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Basal ganglia (BG) circuits help guide and invigorate actions using predictions of future rewards (values). Within the BG, the globus pallidus pars externa (GPe) may play an essential role in aggregating and distributing value information. We recorded from the GPe in unrestrained rats performing both Pavlovian and instrumental tasks to obtain rewards and distinguished neuronal subtypes by their firing properties across the wake/sleep cycle and optogenetic tagging. In both tasks, the parvalbumin-positive (PV + ), faster-firing "prototypical" neurons showed strong, sustained modulation by value, unlike other subtypes, including the "arkypallidal" cells that project back to striatum. Furthermore, we discovered that a distinct minority (7%) of GP cells display slower, pacemaker-like firing and encode reward prediction errors (RPEs) almost identically to midbrain dopamine neurons. These cell-specific forms of GPe value representation help define the circuit mechanisms by which the BG contribute to motivation and reinforcement learning., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Alcohol-associated liver disease (ALD) is a rising indication for liver transplantation (LT). Prolonged opioid use after LT leads to increased graft loss and mortality. The aim is to determine if patients transplanted with a primary diagnosis of ALD had higher risk of post-LT opioid use (p-LTOU) compared to non-ALD patients., Methods: This is a retrospective study of patients who underwent LT between 2015 and 2018 at Medstar Georgetown Transplant Institute. Patients with prolonged hospitalization post-LT (>90 days), death within 90 days post-LT, and re-transplants were excluded., Results: Two hundred and ninety seven patients were transplanted, among 29% for indications of ALD. ALD patients were younger (52 vs. 56 years), more likely to be male (76% vs. 61%), Caucasian (71% vs. 44%), have higher MELD (28.8±8.8 vs. 25±8.8), and psychiatric disease than non-ALD patients (P < .05). There was no difference in pre-LT use of opioids, tobacco, marijuana, or illicit drugs between ALD and non-ALD patients. Pre-LT opioid use (OR = 11.7, P < .001), ALD (OR = 2.5, P = .01), and MELD score (OR = .95, P = .02) independently predicted 90-day p-LTOU., Conclusions: ALD, pre-LT opioid use, and MELD score independently predict p-LTOU. Special attention should be paid to identify post-LT prolonged opioid use in ALD patients., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Long-term liver outcome in hepatitis C virus (HCV)-negative kidney recipients who acquired HCV infection from viremic donors is of intense interest in the transplant community. We evaluated the incidence of fibrosis in liver biopsy specimens of recipients who were transplanted with HCV-infected grafts., Methods: Patients were evaluated in the hepatology clinic, and 29 patients agreed to undergo liver biopsy. The liver histology was scored by the meta-analysis of histological data in viral hepatitis scoring system and was assessed by hepatopathologists. The fibrosis score was compared between patients who initiated direct-acting antiviral (DAA) within 6 wk (n = 6) and after 6 wk (n = 29)., Results: Eighty-nine aviremic patients were transplanted with HCV-infected grafts between March 2018 and October 2019. All patients developed HCV infection and were treated with DAA treatment after kidney transplantation (median, 70 d; interquartile range, 55-85 d). All patients (n = 89) achieved sustained virologic response with DAA. The median follow-up time from kidney transplant to liver biopsy was 28 mo (interquartile range, 26-30 mo). Twenty-five patients (86%) had F0, and 4 patients (14%) had F1 fibrosis. No patient had advanced fibrosis (F3-F4). Grade 1 inflammation was present in 6 (21%) patients, whereas 26 (90%) patients had iron accumulation in the hepatocytes and reticuloendothelial cells. There was no difference in the fibrosis score between patients who received treatment within 6 wk versus after 6 wk ( P = 0.55)., Conclusions: Kidney transplantation of HCV-infected graft to HCV-negative recipients is safe and has no long-term liver-related complications with successful eradication of HCV. In our cohort, delayed treatment did not affect sustained virologic response or liver histology., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Genetically modified mice have become standard tools in neuroscience research. Our understanding of the basal ganglia in particular has been greatly assisted by BAC mutants with selective transgene expression in striatal neurons forming the direct or indirect pathways. However, for more sophisticated behavioral tasks and larger intracranial implants, rat models are preferred. Furthermore, BAC lines can show variable expression patterns depending upon genomic insertion site. We therefore used CRISPR/Cas9 to generate two novel knock-in rat lines specifically encoding Cre recombinase immediately after the dopamine D1 receptor ( Drd1a ) or adenosine 2a receptor ( Adora2a ) loci. Here, we validate these lines using in situ hybridization and viral vector mediated transfection to demonstrate selective, functional Cre expression in the striatal direct and indirect pathways, respectively. We used whole-genome sequencing to confirm the lack of off-target effects and established that both rat lines have normal locomotor activity and learning in simple instrumental and Pavlovian tasks. We expect these new D1-Cre and A2a-Cre rat lines will be widely used to study both normal brain functions and neurological and psychiatric pathophysiology., (Copyright © 2019 Pettibone et al.)

