Insulin-like Growth Factor Binding Proteins and Cellular Senescence Are Involved in the Progression of Non-Alcoholic Fatty Liver Disease and Fibrosis in a Mouse Model.

Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent worldwide. It progresses from simple steatosis to non-alcoholic steatohepatitis (NASH). Fibrosis is often present during NAFLD progression; however, factors determining which subjects develop NASH or fibrosis are unclear. Insulin-like growth factor binding proteins (IGFBPs) are a family of secreted proteins involved in senescence and scarring, mainly synthetized in the liver. Here, we aimed to study the association of IGFBPs and their induced senescence with the progression of NAFLD and liver fibrosis. Materials and Methods: A total of 16-week-old male C57BL/6 mice weighing 23 ± 3 g were fed either methionine/choline-deficient (MCD) or control diet for 2, 8, or 12 weeks. Blood and liver samples were collected, and a histological assessment of NAFLD and fibrosis was performed. Fat contents were measured. Cellular senescence was evaluated in the liver. IGFBP levels were assessed in the liver and serum. Data were expressed as mean ± SD and analyzed by a one-way ANOVA followed by Tukey's test. Lineal regression models were applied for NAFLD and fibrosis progression. p < 0.05 was considered significant. Results: IGFBP-1 and -2 were increased in serum during NAFLD. IGFBP-7 was significantly increased in the serum in NASH compared with the controls. Senescence increased in NAFLD. Serum and liver IGFBP-7 as well as SA-ß-gal activity increased as fibrosis progressed. Both IGFBP-7 and cellular senescence were significantly higher during NAFLD and fibrosis in MCD-fed mice. Conclusions: IGFBP-1, -2, and -7, through their consequent senescence, have a role in the progression of NAFLD and its associated fibrosis, being a plausible determinant in the progression from steatosis to NASH.

In Vitro Lipid Overload Affects Cellular Proliferation, Apoptosis, and Senescence in a Time-Dependent Manner in HepG2 Hepatocytes and LX-2 Hepatic Stellate Cells.

Different cellular mechanisms influence steatotic liver disease (SLD) progression. The influence of different levels of steatogenic inputs has not been studied in hepatocytes and hepatic stellate cells (HSCs). METHODS: HepG2 hepatocytes and LX-2 HSCs were cultured in mild (MS) and severe (SS) steatogenic conditions. TGF-ß stimulation was also tested for HSCs in control (T) and steatogenic conditions (MS-T and SS-T). Steatosis was stained with Oil Red, and the proliferation was assayed via WST-8 reduction, apoptosis via flow cytometry, and senescence via SA-ß-galactosidase activity. RESULTS: Regarding hepatocytes, steatosis progressively increased; proliferation was lower in MS and SS; and the viability of both conditions significantly decreased at 72 h. Apoptosis increased in MS at 72 h, while it decreased in SS. Senescence increased in MS and diminished in SS. Regarding HSCs, the SS and SS-T groups showed no proliferation, and the viability was reduced in MS at 72 h and in SS and SS-T. The LX-2 cells showed increased apoptosis in SS and SS-T at 24 h, and in MS and MS-T at 72 h. Senescence decreased in MS, SS, and SS-T. CONCLUSIONS: Lipid overload induces differential effects depending on the cell type, the steatogenic input level, and the exposure time. Hepatocytes are resilient to mild steatosis but susceptible to high lipotoxicity. HSCs are sensitive to lipid overload, undergoing apoptosis and lowering senescence and proliferation. Collectively, these data may help explain the development of steatosis and fibrosis in SLD.

Coping and risk perception during the COVID-19 pandemic in type 2 diabetes: Does it influence metabolic control?

