Liver paired exchange U.S. single center experience - pairs, chains, and use of compatible pairs'.

BACKGROUND: In the United States, the discrepancy between organ availability and need has persisted despite changes in allocation, innovations in preservation, and policy initiatives. Living donor liver transplant (LDLT) remains an underutilized means of improving access to timely liver transplantation and decreasing waitlist mortality. Liver paired exchange (LPE) represents an opportunity to overcome LDLT pair incompatibility due to size, anatomy, or blood type. METHODS: LPE was adopted as a strategy to augment access to liver transplantation at our institution. Specific educational materials, consent forms, and selection processes were developed to facilitate LPE. RESULTS: From 2019 through October 2023, our center performed 11 LPEs, resulting in 23 LDLT pairs. The series included several types of LPE: those combining complementary incompatible pairs, the inclusion of compatible pairs to overcome incompatibility, and the use of altruistic non-directed donors to initiate chains. These exchanges facilitated transplantation for 23 recipients, including 1 pediatric patient. CONCLUSIONS: LPE improved access to liver transplantation at our institution. The ethical application of LPE includes tailored patient education, assessment and disclosure of exchange balance, mitigation of risk and maximization of benefit for donors and recipients.

Gender Discrepancies in Middle Author Publications in US Academic General Surgery.

INTRODUCTION: To explore gender discrepancies in publications at general surgery departments, we performed a cross-sectional comparing the number of women and men at each academic rank and their number of first author (FA), middle author (MA), last author (LA), and total publications. METHODS: Thirty academic general surgery departments were randomly selected. For each faculty, we tabulated: first, middle, last names, gender, academic rank, educational leadership, year of medical school graduation, and additional graduate degrees. Bibliography, H-index, and citations were downloaded from the Scopus database. RESULTS: One thousand three hundred twenty-six faculty sampled, 881 (66.4%) men and 445 (33.5%) women. Men outnumbered women at all ranks, with increasing disparity at higher ranks. Men outnumbered women in all subspecialties-largest difference in transplant surgery (84.4% versus 15.6%, P < 0.001). Men at all ranks had more MA publications: assistant professor (rate ratio 1.20; 95% confidence interval, 1.01-1.43, P = 0.024), associate professor (1.65; 1.31-2.06, P < 0.001), and professor (1.50; 1.20-1.91, P = 0.008). Men associate professors had more LA publications (1.74; 1.34-2.37, P < 0.001). No differences found in FA publications at any rank, nor LA publications at assistant professor and professor ranks. At subspecialty level, men in surgical oncology (1.95; 1.55-2.45, P < 0.001) and transplant surgery (1.70; 1.09-2.66, P = 0.02) had more MA publications. CONCLUSIONS: While FA and LA publications did not differ significantly across genders, the largest difference lies in MA publications, beginning at junior ranks and persisting with seniority. Discrepancies in MA publications may reflect gender discrepancies in collaborative opportunities, hence total publications should be used cautiously when determining academic productivity.

Risk of peritoneal dialysis catheter-associated peritonitis following kidney transplant.

OBJECTIVE: Peritoneal dialysis (PD) patients have equivalent or slightly better kidney transplant outcomes when compared to hemodialysis (HD) patients. However, given the risk for postoperative infection, we sought to determine the risk factors for PD catheter-associated infections for patients who do not have the PD catheter removed at the time of engraftment. METHODS: Demographic and outcomes data were collected from 313 sequential PD patients who underwent kidney transplant from 2000 to 2015. Risk factors for postoperative peritonitis were analyzed using logistical regression. RESULTS: Of 329 patients with PD catheters at transplant, 16 PD catheters were removed at engraftment. Of the remaining 313 patients, 8.9% suffered post-transplant peritonitis. On univariate analysis, patients with peritonitis were significantly more likely to have used the PD catheter or HD within 6 weeks after transplant. Multivariate analysis had similar findings, with increased risk for those using the PD catheter after transplant, with a trend for those who underwent HD only within 6 weeks of transplant. CONCLUSION: These results suggest that delayed graft function requiring any type of dialysis is associated with increased post-transplant peritonitis risk.

EVIDENCE FOR BENEFICIAL USE OF THE COMPENSATORY RESERVE MEASUREMENT IN GUIDING INTRAOPERATIVE RESUSCITATION: A PROSPECTIVE COHORT STUDY OF ORTHOTOPIC LIVER TRANSPLANT RECIPIENTS.

