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BACKGROUND: Bone Marrow MSCs are an appealing source for several cell-based therapies. Many bioreactors, as the Quantum Cell Expansion System, have been developed to generate a large number of MSCs under Good Manufacturing Practice conditions by using Human Platelet Lysate (HPL). Previously we isolated in the human bone marrow a novel cell population, named Mesodermal Progenitor Cells (MPCs), which we identified as precursors of MSCs. MPCs could represent an important cell source for regenerative medicine applications. As HPL gives rise to a homogeneus MSC population, limiting the harvesting of other cell types, in this study we investigated the efficacy of pooled human AB serum (ABS) to provide clinically relevant numbers of both MSCs and MPCs for regenerative medicine applications by using the Quantum System. METHODS: Bone marrow aspirates were obtained from healthy adult individuals undergoing routine total hip replacement surgery and used to generate primary cultures in the bioreactor. HPL and ABS were tested as supplements to culture medium. Morphological observations, cytofluorimetric analysis, lactate and glucose level assessment were performed. RESULTS: ABS gave rise to both heterogeneous MSC and MPC population. About 95% of cells cultured in HPL showed a fibroblast-like morphology and typical mesenchymal surface markers, but MPCs were scarcely represented. DISCUSSION: The use of ABS appeared to sustain a large scale MSC production, as well as the recovery of a subset of MPCs, and resulted a suitable alternative to HPL in the cell generation based on the Quantum System.
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Reactores Biológicos , Recolección de Muestras de Sangre/métodos , Células de la Médula Ósea/citología , Técnicas de Cultivo de Célula/instrumentación , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Suero/fisiología , Anciano , Anciano de 80 o más Años , Células de la Médula Ósea/fisiología , Técnicas de Cultivo de Célula/métodos , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Medios de Cultivo/farmacología , Humanos , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/fisiología , Persona de Mediana Edad , Datos Preliminares , Células Madre/citología , Células Madre/fisiologíaRESUMEN
The possible cooperation between hypnotizability-related and placebo mechanisms in pain modulation has not been consistently assessed. Here, we investigate possible genetic bases for such cooperation. The OPRM1 gene, which encodes the µ1 opioid receptor-the primary site of action for endogenous and exogenous opioids-is polymorphic in the general population for the missense mutation Asn40Asp (A118G, rs1799971). The minor allele 118G results in decreased levels of OPRM1 mRNA and protein. As a consequence, G carriers are less responsive to opioids. The aim of the study was to investigate whether hypnotizability is associated with the presence of the OPRM1 polymorphism. Forty-three high and 60 low hypnotizable individuals, as well as 162 controls, were genotyped for the A118G polymorphism of OPRM1. The frequency of the G allele was significantly higher in highs compared to both lows and controls. Findings suggest that an inefficient opioid system may be a distinctive characteristic of highs and that hypnotic assessment may predict lower responsiveness to opioids.
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Hipnosis , Receptores Opioides mu/genética , Estudios de Casos y Controles , Frecuencia de los Genes/genética , Humanos , Polimorfismo de Nucleótido Simple/genética , Polimorfismo de Nucleótido Simple/fisiología , Receptores Opioides mu/fisiologíaRESUMEN
BACKGROUND: Hepatitis E virus (HEV) is a zoonotic agent that causes acute hepatitis in humans with sporadic infections and outbreaks in developing countries worldwide. The global spread of HEV remains underestimated because of subclinical infections and lack of sensitive diagnostic assays. AIMS: To study the prevalence of HEV antibodies (anti-HEV) in sera of blood-donors and patients with chronic-liver-disease and chronic-renal-disease, using newly developed anti-HEV assays. METHODS: 396 sera from 199 blood-donors, 109 chronic-liver-disease patients and 88 chronic-renal-disease patients and three standard reference serum panels were tested in parallel with a sensitive reference anti-HEV assay and newly developed assays for IgA, IgM and total anti-HEV based on HEV-like-particles produced by recombinant baculo-viruses. RESULTS: Overall, total anti-HEV was detected in 12.9% (7.0% blood-donors, 9.2% and 30.7% chronic-liver-disease patients and chronic-renal-disease patients, respectively). We observed a higher anti-HEV prevalence in older subjects and in chronic-renal-disease patients in relation with degree on immune-depression (p<0.001). Results from reference serum panels showed an optimal and slightly better performance of the new assay over the commercially available assay. CONCLUSIONS: Newly developed anti-HEV assays using recombinant HEV-like-particles showed optimal diagnostic performances assessing that HEV-infection is endemic in Italy with seroprevalence ranging from 7% to 30% in blood donors and immune-compromised hosts, respectively.
