Maternal smoking during pregnancy increases the risk of gut microbiome-associated childhood overweight and obesity.

Childhood obesity is linked to maternal smoking during pregnancy. Gut microbiota may partially mediate this association and could be potential targets for intervention; however, its role is understudied. We included 1,592 infants from the Canadian Healthy Infants Longitudinal Development Cohort. Data on environmental exposure and lifestyle factors were collected prenatally and throughout the first three years. Weight outcomes were measured at one and three years of age. Stool samples collected at 3 and 12 months were analyzed by sequencing the V4 region of 16S rRNA to profile microbial compositions and magnetic resonance spectroscopy to quantify the metabolites. We showed that quitting smoking during pregnancy did not lower the risk of offspring being overweight. However, exclusive breastfeeding until the third month of age may alleviate these risks. We also reported that maternal smoking during pregnancy significantly increased Firmicutes abundance and diversity. We further revealed that Firmicutes diversity mediates the elevated risk of childhood overweight and obesity linked to maternal prenatal smoking. This effect possibly occurs through excessive microbial butyrate production. These findings add to the evidence that women should quit smoking before their pregnancies to prevent microbiome-mediated childhood overweight and obesity risk, and indicate the potential obesogenic role of excessive butyrate production in early life.

Gut microbiome signatures reflect different subtypes of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a heterogeneous condition with multifactorial pathogenesis. We studied deeply phenotyped individuals with microbiota sequencing enrolled in the American Gut Project. The IBS subjects were matched by age, gender, body mass index, geography, and dietary patterns with non-IBS controls. A total of 942 subjects with IBS-Diarrhea (IBS-D), IBS-Constipation (IBS-C), unclassified IBS (IBS-U), and 942 non-IBS controls were included. We compared taxonomic and functional composition of gut microbiota based on 16S sequencing data and linked them with clinical characteristics and dietary factors. Subjects with IBS-D or IBS-U but not IBS-C showed significantly reduced bacterial diversity (Shannon; p < .01). Distinct bacterial signatures were associated with different IBS subtypes, and the related functional changes were related to IBS pathogenesis, such as the increased hydrogen sulfide production pathway in IBS-D and the increased palmitoleate biosynthesis pathway in IBS-C. IBS subjects with depression showed lower abundance of Bifidobacterium, Sutterella, Butyricimonas and higher abundance of Proteus than those without depression. The relative abundance of microbial short-chain fatty acid production pathways was significantly lower in IBS patients with depression than those without depression in all three subtypes. Female, younger age in IBS-D, and older age in IBS-C were associated with more severe microbiota dysbiosis, and distinct dietary factors had significant effects on the gut microbiota in different IBS subtypes. Our analysis identified the compositional uniqueness of gut microbiota in different IBS subtypes. Distinct associations of the gut microbiota with depression in IBS provide insights into shared pathways in disease pathogenesis. These findings highlight the importance of personalized gut microbiome modulation approaches in different subtypes for optimal therapeutic effects.

Gut microbiota composition is associated with SARS-CoV-2 vaccine immunogenicity and adverse events.

