[Trajectory of a patient with deep brain stimulation (DBS)]. / Stimulation cérébrale profonde: trajectoire du patient.

An eligibility assessment for deep brain stimulation is performed in order to select patients who are likely to benefit from it. Parkinson's patients have to stop dopaminergic drugs the day before surgery. During the operation, the patient must remain awake for recording of neuronal activity and for test stimulations to optimize the position of the electrodes. Postoperatively, the stimulation is increased progressively in parallel with a decrease of dopaminergic treatments. After about ten days, the patient can return to home and controls continue as an outpatient. Three months postoperatively, a complete testing of the neurostimulator is performed and at the one year follow-up visit, the effectiveness of the DBS is assessed.

Isoelectric point is an inadequate descriptor of MS2, Phi X 174 and PRD1 phages adhesion on abiotic surfaces.

MS2, Phi X 174 and PRD1 bacteriophages are commonly used as surrogates to evaluate pathogenic virus behavior in natural aquatic media. The interfacial properties of these model soft bioparticles are herein discussed in connection with their propensities to adhere onto abiotic surfaces that differ in terms of surface charges and hydrophobicities. The phages considered in this work exhibit distinct multilayered surface structures and their electrostatic charges are evaluated from the dependence of their electrophoretic mobilities on electrolyte concentration at neutral pH on the basis of electrokinetic theory for soft (bio)particles. The charges of the viruses probed by electrokinetics vary according to the sequence Phi X 174⩽PRD1≪MS2, where '<' stands for 'less charged than'. The hydrophobic/hydrophilic balances of the phages are further derived from their adhesions onto model hydrophobic and hydrophilic self-assembled mono-layers. The corresponding results lead to the following hydrophobicity sequence Phi X 174≪MS2

Investigation of memory, executive functions, and anatomic correlates in asymptomatic FMR1 premutation carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset movement disorder associated with FMR1 premutation alleles. Asymptomatic premutation (aPM) carriers have preserved cognitive functions, but they present subtle executive deficits. Current efforts are focusing on the identification of specific cognitive markers that can detect aPM carriers at higher risk of developing FXTAS. This study aims at evaluating verbal memory and executive functions as early markers of disease progression while exploring associated brain structure changes using diffusion tensor imaging. We assessed 30 aPM men and 38 intrafamilial controls. The groups perform similarly in the executive domain except for decreased performance in motor planning in aPM carriers. In the memory domain, aPM carriers present a significant decrease in verbal encoding and retrieval. Retrieval is associated with microstructural changes of the white matter (WM) of the left hippocampal fimbria. Encoding is associated with changes in the WM under the right dorsolateral prefrontal cortex, a region implicated in relational memory encoding. These associations were found in the aPM group only and did not show age-related decline. This may be interpreted as a neurodevelopmental effect of the premutation, and longitudinal studies are required to better understand these mechanisms.

Two-day detection of infectious enteric and non-enteric adenoviruses by improved ICC-qPCR.

In order to provide a more suitable response to public health concerns, we improved the detection of infectious human adenoviruses in water by optimising the commonly used integrated cell culture-PCR method. Risk evaluation studies seek for rapid detection of infectious adenoviruses, including the enteric types 40 and 41 that are considered as the second most common agents of gastroenteritis in children next to rotaviruses. The here-employed 293A cell line used for infectious status assessment showed its ability to multiply adenoviruses including type 41. Two modifications were moreover applied to the workflow for viral detection. The first occurred at the nucleic acid extraction step performed directly on all infected cells, while the second was the application of real-time quantitative PCR as detection tool. All adaptations led to a 3-day reduction of the response delay and an improved sensitivity especially for the enteric adenoviral types. The infectious status of laboratory strain types 2 and 41 was demonstrated by a more than 2-log10 increase in genome quantity. These conclusions were confirmed and reinforced by the analysis of water samples applying the improved assay. Naturally occurring infectious adenoviruses were detected in wastewater and river water, within 2 days. Types belonging to the species human adenoviruses C and type 31 were observed, but the most frequently identified type was 41 (71 % of identified sequences, n = 34). This highlights the usefulness of our method for a wide range of types, and especially for the most prevalent and public health-relevant enteric adenoviruses.

Brain structure in asymptomatic FMR1 premutation carriers at risk for fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset movement disorder affecting FMR1 premutation carriers, is associated with cerebral and cerebellar lesions. The aim of this study was to test whether computational anatomy can detect similar patterns in asymptomatic FMR1 premutation carriers (mean age 46.7 years) with qualitatively normal -appearing grey and white matter on brain MRI. We used a multimodal imaging protocol to characterize brain anatomy by automated assessment of gray matter volume and white matter properties. Structural changes in the hippocampus and in the cerebellar motor network with decreased gray matter volume in lobule VI and white matter alterations of the corresponding afferent projections through the middle cerebellar peduncles are demonstrated. Diffuse subcortical white matter changes in both hemispheres, without corresponding gray matter alterations, are only identified through age × group interactions. We interpret the hippocampal fimbria and cerebellar changes as early alterations with a possible neurodevelopmental origin. In contrast, progression of the diffuse cerebral hemispheric white matter changes suggests a neurodegenerative process, leading to late-onset lesions, which may mark the imminent onset of FXTAS.

