RESUMEN
Cytokeratin 5 (CK5) is a marker for pulmonary squamous cell carcinoma; however, CK5 is sometimes present in pulmonary adenocarcinoma (ADC), and there is insufficient information regarding the clinicopathological features of CK5-positive ADC. We aimed to explore the clinicopathological characteristics of CK5-positive ADC using immunohistochemistry. We prepared the following two cohorts: a resected cohort containing 220 resected tumours for primarily studying the detailed morphological characteristics, and a tissue microarray (TMA) cohort containing 337 samples for investigating the associations of CK5 expression with other protein expressions, genetic and prognostic findings. CK5-positive ADC was defined to have ≥ 10% tumour cells and presence of CK5-positive tumour cells in the resected and TMA cohorts, respectively. CK5-positive ADCs were identified in 91 (16.3%) patients in the combined cohort. CK5-positive ADCs had male predominance (P = 0.012), smoking history (P = 0.001), higher stage (P < 0.001), histological high-grade components (P < 0.001), vascular invasion (P < 0.001), mucinous differentiation (P < 0.001), spread through airspaces (P < 0.001), EGFR wild-type (P < 0.001), KRAS mutations (P < 0.001), ALK rearrangement (P < 0.001) and ROS1 rearrangement (P = 0.002). In the resected cohort, more than half the CK5-positive ADCs (19 cases, 65.5%) showed mucinous differentiation; the remaining cases harboured high-grade components. In the TMA cohort, CK5-positive ADCs correlated with TTF-1 negativity (P = 0.002) and MUC5B, MUC5AC and HNF4alpha positivity (P < 0.001, 0.048, < 0.001). Further, CK5-positive ADCs had significantly lower disease-free and overall survival rates than CK5-negative ADCs (P < 0.001 for each). Additionally, multivariate analysis revealed that CK5 expression was an independent poor prognostic factor. CK5-positive ADCs showed aggressive clinical behaviour, with high-grade morphology and mucinous differentiation.
Asunto(s)
Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Masculino , Femenino , Neoplasias Pulmonares/patología , Adenocarcinoma/genética , Queratina-5/análisis , Proteínas Tirosina Quinasas , Biomarcadores de Tumor/análisis , Proteínas Proto-Oncogénicas , PronósticoRESUMEN
The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.
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Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Isoanticuerpos/inmunología , Trasplante de Hígado/efectos adversos , Aloinjertos , Humanos , Informe de InvestigaciónRESUMEN
ZFP521 was previously identified as a putative gene involved in induction of B-cell lymphomagenesis. However, the contribution of ZFP521 to lymphomagenesis has not been confirmed. In this study, we sought to elucidate the role of ZFP521 in B-cell lymphomagenesis. To this end, we used a retroviral insertion method to show that ZFP521 was a target of mutagenesis in pre-B-lymphoblastic lymphoma cells. The pre-B-cell receptor (pre-BCR) signaling molecules BLNK, BTK and BANK1 were positively regulated by the ZFP521 gene, leading to enhancement of the pre-BCR signaling pathway. In addition, c-myc and c-jun were upregulated following activation of ZFP521. Stimulation of pre-BCR signaling using anti-Vpreb antibodies caused aberrant upregulation of c-myc and c-jun and of Ccnd3, which encodes cyclin D3, thereby inducing the growth of pre-B cells. Stimulation with Vpreb affected the growth of pre-B cells, and addition of interleukin (IL)-7 receptor exerted competitive effects on pre-B-cell growth. Knockdown of BTK and BANK1, targets of ZFP521, suppressed the effects of Vpreb stimulation on cell growth. Furthermore, in human lymphoblastic lymphoma, analogous to pre-B-cell lymphoma in mice, the expression of ZNF521, the homolog of ZFP521 in humans, was upregulated. In conclusion, our data showed that the ZFP521 gene comprehensively induced pre-B-cell lymphomagenesis by modulating the pre-B-cell receptor signaling pathway.
