Mussismilia braziliensis White Plague Disease Is Characterized by an Affected Coral Immune System and Dysbiosis.

Infectious diseases are one of the major drivers of coral reef decline worldwide. White plague-like disease (WPL) is a widespread disease with a complex etiology that infects several coral species, including the Brazilian endemic species Mussismilia braziliensis. Gene expression profiles of healthy and WPL-affected M. braziliensis were analyzed in winter and summer seasons. The de novo assembly of the M. braziliensis transcriptome from healthy and white plague samples produced a reference transcriptome containing 119,088 transcripts. WPL-diseased samples were characterized by repression of immune system and cellular defense processes. Autophagy and cellular adhesion transcripts were also repressed in WPL samples, suggesting exhaustion of the coral host defenses. Seasonal variation leads to plasticity in transcription with upregulation of intracellular signal transduction, apoptosis regulation, and oocyte development in the summer. Analysis of the active bacterial rRNA indicated that Pantoea bacteria were more abundant in WPL corals, while Tistlia, Fulvivirga, and Gammaproteobacteria Ga0077536 were more abundant in healthy samples. Cyanobacteria proliferation was also observed in WPL, mostly in the winter. These results indicate a scenario of dysbiosis in WPL-affected M. braziliensis, with the loss of potentially symbiotic bacteria and proliferation of opportunistic microbes after the start of the infection process.

Ecogenomics and metabolic potential of the South Atlantic Ocean microbiome.

The unique combination of depth, salinity, and water masses make the South Atlantic Ocean an ecosystem of special relevance within the global ocean. Yet, the microbiome of this ecosystem has received less attention than other regions of the global Ocean. This has hampered our understanding of the diversity and metabolic potential of the microorganisms that dwell in this habitat. To fill this knowledge gap, we analyzed a collection of 31 metagenomes from the Atlantic Ocean that spanned the epipelagic, mesopelagic and bathypelagic zones (surface to 4000 m). Read-centric and gene-centric analysis revealed the unique taxonomic and functional composition of metagenomes from each depth zone, which was driven by differences in physical and chemical parameters. In parallel, a total of 40 metagenome-assembled genomes were obtained, which recovered one third of the total community. Phylogenomic reconstruction revealed that many of these genomes are derived from poorly characterized taxa of Bacteria and Archaea. Genomes derived from heterotrophic bacteria of the aphotic zone displayed a large apparatus of genes suited for the utilization of recalcitrant organic compounds such as cellulose, chitin and alkanes. In addition, we found genomic evidence suggesting that mixotrophic bacteria from the bathypelagic zone could perform carbon fixation through the Calvin-Benson-Bassham cycle, fueled by sulfur oxidation. Finally, we found that the viral communities shifted throughout the water column regarding their targeted hosts and virus-to-microbe ratio, in response to shifts in the composition and functioning their microbial counterparts. Our findings shed light on the microbial and viral drivers of important biogeochemical processes that take place in the South Atlantic Ocean.

Efecto del praziquantel en los receptores angiogénicos, citocinas inflamatorias y anti-inflamatorias en la esquistosomiasis intestinal murina / The effect of praziquantel in the angiogenic receptors, inflammation and inflammatory cytokines on the murine intestinal schistosomiasis

