Examination of pituitary adenylate cyclase-activating polypeptide in Parkinson’s disease focusing on correlations with motor symptoms

GeroScience - The neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) have been shown in numerous in vitro and in vivo models of Parkinson’s disease (PD)...     

Late-Onset Suicide: A Dementia Prodrome?

ObjectivesThis study examined whether late-onset (versus early-onset) suicidal behavior is associated with worse cognition.MethodsParticipants included 278 adults aged 50+ years (56 nonpsychiatric comparison group; 67 nonsuicidal depressed older adults; 63 depressed suicide ideators; and 44 late-onset (55+ years) and 48 early-onset suicide attempters (<55 years). Using a case-control design, this study examined group differences in global cognition, episodic memory, information processing speed, and executive functioning, assessed using the Repeatable Battery of Neuropsychological Status and the Trail Making Test from the Delis-Kaplan Executive Function System. Linear regression was used for data analyses.ResultsBoth attempter groups displayed worse executive functioning than nonsuicidal depressed older adults. Late-onset attempters additionally displayed poorer global cognition and processing speed than nonsuicidal depressed older adults and poorer memory than early-onset attempters.ConclusionsLate-onset suicidal behavior is associated with worse performance in a broad range of cognitive domains, possibly reflective of a dementia prodrome.     

Bradykinin and angiotensin-converting enzyme inhibition in cardioprotection

OBJECTIVES:

To show that angiotensin-converting enzyme (ACE) inhibition potentiates subthreshold ischemic preconditioning (IPC) via the elevation of bradykinin activity, leading to a fully delayed cardioprotective response.

METHODS:

On day 1 of the experiment, pigs were subjected to sham (group 1, controls) or IPC protocols. In groups 2 and 3, 4×5 min and 2×2 min of IPC, respectively, were elicited by occluding the left anterior descending coronary artery with percutaneous transluminal coronary angioplasty inflatable balloon catheter. Group 4 was subjected to the ACE inhibitor perindoprilate only. In group 5, the pigs were pretreated with perindoprilate (0.06 mg/kg) and then subjected to 2×2 min IPC. In group 6, intracoronary HOE 140 (a selective bradykinin B₂ receptor antagonist) was added before the perindoprilateaugmented subthreshold (2×2 min) PC stimulus. On the second day, all animals underwent 40 min left anterior descending coronary artery ligation and 3 h reperfusion, followed by infarct size analysis using triphenyl tetrazolium chloride staining.

RESULTS:

The rates of infarct size and risk zone were the following in the experimental groups: group 1, 42.8%; group 2,19.5% (P<0.05); group 3, ischemia/reperfusion (I/R) 33.4%; group 4, I/R 18.4% (P<0.05); group 5, I/R 31.2%; and group 6, I/R 36.3%. A significant increase of nuclear factor kappa B activation in groups 2 and 4 was seen.

CONCLUSIONS:

Results confirm that ACE inhibitors do not give total pharmacological IPC, but they enhance the induction effect of small ischemic insults, which raises the ischemic tolerance of myocardium. It was determined that enhanced bradykinin activity leads to downstream nuclear factor kappa B activation in this model.     

Continuous efficacy of etanercept in severe and advanced ankylosing spondylitis: results from a 12-week open-label extension of the SPINE study

