iNOS expression and osteocyte apoptosis in idiopathic, non- traumatic osteonecrosis

Background and purpose Non-traumatic osteonecrosis is a progressive disease with multiple etiologies. It affects younger individuals more and more, often leading to total hip arthroplasty. We investigated whether there is a correlation between inducible nitric oxide synthase (iNOS) expression and osteocyte apoptosis in non-traumatic osteonecrosis. Patients and methods We collected and studied 20 human idiopathic, non-traumatic osteonecrosis femoral heads. Subchondral bone samples in the non-sclerotic region (n = 30), collected from osteoarthritis patients, were used as controls. Spontaneously hypertensive rats were used as a model for osteonecrosis in the study. We used scanning electron microscopy, TUNEL assay, and immunohistochemical staining to study osteocyte changes and apoptosis. Results The morphology of osteocytes in the areas close to the necrotic region changed and the number of apoptotic osteocytes increased in comparison with the same region in control groups. The expression of iNOS and cytochrome C in osteocytes increased while Bax expression was not detectable in osteonecrosis samples. Using spontaneously hypertensive rats, we found a positive correlation between iNOS expression and osteocyte apoptosis in the osteonecrotic region. iNOS inhibitor (aminoguanidine) added to the drinking water for 5 weeks reduced the production of iNOS and osteonecrosis compared to a control group without aminoguanidine. Interpretation Our findings show that increased iNOS expression can lead to osteocyte apopotosis in idiopathic, non-traumatic osteonecrosis and that an iNOS inhibitor may prevent the progression of the disease.

Melanopsin expressing intrinsically photosensitive Retinal Ganglion cells in retinal disease

Melanopsin containing intrinsically photosensitive Retinal Ganglion Cells (ipRGCs) are a class of photoreceptors with established roles in non-image forming processes. Their contributions to image forming vision may include the estimation of brightness. Animal models have been central for understanding the physiological mechanisms of ipRGC function and there is evidence of conservation of function across species. ipRGCs can be divided into 5 ganglion cell subtypes that show morphological and functional diversity. Research in humans has established that ipRGCs signal environmental irradiance to entrain the central body clock to the solar day for regulating circadian processes and sleep. In addition, ipRGCs mediate the pupil light reflex (PLR), making the PLR a readily accessible behavioural marker of ipRGC activity. Less is known about ipRGC function in retinal and optic nerve disease, with emerging research providing insight into their function in diabetes, retinitis pigmentosa, glaucoma and hereditary optic neuropathy. We briefly review the anatomical distributions, projections and basic physiological mechanisms of ipRGCs, their proposed and known functions in animals and humans with and without eye disease. We introduce a paradigm for differentiating inner and outer retinal inputs to the pupillary control pathway in retinal disease and apply this paradigm to patients with age-related macular degeneration (AMD). In these cases of patients with AMD, we provide the initial evidence that ipRGC function is altered, and that the dysfunction is more pronounced in advanced disease. Our perspective is that with refined pupillometry paradigms, the pupil light reflex can be extended to AMD assessment as a tool for the measurement of inner and outer retinal dysfunction.

The effect of hip muscle strengthening on pain and disability for individuals with non-specific low back pain : a randomized controlled trial

