Management of unfavorable outcome after mild traumatic brain injury: Review of physical and cognitive rehabilitation and of psychological care in post-concussive syndrome.

INTRODUCTION: Mild Traumatic Brain Injury (mTBI) is a public health issue with approximately 42 million people worldwide affected yearly. Most patients have a favorable short-term recovery but 10-20% are likely to develop post-concussive syndrome (association of physical, cognitive, and psychological difficulties after injury). Post-concussive syndrome can be associated with Post-Traumatic Stress Disorder (PTSD). There is to date no recommendation on the interventions that could be done to reduce post-concussive syndrome. The present review aims at summarizing the effect of therapeutic education, physical and cognitive rehabilitation and of psychological care in mTBI patients with post-concussive syndrome. METHODS: In the current international literature, we investigated the effects of therapeutic education, physical and cognitive rehabilitation and of psychological care in this population using the Medline database and we discussed the results of these studies. RESULTS: The application of a therapeutic education intervention within 3 months after mTBI has been found appropriate and effective to prevent post-concussion syndrome in several studies but the timeline of this intervention differs among the existing studies. Concerning physical disabilities, several pharmacological, rehabilitative and non-pharmacological techniques have shown some efficacy in reducing headache and vertigo; rTMS seems also promising in this context. The management of fatigue is also crucial and requires a multidisciplinary approach. We did not find any intervention in mTBI patients with post-concussive syndrome suffering from dysosmia and/or dysgueusia. No pharmacological treatment is currently recommended to reduce the cognitive symptoms of post-concussive syndrome after mTBI. Rehabilitation and brain-stimulation techniques have already proven their efficacy to reduce the cognitive impairment in this population. Even if the use of Virtual Reality software seems well tolerated in this population, its efficacy and additional value needs to be demonstrated in larger studies. Concerning the psychological care after mTBI, Cognitive and Behavioral Therapy interventions are the most frequently reported in this population, followed by psychoeducational interventions. PTSD management seems crucial in overall recovery of patients with post-concussive syndrome. CONCLUSION: Many studies have sought to demonstrate the effectiveness of various rehabilitation techniques, including different cognitive rehabilitation programs, technology-assisted rehabilitation, different types of brain stimulation and some pharmacological treatments. However, most of these studies are of a low level of scientific evidence and it would be necessary to carry out well-conducted prospective randomized trials in order to offer an appropriate and effective multidisciplinary management for patients with post-concussive syndrome after mTBI.

Definition and epidemiology of mild traumatic brain injury.

BACKGROUND/OBJECTIVES: The definition of mild traumatic brain injury (mTBI), also known as concussion, has been a matter of controversy, which makes comparison between studies difficult. Incidence varies greatly from one country to another. The present article reviews definitions and epidemiology. METHODS: Literature review. RESULTS: According to the Mild TBI Committee of the American Congress of Rehabilitation Medicine, revised by the World Health Organization (WHO), mTBI is defined by a Glasgow Coma Scale score between 13 and 15 at 30minutes post-injury, and one or more of the following symptoms: <30min loss of consciousness; <24hours post-traumatic amnesia (PTA); impaired mental state at time of accident (confusion, disorientation, etc.); and/or transient neurological deficit. If a focal lesion is found on computed tomography (CT) or magnetic resonance imaging (MRI), the term "complicated mild TBI" has been proposed. Incidence of mTBI is 200-300/100,000 persons per year for hospitalized patients and probably twice as high if non-hospitalized patients are included. However, a few recent population-based studies reported a much higher rate (>700/100,000). A changing pattern of epidemiology has been found in high-income countries, related to a decrease in road-accident injuries in young adults, while conversely the proportion of falls has increased with population aging. CONCLUSION: Mild TBI is a major public health concern, the epidemiology of which has greatly changed in the last twenty years.

Five-year follow-up of persons with brain injury entering the French vocational and social rehabilitation programme UEROS: Return-to-work, life satisfaction, psychosocial and community integration.

