebutolol.

The effects of age on the disposition and hemodynamic responses to the selective beta(1) adrenoceptor antagonist were examined in an integrated manner using a combined pharmacokinetic--pharmacodynamic (PKPD) modeling approach. Thirty subjects were studied to represent, as far as was possible an age continuum. Single doses of acebutolol (20 mg) and placebo were administered intravenously and blood was withdrawn and heart rate and blood pressure were measured at frequent intervals up to 10 h post dose. No significant effects of age on the disposition of acebutolol and its major acetylated metabolite were apparent. Acebutolol when compared with placebo produced significant changes in blood pressure and heart rate and application of PKPD modeling demonstrated a significant negative correlation between blood pressure responsiveness to acebutolol and age.

Effects of Age on the Pharmacokinetics and Pharmacodynamics of Cardiovascular Drugs: Application of Concentration-Effect Modeling. 3. Trimazosin.

The effects of age on the disposition and hemodynamic responses to the selective post-synaptic alpha(1) adrenoceptor antagonist trimazosin were examined in an integrated manner using a combined pharmacokinetic--pharmacodynamic (PKPD) modeling approach. Thirty subjects were studied to represent, as far as was possible an age continuum. Single doses of trimazosin (100 mg) and placebo were administered intravenously and blood was withdrawn and heart rate and blood pressure were measured at frequent intervals up to 10 h post dose. Based on regression analysis there was a statistically significant decline in the clearance of trimazosin with increasing age. In addition, based on the ratio of the AUC values for the major metabolite and parent drug, there was evidence of a decline in the relative clearance of matabolite with increasing age. Trimazosin when compared with placebo produced significant changes in blood pressure and heart rate that were statistically greater in elderly subjects. PKPD modeling revealed that both trimazosin and its metabolite 1-hydroxy trimazosin contributed significantly to the hemodynamic profile of the drug but the blood pressure responsiveness to both parent drug and metabolite were unaffected by age. Thus the greater response in the elderly subjects could be attributed to the decline in drug clearance with age.