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Bipolar Disorder (BD) in children and adolescents is poorly understood and underdiagnosed. We describe its clinical manifestations, its interweaving of comorbidity with frequent psychopathological manifestations

Posttraumatic Stress Disorder (PTSD) occurs generally two months after an acute stress. We challenge the opportunity to observe an increase of PTSD after the end of the confinement induced by the pandemic of covid-19. PTSD can develop in response to exposure to an extremely stressful or traumatic event, or an exceptionally threatening situation. Examples include rape, violent attack, severe accidents, sudden destruction of home or community, or harm to close relatives or friends, but as well after confinement. The present paper tries to prevent from the consequences of fear of pandemic and confinement.

It appears that bipolar patients suffer from cognitive difficulties whereas they are in period of thymic stability. These intercritical cognitive difficulties are fairly stable and their severity is correlated with the functional outcome of patients. Nevertheless, the profile of cognitive impairment varies significantly from study to study quantitatively and qualitatively. According to the studies, the authors find difficulties in terms of learning, verbal memory, visual memory, working memory, sustained attention, speed of information processing, functions executive. On the other hand, deficits of general intelligence, motor functions, selective attention, and language are not usually found. One of the reasons for the heterogeneity of results is the difficulty of exploring cognition in bipolar disorder. Many factors must be taken into account, such as the presence of residual mood symptoms, the longitudinal history of the disorder (age of onset, number of episodes due, among others, the neurotoxic impact of depressive episodes and deleterious cognitive effects). (length of hospitalization), level of disability severity, comorbidities (particularly addictive).

BackgroundThe costimulatory receptor CD137 (also known as 4-1BB and TNFRSF9) plays an important role in sustaining effective cytotoxic T cell immune responses and its agonism has been investigated as a cancer immunotherapy. In clinical trials, the systemic administration of the 1st generation CD137 agonist monotherapies, utomilumab and urelumab, were suspended due to either low anti-tumor efficacy or hepatotoxicity mediated by recognized epitope on CD137 and FcγR ligand-dependent clustering.MethodsM9657, a bispecific antibody was engineered a tetravalent bispecific antibody (mAb2) format with the Fab portion binding to the tumor antigen Mesothelin (MSLN) and a modified CH2-CH3 domain as Fc antigen binding (Fcab) portion binding to CD137. M9657 has a human IgG1 backbone with LALA mutations to abrogate the binding to Fcγ receptor. The biological characteristics and activities of M9657 were investigated in a series of in vitro assays and the in vivo efficacy was investigated in syngeneic tumor models with FS122m, a murine-reactive surrogate with the same protein structure of M9657.ResultsM9657 binds efficiently to both human and Cynomolgus CD137 as well as MSLN. In the cellular functional assay, M9657 displayed MSLN- and TCR/CD3 interaction (signal 1)-dependent cytokine release and tumor cell cytotoxicity associated with Bcl-XL activation and immune memory formation. FS122m demonstrated potent MSLN- and dose- dependent in vivo anti-tumor efficacy (figure 1). Comparing with 3H3, a Urelumab surrogate Ab, FS122m displayed an improved therapeutic window with significantly lower for on-target /off-tumor toxicity.ConclusionsTaken together, M9657 exhibits a promising developability profile as a tumor-targeted immune agonist with potent anti-cancer activity, but without systemic immune activation.Ethics ApprovalAll animal experiments were performed in accordance with EMD Serono Research & Development Institute (protocol 17-008, 20-005) and Wuxi AppTec Animal Care and Use Committee (IACUC) guidelines.Abstract 757 Figure 1FS122m displayed dose-dependent anti-tumor efficacy