BACKGROUND: Social and vocational reintegration of persons with brain injury is an important element in their rehabilitation. AIMS: To evaluate the 5-year outcome of persons with brain injury included in 2008 in the Aquitaine Unit for Evaluation, Training and Social and Vocational Counselling programme (UEROS). METHOD: 57 persons with brain injury were recruited from those who completed the 2008 UEROS programme. Five years later, an interview was done to assess family and vocational status, autonomy and life satisfaction. These results were compared with those from persons completing the 1997-1999 programme. RESULTS: The typical person entered the 2008 UEROS programme 6 years after a severe brain injury (42%) and was male, single and 35 years. At the 5-year follow-up, more persons lived with a partner (+23%) and lived in their own home (+21%). 47% were working vs 11% on entering the programme. Approximately half were satisfied or very satisfied with their quality of life. Having a job in 2013 was associated with a high education level, less cognitive sequelae, having a job in 2008 and no health condition. CONCLUSIONS: The UEROS programme is effective with regard to return-to-work and improvement of autonomy in persons with brain injury, irrespective of length of time from injury.

Eµ and 3'RR IgH enhancers show hierarchic unilateral dependence in mature B-cells.

Enhancer and super-enhancers are master regulators of cell fate. While they act at long-distances on adjacent genes, it is unclear whether they also act on one another. The immunoglobulin heavy chain (IgH) locus is unique in carrying two super-enhancers at both ends of the constant gene cluster: the 5'Eµ super-enhancer promotes VDJ recombination during the earliest steps of B-cell ontogeny while the 3' regulatory region (3'RR) is essential for late differentiation. Since they carry functional synergies in mature B-cells and physically interact during IgH locus DNA looping, we investigated if they were independent engines of locus remodelling or if their function was more intimately intermingled, their optimal activation then requiring physical contact with each other. Analysis of chromatin marks, enhancer RNA transcription and accessibility in Eµ- and 3'RR-deficient mice show, in mature activated B-cells, an unilateral dependence of this pair of enhancers: while the 3'RR acts in autonomy, Eµ in contrast likely falls under control of the 3'RR.

The contribution of virtual reality to the diagnosis of spatial navigation disorders and to the study of the role of navigational aids: A systematic literature review.

INTRODUCTION: Spatial navigation, which involves higher cognitive functions, is frequently implemented in daily activities, and is critical to the participation of human beings in mainstream environments. Virtual reality is an expanding tool, which enables on one hand the assessment of the cognitive functions involved in spatial navigation, and on the other the rehabilitation of patients with spatial navigation difficulties. Topographical disorientation is a frequent deficit among patients suffering from neurological diseases. The use of virtual environments enables the information incorporated into the virtual environment to be manipulated empirically. But the impact of manipulations seems differ according to their nature (quantity, occurrence, and characteristics of the stimuli) and the target population. METHODS: We performed a systematic review of research on virtual spatial navigation covering the period from 2005 to 2015. We focused first on the contribution of virtual spatial navigation for patients with brain injury or schizophrenia, or in the context of ageing and dementia, and then on the impact of visual or auditory stimuli on virtual spatial navigation. RESULTS: On the basis of 6521 abstracts identified in 2 databases (Pubmed and Scopus) with the keywords « navigation ¼ and « virtual ¼, 1103 abstracts were selected by adding the keywords "ageing", "dementia", "brain injury", "stroke", "schizophrenia", "aid", "help", "stimulus" and "cue"; Among these, 63 articles were included in the present qualitative analysis. CONCLUSION: Unlike pencil-and-paper tests, virtual reality is useful to assess large-scale navigation strategies in patients with brain injury or schizophrenia, or in the context of ageing and dementia. Better knowledge about both the impact of the different aids and the cognitive processes involved is essential for the use of aids in neurorehabilitation.

Immunoglobulin genes undergo legitimate repair in human B cells not only after cis- but also frequent trans-class switch recombination.