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Receptores de Células Precursoras de Linfocitos B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Células Precursoras de Linfocitos B/metabolismo , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Agammaglobulinemia Tirosina Quinasa , Animales , Línea Celular , Proliferación Celular/genética , Ciclina D3/genética , Ciclina D3/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Immunoblotting , Inmunohistoquímica , Ratones Endogámicos C57BL , Ratones Endogámicos , Receptores de Células Precursoras de Linfocitos B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-jun/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Factores de Transcripción/genéticaRESUMEN
Abnormally stiff substrates have been shown to trigger cancer progression. However, the detailed molecular mechanisms underlying this trigger are not clear. In this study, we cultured T84 human colorectal cancer cells on plastic dishes to create a stiff substrate or on collagen-I gel to create a soft substrate. The stiff substrate enhanced the expression of matrix metalloproteinase-7 (MMP-7), an indicator of poor prognosis. In addition, we used polyacrylamide gels (2, 67 and 126 kPa) so that the MMP-7 expression on the 126-kPa gel was higher compared with that on the 2-kPa gel. Next, we investigated whether yes-associated protein (YAP) affected the MMP-7 expression. YAP knockdown decreased MMP-7 expression. Treatment with inhibitors of epidermal growth factor receptor (EGFR) and myosin regulatory light chain (MRLC) and integrin-α2 or integrin-ß1 knockdown downregulated MMP-7 expression. Finally, we demonstrated that YAP, EGFR, integrin-α2ß1 and MRLC produced a positive feedback loop that enhanced MMP-7 expression. These findings suggest that stiff substrates enhanced colorectal cancer cell viability by upregulating MMP-7 expression through a positive feedback loop.
RESUMEN
Dexmedetomidine, the most selective α2-adrenoceptor agonist in clinical use, is increasingly being used in both conscious and anaesthetized horses; however, the pharmacokinetics and sedative effects of this drug administered alone as an infusion are not previously described in horses. Seven horses received an infusion of 8 µg dexmedetomidine/kg/h for 150 min, venous blood samples were collected, and dexmedetomidine concentrations were assayed using liquid chromatography-mass spectrometry (LC/MS) and analyzed using noncompartmental pharmacokinetic analysis. Sedation was scored as the distance from the lower lip of the horse to the ground measured in centimetre. The harmonic mean (SD) plasma elimination half-life (Lambda z half-life) for dexmedetomidine was 20.9 (5.1) min, clearance (Cl) was 0.3 (0.20) L/min/kg, and volume of distribution at steady-state (Vdss ) was 13.7 (7.9) L/kg. There was a considerable individual variation in the concentration of dexmedetomidine vs. time profile. The level of sedation covaried with the plasma concentration of dexmedetomidine. This implies that for clinical use of dexmedetomidine constant rate infusion in conscious horses, infusion rates can be easily adjusted to effect, and this is preferable to an infusion at a predetermined value.
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Agonistas de Receptores Adrenérgicos alfa 2/farmacocinética , Dexmedetomidina/farmacocinética , Caballos/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Animales , Área Bajo la Curva , Dexmedetomidina/administración & dosificación , Esquema de Medicación , Femenino , Semivida , Caballos/sangre , MasculinoRESUMEN
Dexmedetomidine and lignocaine IV are used clinically to provide analgesia in horses. The aims of this study were to investigate the antinociceptive effects, plasma concentrations and sedative effects of 2, 4 and 6 µg/kg/h dexmedetomidine IV, with a bolus of 0.96 µg/kg preceding each continuous rate infusion (CRI), and 20, 40 and 60 µg/kg/min lignocaine IV, with a bolus of 550 µg/kg preceding each CRI, in 10 Swiss Warmblood horses. Electrically elicited nociceptive withdrawal reflexes were evaluated by deltoid muscle electromyography. Nociceptive threshold and tolerance were determined by electromyography and behaviour following single and repeated stimulation. Plasma concentrations of drugs were determined by liquid chromatography and mass spectrometry. Sedation was scored on a visual analogue scale. Dexmedetomidine increased nociceptive threshold to single and repeated stimulation for all CRIs, except at 2 µg/kg/h, where no increase in single stimulation nociceptive threshold was observed. Dexmedetomidine increased nociceptive tolerance to single and repeated stimulation at all CRIs. There was large individual variability in dexmedetomidine plasma concentrations and levels of sedation; the median plasma concentration providing antinociceptive effects to all recorded parameters was 0.15 ng/mL, with a range from <0.02 ng/mL (below the lower limit of quantification) to 0.25 ng/mL. Lignocaine increased nociceptive threshold and tolerance to single and repeated stimulation at CRIs of 40 and 60 µg/kg/min, corresponding to plasma lignocaine concentrations >600 ng/mL. Only nociceptive tolerance to repeated stimulation increased at 20 µg/kg/min lignocaine. Lignocaine at 40 µg/kg/min and dexmedetomidine at 4 µg/kg/h were the lowest CRIs resulting in consistent antinociception. Lignocaine did not induce significant sedation.