Diabetes and poor glycemic control are significant predictors of severity and death in the COVID-19 disease. The perception of this risk in individuals with type 2 diabetes (T2D) could modify coping styles, leading to behaviors associated with better self-care and metabolic control. Theoretically, active coping is associated with better glycemic control in patients with T2D. Nonetheless, information during extreme risk like the COVID-19 pandemic is still limited. Our objective was to evaluate the association between coping styles and risk perception in the COVID-19 pandemic and the change in metabolic parameters. This is a prospective study that included individuals with T2D treated in a tertiary care center during the COVID-19 outbreak who returned to follow-up one year later. We assessed coping styles and risk perception with the Extreme Risk Coping Scale and the risk perception questionnaire. Clinical characteristics and metabolic parameters were registered in both visits. Groups were compared using Kruskal Wallis tests, and changes in metabolic parameters were assessed with Wilcoxon rank sum tests. Our sample included 177 participants at baseline, and 118 concluded the study. Passive coping was more frequent in women. Low-risk perception was associated with higher age, lower psychiatric comorbidities, and lower frequency of psychiatric treatment compared with other risk perception groups. Patients with active coping plus high-risk perception did not have a change in metabolic parameters at follow-up, whereas patients with other coping styles and lower risk perception had an increase in total cholesterol, LDL-cholesterol, and triglycerides. There were no differences by coping group or by risk perception in glycemic control.

Differential Association of Glycation Products with Bone Mineral Density and Fat Mass in Healthy and Diabetes Type 2 Subjects from Mexican Southeastern: A Cross Sectional Study.

Background: Glycation products have been linked to decreased bone mineral density (BMD) in a number of clinical settings. This study examined the correlation between early glycation products (HbA1c and glycated albumin (ALB-g)) and advanced glycation end products (pentosidine (PTD)) with BMD in two groups of participants: those with type 2 diabetes mellitus (DM2) and those without diabetes or any other comorbidities (noDM). All of the participants had resided in southeastern Mexico for a minimum of 10 years. Material and Methods: This study included 204 participants: 112 (55%) with DM2 and 92 (45%) healthy subjects. We utilized dual X-ray absorptiometry (DXA) to measure both the total and segment-specific BMD and adipose mass. In addition, the fasting blood glucose, HbA1c, PTD, and ALB-g parameters were measured. Correlation and logistic regression analyses were conducted. Results: There was an inverse correlation between PTD and BMD in all anatomical regions among postmenopausal women (PMW) in the DM2 group, whereas in non-PMW, only the waist-to-height ratio was statistically significant. A negative correlation was observed between HbA1c levels and BMD in the arms and legs of DM2 individuals. However, in the noDM group, a negative correlation was found between HbA1c levels and BMD in the pelvis, while a positive association was observed between HbA1c and indicators of adipose tissue. ALB-g, demonstrated a negative correlation with fat mass. After performing binary logistic regressions, the following odds ratios (OR) for osteopenia/osteoporosis risk were determined: PTD OR 1.1 (p = 0.047) for DM2 PMW, HbA1c OR 1.4 (p = 0.048), and fat mass content OR 1.011 (p = 0.023) for the entire sample. Conclusions: Glycation products are associated with BMD differentially depending on the analyzed anatomical segment, but PTD, HbA1c, and fat mass are significant predictors of low bone mass. In prospective studies, this association could be determined using other techniques involving three-dimensional analysis of bone architecture to evaluate bone architecture.

Evidence for Aerosol Transfer of SARS-CoV-2-Specific Humoral Immunity.

Infectious particles can be shared through aerosols and droplets formed as the result of normal respiration. Whether Abs within the nasal/oral fluids can similarly be shared between hosts has not been investigated. The circumstances of the SARS-CoV-2 pandemic facilitated a unique opportunity to fully examine this provocative idea. The data we show from human nasal swabs provides evidence for the aerosol transfer of Abs between immune and nonimmune hosts.

[Solid pseudopapillary neoplasm. Report of three cases and review of the literature]. / Neoplasia sólida pseudopapilar. Reporte de tres casos y revisión de la literatura.

Background: Solid pseudopapillary neoplasm, or Frantz-Gruber tumor, is a diagnostic challenge for the surgical pathologist. It is classified by the WHO as a malignant epithelial tumor of the pancreas, its prevalence is low, it occurs in only 1 to 2% of all malignant tumors of the pancreas, it usually affects mainly young women, its origin is still unclear, it is generally It presents as a solitary, encapsulated lesion, without invasion of peripancreatic tissues with rare cases of metastasis, which is why it is considered a low-grade malignant tumor by the WHO. The objective of this article is to present three clinical cases and to evaluate the epidemiology, clinical manifestations, morphology and immunohistochemical expression of the tumor in a review of the bibliography, as well as to compare it with the cases already reported on the subject. Clinical case: Three cases of Frantz tumor were diagnosed by the pathology department of a tertiary hospital are presented, which correspond to two women aged 17 and 34, as well as a 52-year-old man whose presentation by age and sex is rare. Conclusions: After the bibliographical review and the analysis of the cases presented, we verified the difficulty to make a correct diagnosis, since its presence is rare in the daily practice of the surgical pathologist. The morphological patterns of the solid pseudopapillary tumor are varied and can often be reminiscent of neuroendocrine tumors of the pancreas, whose presentation rate is higher.

