Co-transplantation of autologous Treg cells in a cell therapy for Parkinson's disease.

The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson's disease, which makes cell replacement a promising therapeutic approach1-4. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes5-8. Here we show that the surgical procedure itself (referred to here as 'needle trauma') triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells and brain cell death. When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH- grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson's disease with 6-hydroxydopamine lesions. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH- grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons. Together, these data emphasize the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson's disease.

EEG microstate co-specificity in schizophrenia and obsessive-compulsive disorder.

The past 20 years of research on EEG microstates has yielded the hypothesis that the imbalance pattern in the temporal dynamics of microstates C (increased) and D (decreased) is specific to schizophrenia. A similar microstate imbalance has been recently found in obsessive-compulsive disorder (OCD). The aim of the present high-density EEG study was to examine whether this pathological microstate pattern is co-specific to schizophrenia and OCD. We compared microstate temporal dynamics using Bayesian analyses, transition probabilities analyses and the Topographic Electrophysiological State Source-Imaging method for source reconstruction in 24 OCD patients and 28 schizophrenia patients, respectively, free of comorbid psychotic and OCD symptoms, and 27 healthy controls. OCD and schizophrenia patients exhibited the same increased contribution of microstate C, decreased duration and contribution of microstate D and greater D → C transition probabilities, compared with controls. A Bayes factor of 4.424 for the contribution of microstate C, 4.600 and 3.824, respectively, for the duration and contribution of microstate D demonstrated that there was no difference in microstate patterns between the two disorders. Source reconstruction further showed undistinguishable dysregulations between the Salience Network (SN), associated with microstate C, and the Executive Control Network (ECN), associated with microstate D, and between the ECN and cognitive cortico-striato-thalamo-cortical (CSTC) loop in the two disorders. The ECN/CSTC loop dysconnectivity was slightly worsened in schizophrenia. Our findings provide substantial evidence for a common aetiological pathway in schizophrenia and OCD, i.e. microstate co-specificity, and same anomalies in salience and external attention processing, leading to co-expression of symptoms.

Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson's Disease.

We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson's disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.).

A Pitx3-deficient developmental mouse model for fine motor, olfactory, and gastrointestinal symptoms of Parkinson's disease.

Parkinson's disease (PD) is characterized by the selective death of substantia nigra pars compacta (SNpc) dopaminergic neurons and includes both motor and non-motor symptoms. While numerous models exist for the study of typical PD motor deficits, fewer exist for non-motor symptoms. Previous studies have shown that a Pitx3-/- mouse model (aphakia or ak mouse) has specific developmental failure of the dopaminergic neuron population in the SNpc and that it can be used for the study of PD-related gross motor dysfunction as well as cognitive functional deficits. It remains unclear whether the aphakia mouse, both male and female, might also be used to model fine motor deficits and for additional studies of non-motor deficits associated with PD. Here, using an extensive battery of behavioral tests, we demonstrate that the aphakia mouse shows both gross and fine motor functional deficits compared with control mice. Furthermore, aphakia mice show deficits of olfactory function in buried pellet, odor discrimination and odor habituation/dishabituation tests. We also found that aphakia mice suffer from gastrointestinal dysfunction (e.g., longer whole gut transit time and colon motility deficits), suggesting that the mutation also affects function of the gut-brain axis in this animal model. Moreover, our data demonstrate that in the aphakia mouse, L-DOPA, the gold standard PD medication, can rescue both gross and fine motor function deficits but neither olfactory nor gastrointestinal symptoms, a pattern much like that seen in PD patients. Altogether, this suggests that the aphakia mouse is a suitable model for fine motor, olfactory and gastrointestinal behavioral studies of PD as well as for the development of novel disease-modifying therapeutics. SIGNIFICANCE STATEMENT: While several animal models are available to study the major motor symptoms of PD, there are fewer that replicate non-motor symptoms, which constitute a major source of morbidity for patients. Moreover, available models often require manipulations resulting in sudden massive cell loss and inflammation, both of which may interfere with understanding of the direct effects of dopaminergic neuronal loss in the SNpc. We describe a model of congenital SNpc cell deficiency in a Pitx3-/- mouse and characterize it with a battery of behavioral tests suggesting that it closely mimics non-motor as well as motor symptoms of PD, providing a useful insight into the effects of the nigrostriatal dopamine deficit. Taken together, these data suggest that the ak mouse represents a useful model to study dopaminergic system function for both motor and non-motor symptoms of PD.

