Enregistrement des fluctuations de la pression intraoculaire sur 24 heures par une lentille de contact intégrant un capteur: tolérance et résultats chez 10 sujets sains

AbstractPurpose: to evaluate the tolerability, comfort and precision of the signal transmission of an ocular Sensor used for 24-hour intraocular pressure fluctuation monitoring in humans.Patients and methods: In this uncontrolled open trial involving 10 healthy volunteers an 8.7 mm radius prototype ocular telemetry Sensor (SENSIMED Triggerfish®, Lausanne, Switzerland) and an orbital bandage containing a loop antenna were applied and connected to a portable recorder after full eye examination. Best corrected visual acuity and position, surface wetting ability and mobility of the Sensor were assessed after 5 and 30 minutes, 4, 12 and 24 hours. Subjective wearing comfort was scored and activities documented in a logbook. After Sensor removal a full eye examination was repeated and the recorded signal analyzed.Results: The comfort score was high and did not fluctuate significantly over time. The mobility of the Sensor was limited across follow-up visits and its surface wetting ability remained good. Best corrected visual acuity was significantly reduced during Sensor wear and immediately after its removal (from 1.07 before, to 0.85 after, P-value 0.008). Three subjects developed a mild, transient corneal abrasion. In all but one participant we obtained usable data of a telemetric signal recording with sufficient sensitivity to depict ocular pulsation.Conclusions: This 24-hour- trial has encouraging results on the tolerability and functionality of the ocular telemetric Sensor for intraocular pressure fluctuation monitoring. Further studies with different Sensor radii conducted on a larger study population are needed to improve comfort, precision and interpretation of the telemetric signal.

Increased therapeutic window for the R91W mutant form of Rpe65 compared to Rpe65 null backgroud

Purpose:Given the advances of gene therapy studies to cure RPE65-derived Leber Congenital Amaurosis (LCA) (clinical trials phase I) and the heterogeneity of the targeted patients both genetically and phenotypically, it is of prime importance to examine the rescue efficiency of gene transfer in different mutant contexts. Indeed, half of these mutations are missense mutations, leading to potential residual RPE65 activity. Consequently, we wanted to evaluate the effect on retinal activity and cone survival of lentivirus-mediated gene therapy in the R91W knock-in mouse model expressing the mutant Rpe65R91W gene (Samardzija et al. 2008), a mutation found in LCA patients. Notably we investigated whether if the therapeutic window is prolonged in comparison to null mutations. Methods:An HIV-1-derived lentiviral vector (LV) expressing either the GFP or the mouse Rpe65 cDNA under the control of a 0.8 kb fragment of the human Rpe65 promoter (R0.8) was produced by transient transfection of 293T cells. LV-R0.8-RPE65 or GFP was injected into 5-days-old (P5) or 1 month-old R91W mice. Functional rescue was assessed by ERG (1 and 4 months post-injection) and pupillary light response (PLR) recordings and cone survival by histological analysis. Results:Increased light sensitivity was detected by scotopic ERG in animals injected with LV-R0.8-RPE65 at both P5 and 1 month compared to GFP-treated animals or untreated mice. PLR was also improved in some eyes and histological analysis of cone markers showed that the density of cones reached the wild type level in the region of wt RPE65 delivery after treatment at P5. However, the rescue effect of the injection at 1 month was limited and attained 60% of the wild type level, but still more cones were observed in the treated area than in 1 month-old untreated Rpe65R91W mice. Conclusions:We were able to show that lentivirus-mediated Rpe65 gene transfer not only increases retinal activity of the Rpe65R91W mouse and survival of cones after treatment at P5 but also after treatment at 1 month. However even if the treatment at 1 month is more limited (60% of the wild type level) than treatment at P5, the amount of cone markers is increased compared to the proportion found at 1 month of age in untreated animals. This results contrast with the lack of cone rescue by treatment at 1 month of age in Rpe65-/- (Bemelmans et al, 2006). Thus patient suffering from R91W mutation might benefit from a prolonged therapeutic window.

Ranibizumab in the management of advanced Coats disease Stages 3B and 4: long-term outcomes.

