Enhancing adult hippocampal neurogenesis with lysophosphatidic acid: a proposal for erasing cocaine contextual memory

Stimulating adult hippocampal neurogenesis (AHN) has been uncovered as a promising approach in the manipulation of retrograde memories. This work aims to study whether increasing AHN with lysophosphatidic acid (LPA, an endogenous lysophospholipid with proneurogenic actions) promotes the forgetting of previously established cocaine-contextual associations. C57BL/6J mice previously trained in a cocaine-induced conditioned place preference (CPP) paradigm were submitted to 23 days of withdrawal, during which they received repeated intracerebroventricular infusions of LPA, ki16425 (a selective LPA1/3 receptors antagonist), or vehicle solution. Then, CPP maintenance was assessed, and the causal role of AHN in this process was evaluated using a mediation analysis. In a complementary experiment, wild-type and LPA1-null mice were acutely infused with LPA or ki16425 to determine the involvement of the LPA1 receptor in the in vivo proneurogenic actions of LPA. The chronic LPA treatment significantly weakened the long-term retention of a previously acquired cocaine-CPP memory, an effect clearly mediated by a LPA-induced increase in the number of adult-born dentate granule cells. In contrast, the ki16425-treated mice displayed aberrant responses of initially decreased CPP retention that progressively increased CPP across the extinction sessions, in absence of effects on AHN. The histological studies suggested that the proneurogenic actions of LPA were related to the enhancement of cell proliferation and critically depended on the LPA1 receptor function. Our results suggest that the LPA/LPA1-pathway acts as a potent in vivo modulator of AHN, and highlight the usefulness of a post-learning increase of adult-born hippocampal neurons as a strategy to promote the forgetting of cocaine-context associations.Plan Propio de Investigación y Transferencia. Campus de Excelencia Internacional Andalucía Tech. Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación), co‐funded by the European Research Development Fund (AEI/FEDER, UE) (PSI2013‐44901‐P and PSI2017‐82604‐R to L.J.S. and PSI2015‐73156‐JIN to E.C.O.); by the National System of Health‐Instituto de Salud Carlos III, which is co‐funded by AEI/FEDER, UE (Red de Trastornos Adictivos; RD16/0017/0001 to F.R.d.F.); and by the Andalusian R&D&I Programme, Regional Ministry of Economy and Knowledge (PAIDI CTS643 to G.E.T.). D.L.G.M. hold a FPU grant from the Spanish Ministry of Education, Culture and Sports (FPU13/04819 ). F.R.d.F. and G.E.T. are supported by Nicolas Monardes Programme, from the Andalusian Regional Ministry of Health. E.C.O. holds a ‘Jóvenes Investigadores’ grant (code: PSI2015‐73156‐JIN) from the Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación), which is co‐funded by the AEI/FEDER, UE

Expression of adrenomedullin and proadrenomedullin N-terminal 20 peptide in human and rat prostate

Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are two recently discovered hypotensive peptides translated from the same message transcript (preproAM mRNA). In this article we report the presence of AM, PAMP, and their mRNA in human and rat prostate and of AM receptor mRNA in rat prostate. PreproAM mRNA was found in the epithelium of normal human and rat prostate glands by in situ hybridization. In humans, it was mainly expressed in the basal cells. In rat, its expression was higher in the ducts than in the acini of all the prostate lobes. Immunocytochemistry identified a similar distribution pattern for AM compared with its mRNA but showed different locations for AM and PAMP immunoreactivity. The former was widespread in the epithelia, whereas the latter was almost exclusively found in neuroendocrine cells. In rat, Western blot analysis confirmed the presence of high levels of AM peptide in the ventral lobe and of its precursor in the ventral and dorsolateral lobes. Immunoreactivity for serotonin, chromogranin A, PAMP, and AM defined four subpopulations of prostate neuroendocrine-like cells in rat, a cell type that has not been previously described

Adrenalectomía laparoscópica por metástasis metácrona. Experiencia en 12 casos

To assess the peroperative and oncological results of laparoscopic adrenalectomy for an isolated metastasis. MATERIAL AND METHODS: A retrospective, descriptive study was conducted of 12 laparoscopic adrenalectomies performed for metastases out of a total of 40 adrenalectomies performed from May 1998 to April 2009. The primary tumor was pulmonary in 7 patients, renal in 3, and colonic in 2. Demographic data collected included median age, operating time, blood loss, complications, tumor size, and length of hospital stay. The Kaplan-Meier method was used to analyze survival. RESULTS: Operating time was 150 min (range, 90-206). Peroperative bleeding was 60 ml (range, 15-150). Peroperative complications occurred in 3% of patients. Tumor size was 4.5 cm (range, 1.3-8.5). No positive margins were seen in the resected specimens. Hospital stay was 3 days (range 3-5). Actuarial survival was 55.6% at 23 months (range, 2-38) with mean and median follow-up times of 20.9 and 23 months. CONCLUSIONS: In selected patients, laparoscopic adrenalectomy for metastasis is a safe procedure with oncological results superimposable to those of open surgery

