Renal and cardiovascular effects of caffeine:a dose-response study

The effects of increasing oral doses of caffeine (45, 90, 180 and 360 mg) on effective renal plasma flow (ERPF), plasma renin activity (PRA), serum electrolytes, plasma noradrenaline, blood pressure and heart rate were studied in eight healthy male volunteers. Urine volume was increased by 360 mg of caffeine only. At caffeine doses greater than 90 mg urinary sodium excretion was significantly increased. There were no changes in ERPF. Serum potassium was significantly reduced by 360 mg of caffeine. Caffeine increased systolic pressure in a dose related manner. Diastolic pressure was also increased, but not in relation to dose. A 360 mg dose of caffeine produced a late increase in heart rate. These changes were not associated with any alterations in PRA or in plasma noradrenaline.

Live Project love: building a framework for Live Projects

Live projects adopt a wide range of approaches: design/ build, community engagement, participation, protest, analysis, etc. They are driven by tutors with passion, expertise and the ability to manage risk, in ways that exhibit fluency and high levels of skill. They also offer sites of student-led and community co-learning, can support research, demonstrate ‘impact’ and satisfy universities’ policies on outreach. Whilst the breadth and reach of Live Projects is now demonstrably wide, we still fail to fully locate Live Projects within a pedagogical context, tending instead to limit our descriptions and hence analysis to the architectural process and outcome. This failure to locate Live Projects within a pedagogical framework means we still struggle to encapsulate, critique, progress, and indeed, elevate the work.

This chapter draws on some of the case studies presented in recent papers and international conferences in order to provide educators with signposts and important overviews around which and in respect to they can develop their own pedagogical frameworks.

Advances in our understanding of diabetic retinopathy

Diabetic retinopathy remains the most common complication of diabetes mellitus and is a leading cause of visual loss in industrialized nations. The clinicopathology of the diabetic retina has been extensively studied, although the precise pathogenesis and cellular and molecular defects that lead to retinal vascular, neural and glial cell dysfunction remain somewhat elusive. This lack of understanding has seriously limited the therapeutic options available for the ophthalmologist and there is a need to identify the definitive pathways that initiate retinal cell damage and drive progression to overt retinopathy. The present review begins by outlining the natural history of diabetic retinopathy, the clinical features and risk factors. Reviewing the histopathological data from clinical specimens and animal models, the recent paradigm that neuroretinal dysfunction may play an important role in the early development of the disease is discussed. The review then focuses on the molecular pathogenesis of diabetic retinopathy with perspective provided on new advances that have furthered our understanding of the key mechanisms underlying early changes in the diabetic retina. Studies have also emerged in the past year suggesting that defective repair of injured retinal vessels by endothelial progenitor cells may contribute to the pathogenesis of diabetic retinopathy. We assess these findings and discuss how they could eventually lead to new therapeutic options for diabetic retinopathy.

The difficult coughing child:prolonged acute cough in children

Cough is one of the most common symptoms that patients bring to the attention of primary care clinicians. Cough can be designated as acute ( 8 weeks in duration). The use of the term 'prolonged acute cough' in a cough guideline allows a period of natural resolution to occur before further investigations are warranted. The common causes are in children with post viral or pertussis like illnesses causing the cough. Persistent bacterial bronchitis typically occurs when an initial dry acute cough due to a viral infection becomes a prolonged wet cough remaining long after the febrile illness has resolved. This cough responds to a completed course of appropriate antibiotics.

Evidence underlying the clinical management of diabetic macular oedema

Diabetic retinopathy (DR) is the leading cause of visual loss in the developed world in those of working age, and its prevalence is predicted to double by 2025. The management of diabetic retinopathy has traditionally relied on screening, on laser treatment delivered by ophthalmologists, and on optimising blood glucose and blood pressure. Recent evidence suggests that the role of systemic factors is more complex than originally thought, and that drugs such as ACE inhibitors, fibrates and glitazones may all influence the course of diabetic macular oedema. Antagonism of vascular endothelial growth factor offers a new therapeutic avenue that may transform the management of diabetic macular oedema. Several other therapeutic options are under investigation and development, including aminoguanidine, sorbinol, ruboxistaurin and autologous stem cell transfusion. © Royal College of Physicians, 2013.