BACKGROUND: Laser photocoagulation and cryotherapy to completely destroy telangiectatic vessels and ischemic retina in Coats disease is barely applicable in advanced cases with total retinal detachment, and globe survival is notoriously poor in Stages 3B and 4. Anti-vascular endothelial growth factor intravitreal injections may offer new prospects for these patients. METHODS: This study is a retrospective review of all consecutive patients with Coats disease treated with neoadjuvant or adjuvant intravitreal ranibizumab plus conventional and amblyopia treatment as appropriate. RESULTS: Nine patients (median age, 13 months) presenting Coats Stages 3B and 4 (5 and 4 eyes, respectively) were included. Iris neovascularization resolved within 2 weeks and retinal reapplication within 4 months in all patients. At last follow-up, globe survival was 100% with anatomical success in 8 of the 9 eyes. With a median follow-up of 50 months, fibrotic vitreoretinopathy was developed in 5 of the 9 cases, one leading to tractional retinal detachment and ultimately phthisis bulbi. The remaining 4 of the 9 eyes achieved some vision (range, 0.02-0.063). CONCLUSION: To the best of the authors' knowledge, this is the largest reported series of late-stage Coats undergoing anti-vascular endothelial growth factor therapy, a homogenous cohort of patients treated with a single agent and with the longest follow-up. This study supports the role of ranibizumab in advanced disease by transient restoration of the hemato-retinal barrier and suppression of neovascularization to facilitate classic treatment. At the last follow-up, the authors report unprecedented anatomical success and functional outcome.

Postpacing abnormal repolarization in catecholaminergic polymorphic ventricular tachycardia associated with a mutation in the cardiac ryanodine receptor gene.

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disease for which electrophysiological studies (EPS) have shown to be of limited value.OBJECTIVE This study presents a CPVT family in which marked postpacing repolarization abnormalities during EPS were the only consistent phenotypic manifestation of ryanodine receptor (RyR2) mutation carriers.METHODS The study was prompted by the observation of transient marked QT prolongation preceding initiation of ventricular fibrillation during atrial fibrillation in a boy with a family history of sudden cardiac death (SCD). Family members underwent exercise and pharmacologic electrocardiographic testing with epinephrine, adenosine, and flecainide. Noninvasive clinical test results were normal in 10 patients evaluated, except for both epinephrine- and exercise-induced ventricular arrhythmias in 1. EPS included bursts of ventricular pacing and programmed ventricular extrastimulation reproducing short-long sequences. Genetic screening involved direct sequencing of genes involved in long QT syndrome as well as RyR2.RESULTS Six patients demonstrated a marked increase in QT interval only in the first beat after cessation of ventricular pacing and/or extrastimulation. All 6 patients were found to have a heterozygous missense mutation (M4109R) in RyR2. Two of them, presenting with aborted SCD, also had a second missense mutation (I406T- RyR2). Four family members without RyR2 mutations did not display prominent postpacing QT changes.CONCLUSION M4109R- RyR2 is associated with a high incidence of SCD. The contribution of I406T to the clinical phenotype is unclear. In contrast to exercise testing, marked postpacing repolarization changes in a single beat accurately predicted carriers of M4109R- RyR2 in this family.

Two functional forms of the Xenopus laevis estrogen receptor translated from a single mRNA species.

Steroid receptors are nuclear proteins that regulate gene transcription in a ligand-dependent manner. Over-expression of the Xenopus estrogen receptor in a vaccinia virus-derived expression system revealed that the receptor localized exclusively in the nucleus of the infected cells, irrespective of the presence or absence of the ligand. Furthermore, two forms of the receptor were produced, a full-length and a N-terminal truncated version, which are translated from a single mRNA species by the use of two AUG within the same reading frame. These 66- and 61-kDa receptors were also observed after in vitro translation of the mRNA as well as in primary Xenopus hepatocytes. Both forms are potent estrogen-dependent transcriptional activators in transient transfection experiments, as well as in in vitro transcription assays.

Increased mobility of major histocompatibility complex I-peptide complexes decreases the sensitivity of antigen recognition.