OBJECTIVE: The gut microbiota plays a key role in modulating host immune response. We conducted a prospective, observational study to examine gut microbiota composition in association with immune responses and adverse events in adults who have received the inactivated vaccine (CoronaVac; Sinovac) or the mRNA vaccine (BNT162b2; BioNTech; Comirnaty). DESIGN: We performed shotgun metagenomic sequencing in stool samples of 138 COVID-19 vaccinees (37 CoronaVac and 101 BNT162b2 vaccinees) collected at baseline and 1 month after second dose of vaccination. Immune markers were measured by SARS-CoV-2 surrogate virus neutralisation test and spike receptor-binding domain IgG ELISA. RESULTS: We found a significantly lower immune response in recipients of CoronaVac than BNT162b2 vaccines (p<0.05). Bifidobacterium adolescentis was persistently higher in subjects with high neutralising antibodies to CoronaVac vaccine (p=0.023) and their baseline gut microbiome was enriched in pathways related to carbohydrate metabolism (linear discriminant analysis (LDA) scores >2 and p<0.05). Neutralising antibodies in BNT162b2 vaccinees showed a positive correlation with the total abundance of bacteria with flagella and fimbriae including Roseburia faecis (p=0.028). The abundance of Prevotella copri and two Megamonas species were enriched in individuals with fewer adverse events following either of the vaccines indicating that these bacteria may play an anti-inflammatory role in host immune response (LDA scores>3 and p<0.05). CONCLUSION: Our study has identified specific gut microbiota markers in association with improved immune response and reduced adverse events following COVID-19 vaccines. Microbiota-targeted interventions have the potential to complement effectiveness of COVID-19 vaccines.

Erratum: Epigenomic characterization of a p53-regulated 3p22.2 tumor suppressor that inhibits STAT3 phosphorylation via protein docking and is frequently methylated in esophageal and other carcinomas: Erratum.

[This corrects the article DOI: 10.7150/thno.20893.].

Risks of post-colonoscopic polypectomy bleeding and thromboembolism with warfarin and direct oral anticoagulants: a population-based analysis.

BACKGROUND: There were limited data on the risk of post-polypectomy bleeding (PPB) in patients on direct oral anticoagulants (DOAC). We aimed to evaluate the PPB and thromboembolic risks among DOAC and warfarin users in a population-based cohort. METHODS: We performed a territory-wide retrospective cohort study involving patients in Hong Kong from 2012 to 2020. Patients who received an oral anticoagulant and had undergone colonoscopy with polypectomy were identified. Propensity-score models with inverse probability of treatment weighting were developed for the warfarin-DOAC and between-DOAC comparisons. The primary outcome was clinically significant delayed PPB, defined as repeat colonoscopy requiring haemostasis within 30 days. The secondary outcomes were 30-day blood transfusion requirement and new thromboembolic event. RESULTS: Apixaban was associated with lower PPB risk than warfarin (adjusted HR (aHR) 0.39, 95% CI 0.24 to 0.63, p<0.001). Dabigatran (aHR 2.23, 95% CI 1.04 to 4.77, adjusted p (ap)=0.035) and rivaroxaban (aHR 2.72, 95% CI 1.35 to 5.48, ap=0.002) were associated with higher PPB risk than apixaban. In subgroup analysis, apixaban was associated with lower PPB risk in patients aged ≥70 years and patients with right-sided colonic polyps.For thromboembolic events, apixaban was associated with lower risk than warfarin (aHR 0.22, 95% CI 0.11 to 0.45, p<0.001). Dabigatran (aHR 2.60, 95% CI 1.06 to 6.41, ap=0.033) and rivaroxaban (aHR 2.96, 95% CI 1.19 to 7.37, ap =0.013) were associated with higher thromboembolic risk than apixaban. CONCLUSIONS: Apixaban was associated with a significantly lower risk of PPB and thromboembolism than warfarin, dabigatran and rivaroxaban, particularly in older patients with right-sided polyps.

Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19.

