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In severe liver injury, ductular reactions (DRs) containing bipotential hepatic progenitor cells (HPCs) branch from the portal tract. Neural cell adhesion molecule (NCAM) marks bile ducts and DRs, but not mature hepatocytes. NCAM mediates interactions between cells and surrounding matrix; however, its role in liver development and regeneration is undefined. Polysialic acid (polySia), a unique posttranslational modifier of NCAM, is produced by the enzymes, ST8SiaII and ST8SiaIV, and weakens NCAM interactions. The role of polySia with NCAM synthesizing enzymes ST8SiaII and ST8SiaIV were examined in HPCs in vivo using the choline-deficient ethionine-supplemented and 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet models of liver injury and regeneration, in vitro using models of proliferation, differentiation, and migration, and by use of mouse models with gene defects in the polysialyltransferases (St8sia 2+/−4+/−, and St8sia2−/−4−/−). We show that, during liver development, polySia is required for the correct formation of bile ducts because gene defects in both the polysialyltransferases (St8sia2+/−4+/− and St8sia2−/−4−/− mice) caused abnormal bile duct development. In normal liver, there is minimal polySia production and few ductular NCAM+ cells. Subsequent to injury, NCAM+ cells expand and polySia is produced by DRs/HPCs through ST8SiaIV. PolySia weakens cell-cell and cell-matrix interactions, facilitating HGF-induced migration. Differentiation of HPCs to hepatocytes in vitro results in both transcriptional down-regulation of polySia and cleavage of polySia-NCAM. Cleavage of polySia by endosialidase (endoN) during liver regeneration reduces migration of DRs into parenchyma. Conclusion: PolySia modification of NCAM+ ductules weakens cell-cell and cell-matrix interactions, allowing DRs/HPCs to migrate for normal development and regeneration. Modulation of polySia levels may provide a therapeutic option in liver regeneration. (Hepatology 2014;60:1727–1740)

Rationale: Thrombotic microangiopathy (TMA) is a group of clinical syndromes characterized by excessive platelet activation and endothelial injury that leads to acute or chronic microvascular obliteration by intimal mucoid and fibrous thickening, with or without associated thrombi. It frequently involves the kidney but may involve any organ or system at variable frequencies depending on the underlying etiology. Among its numerous causes, drug toxicities and complement regulation abnormalities stand out as some of the most common. A more recently described association is with monoclonal gammopathy. Lung involvement by TMA is infrequent, but has been described in Cobalamin C deficiency and post stem-cell transplantation TMA. Patient concerns: This is the case of a patient with smoldering myeloma who received proteasome-inhibitor therapy due to retinopathy and developed acute renal failure within one week of therapy initiation. Diagnoses: A renal biopsy showed thrombotic microangiopathy. At the time, mild pulmonary hypertension was also noted and presumed to be idiopathic. Interventions: Given the known association of proteasome-inhibitor therapy with thrombotic microangiopathy, Bortezomib was discontinued and dialysis was initiated. Outcomes: Drug withdrawal failed to prevent disease progression and development of end-stage renal disease, as well as severe pulmonary hypertension that eventually lead to the patient's death. Lessons: To our knowledge, this is the first reported case of pulmonary involvement by TMA associated with monoclonal gammopathy which appears to have been triggered by proteasome-inhibitor therapy. Clinicians should be aware of this possibility to allow for more prompt recognition of pulmonary hypertension as a potential manifestation of monoclonal gammopathy-associated TMA, especially in patients also receiving proteasome-inhibitors, so that treatment aiming to slow disease progression can be instituted.

Four children who underwent ABO-compatible combined liver and small bowel transplantation developed severe immune-mediated hemolytic anemia. The main management strategies were early and aggressive treatment with steroids, the introduction of rituximab (an anti-CD20 monoclonal antibody), and the use of plasma exchange together with compatible but minimal blood transfusions. Three of the 4 children developed thrombi in the major vessels. In small bowel transplant patients, the early recognition of hemolytic anemia and intensified management with anticoagulation are necessary for the prevention of this complication. Liver Transpl 17:921–924, 2011. © 2011 AASLD.

Functional gastrointestinal disorders are the most common conditions encountered in gastroenterology practice and are also commonly encountered in primary care. Psychosocial factors play an important role in these disorders (along with any chronic digestive disorder) by influencing healthcare seeking, illness behavior, symptom severity, quality of life, and digestive motility and sensation. Identification of relevant psychosocial factors in patients with chronic digestive disorders influences care and is a critical determinant of outcomes. This article provides a review of relevant psychosocial variables, assessment techniques, and therapeutic suggestions that can be of value in assessing patients with functional gastrointestinal disorders.

