Asymmetric Opening of Mitochondrial Permeability Transition Pore in Mouse Brain Hemispheres: A Link to the Mitochondrial Calcium Uniporter Complex

Abstract The prolonged entry of large amounts of calcium into the mitochondria through the mitochondrial calcium uniporter complex (MCUC) may cause the permeability transition pore (mPTP) to open, which contributes to the pathogenesis of several diseases. Tissue-specific differences in mPTP opening due to variable expression of MCUC components may contribute to disease outcomes. We designed this study to determine differential mPTP opening in mitochondria isolated from different regions of mouse brain and kidney and to compare it with the expression of MCUC components. mPTP opening was measured using mitochondria isolated from the left/right brain hemispheres (LH/RH, respectively) and from kidney cortex/medulla, while the expression level of MCUC components was assessed from total cellular RNA. Interestingly, LH mitochondria showed less calcium-induced mPTP opening as compared to RH mitochondria at two different calcium concentrations. Conversely, mPTP opening was similar in the renal cortex and renal medulla mitochondria. However, the kidney mitochondria demonstrated bigger and faster mPTP opening as compared to the brain mitochondria. Furthermore, asymmetric mPTP opening in the LH and RH mitochondria was not associated with the expression of MCUC components. In brief, this study demonstrates thus far unreported asymmetric mPTP opening in mouse brain hemispheres that is not associated with the mRNA levels of MCUC components.

Piracetam-induced neuroprotection in lipopolysaccharides-challenged EOC-20 cells and mouse brain via attenuating oxidative stress

Abstract Therapeutically, piracetam has been used for decades as a cognitive enhancer for memory- related neuronal disorders. The present study aimed to investigate the neuroprotective potential of piracetam on lipopolysaccharides (LPS)-induced neuronal deficit using both in-vitro and in-vivo experimental models. For the in-vitro analysis, EOC-20 murine microglial cells were induced with a neuronal toxicity of 100 µg/ml of LPS, and the formation of intracellular reactive oxygen species (ROS) and nitric oxide (NO) productions were determined. For in-vivo neuroprotective analysis, groups of mice were treated orally with two doses of piracetam (200 and 400 mg/kg) for 30 days. Neuronal toxicity was induced by four intraperitoneal injections of LPS (250 µg/kg/day). The malondialdehyde (MDA) level was measured for oxidative stress, and catalase reduced glutathione (GSH), glutathione reductase (GRD), and superoxide dismutase (SOD) levels were determined as the antioxidant parameters. The result of the cell viability study was that pre-treatment with piracetam significantly protected the LPS-induced cell loss, and attenuated the ROS generation and NO production in LPS-induced EOC-20 cells. Moreover, the treatment of piracetam significantly reduced the MDA levels and improved catalase, GSH, GRD, and SOD activities in LPS-induced mice brains. The overall results from this study supported the neuroprotective effects of piracetam against LPS-induced neuronal toxicity.

Síndrome de Joubert / Joubert syndrome

El síndrome de Joubert es una enfermedad multisistémica poco frecuente. Se caracteriza por una malformación congénita del tronco cerebral e hipoplasia del vermis cerebeloso. Estas alteraciones provocan, entre otros, problemas respiratorios, hipotonía y retraso del desarrollo psicomotor. Puede asociar alteraciones a nivel renal, hepático u ocular, entre otros. No existe un tratamiento curativo de la enfermedad; por ello es importante un diagnóstico precoz, para ofrecer un seguimiento multidisciplinar y así poder mejorar el pronóstico y la calidad de vida de los pacientes y sus familias. (AU)

Joubert syndrome is a rare neurological disorder. It is characterized by the absence or underdevelopment of the cerebellar vermis and a malformed brain stem. These abnormalities cause signs and symptoms that include abnormal breathing patterns, hypotonia and development delay. It may associate kidney, liver or eye abnormalities. Treatment is supportive and depends on the symptoms in each person. This is why early diagnosis is so important, to offer a multidisciplinary strategy for improving the prognosis and quality of life. (AU)

Caracterização inovadora da morfologia da cabeça de bebês nascidos com o vírus zika: uma inovação metodológica para amplas aplicações clínicas / Novel characterization of head morphology of infants born with Zika Virus: a methodological innovation for broad clinical applications

