Management of behavioural symptoms of dementia in a specialized unit care.

BACKGROUND: In France, the Alzheimer Plan 2008-2012 has enabled the development of units specialized in managing the behavioural and psychological disorders found in cognitive pathologies, with an emphasis on both pharmacological and non-pharmacological treatments. The aim of this study was to analyze the evolution of behavioural symptoms, autonomy, and psychotropic drug prescriptions at a cognitive and behavioural unit in Toulouse, France. METHODS: Prospective study, with systematic analyze of data for patients hospitalized in a cognitive and behavioral unit. RESULTS: This 2-year study included 199 patients. Behavioural symptoms were significantly improved during the follow-up period and remained so after discharge. Autonomy, especially in walking, was not altered. The prescription of psychotropic drugs, such as neuroleptics, was significantly lower at discharge. CONCLUSION: This study showed the effectiveness of overall care, with an emphasis on pharmacological and non-pharmacological treatments, in managing disruptive behavioural symptoms in a specialized unit.

Effects of lactoferrin on intestinal epithelial cell growth and differentiation: an in vivo and in vitro study.

This study was designed to analyse the effects of human (h) and bovine lactoferrin (bLF) on the growth and differentiation of intestinal cells using the mice model supplemented with Lactoferrin (LF) and the enterocyte-like model of Caco-2 cells which spontaneously differentiate after confluency. In mice, bLF supplementation increased jejunal villus height and the expression of several intestinal brush border membrane enzymes activities. Addition of bLF or hLF to undifferentiated Caco-2 cells was able to increase cell proliferation with confluency being reached more rapidly. Moreover, when Caco-2 cells were grown in the presence of LF for 3 weeks, brush-border membrane-associated enzyme activities i.e. sucrase, alkaline phosphatase and neutral aminopeptidase, as well as the L-glutamate transporter expression were all increased indicating an increased Caco-2 cell differentiation. Accordingly, cDNA Atlas array and Western blot analysis of cell cycle proteins shown a decreased expression of Cdck2 and an increased TAF1 expression; these proteins being implicated in the regulation of numerous genes related to cellular proliferation and differentiation. These modifications were associated with an inhibition of Caco-2 cell spontaneous apoptosis. Altogether, our results indicate that LF increase in vivo and in vitro enterocyte differentiation. In addition, LF was found to increase in vitro enterocyte proliferation resulting in higher cell density in cell flasks, an effect that was likely partly due to a reduction of the cellular apoptosis. The different stimulation patterns observed for the different parameters associated with cell differentiation in relationship with specific gene regulation is discussed.

Behavioral and psychological subsyndromes in Alzheimer's disease using the Neuropsychiatric Inventory.

OBJECTIVE: Behavioral and psychological symptoms of dementia represent common clinical features of dementias, contributing to the heterogeneous phenotypic expression of Alzheimer's disease (AD). During the last two decades, several studies explored the possible presence of neuropsychiatric subsyndromes in dementia by examining the internal structure of the Neuropsychiatric Inventory (NPI). The aim of the present review is to present available evidence coming from studies adopting factor analysis to explore the NPI and describe neuropsychiatric clusters of symptoms in AD. DESIGN: A systematic review of literature was performed concerning available studies describing neuropsychiatric subsyndromes in AD by adopting the NPI. RESULTS: Overall, our analysis showed a relatively low concordance among available evidence for what concerns the definition and composition of NPI clusters, possibly due (at least in part) to the heterogeneity of the sample populations recruited in the studies. However, we also observed some consistent associations of specific symptoms across studies, defining potential subsyndromes in AD. More consistent results were obtained by studies evaluating the 10-item version of the NPI rather than the more recent 12-item one. CONCLUSIONS: This review represents the first attempt to systematically evaluate evidence coming from factor analyses exploring the internal structure of the NPI in order to facilitate the identification of neuropsychiatric syndromes in AD patients. The NPI may support the definition of behavioral subsyndromes in AD. The evaluation of neuropsychiatric subsyndromes should always take into account the main potential confounders, such as age, severity of disease, and concomitant pharmacological treatment.