New analysis workflow for MALDI imaging mass spectrometry: application to the discovery and identification of potential markers of childhood absence epilepsy.

Childhood absence epilepsy is a prototypic form of generalized nonconvulsive epilepsy characterized by short impairments of consciousness concomitant with synchronous and bilateral spike-and-wave discharges in the electroencephalogram. For scientists in this field, the BS/Orl and BR/Orl mouse lines, derived from a genetic selection, constitute an original mouse model "in mirror" of absence epilepsy. The potential of MALDI imaging mass spectrometry (IMS) for the discovery of potential biomarkers is increasingly recognized. Interestingly, statistical analysis tools specifically adapted to IMS data sets and methods for the identification of detected proteins play an essential role. In this study, a new cross-classification comparative design using a combined discrete wavelet transformation-support vector machine classification was developed to discriminate spectra of brain sections of BS/Orl and BR/Orl mice. Nineteen m/z ratios were thus highlighted as potential markers with very high recognition rates (87-99%). Seven of these potential markers were identified using a top-down approach, in particular a fragment of Synapsin-I. This protein is yet suspected to be involved in epilepsy. Immunohistochemistry and Western Blot experiments confirmed the differential expression of Synapsin-I observed by IMS, thus tending to validate our approach. Functional assays are being performed to confirm the involvement of Synapsin-I in the mechanisms underlying childhood absence epilepsy.

Tumor necrosis factor-like weak inducer of apoptosis induces astrocyte proliferation through the activation of transforming-growth factor-α/epidermal growth factor receptor signaling pathway.

Reactive astrogliosis is beneficial in many aspects; however, it is also detrimental in some pathological states such as the development of lethal brain tumors. It is therefore crucial to understand the mechanisms regulating astrocyte proliferation. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor family, was shown to stimulate astrocyte proliferation in vitro. Herein, we further characterize the mitogenic potential of TWEAK on central nervous system cells. Among these cells, astrocytes express the highest level of TWEAK and Fn14 transcripts, suggesting that they are particularly sensitive to TWEAK stimulation. Using in vitro model systems, we found that TWEAK was as potent as epidermal growth factor (EGF) (a prototypical astrocyte mitogen) in mediating astrocyte proliferation. However, its mitogenic activity was delayed compared with that of EGF, suggesting distinct mechanisms of action. Using cell signaling pathway inhibitors, neutralizing antibodies, and protein assays, we further show that the mitogenic activity of TWEAK on primary astrocytes requires stimulation of the transforming growth factor-α (TGF-α) and of the epidermal growth factor receptor (EGFR) signaling pathway through extracellular signal-regulated kinase and p38 mitogen-activated protein kinase activation. In aggregates, our data demonstrate that TWEAK acts as a potent astrocyte mitogen through the induction of a TGF-α/EGFR signaling pathway. We anticipate that description of such a mechanism may allow novel approaches to human pathologies associated with astrocyte proliferation.

Effects of HIV protease inhibitors on progression of monocrotaline- and hypoxia-induced pulmonary hypertension in rats.

BACKGROUND: Pulmonary hypertension (PH) is among the complications of HIV infection. Combination antiretroviral therapy may influence the progression of HIV-related PH. Because Akt signaling is a potential molecular target of HIV protease inhibitors (HPIs), we hypothesized that these drugs altered monocrotaline- and hypoxia-induced PH in rats by downregulating the Akt pathway, thereby inhibiting pulmonary artery smooth muscle cell proliferation. METHODS AND RESULTS: Daily treatment with each of 3 first-generation HPIs (ritonavir 30 mg/kg, amprenavir 100 mg/kg, and nelfinavir 500 mg/kg) started 3 weeks after a subcutaneous monocrotaline injection (60 mg/kg) substantially diminished pulmonary artery pressure, right ventricular hypertrophy, number of muscularized pulmonary vessels, pulmonary arterial wall thickness, and proliferating pulmonary vascular Ki67-labeled cells without affecting vessel caspase 3 staining. HPI treatment partially prevented the development of hypoxia- and monocrotaline-induced PH. Monocrotaline-induced PH was associated with marked activation of Akt signaling in the lungs and proximal pulmonary arteries, with increases in phosphorylated Akt, phosphorylated glycogen-synthase-kinase-3ß (GSK3), and phosphorylated endothelial nitric oxide synthase, all of which decreased markedly after treatment with each HPI. In contrast, PH-associated increases in phosphorylated extracellular signal-related kinase 1/2 and myosin light-chain phosphatase were unaltered by the HPIs. The 3 HPIs and the phosphatidylinositol 3-kinase inhibitor LY294002 inhibited platelet-derived growth factor-induced phosphorylation of Akt and GSK3 in cultured pulmonary artery smooth muscle cells and blocked cell proliferation; this last effect was abolished by the GSK3 inhibitor SB216763. CONCLUSION: These results support an effect of HPIs on pulmonary vascular remodeling mediated by inhibition of Akt phosphorylation and consequently of pulmonary artery smooth muscle cell proliferation.

