Imaging flow cytometry of tumoroids: A new method for studying GPCR expression.

Fluorescence confocal microscopy is commonly used to analyze the regulation membrane proteins expression such as G protein-coupled receptors (GPCRs). With this approach, the internal movement of GPCRs within the cell can be observed with a high degree of resolution. However, these microscopy techniques led to complex and time-consuming analysis and did not allow a large population of events to be sampled. A recent approach termed imaging flow cytometry (IFC), which combines flow cytometry and fluorescence microscopy, had two main advantages to study the regulation of GPCRs expression such as orexins receptors (OXRs): the ability (1) to analyze large numbers of cells and; (2) to visualize cell integrity and fluorescent markers localization. Here, we compare these two technologies using the orexin A (OxA) ligand coupled to rhodamine (OxA-rho) to investigate anti-tumoral OX1R expression in human digestive cancers. IFC has been adapted for cancer epithelial adherent cells and also to 3D cell culture tumoroids which partially mimic tumoral structures. In the absence of specific antibody, expression of OX1R is examined in the presence of OxA-rho. 2D-culture of colon cancer cells HT-29 exhibits a maximum level of OX1R internalization induced by OxA with 19% ± 3% colocalizing to early endosomes. In 3D-culture of HT-29 cells, internalization of OX1R/OxA-rho reached its maximum at 60 min, with 30.7% ± 6.4% of OX1R colocalizing with early endosomes. This is the first application of IFC to the analysis of the expression of a native GPCR, OX1R, in both 2D and 3D cultures of adherent cancer cells.

Framework Implementation of the INSPIRE ICOPE-CARE Program in Collaboration with the World Health Organization (WHO) in the Occitania Region.

INTRODUCTION: Limiting the number of dependent older people in coming years will be a major economic and human challenge. In response, the World Health Organization (WHO) has developed the «Integrated Care for Older People (ICOPE)¼ approach. The aim of the ICOPE program is to enable as many people as possible to age in good health. To reach this objective, the WHO proposes to follow the trajectory of an individual's intrinsic capacity, which is the composite of all their physical and mental capacities and comprised of multiple domains including mobility, cognition, vitality / nutrition, psychological state, vision, hearing. OBJECTIVE: The main objective of the INSPIRE ICOPE-CARE program is to implement, in clinical practice at a large scale, the WHO ICOPE program in the Occitania region, in France, to promote healthy aging and maintain the autonomy of seniors using digital medicine. METHOD: The target population is independent seniors aged 60 years and over. To follow this population, the 6 domains of intrinsic capacity are systematically monitored with pre-established tools proposed by WHO especially STEP 1 which has been adapted in digital form to make remote and large-scale monitoring possible. Two tools were developed: the ICOPE MONITOR, an application, and the BOTFRAIL, a conversational robot. Both are connected to the Gerontopole frailty database. STEP 1 is performed every 4-6 months by professionals or seniors themselves. If a deterioration in one or more domains of intrinsic capacity is identified, an alert is generated by an algorithm which allows health professionals to quickly intervene. The operational implementation of the INSPIRE ICOPE-CARE program in Occitania is done by the network of Territorial Teams of Aging and Prevention of Dependency (ETVPD) which have more than 2,200 members composed of professionals in the medical, medico-social and social sectors. Targeted actions have started to deploy the use of STEP 1 by healthcare professionals (physicians, nurses, pharmacists,…) or different institutions like French National old age insurance fund (CNAV), complementary pension funds (CEDIP), Departmental Council of Haute Garonne, etc. Perspective: The INSPIRE ICOPE-CARE program draws significantly on numeric tools, e-health and digital medicine to facilitate communication and coordination between professionals and seniors. It seeks to screen and monitor 200,000 older people in Occitania region within 3 to 5 years and promote preventive actions. The French Presidential Plan Grand Age aims to largely implement the WHO ICOPE program in France following the experience of the INSPIRE ICOPE-CARE program in Occitania.

A new solvent system: Hydrothermal molten salt.

This work proposes a new solvent system composed of a molten salt in pressurized water, so-called hydrothermal molten salt (HyMoS). This system changes the paradigm of the solubility of inorganics in supercritical water. Using as an example NaOH, a low melting temperature salt, we show the possibility to precipitate it at a temperature above its melting one, leading to the instantaneous formation of the HyMoS. The molten salt is then capable of dissolving a large amount of inorganic salt, as exemplified with Na2SO4. This solvent system opens innovative ways with a potential to impact applications in many fields including materials synthesis, biomass conversion, recycling, green chemistry, catalysis, sustainable manufacturing and others. Beyond the impact on the hydrothermal community, this work also offers previously unexplored opportunities for the molten salt field with access to flow chemistry and insights regarding salt precipitation mechanism.

