Oxford-AstraZeneca COVID-19 vaccine: need of a reasoned and effective vaccine campaign.

OBJECTIVES: A strong COVID-19 vaccine campaign is needed to reach the herd immunity and reduce this pandemic infection. STUDY DESIGN: In the Foch Hospital, France, in February 2021, 451 healthcare workers were vaccinated by a first dose of AstraZeneca vaccine. METHODS: Adverse effects were reported to our pharmaco-vigilance circuit, by an online and anonymous questionnaire following the first weeks of the vaccinal campaign to healthcare workers. RESULTS: Two hundred seventy-four (60.8%) of them reported multiple adverse effects. Main adverse effects reported were feverish state/chills (65.7%), fatigue/physical discomfort (62.4%), arthralgia/muscle pain (61.0%) and fever (44.5%). CONCLUSIONS: On March 2021 many European countries suspended AstraZeneca vaccine for one week due to safety uncertainty. Thus, confidence in its efficacy is undermined. However, the benefit/risk balance is clearly in favor of vaccination.

Anti-infectious properties of the probiotic Saccharomyces cerevisiae CNCM I-3856 on enterotoxigenic E. coli (ETEC) strain H10407.

Enterotoxigenic Escherichia coli (ETEC) are major food-borne pathogens responsible for traveler's diarrhea. The production of adhesins and the secretion of enterotoxins constitute the major virulence traits of the bacteria. Treatments are mainly symptomatic and can involve antibiotherapy. However, given the rise of antibiotic resistance worldwide, there is an urgent need for the development of new preventive strategies for the control of ETEC infections. Among them, a promising approach is the use of probiotics. The aim of this study was to investigate, using complementary in vitro and in vivo approaches, the inhibitory potential of the yeast Saccharomyces cerevisiae CNCM I-3856 against the human ETEC reference strain H10407. In conventional culture media, S. cerevisiae significantly reduced ETEC growth and toxin production. The yeast also inhibited bacterial adhesion to mucin-agar and intestinal Caco-2/TC7 cells in a dose-dependent manner. Lastly, pre-treatment with S. cerevisiae inhibited interleukin-8 production by ETEC-infected intestinal cells. In streptomycin-treated mice, the probiotic yeast decreased bacterial colonization, mainly in the ileum, the main site of ETEC pathogenesis. For the first time, this study shows that the probiotic yeast S. cerevisiae CNCM I-3856 can exert an anti-infectious activity against a human ETEC strain through a multi-targeted approach, including inhibition of bacterial growth and toxin production, reduction of bacterial adhesion to mucins and intestinal epithelial cells, and suppression of ETEC-induced inflammation. Interestingly, the highest activity was obtained with a prophylactic treatment. Further studies will aim to assess the effect of the yeast on ETEC survival and virulence under human simulated digestive conditions.

[Osteo-cutaneous Mycobacterium marinum infection of the elbow and reconstruction with radial collateral artery perforator-based propeller flap]. / Infection ostéo-cutanée du coude à Mycobacterium marinum et reconstruction par un lambeau en hélice basé sur une perforante de l'artère collatérale radiale postérieure.

Mycobacterium marinum is an atypical and non-tuberculosis mycobacterium that mainly leads to cutaneous infections. Infections occur through inoculation of the organism through injury to the skin in the presence of contaminated water or fish. The patient often presents with unspecific symptoms and the evolution, in the absence of adequate treatment, is characterized by an expansion of the cutaneous lesion and a spread to deep structures. Infections of tendon sheaths and joints are described, rarely osteomyelitis. Sure diagnosis is hard to obtain and is established from the medical history and microbiological examination. There are no specific therapeutic guidelines. Double or triple antibiotherapy is often effective and should be continued several months after complete resolution of clinical signs. Surgical debridement is required in cases of invasive or resistant infections. We report the case of a young immunocompetent fishmonger with a rare osteocutaneous M. marinum infection of the elbow. Treatment included large surgical excision of infected skin and bone areas and a triple antibiotics administration. Reconstruction have been ensured by a radial collateral artery perforator-based propeller flap, satisfying appropriates functional and cosmetical concerns of this anatomical region. Surgery and appropriate antibiotics treatment were effective and allowed healing of an invasive cutaneous and bone M. marinum infection.

Horizons in Endometriosis: Proceedings of the Montreux Reproductive Summit, 14-15 July 2023.