Collagen matrix scaffolds: Future perspectives for the management of chronic liver diseases.

Approximately 1.5 billion chronic liver disease (CLD) cases have been estimated worldwide, encompassing a wide range of liver damage severities. Moreover, liver disease causes approximately 1.75 million deaths per year. CLD is typically characterized by the silent and progressive deterioration of liver parenchyma due to an incessant inflammatory process, cell death, over deposition of extracellular matrix proteins, and dysregulated regeneration. Overall, these processes impair the correct function of this vital organ. Cirrhosis and liver cancer are the main complications of CLD, which accounts for 3.5% of all deaths worldwide. Liver transplantation is the optimal therapeutic option for advanced liver damage. The liver is one of the most common organs transplanted; however, only 10% of liver transplants are successful. In this context, regenerative medicine has made significant progress in the design of biomaterials, such as collagen matrix scaffolds, to address the limitations of organ transplantation (e.g., low donation rates and biocompatibility). Thus, it remains crucial to continue with experimental and clinical studies to validate the use of collagen matrix scaffolds in liver disease.

Pancreatic Cancer: Genetic Conditions and Epigenetic Alterations.

BACKGROUND: Pancreatic cancer is a lethal proliferative disease driven by multiple genetic and epigenetic alterations. Microarrays and omics-based sequencing techniques are potent tools that have facilitated a broader understanding of the complex biological processes that drive pancreatic ductal adenocarcinoma (PDAC). In turn, these tools have resulted in the identification of novel disease markers, prognostic factors, and therapeutic targets. Herein, we provide a review of the genetic and epigenetic drivers of PDAC relative to recent discoveries that impact patient management. METHODS: A review of PubMed, Medline, Clinical Key, and Index Medicus was conducted to identify literature from January 1995 to July 2022 that is related to PDAC genetics and epigenetics. Articles in Spanish and English were considered during selection. RESULTS: Molecular, genetic, and epigenetic diagnostic tools, novel biomarkers, and promising therapeutic targets have emerged in the treatment of pancreatic cancer. The implementation of microarray technology and application of large omics-based data repositories have facilitated recent discoveries in PDAC. Multiple molecular analyses based on RNA interference have been instrumental in the identification of novel therapeutic targets for patients with PDAC. Moreover, microarrays and next-generation omics-based discoveries have been instrumental in the characterization of subtypes of pancreatic cancer, thereby improving prognostication and refining patient selection for available targeted therapies. CONCLUSION: Advances in molecular biology, genetics, and epigenetics have ushered in a new era of discovery in the pathobiology of PDAC. Current efforts are underway to translate these findings into clinical tools and therapies to improve outcomes in patients with PDAC.

Screen-related discord and dismay in low-income Mexican American families with toddlers: A qualitative study.

PURPOSE: Understanding parental experiences with managing their toddler's screen use is important to inform the design of interventions addressing early childhood screen use, yet current evidence is limited. To enhance our understanding of the context of toddler screen use, this study characterizes the screen-related discord and dismay parents experience in families with toddlers. DESIGN AND METHODS: In-depth interviews were conducted to explore everyday experiences with screen use among low-income Mexican American caregivers of toddlers (21 mothers, 10 fathers, 1 grandmother). Transcripts were content analyzed to identify prominent themes. RESULTS: Three themes were identified. Experiences of screen-related discord and dismay arose (1) between parent and child, (2) between parents, and (3) surfaced as parental internal dissonance about toddler screen use. Parent-child discord resulted from parental limit setting and child reactions to parental screen use, which often included tantrums. Parent-partner discord included patterns of agreeing to disagree and direct disagreement between partners. Parents also reported their own feelings of ambivalence and dismay as they struggled to reconcile their preferences against their toddler's actual screen use, while living in a screen-saturated world. CONCLUSIONS: Findings offer insight into types of screen-related discord and dismay low-income Mexican American parents experience as they attempt to manage their toddler's screen use. PRACTICE IMPLICATIONS: Although discord in families is normal, the screen-specific discord reported by participants warrants consideration in efforts promoting healthy screen use in families. Providers can tailor their counseling to consider the range of screen-related discord families of toddlers may experience.

