Loading and composite restoration assessment of various non-carious cervical lesions morphologies - 3D finite element analysis.

BACKGROUND: The present study analysed the effects of different occlusal loading on premolars displaying various non-carious cervical lesions morphologies, restored (or not) with composites, by 3D finite element analysis. METHODS: A three-dimensional digital model of a maxillary premolar was generated using CAD software. Three non-carious cervical lesions morphological types were simulated: wedged-shaped, saucer and mixed. All virtual models underwent three loading types (100 N): vertical, buccal and palatal loading. The simulated non-carious cervical lesions morphologies were analysed with and without restorations to consider specific regions, such as the occlusal and gingival walls as well as the depth of the lesions. Data summarizing the stress distribution were obtained in MPa using Maximum Principal Stress. RESULTS: Palatal loads were responsible for providing the highest values of accumulated tensile stress on the buccal wall; 27.66 MPa and 25.76 MPa for mixed and wedged-shaped morphologies, respectively. The highest tensile values found on non-carious cervical lesions morphologies restored with composite resin were 5.9 MPa in the mixed morphology, similar to those found on sound models despite their morphologies and occlusal loading. CONCLUSIONS: The various non-carious cervical lesions morphologies had little effect on stress distribution patterns, whereas the loading type and presence of composite restorations influenced the biomechanical behaviour of the maxillary premolars.

A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma.

PURPOSE: This study characterized the multiple-dose pharmacokinetics of vemurafenib 240-960 mg twice daily (bid) in BRAF(V600E) mutation-positive metastatic melanoma patients, using the commercial formulation (240-mg microprecipitated bulk powder film-coated tablets). METHODS: Melanoma patients (N = 52) were randomly allocated to four vemurafenib dose cohorts (240, 480, 720, or 960 mg bid for 14 days). After the day 15 morning dose, doses were interrupted until day 22, at which point patients were restarted on vemurafenib. Serial pharmacokinetic samples were collected after the morning dose on days 1, 9, and 15; trough pharmacokinetic samples were collected on day 2. RESULTS: Vemurafenib concentration increased with multiple doses to steady state at day 15; C(max), AUC(0-8h), and AUC(0-168h) increased between 3.3- and 3.8-fold across the fourfold dose range tested. Statistical analysis indicated dose proportionality across the dose range of 240-960 mg bid. Day 15 mean accumulation ratios (ratio of AUC(0-8h) on day 15/AUC(0-8h) on day 1) ranged from ~19 to 25 across cohorts. At steady state, the peak-to-trough ratio for vemurafenib exhibited a relatively flat concentration-time profile throughout the bid dosing interval. During dose interruption (days 15-22), mean vemurafenib trough concentrations decreased to minimal levels; vemurafenib exhibited a mean terminal phase half-life of 31.5-38.4 h. CONCLUSIONS: Vemurafenib plasma concentration accumulates with multiple bid doses of 240 mg. Vemurafenib exposure (AUC and C(max)) is dose proportional over the 240- to 960-mg bid dose range and exhibits constant drug levels over the bid dosing interval.

Safety, tolerability, and pharmacokinetics of ribavirin in hepatitis C virus-infected patients with various degrees of renal impairment.

Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC0-12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC0-12 was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients.

The pharmacokinetics of peginterferon alfa-2a and ribavirin in African American, Hispanic and Caucasian patients with chronic hepatitis C.