Endometriosis is a complex and chronic gynaecological disorder that affects millions of women worldwide, leading to significant morbidity and impacting reproductive health. This condition affects up to 10% of women of reproductive age and is characterised by the presence of endometrial-like tissue outside the uterus, potentially leading to symptoms such as chronic pelvic pain, dysmenorrhoea, dyspareunia, and infertility. The Montreux summit brought a number of experts in this field together to provide a platform for discussion and exchange of ideas. These proceedings summarise the six main topics that were discussed at this summit to shed light on future directions of endometriosis classification, diagnosis, and therapeutical management. The first question addressed the possibility of preventing endometriosis in the future by identifying risk factors, genetic predispositions, and further understanding of the pathophysiology of the condition to develop targeted interventions. The clinical presentation of endometriosis is varied, and the correlation between symptoms severity and disease extent is unclear. While there is currently no universally accepted optimal classification system for endometriosis, several attempts striving towards its optimisation - each with its own advantages and limitations - were discussed. The ideal classification should be able to reconcile disease status based on the various diagnostic tools, and prognosis to guide proper patient tailored management. Regarding diagnosis, we focused on future tools and critically discussed emerging approaches aimed at reducing diagnostic delay. Preserving fertility in endometriosis patients was another debatable aspect of management that was reviewed. Moreover, besides current treatment modalities, potential novel medical therapies that can target underlying mechanisms, provide effective symptom relief, and minimise side effects in endometriotic patients were considered, including hormonal therapies, immunomodulation, and regenerative medicine. Finally, the question of hormonal substitution therapy after radical treatment for endometriosis was debated, weighing the benefits of hormone replacement.

Quantitative brainstem and spinal MRI in amyotrophic lateral sclerosis: implications for predicting noninvasive ventilation needs.

BACKGROUND: Respiratory complications resulting from motor neurons degeneration are the primary cause of death in amyotrophic lateral sclerosis (ALS). Predicting the need for non-invasive ventilation (NIV) in ALS is important for advance care planning and clinical trial design. The aim of this study was to assess the potential of quantitative MRI at the brainstem and spinal cord levels to predict the need for NIV during the first six months after diagnosis. METHODS: Forty-one ALS patients underwent MRI and spirometry shortly after diagnosis. The need for NIV was monitored according to French health guidelines for 6 months. The performance of four regression models based on: clinical variables, brainstem structures volumes, cervical spinal measurements, and combined variables were compared to predict the need for NIV within this period. RESULTS: Both the clinical model (R2 = 0.28, AUC = 0.85, AICc = 42.67, BIC = 49.8) and the brainstem structures' volumes model (R2 = 0.30, AUC = 0.85, AICc = 40.13, BIC = 46.99) demonstrated good predictive performance. In addition, cervical spinal cord measurements model similar performance (R2 = 0.338, AUC = 0.87, AICc = 37.99, BIC = 44.49). Notably, the combined model incorporating predictors from all three models yielded the best performance (R2 = 0.60, AUC = 0.959, AICc = 36.38, BIC = 44.8). These findings are supported by observed positive correlations between brainstem volumes, cervical (C4/C7) cross-sectional area, and spirometry-measured lung volumes. CONCLUSIONS: Our study shows that brainstem volumes and spinal cord area are promising measures to predict respiratory intervention needs in ALS.

Genetic parameters for claw disorders and the effect of preselecting cows for trimming.