Cerebrospinal fluid external leak after penetrating trauma in a neurologic intact infant patient: a case report.

Cranial cerebrospinal fluid (CSF) leak is an extremely rare complication of blunt head trauma causing skull fractures, especially fractures involving the skull base. We present the case of a 10-month-old male who received glass fragments on the midline and posterior tier of his anterior fontanelle producing a cranial cerebrospinal fluid leak without any skull fracture or symptoms. Neurologic exam was completely normal and a superficial stitch wound repair was performed. He was observed for 24 h, had no antibiotic, and left with a 1-week outpatient neurosurgical follow-up. The patient had no negative outcome. Cerebrospinal fluid leak should be included in the differential diagnosis of a head trauma in a patient with open fontanelles. No similar case was found in literature.

Comparison Between Transcranial Color-Coded Duplex Doppler and Contrast Enhanced Transcranial Color-Coded Duplex Doppler After Subarachnoid Aneurysmal Hemorrhage.

BACKGROUND: Transcranial color-coded duplex Doppler (TCCD) is commonly used to detect and monitor vasospasm in subarachnoid aneurysmal hemorrhage (aSAH). However, contrast enhanced TCCD (CE-TCCD) may be more effective. The objective of this study was to compare the accuracy of TCCD and CE-TCCD in the detection of vasospasm. METHODS: This study was a prospective comparison of TCCD and CE-TCCD for the detection of vasospasm, using computed tomography angiography (CT Angio) as a reference examination. The setting was the Department of Anesthesiology and Intensive Care at the Bicêtre University Hospital in Le Kremlin Bicêtre, France. TCCD and CE-TCCD were performed in 47 patients admitted to the intensive care unit (ICU) following aSAH over a 7-month period. TCCD and CE-TCCD were performed at ICU admission and between days 7 and 10. We aimed to visualize the seven intracranial arteries of the circle of Willis. Vasospasm diagnosis was assessed by CT Angio  and graded as moderate when the percentage change in arterial diameter since admission was between 25 and 50% or as severe when the percentage change was greater than 50%. RESULTS: On ICU admission, TCCD allowed visualization of all intracranial arteries in 16 (34%) of 47 patients, whereas CE-TCCD allowed visualization of all vessels in 37 (79%) of 47 patients (p < 0.001). These results were consistent between days 7 and 10. The proportions of middle cerebral arteries (MCAs), anterior cerebral arteries (ACAs) and posterior cerebral arteries (PCAs) visualized were greater with CE-TCCD. There was no difference in the visualization of basilar arteries (BAs). We performed vasospasm analysis on 67 of 94 MCAs in 47 patients. Area under the curve (AUC) of mean flow velocity to detect MCA vasospasm (moderate and severe) was 0.86 (0.58-1.00) for TCCD and 0.90 (0.77-1.00) for CE-TCCD. AUC of mean velocity to detect severe MCA vasospasm was 0.86 (0.58-1.00) for TCCD and 0.90 (0.77-1.00) for CE-TCCD, without any significant difference between the two techniques. For other arteries, the accuracy of TCCD and CE-TCCD to diagnose vasospasm was poor. CONCLUSIONS: CE-TCCD allows better visualization of intracranial arteries in patients with aSAH. The accuracy of CE-TCCD to screen severe MCA vasospasm is similar to that of TCCD. CE-TCCD is an alternative tool for monitoring patients with aSAH without a temporal bone window for an ultrasound.

One-month alcohol abstinence national campaigns: a scoping review of the harm reduction benefits.

Over the last decade, one-month alcohol abstinence campaigns (OMACs) have been implemented within the general population in an increasing number of countries. We identified the published studies reporting data on OMACs to explore the following aspects: profile of participants, rates and factors associated with the completion of the abstinence challenge, and outcomes and harm reduction benefits in participating in the challenges. We screened 322 records, including those found in the grey literature, and reviewed 6 studies and 7 Dry July Annual Reports. Compared to non-participating alcohol users, participants were more likely to be female, have a higher income, and a higher level of education. They were heavier drinkers and were more concerned by the consequences of alcohol on health and by their health in general. Participants who achieved the one-month abstinence challenge were lower drinkers and more likely to have registered on the campaign-related Internet communities. Both successful and unsuccessful participants frequently reported health benefits, including sleep improvement and weight loss. Successful participants were more likely to durably change their alcohol drinking habits. Overall, OMACs provide short- or mid-term harm reduction benefits for both successful and unsuccessful participants. Findings were limited by the paucity of studies, their observational nature, and heterogeneity in the features of the different national campaigns, which would probably gain in enhanced internationalization.

