The use and effectiveness of adaptive servo ventilation in central sleep apnea: a study of consecutive sleep clinic patients.

The use of adaptive servo ventilation to treat central sleep apnea in the clinical setting is incompletely understood and could be under-utilized. We reviewed our experience of adaptive servo ventilation use in patients with central sleep apnea. This study shows the effectiveness of adaptive servo ventilation in treating patients with central sleep apnea, irrespective of a predisposing factor, as assessed during a 4-week treatment trial. Results show that adaptive servo ventilation was effective and superior to continuous positive airway pressure in controlling central sleep apnea and improving symptoms. Only a small proportion of these patients had comorbid heart failure. Early treatment with adaptive servo ventilation may improve long-term adherence to therapy. These findings highlight the utility of adaptive servo ventilation in the management of central sleep apnea.

Patterns of use, survival and prognostic factors in patients receiving home mechanical ventilation in Western Australia: A single centre historical cohort study.

Home mechanical ventilation (HMV) is used in a wide range of disorders associated with chronic hypoventilation. We describe the patterns of use, survival and predictors of death in Western Australia. We identified 240 consecutive patients (60% male; mean age 58 years and body mass index 31 kg m-2) referred for HMV between 2005 and 2010. The patients were grouped into four categories: motor neurone disorders (MND; 39%), pulmonary disease (PULM; 25%, mainly chronic obstructive pulmonary disease), non-MND neuromuscular and chest wall disorders (NMCW; 21%) and the obesity hypoventilation syndrome (OHS; 15%). On average, the patients had moderate ventilatory impairment (forced vital capacity: 51%predicted), sleep apnoea (apnoea-hypopnea index: 25 events h-1), sleep-related hypoventilation (transcutaneous carbon dioxide rise of 20 mmHg) and daytime hypercarbia (PCO2: 54 mmHg). Median durations of survival from HMV initiation were 1.0, 4.2, 9.9 and >11.5 years for MND, PULM, NMCW and OHS, respectively. Independent predictors of death varied between primary indications for HMV; the predictors included (a) age in all groups except for MND (hazard ratios (HRs) 1.03-1.10); (b) cardiovascular disease (HR: 2.35, 95% confidence interval (CI): 1.08-5.10) in MND; (c) obesity (HR: 0.28, 95% CI: 0.13-0.62) and oxygen therapy (HR: 0.33, 95% CI: 0.14-0.79) in PULM; and (d) forced expiratory volume in 1 s (%predicted; HR: 0.93, 95% CI: 0.88-1.00) in OHS.

Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models.

RATIONALE: Studies have demonstrated that angiotensin-converting enzyme 2 (ACE2) plays a protective role against lung diseases, including pulmonary hypertension (PH). Recently, an antitrypanosomal drug, diminazene aceturate (DIZE), was shown to exert an "off-target" effect of enhancing the enzymatic activity of ACE2 in vitro. OBJECTIVES: To evaluate the pharmacological actions of DIZE in experimental models of PH. METHODS: PH was induced in male Sprague Dawley rats by monocrotaline, hypoxia, or bleomycin challenge. Subsets of animals were simultaneously treated with DIZE. In a separate set of experiments, DIZE was administered after 3 weeks of PH induction to determine whether the drug could reverse PH. MEASUREMENTS AND MAIN RESULTS: DIZE treatment significantly prevented the development of PH in all of the animal models studied. The protective effects were associated with an increase in the vasoprotective axis of the lung renin-angiotensin system, decreased inflammatory cytokines, improved pulmonary vasoreactivity, and enhanced cardiac function. These beneficial effects were abolished by C-16, an ACE2 inhibitor. Initiation of DIZE treatment after the induction of PH arrested disease progression. Endothelial dysfunction represents a hallmark of PH pathophysiology, and growing evidence suggests that bone marrow-derived angiogenic progenitor cells contribute to endothelial homeostasis. We observed that angiogenic progenitor cells derived from the bone marrow of monocrotaline-challenged rats were dysfunctional and were repaired by DIZE treatment. Likewise, angiogenic progenitor cells isolated from patients with PH exhibited diminished migratory capacity toward the key chemoattractant stromal-derived factor 1α, which was corrected by in vitro DIZE treatment. CONCLUSIONS: Our results identify a therapeutic potential of DIZE in PH therapy.