Claw disorders are important traits relevant to dairy cattle breeding from an economical and welfare point of view. Selection for reduced claw disorders can be based on hoof trimmer records. Typically, not all cows in a herd are trimmed. Our objectives were to estimate heritabilities and genetic correlations for claw disorders and investigate the effect of selecting cows for trimming. The data set contained 50,238 cows, of which 20,474 cows had at least one claw trimming record, with a total of 29,994 records. Six claw trimmers scored 14 different claw disorders: abscess (AB), corkscrew claw (CC), (inter-)digital dermatitis or heel erosion (DER), double sole (DS), hardship groove (HG), interdigital hyperplasia (IH), interdigital phlegmon (IP), sand crack (SC), super-foul (SF), sole hemorrhage (SH), sole injury (SI), sole ulcer (SU), white line separation (WLS), yellow discoloration of the sole (YD), and a combined claw disorder trait. Frequencies of the claw disorders for trimmed cows ranged from 0.1% (CC, YD, HG) to 23.8% (DER). More than half of the cows scored had at least one claw disorder. Heritability on the observed scale ranged from 0.02 (DS, SH) to 0.14 (IH) and on the underlying scale from 0.05 to 0.43 in trimmed cows. Genetic correlations between laminitis-related claw disorders were moderate to high, and the same was found for hygiene-related claw disorders. The effect of selecting cows for trimming was first investigated by including untrimmed cows in the analyses and assuming they were not affected by claw disorders. Heritabilities on the underlying scale showed only minor changes. Second, different subsets of the data were created based on the percentage of trimmed cows in the herd. Heritabilities for IH, DER, and SU tended to decrease when a higher percentage of cows in the herd were trimmed. Finally, a bivariate model with a claw disorder and the trait "trimming status" was used, but heritabilities were similar. Heritability for trimming status was relatively high (0.09). Genetic correlations of trimming status with claw disorders were generally moderate to high. To conclude, the effect of selecting cows for trimming on the heritability for claw disorders is negligible. Selecting herds with a high fraction of cows being trimmed tended to decrease heritability. Trimming status, as such, is a heritable trait and correlated with claw disorders and is therefore an interesting trait to include in the genetic evaluation.

Comparison of spinal magnetic resonance imaging and classical clinical factors in predicting motor capacity in amyotrophic lateral sclerosis.

BACKGROUND: Motor capacity is crucial in amyotrophic lateral sclerosis (ALS) clinical trial design and patient care. However, few studies have explored the potential of multimodal MRI to predict motor capacity in ALS. This study aims to evaluate the predictive value of cervical spinal cord MRI parameters for motor capacity in ALS compared to clinical prognostic factors. METHODS: Spinal multimodal MRI was performed shortly after diagnosis in 41 ALS patients and 12 healthy participants as part of a prospective multicenter cohort study, the PULSE study (NCT00002013-A00969-36). Motor capacity was assessed using ALSFRS-R scores. Multiple stepwise linear regression models were constructed to predict motor capacity at 3 and 6 months from diagnosis, based on clinical variables, structural MRI measurements, including spinal cord cross-sectional area (CSA), anterior-posterior, and left-to-right cross-section diameters at vertebral levels from C1 to T4, and diffusion parameters in the lateral corticospinal tracts (LCSTs) and dorsal columns. RESULTS: Structural MRI measurements were significantly correlated with the ALSFRS-R score and its sub-scores. And as early as 3 months from diagnosis, structural MRI measurements fit the best multiple linear regression model to predict the total ALSFRS-R (R2 = 0.70, p value = 0.0001) and arm sub-score (R2 = 0.69, p value = 0.0002), and combined with DTI metric in the LCST and clinical factors fit the best multiple linear regression model to predict leg sub-score (R2 = 0.73, p value = 0.0002). CONCLUSIONS: Spinal multimodal MRI could be promising as a tool to enhance prognostic accuracy and serve as a motor function proxy in ALS.

COVID-19 reinfection after pregnancy.

BACKGROUND: There have been reports of COVID-19 reinfections, but the immunological characterization of these cases is partial. We report a case of reinfection with SARS-CoV-2, where the first infection occurred in the course of late pregnancy. CASE PRESENTATION: On May 27, 2020, a 37-year-old woman gave birth at full term, 3 hours after full dilatation. She developed fever (38.3°C) after delivery. Mild biological anomalies compatible with COVID-19 were observed: lymphopenia, thrombocytopenia, elevated D-Dimers, CRP, and LDH. At 6-month follow-up, she reported having contracted COVID-19 with high fever, rhinorrhea, hand frostbites, cough, headache, dysgeusia and anosmia. CONCLUSIONS: We report a case of COVID-19 reinfection with a first mild infection during late pregnancy and a more aggressive second infection 5 months later.

Comparison of five techniques of skin prick tests used routinely in Europe.