Association of crossed renal ectopia and aortic aneurism. Case report

OBJECTIVE: Renal malformations are rare entities and rarely have clinical consequences. Crossed renal ectopia has an incidence of 1/2.000 autopsies. The association with aortic aneurysm is even more exceptional. METHODS: We present our case and perform a bibliographic review. RESULTS: To date and in our knowledge , seven cases of crossed renal ectopia associated with aortic aneurysm were described on the literature. This malformation makes the treatment of the aneurysm more complex. The possibility of renal function decrease caused by injuries to the renal arteries during the surgical procedure is always present. Because of this risk of injury of the kidney during surgery preoperative evaluation of the vascularization must include image technologies as the MRI, CT-angiography or conventional arteriography. During the aortic intervention vascular conservation must be performed and it is necessary to minimize the time of renal ischemia. CONCLUSIONS: The association of crossed renal ectopia and aortic aneurysm is a rare event. The surgical intervention of the aorta does not have to necessarily originate a loss of renal function. Anyway the worsening of the renal clearance must be foreseen

¿Existe un intervalo de tiempo de isquemia fría seguro para el injerto renal?

Objective: It is aimed to characterize the true relationship of the cold ischemia time (CIT) with graft survival and with the principal post-transplantation events.aterial and methods: We analyzed 378 kidney transplants, studying the relationship of the CIT with graft survival using a univariate analysis according to the COX model and seeking the optimum cutoff according to the Kaplan-Meier method and log-rank test. The relationship between CIT and the principal events of the post-transplant was studied using the binary logistic regression. Results: The mean follow-up of all the group was 77.8 months (± 51 SD) and the mean CIT was 14.8 hours (± 5.1 SD). The univariate analysis revealed that the CIT was not related with the graft survival as a continuous variable (OR = 1.04; 95% CI: 0.9-1.08; p > 0.05). On establishing the cutoff at 18 hours, we found differences in the actuarial survival. Survival at 5 years was 91% with CIT 18 h. Each hour of cold ischemia increased risk of delay in the graft function by 10% (OR = 1.1; 95% CI: 1.05-1.15; p < 0.001) and also conditioned a greater incidence of acute rejection (41.5% vs. 55.3%; p = 0.02) and less time to the first rejection episode (72.6 days ± 137 vs. 272.2 days ± 614.8; p = 0.023) after 18 hours. The CIT did not seem to be related (p < 0.05) with the rest of the post-transplantation events, such as surgical complications or hospital admissions. Conclusions: In our experience, cold ischemia under 18 hours does not seem to negatively affect graft survival

Respuesta y supervivencia libre de progresión en tumores vesicales en estadiosT2-T4 tratados con tratamiento trimodal de conservación vesical

Objective: Toevaluatetheresponseandthefree-survivalprogressioninpacientsdiagnosed of invasivebladdercancerwhohavebeentreatedwithtransurethralresection, chemotherapyandradiotherapy.Thismultimodaltreatmentiscomparedwithanot random serieofpatientstreatedbyradicalcistectomy. Material andmethods: Retrospectiveanalysisof43casesofinvasivebladdercancertreated with twoschemesofbladderpreservationbetween1994–2007.Theyarecomparedwith145 cases treatedwithradicalcistectomyinthesameperiodoftime. Pronosticvariablesincludedinthestudyareclinicalstage,gradeofdifferentiation, presence ofureteralobstruction,chemotherapymodality,radiotherapydosesandp53and ki-67 expression. Results: Meanandmediantimeare51and39monthsinpatientswithmultimodal treatment.Completeresponseisachievedin72%ofcasestreatedwithbladder preservation.Ureteralobstructionisaprognosticfactor(OR:7,3;p:0,02).72%patientswith complete responsemantainitattheendofthestudy.Noneofanalyzedvariablesare predictors ofmaintenanceoftheresponse. Survivalrateswithaintactbladderwere6977% and6177% atthreeandfiveyears. Radiotherapydosesgreaterthan60Gy(OR:6,1;po0,001) andtheabsenceofureteral obstruction (OR:7,5;po0,002) werepronosticvariables. Free-survivalinpatientswithcompleteresponsewas8077% and58710% atthreeand five years. At theendofthestudy,53,5%ofpatientshadaintactbladderandfree-disease. Inthesameperiodoftime,145radicalcistectomieswereperformedduetomuscleinvasive bladdercancer.Meanandmediantimeinthisgroupwere29and18monthsrespectively. Stadisticalanalysisrevealsaworseclinicalstageinthegroupofpatientstreatedwith multimodaltreatment(p:0.01). Free-survivalwas7275% and6377%at3and5yearsinthegroupofradical cistectomies.Therewasnotstadisticalsignificantdifferencesbetweencistectomiesand bladderpreservation. Conclusions: Patientstreatedwithbladderpreservationhaveafree-survivalsimilartothose tretedwithradicalcistectomy.Radiotherapy doses greaterthan60Gyandabsenceofureteral obstructionwerefree-survivalprognosticvariables

