Transient peak-strain matching partially recovers the age-impaired mechanoadaptive cortical bone response

Mechanoadaptation maintains bone mass and architecture; its failure underlies age-related decline in bone strength. It is unclear whether this is due to failure of osteocytes to sense strain, osteoblasts to form bone or insufficient mechanical stimulus. Mechanoadaptation can be restored to aged bone by surgical neurectomy, suggesting that changes in loading history can rescue mechanoadaptation. We use non-biased, whole-bone tibial analyses, along with characterisation of surface strains and ensuing mechanoadaptive responses in mice at a range of ages, to explore whether sufficient load magnitude can activate mechanoadaptation in aged bone. We find that younger mice adapt when imposed strains are lower than in mature and aged bone. Intriguingly, imposition of short-term, high magnitude loading effectively primes cortical but not trabecular bone of aged mice to respond. This response was regionally-matched to highest strains measured by digital image correlation and to osteocytic mechanoactivation. These data indicate that aged bone’s loading response can be partially recovered, non-invasively by transient, focal high strain regions. Our results indicate that old murine bone does respond to load when the loading is of sufficient magnitude, and bones’ age-related adaptation failure may be due to insufficient mechanical stimulus to trigger mechanoadaptation

Theoretical assessment of progressive collapse capacity of reinforced concrete structures

The progressive collapse behaviour of reinforced concrete (RC) structures requires consideration of material and geometric non-linearity, concrete crushing and rebar fracture. Compressive arch action (CAA) and catenary action (CTA) are the main resisting mechanisms against progressive collapse following a column loss. Hence, many studies have concentrated on the development of CAA and CTA in RC beams, but without considering the effect of bar fracture and the reduction in beam effective depth due to concrete crushing. Taking these additional factors into account, an analytical model to predict the structural behaviour of RC beams under a column removal scenario was developed. The proposed model was evaluated and validated with the available experimental results. The evaluation and validation indicate that the proposed model can provide a reliable assessment of RC beam capacity against progressive collapse

Benzodiazepine Use and Misuse Among Patients in a Methadone Program

<p>Abstract</p> <p>Background</p> <p>Benzodiazepines (BZD) misuse is a serious public health problem, especially among opiate-dependent patients with anxiety enrolled in methadone program because it puts patients at higher risk of life-threatening multiple drug overdoses. Both elevated anxiety and BZD misuse increase the risk for ex-addicts to relapse. However, there is no recent study to assess how serious the problem is and what factors are associated with BZD misuse. This study estimates the prevalence of BZD misuse in a methadone program, and provides information on the characteristics of BZD users compared to non-users.</p> <p>Methods</p> <p>An anonymous survey was carried out at a methadone program in Baltimore, MD, and all patients were invited to participate through group meetings and fliers around the clinic on a voluntary basis. Of the 205 returned questionnaires, 194 were complete and entered into final data analysis. Those who completed the questionnaire were offered a $5 gift card as an appreciation.</p> <p>Results</p> <p>47% of the respondents had a history of BZD use, and 39.8% used BZD without a prescription. Half of the BZD users (54%) started using BZD after entering the methadone program, and 61% of previous BZD users reported increased or resumed use after entering methadone program. Compared to the non-users, BZD users were more likely to be White, have prescribed medication for mental problems, have preexistent anxiety problems before opiate use, and had anxiety problems before entering methadone program. They reported more mental health problems in the past month, and had higher scores in anxiety state, depression and perceived stress (p < .05).</p> <p>Conclusions</p> <p>Important information on epidemiology of BZD misuse among methadone-maintenance patients suggests that most methadone programs do not address co-occurring anxiety problems, and methadone treatment may trigger onset or worsening of BZD misuse. Further study is needed to explore how to curb misuse and abuse of BZD in the addiction population, and provide effective treatments targeting simultaneously addiction symptoms, anxiety disorders and BZD misuse.</p

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Potential prognostic value of heat-shock protein 90 in the presence of phosphatidylinositol-3-kinase overexpression or loss of PTEN, in invasive breast cancers

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract Introduction Evaluating the expression of signaling molecule proteins from the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol-3-kinase (PI3K) pathway in invasive breast cancers may identify prognostic marker(s) associated with early relapse. Methods Immunohistochemical analyses of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), PI3K-p110α, phospho-AKT, phospho-p70S6 kinase, phospho-S6 ribosomal protein, phospho-RAF, phospho-p44/42 MAPK, and heat-shock protein 90 (HSP90) were performed on tumor samples from 212 patients with invasive breast cancer. Statistically significant relations between protein expression, clinicopathologic factors, and relapse-free survival (RFS) were analyzed. Results Expression of HSP90 was associated with 5-year RFS, as well as T stage, N stage, histologic grade, estrogen receptor (ER) expression, human epidermal growth factor receptor 2 (HER2) expression, and the Ki-67 proliferation index. On multivariate analysis, coexpression of HSP90 and PI3K-p110α or expression of HSP90 along with PTEN loss demonstrated significantly worse RFS. In subgroup analyses, both exhibited strong prognostic significance in HER2-positive cases, but not in HER2-negative cases. Conclusions The coexpression of HSP90 with PI3K-p110α or expression of HSP90 along with PTEN loss has a potential as a molecular prognostic marker to predict early relapse in patients with invasive breast cancers

Patients' perspectives on self-testing of oral anticoagulation therapy: Content analysis of patients' internet blogs

