Social stress is lethal in the mdx model of Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is caused by the loss of dystrophin. Severe and ultimately lethal, DMD progresses relatively slowly in that patients become wheelchair bound only around age twelve with a survival expectancy reaching the third decade of life. METHODS: The mildly-affected mdx mouse model of DMD, and transgenic DysΔMTB-mdx and Fiona-mdx mice expressing dystrophin or utrophin, respectively, were exposed to either mild (scruffing) or severe (subordination stress) stress paradigms and profiled for their behavioral and physiological responses. A subgroup of mdx mice exposed to subordination stress were pretreated with the beta-blocker metoprolol. FINDINGS: Subordination stress caused lethality in ∼30% of mdx mice within 24 h and ∼70% lethality within 48 h, which was not rescued by metoprolol. Lethality was associated with heart damage, waddling gait and hypo-locomotion, as well as marked up-regulation of the hypothalamus-pituitary-adrenocortical axis. A novel cardiovascular phenotype emerged in mdx mice, in that scruffing caused a transient drop in arterial pressure, while subordination stress caused severe and sustained hypotension with concurrent tachycardia. Transgenic expression of dystrophin or utrophin in skeletal muscle protected mdx mice from scruffing and social stress-induced responses including mortality. INTERPRETATION: We have identified a robust new stress phenotype in the otherwise mildly affected mdx mouse that suggests relatively benign handling may impact the outcome of behavioural experiments, but which should also expedite the knowledge-based therapy development for DMD. FUNDING: Greg Marzolf Jr. Foundation, Summer's Wish Fund, NIAMS, Muscular Dystrophy Association, University of Minnesota and John and Cheri Gunvalson Trust.

Is functional mobility an independent mortality risk factor in subjects with dementia?

OBJECTIVE: To investigate whether functional mobility is a predictor of 12-month mortality in elderly subjects with dementia. STUDY DESIGN: Prospective multicentre study performed in nine French university hospitals. Patients aged 75 years or more and hospitalised in medical wards via the emergency department were eligible. Those with a diagnosis of dementia were considered in the analyses. MAIN OUTCOME MEASURES: Patients' characteristics obtained through comprehensive geriatric assessment performed during the first week of hospitalisation. Functional mobility was assessed using the timed "Up & Go" test. The main outcome was time to death within the 12 months of follow-up. Bivariable relationships between each risk factor and mortality were assessed using a Cox regression model with one explanatory variable. For multivariable analysis, the Cox regression model was used in a stepwise method after examining potential confounders and interactions. RESULTS: In all, 589 patients had a diagnosis of dementia, and were considered in the present analyses. Their mean age was 86±6years and most (69%) were female. The prevalence of functional mobility disorders was 86%. After 12 months, 232 (39%) had died. After adjustment for potential confounders, functional mobility was associated with a significantly higher risk of 12-month mortality (HR=1.66; 95% CI=1.02-2.71; p=0.04). CONCLUSIONS: Impaired functional mobility as assessed by the timed Up & Go test identifies subjects with dementia at risk of unfavourable outcome.

Revisit, Subsequent Hospitalization, Recurrent Fall, and Death Within 6 Months After a Fall Among Elderly Emergency Department Patients.

STUDY OBJECTIVE: We seek to describe the risk during 6 months and specific risk factors for recurrent falls, emergency department (ED) revisits, subsequent hospitalizations, and death within 6 months after a fall-related ED presentation. METHODS: This was a secondary analysis of a retrospective cohort of elderly fall patients who presented to the ED from one urban teaching hospital. We included patients aged 65 years and older who had an ED fall visit in 2012. We examined the frequency and risk factors of adverse events (composite of recurrent falls, ED revisits, subsequent hospitalization, and death, selected a priori) at 6 months. RESULTS: Our study included 350 older adults. Adverse events steadily increased, from 7.7% at 7 days, 21.4% at 30 days, and 50.3% at 6 months. Within 6 months, 22.6% of patients had at least one recurrent fall, 42.6% revisited the ED, 31.1% had subsequent hospitalizations, and 2.6% died. In multivariable logistic regression analysis, psychological or sedative drug use predicted recurrent falls, ED revisits, subsequent hospitalizations, and adverse events. CONCLUSION: More than half of fall patients had an adverse event within 6 months of presenting to the ED after a fall. The risk during 6 months of these adverse events increased with psychological or sedative drug use. Larger future studies should confirm this association and investigate methods to minimize recurrent falls through management of such medications.

Ten year survival and outcomes in a prospective cohort of new onset Chinese Parkinson's disease patients.

