Publications by authors named "Isabel Legaz"

32 Publications

Trace elements in forensic human lung: A new approach to the diagnosis of seawater drowning. A preliminary study.

Forensic Sci Int 2021 May 4;323:110815. Epub 2021 May 4.

Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence "Campus Mare Nostrum", Faculty of Medicine, University of Murcia, Murcia, Spain.

The diagnosing of drowning remains one of the most challenging activities for the forensic pathologist. There is little information on the impact on the lung as a target organ in death by drowning. We aimed to investigate the concentration of trace elements in the lungs of people who had suffered different types of death to evaluate the discriminating ability of trace elements to identify seawater drowning (SWD). A total of 11 trace elements were analyzed by Inductively Coupled Plasma-Mass Spectrometry in 74 forensic cases. Sampler scanning electron microscopy and Energy Dispersive X-ray spectroscopy (EDX) were used to identify ultrastructural lung alterations. A Principal Component Analysis (PCA) of trace elements was carried out. The trace elements in SWD lungs were detected in the following order of concentration: Br˃Zn˃Sr˃Cr˃Cu˃As˃Pb˃Se˃Mn˃Ni˃Cd. Our results showed significantly higher concentrations of Br and Sr (P = 0.010 and P = 0.000) and significantly lower concentrations of Zn, Pb, Cu, Cd, and Se in SWD compared with other causes of death. After adjusting by confounder factors, Sr and Br remained as predictive independent factors for diagnosis of drowning (p = 0.042, in both cases). These results were confirmed by PCA, which revealed a wide separation between SWD and the rest of the causes of death. Our SWD cohort was characterized by high concentrations of the trace elements Br and Sr and low concentrations of Zn, Pb, Cu, Cd, and Se in lung tissue, while PCA showed its discriminatory capacity to identify death by seawater drowning. These findings, together with those obtained using other techniques, can be of great importance in the diagnosis of SWD.
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http://dx.doi.org/10.1016/j.forsciint.2021.110815DOI Listing
May 2021

Monitoring of B Cell in Kidney Transplantation: Development of a Novel Clusters Analysis and Role of Transitional B Cells in Transplant Outcome.

Diagnostics (Basel) 2021 Apr 1;11(4). Epub 2021 Apr 1.

Immunology Services, University Clinical Hospital Virgen de la Arrixaca-Biomedical Research Institute of Murcia (IMIB), 30120 Murcia, Spain.

Background: B lymphocytes (BL) seem to play an important role in transplantation, although the and role of different subpopulations in monitoring and outcome is not clear. Our aim was to monitoring immunological profiles based on BL subpopulations in kidney recipients (KR) with the risk of acute rejection (AR).

Methods: Monitoring of BL subpopulations was performed by flow cytometry in PBLs before transplantation and three and six months after transplantation (PTX). We used two methodological approaches, a traditional analysis, and a novel cluster analysis, to determine the association between BL subpopulations, AR incidence, and graft function.

Results: After three months of PTX, KRs with a B phenotype enriched in transitional BL and plasmablasts had better kidney function and lower AR incidence. KRs with decreased transitional BL and plasmablasts were associated with lower kidney function and higher AR PTX. KRs that had an increase in transitional BL PTX had a better clinical outcome. The increase in transitory BL during PTX was also associated with an increase in Tregs. Indeed, KRs receiving thymoglobulin as induction therapy showed a slight decrease in the relative frequency of naive BLs after three months of PTX.

Conclusion: The monitoring of BL subpopulations may serve as a non-invasive tool to improve immunological follow-up of patients after kidney transplantation. However, further studies are needed to confirm the obtained results, define cut-off values, and standardize more optimal and even custom/customized protocols.
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http://dx.doi.org/10.3390/diagnostics11040641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065535PMC
April 2021

PCR Array Technology in Biopsy Samples Identifies Up-Regulated mTOR Pathway Genes as Potential Rejection Biomarkers After Kidney Transplantation.

Front Med (Lausanne) 2021 17;8:547849. Epub 2021 Feb 17.

Department of Immunology, University Clinical Hospital Virgen de la Arrixaca-Biomedical Research Institute of Murcia (IMIB), Murcia, Spain.

Antibody-mediated rejection (AMR) is the major cause of kidney transplant rejection. The donor-specific human leukocyte antigen (HLA) antibody (DSA) response to a renal allograft is not fully understood yet. mTOR complex has been described in the accommodation or rejection of transplants and integrates responses from a wide variety of signals. The aim of this study was to analyze the expression of the mTOR pathway genes in a large cohort of kidney transplant patients to determine its possible influence on the transplant outcome. A total of 269 kidney transplant patients monitored for DSA were studied. The patients were divided into two groups, one with recipients that had transplant rejection (+DSA/+AMR) and a second group of recipients without rejection (+DSA/-AMR and -DSA/-AMR, controls). Total RNA was extracted from kidney biopsies and reverse transcribed to cDNA. Human mTOR-PCR array technology was used to determine the expression of 84 mTOR pathway genes. STRING and REVIGO software were used to simulate gene to gene interaction and to assign a molecular function. The studied groups showed a different expression of the mTOR pathway related genes. Recipients that had transplant rejection showed an over-expressed transcript (≥5-fold) of AKT1S1, DDIT4, EIF4E, HRAS, IGF1, INS, IRS1, PIK3CD, PIK3CG, PRKAG3, PRKCB (>12-fold), PRKCG, RPS6KA2, TELO2, ULK1, and VEGFC, compared with patients that did not have rejection. AKT1S1 transcripts were more expressed in +DSA/-AMR biopsies compared with +DSA/+AMR. The main molecular functions of up-regulated gene products were phosphotransferase activity, insulin-like grown factor receptor and ribonucleoside phosphate binding. The group of patients with transplant rejection also showed an under-expressed transcript (≥5-fold) of VEGFA (>15-fold), RPS6, and RHOA compared with the group without rejection. The molecular function of down-regulated gene products such as protein kinase activity and carbohydrate derivative binding proteins was also analyzed. We have found a higher number of over-expressed mTOR pathway genes than under-expressed ones in biopsies from rejected kidney transplants (+DSA/+AMR) with respect to controls. In addition to this, the molecular function of both types of transcripts (over/under expressed) is different. Therefore, further studies are needed to determine if variations in gene expression profiles can act as predictors of graft loss, and a better understanding of the mechanisms of action of the involved proteins would be necessary.
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http://dx.doi.org/10.3389/fmed.2021.547849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927668PMC
February 2021

Age and education as factors associated with medication literacy: a community pharmacy perspective.

BMC Geriatr 2020 11 25;20(1):501. Epub 2020 Nov 25.

Department of Legal and Forensic Medicine, Institute of Research into Aging. Biomedical Research Institute (IMIB), Regional Campus of International Excellence "Campus Mare Nostrum", Faculty of Medicine, University of Murcia, Murcia, Spain.

