Chronic social defeat stress in prairie voles (Microtus ochrogaster): A preclinical model for the study of depression-related phenotypes.

BACKGROUND: Stress-induced illnesses, like major depression, are among the leading causes of disability across the world. Consequently, there is a dire need for the validation of translationally-suited animal models incorporating social stress to uncover the etiology of depression. Prairie voles (Microtus ochrogaster) are more translationally relevant than many other rodent models as they display monogamous social and bi-parental behaviors. Therefore, we evaluated whether a novel social defeat stress (SDS) model in male prairie voles induces depression-relevant behavioral outcomes. METHODS: Adult sexually-naïve male prairie voles experienced SDS bouts from a conspecific pair-bonded male aggressor, 10 min per day for 10 consecutive days. Non-stressed controls (same-sex siblings) were housed in similar conditions but never experienced physical stress. Twenty-four h later, voles were evaluated in social interaction, sucrose preference, and Morris water maze tests - behavioral endpoints validated to assess social withdrawal, anhedonia-related behavior, and spatial memory performance, respectively. RESULTS: SDS-exposed voles displayed lower sociability and body weight, decreased preference for a sucrose solution, and impairment of spatial memory retrieval. Importantly, no differences in general locomotor activity were observed as a function of SDS exposure. LIMITATIONS: This study does not include female voles in the experimental design. CONCLUSIONS: We found that repeated SDS exposure, in male prairie voles, results in a depression-relevant phenotype resembling an anhedonia-like outcome (per reductions in sucrose preference) along with social withdrawal and spatial memory impairment - highlighting that the prairie vole is a valuable model with potential to study the neurobiology of social stress-induced depression-related outcomes.

Sex-Specific Alterations in Spatial Memory and Hippocampal AKT-mTOR Signaling in Adult Mice Pre-exposed to Ketamine and/or Psychological Stress During Adolescence.

Background: Ketamine (KET) is administered to manage major depression in adolescent patients. However, the long-term effects of juvenile KET exposure on memory-related tasks have not been thoroughly assessed. We examined whether exposure to KET, psychological stress, or both results in long-lasting alterations in spatial memory in C57BL/6 mice. Furthermore, we evaluated how KET and/or psychological stress history influenced hippocampal protein kinase B-mechanistic target of rapamycin (AKT-mTOR)-related signaling. Methods: On postnatal day 35, male and female mice underwent vicarious defeat stress (VDS), a form of psychological stress that reduces sociability in both sexes, with or without KET exposure (20 mg/kg/day, postnatal days 35-44). In adulthood (postnatal day 70), mice were assessed for spatial memory performance on a water maze task or euthanized for hippocampal tissue collection. Results: Juvenile pre-exposure to KET or VDS individually increased the latency (seconds) to locate the escape platform in adult male, but not female, mice. However, juvenile history of concomitant KET and VDS prevented memory impairment. Furthermore, individual KET or VDS pre-exposure, unlike their combined history, decreased hippocampal AKT-mTOR signaling in adult male mice. Conversely, KET pre-exposure alone increased AKT-mTOR in the hippocampus of adult female mice. Lastly, rapamycin-induced decreases of mTOR in naïve adult female mice induced spatial memory retrieval deficits, mimicking adult male mice with a history of exposure to VDS or KET. Conclusions: Our preclinical model shows how KET treatment for the management of adolescent psychological stress-induced sequelae does not impair spatial memory later in life. However, juvenile recreational KET misuse, like psychological stress history, results in long-term spatial memory deficits and hippocampal AKT-mTOR signaling changes in a sex-specific manner.

Recommendations of the Spanish Society of Nephrology for the management of mineral and bone metabolism disorders in patients with chronic kidney disease: 2021 (SEN-MM).

As in 2011, when the Spanish Society of Nephrology (SEN) published the Spanish adaptation to the Kidney Disease: Improving Global Outcomes (KDIGO) universal Guideline on Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), this document contains an update and an adaptation of the 2017 KDIGO guidelines to our setting. In this field, as in many other areas of nephrology, it has been impossible to irrefutably answer many questions, which remain pending. However, there is no doubt that the close relationship between the CKD-MBD/cardiovascular disease/morbidity and mortality complex and new randomised clinical trials in some areas and the development of new drugs have yielded significant advances in this field and created the need for this update. We would therefore highlight the slight divergences that we propose in the ideal objectives for biochemical abnormalities in the CKD-MBD complex compared to the KDIGO suggestions (for example, in relation to parathyroid hormone or phosphate), the role of native vitamin D and analogues in the control of secondary hyperparathyroidism and the contribution of new phosphate binders and calcimimetics. Attention should also be drawn to the adoption of important new developments in the diagnosis of bone abnormalities in patients with kidney disease and to the need to be more proactive in treating them. In any event, the current speed at which innovations are taking place, while perhaps slower than we might like, globally drives the need for more frequent updates (for example, through Nefrología al día).

