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OBJECTIVES: This study aims to examine the sources of stress among first-year medical students; the frequency of their coping strategies; the factors associated with specific stressors and specific coping strategies adopted by the participants. METHODS: We conducted a cross-sectional study with 409 first-year students at the University of Medicine and Pharmacy, Vietnam. The Vietnamese versions of the Higher Education Stress Inventory (V_HESI) and Brief Coping Orientation to Problems Experienced (V_Brief COPE) were validated and were used as measurement instruments for participants' sources of stress and coping strategies frequencies. The survey comprised questions of socioeconomic status, stress-related issues, the six sources of stress (using the V_HESI), and the nine coping strategies (using the V_Brief COPE). RESULTS: Among the six sources of stress, "Worries about future competence/endurance" had the highest mean score (3.02±0.64), while "Mismatch in professional role expectations" had the lowest score (1.60±0.53). "Financial concerns" and "Academic workloads" were also significant sources of stress. Regarding coping strategies, Self-distraction was most frequently adopted by the participants (2.80 ± 0.68). Problem-solving (2.72±0.53) and seeking Social support (2.62±0.70) were also common adaptive strategies. Avoidance (1.87±0.55) and substance-use (1.27±0.55) were the least frequent strategies. Students who experienced acute stress event were more likely to have financial concerns compared to others. Substance use was positively associated with stressors from "Mismatch in professional role expectations", "Non-supportive educational environment", "Having physical issues" and "Having part-time job". Self-blame was more frequent among students with "Worries about future competence/endurance", "Financial concerns", and "Academic workload". Male student tended to adopt humor strategy (ß = 0.19, p = 0.02), while less likely to utilize religious practices (ß = -0.21, p = 0.01). CONCLUSIONS: Two-thirds of the participants reported moderate to high levels of stress. "Worries about future competence/endurance" was the most concerned stressor, followed by "Academic workload", and "Financial concerns". The first-year medical students reported high frequency of utilization "Self-distraction", "Problem-solving" and "Social support" when confronting stress. The findings may help inform the school management to better support students' well-being.
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Adaptación Psicológica , Estrés Psicológico , Estudiantes de Medicina , Humanos , Estudiantes de Medicina/psicología , Masculino , Femenino , Vietnam , Estrés Psicológico/psicología , Estudios Transversales , Adulto Joven , Adulto , Encuestas y Cuestionarios , Apoyo Social , Habilidades de Afrontamiento , Pueblos del Sudeste AsiáticoRESUMEN
Purpose: To assess over 2 weeks, the effect of 3 different low concentrations of atropine on pupillary diameter and accommodative amplitude in children with myopia. Methods: Fifty-eight children with myopia [spherical equivalent (SE) of -0.50 diopters (D) or worse, astigmatism of less than or equal to 2.00 D] were randomly allocated to 3 groups receiving 0.01%, 0.02%, or 0.03% atropine eye drops, once nightly for 2 weeks. The primary outcome was the change from baseline in pupillary diameter and accommodative amplitude with each of the concentrations. Results: Fifty-seven participants (114 eyes), aged between 6 and 12 years, completed the 2-week trial (mean age 9.3 ± 1.7 years and mean SE -3.53 ± 1.79 D). After 2 weeks of use, all the 3 concentrations were found to have a statistically significant effect on both the pupillary diameter and accommodative amplitude. Accommodative amplitude reduced by an average of 5.23 D, 9.28 D, and 9.32 D, and photopic pupil size increased by an average of 0.95 ± 1.05 mm, 1.65 ± 0.93 mm, and 2.16 ± 0.88 mm with 0.01%, 0.02%, and 0.03%, respectively. Of the eyes, a total of 5.3% and 5.9% of the eyes on 0.02% and 0.03% atropine had a mean residual accommodative amplitude of <5 D. The percentage of eyes having a pupillary dilation >3 mm were 4.8%, 10.5%, and 23.5% for 0.01%, 0.02%, and 0.03% atropine, respectively. Conclusions: Low-dose atropine had an effect on pupillary diameter and accommodative amplitude. With the highest concentration assessed, that is, 0.03% nearly 1 of 4 eyes had pupillary dilation of >3 mm. Clinical Trial Registration number: NCT03699423.
