Low infectivity among asymptomatic patients with a positive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) admission test at a tertiary care center, 2020-2022.

We used a strand-specific RT-qPCR to evaluate viral replication as a surrogate for infectiousness among 242 asymptomatic inpatients with a positive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) admission test. Only 21 patients (9%) had detectable SARS-CoV-2 minus-strand RNA. Because most patients were found to be noninfectious, our findings support the suspension of asymptomatic admission testing.

Use of a severe acute respiratory coronavirus virus 2 (SARS-CoV-2) strand-specific assay to evaluate for prolonged viral replication >20 days from illness onset.

Severe acute respiratory coronavirus virus 2 (SARS-CoV-2) real-time reverse-transcription polymerase chain reaction (rRT-PCR) strand-specific assay can be used to identify active SARS-CoV-2 viral replication. We describe the characteristics of 337 hospitalized patients with at least 1 minus-strand SARS-CoV-2 assay performed >20 days after illness onset. This test is a novel tool to identify high-risk hospitalized patients with prolonged SARS-CoV-2 replication.

Influenza aviar H5N1. ¿Debemos preocuparnos?

Desde la segunda mitad de 2022 se ha reportado un aumento de casos de influenza en aves migratorias en Latinoamérica. Los virus influenza A y B son los principales agentes asociados a influenza estacional epidémica en humanos. Los virus influenza A circulan no solo en humanos sino también en animales, incluyendo aves migratorias. El intercambio de segmentos de ARN genómico entre dos virus del mismo tipo aumenta la diversidad de los subtipos circulantes e incluso puede facilitar la generación de progenie viral potencialmente pandémica. La naturaleza zoonótica del virus influenza A puede generar infecciones en humanos con virus de origen animal. El virus influenza A de origen aviar ha ocasionado transmisiones en humanos, incluyendo casos graves y muertes, siendo la influenza A H5N1 la más destacada. Es importante tomar medidas de prevención y control en caso de aumento de casos de influenza en aves migratorias para prevenir posibles pandemias en Chile y el mundo.

Since the second half of 2022, an increase in influenza cases in migratory birds has been reported in Latin America. Influenza A and B viruses are the main agents associated with seasonal epidemic influenza in humans. Influenza A viruses circulate not only in humans but also in animals, including migratory birds. The exchange of genomic RNA segments among two viruses increases the diversity of circulating subtypes and may even facilitate the generation of potentially pandemic viral progeny. The zoonotic nature of influenza A virus can generate infections in humans with animal-origin viruses. Avian-origin influenza A virus has caused transmissions in humans, including severe cases and deaths, with influenza A H5N1 being the most prominent. It is important to take preventive and control measures in case of an increase in influenza cases in migratory birds to prevent possible pandemics in Chile and the world.

An Old Acquaintance: Could Adenoviruses Be Our Next Pandemic Threat?

Human adenoviruses (HAdV) are one of the most important pathogens detected in acute respiratory diseases in pediatrics and immunocompromised patients. In 1953, Wallace Rowe described it for the first time in oropharyngeal lymphatic tissue. To date, more than 110 types of HAdV have been described, with different cellular tropisms. They can cause respiratory and gastrointestinal symptoms, even urinary tract inflammation, although most infections are asymptomatic. However, there is a population at risk that can develop serious and even lethal conditions. These viruses have a double-stranded DNA genome, 25-48 kbp, 90 nm in diameter, without a mantle, are stable in the environment, and resistant to fat-soluble detergents. Currently the diagnosis is made with lateral flow immunochromatography or molecular biology through a polymerase chain reaction. This review aimed to highlight the HAdV variability and the pandemic potential that a HAdV3 and 7 recombinant could have considering the aggressive outbreaks produced in health facilities. Herein, we described the characteristics of HAdV, from the infection to treatment, vaccine development, and the evaluation of the social determinants of health associated with HAdV, suggesting the necessary measures for future sanitary control to prevent disasters such as the SARS-CoV-2 pandemic, with an emphasis on the use of recombinant AdV vaccines to control other potential pandemics.

Human cytomegalovirus: a survey of end-organ diseases and diagnostic challenges in solid organ transplant recipients.