OBJECTIVE: Although COVID-19 is primarily a respiratory illness, there is mounting evidence suggesting that the GI tract is involved in this disease. We investigated whether the gut microbiome is linked to disease severity in patients with COVID-19, and whether perturbations in microbiome composition, if any, resolve with clearance of the SARS-CoV-2 virus. METHODS: In this two-hospital cohort study, we obtained blood, stool and patient records from 100 patients with laboratory-confirmed SARS-CoV-2 infection. Serial stool samples were collected from 27 of the 100 patients up to 30 days after clearance of SARS-CoV-2. Gut microbiome compositions were characterised by shotgun sequencing total DNA extracted from stools. Concentrations of inflammatory cytokines and blood markers were measured from plasma. RESULTS: Gut microbiome composition was significantly altered in patients with COVID-19 compared with non-COVID-19 individuals irrespective of whether patients had received medication (p<0.01). Several gut commensals with known immunomodulatory potential such as Faecalibacterium prausnitzii, Eubacterium rectale and bifidobacteria were underrepresented in patients and remained low in samples collected up to 30 days after disease resolution. Moreover, this perturbed composition exhibited stratification with disease severity concordant with elevated concentrations of inflammatory cytokines and blood markers such as C reactive protein, lactate dehydrogenase, aspartate aminotransferase and gamma-glutamyl transferase. CONCLUSION: Associations between gut microbiota composition, levels of cytokines and inflammatory markers in patients with COVID-19 suggest that the gut microbiome is involved in the magnitude of COVID-19 severity possibly via modulating host immune responses. Furthermore, the gut microbiota dysbiosis after disease resolution could contribute to persistent symptoms, highlighting a need to understand how gut microorganisms are involved in inflammation and COVID-19.

Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19.

OBJECTIVE: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in faeces of patients with COVID-19, the activity and infectivity of the virus in the GI tract during disease course is largely unknown. We investigated temporal transcriptional activity of SARS-CoV-2 and its association with longitudinal faecal microbiome alterations in patients with COVID-19. DESIGN: We performed RNA shotgun metagenomics sequencing on serial faecal viral extractions from 15 hospitalised patients with COVID-19. Sequencing coverage of the SARS-CoV-2 genome was quantified. We assessed faecal microbiome composition and microbiome functionality in association with signatures of faecal SARS-CoV-2 infectivity. RESULTS: Seven (46.7%) of 15 patients with COVID-19 had stool positivity for SARS-CoV-2 by viral RNA metagenomic sequencing. Even in the absence of GI manifestations, all seven patients showed strikingly higher coverage (p=0.0261) and density (p=0.0094) of the 3' vs 5' end of SARS-CoV-2 genome in their faecal viral metagenome profile. Faecal viral metagenome of three patients continued to display active viral infection signature (higher 3' vs 5' end coverage) up to 6 days after clearance of SARS-CoV-2 from respiratory samples. Faecal samples with signature of high SARS-CoV-2 infectivity had higher abundances of bacterial species Collinsella aerofaciens, Collinsella tanakaei, Streptococcus infantis, Morganella morganii, and higher functional capacity for nucleotide de novo biosynthesis, amino acid biosynthesis and glycolysis, whereas faecal samples with signature of low-to-none SARS-CoV-2 infectivity had higher abundances of short-chain fatty acid producing bacteria, Parabacteroides merdae, Bacteroides stercoris, Alistipes onderdonkii and Lachnospiraceae bacterium 1_1_57FAA. CONCLUSION: This pilot study provides evidence for active and prolonged 'quiescent' GI infection even in the absence of GI manifestations and after recovery from respiratory infection of SARS-CoV-2. Gut microbiota of patients with active SARS-CoV-2 GI infection was characterised by enrichment of opportunistic pathogens, loss of salutary bacteria and increased functional capacity for nucleotide and amino acid biosynthesis and carbohydrate metabolism.

Effectiveness of reminder strategies on cancer screening adherence: a randomised controlled trial.

