Loss of hepatic PPARα promotes inflammation and serum hyperlipidemia in diet-induced obesity.

Agonists for PPARα are used clinically to reduce triglycerides and improve high-density lipoprotein (HDL) cholesterol levels in patients with hyperlipidemia. Whether the mechanism of PPARα activation to lower serum lipids occurs in the liver or other tissues is unknown. To determine the function of hepatic PPARα on lipid profiles in diet-induced obese mice, we placed hepatocyte-specific peroxisome proliferator-activated receptor-α (PPARα) knockout (PparaHepKO) and wild-type (Pparafl/fl) mice on high-fat diet (HFD) or normal fat diet (NFD) for 12 wk. There was no significant difference in weight gain, percent body fat mass, or percent body lean mass between the groups of mice in response to HFD or NFD. Interestingly, the PparaHepKO mice on HFD had worsened hepatic inflammation and a significant shift in the proinflammatory M1 macrophage population. These changes were associated with higher hepatic fat mass and decreased hepatic lean mass in the PparαHepKO on HFD but not in NFD as measured by Oil Red O and noninvasive EchoMRI analysis (31.1 ± 2.8 vs. 20.2 ± 1.5, 66.6 ± 2.5 vs. 76.4 ± 1.5%, P < 0.05). We did find that this was related to significantly reduced peroxisomal gene function and lower plasma ß-hydroxybutyrate in the PparaHepKO on HFD, indicative of reduced metabolism of fats in the liver. Together, these provoked higher plasma triglyceride and apolipoprotein B100 levels in the PparaHepKO mice compared with Pparafl/fl on HFD. These data indicate that hepatic PPARα functions to control inflammation and liver triglyceride accumulation that prevent hyperlipidemia.

A randomized controlled feasibility trial exploring partnered ballroom dancing for people with Parkinson's disease.

OBJECTIVE: To determine the feasibility of a Dance Centre delivering a programme of mixed dances to people with Parkinson's and identify suitable outcomes for a future definitive trial. DESIGN: A two-group randomized controlled feasibility trial. METHODS: People with Parkinson's were randomized to a control or experimental group (ratio 15:35), alongside usual care. In addition, participants in the experimental group danced with a partner for one hour, twice-a-week for 10 weeks; professional dance teachers led the classes and field-notes were kept. Control-group participants were given dance class vouchers at the end of the study. Blinded assessments of balance, mobility and function were completed in the home. Qualitative interviews were conducted with a subsample to explore the acceptability of dance. RESULTS: A total of 51 people with Parkinson's (25 male) with Hoehn and Yahr scores of 1-3 and mean age of 71 years (range 49-85 years), were recruited to the study. Dance partners were of similar age (mean 68, range 56-91 years). Feasibility findings focused on recruitment (target achieved); retention (five people dropped out of dancing); outcome measures (three measures were considered feasible, changes were recommended). Proposed sample size for a Phase III trial, based on the 6-minute walk test at six months was 220. Participants described dance as extremely enjoyable and the instructors were skilled in instilling confidence and motivation. The main organizational challenges for a future trial were transport and identifying suitable dance partners. CONCLUSION: We have demonstrated the feasibility of conducting the study through a Dance Centre and recommend a Phase III trial.

Demographic and mortality analysis of hospitalized children at a referral hospital in Addis Ababa, Ethiopia.