PURPOSE OF REVIEW: Human cytomegalovirus (CMV) infection is one of the most important infectious complications in solid organ transplant (SOT) recipients, leading to significant morbidity and mortality. Therefore, early detection and prompt treatment are imperative to improve transplant outcomes. This article highlights the clinical characteristics of the most common CMV end-organ diseases in SOT recipients and their diagnostic modalities and challenges. RECENT FINDINGS: CMV can cause a variety of end-organ diseases in SOT recipients. Although CMV nucleic acid amplification by polymerase chain reaction (PCR) is frequently employed to detect CMV reactivation or infection, its predictive value for various CMV end-organ diseases remains uncertain. Given the limitation of PCR or other noninvasive tests, confirmation of CMV end-organ disease may require tissue biopsy, which may not be feasible or available, or may cause untoward complications. SUMMARY: The utility of PCR to diagnose CMV end-organ disease is limited. As CMV can infect any organ system(s), clinicians caring for SOT recipients need to maintain vigilance for any signs and symptoms of end-organ disease to allow early recognition and prompt treatment. Invasive procedures might be needed to confirm the diagnosis and minimize the empirical use of antiviral therapy that may have substantial drug toxicities.

Cellular Immune Response in Patients Immunized with Three Vaccine Doses of Different Vaccination Schemes Authorized by the Chilean Ministry of Health in January 2022.

In December 2019, a case of atypical pneumonia was reported in Wuhan, China. It was named COVID-19 and caused by SARS-CoV-2. In a few months, scientific groups around the world developed vaccines to reduce the disease's severity. The objective was to evaluate the humoral and cellular immune response post immunization with three different vaccination schedules administered in Chile until January 2022. Sixty volunteers were recruited with a three-dose schedule, who had no history of infection nor close contact with a positive patient. IgG against the spike antigenic domain was detected, and the neutralization capacity against two groups of variants, Original/Alpha and Beta/Gamma, was also measured. Finally, the cellular response with interferon release was measured through IGRA. Results showed that there were significant differences in the neutralizing antibodies for the original and alpha variant when comparing three Comirnaty doses with Coronavac and Vaxzevria. A high number of reactive subjects against the different SARS-CoV-2 variants, alpha, gamma, and delta, were observed, with no significant differences between any of the three schemes, confirming the existence of a cellular immune response against SARS-CoV-2. In conclusion, the three vaccine schemes generated a cellular immune response in these volunteers.

Direct inhibition of CaV2.3 by Gem is dynamin dependent and does not require a direct alfa/beta interaction.

The Rad, Rem, Rem2, and Gem/Kir (RGK) sub-family of small GTP-binding proteins are crucial in regulating high voltage-activated (HVA) calcium channels. RGK proteins inhibit calcium current by either promoting endocytosis or reducing channel activity. They all can associate directly with Ca2+ channel ß subunit (CaVß), and the binding between CaVα1/CaVß appears essential for the endocytic promotion of CaV1.X, CaV2.1, and CaV2.2 channels. In this study, we investigated the inhibition of CaV2.3 channels by RGK proteins in the absence of CaVß. To this end, Xenopus laevis oocytes expressing CaV2.3 channels devoid of auxiliary subunit were injected with purified Gem and Rem and found that only Gem had an effect. Ca currents and charge movements were reduced by injection of Gem, pointing to a reduction in the number of channels in the plasma membrane. Since this reduction was ablated by co-expression of the dominant-negative mutant of dynamin K44A, enhanced endocytosis appears to mediate this reduction in the number of channels. Thus, Gem inhibition of CaV2.3 channels would be the only example of a CaVß independent promotion of dynamin-dependent endocytosis.

The conformational cycle of prestin underlies outer-hair cell electromotility.

The voltage-dependent motor protein prestin (also known as SLC26A5) is responsible for the electromotive behaviour of outer-hair cells and underlies the cochlear amplifier1. Knockout or impairment of prestin causes severe hearing loss2-5. Despite the key role of prestin in hearing, the mechanism by which mammalian prestin senses voltage and transduces it into cellular-scale movements (electromotility) is poorly understood. Here we determined the structure of dolphin prestin in six distinct states using single-particle cryo-electron microscopy. Our structural and functional data suggest that prestin adopts a unique and complex set of states, tunable by the identity of bound anions (Cl- or SO42-). Salicylate, a drug that can cause reversible hearing loss, competes for the anion-binding site of prestin, and inhibits its function by immobilizing prestin in a new conformation. Our data suggest that the bound anion together with its coordinating charged residues and helical dipole act as a dynamic voltage sensor. An analysis of all of the anion-dependent conformations reveals how structural rearrangements in the voltage sensor are coupled to conformational transitions at the protein-membrane interface, suggesting a previously undescribed mechanism of area expansion. Visualization of the electromotility cycle of prestin distinguishes the protein from the closely related SLC26 anion transporters, highlighting the basis for evolutionary specialization of the mammalian cochlear amplifier at a high resolution.