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Analgésicos/farmacología , Dexmedetomidina/farmacología , Caballos/metabolismo , Hipnóticos y Sedantes/farmacología , Lidocaína/farmacología , Reflejo/efectos de los fármacos , Analgésicos/sangre , Animales , Cromatografía Liquida/veterinaria , Estudios Cruzados , Dexmedetomidina/sangre , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Hipnóticos y Sedantes/sangre , Infusiones Intravenosas/veterinaria , Lidocaína/sangre , Masculino , Espectrometría de Masas/veterinaria , Distribución AleatoriaRESUMEN
BACKGROUND: There have been extensive studies regarding which types of T lymphocytes are involved in psoriasis vulgaris (PV). However, it has remained unclear which types of T lymphocytes might directly contribute to psoriasiform epidermal and vascular hyperplasia. OBJECTIVES: To understand the role of T-cell receptor (TCR)Vα24+ invariant natural killer (iNK)T cells in the development of PV. METHODS: Seventeen patients were enrolled in this study. Using biopsy samples of PV plaques, TCRVα24(+) iNKT cells were investigated regarding their cytokine production to understand their roles in development of disease. RESULTS: The number of interferon (IFN)-γ+ iNKT cells correlated with the length of the psoriasiform hyperplasia rete ridge and the Psoriasis Area and Severity Index. IFN-γ+ iNKT cells in psoriatic skin exhibited higher C-C chemokine receptor (CCR)5 expression, and the amount of C-C chemokine ligand (CCL)5, a ligand for CCR5, was increased in capillary veins of psoriasis plaques. CCR5+ iNKT-cell numbers significantly correlated with the number of capillary vein endothelial cells expressing CCL5 in PV. Furthermore, the number of CCL5+ capillary veins correlated with the maximum rete ridge length. CONCLUSIONS: IFN-γ/CCR5 expression in iNKT cells and CCL5 expression in vessels of dermal papillae correlate with the development of psoriasiform hyperplasia and microabscess. We propose that these iNKT cells may become useful targets for development of novel therapeutic approaches to PV.
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Quimiocina CCL5/metabolismo , Interferón gamma/inmunología , Células T Asesinas Naturales/inmunología , Psoriasis/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Adulto , Anciano , Capilares/metabolismo , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We evaluated the effects of rituximab prophylaxis on outcomes of ABO-blood-type-incompatible living donor liver transplantation (ABO-I LDLT) in 381 adult patients in the Japanese registry of ABO-I LDLT. Patients underwent dual or triple immunosuppression with or without B cell desensitization therapies such as plasmapheresis, splenectomy, local infusion, intravenous immunoglobulin and rituximab. Era before 2005, intensive care unit-bound status, high Model for End-Stage Liver Disease score and absence of rituximab prophylaxis were significant risk factors for overall survival and antibody-mediated rejection (AMR) in the univariate analysis. After adjustment for era effects in the multivariate analysis, only absence of rituximab prophylaxis was a significant risk factor for AMR, and there were no significant risk factors for survival. Rituximab prophylaxis significantly decreased the incidence of AMR, especially hepatic necrosis (p < 0.001). In the rituximab group, other B cell desensitization therapies had no add-on effects. Multiple or large rituximab doses significantly increased the incidence of infection, and early administration had no advantage. In conclusion, outcomes in adult ABO-I LDLT have significantly improved in the latest era coincident with the introduction of rituximab.
