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We aim to illustrate the role of complete and transparent reporting coupled with access to data sourced from published systematic reviews, especially assisting in the identification of evidence for subgroups within the context of a rare disease. To accomplish this principle, we provide a real-world example encountered during the revision of the Dutch clinical practice guideline for hepatocellular carcinoma. Specifically, we retrieved insights from two Cochrane reviews to identify direct evidence concerning the diagnostic test accuracy of computed tomography and magnetic resonance imaging for detecting hepatocellular carcinomas in suspected patients without liver cirrhosis. Through reusing the Cochrane review authors' efforts already undertaken in their exhaustive literature search and selection, we successfully identified relevant direct evidence for this subgroup of suspected patients without cirrhosis and performed an evidence synthesis within the constraints of limited resources for the guideline revision. This approach holds the potential for replication in other subgroups in the context of rare diseases, contingent on the transparent and complete reporting of systematic reviews, as well as the availability and accessibility of their extracted data. Consequently, we underscore the importance of adhering to established reporting guidelines for systematic reviews, while simultaneously advocating for increased availability and accessibility to data. Such practices would not only increase the transparency and reproducibility of systematic reviews but could also increase reusability of their data. In turn, the increased reusability could result in reduced resource utilization in other sectors such as the guideline developing community as we show in our example. [ABSTRACT FROM AUTHOR]

Background Steatotic liver disease is suggested to have a higher prevalence and severity in people with HIV (PHIV), including in those with a normal body mass index (BMI). In this study, we used data from the 2000HIV cohort to (1) assess the prevalence of liver steatosis and fibrosis in lean versus overweight/obese PHIV and (2) assess associations in these subgroups between steatosis and fibrosis with traditional risk factors and HIV-specific characteristics. Methods The 2000HIV study cohort comprises 1895 virally suppressed PHIV that were included between 2019 and 2021 in 4 HIV treatment centers in the Netherlands. The majority (58.5%) underwent vibration-controlled transient elastography for the assessment of liver steatosis and fibrosis. The prevalence of steatosis (controlled attenuation parameter ≥263 dB/m) and fibrosis (liver stiffness measurement ≥7.0 kPa) was estimated. Multiple factors including HIV characteristics and antiretroviral drugs were tested in a logistic regression model for association with steatosis and fibrosis. Analyses were performed separately for lean (Asian descent: BMI < 23 kg/m2, other descent: BMI < 25 kg/m2) and overweight/obese (other BMI) participants. Results Of 1050 PHIV including 505 lean and 545 overweight/obese PHIV, liver steatosis was observed in 37.7% of the overall study population, 19.7% of lean, and 54% of overweight/obese PHIV, whereas fibrosis was observed in 9.0% of the overall study population, 5.9% of lean, and 12.0% of overweight/obese PHIV. All associations with fibrosis and most associations with steatosis concerned metabolic factors such as type 2 diabetes mellitus (overall population: adjusted odds ratio [aOR] for steatosis: 2.3 [1.21-4.4], P =.011; aOR for fibrosis: 3.7 [1.82-7.53], P <.001). Furthermore, in lean PLHIV, liver steatosis was associated with CD4 and CD8 counts at enrollment, dual therapy, and history of treatment with raltegravir (aOR: 3.6 [1.53-8.47], P =.003), stavudine (aOR: 3.73 [1.69-8.2], P =.001), and indinavir (aOR: 3.86 [1.59-9.37], P =.003). These associations were not observed in overweight/obese PHIV. Conclusions Liver steatosis was highly prevalent, affecting approximately one-fifth of lean PHIV and half of overweight/obese PHIV. Fibrosis was observed in a minority. Both steatosis and fibrosis were associated with traditional metabolic risk factors. In addition, (prior) exposure to specific antiretroviral drugs was associated liver steatosis in lean, but not in overweight/obese PHIV. Implementing increased screening protocols could enhance the identification of steatotic liver disease in lean PHIV. [ABSTRACT FROM AUTHOR]