Treating the signs and symptoms of anxiety is an everyday challenge in clinical practice. When choosing between treatment options, anxiety needs to be understood in the situational, psychiatric, and biological context in which it arises. Etifoxine, a non-benzodiazepine anxiolytic drug belonging to the benzoxazine class, is an effective treatment for anxiety in response to a stressful situation. In the present review, we focused on several aspects of the cerebral and somatic biological mechanisms involved in anxiety and investigated the extent to which etifoxine’s mode of action can explain its anxiolytic activity. Its two mechanisms of action are the modulation of GABAergic neurotransmission and neurosteroid synthesis. Recent data suggest that the molecule possesses neuroprotective, neuroplastic, and anti-inflammatory properties. Etifoxine was first shown to be an effective anxiolytic in patients in clinical studies comparing it with clobazam, sulpiride, and placebo. Randomized controlled studies have demonstrated its anxiolytic efficacy in patients with adjustment disorders (ADs) with anxiety, showing it to be superior to buspirone and comparable to lorazepam and phenazepam, with a greater number of markedly improved responders and a better therapeutic index. Etifoxine’s noninferiority to alprazolam has also been demonstrated in a comparative trial. Significantly less rebound anxiety was observed after abrupt cessation of etifoxine compared with lorazepam or alprazolam. Consistent with this finding, etifoxine appears to have a very low dependence potential. Unlike lorazepam, it has no effect on psychomotor performance, vigilance, or free recall. Severe adverse events are in general rare. Skin and subcutaneous disorders are the most frequently reported, but these generally resolve after drug cessation. Taken together, its dual mechanisms of action in anxiety and the positive data yielded by clinical trials support the use of etifoxine for treating the anxiety signs and symptoms of individuals with ADs.

Resume Introduction Les metastases cutanees (MC) localisees aux extremites sont des complications exceptionnelles des cancers solides, au pronostic severe. Dans la majorite des cas, elles simulent une infection. Nous en rapportons deux nouvelles observations de presentation originale. Observations Cas no 1 : un homme de 71 ans consultait pour suspicion de botryomycomes de la main gauche evoluant depuis 3 mois. Il avait pour antecedent deux carcinomes epidermoides (lingual et pulmonaire) en remission. L’examen clinique objectivait trois lesions bourgeonnantes de la main gauche. La biopsie d’une des lesions concluait a une metastase de carcinome epidermoide. Au bilan d’extension, on notait l’apparition de micronodules pulmonaires dissemines suspects de localisations secondaires. Cas no 2 : un homme de 68 ans consultait pour un œdeme du membre inferieur droit infiltre, dur, mal limite, qui evoluait depuis plusieurs mois. Six mois auparavant, il avait eu un adenocarcinome bronchique traite par lobectomie superieure gauche et dont le bilan d’extension ne revelait pas de lesion secondaire. Cliniquement, on notait un œdeme indure predominant au pied. La biopsie cutanee objectivait une metastase d’adenocarcinome. Le bilan d’extension montrait des lesions osteolytiques du tarse droit ainsi que des adenomegalies. Discussion Nous rapportons deux cas originaux de MC des extremites ayant permis de diagnostiquer une evolution tumorale. Il s’agit d’une complication rare, de presentation clinique variable, ayant un impact sur la prise en charge du cancer et sur le pronostic vital du patient. Ces observations illustrent l’importance d’evoquer le diagnostic en cas de lesions cutanees distales persistantes, a fortiori en cas d’antecedents neoplasiques.

The discovery of benzodiazepine (BZD) receptors provided the impetus to discover and develop anxioselective anxiolytics. The beginning of an anxioselective mechanism of action was based on the γ-aminobutyric acid A (GABAA) receptor that resulted in clinical trials of multiple compounds. The BZD receptors were found to decrease brain serotonin (5HT) concentrations, so the second step was to find agonists or antagonists of 5HT receptors. Finally, serotonin reuptake inhibitors were used as anxiolytics. The serotonin receptors were explored to better understand the role of serotonin in the mechanism of action of anxiolytics. A part of this mechanism of action could be explained through glutamatergic action or neuropeptide regulation. The most studied neuropeptide was cholecystokinin which is a panicogenic agent, but unfortunately, to date there is no drug issued of this research. Other neuropeptides seem to play a role in anxiety disorders: corticotropin-releasing hormone, substance P and neurokinins, galanin, oxytocin, and atrial natriuretic peptide. Classic antidepressants, like tricyclics and SSRIs, have an anxiolytic activity which seems different from their antidepressant mechanism of action. The mechanism of action of anxiolytics is probably the result of the interaction of GABA and serotonin more or less modulated by neuropeptides. The role of glutamate is questionable as it regulates GABA activity. Adenosine interactions with serotonin and GABA could be an option.