Ecological risk assessment associated with five endocrine-disrupting compounds in wastewater treatment plants of Northeast Mexico.

The ecological risk associated with five endocrine-disrupting compounds (EDCs) was studied in four wastewater treatment plants (WWTPs) in Monterrey, Mexico. The EDCs, 17ß-estradiol (E2), 17α-ethinylestradiol (EE2), bisphenol A (BPA), 4-nonylphenol (4NP), and 4-tert-octylphenol (4TOP) were determined by SPE/GC-MS method, where EE2 and 4TOP were the most abundant in effluents at levels from 1.6 - 26.8 ng/L (EE2) and < LOD - 5.0 ng/L (4TOP), which corroborate that the wastewater discharges represent critical sources of EDCs to the aquatic environments. In this study, the potential risk associated with selected EDCs was assessed through the risk quotients (RQs) and by estimating the estrogenic activity (expressed as EEQ). This study also constitutes the first approach for the ecological risk assessment in effluents of WWTPs in Northeast Mexico. The results demonstrated that the effluents of the WWTPs represent a high risk for the organisms living in the receiving water bodies because the residual estrogens effect E2 and EE2 with RQ values up to 49.1 and 1165.2. EEQ values between 6.3 and 24.6 ngEE2/L were considered the most hazardous compounds among the target EDCs, capable of causing some alterations in the endocrine system of aquatic and terrestrial organisms due to chronic exposition.

Development of an HPLC-DAD method for the simultaneous analysis of four xenoestrogens in water and its application for monitoring photocatalytic degradation.

A high-performance liquid chromatography with diode array detector (HPLC-DAD) method was developed and validated for the simultaneous quantification of 4 xenoestrogens in water for monitoring their photocatalytic degradation in synthetic water. The analytical parameters evaluated were linearity, limits of detection, and quantification (LODs and LOQs), selectivity, and accuracy, according to the US Food and Drug Administration (FDA) and Eurachem guidelines. The developed method shows good linearity (R2 > 0.995 for all compounds), and LODs ranged from 0.02 to 0.04 mg L-1, while LOQs ranged from 0.05 to 0.11 mg L-1. Moreover, accuracy expressed as recovery and precision were within the required limits. Therefore, the developed method was considered accurate, and reliable. In addition, it was successfully applied for monitoring a mixture of 4 xenoestrogens in water during the photocatalytic treatment.•An HPLC-DAD method was developed to quantify 4 xenoestrogens in water simultaneously.•The developed HPLC-DAD method shows excellent linearity, selectivity, and accuracy.•A mixture of 4 xenoestrogens was reliably monitored during their photocatalytic degradation.

Adolescent fluoxetine exposure increases ERK-related signaling within the prefrontal cortex of adult male Sprague-Dawley rats.

There has been a disproportionate increase in fluoxetine (FLX) prescription rates within the juvenile population. Thus, we evaluated how adolescent FLX exposure alters expression/phosphorylation of proteins from the extracellular signal regulated kinase (ERK)-1/2 cascade within the adult prefrontal cortex (PFC). Male Sprague-Dawley rats were exposed to FLX (20 mg/kg) for 15 consecutive days (postnatal-day [PD] 35-49). At PD70 (adulthood), we examined protein markers for ERK1/2, ribosomal S6 kinase (RSK), and mammalian target of rapamycin (mTOR). FLX-pretreatment decreased body weight, while increasing PFC phosphorylation of ERK1/2 and RSK, as well as total mTOR protein expression in adulthood. We provide first-line evidence that juvenile FLX-pretreatment induces long-term decreases in body weight-gain, along with neurobiological changes in the adult PFC - highlighting that early-life antidepressant exposure increases ERK-related signaling markers in later life.

Autophagy Induction and Accumulation of Phosphorylated Tau in the Hippocampus and Prefrontal Cortex of Adult C57BL/6 Mice Subjected to Adolescent Fluoxetine Treatment.