Introduction Clinical guidelines for the treatment of chronic low back pain suggest the use of supervised exercise. Motor control (MC) based exercise is widely used within clinical practice but its efficacy is equivalent to general exercise therapy. MC exercise targets the trunk musculature. Considering the mechanical links between the hip, pelvis, and lumbar spine, surprisingly little focus has been on investigating the contribution of the hip musculature to lumbopelvic support. The purpose of this study is to compare the efficacy of two exercise programs for the treatment of non-specific low back pain (NSLBP). Methods Eighty individuals aged 18-65 years of age were randomized into two groups to participate in this trial. The primary outcome measures included self-reported pain intensity (0-100mm VAS) and percent disability (Oswestry Disability Index V2). Bilateral measures of hip strength (N/kg) and two dimensional frontal plane mechanics (º) were the secondary outcomes. Outcomes were measured at baseline and following a six-week home based exercise program including weekly sessions of real-time ultrasound imaging. Results Within group comparisons revealed clinically meaningful reductions in pain for both groups. The MC exercise only (N= 40, xˉ =-20.9mm, 95%CI -25.7, -16.1) and the combined MC and hip exercise (N= 40, xˉ = -24.9mm, 95%CI -30.8, -19.0). There was no statistical difference in the change of pain (xˉ =-4.0mm, t= -1.07, p=0.29, 95%CI -11.5, 3.5) or disability (xˉ =-0.3%, t=-0.19, p=0.85, 95%CI -11.5, 3.5) between groups. Conclusion Both exercise programs had similar and positive effects on NSLBP which support the use of the home based exercise programs with weekly supervised visits. However, the addition of specific hip strengthening exercises to a MC based exercise program did not result in significantly greater reductions in pain or disability. Trial Registration NCTO1567566 Funding: Worker’s Compensation Board Alberta Research Grant.

A comparison of treatment options for management of end stage kidney disease in elderly patients : a systematic review

Background Chronic kidney disease is a global public health problem of increasing prevalence. There are five stages of kidney disease, with Stage 5 indicating end stage kidney disease (ESKD) requiring dialysis or death will eventually occur. Over the last two decades there have been increasing numbers of people commencing dialysis. A majority of this increase has occurred in the population of people who are 65 years and over. With the older population it is difficult to determine at times whether dialysis will provide any benefit over non-dialysis management. The poor prognosis for the population over 65 years raises issues around management of ESKD in this population. It is therefore important to review any research that has been undertaken in this area which compares outcomes of the older ESKD population who have commenced dialysis with those who have received non-dialysis management. Objective The primary objective was to assess the effect of dialysis compared with non-dialysis management for the population of 65 years and over with ESKD. Inclusion criteria Types of participants This review considered studies that included participants who were 65 years and older. These participants needed to have been diagnosed with ESKD for greater than three months and also be either receiving renal replacement therapy (RRT) (hemodialysis [HD] or peritoneal dialysis [PD]) or non-dialysis management. The settings for the studies included the home, self-care centre, satellite centre, hospital, hospice or nursing home. Types of intervention(s)/phenomena of interest This review considered studies where the intervention was RRT (HD or PD) for the participants with ESKD. There was no restriction on frequency of RRT or length of time the participant received RRT. The comparator was participants who were not undergoing RRT. Types of studies This review considered both experimental and epidemiological study designs including randomized controlled trials, non-randomized controlled trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies, case control studies and analytical cross sectional studies. This review also considered descriptive epidemiological study designs including case series, individual case reports and descriptive cross sectional studies for inclusion. This review included any of the following primary and secondary outcome measures: •Primary outcome – survival measures •Secondary outcomes – functional performance score (e.g. Karnofsky Performance score) •Symptoms and severity of end stage kidney disease •Hospital admissions •Health related quality of life (e.g. KDQOL, SF36 and HRQOL) •Comorbidities (e.g. Charlson Comorbidity index).

Obesity and hypertension have differing oxidant handling molecular pathways in age-related chronic kidney disease