<p>Abstract</p> <p>Background</p> <p>Patients on oral anticoagulant therapy (OAT) require regular testing of the prothrombin time (PT) and the international normalised ratio (INR) to monitor their blood coagulation level to avoid complications of either over or under coagulation. PT/INR can be tested by a healthcare professional or by the patient. The latter mode of the testing is known as patient self-testing or home testing. The objective of this study was to elicit patients' perspectives and experiences regarding PT/INR self-testing using portable coagulometer devices.</p> <p>Methods</p> <p>Internet blog text mining was used to collect 246 blog postings by 108 patients, mainly from the USA and the UK. The content of these qualitative data were analysed using XSight and NVivo software packages.</p> <p>Results</p> <p>The key themes in relation to self-testing of OAT identified were as follows: Patient benefits reported were time saved, personal control, choice, travel reduction, cheaper testing, and peace of mind. Equipment issues included high costs, reliability, quality, and learning how to use the device. PT/INR issues focused on the frequency of testing, INR fluctuations and individual target (therapeutic) INR level. Other themes noted were INR testing at laboratories, the interactions with healthcare professionals in managing and testing OAT and insurance companies' involvement in acquiring the self-testing equipment. Social issues included the pain and stress of taking and testing for OAT.</p> <p>Conclusions</p> <p>Patients' blogs on PT/INR testing provide insightful information that can help in understanding the nature of the experiences and perspectives of patients on self-testing of OAT. The themes identified in this paper highlight the substantial complexities involved in self-testing programmes in the healthcare system. Thus, the issues elicited in this study are very valuable for all stakeholders involved in developing effective self-testing strategies in healthcare that are gaining considerable current momentum particularly for patients with chronic illness.</p

Building an immune-mediated coagulopathy consensus: early recognition and evaluation to enhance post-surgical patient safety

Topical hemostats, fibrin sealants, and surgical adhesives are regularly used in a variety of surgical procedures involving multiple disciplines. Generally, these adjuncts to surgical hemostasis are valuable means for improving wound visualization, reducing blood loss or adding tissue adherence; however, some of these agents are responsible for under-recognized adverse reactions and outcomes. Bovine thrombin, for example, is a topical hemostat with a long history of clinical application that is widely used alone or in combination with other hemostatic agents. Hematologists and coagulation experts are aware that these agents can lead to development of an immune-mediated coagulopathy (IMC). A paucity of data on the incidence of IMC contributes to under-recognition and leaves many surgeons unaware that this clinical entity, originating from normal immune responses to foreign antigen exposure, requires enhanced post-operative vigilance and judicious clinical judgment to achieve best outcomes

The Actin-Binding Protein Capulet Genetically Interacts with the Microtubule Motor Kinesin to Maintain Neuronal Dendrite Homeostasis

BACKGROUND: Neurons require precise cytoskeletal regulation within neurites, containing microtubule tracks for cargo transport in axons and dendrites or within synapses containing organized actin. Due to the unique architecture and specialized function of neurons, neurons are particularly susceptible to perturbation of the cytoskeleton. Numerous actin-binding proteins help maintain proper cytoskeletal regulation. METHODOLOGY/PRINCIPAL FINDINGS: From a Drosophila forward genetic screen, we identified a mutation in capulet--encoding a conserved actin-binding protein--that causes abnormal aggregates of actin within dendrites. Through interaction studies, we demonstrate that simultaneous genetic inactivation of capulet and kinesin heavy chain, a microtubule motor protein, produces elongate cofilin-actin rods within dendrites but not axons. These rods resemble actin-rich structures induced in both mammalian neurodegenerative and Drosophila Alzheimer's models, but have not previously been identified by loss of function mutations in vivo. We further demonstrate that mitochondria, which are transported by Kinesin, have impaired distribution along dendrites in a capulet mutant. While Capulet and Cofilin may biochemically cooperate in certain circumstances, in neuronal dendrites they genetically antagonize each other. CONCLUSIONS/SIGNIFICANCE: The present study is the first molecularly defined loss of function demonstration of actin-cofilin rods in vivo. This study suggests that simultaneous, seemingly minor perturbations in neuronal dendrites can synergize producing severe abnormalities affecting actin, microtubules and mitochondria/energy availability in dendrites. Additionally, as >90% of Alzheimer's and Parkinson's cases are sporadic this study suggests mechanisms by which multiple mutations together may contribute to neurodegeneration instead of reliance on single mutations to produce disease

A Genome-Wide Study of Cytogenetic Changes in Colorectal Cancer Using SNP Microarrays: Opportunities for Future Personalized Treatment

In colorectal cancer (CRC), chromosomal instability (CIN) is typically studied using comparative-genomic hybridization (CGH) arrays. We studied paired (tumor and surrounding healthy) fresh frozen tissue from 86 CRC patients using Illumina's Infinium-based SNP array. This method allowed us to study CIN in CRC, with simultaneous analysis of copy number (CN) and B-allele frequency (BAF) - a representation of allelic composition. These data helped us to detect mono-allelic and bi-allelic amplifications/deletion, copy neutral loss of heterozygosity, and levels of mosaicism for mixed cell populations, some of which can not be assessed with other methods that do not measure BAF. We identified associations between CN abnormalities and different CRC phenotypes (histological diagnosis, location, tumor grade, stage, MSI and presence of lymph node metastasis). We showed commonalities between regions of CN change observed in CRC and the regions reported in previous studies of other solid cancers (e.g. amplifications of 20q, 13q, 8q, 5p and deletions of 18q, 17p and 8p). From Therapeutic Target Database, we identified relevant drugs, targeted to the genes located in these regions with CN changes, approved or in trials for other cancers and common diseases. These drugs may be considered for future therapeutic trials in CRC, based on personalized cytogenetic diagnosis. We also found many regions, harboring genes, which are not currently targeted by any relevant drugs that may be considered for future drug discovery studies. Our study shows the application of high density SNP arrays for cytogenetic study in CRC and its potential utility for personalized treatment