Introduction: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many malignancies in recent years. However, immune-related adverse events (irAE) are a frequent concern in clinical practice. The safety profile of ICI for the treatment of malignancies in patients diagnosedwith autoimmune and cholestatic liver disease (AILD) remains unclear. Due to this uncertainty, these patients were excluded from ICI clinical trials and ICI are withheld from this patient group. In this retrospective multicenter study, we assessed the safety of ICI in patients with AILD. Methods: We contacted tertiary referral hospitals for the identification of AILD patients under ICI treatment in Europe via the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). Fourteen centers contributed data on AILD patients with malignancies being treated with ICI, another three centers did not treat these patients with ICI due to fear of irAEs. Results: In this study, 22 AILD patients under ICI treatment could be identified. Among these patients, 12 had primary biliary cholangitis (PBC), five had primary sclerosing cholangitis (PSC), four had autoimmune hepatitis (AIH), and one patient had an AIH-PSC variant syndrome. Eleven patients had hepatobiliary cancers and the other 11 patients presented with non-hepatic tumors. The applied ICIs were atezolizumab (n=7), durvalumab (n=5), pembrolizumab (n=4), nivolumab (n=4), spartalizumab (n=1), and in one case combined immunotherapy with nivolumab plus ipilimumab. Among eight patients who presented with grade 1 or 2 irAEs, three demonstrated liver irAEs. Cases with grades = 3 irAEs were not reported. No significant changes in liver tests were observed during the first year after the start of ICI. Discussion: This European multicenter study demonstrates that PD-1/PD-L1 inhibitors appear to be safe in patients with AILD. Further studies on the safety of more potent dual immune checkpoint therapy are needed. We conclude that immunotherapy should not categorically be withheld from patients with AILD. [ABSTRACT FROM AUTHOR]

Introduction: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many malignancies in recent years. However, immune--related adverse events (irAE) are a frequent concern in clinical practice. The safety profile of ICI for the treatment ofmalignancies in patients diagnosedwith autoimmune and cholestatic liver disease (AILD) remains unclear. Due to this uncertainty, these patients were excluded from ICI clinical trials and ICI are withheld from this patient group. In this retrospective multicenter study, we assessed the safety of ICI in patients with AILD. Methods: We contacted tertiary referral hospitals for the identification of AILD patients under ICI treatment in Europe via the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). Fourteen centers contributed data on AILD patients with malignancies being treated with ICI, another three centers did not treat these patients with ICI due to fear of irAEs. Results: In this study, 22 AILD patients under ICI treatment could be identified. Among these patients, 12 had primary biliary cholangitis (PBC), five had primary sclerosing cholangitis (PSC), four had autoimmune hepatitis (AIH), and one patient had an AIH-PSC variant syndrome. Eleven patients had hepatobiliary cancers and the other 11 patients presented with non-hepatic tumors. The applied ICIs were atezolizumab (n=7), durvalumab (n=5), pembrolizumab (n=4), nivolumab (n=4), spartalizumab (n=1), and in one case combined immunotherapy with nivolumab plus ipilimumab. Among eight patients who presented with grade 1 or 2 irAEs, three demonstrated liver irAEs. Cases with grades ≥ 3 irAEs were not reported. No significant changes in liver tests were observed during the first year after the start of ICI. Discussion: This European multicenter study demonstrates that PD-1/PD-L1 inhibitors appear to be safe in patients with AILD. Further studies on the safety of more potent dual immune checkpoint therapy are needed. We conclude that immunotherapy should not categorically be withheld from patients with AILD. [ABSTRACT FROM AUTHOR]