Chronic kidney disease (CKD) in ageing is a burden on health systems worldwide. Rat models of age-related CKD linked with obesity and hypertension were used to investigate alterations in oxidant handling and energy metabolism to identify gene targets or markers for age-related CKD. Young adult (3 months) and old (21–24 months) spontaneously-hypertensive (SHR), normotensive Wistar-Kyoto (WKY) and Wistar rats (normotensive, obese in ageing) were compared for renal functional and physiological parameters, renal fibrosis and inflammation, oxidative stress (hemeoxygenase-1/HO-1), apoptosis and cell injury (including Bax:Bcl-2), phosphorylated and non-phosphorylated forms of oxidant and energy sensing proteins (p66Shc, AMPK), signal transduction proteins (ERK1/2, PKB), and transcription factors (NF-κB, FoxO1). All old rats were normoglycemic. Renal fibrosis, tubular epithelial apoptosis, interstitial macrophages and myofibroblasts (all p < 0.05), p66Shc/phospho-p66 (p < 0.05), Bax/Bcl-2 ratio (p < 0.05) and NF-κB expression (p < 0.01) were highest in old obese Wistars. Expression of phospho-FoxO/FoxO was elevated in old Wistars (p < 0.001) and WKYs (p < 0.01). SHRs had high levels in young and old rats. Expression of PKB, phospho-PKB, ERK1/2 and phospho-ERK1/2 were significantly elevated in all aged animals. These results suggest that obesity and hypertension have differing oxidant handling and signalling pathways that act in the pathogenesis of age-related CKD

2nd ESMO consensus conference on lung cancer : early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines in advanced disease, earlystage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on early-stage disease. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Second ESMO consensus conference on lung cancer : pathology and molecular biomarkers for non-small-cell lung cancer

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The Second ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on management of patients with nonsmall- cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, early stage disease, locally advanced disease and advanced (metastatic) disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on recommendations for pathology and molecular biomarkers in relation to the diagnosis of lung cancer, primarily non-small-cell carcinomas.

The effect of the addition of hip strengthening exercises to a lumbopelvic exercise programme for the treatment of non-specific low back pain : a randomized controlled trial

Objectives To compare the efficacy of two exercise programs in reducing pain and disability for individuals with non-specific low back pain and to examine the underlying mechanical factors related to pain and disability for individuals with NSLBP. Design A single-blind, randomized controlled trial. Methods: Eighty participants were recruited from eleven community-based general medical practices and randomized into two groups completing either a lumbopelvic motor control or a combined lumbopelvic motor control and progressive hip strengthening exercise therapy program. All participants received an education session, 6 rehabilitation sessions including real time ultrasound training, and a home based exercise program manual and log book. The primary outcomes were pain (0-100mm visual analogue scale), and disability (Oswestry Disability Index V2). The secondary outcomes were hip strength (N/kg) and two-dimensional frontal plane biomechanics (°) measure during the static Trendelenburg test and while walking. All outcomes were measured at baseline and at 6-week follow up. Results There was no statistical difference in the change in pain (xˉ = -4.0mm, t= -1.07, p =0.29, 95%CI -11.5, 3.5) or disability (xˉ = -0.3%, t= -0.19, p =0.85, 95%CI -3.5, 2.8) between groups. Within group comparisons revealed clinically meaningful reductions in pain for both Group One (xˉ =-20.9mm, 95%CI -25.7, -16.1) and Group Two (xˉ =-24.9, 95%CI -30.8, -19.0). Conclusion Both exercise programs had similar efficacy in reducing pain. The addition of hip strengthening exercises to a motor control exercise program does not appear to result in improved clinical outcome for pain for individuals with non-specific low back pain.

The effectiveness of dietary counselling versus oral nutrition supplements in improving nutritional intake in malnourished patients with Chronic Obstructive Pulmonary Disease (COPD)

