Abstract
BACKGROUND: Understanding the pathophysiologic mechanism of intracranial aneurysm (IA) formation is a prerequisite to assess the potential risk of rupture. Nowadays, there are neither ...reliable biomarkers nor diagnostic tools to predict the formation or the evolution of IA. Increasing evidence suggests a genetic component of IA but genetics studies have failed to identify genetic variation causally related to IA.
OBJECTIVE: To develop diagnostic and predictive tools for the risk of IA formation and rupture.
METHODS: The French ICAN project is a noninterventional nationwide and multicentric research program. Each typical IA of bifurcation will be included. For familial forms, further IA screening will be applied among first-degree relatives. By accurate phenotype description with high-throughput genetic screening, we aim to identify new genes involved in IA. These potential genetic markers will be tested in large groups of patients. Any relevant pathway identified will be further explored in a large cohort of sporadic carriers of IA, which will be well documented with clinical, biological, and imaging data.
EXPECTED OUTCOMES: Discovering genetic risk factors, better understanding the pathophysiology, and identifying molecular mechanisms responsible for IA formation will be essential bases for the development of biomarkers and identification of therapeutic targets.
DISCUSSION: Our protocol has many assets. A nationwide recruitment allows for the inclusion of large pedigrees with familial forms of IA. It will combine accurate phenotyping and comprehensive imaging with high-throughput genetic screening. Last, it will enable exploiting metadata to explore new pathophysiological pathways of interest by crossing clinical, genetic, biological, and imaging information.
BACKGROUND:Autosomal dominant cerebellar ataxia is a rare heterogeneous group of diseases characterized by cerebellar symptoms, often associated with other multisystemic signs. Mild optic neuropathy ...has been associated with spinocerebellar ataxia type 1 (SCA1), but macular dysfunction has been reported in only 2 cases. We report the first family with SCA1 with several members affected by visual loss related to maculopathy.
METHODS:Cross-sectional clinical and electrophysiological study of a family with genetically confirmed SCA1. Patients with unexplained visual loss were included.
RESULTS:Four patients from the same family, carrying the same genetic mutation, were examined. Testing revealed an increased CAG trinucleotide repeat number within the SCA1 gene. Genetic testing results for SCA7 were negative. Visual acuities ranged between 20/20 and 20/200. Visual fields revealed central scotomas in most of the eyes, and funduscopy was unremarkable in most patients. Central retinal thinning of the retina or disorganized photoreceptor layers were found with optical coherence tomography (OCT). In one patient, multifocal electroretinography (mfERG) revealed central retinal dysfunction.
CONCLUSIONS:A clinically subtle or even occult maculopathy can occur in association with SCA1. Macular OCT and mfERG can be abnormal even in asymptomatic patients. Unexplained visual loss in SCA1 patients should prompt evaluation of macular function, even if clinical signs of maculopathy are absent.
During smooth pursuit, the image of the target is stabilized on the fovea, implying that speed judgments made during pursuit must rely on an extraretinal signal providing precise eye speed ...information. To characterize the introduction of such extraretinal signal into the human visual system, we performed a factorial, functional magnetic resonance imaging experiment, in which we manipulated the factor eye movement, with "fixation" and "pursuit" as levels, and the factor task, with "speed" and "form" judgments as levels. We hypothesized that the extraretinal speed signal is reflected as an interaction between speed judgments and pursuit. Random effects analysis yielded an interaction only in dorsal early visual cortex. Retinotopic mapping localized this interaction on the horizontal meridian (HM) between dorsal areas visual 2 and 3 (V2/V3) at 1-2 degrees azimuth. This corresponded to the position the pursuit target would have reached, if moving retinotopically, at the time of the subject's speed judgment. Because the 2 V2/V3 HMs are redundant, both may be involved in speed judgments, the ventral one involving judgments based on retinal motion and the dorsal one judgments requiring an internal signal. These results indicate that an extraretinal speed signal is injected into early visual cortex during pursuit.
The authors attempted to identify the determinants of ocular deviation in a population of patients with esotropia under general anesthesia.
Forty-one patients with esotropia were included. Horizontal ...ocular deviation was evaluated by the photographic Hirschberg test both in the awakened state and under general anesthesia before surgery. Changes in ocular deviation were measured and a multivariate analysis was used to assess its clinical determinants.
The mean age (± standard deviation SD) of study subjects was 13 ± 11 years and 51% were females. The mean spherical equivalent refraction of the right eye was 2.44 ± 2.50 diopters (D), with no significant difference between eyes (P = .26). The mean ocular deviation changed significantly, from 33.5 ± 12.5 prism diopters (PD) at preoperative examination to 8.8 ± 11.4 PD under general anesthesia (P = .0001). The changes in ocular deviation positively correlated with the pre-operative ocular deviation (correlation coefficient r = 0.59, P = .0001) and negatively correlated with patient age (correlation coefficient r = -0.53, P = .0001). These two determinants remained significant after multivariate adjustment of the following variables: preoperative ocular deviation; age; gender; spherical equivalent refraction; and number of previous strabismus surgeries (model r(2) = 0.49, P = .0001).
