Effects of a mastitis J5 bacterin vaccination on the productive performance of dairy cows: An observational study using propensity score matching techniques.

Inferring causal effects between variables when utilizing observational data is challenging due to confounding factors not controlled through a randomized experiment. Propensity score matching can decrease confounding in observational studies and offers insights about potential causal effects of prophylactic management interventions such as vaccinations. The objective of this study was to determine potential causality and impact of vaccination with an Escherichia coli J5 bacterin on the productive performance of dairy cows applying propensity score matching techniques to farm-recorded (e.g., observational) data. Traits of interest included 305-d milk yield (MY305), 305-d fat yield (FY305), 305-d protein yield (PY305), and somatic cell score (SCS). Records from 6,418 lactations generated by 5,121 animals were available for the analysis. Vaccination status of each animal was obtained from producer-recorded information. Confounding variables considered were herd-year-season groups (56 levels), parity (5 levels: 1, 2, 3, 4, and ≥5), and genetic quartile groups (4 levels: top 25% through bottom 25%) derived from genetic predictions for MY305, FY305, PY305, and SCS, as well as for the genetic susceptibility to mastitis. A logistic regression model was applied to estimate the propensity score (PS) for each cow. Subsequently, PS values were used to form pairs of animals (1 vaccinated with 1 unvaccinated control), depending on their PS similarities (difference in PS values of cows within a match required to be <20% of 1 standard deviation of the logit of PS). After the matching process, 2,091 pairs of animals (4,182 records) remained available to infer the causal effects of vaccinating dairy cows with the E. coli J5 bacterin. Causal effects estimation was performed using 2 approaches: simple matching and a bias-corrected matching. According to the PS methodology, causal effects of vaccinating dairy cows with a J5 bacterin on their productive performance were identified for MY305. The simple matched estimator suggested that vaccinated cows produced 163.89 kg more milk over an entire lactation when compared with nonvaccinated counterparts, whereas the bias-corrected estimator suggested that such increment in milk production was of 150.48 kg. Conversely, no causal effects of immunizing dairy cows with a J5 bacterin were identified for FY305, PY305, or SCS. In conclusion, the utilization of PS matching techniques applied to farm-recorded data was feasible and allowed us to identify that vaccination with an E. coli J5 bacterin relates to an overall milk production increment without compromising milk quality.

[Individual and contextual factors associated with violent behaviours during psychiatric hospitalizations]. / Facteurs individuels et contextuels participant à l'apparition de comportements violents en cours d'hospitalisations psychiatriques.