ABSTRACT: Introduction: The compensatory reserve measurement (CRM) is a continuous noninvasive monitoring technology that provides an assessment of the integrated capacity of all physiological mechanisms associated with responses to a hypovolemic stressor such as hemorrhagic shock. No prior studies have analyzed its use for intraoperative resuscitation guidance. Methods: A prospective observational study was conducted of 23 patients undergoing orthotopic liver transplant. Chart review was performed to identify timing of various intraoperative events. Data were compared based on predefined thresholds for existence of hemorrhagic shock: CRM lower than 40%, systolic blood pressure (SBP) lower than 90 mm Hg (SBP90), and heart rate (HR) higher than 100 beats per minute (HR100). Regression analysis was performed for predicting resuscitation events, and nonlinear eXtreme Gradient Boosting (XGBoost) models were used to compare CRM with standard vital sign measures. Results: Events where CRM dropped lower than 40% were 2.25 times more likely to lead to an intervention, whereas HR100 and SBP90 were not associated with intraoperative interventions. XGBoost prediction models showed superior discriminatory capacity of CRM alone compared with the model with SBP and HR and no difference when all three were combined (CRM-HR-SBP). All XGBoost models outperformed equivalent linear regression models. Conclusion: These results demonstrate that CRM can provide an adjunctive clinical tool that can augment early and accurate of hemodynamic compromise and promote goal-directed resuscitation in the perioperative setting.

Imaging update on gallbladder adenomyomatosis and its mimics.

Radiologists across many imaging modalities commonly encounter gallbladder adenomyomatosis. The classic imaging appearances of gallbladder adenomyomatosis are well described and confirm benignity. However, in clinical practice, adenomyomatosis can be challenging to differentiate from other gallbladder pathologies that require cholecystectomy. In this article, we describe the common and uncommon appearances of gallbladder adenomyomatosis on multimodality imaging, helping differentiate adenomyomatosis from non-benign gallbladder abnormalities. Accurately differentiating adenomyomatosis from its mimics provides the surgical team with important clinical and surgical management information, improving patient outcomes.

Liver Transplant Costs and Activity After United Network for Organ Sharing Allocation Policy Changes.

Importance: A new liver allocation policy was implemented by United Network for Organ Sharing (UNOS) in February 2020 with the stated intent of improving access to liver transplant (LT). There are growing concerns nationally regarding the implications this new system may have on LT costs, as well as access to a chance for LT, which have not been captured at a multicenter level. Objective: To characterize LT volume and cost changes across the US and within specific center groups and demographics after the policy implementation. Design, Setting, and Participants: This cross-sectional study collected and reviewed LT volume from multiple centers across the US and cost data with attention to 8 specific center demographics. Two separate 12-month eras were compared, before and after the new UNOS allocation policy: March 4, 2019, to March 4, 2020, and March 5, 2020, to March 5, 2021. Data analysis was performed from May to December 2022. Main Outcomes and Measures: Center volume, changes in cost. Results: A total of 22 of 68 centers responded comparing 1948 LTs before the policy change and 1837 LTs postpolicy, resulting in a 6% volume decrease. Transplants using local donations after brain death decreased 54% (P < .001) while imported donations after brain death increased 133% (P = .003). Imported fly-outs and dry runs increased 163% (median, 19; range, 1-75, vs 50, range, 2-91; P = .009) and 33% (median, 3; range, 0-16, vs 7, range, 0-24; P = .02). Overall hospital costs increased 10.9% to a total of $46 360 176 (P = .94) for participating centers. There was a 77% fly-out cost increase postpolicy ($10 600 234; P = .03). On subanalysis, centers with decreased LT volume postpolicy observed higher overall hospital costs ($41 720 365; P = .048), and specifically, a 122% cost increase for liver imports ($6 508 480; P = .002). Transplant centers from low-income states showed a significant increase in hospital (12%) and import (94%) costs. Centers serving populations with larger proportions of racial and ethnic minority candidates and specifically Black candidates significantly increased costs by more than 90% for imported livers, fly-outs, and dry runs despite lower LT volume. Similarly, costs increased significantly (>100%) for fly-outs and dry runs in centers from worse-performing health systems. Conclusions and Relevance: Based on this large multicenter effort and contrary to current assumptions, the new liver distribution system appears to place a disproportionate burden on populations of the current LT community who already experience disparities in health care. The continuous allocation policies being promoted by UNOS could make the situation even worse.

