Tributyrin reverses the deleterious effect of saturated fat on working memory and synaptic plasticity in juvenile mice: differential effects in males and females.

Short-chain fatty acids, such as butyric acid, derived from the intestinal fermentation of dietary fiber, have been proposed as a treatment for certain pathologies of the central nervous system. Our research group has shown that tributyrin (TB), a butyric acid prodrug, reverses deficits in spatial memory and modulates hippocampal synaptic plasticity. In the present work, diets enriched in either saturated (SOLF; Saturated OiL-enriched Food) or unsaturated (UOLF; Unsaturated OiL-enriched Food) fat were supplied during either 2 h or 8 weeks to 5-week-old male and female mice undergoing a treatment schedule with TB. After the dietary treatment, spatial learning and memory (SLM) was assessed in both the Y-maze and the eight-arm radial maze (RAM). Hippocampal expression of genes involved in glutamatergic transmission as well as synaptic plasticity (long-term potentiation -LTP- and long-term depression -LTD-) were also analyzed. Our results show that 2 h of SOLF intake impaired LTP as well as the performance in the Y-Maze in juvenile male mice whereas no effect was found in females. Moreover, TB reversed both effects in SLM and LTP in males. In the case of chronic intake, both SOLF and UOLF deteriorated SLM measured in the RAM in both sexes whereas TB only reversed LTP impairment induced by SOLF in male mice. These results suggest that TB may have a potentially beneficial influence on learning and memory processes, contingent upon the type of diet and the sex of the individuals.

Schedule-induced alcohol intake during adolescence sex dependently impairs hippocampal synaptic plasticity and spatial memory.

In a previous study, we demonstrated that intermittent ethanol administration in male adolescent animals impaired hippocampus-dependent spatial memory, particularly under conditions of excessive ethanol administration. In this current study, we subjected adolescent male and female Wistar rats an alcohol schedule-induced drinking (SID) procedure to obtain an elevated rate of alcohol self-administration and assessed their hippocampus-dependent spatial memory. We also studied hippocampal synaptic transmission and plasticity, as well as the expression levels of several genes involved in these mechanisms. Both male and female rats exhibited similar drinking patterns throughout the sessions of the SID protocol reaching similar blood alcohol levels in all the groups. However, only male rats that consumed alcohol showed spatial memory deficits which correlated with inhibition of hippocampal synaptic plasticity as long-term potentiation. In contrast, alcohol did not modify hippocampal gene expression of AMPA and NMDA glutamate receptor subunits, although there are differences in the expression levels of several genes relevant to synaptic plasticity mechanisms underlying learning and memory processes, related to alcohol consumption as Ephb2, sex differences as Pi3k or the interaction of both factors such as Pten. In conclusion, elevated alcohol intake during adolescence seems to have a negative impact on spatial memory and hippocampal synaptic plasticity in a sex dependent manner, even both sexes exhibit similar blood alcohol concentrations and drinking patterns.

Effects of saturated versus unsaturated fatty acids on metabolism, gliosis, and hypothalamic leptin sensitivity in male mice.

BACKGROUND: Development of obesity and its comorbidities is not only the result of excess energy intake, but also of dietary composition. Understanding how hypothalamic metabolic circuits interpret nutritional signals is fundamental to advance towards effective dietary interventions. OBJECTIVE: We aimed to determine the metabolic response to diets enriched in specific fatty acids. METHODS: Male mice received a diet enriched in unsaturated fatty acids (UOLF) or saturated fatty acids (SOLF) for 8 weeks. RESULTS: UOLF and SOLF mice gained more weight and adiposity, but with no difference between these two groups. Circulating leptin levels increased on both fatty acid-enriched diet, but were higher in UOLF mice, as were leptin mRNA levels in visceral adipose tissue. In contrast, serum non-esterified fatty acid levels only rose in SOLF mice. Hypothalamic mRNA levels of NPY decreased and of POMC increased in both UOLF and SOLF mice, but only SOLF mice showed signs of hypothalamic astrogliosis and affectation of central fatty acid metabolism. Exogenous leptin activated STAT3 in the hypothalamus of all groups, but the activation of AKT and mTOR and the decrease in AMPK activation in observed in controls and UOLF mice was not found in SOLF mice. CONCLUSIONS: Diets rich in fatty acids increase body weight and adiposity even if energy intake is not increased, while increased intake of saturated and unsaturated fatty acids differentially modify metabolic parameters that could underlie more long-term comorbidities. Thus, more understanding of how specific nutrients affect metabolism, weight gain, and obesity associated complications is necessary.