The Orexin receptors: Structural and anti-tumoral properties.

At the end of the 20th century, two new neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) expressed in hypothalamus as a prepro-orexins precursor, were discovered. These two neuropeptides interacted with two G protein-coupled receptor isoforms named OX1R and OX2R. The orexins/OX receptors system play an important role in the central and peripheral nervous system where it controls wakefulness, addiction, reward seeking, stress, motivation, memory, energy homeostasis, food intake, blood pressure, hormone secretions, reproduction, gut motility and lipolysis. Orexins and their receptors are involved in pathologies including narcolepsy type I, neuro- and chronic inflammation, neurodegenerative diseases, metabolic syndrome, and cancers. Associated with these physiopathological roles, the extensive development of pharmacological molecules including OXR antagonists, has emerged in association with the determination of the structural properties of orexins and their receptors. Moreover, the identification of OX1R expression in digestive cancers encompassing colon, pancreas and liver cancers and its ability to trigger mitochondrial apoptosis in tumoral cells, indicate a new putative therapeutical action of orexins and paradoxically OXR antagonists. The present review focuses on structural and anti-tumoral aspects of orexins and their receptors.

The Orexin-A/OX1R System Induces Cell Death in Pancreatic Cancer Cells Resistant to Gemcitabine and Nab-Paclitaxel Treatment.

Pancreatic ductal adenocarcinoma (PDAC) represents the fourth cause of cancer-associated death in the West. This type of cancer has a very poor prognosis notably due to the development of chemoresistance when treatments including gemcitabine and Abraxane (Nab-paclitaxel) were prescribed. The identification of new treatment circumventing this chemoresistance represents a key challenge. Previous studies demonstrated that the activation of orexin receptor type 1 (OX1R), which was ectopically expressed in PDAC, by its natural ligand named orexin-A (OxA), led to anti-tumoral effect resulting in the activation of mitochondrial pro-apoptotic mechanism. Here, we demonstrated that OxA inhibited the pancreatic cancer cell (AsPC-1) growth and inhibited the tumor volume in preclinical models as effectively as gemcitabine and Nab-paclitaxel. Moreover, the combination therapy including OxA plus gemcitabine or OxA plus Nab-paclitaxel was additive on the inhibition of cancer cell growth and tumor development. More importantly, the treatment by OxA of chemoresistant tumors to gemcitabine or Nab-paclitaxel obtained by successive xenografts in mice revealed that OxA was able to induce a strong inhibition of tumor development, whereas no OxA resistance was identified in tumors. The OX1R/OxA system might be an innovative and powerful alternative treatment of chemoresistant PDAC.

Orexins: A promising target to digestive cancers, inflammation, obesity and metabolism dysfunctions.

Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system. These past 20 years had revealed that orexins/receptors system was also present in the peripheral nervous system where they participated to the regulation of multiple functions including blood pressure regulation, intestinal motility, hormone secretion, lipolyze and reproduction functions. Associated to these peripheral functions, it was found that orexins and their receptors were involved in various diseases such as acute/chronic inflammation, metabolic syndrome and cancers. The present review suggests that orexins or the orexin neural circuitry represent potential therapeutic targets for the treatment of multiple pathologies related to inflammation including intestinal bowel disease, multiple sclerosis and septic shock, obesity and digestive cancers.

Clustering 5-Year Multidimensional Health Care Trajectory Patterns in Alzheimer's Disease and Related Syndromes.