Antibiotic choice is independently associated with risk of surgical site infection after colectomy: a population-based cohort study.

OBJECTIVE: To determine which perioperative care practices are associated with decreased risk of surgical site infection (SSI) after colectomy surgery. BACKGROUND: Optimization of perioperative care has been a common strategy for improving surgical safety, but the relationship between process measure compliance and surgical complication rates is controversial. METHODS: This is a retrospective cohort study performed within the Michigan Surgical Quality Collaborative (MSQC), an organization of hospitals that prospectively collects patient data, processes of care, and 30-day outcomes. Patients undergoing colectomy surgery (n = 4331) were studied. Factors potentially associated with SSI were tested using univariate statistical tests, and a hierarchical generalized linear model was created to test for independent associations between processes of care and SSI, while adjusting for patient risk factors and clustering of patients within hospitals. RESULTS: Several perioperative care practices were independently associated with lower risk of SSI after adjustment for patient risk, procedure type/duration, and clustering of patients by hospital site. Best practices include selection of a Surgical Care Improvement Project (SCIP-2)-compliant prophylactic intravenous antibiotic, postoperative normothermia, postoperative day 1 glucose control, and oral antibiotics given when bowel prep used (SCIP-1 was not significant). Further, several specific prophylactic antibiotic choices were independently associated with lower SSI rates, including cefazolin/metronidazole, ciprofloxacin/metronidazole, and ertapenem. CONCLUSIONS: In Michigan, several perioperative care practices are independently associated with decreased risk of SSI after colectomy, including SCIP-2-compliant prophylactic antibiotics, postoperative normothermia, glucose control, and oral antibiotics. Furthermore, specific prophylactic antibiotic choices are associated with lower risk of SSI. These results account for patient factors and unmeasured hospital effects, suggesting that dissemination of these perioperative care practices may decrease SSI rates.

Modulation of food intake by mTOR signalling in the dorsal motor nucleus of the vagus in male rats: focus on ghrelin and nesfatin-1.

Previous studies have demonstrated that mammalian target of rapamycin (mTOR) signalling in the hypothalamus is involved in the control of energy homeostasis. The aim of this study was to characterize the effect of mTOR signalling in the dorsal motor nucleus of the vagus (DMNV) on energy intake. Phospho-mTOR was detected in the DMNV neurons, and its levels were increased by energy deprivation. Rapamycin significantly inhibited mTOR activity and reduced food intake when administrated into the fourth ventricle. Exposure of DMNV neurons to ghrelin increased the phosphorylation of mTOR. Injection of ghrelin into the fourth ventricle significantly increased food intake relative to the control vehicle. Pretreatment with rapamycin for 15 min attenuated the orexigenic effect of ghrelin. A reduction in the phosphorylation of mTOR was observed following injection of nesfatin-1 into the fourth ventricle. When administrated by injection into the fourth ventricle, nesfatin-1 suppressed food intake in comparison with the control vehicle. The anorexigenic effect of nesfatin-1 was significantly attenuated by pretreatment with leucine for 15 min. All these findings suggest that mTOR signalling in the DMNV neurons regulates both the nutrient and the hormonal signals for the modulation of food intake.

Intraoperative Use of Compensatory Reserve Measurement in Orthotopic Liver Transplant: Improved Sensitivity for the Prediction of Hypovolemic Events.