The evidence for nutritional support in COPD is almost entirely based on oral nutritional supplements (ONS) yet despite this dietary counseling and food fortification (DA) are often used as the first line treatment for malnutrition. This study aimed to investigate the effectiveness of ONS vs. DA in improving nutritional intake in malnourished outpatients with COPD. 70 outpatients (BMI 18.4 SD 1.6 kg/m2, age 73 SD 9 years, severe COPD) were randomised to receive a 12-week intervention of either ONS or DA (n 33 ONS vs. n 37 DA). Paired t-test analysis revealed total energy intakes significantly increased with ONS at week 6 (+302 SD 537 kcal/d; p = 0.002), with a slight reduction at week 12 (+243 SD 718 kcal/d; p = 0.061) returning to baseline levels on stopping supplementation. DA resulted in small increases in energy that only reached significance 3 months post-intervention (week 6: +48 SD 623 kcal/d, p = 0.640; week 12: +157 SD 637 kcal/d, p = 0.139; week 26: +247 SD 592 kcal/d, p = 0.032). Protein intake was significantly higher in the ONS group at both week 6 and 12 (ONS: +19.0 SD 25.0 g/d vs. DA: +1.0 SD 13.0 g/d; p = 0.033 ANOVA) but no differences were found at week 26. Vitamin C, Iron and Zinc intakes significantly increased only in the ONS group. ONS significantly increased energy, protein and several micronutrient intakes in malnourished COPD patients but only during the period of supplementation. Trials investigating the effects of combined nutritional interventions are required.

Prevalence of active foot disease and foot disease risk factors in a subacute inpatient rehabilitation facility: a cross-sectional prevalence study

Background Australian subacute inpatient rehabilitation facilities face significant challenges from the ageing population and the increasing burden of chronic disease. Foot disease complications are a negative consequence of many chronic diseases. With the rapid expansion of subacute rehabilitation inpatient services, it seems imperative to investigate the prevalence of foot disease and foot disease risk factors in this population. The primary aim of this cross-sectional study was to determine the prevalence of active foot disease and foot disease risk factors in a subacute inpatient rehabilitation facility. Methods Eligible participants were all adults admitted at least overnight into a large Australian subacute inpatient rehabilitation facility over two different four week periods. Consenting participants underwent a short non-invasive foot examination by a podiatrist utilising the validated Queensland Health High Risk Foot Form to collect data on age, sex, medical co-morbidity history, foot disease risk factor history and clinically diagnosed foot disease complications and foot disease risk factors. Descriptive statistics were used to determine the prevalence of clinically diagnosed foot disease complications, foot disease risk factors and groups of foot disease risk factors. Logistic regression analyses were used to investigate any associations between defined explanatory variables and appropriate foot disease outcome variables. Results Overall, 85 (88%) of 97 people admitted to the facility during the study periods consented; mean age 80 (±9) years and 71% were female. The prevalence (95% confidence interval) of participants with active foot disease was 11.8% (6.3 – 20.5), 32.9% (23.9 – 43.5) had multiple foot disease risk factors, and overall, 56.5% (45.9 – 66.5) had at least one foot disease risk factor. A self-reported history of peripheral neuropathy diagnosis was independently associated with having multiple foot disease risk factors (OR 13.504, p = 0.001). Conclusion This study highlights the potential significance of the burden of foot disease in subacute inpatient rehabilitation facilities. One in eight subacute inpatients were admitted with active foot disease and one in two with at least one foot disease risk factor in this study. It is recommended that further multi-site studies and management guidelines are required to address the foot disease burden in subacute inpatient rehabilitation facilities. Keywords: Subacute; Inpatient; Foot; Complication; Prevalence

The contribution of major depression to the global burden of ischemic heart disease : a comparative risk assessment