Introdução: A epidemia do vírus Zika em 2016 constituiu uma emergência de saúde pública, com o chamando da OMS para vigilância reforçada na detecção precoce de microcefalia relacionada às condições neurológicas. Métodos: Quarenta e quatro crianças infectadas pelo vírus Zika foram avaliadas e comparadas com crianças saudáveis com o objetivo de identificar as medidas mais confiáveis do formato e tamanho da cabeça, explorando o relacionamento entre fenótipo craniofacial e anormalidades cerebrais. A análise de componentes principais (ACP) foi utilizada para identificar padrões de variação na morfologia craniofacial. As seguintes medições adicionais da abóboda craniana foram realizadas; altura cefálica (AC), comprimento cefálico (ComC), circunferência cefálica (CC) e ângulo naso-frontal (ANF). O nível de anormalidade cerebral presente nas tomografias, a gravidade da perda de volume do parênquima cerebral e ventriculomegalia foram classificadas como leve, moderada ou grave. Resultados: Os 12 primeiros componentes principais das abóbodas analisadas explicaram 91% da variação da abóboda craniana. Correlações significativas foram detectadas entre a pontuação do segundo CP da abóbada craniana e CC (+0,66), AC (+0,87), ComC (+0,80) e ANF (-0,48). Conclusão: Este estudo recomenda mensurar a AC em pacientes com infecção pelo vírus Zika, em vez de CC como recomendado pela OMS, para melhorar a sensibilidade e especificidade da detecção precoce(AU)

Background: The 2016 Zika virus epidemic constituted a public health emergency, with the WHO calling for strengthened surveillance for the early detection of related microcephaly and associated neurological conditions. Methods: We analysed 44 Zika infected infants and matched controls to identify the most reliable measurements of head shape and size and explore the relationship between craniofacial phenotype and brain abnormalities. Principal component analysis (PCA) was applied to identify patterns of variation in the craniofacial morphology of Zika cases relative to controls. We carried out the following additional measurements of the cranial vault, the head circumference (HC), head height (HH), head length (HL) and naso-frontal-angle (NFA). The level of brain abnormality present in the CT scans, mainly the severity of parenchymal volume loss and ventriculomegaly, was classified as being mild, moderate or severe. Results: The first 12 PCs of the vaults we analysed explained 91% of the variation of the cranial vault between Zika cases and controls. Significant correlations were detected between the score of the 2nd PC of the cranial vault and HC (+0.66); HH (+0.87); HL (+0.80) and NFA (-0.48). Conclusion: We recommend measuring HH in Zika patients, rather than HC as recommended by WHO, to improve the sensitivity and specificity of early detection(AU)

Different information by MRI compare to ultrasound in fetal intracranial space occupying lesions.

PURPOSE: The purpose of this study was to evaluate the value of prenatal magnetic resonance imaging (MRI) in characterizing fetal intracranial space occupying lesions in comparison to prenatal ultrasound. METHODS: This retrospective study included 50 fetuses (mean age 26 years, mean gestational weeks 31 + 1 GW) with intracranial space occupying lesions, suspected by prenatal screening ultrasound. T2-weighted, T1-weighted, SSFP, and diffusion-weighted sequences of the fetal brain were obtained on a 1.5 T unit. Pathology (n = 5), postmortem MRI (n = 3), or postnatal US (n = 42) was available as standard of reference. RESULTS: The fetal MRI provided correct diagnosis in 49 cases (98%), while 35 (70%) by ultrasound, and MRI failed in 1 case (2%), while ultrasound failed in 15 cases (30%). Fetal MR and ultrasound were concordant in 35 of 50 cases (70%), completely discordant in 4 (8%), and partially discordant in 11 (22%) cases. CONCLUSIONS: MRI could provide detailed information about the minor lesions, such as focal hemorrhage and periventricular nodules. Meanwhile, it could provide whole view of the lesion in order to delineate the surrounding anatomical structure. But there are still some limitations of its soft-tissue resolution in a case with teratoma; more effort is needed to improve the sequences.

Malformaciones cavernosas supratentoriales en una institución argentina: experiencia del tratamiento quirúrgico / Supratentorial cavernous malformations in an Argentinian institution: experience with surgical treatment