OBJECTIVE: After diagnosis of Alzheimer's disease and related syndromes (ADRS), personalized care adapted to each patient's needs is recommended to provide a care plan and start symptomatic treatments according to guidelines. Over the past decade, dedicated structures and care have been implemented in various settings. Equal access to ADRS care, health care providers and services is crucial to ensure potential health benefits for everyone. However, the extent of use of recommended services and favorable health care utilization trajectories (HUT) may vary according to individual and contextual characteristics. The aim of this article was to (1) describe HUT patterns after multidimensional clustering of similar trajectories, (2) assess the proportion of individuals presenting favorable HUTs, and (3) identify factors associated with favorable HUTs. DESIGN: Cohort study. SETTING AND PARTICIPANTS: A cohort of 103,317 people newly diagnosed with ADRS identified in the French health reimbursement system (SNDS) was followed for 5 years with their monthly utilization on 11 health care dimensions. METHODS: For 3 age groups (65-74, 75-84, ≥85 years), 15 clusters of patients were identified using partitioning around medoids applied to Levenshtein distances. They were qualitatively assessed by pluridisciplinary experts. Individual and contextual determinants of clusters denoting favorable trajectories were identified using mixed random effects multivariable logistic regression models. RESULTS: Clusters with favorable HUTs denoting slow, progressive trajectories centered on at-home care, represented approximatively 25% of the patients. Determinants of favorable HUTs were mostly individual (age, female gender, absence of certain comorbidities, circumstances of ADRS identification, lower deprivation). Contextual determinants were also identified, in particular accessibility to nurses and nursing homes. Inter-territories variance was small but significant in all age groups (from 0.9% to 1.8%). CONCLUSION AND IMPLICATIONS: Favorable HUTs remain the minority and many efforts can still be made to improve HUTs. Qualitative studies could help understanding underlying barriers to favorable HUTs.

Sensory alien hand syndrome in corticobasal degeneration: a cerebral blood flow study.

The presence of alien hand syndrome (AHS) is suggestive of the diagnosis of corticobasal degeneration when it develops in a progressive way. Sensory AHS (sAHS) should be distinguished from the motor form described more commonly. The physiopathology of sAHS remains unclear. The aim of this study is to determine cerebral regions involved in sAHS. We compared perfusion single photon emission computer tomography scans of patients with sAHS (n = 3) and without (n = 4). We observed significant decrease of regional cerebral blood flow over the nondominant thalamus in sAHS+ compared to sAHS- patients. This result suggests the involvement of the nondominant thalamus in sAHS.

Discovery of a functional immunoreceptor tyrosine-based switch motif in a 7-transmembrane-spanning receptor: role in the orexin receptor OX1R-driven apoptosis.

The orexin neuropeptides promote robust apoptosis in cancer cells. We have recently shown that the 7-transmembrane-spanning orexin receptor OX1R mediates apoptosis through an original mechanism. OX1R is equipped with a tyrosine-based inhibitory motif ITIM, which is tyrosine-phosphorylated on receptor activation, allowing the recruitment and activation of the tyrosine phosphatase SHP-2, leading to apoptosis. We show here that another motif, immunoreceptor tyrosine-based switch motif (ITSM), is present in OX1R and is mandatory for OX1R-mediated apoptosis. This conclusion is based on the following observations: 1) a canonical ITSM sequence is present in the first intracellular loop of OX1R; 2) mutation of Y(83) to F within ITSM abolished OX1R-mediated apoptosis but did not alter orexin-induced inositol phosphate formation or calcium transient via coupling of OX1R to G(q) protein; 3) mutation of Y(83) to F further abolished orexin-induced tyrosine phosphorylation in ITSM and subsequent recruitment of SHP-2 by the receptor. Finally, we developed a structural model of OX1R showing that the spatial localization of phosphotyrosines in ITSM and ITIM in OX1R is compatible with their interaction with the two SH2 domains of SHP-2. These data represent the first evidence for a functional role of an ITSM in a 7-transmembrane-spanning receptor.

The impact of a multi-domain intervention on cerebral glucose metabolism: analysis from the randomized ancillary FDG PET MAPT trial.