Saturated and unsaturated triglyceride-enriched diets modify amino acid content in the mice hippocampus.

Elevated intake of fat modulates l-glutamate (l-Glu) turnover within the hippocampus (HIP). Our aim has been to investigate the effect of saturated vs unsaturated fat on the content of l-Glu and other amino acids involved in synaptic transmission within the HIP. The study was carried out in male mice fed (2 h or 8 weeks) with standard chow or with diets enriched either with saturated (SOLF) or unsaturated triglycerides (UOLF). An in vitro assay was performed in HIP slices incubated with palmitic (PA), oleic (OA), or lauric acid (LA). Amino acids were quantified by capillary electrophoresis. While both diets increased the amount of l-Glu and l-aspartate and decreased l-glutamine levels, only UOLF affected d-serine and taurine levels. γ-Aminobutyric acid was specifically decreased by SOLF. In vitro assays revealed that PA and OA modified l-Glu, glycine, l-serine and d-serine concentration. Our results suggest that fatty acids contained in SOLF and UOLF have an impact on HIP amino acid turnover that may account, at least partially, for the functional changes evoked by these diets.

Butyric Acid Precursor Tributyrin Modulates Hippocampal Synaptic Plasticity and Prevents Spatial Memory Deficits: Role of PPARγ and AMPK.

BACKGROUND: Short chain fatty acids (SCFA), such as butyric acid (BA), derived from the intestinal fermentation of dietary fiber and contained in dairy products, are gaining interest in relation to their possible beneficial effects on neuropsychological disorders. METHODS: C57BL/6J male mice were used to investigate the effect of tributyrin (TB), a prodrug of BA, on hippocampus (HIP)-dependent spatial memory, HIP synaptic transmission and plasticity mechanisms, and the expression of genes and proteins relevant to HIP glutamatergic transmission. RESULTS: Ex vivo studies, carried out in HIP slices, revealed that TB can transform early-LTP into late-LTP (l-LTP) and to rescue LTP-inhibition induced by scopolamine. The facilitation of l-LTP induced by TB was blocked both by GW9662 (a PPARγ antagonist) and C-Compound (an AMPK inhibitor), suggesting the involvement of both PPARγ and AMPK on TB effects. Moreover, 48-hour intake of a diet containing 1% TB prevented, in adolescent but not in adult mice, scopolamine-induced impairment of HIP-dependent spatial memory. In the adolescent HIP, TB upregulated gene expression levels of Pparg, leptin, and adiponectin receptors, and that of the glutamate receptor subunits AMPA-2, NMDA-1, NMDA-2A, and NMDA-2B. CONCLUSIONS: Our study shows that TB has a positive influence on LTP and HIP-dependent spatial memory, which suggests that BA may have beneficial effects on memory.

Identification by proximity labeling of novel lipidic and proteinaceous potential partners of the dopamine transporter.

Dopamine (DA) transporters (DATs) are regulated by trafficking and modulatory processes that probably rely on stable and transient interactions with neighboring proteins and lipids. Using proximity-dependent biotin identification (BioID), we found novel potential partners for DAT, including several membrane proteins, such as the transmembrane chaperone 4F2hc, the proteolipid M6a and a potential membrane receptor for progesterone (PGRMC2). We also detected two cytoplasmic proteins: a component of the Cullin1-dependent ubiquitination machinery termed F-box/LRR-repeat protein 2 (FBXL2), and the enzyme inositol 5-phosphatase 2 (SHIP2). Immunoprecipitation (IP) and immunofluorescence studies confirmed either a physical association or a close spatial proximity between these proteins and DAT. M6a, SHIP2 and the Cullin1 system were shown to increase DAT activity in coexpression experiments, suggesting a functional role for their association. Deeper analysis revealed that M6a, which is enriched in neuronal protrusions (filopodia or dendritic spines), colocalized with DAT in these structures. In addition, the product of SHIP2 enzymatic activity (phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2]) was tightly associated with DAT, as shown by co-IP and by colocalization of mCherry-DAT with a specific biosensor for this phospholipid. PI(3,4)P2 strongly stimulated transport activity in electrophysiological recordings, and conversely, inhibition of SHIP2 reduced DA uptake in several experimental systems including striatal synaptosomes and the dopaminergic cell line SH-SY5Y. In summary, here we report several potential new partners for DAT and a novel regulatory lipid, which may represent new pharmacological targets for DAT, a pivotal protein in dopaminergic function of the brain.