Background: Aging implies a higher prevalence of chronic pathologies and a corresponding increase in medication. The correct adherence and use of the medication are prerequisites for reducing risks of disease progression, comorbidity, and mortality. Medication literacy (ML) is the specific ability to safely access and understand the information available concerning medication, and to act accordingly. Currently, there are few specific instruments that ascertain the extent of ML in the general population. The aim of this work was to analyse ML in a large cohort of pharmacy customers.

Methods: A total of 400 community pharmacy clients were analyzed to assess the level of ML (documental and numeracy) through the validated MedLitRxSE tool.

Results: The results showed that out of a total of 400 community pharmacy clients only 136 (34%) had an adequate degree of ML, while the rest of the clients (n = 264; 66%) were adjudged not to have this ability. Statistically significant differences were found between the different age groups in terms of ML (P < 0.001; OR = 0.312; 95% CI: 0.195-0.499), the 51-65 and >65-year age groups having a lower frequency of adequate ML (23.5 and 7.1%, respectively) than the rest of the age groups. A statistically significant increase in adequate ML was observed as the academic level of the clients increased (P < 0.001; OR = 15.403; 95% CI: 8.109-29.257). Multivariate logistic regression confirmed the influence of both variables on ML.

Conclusions: An inadequate ML level was found in community pharmacy clients over the age of 51, and also in those with primary or non-formal studies. Our data add to our knowledge about ML, and should pharmacists and other health professionals to adopt new strategies to prevent, or at least reduce, errors in taking medicines, thus avoiding the undesirable effects of any misuse.
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http://dx.doi.org/10.1186/s12877-020-01881-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687724PMC
November 2020

Impact of the Human Microbiome in Forensic Sciences: a Systematic Review.

Appl Environ Microbiol 2020 10 28;86(22). Epub 2020 Oct 28.

Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence "Campus Mare Nostrum," Faculty of Medicine, University of Murcia, Murcia, Spain

Numerous studies relate differences in microbial communities to human health and disease; however, little is known about microbial changes that occur postmortem or the possible applications of microbiome analysis in the field of forensic science. The aim of this review was to study the microbiome and its applications in forensic sciences and to determine the main lines of investigation that are emerging, as well as its possible contributions to the forensic field. A systematic review of the human microbiome in relation to forensic science was carried out by following PRISMA guidelines. This study sheds light on the role of microbiome research in the postmortem interval during the process of decomposition, identifying death caused by drowning or sudden death, locating the geographical location of death, establishing a connection between the human microbiome and personal items, sexual contact, and the identification of individuals. , , , and play an important role in determining the postmortem interval. can be used to determine the cause of death, and or can be used to ascertain personal identity or geographical location. Several studies point to a promising future for microbiome analysis in the different fields of forensic science, opening up an important new area of research.
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http://dx.doi.org/10.1128/AEM.01451-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642070PMC
October 2020

Aging and trace elements in human coronal tooth dentine.

Sci Rep 2020 06 19;10(1):9964. Epub 2020 Jun 19.

Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence "Campus Mare Nostrum", Faculty of Medicine, University of Murcia, Murcia, Spain.

Teeth are a fundamental tool in forensic odontology for identification in a legal context of those individuals who cannot be identified visually or by other means. Dentine presents physiological exchanges of in trace elements after a period of mineralization and several factors can affect its concentration. The aim of this study was to investigate the concentration of 25 trace elements in the coronal dentine according to sex and type of tooth to determine their relationship with age. A total of 25 trace elements were analyzed in 150 human coronal dentine. Teeth were classified into three age groups, sex and tooth type. The trace elements were grouped as potentially toxic or essential. Inductively Coupled Plasma-Mass Spectrometry and Atomic Emission Spectroscopy were used. The toxic and essential elements were detected in the following order of concentration: Al > Pb > Sn > Li > As > Cd and Ca > P > Mg > Na > S > K > Sr > Zn > Ba > Fe > B > Ti > Mn > Cr > Ni > Cu > Co > Se > V. Our findings show an increase in the concentration of toxic (Pb, Li and Sn) and essential (B, Ba, K, Sr, S and Mg) elements in coronal dentin related to the age of the teeth, regardless of sex. The concentrations of Pb and K in dentin of molars and premolars are the elements that best relate their variations with age. In view of our results, the analysis of these trace elements in dentin in combination with other types of techniques could be established as an element to consider in age dating studies in different forensic situations.
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http://dx.doi.org/10.1038/s41598-020-66472-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305194PMC
June 2020

Influence of Preformed Antibodies in Liver Transplantation.

J Clin Med 2020 Mar 5;9(3). Epub 2020 Mar 5.

Immunology Service, Murcia Institute of Biosanitary Research (IMIB) and Biomedical Research Center in Liver and Digestive Diseases Network (CIBERehd), Virgen de la Arrixaca University Clinical Hospital (HCUVA), 30120 Murcia, Spain.

The significance of human leukocyte antigen (HLA) matching and preformed donor-specific antibodies (DSAs) in liver transplantation remains unclear. The aim of this study was to analyze the presence of DSAs in a large cohort of 810 liver recipients undergoing liver transplant to determine the influence on acute (AR) or chronic liver rejection (CR), graft loss and allograft survival. DSAs were identified using complement dependent cytotoxicity crossmatch (CDC-CM) and multiplexed solid-phase-based flow cytometry assay (Luminex). CDC-CM showed that a 3.2% of liver transplants were positive (+CDC-CM) with an AR frequency of 19.2% which was not different from that observed in negative patients (-CDC-CM, 22.3%). Only two patients transplanted with +CDC-CM (7.6%) developed CR and suffered re-transplant. +CDC-CM patients showed a significantly lower survival rate compared to -CDC-CM patients (23.1% vs. 59.1%, = 0.0003), developing allograft failure within the first three months ( < 0.00001). In conclusion, we have demonstrated a relationship between the presence of preformed DSAs and the low graft liver survival, indicating the important role and the potential interest of performing this analysis before liver transplantation. Our results could help to detect patients with an increased risk of graft loss, a better choice of liver receptors as well as the establishment of individualized immunosuppressive regimens.
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http://dx.doi.org/10.3390/jcm9030708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141359PMC
March 2020

Activating KIRs on Educated NK Cells Support Downregulation of CD226 and Inefficient Tumor Immunosurveillance.

Cancer Immunol Res 2019 08 25;7(8):1307-1317. Epub 2019 Jun 25.

Immunology Service, Instituto Murciano de Investigación Biosanitaria (IMIB), Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.