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Acomodación Ocular , Atropina , Midriáticos , Miopía , Soluciones Oftálmicas , Pupila , Humanos , Atropina/administración & dosificación , Atropina/farmacología , Niño , Miopía/tratamiento farmacológico , Miopía/fisiopatología , Acomodación Ocular/efectos de los fármacos , Pupila/efectos de los fármacos , Masculino , Femenino , Soluciones Oftálmicas/administración & dosificación , Midriáticos/administración & dosificación , Midriáticos/farmacología , Midriáticos/uso terapéutico , Relación Dosis-Respuesta a DrogaRESUMEN
The nematode Caenorhabditis elegans has been a model for studying infection since the early 2000s and many major discoveries have been made regarding its innate immune responses. C. elegans has been found to utilize some key conserved aspects of immune responses and signaling, but new interesting features of innate immunity have also been discovered in the organism that might have broader implications in higher eukaryotes such as mammals. Some of the distinctive features of C. elegans innate immunity involve the mechanisms this bacterivore uses to detect infection and mount specific immune responses to different pathogens, despite lacking putative orthologs of many important innate immune components, including cellular immunity, the inflammasome, complement, or melanization. Even when orthologs of known immune factors exist, there appears to be an absence of canonical functions, most notably the lack of pattern recognition by its sole Toll-like receptor. Instead, recent research suggests that C. elegans senses infection by specific pathogens through contextual information, including unique products produced by the pathogen or infection-induced disruption of host physiology, similar to the proposed detection of patterns of pathogenesis in mammalian systems. Interestingly, C. elegans can also transfer information of past infection to their progeny, providing robust protection for their offspring in face of persisting pathogens, in part through the RNAi pathway as well as potential new mechanisms that remain to be elucidated. Altogether, some of these strategies employed by C. elegans share key conceptual features with vertebrate adaptive immunity, as the animal can differentiate specific microbial features, as well as propagate a form of immune memory to their offspring.
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Proteínas de Caenorhabditis elegans , Nematodos , Animales , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Inmunidad Innata , Transducción de Señal , Mamíferos/metabolismoRESUMEN
OBJECTIVE: Stress is a significant concern in medical education, and identifying effective ways to deal with stress may help with students' mental health and professional development. This study aimed to examine the effects of the Transforming Stress Program (TSP) amongst first-year medical students on their stress mindset and coping strategies when confronted with stressors. METHODS: We conducted a quasi-experimental study at the University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam. A total of 409 first-year students at the Faculty of Medicine were divided into intervention group (205 students) and control group (204 students). The 10-week TSP was delivered as an extra-curricular course. The training adopts psychoeducation based on Dialectical Behavioral Therapy with mindfulness as a fundamental practice incorporated into each component of the program. The intervention group received the training in the first semester; the control group received identical program in the second semester. Stress Mindset Measurement and Brief Coping Orientation to Problems Experienced were measured before the intervention (T0), immediately after intervention on Intervention group (T1), and six months after intervention on Intervention group (T2). RESULTS: At T1, the intervention group showed 65% improvements in stress mindset scores and increases in coping strategies scores in six domains (Problem solving, Social support, Humor, Religion, Venting, and Self-distraction) and decreases in three (Avoidance, Substance use, and Self-blame). The effect sizes were significant in all outcomes (Cohen's d > 0.2). Measurements of the control group did not change significantly in the same period. At T2, effects of the TSP were found decreased in some domains (Avoidance, Substance use, and Self-blame) compared to T1, but largely remained significantly better than T0. CONCLUSIONS: The TSP is a feasible and effective approach that significantly enhanced medical students' stress mindset and coping strategies. Some effects were still observable 6 months after the intervention. The relatively intensive intervention requires support of the school administration and staff.
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Estudiantes de Medicina , Humanos , Adaptación Psicológica , Salud Mental , Instituciones Académicas , Terapia ConductistaRESUMEN
Microsporidia are a large phylum of intracellular parasites that can infect most types of animals. Species in the Nematocida genus can infect nematodes including Caenorhabditis elegans, which has become an important model to study mechanisms of microsporidia infection. To understand the genomic properties and evolution of nematode-infecting microsporidia, we sequenced the genomes of nine species of microsporidia, including two genera, Enteropsectra and Pancytospora, without any previously sequenced genomes. Core cellular processes, including metabolic pathways, are mostly conserved across genera of nematode-infecting microsporidia. Each species encodes unique proteins belonging to large gene families that are likely used to interact with host cells. Most strikingly, we observed one such family, NemLGF1, is present in both Nematocida and Pancytospora species, but not any other microsporidia. To understand how Nematocida phenotypic traits evolved, we measured the host range, tissue specificity, spore size, and polar tube length of several species in the genus. Our phylogenetic analysis shows that Nematocida is composed of two groups of species with distinct traits and that species with longer polar tubes infect multiple tissues. Together, our work details both genomic and trait evolution between related microsporidia species and provides a useful resource for further understanding microsporidia evolution and infection mechanisms.