BACKGROUND: Amongst Caucasian, Hispanic and African Americans with genotype 1 hepatitis C virus (HCV), there is a wide variation in response to treatment with peginterferon alfa-2a (PEG-IFN alfa-2a) and ribavirin. AIM: To evaluate the pharmacokinetics (PK) of PEG-IFN alfa-2a and ribavirin among these three groups. METHODS: Forty-seven patients with genotype 1 CHC (17 African Americans, 14 Hispanics and 16 Caucasians) received 8 weeks of PEG-IFN alfa-2a (180 µg/week) and ribavirin (1000 or 1200 mg/day). PEG-IFN alfa-2a serum concentrations and ribavirin plasma concentrations were measured following the first dose and at week 8. Pharmacokinetic parameters (C(max), T(max), AUC, CL/F) were estimated using noncompartmental methods. RESULTS: There was no difference in the pharmacokinetic parameters for PEG-IFN alfa-2a following single-dose or steady-state administration between African American or Hispanic patients compared with Caucasian patients. Ribavirin pharmacokinetic parameters were similar between Hispanic and Caucasian patients for single-dose and steady-state administration. The single-dose C(max) was 33% lower (P < 0.05) in African American compared with Caucasian patients. Other ribavirin single-dose and steady-state pharmacokinetic parameters were slightly decreased (approximately 20% lower) in African American patients, but were not considered clinically meaningful. CONCLUSIONS: No differences were observed in PEG-IFN alfa-2a pharmacokinetic parameters between African American or Hispanic patients compared with Caucasian patients. For ribavirin, no differences were observed in pharmacokinetic parameters between Hispanic and Caucasian patients. While a trend towards increased ribavirin clearance and decreased exposure was observed in African American patients vs. Caucasian patients, the differences were small and not considered clinically meaningful (Clinical Trial Number: NP17354).

Pharmacokinetically guided phase 1 trial of the IGF-1 receptor antagonist RG1507 in children with recurrent or refractory solid tumors.

PURPOSE: This pediatric phase I study was designed to identify the doses of RG1507, a monoclonal antibody against the Type 1 Insulin-like Growth Factor Receptor (IGF1R), that achieves exposures equivalent to those achieved in adults at recommended doses. EXPERIMENTAL DESIGN: Children with relapsed or refractory solid tumors were treated using the same doses and administration schedules of RG1507 (3 and 9 mg/kg/wk, and 16 mg/kg every 3 weeks [q3W]) as those studied in adults. Detailed pharmacokinetic (PK) sampling was performed after the first dose; selected peak and trough levels were subsequently obtained. Target exposures were ≥85% of mean areas under concentration x time curves (AUCs) in adults at doses of 9 mg/kg/wk and 16 mg/kg q3W. A maximum tolerated dose could be identified if dose-limiting toxicities (DLT) occurred. RESULTS: Thirty-one evaluable patients aged 3-17 years were enrolled at 3 mg/kg/wk (n = 3), 9 mg/kg/wk (n = 18), or 16 mg/kg q3W (n = 10). There were no DLTs. At 9 mg/kg/wk the mean AUC(0-7d) (21,000 µg h/mL) exceeded the target (16,000 µg h/mL). At 16 mg/kg q3W, the mean AUC(021d) (70,000 µg h/mL) exceeded the target (59,400 µg h/mL). Clearance normalized to body weight was age dependent. There were no objective responses. Seven patients had stable disease for >12 weeks, including two patients with osteosarcoma with stable disease for 52+ and 78+ weeks. CONCLUSIONS: The recommended doses of RG1507 in children with solid tumors are 9 mg/kg/wk and 16 mg/kg q3W. This flexible design is well suited for trials of agents associated with limited toxicity.

A comprehensive hepatitis C viral kinetic model explaining cure.

We propose a model that characterizes and links the complexity and diversity of clinically observed hepatitis C viral kinetics to sustained virologic response (SVR)-the primary clinical end point of hepatitis C treatment, defined as an undetectable viral load at 24 weeks after completion of treatment)-in patients with chronic hepatitis C (CHC) who have received treatment with peginterferon alpha-2a +/- ribavirin. The new attributes of our hepatitis C viral kinetic model are (i) the implementation of a cure/viral eradication boundary, (ii) employment of all hepatitis C virus (HCV) RNA measurements, including those below the lower limit of quantification (LLOQ), and (iii) implementation of a population modeling approach. The model demonstrated excellent positive (99.3%) and negative (97.1%) predictive values for SVR as well as high sensitivity (96.6%) and specificity (99.4%). The proposed viral kinetic model provides a framework for mechanistic exploration of treatment outcome and permits evaluation of alternative CHC treatment options with the ultimate aim of developing and testing hypotheses for personalizing treatments in this disease.