BACKGROUND: Few randomised controlled trials (RCTs) have evaluated the different recalling approaches for enhancing adherence to faecal immunochemical test (FIT)-based screening. AIM: The authors evaluated the effectiveness of two telecommunication strategies on improving adherence to yearly FIT screening. DESIGN AND SETTING: A randomised, parallel group trial was performed in a primary care screening practice. METHOD: The authors recruited 629 asymptomatic individuals aged 40-70 years with a negative FIT in 2015 to a population-based screening programme. On participation, they were invited to repeat their second round of FIT in 2016, 12 months after the first test. Each participant was randomly assigned to either interactive telephone reminder (n = 207), short message service reminder (SMS, n = 212), or control, where no additional interventions were delivered after the findings of their first FIT was communicated to the participants (n = 210). Reminders in the intervention groups were delivered 1 month before subjects' expected return. Additional telephone reminders were delivered 2 months after the expected return date to all subjects who defaulted specimen return. The outcomes included rates of FIT collection and specimen return up to 6 months after their expected return. RESULTS: At 6 months, the cumulative FIT collection rate was 95.1%, 90.4%, and 86.5%, respectively, for the telephone, SMS, and control groups (P = 0.010). The corresponding specimen return rate was 94.1%, 90.0%, and 86.0% (P = 0.022). When compared with the control, only subjects in the telephone group were significantly more likely to collect FIT tubes (adjusted odds ratio [AOR] 3.18, 95% confidence interval [CI] = 1.50 to 6.75, P = 0.003) and return completed specimens (AOR = 2.73, 95% CI = 1.35 to 5.53, P = 0.005). CONCLUSION: Interactive telephone reminders are effective at securing previously screened subjects to repeat screening 1 year after a negative finding.

Reduced lysosomal clearance of autophagosomes promotes survival and colonization of Helicobacter pylori.

Evasion of autophagy is key for intracellular survival of bacteria in host cells, but its involvement in persistent infection by Helicobacter pylori, a bacterium identified to invade gastric epithelial cells, remains obscure. The aim of this study was to functionally characterize the role of autophagy in H. pylori infection. Autophagy was assayed in H. pylori-infected human gastric epithelium and the functional role of autophagy was determined via genetic or pharmacological ablation of autophagy in mouse and cell line models of H. pylori infection. Here, we showed that H. pylori inhibited lysosomal function and thereby promoted the accumulation of autophagosomes in gastric epithelial cells. Importantly, inhibiting autophagosome formation by pharmacological inhibitors or genetic ablation of BECN1 or ATG5 reduced H. pylori intracellular survival, whereas inhibition of lysosomal functions exerted an opposite effect. Further experiments demonstrated that H. pylori inhibited lysosomal acidification and the retrograde trafficking of mannose-6-phosphate receptors, both of which are known to positively regulate lysosomal function. We conclude that H. pylori subverts autophagy into a pro-survival mechanism through inhibition of lysosomal clearance of autophagosomes. Disruption of autophagosome formation offers a novel strategy to reduce H. pylori colonization in human stomachs. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Epigenomic characterization of a p53-regulated 3p22.2 tumor suppressor that inhibits STAT3 phosphorylation via protein docking and is frequently methylated in esophageal and other carcinomas.

Rationale: Oncogenic STAT3 signaling activation and 3p22-21.3 locus alteration are common in multiple tumors, especially carcinomas of the nasopharynx, esophagus and lung. Whether these two events are linked remains unclear. Our CpG methylome analysis identified a 3p22.2 gene, DLEC1, as a methylated target in esophageal squamous cell (ESCC), nasopharyngeal (NPC) and lung carcinomas. Thus, we further characterized its epigenetic abnormalities and functions. Methods: CpG methylomes were established by methylated DNA immunoprecipitation. Promoter methylation was analyzed by methylation-specific PCR and bisulfite genomic sequencing. DLEC1 expression and clinical significance were analyzed using TCGA database. DLEC1 functions were analyzed by transfections followed by various cell biology assays. Protein-protein interaction was assessed by docking, Western blot and immunoprecipitation analyses. Results: We defined the DLEC1 promoter within a CpG island and p53-regulated. DLEC1 was frequently downregulated in ESCC, lung and NPC cell lines and primary tumors, but was readily expressed in normal tissues and immortalized normal epithelial cells, with mutations rarely detected. DLEC1 methylation was frequently detected in ESCC tumors and correlated with lymph node metastasis, tumor recurrence and progression, with DLEC1 as the most frequently methylated among the established 3p22.2 tumor suppressors (RASSF1A, PLCD1 and ZMYND10/BLU). DLEC1 inhibits carcinoma cell growth through inducing cell cycle arrest and apoptosis, and also suppresses cell metastasis by reversing epithelial-mesenchymal transition (EMT) and cell stemness. Moreover, DLEC1 represses oncogenic signaling including JAK/STAT3, MAPK/ERK, Wnt/ß-catenin and AKT pathways in multiple carcinoma types. Particularly, DLEC1 inhibits IL-6-induced STAT3 phosphorylation in a dose-dependent manner. DLEC1 contains three YXXQ motifs and forms a protein complex with STAT3 via protein docking, which blocks STAT3-JAK2 interaction and STAT3 phosphorylation. IL-6 stimulation enhances the binding of DLEC1 with STAT3, which diminishes their interaction with JAK2 and further leads to decreased STAT3 phosphorylation. The YXXQ motifs of DLEC1 are crucial for its inhibition of STAT3 phosphorylation, and disruption of these motifs restores STAT3 phosphorylation through abolishing DLEC1 binding to STAT3. Conclusions: Our study demonstrates, for the first time, predominant epigenetic silencing of DLEC1 in ESCC, and a novel mechanistic link of epigenetic DLEC1 disruption with oncogenic STAT3 signaling in multiple carcinomas.