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Microsporidios , Nematodos , Animales , Microsporidios/genética , Filogenia , Nematodos/genética , Caenorhabditis elegans/genética , GenómicaRESUMEN
A central question in the field of aging research is to identify the cellular and molecular basis of neuroresilience. One potential candidate is the small GTPase, Rab10. Here, we used Rab10+/- mice to investigate the molecular mechanisms underlying Rab10-mediated neuroresilience. Brain expression analysis of 880 genes involved in neurodegeneration showed that Rab10+/- mice have increased activation of pathways associated with neuronal metabolism, structural integrity, neurotransmission, and neuroplasticity compared with their Rab10+/+ littermates. Lower activation was observed for pathways involved in neuroinflammation and aging. We identified and validated several differentially expressed genes (DEGs), including Stx2, Stx1b, Vegfa, and Lrrc25 (downregulated) and Prkaa2, Syt4, and Grin2d (upregulated). Behavioral testing showed that Rab10+/- mice perform better in a hippocampal-dependent spatial task (object in place test), while their performance in a classical conditioning task (trace eyeblink classical conditioning, TECC) was significantly impaired. Therefore, our findings indicate that Rab10 differentially controls the brain circuitry of hippocampal-dependent spatial memory and higher-order behavior that requires intact cortex-hippocampal circuitry. Transcriptome and biochemical characterization of these mice suggest that glutamate ionotropic receptor NMDA type subunit 2D (GRIN2D or GluN2D) is affected by Rab10 signaling. Further work is needed to evaluate whether GRIN2D mediates the behavioral phenotypes of the Rab10+/- mice. We conclude that Rab10+/- mice described here can be a valuable tool to study the mechanisms of resilience in Alzheimer's disease (AD) model mice and to identify novel therapeutical targets to prevent cognitive decline associated with normal and pathologic aging.
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Enfermedad de Alzheimer , Ratones , Animales , Ratones Noqueados , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Perfilación de la Expresión Génica , Condicionamiento Clásico/fisiología , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismoRESUMEN
The competency-based undergraduate curriculum reform at the University of Medicine and Pharmacy at Ho Chi Minh City, Faculty of Medicine (UMP-FM) is detailed and reviewed in reference to the instructional and institutional reforms, and enabling actions recommended by the Lancet 2010 Commission for Health Professional Education. Key objectives are to: revise the overall 6-year curriculum to be more integrated and competency-based; reinforce students' knowledge application, problem-solving, clinical competence, self-directed learning and soft skills; develop a comprehensive and performance-based student assessment programme; and establish a comprehensive quality monitoring programme to facilitate changes and improvements. New features include early introduction to the practice of medicine, family- and community-based medicine, professionalism, interprofessional education, electives experiences, and a scholarly project. Institutional reform introduces a faculty development programme, joint planning mechanism, a "culture of critical inquiry", and a transparent faculty reward system. Lessons learnt from the curriculum reform at UMP-FM could be helpful to medical schools from low- and middle-income countries considering transitioning from a traditional to a competency-based curriculum. Funding: This work receives no external funding.
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In response to a call for help during a surge in coronavirus disease-19 (COVID-19) cases in Ho Chi Minh City in July 2021, the University of Medicine and Pharmacy at Ho Chi Minh City developed and implemented a community care model for the management of patients with COVID-19. This was based on three main principles: home care; providing monitoring and care at a distance; and providing timely emergency care if needed. One team supported patients at home with frequent contacts and remote monitoring, while a second team transferred and cared for patients requiring treatment at field emergency care facilities. COVID-19-related mortality rates at the two districts where this approach was implemented (0.43% and 0.57%) were substantially lower than the overall rate in Ho Chi Minh City over the same period (4.95%). Thus, utilization of a community care model can increase the number of patients with COVID-19 who can be effectively managed from home, and use of field emergency care facilities limited the number of patients that had to be referred for tertiary care. Importantly, the community care model also markedly reduced the mortality rate compared with traditional methods of COVID-19 patient management.