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Sistema del Grupo Sanguíneo ABO/inmunología , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Incompatibilidad de Grupos Sanguíneos/tratamiento farmacológico , Desensibilización Inmunológica/métodos , Rechazo de Injerto/prevención & control , Trasplante de Hígado/métodos , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Infecciones Bacterianas/epidemiología , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Terapia de Inmunosupresión , Japón/epidemiología , Trasplante de Hígado/efectos adversos , Donadores Vivos , Masculino , Persona de Mediana Edad , Micosis/epidemiología , Rituximab , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the usefulness of intratesticular and subcutaneous lidocaine in alleviating the intraoperative nociceptive response to castration, measured by pulse rate (PR) and mean arterial pressure (MAP), and to test the applicability of heart rate variability (HRV) analysis in assessing this response. STUDY DESIGN: Randomized, controlled, observer-blinded experimental trial. ANIMALS: Thirty-nine healthy male cats admitted for castration. METHODS: One group received general anaesthesia and served as control group (GA), while the treatment group (LA) additionally received local anaesthesia (lidocaine 2 mg kg(-1)) intratesticularly and subcutaneously. PR and MAP were recorded at anaesthesia baseline (T0), treatment (T1), incision left testicle (T2), traction on spermatic cord (T3), tightening of the autoligature and resection of the cord (T4), incision on the right side (T5), traction on spermatic cord (T6), and tightening of the autoligature and resection of cord (T7). HRV analysis was divided into three 5-minute intervals: baseline (H0), treatment (H1), and surgery (H2). RESULTS: There were significant increases in PR and MAP for both groups during surgery from T3 onwards; however, the increase in the treatment group (LA) was significantly lower than for the control group (GA). For HRV analysis, significant differences were found between groups in the following parameters during surgery: TP (total power), VLF (very low frequency), SDNN (standard deviation of NN intervals [= the interval between two consecutive R-waves in the ECG]), and TI (triangular index), which were lower in the LA group. Mean NN was significantly lower in the GA group, whereas LF (low frequency) and LFn (low frequency, normalized value) were lower in the LA group. HF (high frequency) and HFn (high frequency, normalized value) decreased significantly from H1 to H2 in both groups. CONCLUSIONS AND CLINICAL RELEVANCE: The study showed that the nociceptive response to surgery was alleviated by the use of intratesticular and subcutaneous lidocaine and that HRV analysis is a promising research tool to estimate intraoperative nociception in cats during general anaesthesia.
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Anestésicos Locales , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Lidocaína , Orquiectomía/veterinaria , Anestesia General/veterinaria , Animales , Presión Sanguínea/efectos de los fármacos , Gatos , Inyecciones/veterinaria , Inyecciones Subcutáneas/veterinaria , Periodo Intraoperatorio , Lidocaína/administración & dosificación , Masculino , Orquiectomía/métodos , Testículo/efectos de los fármacosRESUMEN
OBJECTIVE: To characterize acute inflammatory and hemostatic surgical stress responses following castration in cats and to evaluate whether the addition of local anesthesia to the anesthetic protocol attenuates these responses. ANIMALS: 39 male cats. PROCEDURES: Cats undergoing castration were randomly assigned to 2 groups: both groups underwent surgery with general anesthesia, and 1 group additionally received a local anesthetic (lidocaine [2.0 mg/kg in total, divided intratesticularly and SC]) prior to incision. Blood samples were collected after anesthetic induction (baseline) and 1, 5, and 24 hours later. Thromboelastography and coagulation variables (activated partial thromboplastin time [aPTT] and prothrombin time [PT]) were analyzed; fibrinolysis was assessed with plasma D-dimer concentrations. The acute-phase response was evaluated via measurement of plasma fibrinogen and serum amyloid A (last time point, 28 hours) concentrations. Hematologic variables were analyzed at baseline and 1, 5, and 24 hours later. RESULTS: Evidence of hemostatic and inflammatory activation after surgery was detected in both groups. Maximum amplitude and G (global clot strength) were significantly increased at 24 hours, and significant, but not clinically relevant, decreases were detected in aPTT at 5 and 24 hours and in PT at 24 hours, compared with baseline values. Serum amyloid A concentrations were significantly higher at 24 and 28 hours than at baseline, and plasma fibrinogen concentration was significantly increased at 24 hours; WBC and RBC counts and Hct were significantly increased at multiple time points. No differences between groups were detected for any variables. CONCLUSIONS AND CLINICAL RELEVANCE: Castration appeared to induce hypercoagulability and an acute-phase inflammatory response in cats. Local anesthesia with lidocaine did not attenuate this response.
