Improving community ambulation after hip fracture: protocol for a randomised, controlled trial.

INTRODUCTION: After a hip fracture in older persons, significant disability often remains; dependency in functional activities commonly persists beyond 3 months after surgery. Endurance, dynamic balance, quadriceps strength, and function are compromised, and contribute to an inability to walk independently in the community. In the United States, people aged 65 years and older are eligible to receive Medicare funding for physiotherapy for a limited time after a hip fracture. A goal of outpatient physiotherapy is independent and safe household ambulation 2 to 3 months after surgery. Current Medicare-reimbursed post-hip-fracture rehabilitation fails to return many patients to pre-fracture levels of function. Interventions delivered in the home after usual hip fracture physiotherapy has ended could promote higher levels of functional independence in these frail and older adult patients. PRIMARY OBJECTIVE: To evaluate the effect of a specific multi-component physiotherapy intervention (PUSH), compared with a non-specific multi-component control physiotherapy intervention (PULSE), on the ability to ambulate independently in the community 16 weeks after randomisation. DESIGN: Parallel, two-group randomised multicentre trial of 210 older adults with a hip fracture assessed at baseline and 16 weeks after randomisation, and at 40 weeks after randomisation for a subset of approximately 150 participants. PARTICIPANTS AND SETTING: A total of 210 hip fracture patients are being enrolled at three clinical sites and randomised up to 26 weeks after admission. Study inclusion criteria are: closed, non-pathologic, minimal trauma hip fracture with surgical fixation; aged ≥ 60 years at the time of randomisation; community residing at the time of fracture and randomisation; ambulating without human assistance 2 months prior to fracture; and being unable to walk at least 300 m in 6minutes at baseline. Participants are ineligible if the interventions are deemed to be unsafe or unfeasible, or if the participant has low potential to benefit from the interventions. INTERVENTIONS: Participants are randomly assigned to one of two multi-component treatment groups: PUSH or PULSE. PUSH is based on aerobic conditioning, specificity of training, and muscle overload, while PULSE includes transcutaneous electrical nerve stimulation, flexibility activities, and active range of motion exercises. Participants in both groups receive 32 visits in their place of residence from a study physiotherapist (two visits per week on non-consecutive days for 16 weeks). The physiotherapists' adherence to the treatment protocol, and the participants' receipt of the prescribed activities are assessed. Participants also receive counselling from a registered dietician and vitamin D, calcium and multivitamin supplements during the 16-week intervention period. MEASUREMENTS: The primary outcome (community ambulation) is the ability to walk 300 m or more in 6minutes, as assessed by the 6-minute walk test, at 16 weeks after randomisation. Other measures at 16 and 40 weeks include cost-effectiveness, endurance, dynamic balance, walking speed, quadriceps strength, lower extremity function, activities of daily living, balance confidence, quality of life, physical activity, depressive symptoms, increase of ≥ 50 m in distance walked in 6minutes, cognitive status, and nutritional status. ANALYSIS: Analyses for all aims will be performed according to the intention-to-treat paradigm. Except for testing of the primary hypothesis, all statistical tests will be two-sided and not adjusted for multiple comparisons. The test of the primary hypothesis (comparing groups on the proportion who are community ambulators at 16 weeks after randomisation) will be based on a one-sided 0.025-level hypothesis test using a procedure consisting of four interim analyses and one final analysis with critical values chosen by a Hwang-Shih-Decani alpha-spending function. Analyses will be performed to test group differences on other outcome measures and to examine the differential impact of PUSH relative to PULSE in subgroups defined by pre-selected participant characteristics. Generalised estimating equations will be used to explore possible delayed or sustained effects in a subset of participants by comparing the difference between PUSH and PULSE in the proportion of community ambulators at 16 weeks with the difference at 40 weeks. DISCUSSION: This multicentre randomised study will be the first to test whether a home-based multi-component physiotherapy intervention targeting specific precursors of community ambulation (PUSH) is more likely to lead to community ambulation than a home-based non-specific multi-component physiotherapy intervention (PULSE) in older adults after hip fracture. The study will also estimate the potential economic value of the interventions.

The effect of immobilization on the native and repaired tendon-to-bone interface.