BACKGROUND: Fluoxetine (FLX) represents the antidepressant of choice for the management of pediatric mood-related illnesses. Accumulating preclinical evidence suggests that ontogenic FLX exposure leads to deregulated affect-related phenotypes in adulthood. Mood-related symptomatology constitutes a risk-factor for various neurological disorders, including Alzheimer's disease (AD), making it possible for juvenile FLX history to exacerbate the development of neurodegenerative diseases. OBJECTIVE: Because AD is characterized by the pathological accumulation of hyperphosphorylated tau, which can result from impaired function of protein degradation pathways, such as autophagy and the ubiquitin-proteasome system (UPS), we evaluated the long-term effects of adolescent FLX exposure on these pathways, using mice as a model system. METHODS: We subjected C57BL/6 adolescent male mice to FLX (20 mg/kg/day) from postnatal day (PD) 35 to PD49. Twenty-one days after the last FLX injection (i.e., adulthood; PD70), mice were euthanized and, using immunoblotting analysis, we evaluated protein markers of autophagy (Beclin-1, LC3-II, p62) and the UPS (K48-pUb), as well as AD-associated forms of phosphorylated tau, within the hippocampus and prefrontal cortex. RESULTS: Juvenile FLX pre-exposure mediated long-term changes in the expression of protein markers (increased LC3-II and decreased p62) that is consistent with autophagy activation, particularly in the prefrontal cortex. Furthermore, FLX history induced persistent accumulation of AD-associated variants of tau in both the hippocampus and prefrontal cortexConclusion: Adolescent FLX treatment may have enduring effects in the neuronal protein degradation machinery, which could adversely influence clearance of abnormal proteins, potentially predisposing individuals to developing AD in later life.

Adolescent fluoxetine treatment mediates a persistent anxiety-like outcome in female C57BL/6 mice that is ameliorated by fluoxetine re-exposure in adulthood.

The objective of this study was to evaluate whether juvenile fluoxetine (FLX) exposure induces long-term changes in baseline responses to anxiety-inducing environments, and if so, whether its re-exposure in adulthood would ameliorate this anxiety-like phenotype. An additional goal was to assess the impact of adolescent FLX pretreatment, and its re-exposure in adulthood, on serotonin transporters (5-HTT) and brain-derived-neurotrophic-factor (BDNF)-related signaling markers (TrkB-ERK1/2-CREB-proBDNF-mBDNF) within the hippocampus and prefrontal cortex. To do this, female C57BL/6 mice were exposed to FLX in drinking water during postnatal-days (PD) 35-49. After a 21-day washout-period (PD70), mice were either euthanized (tissue collection) or evaluated on anxiety-related tests (open field, light/dark box, elevated plus-maze). Juvenile FLX history resulted in a persistent avoidance-like profile, along with decreases in BDNF-signaling markers, but not 5-HTTs or TrkB receptors, within both brain regions. Interestingly, FLX re-exposure in adulthood reversed the enduring FLX-induced anxiety-related responses across all behavioral tasks, while restoring ERK2-CREB-proBDNF markers to control levels and increasing mBDNF within the prefrontal cortex, but not the hippocampus. Collectively, these results indicate that adolescent FLX history mediates neurobehavioral adaptations that endure into adulthood, which are indicative of a generalized anxiety-like phenotype, and that this persistent effect is ameliorated by later-life FLX re-exposure, in a prefrontal cortex-specific manner.

Characterization of proinflammatory markers in the ventral tegmental area across mouse models of chronic stress.

Despite the high prevalence of major depressive disorder (MDD), understanding of the biological underpinnings remains limited. Rodent models suggest that changes in activity and output of dopamine (DA) neurons in the ventral tegmental area (VTA) are important for depressive-like phenotypes. Additionally, brain inflammatory processes are thought to contribute to MDD pathology and inflammation in the VTA has been linked to changes in VTA DA neuronal activity. Thus, we sought to determine whether there is increased inflammatory signaling in the VTA following forms of chronic stress that induce depressive-like symptoms. First, we subjected male mice to either physical or vicarious chronic social defeat stress (CSDS), paradigms known to induce long-term depressive-like behavior and changes in VTA signaling. Second, we subjected male and female mice to subchronic variable stress (SCVS), a paradigm that induces depressive-like behavior only in female mice. We then isolated mRNA from the VTA and assessed proinflammatory gene regulation via RT-PCR. Our results show that physical, but not vicarious, CSDS increases interleukin 1ß (IL-1ß) mRNA expression and this inversely correlates with social interaction score. In contrast, IL-1ß expression was unchanged in male or female mice following SCVS. No significant increases in VTA ionized calcium binding adapter molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) immunochemistry were detected following CSDS that would be indicative of a robust inflammatory response. In conclusion, we show that chronic stressors distinctively alter expression of proinflammatory genes in the VTA and changes may depend on the severity and time-course of the stress exposure.

