The effects of weight and physical activity change over 20 years on later-life objective and self-reported disability.

Weight and health behaviours are known to affect physical disability; however the evidence exploring the impact of changes to these lifestyle factors over the life course on disability is inconsistent. We aimed to explore the roles of weight and activity change between mid and later life on physical disability

The Effect of a Sustained High-Fat Diet on the Metabolism of White and Brown Adipose Tissue and Its Impact on Insulin Resistance: A Selected Time Point Cross-Sectional Study.

(1) Background: studies on the long-term dynamic changes in fat depot metabolism in response to a high-fat diet (HFD) on hepatic lipid deposition and insulin resistance are sparse. This study investigated the dynamic changes produced by HFD and the production of dysfunctional fat depots on insulin resistance and liver lipid metabolism. (2) Methods: mice fed a chow or HFD (45% kcal fat) diet had three fat depots, liver, and blood collected at 6, 10, 20, and 30 weeks. Anthropometric changes and gene markers for adipogenesis, thermogenesis, ECM remodeling, inflammation, and tissue insulin resistance were measured. (3) Results: early responses to the HFD were increased body weight, minor deposition of lipid in liver, increased adipocyte size, and adipogenesis. Later changes were dysfunctional adipose depots, increased liver fat, insulin resistance (shown by changes in ITT) accompanied by increased inflammatory markers, increased fibrosis (fibrosis > 2-fold, p < 0.05 from week 6), and the presence of crown cells in white fat depots. Later, changes did not increase thermogenic markers in response to the increased calories and decreased UCP1 and PRDM16 proteins in WAT. (4) Conclusions: HFD feeding initially increased adipocyte diameter and number, but later changes caused adipose depots to become dysfunctional, restricting adipose tissue expansion, changing the brown/beige ratios in adipose depots, and causing ectopic lipid deposition and insulin resistance

Medial collateral ligament reconstruction for anteromedial instability of the knee: a biomechanical study in vitro.

BACKGROUND: Although a medial collateral ligament (MCL) injury is associated with anteromedial rotatory instability (AMRI) and often with an anterior cruciate ligament (ACL) injury, there has been little work to develop anteromedial (AM) reconstruction to address this laxity. PURPOSE: To measure the ability of a novel "anatomic" AM reconstruction technique to restore native knee laxity for isolated AM insufficiency and combined AM plus posteromedial insufficiency. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 12 cadaveric knees were mounted in a kinematic testing rig that allowed the tibia to be loaded while the knee flexed-extended 0° to 100° with 88-N anteroposterior translation, 5-N·m internal rotation-external rotation (ER), 8-N·m valgus, and combined anterior translation plus ER to simulate AMRI. Joint motion was measured using optical trackers with the knee intact, after superficial MCL (sMCL) and deep MCL (dMCL) transection, and after AM reconstruction of the sMCL and dMCL with semitendinosus autografts. The posteromedial capsule (PMC)/posterior oblique ligament (POL) was then transected to induce a grade 3 medial injury, and kinematic measurements were repeated afterward and again after removing the grafts. Laxity changes were examined using repeated-measures analysis of variance and post-testing. RESULTS: sMCL and dMCL deficiency increased valgus, ER, and AMRI laxities. These laxities did not differ from native values after AM reconstruction. Additional PMC/POL deficiency did not increase these laxities significantly but did increase internal rotation laxity near knee extension; this was not controlled by AM reconstruction. CONCLUSION: AM reconstruction eliminated AMRI after transection of the dMCL and sMCL, and also eliminated AMRI after additional PMC/POL transection. CLINICAL RELEVANCE: Many MCL injuries occur in combination with ACL injuries, causing AMRI. These injuries may rupture the AM capsule and dMCL. Unaddressed MCL deficiency leads to an increased ACL reconstruction failure rate. A dMCL construct oriented anterodistally across the medial joint line, along with an sMCL graft, can restore native knee ER laxity. PMC/POL lesions did not contribute to AMRI

Successful synthesis of a glial-specific blood-brain barrier shuttle peptide following a fragment condensation approach on a solid-phase resin

Successful manual synthesis of the TD2.2 peptide acting as a blood-brain barrier shuttle was achieved. TD2.2 was successfully synthesised by sequential condensation of four protected peptide fragments on solid-phase settings, after several unsuccessful attempts using the stepwise approach. These fragments were chosen to minimize the number of demanding amino acids (in terms of coupling, Fmoc removal) in each fragment that are expected to hamper the overall synthetic process. Thus, the hydrophobic amino acids as well as Fmoc-Arg (Pbf)-OH were strategically spread over multiple fragments rather than having them congested in one fragment. This study shows how a peptide that shows big challenges in the synthesis using the common stepwise elongation methodology can be synthesised with an acceptable purity. It also emphasises that choosing the right fragment with certain amino acid constituents is key for a successful synthesis. It is worth highlighting that lower amounts of reagents were required to synthesise the final peptide with an identical purity to that obtained by the automatic synthesiser

A triple-strand anatomic medial collateral ligament reconstruction restores knee stability more completely than a double-strand reconstruction: a biomechanical study in vitro.