BACKGROUND: The Multidomain Alzheimer Preventive Trial (MAPT) was designed to assess the efficacy of omega-3 fatty acid supplementation, multidomain intervention (MI), or a combination of both on cognition. Although the MAPT study was negative, an effect of MI in maintaining cognitive functions compared to placebo group was showed in positive amyloid subjects. A FDG PET study (MAPT-NI) was implemented to test the impact of MI on brain glucose metabolism. METHODS: MAPT-NI was a randomized, controlled parallel-group single-center study, exploring the effect of MI on brain glucose metabolism. Participants were non-demented and had memory complaints, limitation in one instrumental activity of daily living, or slow gait. Participants were randomly assigned (1:1) to "MI group" or "No MI group." The MI consisted of group sessions focusing on 3 domains: cognitive stimulation, physical activity, nutrition, and a preventive consultation. [18F]FDG PET scans were performed at baseline, 6 months, and 12 months, and cerebral magnetic resonance imaging scans at baseline. The primary objective was to evaluate the MI effect on brain glucose metabolism assessed by [18F]FDG PET imaging at 6 months. The primary outcome was the quantification of regional metabolism rate for glucose in cerebral regions involved early in Alzheimer disease by relative semi-quantitative SUVr (FDG-based AD biomarker). An exploratory voxel-wise analysis was performed to assess the effect of MI on brain glucose metabolism without anatomical hypothesis. RESULTS: The intention-to-treat population included 67 subjects (34 in the MI group and 33 in the No MI group. No significant MI effect was observed on primary outcome at 6 months. In the exploratory voxel-wise analysis, we observed a difference in favor of MI group on the change of cerebral glucose metabolism in limbic lobe (right hippocampus, right posterior cingulate, left posterior parahippocampal gyrus) at 6 months. CONCLUSIONS: MI failed to show an effect on metabolism in FDG-based AD biomarker, but exploratory analysis suggested positive effect on limbic system metabolism. This finding could suggest a delay effect of MI on AD progression. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT01513252 .

Impact of a Pharmacist-included Mobile Geriatrics team intervention on potentially inappropriate drug prescribing: protocol for a prospective feasibility study (PharMoG study).

INTRODUCTION: Research has shown that potentially inappropriate drug prescription (PIDP) is highly prevalent in older people. The presence of PIDPs is associated with adverse health outcomes. This study aims to evaluate the impact of a PHARmacist-included MObile Geriatrics (PharMoG) team intervention on PIDPs in older patients hospitalised in the medical, surgical and emergency departments of a university hospital. METHODS AND ANALYSIS: The PharMoG study is a prospective, interventional, single-centre feasibility study describing the impact of a PharMoG team on PIDPs in older hospitalised patients. Pharmacist intervention will be a treatment optimisation (clinical medication review) based on a combination of explicit and implicit criteria to detect PIDPs. The primary outcome is the acceptance rate of the mobile team's proposed treatment optimisations related to PIDPs, measured at the patient's discharge from the department. This pharmacist will work in cooperation with the physician of the mobile geriatric team. After the intervention of the mobile geriatric team, the proposals for improving therapy will be sent to the hospital medical team caring for the patient and to the patient's attending physician. The patient will be followed for 3 months after discharge from the hospital. ETHICS AND DISSEMINATION: This study was approved by the South-West and Overseas Territories II Ethics Committee. Oral consent must be obtained prior to participation, either from the patient or from the patient's representative (trusted person and/or a family member). The results will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04151797.

A hallmark of immunoreceptor, the tyrosine-based inhibitory motif ITIM, is present in the G protein-coupled receptor OX1R for orexins and drives apoptosis: a novel mechanism.

Orexins acting at the G protein-coupled receptor (GPCR) OX1R have recently been shown to promote dramatic apoptosis in cancer cells. We report here that orexin-induced apoptosis is driven by an immunoreceptor tyrosine-based inhibitory motif (ITIM) (IIY(358)NFL) present in the OX1R. This effect is mediated by SHP-2 phosphatase recruitment via a mechanism that requires Gq protein but is independent of phospholipase C activation. This is based on the following observations: 1) mutation of Y(358) into F abolished orexin-induced tyrosine phosphorylation in ITIM, orexin-induced apoptosis, and uncoupled OX1R from Gq protein in transfected Chinese hamster ovary (CHO) cells; 2) orexin-induced apoptosis in CHO cells expressing recombinant OX1R and in colon cancer cells expressing the native receptor was abolished by treatment with the tyrosine phosphatase inhibitor PAO and by transfection with a dominant-negative mutant of SHP-2; 3) orexins were unable to promote apoptosis in fibroblast cells invalidated for the G alpha q subunit and transfected with OX1R cDNA, whereas they promoted apoptosis in cells equipped with G alpha q and OX1R; and 4) the phospholipase C inhibitor U-73122 blocked orexin-stimulated inositol phosphate formation, whereas it had no effect on orexin-induced apoptosis in CHO cells expressing OX1R. These data unravel a novel mechanism, whereby ITIM-expressing GPCRs may trigger apoptosis.