BACKGROUND: Skin prick tests represent indispensable tools in allergy, even more than 30 years after their introduction in clinical practice. OBJECTIVES: Few recent European studies have focused on this topic and we thus wanted to compare the instruments most often used today. METHODS: Four instruments were investigated: the 23G intravenous (IV) needle, the ALK Lancet, the Stallergenes (STG) Prick Lancet and the Stallerpoint(®) (using two different methods). Sensitivity, reproducibility, and acceptability were evaluated. In 22 subjects, we calculated the sensitivity and reproducibility (both intra- and interpatient) of these methods by testing the positive control five times. In 50 subjects, we tested the single-blind acceptability of these same five techniques. RESULTS: In terms of sensitivity, the IV needle (100%) and metal lancets (96% for the ALK Lancet and 98% for the STG Prick Lancet) were superior (P < 0.01) to the two Stallerpoint(®) methods (20% and 57%). Intrapatient reproducibility was 16.2%, 14.6%, 15.0%, 97.1% and 18.1%, respectively. The instruments that were best tolerated by the patients were the IV needle and the two metal lancets. CONCLUSION: Metal needles and/or lancets are the tools of choice for skin prick testing.

One-pot synthesis of a new generation of hybrid bisphosphonate polyoxometalate gold nanoparticles as antibiofilm agents.

A reduced polyoxovanadate functionalized with bisphosphonate molecules was synthesized and used to prepare in one step hybrid organic-inorganic polyoxometalate decorated gold nanoparticles. These new composites were shown to strongly inhibit P. aeruginosa and S. epidermidis biofilm growth, with the three components constituting the nanoparticles (Au0 core, vanadium and alendronate) acting synergistically.

Correction: One-pot synthesis of a new generation of hybrid bisphosphonate polyoxometalate gold nanoparticles as antibiofilm agents.

[This corrects the article DOI: 10.1039/C9NA00401G.].

Added Value of Spectroscopy to Perfusion MRI in the Differential Diagnostic Performance of Common Malignant Brain Tumors.

BACKGROUND AND PURPOSE: Perfusion and spectroscopic MR imaging provide noninvasive physiologic and metabolic characterization of tissues, which can help in differentiating brain tumors. We investigated the diagnostic role of perfusion and spectroscopic MR imaging using individual and combined classifiers of these modalities and assessed the added performance value that spectroscopy can provide to perfusion using optimal combined classifiers that have the highest differential diagnostic performance to discriminate lymphomas, glioblastomas, and metastases. MATERIALS AND METHODS: From January 2013 to January 2016, fifty-five consecutive patients with histopathologically proved lymphomas, glioblastomas, and metastases were included after undergoing MR imaging. The perfusion parameters (maximum relative CBV, maximum percentage of signal intensity recovery) and spectroscopic concentration ratios (lactate/Cr, Cho/NAA, Cho/Cr, and lipids/Cr) were analyzed individually and in optimal combinations. Differences among tumor groups, differential diagnostic performance, and differences in discriminatory performance of models with quantification of the added performance value of spectroscopy to perfusion were tested using 1-way ANOVA models, receiver operating characteristic analysis, and comparisons between receiver operating characteristic analysis curves using a bivariate χ2, respectively. RESULTS: The highest differential diagnostic performance was obtained with the following combined classifiers: maximum percentage of signal intensity recovery-Cho/NAA to discriminate lymphomas from glioblastomas and metastases, significantly increasing the sensitivity from 82.1% to 95.7%; relative CBV-Cho/NAA to discriminate glioblastomas from lymphomas and metastases, significantly increasing the specificity from 92.7% to 100%; and maximum percentage of signal intensity recovery-lactate/Cr and maximum percentage of signal intensity recovery-Cho/Cr to discriminate metastases from lymphomas and glioblastomas, significantly increasing the specificity from 83.3% to 97.0% and 100%, respectively. CONCLUSIONS: Spectroscopy yielded an added performance value to perfusion using optimal combined classifiers of these modalities, significantly increasing the differential diagnostic performances for these common brain tumors.

Complex fractures of the acetabulum: Should the enlarged iliofemoral approach be abandoned? Results at 20 years' follow-up.