Ectopic expression of OX1R in ulcerative colitis mediates anti-inflammatory effect of orexin-A.

Orexins (orexin-A and orexin-B) are hypothalamic peptides that are produced by the same precursor and are involved in sleep/wake control, which is mediated by two G protein-coupled receptor subtypes, OX1R and OX2R. Ulcerative colitis (UC) is an inflammatory bowel disease, (IBD) which is characterized by long-lasting inflammation and ulcers that affect the colon and rectum mucosa and is known to be a significant risk factor for colon cancer development. Based on our recent studies showing that OX1R is aberrantly expressed in colon cancer, we wondered whether orexin-A could play a role in UC. Immunohistochemistry studies revealed that OX1R is highly expressed in the affected colonic epithelium of most UC patients, but not in the non-affected colonic mucosa. Injection of exogenous orexin-A specifically improved the inflammatory symptoms in the two colitis murine models. Conversely, injection of inactive orexin-A analog, OxB7-28 or OX1R specific antagonist SB-408124 did not have anti-inflammatory effect. Moreover, treatment with orexin-A in DSS-colitis induced OX1R-/- knockout mice did not have any protective effect. The orexin-A anti-inflammatory effect was due to the decreased expression of pro-inflammatory cytokines in immune cells and specifically in T-cells isolated from colonic mucosa. Moreover, orexin-A inhibited canonical NFκB activation in an immune cell line and in intestinal epithelial cell line. These results suggest that orexin-A might represent a promising alternative to current UC therapies.

Neuropsychological Profile of "Cognitive Frailty" Subjects in MAPT Study.

OBJECTIVES: An international group proposed the existence of "cognitive frailty", a condition defined by simultaneous presence of physical frailty and cognitive impairment in the absence of dementia. The objective was to compare the neuropsychological profiles in subgroups of elders differentiated across their physical frailty (Fried phenotype) and cognitive status (Clinical Dementia Rating score) to characterize the "cognitive frailty" entity. METHOD: We studied baseline characteristics of 1,617 subjects enrolled in Multidomain Alzheimer Disease Preventive Trial (MAPT). Included subjects were aged 70 years or older and presented at least 1 of the 3 following clinical criteria: (1) Memory complaint spontaneously reported to a general practitioner, (2) limitation in one instrumental activity of daily living, (3) slow gait speed. Subjects with dementia were not included in the trial. RESULTS: "Cognitive frailty individuals" significantly differed from "individuals with cognitive impairment and without physical frailty", scoring worse at executive, and attention tests. They presented subcortico-frontal cognitive pattern different of Alzheimer Disease. Cognitive performance of subjects with 3 criteria or more of the frailty phenotype are cognitively more impaired than subjects with only one. DISCUSION: The characterization of "cognitive frailty" must be done in frail subjects to set up specific preventive clinical trials for this population.

Stable Freestanding Thin Films of Copolymer Melts Far from the Glass Transition.

Thin polymer films have attracted attention because of both their broad range of applications and of the fundamental questions they raise regarding the dynamic response of confined polymers. These films are unstable if the temperature is above their glass transition temperature Tg. Here, we describe freestanding thin films of centimetric dimensions made of a comb copolymer melt far from its glass transition that are stable for more than a day. These long lifetimes allowed us to characterize the drainage dynamics and the thickness profile of the films. Stratified regions appear as the film drains. We have evidence that the stability, thinning dynamics, and thickness profile of the films result from structural forces in the melt. Understanding the key mechanisms behind our observations may lead to new developments in polymeric thin films, foams, and emulsions without the use of stabilizing agents.

Cognitive and functional patterns of nondemented subjects with equivocal visual amyloid PET findings.