Background and Aims: While some articles describe outcome of pregnancy in autoimmune hepatitis (AIH), there are less data evaluating influence of AIH control on maternal and perinatal outcomes. This study analysed outcomes of pregnancy and related possible risk factors in AIH. Method: A retrospective multicentre cohort study on pregnancy in AIH was performed in 11 hospitals in the Netherlands. Maternal and neonatal outcomes were collected from records and completed by interview. Risk factors—including incomplete response, relapse and cirrhosis—for adverse outcomes were identified using logistic regression analysis. Results: Ninety‐seven pregnancies in 50 women resulted in 70 deliveries (72%) with a live birth rate of 98.5%. AIH relapse occurred in 6% during pregnancy, and in 27% of post‐partum episodes. Absence of complete biochemical response at conception was identified as risk factor for the occurrence of gestational and post‐partum relapses. Relapse of AIH in the year before conception was a risk factor for the occurrence of both gestational relapses and post‐partum relapses. No complete biochemical response increased the risk for hypertensive disorders during pregnancy and intrahepatic cholestasis of pregnancy (ICP). Cirrhosis was found to be a risk factor for miscarriages, but not for other outcomes. Conclusion: Pregnancy in AIH is related to an increased incidence of maternal and fetal/neonatal complications; in most cases, outcome is good. Incomplete biochemical response at conception or relapse in the year before conception are risk factors for gestational and post‐partum relapses, for hypertensive disorders and for ICP. Cirrhosis was a risk factor for miscarriages. [ABSTRACT FROM AUTHOR]

Background: Perihilar cholangiocarcinoma (pCCA) is a rare tumour that requires complex multidisciplinary management. All known data are almost exclusively derived from expert centres. This study aimed to analyse the outcomes of patients with pCCA in a nationwide cohort. Methods: Data on all patients diagnosed with pCCA in the Netherlands between 2010 and 2018 were obtained from the Netherlands Cancer Registry. Data included type of hospital of diagnosis and the received treatment. Outcomes included the type of treatment and overall survival. Results: A total of 2031 patients were included and the median overall survival for the overall cohort was 5.2 (95% CI 4.7‐5.7) months. Three‐hundred‐ten (15%) patients underwent surgical resection, 271 (13%) underwent palliative systemic treatment, 21 (1%) palliative local anti‐cancer treatment and 1429 (70%) underwent best supportive care. These treatments resulted in a median overall survival of 29.6 (95% CI 25.2‐34.0), 12.2 (95% CI 11.0‐13.3), 14.5 (95%CI 8.2‐20.8) and 2.9 (95% CI 2.6‐3.2) months respectively. Resection rate was 13% in patients who were diagnosed in non‐academic and 32% in academic centres (P <.001), which resulted in a survival difference in favour of academic centres. Median overall survival was 9.7 (95% CI 7.7‐11.7) months in academic centres compared to 4.9 (95% CI 4.3‐5.4) months in non‐academic centres (P <.001). Conclusions: In patients with pCCA, resection rate and overall survival were higher for patients who were diagnosed in academic centres. These results show population‐based outcomes of pCCA and highlight the importance of regional collaboration in the treatment of these patients. [ABSTRACT FROM AUTHOR]

Patients suffering from polycystic liver disease may develop Hepatic Venous Outflow Obstruction, Portal Vein Obstruction and/or Inferior Caval Vein Syndrome because of cystic mass effect. This can cause portal hypertension, leading to ascites, variceal haemorrhage or splenomegaly. For this review, we evaluate the evidence to provide clinical guidance for physicians faced with this complication. Diagnosis is made with imaging such as ultrasound, computed tomography or magnetic resonance imaging. Therapy includes conventional therapy with diuretics and paracentesis, and medical therapy using somatostatin analogues. Based on disease phenotype various (non‐)surgical liver‐volume reducing therapies, hepatic or portal venous stenting, transjugular intrahepatic portosystemic shunts and liver transplantation may be considered. Because of complicated anatomy, use of high‐risk interventions and lack of empirical evidence, patients should be treated in expert centres. [ABSTRACT FROM AUTHOR]