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Anticuerpos Antivirales/sangre , Virus de la Hepatitis E/inmunología , Hepatitis E/sangre , Hepatitis E/epidemiología , Inmunoensayo/métodos , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Donantes de Sangre/estadística & datos numéricos , Enfermedad Crónica , Femenino , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina M/sangre , Italia/epidemiología , Hepatopatías/sangre , Masculino , Persona de Mediana Edad , Prevalencia , Insuficiencia Renal Crónica/sangre , Adulto JovenRESUMEN
BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) modulate the immune response and represent a potential treatment for inflammatory and autoimmune diseases. We hypothesized that this feature could be potentiated by co-administering anti-inflammatory cytokines. In this article, we asked whether engineering of Wharton Jelly-derived human MSCs (WJ-hMSCs) to express an anti-inflammatory cytokine increases cell immunomodulatory properties without altering their native features. METHODS: We used Epstein-Barr virus-derived interleukin-10 (vIL-10), which shares some immunosuppressive properties with human IL-10 but lacks immunostimulatory activity. Engineering was accomplished by transducing WJ-hMSCs with a self-inactivating feline immunodeficiency virus-derived vector co-expressing vIL-10 and herpes simplex virus type-1 thymidine kinase (TK). TK was added to allow future tracking of WJ-hMSC in vivo by positron electron tomography (PET). RESULTS: The results show that (i) expression of TK and/or vIL-10 does not change WJ-hMSC phenotypic and functional properties; (ii) vIL-10 is secreted, biologically active and enhances the immunosuppressing functions of WJ-hMSCs; (iii) v-IL10 and TK can be produced simultaneously by the same cells and do not interfere with each other. DISCUSSION: WJ-hMSCs engineered to secrete vIL-10 could be a powerful tool for adoptive cell therapy of immune-mediated diseases, and therefore, additional studies are warranted to confirm their efficacy in suitable animal disease models.
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Interleucina-10/metabolismo , Timidina Quinasa/metabolismo , Gelatina de Wharton/citología , Animales , Línea Celular , Células HEK293 , Herpesvirus Humano 4/genética , Humanos , Virus de la Inmunodeficiencia Felina/genética , Terapia de Inmunosupresión , Inmunosupresores , Inmunoterapia Adoptiva/métodos , Interleucina-10/genética , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/inmunología , Timidina Quinasa/genética , Gelatina de Wharton/metabolismoAsunto(s)
Sangre Fetal , Educación en Salud , Conocimientos, Actitudes y Práctica en Salud , Madres/psicología , Embarazo/psicología , Donantes de Tejidos , Obtención de Tejidos y Órganos , Adulto , Centros de Asistencia al Embarazo y al Parto , Femenino , Ginecología , Humanos , Italia , Partería , Obstetricia , Servicio de Ginecología y Obstetricia en Hospital , Folletos , Médicos/psicología , Relaciones Profesional-Paciente , Encuestas y Cuestionarios , Donantes de Tejidos/psicologíaRESUMEN
Higher brain dopamine content depending on lower activity of Catechol-O-Methyltransferase (COMT) in subjects with high hypnotizability scores (highs) has been considered responsible for their attentional characteristics. However, the results of the previous genetic studies on association between hypnotizability and the COMT single nucleotide polymorphism (SNP) rs4680 (Val(158)Met) were inconsistent. Here, we used a selective genotyping approach to re-evaluate the association between hypnotizability and COMT in the context of a two-SNP haplotype analysis, considering not only the Val(158)Met polymorphism, but also the closely located rs4818 SNP. An Italian sample of 53 highs, 49 low hypnotizable subjects (lows), and 57 controls, were genotyped for a segment of 805 bp of the COMT gene, including Val(158)Met and the closely located rs4818 SNP. Our selective genotyping approach had 97.1% power to detect the previously reported strongest association at the significance level of 5%. We found no evidence of association at the SNP, haplotype, and diplotype levels. Thus, our results challenge the dopamine-based theory of hypnosis and indirectly support recent neuropsychological and neurophysiological findings reporting the lack of any association between hypnotizability and focused attention abilities.