Clinical and genetic study of developmental and epileptic encephalopathy in Argentinean pediatric patients.

INTRODUCTION: The aim of this study was to extend our knowledge of the genetic background of Argentinean pediatric patients with developmental and epileptic encephalopathy (DEE) applying a next generation sequencing (NGS) panel. METHODS: Thirty one patients with DEE were studied, including these phenotypes: Dravet syndrome (n:7), Dravet like syndrome (n:3), West syndrome (WS) (n:6), WS that evolved to Lennox-Gastaut syndrome (LGS) (n:4), epilepsy of infancy with migrating focal seizures (n:2), continuous spikes and waves during slow sleep evolving to LGS (n:1), LGS (n:1), myoclonic status in non-progressive encephalopathy (n:1), myoclonic atonic epilepsy (n:1), epileptic encephalopathy with multifocal spikes (n:1) and unclassified epileptic encephalopathy (n:4). Fifty-two genes frequently associated with DEE were studied by NGS in genomic DNA from peripheral blood. RESULTS: Relevant variants were detected in 12 cases; 6 novel pathogenic or likely pathogenic variants, 6 previously reported as pathogenic and 1 variant of unknown significance. Single-nucleotide heterozygous variants were identified in the SCN1A (5), GABRG2 (1), STXBP1 (2) genes, a mosaic variant in SCN2A (1) and a homozygous variant in SCN1B (1). Additionally, a heterozygous deletion involving the SCN1A, SCN2A and SCN3A genes (1), and the most frequent triplet repeat expansion in the ARX gene (1) were detected. DISCUSSION: Genetic diagnosis was made in 39% of patients. We emphasize the importance of considering mosaic variants, copy number variants and hereditary forms when designing and interpreting molecular studies, to optimize diagnosis and management of patients. Approximately 42% of the detected variants were novel, expanding the knowledge of the molecular basis of DEEs in Latin-American patients.

Introducción: El objetivo del estudio fue ampliar el conocimiento de las bases moleculares de las encefalopatías epilépticas y del desarrollo (EED) en pacientes pediátricos argentinos aplicando un panel de secuenciación de nueva generación (NGS). Métodos: Se analizaron 31 pacientes con los fenotipos clínicos de síndrome de Dravet (n:7), síndrome símil Dravet (n:3), síndrome de West (SW) (n:6), SW que evoluciona a síndrome de Lennox Gastaut (SLG)(N:4), epilepsia de la infancia con crisis focales migratorias (n:2), actividad de punta onda continua durante el sueño que evolucionan a SLG (n:1), SLG (n:1), encefalopatía no progresiva con estatus mioclónico (n:1), epilepsia mioclónica atónica (n:1), encefalopatía epiléptica con espigas multifocales (n:1) y encefalopatía epiléptica indeterminada (n:4). Se estudiaron los 52 genes más frecuentemente asociados a EED a través de NGS, en ADN extraído de sangre periférica. Resultados: Se identificaron variantes relevantes en 12 casos, de las cuales 5 fueron nuevas y 6 previamente reportadas como patogénicas o posiblemente patogénicas, mientras que una variante fue clasificada como de significado incierto. Variantes heterocigotas, de nucleótido único, se identificaron en los genes SCN1A (5), GABRG2 (1), STXBP1 (2), una variante en mosaico en SCN2A (1) y otra homocigota en SCN1B (1). Además, se detectó una deleción que involucra a los genes SCN1A, SCN2A y SCN3A (1) y la expansión de repeticiones de tripletes más frecuente en el gen ARX (1). Discusión: Se alcanzó el diagnóstico molecular en el 39% de los pacientes. Remarcamos la importancia de considerar variantes en mosaico, variantes en el número de copias y formas heredadas al momento de diseñar e interpretar los estudios moleculares, de tal forma de optimizar el diagnóstico y seguimiento de los pacientes con EED. Cabe destacar, que el 42% de las variantes detectadas fueron nuevas, ampliando nuestro conocimiento sobre las bases moleculares de las EED en población latino americana.