Therapies using NK cells (NKc) expanded/activated or stimulated with new immunostimulatory agents offer alternative opportunities for patients with recurrent/refractory tumors, but relevant biomarkers to guide the selection of patients are required for optimum results. Overall survival of 249 solid cancer patients was evaluated in relation to the genetics and/or the expression on peripheral blood NKcs of inhibitory and activating killer-cell immunoglobulin-like receptors (iKIR and aKIR, respectively), HLA class I ligands, CD226 (also known as DNAM-1), and NKG2A. Compared with patients with higher expression, patients with low expression of CD226 on total NKcs showed shorter mean overall survival (60.7 vs. 98.0 months, < 0.001), which was further reduced in presence of telomeric aKIRs (KIR2DS1-DS5 and/or KIR3DS1, 31.6 vs. 96.8 months, < 0.001). KIR2DL2/S2, KIR3DL1, KIR2DL1, and KIR2DL3 NKc subsets in the presence of their cognate ligands primarily contributed to shortening patients' overall survival by increasing the sensitivity to CD226 downmodulation in aKIR-rich telomeric genotypes. In patients with high tumor burden who died during the follow-up period, aKIR-rich telomeric genotypes were associated with: (i) specific downmodulation of CD226 on educated NKcs but not on CD8 T cells or uneducated NKcs, (ii) lower expression of CD226 and higher expression of NKG2A on aKIR NKcs, and (iii) lower numbers of total CD56 NKcs. The reduced expression of CD226 on NKcs with aKIR-rich genotypes may be a biomarker indicative of NKc hyporesponsiveness in patients that could benefit from new NKc immune-stimulatory therapies.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0847DOI Listing
August 2019

Pretransplant ascites and encephalopathy and their influence on survival and liver graft rejection in alcoholic cirrhosis disease.

Arch Med Sci 2021 18;17(3):682-693. Epub 2019 Jun 18.

Immunology Service, Instituto Murciano de Investigación Biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Murcia, Spain.

Introduction: The Child-Pugh and model for end-stage liver disease (MELD) scores are widely used to predict the outcomes of liver transplant (LT). Both have similar prognostic values in most cases, although their benefits might differ in some specific conditions. The aim of our study was to analyze the influence of pre-transplant ascites and encephalopathy in post-transplant liver rejection development and survival in alcohol cirrhosis (AC) patients undergoing LT to determine the usefulness of the Child-Pugh score for the assessment of prognosis in such patients.

Material And Methods: Two hundred and eighty-one AC patients, classified according to viral infections and pre-transplant complications, were analyzed. Acute (AR) and chronic (CR) liver rejections and Child-Pugh, MELD and albumin-bilirubin (ALBI) scores were studied in all cases.

Results: Similar AC rejection percentages were observed in ascites or encephalopathy groups (18.5% and 16.5%, = 0.735), although a higher but not statistically significant AC rate was observed in patients with grade III ascites ( = 0.777) and with grade II encephalopathy ( = 0.089). Chronic rejection was only developed by 9.1% of AC patients, regardless of the presence of ascites (6.2%) or encephalopathy (5.5%). The presence of ascites and encephalopathy complications did not seem to influence post-transplant survival. Neither the Child-Pugh nor the ALBI score can be considered the best for predicting patient survival in the short or long term.

Conclusions: Ascites and encephalopathy do not seem to influence AC or CR in patient survival, regardless of the presence of viral infections, so in our study neither the Child-Pugh nor ALBI score seems to be the best score to predict the outcomes of these patients.
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http://dx.doi.org/10.5114/aoms.2018.80651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130464PMC
June 2019

KIR2DL2/S2 and KIR2DS5 in alcoholic cirrhotic patients undergoing liver transplantation.

Arch Med Sci 2021 9;17(3):764-774. Epub 2019 Apr 9.

Immunology Service, Instituto Murciano de Investigación Biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Murcia, Spain.

Introduction: The molecular mechanisms underlying alcoholic liver fibrosis and cirrhosis are not completely understood. Hepatic fibrosis involves the interplay of diverse cells and factors, including hepatic stellate cells (HSCs), Kupffer, NK cells, and T-lymphocyte subsets. Killer-cell immunoglobulin-like receptors (KIR) are membrane receptors involved in mediation between NK and activated HSCs, regulating NK cell function through their interaction with HLA-I molecules. The aim of this study was to analyse the genetic association between KIR genes and the susceptibility to or protection from alcoholic cirrhosis (AC) in a cohort of male AC patients undergoing liver transplantation (LT) with and without concomitant viral infections.

Material And Methods: KIR genotyping was performed in nuclear DNA extracted from 281 AC patients and compared with 319 male controls.

Results: Significant differences between total AC patients and healthy controls were only found in the case of KIR2DL2 and KIR2DS5. KIR2DL2 was significantly underrepresented in non-viral AC patients (52.6% vs. 63.3%; = 0.015), while patients heterozygous for KIR2DL2 were also underrepresented in the non-viral AC group compared with controls ( = 0.034). KIR2DS5 was overrepresented in this group compared with healthy controls ( = 0.002). All these observations were only evident in AC patients older than 54 years old.

Conclusions: Our data suggest a contrary effect of KIR2DL2 and KIR2DS5 in AC patients older than 54 years, in whom the presence of KIR2DL2 appears to be protective against AC, whereas the presence of KIR2DS5 seems to promote the fibrotic process, particularly in patients with no associated viral infection.
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http://dx.doi.org/10.5114/aoms.2019.84410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130473PMC
April 2019

Analysis of the information in mandatory reporting in victims of gender violence.

J Public Health Res 2018 Dec 20;7(3):1443. Epub 2018 Dec 20.

Department of Forensic Medicine, School of Medicine, University of Murcia, Murcia, Spain.

The healthcare professional plays a key role in the detection and subsequent channeling of a situation of violence to a judicial level for appropriate investigation. The mandatory reporting of gender violence has become a controversial issue among health care practitioners and victims. The objective of this study was to analyze the quality of the way in which injury reports on victims of gender violence is completed, through an analysis of the information they include, the readability and the degree to which the document can be understood. A retrospective study in a sample of 197 injury reports were performed from health services (primary care, hospital services and emergency services). We analyzed 22 variables related to the content, readability of the document, the victim's identification data as well as identification of the doctor responsible for assistance, the moment of assistance and the characteristics of the injury. The most frequent deficiencies in the data are identification of the doctor responsible for medical attention, the date on which the aggression occurred, a description of the injuries and the judgment of compatibility between the cause of injury (according to the victim) and the actual injury they have. The injury reports do not conform to the legal requirements needed in a document of such extraordinary importance. Greater awareness in health professionals concerning the importance of the injury report as a medicolegal document is needed so that the correct information can be provided to the relevant judicial authority.
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http://dx.doi.org/10.4081/jphr.2018.1443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321945PMC
December 2018

NK Cell Education in Tumor Immune Surveillance: DNAM-1/KIR Receptor Ratios as Predictive Biomarkers for Solid Tumor Outcome.

Cancer Immunol Res 2018 12 21;6(12):1537-1547. Epub 2018 Sep 21.

Immunology Service, Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain.

