Release of interleukin-12 in experimental Escherichia coli septic shock in baboons: relation to plasma levels of interleukin-10 and interferon- gamma

Interleukin (IL)-12 is thought to be a key factor for the induction of interferon gamma (IFN-gamma), a cytokine essential for the lethal effects of endotoxin. We report here on the release of the nonfunctional subunit of IL-12, p40, as well as biologically active heterodimeric IL-12, p70, after administration of a lethal (n = 5) or sublethal (n = 8) dose of live Escherichia coli to baboons. Remarkably, on lethal challenge, peak levels of p40 were observed at 3 hours that were about twofold lower than those elicited after sublethal challenge (2,813 +/- 515 pg/mL v 4,972 +/- 732 pg/mL, P < .05). This disparity was also observed, although to a lesser extent, for IL-12 p70 antigen, of which maximum levels of 91 +/- 47 pg/mL and 151 +/- 41 pg/mL were measured 6 hours after a lethal or sublethal dose of E coli, respectively. Circulating p70 antigen correlated with IL-12 biologic activity (r = 0.869; P < .001). When comparing lethal to sublethal conditions, lower peak levels of IL-12 on lethal E coli sharply contrasted with higher levels of other proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, IL-1beta, IL-6, and IL-8 observed in these animals. Lower IL-12 concentrations in the lethal group may have resulted in part from the enhanced production of IL-10, a known inhibitor of IL-12 synthesis in vitro, as peak levels of this cytokine 3 hours postchallenge inversely correlated with peak levels of IL-12, in particular p40 (r = -0.802; P < .01). Contrary to what might be expected if IFN-gamma were solely induced by IL-12, lethally challenged baboons generated threefold more IFN-gamma at 6 hours than those receiving a sublethal dose (P < .05). Moreover, higher levels of IFN- gamma were associated with lower p40/p70 ratios, suggesting that, in agreement with observations in vitro, IFN-gamma may have preferentially upregulated the release of p70 over p40. These data show that IL-12 is released in experimental septic shock in nonhuman primates and suggest that IL-10 and IFN-gamma are involved in the regulation of this release. Furthermore, this study indicates that the systemic release of IL-12 might be essential, but is not likely sufficient, to promote lethal production of IFN-gamma in sepsis.     

Posttraumatic splenic artery aneurysm presenting as occult gastrointestinal bleeding

A 53-year-old man presented with a 19-month history of gastrointestinal bleeding. Repeated endoscopic investigation of the upper and lower intestine showed no source of bleeding. When the patient collapsed due to massive gastrointestinal hemorrhage he was referred to our center. Gastroscopy showed a large, bulging tumor protruding from the posterior gastric wall. The consistency of this tumor was soft and the overlying mucosa appeared smooth and intact. Endoscopic ultrasound and contrast-enhanced computerized tomography scan identified a partly thrombosized splenic artery aneurysm (SAA). Arteriography of the celiac trunk confirmed the SAA diagnosis; the SAA was subsequently occluded by coils. So far, four months after discharge, the patient is in excellent health and no further episode of gastrointestinal bleeding has occurred. SAA is a very rare cause of upper gastrointestinal bleeding, but it must be considered when no other common bleeding source can be detected.     

Metabolic indicators of oxidative stress correlate with haemichrome attachment to membrane, band 3 aggregation and erythrophagocytosis in beta-thalassaemia intermedia