Introducción. Las malformaciones cavernosas son lesiones vasculares del sistema nervioso central constituidas por endotelio sinusoidal que forma capilares agrupados o cavernas que carecen de los elementos típicos de una pared arterial madura y ausencia de tejido neural interpuesto. El endotelio está rodeado por una densa capa de fibras colágenas que dejan pequeñas hendiduras por las que se extravasa hemosiderina. Se comunican con el sistema vascular a muy baja presión y su tratamiento puede ser por microcirugía o radiocirugía. Objetivos. Analizar las malformaciones cavernosas supratentoriales tratadas quirúrgicamente en nuestra institución (FLENI), determinar la epidemiología y las características intrínsecas, estudiar la clínica de presentación, determinar las indicaciones quirúrgicas y complicaciones, y establecer el pronóstico. Pacientes y métodos. Estudio retrospectivo analítico de historias clínicas e imágenes de pacientes operados de malformaciones cavernosas supratentoriales en la FLENI desde enero de 1996 hasta diciembre de 2013. Resultados. Evaluamos a 51 pacientes, de 34 años de media, seguidos durante una media de 30 meses. El 1,96% de los pacientes presentó diagnóstico incidental y el resto mostró síntomas. El 23,52% presentó hemorragia en el momento del diagnóstico. En todas las cirugías se logró una exéresis total de las malformaciones cavernosas supratentoriales. Se observó un caso de meningitis postoperatoria. Conclusiones. La tasa de sangrado de las malformaciones cavernosas supratentoriales en nuestro medio es del 1,38% por paciente por año. El tratamiento quirúrgico es eficaz para erradicar o disminuir los síntomas y para evitar un posible resangrado. Presenta una tasa muy baja de complicaciones y un pronóstico neurológico favorable (AU)

Introduction. Cavernous malformations are vascular malformations of the central nervous system formed by a group of capillaries not covered by pia mater and communicated to the vascular system at very low pressure with very slow flow. Surgery or radiosurgery are the treatment modalities. Aims. To analyze our results after surgical treatment of supratentorial cavernous malformations, reviewing clinical presentation, surgical indications and postoperative complications. Patients and methods. Analytical retrospective study of medical records and images of patients who underwent resection of supratentorial cavernomas at FLENI from January 1996 until December 2013. Results. We evaluated 51 patients, mean age 34 years, followed for an average of 30 months. In 1.96% of patients diagnosis was incidental, the rest all presented symptoms. Bleeding at diagnosis was observed in 23.52%. Total excision of supratentorial cavernous malformations was possible in all cases. The only postoperative complication was one case of meningitis. Conclusions. The bleeding rate of supratentorial cavernous malformations in our series was 1.38% per patient per year. Surgical treatment effectively eliminated, or at least reduced symptoms, prevented rebleeding, and decreased need for antiepileptic drug therapy. Surgery have a low complication rate and good outcome (AU)

Queratitis neurotrófica secundaria a malformación cerebral / Neurotrophic keratitis secondary to cerebral malformation

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Prognosis of Fetal Parenchymal Cerebral Lesions without Ventriculomegaly in Congenital Toxoplasmosis Infection.

OBJECTIVE: To evaluate the neurodevelopmental and ocular outcome of a continuous retrospective series of fetal toxoplasmosis infections for which prenatal ultrasound (US) follow-up revealed abnormal cerebral findings without associated ventriculomegaly. MATERIALS AND METHODS: We retrospectively reviewed all cases of proven fetal Toxoplasma gondii infection with fetal cerebral anomalies at US examination without significant ventriculomegaly (≥10 mm) evaluated in our center over a 5-year period. US and magnetic resonance imaging findings were collected. The neurodevelopmental and ocular outcomes of the cases were studied. RESULTS: Nine fetuses were included. Hyperechogenic foci of the cerebral parenchyma were isolated in five cases. Among those, four children had normal neurological development. Amblyopia was detected in on case. Hyperechogenic foci were associated with other anomalies of cerebral parenchyma in three cases among which two children had normal neurological development. Termination of pregnancy was performed in three cases: one case within the context of severe maternal schizophrenia with isolated hyperechogenic foci, one case where hyperechogenic foci were associated with extensive lesions of the white matter, and one case for severe fetal hydrops. CONCLUSION: The neurological prognosis of cerebral hyperechogenic lesions without ventriculomegaly in fetal toxoplasmosis infection may be favorable. The risk of ocular damage however remains high and unpredictable in the prenatal period.

Neuroimagen en las encefalopatías epilépticas del lactante / Neuroimaging in epileptic encephalopathies in infants

La resonancia magnética desempeña un papel crucial en el diagnóstico etiológico de las encefalopatías epilépticas, al poder identificar patrones etiológicamente específicos o sugestivos de diferentes entidades. Se revisan los principales hallazgos por resonancia magnética que se objetivan en las encefalopatías epilépticas sintomáticas (AU)

Magnetic resonance plays a vital role in the aetiological diagnosis of epileptic encephalopathies, since it is capable of identifying specific aetiological patterns or patterns which are suggestive of different conditions. We review the main magnetic resonance findings that are observed in symptomatic epileptic encephalopathies (AU)

Central diabetes insipidus: clinical profile that suggests organicity in Peruvian children: Lima - Peru 2001-2013.