Our original review, "Heterogeneity and Diversity of Striatal GABAergic Interneurons," to which this is an invited update, was published in December, 2010 in Frontiers is Neuroanatomy. In that article, we reviewed several decades' worth of anatomical and electrophysiological data on striatal parvalbumin (PV)-, neuropeptide Y (NPY)- and calretinin(CR)-expressing GABAergic interneurons from many laboratories including our own. In addition, we reported on a recently discovered novel tyrosine hydroxylase (TH) expressing GABAergic interneuron class first revealed in transgenic TH EGFP reporter mouse line. In this review, we report on further advances in the understanding of the functional properties of previously reported striatal GABAergic interneurons and their synaptic connections. With the application of new transgenic fluorescent reporter and Cre-driver/reporter lines, plus optogenetic, chemogenetic and viral transduction methods, several additional subtypes of novel striatal GABAergic interneurons have been discovered, as well as the synaptic networks in which they are embedded. These findings make it clear that previous hypotheses in which striatal GABAergic interneurons modulate and/or control the firing of spiny neurons principally by simple feedforward and/or feedback inhibition are at best incomplete. A more accurate picture is one in which there are highly selective and specific afferent inputs, synaptic connections between different interneuron subtypes and spiny neurons and among different GABAergic interneurons that result in the formation of functional networks and ensembles of spiny neurons.

The recent availability of different transgenic mouse lines coupled with other modern molecular techniques has led to the discovery of an unexpectedly large cellular diversity and synaptic specificity in striatal interneuronal circuitry. Prior research has described three spontaneously active interneuron types in mouse striatal slices: the cholinergic interneuron, the neuropeptide Y-low threshold spike interneuron, and the tyrosine hydroxylase interneurons (THINs). Using transgenic Htr3a-Cre mice, we now characterize a fourth population of spontaneously active striatal GABAergic interneurons termed spontaneously active bursty interneurons (SABIs) because of their unique burst-firing pattern in cell-attached recordings. Although they bear some qualitative similarity in intrinsic electrophysiological properties to THINs in whole-cell recordings, detailed analysis revealed significant differences in many intrinsic properties and in their morphology. Furthermore, all previously identified striatal GABAergic interneurons have been shown to innervate striatal spiny projection neurons (SPNs), contributing to the suggestion that the principal function of striatal GABAergic interneurons is to provide feedforward inhibition to SPNs. Here, very surprisingly, paired recordings show that SABIs do not innervate SPNs significantly. Further, optogenetic inhibition of striatal Htr3a-Cre interneurons triggers barrages of IPSCs in SPNs. We hypothesize that these IPSCs result from disinhibition of a population of GABAergic interneurons with activity that is constitutively suppressed by the SABIs. We suggest that the SABIs represent the first example of a striatal interneuron-selective interneuron and, further, that their existence, along with previously defined interneuronal networks, may participate in the formation of SPN ensembles observed by others. SIGNIFICANCE STATEMENT Before ∼2010, the main function of the three known subtypes of striatal GABAergic interneurons was assumed to mediate feedforward inhibition of the spiny neurons (SPNs). During the past decade, we and others have described several novel populations of striatal GABAergic interneurons and their synaptic connections and have shown that striatal interneurons and SPNs interact through extensive and highly cell-type-specific connections that form specialized networks. Here, we describe a novel population of striatal GABAergic interneuron and provide several lines of evidence suggesting that it represents the first interneuron-selective interneuron in striatum. Striatal interneurons and their synaptic connections are suggested to play an important role in the formation of ensembles of striatal SPNs interconnected by inhibitory axon collaterals., (Copyright © 2018 the authors 0270-6474/18/385688-12$15.00/0.)