Removal of 17α-ethinylestradiol and caffeine from wastewater by UASB-Fenton coupled system.

In aquatic systems, some substances considered as endocrine disruptors have been detected, which can be due to their incomplete elimination in wastewater treatment plants (WWTPs) and inadequate disposal of pharmaceuticals. Among these contaminants are 17α-ethinylestradiol (EE2) and caffeine (CAF). Moreover, it has been reported that this kind of contaminants may provoke different adverse effects in many aquatic organisms. Because of that, in the present study, up-flow anaerobic sludge blanket reactors (UASB) coupled with the Fenton process was evaluated for EE2 and CAF removal spiked in wastewater samples. First, the best reaction conditions were established in each process. For UASB reactor, two hydraulic retention times (HRT 8 and 24 h) were evaluated, achieving the highest chemical organic demand (COD) removal (70 %) and drug elimination (84 %-86 %) with HRT 24 h. Subsequently, Fenton process was conducted at pH 3 with different levels of Fe2+ (0.05-0.5 mmol/L) and molar ratios Fe2+:H2O2 (1:1-1:10). Better results were obtained with 0.5 mmol Fe2+/L, and 1:10 ratio molar Fe2+:H2O2. Finally, UASB-Fenton coupled system allowed 80 % of COD decrease, almost complete removal of drugs and the toxicity of samples on Vibrio fischeri was reduced from 73 % to 30 %, demonstrating that this coupled system is a promising and efficient system for pharmaceutical compounds removal from wastewater.

Occurrence and seasonal distribution of five selected endocrine-disrupting compounds in wastewater treatment plants of the Metropolitan Area of Monterrey, Mexico: The role of water quality parameters.

Five endocrine-disrupting compounds (EDCs) were determined in four urban wastewater treatment plants (WWTPs) of the Metropolitan Area of Monterrey (MAM) in two seasonal periods (winter and summer). The MAM, one of the most urbanized areas in Mexico, is characterized by high industrial activity and population density, leading to extensive use of several EDCs. In the MAM, ∼90% of urban and industrial wastewater is treated in WWTPs, where EDCs can be partially eliminated. In this work, dissolved levels of 17ß-estradiol (E2), 17α-ethinyl estradiol (EE2), bisphenol A (BPA), 4-nonylphenol (4NP), and 4-tert-octylphenol (4TOP) in wastewater were determined. The EDCs' determination was carried out through solid-phase extraction (SPE) and gas chromatography coupled to mass spectrometry (GC-MS). High EDCs levels (0.4-450 ng/L) were found in the influents of WWTPs, while concentrations in the effluents ranged from 0.2 to 26.8 ng/L, with E2, EE2, and 4TOP being the most persistent. The Spearman correlation analysis revealed the association between E2 and EE2 (r = 0.4835, p < 0.05), and between BPA and 4NP (r = 0.5180, p < 0.05), suggesting that these EDCs have similar sources. Also, E2, BPA, and 4TOP were positively correlated with the chemical oxygen demand (COD), biochemical oxygen demand (BOD), and total suspended solids (TSS) (r = 0.4080-0.5694, p < 0.05), indicating the association of the EDCs with the organic matter in the wastewater. The factor analysis confirmed the significant correlation of COD, BOD, TSS, temperature, and pH with the high occurrence of 4TOP during the summer. It was also confirmed that summer warmer temperatures favored the removal of BPA and 4NP in the studied WWTPs. Finally, the studied sites were classified by cluster analysis in three groups, revealing the impact that seasonality has on the behavior of the selected EDCs.