BACKGROUND: Central diabetes insipidus (CDI) is a heterogeneous disease caused by arginine vasopressin deficiency; its management implies a profound understanding of the pathophysiology and the clinical spectrum. The aim of the study was to describe the clinical characteristics that indicate organicity in children and adolescents with central diabetes insipidus treated at the Department of Endocrinology from The Child Health's Institute during 2001 to 2013. METHODS: Cross-sectional, retrospective study. 79 cases of patients diagnosed with CDI (51 males and 28 females) from 1 month to 16 years of age were reviewed. For the descriptive analysis, measures of central tendency and dispersion were used; groups of organic and idiopathic CDI were compared using χ2-test and t-test. A p-value<0.05 was considered significant. RESULTS: The average age of patients was 8.1±4.2 years. Organic causes were intracranial tumors, 44 (55.7%), Langerhans cell histiocytosis (LCH), 11 (13.9%) and cerebral malformations in 7 (8.9%) patients, while the idiopathic group was 14 (17.7%) patients. Regarding clinical characteristics suggestive of organicity, headache (p=0.02) and visual disturbances (p=0.01) were found statistically significant. The anterior pituitary hormonal abnormalities were documented in 34 (52.3%) organic CDI patients. Furthermore, we did not find a significant difference in the average daily dose of desmopressin between patients with permanent vs. transitory CDI (0.81±0.65 vs. 0.59±0.62; p=0.363). CONCLUSIONS: The main clinical features suggestive of organicity in pediatric patients with central diabetes insipidus were headache and visual disturbances; furthermore, anterior pituitary hormonal abnormalities suggest an underlying organic etiology.

Six3 dosage mediates the pathogenesis of holoprosencephaly.

Holoprosencephaly (HPE) is defined as the incomplete separation of the two cerebral hemispheres. The pathology of HPE is variable and, based on the severity of the defect, HPE is divided into alobar, semilobar, and lobar. Using a novel hypomorphic Six3 allele, we demonstrate in mice that variability in Six3 dosage results in different HPE phenotypes. Furthermore, we show that whereas the semilobar phenotype results from severe downregulation of Shh expression in the rostral diencephalon ventral midline, the alobar phenotype is caused by downregulation of Foxg1 expression in the anterior neural ectoderm. Consistent with these results, in vivo activation of the Shh signaling pathway rescued the semilobar phenotype but not the alobar phenotype. Our findings show that variations in Six3 dosage result in different forms of HPE.

Diprosopus: Systematic review and report of two cases.

BACKGROUND: Diprosopus is a subtype of symmetric conjoined twins with one head, facial duplication and a single trunk. Diprosopus is a very rare congenital anomaly. METHODS: This is a systematic review of published cases and the presentation of two new cases born in Argentina. We estimated the prevalence of conjoined twins and diprosopus using data from the National Network of Congenital Anomalies of Argentina (RENAC). RESULTS: The prevalence of conjoined twins in RENAC was 19 per 1,000,000 births (95% confidence interval, 12-29). Diprosopus prevalence was 2 per 1,000,000 births (95% confidence interval, 0.2-6.8). In the systematic review, we identified 31 diprosopus cases. The facial structures more frequently duplicated were nose and eyes. Most frequent associated anomalies were: anencephaly, duplication of cerebral hemispheres, craniorachischisis, oral clefts, spinal abnormalities, congenital heart defects, diaphragmatic hernia, thoracic and/or abdominal visceral laterality anomalies. One of the RENAC cases and three cases from the literature had another discordant nonmalformed twin. CONCLUSION: The conjoined twins prevalence was similar to other studies. The prevalence of diprosopus was higher. The etiology is still unknown. The presence of visceral laterality anomalies may indicate the link between diprosopus and the alteration or duplication of the primitive node in the perigastrulation period (12-15 days postfertilization). Pregnancies of more than two embryos may be a risk factor for diprosopus. Given the low prevalence of this defect, it would be useful to perform studies involving several surveillance systems and international consortiums. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:993-1007, 2016. © 2016 Wiley Periodicals, Inc.

Porencephaly in a fennec fox (Vulpes zerda).

A postmortem examination revealed a large brain cavity in the right cerebral hemisphere of a 9-year-old male fennec (Vulpes zerda). The cavity was filled with cerebrospinal fluid and extended to the right lateral ventricle. Swelling and displacement of the right hippocampal area were also observed. Histologic examination revealed no evidence of previous infarct lesions, hemorrhage, inflammation or invasive tumor cells. Observation of the defective part suggested a local circulatory disorder during the fetal stage, although the cause was not detected. No neurological symptoms that could enable a provisional diagnosis were observed during the course of his life. This is the first report of asymptomatic porencephaly in a fennec fox.