Immunoglobulin (Ig) genes specifically recruit activation-induced deaminase (AID) for 'on-target' DNA deamination, initiating either variable (V) region somatic hypermutation, or double-strand break intermediates of class switch recombination (CSR). Such breaks overwhelmingly undergo legitimate intra-Ig repair rather than rare illegitimate and potentially oncogenic junctions outside of Ig loci. We show that in human B cells, legitimate synapsis and repair efficiently join Ig genes whether physically linked on one chromosome or located apart on both alleles. This indicates mechanisms faithfully recognizing and/or pairing loci with homology in structure and accessibility, thus licensing interchromosomal trans-CSR junctions while usually preventing illegitimate interchromosomal recombination with AID off-target genes. Physical linkage of IgH genes in cis on the same allele just increases the likelihood of legitimate repair by another fourfold. The strongest force driving CSR might thus be recognition of legitimate target genes. Formation of IgH intra-allelic loops along this process would then constitute a consequence rather than a pre-requisite of this gene-pairing process.

Abnormal apical-to-basal transport of dietary ovalbumin by secretory IgA stimulates a mucosal Th1 response.

In celiac disease, enhanced permeability to gliadin peptides can result from their apico-basal transport by secretory immunoglobulin A1 (SIgA1) binding to the CD71 receptor ectopically expressed at the gut epithelial surface. Herein, we have established a mouse model in which there is apico-basal transport of the model antigen ovalbumin (OVA) by specific SIgA1 and have analyzed local T-cell activation. Transgenic DO11.10 mice were grafted with a hybridoma-secreting OVA-specific humanized IgA1, which could bind mouse CD71 and which were released in the intestinal lumen as SIgA. CD71 expression was induced at the gut apical surface by treating the mice with tyrphostin A8. Following gavage of the mice with OVA, OVA-specific CD4⁺ T cells isolated from the mesenteric lymph nodes displayed higher expression of the activation marker CD69 and produced more interferon gamma in mice bearing the hybridoma-secreting OVA-specific IgA1, than in ungrafted mice or in mice grafted with an irrelevant hybridoma. These results indicate that the protective role of SIgA1 might be jeopardized in human pathological conditions associated with ectopic expression of CD71 at the gut surface.

IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas.

To clarify the relationships between marginal zone lymphomas (MZLs) and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas (WM/LPLs), immunoglobulin heavy chain variable gene (IGHV) features were analyzed and the occurrence of MYD88 L265P mutations was identified in a series of 123 patients: 53 MZLs from the spleen (SMZLs), 11 from lymph nodes (NMZLs), 28 mucosa-associated lymphatic tissue (MALT) lymphomas and 31 WM/LPLs. SMZLs were characterized by overrepresentation of IGHV1-2 gene rearrangements with a canonical motif, without selection pressure and with long CDR3 segments. NMZLs had increased frequencies of IGHV3 genes. The IGHV gene was unmutated in most cases, often with long CDR3 segments. MALT lymphomas were usually associated with a mutated IGHV gene, but with the absence of selection pressure. WM/LPLs were associated with an IGHV3-23 overrepresentation and high IGHV mutation rate, with features of selection pressure and short CDR3 segments. MYD88 L265P mutations were almost restricted exclusively to WM/LPL patients. Taken all diagnoses together, all patients with MYD88 L265P mutations had an immunoglobulin M peak and almost all patients except one had bone marrow infiltration. These results demonstrate that the history of antigen exposure of the four entities studied was different and MYD88 L265P was specifically associated with WM/LPLs. WM/LPL may thus be functionally associated with constitutive nuclear factor-κB activation.

Quarterly individual outpatients lifestyle counseling after initial inpatients education on type 2 diabetes: the REDIA Prev-2 randomized controlled trial in Reunion Island.