[Subacute sclerosing panencephalitis: fulminant form]. / Panencefalitis esclerosante subaguda: forma fulminante.

INTRODUCTION: Subacute sclerosing panencephalitis (SSPE) has become less frequent as a consequence of massive anti measles vaccination. Early infection or immunological factors could increase the risk of its appearing and of evolved forms of the disease. CASE REPORTS: We describe the cases of four patients with fulminating forms of SSPE: a girl who had measles at the age of eight months; a male who, without actually suffering the clinical disease, came into contact with measles in the family and, despite having been vaccinated, presented SSPE 18 months after the contact; a boy aged 4 years and 4 months who had measles at the age of 6 months, and a boy of a similar age who had the illness when he was one year old. They all developed ataxia, with focal and generalised neurological signs, myoclonic and atonic seizures with rapid deterioration of language and the cognitive functions. In the four cases, the computerised tomography scans were normal, the electroencephalograms showed bilateral paroxysms and periods of recurrent bioelectrical attenuation. The magnetic resonance images of the four patients revealed disseminated hyperintense lesions, and one of the patients presented hyperintense lesions in the cervical spinal cord. The anti measles IgG titres were high in the cerebrospinal fluid. Anti convulsive drugs were ineffective. In the third and fourth patients, intrathecal intraventricular treatment with interferon did not modify the course of the disease and neurological deterioration was seen in the subsequent follow up of all the cases. CONCLUSION: As a consequence of vaccination against measles, SSPE has become less frequent. Infection of infants, prior to the immunisation stage, can induce SSPE with periods of latency that are shorter than usual and with a fast progression of the disease.

Panencefalitis esclerosante subaguda: forma fulminante / Subacute sclerosing panencephalitis: fulminant form

Introducción. La panencefalitis esclerosante subaguda (PEES) ha disminuido su frecuencia como consecuencia de la vacunación masiva antisarampionosa. La precocidad de la infección o factores inmunológicos podrían aumentar el riesgo de aparición y formas evolutivas de la enfermedad. Casos clínicos. Presentación de cuatro pacientes con formas fulminantes de PEES: una niña que padeció sarampión a los ocho meses de vida; un varón que, sin padecer la enfermedad clínica, tuvo contacto con sarampión familiar y, a pesar de haberse vacunado, presentó PEES a los 18 meses del contacto; un niño de 4 años y 4 meses, que tuvo sarampión a los 6 meses de edad, y un niño de similar edad, que padeció la enfermedad al año de vida.Todos desarrollaron ataxia, con signos neurológicos focales y generalizados, crisis mioclónicas y atónicas con un rápido deterioro de las funciones cognitivas y del lenguaje. En los cuatro casos, las tomografías computarizadas fueron normales, los electroencefalogramas mostraron paroxismos bilaterales y períodos de atenuación bioeléctrica periódica. En las resonancias magnéticas de los cuatro pacientes se encontraron lesiones hiperintensas diseminadas, y uno de los pacientes presentó lesiones hiperintensas en la médula cervical. En el líquido cefalorraquídeo, los títulos de IgG antisarampionosas estaban elevados. Los fármacos anticonvulsionantes fueron ineficaces. El tratamiento intratecal-intraventricular con interferón, en el tercer y cuarto pacientes, no modificó el curso de la enfermedad, y el deterioro neurológico fue progresivo en el seguimiento ulterior de todos los casos. Conclusión. Como consecuencia de la vacunación contra el sarampión, la PEES ha disminuido su frecuencia. La infección en lactantes, previa a la etapa de inmunización, puede inducir PEES con períodos de latencia menores a los habituales, con un curso rápido de la enfermedad (AU)