Haematological data, genotype, transfusion requirements, metabolic indicators of oxidative stress (flux via hexose-monophosphate shunt (HMPS); steady state level of GSH and GSSG, NADPH and NADP; activity of anti-oxidant enzymes), parameters of membrane damage (aggregated band 3; membrane-bound haemichromes, autologous immunoglobulins (Igs) and C3 complement fragments) and erythrophagocytosis were measured in erythrocytes (RBC) of 15 beta-thalassaemia intermedia patients (nine splenectomized) with low, if any, transfusion requirements. Patients presented increased aggregated band 3, bound haemichromes, Igs and C3 complement fragments, and increased erythrophagocytosis. Bound haemichromes strongly correlated with aggregated band 3. Anti-band 3 Igs were predominantly associated with aggregated band 3. Erythrophagocytosis positively correlated with aggregated band 3, haemichromes and Igs, suggesting the involvement of haemichrome-induced band 3 aggregation in phagocytic removal of beta-thalassaemic RBC. Splenectomized patients showed higher degrees of membrane damage and phagocytosis, significantly higher numbers of circulating RBC precursors, and tendentially higher numbers of reticulocytes. Basal flux via HMPS was increased twofold, but HMPS stimulation by methylene blue was decreased, as was the glucose flux via HMPS. GSH was remarkably decreased, whereas NADPH was increased. Except for unchanged catalase and glutathione reductase, anti-oxidant enzymes had increased activity. Negative correlation between HMPS stimulation by methylene blue and bound haemichromes indicated that the ability to enhance HMPS may counteract haemichrome precipitation and limit consequent membrane damage leading to erythrophagocytosis.     

Massive progression of diffuse hepatic lymphangiomatosis after liver resection and rapid deterioration after liver transplantation

Hepatic involvement is an exceptional presentation of lymphangiomatosis. In this case report we describe a patient who underwent liver transplantation secondary to progressive hepatic involvement, which occurred 2 yr after partial hepatectomy. Within 1 yr after liver transplantation the disease condition deteriorated, with rapid progression of pre-existing skeletal lesions and development of pulmonary disease. We conclude that liver transplantation may be a treatment option for hepatic lymphangiomatosis. In the presence of pre-existing extrahepatic lesions, however, liver transplantation seems to be contraindicated.     

Genetic variability of TMPRSS6 and its association with iron deficiency anaemia

Transmembrane Protease, Serine 6 (TMPRSS6) has an important role in iron homeostasis and its mutations, performed in TMPRSS6‐deficient mice, have been recently associated with iron‐refractory iron deficiency anaemia (IRIDA). Several variants of TMPRSS6 have been already identified; however the role of polymorphisms and TMPRSS6 haplotypes, causing iron deficiency anaemia, have not yet been investigated. This study sequenced the TMPRSS6 gene in 16 subjects with IRIDA phenotype and identified 27 DNA polymorphisms. Eight single nucleotide polymorphisms and four haplotypes were significantly associated with iron‐refractory anaemia (P < 0·001). Our preliminary results suggest a possible association between specific haplotypes of TMPRSS6 and IRIDA.     

Extensive Surveillance Promotes Early Diagnosis and Improved Survival of De Novo Malignancies in Liver Transplant Recipients

The aim of our study was to examine whether an extensive surveillance protocol will promote early diagnosis and improved survival in patients with de novo cancer following liver transplantation (LT). Of 779 consecutive LT recipients, 96 (12.3%) developed 105 malignancies. The cumulative risk for the development of de novo cancer was 10%, 24%, 32% and 42% at 5, 10, 15 and 20 years after LT, respectively. The most frequent tumor types were skin (17%), lung (16%), oropharyngeal (11%) and prostate cancer (11%). The overall standard incidence ratio as compared to that of the general population was 1.9 (95% CI: 1.5–2.3). The median survival of patients with de novo non-skin cancers was 3.1 years after diagnosis. Only patients with skin cancers and solid tumors, diagnosed at early stages, showed an excellent outcome. After introducing an intensified surveillance protocol, the detection rate of de novo cancers increased from 4.9% to 13% and more de novo malignancies were diagnosed in earlier stages. For non-skin cancers, the median tumor-related survival significantly improved from 1.2 to 3.3 years as well as the median overall survival post-LT. This study indicates that an extensive tumor surveillance program is highly recommendable in LT recipients.     