INTRODUCTION: The compensatory reserve measurement (CRM) is a continuous non-invasive monitoring technology that measures the summation of all physiological mechanisms involved in the compensatory response to central hypovolemia. The CRM is displayed on a 0% to 100% scale. The objective of this study is to characterize the use of CRM in the operative setting and determine its ability to predict hypovolemic events compared to standard vital signs. Orthotopic liver transplant was used as the reference procedure because of the predictable occurrence of significant hemodynamic shifts. METHODS: A prospective observational cohort study was conducted on 22 consecutive patients undergoing orthotopic liver transplant. The subjects were monitored in accordance with the standard of care. The CRM data were collected concurrently with intraoperative staff blinded to the outputs. The data were stored on secure devices on encrypted files. Based on prior literature, subgroup analysis was performed for high-tolerance (good compensators) and low-tolerance (poor compensators) groups, which was based on a shock index threshold of 0.9. Threshold events were defined as follows: CRM below 60% (CRM60), systolic blood pressure (SBP) below 90 mmHg (SBP90), and heart rate (HR) above 100 beats per minute (HR100). RESULTS: Complete data were captured in 22 subjects as a result of device malfunction or procedure cancellation. Sensitivity analysis was performed for the detection of hypovolemia at the time of the event. CRM60 was the most sensitive (62.6%) when compared to other threshold measures such as SBP90 (30.6%), HR100 (23.1%), elevated lactate (54.6%), and a drop in hemoglobin (41.7%). The number of patients meeting the CRM60 threshold at the time of the first transfusion (TFX) was higher when compared to SBP90 and HR100 in the overall group (P = .001 and P < .001, respectively) and both the high-tolerance (P = .002 and P = .001, respectively) and low-tolerance groups (P = .016 and P = .001, respectively). Similar results supporting the higher sensitivity of CRM were observed when comparing the number of patients below the threshold at the time of the first vasopressor administration. Start time was standardized so that the time-to-threshold signals for hemodynamic and laboratory parameters could be compared. The median time-to-CRM signal detection before the TFX event was -15.0 minutes (i.e., 15 minutes before TFX). There was no difference when compared to the SBP threshold (median time -5.0 minutes, P = .64) but was significantly sooner when compared to HR (P = .006), lactate (P = .002), and hemoglobin (P < .001). CONCLUSIONS: At the time of the first TFX, the CRM had a higher rate of detection of a hypovolemic event compared to SBP and HR, indicating a higher sensitivity for the detection of the first hypovolemic event. When combined with all hypovolemic events, sensitivity analysis showed that CRM60 provides the earlier predictive capability. Given that SBP is the clinical standard of care for the initiation of TFX, the finding that median time to event detection was statistically similar between CRM60 and SBP90 was not unexpected. When compared to other measures of hypovolemia, the CRM consistently showed earlier detection of hypovolemic events. Although this study had a small sample size, it produced significant results and can serve as a proof of concept for future large-scale studies.

Nesfatin-1 inhibits gastric acid secretion via a central vagal mechanism in rats.

Nesfatin-1, a novel hypothalamic peptide, inhibits nocturnal feeding behavior and gastrointestinal motility in rodents. The effects of nesfatin-1 on gastrointestinal secretory function, including gastric acid production, have not been evaluated. Nesfatin-1 was injected into the fourth intracerebral ventricle (4V) of chronically cannulated rats to identify a nesfatin dose sufficient to inhibit food intake. Nesfatin-1 (2 µg) inhibited dark-phase food intake, in a dose-dependent fashion, for >3 h. Gastric acid production was evaluated in urethane-anesthetized rats. Nesfatin-1 (2 µg) was introduced via the 4V following endocrine stimulation of gastric acid secretion by pentagastrin (2 µg·kg(-1)·h(-1) iv), vagal stimulation with 2-deoxy-D-glucose (200 mg/kg sc), or no stimulus. Gastric secretions were collected via gastric cannula and neutralized by titration to determine acid content. Nesfatin-1 did not affect basal and pentagastrin-stimulated gastric acid secretion, whereas 2-deoxy-D-glucose-stimulated gastric acid production was inhibited by nesfatin-1 in a dose-dependent manner. c-Fos immunofluorescence in brain sections was used to evaluate in vivo neuronal activation by nesfatin-1 administered via the 4V. Nesfatin-1 caused activation of efferent vagal neurons, as evidenced by a 16-fold increase in the mean number of c-Fos-positive neurons in the dorsal motor nucleus of the vagus (DMNV) in nesfatin-1-treated animals vs. controls (P < 0.01). Finally, nesfatin-induced Ca(2+) signaling was evaluated in primary cultured DMNV neurons from neonatal rats. Nesfatin-1 caused dose-dependent Ca(2+) increments in 95% of cultured DMNV neurons. These studies demonstrate that central administration of nesfatin-1, at doses sufficient to inhibit food intake, results in inhibition of vagally stimulated secretion of gastric acid. Nesfatin-1 activates DMNV efferent vagal neurons in vivo and triggers Ca(2+) signaling in cultured DMNV neurons.