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Anestesia General/veterinaria , Anestesia Local/veterinaria , Inflamación/veterinaria , Orquiectomía/veterinaria , Estrés Fisiológico/efectos de los fármacos , Anestesia por Inhalación/veterinaria , Anestésicos Locales/farmacología , Animales , Gatos , Inflamación/prevención & control , Isoflurano/farmacología , Lidocaína , Masculino , Orquiectomía/métodos , Dolor/prevención & control , Dolor/veterinariaRESUMEN
AIMS/HYPOTHESIS: Epidemiological studies have revealed that obesity and diabetes mellitus are independent risk factors for the development of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma. However, the debate continues on whether insulin resistance as such is directly associated with NASH and liver tumourigenesis. Here, we investigated the incidence of NASH and liver tumourigenesis in Irs1 ( -/- ) mice subjected to a long-term high-fat (HF) diet. Our hypothesis was that hepatic steatosis, rather than insulin resistance may be related to the pathophysiology of these conditions. METHODS: Mice (8 weeks old, C57Bl/6J) were given free access to standard chow (SC) or an HF diet. The development of NASH and liver tumourigenesis was evaluated after mice had been on the above-mentioned diets for 60 weeks. Similarly, Irs1 ( -/- ) mice were also subjected to an HF diet for 60 weeks. RESULTS: Long-term HF diet loading, which causes obesity and insulin resistance, was sufficient to induce NASH and liver tumourigenesis in the C57Bl/6J mice. Obesity and insulin resistance were reduced by switching mice from the HF diet to SC, which also protected these mice against the development of NASH and liver tumourigenesis. However, compared with wild-type mice fed the HF diet, Irs1 ( -/- ) mice fed the HF diet were dramatically protected against NASH and liver tumourigenesis despite the presence of severe insulin resistance and marked postprandial hyperglycaemia. CONCLUSIONS/INTERPRETATION: IRS-1 inhibition might protect against HF diet-induced NASH and liver tumourigenesis, despite the presence of insulin resistance.
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Carcinoma Hepatocelular/patología , Diabetes Mellitus Experimental/patología , Hígado Graso/patología , Proteínas Sustrato del Receptor de Insulina/metabolismo , Neoplasias Hepáticas/patología , Hígado/patología , Animales , Carcinoma Hepatocelular/sangre , Diabetes Mellitus Experimental/sangre , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Hígado Graso/sangre , Prueba de Tolerancia a la Glucosa , Proteínas Sustrato del Receptor de Insulina/genética , Resistencia a la Insulina , Neoplasias Hepáticas/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico , Obesidad/patologíaRESUMEN
Early diagnosis and treatment of acute cellular rejection (ACR) after intestinal transplantation (ITx) is challenging. We report the outcome of three patients: two presented mild ACR improved with steroids. One presented steroid-resistant severe rejection, improved after rabbit anti-thymocyte globulin (r-ATG), but unfortunately died for encephalitis caused by opportunistic infections.
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Suero Antilinfocítico/administración & dosificación , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Intestinos/trasplante , Adolescente , Anastomosis Quirúrgica , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Basiliximab , Niño , Daclizumab , Encefalitis/etiología , Resultado Fatal , Femenino , Humanos , Inmunoglobulina G/uso terapéutico , Enfermedades Intestinales/cirugía , Vólvulo Intestinal/cirugía , Masculino , Enfermedades del Sistema Nervioso/cirugía , Proteínas Recombinantes de Fusión/uso terapéutico , Síndrome del Intestino Corto/cirugía , Tacrolimus/administración & dosificaciónRESUMEN
In this prospective two-phase experimental trial, 10 pigs were anaesthetized twice with isoflurane only. In the first phase, the individual minimum alveolar concentration (MAC) was determined and in the second phase the effects on withdrawal reflexes of increasing end-tidal isoflurane concentrations (from 1.6% to 2.8%) were assessed. Single, 10 and 60 repeated electrical stimulations were used to evoke withdrawal reflexes which were recorded and quantified by electromyography. Recruitment curves for reflex amplitude for increasing stimulation intensities and isoflurane concentrations were constructed. Isoflurane MAC was 1.9 ± 0.3%. Reflexes evoked by repeated stimulation were suppressed at isoflurane concentrations significantly higher than those which suppressed complex movements during MAC determination (P=0.014 and P=0.006 for 10 and 60 repeated stimuli respectively). Isoflurane up to 2.8% was still not able to abolish reflex activity evoked by repeated stimulations in all pigs. Single stimulation reflexes were suppressed at significantly lower concentrations than repeated stimulation reflexes (P=0.008 and P=0.004 for 10 and 60 repeated stimuli, respectively). Reflex amplitude was significantly correlated with isoflurane concentration (P<0.001, r=-0.85) independent of the individual MAC. The findings indicate that the level at which isoflurane suppresses withdrawal reflexes is dependent on the stimulation paradigm (single vs. repeated electrical stimulation), and there is limited value in expressing reflex withdrawal suppression in terms of MAC as purposeful and reflex movements are independently affected by isoflurane in individual animals.
