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.

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.

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.

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.

The use of modern ultrasound tridimensional techniques for the evaluation of fetal cerebral midline structures- a practical approach.

Fetal central nervous system midline structures represent an essential landmark for the confirmation of normality or for the identification of severe pathology. The ultrasound examination of the fetal brain using modern 3D techniques allows the creation of high sensitivity reconstructions. The facility of 3D volume acquisition permits the identification of corpus callosum, median septum, cavum septi pellucid and cerebellar vermis even in difficult cases. The examination should rely on both static (3D) and dynamic acquisition (4D). The use of a practical ultrasound protocol in clinical settings ensures the visualization of the midline cerebral structures in the vast majorities of fetuses. In selected cases MRI can be performed.

Flexible omnidirectional carbon dioxide laser as an effective tool for resection of brainstem, supratentorial, and intramedullary cavernous malformations.

BACKGROUND: Lasers have a long history in neurosurgery, yet bulky designs and difficult ergonomics limit their use. With its ease of manipulation and multiple applications, the OmniGuide CO2 laser has reintroduced laser technology to the microsurgical resection of brain and spine lesions. This laser, delivered through a hollow-core fiber lined with a unidirectional mirror, minimizes energy loss and allows precise targeting. OBJECTIVE: To analyze resections performed by the senior author from April 2009 to March 2013 of 58 cavernous malformations (CMs) in the brain and spine with the use of the OmniGuide CO2 laser, to reflect on lessons learned from laser use in eloquent areas, and to share data on comparisons of laser power calibration and histopathology. METHODS: Data were collected from electronic medical records, radiology reports, operative room records, OmniGuide CO2 laser case logs, and pathology records. RESULTS: Of 58 CMs, approximately 50% were in the brainstem (30) and the rest were in supratentorial (26) and intramedullary spinal locations (2). Fifty-seven, ranging from 5 to 45 mm, were resected, with a subtotal resection in 1. Laser power ranged from 2 to 10 W. Pathology specimens showed minimal thermal damage compared with traditionally resected specimens with bipolar coagulation. CONCLUSION: The OmniGuide CO2 laser is safe and has excellent precision for the resection of supratentorial, brainstem, and spinal intramedullary CMs. No laser-associated complications occurred, and very low energy was used to dissect malformations from their surrounding hemosiderin-stained parenchymas. The authors recommend its use for deep-seated and critically located CMs, along with traditional tools.