BACKGROUND: The prevention of Physical Violent Behavior (VB) toward others during psychiatric hospitalization is a major concern of clinicians. These VBs can have a deleterious impact on the victims, inpatients or caregivers, as well as on the therapeutic milieu. Such violence can also have negative consequences for the assailant patients, such as repeatedly being hospitalized under restraint, stigmatization, and difficulties reintegrating into the community. OBJECTIVES: This study explored individual (age, gender, marital status, living status, diagnostic) and institutional (type of admission, length of stay, number of previous hospitalizations) risk factors, and how their interactions could increase the risk of VB during psychiatric hospitalizations. METHOD: The study was carried out over a period of four years in the psychiatry department of the Lausanne University Hospital, on the 15 wards (219 beds) specialized in acute psychiatric care for adults. All the patients admitted to one of these wards during this period (n=4518), aged between 18 and 65 years, were included in the study. The sample was divided in two groups: non-violent patients (NVPs) and violent patients (VPs). VBs, defined as physical aggressions against another person, were assessed by the Staff Observation Aggression Scale - Revised (SOAS - R). Only physical assaults, associated or not with other types of violence, involving hospitalized patients were analyzed. Personal and institutional factors were extracted from the hospital database. Chi2 independence tests were used to assess differences between groups. Logistic regression models were used to identify the links between each factor and the VB. Classification and regression trees were used to study the hierarchical effect of factors, and combinations of factors, on VBs. RESULTS: During the study period, 414 VBs were reported involving 199 patients (4.40 % of all patients). VPs were significantly younger, male, more likely to be unmarried and living in sheltered housing before hospitalization. In this group, the proportion of patients with diagnoses of schizophrenia, and/or schizophrenia with comorbid substance abuse and cognitive impairment, were higher compared to NVPs. VPs were more frequently admitted involuntarily, had a longer average length of stay and a greater number of previous hospitalizations. The logistic regression model performed on individual factors have shown a significant link between age (OR=0.99; CI: 0.97-1.00; P-value=0.024), living in sheltered housing before admission (OR=2.46; CI: 1.61-3.75; P-value<0.000), schizophrenic disorders (OR=2.18; CI: 1.35-3.57; P-value=0.001), schizophrenic disorders with substance abuse comorbidity (OR=2.00; CI: 1.16-3.37; P-value=0.016), cognitive impairment (OR=3.41; CI: 1,21-8.25; P-value=0.010), and VBs. The logistic regression model on institutional factors have shown a significant link between involuntary hospitalization (OR=4.38; CI: 3.20-6.08; P-value<0.000), length of previous stay (OR=1.01; CI: 1.00-1.01; P-value<0.000), number of previous hospitalizations (OR=1.06; CI: 1.00-1.12; P-value=0.031), and VBs. The logistic regression model on individual and institutional factors have shown a significant link between age (OR=0.99; CI: 0.97-1.00; P-value=0.008), living in sheltered housing before admission (OR=2.46: CI: 1.61-3.75; P-value=0.034), cognitive impairment (OR=3.41; CI: 1.21-8.25; P-value=0.074), involuntary hospitalization (OR=3.46; CI: 2.48-4.87; P-value<0.000), length of previous stay (OR=1.01; CI: 1.00-1.01; P-value<0.000), and VBs. The classification and regression trees have shown that the relationship between long length of stay and repeated hospitalizations mainly potentiate the risk of violence. CONCLUSION: The results of this study have shown the existence of a small group of vulnerable patients who accumulate constrained hospital stays during which violence occurs. Exploring the clinical profiles and institutional pathways of patients could help to better identify these patients and promote a more appropriate mode of support, such as intensive clinical case management. This model could facilitate the development of a clinical network and the links between the structures and partners caring for a patient. This would create a continuous support, avoiding or limiting the lack of continuity of care and care disruption.

[Three clinical risk profiles of violent behavior in a cohort of early psychosis patients]. / Trois profils cliniques à risque de comportements violents dans une cohorte de patients présentant un premier épisode de psychose.

OBJECTIVE: This study aims to determine whether it is possible to identify clinical profiles at risk of violent behaviors (VB) in the early phase of psychotic disorders, on the basis of the main dynamic psychopathological risk factors and describe characteristics of the groups with highest levels of violent behaviors. METHOD: A total of 265 patients, aged 18 to 35, treated at the Treatment and early Intervention in Psychosis Program (TIPP-Lausanne), a specialized early psychosis program, were included in this study. We conducted a latent-class analysis and a discriminative analysis on the basis of the main dynamic VB risk factors: substance use disorder, impulsivity, positive symptoms, insight, aggression, hostility, anger, emotional instability and adherence to treatment. These factors were evaluated by specialized scales and on the basis of the Positive and Negative Syndrome Scale (PANSS). VB were restricted to physical aggression against people, defined as "serious violence". They were assessed on the basis of a questionnaire listing violent offenses (Swiss Criminal Code) and VB such as assault and battery, information through the forensic psychiatric services and on the basis of the Staff Observation Aggression Scale (SOAS-R scale) during inpatient treatment phase. RESULTS: Four heterogeneous subgroups were identified with respect to the studied clinical characteristics, including two groups with high rates of VB. The first group, comprising 46% of patients with VB, is distinguished by the prevalence of a range of dimensions related to hostility, impulsivity and emotional instability, associated with high levels of substance abuse and positive symptoms. These clinical dimensions are very significant at the statistical level, since they explain 70% of the construction of subgroups (discriminant analysis). The second group with 37% of patients with VB, is characterized by a lack of insight, lack of adherence to treatment and substance use. These two clinical profiles could increase the impairment of cognitive, functional and relational abilities and contribute to the development of VB in this early phase of psychosis. The third subgroup, with a violent behaviors rate of 28.6%, is distinguished by its high proportion of diagnoses of substance abuse (100%) and women (54%). A last subgroup of patients, the largest quantitatively, has a low proportion of VB (15%) and the lowest levels on the studied factors, suggesting that the majority of patients with this profile commit few VB. CONCLUSION: Our results show that it is possible to identify groups at risk of violent behaviors during the early phase of psychosis on the basis of clinical characteristics that may evolve and therefore be the focus of preventive care. These results highlight the need to target substance use, impulsivity and lack of insight at follow-up in order to prevent VB.