Natural killer cell (NKc)-based therapies offer promising outcomes in patients with tumors, but they could improve with appropriate selection of donors and optimization of methods to expand NKcs Education through licensing interactions of inhibitory killer cell immunoglobulin-like receptors (iKIR) and NKG2A with their cognate HLA class-I ligands optimizes NKc functional competence. This work has evaluated the role of licensing interactions in NKc differentiation and the survival of cancer patients. We have analyzed KIR and KIR-ligand genes, and the expression of activating (CD16 and DNAM-1/CD226) and inhibitory (NKG2A and iKIRs) receptors on peripheral blood NKcs in 621 healthy controls and 249 solid cancer patients (80 melanoma, 80 bladder, and 89 ovarian). Licensing interactions upregulated the expression of activating CD226, reduced that of iKIR receptors, and shifted the CD226/iKIR receptor ratio on NKc membranes to activating receptors. A high tumor burden decreased CD226 expression, reduced the ratio of CD226/iKIR, and negatively affected patient survival. The progression-free survival (38.1 vs. 67.0 months, < 0.002) and overall survival (56.3 vs. 99.6 months, < 0.00001) were significantly shorter in patients with lower expression of CD226 on NKcs. Hence, transformed cells can downmodulate these licensing-driven receptor rearrangements as a specific mechanism to escape NKc immune surveillance. Our results suggest the importance of the CD226/iKIR receptor ratio of NKcs induced by licensing interactions as critical determinants for solid cancer immune surveillance, and may provide predictive biomarkers for patient survival that may also improve the selection of donors for NKc immunotherapy.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0022DOI Listing
December 2018

Patient Sex in the Setting of Liver Transplant in Alcoholic Liver Disease.

Exp Clin Transplant 2019 06 28;17(3):355-362. Epub 2018 Jun 28.

From the Department of Legal and Forensic Medicine, Biomedical Research Institute, Regional Campus of International Excellence "Campus Mare Nostrum," Faculty of Medicine, University of Murcia, Murcia, Spain; and the Immunology Service, Instituto Murciano de Investigación Biosanitaria and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.

Objectives: The aim of this study was to analyze alcoholic cirrhosis in women who were to undergo liver transplant, including their biochemical and clinical characteristics, main complications, survival rates, and main causes of death compared with men with alcoholic cirrhosis.

Materials And Methods: Our study included 400 patients with alcoholic cirrhosis, which we divided according to sex and viral infections. Biochemical parameters and the presence and degree of ascites and encephalopathy, liver function status, and liver rejection and survival rates were analyzed from 1 to 10 years and the main cause of death at 10 years.

Results: Patients with nonviral alcoholic cirrhosis and liver transplant had significantly better survival rates (84.1%) at 1 year versus those with viral alcoholic cirrhosis (74.5%; P = .036). Men with nonviral alcoholic cirrhosis (14%) and women with hepatitis C virus (29%) had the lowest short-term survival rates. In long-term survival analysis, the lowest rate was observed in women with nonviral alcoholic cirrhosis (26.1%), and the highest rate was observed in women with hepatitis C virus (42.9%). Liver graft failure was one of the main causes of death in male patients (19.5%).

Conclusions: Women with alcoholic cirrhosis showed a higher rate of ascites and encephalopathy but lower liver graft rejection than men with alcoholic cirrhosis. Survival rates were similar between men and women, although slightly lower in women who had hepatitis C virus.
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http://dx.doi.org/10.6002/ect.2017.0302DOI Listing
June 2019

Quantification of nitrogenous bases, DNA and Collagen type I for the estimation of the postmortem interval in bone remains.

Forensic Sci Int 2017 Dec 4;281:106-112. Epub 2017 Nov 4.

Department of Legal and Forensic Medicine, University of Murcia, Spain.

Estimating the postmortem interval (PMI) is an important goal in forensic medicine and continues to be one of the most difficult tasks of the forensic investigator. Few accurate methods exist to determine the time since death of skeletonized human remains due to the great number of intrinsic and external factors that may alter the normal course of postmortem change. The purpose of this research was to assess the usefulness of various biochemical parameters, such as nitrogenous bases (adenine, guanine, purines, cytosine, thymine, pyrimidines, hypoxanthine and xanthine), DNA and Collagen Type I peptides to estimate PMI. These parameters were analysed in cortical bone for the establishment of data in a total of 80 long bones of 80 corpses (50 males, 30 females) with a mean age of 68.31 years (S.D.=18.021, range=20-97). The bones were removed from the cement niches of a cemetery in Murcia (south-eastern Spain), where they had lain for between 5 and 47 years (mean time 23.83 years, S.D.=10.85). Our results show a significant decrease in adenine (p=0.0004), guanine (p=0.0001), purines (p=0.0001), cytosine (p=0.0001), thymine (p=0.0226), pyrimidines (p=0.0002) and the number of peptides of Collagen type I (p=0.0053) in those with a PMI≥20 years. In a curvilinear regression analysis the results show that 30.6% of the variable PMI could be explained by guanine concentration, in bones with a PMI<20 years, while in cases of a PMI≥20 years, the variable that best explained membership of this group was adenine (38.0%). In the discriminant analysis applied to the all the variables as a function of PMI when two groups were established, 86.7% of the cases were correctly classified. These results show that the quantification of Collagen type I proteins and nitrogenous bases could be used as a complementary tool, together with other analyses, in the estimation of PMI.
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http://dx.doi.org/10.1016/j.forsciint.2017.10.039DOI Listing
December 2017

CD28 biomarker quantification and expression level profiles in CD4 T-lymphocytes in solid organ transplantation.

Transpl Immunol 2017 06 6;42:9-17. Epub 2017 Apr 6.

Department of Immunology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain. Electronic address:

The introduction of anti-calcineurin-based therapies has led to an increase in the one-year survival as well as graft function rates in patients undergoing solid organ transplantation (SOT). Nonetheless, early cellular acute rejection (EAR) incidence still remains a major challenge that irrevocably heads to poor outcomes. The mechanisms underlying CD4 T cell activation in SOT are still under research. In this sense, CD28 co-stimulatory molecule plays a pivotal role triggering CD4 T cell activation as well as survival maintenance. Previous own studies stated the role that CD4CD28 circulating T lymphocytes plays before and during EAR episodes. We assessed the percentage as well as the absolute number of CD28 molecules on CD4 T cells as predictive surrogate biomarker of EAR in a prospective cohort of liver and kidney transplant recipients. Quantitative analysis of CD28 was carried out on whole peripheral blood samples by flow cytometry. Decreased pre-transplant expression of CD28 was associated with EAR in both study groups. Furthermore, the expression of CD28 within the rejected group, experimented an up-regulation upon transplantation. These preliminary results suggest that patients undergoing liver or kidney transplant can be stratified at high risk of EAR according to their CD28 molecule expression on peripheral CD4 T lymphocytes.
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http://dx.doi.org/10.1016/j.trim.2017.04.001DOI Listing
June 2017

Killer immunoglobulin-like receptor repertoire analysis in a Caucasian Spanish cohort with inflammatory bowel disease.

Microbiol Immunol 2016 Nov;60(11):787-792

Immunology and Digestive Medicine Service, University Clinical Hospital Virgen de la Arrixaca-IMIB, Murcia 30120 Spain.

