Le multiple evanescent white dot syndrome: une prédisposition génétique [Multiple evanescent white dot syndrome: a genetic predisposition?]

BACKGROUND: Multiple evanescent white dot syndrome (MEWDS) is a benign acquired isolated chorioretinal disorder. Symptoms include photopsia, visual blur and scotomas. Ocular examination reveals multiple white dots at the level of the deep retina. A parainfectious disorder was suggested but the exact mechanism of MEWDS is still unknown. Postulating that MEWDS might be an antigen driven inflammatory reaction, we analyzed HLA subtypes in patients with MEWDS. PATIENTS AND METHODS: Sixteen patients were diagnosed with MEWDS in Lausanne from 1985 to 1994. Blood was withdrawn in 9/16 patients. HLA-A, -B and -DR were sought. RESULTS: HLA-B51 was detected in 4/9 patients (44.4%). Other HLA subtypes were detected sporadically. CONCLUSIONS: The frequency of HLA-B51 haplotype was found to be 3.7 times more elevated than in a normal control caucasian group. This suggests the possibility that MEWDS might be a genetically determined disorder as it is the case for other ocular diseases like Birdshot chorioretinopathy (HLA-A29), Harada's disease (HLA-DRMT3), acute anterior uveitis (HLA-B27) or Behçet's disease (HLA-B51). We have no explanation for the presence of HLA-B51 in both Behçet's disease and MEWDS. The association of HLA-B51 and MEWDS needs confirmation by further testing.

Time Series Input Selection using Multiple Kernel Learning

In this paper we study the relevance of multiple kernel learning (MKL) for the automatic selection of time series inputs. Recently, MKL has gained great attention in the machine learning community due to its flexibility in modelling complex patterns and performing feature selection. In general, MKL constructs the kernel as a weighted linear combination of basis kernels, exploiting different sources of information. An efficient algorithm wrapping a Support Vector Regression model for optimizing the MKL weights, named SimpleMKL, is used for the analysis. In this sense, MKL performs feature selection by discarding inputs/kernels with low or null weights. The approach proposed is tested with simulated linear and nonlinear time series (AutoRegressive, Henon and Lorenz series).

Population pharmacokinetics of ganciclovir in solid-organ transplant recipients receiving oral valganciclovir.

Valganciclovir (VGC) is an oral prodrug of ganciclovir (GCV) recently introduced for prophylaxis and treatment of cytomegalovirus infection. Optimal concentration exposure for effective and safe VGC therapy would require either reproducible VGC absorption and GCV disposition or dosage adjustment based on therapeutic drug monitoring (TDM). We examined GCV population pharmacokinetics in solid organ transplant recipients receiving oral VGC, including the influence of clinical factors, the magnitude of variability, and its impact on efficacy and tolerability. Nonlinear mixed effect model (NONMEM) analysis was performed on plasma samples from 65 transplant recipients under VGC prophylaxis or treatment. A two-compartment model with first-order absorption appropriately described the data. Systemic clearance was markedly influenced by the glomerular filtration rate (GFR), patient gender, and graft type (clearance/GFR = 1.7 in kidney, 0.9 in heart, and 1.2 in lung and liver recipients) with interpatient and interoccasion variabilities of 26 and 12%, respectively. Body weight and sex influenced central volume of distribution (V(1) = 0.34 liter/kg in males and 0.27 liter/kg in females [20% interpatient variability]). No significant drug interaction was detected. The good prophylactic efficacy and tolerability of VGC precluded the demonstration of any relationship with GCV concentrations. In conclusion, this analysis highlights the importance of thorough adjustment of VGC dosage to renal function and body weight. Considering the good predictability and reproducibility of the GCV profile after treatment with oral VGC, routine TDM does not appear to be clinically indicated in solid-organ transplant recipients. However, GCV plasma measurement may still be helpful in specific clinical situations.

Current multiple myeloma treatment strategies with novel agents: a European perspective.

The treatment of multiple myeloma (MM) has undergone significant developments in recent years. The availability of the novel agents thalidomide, bortezomib, and lenalidomide has expanded treatment options and has improved the outcome of patients with MM. Following the introduction of these agents in the relapsed/refractory setting, they are also undergoing investigation in the initial treatment of MM. A number of phase III trials have demonstrated the efficacy of novel agent combinations in the transplant and nontransplant settings, and based on these results standard induction regimens are being challenged and replaced. In the transplant setting, a number of newer induction regimens are now available that have been shown to be superior to the vincristine, doxorubicin, and dexamethasone regimen. Similarly, in the front-line treatment of patients not eligible for transplantation, regimens incorporating novel agents have been found to be superior to the traditional melphalan plus prednisone regimen. Importantly, some of the novel agents appear to be active in patients with high-risk disease, such as adverse cytogenetic features, and certain comorbidities, such as renal impairment. This review presents an overview of the most recent data with these novel agents and summarizes European treatment practices incorporating the novel agents.