Spared and impaired abilities in community-dwelling patients entering the severe stage of Alzheimer's disease.

BACKGROUND: Comprehensive geriatric assessments of patients entering the severe stage of Alzheimer's disease (AD) are scarce. METHODS: Cross-sectional study of 126 patients entering the severe stage of AD in the longitudinal study of REAL.FR cohort. Patients who had a first MMSE score <10 during follow-up underwent cognitive, behavioral, nutritional and functional assessment. Support requirements were also evaluated. RESULTS: The best-preserved cognitive abilities were social interaction and response to own name, while praxis, orientation, memory and language showed the largest declines. Regarding independence in daily living, locomotion was best preserved (71% of patients independent) while personal hygiene deteriorated most (15.5%). Behavioral disorders were frequent, and consisted principally of apathy, aberrant motor behavior, and agitation. The Mini Nutritional Assessment showed that 68.5% of patients were malnourished or at risk of malnutrition. Caregiver burden remained mild to moderate in 69.8% of cases. In addition, 80% of patients still lived at home and 71.6% used at least 2 support services, consisting mainly of physician visits and home help. CONCLUSION: Assessment of remaining cognitive, functional abilities and behavioral disorders at entry to severe AD should help to improve targeted management aimed at preserving these abilities and treating complications, thereby optimizing these patients' quality of life.

Diagnosis and treatment of patients with severe Alzheimer's disease.

In contrast with the earlier stages and, in particular, the predementia stage, of Alzheimer's disease (AD), severe dementia is often neglected. However, the advanced stages of dementia are just as important as the earlier stages because of their frequency, their impact on the lives of patients and their caregivers, and their economic consequences. All patients with moderately severe to severe dementia must be evaluated for cognitive, functional, psychological and behavioural symptoms. Thorough and regular evaluation of patients in the advanced stages of the disease has the following objectives: improving patients' quality of life by encouraging use of their remaining capacities; setting up or modifying a care plan; playing a role in the follow-up of measures instituted; and documenting the natural history of the disease. Therapeutic trials with cholinesterase inhibitors and memantine have been conducted in patients with severe stages of AD. As a consequence, memantine has been approved by numerous drug agencies and donepezil has been approved by the US FDA for use in severe stages of the disease. However, it is important to note that at this stage of AD, and perhaps more than in any other, management must be global and multidisciplinary because of the expression of the disease, its complications and intercurrent disorders. Indeed, thorough knowledge by health professionals of the expression of all disease disorders and intercurrent disorders, and of their significance during the severe stage of AD, is important in the management of these patients to limit complications and facilitate prompt establishment of appropriate care. More effort is needed in both clinical and research settings to ensure that patients with severe AD and their relatives can be offered optimal management.

Predictors of rapid cognitive decline among demented subjects aged 75 or more: ('Sujet Agé Fragile--Evaluation et Suivi' Cohort-SAFES).