INTRODUCTION: Among the various options for internal fixation of acetabular fractures, the enlarged iliofemoral approach is less often used, being more invasive, although providing greater exposure enabling control of all components in complex fractures. Even so, the impact of its invasiveness has not been confirmed, and long-term results are not known. We therefore performed a retrospective study, aiming: to assess long-term functional outcome, and; to assess associated morbidity. HYPOTHESIS: The enlarged iliofemoral approach allows precise reduction, with favorable long-term outcome. MATERIAL AND METHODS: Between 1992 and 1997, 15 patients were operated on for complex acetabular fracture by a single surgeon using an enlarged iliofemoral approach. Two patients were excluded due to lack of follow-up data, leaving 13 patients for analysis: 3 simple transverse fractures, 4 transverse+posterior wall fractures, 4 anterior column+posterior hemi-transverse fractures, one T-shaped fracture and one 2-column fracture. There were 4 cases of posterior dislocation of the hip, and 8 of intrapelvic protrusion. Surgical morbidity was assessed in terms of operative time, number of packed red blood cell transfusions, iatrogenic lesions or postoperative complications, rehabilitation time, and hospital stay. Functional assessment at follow-up used the WOMAC index and Harris score; radiologic assessment used the Kellgren-Lawrence score for osteoarthritis and Brooker score for ossification. RESULTS: Reduction was in all cases anatomic. There were no intra- or post-operative complications. Median number of packed red blood cell transfusions was 5 [range, 3-10]. Median operative time was 4hours [3-6]. Median hospital stay was 6 weeks [6-8], to allow systematic traction with early postoperative mobilization. Weight-bearing was resumed at a median 8 weeks [8-12]. At a median 22 years' follow-up [20-24], median Harris score was 83.5 [63-92] and median WOMAC index 24.5 [1-52]. All patients showed Brooker 1 or 2 ectopic ossification and moderate osteoarthritis. Two underwent subsequent arthroplasty (at 1 and 11 years after the index procedure). DISCUSSION: The enlarged iliofemoral approach allowed anatomic reduction of acetabular fracture. It provided very good long-term results, without excessive morbidity. LEVEL OF EVIDENCE: IV, retrospective non-controlled study.

Genome-wide association study for behavior, type traits, and muscular development in Charolais beef cattle.

Behavior, type traits, and muscular development are of interest for beef cattle breeding. Genome-wide association studies (GWAS) enable the identification of candidate genes, which enables gene-based selection and provides insight in the genetic architecture of these traits. The objective of the current study was to perform a GWAS for 3 behavior traits, 12 type traits, and muscular development in Charolais cattle. Behavior traits, including aggressiveness at parturition, aggressiveness during gestation period, and maternal care, were scored by farmers. Type traits, including udder conformation, teat, feet and legs, and locomotion, were scored by trained classifiers. Data used in the GWAS consisted of 3,274 cows with phenotypic records and genotyping information for 44,930 SNP. When SNP had a false discovery rate (FDR) smaller than 0.05, they were referred to as significant. When SNP had a FDR between 0.05 and 0.20, they were referred to as suggestive. Four significant and 12 suggestive regions were detected for aggressiveness during gestation, maternal care, udder balance, teat thinness, teat length, foot angle, foot depth, and locomotion. These 4 significant and 12 suggestive regions were not supported by other significant SNP in close proximity. No SNP with major effects were detected for behavior and type traits, and SNP associations for these traits were spread across the genome, suggesting that behavior and type traits were influenced by many genes, each explaining a small part of genetic variance. The GWAS identified 1 region on chromosome 2 significantly associated with muscular development, which included the myostatin gene (), which is known to affect muscularity. No other regions associated with muscular development were found. Results showed that the myostatin region associated with muscular development had pleiotropic effects on udder volume, teat thinness, rear leg, and leg angle.

Astrocytes from cerebral cortex or striatum attract adult host serotoninergic axons into intrastriatal ventral mesencephalic co-grafts.

The identification of axon growth inhibitory molecules offers new hopes for repair of the injured CNS. However, the navigational ability of adult CNS axons and the guidance cues they can recognize are still essentially unknown. Astrocytes may express guidance molecules and are known to have different regional phenotypes. To evaluate their influence on the affinity of adult serotoninergic (5-HT) axons for a projection target, we co-implanted astrocytes from the neonatal striatum, cortex, or ventral mesencephalon together with fetal ventral mesencephalic tissue into the striatum of adult rats. Two months after surgery, quantification after in vitro 5-[1,2-(3)H]serotonin ([(3)H]5-HT) uptake and autoradiography showed that ventral mesencephalic grafts with co-grafted cortical or striatal astrocytes were four times and three times, respectively, more densely innervated by host 5-HT axons than control ventral mesencephalic grafts with or without co-grafted ventral mesencephalic astrocytes. Immunohistochemistry for glial fibrillary acidic protein, vimentin, or chondroitin-sulfate proteoglycans revealed no qualitative or quantitative differences in host astroglial scar or production of inhibitory molecules that could explain these differences in 5-HT innervation. These results demonstrate that astrocytes grown in culture from different brain regions have the potential to influence the growth and maintenance of adult 5-HT axons in a graft of neural tissue from another brain region. It should now be feasible to identify the molecules expressed by cultured cortical or striatal, but not by ventral mesencephalic, astrocytes that have these tropic actions on 5-HT axons of the neostriatum.