Interferon-gamma impacts at multiple points during the progression of autoimmune diabetes.

The role of interferon-gamma in autoimmune diabetes was assessed by breeding a null mutation of the interferon-gamma receptor alpha chain into the nonobese diabetic mouse strain, as well as into a simplified T cell receptor transgenic model of diabetes. In contrast to a previous report on abrogation of the interferon-gamma gene, mutation of the gene encoding its receptor led to drastic effects on disease in both mouse lines. Nonobese diabetic mice showed a marked inhibition of insulitis-both the kinetics and penetrance-and no signs of diabetes; the transgenic model exhibited near-normal insulitis, but this never evolved into diabetes, either spontaneously or after experimental provocation. This failure could not be explained by perturbations in the ratio of T helper cell phenotypes; rather, it reflected a defect in antigen-presenting cells or in the islet beta cell targets.

Assessing risks of multiple sclerosis therapies.

Over the last two decades, thanks to the discovery of several pharmaceutical agents, multiple sclerosis (MS) has been transformed into a treatable disorder although the degree of therapeutic response may vary considerably. As more medications find their entry into the MS market, a clinician faces a mounting challenge of comparing risk and benefit profiles of various agents in an attempt to find the best treatment approach for each individual patient. In this review, we aim to summarize the available data on safety profiles of available MS therapies while focusing mostly on serious medication specific potential adverse events without discussing the teratogenic potential of each agent (unless there is a black box warning) or hypersensitivity reactions. Our goal is to provide a clinician with guidance on assuring the appropriate safety monitoring for patients treated with one of the agents discussed. We also comment on the future of risk management in MS and discuss possible enhancements to the current model of drug approval process and general strategies to improve the patient safety.

Dispersal strategies, few dominating or many coexisting: the effect of environmental spatial structure and multiple sources of mortality.

Interspecific competition, life history traits, environmental heterogeneity and spatial structure as well as disturbance are known to impact the successful dispersal strategies in metacommunities. However, studies on the direction of impact of those factors on dispersal have yielded contradictory results and often considered only few competing dispersal strategies at the same time. We used a unifying modeling approach to contrast the combined effects of species traits (adult survival, specialization), environmental heterogeneity and structure (spatial autocorrelation, habitat availability) and disturbance on the selected, maintained and coexisting dispersal strategies in heterogeneous metacommunities. Using a negative exponential dispersal kernel, we allowed for variation of both species dispersal distance and dispersal rate. We showed that strong disturbance promotes species with high dispersal abilities, while low local adult survival and habitat availability select against them. Spatial autocorrelation favors species with higher dispersal ability when adult survival and disturbance rate are low, and selects against them in the opposite situation. Interestingly, several dispersal strategies coexist when disturbance and adult survival act in opposition, as for example when strong disturbance regime favors species with high dispersal abilities while low adult survival selects species with low dispersal. Our results unify apparently contradictory previous results and demonstrate that spatial structure, disturbance and adult survival determine the success and diversity of coexisting dispersal strategies in competing metacommunities.

High-resolution 3D whole-heart coronary MRA: a study on the combination of data acquisition in multiple breath-holds and 1D residual respiratory motion compensation.

OBJECT: To study a scan protocol for coronary magnetic resonance angiography based on multiple breath-holds featuring 1D motion compensation and to compare the resulting image quality to a navigator-gated free-breathing acquisition. Image reconstruction was performed using L1 regularized iterative SENSE. MATERIALS AND METHODS: The effects of respiratory motion on the Cartesian sampling scheme were minimized by performing data acquisition in multiple breath-holds. During the scan, repetitive readouts through a k-space center were used to detect and correct the respiratory displacement of the heart by exploiting the self-navigation principle in image reconstruction. In vivo experiments were performed in nine healthy volunteers and the resulting image quality was compared to a navigator-gated reference in terms of vessel length and sharpness. RESULTS: Acquisition in breath-hold is an effective method to reduce the scan time by more than 30 % compared to the navigator-gated reference. Although an equivalent mean image quality with respect to the reference was achieved with the proposed method, the 1D motion compensation did not work equally well in all cases. CONCLUSION: In general, the image quality scaled with the robustness of the motion compensation. Nevertheless, the featured setup provides a positive basis for future extension with more advanced motion compensation methods.

Cytomegalovirus serology and replication remain associated with solid organ graft rejection and graft loss in the era of prophylactic treatment.