Aims Liver fibrosis and cirrhosis are a consequence of a Fontan physiology, and determine prognosis. It is unclear whether non-invasive assessment of liver pathology is helpful to provide clinically relevant information. The aims of this study were to assess the spectrum of Fontan-associated liver disease (FALD) and usefulness of non-invasive methods to assess biopsy confirmed liver fibrosis. Methods and results Hepatic screening of consecutive patients consisted of a blood panel, ultrasonography, elastography, contrast-enhanced magnetic resonance imaging (MRI)/computed tomography (CT) scan, and liver biopsy (scored with Fontan specific fibrosis scores and collagen proportionate area; CPA). Fibrosis parameters, varices, ascites, and splenomegaly were measured on imaging. Thirty-eight of 49 referred patients (27 ± 6.6 years, 73.7% male) underwent the complete screening protocol. Liver fibrosis on biopsy was present in all patients, and classified as severe (Stages 3–4) in 68%. Median CPA was 22.5% (16.9–29.5) and correlated with individual fibrosis scores. ELF® and liver stiffness were elevated, but MELD-XI scores were low in all patients. Fibrosis severity neither correlated to ELF® and liver stiffness, nor to (semi-) quantitative fibrosis parameters on MRI/CT. Varices were present in 50% and hyperenhancing nodules in 25% of patients, both independent of fibrosis stage, but varices were associated with higher CPA values. Conclusion The FALD spectrum includes both hepatic congestion and severe fibrosis, with signs of portal hypertension and hyperenhancing nodules as significant manifestations. Routine imaging, transient elastography, and serum biomarkers are unable to accurately assess severity of liver fibrosis in this cohort. Future research should focus on validating new diagnostic tools with biopsy as the reference standard. View large Download slide View large Download slide [ABSTRACT FROM AUTHOR]

Aims: The composition of several important extracellular matrix components (ECM) has not yet been elucidated in human non‐alcoholic fatty liver disease (NAFLD). We aim to investigate the proportion of hepatic stellate cells (HSCs) and activity of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) in human NAFLD liver tissue with respect to severity of inflammation and fibrosis. Methods and results: Histopathological features were quantified by NAFLD activity score and grading assignment. The collagen proportionate area (CPA) was measured. Slides were stained with alpha‐smooth muscle actin (α‐SMA), as a marker of activated HSCs, and α‐SMA was quantified digitally. Zymography was performed to measure the proteolytic activity of MMP‐2 and MMP‐9. TIMP‐1 and TIMP‐2 protein concentration was measured with enzyme‐linked immunosorbent assay (ELISA). α‐SMA was higher in severe fibrosis (6.3%, interquartile range 2.9–13.1) than mild and no fibrosis (median 1.1 and 0.9%, P < 0.001) and correlated strongly with CPA (Rs = 0.870, P < 0.001). ProMMP‐2 activity in severe (4.1%, IQR 2.6–16.2) and mild fibrosis (2.7%, IQR 1.9–3.9) was higher than in no fibrosis (1.5%, (IQR 0.95–2.1); P = 0.001 and P = 0.046) and showed a moderate positive correlation with CPA (Rs = 0.495, P = 0.001). TIMP‐1 and TIMP‐2 were significantly higher in severe fibrosis than mild or no fibrosis. Both showed moderate correlation with CPA (TIMP‐1: Rs = 0.471, P = 0.002 and TIMP‐2: Rs = 0.325, P = 0.036). MMP‐9 correlated as the only ECM component to inflammation severity. Conclusions: Advanced human NAFLD‐fibrosis has a distinct ECM composition with increased HSCs and increased TIMP inhibition, but there is also ongoing remodelling activity of MMP‐2. [ABSTRACT FROM AUTHOR]

Objectives:To assess the influence of smoking on histological disease severity and fibrosis in real-world NAFLD patients. Material and methods:Consecutive NAFLD patients were identified with liver biopsies performed between 2008 and 2015. Characteristics such as smoking status and total number of pack years were collected. Biopsies were revised and BRUNT fibrosis and NAFLD activity score (NAS) determined. Patients with a high NAS (≥5) were compared to patients with a low NAS (<5) and with advanced fibrosis (stage 3–4) to patients with no-early fibrosis (stage 0–2). Patients with a history of smoking (current or past smoker) were defined ever smokers. Results:Fifty-six patients were included (mean age 49 ± 14.3, 68.9% males and 39.3% history of smoking). Ever smokers had a higher fibrosis score than never smokers; two (IQR 0–3) versus one (IQR 1–1.5) (p = .040). Patients with advanced fibrosis smoked significantly more pack years than patients with no-early fibrosis; 10.6 (IQR 0–25.8) versus 0 (IQR 0–7) (p = .011). There is a weak to moderate correlation between fibrosis stage and number of pack years (Spearman’s Rho = 0.341,p = .012). There was no difference in NAS between never and ever smokers; 2.8 ± 1.5 versus 3.3 ± 1.4 (p = .205). Patients with NAS <5 had a median number of pack years of 0 (IQR 0–9) versus a median of 10.3 pack years (IQR 0–24) in patients with NAS ≥5 (p = .127). Conclusion:Smoking is associated with severity of NAFLD-related liver fibrosis but not with histological disease severity. This supports the recommendation to cease smoking for NAFLD patients. [ABSTRACT FROM AUTHOR]