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Intracellular pathogens are challenged with limited space and resources while replicating in a single host cell. Mechanisms for direct invasion of neighboring host cells have been discovered in cell culture, but we lack an understanding of how bacteria directly spread between host cells in vivo. Here, we describe the discovery of intracellular bacteria that use filamentation for spreading between the intestinal epithelial cells of a natural host, the rhabditid nematode Oscheius tipulae. The bacteria, which belong to the new species Bordetella atropi, can infect the nematodes following a fecal-oral route, and reduce host life span and fecundity. Filamentation requires UDP-glucose biosynthesis and sensing, a highly conserved pathway that is used by other bacteria to detect rich conditions and inhibit cell division. Our results indicate that B. atropi uses a pathway that normally regulates bacterial cell size to trigger filamentation inside host cells, thus facilitating cell-to-cell dissemination.
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Bordetella/crecimiento & desarrollo , Mucosa Intestinal/citología , Rhabditoidea/citología , Animales , Bordetella/clasificación , Bordetella/patogenicidad , División Celular/genética , Células Epiteliales/microbiología , Células Epiteliales/ultraestructura , Genoma Bacteriano/genética , Interacciones Huésped-Patógeno , Hibridación Fluorescente in Situ , Mucosa Intestinal/microbiología , Espacio Intracelular/microbiología , Redes y Vías Metabólicas/genética , Microscopía Electrónica de Transmisión , Filogenia , ARN Ribosómico 16S/genética , Rhabditoidea/genética , Rhabditoidea/microbiología , Análisis de Secuencia de ADN , VirulenciaRESUMEN
Alzheimer's disease (AD) is characterized by a progressive decline in cognitive function; however, recent evidence suggests that non-cognitive sensorimotor and psychomotor symptoms accompany early stages of the disease in humans and AD models. Although exercise is emerging as an important therapeutic to combat AD progression, little is known about the effect of exercise on sensorimotor domain functions. The purpose of this study was to determine if early sensorimotor symptoms accompany deficits in Morris water maze (MWM) performance in the 3xTg-AD model, and investigate if exercise could protect against early behavioral decline. 3xTg-AD and wild-type (WT) control mice were subjected to 12 weeks of moderate intensity wheel running or remained sedentary. At 6 months of age, animals underwent a series of sensorimotor and MWM testing. 3xTg-AD mice displayed deficits in sensorimotor function (beam traversal, spontaneous activity, and adhesive removal) and MWM performance. Interestingly, 3xTg-AD animals exhibited increased freezing and unusual shaking/tremoring behaviors not displayed by WT controls. Exercise improved beam traversal, adhesive removal, and reduced the unusual motor-related behaviors in 3xTg-AD mice. Our study shows that sensorimotor symptoms coincide with deficits in MWM performance, and suggest that exercise may mitigate deficits associated with early disease in 3xTg-AD mice.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/psicología , Animales , Modelos Animales de Enfermedad , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora , Proteínas tauRESUMEN
PURPOSE: To determine the effect of atropine on pupillary diameter, accommodative amplitude as well as myopia progression. METHODS: Medical databases and Cochrane Library were systematically searched for studies from 1980 until June 2020. The primary and secondary outcomes were: a) change in pupillary diameter (PD) and accommodative amplitude (AA) and b) annualized mean change in spherical equivalent and axial length with various concentrations of atropine compared to control. RESULTS: Thirteen trials (6 RCTs, 7 observational studies) that studied 9 atropine concentrations (0.01-1.0%) were included. The relation between atropine and change in PD and AA was nonlinear; at < 0.10% atropine, the slope of the curve was steep but the change in PD (+0.7âmm; 95% CI: +0.1 to +1.4) and AA (-1.6D; 95% CI: -3.9 to +0.7) was smaller whereas at ≥0.10% atropine, the slope plateaued but change in PD (+3.2âmm, 95% CI: +2.8 to +3.5) and AA (-10.7D; 95% CI: -12.2 to -9.2) was high.Reduction in myopia progression with atropine at <0.10% and ≥0.10% as compared to controls was 0.37D (95% CI: 0.16 to 0.58) versus 0.75D (95% CI: 0.17 to 1.33) for spherical equivalent and -0.10âmm (95% CI: -0.24 to 0.05) versus -0.23âmm (95% CI: -0.34 to -0.13) for axial length. CONCLUSIONS: A nonlinear dose-response relationship exists between atropine and PD and AA. Further work is warranted to determine the concentration that provides maximal efficacy with tolerable side effects.