Clinical and genetic study of developmental and epileptic encephalopathy in argentinean pediatric patients / Estudio clínico y genético de encefalopatía epiléptica y del desarrollo en pacientes pediátricos argentinos

Abstract Introduction: The aim of this study was to extend our knowledge of the genetic background of Argentinean pediatric patients with developmental and epileptic encephalopathy (DEE) applying a next generation sequencing (NGS) panel. Methods: Thirty one patients with DEE were studied, including these phenotypes: Dravet syndrome (n:7), Dravet like syndrome (n:3), West syndrome (WS) (n:6), WS that evolved to Lennox-Gastaut syndrome (LGS) (n:4), epilepsy of infancy with migrating focal seizures (n:2), continuous spikes and waves during slow sleep evolving to LGS (n:1), LGS (n:1), myoclonic status in non-progressive encephalopathy (n:1), myoclonic atonic epilepsy (n:1), epileptic encephalopathy with multifocal spikes (n:1) and unclassified epileptic encephalopathy (n:4). Fifty-two genes frequently associated with DEE were studied by NGS in genomic DNA from peripheral blood. Results: Relevant variants were detected in 12 cases; 6 novel pathogenic or likely pathogenic variants, 6 previously reported as pathogenic and 1 variant of unknown sig nificance. Single-nucleotide heterozygous variants were identified in the SCN1A (5), GABRG2 (1), STXBP1 (2) genes, a mosaic variant in SCN2A (1) and a homozygous variant in SCN1B (1). Additionally, a heterozygous deletion involving the SCN1A, SCN2A and SCN3A genes (1), and the most frequent triplet repeat expansion in the ARX gene (1) were detected. Discussion: Genetic diagnosis was made in 39% of patients. We emphasize the importance of considering mosaic variants, copy number variants and hereditary forms when designing and interpreting molecular studies, to optimize diagnosis and management of patients. Approximately 42% of the de tected variants were novel, expanding the knowledge of the molecular basis of DEEs in Latin-American patients.

Resumen Introducción: El objetivo del estudio fue ampliar el conocimiento de las bases moleculares de las encefalopatías epilépticas y del desarrollo (EED) en pacientes pediátricos argentinos aplicando un panel de secuenciación de nueva generación (NGS). Métodos: Se analizaron 31 pacientes con los fenotipos clínicos de síndrome de Dra vet (n:7), síndrome símil Dravet (n:3), síndrome de West (SW) (n:6), SW que evoluciona a síndrome de Lennox Gastaut (SLG)(N:4), epilepsia de la infancia con crisis focales migratorias (n:2), actividad de punta onda continua durante el sueño que evolucionan a SLG (n:1), SLG (n:1), encefalopatía no progresiva con estatus mioclónico (n:1), epilepsia mioclónica atónica (n:1), encefalopatía epiléptica con espigas multifocales (n:1) y encefalopatía epiléptica indeterminada (n:4). Se estudiaron los 52 genes más frecuentemente asociados a EED a través de NGS, en ADN extraído de sangre periférica. Resultados: Se identificaron variantes relevantes en 12 casos, de las cuales 5 fueron nuevas y 6 previamente reportadas como patogénicas o posiblemente patogénicas, mien tras que una variante fue clasificada como de significado incierto. Variantes heterocigotas, de nucleótido único, se identificaron en los genes SCN1A (5), GABRG2 (1), STXBP1 (2), una variante en mosaico en SCN2A (1) y otra homocigota en SCN1B (1). Además, se detectó una deleción que involucra a los genes SCN1A, SCN2A y SCN3A (1) y la expansión de repeticiones de tripletes más frecuente en el gen ARX (1). Discusión: Se alcanzó el diagnóstico molecular en el 39% de los pacientes. Remarcamos la importancia de considerar variantes en mosaico, variantes en el número de copias y formas heredadas al momento de diseñar e interpretar los estudios moleculares, de tal forma de optimizar el diagnóstico y seguimiento de los pacientes con EED. Cabe destacar, que el 42% de las variantes detectadas fueron nuevas, ampliando nuestro conocimiento sobre las bases mole culares de las EED en población latino americana.

Xenoimplant of Collagen Matrix Scaffold in Liver Tissue as a Niche for Liver Cells.