Assessing the implementation of community-based learning in public health: a mixed methods approach.

BACKGROUND: The French government has set up a community-based learning programme on health promotion for undergraduate health students to involve them in key public health objectives. At the University of Lyon, students first underwent formal instruction, including e-learning, lectures, and interactive seminars, and then became health educators for school pupils. The main objective of the present study was to assess the process of implementing this programme during the 2018-2019 academic year. METHODS: The satisfaction and perception of medical and midwife students with community-based learning experiences were assessed by a questionnaire, semi-directive interviews, and observations. Replies to the questionnaire were described by median and interquartile range or by proportion. A paired Wilcoxon-Mann-Whitney test was used to compare self-evaluated students' competence scores before and after the seminars (alpha risk of 5%). Thematic analyses using grounded theory were performed on recorded and transcribed interviews, and on transcribed notes taken during the observations. RESULTS: Over time the students have evolved from a negative perception of the community-based learning to a positive one. The students were mostly satisfied by interactive seminars that allowed them to gain confidence and competencies in health education. Their involvement in the programme increased their self-esteem. They became more aware of their educative responsibilities regarding public health issues as future professionals. CONCLUSIONS: The students had a positive perception of the implementation of a community-based learning programme in our University, as it appeared a pertinent strategy to raise their awareness of prevention and health education issues.

BET 1: Continuous flow insufflation of oxygen in out-of-hospital cardiac arrest.

A short cut review was carried out to establish whether continuous flow insufflation of oxygen (CFIO) is better than standard ventilation strategies at improving outcome in adults who have suffered an out-of-hospital cardiac arrest (OHCA). Papers were found in Medline and Embase using the reported searches of which four presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that CFIO does not improve survival or return of spontaneous circulation compared with standard ventilation strategies in OHCA.

Effect of RBC Transfusion on Sublingual Microcirculation in Hemorrhagic Shock Patients: A Pilot Study.

OBJECTIVES: The effects of RBC transfusion on microvascular perfusion are not well documented. We investigated the effect of RBC transfusion on sublingual microcirculation in hemorrhagic shock patients. DESIGN: Prospective, preliminary observational study. SETTINGS: A 28-bed, surgical ICU in a university hospital. PATIENTS: Fifteen hemorrhagic shock patients requiring RBC transfusion. INTERVENTION: Transfusion of one unit of RBCs. MEASUREMENTS AND MAIN RESULTS: The sublingual microcirculation was assessed with a Sidestream Dark Field imaging device before and after RBC transfusion. After transfusion of one unit of RBC, hemoglobin concentration increased from 8.5 g/dL (7.6-9.5 g/dL) to 9.6 g/dL (9.1-10.3 g/dL) g/dL (p = 0.02) but no effect on macrocirculatory parameters (arterial pressure, cardiac index, heart rate, and pulse pressure variations) was observed. Transfusion of RBC significantly increased microcirculatory flow index (from 2.3 [1.6-2.5] to 2.7 [2.6-2.9]; p < 0.003), the proportion of perfused vessels (from 79% [57-88%] to 92% [88-97%]; p < 0.004), and the functional capillary density (from 21 [19-22] to 24 [22-26] mm/mm; p = 0.003). Transfusion of RBC significantly decreased the flow heterogeneity index (from 0.51 [0.34-0.62] to 0.16 [0.04-0.29]; p < 0.001). No correlations were observed between other macrovascular parameters and microvascular changes after transfusion. The change in microvascular perfusion after transfusion correlated negatively with baseline microvascular perfusion. CONCLUSIONS: RBC transfusion improves sublingual microcirculation independently of macrocirculation and the hemoglobin level in hemorrhagic shock patients. The change in microvascular perfusion after transfusion correlated negatively with baseline microvascular perfusion. Evaluation of microcirculation perfusion is critical for optimization of microvascular perfusion and to define which patients can benefit from RBC transfusion during cardiovascular resuscitation.