Unlabelled: Synchronous optogenetic activation of striatal cholinergic interneurons ex vivo produces a disynaptic inhibition of spiny projection neurons composed of biophysically distinct GABAAfast and GABAAslow components. This has been shown to be due, at least in part, to activation of nicotinic receptors on GABAergic NPY-neurogliaform interneurons that monosynaptically inhibit striatal spiny projection neurons. Recently, it has been proposed that a significant proportion of this inhibition is actually mediated by activation of presynaptic nicotinic receptors on nigrostriatal terminals that evoke GABA release from the terminals of the dopaminergic nigrostriatal pathway. To disambiguate these the two mechanisms, we crossed mice in which channelrhodopsin is endogenously expressed in cholinergic neurons with Htr3a-Cre mice, in which Cre is selectively targeted to several populations of striatal GABAergic interneurons, including the striatal NPY-neurogliaform interneuron. Htr3a-Cre mice were then virally transduced to express halorhodopsin to allow activation of channelrhodopsin and halorhodopsin, individually or simultaneously. Thus we were able to optogenetically disconnect the interneuron-spiny projection neuron (SPN) cell circuit on a trial-by-trial basis. As expected, optogenetic activation of cholinergic interneurons produced inhibitory currents in SPNs. During simultaneous inhibition of GABAergic interneurons with halorhodopsin, we observed a large, sometimes near complete reduction in both fast and slow components of the cholinergic-evoked inhibition, and a delay in IPSC latency. This demonstrates that the majority of cholinergic-evoked striatal GABAergic inhibition is derived from GABAergic interneurons. These results also reinforce the notion that a semiautonomous circuit of striatal GABAergic interneurons is responsible for transmitting behaviorally relevant cholinergic signals to spiny projection neurons., Significance Statement: The circuitry between neurons of the striatum has been recently described to be far more complex than originally imagined. One example of this phenomenon is that striatal cholinergic interneurons have been shown to provide intrinsic nicotinic excitation of local GABAergic interneurons, which then inhibit the projection neurons of the striatum. As deficits of cholinergic interneurons are reported in patients with Tourette syndrome, the normal functions of these interneurons are of great interest. Whether this novel route of nicotinic input constitutes a major output of cholinergic interneurons remains unknown. The study addressed this question using excitatory and inhibitory optogenetic technology, so that cholinergic interneurons could be selectively activated and GABAergic interneurons selectively inhibited to determine the causal relationship in this circuit., (Copyright © 2016 the authors 0270-6474/16/369505-07$15.00/0.)

Chronic hepatitis C virus (HCV) remains a major healthcare concern. The 24-48 week treatment of pegylated interferon and ribavirin therapy requires a tremendous amount of commitment from patients and providers. Thus, there has been a huge focus on health-related quality of life and various measures to support patient adherence and completion of the recommended HCV treatment regimen. This quality improvement project aimed to develop and test a nurse-driven evidence-based pathway that supports the care of patients receiving hepatitis C medication therapy in a tertiary, academic hepatology practice. All adult patients, 18 years and older, who were started on HCV treatment from January 20 to February 15, 2011, were included in the testing of a nurse-driven HCV pathway for the first 12 weeks of treatment. The majority of the patients treated were male (71.8% prepathway and 83.3% postpathway), of White ethnic background (61.5% prepathway and 58.3% postpathway), genotype 1 (69% prepathway and 91.7% postpathway), and had comorbid conditions classified as "other" (38.5% prepathway and 33.3% postpathway). As for treatment status, the majority of the patients were "treatment naive" in prepathway or had never received prior HCV treatment (59.0%) or "had recurrent HCV after liver transplantation" (41.7%). The 4-week treatment completion rate was 94.9% for the prepathway group and 100.0% for the postpathway group; 12-week completion rate was 87.2% (prepathway) and 58.3% for the postpathway group. The mean 4-week adherence score for the prepathway group was 2.46 and the postpathway group was 2.92. Mean lag time to treatment was decreased with 26 days in the postpathway and 43 in the prepathway. Providers and nurses expressed overall satisfaction with the nurse-driven pathway.