The differentiation of the olfactory placode in Xenopus laevis: a light and electron microscope study

Corticothalamic projections from postcruciate area 4, located on the rostral part of the posterior sigmoid gyms, were traced with the autora-diographic technique in the dog. Injections of tritiated amino acids were made into the lateral and medial parts of area 4 in regions corresponding to the forelimb and hindlimb areas of the primary motor cortex, respectively. In cases with injections placed in the lateral part of areas, dense accu-mulations of label were present in the lateral part of the ventral anterior nucleus (VA), the central part of the ventral lateral nucleus (VL), the ventral half of the ventral posterior inferior nucleus (VPI), the caudal part of the central lateral nucleus (CL), and the centrum medianum (CM). Lighter label was also present in the lateral part of the cytoarchitectonically distinct VL region bordering the ventrobasal complex (VB), as well as in the ventro-lateral part of the mediodorsal nucleus (MD), and in the lateral posterior nucleus (LP). In one case in which the injection site involved an adjacent part of area 3a, label was also seen ventrally in the medial division of the posterior nuclear group (POm). However, no detectable differences in VL, MD, or intralaminar labeling patterns were noted between this case and the four other cases with injections confined to the lateral part of area 4. In two cases with injections restricted to the medial part of area 4, dense label was present in the lateralmost part of VL, the ventral part of VPI, the caudal part of CL, and CM. Lighter label was also present in the VL region bordering the dorsolateral edge of VB and in LP. An additional case in which the injection also involved the rostral border of area 3a showed a similar pattern cf thalamic labeling. Projections from both the lateral and medial parts of area 4 were also noted in the subthalamic nucleus, zona incerta, and nucleus of Darkschewitsch. These results suggest that Corticothalamic projections from postcruciate area 4 to VL are organized topographically such that projections from the lateral part of area 4 project centrally within VL while those from the medial part of area 4 project more laterally. Both parts of area 4 also project top-ographically to a cytoarchitectonically distinct region of VL located im-mediately adjacent to VB, In contrast, the projections to the intralaminar nuclei do not appear to be topographically organized. The data from cases involving spread of the injection into area 3a suggest that projection pat-terns from area 3a to ventral, intralaminar, and medial thalamic nuclei are similar to those from area 4. However, it appears that at least the lateral part of area 3a also projects to POm.     

Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis.

Liver transplantation is the only effective therapeutic option for patients with end-stage liver disease due to primary sclerosing cholangitis (PSC). In this study, we analyzed a single center's experience with 150 consecutive PSC patients who received 174 liver allografts. Mean follow-up was 55 months. Actuarial patient survival at 1, 2, 5, and 10 years was 93.7%, 92.2%, 86.4%, and 69.8%, respectively, whereas graft survival was 83.4%, 83.4%, 79.0%, and 60. 5%, respectively. The main indication for retransplantation was hepatic artery thrombosis, and the major cause of death was severe infection. Patients with PSC had a higher incidence of acute cellular and chronic ductopenic rejection compared to a non-PSC control group. Chronic ductopenic rejection adversely affected patient and graft survival. Biliary strictures, both anastomotic and nonanastomotic, were frequent and occurred in 16.2% and 27.2% of patients, respectively. The incidence of recurrent PSC was 20%. A negative impact on patient survival was not seen in patients with either postoperative biliary strictures or recurrence of PSC. Six patients (4%) had cholangiocarcinoma and 1 patient died related to recurrence of malignant disease. Seventy-eight percent of PSC patients had associated inflammatory bowel disease, most commonly chronic ulcerative colitis, which did not adversely impact patient outcome posttransplantation. Nine patients required proctocolectomy after liver transplantation; 5 because of intractable symptoms related to inflammatory bowel disease and 4 due to the development of colorectal carcinoma/high-grade dysplasia. Our data show that liver transplantation provides excellent long-term patient and graft survival for patients with end-stage PSC.