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AIMS/HYPOTHESIS: Previous work has demonstrated that beta cell amount (whether measured as beta cell mass, beta cell volume or insulin-positive area) is decreased in type 2 diabetes; however, recent findings suggest that mechanisms other than death may contribute to beta cell failure in this disease. To better characterise beta cell mass and function in type 2 diabetes, we performed morphological, ultra-structural and functional studies using histological samples and isolated islets. METHODS: Pancreases from ten non-diabetic (ND) and ten matched type 2 diabetic organ donors were studied by insulin, glucagon and chromogranin A immunocytochemistry and electron microscopy (EM). Glucose-stimulated insulin secretion was assessed using isolated islets and studies were performed using independent ND islet preparations after 24 h exposure to 22.2 mmol/l glucose. RESULTS: Immunocytochemistry showed that the fractional islet insulin-positive area was lower in type 2 diabetic islets (54.9 ± 6.3% vs 72.1 ± 8.7%, p < 0.01), whereas glucagon (23.3 ± 5.4% vs 20.2 ± 5.3%) and chromogranin A (86.4 ± 6.1% vs 89.0 ± 5.5%) staining was similar between the two groups. EM showed that the proportion of beta cells in type 2 diabetic islets was only marginally decreased; marked beta cell degranulation was found in diabetic beta cells; these findings were all reproduced after exposing isolated ND islets to high glucose. Glucose-stimulated insulin secretion was 4050% lower from type 2 diabetic islets (p < 0.01), which again was mimicked by culturing non-diabetic islets in high glucose. CONCLUSIONS/INTERPRETATION: These results suggest that, at least in subgroups of type 2 diabetic patients, the loss of beta cells as assessed so far might be overestimated, possibly due to changes in beta cell phenotype other than death, also contributing to beta cell failure in type 2 diabetes.
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Cromogranina A/metabolismo , Diabetes Mellitus Tipo 2/patología , Glucagón/metabolismo , Células Secretoras de Insulina/patología , Insulina/metabolismo , Páncreas/patología , Anciano , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Microscopía ElectrónicaAsunto(s)
Técnicas de Cultivo de Célula , Sangre Fetal/citología , Células Madre Mesenquimatosas/citología , Antígenos CD/análisis , Dióxido de Carbono/farmacología , Medios de Cultivo/farmacología , Antígenos HLA/análisis , Humanos , Recién Nacido , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/enzimología , Estrés Oxidativo , Oxígeno/farmacología , Compuestos de Sulfhidrilo/sangre , gamma-Glutamiltransferasa/sangreRESUMEN
Cancer development and chemo-resistance are often due to impaired functioning of the p53 tumor suppressor through genetic mutation or sequestration by other proteins. In glioblastoma multiforme (GBM), p53 availability is frequently reduced because it binds to the Murine Double Minute-2 (MDM2) oncoprotein, which accumulates at high concentrations in tumor cells. The use of MDM2 inhibitors that interfere with the binding of p53 and MDM2 has become a valid approach to inhibit cell growth in a number of cancers; however little is known about the efficacy of these inhibitors in GBM. We report that a new small-molecule inhibitor of MDM2 with a spirooxoindolepyrrolidine core structure, named ISA27, effectively reactivated p53 function and inhibited human GBM cell growth in vitro by inducing cell cycle arrest and apoptosis. In immunoincompetent BALB/c nude mice bearing a human GBM xenograft, the administration of ISA27 in vivo activated p53, inhibited cell proliferation and induced apoptosis in tumor tissue. Significantly, ISA27 was non-toxic in an in vitro normal human cell model and an in vivo mouse model. ISA27 administration in combination with temozolomide (TMZ) produced a synergistic inhibitory effect on GBM cell viability in vitro, suggesting the possibility of lowering the dose of TMZ used in the treatment of GBM. In conclusion, our data show that ISA27 releases the powerful antitumor capacities of p53 in GBM cells. The use of this MDM2 inhibitor could become a novel therapy for the treatment of GBM patients.
