Generation of induced pluripotent stem cell lines IRMBi003-A and IRMBi003-B from a healthy donor to model Alzheimer's disease.

Induced Pluripotent Stem Cell (iPSC) lines derived from healthy individuals are helpful and essential tools for disease modelling. Here, we described the reprogramming of skin fibroblasts obtained from a healthy 59-year-old individual without Alzheimer's disease. The generated iPSC lines have a normal karyotype, expressed pluripotency markers, and demonstrated the ability to differentiate into the three germ layers. The iPSC lines will be used as controls to study Alzheimer's disease mechanisms.

Establishment of induced pluripotent stem cells IRMBi005-A from a patient with sporadic Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurological disorder and the most common form of dementia worldwide. Sporadic Alzheimer's disease (sAD) cases are the main forms, over 95% of AD cases, but still poorly understood. Thereby there is a crucial need to develop in vitro models for studying this multifactorial disorder. Here, we report the reprogramming of skin fibroblasts from a 57-years-old male donor. The new generated iPSC cell line has a normal karyotype and, is pluripotent since it demonstrates the ability to differentiate in vitro into the three germ layers. This iPSC line will be used to understand pathological mechanisms of sAD.

How do mobile health applications support behaviour changes? A scoping review of mobile health applications relating to physical activity and eating behaviours.

OBJECTIVE: The objective of this review was to analyse how researchers conducting studies about mobile health applications (MHApps) effectiveness assess the conditions of this effectiveness. STUDY DESIGN: A scoping review according to PRIMSA-ScR checklist. METHODS: We conducted a scoping review of efficacy/effectiveness conditions in high internal validity studies assessing the efficacy of MHApps in changing physical activity behaviours and eating habits. We used the PubMed, Web of Science, SPORTDiscus and PsycINFO databases and processed the review according to the O'Malley and PRISMA-ScR recommendations. We selected studies with high internal validity methodologies (randomised controlled trials, quasi-experimental studies, systematic reviews and meta-analyses), dealing with dietary and/or physical activity behaviours; covering primary, secondary or tertiary prevention and dealing with behaviour change (uptake, maintenance). We excluded articles on MHApps relating to high-level sport and telemedicine. The process for selecting studies followed a set protocol with two authors who independently appraised the studies. RESULTS: Twenty-two articles were finally selected and analysed. We noted that the mechanisms and techniques to support behaviour changes were poorly reported and studied. There was no explanation of how these MHApps work and how they could be transferred or not. Indeed, the main efficacy conditions reported by authors refer to practical aspects of the tools. Moreover, the issue of social inequalities was essentially reduced to access to the technology (the shrinking access divide), and literacy was poorly studied, even though it is an important consideration in digital prevention. All in all, even when they dealt with behaviours, the evaluations were tool-focused rather than intervention-focused and did not allow a comprehensive assessment of MHApps. CONCLUSION: To understand the added value of MHApps in supporting behaviour changes, it seems important to draw on the paradigms relating to health technology assessment considering the characteristics of the technologies and on the evaluation of complex interventions considering the characteristics of prevention. This combined approach may help to clarify how these patient-focused MHApps work and is a condition for improved assessment of MHApps in terms of effectiveness, transferability and scalability.

Generation of induced pluripotent stem cells (iPSCs) IRMBi002-A from an Alzheimer's disease patient carrying a D694N mutation in the APP gene.

Induced pluripotent stem cells (iPSC) were generated from skin fibroblasts obtained from a 58 year-old woman suffering from Alzheimer's disease and carrying a D694N mutation on Amyloid precursor protein (APP). Fibroblasts were reprogrammed into iPSC using the integration-free Sendai Virus which allows the expression of the Yamanaka factors. Verification of their pluripotency was achieved by demonstrating the expression of pluripotency markers and their differentiation potential into the three primary germ layers. The cells have the corresponding mutation and present a normal karyotype. The reported APP-D694N iPSC line may be used to model and study human AD pathology in vitro.

Generation of induced pluripotent stem cells (IRMBi001-A) from an Alzheimer's disease patient carrying a G217D mutation in the PSEN1 gene.