Immunological molecules are implicated in inflammatory disorders, including inflammatory bowel disease (IBD; Crohn disease [CD] and ulcerative colitis [UC]). Killer cell immunoglobulin-like receptors (KIRs) are also genetically variable proteins involved in immune function. They are expressed by NK cells and certain T lymphocytes, regulate specificity and function by interaction with HLA Class I molecules, may be either inhibitory or activating and are polymorphic both in terms of alleles and haplotype gene content. Genetic associations between activating KIRs and certain autoimmune and inflammatory diseases have been reported; however, a possible association between KIR and IBD remains unclear. The aim of this study was to determine the relationship between KIR repertoire and IBD pathologies in a Spanish cohort. KIR variability was analyzed using PCR-sequence specific oligonucleotide probes (SSOP). Inhibitory KIR2DL5 was found more frequently in UC and IBD patient groups than in healthy controls (P = 0.028 and P = 0.01, respectively), as was activating KIR2DS1 (P = 0.02, Pc > 0.05, UC vs. Controls; P = 0.001, Pc = 0.01, IBD vs Controls; P = 0.01, Pc > 0.05, Controls vs CR), KIR2DS5 (P = 0.0028, Pc = 0.04, Controls vs UC; P = 0.0001, Pc = 0.0017, Controls vs IBD; P = 0.01, Pc > 0.05, Controls vs CD) and KIR3DS1 (P = 0.012, Pc > 0.05, Controls vs IBD). Our data suggest that imbalance between activating and inhibitory KIR may partially explain the different pathogeneses of these IBDs and that there is a hypothetical role for the telomeric B region (which contains both KIR2DS5 and KIR2DS1) in these diseases.
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http://dx.doi.org/10.1111/1348-0421.12447DOI Listing
November 2016

Overexpression of KIR inhibitory ligands (HLA-I) determines that immunosurveillance of myeloma depends on diverse and strong NK cell licensing.

Oncoimmunology 2016 Apr 29;5(4):e1093721. Epub 2015 Oct 29.

Immunology Service, Instituto Murciano de investigación biosanitaria (IMIB) and Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), El Palmar , Murcia, Spain.

Missing self recognition makes cancer sensitive to natural killer cell (NKc) reactivity. However, this model disregards the NKc licensing effect, which highly increases NKc reactivity through interactions of inhibitory killer cell immunoglobulin-like receptors (iKIR) with their cognate HLA-I ligands. The influence of iKIR/HLA-ligand (HLA-C1/C2) licensing interactions on the susceptibility to and progression of plasma cell (PC) dyscrasias was evaluated in 164 Caucasian patients and 286 controls. Compared to controls, myeloma accumulates KIR2DL1L2L3 genotypes (2.8% vs. 13.2%,  < 0.01, OR = 5.29) and less diverse peripheral repertoires of NKc clones. Less diverse and weaker-affinity repertoires of iKIR2D/HLA-C licensing interactions increased myeloma susceptibility. Thus, the complete absence of conventional iKIR2D/HLA-C licensing interactions (KIR2DL1L2L3/C2C2, 2.56% vs. 0.35%; < 0.05; OR = 15.014), single-KIR2DL3/C1 (20.51% vs. 10.84%; < 0.05; OR = 2.795) and single-KIR2DL2/C1 (12.82% vs. 4.9%; < 0.01; OR = 5.18) interactions were over-represented in myeloma, compared to controls. Additionally, KIR2DL1L2L3 (20% vs. 83%, < 0.00001) as well as KIR3DL1 (23% vs. 82%, < 0.00001) genotypes had a dramatic negative impact on the 3-y progression-free survival (PFS), particularly in patients with low-tumor burden. Remarkably, myeloma-PCs, compared to K562 and other hematological cancers, showed substantial over-expression of HLA-I ("increasing-self" instead of missing-self), including HLA-C, and mild expression of ligands for NKc activating receptors (aRec) CD112, CD155, ULBP-1 and MICA/B, which apparently renders myeloma-PCs susceptible to lysis mainly by licensed NKc. KIR2DL1L2L3/C2C2 patients (with no conventional iKIR2D/HLA-C licensing interactions) lyse K562 but barely lyse myeloma-PCs (4% vs. 15%; < 0.05, compared to controls). These results support a model where immunosurveillance of no-missing-self cancers, e.g., myeloma, mainly depends on NKc licensing.
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http://dx.doi.org/10.1080/2162402X.2015.1093721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839374PMC
April 2016

Epidemiology, Evolution, and Long-Term Survival of Alcoholic Cirrhosis Patients Submitted to Liver Transplantation in Southeastern Spain.

Alcohol Clin Exp Res 2016 Apr 25;40(4):794-805. Epub 2016 Mar 25.

Immunology Service , Clinic University Hospital Virgen de la Arrixaca, Murcia, Spain.

Background: Alcoholic cirrhosis (AC) is a common cause of death among individuals abusing alcohol. In the last resort, liver transplantation (LT) is considered the only solution to save the patient's life, generating socioeconomic and public health problems. Clinical and sociodemographic characteristics, rejection frequency, and short- and long-term graft survival are not well known in end-term AC patients undergoing LT. The aim was to determine the sociodemographic and clinical characteristics, their incidence in LT, main pre- and posttransplant complications, and short- and long-term post-transplant graft survival in AC patients in southeastern Spain.

Methods: The medical records of 1,026 patients who underwent LT over the last 23 years were retrospectively reviewed, and demographic data and posttransplant survivals were analyzed and compared. Biochemical characteristics, major pre- and posttransplant complications and short- and long-term survivals were analyzed in a total of 398 male patients with AC undergoing LT.

Results: AC and viral cirrhosis are the main indications for LT in our study. Mostly represented in our study are AC men without associated viral infections with a mean age of 53.06 years. Main pretransplant complications in AC patients are ascites (78.3%) and encephalopathy (43.5%), while acute graft rejection is the most common liver posttransplant complication (26.6%), nevertheless with low graft loss frequency (1.1%). AC and autoimmune cirrhosis show the best posttransplant survival in both the short and long term. Patients with AC included on the waiting list for LT were Child-Pugh class B (52.1%) and Model for End-Stage Liver Disease score of 10 to 19 (71.2%). The highest percentage of AC patient survival was observed at 1 year posttransplant (81.2%) and progressively decreased over time up to 10 years posttransplant (69.6%). Pretransplant complications such as ascites and encephalopathy did not have an influence on the percentage of posttransplant survivals, although better survival rates were observed in nonviral AC patients.

Conclusions: AC without viral infections is the main indication for LT in southeastern Spain although its frequency has decreased in last decade. AC is a good indication for LT for its high survival rate and few posttransplant complications. Despite having a high percentage of pretransplant complications (ascites and encephalopathy) but does not appear to influence survivals being observed posttransplant survival rates above those expected. Conversely, viral infections in the patient with AC decrease patient survivals. The main future goals are design new strategies to detect, treat, and reduce AC frequency in our population and know alcoholic recidivism rate posttransplant in our population.
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http://dx.doi.org/10.1111/acer.13013DOI Listing
April 2016

Radial derivatives of the mouse ventral pallium traced with Dbx1-LacZ reporters.