BACKGROUND: Little is known of the cellular events that occur in native or repaired tendons as a result of immobilization after injury. To examine this issue, we compared (1) native tendons without immobilization, (2) native tendons with immobilization, and (3) surgically repaired tendons with immobilization. METHODS: Eighty-one rats underwent either patellar tendon repair followed by immobilization or immobilization of the native tendon without repair. A custom external fixation device was used for immobilization. The tendon-bone insertion site was evaluated after two and four weeks of immobilization with use of histologic, radiographic, and biomechanical analyses. RESULTS: Immobilization of the native tendon led to a significant decrease in the load to failure (p < 0.01) and stiffness (p < 0.05) compared with the native tendon at both two and four weeks. The repaired/immobilized group had a significantly lower load to failure at two weeks compared with the native/immobilized group (p < 0.05); however, by four weeks, the repaired group was significantly stronger (p < 0.01). Micro-computerized tomography demonstrated no significant differences in bone microstructure at two weeks but demonstrated increased bone mineral density and bone volume fraction in the repaired/immobilized group at four weeks. There was significantly more MMP-13 (matrix metalloproteinase-13) staining in the native/immobilized specimens compared with the native specimens at both time points (p < 0.01). CONCLUSIONS: Immobilization had a significant detrimental effect on the bone-tendon complex. At two weeks there was a significant decrease in the mechanical properties of the native tendon, but the immobilized, native tendon remained significantly stronger than the repaired and immobilized tendon. However, four weeks of immobilization led to a significant loss of strength of the bone-tendon complex in the native tendon, such that it was significantly weaker than the repaired and immobilized tendon. Surgeons who manage patients with immobilization should be aware of the changes at the bone-tendon complex.

PPAR-gamma Pro12Ala genotype and risk of cognitive decline in elders.

BACKGROUND: The Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been associated with decreased risk of diabetes and obesity, both disorders linked to cognitive impairment. We tested whether this polymorphism is associated with cognition. METHODS: Two thousand nine hundred sixty-one participants (mean age, 74.1; 41% Black; 52% women) were administered the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and 4 year follow-up. Test scores were adjusted for age, sex, education, cerebrovascular disease, depression and APOE genotype and additionally for race. We determined the association between Ala allele and development of cognitive decline (3MS decline of > or = 5 points). RESULTS: At baseline, unadjusted scores on both cognitive tests were higher for Ala carriers compared to non-carriers (3MS, 94.2 versus 92.5, p<0.001; DSST, 40.2 versus 34.5, p<0.001). Similarly, follow-up scores were higher for Ala carriers. Multivariable adjustment led to similar results; additional adjustment for race attenuated the baseline 3MS results. After 4 years, 17.5% of Ala carriers developed cognitive decline compared to 25% among non-carriers (unadjusted OR=0.61; 95%CI, 0.46-0.82; adjusted OR=0.75; 95%CI, 0.55-1.02). Further adjustment for metabolic variables including fasting blood glucose and lipid level did not change the results. CONCLUSIONS: The PPAR-gamma Ala12 allele carriers may have less risk of developing cognitive decline.

IL-6 gene variation is not associated with increased serum levels of IL-6, muscle, weakness, or frailty in older women.

Elevated levels of the inflammatory cytokine IL-6 are associated with the development of disability, frailty, and mortality in older adults. These outcomes are likely mediated through inflammatory activity that alters hormones, skeletal muscle, and the immune system. Polymorphic variants in the IL-6 gene influence IL-6 expression. We hypothesized that IL-6 alleles associate with increased serum of IL-6, decreased muscle strength, and frailty, and tested this in the Women's Health and Aging cohorts. We genotyped 463 participants age 70-79, and identified three common IL-6 haplotype blocks for the Caucasian (n=363) and African American (n=100) subsets. Using linear and logistic regression, and adjusting for age, BMI, race, and osteoarthritis, we identified no significant or clinically meaningful relationship between any single IL-6 single nucleotide polymorphism (SNP) or any IL-6 haplotype and serum IL-6 level, grip, knee, or hip strength, or frailty. Given that the promoter SNP (rs1800795) has been reported to influence IL-6 levels and health outcomes, we performed a similar association study in the In Chianti population (n=266) and confirmed lack of association. These results suggest that IL-6 gene variation may not be an important factor in the determination of elevated IL-6 levels and related phenotypes found in older women.

Novel neuropeptide Y1 and Y5 receptor gene variants: associations with serum triglyceride and high-density lipoprotein cholesterol levels.