[Epidemiological characterization of infection by SARS-CoV-2 of the healthcare workers of a university hospital in Santiago de Chile]. / Caracterización epidemiológica de infección por SARS-CoV-2 del personal de salud de un hospital universitario en Santiago de Chile.

BACKGROUND: The SARS-CoV-2 outbreak originated in the Hubei province in China spread rapidly throughout the world during the first months of 2020. On March 3, the first case was reported in Chile; at 17 days the first case of COVID-19 healthcare worker (HCW) was notified in our institution. AIM: To describe the demographic characteristics and the incidence of SARS-CoV-2 infection in the HCW of a university hospital in Chile. MATERIAL AND METHOD: Retrospective study of SARS-CoV-2 infection on HCW in a university hospital between March 1 and May 31, 2020. RESULTS: There were 273 positive cases. In the period under study, we had an incidence of 5.8%. When we separated the cases into clinical and non-clinical personnel, it was observed that their incidences were practically identical (5.8 vs. 5.7% p = 0.9430). 88% of the officials were oligosymptomatic or asymptomatic at the beginning of the clinical presentation and only 12% had a fever before the medical consultation. CONCLUSION: The incidence reported in the study was around 5 times that reported in Wuhan. If we apply the current definition of cases, we would lose 4 out of 5 cases. 88% of HPW did not present criteria to be considered suspicious, so it would be advisable in HCW to eliminate fever as a criterion to improve the research and trace their contacts on time.

Caracterización epidemiológica de infección por SARS-CoV-2 del personal de salud de un hospital universitario en Santiago de Chile / Epidemiological characterization of infection by SARS-CoV-2 of the healthcare workers of a university hospital in Santiago de Chile

INTRODUCCIÓN: El brote de SARS-CoV-2 originado en la provincia de Hubei en la República Popular China, se fue extendiendo aceleradamente en el mundo durante los primeros meses del año 2020. El 3 de marzo se notificó el primer caso en Chile; a los 17 días se notificó el primer caso de un Personal de Salud (PS) COVID-19 en nuestra institución. OBJETIVO: Describir las características demográficas y la incidencia de infección por SARS-CoV-2 en el PS de un hospital universitario de alta complejidad. MATERIAL Y MÉTODO: Estudio retrospectivo de los casos de infección por SARS-CoV-2 del PS entre el 1 de marzo y 31 de mayo de 2020. RESULTADOS: Hubo 273 casos positivos, con una incidencia de 5,8% en el período en estudio. Al dividir los casos en personal clínico y no clínico se observó que sus incidencias fueron prácticamente idénticas (5,8 vs 5,7% p = 0,9430). El 88% de los funcionarios fue oligo-sintomático o asintomático al inicio del cuadro clínico y sólo 12% tuvo fiebre antes de la consulta médica. CONCLUSIÓN: La incidencia reportada en el estudio fue alrededor de cinco veces la reportada en Wuhan. Al aplicar la definición de casos vigente, se perderían cuatro de cada cinco casos. Destaca que 88% del PS no presentaba criterios para ser considerado sospechoso, por lo que sería recomendable en el PS eliminar la fiebre como criterio para mejorar la pesquisa y trazar sus contactos de forma oportuna.

