Erectile dysfunction - an update of current practice and future strategies

Erectile dysfunction (ED) is defined as the inability to achieve and maintain a penile erection adequate for satisfactory sexual intercourse.1 Up to 150 million men worldwide suffer from ED and this figure is likely to double by the year 2025.2 A number of studies have attempted to characterise the true prevalence of ED. In a Danish study, Ventegodt reported that 5.4% of all patients had a decreased ability to achieve an erection.3 The prevalence was reported to be highest (18%) in those aged over 58 years. The Massachusetts Male Aging Study (MMAS)4 reported the results of a regional survey of 1709 men aged 40–69 years. In this study 52% reported some degree of ED, with 10% having complete ED. Moreover, the results suggest that the probability of complete ED at age 70 was threefold compared to that at age 40; the probability of moderate ED was two-fold

Whole-body heat stress and exercise stimulate the appearance of platelet microvesicles in plasma with limited influence of vascular shear stress

Intense, large muscle mass exercise increases circulating microvesicles, but our understanding of microvesicle dynamics and mechanisms inducing their release remains limited. However, increased vascular shear stress is generally thought to be involved. Here, we manipulated exercise-independent and exercise-dependent shear stress using systemic heat stress with localized single-leg cooling (low shear) followed by single-leg knee extensor exercise with the cooled or heated leg (Study 1, n = 8) and whole-body passive heat stress followed by cycling (Study 2, n = 8). We quantified femoral artery shear rates (SRs) and arterial and venous platelet microvesicles (PMV-CD41+) and endothelial microvesicles (EMV-CD62E+). In Study 1, mild passive heat stress while one leg remained cooled did not affect [microvesicle] (P ≥ 0.05). Single-leg knee extensor exercise increased active leg SRs by ~12-fold and increased arterial and venous [PMVs] by two- to threefold, even in the nonexercising contralateral leg (P < 0.05). In Study 2, moderate whole-body passive heat stress increased arterial [PMV] compared with baseline (mean±SE, from 19.9 ± 1.5 to 35.5 ± 5.4 PMV.μL-1.103, P < 0.05), and cycling with heat stress increased [PMV] further in the venous circulation (from 27.5 ± 2.2 at baseline to 57.5 ± 7.2 PMV.μL-1.103 during cycling with heat stress, P < 0.05), with a tendency for increased appearance of PMV across exercising limbs. Taken together, these findings demonstrate that whole-body heat stress may increase arterial [PMV], and intense exercise engaging either large or small muscle mass promote PMV formation locally and systemically, with no influence upon [EMV]. Local shear stress, however, does not appear to be the major stimulus modulating PMV formation in healthy humans

Local temperature-sensitive mechanisms are important mediators of limb tissue hyperemia in the heat-stressed human at rest and during small muscle mass exercise.

Limb tissue and systemic blood flow increases with heat stress, but the underlying mechanisms remain poorly understood. Here, we tested the hypothesis that heat stress-induced increases in limb tissue perfusion are primarily mediated by local temperature-sensitive mechanisms. Leg and systemic temperatures and hemodynamics were measured at rest and during incremental single-legged knee extensor exercise in 15 males exposed to 1 h of either systemic passive heat-stress with simultaneous cooling of a single leg (n=8) or isolated leg heating or cooling (n=7). Systemic heat-stress increased core, skin and heated leg blood (Tb) temperatures, cardiac output and heated leg blood flow (LBF, 0.6 ± 0.1 l.min(-1); P0.05). Increased heated leg deep tissue BF was closely related to Tb (R(2) = 0.50; P0.05), despite unchanged systemic temperatures and hemodynamics. During incremental exercise, heated LBF was consistently maintained ~ 0.6 l.min(-1) higher than that in the cooled leg (P<0.01), with LBF and vascular conductance in both legs showing a strong correlation with their respective local Tb (R(2) = 0.85 and 0.95, P<0.05). We conclude that local temperature-sensitive mechanisms are important mediators in limb tissue perfusion regulation both at rest and during small-muscle mass exercise in hyperthermic humans.The invasive study was partially funded by Gatorade Sports Science Institute, PepsiCo

Fuel economy analysis of part-load variable camshaft timing strategies in two modern small-capacity spark ignition engines

Variable Camshaft Timing strategies have been investigated at part-load operating conditions in two 3-cylinder, 1.0-litre, Spark Ignition engines. The two small-size engines are different variants of the same 4-valve/cylinder, pent-roof design platform. The first engine is naturally aspirated, port fuel injection and features high nominal compression ratio of 12:1. The second one is the turbo-charged, direct injection version, featuring lower compression ratio of 10:1. The aim of the investigation has been to identify optimal camshaft timing strategies which maximise engine thermal efficiency through improvements in brake specific fuel consumption at fixed engine load. The results of the investigation show that the two engines demonstrate consistent thermal efficiency response to valve timing changes in the low and mid part-load envelope, up to a load of 4 bar BMEP. At the lower engine loads investigated, reduced intake valve opening advance limits the hot burned gas internal recirculation, while increasingly retarded exhaust valve opening timing favours engine efficiency through greater effective expansion ratio. At mid load (4 bar BMEP), a degree of intake advance becomes beneficial, owing mostly to the associated intake de-throttling. In the upper part-load domain, for engine load of 5 bar BMEP and above, the differences between the two engines determine very different efficiency response to the valve timing setting. The lower compression ratio engine continues to benefit from advanced intake valve timing, with a moderate degree of exhaust timing retard, which minimises the exhaust blow-down losses. The higher compression ratio engine is knock-limited, forcing the valve timing strategy towards regions of lower intake advance and lower hot gas recirculation. The theoretical best valve timing strategy determined peak fuel economy improvements in excess of 8% for the port fuel injection engine; the peak improvement was 5% for the more efficient direct injection engine platform

Dehydration accelerates reductions in cerebral blood flow during prolonged exercise in the heat without compromising brain metabolism

Dehydration hastens the decline in cerebral blood flow (CBF) during incremental exercise, while the cerebral metabolic rate for oxygen (CMRO2) is preserved. It remains unknown whether CMRO2 is also maintained during prolonged exercise in the heat and whether an eventual decline in CBF is coupled to fatigue. Two studies were undertaken. In study 1, ten male cyclists cycled in the heat for ~2 h with (control) and without fluid replacement (dehydration) while internal (ICA) and external (ECA) carotid artery blood flow and core and blood temperature were obtained. Arterial and internal jugular venous blood samples were assessed with dehydration to evaluate the CMRO2. In study 2 (8 males), middle cerebral artery blood velocity (MCA Vmean) was measured during prolonged exercise to exhaustion in both dehydrated and euhydrated states. After a rise at the onset of exercise, ICA flow declined to baseline with progressive dehydration (P < 0.05). However, cerebral metabolism remained stable through enhanced oxygen and glucose extraction (P < 0.05). ECA flow increased for one hour but declined prior to exhaustion. Fluid ingestion maintained cerebral and extra-cranial perfusion throughout non-fatiguing exercise. During exhaustive exercise, however, euhydration delayed but did not prevent the decline in cerebral perfusion. In conclusion, during prolonged exercise in the heat dehydration accelerates the decline in CBF without affecting CMRO2 and also restricts extra-cranial perfusion. Thus fatigue is related to reduction in CBF and extra-cranial perfusion rather than in CMRO2.The study was supported by a grant from the Gatorade Sports Science Institute, PepsiCo Inc, USA

Type and Timing of Rehabilitation Following Acute and Subacute Spinal Cord Injury: A Systematic Review

Objectives: The objective of this study was to conduct a systematic review of the literature to address the following clinical questions: In adult patients with acute and subacute complete or incomplete traumatic SCI, (1) does the time interval between injury and commencing rehabilitation affect outcome?; (2) what is the comparative effectiveness of different rehabilitation strategies, including different intensities and durations of treatment?; (3) are there patient or injury characteristics that affect the efficacy of rehabilitation?; and (4) what is the cost-effectiveness of various rehabilitation strategies? Methods: A systematic search was conducted for literature published through March 31, 2015 that evaluated rehabilitation strategies in adults with acute or subacute traumatic SCI at any level. Studies were critically appraised individually and the overall strength of evidence was evaluated using methods proposed by the GRADE (Grades of Recommendation Assessment, Development and Evaluation) working group. Results: The search strategy yielded 384 articles, 19 of which met our inclusion criteria. Based on our results, there was no difference between body weight–supported treadmill training and conventional rehabilitation with respect to improvements in Functional Independence Measure (FIM) Locomotor score, Lower Extremity Motor Scores, the distance walked in 6 minutes or gait velocity over 15.2 m. Functional electrical therapy resulted in slightly better FIM Motor, FIM Self-Care, and Spinal Cord Independence Measure Self-Care subscores compared with conventional occupational therapy. Comparisons using the Toronto Rehabilitation Institute Hand Function Test demonstrated no differences between groups in 7 of 9 domains. There were no clinically important differences in Maximal Lean Test, Maximal Sidewards Reach Test, T-shirt Test, or the Canadian Occupational Performance Measure between unsupported sitting training and standard in-patient rehabilitation. Conclusion: The current evidence base for rehabilitation following acute and subacute spinal cord injury is limited. Methodological challenges have contributed to this and further research is still needed. © 2017, © The Author(s) 2017

Socioeconomic indicators of health inequalities and female mortality: a nested cohort study within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Evidence is mounting that area-level socioeconomic indicators are important tools for predicting health outcomes. However, few studies have examined these alongside individual-level education. This nested cohort study within the control arm of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) assesses the association of mutually adjusted individual (education) and area-level (Index of Multiple Deprivation-IMD 2007) socioeconomic status indicators and all-cause female mortality