PURPOSE: Despite good to excellent inter-reader agreement in the evaluation of amyloid load on PET scans in subjects with Alzheimer's disease, some equivocal findings have been reported in the literature. We aimed to describe the clinical characteristics of subjects with equivocal PET images. METHODS: Nondemented subjects aged 70 years or more were enrolled from the MAPT trial. Cognitive and functional assessments were conducted at baseline, at 6 months, and annually for 3 years. During the follow-up period, 271 subjects had (18)F-AV45 PET scans. Images were visually assessed by three observers and classified as positive, negative or equivocal (if one observer disagreed). After debate, equivocal images were reclassified as positive (EP+) or negative (EP-). Scans were also classified by semiautomated quantitative analysis using mean amyloid uptake of cortical regions. We evaluated agreement among the observers, and between visual and quantitative assessments using kappa coefficients, and compared the clinical characteristics of the subjects according to their PET results. RESULTS: In 158 subjects (58.30 %) the PET scan was negative for amyloid, in 77 (28.41 %) the scan was positive and in 36 (13.28 %) the scan was equivocal. Agreement among the three observers was excellent (kappa 0.80). Subjects with equivocal images were more frequently men (58 % vs. 37 %) and exhibited intermediate scores on cognitive and functional scales between those of subjects with positive and negative scans. Amyloid load differed between the EP- and negative groups and between the EP+ and positive groups after reclassification. CONCLUSION: Equivocal amyloid PET images could represent a neuroimaging entity with intermediate amyloid load but without a specific neuropsychological pattern. Clinical follow-up to assess cognitive evolution in subjects with equivocal scans is needed.

Amyloid beta peptide immunotherapy in Alzheimer disease.

Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid ß peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid ß peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid ß peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid ß peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation.

Amyloid imaging in Alzheimer's disease: a literature review.

Therapies targeting amyloid-ß peptide currently represent approximately 50% of drugs now being developed for Alzheimer's disease. Some, including active and passive anti-Aß immunotherapy, directly target the amyloid plaques. The new amyloid tracers are increasingly being included in the proposed updated diagnostic criteria, and may allow earlier diagnosis. Those targeting amyloid-ß peptide allow identification of amyloid plaques in vivo. We need to gain insight into all aspects of their application. As florbetapir (Amyvid™) and flutemetamol (Vizamyl™) have received marketing authorization, clinicians require deeper knowledge to be rationally used in diagnosis. In this paper, we review both completed and ongoing observational, longitudinal and interventional studies of these tracers, our main objective being to show the performance of the four most commonly used tracers and their validation.

MAPT STUDY: A MULTIDOMAIN APPROACH FOR PREVENTING ALZHEIMER'S DISEASE: DESIGN AND BASELINE DATA.

OBJECTIVE: The Multidomain Alzheimer Preventive Trial (MAPT study) was designed to assess the efficacy of isolated supplementation with omega-3 fatty acid, an isolated multidomain intervention (consisting of nutritional counseling, physical exercise, cognitive stimulation) or a combination of the two interventions on the change of cognitive functions in frail subjects aged 70 years and older for a period of 3 years. Ancillary neuroimaging studies were additionally implemented to evaluate the impact of interventions on cerebral metabolism (FDG PET scans) and atrophy rate (MRIs), as well as brain amyloïd deposit (AV45 PET scans). DESIGN PATIENTS: 1680 subjects (mean age: 75.3 years; female: 64.8 %), enrolled by 13 memory clinics, were randomized into one of the following four groups: omega-3 supplementation alone, multidomain intervention alone, omega-3 plus multidomain intervention, or placebo. Participants underwent cognitive, functional and biological assessments at M6, M12, M24 and M36 visits. The primary endpoint is a change of memory function at 3 years, as assessed by the Free and Cued Selective Reminding test. All participants will be followed for 2 additional years after the 3-years intervention (MAPT PLUS extension study). INTERVENTIONS: 1/Omega-3 supplementation: two soft capsules daily as a single dose, containing a total of 400 mg docosahexaenoic acid (DHA), i.e., 800 mg docosahexaenoic acid per day, for 3 years. 2/ Multidomain intervention: collective training sessions conducted in small groups (6-8 participants) in twelve 120-minute sessions over the first 2 months (two sessions a week for the first month, and one session a week the second month) then a 60-minute session per month in the following three areas: nutrition, physical activity, and cognition until the end of the 3 years. In addition to the collective sessions, individualized preventive outpatient visits exploring possible risk factors for cognitive decline are performed at baseline, M12 and M24. BASELINE POPULATION: For cognition, the mean MMSE at baseline was 28.1 (± 1.6). About 58% and 42% of participants had a CDR score equal to 0 and 0.5, respectively. Regarding mobility status, 200 (11.9%) had a 4-m gait speed lower or equal to 0.8 m/s. According to the Fried criteria, 673 (42.1%) participants were considered pre frail, and 51 (3.2%) frail. The red blood cell DHA content was 26.1 ± 8.1 µg/g. Five hundred and three participants underwent baseline MRI. AV45 PET scans were performed in 271 individuals and preliminary results showed that 38.0% had a cortical SUVR > 1.17, which gave an indication of significant brain amyloïd deposit. DISCUSSION: The MAPT trial is presently the first largest and longest multidomain preventive trial relevant to cognitive decline in older adults with subjective memory complaints. The multidomain intervention designed for the MAPT trial is likely to be easily implemented within the general population.