Los estudios en torno al papel patogénico del Schistosoma mansoni se enfocan en el daño hepático y la respuesta inmune en el hospedador definitivo, en contraste a la escasa información en relación a la patología intestinal. A tal fin, se evaluó el efecto del praziquantel en los receptores angiogenicos, citocinas inflamatorias y anti-inflamatorias en la esquitosomiasis intestinal murina. La respuesta inflamatoria granulomatosa intestinal se midió en secciones histológicas teñidas con H&E; la detección de TNF-α, IL-10, TGF-ß, el VEGF y sus receptores (FLK1 y FLT1) mediante inmunohistoquímica y ELISA, en suero e intestino de ratones BALB/c infectados con S. mansoni a las 8 (RI8S) y 20 semanas (RI20S), y ratones con 8 semanas de infección a los quince días de post-tratamiento, con praziquantel 40 µgr/gr (RPT). En RI8S se observaron granulomas pequeños (11304 µm2 en promedio), sin bordes definidos ni zonas marcadas dentro del granuloma, y granulomas de gran tamaño con bordes definidos (70650 µm2) sin zonas definidas dentro del granuloma, ambos con predominio de macrófagos y presencia de plasmocitos. En RI20S, los granulomas presentan una zona interna constituida por abundantes macrófagos y escasos plasmocitos, y una externa constituida solo por macrófagos (11985 µm2). En RPT no se apreciaron granulomas, solo algunos focos inflamatorios cercanos a la muscularis mucosae y las glándulas de Lieberkuhn. La Inmunolocalización en el intestino solo fue positiva en RPT para VEGF y sus receptores, TGP-ß e IL-10; Los resultados muestran una discreta respuesta en cuanto a tamaño del granuloma, celularidad y la expresión de citocinas a nivel intestinal.

The studies on the pathogenic role of the Schistosoma mansoni focus on the hepatic damage and the immune response of the final host, in constrast to the limited information regarding intestinal lesion. This work evaluates. Intestinal granulomatous inflammation was measured in histological sections the effect of praziquantel in the angiogenic receptors (FLK1 and FLT1), inflammation and inflammatory cytokines on the murine intestinal schistosomiasis stained with H&E; the detection of TNF-α, IL-10, TGF-ß, VEGF and its receptors was carried out by immunohistochemistry and ELISA, in serum and intestine sections of BALB/c mice infected with S. mansoni at 8 (RI8S) and 20 (RI20S) weeks post-infection, and mice infected for 8 weeks and evaluated 15 days post-treatment with praziquantel 40 µg/(RPT). In RI8S small granulomas (11.304 µm2 average), without sharp or marked edges within the granuloma; and large granulomas (70.650 µm2) with defined borders without defined zones within the granuloma, In both groups of mice macrophages predominated and plasma cells were present. In RI20S, granulomas have an inner zone composed by abundant macrophages and few plasma cells, and external zone constituted only by macrophages (11.985 µm2). In RPT, granulomas were not observed, only a few inflammatory foci nearby the muscularis mucosae and the Lieberkuhn glands. Localization of immune molecules in the intestine was only positive in RPT for VEGF, its receptors, TGF-ß and IL-10; the results show a discrete response over the granuloma size, cellularity and cytokine expression at intestinal level.

Respuesta humoral IgM e IgG frente a antigenos de excreción-secreción de Schistosoma mansoni en murinos infectados y su relación con las citoquinas Il-10 y TNF-α / Humoral IgM and IgG against excretory-secretory antigens of infected murine with Schistosoma mansoni and its relationship with the cytokines Il-10 and TNF- α

El diagnóstico de fase en la esquistosomiasis es complejo. Se evaluó la respuesta IgM e IgGmurina contra productos de excreción-secreción de Schistosoma mansoni machos (PESGM), hembras (PESGH) y huevos (PESH), su relación con la histopatología y expresión de IL-10 y TNF-α, mediante ELISA, en suero de ratones Balb/c con 8 y 20 semanas de infección (RI8 y RI20) y Ratones sanos(RS). En RI8, se observaron granulomas constituidos por plasmocitos, macrófagos y neutrófilos, depósitos de colágeno alrededor de los granulomas y en la zona interna del huevo. En R20SI, se observaron fibroblastos alrededor del huevo y acúmulos de macrófagos y plasmocito, aumento de los depósitos de colágeno en áreas del granuloma. IgM sérica RI8, presentó un mayor porcentaje de positividad frente PESGH (35%), mientras que IgG el mayor porcentaje de positividad fue PESGH (60%) y PESH (30%). En R20SI, IgM fue 20% positiva frente PESH e IgG 10% frente PESGM, y 25% positiva con PESGH. No se observaron diferencias en IL-10 entre los RS y RI8. TNF-α en RS vs RI8 y RS vs RI20 fue diferente y estadísticamente significativo. Los PESGH podrían detectar fase aguda y PESH fase crónica. El empleo de varios antígenos sería de utilidad en el diagnóstico de fase.