J Chem Neuroanat 2016 09 31;75(Pt A):2-19. Epub 2015 Dec 31.

Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California at San Francisco, San Francisco, CA 94158, USA.

The progeny of Dbx1-expressing progenitors was studied in the developing mouse pallium, using two transgenic mouse lines: (1) Dbx1(nlslacZ) mice, in which the gene of the β-galactosidase reporter (LacZ) is inserted directly under the control of the Dbx1 promoter, allowing short-term lineage tracing of Dbx1-derived cells; and (2) Dbx1(CRE) mice crossed with a Cre-dependent reporter strain (ROSA26(loxP-stop-loxP-LacZ)), in which the Dbx1-derived cells result permanently labeled (Bielle et al., 2005). We thus examined in detail the derivatives of the postulated longitudinal ventral pallium (VPall) sector, which has been defined among other features by its selective ventricular zone expression of Dbx1 (the recent ascription by Puelles, 2014 of the whole olfactory cortex primordium to the VPall was tested). Earlier notions about a gradiental caudorostral reduction of Dbx1 signal were corroborated, so that virtually no signal was found at the olfactory bulb and the anterior olfactory area. The piriform cortex was increasingly labeled caudalwards. The only endopiriform grisea labeled were the ventral endopiriform nucleus and the bed nucleus of the external capsule. Anterior and basolateral parts of the whole pallial amygdala also were densely marked, in contrast to the negative posterior parts of these pallial amygdalar nuclei (leaving apart medial amygdalar parts ascribed to subpallial or extratelencephalic sources of Dbx1-derived GABAergic and non-GABAergic neurons). Alternative tentative interpretations are discussed to explain the partial labeling obtained of both olfactory and amygdaloid structures. This includes the hypothesis of an as yet undefined part of the pallium, potentially responsible for the posterior amygdala, or the hypothesis that the VPall may not be wholly characterized by Dbx1 expression (this gene not being necessary for VPall molecular distinctness and histogenetic potency), which would leave a dorsal Dbx1-negative VPall subdomain of variable size that might contribute partially to olfactory and posterior amygdalar structures.
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http://dx.doi.org/10.1016/j.jchemneu.2015.10.011DOI Listing
September 2016

MHC class I chain-related gene a diversity in patients with cutaneous malignant melanoma from southeastern Spain.

Dis Markers 2015 9;2015:831864. Epub 2015 Mar 9.

Immunology Department, University Clinical Hospital Virgen de la Arrixaca, Carretera Madrid-Cartagena, El Palmar, 30120 Murcia, Spain.

A limited number of studies have been performed so far on the polymorphism in the transmembrane region (exon 5) of the major histocompatibility complex class I chain-related gene A (MICA) in patients with melanoma. However, the influence of MICA polymorphism in extracellular domains (exons 2, 3, and 4) has not been investigated on melanoma disease. This study aims to characterize the influence of extracellular MICA polymorphism, and its previously described linkage disequilibrium with HLA-B locus, on patients with cutaneous melanoma from southeastern Spain. For this purpose, MICA and HLA-B genotyping was performed in 233 patients and 200 ethnically matched controls by luminex technology. Patients were classified according to the presence of methionine or valine at codon 129 of MICA gene. We found a high frequency of MICA(*)009 in melanoma patients compared with controls (P = 0.002, Pc = 0.03). Our results also showed an association between MICA(*)009 and HLA-B(*)51 alleles in both patients and controls. This association was stronger in patients than controls (P = 0.015). However, a multivariate logistic regression model showed that neither MICA(*)009 nor the combination MICA(*)009/HLA-B(*)51 was associated with melanoma susceptibility. No relationship was observed between MICA-129 dimorphism and melanoma nor when MICA polymorphism was evaluated according to clinical findings at diagnosis.
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http://dx.doi.org/10.1155/2015/831864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370202PMC
December 2015

KIR3DL2 is a coinhibitory receptor on Sézary syndrome malignant T cells that promotes resistance to activation-induced cell death.

Blood 2014 Nov;124(22):3330-2

Institut National de la Santé et de la Recherche Médicale U976, Onco-Dermatology, Immunology and Cutaneous Stem Cells, Paris, France University Paris Diderot, Sorbonne Paris Cité, Paris, France.

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http://dx.doi.org/10.1182/blood-2014-09-598995DOI Listing
November 2014

KIR gene mismatching and KIR/C ligands in liver transplantation: consequences for short-term liver allograft injury.

Transplantation 2013 Apr;95(8):1037-44

Immunology Service, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas and Instituto Murciano de Investigación Biomédica, Murcia, Spain.

Background: Killer immunoglobulin-like receptors (KIRs) bind human leukocyte antigen (HLA) class-I (HLA-I) ligands and regulate functions of natural killer cells and subsets of T cells. KIR/HLA-I interactions allow predicting natural killer cell alloreactivity in hematopoietic stem cell transplantation and in HLA-compatible kidney transplants, but its meaning in liver transplantation remains controversial.

Methods: KIR and HLA genotypes were studied in 402 liver transplants, using sequence-specific oligonucleotides and primer methods. Recipients and donor KIRs, HLA-C genotypes, KIR gene mismatches (MMs) between recipient-donor pairs, and KIR/HLA-ligand combinations were analyzed in overall transplantations, in the acute rejection (AR; n=110) and non-AR (n=292) groups.

Results: KIR gene MMs between recipients and donors, mainly in activating KIRs, and KIR2DL3 and KIR2DS1 of recipients in the presence of donor C2 ligands, significantly enhanced early AR rate (P<0.05), with KIR2DL3 and KIR2DS1 exhibiting a synergic effect in dependence of the donor C2 ligand number (χ2=7.662, P=0.022). KIR2DL3, KIR2DS1, and also KIR2DS4 significantly influenced short-term graft survival, with a benefit for transplantations combining KIR2DL3 recipients and donors having C1 ligands (log rank, P<0.019 at 1 year; hazards ratio [HR], 0.321; 95% confidence interval [CI], 0.107-0.962; P=0.042), whereas KIR2DS1 and KIR2DS4 recipients combined with donors lacking C1 ligands (C2/C2) exhibited a worse graft survival (log rank, P=0.035 at 6 months; HR, 7.713; 95% CI, 2.156-27.369; P=0.002 for KIR2DS1; and log rank, P=0.006 at 1 year; HR, 3.794; 95% CI, 1.267-11.365; P=0.017 for KIR2DS4).

Conclusions: This study shows that KIR gene-gene MMs increase AR and that KIRs/C ligands associated to AR and KIR2DS4/C ligands also influence short-term graft survival.
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http://dx.doi.org/10.1097/TP.0b013e318286486cDOI Listing
April 2013

KIR gene variability in cutaneous malignant melanoma: influence of KIR2D/HLA-C pairings on disease susceptibility and prognosis.

Immunogenetics 2013 May 31;65(5):333-43. Epub 2013 Jan 31.

Immunology Department, Virgen de la Arrixaca University Hospital, El Palmar, Murcia, Spain.