Características del diagnóstico prenatal por hibridación fluorescente in situ en Cuba / Features of the prenatal diagnosis by fluorescence in situ hybridization in Cuba

Introducción: El diagnóstico prenatal mediante la hibridación fluorescente in situ disminuye el tiempo de diagnóstico al no ser necesario el cultivo celular. Objetivo: Describir las características y experiencias del diagnóstico prenatal por hibridación fluorescente in situ en Cuba. Método: En amniocitos in situ se aplicaron sondas CEP y LSI para la detección de aneuploidías de los cromosomas 21,18,13, X y Y y sondas LSI para la detección de deleciones asociadas a síndromes de microdeleción. Resultados: Se remitieron al Centro Nacional de Genética Médica 629 casos de alto riesgo genético. Prevaleció la indicación de alteraciones fetales detectadas por ecografía. En 612 (97 por ciento) casos se obtuvo un diagnóstico satisfactorio, entre ellos, 50 (8,1 por ciento) casos positivos, con predominio del síndrome Down en 26 casos. Se corroboraron por citogenética convencional 312 casos con 98 por ciento de concordancia con los resultados obtenidos por hibridación fluorescente in situ. Se utilizó el líquido amniótico refrigerado para corroborar casos de diagnóstico dudoso obtenido por citogenética y se detectaron 3 fetos con mosaicos cromosómicos, el origen de un cromosoma marcador y la definición del sexo fetal en un caso. Conclusiones: Con la tecnología por hibridación fluorescente in situ el diagnóstico prenatal logra una segura opción de análisis en aquellos casos de embarazos de alto riesgo genético. Debido a limitaciones tecnológicas, la prueba por hibridación fluorescente in situ en células amnióticas en interfase, se ha adaptado a nuestras condiciones, para lograr siempre un diagnóstico seguro con el menor perjuicio posible a la embarazada, el feto y su familia(AU)

Introduction: Prenatal diagnosis by fluorescent in situ hybridization decreases the time of diagnosis not being necessary the cell culture. Objective: To describe the characteristics and experiences of prenatal diagnosis by fluorescent in situ hybridization in Cuba. Method: In in situ amniocytes CEP catheters were applied and LSI for the detection of aneuploidies of the 21,18,13, X and Y chromosomes, and LSI catheters for the detection of deletions associated with microdeletion syndromes. Results: 629 cases of high genetic risk were referred to the National Center of Medical Genetics. There was a prevalence of the indication of fetal abnormalities detected by ultrasound. In 612 (97 percent) cases the diagnosis was achieved in a satisfactory form, among them 50 (8.1 percent) positive cases, with predominance of Down syndrome in 26 cases. There were corroborated 312 cases by conventional cytogenetics with 98 percent of agreement with the results obtained by fluorescent in situ hybridization. It was used the cooled amniotic fluid to corroborate cases of uncertain diagnosis obtained by cytogenetics and there were detected 3 fetuses with chromosomal mosaics, the origin of a marker chromosome and the definition of fetal sex in one case. Conclusions: With the technology by fluorescent in situ hybridization, the prenatal diagnosis achieved a safe analysis option in cases of genetic high-risk pregnancies. Due to technological limitations, the test by fluorescent in situ hybridization in amniotic cells in interphase has adapted to the conditions in order to always achieve a safe diagnosis with the less possible damage to the pregnant women, the fetus and its family(AU)

Adolescent fluoxetine history impairs spatial memory in adult male, but not female, C57BL/6 mice.

BACKGROUND: Epidemiological reports indicate that mood-related disorders are common in the adolescent population. The prevalence of juvenile major depressive disorder has resulted in a parallel increase in the prescription rates of fluoxetine (FLX) within this age group. Although such treatment can last for years, little is known about the enduring consequences of adolescent antidepressant exposure on memory-related performance. METHODS: We exposed separate groups of adolescent (postnatal day [PD] 35) male and female C57BL/6 mice to FLX (20 mg/kg) for 15 consecutive days (PD35-49). Three weeks after FLX exposure (PD70), we assessed learning and memory performance on a single-day training object novelty recognition test, or a spatial memory task on the Morris water maze (MWM). RESULTS: We found that FLX pretreatment did not influence performance on either the object novelty recognition task or the MWM, 24 h after training. Conversely, 48 h post spatial-training on the MWM, FLX pretreated male mice spent significantly less time on the quadrant of the missing platform during a standard probe trial. No differences in MWM performance were observed in the adult female mice pretreated with FLX. LIMITATIONS: A limitation of this study is that normal adolescent mice (i.e., non-stressed) were evaluated for memory-related behavior three weeks after antidepressant exposure. Thus, it is possible that FLX pre-exposure in combination with animal models for the study of depression may yield different results. CONCLUSION: Together, these results demonstrate enduring spatial memory-related deficiencies after pre-exposure to FLX during adolescence in male, but not female, C57BL/6 mice.