Previous work suggests that neostriatal cholinergic interneurons control the activity of several classes of GABAergic interneurons through fast nicotinic receptor-mediated synaptic inputs. Although indirect evidence has suggested the existence of several classes of interneurons controlled by this mechanism, only one such cell type, the neuropeptide-Y-expressing neurogliaform neuron, has been identified to date. Here we tested the hypothesis that in addition to the neurogliaform neurons that elicit slow GABAergic inhibitory responses, another interneuron type exists in the striatum that receives strong nicotinic cholinergic input and elicits conventional fast GABAergic synaptic responses in projection neurons. We obtained in vitro slice recordings from double transgenic mice in which Channelrhodopsin-2 was natively expressed in cholinergic neurons and a population of serotonin receptor-3a-Cre-expressing GABAergic interneurons were visualized with tdTomato. We show that among the targeted GABAergic interneurons a novel type of interneuron, termed the fast-adapting interneuron, can be identified that is distinct from previously known interneurons based on immunocytochemical and electrophysiological criteria. We show using optogenetic activation of cholinergic inputs that fast-adapting interneurons receive a powerful supra-threshold nicotinic cholinergic input in vitro. Moreover, fast adapting neurons are densely connected to projection neurons and elicit fast, GABAA receptor-mediated inhibitory postsynaptic current responses. The nicotinic receptor-mediated activation of fast-adapting interneurons may constitute an important mechanism through which cholinergic interneurons control the activity of projection neurons and perhaps the plasticity of their synaptic inputs when animals encounter reinforcing or otherwise salient stimuli., (© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

N-methyl-D-aspartate receptors (NMDAR) in the hippocampus participate in encoding and recalling the location of objects in the environment, but the ensemble mechanisms by which NMDARs mediate these processes have not been completely elucidated. To address this issue, we examined the firing patterns of place cells in the dorsal CA1 area of the hippocampus of mice (n = 7) that performed an object place memory (OPM) task, consisting of familiarization (T1), sample (T2), and choice (T3) trials, after systemic injection of 3-[(±)2-carboxypiperazin-4yl]propyl-1-phosphate (CPP), a specific NMDAR antagonist. Place cell properties under CPP (CPP-PCs) were compared to those after control saline injection (SAL-PCs) in the same mice. We analyzed place cells across the OPM task to determine whether they signaled the introduction or movement of objects by NMDAR-mediated changes of their spatial coding. On T2, when two objects were first introduced to a familiar chamber, CPP-PCs and SAL-PCs showed stable, vanishing or moving place fields in addition to changes in spatial information (SI). These metrics were comparable between groups. Remarkably, previously inactive CPP-PCs (with place fields emerging de novo on T2) had significantly weaker SI increases than SAL-PCs. On T3, when one object was moved, CPP-PCs showed reduced center-of-mass (COM) shift of their place fields. Indeed, a subset of SAL-PCs with large COM shifts (>7 cm) was largely absent in the CPP condition. Notably, for SAL-PCs that exhibited COM shifts, those initially close to the moving object followed the trajectory of the object, whereas those far from the object did the opposite. Our results strongly suggest that the SI changes and COM shifts of place fields that occur during the OPM task reflect key dynamic properties that are mediated by NMDARs and might be responsible for binding object identity with location.

Systemic lupus erythematosus (SLE), a disease of women during childbearing years, is characterized by the production of double-stranded DNA antibodies. A subset of these antibodies, present in 40% of patients, cross-reacts with the NR2A and NR2B subunits of the N-methyl-d-aspartate receptor (NMDAR). In this study, we show that, in mouse models, these antibodies cause a loss of female fetus viability by inducing apoptosis of NR2A-expressing neurons within the brainstem late in fetal development; gender specificity derives from a time-dependent increased expression of NR2A in female brainstem or increased vulnerability of female fetal neurons to signaling through NR2A-containing NMDARs. This paradigm is consistent with available data on the sex ratio of live births of women with SLE. It represents a novel mechanism by which maternal autoantibodies can severely affect fetal health in a gender-specific fashion and raises the question of how many maternal antibodies affect brain development or exhibit gender-specific fetal effects.