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Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Glioblastoma/tratamiento farmacológico , Indoles/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Compuestos de Espiro/farmacología , Proteína p53 Supresora de Tumor/agonistas , Animales , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Proliferación Celular/efectos de los fármacos , Femenino , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Transducción de Señal , Carga Tumoral/efectos de los fármacos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Despite the mounting importance of granulocytapheresis (GCAP) for inflammatory bowel disease (IBD) treatment, its effectiveness in steroid-dependent (SD) and steroid-resistant (SR) patients has not been clearly evaluated. This prospective observational study describes the use of GCAP in SD and SR patients with either Ulcerative Colitis (UC) or Crohn's Disease (CD). METHODS: 118 patients, 83 affected by UC (55 SD and 28 SR) and 35 by CD (22 SD and 13 SR), were treated with GCAP, using Adacolumn™, for 5 consecutive weeks, 1 session/week. All patients were followed for 12 months after the end of GCAP. Clinical remission was defined as Clinical Activity Index (CAI) ≤6 for UC patients and Crohn's Disease Activity Index (CDAI) <150 for CD patients. RESULTS: All patients completed the study; no major complications were reported. At the end of GCAP 71% of UC and 63% of CD patients showed clinical remission. At 6 months the remission was maintained by 66% and 54% of UC and CD patients respectively, while at 12 months the percentages were 48% and 43%, respectively. No differences between SD and SR subgroups were reported at any timepoint. CAI and CDAI values significantly dropped after GCAP treatment and at 6 and 12 months' follow-up (p<0.05 vs baseline for both timepoints). No differences were measured in CAI and CDAI between SD and SR patients. CONCLUSION: GCAP therapy is safe and effective in inducing and maintaining clinical remission both in SD and in SR patients affected by either UC or CD.
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Colitis Ulcerosa/terapia , Enfermedad de Crohn/terapia , Granulocitos , Leucaféresis , Adulto , Antiinflamatorios/uso terapéutico , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Colitis Ulcerosa/sangre , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/sangre , Enfermedad de Crohn/tratamiento farmacológico , Resistencia a Medicamentos , Heces/química , Femenino , Estudios de Seguimiento , Humanos , Complejo de Antígeno L1 de Leucocito/análisis , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Inducción de Remisión , Índice de Severidad de la EnfermedadAsunto(s)
Antígenos CD34/metabolismo , Infecciones por Circoviridae/diagnóstico , Gyrovirus/aislamiento & purificación , Células Madre Hematopoyéticas/virología , Linfoma/virología , Cordón Umbilical/citología , Adulto , Anciano , Niño , Infecciones por Circoviridae/virología , ADN Viral/análisis , Femenino , Gyrovirus/genética , Células Madre Hematopoyéticas/citología , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa/métodos , Adulto JovenRESUMEN
The biological significance of donor-specific microchimerism (DSM) in solid organ transplantation is unresolved. It has been reported both as a favourable feature, which may facilitate induction and maintenance of tolerance, and as a sign of graft-vs-host disease. Here, we applied a quantitative real-time PCR assay (qRT-PCR) to a selected series of kidney transplant recipients to measure the level of microchimerism in relation to allograft function and survival. DSM level was assessed by scoring the HLA-DRB1 locus in 54 patients (42 males, 12 females) with more than 2 years of follow-up after transplantation; 38 patients were considered to have stable renal function (SRF) and 16 had allograft dysfunction (AD). Among patients with AD, 12 (75%) showed detectable level of microchimerism, compared to 11 (29%) SRF patients (Odds Ratio 7.36, 95% CI 1.7-35.2; p<0.01). In addition, AD patients showed a higher mean donor genome equivalents (6.5×10(-5) vs. 2.4×10(-5); p<0.001). SRF patients were re-evaluated two years later; 2 out of 27 DSM negative vs. 2 out of 11 DSM positive had lost their transplanted organ. In conclusion, qRT-PCR applied to peripheral blood shows significant association between DSM and allograft dysfunction in kidney transplant patients.