Introduction. Subacute sclerosing panencephalitis (SSPE) has become less frequent as a consequence of massive antimeasles vaccination. Early infection or immunological factors could increase the risk of its appearing and of evolved forms of the disease. Case reports. We describe the cases of four patients with fulminating forms of SSPE: a girl who had measles at the age of eight months; a male who, without actually suffering the clinical disease, came into contact with measles in the family and, despite having been vaccinated, presented SSPE 18 months after the contact; a boy aged 4 years and 4 months who had measles at the age of 6 months, and a boy of a similar age who had the illness when he was one year old. They all developed ataxia, with focal and generalised neurological signs, myoclonic and atonic seizures with rapid deterioration of language and the cognitive functions. In the four cases, the computerised tomography scans were normal, the electroencephalograms showed bilateral paroxysms and periods of recurrent bioelectrical attenuation. The magnetic resonance images of the four patients revealed disseminated hyperintense lesions, and one of the patients presented hyperintense lesions in the cervical spinal cord. The antimeasles IgG titres were high in the cerebrospinal fluid. Anti-convulsive drugs were ineffective. In the third and fourth patients, intrathecal-intraventricular treatment with interferon did not modify the course of the disease and neurological deterioration was seen in the subsequent follow-up of all the cases. Conclusion. As a consequence of vaccination against measles, SSPE has become less frequent. Infection of infants, prior to the immunisation stage, can induce SSPE with periods of latency that are shorter than usual and with a fast progression of the disease (AU)

Daño de la médula espinal, sin evidencia de lesión, en un niño hemofílico / Spinal cord injury without evidence of lesion in an hemophilic child

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[Behçet's disease in children: cortical calcifications]. / Enfermedad de Behçet en la infancia: calcificaciones corticoencefálicas.

INTRODUCTION: Between 5 and 48% of the patients with Behçet s disease have neurological abnormalities. In children, meningoencephalitis as an initial manifestation of the disease is not frequent. CASE REPORT: We present a four years old girl with a Behçet s disease. When she was six months of age, during an hospitalization caused by malnutrition and respiratory infection, she had developed an aseptic meningoencephalitis and laboratory test showed hypergammaglobulinemia. When she was 21 months old, she had seizures as epilepticus status, and good response was achieve treating with anticonvulsive drugs. She did not repeat episodes of epileptic seizures, but the patient showed language and neuromotor problems. CT was abnormal with asymmetric ventricular dilatation and increased subarachnoides cortical sulci with multiple calcifications in those areas. She also suffered respiratory and gastrointestinal infections that required hospitalization. At the age of 3 years and 6 months, she had occular affection with uveitis, oral and genital ulceration. The clinical history of the girl consisting of meningoencephalitis, gastrointestinal and respiratory disorders, later presentation of uveitis and oral and genital ulcers confirmed the Behçet s disease diagnosis. CONCLUSION: We present a girl with multisystemic disorders characteristic of the Behçet s disease. Initially she had an aseptic meningoencephalitis developing cortical calcifications.

Enfermedad de Behçet en la infancia:calcificaciones corticoencefálicas / Behçet's disease in children: cortical calcifications

Introducción. Entre el 5 y el 48 por ciento de los pacientes con enfermedad de Behçet, presentan alteraciones neurológicas. La meningoencefalitis en la lactancia es infrecuente como manifestación inicial. Caso clínico. Presentamos una niña de 4 años y 10 meses de edad, que a los 6 meses de vida padecía meningoencefalitis aséptica, después de una prolongada internación por un cuadro de desnutrición moderada y neumopatía. Se constató hipergammaglobulinemia. Al año y 9 meses de vida presentó status convulsivo. Posteriormente las crisis epilépticas se controlaron. La paciente presenta un retraso neuromotor y lingüístico. La tomografía axial computarizada demuestra una dilatación ventricular asimétrica, con un aumento de los espacios subaracnoideos corticales que presentaban calcificaciones múltiples. Fue internada en numerosas ocasiones por intercurrencias respiratorias y gastrointestinales. A los 3 años y 6 meses de vida presentaba una afección ocular, uveítis, lesiones bucales y genitales. La historia previa de la niña, su cuadro de meningoencefalitis, trastornos gastrointestinales y respiratorios, la aparición de uveítis, úlceras perianales y bucales e hipergammaglobulinemia corresponden a las características clínicas de la enfermedad de Behçet. Conclusión. Se presenta una niña con alteraciones multisistémicas características de la enfermedad de Behçet, afectada de meningoencefalitis precoz con aparición de calcificaciones corticales (AU)