The improved life expectancy of patients with cystic fibrosis (CF) has led to a change in the impact of liver disease on the prognosis of this population. Liver transplantation has emerged as the procedure of choice for patients with CF and features of hepatic decompensation and for intractable variceal bleeding as a major manifestation. We retrospectively reviewed the United Network for Organ Sharing database to analyze the outcomes of 55 adults and 148 children with CF who underwent liver transplantation, and we compared them to patients who underwent transplantation for other etiologies. We additionally compared the benefits of liver transplantation among patients who underwent transplantation for cystic fibrosis-related liver disease (CFLD) and those who remained on the waiting list. The 5-year survival rates for children and adults undergoing liver transplantation were 85.8% and 72.7%, respectively (P = 0.016). A multivariate Cox regression analysis comparing pediatric and adult CF patients to patients who underwent transplantation for other etiologies noted lower 5-year survival rates (P < 0.0001). However, compared to those remaining on the waiting list, pediatric transplant recipients with CF (hazard ratio = 0.33, 95% confidence interval = 0.16-0.70, P = 0.004) and adult transplant recipients with CF (hazard ratio = 0.25, 95% confidence interval = 0.11-0.57, P = 0.001) gained a significant survival benefit. In conclusion, long-term outcomes in patients with CFLD are acceptable but are inferior in comparison with the outcomes of those undergoing transplantation for other etiologies. Despite such observations, a survival benefit was noted in transplant patients versus those who remained on the waiting list., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Damaging interactions between antibodies and brain antigenic targets may be responsible for an expanding range of neurological disorders. In the case of systemic lupus erythematosus (SLE), patients generate autoantibodies (AAbs) that frequently bind dsDNA. Although some symptoms of SLE may arise from direct reactivity to dsDNA, much of the AAb-mediated damage originates from cross-reactivity with other antigens. We have studied lupus AAbs that bind dsDNA and cross-react with the NR2A and NR2B subunits of the NMDA receptor (NMDAR). In adult mouse models, when the blood-brain barrier is compromised, these NMDAR-reactive AAbs access the brain and elicit neuronal death with ensuing cognitive dysfunction and emotional disturbance. The cellular mechanisms that underlie these deleterious effects remain incompletely understood. Here, we show that, at low concentration, the NMDAR-reactive AAbs are positive modulators of receptor function that increase the size of NMDAR-mediated excitatory postsynaptic potentials, whereas at high concentration, the AAbs promote excitotoxicity through enhanced mitochondrial permeability transition. Other synaptic receptors are completely unaffected by the AAbs. NMDAR activation is required for producing both the synaptic and the mitochondrial effects. Our study thus reveals the mechanisms by which NMDAR-reactive AAbs trigger graded cellular alterations, which are likely to be responsible for the transient and permanent neuropsychiatric symptoms observed in patients with SLE. Our study also provides a model in which local AAb concentration determines the exact nature of the cellular response.

Purpose: It was postulated that a transjugular intrahepatic portosystemic shunt (TIPS) produces arterioportal shunting and accounts for reversed flow in the intrahepatic portal veins (PVs) after creation of the TIPS. This study sought to quantify this shunting in patients undergoing TIPS creation and/or revision with use of a direct catheter-based technique and by measuring changes in blood oxygenation within the TIPS and the PV., Materials and Methods: This prospective study consisted of 26 patients. Median Model for End-stage Liver Disease and Child-Pugh scores were 13 and 9, respectively. Primary TIPS creation was attempted in 21 patients and revision of failing TIPS was undertaken in five. In two patients, TIPS creation was unsuccessful. All TIPS creation procedures but one were performed with use of polytetrafluoroethylene-covered stent-grafts. Flow within the main PV (Q(portal)) was measured with use of a retrograde thermodilutional catheter before and after TIPS creation/revision, and TIPS flow (Q(TIPS)) was measured at procedure completion. The amount of arterioportal shunting was assumed to be the increase between final Q(portal) and Q(TIPS), assuming Q(TIPS) was equivalent to the final Q(portal) plus the reversed flow in the right and left PVs. Oxygen saturation within the TIPS and the PV was determined from samples obtained during TIPS creation and revision., Results: Mean Q(portal) before TIPS creation was 691 mL/min; mean Q(portal) after TIPS creation was 1,136 mL/min, representing a 64% increase (P = .049). Mean Q(TIPS) was 1,631 mL/min, a 44% increase from final Q(portal) (P = .0009). Among cases of revision, baseline Q(portal) was 1,010 mL/min and mean Q(portal) after TIPS revision was 1,415 mL/min, a 40% increase. Mean Q(TIPS) was 1,693 mL/min, a 20% increase from final Q(portal) (P = .42). Arterioportal shunting rates were 494 mL/min after TIPS creation and 277 mL/min after TIPS revision, representing 30% of total Q(TIPS) after TIPS creation and 16% of Q(TIPS) after TIPS revision. No increase in oxygen tension or saturation was seen in the PV or TIPS compared with initial PV levels. Q(TIPS) did not correlate with the portosystemic gradient., Conclusion: TIPS creation results in significant arterioportal shunting, with less arterioportal shunting seen among patients who undergo TIPS revision. Further work is necessary to correlate Q(TIPS) with the risk of hepatic encephalopathy and liver failure.

Once a medical curiosity, solid organ transplantation is now a commonplace occurrence, with more than 27,000 procedures performed in the United States in 2004 alone. This article offers an overview of the various solid organ transplant procedures to provide a context within which subsequent articles on pulmonary complications can be viewed.