CD8(+) cytotoxic T lymphocytes (CTL) can recognize and kill target cells expressing only a few cognate major histocompatibility complex (MHC) I-peptide complexes. This high sensitivity requires efficient scanning of a vast number of highly diverse MHC I-peptide complexes by the T cell receptor in the contact site of transient conjugates formed mainly by nonspecific interactions of ICAM-1 and LFA-1. Tracking of single H-2K(d) molecules loaded with fluorescent peptides on target cells and nascent conjugates with CTL showed dynamic transitions between states of free diffusion and immobility. The immobilizations were explained by association of MHC I-peptide complexes with ICAM-1 and strongly increased their local concentration in cell adhesion sites and hence their scanning by T cell receptor. In nascent immunological synapses cognate complexes became immobile, whereas noncognate ones diffused out again. Interfering with this mobility modulation-based concentration and sorting of MHC I-peptide complexes strongly impaired the sensitivity of antigen recognition by CTL, demonstrating that it constitutes a new basic aspect of antigen presentation by MHC I molecules.

The Acute STroke Registry and Analysis of Lausanne (ASTRAL): design and baseline analysis of an ischemic stroke registry including acute multimodal imaging.

BACKGROUND AND PURPOSE: Stroke registries are valuable tools for obtaining information about stroke epidemiology and management. The Acute STroke Registry and Analysis of Lausanne (ASTRAL) prospectively collects epidemiological, clinical, laboratory and multimodal brain imaging data of acute ischemic stroke patients in the Centre Hospitalier Universitaire Vaudois (CHUV). Here, we provide design and methods used to create ASTRAL and present baseline data of our patients (2003 to 2008). METHODS: All consecutive patients admitted to CHUV between January 1, 2003 and December 31, 2008 with acute ischemic stroke within 24 hours of symptom onset were included in ASTRAL. Patients arriving beyond 24 hours, with transient ischemic attack, intracerebral hemorrhage, subarachnoidal hemorrhage, or cerebral sinus venous thrombosis, were excluded. Recurrent ischemic strokes were registered as new events. RESULTS: Between 2003 and 2008, 1633 patients and 1742 events were registered in ASTRAL. There was a preponderance of males, even in the elderly. Cardioembolic stroke was the most frequent type of stroke. Most strokes were of minor severity (National Institute of Health Stroke Scale [NIHSS] score ≤ 4 in 40.8% of patients). Cardioembolic stroke and dissections presented with the most severe clinical picture. There was a significant number of patients with unknown onset stroke, including wake-up stroke (n=568, 33.1%). Median time from last-well time to hospital arrival was 142 minutes for known onset and 759 minutes for unknown-onset stroke. The rate of intravenous or intraarterial thrombolysis between 2003 and 2008 increased from 10.8% to 20.8% in patients admitted within 24 hours of last-well time. Acute brain imaging was performed in 1695 patients (97.3%) within 24 hours. In 1358 patients (78%) who underwent acute computed tomography angiography, 717 patients (52.8%) had significant abnormalities. Of the 1068 supratentorial stroke patients who underwent acute perfusion computed tomography (61.3%), focal hypoperfusion was demonstrated in 786 patients (73.6%). CONCLUSIONS: This hospital-based prospective registry of consecutive acute ischemic strokes incorporates demographic, clinical, metabolic, acute perfusion, and arterial imaging. It is characterized by a high proportion of minor and unknown-onset strokes, short onset-to-admission time for known-onset patients, rapidly increasing thrombolysis rates, and significant vascular and perfusion imaging abnormalities in the majority of patients.

Modulation of cdk2, cyclin D1, p16INK4a, p21WAF and p27Kip1 expression in endothelial cells by TNF/IFN gamma.