Carbon-11-Pittsburgh compound B positron emission tomography imaging of amyloid deposition in presenilin 1 mutation carriers.

(11)Carbon-Pittsburgh compound B positron emission tomography studies have suggested early and prominent amyloid deposition in the striatum in presenilin 1 mutation carriers. This cross-sectional study examines the (11)Carbon-Pittsburgh compound B positron emission tomography imaging profiles of presymptomatic and mildly affected (mini-mental state examination ≥ 20) carriers of seven presenilin 1 mutations, comparing them with groups of controls and symptomatic sporadic Alzheimer's disease cases. Parametric ratio images representing (11)Carbon-Pittsburgh compound B retention from 60 to 90 min were created using the pons as a reference region and nine regions of interest were studied. We confirmed that increased amyloid load may be detected in presymptomatic presenilin 1 mutation carriers with (11)Carbon-Pittsburgh compound B positron emission tomography and that the pattern of retention is heterogeneous. Comparison of presenilin 1 and sporadic Alzheimer's disease groups revealed significantly greater thalamic retention in the presenilin 1 group and significantly greater frontotemporal retention in the sporadic Alzheimer's disease group. A few individuals with presenilin 1 mutations showed increased cerebellar (11)Carbon-Pittsburgh compound B retention suggesting that this region may not be as suitable a reference region in familial Alzheimer's disease.

Conceptualizing the benefits of a group exercise program developed for those with chronic fatigue: a mixed methods clinical evaluation.

PURPOSE: Fatigue is a disabling and prevalent feature of many long-term conditions. Orthostatic dizziness is a commonly experienced by those with fatigue. The purpose was; to evaluate factors contributing to successful delivery of a novel group exercise program designed for people with chronic fatigue and orthostatic symptoms and identify targets to improve future program content and delivery. RESEARCH METHODS: We used group concept mapping methodology. Participants of the exercise program with a long-term physical health condition and chronic fatigue- contributed ideas in response to a focus question. They sorted these ideas into themed piles and rated them for importance and success of the program delivery. Multidimensional scaling and cluster analysis were applied to the sort data to produce ideas clusters within a concept map. Value ratings were compared to evaluate the success of the program. RESULTS: The resulting concept map depicted seven key themed clusters of ideas: Exercises, Group atmosphere, Physical benefits, Self-management of symptoms, Acceptance and Education. Value plots of the rating data identified important and successful conceptual ideas. CONCLUSIONS: The concept maps have depicted key concepts relating to the successful delivery of a novel exercise program for people with fatigue and identified specific targets for future program enhancements.Implications for rehabilitationOrthostatic symptoms are common in those with fatigue and might be a target for group-based exercise programs.People with fatigue value a group-based exercise program that targets orthostatic symptoms.The key concepts of a group-based exercise program valued by those with fatigue are the exercises, group atmosphere, physical benefits, self-management support, acceptance, education and support with looking forwards following the program.

Parkinson's Disease and Current Treatments for Its Gastrointestinal Neurogastromotility Effects.

PURPOSE OF REVIEW: Gastrointestinal disturbances are seen in nearly all patients with Parkinson's disease and lead to impaired quality of life, affect drug pharmacodynamics, and potentially worsen patient's existing motor fluctuations, leading to further disability. Recent evidence links abnormal accumulations of α-synuclein aggregates in the periphery (gut) as seen in the cortex which causes dysfunctions impacting every level of the gastrointestinal tract from the esophagus, to the stomach, small bowel, colon, and rectum and can even predate the onset of the central neurologic disorder itself. Many treatments exist for the clinical phenotypes that result from the autonomic dysfunction and neuropathy involved in this neurodegenerative disorder. The treatments for the gut dysfunction seen in Parkinson's disease (PD) depend on the specific area of the gastrointestinal tract affected. For dysphagia, behavioral therapies with speech pathology, neuromuscular electrical stimulation, or botulinum toxin injection may be helpful. For gastroparesis, domperidone may serve as an antiemetic while also blunting the hypotensive potential of Levodopa while new treatments such as ghrelin agonists may prove beneficial to help appetite, satiety, gastric emptying in those with constipation, and even improve constipation. Antibiotics such as rifaximin with poor systemic absorption may be used to treat small bacterial overgrowth also found in those with PD while the benefits of probiotics is yet to be determined. Finally, constipation in PD can be a reflection of pelvic floor dyssynergia, slow transit constipation, or both, thus treatments targeting the specific anorectal dysfunction is necessary for better outcomes.