Induced pluripotent stem cells (iPSC) were generated from skin fibroblasts obtained from a 50 year-old patient suffering from Alzheimer's disease and carrying a G217D causal mutation on presenilin 1 (PSEN1). iPSCs were obtained following reprogramming using the integration-free Sendai Virus system which allows expression of the Yamanaka factors. Verification of their pluripotency was achieved by demonstrating the expression of pluripotency markers and their differentiation potential into the three primary germ layers. iPS cells carry the patient G217D mutation and present a normal karyotype. The reported PS1-G217D iPSC line may be used to model and study human AD pathology in vitro.

Lithium as a disease-modifying agent for prion diseases.

Prion diseases still remain incurable despite multiple efforts to develop a treatment. Therefore, it is important to find strategies to at least reduce the symptoms. Lithium has been considered as a neuroprotective agent for years, and the objective of this preclinical study was to evaluate the efficacy of lithium delivered as a water-in-oil microemulsion (Aonys®). This delivery system allows using low doses of lithium and to avoid the toxicity observed in chronic treatments. C57BL/6J mice were intracranially inoculated with ME7 prion-infected brain homogenates and then were treated with lithium from day 90 post inoculation until their death. Lithium was administered at traditional doses (16 mg/kg/day) by the gavage route and at lower doses (40 or 160 µg/kg/day; Aonys®) by the rectal mucosa route. Low doses of lithium (Aonys®) improved the survival of prion-inoculated mice, and also decreased vacuolization, astrogliosis, and neuronal loss compared with controls (vehicle alone). The extent of the protective effects in mice treated with low-dose lithium was comparable or even higher than what was observed in mice that received lithium at the traditional dose. These results indicate that lithium administered using this innovative delivery system could represent a potential therapeutic approach not only for prion diseases but also for other neurodegenerative diseases.

What do we mean by multimorbidity? An analysis of the literature on multimorbidity measures, associated factors, and impact on health services organization.

BACKGROUND: Multimorbidity is a consequence of both epidemiological and demographic transition. Unlike comorbidity, it currently has no consensus definition, making it difficult to assess its epidemiological and socioeconomic burden, to organize healthcare services rationally, and to determine the skills needed for patient self-reliance. The aim of this study is to define the spectrum of multimorbidity and to discuss current implications for the organization of care. METHODS: Two independent readers analyzed the literature indexed in PubMed, Embase, CINAHL, and Scopus. RESULTS: The bibliographic search conducted on July 16, 2013, retrieved 2287 articles (670 in PubMed, 666 in Embase, 582 in Scopus, and 369 in CINAHL). Of these, 108 articles were retained. Multimorbidity is designated by a variety of terms, none of them being MeSH terms. There is no single measure of multimorbidity, as this entity is usually studied for its functional or economic impact, rather than its causes. The prevalence varies considerably, depending on the measure used and the population studied. Factors associated with multimorbidity are age, gender, and socioeconomic characteristics of the populations studied. Studies evaluating the organization-of-care are inconclusive or insufficient. CONCLUSIONS: Multimorbidity serves as an avatar for the fundamental, recurrent problems of modern medicine and the organization-of-care. It may be defined by its causes or its consequences and reflects our concept of both individual health and its collective management. Tools that would allow a more appropriate measurement of this entity are available; we should use them to match medical reality to the needs of patients.

Gene and cell therapy for prion diseases.

Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal prion protein named PrP(Sc). PrP(Sc) results from the post-translational conformational modification of the host-encoded protein PrP(C). To date there is no treatment for this inexorably fatal disease. Hence, a major focus of research consists in the identification of new molecules that could interfere with in vivo prion propagation. Promising therapeutic approaches to block the production of PrP(Sc) are based on PrP RNA interference, passive or active immunization, dominant negative inhibition of PrP(Sc) formation, as well as inhibition of interactions between PrP(Sc) and other cofactors. Although these anti-prion molecules can be directly administered in vivo, the process to produce and purify them in high quantity is often challenging and expensive. An alternative strategy consists in the development of gene therapy systems of delivery. Importantly, the diagnosis of prion disease in humans remains difficult and often leaves a short therapeutic window after the appearance of the first clinical signs. As serious damages to the brain generally occur before clinical symptoms manifest, an ideal therapeutic strategy must target not only the formation of toxic aggregates, but also the brain destruction already incurred. This could be achieved by combining gene therapy with cell therapy. In this review we have chosen to highlight the multiple targets and potential gene or cell replacement therapeutic approaches. This review also presents the evidence for the transplantation of stem cells as well as the combination of cell and gene therapy as promising strategies against prion diseases.