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Atropina , Miopía , Progresión de la Enfermedad , Humanos , Miopía/tratamiento farmacológico , Soluciones Oftálmicas , Refracción OcularRESUMEN
Myopia is a global public health issue with a worldwide prevalence of â¼30% and is estimated to rise to 50% by 2050. In addition to the burden associated with routine management of the condition, high myopia predisposes the eye to sight-threatening complications such as myopic maculopathy and glaucoma in adult life. Controlling onset and progression of myopia at a young age can reduce the risk of morbidity associated with high myopia. Progression of myopia can be slowed with various optical, environmental, and pharmaceutical strategies, of which atropine has proven to be the most effective. High-dose atropine (0.5%-1%) is the most effective, but it has significant trade-offs with respect to rebound of myopia on discontinuation and side effects such as photophobia and difficulty with near work (decreased accommodation). Low doses of atropine have been trialed and show a dose-dependent efficacy. However, its mode of action on the ocular tissues leading to slowing eye growth remains unclear and multiple mechanisms and sites in the eye have been postulated to play a role. This review summarizes the role of atropine in controlling myopia and the mechanisms studied to date.
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Atropina/uso terapéutico , Miopía/tratamiento farmacológico , Soluciones Oftálmicas/uso terapéutico , Atropina/administración & dosificación , Humanos , Soluciones Oftálmicas/administración & dosificaciónRESUMEN
Neonatal rats were administered a relatively high concentration of ethyl alcohol (11.9% v/v) during postnatal days 4-9, a time when the fetal brain undergoes rapid organizational change and is similar to accelerated brain changes that occur during the third trimester in humans. This model of fetal alcohol spectrum disorders (FASDs) produces severe brain damage, mimicking the amount and pattern of binge-drinking that occurs in some pregnant alcoholic mothers. We describe the use of trace eyeblink classical conditioning (ECC), a higher-order variant of associative learning, to assess long-term hippocampal dysfunction that is typically seen in alcohol-exposed adult offspring. At 90 days of age, rodents were surgically prepared with recording and stimulating electrodes, which measured electromyographic (EMG) blink activity from the left eyelid muscle and delivered mild shock posterior to the left eye, respectively. After a 5 day recovery period, they underwent 6 sessions of trace ECC to determine associative learning differences between alcohol-exposed and control rats. Trace ECC is one of many possible ECC procedures that can be easily modified using the same equipment and software, so that different neural systems can be assessed. ECC procedures in general, can be used as diagnostic tools for detecting neural pathology in different brain systems and different conditions that insult the brain.
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Condicionamiento Palpebral/fisiología , Trastornos del Espectro Alcohólico Fetal/fisiopatología , Hipocampo/fisiopatología , Animales , Parpadeo , Condicionamiento Clásico/fisiología , Modelos Animales de Enfermedad , Electromiografía/instrumentación , Electromiografía/métodos , Femenino , Trastornos del Espectro Alcohólico Fetal/diagnóstico , Humanos , Masculino , Embarazo , Ratas Long-EvansRESUMEN
BACKGROUND: Gestational alcohol exposure causes lifelong physical and neurocognitive deficits collectively referred to as fetal alcohol spectrum disorders (FASDs). Micronutrient deficiencies are common in pregnancies of alcohol-abusing women. Here we show the most common micronutrient deficiency of pregnancy-iron deficiency without anemia-significantly worsens neurocognitive outcomes following perinatal alcohol exposure. METHODS: Pregnant rats were fed iron-deficient (ID) or iron-sufficient diets from gestational day 13 to postnatal day (P) 7. Pups received alcohol (0, 3.5, 5.0 g/kg) from P 4 to P 9, targeting the brain growth spurt. At P 32, learning was assessed using delay or trace eyeblink classical conditioning (ECC). Cerebellar interpositus nucleus (IPN) and hippocampal CA1 cellularity was quantified using unbiased stereology. RESULTS: Global analysis of variance revealed that ID and alcohol separately and significantly reduced ECC learning with respect to amplitude (ps ≤ 0.001) and conditioned response [CR] percentage (ps ≤ 0.001). Iron and alcohol interacted to reduce CR percentage in the trace ECC task (p = 0.013). Both ID and alcohol significantly reduced IPN (ps < 0.001) and CA1 cellularity (ps < 0.005). CR amplitude correlated with IPN cellularity (delay: r = 0.871, trace: r = 0.703, ps < 0.001) and CA1 cellularity (delay: r = 0.792, trace: r = 0.846, ps < 0.001) across both tasks. The learning impairments persisted even though the offsprings' iron status had normalized. CONCLUSIONS: Supporting our previous work, gestational ID exacerbates the associative learning deficits in this rat model of FASD. This is strongly associated with cellular reductions within the ECC neurocircuitry. Significant learning impairments in FASD could be the consequence, in part, of pregnancies in which the mother was also iron inadequate.
