Cortical Synaptic Reorganization Under Chronic Arsenic Exposure.

There is solid epidemiological evidence that arsenic exposure leads to cognitive impairment, while experimental work supports the hypothesis that it also contributes to neurodegeneration. Energy deficit, oxidative stress, demyelination, and defective neurotransmission are demonstrated arsenic effects, but it remains unclear whether synaptic structure is also affected. Employing both a triple-transgenic Alzheimer's disease model and Wistar rats, the cortical microstructure and synapses were analyzed under chronic arsenic exposure. Male animals were studied at 2 and 4 months of age, after exposure to 3 ppm sodium arsenite in drinking water during gestation, lactation, and postnatal development. Through nuclear magnetic resonance, diffusion-weighted images were acquired and anisotropy (integrity; FA) and apparent diffusion coefficient (dispersion degree; ADC) metrics were derived. Postsynaptic density protein and synaptophysin were analyzed by means of immunoblot and immunohistochemistry, while dendritic spine density and morphology of cortical pyramidal neurons were quantified after Golgi staining. A structural reorganization of the cortex was evidenced through high-ADC and low-FA values in the exposed group. Similar changes in synaptic protein levels in the 2 models suggest a decreased synaptic connectivity at 4 months of age. An abnormal dendritic arborization was observed at 4 months of age, after increased spine density at 2 months. These findings demonstrate alterations of cortical synaptic connectivity and microstructure associated to arsenic exposure appearing in young rodents and adults, and these subtle and non-adaptive plastic changes in dendritic spines and in synaptic markers may further progress to the degeneration observed at older ages.

Pentylenetetrazol-induced seizures in adult rats are associated with plastic changes to the dendritic spines on hippocampal CA1 pyramidal neurons.

Epilepsy is a chronic neurobehavioral disorder whereby an imbalance between neurochemical excitation and inhibition at the synaptic level provokes seizures. Various experimental models have been used to study epilepsy, including that based on acute or chronic administration of Pentylenetetrazol (PTZ). In this study, a single PTZ dose (60 mg/kg) was administered to adult male rats and 30 min later, various neurobiological parameters were studied related to the transmission and modulation of excitatory impulses in pyramidal neurons of the hippocampal CA1 field. Rats experienced generalized seizures 1-3 min after PTZ administration, accompanied by elevated levels of Synaptophysin and Glutaminase. This response suggests presynaptic glutamate release is exacerbated to toxic levels, which eventually provokes neuronal death as witnessed by the higher levels of Caspase-3, TUNEL and GFAP. Similarly, the increase in PSD-95 suggests that viable dendritic spines are functional. Indeed, the increase in stubby and wide spines is likely related to de novo spinogenesis, and the regulation of neuronal excitability, which could represent a plastic response to the synaptic over-excitation. Furthermore, the increase in mushroom spines could be associated with the storage of cognitive information and the potentiation of thin spines until they are transformed into mushroom spines. However, the reduction in BDNF suggests that the activity of these spines would be down-regulated, may in part be responsible for the cognitive decline related to hippocampal function in patients with epilepsy.

Ibotenic acid induced lesions impair the modulation of dendritic spine plasticity in the prefrontal cortex and amygdala, a phenomenon that underlies working memory and social behavior.

The lesions induced by Ibotenic acid (IA) emulate some of the symptoms associated with schizophrenia, such as impaired working memory that is predominantly organized by the medial prefrontal cortex (mPFC), or difficulties in social interactions that aremainly organized by the amygdala (AMG). The plastic capacity of dendritic spines in neurons of the mPFC and AMG is modulated by molecules that participate in the known deterioration of working memory, although the influence of these on the socialization of schizophrenic patients is unknown. Here, the effect of a neonatal IA induced lesion on social behavior and working memory was evaluated in adult rats, along with the changes in cytoarchitecture of dendritic spines and their protein content, specifically the postsynaptic density protein 95 (PSD-95), Synaptophysin (Syn), AMPA receptors, and brain-derived neurotrophic factor (BDNF). Both working memory and social behavior were impaired, and the density of the spines, as well as their PSD-95, Syn, AMPA receptor and BDNF content was lower in IA lesioned animals. The proportional density of thin, mushroom, stubby and wide spines resulted in plastic changes that suggest the activation of compensatory processes in the face of the adverse effects of the lesion. In addition, the reduction in the levels of the modulating factors also suggests that the signaling pathways in which such factors are implicated would be altered in the brains of patients with schizophrenia. Accordingly, the experimental study of such signaling pathways is likely to aid the development of more effective pharmacological strategies for the treatment of schizophrenia.

Pilot study: Evaluation of potential drug-drug interactions in hospitalized pediatric patients.