Discovered in the 1950s, melatonin is a natural hormone produced by our body. Its secretion is influenced by the alternation of day and night and by environmental factors. Because of its pharmacological properties, it is given many properties, some of which are still to be explored, such as antioxidant effects, oncostatic, antiaging, or a role in the immune system. More recently, more and more research on this molecule has focused on the potential hypnotic power of melatonin, nicknamed “sleep hormone.” Because of its pharmacological properties, it has many properties, some of which are still to be explored, such as antioxidant effects, oncostatic, anti-aging, or a role in the immune system. More recently, more and more research on this molecule has focused on the potential hypnotic power of melatonin, nicknamed “sleep hormone.” Indeed, insomnia is a widespread phenomenon in the population, and we find sleep disorders at any age of life. Insomnia affects nearly a quarter of French people, especially women and the elderly. Melatonin has a certain role in the resynchronization of our biological clock; it is wise to ask if this hormone can bring a benefit in insomnia, in a country that remains the leading consumer of sleeping pills in Europe and at a time when we find more and more a desire to heal by natural methods. Its efficacy has been demonstrated in the treatment of circadian rhythm desynchronization syndromes; this thesis aims to clarify the place that a melatonin intake can occupy in the therapeutic arsenal of the management of insomnia and to recall the advice promoting better sleep.

As people grow older, side effects due to the modification of pharmacokinetics are the main disadvantage in the use of psychotropic drugs in geriatrics. This is why it is important to know the large variations of the pharmacokinetic parameters in the elderly subject. The main modifications are related with kidney functions. However, aging can alter the sensitivity of central nervous system receptors, mainly dopaminergic receptors.

Context: Nowadays, clinical tools are available to evaluate the functional impact of speech disorders in neurological conditions, but few are validated in oncology. Because of their location, cancers of the upper aerodigestive tract directly impact patients’ communication skills. Two questionnaires exist in French, the Speech Handicap Index (SHI) and the Phonation Handicap Index (PHI), but none are specifically validated for the head and neck cancer population. Our aim is to evaluate the validity of these 2 questionnaires in a population of patients treated for oral cavity or oropharyngeal cancer. Material and Method: Eighty-seven patients treated for cancer of the oral cavity or oropharynx, and 21 controls filled in the questionnaires during a consultation or 1-day hospitalization. Validation was studied by the analysis of convergent and discriminant validity, clinical validity, criterion validity, and internal consistency. Results: The 2 questionnaires present a coherent structure in 2 distinct dimensions for the SHI, and in 3 dimensions for the PHI. Both tools discriminate patients and healthy subjects (p value 0.42). Lastly, the internal consistency is good (Cronbach’s α > 0.71). Conclusion: In patients treated for oral cavity or oropharyngeal cancer, the SHI and PHI are 2 valid and reliable tools for the self-assessment of speech disability. A limitation can be found about criterion validity, because a true gold standard does not exist at the moment. However, the reduced number of questions of the PHI, which implies a shorter completion, leads to prefer this tool over the SHI.

International audience

The depressive states of the elderly are frequent and difficult to diagnose due mainly to their clinical heterogeneity. One of the reasons for the increase in the rate of suicide in the over 80 years is probably the non-recognition of depressive states.

It is increasingly diffi cult to defi ne what an anxiolytic is, since anxiety is multiple although many symptoms are common. On the other hand the most used drugs in different forms of anxiety were fi rst used as antidepressants. This article tries to put together the different effective anxiolytics used and describe their pharmacology.

Bringing a child into the world causes a lot of upheaval and it is normal, after childbirth, to feel sometimes happy, sometimes sad and irritable.