Epigenomic and Functional Characterization of Junctophilin 3 (JPH3) as a Novel Tumor Suppressor Being Frequently Inactivated by Promoter CpG Methylation in Digestive Cancers.

Junctophilin (JPH) proteins stabilize junctional membrane complexes between plasma membrane and endoplasmic reticulum, also implicated in some human diseases. JPH3 mutations are linked to Huntington's disease-like 2 syndrome. Through epigenomic study of a colon cancer cell line pair (HCT116 and DKO), we identified JPH3 as a methylated novel tumor suppressor gene (TSG) candidate at 16q24. We further studied its epigenetic alterations and functions in digestive tumorigenesis. JPH3 expression at the RNA level was found to be frequently silenced or reduced in colorectal and gastric cancers due to its promoter CpG methylation, which is associated with tumor progression and poor survival of digestive cancer patients. Ectopic expression of JPH3 inhibited tumor cell growth in vitro and in vivo. JPH3 expression upregulated the cytosolic Ca2+ levels, and unfolded protein response gene expression upon endoplasmic reticulum stress. JPH3 also induced calpain activation and subsequent mitochondrial membrane depolarization and cell apoptosis. Thus, JPH3 was identified as a novel TSG methylated in colorectal and gastric tumors which promotes mitochondrial-mediated apoptosis, also as a potential metastasis and survival biomarker for digestive cancers.

Epigenetic inactivation of the CpG demethylase TET1 as a DNA methylation feedback loop in human cancers.

Promoter CpG methylation is a fundamental regulatory process of gene expression. TET proteins are active CpG demethylases converting 5-methylcytosine to 5-hydroxymethylcytosine, with loss of 5 hmC as an epigenetic hallmark of cancers, indicating critical roles of TET proteins in epigenetic tumorigenesis. Through analysis of tumor methylomes, we discovered TET1 as a methylated target, and further confirmed its frequent downregulation/methylation in cell lines and primary tumors of multiple carcinomas and lymphomas, including nasopharyngeal, esophageal, gastric, colorectal, renal, breast and cervical carcinomas, as well as non-Hodgkin, Hodgkin and nasal natural killer/T-cell lymphomas, although all three TET family genes are ubiquitously expressed in normal tissues. Ectopic expression of TET1 catalytic domain suppressed colony formation and induced apoptosis of tumor cells of multiple tissue types, supporting its role as a broad bona fide tumor suppressor. Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9. As only infrequent mutations of TET1 have been reported, compared to TET2, epigenetic silencing therefore appears to be the dominant mechanism for TET1 inactivation in cancers, which also forms a feedback loop of CpG methylation during tumorigenesis.

Carbonic anhydrase IV inhibits colon cancer development by inhibiting the Wnt signalling pathway through targeting the WTAP-WT1-TBL1 axis.

OBJECTIVE: We found that carbonic anhydrase IV (CA4), a member of the carbonic anhydrases, is silenced in colorectal cancer (CRC). We analysed its epigenetic inactivation, biological effects and prognostic significance in CRC. DESIGN: The biological functions of CA4 were determined by in vitro and in vivo tumorigenicity assays. The CA4 co-operator was identified by immunoprecipitation and mass spectrometry. CA4 downstream effectors and signalling pathways were elucidated by promoter luciferase assay, electrophoretic mobility shift assay and chromatin immunoprecipitation. The clinical impact of CA4 was assessed in 115 patients with CRC. RESULTS: CA4 was silenced in all nine CRC cell lines and 92.6% of CRC tumours. The promoter hypermethylation contributed to the inactivation of CA4, and it was detected in 75.7% of the patients with CRC. After a median follow-up of 49.3 months, multivariate analysis showed that the patients with CA4 hypermethylation had a recurrence of Stage II/III CRC. The re-expression of CA4 inhibited cell proliferation, induced apoptosis and cell cycle arrest in the G1 phase. CA4 inhibited the activity of the Wnt signalling pathway and mediated the degradation of ß-catenin. CA4 interacted with Wilms' tumour 1-associating protein (WTAP) and induced WTAP protein degradation through polyubiquitination. Moreover, CA4 promoted the transcriptional activity of Wilms' tumour 1 (WT1), an antagonist of the Wnt pathway, which resulted in the induction of transducin ß-like protein 1 (TBL1) and the degradation of ß-catenin. CONCLUSIONS: CA4 is a novel tumour suppressor in CRC through the inhibition of the Wnt signalling pathway by targeting the WTAP-WT1-TBL1 axis. CA4 methylation may serve as an independent biomarker for the recurrence of CRC.

Characterization of the nasopharyngeal carcinoma methylome identifies aberrant disruption of key signaling pathways and methylated tumor suppressor genes.

AIMS: Nasopharyngeal carcinoma (NPC) is a common tumor consistently associated with Epstein-Barr virus infection and prevalent in South China, including Hong Kong, and southeast Asia. Current genomic sequencing studies found only rare mutations in NPC, indicating its critical epigenetic etiology, while no epigenome exists for NPC as yet. MATERIALS & METHODS: We profiled the methylomes of NPC cell lines and primary tumors, together with normal nasopharyngeal epithelial cells, using methylated DNA immunoprecipitation (MeDIP). RESULTS: We observed extensive, genome-wide methylation of cellular genes. Epigenetic disruption of Wnt, MAPK, TGF-ß and Hedgehog signaling pathways was detected. Methylation of Wnt signaling regulators (SFRP1, 2, 4 and 5, DACT2, DKK2 and DKK3) was frequently detected in tumor and nasal swab samples from NPC patients. Functional studies showed that these genes are bona fide tumor-suppressor genes for NPC. CONCLUSION: The NPC methylome shows a special high-degree CpG methylation epigenotype, similar to the Epstein-Barr virus-infected gastric cancer, indicating a critical epigenetic etiology for NPC pathogenesis.

microRNA-139-5p exerts tumor suppressor function by targeting NOTCH1 in colorectal cancer.