Dystonin Is Essential for Maintaining Neuronal Cytoskeleton Organization.

The mouse neurological mutant dystonia musculorum (dt) suffers from a hereditary sensory neuropathy. We have previously described the cloning and characterization of the dt gene, which we named dystonin (Dst). We had shown that dystonin is a neural isoform of bullous pemphigoid antigen 1 (Bpag1) with an N-terminal actin-binding domain. It has been shown previously that dystonin is a cytoskeletal linker protein, forming a bridge between F-actin and intermediate filaments. Here, we have used two different antibody preparations against dystonin and detected a high-molecular-weight protein in immunoblot analysis of spinal cord extracts. We also show that this high-molecular-weight protein was not detectable in the nervous system of all dt alleles tested. Immunohistochemical analysis revealed that dystonin was present in different compartments of neurons-cell bodies, dendrites, and axons, regions which are rich in the three elements of the cytoskeleton (F-actin, neurofilaments, and microtubules). Ultrastructural analysis of dt dorsal root axons revealed disorganization of the neurofilament network and surprisingly also of the microtubule network. In this context it is of interest that we observed altered levels of the microtubule-associated proteins MAP2 and tau in spinal cord neurons of different dt alleles. Finally, dt dorsal root ganglion neurons formed neurites in culture, but the cytoskeleton was disorganized within these neurites. Our results demonstrate that dystonin is essential for maintaining neuronal cytoskeleton integrity but is not required for establishing neuronal morphology. Copyright 1998 Academic Press.

Genetic parameters for large-scale behavior traits and type traits in Charolais beef cows.

In the last decades, beef cattle breeding mainly focused on improving production and reproduction traits. Nowadays, there is a growing interest to include behavior and type traits in the breeding goal. There is an interest in behavior as it is associated with human safety and workability and in type traits as they might be associated with longevity of cows. The objective of the current study was to estimate the heritability for behavior and type traits in Charolais and to estimate the genetic correlations among these traits. Behavior traits, including aggressiveness at parturition, aggressiveness during gestation period, and maternal care, were scored by farmers using an on-farm recording system to enable large-scale collection of phenotypes. Type traits, including udder traits ( = 3), teat traits (3), feet and leg traits (5), and locomotion (1), were scored by 10 trained classifiers. Data was available on 6,649 cows in parity 1 to 12 and located in 380 herds. Results showed that differences between herds explained up to 23% of the total phenotypic variance in behavior traits. This might be due to differences in management or to consistent differences in scoring between farmers. Aggressiveness at parturition had higher heritability (0.19) and higher genetic coefficient of variation (CV = 11%) than aggressiveness during gestation ( = 0.06 and CV = 4%) and maternal care ( = 0.02 and CV = 2%). Heritabilities for udder traits (0.14 to 0.20) and teat traits (0.17 to 0.35) were higher than for feet and leg traits (0.02 to 0.19). Genetic coefficients of variation for udder and teat traits were also higher (up to 21%) than for feet and leg traits (up to 11%). Strong genetic correlations were found between behavior traits (with absolute values from 0.71 to 0.98). The genetic correlations indicate that it is difficulty to simultaneously improve maternal care and reduce aggressiveness. We concluded that there are good opportunities to implement selection for improved udder and teat traits and against aggressiveness at parturition using a simple on-farm recording system of behavior.

Repetitive transcranial magnetic stimulation and transcranial direct current stimulation in motor rehabilitation after stroke: an update.

Stroke is a leading cause of adult motor disability. The number of stroke survivors is increasing in industrialized countries, and despite available treatments used in rehabilitation, the recovery of motor functions after stroke is often incomplete. Studies in the 1980s showed that non-invasive brain stimulation (mainly repetitive transcranial magnetic stimulation [rTMS] and transcranial direct current stimulation [tDCS]) could modulate cortical excitability and induce plasticity in healthy humans. These findings have opened the way to the therapeutic use of the 2 techniques for stroke. The mechanisms underlying the cortical effect of rTMS and tDCS differ. This paper summarizes data obtained in healthy subjects and gives a general review of the use of rTMS and tDCS in stroke patients with altered motor functions. From 1988 to 2012, approximately 1400 publications were devoted to the study of non-invasive brain stimulation in humans. However, for stroke patients with limb motor deficit, only 141 publications have been devoted to the effects of rTMS and 132 to those of tDCS. The Cochrane review devoted to the effects of rTMS found 19 randomized controlled trials involving 588 patients, and that devoted to tDCS found 18 randomized controlled trials involving 450 patients. Without doubt, rTMS and tDCS contribute to physiological and pathophysiological studies in motor control. However, despite the increasing number of studies devoted to the possible therapeutic use of non-invasive brain stimulation to improve motor recovery after stroke, further studies will be necessary to specify their use in rehabilitation.