Alcohol use disorder or alcoholism is characterized by uncontrollable alcohol use and intoxication, as well as a heightened state of anxiety after alcohol withdrawal. Ethanol-associated stimuli also drive the urge to drink by means of classical conditioning. Alcoholism has been considered a dopamine (DA) dysregulation syndrome that involves the activity of the central amygdala circuitry of anxiety. Cholecystokinin (CCK) is the most abundant neuropeptide in the mammal brain, where it activates two receptors, CCK1 and CCK2. Genetic evidence relates CCK1 receptors to alcoholism in humans. CCK2 activity has been associated with the onset of human anxiety. CCK modulates DA release in the nucleus accumbens (NAc) and it is expressed in the γ-aminobutyric acid (GABA)-expressing basket interneurons in the cerebral cortex. CCK interacts with serotonin (5-HT) neurotransmission through 5-HT3 receptors to regulate mesocorticolimbic pathways and with GABA to attenuate anxiety in the amygdala. Finally, CCK stimulates the release of orexins and oxytocin in the hypothalamus, two relevant hypothalamic neuropeptides involved in signaling satiety for ethanol and well-being respectively. Given the "dimmer-switch" function of endogenous CCK in the neurotransmission by 5-HT, DA, GABA, and glutamate in normal and pathological behaviors (Ballaz and Bourin, 2020), we hypothesize that CCK adjusts functioning of the reward and anxiety circuitries altered by ethanol. This review gathers data supporting this hypothesis, and suggests mechanisms underlying a role for endogenous CCK in alcoholism.

Disorders now well identified and recognized by caregivers are observed post stroke especially fatigue and depression. The patient and especially his family must be informed, to reduce the destabilizing effect of finding a loved one different from that known before the stroke, especially when returning home. The disorders can change over time or be improved by medication. Sometimes, they will permanently alter the character or behavior of the person, psychological help to the patient and his relatives is often useful.

Multiple myeloma (MM) is an incurable B cell neoplasia characterized by the accumulation of tumor plasma cells within the bone marrow (BM). As a consequence, bone osteolytic lesions develop in 80% of patients and remain even after complete disease remission. We and others had demonstrated that BM-derived mesenchymal stromal cells (MSCs) are abnormal in MM and thus cannot be used for autologous treatment to repair bone damage. Adipose stromal cells (ASCs) represent an interesting alternative to MSCs for cellular therapy. Thus, in this study, we wondered whether they could be a good candidate in repairing MM bone lesions. For the first time, we present a transcriptomic, phenotypic, and functional comparison of ASCs from MM patients and healthy donors (HDs) relying on their autologous MSC counterparts. In contrast to MM MSCs, MM ASCs did not exhibit major abnormalities. However, the changes observed in MM ASCs and the supportive property of ASCs on MM cells question their putative and safety uses at an autologous or allogenic level.

Cholecystokinin (CCK), through the CCK-2 receptor, exerts complex effects on anxiety. While CCK agonists are panicogenic, CCK-2 antagonists fail to alleviate human anxiety. Preclinical studies with CCK-2 antagonists are also inconsistent because their anxiolytic effects largely depend on the behavioral paradigm and antecedent stress. The controversy might be accounted by the neuromodulatory role for CCK in anxiety which is ill-defined. If this is its actual role, blocking CCK-2 will have carry-over effects on the anxiety baseline over time. To test this hypothesis, the consequences of acute administration of the CCK-2 antagonist Ly225.910 (0.1 mg Kg(−1)) was evaluated in the temporal expression of aversion toward exploration-conflicting tasks. Ly225.910 effects were evaluated in rats exposed to the elevated plus-maze (EPM) twice, an approach-avoidance anxiety-like test. While LY225.910-treated rats had less anxiety than vehicle-treated rats, the difference was reversed during the EPM retest 24 hours later without drug. Moreover, Ly225.910 effects in stress-induced cognitive impairment was measured giving the novel-object discrimination (NOD) test to rats not habituated to the exploration apparatus to elicit neophobia. After a first encounter with objects (“old”), Ly225.910-treated rats did not recognize the “novel” object introduced 6 hours later. Ly225.910-exposed rats did not discriminate the new location of the “novel object” when it was repositioned in the arena 24 hours later. Ly225.910-treated rats also failed to explore objects. In line with its neuromodulatory role, aversive carry-over effects of Ly225.910 suggest that CCK-2 activation by endogenous CCK, rather than triggering anxiety, may return the anxiety state to its normal level.

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.