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Anemia Ferropénica/patología , Aprendizaje por Asociación/fisiología , Cerebelo/patología , Etanol/toxicidad , Trastornos del Espectro Alcohólico Fetal/patología , Hipocampo/patología , Anemia Ferropénica/complicaciones , Animales , Animales Recién Nacidos , Aprendizaje por Asociación/efectos de los fármacos , Cerebelo/efectos de los fármacos , Condicionamiento Palpebral/efectos de los fármacos , Condicionamiento Palpebral/fisiología , Modelos Animales de Enfermedad , Etanol/administración & dosificación , Femenino , Trastornos del Espectro Alcohólico Fetal/etiología , Hipocampo/efectos de los fármacos , Embarazo , Ratas , Ratas Long-EvansRESUMEN
Fetal alcohol spectrum disorders (FASD) are the leading non-genetic cause of neurodevelopmental disability in children. Although alcohol is clearly teratogenic, environmental factors such as gravidity and socioeconomic status significantly modify individual FASD risk despite equivalent alcohol intake. An explanation for this variability could inform FASD prevention. Here we show that the most common nutritional deficiency of pregnancy, iron deficiency without anemia (ID), is a potent and synergistic modifier of FASD risk. Using an established rat model of third trimester-equivalent binge drinking, we show that ID significantly interacts with alcohol to impair postnatal somatic growth, associative learning, and white matter formation, as compared with either insult separately. For the associative learning and myelination deficits, the ID-alcohol interaction was synergistic and the deficits persisted even after the offsprings' iron status had normalized. Importantly, the observed deficits in the ID-alcohol animals comprise key diagnostic criteria of FASD. Other neurobehaviors were normal, showing the ID-alcohol interaction was selective and did not reflect a generalized malnutrition. Importantly ID worsened FASD outcome even though the mothers lacked overt anemia; thus diagnostics that emphasize hematological markers will not identify pregnancies at-risk. This is the first direct demonstration that, as suggested by clinical studies, maternal iron status has a unique influence upon FASD outcome. While alcohol is unquestionably teratogenic, this ID-alcohol interaction likely represents a significant portion of FASD diagnoses because ID is more common in alcohol-abusing pregnancies than generally appreciated. Iron status may also underlie the associations between FASD and parity or socioeconomic status. We propose that increased attention to normalizing maternal iron status will substantially improve FASD outcome, even if maternal alcohol abuse continues. These findings offer novel insights into how alcohol damages the developing brain.
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Consumo Excesivo de Bebidas Alcohólicas/metabolismo , Etanol/farmacología , Trastornos del Espectro Alcohólico Fetal/metabolismo , Deficiencias de Hierro , Intercambio Materno-Fetal , Complicaciones del Embarazo/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Animales , Animales Recién Nacidos , Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Trastornos del Espectro Alcohólico Fetal/etiología , Trastornos del Espectro Alcohólico Fetal/patología , Trastornos del Espectro Alcohólico Fetal/fisiopatología , Feto/efectos de los fármacos , Número de Embarazos , Aprendizaje/efectos de los fármacos , Embarazo , Complicaciones del Embarazo/fisiopatología , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/patología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ratas , Factores de RiesgoRESUMEN
Children exposed to alcohol prenatally suffer from a range of physical, neuropathological, and behavioral alterations, referred to as fetal alcohol spectrum disorders (FASD). Both the cerebellum and hippocampus are affected by alcohol exposure during development, which may contribute to behavioral and cognitive deficits observed in children with FASD. Despite the known neuropathology associated with prenatal alcohol exposure, many pregnant women continue to drink (heavy drinkers, in particular), creating a need to identify effective treatments for their children who are adversely affected by alcohol. We previously reported that choline supplementation can mitigate alcohol's effects on cognitive development, specifically on tasks which depend on the functional integrity of the hippocampus. The present study examined whether choline supplementation could differentially mitigate alcohol's effects on trace eyeblink classical conditioning (ECC, a hippocampal-dependent task) and delay ECC (a cerebellar-dependent task). Long-Evans rats were exposed to 5.25 g/kg/day alcohol via gastric intubation from postnatal days (PD) 4-9, a period of brain development equivalent to late gestation in humans. A sham-intubated control group was included. From PD 10-30, subjects received subcutaneous injections of 100 mg/kg choline chloride or vehicle. Beginning on PD 32-34, subjects were trained on either delay or trace eyeblink conditioning. Performance of subjects exposed to alcohol was significantly impaired on both tasks, as indicated by significant reductions in percentage and amplitude of conditioned eyeblink responses, an effect that was attenuated by choline supplementation on the trace, but not delay conditioning task. Indeed, alcohol-exposed subjects treated with choline performed at control levels on the trace eyeblink conditioning task. There were no significant main or interactive effects of sex. These data indicate that choline supplementation can significantly reduce the severity of trace eyeblink conditioning deficits associated with early alcohol exposure, even when administered after the alcohol insult is complete. These findings have important implications for the treatment of fetal alcohol spectrum disorders.