Dosimetric analysis of rectal filling on rectal doses during vaginal cuff brachytherapy.

PURPOSE: Several studies have analyzed the effect of bladder filling during vaginal cuff brachytherapy (VCB), but the effect of rectum filling has not been studied. We sought to evaluate the effects of rectal volume on rectal doses during postoperative VCB. METHODS AND MATERIALS: Brachytherapy planning CT scans (334 sets) obtained from 92 consecutive patients treated with VCB were resegmented (bladder and rectum) and replanned retrospectively using the same parameters to homogenize data and improve analysis. Rectal volume and a set of values derived from dose-volume histograms (DVHs) were extracted (maximal dose [Dmax], D0.1cc, D1cc, and D2cc). Univariate and multivariate analyses were carried out to evaluate the association between rectal volume and DVH metrics after adjusting for other clinical factors. RESULTS: A positive significant correlation was observed between rectal volume correlated and Dmax, D0.1cc, D1cc, and D2cc. Multiple linear regression models found that rectal volume, cylinder angle position, and cylinder diameter variables correlated significantly with the different DVH parameters analyzed. These variables explained the 14.5% and 18% of variance on regression models. CONCLUSIONS: Larger rectal volumes are associated with higher rectal dose parameters during VCB fractions. Prospective studies are needed to investigate whether these data are linked to differences in rectal toxicity.

Body Mass Index and Doses at Organs at Risk in a Mediterranean Population Treated with Postoperative Vaginal Cuff Brachytherapy.

PURPOSE: Association between body mass index (BMI) and doses in organs at risk during postoperative vaginal cuff brachytherapy (VCB) treatment has not been evaluated. The aim of this study was to analyse the impact of BMI on the dose delivered to bladder and rectum during high-dose-rate VCB using computed tomography (CT) scans at every fraction. MATERIALS AND METHODS: A retrospective analysis of 220 planning CT sets derived from 59 patients was conducted. Every planning CT was re-segmented and re-planned under the same parameters. Rectum and bladder dose-volume histogram values (D0.1cc, D1cc, and D2cc) were extracted and evaluated. The mean values for all applications per patient were calculated and correlated with BMI, as well as other factors influencing rectal and bladder doses. Multiple regression analysis performed to model organ at risk dose-volume parameters. RESULTS: According to World Health Organization (WHO), 6.8% of patients were normal, 35.6% were overweight, and 57.6% were class I obese. Median rectal doses were 133.5%, 110.9%, and 99.3% for D0.1cc, D1cc, and D2cc, respectively. The corresponding median bladder doses were 96.2%, 80.6%, and 73.3%, respectively. BMI did not show significant association with rectal doses. However, BMI did show a significant association with evaluated bladder dose metrics (D0.1cc, r=-0.366, p=0.004; D1cc, r=-0.454, p < 0.001; D2cc, r=-0.451, p < 0.001). BMI was retained in the multivariate regression models (D0.1cc, p=0.004; D1cc, p < 0.001; D2cc, p=0.001). CONCLUSION: In this group of Mediterranean, overweight, and moderately obese patients, BMI showed association with lower bladder dose values, but not with rectal doses.

How air influences radiation dose deposition in multiwell culture plates: a Monte Carlo simulation of radiation geometry.

Radiation of experimental culture cells on plates with various wells can cause a risk of underdosage as a result of the existence of multiple air-water interfaces. The objective of our study was to quantify this error in culture plates with multiple wells. Radiation conditions were simulated with the GAMOS code, based on the GEANT4 code, and this was compared with a simulation performed with PENELOPE and measured data. We observed a slight underdosage of ∼ 4% on the most superficial half of the culture medium. We believe that this underdosage does not have a significant effect on the dose received by culture cells deposited in a monolayer and adhered to the base of the wells.