PURPOSE: Evaluate the type and severity of potential drug-drug interactions and identify risk factors involved, in pediatric patients admitted in a hospital setting. METHODS: Transversal retrospective analytical study was carried out with hospitalized pediatric patients from a Hospital in the West of Mexico, second and third level. The patients included were ≤18 years old hospitalized in the children wards; those admitted at the emergency room, neonatal intermediate and intensive therapy units were not included. Medical prescriptions were reviewed taking into consideration anthropometric characteristics, diagnosis and number of drugs prescribed to identify potential drug-drug interactions using Micromedex 2.0 database. RESULTS: 88 patients were included, an average of 4.6 ± 2.8 of drugs were prescribed per patient. 37 subjects (42%) presented some degree of potential drug-drug interactions of which 25.5% were major and 27.7% moderate according to the software. Identified risk factors were: age ≥ 4 years (OR 1.917; 95% CI 1.081-3.399), BSA ≥ 0.8m2(OR 1.825; 95% CI 1.021-3.263), height ≥ 1 m (OR 2.556;95% CI 1.322 - 4.941), and number of prescribed medications ≥ 4 (OR 2.106;95% CI 1.248 - 3.556). CONCLUSION: Some of the interactions found were for the benefit of the patient, but others were considered undesirable because they altered the pharmacokinetics of some of the medications administered. Detecting in time the harmful interactions for a patient may favor the patient's safety.

HPV genotypes detected by linear array and next-generation sequencing in anal samples from HIV positive men who have sex with men in Mexico.

The incidence of anal cancer has been rising, especially in HIV+ patients and has been associated with HPV infection. HIV+ patients are more at risk of HPV coinfection and are seven times more likely to have persistent HPV infection; moreover, HIV+ men have an increased risk of developing anal cancer compared to HIV+ women. The development of screening strategies for the detection of HPV in HIV+ men is of major importance; however, there is not enough information about the HPV genotypes and variants that are colonizing the anal epithelia of HIV+ men in diverse geographical regions. Therefore, this work was aimed at identifying HPV genotypes present in the anal epithelium of HIV+ men who have sex with men (MSM), with or without anal lesions (n = 75). For HPV genotyping, two approaches were performed: Linear Array HPV Genotyping Test and next-generation sequencing (NGS). In general, the six most frequent HPV genotypes found by Linear Array were HPV6, 62, 61, 81, 16 and 51. On the other hand, employing NGS, a total of 36 HPV genotypes belonging to both alpha and beta genera were found. The genotypes with the greatest number of reads, according to the diagnostic group, were: HPV81, 45, 6, 51 and 61 in MSM without anal lesions (WAIN); HPV6, 61, 70, 62 and 66 in MSM with atypical lesions (AAL); HPV6, 11, 66, 81 and 61 in MSM with anal intraepithelial neoplasia grade I (AIN I); and HPV16, 81, 58, 61 and 52 with AIN III. Additionally, a great diversity of L1 variants was observed, especially in genotypes HPV16, 58, 61, 52, 45 and 59.

Pharmacokinetics and dosing requirements of digoxin in pregnant women treated for fetal supraventricular tachycardia.

BACKGROUND: The objective of this study was to characterize the pharmacokinetics (PK) of digoxin in pregnant women and its potential implications for drug dosing. METHODS: Serum digoxin concentrations (SDCs) obtained in pregnant women treated for fetal supraventricular tachycardia (SVT) was retrospectively collected. PK analysis was comparatively performed using a two-stage approach (PKS™) and a Population PK approach (NONMEM™). As clinical outcome the fetal heart rate was recorded. RESULTS: A total of 42 SDCs were obtained from 8 women in the 3rd trimester of pregnancy (mean age 33.0 years). The PK parameters estimated by both two-stage (volume of distribution (Vd) = 682.0 L, CV = 47.5%; serum clearance (CL) = 16.1 L/h, CV = 19%) and population approaches (Vd = 731.3 L, CV = 30.5%; CL = 18.7 L/h, CV = 17.8%) are very similar and show a clear trend of increasing drug disposition in the third trimester of pregnancy. An oral loading dose of 0.5 mg/8 h during 24 h followed by a maintenance regimen of 0.5 mg/12 h been recommended to start treatment. CONCLUSIONS: Despite the small population, these parameters could be used as a guide to calculate the initial dosage requirements in the third trimester of pregnancy for treating fetal SVT. In addition, maternal SDCs should be routinely monitored for dosage adjustment purposes.

Capturing change in a community--university partnership: Si Se Puede! Project.

BACKGROUND: Community health interventions are increasingly employing partnerships combined with multilevel intervention models to achieve their objectives. Resources and methods for project evaluation are often limited to changes in population health status or health behaviors, while broader contextual questions that may illuminate mechanisms for change across ecological levels and project sustainability may not be addressed. CONTEXT: This paper describes a project to prevent and control diabetes in a Latino community and presents practical methods for addressing some challenges to evaluation, using data sources that often may be overlooked. METHODS: A case study method was used to examine approaches to capture data that can help explain changes across ecological levels. An ecological framework was used to organize sources of data. Data sources and findings are related to project timelines and goals. CONSEQUENCES: Although not a direct focus of the original research, substantial changes in community capacity were observed and measured over the course of the five-year project. Documentation on community change was found in routine project reports, logs, the news media, meeting minutes, and community documents. INTERPRETATION: A logical progression of community change across ecological levels became evident. A modest post hoc evaluation was feasible, using data routinely available from project and target community sources. Specific questions for future research on how community change occurs and how such changes may relate to population health and sustainability are suggested.