Background and study aims: Hemospray (Cook Medical Inc., Winston-Salem, North Carolina, USA) is a novel, hemostatic, powder spray that has been developed for gastrointestinal use. The powder is thought to achieve hemostasis by concentrating clotting factors and forming amechanical plug on the injured blood vessel. However, no detailed studies on the hemostatic mode of action have been performed. The aim of this studywas to examine the effects of Hemospray on coagulation and clot formation both in vitro and in vivo. Materials and methods: Recalcification time, thromboelastometry using EXTEM and INTEM assays, and plasma coagulation tests (activated partial thromboplastin time and prothrombin time) were carried out on blood samples mixed with Hemospray, and compared with talcum powder (negative control) and kaolin (positive control) at 1mg/mL and 10mg/mL. Scanning electron microscopy (SEM) and light microscopy were performed on in vitro thrombi and on gastric thrombi from an animal model of gastrointestinal hemorrhage treated with Hemospray. Results: The median recalcification time of whole bloodwas 187.5 seconds. The addition of 1mg/mL and 10mg/mL Hemospray significantly shortened this time (median 60 and 45 seconds, respectively; P<0.05). The median clotting time of whole blood, measured using the INTEM assay, was 160 seconds (interquartile range [IQR] 159-176.5) and this was also significantly reduced by the addition of Hemospray (91 seconds [IQR 84- 102]; P=0.005). The plasma prothrombin time of 11.6 seconds was significantly reduced by Hemospray (9.5 seconds; P=0.011). SEM of in vivo clots demonstrated that Hemospray rapidly interacted with whole blood, forming one confluent mass over the bleeding site. In sufficient amounts, Hemospray was able to deform and pack erythrocytes. Conclusions: Hemospray covered the bleeding site and enhanced clot formation in vivo, and shortened coagulation time in vitro. Elaboration of these unique properties in clinical practice will help to optimize future endoscopic hemostasis with Hemospray. [ABSTRACT FROM AUTHOR]

Chronic gastrointestinal ischemia (CGI) is the result of decreased mucosal perfusion. Typical histological characteristics are lacking which hamper its early diagnosis. Hypoxia-inducible factor-1α (HIF-1α) is expressed under acute hypoxia. We investigated HIF-1α expression in chronic ischemic and inflammatory conditions of the human gastrointestinal (GI) tract. Immunohistochemical expression of HIF-1α was analyzed in 61 patients, including patients with CGI, Helicobacter pylori gastritis, ischemic colitis (IC), infectious colitis, and inflammatory bowel disease (IBD), and 22 controls. HIF-1α expression in >10 % of the cells was regarded as positive staining, and expression <10 % of the cells was considered as negative staining. In the upper GI tract, HIF-1α expression was found in 5/20 CGI patients, but not in controls (p = 0.08). The sensitivity and specificity of HIF-1α expression for diagnosing CGI were 25 and 84%, respectively. In the lower GI tract, HIF-1α was expressed in all patients with IC and infectious colitis and in a majority of IBD patients as well as in 7/12 controls. The sensitivity and specificity of HIF-1α for diagnosing IC were 100 and 51%, respectively. HIF-1α expression was more often (p = 0.02) observed in patients with histological signs of inflammation in the lower GI tract. HIF-1α is expressed in acute and chronic ischemic tissue, but also in normal colon tissue and inflammatory disorders. [ABSTRACT FROM AUTHOR]