Building a Low-Cost and Low-Fidelity Kidney Transplant Model: A Technical Report on the San Antonio Kidney Transplant Model.

One of the most challenging aspects of the kidney transplant operation is performing vascular anastomoses in the confines and depths of the iliac fossa. General surgery residents need to be adequately trained in this skill to maximize their intraoperative experience during their transplant surgery rotation. While several kidney transplant models have been developed, they are limited in their ability to simulate the challenges of performing anastomoses at varying depths and in confined spaces. Furthermore, they may be expensive or require specialized equipment, such as three-dimensional printers, to build. In this technical report, we describe how to build a low-fidelity, low-cost, and portable kidney transplant model capable of simulating vascular anastomoses at varying depths. Our model can be easily replicated for less than 30 USD using materials available in local stores. It uses inexpensive and reusable parts, allowing trainees a high volume of repetitions.

Ankyrin repeat and SOCS box containing protein 4 (Asb-4) colocalizes with insulin receptor substrate 4 (IRS4) in the hypothalamic neurons and mediates IRS4 degradation.

BACKGROUND: The arcuate nucleus of the hypothalamus regulates food intake. Ankyrin repeat and SOCS box containing protein 4 (Asb-4) is expressed in neuropeptide Y and proopiomelanocortin (POMC) neurons in the arcuate nucleus, target neurons in the regulation of food intake and metabolism by insulin and leptin. However, the target protein(s) of Asb-4 in these neurons remains unknown. Insulin receptor substrate 4 (IRS4) is an adaptor molecule involved in the signal transduction by both insulin and leptin. In the present study we examined the colocalization and interaction of Asb-4 with IRS4 and the involvement of Asb-4 in insulin signaling. RESULTS: In situ hybridization showed that the expression pattern of Asb-4 was consistent with that of IRS4 in the rat brain. Double in situ hybridization showed that IRS4 colocalized with Asb-4, and both Asb-4 and IRS4 mRNA were expressed in proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons within the arcuate nucleus of the hypothalamus. In HEK293 cells co-transfected with Myc-tagged Asb-4 and Flag-tagged IRS4, Asb-4 co-immunoprecipitated with IRS4; In these cells endogenous IRS4 also co-immunoprecipitated with transfected Myc-Asb-4; Furthermore, Asb-4 co-immunoprecipitated with IRS4 in rat hypothalamic extracts. In HEK293 cells over expression of Asb-4 decreased IRS4 protein levels and deletion of the SOCS box abolished this effect. Asb-4 increased the ubiquitination of IRS4; Deletion of SOCS box abolished this effect. Expression of Asb-4 decreased both basal and insulin-stimulated phosphorylation of AKT at Thr308. CONCLUSIONS: These data demonstrated that Asb-4 co-localizes and interacts with IRS4 in hypothalamic neurons. The interaction of Asb-4 with IRS4 in cell lines mediates the degradation of IRS4 and decreases insulin signaling.

Characteristics and Outcomes of Liver Transplantation for Primary Biliary Cholangitis in Young Patients: Analysis of the United Network for Organ Sharing Database.

BACKGROUND: Primary biliary cholangitis (PBC) in younger patients has been suggested to require liver transplantation (LT) in early adulthood, but data is limited on its outcomes. We aimed to evaluate the characteristics and outcome of LT in young patients with PBC in comparison with older adults. METHODS: The United Network for Organ Sharing database was analyzed for all patients with PBC who underwent LT between 2000 and 2012. Based on age at the time of LT, subjects were divided into 2 groups: young patients (≤40 y) and older adults (≥41 y). Baseline demographics, clinical parameters, and outcomes of LT were then compared between the 2 groups. Univariable and multivariable analyses were performed to assess the factors associated with outcomes of LT. RESULTS: A total of 2084 patients with PBC were included in the analysis with 158 young patients. Compared with older adults, younger patients were more likely to be male (27.2% versus 15.4%) and nonwhite (43.7% versus 21.5%), but they were less likely to have obesity, diabetes, or hypertension (P < 0.05) and had a lower mortality (8.2% versus 15.1%) but higher retransplantation rate (14.6% versus 4.7%) (P < 0.001). On multivariable analysis, older age, dialysis or ventilator use, and lower albumin were associated with high post-LT mortality. CONCLUSIONS: Compared with older adults, early-onset PBC in younger patients requiring LT had higher percentage of males and nonwhites and had a lower prevalence of metabolic comorbidities but higher retransplantation rates. Further studies are warranted to confirm these findings.