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Supervivencia de Injerto , Trasplante de Riñón , Disfunción Primaria del Injerto/sangre , Quimera por Trasplante/sangre , Femenino , Estudios de Seguimiento , Humanos , Masculino , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Estudios Retrospectivos , Factores de TiempoRESUMEN
Donor-specific antihuman leukocyte antigen antibodies (DSHA) have been clearly implicated in graft rejection in solid organ transplantation. Their role in allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains unclear. We summarize here evidence supporting a role for DSHA in graft failure in animal models of allo-HSCT and in clinical settings whenever no full HLA matching occurs.
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Autoanticuerpos/inmunología , Rechazo de Injerto/inmunología , Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Animales , Modelos Animales de Enfermedad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , HumanosRESUMEN
BACKGROUND: Periodontitis is a complex multifactorial disease and is typically polygenic in origin. Genes play a fundamental part in each biologic process forming complex networks of interactions. However, only some genes have a high number of interactions with other genes in the network and may, therefore, be considered to play an important role. In a preliminary bioinformatic analysis, five genes that showed a higher number of interactions were identified and termed leader genes. In the present study, we use real-time quantitative polymerase chain reaction (PCR) technology to evaluate the expression levels of leader genes in the leukocytes of 10 patients with refractory chronic periodontitis and compare the expression levels with those of the same genes in 24 healthy patients. METHODS: Blood was collected from 24 healthy human subjects and 10 patients with refractory chronic periodontitis and placed into heparinized blood collection tubes by personnel trained in phlebotomy using a sterile technique. Blood leukocyte cells were immediately lysed by using a kit for total RNA purification from human whole blood. Complementary DNA (cDNA) synthesis was obtained from total RNA and then real-time quantitative PCR was performed. PCR efficiencies were calculated with a relative standard curve derived from a five cDNA dilution series in triplicate that gave regression coefficients >0.98 and efficiencies >96%. The standard curves were obtained using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and growth factor receptor binding protein 2 (GRB2), casitas B-lineage lymphoma (CBL), nuclear factor-KB1 (NFKB1), and REL-A (gene for transcription factor p65) gene primers and amplified with 1.6, 8, 40, 200, and 1,000 ng/µL total cDNA. Curves obtained for each sample showed a linear relationship between RNA concentrations and the cycle threshold value of real-time quantitative PCR for all genes. Data were expressed as mean ± SE (SEM). The groups were compared to the analysis of variance. A probability value <0.01 was considered statistically significant. RESULTS: The present study agrees with the preliminary bioinformatics analysis. In our experiments, the association of pathology with the genes was statistically significant for GRB2 and CBL (P <0.01), and it was not statistically significant for REL-A and NFKB1. CONCLUSION: This article lends support to our preliminary hypothesis that assigned an important role in refractory aggressive periodontitis to leader genes.
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Periodontitis Agresiva/genética , Periodontitis Crónica/genética , Reacción en Cadena de la Polimerasa/métodos , Adulto , Biología Computacional , Progresión de la Enfermedad , Femenino , Proteína Adaptadora GRB2/genética , Regulación de la Expresión Génica/genética , Predisposición Genética a la Enfermedad/genética , Gliceraldehído-3-Fosfato Deshidrogenasas/genética , Humanos , Masculino , Persona de Mediana Edad , Subunidad p50 de NF-kappa B/genética , Proteína Oncogénica v-cbl/genética , Factor de Transcripción ReIA/genéticaRESUMEN
The axiom of human leukocyte incompatibility (HLA) incompatibility has always led scientists to consider cancer transmission between HLA-different individuals impossible. In fact, cancer transmission between individuals represents a frightening possibility in animal populations with limited HLA diversity or for rare cancers exploiting downregulation of HLA expression. We review here evidence from nonhuman models and settings for interhuman transmission.
