Individuals with neurological diseases are at increased risk of fractures within 180 days of admission to long-term care in Ontario.

BACKGROUND: Individuals residing in long-term care (LTC) are more likely to have a fragility fracture than community-dwelling seniors. The purpose of this study was to determine whether the presence of neurological diseases was associated with an increased risk of fracture within 180 days of admission to LTC. METHODS: This retrospective cohort study used data collected in the LTC setting using the Resident Assessment Instrument (RAI) 2.0 during the period from 2006 to 2011 (N=42,089). Multivariable logistic regression analyses were conducted to determine the associations between the presence of neurological conditions and incident fractures, with and without adjustment for clinical variables. RESULTS: The incident fracture rate for all LTC residents was 2.6% (N=1,094). Neurological condition group size ranged from n=21,015 for Alzheimer's disease or related dementias (ADRD) to n=21 for muscular dystrophy (MD). The incidence of fracture among residents with specific neurological diseases was as follows: ADRD, 3.2% (n=672), MD, 4.8% (n=1), Parkinson's disease, 2.5% (n=57), stroke, 2.3% (n=166), epilepsy, 2.5% (n=38), Huntington's disease, 1.4% (n=1), multiple sclerosis, 0.3% (n=1) and traumatic brain injury, 3.8% (n=11); among the comparison group with no neurological conditions, the fracture rate was 2.0% (n=366). The neurological diseases that were associated with a significantly greater odds of having an incident fracture in the first 180 days of LTC admission were as follows: ADRD (1.3; 95% CI: 1.1-1.5), epilepsy (1.5; 95% CI: 1.0-2.1) and traumatic brain injury (2.7; 95% CI: 1.4-5.0). CONCLUSION: LTC residents with ADRD, epilepsy and traumatic brain injury are at a higher risk for sustaining an incident fracture in the first 180 days of admission and should be considered for fracture prevention strategies.

Implementation of bedside handover that includes patients or carers in hospital settings: A systematic review.

OBJECTIVE: Increasing complexity in healthcare systems necessitates effective handover. While a universal structure is often recommended, many frameworks do not include the patient. A systematic review was completed examining outcomes following handover that included patients or carers using a realist-orientated paradigm. METHODS: The research group used Covidence™ software and followed PRISMA guidelines. A librarian-led search of Embase, Medline, PsycINFO and SCOPUS yielded 5,790 relevant studies for screening. Included studies reported on peer-reviewed studies that assessed qualitative or quantitative outcomes resulting from patient-centred handover. To assess quality, we used the McMaster Mixed Methods Appraisal Tool (MMAT). Patient-orientated and quantitative outcomes are reported descriptively. For qualitative outcomes, we employed a deductive analytical approach. Braun and Clarke's steps were followed to develop themes with group work used to clarify and discuss the various codes. Heterogenous reporting precluded meta-analysis. RESULTS: Thirty studies were eligible (10 mixed methods; 11 quantitative; 9 qualitative) with variable quality and scope. Most studies related to nursing-led bedside handover and originated in Anglophone countries. Positive effects were reported for patient satisfaction, engagement, autonomy and effective information exchange. Providers reported a positive experience but also barriers to implementation, cognitive load and reducing compliance over time. There were contradicting findings for patient-orientated outcomes including falls risk. Publication bias may have led to under reporting of negative trials. There was limited reporting on physician-led handovers that included patients. CONCLUSIONS: Patient-centred handover was associated with self-reported benefits for patients and providers but potential advantages over conventional handover could be undermined by barriers such as time, implementation challenges and a perceived increase in staff workload.

AMP-activated protein kinase is required for exercise-induced peroxisome proliferator-activated receptor co-activator 1 translocation to subsarcolemmal mitochondria in skeletal muscle.