Abnormal LCTs after surgery are common, and consultants are frequently called on to evaluate critically ill patients with abnormal tests. All patients undergoing consideration for elective surgery and a history of either acute or chronic liver disease require careful presurgical evaluation. A thorough history and physical examination, complete blood count, routine electrolytes, LCTs, and a coagulation profile should be ordered. For patients with marginal hepatic reserve, it is important that patient well-being be maximized before any elective operation. The type of surgery to be performed should also be reviewed. All patients with postoperative jaundice should be evaluated for a history of liver disease. The consultant should also review the surgical procedure performed, anesthetic agents administered, other medications used, and whether blood products were given during the perioperative and postoperative periods. The pattern and timing of LCT abnormalities may also give a clue to the underlying disorder. As in the preoperative assessment, a routine complete blood count,electrolyte panel, LCTs, and coagulation profile should be ordered. Unconjugated hyperbilirubinemia can develop as a consequence of blood transfusions, underlying hemolytic disorders, resorbing hematomas, drug effects, or Gilbert's syndrome. A haptoglobin, reticulocyte count, LDH, and Coomb's test should be considered in patients with unconjugated hyperbilirubinemia. Treatment is directed toward the underlying condition. Conjugated hyperbilirubinemia can occur as a result of either intrahepatic or extrahepatic disorders. Markedly abnormal aminotransferases and LDH in conjunction with a normal abdominal ultrasound scan suggest ischemic liver injury, drug-induced hepatitis, or viral infections of the liver. Treatment entails restoration of hepatic perfusion, removal of offending medications, and supportive care or antiviral agents, respectively. Extrahepatic biliary obstruction must be considered in all patients with conjugated hyperbilirubinemia. Abdominal sonography is the best screening test to assess for obstruction. Patients with common bile duct stones usually require ERCP with sphincterotomy and stone removal. Biliary strictures or leaks may require ERCP with balloon dilation of strictures or stent placement for strictures and leaks; percutaneous drainage of bilomas in combination with broad-spectrum antibiotic agents is recommended for patients with bile leaks and large intra-abdominal fluid collections. Surgery may be required for patients with strictures or leaks not amenable to either endoscopic or percutaneous intervention or for patients who have transected bile ducts after laparoscopic cholecystectomy. Medication effects, benign postoperative jaundice, sepsis, TPN, and acalculous cholecystitis are responsible for intrahepatic cholestasis and conjugated hyperbilirubinemia. Treatment includes removal of offending drugs, supportive care, broad-spectrum antibiotic agents with drainage of infected fluid collections, adjustment of TPN, and either cholecystectomy or cholecystostomy, respectively.

Varicella infection may result in significant morbidity and mortality in patients who have received an orthotopic liver transplant (OLT). It is unclear if vaccinating these patients against varicella-zoster virus (VZV) infection is safe or effective. We report on a liver transplant recipient with no prior history of VZV infection who was given the varicella vaccine after an indirect VZV exposure. The patient was subsequently hospitalized twice for treatment of cutaneous varicella infection. We will discuss VZV infection, particularly in relation to liver transplantation, and review the prophylaxis and management of VZV infection after OLT.

1. Recurrent primary biliary cirrhosis (PBC) after transplantation is controversial, but most studies support disease recurrence within the graft. 2. Granulomatous destructive cholangitis should be present, and exclusion of acute and chronic rejection, graft-versus-host disease, biliary obstruction, viral hepatitis, and drug effects is mandatory before making a diagnosis of recurrent PBC. 3. Recurrent primary sclerosing cholangitis (PSC) after transplantation is difficult to diagnose because of the lack of a diagnostic gold standard. 4. Well-defined cholangiographic and histological criteria should be present, and exclusion of preservation injury, blood group type incompatibility between donor and recipient, chronic rejection, hepatic arterial occlusion, and viral infection is mandatory before making a diagnosis of recurrent PSC. 5. Most studies support recurrent autoimmune hepatitis (AIH) after transplantation based on clinical, biochemical, serological, and histological criteria. Exclusion of rejection, viral infection, drug effects, and biliary obstruction is mandatory before making a diagnosis of recurrent AIH. 6. Intermediate-term patient and graft survival are excellent for patients with recurrent autoimmune liver diseases within the transplanted liver, but additional studies are required to address the impact of disease recurrence on long-term patient and graft survival.