The diagnosis of schistosomiasis phase is complex. The murine IgM and IgG response against excretory-secretory products of Schistosoma mansoni males (PESGM), females (PESGH) and eggs (PESH), its relation to histopathology and expression of IL-10 and TNF-α was assessed by ELISA in serum of Balb / c mice with 8 and 20 weeks of infection (RI8 and RI20) and healthy mice, RS. In RI8, were observed granulomas consisting of plasma cells, macrophages and neutrophils, deposits of collagen around the granulomas and internal area of the egg. In R20SI, fibroblasts around the egg and accumulation of macrophages and plasmocito, increased collagen deposits in areas of granuloma were observed.RI8 serum IgM had a higher percentage of positivity PESGH (35%), while the highest percentage of IgG positivity was PESGH (60%) and PESH (30%). In R20SI, was 20% IgM positive and IgG against PESH PESGM 10% against and 25% positive with PESGH. No differences in IL-10 between the RS and RI8 were observed. TNF-α in RS vs RI8 and RS vs RI20 was different and statistically significant. The PESGH could detect phase acute while PESH chronic phase. The use of several antigens would be useful in the diagnosis phase.

Evolutionary screening and adsorption behavior of engineered M13 bacteriophage and derived dodecapeptide for selective decoration of gold interfaces.

There is a growing interest in identifying biomacromolecules such as proteins and peptides to functionalize metallic surfaces through noncovalent binding. One method for functionalizing materials without fundamentally changing their inherent structure is using biorecognition moieties. Here, we proved a general route to select a biomolecule adhesive motif for surface functionalization by comprehensively screening phage displayed peptides. In particular, we selected a genetically engineered M13 bacteriophage and a linear dodecapeptide derived from its pIII domain for recognizing gold surfaces in a specific and selective manner. In the phage context, we demonstrated the adhesive motif was capable to adsorb on gold in a preferential way with a morphological and viscoelastic signature of the adsorbed layer as evidenced by QCM-D and AFM investigations. Out of the phage context, the linear dodecapeptide is reproducibly found to adhere to the gold surface, and by quantitative SPR measurements, high affinity constants (K(eq)~10(6)M(-1), binding energy ~-8 kcal/mol) were determined. We proved that the interactions occurring at gold interface were mainly hydrophobic as a consequence of high frequency of hydrophobic residues in the peptide sequence. Moreover, by CD, molecular dynamics and steered molecular dynamics, we demonstrated that the molecular flexibility only played a minor role in the peptide adsorption. Such noncovalent but specific modification of inorganic surfaces through high affinity biomolecule adsorption represents a general strategy to modulate the functionality of multipurpose metallic surfaces.

Groundwater vulnerability and risk mapping using GIS, modeling and a fuzzy logic tool.

A groundwater vulnerability and risk mapping assessment, based on a source-pathway-receptor approach, is presented for an urban coastal aquifer in northeastern Brazil. A modified version of the DRASTIC methodology was used to map the intrinsic and specific groundwater vulnerability of a 292 km(2) study area. A fuzzy hierarchy methodology was adopted to evaluate the potential contaminant source index, including diffuse and point sources. Numerical modeling was performed for delineation of well capture zones, using MODFLOW and MODPATH. The integration of these elements provided the mechanism to assess groundwater pollution risks and identify areas that must be prioritized in terms of groundwater monitoring and restriction on use. A groundwater quality index based on nitrate and chloride concentrations was calculated, which had a positive correlation with the specific vulnerability index.

