RESUMEN
With the success of pediatric live donor liver transplantation (LDLT) and the continued shortage of cadaveric donors, adult-to-adult LDLT has been performed at some centers, including ours. We performed a detailed histologic review of all liver specimens obtained from 9 adult recipients at and after LDLT and correlated these findings with the patients' course and outcome. Five patients had histologic evidence of biliary tract pathology; 3 of 5 required surgical or radiologic intervention. The other 2 had clinically insignificant biliary disease. Diffuse hepatocytic hemorrhagic necrosis secondary to massive portal blood flow after portal venous revascularization resulted in graft failure and retransplantation in a single patient with severe preoperative portal hypertension. Two perioperative deaths were caused by sepsis and multiorgan failure (day 25) and generalized thrombosis related to factor V Leiden (day 6). The preoperative diagnosis, presence of portal vein thrombosis in the native liver, postoperative cholangiopathy, and subcapsular hemorrhagic necrosis in donor liver wedge biopsies did not affect the short-term outcome. In conclusion, biliary tract pathology is common after adult-to-adult LDLT but does not negatively affect graft or patient survival. Infrequent but catastrophic vascular complications related to portal hemodynamics or thrombosis can result in graft loss and/or patient death.
Asunto(s)
Trasplante de Hígado/métodos , Hígado/cirugía , Donadores Vivos , Adulto , Femenino , Rechazo de Injerto/patología , Rechazo de Injerto/fisiopatología , Supervivencia de Injerto/fisiología , Humanos , Hígado/patología , Hígado/fisiología , Cirrosis Hepática/patología , Cirrosis Hepática/cirugía , Trasplante de Hígado/fisiología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Resultado del TratamientoRESUMEN
Autoimmune hepatitis (AIH) after liver transplantation (LT) may recur and is difficult to diagnose. Our aims were to define the histopathology of and factors related to AIH recurrence. Fourteen of 475 patients received LT for AIH; 2 died perioperatively. Liver specimens (native and post-LT biopsies) from 12 other patients were reviewed and correlated with pre- and post-LT clinical course and outcome. Recurrent AIH was seen in 5 of 12 patients, 35 to 280 days post-LT as lobular hepatitis with acidophil bodies and lymphoplasmacytic infiltrate. Portal/interface hepatitis was seen with disease progression and 2 of 5 patients developed cirrhosis. Of 7 nonrecurrent patients, 1 had acquired hepatitis C with lobular/portal hepatitis and none developed cirrhosis. Histology suggestive of overlap syndrome was seen in 3 of 12 native livers with no effect on post-LT course or pathology. High-grade necroinflammation was present in native livers at LT in 5 of 5 cases with recurrent AIH and in 1 of 7 without recurrence (P <.01). Pre-LT disease duration, donor/recipient gender distribution, HLA studies, and rejection episodes did not correlate with AIH recurrence. We conclude that (1) recurrent AIH is not uncommon and was seen in 42% of patients with lymphoplasmacytic lobular, portal, and interface hepatitis; (2) acidophil bodies with lymphoplasmacytic cells are seen in early recurrent AIH; (3) recurrent AIH appears at variable time periods post-LT, and the progression is slow; and (4) high-grade inflammation in native liver at LT is a strong predictor of recurrent AIH.