OBJECTIVE: The 10 year outcomes and impact of motor and non-motor features on survival of a cohort of new onset Chinese Parkinson's disease (PD) patients were prospectively studied. METHOD: A cohort of new onset PD patients from 1995 to 2002 was recruited from a regional hospital based movement disorder clinic. Subjects were classified into postural instability gait disorder (PIGD), tremor predominant type or mixed subtypes at presentation. All were evaluated yearly for development of sensory complaints, first significant fall, hallucinations, dementia, postural hypotension, speech disturbances, dysphagia and postural instability persisted during 'on' medication state (PIPon). Mortality and predictors of death were determined. RESULTS: 171 new onset PD patients were recruited. After a mean follow-up of 11.3±2.6 years, 50 (29%) patients died. The standardised mortality ratio was 1.1 (CI 0.8 to 1.5, p=0.34). 83 (49%) developed dementia, 81 (47%) had psychosis and 103 (60%) had sensory complaints. Postural hypotension was found in 58 (34%) patients, 108 (63%) had PIPon, 101 (59%) had falls, 102 (60%) had dysphagia, 148 (87%) had freezing of gait and 117 (68%) had speech disturbances. 46 (27%) were institutionalised whereas 54 (32%) lived independently. Dementia (HR 5.0, 95% CI 2.1 to 13.0), PIPon (HR 2.8, 95% CI 1.2 to 6.8), older onset (HR 1.05, 1 year increase in age, 95% CI 1.0 to 1.1) and PIGD type (HR 2.1, 95% CI 1.2 to 3.7) were independent predictors of death. CONCLUSIONS: 10 years into PD, a significant proportion of patients developed dopa resistant motor and non-motor features. Older onset, PIGD type, PIPon and dementia had a negative impact on survival. Standardised mortality ratio was 1.1.

Mortality associated with acute Charcot foot and neuropathic foot ulceration.

OBJECTIVE: To compare the mortality of patients with an acute Charcot foot with a matched population with uninfected neuropathic foot ulcers (NFUs). RESEARCH DESIGN AND METHODS: Data were extracted from a specialist departmental database, supplemented by hospital records. The findings were compared with the results of earlier populations with Charcot foot and uninfected NFUs managed from 1980. Finally, the results of all patients with acute Charcot foot and all control subjects managed between 1980 and 2007 were compared with normative mortality data for the U.K. population. RESULTS: A total of 70 patients presented with an acute Charcot foot (mean age 57.4 +/- 12.0 years; 48 male [68.6%]) between 2001 and 2007; there were 66 matched control subjects. By 1 October 2008, 13 (eight male; 18.6%) patients with a Charcot foot had died, after a median of 2.1 years (interquartile range 1.1-3.3). Twenty-two (20 male; 33.3%) control subjects had also died after a median of 1.3 years (0.6-2.5). There was no difference in survival between the two groups (log-rank P > 0.05). Median survival of all 117 patients with acute Charcot foot managed between 1980 and 2007 was 7.88 years (4.0-15.4) and was not significantly different from the control NFU patients (8.43 years [3.4-15.8]). When compared with normative U.K. population data, life expectancy in the two groups was reduced by 14.4 and 13.9 years, respectively. CONCLUSIONS: These data confirm that the mortality in patients presenting to our unit with either an acute Charcot foot and an uninfected neuropathic ulcer was unexpectedly high.

Falls and the falls efficacy scale in Parkinson's disease.

The purpose of this study was to investigate the relationship between fear of falling and fall frequency among patients with idiopathic Parkinson's disease (PD). One hundred-two participants with idiopathic PD were interviewed and examined. Participants reported the number of falls they had experienced in the preceding 3 months. They completed a mini-mental state exam (MMSE) and the falls efficacy scale (FES) questionnaire. Disease severity was determined by clinical examination using the Hoehn-Yahr staging system. Excluding two outliers who fell more than once each day, the subjects fell an average of 1.2 times in a 3 month period. There was a positive correlation between the number of falls, freezing of gait and Hoehn-Yahr score, and a negative correlation with the MMSE. In a post-hoc analysis the participants were divided into four groups based on fall frequency. The outliers had the lowest FES scores on average, similar to the scores seen in the rare fallers group. This study suggests that many factors are associated with fear of falling, including fall frequency, disease severity, and mental status. In the present study, the patients who fell the most often did not report the most fear. The lack of fear of falling but frequent falls in this small subgroup may suggest that special techniques to instill suitable caution to prevent falls are necessary, or may make training of these patients impossible.

Sustained sensorimotor impairments after endothelin-1 induced focal cerebral ischemia (stroke) in aged rats.

Despite recent advances, stroke remains a leading cause of neurological disability with the vast majority of victims being the elderly, who exhibit more severe neurological deficits and a reduced capacity to recover from these disabilities in comparison to young stroke survivors. The objective of the present study was to develop a model of focal ischemic stroke in aged rats using endothelin-1 (ET-1) to produce low mortality rates as well as reliable, robust sensorimotor deficits that resemble functional impairments associated with stroke in humans. Here, we studied the functional and histological outcome following unilateral ET-1 infusions into the sensorimotor cortex of aged rats (20-23 months old). This procedure resulted in low mortality rates (13.3%) and no loss in body weight one week following surgery. Functional assessment was performed using a number of reliable behavioural tests: staircase test (fine motor function), horizontal ladder (skilled locomotion), bilateral tactile stimulation test (somatosensory function) and cylinder test (postural weight support). Following ET-1 induced stroke, all tests demonstrated large and sustained sensorimotor deficits in both forelimb and hindlimb function that failed to improve over the 28-day testing period. In addition, histological assessment revealed a substantial loss of retrogradely labelled corticospinal neurons in the ipsilesional hemisphere following stroke. Our results establish a model for the use of aged rats in future preclinical studies, which will enhance assessment of the long-term benefit of potential neural repair and regenerative strategies.

