The natural history of epilepsy in tuberous sclerosis complex

Background: Although epilepsy affects most patients with tuberous sclerosis complex (TSC), little is known about the natural history of epilepsy in this genetic disease. Methods: A retrospective chart review of all patients with TSC seen between January 2002 and October 2008. Charts were reviewed for a history of infantile spasms (IS), seizure other than IS, refractory epilepsy, Lennox-Gastaut syndrome (LGS), anticonvulsant medication use, ages of seizure onset, last seizure, last clinic visit, clinical seizure phenotype(s), cognitive impairment, and genetic mutation. Results: Two hundred ninety-one patients were included. Among these patients, 37.8% had a history of IS; 85.2% had a history of seizure; 54.1% developed multiple seizure types, not including IS; 63.2% had seizure onset in the first year of life; and 12.1% of adults without a seizure history developed epilepsy. Of epilepsy patients, 62.5% developed refractory epilepsy and 33.5% achieved epilepsy remission; 37.5% of these patients achieved medication freedom. IS was a risk factor for refractory epilepsy (p<0.0001) and LGS (p<0.0001). History of seizure, IS, age at seizure onset, and refractory epilepsy each correlated with poor cognitive outcome (p<0.0001). Epilepsy remission correlated with better cognitive outcome (p<0.0001). TSC2 was a risk factor for IS and epilepsy; patients without an identified mutation were more likely to achieve remission. Conclusion: Most patients with TSC develop epilepsy and most develop multiple seizure types. Onset typically occurs in the first year of life; however, adults remain at risk. Although refractory epilepsy is common, many patients achieve seizure control. Many features of seizure history are predictive of cognitive and epilepsy outcome

Localization of the Epileptogenic Foci in Tuberous Sclerosis Complex: A Pediatric Case Report

Tuberous sclerosis complex (TSC) is a rare disorder of tissue growth and differentiation, characterized by benign hamartomas in the brain and other organs. Up to 90% of TSC patients develop epilepsy and 50% become medically intractable requiring resective surgery. The surgical outcome of TSC patients depends on the accurate identification of the epileptogenic zone consisting of tubers and the surrounding epileptogenic tissue. There is conflicting evidence whether the epileptogenic zone is in the tuber itself or in abnormally developed surrounding cortex. Here, we report the localization of the epileptiform activity among the many cortical tubers in a 4-year-old patient with TSC-related refractory epilepsy undergoing magnetoencephalography (MEG), electroencephalography (EEG), and diffusion tensor imaging (DTI). For MEG, we used a prototype system that offers higher spatial resolution and sensitivity compared to the conventional adult systems. The generators of interictal activity were localized using both EEG and MEG with equivalent current dipole (ECD) and minimum norm estimation (MNE) methods according to the current clinical standards. For DTI, we calculated four diffusion scalar parameters for the fibers passing through four ROIs defined: (i) at a large cortical tuber identified at the right quadrant, (ii) at the normal appearing tissue contralateral to the tuber, (iii) at the cluster formed by ECDs fitted at the peak of interictal spikes, and (iv) at the normal appearing tissue contralateral to the cluster. ECDs were consistently clustered at the vicinity of the large calcified cortical tuber. MNE and ECDs indicated epileptiform activity in the same areas. DTI analysis showed differences between the scalar values of the tracks passing through the tuber and the ECD cluster. In this illustrative case, we provide evidence from different neuroimaging modalities, which support the view that epileptiform activity may derive from abnormally developed tissue surrounding the tuber rather than the tuber itself

Multicenter Phase 2 Trial of Sirolimus for Tuberous Sclerosis: Kidney Angiomyolipomas and Other Tumors Regress and VEGF- D Levels Decrease

Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2.We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas.36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1-2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline).Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC.Clinicaltrials.gov NCT00126672

Auditoría forense aplicada al sistema de créditos de la Cooperativa de Ahorro y Crédito Jardín Azuayo oficina-Cuenca