Chronic gastrointestinal ischemia (CGI) is the result of decreased mucosal perfusion. Typical histological characteristics are lacking which hamper its early diagnosis. Hypoxia-inducible factor-1α (HIF-1α) is expressed under acute hypoxia. We investigated HIF-1α expression in chronic ischemic and inflammatory conditions of the human gastrointestinal (GI) tract. Immunohistochemical expression of HIF-1α was analyzed in 61 patients, including patients with CGI, Helicobacter pylori gastritis, ischemic colitis (IC), infectious colitis, and inflammatory bowel disease (IBD), and 22 controls. HIF-1α expression in >10 % of the cells was regarded as positive staining, and expression <10 % of the cells was considered as negative staining. In the upper GI tract, HIF-1α expression was found in 5/20 CGI patients, but not in controls ( p = 0.08). The sensitivity and specificity of HIF-1α expression for diagnosing CGI were 25 and 84 %, respectively. In the lower GI tract, HIF-1α was expressed in all patients with IC and infectious colitis and in a majority of IBD patients as well as in 7/12 controls. The sensitivity and specificity of HIF-1α for diagnosing IC were 100 and 51 %, respectively. HIF-1α expression was more often ( p = 0.02) observed in patients with histological signs of inflammation in the lower GI tract. HIF-1α is expressed in acute and chronic ischemic tissue, but also in normal colon tissue and inflammatory disorders. [ABSTRACT FROM AUTHOR]

Background & Aims Natural killer ( NK) cells play an important role in the immune response to viruses. As the hepatitis B virus ( HBV) replicates in hepatocytes, examination of the liver of chronic hepatitis B ( CHB) patients is crucial to better understand the role of NK cells in HBV. HBeAg-negative CHB differs in many aspects from HBeAg-positive CHB, and until now little is known about the intrahepatic NK cell response in HBeAg-negative patients. Intrahepatic immune control might be different in HBeAg-negative as compared with HBeAg-positive patients. Methods Liver NK cells were investigated in 21 HBeAg-positive and 35 HBeAg-negative CHB patients. Biopsy specimens were processed for routine histopathology and staging according to Ishak scores. Intrahepatic and blood NK cell frequencies, activation status and function of NK cells were analysed by flow cytometry. Results In HBeAg-negative CHB patients, compared to blood, liver NK cells displayed a more activated phenotype and stimulation further increased the activation status, but production of IFN-γ was markedly less. There was no difference with HBeAg-positive CHB. Only in HBeAg-negative CHB, but not in HBeAg-positive CHB, NK cell activation was inversely correlated with HBsAg levels. Conclusions The present study indicates that liver NK cells of CHB have a higher activation status compared to blood. However, they are not capable to increase cytokine production above levels reached by activated blood NK cells. In HBeAg-negative CHB, the levels of HBsAg may contribute to the incapacity of activated liver NK cells to increase cytokine production. [ABSTRACT FROM AUTHOR]

Acute lower gastrointestinal bleeding (LGIB) is diverse in origin and can be substantial, requiring urgent hemostasis. Hemospray is a promising novel hemostatic agent for upper gastrointestinal bleeding (UGIB). It has been claimed in a small series that the use of Hemospray is also feasible in LGIB. We aimed to expand our knowledge of the application of Hemospray for the treatment of LGIB in a wider range of conditions to further define the optimal patient population for this new therapeutic modality. We analyzed the outcomes of nine unselected consecutive patients with active LGIB treated with Hemospray in two major hospitals in Europe. Initial hemostasis was achieved after Hemospray application in all patients. Rebleeding occurred in two patients (22 %) who were on acetyl salicylic acid and presented with spurting bleeds. These preliminary data show that Hemospray can be effective in the management of LGIB, but suggest cautious use for patients on antithrombotic therapy and spurting bleeds. [ABSTRACT FROM AUTHOR]

LINKED CONTENT This article is linked to McDowell et al paper. To view this article, visit https://doi.org/10.1111/apt.16189 [ABSTRACT FROM AUTHOR]

The article presents a case study of a 31-year-old man who was diagnosed with pulmonary arterial hypertension due to an Abernethy malformation. He had experienced hemoptysis and dyspnea on a hiking trip and was having difficulty keeping up with his companions. The clinical features of the disease, along with its treatment considerations was also discussed.