OBJECTIVE: To identify factors predictive of rapid cognitive decline (RCD) among elderly subjects aged 75 or over suffering from dementia. METHODS: The analysis concerned 250 patients drawn from the 'Sujet Agé Fragile--Evaluation et Suivi' (SAFES) cohort, presenting a dementia syndrome at inclusion and followed-up for at least 1 year. RCD was defined as the loss of at least 3 points on the Mini-Mental State Examination (MMSE) in the follow-up period of 12 months. All patients underwent a standardised geriatric evaluation. Logistic regression was used to identify factors predictive of RCD. RESULTS: In the study sample, 84 patients (33.6%) presented RCD. The factors identified in multivariate analysis as predictive of RCD were: high level of education (OR = 7.8, 95% CI = [1.9-31.2], p = 0.004), risk of depression (OR = 1.8, 95% CI = [1.02-3.18], p = 0.048, and the initial MMSE score (OR = 1.1, 95% CI = [1.0-1.2], p = 0.002). Among subjects with a main caregiver (n = 177), the predictive factors were malnutrition or risk thereof (OR = 4.2, 95% CI = [1.3-14.1], p = 0.02), risk of a fall (OR = 2.6, 95% CI = [1.1-6.1], p = 0.03, caregiver burden (OR = 2.6, 95% CI = [1.1-6.4], p = 0.04) and initial MMSE score (OR = 1.1, 95% CI = [1.0-1.3], p = 0.004). CONCLUSIONS: As soon as dementia is diagnosed in elderly subjects, information should be collected about the subject's socioeconomic status, nutritional status, risk of falling, mood state, and caregiver burden. This would enable the provision of appropriate therapeutic care, and make it possible to adapt follow-up in case of a risk of accelerated cognitive deterioration.

Use of a robotic walking aid in rehabilitation to reduce fear of falling is feasible and acceptable from the end user's perspective: A randomised comparative study.

Objectives To determine the acceptability and feasibility of the use of a robotic walking aid to support the work of physiotherapists in reducing fear of falling in the rehabilitation of elderly patients with 'psychomotor disadaptation' (the most severe form of post-fall syndrome). Study design 20 participants with psychomotor disadaptation admitted to an academic rehabilitation ward were randomised to receive physiotherapist care supported by the SafeWalker® robotic walking aid or standard care only, for ten days. SafeWalker® supports the body weight whilst securing postural stability without relying on upper body strength or high cognitive demand. Main outcome measures The primary outcome was the feasibility and acceptability of rehabilitation sessions at five and ten days based on (i) questionnaires completed by patient and physiotherapist, (ii) the number of steps performed during sessions, (iii) replacement of a robotic session by a conventional one. Results The mean age of the participants was 85.2 years. They had lost their ability to perform some basic living activities. Patients in the intervention group found that the rehabilitation sessions were easier (p = 0.048). No robotic rehabilitation session had to be replaced by conventional rehabilitation. There were no statistical differences between the two groups on the other outcome measures. Conclusion We demonstrated the feasibility and acceptability of the use of a robotic walking aid from the perspective of both older individuals and physiotherapists. This could fill the gap between devices that fully compensate for walking and those which allow patients to maintain residual mobility.

Orexins as Novel Therapeutic Targets in Inflammatory and Neurodegenerative Diseases.

Orexins [orexin-A (OXA) and orexin-B (OXB)] are two isoforms of neuropeptides produced by the hypothalamus. The main biological actions of orexins, focused on the central nervous system, are to control the sleep/wake process, appetite and feeding, energy homeostasis, drug addiction, and cognitive processes. These effects are mediated by two G protein-coupled receptor (GPCR) subtypes named OX1R and OX2R. In accordance with the synergic and dynamic relationship between the nervous and immune systems, orexins also have neuroprotective and immuno-regulatory (i.e., anti-inflammatory) properties. The present review gathers recent data demonstrating that orexins may have a therapeutic potential in several pathologies with an immune component including multiple sclerosis, Alzheimer's disease, narcolepsy, obesity, intestinal bowel diseases, septic shock, and cancers.

Incidence and main factors associated with early unplanned hospital readmission among French medical inpatients aged 75 and over admitted through emergency units.

BACKGROUND: among elderly patients, readmission in the month following hospital discharge is a frequent occurrence which involves a risk of functional decline, particularly among frail subjects. While previous studies have identified risk factors of early readmission, geriatric syndromes, as markers of frailty have not been assessed as potential predictors. OBJECTIVE: to evaluate the risk of early unplanned readmission, and to identify predictors in inpatients aged 75 and over, admitted to medical wards through emergency departments. DESIGN: prospective multi-centre study. SETTING: nine French hospitals. SUBJECTS: one thousand three hundred and six medical inpatients, aged 75 and older admitted through emergency departments (SAFES cohort). METHODS: using logistic regressions, factors associated with early unplanned re-hospitalisation (defined as first unplanned readmission in the thirty days after discharge) were identified using data from the first week of hospital index stay obtained by comprehensive geriatric assessment. RESULTS: data from a thousand out of 1,306 inpatients were analysed. Early unplanned readmission occurred in 14.2% of inpatients and was not related with sociodemographic characteristics, comorbidity burden or cognitive impairment. Pressure sores (OR = 2.05, 95% CI = 1.0-3.9), poor overall condition (OR = 2.01, 95% CI = 1.3-3.0), recent loss of ability for self-feeding (OR = 1.9, 95% CI = 1.2-2.9), prior hospitalisation during the last 3 months (OR = 1.6, 95% CI = 1.1-2.5) were found to be risk factors, while sight disorders appeared as negatively associated (OR = 0.5, 95% CI = 0.3--0.8). CONCLUSIONS: markers of frailty (poor overall condition, pressure sores, prior hospitalisation) or severe disability (for self-feeding) were the most important predictors of early readmission among elderly medical inpatients. Early identification could facilitate preventive strategies in risk group.

The Anti-tumoral Properties of Orexin/Hypocretin Hypothalamic Neuropeptides: An Unexpected Therapeutic Role.

Orexins (OxA and OxB) also termed hypocretins are hypothalamic neuropeptides involved in central nervous system (CNS) to control the sleep/wake process which is mediated by two G protein-coupled receptor subtypes, OX1R, and OX2R. Beside these central effects, orexins also play a role in various peripheral organs such as the intestine, pancreas, adrenal glands, kidney, adipose tissue and reproductive tract.In the past few years, an unexpected anti-tumoral role of orexins mediated by a new signaling pathway involving the presence of two immunoreceptor tyrosine-based inhibitory motifs (ITIM) in both orexin receptors subtypes, the recruitment of the phosphotyrosine phosphatase SHP2 and the induction of mitochondrial apoptosis has been elucidated. In the present review, we will discuss the anti-tumoral effect of orexin/OXR system in colon, pancreas, prostate and other cancers, and its interest as a possible therapeutic target.

In vitro, in vivo and ex vivo demonstration of the antitumoral role of hypocretin-1/orexin-A and almorexant in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is still the poorest prognostic tumor of the digestive system. We investigated the antitumoral role of orexin-A and almorexant in PDAC. We analyzed the orexin receptor type 1 (OX1R) expression by immunohistochemistry in human normal pancreas, PDAC and its precursor dysplastic intraepithelial lesions. We used PDAC-derived cell lines and fresh tissue slices to study the apoptotic role of hypocretin-1/orexin-A and almorexant in vitro and ex vivo. We analyzed in vivo the hypocretin-1/orexin-A and almorexant effect on tumor growth in mice xenografted with PDAC cell lines expressing, or not, OX1R. Ninety-six percent of PDAC expressed OX1R, while adjacent normal exocrine pancreas did not. OX1R was expressed in pre-cancerous lesions. In vitro, under hypocretin-1/orexin-A and almorexant, the OX1R-positive AsPC-1 cells underwent apoptosis, abolished by the tyrosine phosphatase SHP2 inhibitor, NSC-87877, whereas the OX1R-negative HPAF-II cell line did not. These effects were mediated by phosphorylation of OX1R and recruitment of SHP2. Ex vivo, caspase-3 positive tumor cells were significantly higher in fresh tumour slices treated 48h with hypocretin-1/orexin-A, as compared to control, whereas cellular proliferation, assessed by Ki-67 index, was not modified. In vivo, when AsPC-1 cells or patient-derived cells were xenografted in nude mice, hypocretin-1/orexin-A or almorexant, administrated both starting the day of cell line inoculation or after tumoral development, strongly slowed tumor growth. Hypocretin-1/orexin-A and almorexant induce, through OX1R, the inhibition of PDAC cellular growth by apoptosis. Hypocretins/orexins and almorexant might be powerful candidates for the treatment of PDAC.