Neuropeptide Y (NPY) appears to play a critical role in the integration of appetite and energy expenditure through NPY Y1 and Y5 receptor subtypes. Moreover, the NPY Y1 receptor is highly expressed on human adipocytes, where it inhibits lipolysis. The genes encoding these receptors are transcribed co-ordinately in opposite directions from a common promoter in a region of chromosome 4 that has been previously linked to triglyceride and small low-density lipoprotein (LDL) particle concentration. Therefore, the purpose of this investigation was to examine the relationship between polymorphisms in the genes encoding NPY Y1 and Y5 and the development of obesity and dyslipidemia. We screened the promoter and coding regions and identified four polymorphic variants. One of these, a cytosine to thymine (C-->T) substitution in the untranslated region between the genes for NPY Y1 and Y5 (allele frequency 0.11), was significantly associated with both lower fasting triglyceride level (152 vs 125 mg/dl), and higher high-density lipoprotein (HDL) concentrations (49 vs 45 mg/dl) (p < 0.01) in 306 obese subjects. Given the stimulatory effect of NPY on adipocyte lipoprotein lipase (LPL) activity, and the lack of association of other polymorphisms with serum lipid levels, we hypothesize that this is a gain-in-function polymorphism.

Interactions between variants in the beta3-adrenergic receptor and peroxisome proliferator-activated receptor-gamma2 genes and obesity.

OBJECTIVE: Previous studies have reported modest associations between measures of obesity and the Trp64-Arg variant of the beta3-adrenergic receptor (ADRbeta3) and the Pro12Ala variant of the peronisome proliferator-activated receptor (PPAR)-gamma2. We hypothesized that these single gene variants may mark mutations that act through convergent pathways to produce synergistic effects on obesity. RESEARCH DESIGN AND METHODS: The sample included 453 subjects from 10 large Mexican-American families participating in the population-based San Antonio Family Heart Study. The effects of each gene variant singly and jointly were estimated as fixed effects using the measured genotype approach framework. Analyses were conditioned on the pedigree structures to account for the correlations among family members. Statistical significance was evaluated by the likelihood ratio test with adjustment for age, sex and diabetes status. RESULTS: The allele frequencies for the ADRbeta3 Trp64Arg and PPARgamma2 Pro12Ala variants were 18 and 12%, respectively. The ADRbeta3 variant was not significantly associated with any of the obesity-related traits, but subjects with the PPAR-gamma2 variant (n = 98) had significantly higher levels of lasting insulin (P = 0.03), leptin (P = 0.009), and waist circumference (P = 0.03) than those without. Subjects with the gene variants (n = 32) had significantly higher BMI, insulin, and leprtin levels than those with only the PPARgamma2 variant (n = 66) (P for interaction: 0.04, 0.02, and 0.01 for BMI, fasting insulin, and leptin, respectively). CONCLUSIONS: Our results suggest that epistatic models with genes that have modest individual effects may be useful in understanding the genetic underpinnings of typical obesity in humans.

Insulin response to glucose is lower in individuals homozygous for the Arg 64 variant of the beta-3-adrenergic receptor.

Type 2 diabetes mellitus (type 2 DM) is a polygenic disorder with a variable phenotype that includes both insulin resistance and insulin secretory dysfunction. The Arg 64 beta-3-adrenergic receptor variant allele is associated with an earlier age of onset of type 2 DM. The purpose of this study was to examine the in vivo pathophysiology of this variant allele to determine its contribution to the components of glucose metabolism. We used the frequently sampled iv glucose tolerance tests, minimal model analysis, and analysis of covariance to examine age- and fat-mass-adjusted differences among genotypes. The results demonstrate that individuals homozygous for the Arg 64 allele secrete significantly less insulin in response to a glucose infusion (562+/-116 vs. 962+/-94 pmol/microL), have the highest fasting glucose levels (100.4+/-1.9 vs. 92.48+/-1.60 mg/dL), and have lower glucose effectiveness (0.014+/-0.003 vs. 0.019+/-0.002 min(-1)), compared with those homozygous for the Trp 64 allele. This first report of decreased acute insulin release and lower glucose effectiveness in the Arg 64 genotype may help explain the earlier onset of type 2 DM observed in several populations of individuals with the Arg64 beta-3-adrenergic receptor variant allele.

The Pro12Ala variant of peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) is associated with measures of obesity in Mexican Americans.

Peroxisome proliferator-activated receptors (PPAR) are transcription factors that regulate adipocyte differentiation and gene expression. We tested the hypothesis that the Pro12Ala variant of PPAR-gamma2 is associated with obesity and type 2 diabetes-related traits in 921 subjects from the San Antonio Family Heart Study. Subjects with at least one Ala allele (n=210) had significantly higher body mass index (P=0.015) and waist circumference (P=0.028) and significantly higher levels of serum leptin (P= 0.022) than those without the allele. Further studies will determine whether the Pro12Ala variant itself, or other genetic variation at PPAR-gamma, is responsible for this association with measures of obesity in Mexican Americans.