Monitorización prolongada por videoelectroencefalografía de pacientes con diagnóstico ambulatorio de epilepsia del lóbulo temporal de difícil control: aplicación del modelo de lógica fuzzy / Video-electroencephalography prolonged monitoring in patients with ambulatory diagnosis of medically refractory temporal lobe epilepsy: application of fuzzy logic’s model

Introducción. La monitorización prolongada por videoelectroencefalografía(vídeo-EEG) constituye un instrumento importantede auxilio al diagnóstico de epilepsia; facilita informacionesvaliosas con relación a la clasificación de los tipos de crisis ysíndromes epilépticos y la localización de la zona epileptógena. Lalógica fuzzy provee un método de análisis eficaz e inteligente,capaz de realizar inferencias sobre sistemas ambiguos y cada vezse utiliza más en diferentes áreas. Objetivos. Correlacionar datosclínicos y electroencefalográficos obtenidos por la monitorizaciónprolongada por vídeo-EEG de pacientes con diagnóstico en elambulatorio de epilepsia del lobo temporal (ELT) de difícil controle inferir los grados de precisión del diagnóstico por la aplicacióndel modelo COPPE/Cosenza de jerarquía fuzzy; investigar conqué frecuencia la monitorización puede corroborar o modificar eldiagnóstico clínico, sindrómico y topográfico de los pacientes estudiados;evaluar la utilidad y aplicabilidad de la lógica fuzzy en elanálisis de ese tipo de estudio. Pacientes y métodos. Estudio prospectivo,transversal, que incluye a 22 pacientes adultos con diagnósticoen el ambulatorio de ELT de difícil control, sometidos amonitorización por vídeo-EEG. Resultados. El diagnóstico clínicose modificó en dos pacientes (9%), el sindrómico en seis (27,2%), yel topográfico en 16 (72,7%). Los indicadores fuzzy de precisióndel diagnóstico en el ambulatorio fueron: 0,91 para diagnósticoclínico, 0,74 para diagnóstico sindrómico y 0,36 para diagnósticotopográfico; se considera 1 el valor de máxima precisión dediagnóstico (se atribuye a los resultados de la monitorización porvídeo-EEG). Conclusiones. La monitorización prolongada por vídeo-EEG estableció el diagnóstico clínico, sindrómico y topográficoen esos pacientes; la lógica fuzzy mostró definir mejor un valormatemático de la correspondencia entre el diagnóstico en el ambulatoriode ELT y la monitorización prolongada por vídeo-EEG

Introduction. The video-electroencephalography (video-EEG) prolonged monitoring is an important auxiliarydiagnostic instrument in epilepsy, and provides valuable information to classify the type of crisis and epileptic syndromes andto localize the epileptogenic zone. The fuzzy logic gives an efficient and intelligent analysis method, able to make inferencesover ambiguous systems, and has been increasing used in several areas. Aims. To correlate clinical and electroencephalographicdata obtained with video-EEG of patients with clinical and interictal electroencephalography criteria ofmedically refractory temporal lobe epilepsy (TLE) and to make inferences of diagnosis precision with the application of theFuzzy Hierarchy COPPE/Cosenza Model; to investigate the frequency in which the clinical, syndromic and topographicdiagnosis can be modified in these patients; to evaluate the usefulness and applicability of fuzzy logic on the analysis of thistype of study. Patients and methods. Transversal, prospective study, that included 22 adult outpatients with ambulatorydiagnosis of medically refractory TLE, submitted to video-EEG monitoring that varied from 48 hours to 10 days. The grade ofdiagnosis precision was infered by fuzzy logic. Results. The clinical diagnosis of epilepsy was modified in two (9%) patients,the syndromic in six (27.2%) and the topographic in 16 (72.7%). The fuzzy indicators of ambulatory diagnostic precisionwere: 0.91 to clinical diagnosis; 0.74 to syndromic diagnosis and 0.36 to topographic diagnosis, considering 1 the maximalprecision diagnostic value (attributed to the video-EEG results). Conclusions. The video-EEG prolonged monitoring establishedthe clinical, syndromic and topographic correct diagnosis in these patients; the fuzzy logic best defined a mathematical valueof the correspondence between ambulatorial diagnosis of TLE and the video-EEG prolonged monitoring

[Video-electroencephalography prolonged monitoring in patients with ambulatory diagnosis of medically refractory temporal lobe epilepsy: application of fuzzy logic's model]. / Monitorización prolongada por videoelectroencefalografía de pacientes con diagnóstico ambulatorio de epilepsia del lóbulo temporal de difícil control: aplicación del modelo de lógica fuzzy