Este presente trabajo de investigación titulado “Auditoría Forense Aplicada al Sistema de Créditos de la Cooperativa de Ahorro y Crédito Jardín Azuayo Oficina-Cuenca”, aborda aspectos generales de la cooperativa, un breve marco teórico del proceso de auditoría forense, la planificación, ejecución y comunicación de resultados. El objetivo es la revisión y el análisis Forense al Sistema de Créditos de la Cooperativa de Ahorro y Crédito “Jardín Azuayo” Oficina Cuenca, para emitir un informe sobre los riesgos de fraude, si los hubiere, con el fin de mejorar los controles internos. Como resultado de la aplicación del examen forense al sistema de créditos se obtuvo el informe donde se evidencia: Inexistencia de manual anti fraude que contenga políticas y procedimientos, falta de capacitación que permitirá prevenir actos fraudulentos, no existe una evaluación periódica al desempeño del personal, no hay un departamento que maneje asuntos relacionados con el fraude y/o anti fraude. A demás la Cooperativa no cuenta con un protocolo de investigación y la aplicación de indicadores de morosidad permita conocer el manejo equitativo de las carteras.This present research work entitled "to "" Forensic Audit applied to the system of credits of cooperative savings and credit Jardín Azuayo Office-Cuenca", deals with General aspects of the cooperative, a brief theoretical framework of the forensic audit process, planning, execution and communication ofresults. The objective is to review and forensic analysis to the credit system of the Cooperativa de Ahorro y Crédito "Jardín Azuayo" Office-Cuenca, to issue a report on the risks of fraud, if any, in order to improve internal controls. As a result of the application of forensic examination to the credit system was obtained the report where there is evidence: lack of manual anti fraud that contains policies and procedures, lack of training which will prevent acts of fraud, there is a periodic evaluation of staff performance, there is a Department that handles issues related to fraud or anti fraud. Other cooperative does not have a research protocol and the application of indicators of default allows to know the equitable management of the portfolios.Contador Público AuditorCuenc

Dislexia Evolutiva: un Modelo Exitoso de Neuropsicología Genética

La neurosicología clásica ha tenido gran éxito en establecer asociaciones entre estructura y ?siología cerebrales y sus respectivas funciones perceptivas, cognicitivas, metacognicitivas y conductuales. Considerando los grandes avances de la genética molecular y de la neurociencia de sistemas, es posible pretender que uno de los objetivos importantes de la neurosicología moderna es encontrar los vínculos asociativos o causales que existen entre estructuras y funciones genéticas y las conductas que éstas apoyan, sea a través de sus efectos sobre la construcción y mantención de regiones cerebrales relevantes, o a través de proteínas funcionales que estos genes producen. La dislexia evolutiva representa un síndrome conductual complejo que ha comenzado a analizarse experimentalmente, logrando establecer un recorrido por lo menos aproximativo entre un gen especí?co y una función cognitiva puntual

Migración y descomposición social de la comunidad campesina de la parroquia Ludo del cantón Sigsig

Licenciado en Ciencias Políticas y SocialesCuenc

Análisis, investigación y estrategias aplicables al mercado de las pilas alcalinas en Guayaquil y Quito

El presente proyecto se desarrolla en la empresa Gillette del ecuador, estudia el mercado de pilas alcalinas, la percepción del consumidor hacia el producto y como este percibe al líder del mercado y a su competidor. En su desarrollo toma en consideración varias herramientas indispensables para el estudio de mercado, como son: estudios cualitativos y estudios cuantitativos. Además se realiza estrategias de promoción y ventas, servicio, distribución y publicidad aplicables al mercado. Los datos obtenidos en las encuestas fueron íntegramente tabulados en el programa spss haciendo posible estudiar por ciudad tablas cruzadas y respuestas múltiples. También se desarrolla un análisis multivariante identificando grupos de consumidores con iguales características

IQ predictors in pediatric opsoclonus myoclonus syndrome: a large international cohort study.

AIM To determine predictors of full-scale IQ (FSIQ) in an international pediatric opsoclonus myoclonus syndrome (OMS) cohort. METHOD In this retrospective and prospective cohort study at three academic medical centers (2006-2013), the primary outcome measure, FSIQ, was categorized based on z-score: above average (≥+1), average (+1 to -1), mildly impaired (-1 to -2), and impaired (<-2). Univariate analysis and multivariable linear regression modeling using stepwise selection with Akaike's information criterion was performed to understand the relationship between exposures and FSIQ. RESULTS Of 81 participants, 37 with sufficient data had mean FSIQ 84.38 (SD 20.55) and median 90 (40-114) at latest available evaluation (mean age 8y 5mo). Twenty (54%), nine (24.3%), and eight (21.6%) had normal, mildly impaired, and impaired FSIQ respectively. The final multivariable linear regression model included 34 participants with evaluable data: number of relapses occurring before neuropsychological testing (p<0.001) and OMS severity score at last follow-up (p<0.001) predicted FSIQ (adjusted R2 =0.64). There was a mean decrease of 2.4 FSIQ points per OMS relapse. INTERPRETATION Number of relapses negatively correlates with FSIQ in pediatric OMS. Demographic and clinical measures available at OMS onset did not predict FSIQ. Strategies to reduce OMS relapses may improve intellectual outcomes

