Versican splice variant messenger RNA expression in normal human Achilles tendon and tendinopathies

Versican is the principal large proteoglycan expressed in mid-tendon, but its role in tendon pathology is unknown. Our objective was to define the expression of versican isoform splice variant messenger ribonucleic acid (mRNA) in normal Achilles tendons, in chronic painful tendinopathy and in ruptured tendons. Total RNA isolated from frozen tendon samples (normal n = 14; chronic painful tendinopathy n = 10; ruptured n = 8) was assayed by relative quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for total versican, versican variants V0, V1, V2, V3 and type I collagen a1 mRNA, normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Differences between sample groups were tested by Wilcoxon statistics. Painful and ruptured tendons showed a significant decrease (median 2-fold) in the expression of versican mRNA, in contrast to an increased expression (median 8-fold) of type I collagen a1 mRNA in painful tendons. Versican splice variants V0 and V1 mRNA were readily detected in normal samples, V3 levels were substantially lower, and V2 levels were more variable. Each of V1, V2 and V3 mRNA showed significant decreases in expression in painful and ruptured tendons, but V0 was not significantly changed. Changes in versican expression relative to that of collagen, and alterations in the balance of versican splice variants, may contribute to changes in matrix structure and function in tendinopathies

Exposure to benzene at work and the risk of leukemia: a systematic review and meta-analysis

Background A substantial number of epidemiologic studies have provided estimates of the relation between exposure to benzene at work and the risk of leukemia, but the results have been heterogeneous. To bridge this gap in knowledge, we synthesized the existing epidemiologic evidence on the relation between occupational exposure to benzene and the risk of leukemia, including all types combined and the four main subgroups acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). Methods A systematic literature review was carried out using two databases 'Medline' and 'Embase' from 1950 through to July 2009. We selected articles which provided information that can be used to estimate the relation between benzene exposure and cancer risk (effect size). Results In total 15 studies were identified in the search, providing 16 effect estimates for the main analysis. The summary effect size for any leukemia from the fixed-effects model was 1.40 (95% CI, 1.23-1.57), but the study-specific estimates were strongly heterogeneous (I2 = 56.5%, Q stat = 34.47, p = 0.003). The random-effects model yielded a summary- effect size estimate of 1.72 (95% CI, 1.37-2.17). Effect estimates from 9 studies were based on cumulative exposures. In these studies the risk of leukemia increased with a dose-response pattern with a summary-effect estimate of 1.64 (95% CI, 1.13-2.39) for low (< 40 ppm-years), 1.90 (95% CI, 1.26-2.89) for medium (40-99.9 ppm-years), and 2.62 (95% CI, 1.57-4.39) for high exposure category (> 100 ppm-years). In a meta-regression, the trend was statistically significant (P = 0.015). Use of cumulative exposure eliminated heterogeneity. The risk of AML also increased from low (1.94, 95% CI, 0.95-3.95), medium (2.32, 95% CI, 0.91-5.94) to high exposure category (3.20, 95% CI, 1.09-9.45), but the trend was not statistically significant. Conclusions Our study provides consistent evidence that exposure to benzene at work increases the risk of leukemia with a dose-response pattern. There was some evidence of an increased risk of AML and CLL. The meta-analysis indicated a lack of association between benzene exposure and the risk of CML

Dissecting the oxidative folding of circular cystine knot miniproteins

Cyclotides are plant proteins with exceptional stability owing to the presence of a cyclic backbone and three disulfide bonds arranged in a cystine knot motif. Accordingly, they have been proposed as templates to stabilize bioactive epitopes in drug-design applications. The two main subfamilies, referred to as the Möbius and bracelet cyclotides, require dramatically different in vitro folding conditions to achieve the native fold. To determine the underlying elements that influence cyclotide folding, we examined the in vitro folding of a suite of hybrid cyclotides based on combination of the Möbius cyclotide kalata B1 and the bracelet cyclotide cycloviolacin O1. The folding pathways of the two cyclotide subfamilies were found to be different and influenced by specific residues within intercysteine loops 2 and 6. Two changes in these loops, a substitution in loop 2 and an addition in loop 6, enabled the folding of a cycloviolacin O1 analogue under conditions in which folding does not occur in vitro for the native peptide. A key intermediate contains a native-like hairpin structure that appears to be a nucleation locus early in the folding process. Overall, these mechanistic findings on the folding of cyclotides are potentially valuable for the design of new drug leads. Copyright Mary Ann Liebert, Inc

Major life events as predictors of loneliness in adolescence

© 2015, Springer Science+Business Media New York. The present study investigates the validity of early major life events as predictors of loneliness among 978 high-school students. A cross-sectional research design was utilized to examine the relationship between latent classes of six major life events and feelings of family-related and peer-related loneliness. Latent class analysis revealed three distinct event typologies: a normative group, a mover and divorce group, and a loss and illness group. Subsequent logistic regression revealed that membership of the movers and divorce group was associated with family-related loneliness, but not with peer-related loneliness. Membership of the loss and illness group was not associated with family-related or peer-related loneliness. The study lends some support to theoretical approaches that associate loneliness with major life events. However, the mixed study results underscore the relevance of investigating a spectrum of life events and distinguishing between different sources of loneliness.status: publishe

Exploring synergies and trade-offs among the sustainable development goals: collective action and adaptive capacity in marginal mountainous areas of India

Global environmental change (GEC) threatens to undermine the sustainable development goals (SDGs). Smallholders in marginal mountainous areas (MMA) are particularly vulnerable due to precarious livelihoods in challenging environments. Acting collectively can enable and constrain the ability of smallholders to adapt to GEC. The objectives of this paper are: (i) identify collective actions in four MMA of the central Indian Himalaya Region, each with differing institutional contexts; (ii) assess the adaptive capacity of each village by measuring livelihood capital assets, diversity, and sustainable land management practices. Engaging with adaptive capacity and collective action literatures, we identify three broad approaches to adaptive capacity relating to the SDGs: natural hazard mitigation (SDG 13), social vulnerability (SDG 1, 2 and 5), and social–ecological resilience (SDG 15). We then develop a conceptual framework to understand the institutional context and identify SDG synergies and trade-offs. Adopting a mixed method approach, we analyse the relationships between collective action and the adaptive capacity of each village, the sites where apparent trade-offs and synergies among SDGs occur. Results illustrate each village has unique socio-environmental characteristics, implying distinct development challenges, vulnerabilities and adaptive capacities exist. Subsequently, specific SDG synergies and trade-offs occur even within MMA, and it is therefore crucial that institutions facilitate locally appropriate collective actions in order to achieve the SDGs. We suggest that co-production in the identification, prioritisation and potential solutions to the distinct challenges facing MMA can increase understandings of the specific dynamics and feedbacks necessary to achieve the SDGs in the context of GEC

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Thrombomodulin Ala455Val Polymorphism and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study

BACKGROUND: The genes encoding proteins in the thrombomodulin-protein C pathway are promising candidate genes for stroke susceptibility because of their importance in thrombosis regulation and inflammatory response. Several published studies have shown that the Ala455Val thrombomodulin polymorphism is associated with ischemic heart disease, but none has examined the association with stroke. Using data from the Stroke Prevention in Young Women Study, we sought to determine the association between the Ala455Val thrombomodulin polymorphism and the occurrence of ischemic stroke in young women. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. We compared 141 cases of first ischemic stroke (44% black) among women 15 to 44 years of age with 210 control subjects (35% black) who were identified by random digit dialing and frequency matched to the cases by age and geographical region of residence. Data on historical risk factors were collected by standardized interview. Genotyping of the thrombomodulin Ala455Val polymorphism was performed by pyrosequencing. RESULTS: The A allele (frequency = 0.85) was associated with stroke under the recessive model. After adjustment for age, race, cigarette smoking, hypertension, and diabetes, the AA genotype, compared with the AV and VV genotypes combined, was significantly associated with stroke (odds ratio 1.9, 95% CI 1.1–3.3). The AA genotype was more common among black than white control subjects (81% versus 68%) but there was no significant interaction between the risk genotype and race (adjusted odds ratio 2.7 for blacks and 1.6 for whites). A secondary analysis removing all probable (n = 16) and possible (n = 15) cardioembolic strokes demonstrated an increased association (odds ratio 2.2, 95% CI 1.2–4.2). CONCLUSIONS: Among women aged 15 to 44 years, the AA genotype is more prevalent among blacks than whites and is associated with increased risk of early onset ischemic stroke. Removing strokes potentially related to cardioembolic phenomena increased this association. Further studies are needed to determine whether this polymorphism is functionally related to thrombomodulin expression or whether the association is due to population stratification or linkage to a nearby functional polymorphism

Tennis Service Stroke Benefits Humerus Bone: Is Torsion the Cause?

Regular tennis play is associated with impressive asymmetries in bone strength in favor of the racquet arm, particularly in the humerus. However, the relative effects of service and ground strokes are not known. Serendipitously, we encountered a 46-year-old regular tennis player who has played service and ground strokes with different arms for over 30 years, and thus allowed differentiation of stroke effects. Grip strength and peripheral quantitative computed tomography scans of both arms of radius at 4 % distal–proximal ulna length, radius and ulna at 60 % distal–proximal ulna length, and at distal (35 % length) humerus were analyzed in this player, and 12 male veteran players of similar age, height, and mass who played a conventional single-sided style. Confidence intervals (95 %) were calculated for asymmetries and bone, muscle and force parameters in the control players—values in the case study player were compared to these intervals. Sizeable differences in bone strength in favor of the serving arm humerus were observed in this player—comparable to those found in the control players. While asymmetries in favor of the ground stroke arm ulna were also evident, no sizeable asymmetry was found in proximal or distal radius, forearm or upper arm muscle size or hand grip force. These results suggest that the service stroke is responsible for the humeral hypertrophy observed in tennis players, and that ulna adaptation may be attributable to the ground strokes. The osteogenic potential of the service stroke may be related to the large torsional stresses it produces

Hip abduction weakness in elite junior footballers is common but easy to correct quickly: a prospective sports team cohort based study

Background: Hip abduction weakness has never been documented on a population basis as a common finding in a healthy group of athletes and would not normally be found in an elite adolescent athlete. This study aimed to show that hip abduction weakness not only occurs in this group but also is common and easy to correct with an unsupervised home based program. Methods: A prospective sports team cohort based study was performed with thirty elite adolescent under-17 Australian Rules Footballers in the Australian Institute of Sport/Australian Football League Under-17 training academy. The players had their hip abduction performance assessed and were then instructed in a hip abduction muscle training exercise. This was performed on a daily basis for two months and then they were reassessed.Results: The results showed 14 of 28 athletes who completed the protocol had marked weakness or a side-to-side difference of more than 25% at baseline. Two months later ten players recorded an improvement of ≥ 80% in their recorded scores. The mean muscle performance on the right side improved from 151 Newton (N) to 202 N (p<0.001) while on the left, the recorded results improved from 158 N to 223 N (p<0.001). Conclusions: The baseline values show widespread profound deficiencies in hip abduction performance not previously reported. Very large performance increases can be achieved, unsupervised, in a short period of time to potentially allow large clinically significant gains. This assessment should be an integral part of preparticipation screening and assessed in those with lower limb injuries. This particular exercise should be used clinically and more research is needed to determine its injury prevention and performance enhancement implications