Six-month outcome of elderly people hospitalized via the emergency department: the SAFES cohort.

BACKGROUND: The objective of the study was to identify factors predictive of 6-month institutionalization or mortality in frail elderly patients after acute hospitalization. METHODS: A prospective cohort of elderly subjects 75 years and older was set up in nine French teaching hospitals. Data obtained from a comprehensive geriatric assessment were used in a Cox model to predict 6-month institutionalization or mortality. Institutionalization was defined as incident admission either to a nursing home or other long-term care facility during the follow-up period. RESULTS: Crude institutionalization and death rates after 6 months of follow-up were 18% and 24%, respectively. Independent predictors of institutionalization were: living alone (HR=1.83; 95% CI=1.27-2.62) or a higher number of children (HR=0.86; 95% CI=0.78-0.96), balance problems (HR=1.72; 95% CI=1.19-2.47), malnutrition or risk thereof (HR=1.93; 95% CI=1.24-3.01), and dementia syndrome (HR=1.88; 95% CI=1.32-2.67). Factors found to be independently related to 6-month mortality were exclusively medical factors: malnutrition or risk thereof (HR=1.92; 95% CI=1.17-3.16), delirium (HR=1.80; 95% CI=1.24-2.62), and a high level of comorbidity (HR=1.62; 95% CI=1.09-2.40). Institutionalization (HR=1.92; 95% CI=1.37-2.71) and unplanned readmission (HR=4.47; 95% CI=3.16-2.71) within the follow-up period were also found as independent predictors. CONCLUSION: The main factors predictive of 6-month outcome identified in this study are modifiable by global and multidisciplinary interventions. Their early identification and management would make it possible to modify frail elderly subjects' prognosis favorably.

Using PET with 18F-AV-45 (florbetapir) to quantify brain amyloid load in a clinical environment.

PURPOSE: Positron emission tomography (PET) imaging of brain amyloid load has been suggested as a core biomarker for Alzheimer's disease (AD). The aim of this study was to test the feasibility of using PET imaging with (18)F-AV-45 (florbetapir) in a routine clinical environment to differentiate between patients with mild to moderate AD and mild cognitive impairment (MCI) from normal healthy controls (HC). METHODS: In this study, 46 subjects (20 men and 26 women, mean age of 69.0 ± 7.6 years), including 13 with AD, 12 with MCI and 21 HC subjects, were enrolled from three academic memory clinics. PET images were acquired over a 10-min period 50 min after injection of florbetapir (mean ± SD of radioactivity injected, 259 ± 57 MBq). PET images were assessed visually by two individuals blinded to any clinical information and quantitatively via the standard uptake value ratio (SUVr) in the specific regions of interest, which were defined in relation to the cerebellum as the reference region. RESULTS: The mean values of SUVr were higher in AD patients (median 1.20, Q1-Q3 1.16-1.30) than in HC subjects (median 1.05, Q1-Q3 1.04-1.08; p = 0.0001) in the overall cortex and all cortical regions (precuneus, anterior and posterior cingulate, and frontal median, temporal, parietal and occipital cortex). The MCI subjects also showed a higher uptake of florbetapir in the posterior cingulate cortex (median 1.06, Q1-Q3 0.97-1.28) compared with HC subjects (median 0.95, Q1-Q3 0.82-1.02; p = 0.03). Qualitative visual assessment of the PET scans showed a sensitivity of 84.6% (95% CI 0.55-0.98) and a specificity of 38.1% (95% CI 0.18-0.62) for discriminating AD patients from HC subjects; however, the quantitative assessment of the global cortex SUVr showed a sensitivity of 92.3% and specificity of 90.5% with a cut-off value of 1.122 (area under the curve 0.894). CONCLUSION: These preliminary results suggest that PET with florbetapir is a safe and suitable biomarker for AD that can be used routinely in a clinical environment. However, the low specificity of the visual PET scan assessment could be improved by the use of specific training and automatic or semiautomatic quantification tools.