Fulminant hepatic failure carries a high mortality regardless of etiology. Liver transplantation may be lifesaving. Hepatic invasion by malignant lymphoma is a rare cause of liver failure, but one that is potentially responsive to treatment. Lymphoma (non-Hodgkin's or Hodgkin's) should be included in the differential diagnosis of fulminant hepatic failure so that liver transplantation is avoided and appropriate therapy can be instituted. The findings and clinical course of 4 patients with liver failure due to hepatic lymphoma, who were referred to our institution for liver transplant evaluation, are presented and discussed. Medical records, imaging studies, and histological material were examined. Review of the literature revealed less than 40 cases of lymphoma presenting as fulminant hepatic failure. The diagnosis of malignant lymphoma may be difficult. The presenting symptoms and signs are indistinguishable from other causes of fulminant hepatic failure. Early liver biopsy with adequate tissue and immunologic studies is mandatory for diagnosis. This condition may be reversible and may respond to chemotherapy if the diagnosis is made prior to multiorgan system failure. The presence of malignant lymphoma is considered a contraindication to liver transplantation, although firm data are lacking.

Hepatic angiosarcoma is a rare form of liver cancer. The history, physical examination, and liver biopsy are nonspecific. As a result, diagnosis of angiosarcoma can be challenging. We report the case of an elderly woman with congestive heart failure caused by a hepatic angiosarcoma. The massive tumor burden created extensive arteriovenous shunting and a high-cardiac-output state.

The current treatment of posttransplant lymphoproliferative disease (PTLD) includes prophylaxis at the time of transplant, decreasing or stopping immunosuppresion and initiation of antiviral therapy in patients with polymerase chain reaction or clinical evidence of PTLD, and judicial reintroduction of immunosuppression in patients who have cleared their PTLD and have begun to have rejection. The pharmacology, pharmacokinetics, notable side effects, and toxicities of the immunosuppressive agents are described in this article. At the conclusion of each section the author's current practice with these agents and treatment strategies are described.

Viral hepatitis and malignancy frequently recur after transplantation, but recurrence of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis is controversial. Differences in study design, number of patients, immunosuppressive treatment, length of follow-up, and criteria for recurrence account for discrepant results. Most patients with suspected recurrent disease are asymptomatic after transplantation. In patients transplanted for PBC, antimitochondrial antibodies frequently persist and do not correlate with disease recurrence; liver biopsy remains the gold standard for diagnosis. Exclusion of other disorders that can mimic PBC is paramount prior to making a diagnosis of recurrent disease. The effects of immunosuppression may modify or delay disease expression within the graft. If PBC recurs, intermediate-term patient and graft survival is excellent, but long-term studies will be necessary to address the impact of disease recurrence on the allograft. Due to lack of a diagnostic gold standard, a diagnosis of recurrent PSC after transplantation is difficult to make. An accurate diagnosis of PSC recurrence requires well-defined cholangiographic and histologic criteria. Other disorders that can produce biliary strictures after transplantation should be excluded. As with PBC, the effects of immunosuppression may modify or delay disease expression within the graft; medium-term patient and graft survival is excellent. Recurrence of autoimmune hepatitis is based on clinical, biochemical, serologic, and histologic criteria. As in patients transplanted for PBC and PSC, other conditions that can mimic autoimmune hepatitis require exclusion prior to making a diagnosis of recurrence. Most adult recipients respond to an increase in immunosuppression, whereas pediatric recipients do not respond as well. A cautious approach to withdrawal of immunosuppression is warranted in all patients transplanted for autoimmune hepatitis and the consequences of recurrent disease within the graft will require prolonged follow-up. Future studies should focus on preventive and therapeutic strategies for recurrent autoimmune diseases after transplantation.