In skeletal muscle, mitochondria exist as two subcellular populations known as subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria. SS mitochondria preferentially respond to exercise training, suggesting divergent transcriptional control of the mitochondrial genomes. The transcriptional co-activator peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and mitochondrial transcription factor A (Tfam) have been implicated in the direct regulation of the mitochondrial genome in mice, although SS and IMF differences may exist, and the potential signalling events regulating the mitochondrial content of these proteins have not been elucidated. Therefore, we examined the potential for PGC-1α and Tfam to translocate to SS and IMF mitochondria in human subjects, and performed experiments in rodents to identify signalling mechanisms regulating these translocation events. Acute exercise in humans and rats increased PGC-1α content in SS but not IMF mitochondria. Acute exposure to 5-aminoimidazole-4-carboxamide-1-ß-ribofuranoside in rats recapitulated the exercise effect of increased PGC-1α protein within SS mitochondria only, suggesting that AMP-activated protein kinase (AMPK) signalling is involved. In addition, rendering AMPK inactive (AMPK kinase dead mice) prevented exercise-induced PGC-1α translocation to SS mitochondria, further suggesting that AMPK plays an integral role in these translocation events. In contrast to the conserved PGC-1α translocation to SS mitochondria across species (humans, rats and mice), acute exercise only increased mitochondrial Tfam in rats. Nevertheless, in rat resting muscle PGC-1α and Tfam co-immunoprecipate with α-tubulin, suggesting a common cytosolic localization. These data suggest that exercise causes translocation of PGC-1α preferentially to SS mitochondria in an AMPK-dependent manner.

Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice.

Disruptions of ovarian function in women are associated with increased risk of metabolic disease due to dysregulation of peripheral glucose homeostasis in skeletal muscle. Our previous evidence suggests that alterations in skeletal muscle lipid metabolism coupled with altered mitochondrial function may also develop. The objective of this study was to use an integrative metabolic approach to identify potential areas of dysfunction that develop in skeletal muscle from ovariectomized (OVX) female mice compared with age-matched ovary-intact adult female mice (sham). The OVX mice exhibited significant increases in body weight, visceral, and inguinal fat mass compared with sham mice. OVX mice also had significant increases in skeletal muscle intramyocellular lipids (IMCL) compared with the sham animals, which corresponded to significant increases in the protein content of the fatty acid transporters CD36/FAT and FABPpm. A targeted metabolic profiling approach identified significantly lower levels of specific acyl carnitine species and various amino acids in skeletal muscle from OVX mice compared with the sham animals, suggesting a potential dysfunction in lipid and amino acid metabolism, respectively. Basal and maximal mitochondrial oxygen consumption rates were significantly impaired in skeletal muscle fibers from OVX mice compared with sham animals. Collectively, these data indicate that loss of ovarian function results in increased IMCL storage that is coupled with alterations in mitochondrial function and changes in the skeletal muscle metabolic profile.

Men supplemented with 17beta-estradiol have increased beta-oxidation capacity in skeletal muscle.

During endurance exercise women have lower carbohydrate and higher lipid oxidation compared with men. Supplementation of humans and rodents with 17beta-estradiol (E(2)) lowers the respiratory exchange ratio, the glucose rate of appearance and disappearance, and the metabolic clearance rate. The mechanism(s) for the observed estrogen effects in substrate utilization remains to be determined. We hypothesized that estrogen would increase the mRNA and protein content for genes involved in the regulation of beta-oxidation. Ten moderately active men were supplemented with placebo or E(2) for 8 days in a randomized double-blind crossover design. After supplementation muscle biopsies were obtained from the vastus lateralis and examined for differences in mRNA, microRNA, and protein content of genes involved in lipid oxidation. E(2) increased the protein abundance of medium-chain acyl-CoA dehydrogenase (MCAD) 42% (P

Low expression of long-chain acyl-CoA dehydrogenase in human skeletal muscle.

PURPOSE: Long-chain acyl-CoA dehydrogenase (LCAD) is a mitochondrial flavoenzyme thought to be one of the major enzymes responsible for the first step of long-chain fatty acid (LCFA) beta-oxidation. Surprisingly, recent studies have shown LCAD is hardly detectable in human tissues such as liver and heart. Skeletal muscle is the largest organ in the body in terms of mass, and accounts for the majority of LCFA oxidation, especially during exercise. The purpose of this study was to investigate the expression levels of LCAD in human skeletal muscle. METHODS: Muscle biopsies were obtained from the vastus lateralis of healthy athletic men and women, and examined for mRNA abundance, protein content, and enzyme activity of LCAD. We compared LCAD content with that of very-long chain acyl-CoA dehydrogenase (VLCAD) and medium chain acyl-CoA dehydrogenase (MCAD); two mitochondrial beta-oxidation enzymes that have overlapping chain-length specificity to that of LCAD. LCAD protein content and enzyme activity were also examined in enriched mitochondrial protein fractions. As controls, LCAD presence in skeletal muscle was compared to human heart, liver, and mouse skeletal muscle. RESULTS: The mRNA presence of LCAD in human skeletal muscle is significantly less than VLCAD and MCAD (0.08+/-0.01 vs 7.3+/-0.5 vs 2.4+/-0.2 respectively, P

A randomized trial of coenzyme Q10 in mitochondrial disorders.