Antidepressants regardless of the mechanism of action can cure only 70% of depressed patients. There is therefore a category of depression that is called resistant. The co-administration of antidepressants of a different nature can alleviate this deficit. However, it seems necessary to develop active drugs in the resistant depression to develop animal models or even experimental strategies. The purpose of this chapter is to suggest ways to develop new drugs that may be effective in the treatment of resistant depression. Animal models of depression have been developed with a focus on those likely to demonstrate useful drugs in resistant depression or associations. Genetic or pharmacological leads are also mentioned.

Introduction: Anxiety disorders manifest in women more than in men by almost twofold. This narrative review aims to summarize the sex-related biological factors, which underpin anxiety, focusing on the interactions of sex and tryptophan/serotonin with anxiety. Methods: A literature search was conducted using Google Scholar, PubMed/MEDLINE, Scopus, and EMBASE databases from inception until December 31, 2017. Results: This review shows that sex may interact with many serotonin functions thereby modulating anxiety, including 5-HT1A and 5-HT2C receptors, 5-HT transporter and central 5-HT concentrations and metabolism. Sex-steroids modulate the expression of serotonin transporter genes, creating a difference in serotonin availability. Sex and estrous cycle phases lead to varying anxiety responses to tryptophan depletion. Testosterone, progesterone and estrogen are important factors in mediating sex differences in serotonin responses to anxiety-generating behavioral tests. At prenatal levels, there are sexrelated differences in the reciprocal relationships between serotonin and the HPA-axis, which modulate anxiety-like behaviors. Activated immune-inflammatory pathways induce indoleamine-2,3-dioxynease (IDO) and the tryptophan catabolite (TRYCAT) pathway thereby increasing tryptophan degradation and increasing the production of TRYCATs including kynurenine and quinolinic acid, which may create an overall anxiogenic effect. The effects of immune activation on IDO are significantly more pronounced in women than men, and therefore, females may show increased levels of anxiogenic TRYCAT following immune challenge. Aberrations in the IDO-activated TRYCAT pathway are found in pregnant females and parturients and are associated with increased anxiety levels in the postnatal period. Conclusion: The results of this review underscore the necessity of studying the associations between serotonin and anxiety in both sexes taking into account the effects of immune activation on IDO and production of anxiogenic TRYCATs. Future anxiety research should focus on the interactions between serotonin/tryptophan and sex, sex hormones, the menstrual cycle, pregnancy, the HPA axis and the immune system through the production of anxiogenic TRYCATs.

Until recently, there was the belief that people with bipolar disorder were not fi t to be treated with psychological therapies, which has been widely denied in recent years. While it is true that the effects of therapy are not immediate, psychoeducation also demonstrates its long-term benefi ts in people with bipolar disorder who have attended these therapies on an ongoing basis. Psychoeducation is a very important topic often neglected, but it is a very important task of physicians to well explain to patients and their families what is the illness and to prevent depression or manic and hypomanic episodes. Psychoeducation for patients with bipolar disorder aims to overcome the therapeutic challenges posed by the disease by making patients actors in their care [1].

Objective To examine the effect of different sources of Good Manufacturing Practice clinical grade adipose-derived mesenchymal stem cells (AD-MSCs) on inflammatory factors in osteoarthritic (OA) chondrocytes and synoviocytes. Methods AD-MSCs from infrapatellar Hoffa fat, subcutaneous (SC) hip fat, and SC abdominal fat were cocultured in Transwells with chondrocytes or synoviocytes. Inflammatory factors (interleukin-1β [IL-1β], tumor necrosis factor α, IL-6, CXCL1/growth-related oncogene α, CXCL8/IL-8, CCL2/monocyte chemotactic protein 1, CCL3/macrophage inflammatory protein 1α, and CCL5/RANTES) were evaluated by quantitative reverse transcription–polymerase chain reaction or multiplex bead–based immunoassay. The role of different immunomodulators was analyzed. Results All the inflammatory factors analyzed were down-modulated at the messenger RNA or protein level independently by all 3 AD-MSC sources or by allogeneic AD-MSCs used in coculture with chondrocytes or synoviocytes. Inflammatory factor down-modulation was observed only when AD-MSCs were cocultured with chondrocytes or synoviocytes that produced high levels of inflammatory factors, but no effect was observed in cells that produced low levels of those factors, thus highlighting a dependence of the AD-MSC effect on existing inflammation. The immunomodulators IL-10, IL-1 receptor antagonist, fibroblast growth factor 2, indoleamine 2,3-dioxygenase 1, and galectin 1 were not involved in AD-MSC effects, whereas the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) pathway exerted a role in the mechanism of antiinflammatory AD-MSC action. Conclusion The antiinflammatory effects of AD-MSCs are probably not dependent on AD-MSC adipose tissue sources and donors but rather on the inflammatory status of OA chondrocytes and synoviocytes. AD-MSCs seem to be able to sense and respond to the local environment. Even though a combination of different molecules may be involved in AD-MSC effects, the COX-2/PGE2 pathway may play a role, suggesting that AD-MSCs may be useful for therapies in osteoarticular diseases.