[Hereditary progressive levodopa sensible: Segawa's syndrome]. / Distonía hereditaria sensible a levodopa: síndrome de Segawa.

INTRODUCTION: Hereditary progressive childhood dystonia with diurnal fluctuation of symptoms, belongs to the dopa responsive dystonias. It is dominantly inherited with variable penetrance, with deficiency in the cyclohydrolase I GTP gene. OBJECTIVE: Levodopa treatment is useful and diagnosis may be done on fluctuant dystonia in the childhood. CASE REPORTS: . We present four patients, one boy and three girls (two sisters) between 7 and 17 years of age. Neurological symptoms appears at 5, 15, 2.5 and 4 years of age respectively, with incoordination of movements ataxo paretic gait and postural dystonia. Symptoms were progressive with diurnal fluctuation. All laboratory test and image diagnosis were normal. Levodopa response, with lower doses (30 60 mg/day), were excellent. The four patients respectively are asymptomatic after 8, 4, 6 and 5 years of treatment. CONCLUSIONS: Hereditary progressive dystonia, with diurnal fluctuations is dopa responsive at lower doses, with neurological normalization and without side effects during a prolongated treatment.

Distonía hereditaria sensible a levodopa: síndrome de Segawa / Hereditary progressive levodopa sensible: Segawa's syndrome

Introducción. La distonía hereditaria progresiva con fluctuaciones diurnas es de carácter autosómico dominante, producida por deficiencia en el gen GTP ciclohidrolasa I. Objetivo. El tratamiento con levodopa es eficaz y, por ese motivo, debe considerarse ese diagnóstico en distonías fluctuantes en la infancia. Casos clínicos. Se presentan cuatro pacientes, un varón y tres mujeres (dos hermanas), cuyas edades variaron entre los 7 y 17 años. La sintomatología neurológica comenzó a los 5, 15, 2,5 y 4 años, respectivamente, y se manifestó en todos los pacientes con incoordinación de los movimientos, marcha ataxoparética y distonía postural. La sintomatología fue progresiva, con fluctuaciones diurnas. Los estudios de laboratorio, neurofisiológicos y por imágenes, fueron normales. La respuesta terapéutica fue excelente, mediante levodopa en dosis menores (30-60 mg/ día). Los cuatro pacientes permanecieron asintomáticos después de 8, 4, 6 y 5 años de seguimiento, respectivamente. Conclusión. La distonía hereditaria progresiva con fluctuaciones diurnas responde con dosis bajas de levodopa, con resolución de los síntomas y sin efectos adversos en el curso del tratamiento prolongado, en los cuatro pacientes presentados (AU)

[Acute encephalitis: bilateral lesions of the basal ganglia]. / Encefalitis aguda: lesiones bilaterales de los ganglios basales.

OBJECTIVE: To refer two children with acute encephalitis and bilateral basal ganglia lesion and its neurological outcome. CLINICAL CASES: Two girls, one of 9 years and the other of 15 months of age were affected by acute encephalitis, bilateral basal ganglia lesion was found on MRI in both children. Abnormal movements (tremor, choreoatetosis) and dystonia were the main symptomatology. In the first girl a mild dystonic posture on her hand and minor bradykinesia was the only found after a 4 year follow up. The other child, after 17 months of the beginning of her disease, still has generalized dystonia and choreoatetosis movements. Control MRI studies, in both patients remain without changes. CONCLUSION: In acute encephalitis, basal ganglia lesion in two children, produced different neurological sequelae, probably related to the age of the presentation of the disease.