Background Cardiovascular disease and mental health both hold enormous public health importance, both ranking highly in results of the recent Global Burden of Disease Study 2010 (GBD 2010). For the first time, the GBD 2010 has systematically and quantitatively assessed major depression as an independent risk factor for the development of ischemic heart disease (IHD) using comparative risk assessment methodology. Methods A pooled relative risk (RR) was calculated from studies identified through a systematic review with strict inclusion criteria designed to provide evidence of independent risk factor status. Accepted case definitions of depression include diagnosis by a clinician or by non-clinician raters adhering to Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) classifications. We therefore refer to the exposure in this paper as major depression as opposed to the DSM-IV category of major depressive disorder (MDD). The population attributable fraction (PAF) was calculated using the pooled RR estimate. Attributable burden was calculated by multiplying the PAF by the underlying burden of IHD estimated as part of GBD 2010. Results The pooled relative risk of developing IHD in those with major depression was 1.56 (95% CI 1.30 to 1.87). Globally there were almost 4 million estimated IHD disability-adjusted life years (DALYs), which can be attributed to major depression in 2010; 3.5 million years of life lost and 250,000 years of life lived with a disability. These findings highlight a previously underestimated mortality component of the burden of major depression. As a proportion of overall IHD burden, 2.95% (95% CI 1.48 to 4.46%) of IHD DALYs were estimated to be attributable to MDD in 2010. Eastern Europe and North Africa/Middle East demonstrate the highest proportion with Asia Pacific, high income representing the lowest. Conclusions The present work comprises the most robust systematic review of its kind to date. The key finding that major depression may be responsible for approximately 3% of global IHD DALYs warrants assessment for depression in patients at high risk of developing IHD or at risk of a repeat IHD event.

Estimating the burden of disease attributable to smoking in South Africa in 2000

Objectives To quantify the burden of disease attributable to smoking in South Africa for 2000. Design The absolute difference between observed lung cancer death rate and the level in non-smokers, adjusted for occupational and indoor exposure to lung carcinogens, was used to estimate the proportion of lung cancer deaths attributable to smoking and the smoking impact ratio (SIR). The SIR was substituted for smoking prevalence in the attributable fraction formula for chronic obstructive pulmonary disease (COPD) and cancers to allow for the long lag between exposure and outcome. Assuming a shorter lag between exposure and disease, the current prevalence of smoking was used to estimate the population-attributable fractions (PAF) for the other outcomes. Relative risks (RR) from the American Cancer Society cancer prevention study (CPS-II) were used to calculate PAF. Setting South Africa. Outcome measures Deaths and disability-adjusted life years (DALYs) due to lung and other cancers, COPD, cardiovascular conditions, respiratory tuberculosis, and other respiratory and medical conditions. Results Smoking caused between 41 632 and 46 656 deaths in South Africa, accounting for 8.0 - 9.0% of deaths and 3.7 - 4.3% of DALYs in 2000. Smoking ranked third (after unsafe sex/sexually transmitted disease and high blood pressure) in terms of mortality among 17 risk factors evaluated. Three times as many males as females died from smoking. Lung cancer had the largest attributable fraction due to smoking. However, cardiovascular diseases accounted for the largest proportion of deaths attributed to smoking. Conclusion Cigarette smoking accounts for a large burden of preventable disease in South Africa. While the government has taken bold legislative action to discourage tobacco use since 1994, it still remains a major public health priority.

Estimating the burden of disease attributable to excess body weight in South Africa in 2000

Objective. To estimate the burden of disease attributable to excess body weight using the body mass index (BMI), by age and sex, in South Africa in 2000. Design. World Health Organization comparative risk assessment (CRA) methodology was followed. Re-analysis of the 1998 South Africa Demographic and Health Survey data provided mean BMI estimates by age and sex. Populationattributable fractions were calculated and applied to revised burden of disease estimates. Monte Carlo simulation-modelling techniques were used for the uncertainty analysis. Setting. South Africa. Subjects. Adults 30 years of age. Outcome measures. Deaths and disability-adjusted life years (DALYs) from ischaemic heart disease, ischaemic stroke, hypertensive disease, osteoarthritis, type 2 diabetes mellitus, and selected cancers. Results. Overall, 87% of type 2 diabetes, 68% of hypertensive disease, 61% of endometrial cancer, 45% of ischaemic stroke, 38% of ischaemic heart disease, 31% of kidney cancer, 24% of osteoarthritis, 17% of colon cancer, and 13% of postmenopausal breast cancer were attributable to a BMI 21 kg/m2. Excess body weight is estimated to have caused 36 504 deaths (95% uncertainty interval 31 018 - 38 637) or 7% (95% uncertainty interval 6.0 - 7.4%) of all deaths in 2000, and 462 338 DALYs (95% uncertainty interval 396 512 - 478 847) or 2.9% of all DALYs (95% uncertainty interval 2.4 - 3.0%). The burden in females was approximately double that in males. Conclusions. This study shows the importance of recognising excess body weight as a major risk to health, particularly among females, highlighting the need to develop, implement and evaluate comprehensive interventions to achieve lasting change in the determinants and impact of excess body weight.