Mid-regional pro-adrenomedullin (MR-proADM), a marker of positive fluid balance in critically ill patients: results of the ENVOL study.

BACKGROUND: The optimal control of blood volume without fluid overload is a main challenge in the daily care of intensive care unit (ICU) patients. Accordingly this study focused on the identification of biomarkers to help characterize fluid overload status. METHODS: Sixty-seven patients were studied from ICU admission to day 7 (D7). Blood and urine samples were taken daily and sodium and water balance strictly calculated resulting in a total cumulative assessment of ∆Na+ and ∆H2O. Furthermore, plasmatic biomarkers (cortisol, epinephrine, norepinephrine, renin, angiotensin II, aldosterone, pro-endothelin, copeptine, atrial natriuretic peptide, erythropoietin, mid-regional pro-adrenomedullin (MR-proADM)) and Sequential Organ Failure Assessment (SOFA) scores were measured at D2, D5 and D7. Blood volumes were measured with 51Cr fixed on red blood cells at D2 and D7. RESULTS: The ∆Na+ or ∆H2O were increased in all patients but never related to blood volumes at D2 nor D7. Total blood volumes were at normal values with constantly low red blood cell volumes and normal or decreased plasmatic volume. Weight, plasmatic proteins, and hemoglobin were weakly related to ∆Na+ or ∆H2O. Amongst all tested biomarkers, only MR-proADM was related to sodium and fluid overload. This biomarker was also a predictor of SOFA scores. CONCLUSIONS: Plasmatic concentration in MR-proADM seems to be a good surrogate for evaluation of ∆Na+ or ∆H2O and predicts sodium and extracellular fluid overload. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01858675 in May 13, 2013.

Correlation between orphan nuclear receptor Nurr1 expression and amyloid deposition in 5XFAD mice, an animal model of Alzheimer's disease.

The functional roles of the orphan nuclear receptor, Nurr1, have been extensively studied and well established in the development and survival of midbrain dopamine neurons. As Nurr1 and other NR4A members are widely expressed in the brain in overlapping and distinct manners, it has been an open question whether Nurr1 has important function(s) in other brain areas. Recent studies suggest that up-regulation of Nurr1 expression is critical for cognitive functions and/or long-term memory in forebrain areas including hippocampal formation. Questions remain about the association between Nurr1 expression and Alzheimer's disease (AD) brain pathology. Here, using our newly developed Nurr1-selective antibody, we report that Nurr1 protein is prominently expressed in brain areas with Aß accumulation, that is, the subiculum and the frontal cortex, in the 5XFAD mouse and that Nurr1 is highly co-expressed with Aß at early stages. Furthermore, the number of Nurr1-expressing cells significantly declines in the 5XFAD mouse in an age-dependent manner, accompanied by increased plaque deposition. Thus, our findings suggest that altered expression of Nurr1 is associated with AD progression. Using our newly developed Nurr1-selective antibody, we show that Nurr1 protein is prominently expressed in brain areas accumulating amyloid-beta (Aß) in the transgenic mouse model of Alzheimer's disease (AD) and that Nurr1 is highly co-expressed with Aß at early stages (upper panel). Furthermore, in the AD brain the number of Nurr1-expressing cells significantly declines in an age-dependent manner concomitant with increased Aß accumulation (lower diagram) highlighting a possible Nurr1 involvement in AD pathology.

Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy.

The recent approval of a prostate cancer vaccine has renewed hope for anticancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they often are used at high doses in the clinic to prune tumor vessels and paradoxically may compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower vascular-normalizing doses, but not high antivascular/antiangiogenic doses, of an anti-VEGF receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels. Furthermore, lower doses are superior to the high doses in polarizing tumor-associated macrophages from an immune inhibitory M2-like phenotype toward an immune stimulatory M1-like phenotype and in facilitating CD4(+) and CD8(+) T-cell tumor infiltration. Based on this mechanism, scheduling lower-dose anti-VEGFR2 therapy with T-cell activation induced by a whole cancer cell vaccine therapy enhanced anticancer efficacy in a CD8(+) T-cell-dependent manner in both immune-tolerant and immunogenic murine breast cancer models. These findings indicate that vascular-normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a strategy to use antiangiogenic agents in breast cancer more effectively with active immunotherapy and potentially other anticancer therapies.