Translating the combination of gene therapy and tissue engineering for treating recessive dystrophic epidermolysis bullosa.

The combination of gene therapy and tissue engineering is one of the most promising strategies for the treatment of recessive dystrophic epidermolysis bullosa (RDEB). RDEB is a rare genetic disease characterised by mutations in the COL7A1 gene, encoding type VII collagen (COLVII), which forms anchoring fibrils at the dermal-epidermal junction of the skin. This disease causes severe blistering and only palliative treatments are offered. In this study, the base of a strategy combining gene therapy and a tissue-engineered skin substitute (TES), which would be suitable for the permanent closure of skin wounds, was set-up. As a high transduction efficiency into fibroblasts and/or keratinocytes seems to be a prerequisite for a robust and sustained correction of RDEB, different envelope pseudotyped retroviral vectors and the transduction enhancer EF-C were tested. When green fluorescent protein (GFP) was used as a reporter gene to evaluate the retroviral-mediated gene transfer, the fibroblast infection efficiency was 30 % higher with the Ampho pseudotyped vector as compared with the other pseudotypes. At least a 3.1-fold and a 1.3-fold increased transduction were obtained in fibroblasts and keratinocytes, respectively, with EF-C as compared with polybrene. A continuous and intense deposit of haemagglutinin (HA)-COLVII was observed at the dermal-epidermal junction of self-assembled TESs made of cells transduced with a HA-tagged COL7A1 vector. Furthermore, HA-tagged basal epidermal cells expressing keratin 19 were observed in TESs, suggesting stem cell transduction. This approach could be a valuable therapeutic option to further develop, in order to improve the long-term life quality of RDEB patients.

Autologous bilayered self-assembled skin substitutes (SASSs) as permanent grafts: a case series of 14 severely burned patients indicating clinical effectiveness.

Split-thickness skin autografts (AGs) are the standard surgical treatment for severe burn injuries. However, the treatment of patients with substantial skin loss is limited by the availability of donor sites for skin harvesting. As an alternative to skin autografts, our research group developed autologous self-assembled skin substitutes (SASSs), allowing the replacement of both dermis and epidermis in a single surgical procedure. The aim of the study was to assess the clinical outcome of the SASSs as a permanent coverage for full-thickness burn wounds. Patients were recruited through the Health Canada's Special Access Program. SASSs were grafted on debrided full-thickness wounds according to similar protocols used for AGs. The graft-take and the persistence of the SASS epithelium over time were evaluated. 14 patients received surgical care with SASSs. The mean percentage of the SASS graft-take was 98 % (standard deviation = 5) at 5 to 7 d after surgery. SASS integrity persisted over time (average follow-up time: 3.2 years), without noticeable deficiency in epidermal regeneration. Assessment of scar quality (skin elasticity, erythema, thickness) was performed on a subset of patients. Non-homogeneous pigmentation was noticed in several patients. These results indicated that the SASS allowed the successful coverage of full-thickness burns given its high graft-take, aesthetic outcome equivalent to autografting and the promotion of long-term tissue regeneration. When skin donor sites are in short supply, SASSs could be a valuable alternative to treat patients with full-thickness burns covering more than 50 % of their total body surface area.