BACKGROUND: The SARS-CoV-2 outbreak originated in the Hubei province in China spread rapidly throughout the world during the first months of 2020. On March 3, the first case was reported in Chile; at 17 days the first case of COVID-19 healthcare worker (HCW) was notified in our institution. AIM: To describe the demographic characteristics and the incidence of SARS-CoV-2 infection in the HCW of a university hospital in Chile. MATERIAL AND METHOD: Retrospective study of SARS-CoV-2 infection on HCW in a university hospital between March 1 and May 31, 2020. RESULTS: There were 273 positive cases. In the period under study, we had an incidence of 5.8%. When we separated the cases into clinical and non-clinical personnel, it was observed that their incidences were practically identical (5.8 vs. 5.7% p = 0.9430). 88% of the officials were oligosymptomatic or asymptomatic at the beginning of the clinical presentation and only 12% had a fever before the medical consultation. CONCLUSION: The incidence reported in the study was around 5 times that reported in Wuhan. If we apply the current definition of cases, we would lose 4 out of 5 cases. 88% of HPW did not present criteria to be considered suspicious, so it would be advisable in HCW to eliminate fever as a criterion to improve the research and trace their contacts on time.

Electromechanical coupling in the hyperpolarization-activated K+ channel KAT1.

Voltage-gated potassium (Kv) channels coordinate electrical signalling and control cell volume by gating in response to membrane depolarization or hyperpolarization. However, although voltage-sensing domains transduce transmembrane electric field changes by a common mechanism involving the outward or inward translocation of gating charges1-3, the general determinants of channel gating polarity remain poorly understood4. Here we suggest a molecular mechanism for electromechanical coupling and gating polarity in non-domain-swapped Kv channels on the basis of the cryo-electron microscopy structure of KAT1, the hyperpolarization-activated Kv channel from Arabidopsis thaliana. KAT1 displays a depolarized voltage sensor, which interacts with a closed pore domain directly via two interfaces and indirectly via an intercalated phospholipid. Functional evaluation of KAT1 structure-guided mutants at the sensor-pore interfaces suggests a mechanism in which direct interaction between the sensor and the C-linker hairpin in the adjacent pore subunit is the primary determinant of gating polarity. We suggest that an inward motion of the S4 sensor helix of approximately 5-7 Å can underlie a direct-coupling mechanism, driving a conformational reorientation of the C-linker and ultimately opening the activation gate formed by the S6 intracellular bundle. This direct-coupling mechanism contrasts with allosteric mechanisms proposed for hyperpolarization-activated cyclic nucleotide-gated channels5, and may represent an unexpected link between depolarization- and hyperpolarization-activated channels.

Diagnóstico tardío de VIH/sida en pacientes rurales dado por baja sospecha diagnostica en la comunidad médica. Reportes de caso / Late diagnosis of HIV/AIDS in rural patients due to low diagnostic suspicion among the medical community. Case reports

Resumen Introducción. La prevalencia de la infección por el virus de inmunodeficiencia humana (VIH) en Latinoamérica no ha sido estudiada de forma adecuada, pero se calcula que en Chile la mitad de los pacientes que están infectados no han sido diagnosticados y no están bajo control ni tratamiento. Presentación de los casos. Se presentan dos casos clínicos de pacientes masculinos de 22 y 33 años, sin antecedentes mórbidos, con múltiples consultas en diversos servicios clínicos. El diagnóstico se hizo en etapa sida (síndrome de inmunodeficiencia adquirida), con las complicaciones que se asocian cuando se diagnostica de manera tardía. Conclusiones. El VIH es una patología subdiagnosticada, en su mayoría por falta de sospecha y por los prejuicios de la población respecto a la realización del test de VIH. El cuerpo médico debe tomar la responsabilidad de pesquisar los casos de manera temprana para disminuir el impacto de la enfermedad, en especial en lugares con población vulnerable.

Abstract Introduction: The prevalence of the human immunodeficiency virus (HIV) infection in Latin America has not been adequately studied, but it is estimated that in Chile half of the patients who are infected have not been diagnosed and are not controlled or receiving treatment. Case presentation: This paper presents two clinical cases of male patients aged 22 and 33, without a medical history, and with multiple consultations for different reasons in various clinical services. The diagnosis was made at the AIDS stage (acquired immunodeficiency syndrome), with the complications associated with late diagnosis. Conclusions: HIV is an underdiagnosed pathology, mostly due to lack of suspicion and prejudiced attitudes towards HIV testing. The medical staff should take responsibility for the early study of these cases to reduce the impact of the disease, especially in places where vulnerable populations live.

The syndromic deafness mutation G12R impairs fast and slow gating in Cx26 hemichannels.