Morbidity and mortality in patients with cancer who become nonambulatory after spinal cord compression: a case series on end-of-life care.

BACKGROUND: Few studies have focused on the outcomes of nonambulatory patients diagnosed with spinal cord compression from metastatic cancer. The purpose of this study was to review the morbidity and mortality suffered by these patients. METHODS: Over a 10-year period (1996-2006), a retrospective review was undertaken to assess the outcomes of 39 nonambulatory patients diagnosed with spinal cord compression from metastatic cancer. RESULTS: Treatment for cord compression included corticosteroids (n = 33), radiation (n = 25), and surgical decompression (n = 13). Nonetheless, 23 patients (59%) required bowel and/or bladder catheterization, and 33 (85%) required pain medications. Twenty-five (64%) did not regain ambulation. Only 13 patients (33%) went home without assistance. In contrast, 10 (26%) were transferred to a nursing home, 6 (15%) were sent home with hospice, 5 (13%) went home with home health care, and 1 (3%) was moved to a hospice inpatient facility. At the time of this report, all patients had died with a median survival of 76 days (range, 4-1975 days). Long-term survivors who lived beyond a year were primarily patients who had regained ambulation. CONCLUSION: Metastatic cord compression causes severe morbidity and compromised survival in patients who become nonambulatory. Future palliative care efforts should focus on further characterizing and addressing these needs.

Change in frailty and risk of death in older persons.

The authors developed and validated a continuous composite measure of frailty and examined its rate of change in 832 older persons with annual evaluations for up to 8 years. In generalized estimating equation models adjusted for age, sex, and education, there was a significant increase in frailty during follow-up. In a proportional hazards model controlling for age, sex, education, and baseline frailty, each 1-unit increase in annual change in frailty was associated with an almost 5 times the risk of mortality. Using a continuous measure, the authors document that frailty is progressive in some older persons and that its rate of progression is associated with mortality.

Progression of gait disorder and rigidity and risk of death in older persons.

BACKGROUND: Bradykinesia, gait disturbance, rigidity, and tremor are common motor signs in old age. All of these signs are associated with increased morbidity and mortality, but the extent to which they are progressive is unknown. METHODS: Study participants were 787 older Catholic clergy members without clinically diagnosed PD, related conditions, or dementia at baseline. They were evaluated annually for up to 7 years, with >95% follow-up participation by survivors. Evaluations included administration of a modified version of the motor portion of the Unified PD Rating Scale (UPDRS), from which previously established measures of the global UPDRS and four specific motor signs were derived. Scores represent the percent of the total possible UPDRS score obtained. RESULTS: At baseline, the global UPDRS score ranged from 0 to 36.3 (mean +/- SD, 7.3 +/- 6.4). It increased by an average of 0.69 unit per year during follow-up, with more rapid progression in older persons, but there was wide variability with no progression in 21% of subjects and annual increases of up to 8.23 units in the remaining 79%. Of 129 persons who died, 106 had follow-up UPDRS data. In a proportional hazards model, risk of death was associated with both the level of the global UPDRS score at baseline and the annual rate of progression (both p < 0.001). Overall, risk of death in subjects who had some worsening of the global UPDRS score was 2.93 times the rate among those without progression (95% CI, 1.32-6.50). Gait disorder/postural reflex impairment and rigidity worsened, but bradykinesia and tremor did not. Risk of death was associated with worsening of gait/posture but not with the other signs. CONCLUSION: Gait disorder and rigidity, as assessed with the modified UPDRS, are usually progressive in old age. Both the severity of the gait disorder and its rate of progression are strongly associated with risk of death.

Falls in the elderly. I. Identification of risk factors.

Falls severely threaten the health of elderly persons and pose high costs to the public health service. Unfortunately, falls are often regarded as unavoidable and untreatable features of aging. Therefore, many clinicians merely treat the physical injuries of a fall. However, falls and gait limitations are markers of underlying (sometimes otherwise subclinical) diseases that can be amenable to treatment. Moreover, falls and gait limitations herald the onset of repeated falls, physical decline, serious psychosocial consequences and a reduced survival. We review how clinically relevant risk factors can be traced by reviewing the medical notes, by careful history taking and by physical examination. The identified risk factors can serve as a template for the design of prevention strategies, which are discussed in the companion article.