The Pro115Gln and Pro12Ala PPAR gamma gene mutations in obesity and type 2 diabetes.

OBJECTIVE: Peroxisome-proliferator-activated receptors gamma (PPAR gamma), is a key regulator of adipocyte differentiation and energy balance. Two naturally occurring mutations in the PPAR gamma gene, Pro115Gln and Pro12Ala, have recently been shown to impair the function of the PPAR gamma2 isoform of the receptor and to be associated with obesity or diabetes-related phenotypes in different populations. SUBJECTS: We studied the occurrence and possible associations of the Pro115Gln and Pro12Ala in the PPAR gamma2 gene with several clinical and metabolic phenotypes in three independent large populations of non-obese non-diabetic, type 2 diabetic, and morbidly obese French Caucasians. RESULTS: The Pro115Gln mutation was not found in any of the 1069 subjects screened including 626 obese patients. The frequency of the Pro12Ala mutation was similar in all groups (0.08, 0.11, 0.09) and was not associated with BMI or any of the clinical parameters tested. CONCLUSIONS: We conclude that the Pro115Gln mutation is not a frequent cause of morbid obesity in Caucasians and that the Pro12Ala mutation is not associated with clinically significant changes in these populations.

Analysis of the peroxisome proliferator activated receptor gamma (PPARgamma) gene in HAIRAN syndrome with obesity.

OBJECTIVES: To test the hypothesis that the triad of hyperandrogenism, insulin resistance and acanthosis nigricans (HAIRAN syndrome) in the presence of obesity, also known as type C insulin resistance, is caused by mutations in the gene for peroxisome proliferator activated receptor gamma (PPARgamma), a receptor for the thiazolidinedione drugs that enhance sensitivity to insulin. To investigate possible correlations between mutations in PPARgamma and the degree of insulin resistance. DESIGN: A candidate gene approach to study the molecular basis for a syndrome of obesity; a comparison of genotype with in vivo phenotype. PATIENTS: Fifteen unrelated patients with HAIRAN syndrome and obesity. Controls for the gene analysis: 25 unrelated non-diabetic non-obese individuals. Controls for the metabolic studies: six unrelated patients with type 2 diabetes mellitus and nine unrelated non-diabetic non-obese individuals. MEASUREMENTS: Analysis of polymerase chain reaction (PCR) products of the 7 exons that constitute the entire coding region of both PPARgamma isoforms (PPARgamma1 and PPARgamma2) for single-stranded conformational polymorphisms (SSCP); in exons with variant patterns: restriction fragment length polymorphism (RFLP) analysis; and, where relevant, direct sequencing. Evaluation of insulin resistance using the insulin euglycaemic clamp technique. RESULTS: A synonymous substitution in codon 477 (CACHis --> CATHis) was found in one patient. A missense mutation in codon 12 of PPARgamma2 (CCAPro --> GCAAla) was found in another patient, but not in any of 25 non-diabetic, non-obese control individuals. The patient with the Pro12Ala variant had the highest steady state glucose infusion rate (SSGIR) and most marked suppression of hepatic glucose production rate (HGPR) of all of the patients studied. CONCLUSIONS: Mutations in the PPARgamma gene are unlikely to be major contributors to HAIRAN syndrome with obesity. The Pro12Ala variant may correlate with a lesser degree of insulin resistance in these patients.

Exercise to prevent and treat diabetes mellitus.

Diabetes mellitus is a large and growing health problem in the United States, and as such constitutes a target for many health initiatives. Exercise provides beneficial effects on excess weight, insulin resistance, and atherosclerosis, making it an important tool to mitigate diabetes symptoms and sequelae.

Effect of the Pro12Ala variant of the human peroxisome proliferator-activated receptor gamma 2 gene on adiposity, fat distribution, and insulin sensitivity in Japanese men.

To examine the role of the Pro12Ala variant of the human PPARgamma2 gene on adiposity and insulin resistance, we studied the effect of the variant on fat distribution assessed by CT scan, plasma glucose, and insulin levels during a 75g oral glucose load in 215 non-diabetic Japanese men. The allele frequency of the variant was 0. 03 in this population. There were no differences in body mass index (BMI), subcutaneous fat area (S), visceral fat area (V), V/S ratio, fasting plasma insulin levels, or insulin resistance index in homeostatic model assessment between 203 subjects who were homozygous for the wild-type Pro12 allele and 12 subjects with the variant Ala12 allele (11 heterozygotes and one homozygote). These data suggest that the Pro12Ala variant is not a major contributor to adiposity, fat distribution, or insulin resistance in Japanese men.