Hábitos de alimentación en pacientes atendidos en un servicio de salud mental / Food habits in patients attended in a mental health service

Este trabajo tiene como objetivo conocer los hábitos de alimentación de la población adulta que consulta en un Servicio de Salud Mental, así como establecer relaciones entre los hábitos alimentarios y las variables clínicas, sociodemográficas, relacionales y el grado de satisfacción con la propia pauta alimenticia, peso e imagen corporal. Para ello se empleó un diseño observacional con una muestra de 175 pacientes (siendo un 39,7% casos nuevos) que consultan en el C.S.M. de Parla entre febrero y junio de 2009, siendo 29,1% varones y 70,9% mujeres. Se administró un protocolo de recogida de datos heteroaplicado. La distribución agrupada de los diagnósticos fue: 25,7% trastornos afectivos, 18,9% trastornos neuróticos, 28,6% trastornos reactivos, 8% trastornos de personalidad, 9,1% trastornos psicóticos, 4% trastornos alimentarios y el 5,7% restante otros diagnósticos. La variedad de la ingesta resulta incompleta (media de platos en la comida: 1,83, D.T.: 0,66; media de platos en la cena: 1,44, D.T.: 0,64). Encontramos una correlación significativa y positiva (p<0,01) en la preferencia de determinados alimentos (verduras, fruta, legumbres, pescado, por un lado; y pasta, carne, fiambres, por otro). El IMC medio fue 25,48 (D.T.: 4,93). Se encontraron diferencias significativas (χ2:31,94; p=0,004) en cuanto a la satisfacción con la propia imagen en función del diagnóstico, están más insatisfechos los trastornos alimentarios (71,4% poco satisfechos), de personalidad (64,3%) y neuróticos (42,4%). De estos datos concluimos que existen deficiencias en la organización, cantidad y calidad de los hábitos alimentarios de los pacientes, a cuya mejora seria necesario prestar atención (AU)

This work aims to study nourishment habits of adult population who consults in a Mental Health Service, as well as establish relations among food habits and clinical and demographic variables and the satisfaction level to the own nourishing pattern, weight and body image. For it we used a observation design with a sample of 175 patients (being 39,7 % new cases) that consult in the Mental Health Center of Parla between February and June 2009, being 29,1 % males and 70,9 % women. We used a heteroapplied proctocol for data collection. The grouped distribution of diagnoses was: 25,7 % affective disorders, 18,9 % neurotic disorders, 28,6 % adaptative disorders, 8% personality disorders, 9,1 % psychotic disorders, 4 % eating disorders and 5,7 % remaining other diagnoses. The variety of food turned out to be incomplete (average of plates in the food: 1,83, S.D.: 0,66; average of plates in the dinner: 1,44, S.D.: 0,64). We found a significant and positive correlation (p < 0,01) in the preference of certain food (vegetables, fruit, vegetables, fish, on the one hand; and noodles, meat, cold cuts, for other one). The average CMI was 25,48 (D.T.: 4,93). We found significant differences ((χ2:31,94; p=0,004) as for the satisfaction with the own image depending on the diagnosis, being the eating disorders the most unsatisfied group (71,4% slightly satisfied), followed by personality disorders (64,3 %) and neurotic disorders (42,4 %). We conclude that exist deficiencies in the organization, quantity and quality of the food habits of the patients, so it would be necessary to give more attention for its improvement (AU)

Diabetes mellitus en inmigrantes indostanos jóvenes. Un estudio descriptivo / Diabetes mellitus in young immigrants from hindustan. A descriptive study

Objetivo: analizar las características fisiopatológicas y clínicas de la diabetes mellitus (DM) en pacientes inmigrantes indostanos jóvenes. Material y métodos: Diabéticos indostanos de 15-40 años. Analisis descriptivo de variables clínicas y analíticas relacionadas con la DM. Cálculo del índice de masa corporal (IMC) y el perímetro de la cintura(PC). Estudio de la inmunología de la DM, péptido C basal y resistencia ala insulina (RI) mediante el Homeostasis Model Assessment: Insulin Resistance (HOMA-IR).Resultados: Muestra final de 30 casos. Prevalencia de DM del 0,84%.Todos los casos fueron DM2, el 50% con manifiesta RI. Secreción basal depéptido C conservada en todos los casos. El IMC > 25 y el PC > 95 cm fueron los puntos de corte que mejor predijeron la RI en este grupoétnico. Conclusiones: La mayoría de los sujetos diabéticos indostanos jóvenes presentan DM2 con reserva insulínica basal conservada y RI. Grados menores de obesidad que en la población española ya se relacionan con RI (AU)