Reducing "iatrogenic disability" in the hospitalized frail elderly.

BACKGROUND: Hospitalization is the first cause of functional decline in the elderly: 30 to 60% of elderly patients lose some independence in basic activities of daily living (ADL) during a stay in hospital. This loss of independence results from the acute condition that led to admission, but is also related to the mode of management. OBJECTIVE: This paper is a review of the literature on functional decline in elderly hospitalized patients. It is the first stage in a project aiming to prevent dependence that is induced during the course of care. METHODS: During a 2-day workshop in Monaco, a task force of 20 international experts discussed and defined the concept of "iatrogenic disability". RESULTS: 1- "Iatrogenic disability" was defined by the task force as the avoidable dependence which often occurs during the course of care. It involves three components that interact and have a cumulative effect: a) the patient's pre-existing frailty, b) the severity of the disorder that led to the patient's admission, and lastly c) the hospital structure and the process of care. 2- The prevention of "iatrogenic disability" involves successive stages. - becoming aware that hospitalization may induce dependence. Epidemiological studies have identified at-risk populations by the use of composite scores (HARP, ISAR, SHERPA, COMPRI, etc). - considering that functional decline is not a fatality. Quality references have already been defined. Interventions to prevent dependence in targeted populations have been set up: simple geriatric consultation teams, single-factor interventions (aimed for example at mobility, delirium, iatrogenic disorders) or multidomain interventions (such as GEM and ACE units, HELP, Fast Track, NICHE). These interventions are essentially centered on the patient's frailty and have limited results, as they take little account of the way the institution functions, which is not aimed at prevention of functional decline. The process of care reveals shortcomings: lack of geriatric knowledge, inadequate evaluation and management of functional status. The group suggests that interventions must not only identify at-risk patients so that they may benefit from specialized management, but they must also target the hospital structure and the process of care. This requires a graded "quality approach" and rethinking of the organization of the hospital around the elderly person.

Rapid cognitive decline, one-year institutional admission and one-year mortality: analysis of the ability to predict and inter-tool agreement of four validated clinical frailty indexes in the SAFEs cohort.

OBJECTIVES: To evaluate the predictive ability of four clinical frailty indexes as regards one-year rapid cognitive decline (RCD - defined as the loss of at least 3 points on the MMSE score), and one-year institutional admission (IA) and mortality respectively; and to measure their agreement for identifying groups at risk of these severe outcomes. DESIGN: One-year follow-up and multicentre study of old patients participating in the SAFEs cohort study. SETTING: Nine university hospitals in France. PARTICIPANTS: 1,306 patients aged 75 or older (mean age 85±6 years; 65% female) hospitalized in medical divisions through an Emergency department. MEASUREMENTS: Four frailty indexes (Winograd; Rockwood; Donini; and Schoevaerdts) reflecting the multidimensionality of the frailty concept, using an ordinal scoring system able to discriminate different grades of frailty, and constructed based on the accumulation of identified deficits after comprehensive geriatric assessment conducted during the first week of hospital stay, were used to categorize participants into three different grades of frailty: G1 - not frail; G2 - moderately frail; and G3 - severely frail. Comparisons between groups were performed using Fisher's exact test. Agreement between indexes was evaluated using Cohen's Kappa coefficient. RESULTS: All patients were classified as frail by at least one of the four indexes. The Winograd and Rockwood indexes mainly classified subjects as G2 (85% and 96%), and the Donini and Schoevaerdts indexes mainly as G3 (71% and 67%). Among the SAFEs cohort population, 250, 1047 and 1,306 subjects were eligible for analyses of predictability for RCD, 1-year IA and 1-year mortality respectively. At 1 year, 84 subjects (34%) experienced RCD, 377 (36%) were admitted into an institutional setting, and 445 (34%) had died. With the Rockwood index, all subjects who experienced RCD were classified in G2; and in G2 and G3 when the Donini and Schoevaerdts indexes were used. No significant difference was found between frailty grade and RCD, whereas frailty grade was significantly associated with an increased risk of IA and death, whatever the frailty index considered. Agreement between the different indexes of frailty was poor with Kappa coefficients ranging from -0.02 to 0.15. CONCLUSION: These findings confirm the poor clinimetric properties of these current indexes to measure frailty, underlining the fact that further work is needed to develop a better and more widely-accepted definition of frailty and therefore a better understanding of its pathophysiology.