BACKGROUND: Global childhood mortality rates remain high. Millennium Development Goal 4 focused efforts on reducing rates by two-thirds between 1990 and 2015. In Ethiopia, child mortality rates dropped 71 % from 1990 to 2015, however it is estimated that 184,000 Ethiopian children die each year. There is limited information about pediatric hospital admissions in Ethiopia. Our aims were to examine the temporal relationship of mortality to admission, describe the demographics, and identify cause mortality of children admitted to the Zewditu Memorial Hospital (ZMH). METHODS: A four-year retrospective review of pediatric admissions was conducted at the pediatric emergency room and pediatric hospital ward at ZMH in Addis Ababa, Ethiopia. Admission entries from 2011-2014 of children age 29 days-14 years were reviewed. Age, gender, admission date, disease classification, discharge status and date were obtained. Patient gender was compared using Chi-square analysis. A descriptive analysis was used for age and cause mortality. RESULTS: A total of 6866 patient entries were reviewed. The proportion of admissions younger than age 5 was 0.747 (95 % CI 0.736-0.757). Overall mortality was 0.042 (95 % CI, 0.037-0.047). The proportion of recorded deaths occurring within 2 days of admission was 0.437 (95 % CI 0.380-0.494). The proportion of male admissions was significantly higher than female admissions in all age groups (male 0.575, p < 0.0001, 95 % CI 0.562-0.586). The main causes of mortality were pneumonia (0.253, 95 % CI, 0.203-0.303), severe acute malnutrition (0.222, 95 % CI 0.174-0.27), HIV/AIDS-related complications (0.056, 95 % CI 0.029-0.083), spina bifida (0.049, 95 % CI 0.024-0.074), and hydrocephalus (0.045, 95 % CI 0.021-0.069). CONCLUSIONS: Our study revealed a lower mortality rate than previously reported in Ethiopia. Despite this, 44 % of pediatric hospital mortality occurred early during hospitalization, higher than reported at other Ethiopian hospitals. This adds further evidence that systematic efforts should be dedicated to improve pediatric emergency care. Admissions included 58 % male patients, similar to other reports in Ethiopia implying that this may be a nation-wide phenomenon. The observed disparity may be due to societal factors regarding care-seeking behaviors or male predilection for respiratory illness warranting further investigation. Cause mortality patterns were similar to reports in analogous settings.

Eccentric Torque-Producing Capacity is Influenced by Muscle Length in Older Healthy Adults.

Considering the importance of muscle strength to functional capacity in the elderly, the study investigated the effects of age on isokinetic performance and torque production as a function of muscle length. Eleven younger (24.2 ± 2.9 years) and 16 older men (62.7 ± 2.5 years) were subjected to concentric and eccentric isokinetic knee extension/flexion at 60 and 120° · s(-1) through a functional range of motion. The older group presented lower peak torque (in newton-meters) than the young group for both isokinetic contraction types (age effect, p < 0.001). Peak torque deficits in the older group were near 30 and 29% for concentric and eccentric contraction, respectively. Concentric peak torque was lower at 120° · s(-1) than at 60° · s(-1) for both groups (angular velocity effect, p < 0.001). Eccentric knee extension torque was the only exercise tested that showed an interaction effect between age and muscle length (p < 0.001), which suggested different torque responses to the muscle length between groups. Compared with the young group, the eccentric knee extension torque was 22-56% lower in the older group, with the deficits being lower in the shortened muscle length (22-27%) and higher (33-56%) in the stretched muscle length. In older men, the production of eccentric knee strength seems to be dependent on the muscle length. At more stretched positions, older subjects lose the capacity to generate eccentric knee extension torque. More studies are needed to assess the mechanisms involved in eccentric strength preservation with aging and its relationship with muscle length.

Obesity Treatment in Orthopaedic Surgery.

According to the World Health Organization, obesity is a global health epidemic, which has nearly tripled in prevalence since 1975. Worldwide in 2016, 13% of adults 18 years and older had obesity (body mass index ≥ 30 kg/m2) and 39% were overweight (body mass index 25.0 to 29.9 kg/m2). In the United States, approximately 35% of adults have obesity and 31% are overweight. Obesity increases stress throughout the musculoskeletal system and carries a higher risk for the development of osteoarthritis and various other musculoskeletal conditions. When patients with obesity undergo orthopaedic procedures, weight loss is a critical aspect to appropriate preoperative counseling and treatment. Weight loss can improve obesity-related comorbidities such as metabolic syndrome, diabetes, cardiovascular disease, and obstructive sleep apnea, which in turn may reduce complications, minimize long-term joint stress, and improve outcomes among patients undergoing orthopaedic procedures. The effects of obesity on patients undergoing total joint arthroplasty has been previously described, with reported associations of increased risk of infection, revision, blood loss, venous thromboembolism, and overall costs. The purpose of this article was to provide orthopaedic surgeons with strategies for obesity treatment.