Degradation of anti-inflammatory drugs in municipal wastewater by heterogeneous photocatalysis and electro-Fenton process.

Non-steroidal anti-inflammatory drugs (NSAID) are compounds frequently found in municipal wastewater and their degradation by conventional wastewater treatment plants (WWTP) is generally incomplete. This study compared the efficiency of two advanced oxidation processes (AOP), namely heterogeneous photocatalysis (HP) and electro-Fenton (EF), in the degradation of a mixture of common NSAID (diclofenac, ibuprofen and naproxen) dissolved in either deionized water or effluent from a WWTP. Both processes were effective in degrading the NSAID mixture and the trend of degradation was as follows, diclofenac > naproxen > ibuprofen. EF with a current density of 40 mA cm-2 and 0.3 mmol Fe2+ L-1 was the most efficient process to mineralize the organic compounds, achieving up to 92% TOC removal in deionized water and 90% in the WWTP effluent after 3 h of reaction. HP with 1.4 g TiO2 L-1 at pH 7 under sunlight, produced 85% TOC removal in deionized water and 39% in WWTP effluent also after 3 h treatment. The lower TOC removal efficiency shown by HP with the WWTP effluent was attributed mainly to the scavenging of reactive species by background organic matter in the wastewater. On the contrary, inorganic ions in the wastewater may produce oxidazing species during the EF process, which contributes to a higher degradation efficiency. EF is a promising option for the treatment of anti-inflammatory pharmaceuticals in municipal WWTP at competitive electrical energy efficiencies.

Performance of Bi2O3/TiO2 prepared by sol-gel on p-Cresol degradation under solar and visible light.

Photocatalytic degradation of p-Cresol was evaluated using the mixed oxide Bi2O3/TiO2 (containing 2 and 20% wt. Bi2O3 referred as TB2 and TB20) and was compared with bare TiO2 under simulated solar radiation. Materials were prepared by the classic sol-gel method. All solids exhibited the anatase phase by X-ray diffraction (XRD) and Raman spectroscopy. The synthesized materials presented lower crystallite size and Eg value, and also higher surface area as Bi2O3 amount was increased. Bi content was quantified showing near to 70% of theoretical values in TB2 and TB20. Bi2O3 incorporation also was demonstrated by X-ray photoelectron spectroscopy (XPS). Characterization of mixed oxides suggests a homogeneous distribution of Bi2O3 on TiO2 surface. Photocatalytic tests were carried out using a catalyst loading of 1 g L-1 under simulated solar light and visible light. The incorporation of Bi2O3 in TiO2 improved the photocatalytic properties of the synthesized materials obtaining better results with TB20 than the unmodified TiO2 under both radiation sources.

Randomized Controlled Trial Assessing the Impact of Tacrolimus Versus Cyclosporine on the Incidence of Posttransplant Diabetes Mellitus.

INTRODUCTION: Despite the high incidence of posttransplant diabetes mellitus (PTDM) among high-risk recipients, no studies have investigated its prevention by immunosuppression optimization. METHODS: We conducted an open-label, multicenter, randomized trial testing whether a tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) or cyclosporine A (CsA) with steroid minimization (SM) (CsA-SM), decreased the incidence of PTDM compared with tacrolimus with SM (Tac-SM). All arms received basiliximab and mycophenolate mofetil. High risk was defined by age >60 or >45 years plus metabolic criteria based on body mass index, triglycerides, and high-density lipoprotein-cholesterol levels. The primary endpoint was the incidence of PTDM after 12 months. RESULTS: The study comprised 128 de novo renal transplant recipients without pretransplant diabetes (Tac-SW: 44, Tac-SM: 42, CsA-SM: 42). The 1-year incidence of PTDM in each arm was 37.8% for Tac-SW, 25.7% for Tac-SM, and 9.7% for CsA-SM (relative risk [RR] Tac-SW vs. CsA-SM 3.9 [1.2-12.4; P = 0.01]; RR Tac-SM vs. CsA-SM 2.7 [0.8-8.9; P = 0.1]). Antidiabetic therapy was required less commonly in the CsA-SM arm (P = 0.06); however, acute rejection rate was higher in CsA-SM arm (Tac-SW 11.4%, Tac-SM 4.8%, and CsA-SM 21.4% of patients; cumulative incidence P = 0.04). Graft and patient survival, and graft function were similar among arms. CONCLUSION: In high-risk patients, tacrolimus-based immunosuppression with SM provides the best balance between PTDM and acute rejection incidence.