Chromosomal localization and partial genomic structure of the human peroxisome proliferator activated receptor-gamma (hPPAR gamma) gene.

We determined the chromosomal localization and partial genomic structure of the coding region of the human PPAR gamma gene (hPPAR gamma), a nuclear receptor important for adipocyte differentiation and function. Sequence analysis and long PCR of human genomic DNA with primers that span putative introns revealed that intron positions and sizes of hPPAR gamma are similar to those previously determined for the mouse PPAR gamma gene[13]. Fluorescent in situ hybridization localized hPPAR gamma to chromosome 3, band 3p25. Radiation hybrid mapping with two independent primer pairs was consistent with hPPAR gamma being within 1.5 Mb of marker D3S1263 on 3p25-p24.2. These sequences of the intron/exon junctions of the 6 coding exons shared by hPPAR gamma 1 and hPPAR gamma 2 will facilitate screening for possible mutations. Furthermore, D3S1263 is a suitable polymorphic marker for linkage analysis to evaluate PPAR gamma's potential contribution to genetic susceptibility to obesity, lipoatrophy, insulin resistance, and diabetes.

Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation.

Peroxisome proliferator activated receptor-gamma (PPAR gamma) is a nuclear receptor that regulates adipocyte differentiation, and possibly lipid metabolism and insulin sensitivity. As such, PPAR gamma is a promising candidate gene for several human disorders including obesity and type 2 diabetes mellitus. Screening for mutations in the entire coding region of the PPAR gamma gene (both gamma 1 and gamma 2 isoforms) was performed with DNA of 26 diabetic Caucasians with or without obesity. Two base substitutions were identified: a silent mutation at nucleotide 1431 (CACHis-->CATHis) and a missense mutation (CCGPro-->GCGAla) at codon 12 of PPAR gamma 2. The allele frequency of the Pro12Ala PPAR gamma 2 variant was 0.12 in Caucasian Americans, 0.10 in Mexican Americans, 0.08 in Samoans, 0.03 in African Americans, 0.02 in Nauruans, and 0.01 in Chinese. We conclude that the Pro12Ala PPAR gamma 2 gene variant is present in diverse populations. Further studies of the Pro12Ala variant will determine its relevance to obesity, insulin resistance, and type 2 diabetes.

Ligature-induced peri-implant infection in cynomolgus monkeys. I. Clinical and radiographic findings.

The purpose of this study was to compare the effect of plaque accumulation in conjunction with or without placement of plaque-retaining ligatures on peri-implant and periodontal tissues. Four cynomolgus monkeys received 2 ITI (Type F) dental implants in edentulous areas of each side of the mandible. Following a healing period of 2 months with regular prophylaxis procedures twice per week, plaque was allowed to accumulate. After 1 month (day 0), silk ligatures were placed around 1 of the 2 implants. The third molars served as controls and were ligated as well. Clinical examinations comprising Plaque Index (PlI), Gingival Index (GI), probing depth (PD) and loss of attachment (LA) were performed at the test and control sites before and 1, 2, 3, 4, 5, 6, 7 and 8 months after ligature placement. Sixty and 30 days prior to ligation and at 2, 5, 6 and 8 months following ligation, standardized radiographs were obtained and subtracted from a baseline radiograph obtained at the time of ligation. PlI and GI scores increased significantly following the elimination of prophylaxis procedures. After ligation, these indices continued to increase and reached values significantly higher in ligated implant (LI) and ligated teeth (LT) sites than in non-ligated teeth (NLI) sites. PD also increased after plawue accumulation and ligature placement. Significantly greater PD values were noted in LI and LT sites than in NLI sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Colonisation with digoxin-reducing strains of Eubacterium lentum and Clostridium difficile infection in nursing home patients.

Stool specimens obtained from 77 residents of a nursing home were analysed to determine the relationship between colonisation with digoxin-reducing strains of Eubacterium lentum and infection with Clostridium difficile. Patients were categorised according to previous antibiotic treatment, prescription of enteral feedings, and pattern of bowel habits. Colonisation with digoxin-reducing E. lentum was less common in subjects infected with C. difficile, in those treated with antibiotics previously, and in those prescribed enteral feedings. Normal bowel habits were more common in those without C. difficile. The lowest incidence of diarrhoea was seen in patients without C. difficile who were colonised with digoxin-reducing species. This study establishes an inverse relationship between the presence of C. difficile and E. lentum that reduce digoxin which is related to previous treatment with antibiotics and prescription of enteral feedings. Bacterial markers may prove to be a useful tool for predicting clinical disturbances in bowel function.