Mutations in connexin 26 (Cx26) hemichannels can lead to syndromic deafness that affects the cochlea and skin. These mutations lead to gain-of-function hemichannel phenotypes by unknown molecular mechanisms. In this study, we investigate the biophysical properties of the syndromic mutant Cx26G12R (G12R). Unlike wild-type Cx26, G12R macroscopic hemichannel currents do not saturate upon depolarization, and deactivation is faster during hyperpolarization, suggesting that these channels have impaired fast and slow gating. Single G12R hemichannels show a large increase in open probability, and transitions to the subconductance state are rare and short-lived, demonstrating an inoperative fast gating mechanism. Molecular dynamics simulations indicate that G12R causes a displacement of the N terminus toward the cytoplasm, favoring an interaction between R12 in the N terminus and R99 in the intracellular loop. Disruption of this interaction recovers the fast and slow voltage-dependent gating mechanisms. These results suggest that the mechanisms of fast and slow gating in connexin hemichannels are coupled and provide a molecular mechanism for the gain-of-function phenotype displayed by the syndromic G12R mutation.

Osteocondroma como hallazgo Incidental en Úlcera Varicosa Sobreinfectada en miembro inferior / Osteochondroma as an incidental finding in Superinfected Varicose Ulcer in the lower limb

El osteocondroma es la lesión tumoral más frecuente del hueso. Éste presenta características radiológicas patognomónicas con continuidad cortical y medular, con lesión exofítica iniciada en metáfisis, protruyendo hasta la diáfisis de huesos largos, con predominio en la porción distal del fémur, fíbula y tibia proximal. Para el diagnóstico de esta patología, por lo general sólo se necesita una imagen radiológica simple en dos planos, en casos ocasionales necesitando tomografía computarizada para verificarlo. En la mayoría de los casos el diagnóstico ocurre de forma incidental, en pacientes asintomáticos, en contados casos, se observa impotencia funcional, bursitis, parestesias o fracturas en hueso patológico. El riesgo de transformación es menor al 1 %, siendo el tumor maligno más frecuente el condrosarcoma. Se describe el reporte de un hallazgo imagenológico incidental de un tumor óseo en un paciente de 65 años con úlcera varicosa sobreinfectada en conjunto con la discusión sobre la importancia de la imagenología para estos diagnósticos.

Osteochondroma is the most frequent tumor lesion in bone. This presents pathognomonic radiological features with cortical and medullary continuity, with exophytic lesion initiated in metaphysis, protruding to the diaphysis of long bones, predominating in the distal portion of the femur, fibula and proximal tibia. For the diagnosis of this pathology, usually only a simple radiological image is needed in two planes, in occasional cases needing computed tomography to verify it. In most cases the diagnosis occurs incidentally, in asymptomatic patients, in few cases, functional impotence, bursitis, paresthesias or fractures in pathological bone are observed. The risk of transformation is less than 1 %, with the malignant tumor being more frequent chondrosarcoma. Following the report of an incidental imaging finding of a bone tumor on 65 years old patient with varicose ulcer infected in conjunction with the discussion of the importance of these diagnostic imaging to be described.

Desarrollo neuroembriológico: el camino desde la proliferación hasta la perfección / Neuronal Embryonic Development: A Pathway from Proliferation to Perfection

El desarrollo neurológico humano requiere una serie de pasos que permitan orientar, regular y diferenciar los diversos componentes cerebrales, para así garantizar, de una manera bastante precisa, la correcta organización y funcionamiento de las estructuras neuronales. La neurogénesis está clásicamente dividida en cuatro etapas consecutivas: proliferación, migración, diferenciación y maduración. En los humanos, estas ocurren desde la tercera semana de gestación hasta la vida adulta y precisan de un complejo grupo de paquetes genéticos, así como de algunos factores asociados, que se han ido descubriendo gracias a los avances en la biología molecular. El artículo es una revisión acerca del desarrollo neuroembriológico humano y los componentes genéticos más relevantes encontrados en la literatura.

The human neuronal development requires a number of concrete steps which lead to orientation, regulation and differentiation of several brain components. They must be done to guarantee, in a very precise way, the correct organization and functioning of the neuronal structures. Neurogenesis is commonly divided into four consecutive stages: proliferation, migration, differentiation and maturation. In humans, those stages take place since the third week of prenatal Iife until the adult Iife. They also require a complex group of genetic packs and associated molecular factors, most of which have been recen tly discovered by the molecular biology technology. A review was made about the human neuronal and embryological development and the most relevant genetic components described by the literature so far.