Fluoxetine exposure in adolescent and adult female mice decreases cocaine and sucrose preference later in life.

BACKGROUND: Preclinical evidence from male subjects indicates that exposure to psychotropic medications, during early development, results in long-lasting altered responses to reward-related stimuli. However, it is not known if exposure to the antidepressant fluoxetine, in female subjects specifically, changes sensitivity to natural and drug rewards, later in life. AIMS: The aim of this work was to investigate if exposure to fluoxetine mediates enduring changes in sensitivity to the rewarding properties of cocaine and sucrose, using female mice as a model system. METHODS: We exposed C57BL/6 female mice to fluoxetine (250 mg/L in their drinking water) for 15 consecutive days, either during adolescence (postnatal day 35-49) or adulthood (postnatal day 70-84). Twenty-one days later, mice were examined on their behavioral reactivity to cocaine (0, 2.5, 5, 7.5 mg/kg) using the conditioned place preference paradigm, or assessed on the two-bottle sucrose (1%) test. RESULTS: We found that regardless of age of antidepressant exposure, female mice pre-exposed to fluoxetine displayed reliable conditioning to the cocaine-paired compartment. However, when compared to respective age-matched controls, antidepressant pre-exposure decreased the magnitude of conditioning at the 5 and 7.5 mg/kg cocaine doses. Furthermore, fluoxetine pre-exposure reduced sucrose preference without altering total liquid intake. CONCLUSIONS: The data suggest that pre-exposure to fluoxetine, during adolescence or adulthood, results in a prolonged decrease in sensitivity to the rewarding properties of both natural and drug rewards in female C57BL/6 mice.

Levels of anti-CMV antibodies are modulated by the frequency and intensity of virus reactivations in kidney transplant patients.

Anti-CMV (cytomegalovirus) antibody titers are related to immune alterations and increased risk of mortality. To test whether they represent a marker of infection history, we analyzed the effect of viral reactivations on the production of specific antibodies in kidney transplant patients. We quantified CMV-DNAemia and antibody titers in 58 kidney transplant patients before transplantation and during a follow-up of 315 days (standard deviation, SD: 134.5 days). In order to calculate the intensity of the infection, we plotted the follow-up time of the infection on the x-axis and the number of DNA-CMV copies on the y-axis and calculated the area under the curve (CMV-AUC). The degree of T-lymphocyte differentiation was analyzed with flow cytometry, the cells were labelled with different monoclonal antibodies in order to distinguish their differentiation state, from naive T-cells to senescent T-cells. Peak viremia was significantly higher in patients experiencing a primary infection (VI) compared to patients experiencing viral reactivation (VR). Our data indicate that the overall CMV viral load over the course of a primary infection is significantly higher than in a reactivation of a previously established infection. Whereas patients who experienced an episode of CMV reactivation during the course of our observation showed increased levels of CMV-specific antibodies, patients who did not experience CMV reactivation (WVR) showed a drop in CMV antibody levels that corresponds to an overall drop in antibody levels, probably due to the continuing immunosuppression after the renal transplant. We found a positive correlation between the CMV viremia over the course of the infection or reactivation and the CMV-specific antibody titers in the examined patients. We also observed a positive correlation between anti-CMV titers and T-cell differentiation. In conclusion, our data show that anti-CMV antibody titers are related to the course of CMV infection in kidney transplant patients.

Mosaicismo diploide/tetraploide en fibroblastos. Presentación de un caso / Diploid/tetraploid mosaicism in fibroblasts. A case presentation

Las poliploidías como aberración cromosómica han sido estudiadas como una condición concerniente únicamente al reino vegetal; sin embargo, en los humanos eran consideradas como condición letal. Las más frecuentemente detectadas son las triploidías y tetraploidías completas, además de mixoploides diploide/triploide y diploide/tetraploide. Con el objetivo de contribuir al diagnóstico de los mosaicismos pigmentarios, presentamos un caso en el que fue confirmado un mosaicismo 2n/4n en fibroblastos mediante estudio citogenético. Se trata de un paciente masculino de 12 años de edad, remitido a la consulta de genética del Instituto de Endocrinología por presentar debilidad muscular y trastornos neurovegetativos. Al examen físico se observó discreta asimetría con un hipocrecimiento del hemicuerpo derecho, ligera ptosis palpebral y zonas hiperpigmentadas en forma de parches en piel, sobre todo a nivel del tórax. Fue evaluado por especialistas en neurología y dermatología. Se realizó estudio cromosómico en sangre, se realizaron biopsias de piel para realizar estudios anatomopatológicos y citogenéticos. En las zonas hiperpigmentadas se observó: hiperqueratosis, hiperpigmentación irregular de la capa basal de la epidermis, escasa incontinencia pigmentaria. El estudio cromosómico en fibroblastos mostró un mosaicismo diploide/ tetraploide y el estudio en sangre resultó normal, esto contrasta con lo reportado por otros autores cuyo hallazgo de mosaicismo diploide/tetraploide ha sido en sangre, piel y hueso, indistintamente. La observación de asimetría corporal y mosaicismos pigmentarios en piel, debe hacer sospechar la presencia de mixoploidía…(AU)