Update in the myeloproliferative neoplasms

The differential diagnosis of haematological abnormalities, such as leucocytosis, erythocytosis, thrombocytosis or indeed anaemia, is wide and disarming. Here we report on significant updates in the differential diagnosis of erythrocyosis and thrombocytosis presenting a simplified schema for the clinician. We then move to discuss significant advances in this field which have followed a series of key molecular findings, most specifically those affecting the JAK/STAT pathway.

Randomized Phase II trial of nintedanib, afatinib and sequential combination in castration-resistant prostate cancer

AIMS: The aim of this article was to evaluate afatinib (BIBW 2992), an ErbB family blocker, and nintedanib (BIBF 1120), a triple angiokinase inhibitor, in castration-resistant prostate cancer patients.

PATIENTS & METHODS: Patients were randomized to receive nintedanib (250 mg twice daily), afatinib (40 mg once daily [q.d.]), or alternating sequential 7-day nintedanib (250 mg twice daily) and afatinib (70 mg q.d. [Combi70]), which was reduced to 40 mg q.d. (Combi40) due to adverse events. The primary end point was progression-free rate at 12 weeks.

RESULTS: Of the 85 patients treated 46, 20, 16 and three received nintedanib, afatinib, Combi40 and Combi70, respectively. At 12 weeks, the progression-free rate was 26% (seven out of 27 patients) for nintedanib, and 0% for afatinib and Combi40 groups. Two patients had a ≥50% decline in PSA (nintedanib and the Combi40 groups). The most common drug-related adverse events were diarrhea, nausea, vomiting and lethargy.

CONCLUSION: Nintedanib and/or afatinib demonstrated limited anti-tumor activity in unselected advanced castration-resistant prostate cancer patients.

Drug therapies in severe asthma - the era of stratified medicine

Difficult-to-treat asthma affects up to 20% of patients with asthma and is associated with significant healthcare cost. It is an umbrella term that defines a heterogeneous clinical problem including incorrect diagnosis, comorbid conditions and treatment non-adherence; when these are effectively addressed, good symptom control is frequently achieved. However, in 3–5% of adults with difficult-to-treat asthma, the problem is severe disease that is unresponsive to currently available treatments. Current treatment guidelines advise the ‘stepwise’ increase of corticosteroids, but it is now recognised that many aspects of asthma are not corticosteroid responsive, and that this ‘one size fits all’ approach does not deliver clinical benefit in many patients and can also lead to side effects. The future of management of severe asthma will involve optimisation with currently available treatments, particularly corticosteroids, including addressing non-adherence and defining an ‘optimised’ corticosteroid dose, allied with the use of ‘add-on’ target-specific novel treatments. This review examines the current status of novel treatments and research efforts to identify novel targets in the era of stratified medicines in severe asthma.

Epidemiology of painful procedures performed in neonates: A systematic review of observational studies

Procedural pain in neonates has been a concern in the last two decades. The purpose of this review was to provide a critical appraisal and a synthesis of the published epidemiological studies about procedural pain in neonates admitted to intensive care units. The aims were to determine the frequency of painful procedures and pain management interventions as well as to identify their predictors. Academic Search, CINAHL, LILACS, Medic Latina, MEDLINE and SciELO databases were searched for observational studies on procedural pain in neonates admitted to intensive care units. Studies in which neonatal data could not be extracted from the paediatric population were excluded. Eighteen studies were included in the review. Six studies with the same study duration, the first 14 days of the neonate life or admission in the unit of care, identified 6832 to 42,413 invasive procedures, with an average of 7.5-17.3 per neonate per day. The most frequent procedures were heel lance, suctioning, venepuncture and insertion of peripheral venous catheter. Pharmacological and nonpharmacological approaches were inconsistently applied. Predictors of the frequency of procedures and analgesic use included the neonate's clinical condition, day of unit stay, type of procedure, parental presence and pain assessment. The existence of pain protocols was not a predictor of analgesia. Painful procedures were performed frequently and often with inadequate pain management. Unlike neonate clinical factors, organizational factors may be modified to promote a context of care more favourable to pain management. © 2015 European Pain Federation - EFIC®