INTRODUCTION: The video-electroencephalography (video-EEG) prolonged monitoring is an important auxiliary diagnostic instrument in epilepsy, and provides valuable information to classify the type of crisis and epileptic syndromes and to localize the epileptogenic zone. The fuzzy logic gives an efficient and intelligent analysis method, able to make inferences over ambiguous systems, and has been increasing used in several areas. AIMS: To correlate clinical and electroencephalographic data obtained with video-EEG of patients with clinical and interictal electroencephalography criteria of medically refractory temporal lobe epilepsy (TLE) and to make inferences of diagnosis precision with the application of the Fuzzy Hierarchy COPPE/Cosenza Model; to investigate the frequency in which the clinical, syndromic and topographic diagnosis can be modified in these patients; to evaluate the usefulness and applicability of fuzzy logic on the analysis of this type of study. PATIENTS AND METHODS: Transversal, prospective study, that included 22 adult outpatients with ambulatory diagnosis of medically refractory TLE, submitted to video-EEG monitoring that varied from 48 hours to 10 days. The grade of diagnosis precision was infered by fuzzy logic. RESULTS: The clinical diagnosis of epilepsy was modified in two (9%) patients, the syndromic in six (27.2%) and the topographic in 16 (72.7%). The fuzzy indicators of ambulatory diagnostic precision were: 0.91 to clinical diagnosis; 0.74 to syndromic diagnosis and 0.36 to topographic diagnosis, considering 1 the maximal precision diagnostic value (attributed to the video-EEG results). CONCLUSIONS: The video-EEG prolonged monitoring established the clinical, syndromic and topographic correct diagnosis in these patients; the fuzzy logic best defined a mathematical value of the correspondence between ambulatorial diagnosis of TLE and the video-EEG prolonged monitoring.

Long-term results of metallic stents for benign biliary strictures.

BACKGROUND: Historically, surgical correction has been the treatment of choice for benign biliary strictures (BBS). Self-expandable metallic stents (MSs) have been useful for inoperable malignant biliary strictures; however, their use for BBS is controversial and their natural history unknown. HYPOTHESIS: To test our hypothesis that MSs provide only short-term benefit, we examined the long-term outcome of MSs for the treatment of BBS. Our goal was to develop a rational approach for treating BBS. DATA EXTRACTION: Between July 1990 and December 1995, 15 patients had MSs placed for BBS and have been followed up for a mean of 86.3 months (range, 55-120 months). The mean age of the patients was 66.6 years and 12 were women. Stents were placed for surgical injury in 5 patients and underlying disease in 10 patients (lithiasis, 7; pancreatitis, 2; and primary sclerosing cholangitis, 1). One or more MSs (Gianturco-Rosch "Z" for 4 patients and Wallstents for 11 patients) were placed by percutaneous, endoscopic, or combined approaches. We considered patients to have a good clinical outcome if the stent remained patent, they required 2 or fewer invasive interventions, and they had no biliary dilation on subsequent imaging. DATA SYNTHESIS: Metallic stents were successfully placed in all 15 patients, and the mean patency rate was 30.6 months (range, 7-120 months). Five patients (33%) had a good clinical result with stent patency from 55 to 120 months. Ten patients (67%) required more than 2 radiologic and/or endoscopic procedures for recurrent cholangitis and/or obstruction (range, 7-120 months). Five of the 10 patients developed complete stent obstruction at 8, 9, 10, 15, and 120 months and underwent surgical removal of the stent and bilioenteric anastomosis. Four of these 5 patients had strictures from surgical injuries. The patient who had surgical removal 10 years after MS placement developed cholangiocarcinoma. CONCLUSIONS: Surgical repair remains the treatment of choice for BBS. Metallic stents should only be considered for poor surgical candidates, intrahepatic biliary strictures, or failed attempts at surgical repair. Most patients with MSs will develop recurrent cholangitis or stent obstruction and require intervention. Chronic inflammation and obstruction may predispose the patient to cholangiocarcinoma.