Objective: To determine the hemodynamic consequences of aortic occlusion during controlled hemorrhagic arrest. Methods: Ten anesthetized, hemodynamically monitored swine were subjected to a 40 mL/kg hemorrhage over 10 minutes, followed by a 5-minute period of apnea. At this time (T15), they were randomized into an UP group (n = 5) in which the thoracic aorta was occluded or a DOWN group (n = 5) in which the aorta was not occluded. Simultaneously, volume resuscitation with shed blood plus 20 mL/kg of normal saline was performed over a 10-minute period. Cardiac massage was performed until return of spontaneous circulation (ROSC), which was defined as a sustained systolic blood pressure > 60 mm Hg. After 30 minutes of occlusion (T45), the aortic occlusion was released. Parameters measured include mixed venous and arterial blood gases, serum lactic acid levels, cardiac index, mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), coronary perfusion pressure (CoPP), and left ventricular stroke work index (LVSWI). Oxygen delivery index (Do 2 I) was measured using a pulmonary artery catheter, and oxygen consumption index (Vo 2 I) was measured by direct calorimetry (Delta Trac metabolic monitor). Results: Four animals in each group achieved ROSC after 3.0 ± 1.8 and 2.2 ± 1.8 minutes in the occluded and nonoccluded groups, respectively. During cardiac compressions and volume resuscitation, the CoPP, MAP, and MPAP were greater in the UP group, although the differences did not achieve statistical significance. After volume resuscitation was complete and during the period of aortic occlusion (T25-T45), the UP group had significantly greater MAP (mm Hg), with a difference of 42.5 ± 20.75 mm Hg at T25 and 44.7 ± 19 mm Hg at T35 (p < 0.03). Despite no difference in Do 2 I, Vo 2 I (mL/min/kg) was significantly lower in the UP group than in the DOWN group, 4.28 ± 0.48 versus 8.33 ± 0.85 at T25 (p = 0.0002) and 4.62 ± 0.9 versus 7.09 ± 0.72 at T35 (p = 0.0005). After release of aortic occlusion at T45, the UP group had significantly lower CoPP (mm Hg) than the DOWN group (20.5 ± 17.3 versus 66.5 ± 28.2 at T45, p = 0.03). LVSWI (g/kg) was also lower in the UP than in the DOWN group (18.6 ± 8.28 versus 36.5 ± 10.2 at T60 [p = 0.03] and 23.6 ± 6.48 versus 48.8 ± 15.3 at T240 [p = 0.02]). After release of the occlusion, there were trends toward increased acidosis and lactic acid levels in the UP group. Conclusions: Aortic occlusion in this controlled hemorrhagic arrest model does not result in improved salvage but is associated with impaired left ventricular function, systemic oxygen utilization, and coronary perfusion pressure in the postresuscitation period.

Summary Compounds that activate neuronal nicotinic acetylcholine receptors (nAChRs) may have potential benefit in the treatment of dementia, especially Alzheimer disease (AD). This article summarizes the preclinical pharmacology of ABT-418 [(S)3-methyl-5-( 1-methyl-2-pyrrolidinyl) isoxazole], a novel analog of (-)-nicotine that is being clinically evaluated for the treatment of AD. ABT-418 is a cholinergic channel activator (ChCA) with cognitive enhancement and anxiolytic-like activity possessing a substantially reduced side-effect profile compared to (-)-nicotine [Arneric SP, Sullivan JP, Briggs CA, et al. (S)-3-Methyl-5-( l-Methyl-2-Pyrrolidinyl)lsoxazole (ABT-418): A novel cholinergic lig-and with cognition enhancing and anxiolytic activity. 1. In vitro activity. J Pharmacol Exp Ther 1994;270:310–318; Decker MW, Brioni JD, Sullivan JP, et al. (S)-3-Methyl-5-(l-Methyl-2-Pyrrolidinyl)Isoxazole (ABT-418): A novel cholinergic ligand with cognitionenhancing and anxiolytic activities: II. In vivo characterization. J Pharmacol Exp Ther 1994a;270:319–328; Decker MW. Curzon P, Brioni JD, Arneric SP. Effects of ABT-418, a novel cholinergic channel ligand, on place learning in septal-lesioned rats. Eur J Pharmacol 1994;261:217–222; Garvey DS, Wasicak JT, Decker MW, et al. Novel isoxazoles which interact with brain cholinergic channel receptors have intrinsic cognitive enhancing and anxiolytic activities. J Med Chem 1994;37:1055–1059]. ABT-418 may be the first agonist of nAChRs to be developed and evaluated specifically for the treatment of AD. Some brief speculation will be given on the potential benefits that this or other ChCAs may have in treating neurodegenerative disorders as compared with (-)-nicotine, and how this differs from other potential treatment approaches.