Edad del donante y su influencia en la supervivencia del injerto

INTRODUCTION: In 2007 in Spain 43% of donors were older than 60 years. This produces a worse graft quality and probably a worse survival. OBJECTIVE: Our objective is to analyze the influence of donor age on graft survival. MATERIAL AND METHODS: We analyze retrospectively 216 renal consecutive transplants realized between 2000 and 2008. A univaried and multivaried study (Cox regression) was performed and Kaplan-Meyer test with log rank for graft survival. RESULTS: Follow-up mean of 40 months (+/-33,4 SD). The univaried analysis of graft survival showed that donor age had a significative influence on graft survival. (OR=1,03; 95% CI 1,01-1,05) (p: 0,009). Studying the relation between donor and recipient age we find an inverse correlation (Pearson's Correlation: 0,55. p<0,0001), but there are significative differences after the adjustment for recipient age. (OR: 1,02; 95% CI 1,01-1,04) (p: 0,04). Optimal cut-point value determined by the ROC analysis was 60 years. The graft survival of donors over 60 years is 79% (95% CI; 74-84%) and 71% (95% CI; 65-77%) at 3 and 5 years in contrast with 94% (95% CI; 94-96%) and 90% (95% CI; 88-92 in donors under 60. (p: 0,002). The multivaried study of the influential factors on graft survival reveals that donor age dichotomized in older or younger than 60, the presence of a surgical immediate reintervention and a delayed graft function were independent influence factors. CONCLUSIONS: Donor age over 60 years has a negative and independent prognostic influence on graft survival

More adult-born dentate gyrus neurons to weaken cocaine-related retrograde memories: an in vivo strategy employing exogenous lysophosphatidic acid

The post-training enhancement of adult hippocampal neurogenesis (AHN) has been receiving growing interest as a potential method to manipulate retrograde memories. Recent hypothesis suggest that the addition of adult-born dentate granule cells might promotes remodeling of pre-existing hippocampal circuits, which might both clear cocaine-related memories and facilitate the learning of new adaptive information. Here, we study the effect of stimulating AHN in vivo with exogenous lysophosphatidic acid (LPA) on the maintenance of retrograde cocaine-contextual associative memories. Male C57BL/6J mice trained in a cocaine-induced Conditioned Place Preference (CPP) model were later submitted to repeated intracerebroventricular (i.c.v.) injections of LPA, Ki16425 or vehicle solution during withdrawal. Afterwards, the long-term persistence of the cocaine-CPP was assessed and the mediational role of AHN in this process was evaluated. In addition, wild-type and mice lacking the LPA1 receptor received a single i.c.v. injection of LPA, Ki16425 or vehicle to assess the role of the LPA1 receptor in the LPA-induced increase of AHN. Our results revealed that the chronic administration of LPA decreased the retention of a previously acquired cocaine-induced CPP. This effect was mediated by an LPA-induced increase of AHN. In contrast, mice treated with Ki16425 showed reduced cocaine-CPP retention, but they increased their preference for the cocaine-paired compartment throughout CPP extinction. Besides, no effects of Ki16425 on AHN were found. Immunohistochemical studies suggested that LPA stimulated cell proliferation and promoted neuronal maturation with a key role of the LPA1 receptor. These findings emphasize the relevance of LPA and its LPA1 receptor as an in vivo modulator of AHN and the utility of the post-training increase of adult-born hippocampal neurons to weaken cocaine-context associations.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Lysophosphatidic acid-induced increase in adult hippocampal neurogenesis facilitates the forgetting of cocaine-contextual memory