Going home to get on with life: patients and carers experiences of being discharged from hospital following a stroke.

PURPOSE: In this paper we aim to develop the understanding of what constitutes a 'good' or 'poor' experience in relation to the transition from hospital to home following a stroke. METHOD: Semi-structured interviews were carried out with 20 people and 13 carers within one month of being discharged from hospital following a stroke. Interviews covered views of mobility recovery and support from therapy and services. Interviews were transcribed verbatim, coded and analysed in depth in order to explore the discharge process. RESULTS: Participants described models of recovery, which involved a sense of momentum and getting on with their life. Discharge was successful if: (i) This sense of momentum was maintained, (ii) they felt supported, and (iii) they felt informed about what was happening. Discharge was seen as difficult when: (a) Momentum was perceived to be lost, (b) people did not feel supported, or (c) they felt in the dark about the plans or their recovery. CONCLUSIONS: The discharge experience could be improved by healthcare professionals understanding and exploring patients' individual models of recovery. This would allow professionals to: (a) Access patients concerns, (b) develop programmes addressing these, (c) correct misinterpretations, (d) keep people fully informed, and (e) share and validate the experience, to reduce their sense of isolation.

Resuming previously valued activities post-stroke: who or what helps?

PURPOSE: In this article, we aim to develop the understanding of what helps or hinders resumption of valued activities up to 12-months post-stroke. METHOD: As part of a longitudinal study, semi-structured interviews were conducted with 19 people with stroke and eight informal carers 12-months post-stroke. Interviews covered ongoing effects of stroke, experience of trying to resume activities highlighted as important pre-stroke and factors that influenced progress. Interviews were transcribed, coded and analysed in depth to explore this aspect of the experience of living with stroke. RESULTS: Valued activities discussed related to employment; domestic and social roles including driving; hobbies, sports and socialising. Outcomes for individuals were influenced by: aspects of physical or cognitive disability; environmental factors; the adaptability of the individual; support from others and professional help. Inability to resume activities impacted on people's sense of self and quality of life, but some tolerated change and presented themselves as adaptable. CONCLUSIONS: This study indicates a long-term role for rehabilitation services such as: identifying the significance of different types of activities; providing access to support and treatment for debilitating symptoms such as fatigue and dizziness; addressing patients' emotional and behavioural responses to their condition; working with patients' wider social networks and where appropriate, supporting adaptation to a changed way of life.

Morphometric evaluation of effects of two sex steroids on mammary gland of female rats.

OBJECTIVE: The purpose of this study was to evaluate the effects of two sex hormones on normal mammary gland of female rats. METHODS: Forty 250-day-old female rats, 20 of them with offspring and 20 not, were ovariectomized and, divided into 4 subgroups in order to receive one of the following subcutaneous treatment: estradiol benzoate (EB), medroxyprogesterone (MPA), EB+MPA or placebo, for 10 weeks. After treatment, mammary glands were studied with optical microscope. Whole gland, lobule, ductule and lumen compartments were evaluated by morphometric methods. Also a qualitative evaluation were performed seeking for secretion, microcalcification and trophic status. RESULTS: It was found that (a) MPA-only and placebo were similar for all parameters; (b) the same between EB and EB+MPA; (c) EB and EB+MPA increased lobule, ductule and lumen compartments significantly compared to MPA-only or placebo; (d) EB increased epithelium but without significance and EB+MPA increased it significantly compared to placebo or MPA; (e) EB and EB+MPA incremented secretion. CONCLUSIONS: In normal mammary gland of female rats: progestin action depends on estrogen presence. MPA does not revert estrogen-dependent proliferation, but it magnifies estradiol effect. Both EB and EB+MPA stimulate differentiation. Rats without offspring presented a greater epithelial proliferation under treatment with these sex hormones.

Clinical investigation of Duchenne muscular dystrophy. A methodology for therapeutic trials based on natural history controls.