Analysis of the 2004-2007 literature on therapeutic patient education in diabetes: results and trends.

The purpose of this study is to identify the recent characteristics and the developments of therapeutic education in diabetes through an analysis of the international articles published from 2004 to 2007. Studies were selected from several databases: Medline, Embase, Eric, Cochrane central database, using the following keywords: diabetes, patient education, self management, programs. Two authors independently reviewed each study and selected the data using the same categories of analysis. Articles consistently related to patient education in diabetes (80 among 118) were included. The selected articles have been published in 43 scientific journals. The majority of them concern TPE for adult patients with type 2 diabetes. TPE is delivered in several structures and education to groups of patients represents the most widespread educational strategy mostly provided by a multiprofessional team. A total of 70% of the studies show the effectiveness of TPE based on bioclinical, educational, psychosocial, economical criteria. The problem of barriers to TPE concerns 21% of the studies we have analysed and most of the authors propose the implementation of specifically-designed TPE programs as strategy to overcome them. A large number of studies still assess the positive effects of TPE. Nowadays the problems of accessibility to TPE and the barriers to this practice have become a major issue for research.

[A concept mapping study of nutritional knowledge in diabetic children and their parents]. / Etude par cartes conceptuelles des connaissances sur l'alimentation des enfants diabétiques et de leurs parents.

This study describes, using concept mapping, the nature, organization of knowledge on nutrition and its evolution following therapeutic patient education program in 5 diabetic children (8 to 9 years old) and their mothers. Before the education session, mothers and children are highly knowledgeable about food. The organization of knowledge in children is conceptual and differs from that found in mothers which is based on problems solving. After education, new knowledge and new links between old and recent knowledge testify of learning. A comparison between the maps of children and their mother reveals similarities but also differences in their preoccupations. This research shows that using the preexisting knowledge networks of parents and children could contribute to improve their education on nutrition.

[Abdomen pendulum and subcutaneous injections: the complications. Two case reports]. / Abdomen pendulum et injections sous-cutanées: les complications. A propos de deux cas.

The authors present the complications due to subcutaneous injections on two patients suffering from morbid obesity with an abdomen pendulum. In the first case, injections of heparin of low molecular weight at curative dose, for treatment of a pulmonary embolism, have been complicated with a giant abdominal wall haematoma, the biggest ever reported. The initial treatment was insufficient so we had to practice a dermolipectomy to take off the haematoma of four litters. In the second case, insulin injections were complicated with cellulitis of the abdominal wall and a surgical treatment has been practiced in emergency. The first case reminds us the importance to change the sites of injections and to accommodate the dose, surgical treatment staying as simple as possible. The second case allows us to report a rare complication, not often published but known with obese patients. These two cases illustrate the importance of therapeutic education of the patient and the fact that a simple injection can be life threatening.

Transmission and characterization of bovine spongiform encephalopathy sources in two ovine transgenic mouse lines (TgOvPrP4 and TgOvPrP59).