Hepatitis C virus-induced liver damage, chronic liver damage due to alcohol, and non-alcoholic liver disease-induced cellular alterations promote fibrosis, cirrhosis, and/or hepatocellular carcinoma. The recommended therapeutic option for advanced liver damage is liver transplantation. Extracellular matrix scaffolds have been evaluated as an alternative for tissue restoration. Studies on the biocompatibility and rejection of synthetic and natural scaffolds as an alternative to organ transplantation have been evaluated. Our group has recently described the xenoimplant of collagen matrix scaffold (CMS) in a rat model. However, no complete macroscopic and histological description of the liver parenchyma at the initial (day 3), intermediate (day 14), and advanced (day 21) stages has been obtained. In this study, we described and compared liver tissue from the CMS zone (CZ, CMS, and liver parenchyma), liver tissue from the normal zone (liver parenchyma close to the CMS), and basal tissue (resected tissue from the CMS implantation site). Our data strongly suggest that the collagen matrix xenoimplant is a good niche for hepatocytes, with no rejection, and does not affect liver function tests. The liver can regenerate after damage, but this capacity is inhibited in a chronic injury. At present, the use of CMS after liver damage has not been reported. This biomaterial could be a novel alternative in the field of regenerative medicine for liver diseases.

Production and activity of matrix metalloproteinases during liver fibrosis progression of chronic hepatitis C patients.

BACKGROUND: Matrix metalloproteinases (MMPs) participate in the degradation of extracellular matrix compounds, maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver. However, there are few studies on the regulation of liver MMPs in fibrosis progression in humans. AIM: To assess the production activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C (CHC). METHODS: A prospective, cross-sectional, multicenter study was conducted. CHC patients were categorized in fibrosis grades through FibroTest ® and/or FibroScan ® . Serum MMP-2, -7, and -9 were determined by western blot and multiplex suspension array assays. Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests. The Spearman correlation coefficient and area under the receiver operating characteristic curve were calculated. Collagenolytic and gelatinase activity was determined through the Azocoll substrate and zymogram test, whereas tissue inhibitor of metalloproteinase-1 production was determined by dot blot assays. RESULTS: Serum concentrations of the MMPs evaluated were higher in CHC patients than in healthy subjects. MMP-7 distinguished early and advanced stages, with a correlation of 0.32 (P < 0.001), and the area under the receiver operating characteristic displayed moderate sensitivity and specificity for MMP-7 in F4 (area under the receiver operating characteristic, 0.705; 95% confidence interval: 0.605-0.805; P < 0.001). Collagenolytic activity was detected at F0 and F1, whereas gelatinase activity was not detected at any fibrosis stage. Tissue inhibitor of metalloproteinase-1 determination showed upregulation in F0 and F1 but downregulation in F2 (P < 0.001). CONCLUSION: High concentrations of inactive MMPs were present in the serum of CHC patients, reflecting the impossibility to restrain liver fibrosis progression. MMPs could be good diagnostic candidates and therapeutic targets for improving novel strategies to reverse liver fibrosis in CHC.

Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy.

Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil-based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3-19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9-6.2), 49.6 ng/mL (14.4-302.0), and 226.3 ng ⋅ h/mL (70.5-861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine-CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring.

Antigenotoxic effects of (-)-epigallocatechin-3-gallate (EGCG) and its relationship with the endogenous antioxidant system, 8-hydroxydeoxyguanosine adduct repair (8-OHdG), and apoptosis in mice exposed to chromium(VI).

This study aimed to investigate the relationship between endogenous antioxidant system, 8-hydroxydeoxyguanosine adduct (8-OHdG) repair, and apoptosis in mice treated with chromium(VI) alone and in the presence of the antigenotoxic compound (-)-epigallocatechin-3-gallate (EGCG). Groups of 5 Hsd:ICR male mice were divided and treated as follows: (1) control, vehicle only; (2) EGCG, 8.5 mg/kg by gavage alone; (3) CrO3, 20 mg/kg intraperitoneally alone; and (4) EGCG combined with CrO3, EGCG was administered 4 hr prior to CrO3. Peripheral blood parameters were analyzed before treatment administration (time 0), and 48 hr after exposure. The administration of EGCG increased 8-OHdG levels and superoxide dismutase (SOD) activity. Treatment with CrO3 increased number of micronucleus (MN) presence, elevated apoptotic/necrotic cells frequencies, decreased 8-OHdG levels, diminished total antioxidant capacity (TAC), increased glutathione (GSH) total levels, and lowered SOD activity. Administration of EGCG prior to treatment with CrO3 resulted in lower concentrations of MN, reduced apoptotic and necrotic cell number, and restored TAC and SOD activity to control levels. It is conceivable that the dose of EGCG plays an important role in the genotoxic damage protection pathways. Thus, this study confirms the action of EGCG as an antigenotoxic agent against chromium(VI)-induced oxidative insults and demonstrates potential protective pathways for EGCG actions to counteract genotoxic damage induced by this metal.