Asunto(s)
Hepatitis Autoinmune/patología , Hepatitis Autoinmune/cirugía , Trasplante de Hígado , Hígado/patología , Adulto , Anciano , Biopsia , Femenino , Hepatitis Autoinmune/etiología , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Recurrencia , Trasplante HomólogoRESUMEN
We studied the effects of PNU-109291 [(S)-(-)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-N-methyl-isoc hroman-6-carboxamide], a receptor agonist showing 5000-fold selectivity for primate 5-HT1D versus 5-HT1B receptors (Ennis et al., J. Med. Chem. 41, 2180-2183), on dural neurogenic inflammation and on c-fos like immunoreactivity within trigeminal nucleus caudalis evoked by electrical and chemical activation of trigeminal afferents, respectively. Subcutaneous injection of PNU-109291 in male guinea pigs dose-dependently reduced dural extravasation of [125I]-labeled bovine serum albumin evoked by trigeminal ganglion stimulation with an IC50 of 4.2 nmol kg(-1). A dose of 73.3 nmol kg(-1) blocked the response completely. The selective 5-HT1B/1D receptor antagonist GR-127935 (> or = 2 micromol kg(-1) i.v.) prevented this effect. In addition, the number of c-fos immunoreactive cells within guinea pig trigeminal nucleus caudalis induced by chemical meningeal stimulation (intracisternally administered capsaicin) was reduced by more than 50% with PNU-109291 (> or = 122.2 nmol kg(-1) administered s.c. 45 min before and 15 min after capsaicin). These data indicate that the 5-HT1D receptor subtype plays a significant role in suppressing meningeal neurogenic inflammation and attenuating trigeminal nociception in these guinea pig models. Since 5-HT1D receptor mRNA and protein are expressed in trigeminal ganglia but not vascular smooth muscle, the 5-HT1D receptor subtype may become a useful therapeutic target for migraine and related headaches.
Asunto(s)
Benzopiranos/farmacología , Duramadre/efectos de los fármacos , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacocinética , Núcleos del Trigémino/inmunología , Núcleos del Trigémino/metabolismo , Animales , Benzopiranos/farmacocinética , Unión Competitiva , Presión Sanguínea/efectos de los fármacos , Proteínas Sanguíneas/metabolismo , Capsaicina/farmacología , Duramadre/inmunología , Duramadre/metabolismo , Estimulación Eléctrica , Cobayas , Masculino , Oxadiazoles/farmacología , Piperazinas/farmacocinética , Receptor de Serotonina 5-HT1D , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Núcleos del Trigémino/efectos de los fármacosRESUMEN
We examined the effects of butalbital (30, 100, and 1000 micrograms/kg) on the number of cells expressing c-fos-like immunoreactivity (c-fos-LI), a marker of neuronal activation, within lamina I, IIo of the trigeminal nucleus caudalis and the nucleus of the solitary tract 2 hours after the intracisternal injection of capsaicin (0.1 mL; 15.25 mg/mL) or vehicle in urethane-anesthetized guinea pigs (N = 45). Robust c-fos-LI was observed within nuclei of cells in the trigeminal nucleus caudalis after capsaicin (329 +/- 35). Butalbital dose-dependently reduced the number of labeled cells to a maximum of 66% (1000 micrograms/kg intraperitoneally [i.p.], P < .01) in lamina I, IIo but not within area postrema, medial reticular nucleus, or the nucleus of the solitary tract. Pretreatment with bicuculline (30 micrograms/kg i.p.) blocked the effect of butalbital, thereby suggesting the importance of the GABAA receptor to activation involved in the transmission of nociceptive information. Our studies suggest the possibility that GABAA receptors might provide an important therapeutic target in migraine and related headache disorders.