Development of CBCT-based prostate setup correction strategies and impact of rectal distension.

BACKGROUND: Cone-beam computed tomography (CBCT) image-guided radiotherapy (IGRT) systems are widely used tools to verify and correct the target position before each fraction, allowing to maximize treatment accuracy and precision. In this study, we evaluate automatic three-dimensional intensity-based rigid registration (RR) methods for prostate setup correction using CBCT scans and study the impact of rectal distension on registration quality. METHODS: We retrospectively analyzed 115 CBCT scans of 10 prostate patients. CT-to-CBCT registration was performed using (a) global RR, (b) bony RR, or (c) bony RR refined by a local prostate RR using the CT clinical target volume (CTV) expanded with 1-to-20-mm varying margins. After propagation of the manual CT contours, automatic CBCT contours were generated. For evaluation, a radiation oncologist manually delineated the CTV on the CBCT scans. The propagated and manual CBCT contours were compared using the Dice similarity and a measure based on the bidirectional local distance (BLD). We also conducted a blind visual assessment of the quality of the propagated segmentations. Moreover, we automatically quantified rectal distension between the CT and CBCT scans without using the manual CBCT contours and we investigated its correlation with the registration failures. To improve the registration quality, the air in the rectum was replaced with soft tissue using a filter. The results with and without filtering were compared. RESULTS: The statistical analysis of the Dice coefficients and the BLD values resulted in highly significant differences (p<10(-6)) for the 5-mm and 8-mm local RRs vs the global, bony and 1-mm local RRs. The 8-mm local RR provided the best compromise between accuracy and robustness (Dice median of 0.814 and 97% of success with filtering the air in the rectum). We observed that all failures were due to high rectal distension. Moreover, the visual assessment confirmed the superiority of the 8-mm local RR over the bony RR. CONCLUSION: The most successful CT-to-CBCT RR method proved to be the 8-mm local RR. We have shown the correlation between its registration failures and rectal distension. Furthermore, we have provided a simple (easily applicable in routine) and automatic method to quantify rectal distension and to predict registration failure using only the manual CT contours.

Cost evaluation and comparison of three decision strategies for cardiac revascularization : results of the suspected CAD protocol of the European CMR registry

Background: The public health burden of coronary artery disease (CAD) is important. Perfusion cardiac magnetic resonance (CMR) is generally accepted to detect and monitor CAD. Few studies have so far addressed its costs and costeffectiveness. Objectives: To compare in a large CMR registry the costs of a CMR-guided strategy vs two hypothetical invasive strategies for the diagnosis and the treatment of patients with suspected CAD. Methods: In 3'647 patients with suspected CAD included prospectively in the EuroCMR Registry (59 centers; 18 countries) costs were calculated for diagnostic examinations, revascularizations as well as for complication management over a 1-year follow-up. Patients with ischemia-positive CMR underwent an invasive X-ray coronary angiography (CXA) and revascularization at the discretion of the treating physician (=CMR+CXA strategy). Ischemia was found in 20.9% of patients and 17.4% of them were revascularized. In ischemia-negative patients by CMR, cardiac death and non-fatal myocardial infarctions occurred in 0.38%/y. In a hypothetical invasive arm the costs were calculated for an initial CXA followed by FFR testing in vessels with ≥50% diameter stenoses (=CXA+FFR strategy). To model this hypothetical arm, the same proportion of ischemic patients and outcome was assumed as for the CMR+CXA strategy. The coronary stenosis - FFR relationship reported in the literature was used to derive the proportion of patients with ≥50% diameter stenoses (Psten) in the study cohort. The costs of a CXA-only strategy were also calculated. Calculations were performed from a third payer perspective for the German, UK, Swiss, and US healthcare systems.

Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants.

One of the global targets for non-communicable diseases is to halt, by 2025, the rise in the age-standardised adult prevalence of diabetes at its 2010 levels. We aimed to estimate worldwide trends in diabetes, how likely it is for countries to achieve the global target, and how changes in prevalence, together with population growth and ageing, are affecting the number of adults with diabetes. We pooled data from population-based studies that had collected data on diabetes through measurement of its biomarkers. We used a Bayesian hierarchical model to estimate trends in diabetes prevalence-defined as fasting plasma glucose of 7.0 mmol/L or higher, or history of diagnosis with diabetes, or use of insulin or oral hypoglycaemic drugs-in 200 countries and territories in 21 regions, by sex and from 1980 to 2014. We also calculated the posterior probability of meeting the global diabetes target if post-2000 trends continue. We used data from 751 studies including 4,372,000 adults from 146 of the 200 countries we make estimates for. Global age-standardised diabetes prevalence increased from 4.3% (95% credible interval 2.4-7.0) in 1980 to 9.0% (7.2-11.1) in 2014 in men, and from 5.0% (2.9-7.9) to 7.9% (6.4-9.7) in women. The number of adults with diabetes in the world increased from 108 million in 1980 to 422 million in 2014 (28.5% due to the rise in prevalence, 39.7% due to population growth and ageing, and 31.8% due to interaction of these two factors). Age-standardised adult diabetes prevalence in 2014 was lowest in northwestern Europe, and highest in Polynesia and Micronesia, at nearly 25%, followed by Melanesia and the Middle East and north Africa. Between 1980 and 2014 there was little change in age-standardised diabetes prevalence in adult women in continental western Europe, although crude prevalence rose because of ageing of the population. By contrast, age-standardised adult prevalence rose by 15 percentage points in men and women in Polynesia and Micronesia. In 2014, American Samoa had the highest national prevalence of diabetes (>30% in both sexes), with age-standardised adult prevalence also higher than 25% in some other islands in Polynesia and Micronesia. If post-2000 trends continue, the probability of meeting the global target of halting the rise in the prevalence of diabetes by 2025 at the 2010 level worldwide is lower than 1% for men and is 1% for women. Only nine countries for men and 29 countries for women, mostly in western Europe, have a 50% or higher probability of meeting the global target. Since 1980, age-standardised diabetes prevalence in adults has increased, or at best remained unchanged, in every country. Together with population growth and ageing, this rise has led to a near quadrupling of the number of adults with diabetes worldwide. The burden of diabetes, both in terms of prevalence and number of adults affected, has increased faster in low-income and middle-income countries than in high-income countries. Wellcome Trust.

Recreational Development and the Lake Erie Shore Photographs,1967

John N. Jackson was born and raised in London England. He served in the Royal Navy, acquired a B.A. and a Ph.D, conducted research for a city planning office and lectured at the University of Manchester. He joined Brock University’s faculty in 1965 as a Professor of Applied Geography. Since his retirement in 1991 he has been Professor Emeritus to Brock. Throughout his time in academia Jackson has focused his research on the history of the modern city, both throughout Europe and Canada. Jackson has also completed specific research on the Niagara Peninsula; including industrial geography, recreation along the Lake Erie shore, St. Catharines early history, the Welland Canals, railway development, comparisons across the Niagara River. While living in the Niagara region Jackson has become involved in many community events. He has been the Director for the Bruce Trail Association, President of the Welland Canals Foundation, and been involved in local historical groups throughout the Niagara region.