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Antígenos de Histocompatibilidad Clase I/inmunología , Inmunocompetencia/inmunología , Neoplasias/inmunología , Tumores Venéreos Veterinarios/inmunología , Animales , Transfusión Sanguínea , Humanos , Neoplasias/epidemiología , Neoplasias/cirugía , Trasplante , Tumores Venéreos Veterinarios/epidemiologíaRESUMEN
The amnion is a particular tissue whose cells show features of multipotent stem cells proposed for use in cellular therapy and regenerative medicine. From equine amnion collected after the foal birth we have isolated MSCs (mesenchymal stem cells), namely EAMSCs (equine amnion mesenchymal stem cells), from the mesoblastic layer. The cells were grown in α-MEM (α-modified minimum essential medium) and the effect of EGF (epidermal growth factor) supplementation was evaluated. To assess the growth kinetic of EAMSCs we have taken into account some parameters [PD (population doubling), fold increase and DT (doubling time)]. The differentiation in chondrogenic, adipogenic and osteogenic types of cells and their epitope expression by a cytofluorimetric study have been reported. EGF supplementation of the culture medium resulted in a significant increase in PD growth parameter and in the formation of bone nodules for the osteogenic differentiation. By immunohistochemistry the amnion tissue shows a positivity for the c-Kit (cluster tyrosine-protein kinase), CD105 and Oct-4 (octamer-binding transcription factor 4) antigens that confirmed the presence of MSCs with embryonic phenotype.
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Thrombotic thrombocytopenic purpura (TTP) is associated with high mortality rates. TTP may have various and different presentations depending on the organs involved. It is now recognized to be the consequence of reduction of blood levels of the disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)-13. Prompt diagnosis of TTP is paramount, because plasma exchange is the only treatment capable of improving patient's survival with a dual mechanism: removal of anti-ADAMTS-13 auto-antibodies and infusion of the active protease available in the fresh frozen plasma. We report herein on the challenges in diagnosing TTP-like complications of post-surgical facial surgery in a young male patient.
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Púrpura Trombocitopénica Trombótica/diagnóstico , Proteínas ADAM/sangre , Proteína ADAMTS13 , Adulto , Autoanticuerpos/química , Criopreservación , Cara/cirugía , Estudios de Seguimiento , Humanos , Masculino , Plasma/metabolismo , Intercambio Plasmático/métodos , Complicaciones Posoperatorias/diagnósticoRESUMEN
BACKGROUND: Serum gamma-glutamyltransferase activity (GGT), even when within its normal reference range, catalyzes low density lipoprotein oxidation in vitro and predicts cardiovascular events. Of the four GGT fractions (b-GGT, m-GGT, s-GGT, and f-GGT) recently identified in blood, only b-GGT is found within atherosclerotic plaques. Our goal was to identify the determinants of the GGT fractions (b-, m-, s-, and f-GGT) and their association with established cardiovascular risk factors in healthy subjects. METHODS: Multiple linear regression analysis was applied to estimate the association of fractional GGT with gender, age, body mass index, arterial pressure (AP), plasma glucose, alanine aminotransferase (ALT), high and low density lipoproteins (LDL-C) cholesterol (HDL-C), triglycerides (TG) and C-reactive protein (CRP) in 200 healthy subjects. RESULTS: All GGT fractions were associated with ALT; b-GGT with AP, TG, and CRP; m-GGT with LDL-C, TG and CRP; s-GGT with TG and CRP, and f-GGT only with LDL-C, whereas gender was associated with s-GGT and f-GGT only. CONCLUSIONS: In healthy individuals, cardiovascular risk factors are associated with high molecular weight GGT fractions, namely with b-GGT, the only form present within the plaque. This finding adds to the present knowledge concerning the relevance of GGT, within its reference range, for atherosclerosis-related events.