Rol de la vitamina E en el tubo neural de embriones y fetos de ratón (Mus musculus) tratados con ácido valproico: estudio inmunohistoquímico de sonic hedgehog / Role of vitamin E in neural tube of mouse (Mus musculus) embryos and fetuses treated with valproic acid: immunohistochemical study of sonic hedgehog

Sonic hedgehog (SHH) es un morfógeno esencial para el desarrollo del tubo neural, miembros y somitos. Variaciones en su expresión pueden ocasionar alteraciones en el sistema nervioso. Esto lo producen teratógenos, como el ácido valproico (VPA), el cual aumenta las especies reactivas de oxígeno, pudiendo contrarrestarse con la administración de vitamina E (VE). Se buscó determinar la expresión de SHH en tubo neural y médula espinal en embriones y fetos de ratones expuestos a VPA, VPA + VE y VE. Se conformaron 8 grupos de ratones hembra (Mus musculus). A los 8 días post-coito (p.c.) se les administró a los grupos 1 y 5 suero fisiológico 0,3 ml; grupos 2 y 6 VPA 600 mg/kg; grupos 3 y 7 VPA 600 mg/kg + VE 200 UI/kg; grupos 4 y 8 VE 200 UI/kg, todos los tratamientos vía oral. A los 12 días p.c., se sacrificaron los grupos 1, 2, 3 y 4, y a los 17 días los restantes. Fueron fijados en solución Bouin e incluidos en paraplast. Se realizaron cortes transversales a nivel torácico. Se utilizó anticuerpo policlonal anti-SHH (Santa Cruz, H-160, conejo), dilución 1:100. Se describió la morfología de las muestras marcadas positivamente, se midió la densidad óptica integrada y porcentaje de área inmunoreactiva. La expresión de SHH fue inmunopositiva en notocorda y placa del piso del tubo neural solo en embriones de 12 días p.c. Los grupos tratados con VPA+VE y VE presentaron mayor intensidad inmunohistoquímica y porcentaje de área inmunoreactiva en comparación al grupo tratado con VPA (p 0,0001) en la placa del piso, siendo similar al grupo control. En la notocorda, la intensidad de inmunoreacción fue similar a lo demostrado en la placa del piso, con diferencias significativas (p 0,0001), pero el porcentaje de área no arrojó diferencias. Los grupos de 17 días de gestación resultaron negativos a la expresión de SHH. La vitamina E regula la expresión de SHH en tubo neural, atenuando así los efectos del VPA.

Sonic hedgehog (SHH) is an essential morphogen for the development of neural tube, members and somites. Variations in expression can cause abnormalities in the nervous system. This will produce teratogens, such as valproic acid (VPA), which increases the reactive oxygen species and can be counteracted with the administration of vitamin E (VE). We sought to determine the expression of SHH in the neural tube and spinal cord in mice embryos and fetuses exposed to VPA, VPA + VE and VE. For the study we used 8 groups of female mice (Mus musculus). At day 8 post-coitus (p.c.) the groups were administered as follows: groups 1 and 5,0.3ml saline; groups 2 and 6, VPA 600 mg/kg; groups 3 and 7, VPA 600 mg / kg + VE 200 IU/kg; groups 4 and 8, VE 200 IU/kg, all treatments were given orally. On the 12th day p.c., groups 1, 2, 3 and 4 were euthanized and the remaining groups at day 17. They were fixed in Bouin solution and included in paraplast; thoracic cross sections were performed, anti-SHH polyclonal antibody (Santa Cruz, H-160, rabbit) dilution 1:100 was used. We described morphology of the positively labeled samples and measured integrated optic density and percentage of immunoreactivearea.SHH expression was immunopositive in notochord and floor plate of the neural tube in embryos only 12 day p.c. In the groups treated with VPA + VE and VE immunohistochemistry showed greater intensity and percentage of immunoreactive area compared to those in the group treated with VPA (p0.0001) in the floor plate, being similar to the control group. In the notochord, immunoreaction intensity was similar to that shown in the floor plate, with significant differences (p 0.0001), but the percentage of area showed no differences. The groups at day 17 of gestation were negative for the expression of SHH. VE regulates expression of SHH in neural tube, thus attenuating the effects of VPA.