Characterization of patients with both alcoholic and nonalcoholic fatty liver disease in a large United States cohort.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome (MetS) and is characterized by steatosis in the absence of significant alcohol consumption. However, MetS and significant alcohol intake coexist in certain individuals which may lead to the development of BAFLD. AIM: To assess the clinical characteristics of patients with both alcoholic and NAFLD (BAFLD) in a large cohort in the United States. METHODS: Adults from the National Health and Nutrition Examination Survey between 2003-2014 were included. NAFLD was diagnosed based on elevated alanine aminotransferase (ALT) and being overweight or obese in the absence of other liver diseases. BAFLD patients met the criteria for NAFLD but also had either MetS or type 2 diabetes and consumed excessive amounts of alcohol. Univariable and multivariable analysis were performed to assess differences between NAFLD and BAFLD and to compare severity based on a validated fibrosis score (FIB4 index). RESULTS: The prevalence of NAFLD was at 25.9% (95%CI; 25.1-26.8) and that of BAFLD was 0.84% (0.67, 1.02) which corresponds to an estimated 1.24 million Americans affected by BAFLD. Compared to NAFLD, patients with BAFLD were more likely to be male, smokers, have higher ALT, aspartate aminotransferase, triglycerides, and lower platelets; P < 0.01 for all. More importantly, after adjusting for MetS components, BAFLD patients were significantly more likely to have advanced fibrosis [adjusted OR (95%CI) based on FIB4 index > 2.67 was 3.2 (1.4, 7.0), P = 0.004]. CONCLUSION: A significant percentage of the American general population is afflicted by BAFLD and these patients tend to have more advanced liver fibrosis.

The Mammalian Spermatogenesis Single-Cell Transcriptome, from Spermatogonial Stem Cells to Spermatids.

Spermatogenesis is a complex and dynamic cellular differentiation process critical to male reproduction and sustained by spermatogonial stem cells (SSCs). Although patterns of gene expression have been described for aggregates of certain spermatogenic cell types, the full continuum of gene expression patterns underlying ongoing spermatogenesis in steady state was previously unclear. Here, we catalog single-cell transcriptomes for >62,000 individual spermatogenic cells from immature (postnatal day 6) and adult male mice and adult men. This allowed us to resolve SSC and progenitor spermatogonia, elucidate the full range of gene expression changes during male meiosis and spermiogenesis, and derive unique gene expression signatures for multiple mouse and human spermatogenic cell types and/or subtypes. These transcriptome datasets provide an information-rich resource for studies of SSCs, male meiosis, testicular cancer, male infertility, or contraceptive development, as well as a gene expression roadmap to be emulated in efforts to achieve spermatogenesis in vitro.

Incidence of and Risk Assessment for Adverse Cardiovascular Outcomes After Liver Transplantation: A Systematic Review.

BACKGROUND: Cardiovascular events represent a major source of morbidity and mortality after liver transplantation and will likely increase given the aging population and nonalcoholic fatty liver disease as a leading indication for transplant. The optimal cardiovascular risk stratification approach in this evolving patient population remains unclear. The aims of this systematic review are to: (1) refine the definition, (2) characterize the incidence, and (3) identify risk factors for cardiovascular events post-liver transplantation. Additionally, we evaluated performance characteristics of different cardiac testing modalities. METHODS: MEDLINE via PubMed, EMBASE, Web of Science, and Scopus were searched for studies published between 2002 and 2016 (model of end-stage liver disease era). Two authors independently reviewed articles to select eligible studies and performed data abstraction. RESULTS: Twenty-nine studies representing 57 493 patients from 26 unique cohorts were included. Definitions of cardiovascular outcomes were highly inconsistent. Incidence rates were widely variable: 1% to 41% for outcomes of 6 months or shorter and 0% to 31% for outcomes longer than 6 months. Multivariate analyses demonstrated that older age and history of cardiac disease were the most consistent predictors of cardiovascular events posttransplant (significant in 8/23 and 7/22, studies, respectively). Predictive capacity of various cardiac imaging modalities was also discrepant. CONCLUSIONS: The true incidence of cardiovascular outcomes post-liver transplant remains unknown in large part due to lack of consensus regarding outcome definition. Overall, poor data quality and gaps in knowledge limit the ability to clearly identify predictors of outcomes, but existing data support a more aggressive risk stratification protocol for patients of advanced age and/or with preexisting cardiac disease.