Renal cell carcinoma metastatic to the pancreas: a single-institution series and review of the literature.

OBJECTIVES: To present a series of 5 patients with solitary metastatic renal cell carcinoma (RCC) to the pancreas after radical nephrectomy at our institution and review the published reports of this rare event. METHODS: A retrospective review of the records of 5 patients with histologically confirmed RCC metastatic to the pancreas after radical nephrectomy was performed. A total of 5 patients (4 men, 1 woman) with a median age of 56 years (range 54 to 68) underwent radical nephrectomy for primary RCC. The pathologic stage was Robson I (n = 3) or Robson III (n = 2), with a left-sided tumor occurring in 3 patients and a right-sided tumor in 2 patients. The median interval from nephrectomy to the diagnosis of the pancreatic metastasis was 12 years (range 4 to 15). All patients were symptomatic at presentation, including weight loss (n = 3), abdominal pain (n = 3), early satiety (n = 1), steatorrhea (n = 1), and/or hemosuccus pancreaticus (n = 1). RESULTS: All pancreatic metastases were hypervascular on imaging studies, and surgical removal was accomplished by pancreaticoduodenectomy (n = 3), partial pancreatectomy (n = 1), or subtotal pancreatectomy (n = 1). One patient died of disseminated disease 12 months after pancreatic resection. Two other patients had recurrences in the lung (n = 1) at 5 months or the pancreas/liver (n = 1) at 48 months. Both of these patients underwent a second resection and were disease free at 2 and 12 months afterward. The two remaining patients were disease free at 7 and 24 months after pancreatic resection. CONCLUSIONS: RCC is an unpredictable tumor that may demonstrate very late metastases even from early-stage lesions. Aggressive surgical management of isolated pancreatic lesions offers a chance of long-term survival.

Current management of recurrent pyogenic cholangitis.

Recurrent pyogenic cholangitis (RPC) is a chronic disease with multiple exacerbations requiring repeated biliary dilatation and stone removal. Even after adequate biliary drainage, most patients will have progression of intrahepatic disease. Management of patients with RPC is a multidisciplinary challenge for endoscopists, interventional radiologists, and surgeons because of the frequency and inaccessibility of strictures and stones. Complete stone clearance at any one operation is difficult. Hepaticojejunostomy with a subcutaneous afferent limb is a safe and effective way to provide access to the biliary tree for the management of patients with RPC. In our experience, trans-stomal cholangioscopic stricture dilatation followed by stone removal remains the basis of therapy in patients with RPC. By diligent surveillance, we should be able to eliminate or decrease the number of stones and prevent cholangitis and its sequelae.

Metastasis of hepatocellular carcinoma to the right colon manifested by gastrointestinal bleeding.

An 82-year-old black woman with a history of hepatocellular carcinoma presented with gastrointestinal bleeding. Barium enema and fibrocolonoscopy revealed a 4-cm polypoid mass at the level of the ascending colon with evidence of active bleeding. Biopsies of the lesion proved it to be metastatic hepatocellular carcinoma. Exploratory laparotomy revealed no further dissemination of the tumor, and the patient underwent an ileocolectomy. The serosal side of the colonic lesion was free from tumor, and there was no peritoneal implantation, direct extension, or lymph node involvement. This case represents an extremely rare presentation of metastatic hepatocellular carcinoma.

Surgical management of biliary gallstone disease during pregnancy.

BACKGROUND: Biliopancreatic gallstone disorders (BPD) manifesting during pregnancy are relatively rare. The management of these conditions remains controversial. Although perioperative problems and fetal loss have been reported, recent publications have advocated an early surgical approach. PATIENTS AND METHODS: Thirty-two pregnant women underwent operation for BPD between January 1993 and December 1997. The mean age was 29 years and ranged from 18 to 41 years. RESULTS: Twelve patients underwent a laparoscopic cholecystectomy (LC), and 20 open cholecystectomies (OC), including two conversions from laparoscopic. Seven of the OC patients required additional open CBD exploration and intraoperative choledochoscopy for CBD stones. No maternal mortality was observed. A single fetal demise (3%) occurred for a patient with gallstone pancreatitis who underwent open cholecystectomy during her 14th week of gestation. CONCLUSIONS: Early involvement of the obstetric team, with preoperative and postoperative fetal monitoring, and adequate management of anesthetic and tocolytic agents make cholecystectomy a safe procedure at any stage of pregnancy.