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Anestésicos por Inhalación/administración & dosificación , Miembro Anterior/fisiología , Isoflurano/administración & dosificación , Actividad Motora/efectos de los fármacos , Reflejo/efectos de los fármacos , Porcinos/fisiología , Animales , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Electromiografía/veterinaria , Femenino , Masculino , Estudios Prospectivos , Estimulación Eléctrica Transcutánea del Nervio/veterinariaRESUMEN
Blockade of the CD40-CD154 costimulatory signal is an attractive strategy for immunosuppression and tolerance induction in organ transplantation. Treatment with anti-CD154 monoclonal antibodies (mAbs) results in potent immunosuppression in nonhuman primates (NHPs). Despite plans for future clinical use, further development of these treatments was halted by complications. As an alternative approach, we have been focusing on the inhibition of the counter receptor, CD40 and have shown that a novel human anti-CD40 mAb, ASKP1240, markedly prolongs renal allograft survival in NHPs, although allografts eventually underwent chronic allograft nephropathy. On the basis of our previous findings that a CD40-CD154 costimulation blockade induces tolerance to hepatic, but not cardiac, allografts in rodents, we tested here our hypothesis that a blockade of CD40 by ASKP1240 allows acceptance of hepatic allografts in NHPs. A 2-week ASKP1240 induction treatment prolonged liver allograft survival in NHPs; however, the graft function deteriorated due to chronic rejection. In contrast, a 6-month ASKP1240 maintenance monotherapy efficiently suppressed both cellular and humoral alloimmune responses and prevented rejection on the hepatic allograft. No serious side effects, including thromboembolic complications, were noted in the ASKP1240-treated monkeys. We conclude that CD40 blockade by ASKP1240 would be a desirable immunosuppressant for clinical liver transplantation.
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Anticuerpos Monoclonales/inmunología , Antígenos CD40/inmunología , Trasplante de Hígado , Animales , Anticuerpos Monoclonales Humanizados , Humanos , Memoria Inmunológica , Prueba de Cultivo Mixto de Linfocitos , Macaca fascicularis , Masculino , Trasplante HomólogoRESUMEN
Approximately 30% of patients who have recurrent hepatitis C after liver transplantation achieve sustained virological response (SVR) by taking a combination therapy of pegylated interferon and ribavirin. For the remaining non-SVR patients, an effective management treatment has not yet been established. In this study, efficacy of long-term peginterferon maintenance therapy for non-SVR patients was evaluated. Forty patients who had previously received the combination therapy for hepatitis C after living donor liver transplantation were classified into one of the following three groups: the SVR group (n = 11); the non-SVR-IFN group (n =17), which received low-dose peginterferon maintenance therapy for non-SVR patients; and the non-SVR-Withdrawal group (n = 12), which discontinued the interferon treatment. We then compared histological changes among these three groups after 2 or more years follow-up. Activity grade of liver histology improved or remained stable in patients in the SVR and non-SVR-IFN groups, but deteriorated in half of the patients in the non-SVR-Withdrawal group. Fibrosis improved or remained stable in 10 of 11 SVR patients and in 13 of 17 non-SVR-IFN patients, but deteriorated in all non-SVR-Withdrawal patients. Mean changes in fibrosis stage between pretreatment and final liver biopsy were -0.18, +0.06 and +2.2 in the SVR, non-SVR-IFN and non-SVR-Withdrawal groups, respectively. Fibrosis stage deteriorated to F3 or F4 significantly more rapidly in the non-SVR-Withdrawal group than in the other two groups. In conclusion, continuing long-term maintenance therapy with peginterferon prevented histological progression of hepatitis C in patients who had undergone living donor liver transplantation.