Mosaic and Intronic Mutations in TSC1/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing.

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor gene syndrome due to germline mutations in either TSC1 or TSC2. 10-15% of TSC individuals have no mutation identified (NMI) after thorough conventional molecular diagnostic assessment. 53 TSC subjects who were NMI were studied using next generation sequencing to search for mutations in these genes. Blood/saliva DNA including parental samples were available from all subjects, and skin tumor biopsy DNA was available from six subjects. We identified mutations in 45 of 53 subjects (85%). Mosaicism was observed in the majority (26 of 45, 58%), and intronic mutations were also unusually common, seen in 18 of 45 subjects (40%). Seventeen (38%) mutations were seen at an allele frequency < 5%, five at an allele frequency < 1%, and two were identified in skin tumor biopsies only, and were not seen at appreciable frequency in blood or saliva DNA. These findings illuminate the extent of mosaicism in TSC, indicate the importance of full gene coverage and next generation sequencing for mutation detection, show that analysis of TSC-related tumors can increase the mutation detection rate, indicate that it is not likely that a third TSC gene exists, and enable provision of genetic counseling to the substantial population of TSC individuals who are currently NMI

Similar Trends in Serum VEGF-D Levels and Kidney Angiomyolipoma Responses with Longer Duration Sirolimus Treatment in Adults with Tuberous Sclerosis

<div><p>Context</p><p>We have previously shown that serum VEGF-D is elevated at baseline, correlates with kidney angiomyolipoma size at baseline and 12 months, and decreases with sirolimus treatment in adults with tuberous sclerosis complex (TSC). To further investigate the utility of serum VEGF-D for longer term monitoring of TSC kidney disease, we present VEGF-D level results with 24 month follow-up.</p> <p>Objective</p><p>To compare 24 month VEGF-D levels in two subgroups of sirolimus treated patients (OFF SIROLIMUS AFTER 12 MONTHS or ON SIROLIMUS AFTER 12 MONTHS).</p> <p>Design and Intervention(s)</p><p>Serum VEGF-D was measured in samples collected from subjects enrolled in a phase 2 multicenter trial evaluating sirolimus for the treatment of kidney angiomyolipomas associated with TSC or TSC/LAM. All participants were treated with sirolimus from 0–12 months. During months 12–24, sirolimus was discontinued in one subgroup. The other subgroup was treated with additional sirolimus.</p> <p>Setting</p><p>Adult TSC participants were recruited from six clinical sites in the United States (comprehensive TSC clinics, 5; urology clinic, 1).</p> <p>Patients</p><p>There were 28 TSC patients who completed all 24 months of the study and serum samples were available at 24 months from 18/28 patients.</p> <p>Main Outcome Measure(s)</p><p>We compared the percent change in VEGF-D levels (baseline to 24 months) in patients from the two treatment subgroups.</p> <p>Results</p><p>At 24 months, VEGF-D levels decreased by 67% compared with baseline (to 787±426 pg/ml) in the ON SIROLIMUS AFTER 12 MONTHS group versus a 13% decrease (to 2971±4014 pg/ml) in the OFF SIROLIMUS AFTER 12 MONTHS group (p = 0.013, Mann-Whitney test). A similar trend was observed in kidney angiomyolipoma size but not in pulmonary function tests.</p> <p><i>Conclusions</i> Serum VEGF-D may be useful for monitoring response to treatment with sirolimus and kidney angiomyolipoma size in patients with TSC, but confirmation is needed.</p> <p>Trial Registration</p><p>Clinical trials.gov <a href="http://clinicaltrials.gov/show/NCT00126672" target="_blank">NCT00126672</a>.</p> </div