Quantitative and morphometric data indicate precise cellular interactions between serotonin terminals and postsynaptic targets in rat substantia nigra.

We have quantified the density of serotonin axonal varicosities, their synaptic incidence and their distribution among potential targets in the pars reticulata and pars compacta of the rat substantia nigra. Serotonin axonal varicosities, counted at the light microscopic level following in vitro [3H]serotonin uptake and autoradiography, amounted to 9 x 10(6)/mm3 in the pars reticulata and 6 x 10(6)/mm3 in the pars compacta, among the densest serotonin innervations in brain. As determined at the electron microscopic level following immunolabelling for serotonin, virtually all serotonin varicosities in the pars reticulata and 50% of those in the pars compacta formed a synapse, essentially with dendrites. The combination of serotonin immunocytochemistry with tyrosine hydroxylase immunolabelling of dopamine neurons reveals that 20% of the serotonin synaptic contacts in the pars reticulata are on dopamine dendrites and 6% are on a type of unlabelled dendrite characterized by its peculiarly high cytoplasmic content of microtubules. The comparison of the diameter of the dendritic profiles that were in synaptic contact with serotonin-immunoreactive varicosities with the diameter of all other dendritic profiles of the same type suggests that serotoninergic varicosities innervate dopamine dendrites uniformly along their length, whereas they tend to contact microtubule-filled dendrites in more proximal regions and the other, unidentified dendrites in more distal regions. Furthermore, the size of the serotonin-immunoreactive varicosities and of their synaptic junctions is significantly smaller on dopamine dendrites and larger on microtubule-filled dendrites than on other, unidentified dendrites, indicating that the nature of the postsynaptic target is an important determinant of synaptic dimensions. These data should help to clarify the role of serotonin in the nigral control of motor functions. They indicate that this dense serotonin input to the substantia nigra is very precisely organized, acting through both "non-junctional" and "junctional" modes of neurotransmission in the pars compacta, which projects to the neostriatum and the limbic system, whereas the predominant mode of serotonin transmission appears to be of the "junctional" type in the pars reticulata, where serotonin can finely control the motor output of the basal ganglia by acting on the GABA projection neurons either directly or through the local release of dopamine by dopaminergic dendrites. The data also raise the possibility that the postsynaptic targets have trophic retrograde influences on serotoninergic terminals.

Cellular and subcellular localization of Ras guanyl nucleotide-releasing protein in the rat hippocampus.

Ras guanyl nucleotide-releasing protein (RasGRP) is a recently discovered Ras guanyl nucleotide exchange factor that is expressed in selected regions of the rodent CNS, with high levels of expression in the hippocampus. Biochemical studies suggest that RasGRP can activate the Ras signal pathway in response to changes in diacylglycerol and possibly calcium. To investigate potential sites for RasGRP signaling, we have determined the cellular and subcellular localization of RasGRP protein in adult rat hippocampus, and have also examined the appearance of RasGRP mRNA and protein during hippocampal development. RasGRP immunoreactivity is predominately localized to those neurons participating in the direct cortico-hippocampo-cortical loop. In both hippocampal and entorhinal neurons, RasGRP protein appeared to be localized to both dendrites and somata, but not to axons. Electron microscopy of hippocampal pyramidal cells confirmed RasGRP immunoreactivity in neuronal cell bodies and dendrites, where it appeared to be associated with microtubules. The localization of RasGRP to dendrites suggests a role for this pathway in the regulation of dendritic function. Examination of developing hippocampal structures indicated that RasGRP mRNA and protein appear synchronously during the first 2 weeks of postnatal development as these neurons become fully mature. This result indicates that the RasGRP signal transduction pathway is not required during early hippocampal development, but is a feature of mature neurons during the later stages of development.