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Alcoholes/farmacología , Colina/farmacología , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Palpebral/efectos de los fármacos , Etanol/farmacología , Animales , Femenino , Masculino , Ratas , Ratas Long-EvansRESUMEN
BACKGROUND: Brief heat stimuli that excite nociceptors innervated by finely myelinated (Aδ) fibers evoke an initial, sharp, well-localized pain ("first pain") that is distinguishable from the delayed, less intense, more prolonged dull pain attributed to nociceptors innervated by unmyelinated (C) fibers ("second pain"). In the present study, we address the question of whether a brief, noxious heat stimulus that excites cutaneous Aδ fibers activates a distinct set of forebrain structures preferentially in addition to those with similar responses to converging input from C fibers. Heat stimuli at two temperatures were applied to the dorsum of the left hand of healthy volunteers in a functional brain imaging (fMRI) paradigm and responses analyzed in a set of volumes of interest (VOI). RESULTS: Brief 41°C stimuli were painless and evoked only C fiber responses, but 51°C stimuli were at pain threshold and preferentially evoked Aδ fiber responses. Most VOI responded to both intensities of stimulation. However, within volumes of interest, a contrast analysis and comparison of BOLD response latencies showed that the bilateral anterior insulae, the contralateral hippocampus, and the ipsilateral posterior insula were preferentially activated by painful heat stimulation that excited Aδ fibers. CONCLUSIONS: These findings show that two sets of forebrain structures mediate the initial sharp pain evoked by brief cutaneous heat stimulation: those responding preferentially to the brief stimulation of Aδ heat nociceptors and those with similar responses to converging inputs from the painless stimulation of C fibers. Our results suggest a unique and specific physiological basis, at the forebrain level, for the "first pain" sensation that has long been attributed to Aδ fiber stimulation and support the concept that both specific and convergent mechanisms act concurrently to mediate pain.
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Dolor/fisiopatología , Prosencéfalo/fisiopatología , Adolescente , Adulto , Femenino , Mano/fisiología , Calor , Humanos , Imagen por Resonancia Magnética/métodos , Fibras Nerviosas Mielínicas , Fibras Nerviosas Amielínicas/fisiología , Nociceptores/fisiología , Umbral del Dolor/fisiología , Tiempo de Reacción , Temperatura , Factores de Tiempo , Adulto JovenRESUMEN
Noxious cutaneous contact heat stimuli (48 degrees C) are perceived as increasingly painful when the stimulus duration is extended from 5 to 10s, reflecting the temporal summation of central neuronal activity mediating heat pain. However, the sensation of increasing heat pain disappears, reaching a plateau as stimulus duration increases from 10 to 20s. We used functional magnetic resonance imaging (fMRI) in 10 healthy subjects to determine if active central mechanisms could contribute to this psychophysical plateau. During heat pain durations ranging from 5 to 20s, activation intensities in the bilateral orbitofrontal cortices and the activation volume in the left primary (S1) somatosensory cortex correlated only with perceived stimulus intensity and not with stimulus duration. Activation volumes increased with both stimulus duration and perceived intensity in the left lateral thalamus, posterior insula, inferior parietal cortex, and hippocampus. In contrast, during the psychophysical plateau, both the intensity and volume of thalamic and cortical activations in the right medial thalamus, right posterior insula, and left secondary (S2) somatosensory cortex continued to increase with stimulus duration but not with perceived stimulus intensity. Activation volumes in the left medial and right lateral thalamus, and the bilateral mid-anterior cingulate, left orbitofrontal, and right S2 cortices also increased only with stimulus duration. The increased activity of specific thalamic and cortical structures as stimulus duration, but not perceived intensity, increases is consistent with the recruitment of a thalamocortical mechanism that participates in the modulation of pain-related cortical responses and the temporal summation of heat pain.