Fos expression was used to assess whether the proinflammatory cytokine interleukin-1β (IL-1β) activated specific, chemically coded neuronal populations in isolated preparations of guinea pig ileum and colon. Whether the effects of IL-1β were mediated through a prostaglandin pathway and whether IL-1β induced the expression of cyclooxygenase (COX)-2 was also examined. Single- and double-labeling immunohistochemistry was used after treatment of isolated tissues with IL-1β (0.1-10 ng/ml). IL-1β induced Fos expression in enteric neurons and also in enteric glia in the ileum and colon. For enteric neurons, activation was concentration-dependent and sensitive to indomethacin, in both the myenteric and submucosal plexuses in both regions of the gut. The maximum proportion of activated neurons differed between the ileal (∼15%) and colonic (∼42%) myenteric and ileal (∼60%) and colonic (∼75%) submucosal plexuses. The majority of neurons activated in the myenteric plexus of the ileum expressed nitric oxide synthase (NOS) or enkephalin immunoreactivity. In the colon, activated myenteric neurons expressed NOS. In the submucosal plexus of both regions of the gut, the majority of activated neurons were vasoactive intestinal polypeptide (VIP) immunoreactive. After treatment with IL-1β, COX-2 immunoreactivity was detected in the wall of the gut in both neurons and nonneuronal cells. In conclusion, we have found that the proinflammatory cytokine IL-1β specifically activates certain neurochemically defined neural pathways and that these changes may lead to disturbances in motility observed in the inflamed bowel. [ABSTRACT FROM AUTHOR]

CD4+type 1 T regulatory (Tr1) cells have a crucial role in inducing tolerance. Immune regulation by these cells is mainly mediated through the secretion of high amounts of IL-10. Several studies have suggested that this regulatory population may be involved in tumor-mediated immune-suppression. However, direct evidence of a role for Tr1 cells in human solid tumors is lacking. Usingex vivoisolated cells from individuals with hepatocellular carcinoma (HCC;n= 39) or liver metastases from colorectal cancer (LM-CRC;n= 60) we identify a CD4+FoxP3−IL-13−IL-10+T cell population in tumors of individuals with primary or secondary liver cancer that is characterized as Tr1 cells by the expression of CD49b and the lymphocyte activation gene 3 (LAG-3) and strong suppression activity of T cell responses in an IL-10 dependent manner. Importantly, the presence of tumor-infiltrating Tr1 cells is correlated with tumor infiltration of plasmacytoid dendritic cells (pDCs). pDCs exposed to tumor-derived factors enhance IL-10 production by Tr1 cells through up-regulation of the inducible co-stimulatory ligand (ICOS-L). These findings suggest a role for pDCs and ICOS-L in promoting intra-tumoral immunosuppression by Tr1 cells in human liver cancer, which may foster tumor progression and which might interfere with attempts of immunotherapeutic intervention. [ABSTRACT FROM AUTHOR]

Antiphospholipid syndrome is an autoimmune disorder characterized by a hypercoagulable state, leading to arterial and venous thrombosis. We present a 23-year-old patient, suspected of having Budd-Chiari syndrome due to antiphospholipid syndrome, who developed severe and progressive hypoxemia, requiring prolonged mechanical ventilation. After a detailed but unsuccessful workup, a contrast CT scan revealed an occluded superior vena cava and azygos vein-superior vena cava junction and massive right-to-left shunting through a network of systemic to pulmonary venous collaterals. Restoring normal blood flow from the azygos vein into the right atrium by stenting the azygos-superior vena cava junction resolved the hypoxemia immediately. Within the same procedure, the hepatic outflow obstruction was successfully treated by stenting a severe stenosis of the suprahepatic inferior vena cava caused by calcified thrombus. [ABSTRACT FROM AUTHOR]