Enhanced neuronal Met signalling levels in ALS mice delay disease onset

Signalling by receptor tyrosine kinases (RTKs) coordinates basic cellular processes during development and in adulthood. Whereas aberrant RTK signalling can lead to cancer, reactivation of RTKs is often found following stress or cell damage. This has led to the common belief that RTKs can counteract degenerative processes and so strategies to exploit them for therapy have been extensively explored. An understanding of how RTK stimuli act at cellular levels is needed, however, to evaluate their mechanism of therapeutic action. In this study, we genetically explored the biological and functional significance of enhanced signalling by the Met RTK in neurons, in the context of a neurodegenerative disease. Conditional met-transgenic mice, namely Rosa26LacZ−stop−Met, have been engineered to trigger increased Met signalling in a temporal and tissue-specific regulated manner. Enhancing Met levels in neurons does not affect either motor neuron (MN) development or maintenance. In contrast, increased neuronal Met in amyotrophic lateral sclerosis (ALS) mice prolongs life span, retards MN loss, and ameliorates motor performance, by selectively delaying disease onset. Thus, our studies highlight the properties of RTKs to counteract toxic signals in a disease characterized by dysfunction of multiple cell types by acting in MNs. Moreover, they emphasize the relevance of genetically assessing the effectiveness of agents targeting neurons during ALS evolution

No Effect of One-Year Treatment with Indomethacin on Alzheimer's Disease Progression: A Randomized Controlled Trial

Contains fulltext : 71117.pdf (publisher's version ) (Open Access)BACKGROUND: The objective of this study was to determine whether treatment with the nonselective nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows cognitive decline in patients with Alzheimer's disease (AD). METHODOLOGY/PRINCIPAL FINDINGS: This double-blind, randomized, placebo-controlled trial was conducted between May 2000 and September 2005 in two hospitals in the Netherlands. 51 patients with mild to moderate AD were enrolled into the study. Patients received 100 mg indomethacin or placebo daily for 12 months. Additionally, all patients received omeprazole. The primary outcome measure was the change from baseline after one year of treatment on the cognitive subscale of the AD Assessment Scale (ADAS-cog). Secondary outcome measures included the Mini-Mental State Examination, the Clinician's Interview Based Impression of Change with caregiver input, the noncognitive subscale of the ADAS, the Neuropsychiatric Inventory, and the Interview for Deterioration in Daily life in Dementia. Considerable recruitment problems of participants were encountered, leading to an underpowered study. In the placebo group, 19 out of 25 patients completed the study, and 19 out of 26 patients in the indomethacin group. The deterioration on the ADAS-cog was less in the indomethacin group (7.8+/-7.6), than in the placebo group (9.3+/-10.0). This difference (1.5 points; CI -4.5-7.5) was not statistically significant, and neither were any of the secondary outcome measures. CONCLUSIONS/SIGNIFICANCE: The results of this study are inconclusive with respect to the hypothesis that indomethacin slows the progression of AD

Frequency and Documentation of Medication Decisions on Discharge from the Hospital to Hospice Care

OBJECTIVES: To quantify the frequency and type of medication decisions on discharge from the hospital to hospice care. DESIGN: Retrospective cohort study. SETTING: A 544-bed academic tertiary care hospital in Portland, Oregon. PARTICIPANTS: A total of 348 adult patients (age \u3e /=18 y) discharged to hospice care between January 1, 2010, and December 31, 2016. MEASUREMENTS: Data were collected from an electronic repository of medical record data and a manual review of patients\u27 discharge summaries. Our outcomes of interest were the frequency and type of medication decisions documented in patients\u27 discharge summaries. Medication decisions were categorized as continuation, continuation but with changes in dose, route of administration, and/or frequency, discontinuation, and initiation of new medications. We also collected data on the frequency of patient/family in the participation of medication-related decisions. RESULTS: Patients were prescribed a mean of 7.1 medications (standard deviation [SD] = 4.8) on discharge to hospice care. The most prevalent medications prescribed on discharge were strong opioids (82.5%), anxiolytics/sedatives (62.9%), laxatives (57.5%), antiemetics (54.3%), and nonopioid analgesics (45.4%). However, only 67.8% (213/341) of patients who were prescribed an opioid on discharge to hospice care were also prescribed a laxative. Discharging providers made a mean of 15.0 decisions (SD = 7.2) per patient of which 28.5% were to continue medications without changes, 6.7% were to continue medications with changes, 30.3% were to initiate new medications, and 34.5% were to discontinue existing medications. Patients and/or family members were involved in medication decisions during 21.6% of discharges; patients were involved in 15.2% of decisions. CONCLUSION: Patients averaged more than 15 medication decisions on discharge to hospice care. However, it was rarely documented that patients and/or their families participated in these decisions. J Am Geriatr Soc, 2019