A double-blind placebo-controlled cross-over clinical trial of DONepezil In Posterior cortical atrophy due to underlying Alzheimer's Disease: DONIPAD study.

BACKGROUND: The study investigated whether donepezil exerts symptomatic benefit in patients with posterior cortical atrophy (PCA), an atypical variant of Alzheimer's disease. METHODS: A single-centre, double-blind, placebo-controlled, cross-over clinical trial was performed to assess the efficacy of donepezil in patients with PCA. Each patient received either donepezil (5 mg once daily in the first 6 weeks and 10 mg once daily in the second 6 weeks) or placebo for 12 weeks. After a 2-week washout period, each patient received the other treatment arm during the following 12 weeks followed by another 2-week washout period. The primary outcome was the Mini-Mental State Examination (MMSE) at 12 weeks. Secondary outcome measures were five neuropsychological tests reflecting parieto-occipital function. Intention-to-treat analysis was used. For each outcome measure, carry-over effects were first assessed. If present, then analysis was restricted to the first 12-week period. Otherwise, the standard approach to the analysis of a 2 × 2 cross-over trial was used. RESULTS: Eighteen patients (13 females) were recruited (mean age 61.6 years). There was a protocol violation in one patient, who subsequently withdrew from the study due to gastrointestinal side effects. There was statistically significant (p < 0.05) evidence of a carry-over effect on MMSE. Therefore, the analysis of treatment effect on MMSE was restricted to the first 12-week period. Treatment effect at 6 weeks was statistically significant (difference = 2.5 in favour of donepezil, 95% CI 0.1 to 5.0, p < 0.05). Treatment effect at 12 weeks was close, but not statistically significant (difference = 2.0 in favour of donepezil, 95% CI -0.1 to 4.5, p > 0.05). There were no statistically significant treatment effects on any of the five neuropsychological tests, except for digit span at 12 weeks (higher by 0.5 digits in favour of placebo, 95% CI 0.1 to 0.9). Gastrointestinal side effects occurred most frequently, affecting 13/18 subjects (72%), and were the cause of study discontinuation in one subject. Nightmares and vivid dreams occurred in 8/18 subjects (44%), and were statistically more frequent during treatment with donepezil. CONCLUSIONS: In this small study, there was no statistically significant treatment effect of donepezil on the primary outcome measure (MMSE score at 12 weeks) in PCA patients, who appear to be particularly susceptible to the development of nightmares and vivid dreams when treated. TRIAL REGISTRATION: Trial registration: Current Controlled Trials ISRCTN22636071 . Retrospectively registered 19 May 2010.

The relationship between vital exhaustion, depression and comorbid illnesses in patients following first myocardial infarction.

OBJECTIVE: Vital exhaustion and depression are both independent risk factors for cardiovascular disease, yet the relationship between these highly similar dimensions remains unclear. We have examined the association between depression and vital exhaustion and investigated the extent to which any association is the result of comorbid illnesses. METHODS: Three hundred and five consecutive patients were examined on average 3.6 days following hospital admission with first myocardial infarction (MI). The Maastricht Questionnaire (MQ; vital exhaustion) was administered together with the Hospital Anxiety and Depression Scale (HADS), and details of comorbid physical illness were recorded. The factor structure of the MQ was explored using factor analysis. RESULTS: Depression and vital exhaustion were highly correlated (r=.61, P<.01). This correlation did not diminish on controlling for age, sex, and comorbidity (r=.59, P<.01). Factor analysis of MQ score gave a four-factor solution: fatigue (18.2% of variance), depression (17.9%), lack of concentration (9.5%), and sleep difficulties (8.1%). The fatigue dimension of the MQ remained highly associated with HADS depression score (r=.50, P<.01), controlling for age, sex, and comorbidity. CONCLUSIONS: Depression and fatigue are highly correlated and their association is not attributable to comorbid physical illnesses or the tendency of the MQ to measure depression. Future studies should investigate fatigue instead of vital exhaustion as a potential risk factor for poor cardiac prognosis independent of the influence of depression.