A qualitative study of adolescents with medically unexplained symptoms and their parents. Part 2: How is healthcare perceived?

Medically unexplained symptoms (MUS) are common among adolescents and an important cause of clinical visits. This study sought to understand the experiences with, and perceptions of, the healthcare of adolescents who have MUS and their parents. Using a qualitative approach, six focus groups and two individual interviews were conducted with a total of ten adolescents and sixteen parents. The participants were recruited in a university hospital in Switzerland. A thematic analysis was conducted in accordance with the Grounded Theory. Six main themes emerged: needing a label for the symptoms, seeking an etiology to explain the symptoms, negotiating the medical system, medication and treatments, interactions with doctors, and the inclusion of parents during consultations. Transcending these themes, however, was the need for good communication between the adolescents, their parents and the clinicians. When explaining the symptoms, clinicians should make sure to discuss the results, investigations and lack of organic origin.

[Neuroscience in the Courtroom: From responsibility to dangerousness, ethical issues raised by the new French law]. / Les neurosciences au Tribunal : de la responsabilité à la dangerosité, enjeux éthiques soulevés par la nouvelle loi française.

AIM: In the past few years, spectacular progress in neuroscience has led to the emergence of a new interdisciplinary field, the so-called "neurolaw" whose goal is to explore the effects of neuroscientific discoveries on legal proceedings and legal rules and standards. In the United States, a number of neuroscientific researches are designed specifically to explore legally relevant topics and a case-law has already been developed. In Europe, neuroscientific evidence is increasingly being used in criminal courtrooms, as part of psychiatric testimony, nourishing the debate about the legal implications of brain research in psychiatric-legal settings. Though largely debated, up to now the use of neuroscience in legal contexts had not specifically been regulated by any legislation. In 2011, with the new bioethics law, France has become the first country to admit by law the use of brain imaging in judicial expertise. According to the new law, brain imaging techniques can be used only for medical purposes, or scientific research, or in the context of judicial expertise. This study aims to give an overview of the current state of the neurolaw in the US and Europe, and to investigate the ethical issues raised by this new law and its potential impact on the rights and civil liberties of the offenders. METHOD: An overview of the emergence and development of "neurolaw" in the United States and Europe is given. Then, the new French law is examined in the light of the relevant debates in the French parliament. Consequently, we outline the current tendencies in Neurolaw literature to focus on assessments of responsibility, rather than dangerousness. This tendency is analysed notably in relation to the legal context relevant to criminal policies in France, where recent changes in the legislation and practice of forensic psychiatry show that dangerousness assessments have become paramount in the process of judicial decision. Finally, the potential interpretations of neuroscientific data introduced into psychiatric testimonies by judges are explored. RESULTS: The examination of parliamentary debates showed that the new French law allowing neuroimaging techniques in judicial expertise was introduced in the aim to provide a legal framework that would protect the subject against potential misuses of neuroscience. The underlying fear above all, was that this technology be used as a lie detector, or as a means to predict the subject's behaviour. However, the possibility of such misuse remains open. Contrary to the legislator's wish, the defendant is not fully guaranteed against uses of neuroimaging techniques in criminal courts that would go against their interests and rights. In fact, the examination of the recently adopted legislation in France shows that assessments of dangerousness and of risk of recidivism have become central elements of the criminal policy, which makes it possible, if not likely that neuroimaging techniques be used for the evaluation of the dangerousness of the defendant. This could entail risks for the latter, as judges could perceive neuroscientific data as hard evidence, more scientific and reliable than the soft data of traditional psychiatry. If such neuroscientific data are interpreted as signs of potential dangerousness of a subject rather than as signs of criminal responsibility, defendants may become subjected to longer penalties or measures aiming to ensure public safety in the detriment of their freedom. CONCLUSION: In the current context of accentuated societal need for security, the judge and the expert-psychiatrist are increasingly asked to evaluate the dangerousness of a subject, regardless of their responsibility. Influenced by this policy model, the judge might tend to use neuroscientific data introduced by an expert as signs of dangerousness. Such uses, especially when they subjugate an individual's interest to those of society, might entail serious threats to an individual's freedom and civil liberties.

[Risk assessment in forensic psychiatric reports: what kind assessment instrument? What indicator? What practical?]. / Evaluation du risque de récidive dans les expertises pénales: quels outils? Quets indicateurs? Quelles pratiques?

Here we present results of studies conducted by the Research Unit of Legal Psychiatry and Psychology of Lausanne about risk assessment and protective factors in the evaluation of violence recidivism. It aims to help experts in considering the relevance and use of tools at their disposal. Particular attention is given to the significance of protective factors and impulsive dimensions, as to the inter-raters process that leads to the final deliberations.

Triplet chemotherapy with or without bevacizumab as first line treatment for metastatic colorectal cancer: An AGEO multicenter real-world study.

BACKGROUND: Prior trials validated triplet chemotherapy (Tri-CT) with bevacizumab as first line treatment for metastatic colorectal cancer (mCRC) but real-world data are scarce and practices remain heterogeneous. AIMS: To evaluate Tri-CT +/- bevacizumab efficacy and safety, and to identify factors influencing treatment decisions. METHODS: The COLOTRIP retrospective study enrolled mCRC patients treated from 2014 to 2019 in 14 French centers. RESULTS: Of 299 patients (81% PS 0-1, 58% RAS-mutated and 19% BRAF-mutated), 51% received Tri-CT and 49% Tri-CT + bevacizumab. Metastatic disease was classified as resectable (6.5%), potentially resectable (40%), and unresectable (54%). Bevacizumab use was associated with primary tumor location, mutational status and number of metastases. Median overall survival was 33.5 months in the Tri-CT group and 23.9 months in the Tri-CT + bevacizumab group, with median progression-free survival being 14.5 and 11.4 months. After adjusting for initial characteristics, no difference in survival was noted. Around 30% of patients experienced grade ≥3 adverse events. CONCLUSIONS: This study highlights several factors influencing Tri-CT use +/- bevacizumab decision and confirms the real-world good oncological outcomes and tolerability of these regimens in mCRC patients. Our results suggest that Tri-CT alone may by an appropriate option for specific subgroups of patients.

[Benefits and limitations of risk assessment for criminal recidivism]. / Interét et limites de l'evaluation du risque de récidive d'actes illégaux dans les expertises psychiatriques.

The legislatives evolutions imply an important recourse to the psychiatric expertise in order to evaluate the potential dangerousness of a subject. However, in spite of the development of techniques and tools for this evaluation, the dangerousness assessment of a subject is in practice extremely complex and discussed in the scientific literature. The evolution of the concept of dangerousness to the risk assessment involved a technicisation of this evaluation which should not make forget the limits of these tools and the need for restoring the subject, the meaning and the clinic in this evaluation.

B lymphocytes regulate dendritic cell (DC) function in vivo: increased interleukin 12 production by DCs from B cell-deficient mice results in T helper cell type 1 deviation.

Increasing evidence indicates that dendritic cells (DCs) are the antigen-presenting cells of the primary immune response. However, several reports suggest that B lymphocytes could be required for optimal T cell sensitization. We compared the immune responses of wild-type and B cell-deficient (muMT) mice, induced by antigen emulsified in adjuvant or pulsed on splenic dendritic cells. Our data show that lymph node cells from both control and muMT animals were primed, but each released distinct cytokine profiles. Lymph node T cells from control animals secreted interferon (IFN)-gamma, interleukin (IL)-2, and IL-4, whereas those from muMT mice produced IFN-gamma and IL-2 but no IL-4. To test whether B cells may influence the T helper cell type 1 (Th1)/Th2 balance by affecting the function of DCs, we immunized mice by transferring antigen-pulsed DCs from wild-type or mutant mice. Injection of control DCs induced the secretion of IL-4, IFN-gamma, and IL-2, whereas administration of DCs from muMT animals failed to sensitize cells to produce IL-4. Analysis of IL-12 production revealed that DCs from muMT mice produce higher levels of IL-12p70 than do DCs from wild-type animals. These data suggest that B lymphocytes regulate the capacity of DCs to promote IL-4 secretion, possibly by downregulating their secretion of IL-12, thereby favoring the induction of a nonpolarized immune response.

Chemotherapy of advanced small-bowel adenocarcinoma: a multicenter AGEO study.

BACKGROUND: Small-bowel adenocarcinoma (SBA) is a rare tumor of poor prognosis. Data on the efficacy of chemotherapy for advanced SBA are scarce. PATIENTS AND METHODS: All patients with advanced SBA who received frontline chemotherapy from 1996 to 2008 were eligible for this retrospective multicenter study. RESULTS: Ninety-three consecutive patients were included. In the entire population, the median progression-free survival (PFS) and overall survival (OS) times were 6.6 and 15.1 months, respectively. Median PFS times among patients treated with LV5FU2 (n = 10), FOLFOX (n = 48), FOLFIRI (n = 19) and LV5FU2-cisplatin (n = 16) were 7.7, 6.9, 6.0 and 4.8 months, respectively, while median OS times were 13.5, 17.8, 10.6 and 9.3 months, respectively. In multivariate analysis, World Health Organization performance status (PS) (P < 0.0001) and elevated serum levels of carcinoembryonic antigen (CEA) (P = 0.02) and carbohydrate antigen 19-9 (CA 19-9) (P = 0.03) were the only variables significantly associated with poor OS. In the subgroup of patients treated with platinum-based chemotherapy, multivariate analysis showed that LV5FU2-cisplatin was associated with poorer PFS (P < 0.0001) and OS (P = 0.02) compared with FOLFOX. CONCLUSIONS: This is the largest study of chemotherapy in advanced SBA. Baseline PS and CEA and CA 19-9 levels were the main prognostic factors. FOLFOX seems to be the most effective platinum-based chemotherapy regimen.

[Value of multidetector-row CT in the management of sigmoid volvulus]. / Apport du scanner multi-détecteurs dans la prise en charge des volvulus du sigmoïde.

PURPOSE: To determine the value of multidetector-row CT (MDCT) in the management of sigmoid volvulus. MATERIALS AND METHODS: Twenty-three MDCT examinations showing sigmoid volvulus were retrospectively evaluated and analyzed based on the type of volvulus (mesentericoaxial versus organoaxial), degree of rotation (180 degrees or 360 degrees ), maximum diameter of the volvulized sigmoid loop and presence or absence of the northern exposure sign, signs of bowel wall ischemia, and ascitis. A statistical analysis was performed to determine the correlation between patients characteristics, CT findings, type of management, and histological findings when available. RESULTS: In our study, organoaxial volvulus occurred in older patients (p=0.047), had a higher risk of recurrence (p=0.015) and more frequently required urgent surgical management than mesentericoaxial volvulus. A higher degree of rotation was associated with a more distended volvulized sigmoid colon (p=0.033) and more frequently required surgery. CONCLUSION: In addition to detection of volvulus and signs of bowel wall ischemic, MDCT can characterize the type of volvulus and degree of rotation, findings that may assist in determining the severity of the process and direct towards optimal management, endoscopic or surgical.

Impulsivity in early psychosis: A complex link with violent behaviour and a target for intervention.

BACKGROUND: Violent behaviour (VB) occurs in first episode of schizophrenia and can have devastating impact both on victims and patients themselves. A better knowledge of the underlying mechanisms of VB may pave the way to preventive treatments. OBJECTIVES: 1) To explore the nature of the link between impulsivity and VB in early psychosis (EP) patients; 2) To explore the interactions between impulsivity and substance abuse, insight, and positive symptoms, the main dynamic risk factors of VB described to date. DESIGN AND METHODS: Post hoc analysis of data acquired in the frame of a 36-months EP cohort study. A total of 265 EP patients, aged 18 to 35, treated at TIPP (Treatment and early Intervention in Psychosis Program), at the Department of Psychiatry in Lausanne, Switzerland, were included in the study. Logistic regression analyzes were performed as well as mediation analysis and interaction analysis RESULTS: Our data suggest that impulsivity is a predictor of VB when analyzed independently and as part of a multi-factorial model. Impulsivity continues to differentiate violent patients from non-violent ones at the end of the program. In addition, the relationship between impulsivity and VB is not mediated by substance abuse. Finally, the effect of impulsivity on the probability of VB is potentiated by the interaction of different levels of insight and positive symptoms. CONCLUSIONS: Early intervention strategies in psychotic disorders should include evaluation of impulsivity considering it is linked to increased risk of VB and may respond to treatment.

Development of a database: DACTARI for a radiotoxic element ranking methodology.

Dosimetric impact studies aim at evaluating potential radiological effects of chronic or acute releases from nuclear facilities. A methodology for ranking radionuclides (RN) in terms of their health-related impact on the human population was first developed at CEA with specific criteria for each RN that could be applied to a variety of situations. It is based, in particular, on applying physico-chemical criteria to the complete RN inventory (present in the release or in the source term) and on applying norms related to radiation protection and chemical toxicology. The initial step consisted in identifying and collecting data necessary to apply the methodology, with reference to a previous database of long-lived radionuclides (LLRN, with half-lives ranging from 30 to 10(14) y) containing 95 radionuclides. The initial results have allowed us to identify missing data and revealed the need to complete the study for both toxic and radiotoxic aspects. This led us to the next step, developing a specific database, DAtabase for Chemical Toxicity and Radiotoxicity Assessment of RadIonuclides (DACTARI), to collect data on chemical toxicity and radiotoxicity, including acute or chronic toxicity, the chemical form of the compounds, the contamination route (ingestion, inhalation), lethal doses, target organs, intestinal and maternal-foetal transfer, drinking water guidelines and the mutagenic and carcinogenic properties.

Current and future radionuclide speciation studies in biological media.

Radionuclides may be released into the environment accidentally or incidentally, which could raise health risks when ingested or inhaled by humans. In order to study the behaviour of radionuclides in the human organism (metabolism, retention, excretion), knowledge of radionuclide speciation is indispensable: speciation governs the transfer, bioavailability and toxicity of elements and is also of considerable interest for decorporation. In this context, the Commissariat à l'Energie Atomique has created a working group on speciation to share data both on thermodynamic constants and on speciation analysis methods of interest to chemists, environmentalists and biologists. The initial focus was on the 31 radionuclides described in different International Commission on Radiological Protection models (HRTM, HAT) and the National Council on Radiation Protection model (wound). Particular attention was devoted to selecting the inorganic and organic ligands, most representative of biological media. The base applied to speciation in solution and at interfaces and solubility (BASSIST) thermodynamic database was developed for this purpose. The aim of this paper is to present the state of the art on radionuclide speciation tools within biological media and to emphasise some missing data in order to orient future research.

Protection against autoimmune diabetes with oral insulin is associated with the presence of IL-4 type 2 T-cells in the pancreas and pancreatic lymph nodes.