Asunto(s)
Barbitúricos/farmacología , Capsaicina/farmacología , Proteínas Proto-Oncogénicas c-fos/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-fos/metabolismo , Núcleo Caudal del Trigémino/metabolismo , Animales , Cobayas , MasculinoRESUMEN
We investigated the role of neuronal (type I) nitric oxide synthase (nNOS) in NMDA-mediated excitotoxicity in wild-type (SV129 and C57BL/6J) and type I NOS knock-out (nNOS-/-) mice and examined its relationship to apoptosis. Excitotoxic lesions were produced by intrastriatal stereotactic NMDA microinjections (10-20 nmol). Lesion size was dose- and time-dependent, completely blocked by MK-801 pretreatment, and smaller in nNOS knock-out mice compared with wild-type littermates (nNOS+/+, 11.7 +/- 1.7 mm3; n = 8; nNOS-/-, 6. 4 +/- 1.8 mm3; n = 7). The density and distribution of striatal NMDA binding sites, determined by NMDA receptor autoradiography, did not differ between strains. Pharmacological inhibition of nNOS by 7-nitroindazole (50 mg/kg, i.p.) decreased NMDA lesion size by 32% in wild-type mice (n = 7). Neurochemical and immunohistochemical measurements of brain nitrotyrosine, a product of peroxynitrite formation, were increased markedly in wild-type but not in the nNOS-/- mice. Moreover, elevations in 2,3- and 2,5-dihydroxybenzoic acid levels were significantly reduced in the mutant striatum, as a measure of hydroxyl radical production. The importance of apoptosis to NMDA receptor-mediated toxicity was evaluated by DNA laddering and by quantitative histochemistry [terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) staining]. DNA laddering was first detected within lesioned tissue after 12-24 hr. TUNEL-positive cells were first observed at 12 hr, increased in number at 48 hr and 7 d, and were located predominantly in proximity to the lesion border. The density was significantly lower in nNOS-/- mice. Hence, oligonucleosomal DNA breakdown suggesting apoptosis develops as a late consequence of NMDA microinjection and is reduced in nNOS mutants. The mechanism of protection in nNOS-/- mice may relate to decreased oxygen free radical production and related NO reaction products and, in part, involves mechanisms of neuronal death associated with the delayed appearance of apoptosis.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , N-Metilaspartato/toxicidad , Óxido Nítrico Sintasa/fisiología , Animales , Apoptosis , Sitios de Unión , Cuerpo Estriado/metabolismo , Fragmentación del ADN , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Radical Hidroxilo/metabolismo , Ácido Kaínico/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa/genética , Receptores de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Tirosina/análogos & derivados , Tirosina/biosíntesis , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismoRESUMEN
We investigated the density and distribution of nitric oxide synthase (NOS) binding by quantitative autoradiography using [3H]L-NG-nitroarginine ([3H]L-NNA) after transient focal ischemia or intrastriatal injection of N-methyl-D-aspartate (NMDA) in wild-type (SV-129 and C57black/6) and type I (neuronal) and type III (endothelial) NOS-deficient mice. The middle cerebral artery (MCA) was occluded by an intraluminal filament for 3 h followed by 10 min to 7 days of reperfusion. Specific [3H]L-NNA binding, observed in the wild-type and type III mutant mouse at baseline, increased by 50-250% in the MCA territory during ischemia and the first 3 h of reperfusion. The density of binding sites (Bmax), but not the dissociation constant (Kd), increased significantly during the ischemic period as did type I NOS mRNA as detected by quantitative reverse transcription polymerase chain reaction. [3H]L-NNA binding after intrastriatal NMDA injection also increased by 20-230%. In the type I NOS-deficient mouse, [3H]L-NNA binding was low and only a very small increase was observed after ischemia or excitotoxicity. Under conditions of this study, [3H]L-NNA did not bind to type II NOS as there was no difference in the distribution or density of [3H]L-NNA binding in the rat spleen obtained after lipopolysaccharide treatment despite induction of NOS type II catalytic activity. Our data suggest that an ischemic/excitotoxic insult up-regulates type I NOS gene expression and [3H]L-NNA binding and that this up-regulation may play a pivotal role in the pathogenesis of ischemic/excitotoxic diseases.