AIMS: This study aimed to describe the 1-year evolution of type 2 diabetes (T2D) patients who attended inpatients education, and to assess whether quarterly outpatients counseling visits by nurses and dietitians can improve metabolic control and health-related behaviours. METHODS: Following in-hospital educational sessions, 398 adult T2D patients were randomized to either attend quarterly individual lifestyle counseling visits by a nurse and a dietitian (intervention group), or receive the usual care (control group). Primary (HbA(1c)) and secondary endpoints (fasting blood glucose, lipids, body mass index, waist circumference, fat mass, blood pressure, diet, physical activity) were assessed at baseline and at 12 months. RESULTS: HbA(1c) changes from baseline to 12 months were -1.74±2.64% (P<0.0001) for the intervention group and -2.02±2.57% (P<0.0001) for the control group. There was no statistically significant difference between the intervention group (n=153) and the controls (n=166) for any of the clinical and biological outcomes. In both groups, total energy and fat intakes decreased significantly from baseline levels. Also, no difference was found between the groups for any dietary outcome. A slight enhancement in sports activity was observed in the intervention group, but the difference between the two groups did not reach statistical significance, and no difference was found concerning any other physical activity scores. CONCLUSION: In this study of adults with T2D, patients significantly improved their metabolic control, and dietary and exercise habits, 1 year after receiving intensive inpatients education, whereas subsequent quarterly outpatients counseling visits with nurses and dietitians have not demonstrated any superiority compared with the usual care.

Complexes between nuclear factor-κB p65 and signal transducer and activator of transcription 3 are key actors in inducing activation-induced cytidine deaminase expression and immunoglobulin A production in CD40L plus interleukin-10-treated human blood B cells.

The signal transducer and activator of transcription 3 (STAT3) transcription factor pathway plays an important role in many biological phenomena. STAT3 transcription is triggered by cytokine-associated signals. Here, we use isolated human B cells to analyse the role of STAT3 in interleukin (IL)-10 induced terminal B cell differentiation and in immunoglobulin (Ig)A production as a characteristic readout of IL-10 signalling. We identified optimal conditions for inducing in-vitro IgA production by purified blood naive B cells using IL-10 and soluble CD40L. We show that soluble CD40L consistently induces the phosphorylation of nuclear factor (NF)-κB p65 but not of STAT3, while IL-10 induces the phosphorylation of STAT3 but not of NF-κB p65. Interestingly, while soluble CD40L and IL-10 were synergistic in driving the terminal maturation of B cells into IgA-producing plasma cells, they did not co-operate earlier in the pathway with regard to the transcription factors NF-κB p65 or STAT3. Blocking either NF-κB p65 or STAT3 profoundly altered the production of IgA and mRNA for activation-induced cytidine deaminase (AID), an enzyme strictly necessary for Ig heavy chain recombination. Finally, the STAT3 pathway was directly activated by IL-10, while IL-6, the main cytokine otherwise known for activating the STAT3 pathway, did not appear to be involved in IL-10-induced-STAT3 activation. Our results suggest that STAT3 and NF-κB pathways co-operate in IgA production, with soluble CD40L rapidly activating the NF-κB pathway, probably rendering STAT3 probably more reactive to IL-10 signalling. This novel role for STAT3 in B cell development reveals a potential therapeutic or vaccine target for eliciting IgA humoral responses at mucosal interfaces.

Use of both CD63 up regulation and IgE down regulation for the flow cytometric analysis of allergen induced basophil activation. Definition of an activation index.