BACKGROUND: There are many descriptions of medial collateral ligament (MCL) reconstruction, but they may not reproduce the anatomic structures and there is little evidence of their biomechanical performance. PURPOSE: To investigate the ability of "anatomic" MCL reconstruction to restore native stability after grade III MCL plus posteromedial capsule/posterior oblique ligament injuries in vitro. STUDY DESIGN: Controlled laboratory study. METHODS: Twelve cadaveric knees were mounted in a kinematic testing rig to impose tibial displacing loads while the knee was flexed-extended: 88-N anteroposterior translation, 5-N·m internal-external rotation, 8-N·m valgus-varus, and combined anterior translation plus external rotation (anteromedial rotatory instability). Joint motion was measured via optical trackers with the knee intact; after superficial MCL (sMCL), deep MCL (dMCL), and posterior oblique ligament transection; and then after MCL double- and triple-strand reconstructions. Double strands reproduced the sMCL and posterior oblique ligament and triple-strands the sMCL, dMCL, and posterior oblique ligament. The sMCL was placed 5 mm posterior to the epicondyle in the double-strand technique and at the epicondyle in the triple-strand technique. Kinematic changes were examined by repeated measures 2-way analysis of variance with posttesting. RESULTS: Transection of the sMCL, dMCL, and posterior oblique ligament increased valgus rotation (5° mean) and external rotation (9° mean). The double-strand reconstruction controlled valgus in extension but allowed 5° excess valgus in flexion and did not restore external rotation (7° excess). The triple-strand reconstruction restored both external rotation and valgus throughout flexion. CONCLUSION: In a cadaveric model, a triple-strand reconstruction including a dMCL graft restored native external rotation, while a double-strand reconstruction without a dMCL graft did not. A reconstruction with the sMCL graft placed isometrically on the medial epicondyle restored valgus rotation across the arc of knee flexion, whereas a reconstruction with a more posteriorly placed sMCL graft slackened with knee flexion. CLINICAL RELEVANCE: An MCL injury may rupture the anteromedial capsule and dMCL, causing anteromedial rotatory instability. Persistent MCL instability increases the likelihood of ACL graft failure after combined injury. A reconstruction with an anteromedial dMCL graft restored native external rotation, which may help to unload/protect an ACL graft. It is important to locate the sMCL graft isometrically at the femoral epicondyle to restore valgus across flexion

Fibroblast growth factor receptor (FGFR) alterations in squamous differentiated bladder cancer: a putative therapeutic target for a small subgroup.

Although drugable fibroblast growth factor receptor (FGFR) alterations in squamous cell carcinomas (SCC) of various entities are well known, little is known about FGFR modifications in squamous differentiated bladder cancer. Therefore, our study evaluated FGFR1-3 alterations as a putative therapeutic target in this subgroup. We analyzed 73 squamous differentiated bladder cancers (n = 10 pT2, n = 55 pT3, n = 8 pT4) for FGFR1-3 protein expression, FGFR1-3 copy number variations, FGFR3 chromosomal rearrangements (fluorescence in situ hybridization (FISH)) and FGFR3 mutations (SNapShot analysis). Only single cases displayed enhanced protein expression, most frequently FGFR3 overexpression (9.4% (6/64)). FISH showed no amplifications of FGFR1, 2 or 3. Break apart events were only slightly above the cut off in 12.1% (8/66) of cases and no FGFR3-TACC3 rearrangements could be proven by qPCR. FGFR3 mutations (p.S249C) were found in 8.5% (6/71) of tumors and were significantly associated with FGFR3 protein overexpression (p < 0.001), and unfavourable clinical outcome (p = 0.001). Our findings are consistent with the results of the TCGA data set for the "squamous-like" subtype of bladder cancer (n = 85), which revealed reduced overall expression of FGFR1 and FGFR2 in tumors compared to normal tissue, while expression of FGFR3 remained high. In the TCGA "squamous-like" subtype FGFR3 mutations were found in 4.9% and correlated with high FGFR3 RNA expression. Mutations of FGFR1 and FGFR2 were less frequent (2.4% and 1.2%). Hence, our comprehensive study provides novel insights into a subgroup of squamous differentiated bladder tumors that hold clues for novel therapeutic regimens and may benefit from FGFR3-targeted therapies

A place for precision medicine in bladder cancer: targeting the FGFRs

Bladder tumors show diverse molecular features and clinical outcome. Muscle-invasive bladder cancer has poor prognosis and novel approaches to systemic therapy are urgently required. Non-muscle-invasive bladder cancer has good prognosis, but high recurrence rate and the requirement for life-long disease monitoring places a major burden on patients and healthcare providers. Studies of tumor tissues from both disease groups have identified frequent alterations of FGFRs, including mutations of FGFR3 and dysregulated expression of FGFR1 and FGFR3 that suggest that these may be valid therapeutic targets. We summarize current understanding of the molecular alterations affecting these receptors in bladder tumors, preclinical studies validating them as therapeutic targets, available FGFR-targeted agents and results from early clinical trials in bladder cancer patients

Genes Suggest Ancestral Colour Polymorphisms Are Shared across Morphologically Cryptic Species in Arctic Bumblebees

email Suzanne orcd idCopyright: © 2015 Williams et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited