The roles of the NADPH phagocyte oxidase (phox) and inducible nitric oxide synthase (iNOS) in host resistance to virulent Salmonella typhimurium were investigated in gp91phox−/−, iNOS−/−, and congenic wild-type mice. Although both gp91phox−/− and iNOS−/− mice demonstrated increased susceptibility to infection with S. typhimurium compared with wild-type mice, the kinetics of bacterial replication were dramatically different in the gp91phox−/− and iNOS−/− mouse strains. Greater bacterial numbers were present in the spleens and livers of gp91phox−/− mice compared with C57BL/6 controls as early as day 1 of infection, and all of the gp91phox−/− mice succumbed to infection within 5 d. In contrast, an increased bacterial burden was detected within reticuloendothelial organs of iNOS−/− mice only beyond the first week of infection. Influx of inflammatory CD11b+ cells, granuloma formation, and serum interferon γ levels were unimpaired in iNOS−/− mice, but the iNOS-deficient granulomas were unable to limit bacterial replication. The NADPH phagocye oxidase and iNOS are both required for host resistance to wild-type Salmonella, but appear to operate principally at different stages of infection.
Intrahepatic cholestasis of pregnancy (ICP) has a complex aetiology. Genes mutated in progressive familial intrahepatic cholestasis (PFIC) have been implicated in disease pathogenesis. Heterozygous mutations of these canalicular transporters occur in a subset of ICP cases. Genetic variation around the bile acid sensor FXR (NR1H4) has also been described, and a susceptibility allele (444A, ABCB11) identified. We expanded genetic analysis of ICP by investigating of common variation around six loci with biological plausibility for a role in ICP: ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, FGF19. 563 ICP patients of white western European origin together with 642 controls from the Rotunda Thrombophilia study were analysed. 83 markers were selected from the HapMap dataset (Tagger, Haploview 4.1, b22) capturing the majority of common genetic variation around the loci. Genotyping was performed by a proprietary allelic discrimination assay. Following QC including conformation of Hardy-Weinberg equilibrium (HWE), SNP data and haplotyes were analysed (trend testing, haplostats). 78 markers passed quality control and HWE tests. Single SNP analysis identified six SNPs in ABCB11 and six in ABCB4 that showed significant evidence of association. The minimum Bonferroni corrected p-value for ABCB11 was 3.7×10–4 (rs3815676) and for ABCB4 3.4×10–7 (rs2109505). Haplotype analysis identified significant differences in frequencies between cases and controls for ABCB4 (p=9.6×10–6) and ABCB11 (p=0.0036). Our analysis of a large cohort of ICP cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, expanding on the genetic factors known to play a role in susceptibility to this disease.
Purpose of review Cholangiocarcinoma is the second most common primary liver tumour, worldwide. Its incidence and mortality are rising, the cause of which is unclear. Cholangiocarcinoma usually presents late, with obstructive jaundice, malaise, weight loss and discomfort. For most patients, complete surgical resection, the only potential cure, is not possible. Survival length and palliation of symptoms become paramount and often this centres on restoration of bile flow to relieve jaundice and improve general well being. There are now multiple options to achieve this goal and emerging evidence supports certain methods over others. Recent findings For advanced cholangiocarcinoma, endoscopic biliary stenting has become an established treatment. Recent evidence supports the use of metal stents over plastic to improve survival and stent patency. Locoregional therapies, such as radiofrequency ablation, transarterial chemoembolisation and radiotherapy have shown promise in preliminary studies. Landmark studies have established the use of cisplatin and gemcitabine as first-line chemotherapy in advanced cholangiocarcinoma. Summary The rise in incidence of advanced cholangiocarcinoma, has necessitated the development of novel therapies to optimize palliation. This article discusses the current options for palliation of cholangiocarcinoma, including stenting, locoregional therapy, surgery, endoscopic ultrasound and palliative chemotherapy.
Acute pancreatitis is a relatively common and potentially fatal condition, but the presenting symptoms are non-specific and diagnosis relies largely on the measurement of amylase activity by the hospital clinical laboratory. In this work we develop a point of care test for pancreatitis measuring concentration of secretory phospholipase A2 group IB (sPLA2-IB). Novel antibodies for sPLA2-IB were raised and used to design an ELISA and a lateral flow device (LFD) for the point of care measurement of sPLA2-IB concentration, which was compared to pancreatic amylase activity, lipase activity, and sPLA2-IB activity in 153 serum samples. 98 of these samples were obtained from the pathology unit of a major hospital and classified retrospectively according to presence or absence of pancreatitis, and the remaining 55 were obtained from commercial sources to serve as high lipase (n = 20), CA19-9 positive (n = 15), and healthy (n = 20) controls. sPLA2-IB concentration correlated well with the serum activity of both amylase and lipase, and performed at least as well as either markers in the differentiation of pancreatitis from controls.
There is no clinically applicable biomarker for surveillance of hepatocellular carcinoma (HCC), because the sensitivity of serum alpha-fetoprotein (AFP) is too low for this purpose. Here, we determined the diagnostic performance of a panel of urinary metabolites of HCC patients from West Africa. Urine samples were collected from Nigerian and Gambian patients recruited on the case-control platform of the Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) program. Urinary proton nuclear magnetic resonance ((1) H-NMR) spectroscopy was used to metabolically phenotype 290 subjects: 63 with HCC; 32 with cirrhosis (Cir); 107 with noncirrhotic liver disease (DC); and 88 normal control (NC) healthy volunteers. Urine samples from a further cohort of 463 subjects (141 HCC, 56 Cir, 178 DC, and 88 NC) were analyzed, the results of which validated the initial cohort. The urinary metabotype of patients with HCC was distinct from those with Cir, DC, and NC with areas under the receiver operating characteristic (AUROC) curves of 0.86 (0.78-0.94), 0.93 (0.89-0.97), and 0.89 (0.80-0.98) in the training set and 0.81 (0.73-0.89), 0.96 (0.94-0.99), and 0.90 (0.85-0.96), respectively, in the validation cohort. A urinary metabolite panel, comprising inosine, indole-3-acetate, galactose, and an N-acetylated amino acid (NAA), showed a high sensitivity (86.9% [75.8-94.2]) and specificity (90.3% [74.2-98.0]) in the discrimination of HCC from cirrhosis, a finding that was corroborated in a validation cohort (AUROC: urinary panel = 0.72; AFP = 0.58). Metabolites that were significantly increased in urine of HCC patients, and which correlated with clinical stage of HCC, were NAA, dimethylglycine, 1-methylnicotinamide, methionine, acetylcarnitine, 2-oxoglutarate, choline, and creatine. The urinary metabotyping of this West African cohort identified and validated a metabolite panel that diagnostically outperforms serum AFP.
Summary Cholangiocarcinoma is the second most common liver cancer in the world. The aetiology of the disease is diverse incorporating a variety of conditions leading to biliary stasis, biliary and liver inflammation, but a large number of cases still occur in the absence of established risk factors. Its incidence and mortality is increasing, which has intensified the search for alternative aetiological agents and pathogenetic mechanisms. Chronic infection with hepatitis B and hepatitis C viruses are the primary risk factor for hepatocellular cancer. This review focuses on the epidemiological evidence of a role for these viruses in cholangiocarcinoma and the pathogenetic mechanisms that might be involved.
Developing countries shoulder a considerable burden of gastroenterological disease. Infectious diseases in particular cause enormous morbidity and mortality. Diseases which afflict both western and developing countries are often seen in more florid forms in poorer countries. Innovative techniques continuously improve and update gastroenterological practice. However, advances in diagnosis and treatment which are commonplace in the West, have yet to reach many developing countries. Clinical guidelines, based on these advances and collated in resource-rich environments, lose their relevance outside these settings. In this two-part review, we first highlight the global burden of gastroenterological disease in three major areas: diarrhoeal diseases, hepatitis B, and Helicobacter pylori. Recent progress in their management is explored, with consideration of future solutions. The second part of the review focuses on the delivery of clinical services in developing countries. Inadequate numbers of healthcare workers hamper efforts to combat gastroenterological disease. Reasons for this shortage are examined, along with possibilities for increased specialist training. Endoscopy services, the mainstay of gastroenterology in the West, are in their infancy in many developing countries. The challenges faced by those setting up a service are illustrated by the example of a Nigerian endoscopy unit. Finally, we highlight the limited scope of many clinical guidelines produced in western countries. Guidelines which take account of resource limitations in the form of "cascades" are advocated in order to make these guidelines truly global. Recognition of the different working conditions facing practitioners worldwide is an important step towards narrowing the gap between gastroenterology in rich and poor countries.
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