Author manuscriptErasing memories of cocaine-stimuli associations might have important clinical implications for addiction therapy. Stimulating hippocampal plasticity by enhancing adult hippocampal neurogenesis (AHN) is a promising strategy because the addition of new neurons may not only facilitate new learning but also modify previous connections and weaken retrograde memories. To investigate whether increasing AHN prompted the forgetting of previous contextual cocaine associations, mice trained in a cocaine-induced conditioned place preference (CPP) paradigm were administered chronic intracerebroventricular infusions of lysophosphatidic acid (LPA, an endogenous lysophospholipid with pro-neurogenic actions), ki16425 (a LPA1/3 receptor antagonist), or a vehicle solution, and they were tested 23 days later for CPP retention and extinction. The results of immunohistochemical experiments showed that the LPA-treated mice exhibited reduced long-term CPP retention and an ~two-fold increase in the number of adult-born hippocampal cells that differentiated into mature neurons. Importantly, mediation analyses confirmed a causal role of AHN in reducing CPP maintenance. In contrast, the ki16425-treated mice displayed aberrant responses, with initially decreased CPP retention that progressively increased across the extinction sessions, leading to no effect on AHN. The pharmacological treatments did not affect locomotion or general exploratory or anxiety-like responses. In a second experiment, normal and LPA1 receptor-deficient mice were acutely infused with LPA, which revealed that LPA1-mediated signaling was required for LPA-induced proliferative actions. These results suggest that the LPA/LPA1-pathway acts as a potent in vivo modulator of AHN and highlight the potential usefulness of pro-AHN strategies to treat aberrant cognition in those addicted to cocaine.This study was funded by grants from the Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación), which is cofunded by the European Research Development Fund AEI/FEDER, UE- (PSI2013-44901-P and PSI2017-82604-R to LJS and PSI2015-73156-JIN to ECO); by the National System of Health-Instituto de Salud Carlos III, which is co-funded by AEI/FEDER, UE (Red de Trastornos Adictivos; RD16/0017/0001 to FRdF); and by the Andalusian R&D&I Programme, Regional Ministry of Economy and Knowledge (PAIDI CTS643 to GET). DLGM and RDMF hold FPU grants from the Spanish Ministry of Education, Culture and Sports (FPU13/04819 and FPU14-01610, respectively). CRV received a ‘Plan Propio’ grant from the University of Malaga. FJP and AS hold ‘Miguel Servet’ grants (CP14/00212 and CP14/00173, respectively) from the National System of Health-Instituto de Salud Carlos III, which is co-funded by AEI/FEDER, UE. FRdF and GET are supported by Nicolas Monardes Programme, from the Andalusian Regional Ministry of Health. ECO holds a ‘Jóvenes Investigadores’ grant (code: PSI2015- 73156-JIN) from the Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación) which is co-funded by the European Research Development Fund (AEI/FEDER, UE)

Impact of renal retransplantation on graft and recipient survival

The aim of this study was to evaluate the influence of retransplantation in graft and recipient survival. METHODS: We carried out a retrospective study in 419 renal transplants and studied the influence of retransplantation in graft and patient survival. A homogeneity study was performed between the two groups with a Student`s T and a chi-square tests. Graft survival analysis was performed with Kaplan-Meyer and log rank tests. RESULTS: Of 419 transplants, 370 (88.3%) were first transplantations, 45 (10.7%) second transplantations and 4(1%) third ones. Mean follow-up of the whole group was 72.5 months (+/-54.1 SD). There were no differences in follow-up between groups (Mean Follow-up 73.1 months +/-54.4 SD in first transplantations vs. 61.6 months +/-51.2 SD in repeat transplantation. p >0.05). The actuarial graft survival showed no differences between patients with first transplantation and those with a repeat one. [3 and 5 year SV of 89% (95% CI: 87-91%) and 84%(95% CI: 82-86%) Vs 88% (95% CI; 83-93%) and 85% (95% CI:i; 80-90%) respectively]. After adjusting for all the heterogeneity variables we still did not find differences on graft survival. The actuarial recipient survival showed no differences between patients with first transplantation and those with a repeat one. [3 and 5 year SV of 98% and 96% Vs.97%]. CONCLUSIONS: There are no differences of graft and recipient survival between patients with a first transplantation and those with a repeat one