The ocular position under general anesthesia was reported as a key factor in the surgical treatment of subjects with esotropia; therefore, its clinical determinants were assessed. The authors observed that preoperative ocular deviation and patient age were the main factors that influenced the ocular position under general anesthesia.
La maltraitance à enfants a longtemps été ignorée. Les récents plans ministériels prévoient de nombreuses mesures de protection dont le déploiement d’unités d’accueil pédiatriques des enfants en ...danger (UAPED). Malgré toutes ces avancées, le diagnostic reste sous-estimé dans le secteur de la santé avec une prévalence de l’ordre de 1 enfant sur 10 dans les pays à hauts revenus, toutes catégories de maltraitance confondues. La fréquence de décès serait de 1 enfant tous les 5jours en France. Les violences subies durant l’enfance représentent une lourde perte de chance en termes d’espérance de vie, de santé, de développement et d’insertion. Le rapport est limité aux maltraitances physiques chez l’enfant (MPE) et n’aborde donc pas les maltraitances sexuelles. Le maître-mot est la nécessité d’hospitaliser l’enfant pour une protection immédiate, une évaluation multidisciplinaire, les soins et l’alerte des autorités en temps utile. Les résultats de l’étude montrent une réelle prise de conscience de la MPE dans le secteur pédiatrique. Toutefois, le diagnostic peut être sous-estimé et banalisé chez l’enfant, ce qui signifie que l’étiologie « traumatisme infligé » doit être évoquée largement par le médecin quel que soit son lieu d’intervention. Il y a une amélioration nette de la formation dans ce domaine. Toutefois, le rapport met en évidence une insuffisance persistante des moyens humains dans les secteurs des UAPED, de médecine scolaire, de PMI et de pédopsychiatrie. Le psychotraumatisme doit être pris en charge à court, moyen et long terme. Le diagnostic différentiel permet d’éliminer toutes les étiologies confondantes telles que traumatisme accidentel, maladie rare ou autres. Tout médecin doit pouvoir être guidé, accompagné et protégé pour les situations de MPE. Les médecins référents « Violences » des conseils départementaux de l’Ordre des médecins (CDOM) doivent avoir une compétence dans le domaine de la MPE. L’Académie nationale de médecine propose 6 recommandations : une hospitalisation prioritaire de tout enfant victime ou suspect de MPE jusqu’à ce que tous les éléments du diagnostic soient établis ; un renforcement des moyens humains des UAPED en y intégrant un temps de pédopsychiatrie ; un renforcement du repérage des situations à risque dès la maternité ; un renforcement de la protection et de l’accompagnement des médecins afin que ceux-ci n’hésitent plus à signaler les situations de MPE ; l’extension du périmètre du numéro 119 aux médecins et personnels de santé ; la création d’un registre national pour suivre l’épidémiologie et juger de l’efficacité des mesures prises.
Child abuse has long been ignored. Recent ministerial plans provide numerous protection measures including the implementation of pediatric units for children in danger (UAPED). However, the diagnosis remains underestimated in the health sector with a prevalence of about 1 in 10 children in high-income countries, all categories of abuse combined. Death frequency could be up to 1 child every 5 days. Violence suffered during childhood represents a serious loss of opportunity in terms of life expectancy, development, and integration. This report is limited to child physical abuse (CPM) and does not address abuse of sexual origin. The key message is the need to hospitalize any suspected child for immediate protection, multidisciplinary assessment, decision on care and alert of the authorities in due time. The results show an awareness of CPM in the pediatric healthcare sector. However, the diagnosis can be overlooked in children, meaning that the etiology “inflicted trauma” must be considered by any physician regardless of the place of intervention. There is a clear improvement in training on this subject. However, the report highlights a persistent shortage of human resources in UAPEDs, school medicine, maternal and child protection (PMI) and child psychiatry sectors. Psycho-trauma must be managed in the short, medium and long term. Differential diagnosis makes it possible to eliminate all confusing etiologies such as accidental trauma, rare diseases or any others. Every physician should be guided, supported, and protected in CPM situations. CDOM violence referral physicians must have expertise in the CPM field. The National Academy of Medicine proposes 6 recommendations: mandatory hospitalization of any child victim or suspected of CPM until all elements of the diagnosis are established; improving the human resources of UAPEDs including child psychiatric monitoring; strengthening the identification of risk situations from pregnancy care period; protection and support of physicians so that they are not weary to report CPM situations; the extension of the scope of 119 phone number to physicians and health professionals; the creation of a national registry to monitor epidemiology and evaluate the effectiveness of the measures taken.