Efficacy of tacrolimus as rescue therapy for chronic rejection in orthotopic liver transplantation: a report of the U.S. Multicenter Liver Study Group.

BACKGROUND: A study was performed by 17 different U.S. liver transplantation centers to determine the safety and efficacy of conversion from cyclosporine to tacrolimus for chronic allograft rejection. METHODS: Ninety-one patients were converted to tacrolimus a mean of 319 days after liver transplantation. The indication for conversion was ongoing chronic rejection confirmed by biochemical and histologic criteria. Patients were followed for a mean of 251 days until the end of the study. RESULTS: Sixty-four patients (70.3%) were alive with their initial hepatic allograft at the conclusion of the study period and were defined as the responder group. Twenty-seven patients (29.7%) failed to respond to treatment, and 20 of them required a second liver graft. The actuarial graft survival for the total patient group was 69.9% and 48.5% at 1 and 2 years, respectively. The actuarial patient survival at 1 and 2 years was 84.4% and 81.2%, respectively. Two significant positive prognostic factors were identified. Patients with a total bilirubin of < or = 10 mg/dl at the time of conversion had a significantly better graft and patient survival than patients converted with a total bilirubin > 10 mg/dl (P=0.00002 and P=0.00125, respectively). The time between liver transplantation and conversion also affected graft and patient survival. Patients converted to tacrolimus < or = 90 days after transplantation had a 1-year actuarial graft and patient survival of 51.9% and 65.9%, respectively, compared with 73.2% and 87.7% for those converted > 90 days after transplantation. The mean total bilirubin level for the responder group was 7.1 mg/dl at the time of conversion and decreased significantly to a mean of 3.4 mg/dl at the end of the study (P=0.0018). Thirteen patients (14.3%) died during the study. Sepsis was the major contributing cause of death in most of these patients. CONCLUSIONS: Our results suggest that conversion to tacrolimus for chronic rejection after orthotopic liver transplantation represents an effective therapeutic option. Conversion to tacrolimus before development of elevated total bilirubin levels showed a significant impact on long-term outcome.

Transjugular intrahepatic portosystemic shunt: efficacy for the treatment of portal hypertension and impact on liver transplantation.

Variceal bleeding (VB) and ascites refractory to diuretics (RA) represent a significant cause of morbidity and mortality in patients with portal hypertension. Transjugular intrahepatic portosystemic shunts (TIPS) have been used effectively in patients with these complications, especially those individuals awaiting orthotopic liver transplantation (OLT). From April 1992 to July 1995, 41 adult patients underwent an attempt at TIPS placement for refractory VB or ascites at Cedars-Sinai Medical Center. Technical success was achieved in 37 of 41 cases (90.3%) with only two technical complications. Immediate control of hemorrhage and significant improvement of ascites was obtained in 91.9% and 83.5% of the patients, respectively. Six patients (16.2%) died within a week of TIPS placement due to uncontrollable ascites and multiorgan failure. Four of 31 patients (12.9%) developed mild to moderate grades of hepatic encephalopathy that was controlled with lactulose. Rebleeding from recurrent portal hypertension was noted in 5 of 31 cases (16.1%). Shunt stenosis or occlusion was seen in 7 of 31 cases (22.6%) at an average of 6.3 months following TIPS placement. Six patients underwent OLT within an average of 87 days after TIPS. These results indicate that TIPS appears to be an effective method for treatment of refractory VB and RA, especially for patients who are poor candidates for a surgical shunt or awaiting OLT. However, TIPS may not be considered a definitive solution for all patients with portal hypertension because of its current rate of shunt occlusion or stenosis.

Hepatic resection for malignancy in the elderly.