Case reports and open-label studies suggest that coenzyme Q(10) (CoQ(10)) treatment may have beneficial effects in mitochondrial disease patients; however, controlled trials are warranted to clinically prove its effectiveness. Thirty patients with mitochondrial cytopathy received 1200 mg/day CoQ(10) for 60 days in a randomized, double-blind, cross-over trial. Blood lactate, urinary markers of oxidative stress, body composition, activities of daily living, quality of life, forearm handgrip strength and oxygen desaturation, cycle exercise cardiorespiratory variables, and brain metabolites were measured. CoQ(10) treatment attenuated the rise in lactate after cycle ergometry, increased (∽1.93 ml) VO(2)/kg lean mass after 5 minutes of cycling (P < 0.005), and decreased gray matter choline-containing compounds (P < 0.05). Sixty days of moderate- to high-dose CoQ(10) treatment had minor effects on cycle exercise aerobic capacity and post-exercise lactate but did not affect other clinically relevant variables such as strength or resting lactate.

Exercise, sex, menstrual cycle phase, and 17beta-estradiol influence metabolism-related genes in human skeletal muscle.

Higher fat and lower carbohydrate and amino acid oxidation are observed in women compared with men during endurance exercise. We hypothesized that the observed sex difference is due to estrogen and that menstrual cycle phase or supplementation of men with 17beta-estradiol (E(2)) would coordinately influence the mRNA content of genes involved in lipid and/or carbohydrate metabolism in skeletal muscle. Twelve men and twelve women had muscle biopsies taken before and immediately after 90 min of cycling at 65% peak oxygen consumption (Vo(2peak)). Women were studied in the midfollicular (Fol) and midluteal (Lut) phases, and men were studied after 8 days of E(2) or placebo supplementation. Targeted RT-PCR was used to compare mRNA content for genes involved in transcriptional regulation and lipid, carbohydrate, and amino acid metabolism. Sex was the greatest predictor of substrate metabolism gene content. Sex affected the mRNA content of FATm, FABPc, SREBP-1c, mtGPAT, PPARdelta, PPARalpha, CPTI, TFP-alpha, GLUT4, HKII, PFK, and BCOADK (P < 0.05). E(2) administration significantly (P < 0.05) affected the mRNA content of PGC-1alpha, PPARalpha, PPARdelta, TFP-alpha, CPTI, SREBP-1c, mtGPAT, GLUT4, GS-1, and AST. Acute exercise increased the mRNA abundance for PGC-1alpha, HSL, FABPc, CPTI, GLUT4, HKII, and AST (P < 0.05). Menstrual cycle had a small effect on PPARdelta, GP, and glycogenin mRNA content. Overall, women have greater mRNA content for several genes involved in lipid metabolism, which is partially due to an effect of E(2).

Rat epidermal keratinocytes as an organotypic model for examining the role of Cx43 and Cx26 in skin differentiation.

In order to characterize connexin expression and regulation in the epidermis, we have characterized a rat epidermal keratinocyte (REK) cell line that is phenotypically similar to basal keratinocytes in that they have the ability to differentiate into organotypic epidermis consisting of a basal cell layer, 2-3 suprabasal cell layers, and a cornified layer. RT-PCR revealed that REK cells express mRNA for Cx26, Cx31, Cx31.1, Cx37, and Cx43, which mimics the reported connexin profile for rat tissue. In addition, we report the expression of Cx30, Cx30.3, Cx40, and Cx45 in rat keratinocytes, highlighting the complexity of the connexin complement in rat epidermis. Furthermore, 3-dimensional analysis of organotypic skin revealed that Cx26 and Cx43 are exquisitely regulated during the differentiation process. The life-cycle of these connexins including their expression, transport, assembly into gap junctions, internalization, and degradation are elegantly depicted in organotypic epidermis as keratinocytes proceed from differentiation to programmed cell death.

