Mechanisms of modified LDL-induced pericyte loss and retinal injury in diabetic retinopathy

Aims/hypothesis: In previous studies we have shown that extravasated, modified LDL is associated with pericyte loss, an early feature of diabetic retinopathy (DR). Here we sought to determine detailed mechanisms of this LDLinduced pericyte loss.

Methods: Human retinal capillary pericytes (HRCP) were exposed to ‘highly-oxidised glycated’ LDL (HOG-LDL) (a model of extravasated and modified LDL) and to 4-hydroxynonenal or 7-ketocholesterol (components of oxidised LDL), or to native LDL for 1 to 24 h with or without 1 h of pretreatment with inhibitors of the following: (1) the scavenger receptor (polyinosinic acid); (2) oxidative stress (N-acetyl cysteine); (3) endoplasmic reticulum (ER) stress (4-phenyl butyric acid); and (4) mitochondrial dysfunction (cyclosporin A). Oxidative stress, ER stress, mitochondrial dysfunction, apoptosis and autophagy were assessed using techniques including western blotting, immunofluorescence, RT-PCR, flow cytometry and TUNEL assay. To assess the relevance of the results in vivo, immunohistochemistry was used to detect the ER stress chaperon, 78 kDa glucose-regulated protein, and the ER sensor, activating transcription factor 6, in retinas from a mouse model of DR that mimics exposure of the retina to elevated glucose and elevated LDL levels, and in retinas from human participants with and without diabetes and DR.

Results: Compared with native LDL, HOG-LDL activated oxidative and ER stress in HRCP, resulting in mitochondrial dysfunction, apoptosis and autophagy. In a mouse model of diabetes and hyperlipidaemia (vs mouse models of either condition alone), retinal ER stress was enhanced. ER stress was also enhanced in diabetic human retina and correlated with the severity of DR.

Conclusions/interpretation: Cell culture, animal, and human data suggest that oxidative stress and ER stress are induced by modified LDL, and are implicated in pericyte loss in DR.

A low-cost solution for the restoration of femoral head centre during total hip arthroplasty

Restoration of joint centre during total hip arthroplasty is critical. While computer-aided navigation can improve accuracy during total hip arthroplasty, its expense makes it inaccessible to the majority of surgeons. This article evaluates the use, in the laboratory, of a calliper with a simple computer application to measure changes in femoral head centres during total hip arthroplasty. The computer application was designed using Microsoft Excel and used calliper measurements taken pre- and post-femoral head resection to predict the change in head centre in terms of offset and vertical height between the femoral head and newly inserted prosthesis. Its accuracy was assessed using a coordinate measuring machine to compare changes in preoperative and post-operative head centre when simulating stem insertion on 10 sawbone femurs. A femoral stem with a modular neck was used, which meant nine possible head centre configurations were available for each femur, giving 90 results. The results show that using this technique during a simulated total hip arthroplasty, it was possible to restore femoral head centre to within 6?mm for offset (mean 1.67?±?1.16?mm) and vertical height (mean 2.14?±?1.51?mm). It is intended that this low-cost technique be extended to inform the surgeon of a best-fit solution in terms of neck length and neck type for a specific prosthesis.

The lived experience of patients receiving radiotherapy for head and neck cancer: A literature review

It is estimated that 60% of patients diagnosed with head and neck cancer will receive radiotherapy at some stage in their disease trajectory. The aim of this literature review was to find and analyse papers pertaining to the lived experiences of patients with head and neck cancer receiving radiotherapy. The review identified a limited number of high-quality research papers focusing on this topic, with only 10 papers fitting the inclusion/exclusion criteria. The majority of the investigative studies were not generalisable owing to small sample sizes and many of them being conducted in only one centre. However, the findings do highlight and contribute to the understanding of the lived experiences of this patient group and provide some insight into the unique physical, social, and psychological difficulties they encounter as a result of their treatment. There appears to be a need for further high-level research into these patients, particularly focusing on the provision of support and information prior to, during, and following radiotherapy. Further attention needs to be paid to preparing patients for the slow recovery following radiotherapy. Interventional studies are also required to develop clinical guidelines and protocols that can assist health professionals in meeting the holistic needs of this patient group.

Distributed closed-loop spatial multiplexing for uplink multiuser systems

Focusing on the uplink, where mobile users (each with a single transmit antenna) communicate with a base station with multiple antennas, we treat multiple users as antennas to enable spatial multiplexing across users. Introducing distributed closed-loop spatial multiplexing with threshold-based user selection, we propose two uplink channel-assigning strategies with limited feedback. We prove that the proposed system also outperforms the standard greedy scheme with respect to the degree of fairness, measured by the variance of the time averaged throughput. For uplink multi-antenna systems, we show that the proposed scheduling is a better choice than the greedy scheme in terms of the average BER, feedback complexity, and fairness. The numerical results corroborate our findings

Threshold-based substream selection for closed-loop spatial multiplexing

We propose a low-complexity closed-loop spatial multiplexing method with limited feedback over multi-input-multi-output (MIMO) fading channels. The transmit adaptation is simply performed by selecting transmit antennas (or substreams) by comparing their signal-to-noise ratios to a given threshold with a fixed nonadaptive constellation and fixed transmit power per substream. We analyze the performance of the proposed system by deriving closed-form expressions for spectral efficiency, average transmit power, and bit error rate (BER). Depending on practical system design constraints, the threshold is chosen to maximize the spectral efficiency (or minimize the average BER) subject to average transmit power and average BER (or spectral efficiency) constraints, respectively. We present numerical and Monte Carlo simulation results that validate our analysis. Compared to open-loop spatial multiplexing and other approaches that select the best antenna subset in spatial multiplexing, the numerical results illustrate that the proposed technique obtains significant power gains for the same BER and spectral efficiency. We also provide numerical results that show improvement over rate-adaptive orthogonal space-time block coding, which requires highly complex constellation adaptation. We analyze the impact of feedback delay using analytical and Monte Carlo approaches. The proposed approach is arguably the simplest possible adaptive spatial multiplexing system from an implementation point of view. However, our approach and analysis can be extended to other systems using multiple constellations and power levels.

Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial: study protocol for a randomized controlled trial

Background: Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI.

Methods/Design: Patients fulfilling the American-European Consensus Conference Definition of ALI will be randomized in a 1: 1 ratio to receive enteral simvastatin 80 mg or placebo once daily for a maximum of 28 days. Allocation to randomized groups will be stratified with respect to hospital of recruitment and vasopressor requirement. Data will be recorded by participating ICUs until hospital discharge, and surviving patients will be followed up by post at 3, 6 and 12 months post randomization. The primary outcome is number of ventilator-free days to day 28. Secondary outcomes are: change in oxygenation index and sequential organ failure assessment score up to day 28, number of non pulmonary organ failure free days to day 28, critical care unit mortality; hospital mortality; 28 day post randomization mortality and 12 month post randomization mortality; health related quality of life at discharge, 3, 6 and 12 months post randomization; length of critical care unit and hospital stay; health service use up to 12 months post-randomization; and safety. A total of 540 patients will be recruited from approximately 35 ICUs in the UK and Ireland. An economic evaluation will be conducted alongside the trial. Plasma and urine samples will be taken up to day 28 to investigate potential mechanisms by which simvastatin might act to improve clinical outcomes.

Obesity and occupational injury:a prospective cohort study of 69,515 public sector employees

Obesity and overweight are suggested to increase the risk of occupational injury but longitudinal evidence to confirm this is rare. We sought to evaluate obesity and overweight as risk factors for occupational injuries.

Simvastatin decreases the level of heparin-binding protein in patients with acute lung injury

Heparin-binding protein is released by neutrophils during inflammation and disrupts the integrity of the alveolar and capillary endothelial barrier implicated in the development of acute lung injury and systemic organ failure. We sought to investigate whether oral administration of simvastatin to patients with acute lung injury reduces plasma heparin-binding protein levels and improves intensive care unit outcome.

Keratinocyte growth factor in acute lung injury to reduce pulmonary dysfunction--a randomised placebo-controlled trial (KARE):study protocol

Acute lung injury is a common, devastating clinical syndrome associated with substantial mortality and morbidity with currently no proven therapeutic interventional strategy to improve patient outcomes. The objectives of this study are to test the potential therapeutic effects of keratinocyte growth factor for patients with acute lung injury on oxygenation and biological indicators of acute inflammation, lung epithelial and endothelial function, protease:antiprotease balance, and lung extracellular matrix degradation and turnover.