Asunto(s)
Dolor/fisiopatología , Corteza Somatosensorial/fisiopatología , Tálamo/fisiopatología , Adulto , Análisis de Varianza , Mapeo Encefálico/métodos , Femenino , Calor , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Dimensión del Dolor/métodos , Umbral del Dolor/fisiologíaRESUMEN
Binge-like ethanol exposure on postnatal days (PD) 4-9 in rodents causes cerebellar cell loss and impaired acquisition of conditioned responses (CRs) during "short-delay" eyeblink classical conditioning (ECC), using optimal (280-350 ms) interstimulus intervals (ISIs). We extended those earlier findings by comparing acquisition of delay ECC under two different ISIs. From PD 4 to 9, rats were intubated with either 5.25 g/kg of ethanol (2/day), sham intubated, or were not intubated. They were then trained either as periadolescents (about PD 35) or as adults (>PD 90) with either the optimal short-delay (280-ms) ISI, a long-delay (880-ms) ISI, or explicitly unpaired CS and US presentations. Neonatal binge ethanol treatment significantly impaired acquisition of conditioning at both ages regardless of ISI, and deficits in the acquisition and expression of CRs were comparable across ISIs. These deficits are consistent with the previously documented ethanol-induced damage to the cerebellar-brainstem circuit essential for Pavlovian ECC.
Asunto(s)
Consumo de Bebidas Alcohólicas , Parpadeo/efectos de los fármacos , Depresores del Sistema Nervioso Central/administración & dosificación , Depresores del Sistema Nervioso Central/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Etanol/administración & dosificación , Etanol/farmacología , Periodicidad , Factores de Edad , Animales , Animales Recién Nacidos , Electromiografía , Distribución Aleatoria , Ratas , Ratas Long-Evans , Factores de TiempoRESUMEN
BACKGROUND: Rodent studies have shown that heavy binge-like ethanol (EtOH) exposure during the brain growth spurt [postnatal days (PD) 4-9] causes cerebellar neuronal loss and deficits in cerebellar-mediated eyeblink classical conditioning (ECC). Oxidative stress has been implicated in EtOH-mediated brain damage, and studies using vitamin E have reported amelioration of EtOH-induced tissue damage, including protection in rats against EtOH-induced cerebellar Purkinje cell (PC) loss on PD 4 to 5. The purpose of this study was to determine whether dietary supplementation with vitamin E concurrent with binge EtOH exposure on PD 4 to 9 in rats would attenuate the cerebellar cell death and ECC deficits. METHODS: Rat pups were given one of five different neonatal treatments: (1) intubation with EtOH in milk formula (twice daily, total dose 5.25 g/kg/day), (2) intubation with EtOH in milk formula supplemented with vitamin E (12.26 mg/kg/feeding), (3) intubation with milk formula that contained vitamin E only, (4) sham intubations, or (5) normally reared unintubated controls. Between PD 26 and 33, subjects received short-delay ECC for 3 consecutive days. Unbiased stereological cell counts were performed on cerebellar PCs of left cerebellar lobules I to VI and neurons of the interpositus nucleus. In a separate study with PD 4 pups, the effects of vitamin E on EtOH-induced expression of caspase-3 active subunits were assessed using Western blot analysis. RESULTS: EtOH-treated groups showed significant deficits in acquisition of conditioned eyeblink responses and reductions in cerebellar PCs and interpositus nucleus neurons compared with controls. Vitamin E supplementation failed to protect against these deficits. Vitamin E also failed to protect against increases in caspase-3 active subunit expression induced by acute binge EtOH exposure on PD 4. CONCLUSIONS: In contrast to the previously reported neuroprotective potential of antioxidants on EtOH-mediated cerebellar damage, vitamin E supplementation did not diminish EtOH-induced structural and functional damage to the cerebellum in this model of binge EtOH exposure during the brain growth spurt in rats.