Disparities in Quality of Park Play Spaces between Two Cities with Diverse Income and Race/Ethnicity Composition: A Pilot Study.

This study investigated the differences in the quality of park play spaces between an affluent and a non-affluent community in a large US Southeastern metropolitan area. Two cities were purposefully selected to reflect differences in household income and race/ethnicity characteristics. Using the Playable Space Quality Assessment Tool (PSQAT), all parks (n = 11, with six in the affluent city, and five in the non-affluent city) in these two cities were evaluated. The data were analyzed across three aspects of environmental features of the PSQAT: Location, Play Value and Care and Maintenance between parks in the two cities. The Mann-Whitney U test was used to test the study hypotheses. Results indicated significant differences between parks in the two cities in all three aspects of the PSQAT with p-values ≤ 0.03 and effect sizes of > 0.65, suggesting that the affluent city had parks of a higher quality than the non-affluent city. Significant disparity in Play Value (p = 0.009) in parks between these two communities suggests that children and young people are likely to have different experiences of the play spaces in their locality and therefore may experience different physical and psychological health benefits.

Over-expressing mitofusin-2 in healthy mature mammalian skeletal muscle does not alter mitochondrial bioenergetics.

The role of mitofusin-2 (MFN-2) in regulating mitochondrial dynamics has been well-characterized in lower order eukaryotic cell lines through the complete ablation of MFN-2 protein. However, to support the contractile function of mature skeletal muscle, the subcellular architecture and constituent proteins of this tissue differ substantially from simpler cellular organisms. Such differences may also impact the role of MFN-2 in mature mammalian muscle, and it is unclear if minor fluctuations in MFN-2, as observed in response to physiological perturbations, has a functional consequence. Therefore, we have transiently transfected MFN-2 cDNA into rat tibialis anterior muscle to determine the effect of physiolgically relevant increases in MFN-2 protein on mitochondrial bioenergetics. Permeabilized muscle fibres generated from muscle following MFN-2-transfection were used for functional assessments of mitochondrial bioenergetics. In addition, we have further established a novel method for selecting fibre bundles that are positively transfected, and using this approach transient transfection increased MFN-2 protein ∼2.3 fold in selected muscle fibres. However, this did not alter maximal rates of oxygen consumption or the sensitivity for ADP-stimulated respiration. In addition, MFN-2 over-expression did not alter rates of H(2)O(2) emission. Altogether, and contrary to evidence from lower order cell lines, our results indicate that over-expressing MFN-2 in healthy muscle does not influence mitochondrial bioenergetics in mature mammalian skeletal muscle.

Women have higher protein content of beta-oxidation enzymes in skeletal muscle than men.

It is well recognized that compared with men, women have better ultra-endurance capacity, oxidize more fat during endurance exercise, and are more resistant to fat oxidation defects i.e. diet-induced insulin resistance. Several groups have shown that the mRNA and protein transcribed and translated from genes related to transport of fatty acids into the muscle are greater in women than men; however, the mechanism(s) for the observed sex differences in fat oxidation remains to be determined. Muscle biopsies from the vastus lateralis were obtained from moderately active men (N=12) and women (N=11) at rest to examine mRNA and protein content of genes involved in lipid oxidation. Our results show that women have significantly higher protein content for tri-functional protein alpha (TFPalpha), very long chain acyl-CoA dehydrogenase (VLCAD), and medium chain acyl-CoA dehydrogenase (MCAD) (P<0.05). There was no significant sex difference in the expression of short-chain hydroxyacyl-CoA dehydrogenase (SCHAD), or peroxisome proliferator activated receptor alpha (PPARalpha), or PPARgamma, genes potentially involved in the transcriptional regulation of lipid metabolism. In conclusion, women have more protein content of the major enzymes involved in long and medium chain fatty acid oxidation which could account for the observed differences in fat oxidation during exercise.

Sex differences in global mRNA content of human skeletal muscle.