OBJECTIVE AND DESIGN: The aim of this study was to compare the use of a late (CD63) and an early (IgE) marker of basophil activation in the flow cytometric diagnosis of beta-lactam induced allergic hypersensitivity reactions. SUBJECTS: Twelve patients who had had a clear cut betalactam induced immediate reaction and 16 controls were selected, as well as 11 patients who had had an immediate reaction to bee or wasp stings. METHODS: Leukocyte suspensions were incubated with allergen dilutions as well as 2 positive controls (anti-IgE and NFormyl- Methionyl-Leucyl-Phenylalanine (fMLP)). Basophils were labelled with an anti-IgE FITC (fluorescein isothiocyanate) and an anti-CD63 PE (phycoerythrin). Results were expressed as percentage CD63 expression and index calculated according to a specific algorithm including the two activation markers. RESULTS: Significant CD63 expression (>5 %) was observed in 3/12 cases for the beta-lactam sensitized population, in 0/16 cases for the controls and in 11/11 cases for the venom sensitized population. A significant index (determined by a ROC analysis) was observed in 11/12 beta-lactam sensitized patients and in 0/16 controls. CONCLUSION: These results show that IgE (an early activation marker) is more sensitive than CD63 (a later activation marker) in the diagnosis of beta-lactam allergy.

Light chain inclusion permits terminal B cell differentiation and does not necessarily result in autoreactivity.

Mice in which the Jkappa cluster was replaced with a VkappaJkappa rearranged gene were studied. More than 90% of B cells from homozygous mutant mice expressed the transgenic kappa chain but showed a slightly reduced level of kappa transcripts compared with WT B lymphocytes. Light chain inclusion was apparent in 10% of B cells from these mice and raised 25% in hemizygous mice with a still lower expression of the knockin kappa chain. Beyond the rules of clonal selection, peripheral B cells developed in such animals, with included cells being activated and differentiating into class-switched or antibody-secreting cells. The high amount of included mature B cells was associated with an increase of hybrid kappa/lambda immunoglobulins but not with the increased prevalence of autoantibodies. Altogether, these data suggest that light chain exclusion prevalent in normal B cells mostly results from ordered rearrangements and stochastic mechanisms but is neither tightly ensured by a stringent cell selection process nor absolutely required for normal B cell function.

[Therapeutic strategies in somatotroph adenomas with extrasellar extension: role of the medical approach, a consensus study of the French Acromegaly Registry]. / Stratégies thérapeutiques dans les adénomes somatotropes avec extension extrasellaire. Place du traitement médical. Etude consensus du Répetoire français de l'Acromégalie.

UNLABELLED: From the first 198 patient files included into the French Acromegaly Registry, we analyzed 68 patients harboring a somatotroph adenoma with extrasellar extension, after exclusion of those treated by stereotactic or conventional radiotherapy. In these patients (including 37 women), aged 21-77 yr. (45.7 +/- 13.3), GH concentrations ranged from 2-260 microg/L (38.6 +/- 44.3), and IGF I from 86-967% of age-matched upper limit of normal (303 +/- 164). Maximal diameter of the adenoma at MRI was 11-36.5 mm (20.4 +/- 6.5), with cavernous sinus involvement in 68% of cases. Three subgroups were defined: 20 patients treated by long-acting somatostatin analogs only (group M), for a mean duration of 3 yr. (extremes 1-7 yr.), 48 patients initially treated by transsphenoidal surgery (group C), of whom 21 were secondarily treated by long-acting somatostatin analogs (group CM) for a mean duration of 1.2 yr. (extremes 0.2-2 yr.). All 3 groups were not statistically different in terms of tumor mass and initial levels of GH and IGF-1. Patients from group M were significantly older than those of the other groups (p<0.05). RESULTS: 46% of patients from group C after surgery vs. 45% of patients from group M had a mean GH below 2.5 microg/L. Biochemical remission (GH<2.5 microg/L and normal IGF1 normal) was obtained in 31% of cases in group C, vs. 25% in group M. In this group, a decrease of the largest tumor diameter was observed in 10 patients (71.5%), ranging from 10-25% in 7 (50%) and exceeded 50% in 3 (21.5%). In group CM, the biochemical remission rate (42%) and final GH or IGF1 values were not significantly different from group M. In conclusion, these data suggest that surgery or long-acting somatostatin analogs have a comparable efficacy in terms of remission rates in somatotroph macroadenomas with extrasellar extensions.