Transgenic mice expressing the prion protein (PrP) of species affected by transmissible spongiform encephalopathies (TSEs) have recently been produced to facilitate experimental transmission of these diseases by comparison with wild-type mice. However, whilst wild-type mice have largely been described for the discrimination of different TSE strains, including differentiation of agents involved in bovine spongiform encephalopathy (BSE) and scrapie, this has been only poorly described in transgenic mice. Here, two ovine transgenic mouse lines (TgOvPrP4 and TgOvPrP59), expressing the ovine PrP (A136 R154 Q171) under control of the neuron-specific enolase promoter, were studied; they were challenged with brainstem or spinal cord from experimentally BSE-infected sheep (AA136 RR154 QQ171 and AA136 RR154 RR171 genotypes) or brainstem from cattle BSE and natural sheep scrapie. The disease was transmitted successfully from all of these sources, with a mean of approximately 300 days survival following challenge with material from two ARQ-homozygous BSE-infected sheep in TgOvPrP4 mice, whereas the survival period in mice challenged with material from the ARR-homozygous BSE-infected sheep was 423 days on average. It was shown that, in the two ovine transgenic mouse lines, the Western blot characteristics of protease-resistant PrP (PrP(res)) were similar, whatever the BSE source, with a low apparent molecular mass of the unglycosylated glycoform, a poor labelling by P4 monoclonal antibody and high proportions of the diglycosylated form. With all BSE sources, but not with scrapie, florid plaques were observed in the brains of mice from both transgenic lines. These data reinforce the potential of this recently developed experimental model for the discrimination of BSE from scrapie agents.

[Knowledges and beliefs related to nutrition of obese and overweight patients subjects: a study in Southern Italy]. / Connaissances et croyances sur l'alimentation de patients en surpoids et obèses: enquête en Italie du Sud.

303 obese and overweight south Italian patients (240 women and 63 men), volunteers to participate in a patient education programme delivered by the university hospital of Foggia, have fullfiled a 50 items true/false test exploring the knowledges and the beliefs on obesity, nutrition, physical activities. The majority of the subjects has both low socio economical status and education level. Women have better performed than men (p<0.005) and obese patients, better than overweight subjects (p<0.005). The more frequent mistakes have concerned items on nutrition, meanwhile a better performance has been observed with the items on beliefs.

Florid plaques in ovine PrP transgenic mice infected with an experimental ovine BSE.

The occurrence of the variant Creutzfeldt-Jakob disease (vCJD), related to bovine spongiform encephalopathy (BSE), raises the important question of the sources of human contamination. The possibility that sheep may have been fed with BSE-contaminated foodstuff raises the serious concern that BSE may now be present in sheep without being distinguishable from scrapie. Sensitive models are urgently needed given the dramatic consequences of such a possible contamination on animal and human health. We inoculated transgenic mice expressing the ovine PrP gene with a brain homogenate from sheep experimentally infected with BSE. We found numerous typical florid plaques in their brains. Such florid plaques are a feature of vCJD in humans and experimental BSE infection in macaques. Our observation represents the first description, after a primary infection, of this hallmark in a transgenic mouse model. Moreover, these mice appear to be a promising tool in the search for BSE in sheep.

Efficient transmission of two different sheep scrapie isolates in transgenic mice expressing the ovine PrP gene.

We produced transgenic mice expressing the sheep prion protein to obtain a sensitive model for sheep spongiform encephalopathies (scrapie). The complete open reading frame, with alanine, arginine, and glutamine at susceptibility codons 136, 154, and 171, respectively, was inserted downstream from the neuron-specific enolase promoter. A mouse line, Tg(OvPrP4), devoid of the murine PrP gene, was obtained by crossing with PrP knockout mice. Tg(OvPrP4) mice were shown to selectively express sheep PrP in their brains, as demonstrated in mRNA and protein analysis. We showed that these mice were susceptible to infection by sheep scrapie following intracerebral inoculation with two natural sheep scrapie isolates, as demonstrated not only by the occurrence of neurological signs but also by the presence of the spongiform changes and abnormal prion protein accumulation in their brains. Mean times to death of 238 and 290 days were observed with these isolates, but the clinical course of the disease was strikingly different in the two cases. One isolate led to a very early onset of neurological signs which could last for prolonged periods before death. Independently of the incubation periods, some of the mice inoculated with this isolate showed low or undetectable levels of PrPsc, as detected by both Western blotting and immunohistochemistry. The development of experimental scrapie in these mice following inoculation of the scrapie infectious agent further confirms that neuronal expression of the PrP open reading frame alone is sufficient to mediate susceptibility to spongiform encephalopathies. More importantly, these mice provide a new and promising tool for studying the infectious agents in sheep spongiform encephalopathies.