Asunto(s)
Inhibidores Enzimáticos/farmacocinética , Agonistas de Aminoácidos Excitadores/toxicidad , Ataque Isquémico Transitorio/enzimología , N-Metilaspartato/toxicidad , Óxido Nítrico Sintasa/deficiencia , Nitroarginina/farmacocinética , Animales , Autorradiografía , Inhibidores Enzimáticos/administración & dosificación , Agonistas de Aminoácidos Excitadores/administración & dosificación , Femenino , Masculino , Ratones , Ratones Mutantes , N-Metilaspartato/administración & dosificación , Óxido Nítrico Sintasa/análisis , Óxido Nítrico Sintasa/genética , Nitroarginina/administración & dosificación , Ensayo de Unión Radioligante , Ratas , Distribución Tisular , TritioRESUMEN
Changes in the regional distribution of protein kinase C (PKC) after transient focal cerebral ischemia in SV-129 mice were assessed by quantitative autoradiography using [3H]phorbol-12,13-dibutyrate ([3H]PDBu) binding. [3H]PDBu binding did not change up to 10 min after reperfusion of 3 h ischemia, but at 1 h after reperfusion markedly decreased to 40-50% of control (pre-ischemia) in the ipsilateral striatum and the middle cerebral artery (MCA) region of cortex in SV-129 mice. The binding decreased to 20% of control at 3-7 days after reperfusion, but did not change in the ipsilateral anterior cerebral artery (ACA) territory or the contralateral brain. In the ipsilateral substantia nigra, which lies outside the ischemic zone, [3H]PDBu binding was not significantly changed compared to the control values (pre-ischemia) at early phase (up to 3 h after reperfusion), but marked reduction of the binding was observed 1 day after reperfusion. After 3 h ischemia followed by 3 h reperfusion, the morphological damage and the decrease in [3H]PDBu binding in the ipsilateral striatum and the MCA region of cortex was smaller in mice lacking the expression of neuronal nitric oxide synthase (type I NOS) gene mutant mice compared to wild-type (SV-129 and C57black/6) mice. Our data suggest that postischemic alterations of PKC binding activity were observed in the ischemic and non-ischemic lesions in the mouse brain.
Asunto(s)
Ataque Isquémico Transitorio/metabolismo , Forbol 12,13-Dibutirato/metabolismo , Proteína Quinasa C/metabolismo , Animales , Autorradiografía , Encéfalo/metabolismo , Encéfalo/patología , Femenino , Ataque Isquémico Transitorio/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos/metabolismo , Ratones Mutantes , Reperfusión , Factores de Tiempo , Distribución Tisular , TritioRESUMEN
1. Valproic acid, useful in the treatment of migraine, is an inhibitor of gamma aminobutyric acid (GABA) aminotransferase and activator of glutamic acid decarboxylase. Its mechanism in migraine remains obscure. The effects of valproic acid (2-propylpentanoic acid) were examined on the number of cells expressing c-fos-like immunoreactivity (c-fos-LI), a marker of neuronal activation, within the trigeminal nucleus caudalis (lamina I, IIo, TNC) 2 h after intracisternal injection of the irritant, capsaicin (0.1 ml; 15.25 micrograms ml-1), in urethane-anaesthetized Hartley guinea-pigs. Positive cells were counted in eighteen sections (50 microns) at three representative levels (rostral, middle and caudal) within lamina I, IIo of the TNC in 90 animals. 2. Numerous cells were labelled after capsaicin instillation (244 +/- 25; 1 ml; 15.25 mM) but not after capsaicin vehicle (11 +/- 1). Positive cells were also found within the medial reticular nucleus, the area postrema and the nucleus of the solitary tract. A similar distribution has been demonstrated previously after application of intracisternal irritants such as autologous blood or carrageenin. 3. Valproate (> or = 10 mg kg-1, i.p.) reduced labelled cells by 52% (P < 0.05) in lamina I, IIo but not within the area postrema, the nucleus of the solitary tract or the medial reticular nucleus. A similar finding was obtained previously after administration of sumatriptan, dihydroergotamine or the NK1 receptor antagonist RPR 100,893. 4. Pretreatment with bicuculline (30 micrograms kg-1; i.p.), a GABAA antagonist, but not phaclofen (1 mg kg-1) a GABAB antagonist, reversed the effect of valproate and increased c-fos positive cells within lamina I, IIo. Somewhat paradoxically, bicuculline by itself (30 micrograms kg-1 i.p.) decreased the number of labelled cells suggesting that more than a single GABAergic mechanism can suppress c-fos expression. 5. We conclude that the mechanism of action of valproate is mediated via GABAA receptors. Since valproate decreases both c-fos expression and as previously shown, neurogenic inflammation within the meninges, the GABAA receptor complex might provide an important target for drug development in migraine and related headaches.