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Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Trasplante de Hígado , Polietilenglicoles/uso terapéutico , Adolescente , Adulto , Anciano , Antivirales/administración & dosificación , Progresión de la Enfermedad , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/patología , Humanos , Hígado/patología , Donadores Vivos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéutico , Recurrencia , Ribavirina/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
To overcome severe donor shortage, Japanese doctors over the years have developed innovative strategies to maximize organs transplanted per brain death donor and expanded the donor pool using living donors. They also used living and marginal organs and drastically improved living donor lung, liver, pancreas and kidney transplantations. Moreover, they initiated ABO blood type incompatible liver transplantation advancements and succeeded in overcoming the blood type barrier in kidney and liver transplantations. Similar efforts are underway for pancreas transplantation. Furthermore, Japanese doctors have developed a nonaggressive step to achieve immunosuppression following organ transplantation by carefully monitoring donor-specific hyporesponsiveness and infectious immunostatus. However, the institution of amendments to allocation systems and the intensification of efforts to decrease living donor morbidity and to increase the number of brain death donors have remained important issues needing attention. Overall, the strategies Japan has adopted to overcome donor shortage can provide useful insights on how to increase organ transplantations.
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Trasplante de Órganos/métodos , Trasplante de Órganos/tendencias , Donantes de Tejidos/provisión & distribución , Humanos , JapónRESUMEN
The pharmacokinetics and the analgesic, anti-inflammatory and antipyretic effects of meloxicam were investigated in a placebo controlled study in 2-week-old piglets. Inflammation was induced by a subcutaneous injection of kaolin in the left metacarpus, and 16 h later, meloxicam (0.6 mg/kg) or saline was administered intramuscularly. The absorption half-life was relatively short (0.19 h) and the elimination half-life was 2.6 h. Mechanical nociceptive threshold testing was used to evaluate the analgesic effect, but no significant effect of the meloxicam treatment was found. The skin temperature of the inflamed area increased after the kaolin injection, but no significant decrease in temperature was found after administration of meloxicam. Only limited pyresis was observed after the kaolin injection, and no significant antipyretic effect of meloxicam was found. The results indicated that this dose of meloxicam had very limited anti-inflammatory and analgesic effects in piglets.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Inflamación/veterinaria , Enfermedades de los Porcinos/tratamiento farmacológico , Porcinos/metabolismo , Tiazinas/farmacocinética , Tiazoles/farmacocinética , Animales , Antiinflamatorios no Esteroideos/sangre , Antiinflamatorios no Esteroideos/uso terapéutico , Temperatura Corporal , Cromatografía Liquida/veterinaria , Esquema de Medicación/veterinaria , Femenino , Fiebre/inducido químicamente , Fiebre/tratamiento farmacológico , Fiebre/veterinaria , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inyecciones Intramusculares/veterinaria , Caolín , Masculino , Meloxicam , Dimensión del Dolor/veterinaria , Enfermedades de los Porcinos/inducido químicamente , Espectrometría de Masas en Tándem/veterinaria , Tiazinas/sangre , Tiazinas/uso terapéutico , Tiazoles/sangre , Tiazoles/uso terapéuticoRESUMEN