Estimating the burden of disease attributable to physical inactivity in South Africa in 2000

Objectives. To quantify the burden of disease attributable to physical inactivity in persons 15 years or older, by age group and sex, in South Africa for 2000. Design. The global comparative risk assessment (CRA) methodology of the World Health Organization was followed to estimate the disease burden attributable to physical inactivity. Levels of physical activity for South Africa were obtained from the World Health Survey 2003. A theoretical minimum risk exposure of zero, associated outcomes, relative risks, and revised burden of disease estimates were used to calculate population-attributable fractions and the burden attributed to physical inactivity. Monte Carlo simulation-modelling techniques were used for the uncertainty analysis. Setting. South Africa. Subjects. Adults ≥ 15 years. Outcome measures. Deaths and disability-adjusted life years (DALYs) from ischaemic heart disease, ischaemic stroke, breast cancer, colon cancer, and type 2 diabetes mellitus. Results. Overall in adults ≥ 15 years in 2000, 30% of ischaemic heart disease, 27% of colon cancer, 22% of ischaemic stroke, 20% of type 2 diabetes, and 17% of breast cancer were attributable to physical inactivity. Physical inactivity was estimated to have caused 17 037 (95% uncertainty interval 11 394 - 20 407), or 3.3% (95% uncertainty interval 2.2 - 3.9%) of all deaths in 2000, and 176 252 (95% uncertainty interval 133 733 - 203 628) DALYs, or 1.1% (95% uncertainty interval 0.8 - 1.3%) of all DALYs in 2000. Conclusions. Compared with other regions and the global average, South African adults have a particularly high prevalence of physical inactivity. In terms of attributable deaths, physical inactivity ranked 9th compared with other risk factors, and 12th in terms of DALYs. There is a clear need to assess why South Africans are particularly inactive, and to ensure that physical activity/inactivity is addressed as a national health priority.

Resistance to amoebic gill disease (AGD) is characterised by the transcriptional dysregulation of immune and cell cycle pathways

Amoebic gill disease (AGD) is a parasite-mediated proliferative gill disease capable of affecting a range of teleost hosts. While a moderate heritability for AGD resistance in Atlantic salmon has been reported previously, the mechanisms by which individuals resist the proliferative effects remain poorly understood. To gain more knowledge of this commercially important trait, we compared gill transcriptomes of two groups of Atlantic salmon, one designated putatively resistant, and one designated putatively susceptible to AGD. Utilising a 17k Atlantic salmon cDNA microarray we identified 196 transcripts that were differentially expressed between the two groups. Expression of 11 transcripts were further examined with real-time quantitative RT-PCR (qPCR) in the AGD-resistant and AGD-susceptible animals, as well as non-infected naïve fish. Gene expression determined by qPCR was in strong agreement with the microarray analysis. A large number of differentially expressed genes were involved in immune and cell cycle responses. Resistant individuals displayed significantly higher expression of genes involved in adaptive immunity and negative regulation of the cell cycle. In contrast, AGD-susceptible individuals showed higher expression of acute phase proteins and positive regulators of the cell cycle. Combined with the gill histopathology, our results suggest AGD resistance is acquired rather than innately present, and that this resistance is for the most part associated with the dysregulation of immune and cell cycle pathways. © 2008 Elsevier Ltd. All rights reserved.