Aim: To analyze the physiological and clinical characteristics of diabetes mellitus(DM) in young immigrants from Hindustan. Material and methods: We performed a descriptive analysis of clinical and laboratory variables related to DM indiabetic Hindustanis aged between 15 and40 years old. Body mass index (BMI) and waist perimeter (WP) were calculated. The immunology of DM and baseline C-peptide were studied and insulin resistance (IR)was determined by Homeostasis Model Assessment: Insulin Resistance (HOMA-IR).Results: The final sample consisted of 30patients. The prevalence of DM was 0.84%.All patients had DM2 and 50% had high IR. aseline C-peptide secretion wasp reserved in all patients. The cut-off points that best predicted IR in this ethnic group were a BMI higher than 25 and a WC of more than 95 cm. Conclusions: Most young Hindustani immigrants with diabetes have DM2 with preserved baseline insulin secretion and IR. Lower degrees of obesity than in the Spanish population were associated withIR (AU)

Diabetes mellitus in young immigrants from hindustan. A descriptive study.

AIM: To analyze the physiological and clinical characteristics of diabetes mellitus (DM) in young immigrants from Hindustan. MATERIAL AND METHODS: We performed a descriptive analysis of clinical and laboratory variables related to DM in diabetic Hindustanis aged between 15 and 40 years old. Body mass index (BMI) and waist perimeter (WP) were calculated. The immunology of DM and baseline C-peptide were studied and insulin resistance (IR) was determined by Homeostasis Model Assessment: Insulin Resistance (HOMA-IR). RESULTS: The final sample consisted of 30 patients. The prevalence of DM was 0.84%. All patients had DM2 and 50% had high IR. Baseline C-peptide secretion was preserved in all patients. The cut-off points that best predicted IR in this ethnic group were a BMI higher than 25 and a WC of more than 95 cm. CONCLUSIONS: Most young Hindustani immigrants with diabetes have DM2 with preserved baseline insulin secretion and IR. Lower degrees of obesity than in the Spanish population were associated with IR.

Acute effects of maprotiline on learning, anxiety, activity and analgesia in male and female mice.

The acute effects of maprotiline (2.5, 5, 10, 15, 20 or 25 mg/kg) on learning, anxiety, activity and analgesia in male and female mice were evaluated. In addition to inhibitory avoidance learning, anxiety and locomotor activity were measured in the same animals using an elevated plus-maze. A study of the acute effects of maprotiline (15, 20 or 25 mg/kg) on analgesia was carried out in naive animals of both sexes. Maprotiline impaired inhibitory avoidance at doses of 15, 20 or 25 mg/kg. The highest dose produced an anxiolytic effect in females, and the doses of 20 and 25 mg/kg reduced locomotor activity. Analgesia was observed with the highest dose. The impairment of inhibitory avoidance by maprotiline would seem to be independent of the drug's influence on anxiety, is not shadowed by an instrumental performance deficit and, at least in the case of the highest dose, could be influenced by the drug's effects on analgesia. It is hypothesized that acquisition is the memory process principally affected by maprotiline, and in particular stimuli processing. The lack of sex differences in the effects of maprotiline on inhibitory avoidance supports the generalization of findings previously obtained only in males.

Are the effects of the antidepressants amitriptyline, maprotiline, and fluoxetine on inhibitory avoidance state-dependent?

State-dependent learning (SDL) is a phenomenon in which the retrieval of newly acquired information is possible if the subject is in the same physiological state as during the encoding phase. SDL makes it possible to separate the effects of drugs per se on learning from the effects due to changes in drug state during the task. The present work was designed to investigate whether the antidepressants amitriptyline (30 mg/kg), maprotiline (25 mg/kg), and fluoxetine (15 mg/kg) produce SDL of the inhibitory avoidance conditioning in male and female CD1 mice. In three separate experiments, independent groups were used for each pharmacological treatment and for each sex using a 2 x 2 experimental design. The results do not show SDL in any of the drugs. In the case of amitriptilyline, the data can be attributed to a memorization deficit, while the maprotiline results are interpreted as simultaneously influenced by memorization deficit and performance facilitation due to motor impairment. Fluoxetine treatment did not produce any deteriorating effect on the conditioning. Drugs had some different effects on the performance of males and females, males showing a slightly higher deterioration than females with administration of amitriptyline and maprotiline. This study shows that these antidepressants affect the acquisition/consolidation but not the retrieval process in the inhibitory avoidance learning.

Prevalencia de hepatitis virales en inmigrantes adultos pakistaníes atendidos en un centro de salud / Prevalence of viral hepatitis in a Pakistani population of immigrant adults attended in a health center

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