Traffic in the operating room during joint replacement is a multidisciplinary problem.

BACKGROUND: Door openings disrupt the laminar air flow and increase the bacterial count in the operating room (OR). We aimed to define the incidence of door openings in the OR during primary total joint arthroplasty (TJA) surgeries and determine whether measures were needed and/or possible to reduce OR staff traffic. METHODS: We recorded the number of door openings during 100 primary elective TJA surgeries; the OR personnel were unaware of the observer's intention. Operating time was divided into the preincision period, defined as the time from the opening of surgical trays to skin incision, and the postincision period, defined as time from incision to dressing application. RESULTS: The mean number of door openings during primary TJA was 71.1 (range 35-176) with a mean operative time of 111.9 (range 53-220) minutes, for an average of 0.64 (range 0.36-1.05) door openings/min. Nursing staff were responsible for 52.2% of total door openings, followed by anesthesia staff at 23.9% and orthopedic staff at 12.7%. In the preincision period, we observed an average of 0.84 door openings/ min, with nursing and orthopedic personnel responsible for most of the door openings. The postincision period yielded an average of 0.54 door openings/min, with nursing and anesthesia personnel being responsible for most of the door openings. CONCLUSION: There is a high incidence of door openings during TJA. Because we observed a range in the number of door openings per surgery, we believe it is possible to reduce this number during TJA.

CONTEXTE: Les ouvertures de porte perturbent le flux laminaire et accroissent la numération bactérienne au bloc opératoire. Nous avons voulu mesurer l'incidence des ouvertures de porte au bloc opératoire durant les chirurgies pour prothèse articulaire totale (PAT) et déterminer si des correctifs étaient requis ou s'il était possible de réduire la circulation du personnel au bloc opératoire. MÉTHODES: Nous avons dénombré les ouvertures de porte durant 100 chirurgies électives primaires pour PAT; le personnel du bloc opératoire n'était pas au courant de l'intention de l'observateur. Le temps opératoire a été subdivisé en une période pré-incision, définie par l'intervalle entre l'ouverture des plateaux chirurgicaux et l'incision chirurgicale, et une période post-incision, définie par l'intervalle entre l'incision et l'application du pansement. RÉSULTATS: Le nombre moyen d'ouvertures de porte par intervention pour PAT primaire a été de 71,1 (entre 35 et 176) et la durée moyenne des interventions a été de 111,9 (entre 53 et 220) minutes, pour une moyenne de 0,65 (entre 0,36 et 1,05) ouverture/ minute. Le personnel infirmier était responsable de 52,2 % du nombre total d'ouvertures de porte, suivi du personnel d'anesthésie avec 23,9 % et du personnel d'orthopédie avec 12,7 %. Durant la période pré-incision, nous avons observé une moyenne de 0,84 ouverture de porte/minute, le personnel infirmier et d'orthopédie ayant été responsable de la majorité des ouvertures de porte. La période post-incision a donné lieu à une moyenne de 0,54 ouverture de porte/minute, le personnel infirmier et d'anesthésie ayant été responsable de la majorité des ouvertures de porte. CONCLUSION: On observe un nombre important d'ouvertures de porte durant les interventions pour PAT. Étant donné que ce nombre varie, nous croyons qu'il est possible de le réduire.

Factors for the integration of prevention in primary care: an overview of reviews.

BACKGROUND: The global burden of non-communicable diseases is increasing and the need for prevention is huge. Policies have yet to produce results and prevention indicators remain low. Primary care (PC) represents an opportunity to optimise the practice of prevention, but GPs are coming up against barriers that are holding back their prevention practices. AIM: The aim of this overview of reviews is to identify the barriers and facilitators for the implementation of routine prevention practices in PC. DESIGN AND SETTING: This study is an international overview of reviews focusing on the integration of prevention in PC settings. METHOD: The search was conducted on July 2022 in MEDLINE, EMBASE, Web of Science and the Cochrane Database of Systematic Reviews. Included reviews are: systematic reviews or scoping reviews adopting a systematic approach. RESULTS: The 35 reviews included identify multiple barriers and facilitators related to the integration of prevention in PC. These factors are very heterogeneous as regards their source (the patient, the professional and the health system) and their level of action (individual, organisational or contextual). The results show the need to organise PC at the professional level (e.g. in training), at the local level (e.g. partnerships) and at the political level (e.g. funding model). CONCLUSION: The factors influencing the integration of prevention in PC are multiple and act at different levels (individual, organisational and health system level). Organisation factors play a major role and seem to be a means of overcoming the difficulties encountered by healthcare professionals in developing preventive practices.

