Effect of a multi-domain intervention on the quality of life in older adults with major neurocognitive disorder: A pilot study.

PURPOSE: Major neurocognitive disorders (MND) have multiple negative consequences on patients' lives and on their caregivers' health. Occupational therapy and cognitive stimulation have failed to show any significant efficacy on quality of life (QoL), cognitive functioning and behavioural symptoms. Bretonneau Hospital's Day Care Unit offers personalized and structured multi-domain interventions to cognitively impaired older patients on a weekly basis, for a 3-month period. OBJECTIVES: Our objective was to determine whether a specific rehabilitation day care unit (RDCU) could influence the QoL of cognitively impaired community-dwelling elderly patients. We also aimed to better understand the characteristics of patients who had the most benefited from the RDCU. METHODS: Retrospective study based on a sample of outpatients participating in RDCU during three months. All patients underwent a cognitive (MMS), functional (IADl, ADL) and behavioral (NPI) assessment. We compared QoL using the QoL-Alzheimer's Disease (QoL-AD) scale before and after RDCU. RESULTS: Overall, we included 60 outpatients in our study (mean age 83.3±5.8; women=70%). We found a statistically significant improvement of QoL-AD scores after RDCU (31.8±4.9 to 32.9±5.2, P=0.008). Patients who benefitted the most from RDCU were older (P=0.01) and had lower baseline QoL (P=0.04). We did not find any other characteristics associated with QoL-AD score improvement in our population. CONCLUSION: RDCU showed positive effects on QoL in this uncontrolled pilot study of older adults with MND. These findings should be confirmed in a future randomized controlled trial to corroborate the potential benefits of RDCU on QoL in older cognitively impaired patients.

Mesenchymal Stromal Cells Accelerate Epithelial Tight Junction Assembly via the AMP-Activated Protein Kinase Pathway, Independently of Liver Kinase B1.

BACKGROUND: Mesenchymal stromal cells (MSC) are fibroblast-like multipotent cells capable of tissue-repair properties. Given the essentiality of tight junctions (TJ) in epithelial integrity, we hypothesized that MSC modulate TJ formation, via the AMP-activated kinase (AMPK) pathway. Liver kinase-ß1 (LKB1) and Ca2+-calmodulin-dependent protein kinase kinase (CaMKK) represent the main kinases that activate AMPK. METHODS: The in vitro Ca2+ switch from 5 µM to 1.8 mM was performed using epithelial Madin-Darby canine kidney (MDCK) cells cultured alone or cocultured with rat bone marrow-derived MSC or preexposed to MSC-conditioned medium. TJ assembly was measured by assessing ZO-1 relocation to cell-cell contacts. Experiments were conducted using MDCK stably expressing short-hairpin-RNA (shRNA) against LKB1 or luciferase (LUC, as controls). Compound STO-609 (50 µM) was used as CaMKK inhibitor. RESULTS: Following Ca2+ switch, ZO-1 relocation and phosphorylation/activation of AMPK were significantly higher in MDCK/MSC compared to MDCK. No difference in AMPK phosphorylation was observed between LKB1-shRNA and Luc-shRNA MDCK following Ca2+ switch. Conversely, incubation with STO-609 prior to Ca2+ switch prevented AMPK phosphorylation and ZO-1 relocation. MSC-conditioned medium slightly but significantly increased AMPK activation and accelerated TJ-associated distribution of ZO-1 post Ca2+ switch in comparison to regular medium. CONCLUSIONS: MSC modulate the assembly of epithelial TJ, via the CaMKK/AMPK pathway independently of LKB1.

A mitochondrial block and expression of XIAP lead to resistance to TRAIL-induced apoptosis during progression to metastasis of a colon carcinoma.

A pair of isogenic colon carcinoma cells, SW480 and 620, was used to investigate the mechanisms of acquired tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistance during tumour progression. Whereas primary tumour SW480 cells are sensitive to TRAIL-induced apoptosis, metastatic SW620 cells are resistant. The apoptotic signalling activated by TRAIL in SW480 cells is a type II pathway. We show that in SW620 cells, although caspase-8 is recruited and activated at the death-inducing-signalling complex and Bid is cleaved, this does not lead to caspase-9 activation. Comparison of Bcl-2, Bcl-xL and Mcl-1 levels in both cell lines showed no difference. In SW620 cells transfected with a tBid-GFP construct, tBid-GFP was correctly localized to the mitochondria. Thus, the resistance of SW620 cells is at the level of the mitochondria that can withstand large amounts of tBid. Although caspase-3 was directly cleaved by caspase-8 in SW620 cells to yield the p20 fragment, no further autocatalytic maturation into the p17 fragment was observed. We show that, in contrast to SW480 cells, the SW620 cell line expresses high amounts of X-linked inhibitor of apoptosis (XIAP). Downregulation of XIAP with bortezomib or small-interfering RNA was sufficient to restore the sensitivity of SW620 cells to TRAIL-induced apoptosis in the absence of SMAC/Diablo or cytochrome c release from the mitochondria. Thus, SW620 cells have developed a dual resistance to TRAIL-induced apoptosis: a block at the level of the mitochondria and, after a conversion to a type I pathway, an increased expression of XIAP which inhibits this pathway.

Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing.

Increased phosphorylation of myosin light chain (MLC) is necessary for the dynamic membrane blebbing that is observed at the onset of apoptosis. Here we identify ROCK I, an effector of the small GTPase Rho, as a new substrate for caspases. ROCK I is cleaved by caspase-3 at a conserved DETD1113/G sequence and its carboxy-terminal inhibitory domain is removed, resulting in deregulated and constitutive kinase activity. ROCK proteins are known to regulate MLC-phosphorylation, and apoptotic cells exhibit a gradual increase in levels of phosphorylated MLC concomitant with ROCK I cleavage. This phosphorylation, as well as membrane blebbing, is abrogated by inhibition of caspases or ROCK proteins, but both processes are independent of Rho activity. We also show that expression of active truncated ROCK I induces cell blebbing. Thus, activation of ROCK I by caspase-3 seems to be responsible for bleb formation in apoptotic cells.