Many options are available to diagnose and treat patients with the Budd-Chiari syndrome who present with either thrombotic or non-thrombotic occlusion of the major hepatic veins and or vena cava. The goal of therapy is to alleviate venous obstruction and to preserve hepatic function. Low-sodium diets, diuretics, and therapeutic paracentesis are generally ineffective, except for the rare patient who presents with volume overload and incomplete hepatic venous occlusion. Anticoagulants and thrombolytics may be appropriate for selected patients with acute thrombotic venous obstruction. Percutaneous transluminal angioplasty (PTA) of hepatic venous stenoses or caval webs with or without placement of intraluminal stents yield excellent short-term results, but additional studies are warranted to assess long-term efficacy. Transjugular intrahepatic portosystemic shunts (TIPS) may be effective for patients with subacute or chronic disease and ascites refractory to sodium restriction and diuretics. Intrahepatic stents may also serve as a bridge to transplantation for selected patients presenting with fulminant hepatic failure consequent to hepatic venous occlusion. Additional studies will be necessary to assess the role of TIPS in the armamentarium of therapies for patients with the Budd-Chiari syndrome. Decompressive shunts, reconstruction of the vena cava and hepatic venous ostia, transatrial membranotomy, and dorsocranial resection of the liver with hepatoatrial anastomosis are appropriate options for patients with acute or subacute disease who are not candidates for, or fail less invasive therapies. The majority of patients benefit with improvement in liver function tests, ascites, and liver histology; however, hepatic function may deteriorate in patients with marginal reserve. Liver transplantation is reserved for patients with Budd-Chiari syndrome who present with fulminant hepatic failure or end-stage liver disease with portal hypertensive complications. Transplantation is also appropriate for patients who deteriorate after failed attempts at surgical shunting.

For patients who present with variceal bleeding refractory to endoscopic and pharmacologic methods, TIPS is a new and effective therapy. Stents are used in selected patients with decompensated liver disease and those who anticipate liver transplantation within 6 to 12 months. Surveillance of TIPS with ultrasound, with or without venography, is recommended to diagnose and treat stenosis or occlusion before variceal hemorrhage recurs. Hepatic encephalopathy may develop in a subset of patients, but it is usually well controlled with conservative measures. Child-Pugh and APACHE scores are predictive of patient survival after TIPS. Randomized controlled trials will be necessary to assess whether TIPS is useful, safe, and cost effective for the management of variceal bleeding in patients with end stage liver disease.

We measured gastric and duodenal mucosal prostaglandin concentrations in 69 patients with active or inactive duodenal or gastric ulcer disease and 26 non-ulcer controls. Each underwent endoscopy enabling us to obtain multiple biopsies from the gastric body and antrum and from the duodenal bulb and postbulbar duodenum for measurement of mucosal prostaglandin concentrations, as well as a single biopsy from each region for mucosal histology. Using a multivariate linear regression model, we found that neither gastric nor duodenal ulcer disease significantly affected gastric or duodenal mucosal prostaglandin concentrations. Mucosal prostaglandin concentrations were similar at the edge of the ulcer and in the adjacent non-ulcerated mucosa. Neither gender symptoms, smoking, use of H2-receptor antagonists, disease activity, nor Helicobacter pylori infection had an independent effect on mucosal prostaglandins in any region. Gastritis in the body of the stomach was associated with significantly higher prostaglandins, while older age was associated with significantly lower gastric and duodenal prostaglandins. Gastroduodenal mucosal prostaglandins are thus not altered in patients with active or inactive peptic ulcer disease, even when multiple demographic and histologic variables are taken into consideration.

Gastric mucosal prostaglandin E2 and F2 alpha content was evaluated in healthy human subjects who received either fish oil or olive oil (control) daily for 3 wk before exposure to aspirin or no aspirin. Two hours after aspirin administration, when mean serum salicylate concentration was approximately 12 mg/dl, gastric mucosal prostaglandin E2 and F2 alpha content was reduced by greater than 95% in the fundus and antrum (p less than 0.001) and there was endoscopic evidence of gastric mucosal damage (erosions, submucosal hemorrhages). Fish oil feeding had no significant effect on mucosal prostaglandin E2 or F2 alpha content or on the damaging effect of aspirin on the stomach, despite the fact that fish oil reduced serum triglyceride concentrations significantly. These studies indicate that the damaging effects of aspirin on the gastric mucosa are not influenced by dietary fish oil.

In humans eicosapentaenoic acid can be converted to 3-series prostaglandins (PGF3 alpha, PGI3, and PGE3). Whether 3-series prostaglandins can protect the gastric mucosa from injury as effectively as their 2-series analogs is unknown. Therefore, we compared the protective effects of PGF3 alpha and PGF2 alpha against gross and microscopic gastric mucosal injury in rats. Animals received a subcutaneous injection of either PGF3 alpha or PGF2 alpha in doses ranging from 0 (vehicle) to 16.8 mumol/kg and 30 min later they received intragastric administration of 1 ml of absolute ethanol. Whether mucosal injury was assessed 60 min or 5 min after ethanol, PGF3 alpha was significantly less protective against ethanol-induced damage than PGF2 alpha. These findings indicate that the presence of a third double bond in the prostaglandin F molecule between carbons 17 and 18 markedly reduces the protective effects of this prostaglandin on the gastric mucosa.