BACKGROUND: Cytomegalovirus (CMV) replication has been associated with more risk for solid organ graft rejection. We wondered whether this association still holds when patients at risk receive prophylactic treatment for CMV. METHODS: We correlated CMV infection, biopsy-proven graft rejection, and graft loss in 1,414 patients receiving heart (n=97), kidney (n=917), liver (n=237), or lung (n=163) allografts reported to the Swiss Transplant Cohort Study. RESULTS: Recipients of all organs were at an increased risk for biopsy-proven graft rejection within 4 weeks after detection of CMV replication (hazard ratio [HR] after heart transplantation, 2.60; 95% confidence interval [CI], 1.34-4.94, P<0.001; HR after kidney transplantation, 1.58; 95% CI, 1.16-2.16, P=0.02; HR after liver transplantation, 2.21; 95% CI, 1.53-3.17, P<0.001; HR after lung transplantation, 5.83; 95% CI, 3.12-10.9, P<0.001. Relative hazards were comparable in patients with asymptomatic or symptomatic CMV infection. The CMV donor or recipient serological constellation also predicted the incidence of graft rejection after liver and lung transplantation, with significantly higher rates of rejection in transplants in which donor or recipient were CMV seropositive (non-D-/R-), compared with D- transplant or R- transplant (HR, 3.05; P=0.002 for liver and HR, 2.42; P=0.01 for lung transplants). Finally, graft loss occurred more frequently in non-D- or non-R- compared with D- transplant or R- transplant in all organs analyzed. Valganciclovir prophylactic treatment seemed to delay, but not prevent, graft loss in non-D- or non-R- transplants. CONCLUSION: Cytomegalovirus replication and donor or recipient seroconstellation remains associated with graft rejection and graft loss in the era of prophylactic CMV treatment.

Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions.

To ensure efficient energy supply to the high demanding brain, nutrients are transported into brain cells via specific glucose (GLUT) and monocarboxylate transporters (MCT). Mitochondrial dysfunction and altered glucose metabolism are thought to play an important role in the progression of neurodegenerative diseases, including multiple sclerosis (MS). Here, we investigated the cellular localization of key GLUT and MCT proteins in human brain tissue of non-neurological controls and MS patients. We show that in control brain tissue GLUT and MCT proteins were abundantly expressed in a variety of central nervous system cells, particularly in microglia and endothelial cells. In active MS lesions, GLUTs and MCTs were highly expressed in infiltrating leukocytes and reactive astrocytes. Astrocytes manifest increased MCT1 staining and maintain GLUT expression in inactive lesions, whereas demyelinated axons exhibit significantly reduced GLUT3 and MCT2 immunoreactivity in inactive lesions. Finally, we demonstrated that the co-transcription factor peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), an important protein involved in energy metabolism, is highly expressed in reactive astrocytes in active MS lesions. Overexpression of PGC-1α in astrocyte-like cells resulted in increased production of several GLUT and MCT proteins. In conclusion, we provide for the first time a comprehensive overview of key nutrient transporters in white matter brain samples. Moreover, our data demonstrate an altered expression of these nutrient transporters in MS brain tissue, including a marked reduction of axonal GLUT3 and MCT2 expression in chronic lesions, which may impede efficient nutrient supply to the hypoxic demyelinated axons thereby contributing to the ongoing neurodegeneration in MS. GLIA 2014;62:1125-1141.

L'enseignement du patient diabétique et son évaluation par un questionnaire à choix multiple. [Education of the diabetic patient and its evaluation by a multiple-choice questionnaire].

37 insulin-dependent and non-insulin-dependent diabetics answered a multiple-choice questionnaire during inpatient educational sessions. 12 dietetic and 12 pathophysiologic questions had to be answered. Statistical analysis of factors influencing the number of errors can be summed up as follows: there is a direct correlation between age of the patient and number of errors; the older the patient, the greater the number of errors. However, insulin-dependent diabetics committed fewer errors than non-insulin-dependent subjects of the same age, which suggests greater motivation in the first group due to their treatment. The test likewise affords the patients an opportunity of reviewing unclear topics and enables the educational team to adapt their teaching to the patients.

Multiple reproductives in nests of the Neotropical termite Constrictotermes cyphergaster (Isoptera, Termitidae, Nasutitermitinae)

Constrictotermes cyphergaster (Silvester, 1901) builds arboreal nests in Brazilian Cerrado stricto sensu, which are frequently cohabited by inquilines termites and by termitophiles. In a study made at the Parque Estadual da Serra de Caldas Novas, Goiás, Brazil, there were four nests with multiple reproductives, and secondary reproductives were found in 26 nests. Nymphs of Inquilinitermes were more abundant (9,47%) than nymphs of C. cyphergaster (0,78%).