Bone marrow-CNS connections: implications in the pathogenesis of diabetic retinopathy.

Diabetic retinopathy is the fourth most common cause of blindness in adults. Current therapies, including anti-VEGF therapy, have partial efficacy in arresting the progression of proliferative diabetic retinopathy and diabetic macular edema. This review provides an overview of a novel, innovative approach to viewing diabetic retinopathy as the result of an inflammatory cycle that affects the bone marrow (BM) and the central and sympathetic nervous systems. Diabetes associated inflammation may be the result of BM neuropathy which skews haematopoiesis towards generation of increased inflammatory cells but also reduces production of endothelial progenitor cells responsible for maintaining healthy endothelial function and renewal. The resulting systemic inflammation further impacts the hypothalamus, promoting insulin resistance and diabetes, and initiates an inflammatory cascade that adversely impacts both macrovascular and microvascular complications, including diabetic retinopathy (DR). This review examines the idea of using anti-inflammatory agents that cross not only the blood-retinal barrier to enter the retina but also have the capability to target the central nervous system and cross the blood-brain barrier to reduce neuroinflammation. This neuroinflammation in key sympathetic centers serves to not only perpetuate BM pathology but promote insulin resistance which is characteristic of type 2 diabetic patients (T2D) but is also seen in T1D. A case series of morbidly obese T2D patients with retinopathy and neuropathy treated with minocycline, a well-tolerated antibiotic that crosses both the blood-retina and blood-brain barrier is presented. Our results indicates that minocycine shows promise for improving visual acuity, reducing pain from peripheral neuropathy, promoting weight loss and improving blood pressure control and we postulate that these observed beneficial effects are due to a reduction of chronic inflammation.

Direct, quantitative clinical assessment of hand function: usefulness and reproducibility.

Methods of assessing functional impairment in arthritic hands include pain assessments and disability scoring scales which are subjective, variable over time and fail to take account of the patients' need to adapt to deformities. The aim of this study was to evaluate measures of functional strength and joint motion in the assessment of the rheumatoid (RA) and osteoarthritic (OA) hand. Ten control subjects, ten RA and ten OA patients were recruited for the study. All underwent pain and disability scoring and functional assessment of the hand using measures of pinch/grip strength and range of joint motion (ROM). Functional assessments including ROM analyses at interphalangeal (IP), metacarpophalangeal (MCP) and wrist joints along with pinch/grip strength clearly discriminated between patient groups (RA vs. OA MCP ROM P<0.0001), pain and disability scales were unable to. In the RA there were demonstrable relationships between ROM measurements and disability (R2=0.31) as well as disease duration (R2=0.37). Intra-patient measures of strength were robust whereas inter-patient comparisons showed variability. In conclusion, pinch/grip strength and ROM are clinically reproducible assessments that may more accurately reflect functional impairment associated with arthritis.

Association between depressive episode before first myocardial infarction and worse cardiac failure following infarction.

Depression following myocardial infarction is associated with a higher mortality rate. The authors studied 314 patients admitted to the hospital with a first myocardial infarction to assess whether cardiac failure after the infarction, which is also linked to a higher mortality rate, was predicted by psychosocial characteristics present before the myocardial infarction. One-fifth (20.7%) of the subjects met the ICD-10 criteria for depressive episode in the 1 month before the attack. Variables independently associated with worse cardiac failure after the myocardial infarction were greater age, a history of angina preceding the infarction, and a previous depressive episode. The impact of depression on postinfarction outcome may result from the influence of preinfarction depression on the degree of cardiac failure.