Animal models of depression are widely used by the pharmaceutical industry to find new molecules that are likely to have antidepressant activity in humans but also to better understand the mechanism of action of antidepressants. It is difficult to choose a model that is relevant to the purpose that has been set. These models are compromises between clinical complexity and the simplicity of the development of the experimental paradigm. Five of the most commonly utilised behavioural animal models of depression, the mouse forced swimming test (FST), the rat FST, the tail suspension test (TST), the chronic mild stress (CMS) model, the learned helplessness (LH) paradigm and a model based on neuronal deficit, the olfactory bulbectomy (OB), are discussed in this review. All these models present various symptoms of depression in animals suggested to resemble specific aspects of the human illness. Their use enables the investigation of the underlying neurobiology of depression, as well as the mechanism of action of antidepressants and the screening of potential antidepressants. It appears that the mouse FST is the most suitable animal of depression in predicting antidepressant response as it is easily and rapidly performed, robust, specific for antidepressant drugs and reproducible. Moreover, it permits a good correlation with clinical studies in a translational approach.

BACKGROUND AND OBJECTIVES: Patients with Prader–Willi syndrome (PWS) display poor feeding and social skills as infants and fewer hypothalamic oxytocin (OXT)-producing neurons were documented in adults. Animal data demonstrated that early treatment with OXT restores sucking after birth. Our aim is to reproduce these data in infants with PWS. METHODS: We conducted a phase 2 escalating dose study of a short course (7 days) of intranasal OXT administration. We enrolled 18 infants with PWS under 6 months old (6 infants in each step) who received 4 IU of OXT either every other day, daily, or twice daily. We investigated the tolerance and the effects on feeding and social skills and changes in circulating ghrelin and brain connectivity by functional MRI. RESULTS: No adverse events were reported. No dose effect was observed. Sucking assessed by the Neonatal Oral-Motor Scale was abnormal in all infants at baseline and normalized in 88% after treatment. The scores of Neonatal Oral-Motor Scale and videofluoroscopy of swallowing significantly decreased from 16 to 9 (P < .001) and from 18 to 12.5 (P < .001), respectively. Significant improvements in Clinical Global Impression scale scores, social withdrawal behavior, and mother–infant interactions were observed. We documented a significant increase in acylated ghrelin and connectivity of the right superior orbitofrontal network that correlated with changes in sucking and behavior. CONCLUSIONS: OXT is well tolerated in infants with PWS and improves feeding and social skills. These results open perspectives for early treatment in neurodevelopment diseases with feeding problems.

Air pollution in trace elements (TE) remains a concern for public health in Europe. For this reasons, networks of air pollution concentrations or exposure are deployed, including a moss bio-monitoring programme in Europe. Spatial determinants of TE concentrations in mosses remain unclear. In this study, the French dataset of TE in mosses is analyzed by spatial autoregressive model to account for spatial structure of the data and several variables proven or suspected to affect TE concentrations in mosses. Such variables include source (atmospheric deposition and soil concentrations), protocol (sampling month, collector, and moss species), and environment (forest type and canopy density, distance to the coast or the highway, and elevation). Modeled atmospheric deposition was only available for Cd and Pb and was one of the main explanatory variables of the concentrations in mosses. Predicted soil content was also an important explanatory variable except for Cr, Ni, and Zn. However, the moss species was the main factor for all the studied TE. The other environmental variables affected differently the TE. In particular, the forest type and canopy density were important in most cases. These results stress the need for further research on the effect of the moss species on the capture and retention of TE, as well as for accounting for several variables and the spatial structure of the data in statistical analyses.