Oral administration of antigens has been proposed in the prevention and treatment of autoimmune diseases. We reported that oral administration of 0.8 mg of recombinant human insulin to 6-week-old NOD mice every other day for a month generated regulatory T-cells that were able to reduce the severity of insulitis and the percentage of clinical diabetes in naive irradiated recipients when co-injected with diabetogenic T-cells. In the present study, immunohistochemical analysis of the pancreatic glands revealed that injection of T-cells from insulin-fed mice upregulated the number of interleukin (IL)-4-secreting cells within the islets. Using two strains of NOD mice congenic at the Tbeta, or Thy1, locus, we observed a higher proportion of T-cells from insulin-fed mice in both the spleen (7.73 +/- 0.3 vs. 5.57 +/- 0.2%; P < 0.001) and the pancreatic lymph nodes (10.1 +/- 0.8 vs. 7.2 +/- 0.7%; P < 0.05) of cotransferred mice. By reverse transcription-polymerase chain reaction (RT-PCR) analysis, mice reconstituted with T-cells from insulin-fed animals had detectable amounts of IL-4 mRNA, specifically in the pancreatic lymph nodes (8 of 9 experimental mice vs. 1 of 9 control mice) and the pancreas (3 of 3 experimental mice vs. 0 of 3 control mice). Gamma-interferon mRNA was detectable in all cotransferred animals, but IL-10 mRNA and transforming growth factor beta mRNA were undetectable. These results suggested a shift from a T-helper 1 (Th1) to a Th2 pattern of cytokine expression and underlined the role of pancreatic lymph nodes in the protection. Repeated injections of 500 microg s.c. of anti-IL-4 monoclonal antibody led to an accentuation of the severity of islet infiltration and to the development of clinical diabetes. We concluded that oral administration of insulin can induce the presence of regulatory T-cells in the pancreas and the corresponding draining lymph nodes, initiate the secretion of IL-4 in this microenvironment sufficiently to suppress the activity of Th1 autoreactive T-cell clones, and ultimately provide protection against autoimmune diabetes.

Mechanisms of wound reepithelialization: hints from a tissue-engineered reconstructed skin to long-standing questions.

Wound closure of epithelial tissues must occur efficiently to restore rapidly their barrier function. We have developed a tissue-engineered wound-healing model composed of human skin keratinocytes and fibroblasts to better understand the mechanisms of reepithelialization. It allowed us to quantify the reepithelialization rate, which was significantly accelerated in the presence of fibrin or platelet-rich plasma. The reepithelialization of these 6 mm excisional wounds required the contribution of keratinocyte proliferation, migration, stratification, and differentiation. The epidermis regenerated progressively from the surrounding wound margins. After 3 days, the neoepidermis showed a complete spectrum of changes. Near the wound margin, the differentiation of the neoepidermis (keratins 1/10, filaggrin, and loricrin) and regeneration of the dermoepidermal junction (laminin 5 and collagen IV) were more advanced than toward the wound center, where the proliferative index was significantly increased. The spatial distribution of keratinocytes distinguished by particular features suggests two complementary mechanisms of reepithelialization: 1) the passive displacement of the superficial layers near the wound margin that would rapidly regenerate a barrier function and 2) the crawling of keratinocytes over each other at the tip of the progressing neoepidermis. Therefore, this study brings a new perspective to long-standing questions concerning wound reepithelialization.

Growth factors in skin wound healing.

The healing of skin involves a wide range of cellular, molecular, physiological and biochemical events. During the healing process, cells migrate to wound sites where they proliferate and synthesize extracellular matrix components in order to reconstitute a tissue closely similar to the original one. This activity is regulated by mediators secreted from the wound border cells such as PDGF, EGF, TGF beta and many other cytokines. Their effects on cells has been demonstrated in vivo and in vitro. The aim of this article is to summarize the sequential events that occur during wound healing notably cell migration, proliferation and phenotypic differentiation and to describe the cellular interactions involving growth factors at the molecular level.