The goal of this study was to determine the roles of the organic anion–transporting polypeptides (OATPs) OATP1A2, OATP1B1, and OATP1B3 and their genetic variants in the pharmacokinetics of the ...immunosuppressive drug mycophenolate mofetil (MMF). Using OATP‐transfected human embryonic kidney (HEK) cells, we measured the uptake of mycophenolic acid (MPA) and its glucuronide (MPAG). MPAG, but not MPA, significantly accumulated in cells expressing OATP1B3 or OATP1B1 (P < 0.05). The pharmacokinetics of both MPA and MPAG were significantly influenced by the OATP1B3 polymorphism 334T>G/699G>A in 70 renal transplant patients receiving combination treatment of MMF with either tacrolimus or sirolimus, but not in 115 patients receiving MMF and cyclosporine. The decrease in dose‐normalized (dn) MPA exposure and the concomitant increase in the MPAG/MPA metabolic ratio are consistent with reduced enterohepatic cycling in patients carrying the OATP1B3 334G–699A haplotype. Further studies demonstrated that this variant of OATP1B3 exhibited a reduced maximal velocity (Vmax) in transfected HEK cells, thereby providing functional evidence to support our clinical findings.
Clinical Pharmacology & Therapeutics (2010) 87 1, 100–108. doi:10.1038/clpt.2009.205
BACKGROUNDTreatment of acute antibody-mediated rejection (AMR) is based on a combination of plasma exchange (PE), IVIg, corticosteroids (CS), and rituximab, but the place of rituximab is not clearly ...specified in the absence of randomized trials.
METHODSIn this phase III, multicenter, double-blind, placebo-controlled trial, we randomly assigned patients with biopsy-proven AMR to receive rituximab (375 mg/m) or placebo at day 5. All patients received PE, IVIg, and CS. The primary endpoint was a composite of graft loss or no improvement in renal function at day 12.
RESULTSAmong the 38 patients included, at 1 year, no deaths occurred, but 1 graft loss occurred in each group. The primary endpoint frequency was 52.6% (10/19) and 57.9% (11/19) in the rituximab and placebo groups, respectively (P = 0.744). Renal function improved in both groups, as soon as day 12 with no difference in serum creatinine level and proteinuria at 1, 3, 6, and 12 months. Supplementary administration of rituximab and total number of IVIg and PE treatments did not differ between the 2 groups. Both groups showed improved histological features of AMR and Banff scores at 1 and 6 months, with no significant difference between groups but with a trend in favor of the rituximab group. Both groups showed decreased mean fluorescence intensity of donor-specific antibodies as soon as day 12, with no significant difference between them but with a trend in favor of the rituximab group at 12 months.
CONCLUSIONSAfter 1 year of follow-up, we observed no additional effect of rituximab in patients receiving PE, IVIg, and CS for AMR. Nevertheless, our study was underpowered and important differences between groups may have been missed. Complementary trials with long-term follow-up are needed.
BACKGROUNDThe differential pathogenicity of anti-HLA donor-specific antibodies (DSAs) is not fully understood. The presence of complement-binding DSAs helps in better defining the prognosis of acute ...antibody-mediated rejection (ABMR). The evolution of these antibodies after the treatment of ABMR is unknown.
METHODSWe included patients from the French multicenter RITUX ERAH study diagnosed with acute ABMR within the first year of renal transplantation, with circulating anti-HLA DSAs and treated randomly by rituximab or placebo (and intravenous immunoglobulins, plasma exchange). We centrally analyzed serum samples at the time of ABMR, 3 and 6 months after ABMR, with anti-HLA DSAs specificities and C1q-binding capacity assessment.
RESULTSTwenty-five patients were included68% had C1q-binding DSAs at the time of ABMR. The presence of C1q-binding DSAs was associated with a poorer evolution of chronic glomerulopathy at 6 months (P = 0.036). The persistence of C1q-binding DSAs at 3 and/or 6 months after ABMR was associated with more severe chronic glomerulopathy (P = 0.006), greater C4d score deposition score at 6 months after ABMR (P = 0.008), and graft loss 5 years after ABMR (P = 0.029). C1q-binding capacity was associated with the DSA MFI but 5 C1q-binding DSAs in 4 patients had low MFI values without a prozone effect.
CONCLUSIONThe presence and persistence of anti-HLA C1q-binding DSAs after ABMR is a detrimental marker, leading to transplant glomerulopathy and graft loss. Assessment of the complement-binding capacities of DSAs could help decide treatment intensification.
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