Predictors of institution admission in the year following acute hospitalisation of elderly people.

OBJECTIVES: The aim of the study was to identify factors related to institutionalisation within one-year follow up of subjects aged 75 or over, hospitalised via the emergency department (ED). DESIGN: Prospective multicentre cohort. SETTING: Nine French university teaching hospitals. PARTICIPANTS: One thousand and forty seven (1 047) non institutionalised subjects aged 75 or over, hospitalised via ED. A sub-group analysis was performed on the 894 subjects with a caregiver. MEASUREMENTS: Patients were assessed using Comprehensive Geriatric Assessment (CGA) tools. Cox survival analysis was performed to identify predictors of institutionalisation at one year. RESULTS: Within one year after hospital admission, 210 (20.1%) subjects were institutionalised. For the overall study population, age >85 years (HR 1.6; 95%CI 1.1-2.1; p=0.005), inability to use the toilet (HR 1.6; 95%CI 1.1-2.4; p=0.007), balance disorders (HR 1.6; 95%CI 1.1-2.1; p=0.005) and presence of dementia syndrome (HR 1.9; 95%CI 1.4-2.6; p<0.001) proved to be independent predictors of institutionalisation; while a greater number of children was inversely linked to institutionalisation (HR 0.8; 95%CI 0.7-0.9; p<0.001). Bathing was of borderline significance (p=.09). For subjects with a caregiver, initial caregiver burden was significantly linked to institutionalisation within one year, in addition to the predictors observed in the overall study population. CONCLUSIONS: CGA performed at the beginning of hospitalisation in acute medical wards is useful to predict institutionalisation. Most of the predictors identified can lead to targeted therapeutic options with a view to preventing or delaying institution admission.

The geriatric patient: use of acute geriatrics units in the emergency care of elderly patients in France.

We studied the factors influencing the choice of admission to Geriatrics units, instead of other acute hospital units after an emergency visit. We report the results from a cohort of 1283 randomly selected patients aged >75 years hospitalized in emergency and representative of the French University hospital system. All patients underwent geriatric assessment. Baseline characteristics of patients admitted to Geriatrics and other units were compared. A center effect influencing the use of Geriatrics units during emergencies was also investigated. Admission to a Geriatrics unit during the acute care episode occurred in 499 cases (40.3%). By multivariate analysis, 4 factors were related to admission to a Geriatrics unit: cognitive disorder: odds ratio (OR)=1.79 (1.38-2.32) (95% confidence interval=95% CI); "failure to thrive" syndrome OR=1.54 (1.01-2.35), depression: OR=1.42 (1.12-1.83) or loss of Activities of Daily Living (ADL): OR=1.35 (1.04-1.75). The emergency volume of the hospital was inversely related to the use of Geriatrics units, with high variation that could be explained by other unstudied factors. In the French University Emergency Healthcare system, the "geriatrics patient" is defined by the existence of cognitive disorder, psychological symptoms or installed loss of autonomy. Nevertheless, considerable nation-wide variation was observed underlining the need to clarify and reinforce this discipline in the emergency healthcare system.

Predictive factors of hospitalizations in Alzheimer's disease: a two-year prospective study in 686 patients of the REAL.FR study.

BACKGROUND: During the course of the Alzheimer's disease (AD), many patients need to be hospitalized either due to the direct consequences of the disease itself, or due to associated diseases or life event. The objective of the present study was to determine predictive factors for hospitalisation in AD patients. METHODS: Six hundred eighty-six AD patients from the French Network on AD (REAL-FR) were follow up and assessed every 6 months for 2 years. During follow-up, all events occurring between two visits, in particular hospital admissions were carefully recorded. RESULTS: Annual incidences for hospitalizations were 26.13% (95% CI, 22.52 to 29.74). After two years, 202 subjects were hospitalized for 296 hospitalizations. Three variables were found to be significant predictors of hospitalisations in the multivariate regression model: dependency for ADL (RR=0.81; 95% CI: 0.70-0.95, p=0.0091), the drug use (use of four or more drugs) (RR=1.83; 95% CI: 1.31-2.58, p=0.0005) and the NPI score (RR=1.011; 95% CI: 1.001-1.022, p=0.0427). For hospitalizations due to the direct consequences of the disease itself, three variables were found to be significant predictors of hospitalisations: dependency for ADL (RR=0.69; 95% CI: 0.53-0.88, p=0.0033), the caregiver burden Zarit score (RR=1.03; 95% CI: 1.01-1.05, p=0.0079) and the NPI score (RR=1.07; 95% CI: 1.03-1.12, p=0.0007). CONCLUSIONS: Intervention to support patients and caregivers to manage loss of ADL may be a practical approach to reduce hospitalisation. Prevention of drug use or optimal treatment of associated diseases in AD seem to be also a challenge to decrease the rates of hospitalization or readmission, and the costs of providing care.