Síndrome hiperatencional en niños / Hyperattentional syndrome in children

Introducción. La atención posee un mecanismo complejo que depende de múltiples estructuras encefálicas, que actúan interrelacionadas. Durante la atención se acumula la información del medio externo, a través de la memoria de trabajo. La integridad funcional del lóbulo frontal permite el desarrollo de la atención y el mecanismo del aprendizaje. Su alteración está asociada al síndrome de deficiencia atencional con hiperactividad. La atención habitualmente es selectiva a determinados estímulos. En el síndrome hiperatencional los niños presentan atención visual fija y sostenida a variados estímulos ambientales. Casos clínicos. Se presentan tres niños con alteraciones de la vigilancia caracterizadas por atención visual uniformemente selectiva a estímulos habituales del medio ambiente, con latencias prolongadas, sin otras manifestaciones a nivel neuropsíquico. Conclusiones. Los niños con deficiencia atencional presentan habitualmente atención selectiva a determinados estímulos ambientales. El síndrome hiperatencional es una variante con atención visual selectiva, con prolongadas latencias sobre el objeto blanco seleccionado (AU)

Canalopatías en neurología / Channelopathies in neurology

Introducción. Los canales iónicos poseen funciones de conducción, reconocimiento y selección de iones específicos. Su abertura o cierre se produce como respuesta a estímulos eléctricos, mecánicos y químicos, y actúan en la excitación o transmisión de energía a través de las membranas de diversos tejidos. Desarrollo. Las manifestaciones clínicas y moleculares de las canalopatías son variadas y suelen expresarse en forma continua o paroxística. Las alteraciones de los canales de Ca producen trastornos musculares, parálisis periódicas, con o sin modificación del potasio, miastenia o cuadros miasténicos, esclerosis lateral amiotrófica, miopatías (núcleo central) e hipertermia maligna. Las disfunciones de los canales de Cl y Na producen fenómenos miotónicos (enfermedad de Thomsen, Becker), paramiotonías, parálisis sensibles al potasio, miotonía congénita fluctuante, síndrome de Andersen. Las canalopatías ocurren en fenómenos paroxísticos atáxicos: ataxia episódica tipo 1, tipo 2, espinocerebelosa 6 y algunas formas de migraña (hemipléjica familiar). Hay movimientos anormales paroxísticos como consecuencia de alteraciones de canales iónicos: distonía nocturna paroxística, discinesia paroxística. En algunas familias existe asociación de movimientos anormales paroxísticos y epilepsia. Existen también formas de epilepsias: epilepsia nocturna del lóbulo frontal, convulsiones con coreoatetosis, convulsiones neonatales benignas, epilepsias generalizadas con convulsiones febriles plus. Conclusión. Las alteraciones moleculares de los canales iónicos producen enfermedades caracterizadas por fenómenos paroxísticos o condiciones permanentes ligadas a funciones musculares o del tejido neuronal, con manifestaciones clínicas y genéticas heterogéneas (AU)

[Limbic system and partial seizures with psychoaffective signs]. / Sistema límbico y crisis parciales con manifestaciones psicoafectivas.

INTRODUCTION: The limbic system, is associate to emotional behavior. Partial epileptic seizures are the expression of alterations of the temporal lobe, hippocampus and amygdala. In nonconvulsive episodes, autonomic alterations, visceral dysfunction and abnormal emotional states illustrate epileptic symptomatology. Fear responses, with possible connections to amygdala are presents in partial epileptic seizures. CLINICAL CASE: We present five patients with symptomatology mainly in emotional expression. Four had a structural lesion: one, multiple phacomatosis, two, tumors of the amygdala region (ganglioglioma) and one, a pineal cyst. The fifth child lacking a structural lesion, showed spike waves in the temporal lobe. CONCLUSION: It is essential to search for structural or functional alterations in patients with paroxysmal fear reactions, as probable partial crisis with psychoaffective manifestation.