Epilepsia lesional de origen cerebeloso / Lesional epilepsy of cerebellar origin

El origen subcortical de la epilepsia ha sido tema de profundo debate durante muchísimo tiempo y solo se le otorgaba a las estructural subcorticales un rol en la distribución, modulación y alteración de la actividad cortical. Sin embargo, los estudios neurofisiológicos y de neuroimágenes de las últimas décadas han provisto de la información suficiente como para confirmar que algunas crisis epilépticas pueden iniciarse en estructuras subcorticales. Presentamos 4 pacientes pediátricos con lesiones cerebelosas y epilepsia refractaria, revisamos la bibliografía, analizamos las formas de presentación, los hallazgos neurofisiológicos y resultados a largo plazo con cirugía

The subcortical origin of epilepsy has been a subject of debate and only the subcortical structures were given a role in the distribution, modulation and alteration of cortical activity. However, neurophysiological and neuroimaging studies of recent decades have provided enough information to confirm the onset of some epileptic seizures in subcortical structures. We present 4 pediatric patients with cerebellar lesions and refractory epilepsy, we reviewed the literature, analyzed the forms of presentation, the neurophysiological findings and long-term results with surgery

Severe Leptospirosis in a Mexican Woman.

OBJECTIVE: To describe a severe case of infection by Leptospira in a woman in the northwest of Mexico. CASE REPORT: A 55-yearold woman from Sonora, México arrived at the Intensive Care Unit due to severe multiple organ failure primarily affecting the respiratory, renal and hepatic systems. Diagnostic tests were performed, and they were positive for anti-Leptospira antibodies, IgM and IgG; and spirochetes were observed on dark field microscopy and confirmed by Polymerase Chain Reaction (PCR). Doxycycline and platelet apheresis transfusion were used as treatment, which led to a very slow recovery. CONCLUSION: The information presented in this study may help in the identification of pathology caused by spirochetes. This case report is the first to present a case of severe leptospirosis in Sonora, México.

Molecular diagnosis of epileptic encephalopathy of the first year of life applying a customized gene panel in a group of Argentinean patients.

OBJECTIVE: The aim of this study was to perform a molecular characterization of 17 Argentinean pediatric patients with diagnosis of having epileptic encephalopathies (EEs) of the first year of life without known etiology, applying next-generation sequencing (NGS). METHODS: We included 17 patients with EE with age of onset under 12 months without known etiology after ruling out structural abnormalities, metabolic disorders, and large chromosomal abnormalities. They presented with the following clinical phenotypes: Dravet syndrome (DS; n: 7), epilepsy of infancy with migrating focal seizures (EIMFS; n: 3), West syndrome (WS; n: 2), and undetermined epileptic encephalopathy (UEE; n: 5). Neurologic examinations, seizure semiology, brain magnetic resonance imaging, and standard electroencephalography (EEG) or video-EEG studies were performed in all cases. Using a custom amplicon strategy, we designed an NGS panel to study 47 genes associated with EEs. RESULTS: Pathogenic variants were detected in 8 cases (47%), including seven novel pathogenic variants and one previously reported as being pathogenic. The pathogenic variants were identified in 6 patients with DS (SCN1A gene), one with EIMFS (SCN2A gene), and one with UEE (SLC2A1 gene). Nonrelevant variants were identified in the patients with WS. CONCLUSION: We demonstrated the feasibility of an NGS-gene panel approach for the analysis of patients with EE in our setting. A genetic diagnosis was achieved in nearly 50% of patients, 87% of them presenting with nonpreviously reported variants. The early identification of the underlying causative genetic alteration will be a valuable tool for providing prognostic information and genetic counselling and also to improve therapeutic decisions in Argentinean patients.