Improved early detection of ovarian cancer using longitudinal multimarker models

© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Background: Ovarian cancer has a poor survival rate due to late diagnosis and improved methods are needed for its early detection. Our primary objective was to identify and incorporate additional biomarkers into longitudinal models to improve on the performance of CA125 as a first-line screening test for ovarian cancer. Methods: This case–control study nested within UKCTOCS used 490 serial serum samples from 49 women later diagnosed with ovarian cancer and 31 control women who were cancer-free. Proteomics-based biomarker discovery was carried out using pooled samples and selected candidates, including those from the literature, assayed in all serial samples. Multimarker longitudinal models were derived and tested against CA125 for early detection of ovarian cancer. Results: The best performing models, incorporating CA125, HE4, CHI3L1, PEBP4 and/or AGR2, provided 85.7% sensitivity at 95.4% specificity up to 1 year before diagnosis, significantly improving on CA125 alone. For Type II cases (mostly high-grade serous), models achieved 95.5% sensitivity at 95.4% specificity. Predictive values were elevated earlier than CA125, showing the potential of models to improve lead time. Conclusions: We have identified candidate biomarkers and tested longitudinal multimarker models that significantly improve on CA125 for early detection of ovarian cancer. These models now warrant independent validation.Peer reviewe

Whole body hyperthermia, but not skin hyperthermia, accelerates brain and locomotor limb circulatory strain and impairs exercise capacity in humans

Cardiovascular strain and hyperthermia are thought to be important factors limiting exercise capacity in heat-stressed humans; however, the contribution of elevations in skin (Tsk) vs. whole body temperatures on exercise capacity has not been characterised. To ascertain their relationships with exercise capacity, blood temperature (TB), oxygen uptake (V̇O2), brain perfusion (MCA Vmean), locomotor limb haemodynamics, and haematological parameters were assessed during incremental cycling exercise with elevated skin (mild hyperthermia; HYPmild), combined core and skin temperatures (moderate hyperthermia; HYPmod), and under control conditions. Both hyperthermic conditions increased Tsk vs. control (6.2 ± 0.2 °C; P < 0.001), however, only HYPmod increased resting TB, leg blood flow and cardiac output (Q̇), but not MCA Vmean. Throughout exercise, Tsk remained elevated in both hyperthermic conditions, whereas only TB was greater in HYPmod. At exhaustion, oxygen uptake and exercise capacity were reduced in HYPmod in association with lower leg blood flow, MCA Vmean and MAP, but similar maximal heart rate and TB. The attenuated brain and leg perfusion with hyperthermia was associated with a plateau in MCA and two-legged vascular conductance (VC). Mechanistically, the falling MCA VC was coupled to reductions in PaCO2 whereas the plateau in leg vascular conductance was related to markedly elevated plasma [NA] and a plateau in plasma ATP. These findings reveal that whole-body hyperthermia, but not skin hyperthermia, compromises exercise capacity in heat-stressed humans through the early attenuation of brain and active muscle blood flow.This study was supported by a grant from the Gatorade Sports Science Institute, PepsiCo Inc, USA. The views contained within this document are those of the authors and do not necessarily reflect those of PepsiCo Inc

Fructose transport-deficient Staphylococcus aureus reveals important role of epithelial glucose transporters in limiting sugar-driven bacterial growth in airway surface liquid.

Hyperglycaemia as a result of diabetes mellitus or acute illness is associated with increased susceptibility to respiratory infection with Staphylococcus aureus. Hyperglycaemia increases the concentration of glucose in airway surface liquid (ASL) and promotes the growth of S. aureus in vitro and in vivo. Whether elevation of other sugars in the blood, such as fructose, also results in increased concentrations in ASL is unknown and whether sugars in ASL are directly utilised by S. aureus for growth has not been investigated. We obtained mutant S. aureus JE2 strains with transposon disrupted sugar transport genes. NE768(fruA) exhibited restricted growth in 10 mM fructose. In H441 airway epithelial-bacterial co-culture, elevation of basolateral sugar concentration (5-20 mM) increased the apical growth of JE2. However, sugar-induced growth of NE768(fruA) was significantly less when basolateral fructose rather than glucose was elevated. This is the first experimental evidence to show that S. aureus directly utilises sugars present in the ASL for growth. Interestingly, JE2 growth was promoted less by glucose than fructose. Net transepithelial flux of D-glucose was lower than D-fructose. However, uptake of D-glucose was higher than D-fructose across both apical and basolateral membranes consistent with the presence of GLUT1/10 in the airway epithelium. Therefore, we propose that the preferential uptake of glucose (compared to fructose) limits its accumulation in ASL. Pre-treatment with metformin increased transepithelial resistance and reduced the sugar-dependent growth of S. aureus. Thus, epithelial paracellular permeability and glucose transport mechanisms are vital to maintain low glucose concentration in ASL and limit bacterial nutrient sources as a defence against infection