Between 1979 and 1987 we documented the natural history of Duchenne muscular dystrophy in 170 patients, aged from 3 to 23 years, by making serial measurements in over 5000 individual evaluations. This database makes it possible to design and conduct therapeutic trials using natural history controls. Such trials do not replace the need for randomized placebo-controlled trials of promising agents but they do require fewer patients, are cost-effective, and permit the use of high-risk therapy where toxicity monitoring may be important. Natural history-controlled trials, therefore, may serve as a screening method for new therapeutic agents. Drugs showing a significant benefit can then be evaluated in a randomized controlled trial.

A comparison of daily and alternate-day prednisone therapy in the treatment of Duchenne muscular dystrophy.

We previously reported the results of a randomized, double-blind 6-month trial of prednisone therapy in which 102 boys aged 5 to 15 years with Duchenne muscular dystrophy received daily doses of 1.5 and 0.75 mg/kg per day and were compared with those receiving placebo. The strength and function in both prednisone-treated groups improved equally and were significantly better than in the placebo group. To compare alternate-day and daily dosing of prednisone with respect to benefits and adverse side effects, the placebo group was started on alternate-day prednisone therapy, and the treatment group regimens were changed to equivalent doses of alternate-day prednisone without breaking the double-blind nature. At the end of 6 months, the group that was changed from daily to alternate-day therapy had declined in strength back to levels observed 12 months previously, at the start of daily therapy. The group in which alternate-day therapy was started showed a significant improvement in strength at 3 months, similar in magnitude to the response of boys treated with daily therapy. However, their strength declined significantly in the subsequent 3 months compared with boys who received daily therapy. The frequency of side effects was not significantly different for alternate-day therapy compared with daily therapy. We conclude that alternate-day prednisone therapy effectively increases strength but does not sustain the improvement to the same extent as daily therapy or mitigate side effects.

Duchenne muscular dystrophy: patterns of clinical progression and effects of supportive therapy.

Two-hundred eighty-three boys with Duchenne dystrophy and 10 with Becker dystrophy have been followed for up to 10 years in a protocol that accurately measured their function, strength, contractures, and back curvature. Clinical heterogeneity is noted. Patients whose muscles were stronger were more likely to die from a cardiomyopathy. Weaker patients died from respiratory failure. A series of milestones is defined, which is of use in following the illness in an individual patient. This approach permits a scoring system that allows the severity of the disease to be defined in an individual boy. Evaluation of physical therapy and surgical intervention shows that night splints and scoliosis surgery are effective forms of treatment.

Duchenne dystrophy: randomized, controlled trial of prednisone (18 months) and azathioprine (12 months)

Prednisone has been shown to improve strength in Duchenne dystrophy. Azathioprine often benefits corticosteroid-responsive diseases and can reduce the dose of prednisone needed. The present study reports a randomized, controlled trial of prednisone and azathioprine designed to assess the longer-term effects of prednisone and to determine whether azathioprine alone, or in combination with prednisone, improves strength. Ninety-nine boys (aged five to 15 years) with Duchenne dystrophy were randomized to one of three groups: (I) placebo; (II) prednisone 0.3 mg/kg/d; or (III) prednisone 0.75 mg/kg/d. After 6 months, azathioprine 2 to 2.5 mg/kg/d was added in groups I and II and placebo added in group III. The study showed that the beneficial effect of prednisone (0.75 mg/kg/d) is maintained for at least 18 months and is associated with a 36% increase in muscle mass. There was weight gain, growth retardation, and other side effects. Azathioprine did not have a beneficial effect. This study suggests that prednisone's beneficial effect is not due to immunosuppression.

Long-term benefit from prednisone therapy in Duchenne muscular dystrophy.

Two successive, 6-month, randomized, double-blind, controlled trials of prednisone showed that 0.75 mg/kg/d was the optimal dose to improve strength in boys with Duchenne muscular dystrophy (DMD). We attempted to maintain 93 boys on that dose for an additional 2 years. During the 3 years of observation, the decline in average muscle strength scores of all boys taking prednisone was 0.072 units/yr, as compared with an expected decline of 0.341 units/yr from natural history controls. The occurrence of side effects in some boys prevented maintenance of the full dose, which may have lessened the response. At the time of last visit, dosages ranged from 0.15 mg/kg to 0.75 mg/kg. In addition to maintaining their strength, several of the boys actually improved their performance in lifting kilogram weights and in some timed function tests. Treatment of DMD with prednisone significantly slows the progression of weakness and loss of function for at least 3 years.