Mineral metabolism disorders, vertebral fractures and aortic calcifications in stable kidney transplant recipients: The role of gender (EMITRAL study) / Alteraciones del metabolismo mineral, fracturas vertebrales, y calcificaciones aórticas en receptores estables de trasplante renal: papel del género (estudio EMITRAL)

Antecedentes y objetivos: La relación entre las alteraciones del metabolismo mineral, las fracturas óseas y las calcificaciones vasculares en receptores de un trasplante renal no han sido establecidas. Método: Realizamos un estudio transversal en 727 receptores estables procedentes de 28 centros de trasplante españoles. Se determinaron de manera centralizada los parámetros del metabolismo mineral; también se centralizó la semicuantificación de las fracturas vertebrales y de las calcificaciones de la aorta abdominal. Resultados: La deficiencia de vitamina D (25OHD3 < 15ng/ml) fue más frecuente en mujeres y en los estadios CKD-T I-III (29,6 vs. 44,4%; p=0,003). La relación inversa y significativa observada entre los niveles de 25OHD3 y PTH fue modificada por el género de tal manera que la pendiente fue mayor en las mujeres que en los hombres (p=0,01). Un 15% de los receptores mostró alguna fractura vertebral (VFx) con un grado de deformidad ≥2. Los factores relacionados con la VFx diferían en función del género: en los hombres, la edad (OR: 1,04; IC 95%: 1,01-1,06) y el tratamiento con CsA (OR: 3,2; IC 95: 1,6-6,3); en las mujeres la edad (OR: 1,07; IC 95%: 1,03-1,12) y los niveles de PTH (OR per 100pg/ml increase: 1,27; IC 95%: 1,043-1,542). Las calcificaciones de la aorta abdominal fueron comunes (67,2%) y se relacionaron con los factores de riesgo clásicos, pero no con los parámetros del metabolismo mineral. Conclusiones: La deficiencia de vitamina D es más frecuente en las mujeres receptoras de un trasplante renal y en los estadios más tempranos de la CKD-T, y es un factor que contribuye al desarrollo de hiperparatiroidismo secundario. Las VFx prevalentes están relacionadas con unos niveles más elevados de PTH solamente en las mujeres (AU)

Background and objectives: The relationship between mineral metabolism disorders, bone fractures and vascular calcifications in kidney transplant recipients has not been established. Method: We performed a cross-sectional study in 727 stable recipients from 28 Spanish transplant clinics. Mineral metabolism parameters, the semi-quantification of vertebral fractures and abdominal aortic calcifications were determined centrally. Results: Vitamin D deficiency (25OHD3 < 15 ng/ml) was more common in female recipients at CKD-T stages I–III (29.6% vs 44.4%; p=0.003). The inverse and significant correlation between 25OHD3 and PTH was gender-specific and women exhibited a steeper slope than men (p=0.01). Vertebral fractures (VFx) with deformity grade ≥2 were observed in 15% of recipients. Factors related to VFx differed by gender; in males, age (OR 1.04; 95% CI 1.01-1.06) and CsA treatment (OR: 3.2; 95% CI: 1.6-6.3); in females, age (OR 1.07; 95% CI: 1.03-1.12) and PTH levels (OR per 100 pg/ml increase: 1.27; 95% CI: 1.043-1.542). Abdominal aortic calcifications were common (67.2%) and related to classical risk factors but not to mineral metabolism parameters. Conclusions: Vitamin D deficiency is more common among female kidney transplant recipients at earlier CKD-T stages, and it contributes to secondary hyperparathyroidism. Prevalent vertebral fractures are only related to high serum PTH levels in female recipients (AU)