Although elderly patients are accounted for in all large series of major hepatic resections, the role of age as a determinant of outcome remains unclear. At Cedars-Sinai Medical Center, we review a series of 20 major hepatectomies for neoplasia performed in patients older than 66 years of age (4 of them > or = 80 years old) over a 5-year period. A retrospective comparison was conducted with a group of 22 hepatectomies for malignancy performed in 20 patients younger than 59 years of age during the same time period. The younger group had a significantly greater degree of liver resected (12 trisegmentectomies vs 3). Although one operative death (5% mortality) was observed in the elderly group, no statistically significant difference was noted, when compared to the younger group (Chi-square, P = 0.48). Likewise, no significant difference in the complication rate (20% vs 33%) was noticed (Chi-square, P = 0.8). Severe postoperative liver dysfunction was present in 2 cases (10%) in the elderly group and one (4%) in the younger group. These patients underwent a right trisegmentectomy (TS). Nine patients from each group were resected without red blood cell transfusion. We conclude that major hepatic resection in elderly patients without severe comorbid disease is a safe procedure that is not associated with an increased perioperative morbidity or mortality rate.

The use of a pig liver xenograft for temporary support of a patient with fulminant hepatic failure.

A 26-year-old female patient with fulminant hepatic failure and a history of autoimmune hepatitis was heterotopically transplanted with a pig hepatic xenograft to provide temporary metabolic support prior to transplantation with a human donor organ. Circulating natural antipig antibodies were removed prior to transplantation by plasmapheresis and ex vivo en bloc perfusion of the donor pig kidneys. The liver xenograft functioned after transplantation as measured by active bile production, stabilization of prothrombin levels, and reduction in the circulating levels of lactic acid and the enzymes AST and ALT. Despite the removal of greater than 90% of the recipient's natural xenoantibodies prior to transplantation, the levels of antibody rapidly returned and were associated with antibody and complement-mediated rejection of the donor graft. Immunohistochemical evidence of graft rejection could be detected by the deposition of antibody, complement components including properdin, and endothelial swelling as early as 3 hr posttransplantation. These lesions progressed in severity and were accompanied by evidence of thrombosis and ischemic necrosis of the liver xenograft by 34 hrs posttransplantation. The main portal vein, hepatic artery, and vena cava were patent. The placement of the liver graft did not result in any improvement in the neurological status of the patient and she died 34 hr after xenografting due to irreversible brain damage. The information derived from this case has renewed interest in the clinical use of bioartificial devices and whole organ perfusion using xenogeneic tissue for temporary bridging of patients prior to allografting.

Intragraft cytokine gene expression in human liver allografts.

Cytokines are thought to play an important role in the inflammatory and immune responses of allograft rejection. We evaluated the pattern of cytokine gene expression in 36 liver biopsy specimens obtained from 20 recipients of primary orthotopic liver allografts. Specific mRNA expression was identified by a polymerase chain reaction (PCR) using oligonucleotide primers specific for human interleukin (IL)-1 beta, IL-2, IL-4, IL-6, IL-10 Interferon (IFN) gamma, tumor necrosis factor (TNF)-alpha and beta-actin. We detected IL-1 beta, IL-6 and IFN-gamma cytokine message most consistently in patients with rejecting liver allografts. TNF-alpha and IL-2 were also observed in rejecting livers, but only during the early phases of the reaction. IL-4 was expressed in the majority of liver allograft biopsy specimens, regardless of the presence or absence of clinical or pathological evidence of rejection. Sequential biopsy specimens in rejecting allografts showed decreased cytokine expression after the induction of a positive response to immunosuppressive therapy. The analysis of biopsy specimens from stable liver grafts showed a predominance in the expression of IL-10. These results may reflect a differential production of inflammatory and regulatory cytokines in response to liver allograft rejection in transplant recipients. They suggest that three cytokines, IL-1 beta, IL-6 and IFN-gamma, may play an important role as markers for liver allograft rejection. Conversely, IL-10 expression was noted in patients with stable graft function. This pattern of expression may correlate with host immune responses that allow for prolonged, rejection-free survival of the graft.