Thrombin mediates vagal apoptosis and dysfunction in inflammatory bowel disease.

BACKGROUND: In inflammatory bowel disease, autonomic dysfunction contributes to symptoms, morbidity, and health care resource utilization. Efferent vagal neurons, which provide the primary parasympathetic input to the gastrointestinal tract, are housed in the dorsal motor nucleus of the vagus (DMV) in the brainstem. This study seeks to characterize the effects of IBD on DMV neuronal survival and function. METHODS: TNBS (picrylsulfonic acid) was administered by enema to induce colitis in rats. Brain sections through the DMV were examined for neuronal apoptosis using TUNEL labeling, and for glial cell activation by immunofluorescence. Prothrombin production was evaluated via quantitative RT-PCR from DMV tissue, as well as by double immunofluorescence in DMV sections. To investigate the effects of thrombin in the DMV, thrombin or thrombin and an antagonist to its receptor were administered into the fourth ventricle via a stereotactically placed cannula. DMV sections were then examined for apoptosis by TUNEL assay. To evaluate the effect of thrombin on DMV neuronal function, we examined calcium signaling in primary DMV neuron cultures following exposure to thrombin and other neurotransmitters. RESULTS: TNBS colitis is associated with significantly increased rates of DMV neuronal apoptosis, affecting 12.7 % of DMV neurons in animals with colitis, compared to 3.4 % in controls. There was a corresponding increase in DMV neuron activated caspase-3 immunoreactivity (14.8 vs. 2.6 % of DMV neurons). TNBS-treated animals also demonstrated significantly increased DMV astrocyte and microglial immunoreactivity, indicating glial cell activation. DMV prothrombin production was significantly increased in TNBS colitis, with a close anatomic relationship between prothrombin and microglia. Direct DMV exposure to thrombin replicated the apoptosis and activation of caspase-3 seen in TNBS colitis; these effects were prevented by coadministration of the PAR-1 inhibitor FR171113. Cultured DMV neurons exhibited impaired calcium signaling in response to neurotransmitters following exposure to thrombin. Glutamate-induced calcium transients decreased by 59 %, and those triggered by GABA were reduced by 61 %. PAR-1 antagonism prevented these thrombin-induced changes in calcium signaling. CONCLUSIONS: IBD is associated with DMV microglial activation and production of prothrombin. Thrombin in the DMV causes vagal neuron apoptosis and decreased sensitivity to neurotransmitters.

LGR4 and its ligands, R-spondin 1 and R-spondin 3, regulate food intake in the hypothalamus of male rats.

The hypothalamus plays a key role in the regulation of feeding behavior. Several hypothalamic nuclei, including the arcuate nucleus (ARC), paraventricular nucleus, and ventromedial nucleus of the hypothalamus (VMH), are involved in energy homeostasis. Analysis of microarray data derived from ARC revealed that leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) is highly expressed. LGR4, LGR5, and LGR6 form a subfamily of closely related receptors. Recently, R-spondin (Rspo) family proteins were identified as ligands of the LGR4 subfamily. In the present study, we investigated the distribution and function of LGR4-LGR6 and Rspos (1-4) in the brain of male rat. In situ hybridization showed that LGR4 is expressed in the ARC, VMH, and median eminence of the hypothalamus. LGR4 colocalizes with neuropeptide Y, proopiomelanocortin, and brain-derived neurotrophic factor neurons. LGR5 is not detectable with in situ hybridization; LGR6 is only expressed in the epithelial lining of the lower portion of the third ventricle and median eminence. Rspo1 is expressed in the VMH and down-regulated with fasting. Rspo3 is expressed in the paraventricular nucleus and also down-regulated with fasting. Rspos 1 and 3 colocalize with the neuronal marker HuD, indicating that they are expressed by neurons. Injection of Rspo1 or Rspo3 into the third brain ventricle inhibited food intake. Rspo1 decreased neuropeptide Y and increased proopiomelanocortin expression in the ARC. Rspo1 and Rspo3 mRNA is up-regulated by insulin. These data indicate that Rspo1 and Rspo3 and their receptor LGR4 form novel circuits in the brain to regulate energy homeostasis.