Following intravenous dose of 6mg/kg racemic ketoprofen, the chiral pharmacokinetics of ketoprofen was investigated in eight piglets aged 6 and 21days old. S-ketoprofen predominated over R-ketoprofen in plasma of the piglets in both age groups. The volumes of distribution of S-ketoprofen for the 6- and 21-day-old piglets were 241.7 (211.3-276.5) mL/kg and 155.0 (138.7-173.1) mL/kg, respectively, while the corresponding parameters for R-ketoprofen were 289.2 (250.3-334.2) mL/kg and 193.0 (168.7-220.8) mL/kg. The clearances of R-ketoprofen [948.4 (768.0-1171.2) mL/h/kg and 425 (319.1-566.0) mL/h/kg for the 6- and 21-day-old piglets, respectively] were significantly higher compared to the clearances of S-ketoprofen [57.3 (46.6-70.4) mL/h/kg and 33.8 (27.0-42.2) mL/h/kg for 6- and 21-day-old piglets, respectively]. The elimination half-life of S-ketoprofen was 3.4h for both age groups, while the elimination half-life of R-ketoprofen was 0.2h for the 6-day-old and 0.4h for the 21-day-old piglets. The clearances of both R- and S-ketoprofen were significantly higher in the 6-day-old piglets compared to when they were 21 days old. Furthermore, the volumes of distribution were larger in the youngest age group.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Cetoprofeno/farmacocinética , Porcinos/metabolismo , Factores de Edad , Animales , Animales Recién Nacidos/metabolismo , Antiinflamatorios no Esteroideos/química , Área Bajo la Curva , Femenino , Semivida , Inyecciones Intravenosas/veterinaria , Cetoprofeno/química , Masculino , Relación Estructura-ActividadRESUMEN
The chiral pharmacokinetics and pharmacodynamics of ketoprofen were investigated in a placebo-controlled study in piglets after intramuscular administration of 6 mg/kg racemic ketoprofen. The absorption half-lives of both enantiomers were short, and S-ketoprofen predominated over R-ketoprofen in plasma. A kaolin-induced inflammation model was used to evaluate the anti-inflammatory, antipyretic and analgesic effects of ketoprofen. Skin temperatures increased after the kaolin injection, but the effect of ketoprofen was small. No significant antipyretic effects could be detected, but body temperatures tended to be lower in the ketoprofen-treated piglets. Mechanical nociceptive threshold testing was used to evaluate the analgesic effects. The piglets in the ketoprofen-treated group had significantly higher mechanical nociceptive thresholds compared to the piglets in the placebo group for 12-24 h following the treatment. Pharmacokinetic/pharmacodynamic modelling of the results from the mechanical nociceptive threshold testing gave a median IC(50) for S-ketoprofen of 26.7 µg/mL and an IC(50) for R-ketoprofen of 1.6 µg/mL. This indicates that R-ketoprofen is a more potent analgesic than S-ketoprofen in piglets. Estimated ED(50) for racemic ketoprofen was 2.5 mg/kg.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Fiebre/veterinaria , Inflamación/veterinaria , Cetoprofeno/farmacocinética , Enfermedades de los Porcinos/metabolismo , Porcinos/metabolismo , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/uso terapéutico , Temperatura Corporal , Femenino , Fiebre/inducido químicamente , Fiebre/tratamiento farmacológico , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Caolín , Cetoprofeno/química , Cetoprofeno/uso terapéutico , Masculino , Modelos Biológicos , Dolor/tratamiento farmacológico , Dolor/veterinaria , Dimensión del Dolor/veterinaria , Enfermedades de los Porcinos/inducido químicamente , Enfermedades de los Porcinos/tratamiento farmacológicoRESUMEN
The ontogenetic pattern of gyrification and its relationship with cerebral cortical volume were examined in cynomolgus monkey fetuses. T(1)-weighted coronal magnetic resonance (MR) images at 7 T were acquired from the fixed cerebra of three male fetuses, each at embryonic days (EDs) 70 to 150, and the gyrification index (GI) of each slice was estimated. The mean GI was low (1.1-1.2) during EDs 70 to 90, and then increased dramatically on ED 100. The developmental profiles of the rostrocaudal GI distribution revealed that cortical convolution was more frequent in the parietooccipital region than in other regions during EDs 100 to 150, forming an adult-like pattern by ED 150. The mean GI was closely correlated with the volume of cortical gray matter (r=0.9877), and also with the volume of white matter/intermediate zone (r=0.8961). These findings suggest that cortical convolution is correlated with either the maturation of cortical gray matter or the development of white matter bundles. The characteristic GI distribution pattern of catarrhines was formed by ED 150 in correlation with the progressive sulcal infolding in the parietooccipital region of the cerebrum.