BACKGROUND: Regional administration of high doses of tumor necrosis factor (TNF) and interferon gamma (IFN gamma) to metastatic melanoma patients causes selective disruption of the tumor vasculature. This effect is paralleled by decreased endothelial cell proliferation and suppressed integrin alpha V beta 3-mediated adhesion in vitro. Overexpression of the cyclin-dependent kinase (cdk) inhibitory protein p16INK4a was reported to interfere with integrin alpha V beta 3-dependent melanoma cell adhesion. MATERIALS AND METHODS: TNF- and IFN gamma-treated HUVEC were analyzed for cell cycle progression and for protein expression by flow cytometry and Western blotting, respectively. p16INK4a was overexpressed by transient transfection, and HUVEC adhesion was tested in short-term adhesion assays. RESULTS: TNF and IFN gamma synergistically induced a G1 arrest associated with reduced levels of cyclin D1 and cdk2, and increased expression of the cdk inhibitors p16INK4a, p21WAF and p27Kip1. p16INK4a overexpression, however, had no effect on alpha V beta 3-mediated adhesion. CONCLUSION: These results implicate the down-regulation of cyclin D1 and cdk-2, and up-regulation of p16INK4a, p21WAF and p27Kip1 in the suppression of endothelial cell proliferation induced by TNF/IFN gamma and demonstrate that increased p16INK4a levels are not sufficient to suppress alpha V beta 3-mediated endothelial cell adhesion.

A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy.

Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy. Familial narcolepsy accounts for less than 10% of all narcolepsy cases. However, documented multiplex families are very rare and causative mutations have not been identified to date. To identify a causative mutation in familial narcolepsy, we performed linkage analysis in the largest ever reported family, which has 12 affected members, and sequenced coding regions of the genome (exome sequencing) of three affected members with narcolepsy and cataplexy. We successfully mapped a candidate locus on chromosomal region 6p22.1 (LOD score ¼ 3.85) by linkage analysis. Exome sequencing identified a missense mutation in the second exon of MOG within the linkage region. A c.398C>G mutation was present in all affected family members but absent in unaffected members and 775 unrelated control subjects. Transient expression of mutant myelin oligodendrocyte glycoprotein (MOG) in mouse oligodendrocytes showed abnormal subcellular localization, suggesting an altered function of the mutant MOG. MOG has recently been linked to various neuropsychiatric disorders and is considered as a key autoantigen in multiple sclerosis and in its animal model, experimental autoimmune encephalitis. Our finding of a pathogenic MOG mutation highlights a major role for myelin and oligodendrocytes in narcolepsy and further emphasizes glial involvement in neurodegeneration and neurobehavioral disorders. [corrected].

The impact of personality characteristics on the clinical expression in neurodegenerative disorders--a review.

Clinical experience suggests that longstanding personality characteristics as a person's most distinctive features of all are likely to play a role in how someone with dementia copes with his increasing deficiencies. Personality characteristics may have a pathoplastic effect on both behavioral and psychological symptoms (BPS) or on cognition as well as cognitive decline. Cognitive disorders accompanied by BPS are a tremendous burden for both the patient and their proxies. This review suggests that premorbid personality characteristics are co-determinants of BPS in cognitive disorders, but much effort is needed to clarify whether or not specific premorbid personality traits are associated with specific BPS as no strong links have so far emerged. This review further shows that a growing field of research is interested in the links not only between quite short-lived emotional states and cognitive processes, but also between longstanding personality traits and cognition in both healthy individuals and patients with neurodegenerative disorders. Furthermore, a few studies found that specific premorbid personality traits may be risk factors for neurodegenerative diseases. However, research findings in this area remain scarce despite a huge literature on personality and cognitive disorders in general. An important shortcoming that hampers so far the progress of our understanding in these domains is the confusion in the literature between longstanding premorbid personality traits and transient personality changes observed in neurodegenerative diseases. Few studies have based their assessments on accepted personality theories and carefully investigated premorbid personality traits in patients with cognitive disorders, although assessing personality may be complicated in these patients. Studying the impact of personality characteristics in cognitive disorders is an especially promising field of research in particular when concomitantly using neurobiological approaches, in particular structural brain imaging and genetic studies as suggested by as yet rare studies. Improved understanding of premorbid personality characteristics as determinants of both BPS or cognitive capacities or decline is likely to influence our attitudes towards the treatment of demented patients and ultimately to help in alleviating a patient's and their proxies' burden.