Women oxidize more fat as compared to men during endurance exercise and several groups have shown that the mRNA content of selected genes related to fat oxidation are higher in women (e.g. hormone sensitive lipase, beta-hydroxyacyl-CoA dehydrogenase, CD36). One of the possible mechanisms is that women tend to have a higher area percentage of type I skeletal muscle fibers as compared with men. Consequently, we hypothesized that sex would influence the basal mRNA and protein content for genes involved in metabolism and the determination of muscle fiber type. Muscle biopsies from the vastus lateralis were collected from healthy men and women. We examined mRNA content globally using Affymetrix GeneChips, and selected genes were examined and/or confirmed by RT-PCR. Furthermore, we examined protein content by Western blot analysis. Stringent gene array analysis revealed 66 differentially expressed genes representing metabolism, mitochondrial function, transport, protein biosynthesis, cell proliferation, signal transduction pathways, transcription and translation. Stringent gene array analysis and RT-PCR confirmed that mRNA for; acyl-coenzyme A acyltransferase 2 (ACAA2), trifunctional protein beta (HADHB), catalase, lipoprotein lipase (LPL), and uncoupling protein-2 (UCP-2) were higher in women. Targeted gene analysis revealed that myosin heavy chain I (MHCI), peroxisome proliferator-activated receptor (PPAR)delta were higher in women compared with men. Surprisingly, there were no significant sex based differences in protein content for HADHB, ACAA2, catalase, PPARdelta, and MHC1. In conclusion, the differences in the basal mRNA content in resting skeletal muscle suggest that men and women are transcriptionally "primed" for known physiological differences in metabolism however the mechanism behind sex differences in fiber type remains to be determined.

Connexin levels regulate keratinocyte differentiation in the epidermis.

To understand the role of connexin43 (Cx43) in epidermal differentiation, we reduced Cx43 levels by RNA-mediated interference knockdown and impaired its functional status by overexpressing loss-of-function Cx43 mutants associated with the human disease oculodentodigital dysplasia (ODDD) in rat epidermal keratinocytes. When Cx43 expression was knocked down by 50-75%, there was a coordinate 55-65% reduction in Cx26 level, gap junction-based dye coupling was reduced by 60%, and transepithelial resistance decreased. Importantly, the overall growth and differentiation of Cx43 knockdown organotypic epidermis was severely impaired as revealed by alterations in the levels of the differentiation markers loricrin and involucrin and by reductions in vital and cornified layer thicknesses. Conversely, although the expression of Cx43 mutants reduced the coupling status of rat epidermal keratinocytes by approximately 80% without altering the levels of endogenous Cx43 or Cx26, their ability to differentiate was not altered. In addition, we used a mouse model of ODDD and found that newborn mice harboring the loss-of-function Cx43(G60S) mutant had slightly reduced Cx43 levels, whereas Cx26 levels, epidermis differentiation, and barrier function remained unaltered. This properly differentiated epidermis was maintained even when Cx43 and Cx26 levels decreased by more than 70% in 3-week-old mutant mice. Our studies indicate that Cx43 and Cx26 collectively co-regulate epidermal differentiation from basal keratinocytes but play a more minimal role in the maintenance of established epidermis. Altogether, these studies provide an explanation as to why the vast majority of ODDD patients, where Cx43 function is highly compromised, do not suffer from skin disease.

E2F-1 is essential for normal epidermal wound repair.

E2F factors are involved in proliferation and apoptosis. To understand the role of E2F-1 in the epidermis, we screened wild type and E2F-1(-/-) keratinocyte mRNA for genes differentially expressed in the two cell populations. We demonstrate the reduced expression of integrins alpha(5), alpha(6), beta(1), and beta(4) in E2F-1(-/-) keratinocytes associated with reduced activation of Jun terminal kinase and Erk upon integrin stimulation. As a consequence of altered integrin expression and function, E2F-1(-/-) keratinocytes also show impaired migration, adhesion to extracellular matrix proteins, and a blunted chemotactic response to transforming growth factor-gamma1. E2F-1(-/-) keratinocytes, but not dermal fibroblasts, exhibit altered patterns of proliferation, including significant delays in transit through both G(1) and S phases of the cell cycle. Recognizing that proliferation and migration are key for proper wound healing in vivo, we postulated that E2F-1(-/-) mice may exhibit abnormal epidermal repair upon injury. Consistent with our hypothesis, E2F-1(-/-) mice exhibited impaired cutaneous wound healing. This defect is associated with substantially reduced local inflammatory responses and rates of re-epithelialization. Thus, we demonstrate that E2F-1 is indispensable for a hitherto unidentified cell type-specific and unique role in keratinocyte proliferation, adhesion, and migration as well as in proper wound repair and epidermal regeneration in vivo.