Orexins/hypocretins and orexin receptors in apoptosis: a mini-review.

An unexpected and fascinating aspect of the neuropeptides orexins has recently emerged when it was shown that orexins acting at orexin receptors OX1R or OX2R induce dramatic apoptosis resulting in massive reduction in cell growth in various cancer cell lines. This mini-review will provide the reader with recent findings related to the proapoptotic actions of orexins and the entirely novel mechanism whereby the seven membrane-spanning G-protein-coupled receptor (GPCR) OX1R triggers apoptosis. Recent data show that orexins induce tyrosine phosphorylation of the tyrosine-based motifs - immunoreceptor tyrosine-based inhibitory motif and immunoreceptor tyrosine-based switch motif - in OX1R. These phosphorylations result in the recruitment and activation of the phosphotyrosine phosphatase SHP-2 and subsequent cytochrome c-mediated mitochondrial apoptosis. Finally, this mini-review will also speculate on: (1) the potential importance of tyrosine-based motifs in the large family of GPCRs; (2) the interest of orexin receptors as therapeutic targets in cancer therapy; (3) the possible role of orexin receptor-mediated apoptosis in physiology and pathophysiology in the brain (neurodevelopment, neurodegenerative diseases) and in the periphery.

Descriptive analysis of hospitalizations of patients with Alzheimer's disease: a two-year prospective study of 686 patients from the REAL.FR study.

OBJECTIVES: There is lack of data on the frequency and the causes of hospitalization in mild to moderate Alzheimer's disease (AD) patients. The aims of the present study were to evaluate the frequency and the causes of hospitalization in a large prospective cohort of mild to moderate patients with AD. DESIGN: Six hundred and eighty-six AD patients from the French Network on AD (REAL.FR) were followed up and assessed every 6 months for 2 years. During follow-up, all events occurring between two visits, in particular hospital admissions or nursing home placements were carefully recorded. RESULTS: Annual incidences for hospitalizations were 26.2% (95% CI, 22.5 to 29.7). After two years, 202 subjects were hospitalized for 296 hospitalizations. 139 subjects were hospitalized once, 40 twice, 13 three times, 4 four times and 2 five times during the two-year follow-up. The duration of hospitalization was 14.3 +/- 23.5 days. For repeated hospitalizations, the time interval between the first and the second hospitalization was 176.4 days (SD 150.2) and the cause of multiple hospitalizations was most different. Fractures and falls not causing fracture were the main reasons for hospital admission (20.9%), followed by cardiovascular disorders (14.5%) and by behavioural disorders (11.0%). Admission due to associated diseases or life events was the main reason for hospitalization (75.7%). CONCLUSIONS: Hospitalization is a frequent event for AD patients even at mild to moderate stage of the disease. In this cohort, the major causes for hospital admission were due to associated diseases or life events and not due to the direct consequences of the disease itself.

Biomarkers in Alzheimer's disease: not yet surrogate endpoints.

Clinical tests are currently used as endpoints in Alzheimer's disease (AD) trials to measure disease progression based on cognitive, functional, or overall decline. These endpoints are not a perfect reflection of the underlying disease pathology and may be insensitive to disease progression, especially in early AD. Furthermore, they are subject to high variability, leading to large sample sizes and long trial durations. A biomarker that could better reflect AD progression and also predict clinical benefits of drug treatments-a surrogate endpoint-would be of great use. Currently, no surrogate endpoints have been validated in AD. Structural imaging seems to be a better candidate than plasma or CSF biomarkers, but is not yet validated as a surrogate endpoint. More prospective clinical trials are needed for the validation process. While AD biomarkers cannot currently be used as formal surrogate markers, they may nonetheless be useful measures in clinical trials alongside clinical outcomes.