Evaluation of the roche AMPLICOR enterovirus PCR assay in the diagnosis of enteroviral central nervous system infections.

BACKGROUND: Enteroviruses cause a substantial number of cases of aseptic meningitis annually in the USA. While culture has been useful in the detection of patients with viral meningitis it is time-consuming and lacks sensitivity. Detection of viral nucleic acid in patient specimens has been demonstrated to improve enteroviral detection. OBJECTIVES: A research use only commercial amplification assay, the Roche AMPLICOR EV test, was compared to culture for the diagnosis of enteroviral meningoencephalitis. STUDY DESIGN: Four-hundred and sixty-five consecutive CSF samples sent prospectively for suspicion of enteroviral infection were evaluated by PCR and shell-vial culture. Clinical information and CSF analysis were used to resolve PCR positive, culture negative samples. Sensitivity and specificity were calculated using resolved data. RESULTS: There were 138 samples which met the definition of a true positive. Of these culture detected 77 (sensitivity 55.8%) and PCR detected 136 (sensitivity 98.6%). PCR missed two culture positive samples. Upon repeat testing, these CSF samples were found to contain inhibitors. CONCLUSIONS: The Roche AMPLICOR EV-PCR test was statistically more sensitive than culture (P<0.001) in the detection of enteroviruses in CSF in patients suspected of having enteroviral meningitis. This assay also has the advantage of a rapid turnaround time of 5-6 h compared to 3-5 days for culture.

Screening for dementia in the outpatient setting: the time and change test.

OBJECTIVE: To develop and validate the Time and Change (T&C) test, a simple, standardized method for detecting dementia in a diverse older outpatient population with varying levels of education. DESIGN: A prospective cohort validation study. SETTING: Two outpatient clinics at an urban teaching hospital. PARTICIPANTS: The concurrent validation sample consisted of 100 consecutive outpatients 70 years of age or older who were 58% non-white and had a 16% dementia prevalence rate and educational levels ranging from 0 to 17+ years. Reliability was tested in a sample of 42 consecutive outpatients 75 years of age or older with a 36% dementia prevalence rate. MEASUREMENTS: T&C ratings were validated against a reference standard based on the Blessed Dementia Rating Scale and the Mini-Mental State Examination. Reliability, contribution to physician recognition of dementia, and ease of use were assessed. RESULTS: In the outpatient setting, the T&C had a sensitivity of 63%, specificity of 96%, a negative predictive value of 93%, a positive predictive value of 77%, and test-retest and inter-observer reliability agreement rates of 95% and 100%, respectively. When T&C results were added to the physician's documentation of dementia, the number of missed cases decreased from 44% to 19%, and the number of overcalled cases decreased by 100%. When timed cut points were added, the T&C test had a sensitivity of 94 to 100%, specificity of 37 to 46%, negative predictive value of 98 to 100%, positive predictive value of 23 to 25%, and test-retest and inter-observer agreement rates of 82% and 70 to 75%, respectively. CONCLUSION: The T&C test is a simple, accurate, reliable, performance-based tool that can improve physician ability to recognize dementia in diverse outpatient populations.

Life-sustaining treatment and assisted death choices in depressed older patients.