Pediatric dysphagia is specific because of the different developmental stages from the neonatal period to the infancy. Diagnosis and treatment will be different if it concerns a newborn or a young child having already experienced oral feeding. Furthermore, swallowing and feeding disorders, having a direct impact on the nourishment function of the parents, will have repercussions on the child–parents relationship. Swallowing disorders are frequently multifaceted, and impairments can be morphological, functional or induced. The assessment of these disorders includes anamnesis (reviewing family, medical, developmental, and feeding history), physical examination (searching for nutritional impact, cardiopulmonary state and looking for developmental anomalies or genetic dysmorphism), swallowing evaluation (analyzing oropharyngolaryngeal structure and function by observation, fiber-optic endoscopy, videofluoroscopy, ultrasonography), and feeding evaluation (implicating parents and caregivers). Management of these disorders is a complex task, thus an interdisciplinary team and recurrent assessments are required so as to match the child’s development and capacities. Its main aims are to prevent repercussions on developmental milestones and to assure the safety of the child and the psychological balance of child–parents relationship.

Non-revascularizable critical limb ischemia (CLI) is the most severe stage of peripheral arterial disease, with no therapeutic option. Extensive preclinical studies have demonstrated that adipose-derived stroma cell (ASC) transplantation strongly improves revascularization and tissue perfusion in ischemic limbs. This study, named ACellDREAM, is the first phase I trial to evaluate the feasibility and safety of intramuscular injections of autologous ASC in non-revascularizable CLI patients.Seven patients were consecutively enrolled, on the basis of the following criteria: (i) lower-limb rest pain or ulcer; (ii) ankle systolic oxygen pressure 50 or 70 mm Hg for non-diabetic and diabetic patients, respectively, or first-toe systolic oxygen pressure 30 mm Hg or 50 mm Hg for non-diabetic and diabetic patients, respectively; (iii) not suitable for revascularization. ASCs from abdominal fat were grown for 2 weeks and were then characterized.More than 200 million cells were obtained, with almost total homogeneity and no karyotype abnormality. The expressions of stemness markers Oct4 and Nanog were very low, whereas expression of telomerase was undetectable in human ASCs compared with human embryonic stem cells. ASCs (10(8)) were then intramuscularly injected into the ischemic leg of patients, with no complication, as judged by an independent committee. Trans-cutaneous oxygen pressure tended to increase in most patients. Ulcer evolution and wound healing showed improvement.These data demonstrate the feasibility and safety of autologous ASC transplantation in patients with objectively proven CLI not suitable for revascularization. The improved wound healing also supports a putative functional efficiency.

Objective Mesenchymal stem cells (MSCs) represent a promising tool for cell therapy for several disorders, among them the osteoarticular diseases. For such clinical applications, intraarticular (IA) injection of MSCs may be favored for higher levels of safety and targeting of specific joints. Although the safety of intravenous (IV) administration of MSCs has been reported in a number of clinical trials, the safety and biodistribution of MSCs after IA injection have not been tested. Our objective was to assess the toxicity of clinical-grade human adipose-derived MSCs (AD-MSCs), as well as their biodistribution, after IA injection into SCID mice. Methods SCID mice received IA or IV administration of 106 human AD-MSCs. Several tissues were recovered at different time points and processed for histologic assessment or real-time polymerase chain reaction (PCR) analysis. A highly sensitive assay was used to monitor the distribution of AD-MSCs, based on amplification of human-specific Alu sequences. Results Absence of toxicity was observed after AD-MSC infusion. Alu PCR assay revealed a high sensitivity (1 human AD-MSC/105 murine cells), with a large linear range (1–5 × 104/105 murine cells). Importantly, 15% of the IA-injected AD-MSCs were detectable in the joint for the first month and 1.5% of the AD-MSCs engrafted over the long term, at least 6 months. AD-MSCs were observed in the injected joints and in areas of tissue referred to as stem cell niches, such as the bone marrow, adipose tissue, and muscle. Conclusion These data support the feasibility and safety of using IA delivery of human AD-MSCs in the treatment of rheumatic diseases that affect the joints.