Natural killer and CD8(+) T cells are believed to be involved in the immune protection against melanoma. Their function may be regulated by a group of receptors defined as killer immunoglobulin-like receptors (KIRs) and their cognate HLA class I ligands. In this study, we analyzed the influence of KIR genes and KIR/HLA-I combinations on melanoma susceptibility and/or prognosis in a Spanish Caucasian population. For this purpose, KIR genotyping by PCR-SSP and HLA-C genotyping by reverse PCR-SSO were performed in 187 melanoma patients and 200 matched controls. We found a significantly low frequency of KIR2DL3 in nodular melanoma (NM) patients (P = 0.001) and in ulcerated melanoma patients (P < 0.0001). Similarly, the KIR2DL3/C1 combination was significantly decreased in melanoma patients (Pc = 0.008) and in patients with sentinel lymph node (SLN) melanoma metastasis (Pc = 0.002). Multivariate logistic regression models showed that KIR2DL3 behaves as a protective marker for NM and ulcerated melanoma (P = 0.02, odds ratio (OR) = 0.14 and P = 0.04, OR = 0.28, respectively), whereas the KIR2DL3/C1 pair acts as a protective marker for melanoma (P = 0.017, OR = 0.54), particularly superficial spreading melanoma (P = 0.02, OR = 0.52), and SLN metastasis (P = 0.0004, OR = 0.14). In contrast, the KIR2DL3(-)/C1C2 genotype seems to be correlated with NM and ulceration. We also report that the KIR2DL1(+)/S1(-)/C2C2 genotype is associated with susceptibility to melanoma and SLN metastasis. Altogether, the study of KIR2D genes and HLA-C ligands may help in assessing cutaneous melanoma risk and prognosis.
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http://dx.doi.org/10.1007/s00251-013-0682-0DOI Listing
May 2013

Multiple telencephalic and extratelencephalic embryonic domains contribute neurons to the medial extended amygdala.

J Comp Neurol 2011 Jun;519(8):1505-25

Department of Experimental Medicine, Faculty of Medicine, University of Lleida, Institut of Biomedical Research of Lleida (IRBLLEIDA), Lleida, Spain.

Dysfunctions in emotional control and social behavior are behind human neuropsychiatric disorders, some of which are associated with an alteration of amygdalar development. The medial extended amygdala is a key telencephalic center for control of social behavior, but very little is known about its development. We used in vitro migration assays for analyzing the origin of the neurons of the medial extended amygdala in mouse embryos (E13.5-E16.5). We compared the migration assays with immunofluorescence/immunohistochemistry for calbindin and radial glial fibers and with mRNA expression of several genetic markers of distinct forebrain subdivisions. We provide experimental evidence for multiple embryonic origins of the principal neurons of the medial extended amygdala. In particular, we provide novel evidence indicating that a major part of the neurons derives from a caudoventral pallidal subdivision (previously called or included as part of the anterior peduncular area), forming a cell corridor with similar molecular features (expression of Lhx6 and calbindin), connectivity, and function, which relates to reproductive behavior. We also provide novel experimental evidence indicating that the ventral pallium produces some neurons for the medial amygdala, which correlates with data from Lhx9 expression. Our results also confirm that some neurons of the medial extended amygdala originate in the preoptic area (our results indicate that these cells specifically originate in its commissural subdivision) and the supraoptoparaventricular domain of the hypothalamus. Our study helps to set up the foundations for a better understanding of medial amygdalar control of behavior in normal and abnormal conditions.
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http://dx.doi.org/10.1002/cne.22581DOI Listing
June 2011

Olfactory and amygdalar structures of the chicken ventral pallium based on the combinatorial expression patterns of LIM and other developmental regulatory genes.

J Comp Neurol 2009 Sep;516(3):166-86

Laboratory of Brain Development and Evolution, Department of Experimental Medicine, Faculty of Medicine, University of Lleida, Institut of Biomedical Research of Lleida (IRBLLEIDA), 25008 Lleida, Spain.

We compared the combinatorial expression patterns of several LIM domain-containing regulatory genes in the ventrolateral pallium of mouse and chicken, in order to identify the homologues of the ventral pallial amygdala and other olfactory structures in birds. Lmo3, Lmo4, Lhx2, and Lhx9 showed comparable expression patterns in the telencephalon of mouse and chicken, which allowed distinction of the ventrolateral pallium and, particularly, the ventral pallial amygdala and entorhinal cortex. Lmo3 was expressed in most of the ventrolateral pallium in both species, including, in chicken, the piriform cortex and dorsal ventricular ridge (mesopallium, nidopallium, and arcopallium) and, in mouse, the piriform cortex, most of the claustral complex, and the pallial amygdala. Lhx9 was differentially expressed in the ventral pallium, where it was restricted to its rostral (olfactory bulb) and caudal (amygdalar and entorhinal) poles. In the caudal pole, expression of Lhx9 overlapped that of its paralog Lhx2. According to these expression patterns, the chicken ventral pallial amygdala appears to include the caudal dorsolateral pallium, the caudal nidopallium, and the whole arcopallium, and each one relates to a distinct ventricular sector. Finally, the combinatorial expression patterns of Lmo3, Lhx9, and Lmo4 distinguished four distinct subdivisions in the superficial, olfactorecipient area of the chicken ventral pallium, which appear comparable to the piriform, entorhinal, amygdalopiriform, and amygdalar cortices of mammals. The results are discussed in the context of the two existing, opposite views on the homology of the dorsal ventricular ridge of sauropsids and in terms of the evolution of pallial derivatives.
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http://dx.doi.org/10.1002/cne.22102DOI Listing
September 2009

Histogenetic compartments of the mouse centromedial and extended amygdala based on gene expression patterns during development.

J Comp Neurol 2008 Jan;506(1):46-74

Department of Human Anatomy, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain.

The amygdala controls emotional and social behavior and regulates instinctive reflexes such as defense and reproduction by way of descending projections to the hypothalamus and brainstem. The descending amygdalar projections are suggested to show a cortico-striato-pallidal organization similar to that of the basal ganglia (Swanson [2000] Brain Res 886:113-164). To test this model we investigated the embryological origin and molecular properties of the mouse centromedial and extended amygdalar subdivisions, which constitute major sources of descending projections. We analyzed the distribution of key regulatory genes that show restricted expression patterns within the subpallium (Dlx5, Nkx2.1, Lhx6, Lhx7/8, Lhx9, Shh, and Gbx1), as well as genes considered markers for specific subpallial neuronal subpopulations. Our results indicate that most of the centromedial and extended amygdala is formed by cells derived from multiple subpallial subdivisions. Contrary to a previous suggestion, only the central--but not the medial--amygdala derives from the lateral ganglionic eminence and has striatal-like features. The medial amygdala and a large part of the extended amygdala (including the bed nucleus of the stria terminalis) consist of subdivisions or cell groups that derive from subpallial, pallial (ventral pallium), or extratelencephalic progenitor domains. The subpallial part includes derivatives from the medial ganglionic eminence, the anterior peduncular area, and possibly a novel subdivision, called here commissural preoptic area, located at the base of the septum and related to the anterior commissure. Our study provides a molecular and morphological foundation for understanding the complex embryonic origins and adult organization of the centromedial and extended amygdala.
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http://dx.doi.org/10.1002/cne.21524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916653PMC
January 2008

Dynamic patterns of colocalization of calbindin, parvalbumin and GABA in subpopulations of mouse basolateral amygdalar cells during development.