OBJECTIVES: The major purpose of this study was to examine the effect of depressed mood in older, medically ill, hospitalized patients on their preferences regarding life-sustaining treatments, physician-assisted suicide (PAS), and euthanasia and to determine the degree to which financial constraints affected their choices. DESIGN: Cross-sectional study. SETTING: General medical hospital. PARTICIPANTS: One hundred fifty-eight medically hospitalized, nondemented patients age 60 or older, mean age 74.1 (range 60-94). The sample was divided, based on Center for Epidemiologic Studies-Depression (CES-D) scores, into a depressed group (n = 71) and a nondepressed control group. MEASUREMENTS: Subjects underwent a structured interview evaluating their life-sustaining treatment choices and whether they would accept or refuse PAS or euthanasia under a variety of hypothetical conditions. These choices were reevaluated with the introduction of financial impact. In addition, assessment included measures of depression, suicide, cognition, social support, functioning, and religiosity. RESULTS: Depression was found to be highly associated with acceptance of PAS and euthanasia in most hypothetical clinical scenarios in addition to patients' current condition. Compared with nondepressed people, depressed respondents were 13 times as likely to accept PAS when considering their current condition (95% confidence interval [CI] 1.68-110.98), and over twice as likely to accept PAS when facing a hypothetical terminal illness or coma. Depression alone was weakly associated with life-sustaining treatment choices but, when financial impact was introduced, significantly more depressed subjects refused treatment options they had previously desired than did nondepressed subjects. The presence of suicidal ideation, even passive ideation, was strongly predictive of life-sustaining treatment refusals and increased interest in PAS and euthanasia. Depression's effect on acceptance of PAS was confirmed by logistic regression, which also showed that religious coping was significantly correlated with less interest in PAS in two hypothetical scenarios. CONCLUSION. Depressed subjects and even subjects with subtle, passive suicidal ideation were markedly more interested in PAS and euthanasia than nondepressed subjects in hypothetical situations. Depressed subjects were also particularly vulnerable to rejecting treatments if financial consequences might have resulted.

Mismatches between the home environment and physical capabilities among community-living older persons.

OBJECTIVE: To determine whether environmental hazards related to transfers, balance, and gait are any less prevalent in the homes of older persons with specific deficits in physical capabilities than they are in the homes of older persons without the same deficits. DESIGN: Cross-sectional study of a population-based cohort. SETTING: The general community in New Haven, Connecticut. PARTICIPANTS: A total of 1088 persons, aged 72 years and older, who had an environmental assessment of their homes. MEASUREMENTS: Each participant underwent a physical performance assessment and comprehensive interview to document the presence of underlying deficits in physical capabilities. Items from the environmental assessment that were potentially hazardous for participants with specific deficits in transfers, balance, or gait were identified. RESULTS: With the exception of no grab bars in the tub/shower, environmental hazards were as prevalent in the homes of participants with specific deficits in physical capabilities as they were in the homes of participants without the same deficits, and, in many cases, they were actually more prevalent. Among participants with and without observed difficulty standing from a chair, for example, the prevalence of a low lying chair was 24% versus 14% (chi2 = 13.4; P < .001), respectively. Among participants with and without an observed deficit in turning, the prevalence of an obstructed pathway was 47% versus 37% (chi2 = 8.7; P = .003), respectively; and the prevalence of loose throw rugs was 72% in both groups. CONCLUSIONS: If the epidemiologic link between environmental hazards and adverse functional outcomes can be strengthened, then interventions designed to enhance the everyday function of frail, older persons should focus on the environment as well as the individual.

The time and change test: a simple screening test for dementia.

BACKGROUND: Although dementia screening tests are available, they have not gained widespread use in hospital or primary care settings. Our goal was to develop a simple, standardized, performance-based test incorporating real-world activities to augment screening efforts in older populations: the Time and Change (T&C) Test. METHODS: The study followed a prospective cohort design, involving medicine and surgery services at an urban teaching hospital. From consecutive admissions, 776 participants aged 70-98 years, 14% with dementia, were enrolled. T&C ratings were validated against a reference standard based on the modified Blessed Dementia Rating Scale and the Mini-Mental State Examination (MMSE). Convergent validity with other cognitive measures, test-retest agreement, and interobserver reliability were assessed. RESULTS: The T&C Test had a sensitivity of 86%, specificity of 71%, and negative predictive value of 97%. The T&C Test demonstrated convergent agreement with three cognitive measures, agreeing most strongly with the MMSE (r = .58). Test-retest and interobserver agreement rates were 88% and 78%, respectively. Education explained 3% of the variance of the T&C Test, compared with 13% of the MMSE. The T&C Test took a mean of 22.9 seconds to complete and was acceptable to participants. Refusal of any test component occurred in 39 individuals (5%). CONCLUSIONS: The T&C Test is a simple, accurate, reliable, performance-based tool for detection of dementia. With its quick, easy-to-use, real-world nature, we hope the T&C Test will be used for widespread cognitive screening in older populations.