Delay of punishment highlights differential vulnerability to developing addiction-like behavior toward sweet food.

Resistance to punishment is commonly used to measure the difficulty in refraining from rewarding activities when negative consequences ensue, which is a hallmark of addictive behavior. We recently developed a progressive shock strength (PSS) procedure in which individual rats can titrate the amount of punishment that they are willing to tolerate to obtain food rewards. Here, we investigated the effects of a range of delays (0-12 s) on resistance to punishment measured by PSS break points. As expected from delay discounting principles, we found that delayed shock was less effective as a punisher, as revealed by higher PSS breakpoints. However, this discounting effect was not equally distributed in the population of rats, and the introduction of a delay highlighted the existence of two populations: rats that were sensitive to immediate punishment were also sensitive to delayed shock, whereas rats that were resistant to immediate punishment showed strong temporal discounting of delayed punishment. Importantly, shock-sensitive rats suppressed responding even in subsequent non-punishment sessions, and they differed from shock-resistant rats in anxiety-like behavior, but not in sensitivity to pain. These results show that manipulation of temporal contingencies of punishment in the PSS procedure provides a valuable tool to identify individuals with a double vulnerability to addiction: low sensitivity to aversion and excessive discounting of negative future consequences. Conversely, the shock-sensitive population may provide a model of humans who are vulnerable to opportunity loss due to excessive anxiety.

Occupational, academic, and personal determinants of wellbeing and psychological distress in residents: results of a survey in Lyon, France.

Introduction: The mental health of residents is a growing significant concern, particularly with respect to hospital and university training conditions. Our goal was to assess the professional, academic, and psychological determinants of the mental health status of all residents of the academy of Lyon, France. Materials and methods: The Health Barometer of Lyon Subdivision Residents (BASIL) is an initiative which consists in proposing a recurrent online survey to all residents in medicine, pharmacy, and dentistry, belonging to the Lyon subdivision. The first of these surveys was conducted from May to July 2022. Participants should complete a series of validated questionnaires, including the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS), and the Kessler Psychological Distress Scale (K6), respectively, and ad-hoc questions assessing their global health and hospital and academic working conditions. A Directed Acyclic Graph (DAG) analysis was conducted prior to multivariable analyses, to explore the determinants associated with low wellbeing (WEMWBS <43) and high psychological distress (K6 ≥ 13). Results: A total of 904 residents (response rate: 46.7%) participated in the survey. A low level of wellbeing was observed in 23% of participants, and was significantly associated to job strain (OR = 2.18; 95%CI = [1.32-3.60]), low social support (OR = 3.13; 95%CI = [2.05-4.78]) and the experience of very poor university teaching (OR = 2.51; 95%CI = [1.29-4.91]). A high level of psychological distress was identified for 13% of participants, and associated with low social support (OR = 2.41; 95%CI = [1.48-3.93]) and the experience of very poor university teaching (OR = 2.89, 95%CI = [1.16-7.21]). Conclusion: Hospital working conditions, social support, and the perception of teaching quality, were three major determinants of wellbeing and psychological distress among health profession residents. Demographic determinants, personal life and lifestyle habits were also associated. This supports a multilevel action in prevention programs aiming to enhance wellbeing and reduce mental distress in this specific population and local organizational specificities.