Objective. To evaluate the longer-term efficacy of etanercept in patients with severe and advanced active AS. Methods. Seventy-seven patients who completed the randomized, double-blind, placebo-controlled 12-week SPINE study enrolled in a 12-week open-label extension and received s.c. etanercept 50?mg once weekly. The etanercept/etanercept group received a total of 24 weeks treatment with etanercept (n?=?38); the placebo/etanercept group received placebo during the double-blind study then 12 weeks' etanercept treatment during the open-label extension (n?=?39). Results. At the end of the open-label extension, BASDAI scores in the etanercept/etanercept group had further decreased beyond reductions observed during the double-blind study [mean (s.d.) change from baseline -37.6 (22.4) at end of extension vs -27.4 (23.8) at end of double-blind study]. Mean (s.d.) BASDAI scores also improved in the placebo/etanercept group once switched to etanercept [-28.6 (24.3) vs -15.0 (20.0)]. Similar trends were observed in BASFI and BASMI scores. In the placebo/etanercept group, total back pain decreased to similar levels achieved in the etanercept group in the double-blind study. Pain levels continued to decrease with longer-term etanercept therapy in the etanercept/etanercept group. Conclusion. Despite the improvements in symptoms and inflammatory markers observed shortly after initiation of once-weekly etanercept, there was no notable plateauing effect on patient-reported outcomes. Indeed, signs and symptoms of severe and advanced active AS continued to improve after up to 24 weeks, treatment with etanercept. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov/ct2/home, NCT00420238.     

Real-life experience with switching TNF-α inhibitors in ankylosing spondylitis

Background

Published economic evaluations of trastuzumab for the treatment of HER2-positive metastatic breast cancer have arrived at different conclusions regarding the cost-effectiveness of trastuzumab, despite comparative efficacy being demonstrated by a small set of randomised controlled trials (RCTs).

Objectives

This article aims to provide insight into the quality of the evaluations and explore the possible drivers of the conflicting conclusions.

Methods

A systematic literature review was conducted to identify all published economic evaluations that compared the incremental costs and outcomes of trastuzumab versus a comparator.

Results

Fifteen economic evaluations were identified. In the evaluations that estimated efficacy using an RCT, the key drivers of the conclusions regarding cost-effectiveness were: the approach used to estimate overall survival in the control group given crossover to trastuzumab following progression in the trials; the inclusion of treatment beyond progression; inclusion of wastage due to unused vial portions, adverse events, and the cost of HER2 testing. Four evaluations used non-randomised approaches to estimate efficacy, thus introducing the potential for confounding. As a result these evaluations reported relatively optimistic estimates of comparative effectiveness. Finally the evaluations used different thresholds to determine whether treatment with trastuzumab was cost-effective.

Conclusion

There were numerous drivers of the different conclusions regarding the cost-effectiveness of trastuzumab, many of which are due to judgements made by the authors when translating data from RCTs. Many of the potential drivers were not identified by the published systematic reviews of economic evaluations and perhaps more remain unidentified because of inconsistent and limited reporting.     

Stimulation of retrotrapezoid nucleus Phox2b‐expressing neurons rescues breathing dysfunction in an experimental Parkinson’s disease rat model

Emerging evidence from multiple studies indicates that Parkinson’s disease (PD) patients suffer from a spectrum of autonomic and respiratory motor deficiencies in addition to the classical motor symptoms attributed to substantia nigra degeneration of dopaminergic neurons. Animal models of PD show a decrease in the resting respiratory rate as well as a decrease in the number of Phox2b‐expressing retrotrapezoid nucleus (RTN) neurons. The aim of this study was to determine the extent to which substantia nigra pars compact (SNc) degeneration induced RTN biomolecular changes and to identify the extent to which RTN pharmacological or optogenetic stimulations rescue respiratory function following PD‐induction. SNc degeneration was achieved in adult male Wistar rats by bilateral striatal 6‐hydroxydopamine injection. For proteomic analysis, laser capture microdissection and pressure catapulting were used to isolate the RTN for subsequent comparative proteomic analysis and Ingenuity Pathway Analysis (IPA). The respiratory parameters were evaluated by whole‐body plethysmography and electromyographic analysis of respiratory muscles. The results confirmed reduction in the number of dopaminergic neurons of SNc and respiratory rate in the PD‐animals. Our proteomic data suggested extensive RTN remodeling, and that pharmacological or optogenetic stimulations of the diseased RTN neurons promoted rescued the respiratory deficiency. Our data indicate that despite neuroanatomical and biomolecular RTN pathologies, that RTN‐directed interventions can rescue respiratory control dysfunction.