J Chem Neuroanat 2008 Jan 5;35(1):67-76. Epub 2007 Jul 5.

Department of Cell Biology, Genetics, and Physiology, Faculty of Sciences, University of Málaga, 29071 Málaga, Spain.

Calbindin cells represent a major interneuron subtype of the cortical/pallial regions, such as the basolateral amygdala, which are often analyzed in studies of tangential migration of interneurons from the subpallial ganglionic eminences to the pallium/cortex. However, previous evidence suggests that during development the calbindin cells may include more than one of the interneuron subtypes found in the adult pallium/cortex. Furthermore, in the adult basolateral amygdala, calbindin cells include a subpopulation of non-GABAergic (non-interneuron) cells. To better characterize these cells throughout development, in the present study we investigated the colocalization of calbindin, parvalbumin and GABA in cells of the mouse basolateral amygdala during late embryonic (E16.5) and several postnatal ages from birth until 4 weeks after birth (P0, P10 and P28). Our results indicate that CB, PV and GABA show a dynamic pattern of colocalization in cells of the mouse basolateral amygdalar nucleus throughout development. From E16.5 through P28, the majority of CB+ neurons and virtually all PV+ neurons are GABAergic. However, after P10, the percentage of GABAergic CB+ cells decline from 96% to 70%. Furthermore, while only 9% of CB+ neurons are PV+ at P10, this percentage raises to 42% at P28. At all postnatal ages studied, the majority of the PV+ cells are CB+, suggesting that PV+ interneurons develop postnatally mainly as a subpopulation within the CB+ cells of the basolateral amygdalar nucleus. These results are important for interpreting data from interneuron migration.
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http://dx.doi.org/10.1016/j.jchemneu.2007.06.003DOI Listing
January 2008

Subpallial origin of part of the calbindin-positive neurons of the claustral complex and piriform cortex.

Brain Res Bull 2005 Sep;66(4-6):470-4

Department of Human Anatomy, Faculty of Medicine, University of Murcia, Spain.

The aim of the present study was to investigate whether part of the calbindin-positive neurons of the claustral complex and piriform cortex originate in the subpallium. To that end, we prepared organotypic cultures of embryonic telencephalic slices, and applied the cell tracker CMTMR to the ventricular/subventricular zone of the lateral or medial ganglionic eminence. Following 48 h of incubation, we observed a number of CMTMR-labeled cells (showing red fluorescence) of subpallial origin in the claustral complex and piriform cortex. To know whether some of these cells of subpallial origin were calbindin-positive, we performed immunofluorescence for calbindin using an Alexa 488-conjugated secondary antiserum (green fluorescence). Our results showed that some of the CMTMR-labeled cells of subpallial origin in the claustral complex and piriform cortex are calbindin-positive (and possibly GABAergic). The subpallial origin of part of these cells was confirmed by observation of double labeled neurons in the claustral complex that expressed both Lhx6 mRNA (a marker of cells derived from the medial ganglionic eminence) and calbindin. Future studies will be required to analyze the existence of a subpopulation of non-GABAergic calbindin cells in the claustral complex and piriform cortex, and to know their origin.
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http://dx.doi.org/10.1016/j.brainresbull.2005.05.006DOI Listing
September 2005

Expression patterns of developmental regulatory genes show comparable divisions in the telencephalon of Xenopus and mouse: insights into the evolution of the forebrain.

Brain Res Bull 2005 Sep 24;66(4-6):297-302. Epub 2005 Feb 24.

Department of Human Anatomy, Faculty of Medicine, University of Murcia, Spain.

In this study, we review data on the existence of comparable divisions and subdivisions in the telencephalon of different groups of tetrapods based on expression of some developmental regulatory genes, having a particular focus in the comparison of the anuran amphibian Xenopus and the mouse. The available data on Xenopus, mouse, chick and turtle indicate that apparently all tetrapod groups possess the same molecularly distinct divisions and subdivisions in the telencephalon. This basic organization was likely present in the telencephalon of stem tetrapods. Each division/subdivision is characterized by expression of a unique combination of developmental regulatory genes, and appears to represent a self-regulated and topologically constant histogenetic brain compartment that gives rise to specific groups of cells. This interpretation has an important consequence for searching homologies, since a basic condition for cell groups in different vertebrates to be considered homologous is that they originate in the same compartment. However, evolution may allow individual cell groups derived from comparable (field homologous) subdivisions to be either similar or dissimilar across the vertebrate groups, giving rise to several possible scenarios of evolution, which include both the evolutionary conservation of similar (homologous) cells or the production of novel cell groups. Finally, available data in the lamprey, a jawless fish, suggest that not all telencephalic subdivisions were present at the origin of vertebrates, raising important questions about their evolution.
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http://dx.doi.org/10.1016/j.brainresbull.2005.02.003DOI Listing
September 2005

Development of neurons and fibers containing calcium binding proteins in the pallial amygdala of mouse, with special emphasis on those of the basolateral amygdalar complex.

J Comp Neurol 2005 Aug;488(4):492-513

Department of Human Anatomy, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain.

We studied the development of neurons and fibers containing calbindin, calretinin, and parvalbumin in the mouse pallial amygdala, with special emphasis on those of the basolateral amygdalar complex. Numerous calbindin-immunoreactive (CB+) cells were observed in the incipient basolateral amygdalar complex and cortical amygdalar area from E13.5. At E16.5, CB+ cells became more abundant in the lateral and basolateral nuclei than in the basomedial nucleus, showing a pattern very similar to that of gamma-aminobutyric acid (GABA)ergic neurons. Many CB+ cells observed in the pallial amygdala appeared to originate in the anterior entopeduncular area/ganglionic eminences of the subpallium. The density of CB+ cells gradually increased in the pallial amygdala until the first postnatal week and appeared to decrease later, coinciding with the postnatal appearance of parvalbumin cells and raising the possibility of a partial phenotypic shift. Calretinin (CR) immunoreactivity could be observed in a few cells and fibers in the pallial amygdala at E14.5, and by E16.5 it became a good marker of the different nuclei of the basolateral amygdalar complex. Numerous CB+ and CR+ varicosities, part of which have an intrinsic origin, were observed in the basolateral amygdalar complex from E16.5, and some surrounded unstained perikarya and/or processes before birth, indicating an early formation of inhibitory networks. Each calcium binding protein showed a distinct spatiotemporal expression pattern of development in the mouse pallial amygdala. Any alteration in the development of neurons and fibers containing calcium binding proteins of the pallial amygdala may result in important disorders of emotional and social behavior.
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http://dx.doi.org/10.1002/cne.20608DOI Listing
August 2005