Current Status and Future Perspectives on Stem Cell-Based Therapies for Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, affecting 1%-2% of the population over the age of 65. As the population ages, it is anticipated that the burden on society will significantly escalate. Although symptom reduction by currently available pharmacological and/or surgical treatments improves the quality of life of many PD patients, there are no treatments that can slow down, halt, or reverse disease progression. Because the loss of a specific cell type, midbrain dopamine neurons in the substantia nigra, is the main cause of motor dysfunction in PD, it is considered a promising target for cell replacement therapy. Indeed, numerous preclinical and clinical studies using fetal cell transplantation have provided proof of concept that cell replacement therapy may be a viable therapeutic approach for PD. However, the use of human fetal cells remains fraught with controversy due to fundamental ethical, practical, and clinical limitations. Groundbreaking work on human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, coupled with extensive basic research in the stem cell field offers promising potential for hPSC-based cell replacement to become a realistic treatment regimen for PD once several major issues can be successfully addressed. In this review, we will discuss the prospects and challenges of hPSC-based cell therapy for PD.

Femoral blood gas analysis, another tool to assess hemorrhage severity following trauma: an exploratory prospective study.

BACKGROUND: Veno-arterial carbon dioxide tension difference (ΔPCO2) and mixed venous oxygen saturation (SvO2) have been shown to be markers of the adequacy between cardiac output and metabolic needs in critical care patients. However, they have hardly been assessed in trauma patients. We hypothesized that femoral ΔPCO2 (ΔPCO2 fem) and SvO2 (SvO2 fem) could predict the need for red blood cell (RBC) transfusion following severe trauma. METHODS: We conducted a prospective and observational study in a French level I trauma center. Patients admitted to the trauma room following severe trauma with an Injury Severity Score (ISS) > 15, who had arterial and venous femoral catheters inserted were included. ΔPCO2 fem, SvO2 fem and arterial blood lactate were measured over the first 24 h of admission. Their abilities to predict the transfusion of at least one pack of RBC (pRBCH6) or hemostatic procedure during the first six hours of admission were assessed using receiver operating characteristics curve. RESULTS: 59 trauma patients were included in the study. Median ISS was 26 (22-32). 28 patients (47%) received at least one pRBCH6 and 21 patients (35,6%) had a hemostatic procedure performed during the first six hours of admission. At admission, ΔPCO2 fem was 9.1 ± 6.0 mmHg, SvO2 fem 61.5 ± 21.6% and blood lactate was 2.7 ± 1.9 mmol/l. ΔPCO2 fem was significantly higher (11.6 ± 7.1 mmHg vs. 6.8 ± 3.7 mmHg, P = 0.003) and SvO2 fem was significantly lower (50 ± 23 mmHg vs. 71.8 ± 14.1 mmHg, P < 0.001) in patients who were transfused than in those who were not transfused. Best thresholds to predict pRBCH6 were 8.1 mmHg for ΔPCO2 fem and 63% for SvO2 fem. Best thresholds to predict the need for a hemostatic procedure were 5.9 mmHg for ΔPCO2 fem and 63% for SvO2 fem. Blood lactate was not predictive of pRBCH6 or the need for a hemostatic procedure. CONCLUSION: In severe trauma patients, ΔPCO2 fem and SvO2 fem at admission were predictive for the need of RBC transfusion and hemostatic procedures during the first six hours of management while admission lactate was not. ΔPCO2 fem and SvO2 fem appear thus to be more sensitive to blood loss than blood lactate in trauma patients, which might be of importance to early assess the adequation of tissue blood flow with metabolic needs.

Norepinephrine deficiency is caused by combined abnormal mRNA processing and defective protein trafficking of dopamine beta-hydroxylase.

Human norepinephrine (NE) deficiency (or dopamine ß-hydroxylase (DBH) deficiency) is a rare congenital disorder of primary autonomic failure, in which neurotransmitters NE and epinephrine are undetectable. Although potential pathogenic mutations, such as a common splice donor site mutation (IVS1+2T→C) and various missense mutations, in NE deficiency patients were identified, molecular mechanisms underlying this disease remain unknown. Here, we show that the IVS1+2T→C mutation results in a non-detectable level of DBH protein production and that all three missense mutations tested lead to the DBH protein being trapped in the endoplasmic reticulum (ER). Supporting the view that mutant DBH induces an ER stress response, exogenous expression of mutant DBH dramatically induced expression of BiP, a master ER chaperone. Furthermore, we found that a pharmacological chaperone, glycerol, significantly rescued defective trafficking of mutant DBH proteins. Taken together, we propose that NE deficiency is caused by the combined abnormal processing of DBH mRNA and defective protein trafficking and that this disease could be treated by a pharmacological chaperone(s).