Previous studies have indicated that a deficiency in the formation of 20-HETE in the proximal tubule and thick ascending limb of Henle in Dahl S rats increases sodium reabsorption and contributes to the development of hypertension. The present study examined whether the lack of 20-HETE production in the renal vasculature contributes to the progression of renal injury by altering the myogenic or tubuloglomerular feedback (TGF) response of the afferent arteriole (Af-Art). The production of 20-HETE was significantly lower by 54% in renal microvessels isolated from the kidneys of Dahl S rats versus that seen than in SS.5BN consomic strain in which chromosome 5 from the Brown Norway (BN) rat containing the CYP4A genes responsible for the formation of 20-HETE was transferred into the Dahl S genetic background. The luminal diameter of the Af-Art decreased by 14.7± 1.5% (from 20.5 ± 0.7 to 17.5 ± 0.8 μm, n=6) in SS.5BN rats whereas the diameter of the Af-Art remained unaltered in Dahl S rats (from 20.1 ± 0.6 to 21.7 ± 0.6 μm, n=7) when the perfusion pressure was increased from 60 mmHg to 120 mmHg. In other experiments, adenosine (1 μM) reduced the diameter of the Af-Art in the SS.5BN rats by 15±0.7% (from 20.1 ±0.4 to 17.1 ± 0.9 μm, n=3) whereas the Af-Art of Dahl S rats was unaltered. However, administration of a 20-HETE synthesis inhibitor, HET0016 (1 μM, n=6), or a selective 20-HETE antagonist, 6, 15-20-HEDE (10 μM, n=6) completely blocked the myogenic and adenosine responses in the Af-Art of SS.5BN rats but it had no effect in Dahl S rats. Administration of a 20-HETE agonist, 5, 14-20-HEDE (1 μM) restored the myogenic response (from 20.7 ± 0.7 to 17.6 ± 0.6 μm, n=7) and vasoconstrictor response to adenosine in the Af-Art of Dahl S rats. These studies confirm the key role of 20-HETE in modulating the responsiveness of the Af-Art and indicate that a deficiency in the formation of 20-HETE in renal microvessels contributes to the marked susceptibility of Dahl S rats to develop hypertension induced renal injury.

Lethally irradiated and syngeneic bone marrow-reconstituted (C57BL/6JxDBA/2J) F1 female mice demonstrated prolonged survival following challenge with the DBA/2 mastocytoma P815-X2 compared with non-irradiated littermate controls. This radiation-induced augmentation of host resistance to P815-X2 was not abolished by the adoptive transfer of normal syngeneic spleen cells. In addition, this phenomenon was not detectable in adult thymectomized recipients, suggesting the requirement for an intact host thymus. This effect was also absent in syngeneic F1 male recipients. We suggest that lethal irradiation and marrow reconstitution may result in activation of a nonspecific immune effector mechanism against tumor cells--and, as such, may serve as a model to explore the graft-antitumor effect of bone marrow transplantation.

Incubation of a primary culture of rat striatal neurons with sodium nitroprusside (SNP), a known source of nitric oxide (NO), showed a concentration-dependent increase in cyclic GMP levels with an EC50 value of 13.7 microM. Twenty-four hours following incubation with 10 microM SNP, striatal neurons underwent degeneration as assessed immunohistochemically and biochemically. In contrast, potassium ferricyanate at concentrations up to 1 mM had no effect on striatal neuron viability. These results indicate that SNP has neurotoxic actions in-vitro, an effect that may involve NO as a second messenger.

P11 Objectives: Current TCD criteria for VSP is based on CBFV alone but factors such as age and day after SAH also affect CBFV, making the current criteria unreliable. Our objective is to describe MCA and ICA CBFV trend taking into account clinically significant variables. Methods: Patients with the diagnosis of aneurysmal SAH between 1991 and 1999 were identified using a prospective TCD database. Linear and non-linear regression analysis were performed. We included the following variables in the model: 1)age, 2)age 2 =(Age-38) 2 , 3)PSAHD:post SAH day, 4)SAHC=0 if SAH day12 day , 5)CSPASM: clinical spasm (0,1 for absent, present respectively). Results: We identified 399 TCD examinations that included the vessels of interest. Curve fit analysis demonstrated that the quadratic model for both MCA(R2=0.14,P2 + 2.65 PSAHD - 5.05 SAHC + 14.5 CSPASM (2)ICA CBFV quadratic model equation: Y=96.37–1.12 Age + 0.007 Age 2 + 2.97 PSAHD-8.08 SAHC+ 12.95 CSPASM When controlling for other variables in the model, we report: 1)A daily increase of 2.65 cm/s(MCA)and 2.97 cm/s(ICA) up to day 12, a daily decrease by 2.4 cm/s(MCA) and 5.1 cm/s(ICA)after day 12. 2)Effect of age on MCA CBFV is an increase of 1.3 cm/s per year of age until 38 and a 3.4% decrease after 38 at any given day after SAH. 3)Effect of age on ICA CBFV is a decrease of 1.1 cm/s per year of age until 38 and a 1.4% decrease after 38 at any given day after SAH. 4)When clinical vasospasm is present the CBFV increases by 14.5 cm/s(MCA) and 12.95 cm/s(ICA). Conclusion: our model suggests that the TCD criteria for VSP may be dependent on multiple variables. Prospective evaluation may lead to improved TCD criteria for the diagnosis of VSP.