Hippocampal atrophy predicts conversion to dementia after STN-DBS in Parkinson's disease.

BACKGROUND: Hippocampal atrophy (HA) is a known predictor of dementia in Alzheimer's disease. HA has been found in advanced Parkinson's disease (PD), but no predicting value has been demonstrated yet. The identification of such a predictor in candidates for subthalamic deep brain stimulation (STN-DBS) would be of value. Our objective was to compare preoperative hippocampal volumes (HV) between PD patients who subsequently converted to dementia (PDD) after STN-DBS and those who did not (PDnD). METHODS: From a cohort of 70 consecutive STN-DBS treated PD patients, 14 converted to dementia over 25.6+/-20.2 months (PDD). They were compared to 14 matched controls (PDnD) who did not convert to dementia after 43.9+/-11.7 months. On the preoperative 3D MPRAGE MRI images, HV and total brain volumes (TBV) were measured by a blinded investigator using manual and automatic segmentation respectively. RESULTS: PDD had smaller preoperative HV than PDnD (1.95+/-0.29 ml; 2.28+/-0.33 ml; p<0.01). This difference reinforced after normalization for TBV (3.28+/-0.48, 3.93+/-0.60; p<0.01). Every 0.1 ml decrease of HV increased the likelihood to develop dementia by 24.6%. A large overlap was found between PD and PDnD HVs, precluding the identification of a cut-off score. CONCLUSIONS: As in Alzheimer's disease, HA may be a predictor of the conversion to dementia in PD. This preoperative predictor suggests that the development of dementia after STN-DBS is related to the disease progression, rather then the procedure. Further studies are needed to define a cut-off score for HA, in order to affine its predictive value for an individual patient.

Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease.

Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that CD8+ and CD4+ T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (Rag1-/- and Tcrb-/- mice). Importantly, similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in Rag1-/- mice reconstituted with FasL-deficient splenocytes. However, mice lacking CD8 and Rag1-/- mice reconstituted with IFN-gamma-deficient splenocytes were not protected. These data indicate that T cell-mediated dopaminergic toxicity is almost exclusively arbitrated by CD4+ T cells and requires the expression of FasL but not IFNgamma. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD.

Long-term cognitive profile and incidence of dementia after STN-DBS in Parkinson's disease.

An effect of subthalamic nucleus deep brain stimulation (STN-DBS) on cognition has been suspected but long-term observations are lacking. The aim of this study was to evaluate the long-term cognitive profile and the incidence of dementia in a cohort of Parkinson's disease (PD) patients treated by STN-DBS. 57 consecutive patients were prospectively assessed by the mean of a neuropsychological battery over 3 years after surgery. Dementia (DSM-IV) and UPDRS I to IV were recorded. 24.5% of patients converted to dementia over 3 years (incidence of 89 of 1,000 per year). This group of patients cognitively continuously worsened over 3 years up to fulfilling dementia criteria (PDD). The rest of the cohort remained cognitively stable (PD) over the whole follow-up. Preoperative differences between PDD and PD included older age (69.2 +/- 5.8 years; 62.6 +/- 8 years), presence of hallucinations and poorer executive score (10.1 +/- 5.9; 5.5 +/- 4.4). The incidence of dementia over 3 years after STN-DBS is similar to the one reported in medically treated patients. The PDD presented preoperative risk factors of developing dementia similar to those described in medically treated patients. These observations suggest dementia being secondary to the natural evolution of PD rather than a direct effect of STN-DBS.

Does subthalamic nucleus deep brain stimulation really improve quality of life in Parkinson's disease?

We investigated the impact of subthalamic nucleus (STN) deep brain stimulation (DBS) on quality of life (QOL) in patients with advanced Parkinson's disease, as self-assessed before and after surgery by completing the Parkinson's Disease Questionnaire (PDQ39). In addition to this prospective evaluation, we asked patients postoperatively to evaluate their preoperative QOL. In the prospective assessment, results showed that patients perceived a general improvement of QOL after the STN DBS. However, when evaluated retrospectively, they tended to overestimate their preoperative functioning, therefore obscuring the improvement found prospectively. This observation highlights the impact of the method used on obtained results when assessing the effects of STN DBS.