Background aims Adipose tissue is a rich and very convenient source of cells for regenerative medicine therapeutic approaches. However, a characterization of the population of adipose-derived stromal and stem cells (ASCs) with the greatest therapeutic potential remains unclear. Under the authority of International Federation of Adipose Therapeutics and International Society for Cellular Therapy, this paper sets out to establish minimal definitions of stromal cells both as uncultured stromal vascular fraction (SVF) and as an adherent stromal/stem cells population. Methods Phenotypic and functional criteria for the identification of adipose-derived cells were drawn from the literature. Results In the SVF, cells are identified phenotypically by the following markers: CD45-CD235a-CD31-CD34+. Added value may be provided by both a viability marker and the following surface antigens: CD13, CD73, CD90 and CD105. The fibroblastoid colony-forming unit assay permits the evaluation of progenitor frequency in the SVF population. In culture, ASCs retain markers in common with other mesenchymal stromal/stem cells (MSCs), including CD90, CD73, CD105, and CD44 and remain negative for CD45 and CD31. They can be distinguished from bone-marrow-derived MSCs by their positivity for CD36 and negativity for CD106. The CFU-F assay is recommended to calculate population doublings capacity of ASCs. The adipocytic, chondroblastic and osteoblastic differentiation assays serve to complete the cell identification and potency assessment in conjunction with a quantitative evaluation of the differentiation either biochemically or by reverse transcription polymerase chain reaction. Conclusions The goal of this paper is to provide initial guidance for the scientific community working with adipose-derived cells and to facilitate development of international standards based on reproducible parameters.

International audience; An innovative experimental setup, PELIICAEN, allowing the modification of materials and the study of the effects induced by multiply charged ion beams at the nanoscale is presented. This ultra-high vacuum (below 5 × 10−10 mbar) apparatus is equipped with a focused ion beam column using multiply charged ions and a scanning electron microscope developed by Orsay Physics, as well as a scanning probe microscope. The dual beam approach coupled to the scanning probe microscope achieves nanometer scale in situ topological analysis of the surface modifications induced by the ion beams. Preliminary results using the different on-line characterization techniques to study the formation of nano-hillocks on silicon and mica substrates are presented to illustrate the performances of the setup

Background: The MESAMI 1 trial was a bicentric pilot study designed to test the feasibility and safety of intramyocardially injected autologous bone marrow-derived mesenchymal stromal cells (MSCs) for the treatment of ischemic cardiomyopathy. Methods and Results: The study included 10 patients with chronic myocardial ischemia, left ventricular (LV) ejection fractions (EFs) of ≤35%, and reversible perfusion defects who were on stable optimal medical therapy and were not candidates for revascularization. MSCs (mean: 61.5×106 cells per patient) were injected into 10-16 viable sites at the border of the LV scar via a NOGA-guided catheter. Both primary endpoints, feasibility (successful harvest, expansion, and injection of autologous MSCs) and safety (absence of severe adverse events [SAEs]) were met in all 10 patients at the 1-month follow-up time point, and none of the SAEs reported during the full 2-year follow-up period were attributable to the study intervention. The results of secondary efficacy endpoint analyses identified significant improvements from baseline to Month 12 in LVEF (29.4±2.0% versus 35.7±2.5%; p=0.003), LV end-systolic volume (167.8±18.8 mL versus 156.1±28.6 mL; p=0.04), 6- minute walk test and NYHA functional class. Conclusions: Our results suggest that autologous MSCs can be safely administered to the hearts of patients with severe, chronic, reversible myocardial ischemia and impaired cardiac function and may be associated with improvements in cardiac performance, LV remodeling, and patient functional status. A randomized, double blind, multicenter, placebo-controlled clinical trial (MESAMI 2) will evaluate the efficacy of this treatment approach in a larger patient population. Clinical Trial Registration: Unique identifier: NCT01076920