BACKGROUND: miR-139-5p was identified to be significantly down-regulated in colon tumor tissues by miRNA array. We aimed to clarify its biological function, molecular mechanisms and direct target gene in colorectal cancer (CRC). METHODS: The biological function of miR-139-5p was examined by cell growth, cell cycle and apoptosis analysis in vitro and in vivo. miR-139-5p target gene and signaling pathway was identified by luciferase activity assay and western blot. RESULTS: miR-139-5p was significantly down-regulated in primary tumor tissues (P < 0.0001). Ectopic expression of miR-139-5p in colon cancer cell lines significantly suppressed cell growth as evidenced by cell viability assay (P < 0.001) and colony formation assay (P < 0.01) and in xenograft tumor growth in nude mice (P < 0.01). miR-139-5p induced apoptosis (P < 0.01), concomitantly with up-regulation of key apoptosis genes including cleaved caspase-8, caspase-3, caspase-7 and PARP. miR-139-5p also caused cell cycle arrest in G0/G1 phase (P < 0.01), with upregulation of key G0/G1 phase regulators p21Cip1/Waf1 and p27Kip1. Moreover, miR-139-5p inhibited cellular migration (P < 0.001) and invasiveness (P < 0.001) through the inhibition of matrix metalloproteinases (MMP)7 and MMP9. Oncogene NOTCH1 was revealed to be a putative target of miR-139-5p, which was inversely correlated with miR-139-5p expression (r = -0.3862, P = 0.0002). CONCLUSIONS: miR-139-5p plays a pivotal role in colon cancer through inhibiting cell proliferation, metastasis, and promoting apoptosis and cell cycle arrest by targeting oncogenic NOTCH1.

Non-alcoholic fatty liver disease: spectral patterns observed from an in vivo phosphorus magnetic resonance spectroscopy study.

BACKGROUND & AIMS: Liver biopsy is the gold standard for diagnosing non-alcoholic fatty liver disease (NAFLD) but with practical constraints. Phosphorus magnetic resonance spectroscopy ((31)P-MRS) allows in vivo assessment of hepatocellular metabolism and has shown potential for biochemical differentiation in diffuse liver disease. Our aims were to describe spectroscopic signatures in biopsy-proven NAFLD and to determine diagnostic performance of (31)P-MRS for non-alcoholic steatohepatitis (NASH). METHODS: (31)P-MRS was performed in 151 subjects, comprised of healthy controls (n=19) and NAFLD patients with non-NASH (n=37) and NASH (n=95). Signal intensity ratios for phosphomonoesters (PME) including phosphoethanolamine (PE), phosphodiesters (PDE) including glycerophosphocholine (GPC), total nucleotide triphosphate (NTP) including α-NTP, and inorganic phosphate (Pi), expressed relative to total phosphate (TP) or [PME+PDE] and converted to percentage, were obtained. RESULTS: Compared to controls, both NAFLD groups had increased PDE/TP (p<0.001) and decreased Pi/TP (p=0.011). Non-NASH patients showed decreased PE/[PME+PDE] (p=0.048), increased GPC/[PME+PDE] (p<0.001), and normal NTP/TP and α-NTP/TP. Whereas, NASH patients had normal PE/[PME+PDE] and GPC/[PME+PDE], but decreased NTP/TP (p=0.004) and α-NTP/TP (p<0.001). The latter was significantly different between non-NASH and NASH (p=0.047) and selected as discriminating parameter, with area under the receiver-operating characteristics curve of 0.71 (95% confidence interval, 0.62-0.79). An α-NTP/TP cutoff of 16.36% gave 91% sensitivity and cutoff of 10.57% gave 91% specificity for NASH. CONCLUSIONS: (31)P-MRS shows distinct biochemical changes in different NAFLD states, and has fair diagnostic accuracy for NASH.

Infections and inflammatory bowel disease: challenges in Asia.

The diagnosis and management of inflammatory bowel disease (IBD) in Asia can be challenging as certain infections can mimic IBD and lead to a misdiagnosis. Colitis can be caused by bacterial infections, ileitis can result from Yersinia and Salmonella infections and ileocolonic ulcers can be seen in intestinal tuberculosis and amebiasis. In addition, cytomegalovirus and Clostridium difficile infection may mimic a flare of IBD and their presence is associated with an increased risk of colectomy and mortality. Because of the increasing use of corticosteroids, immunosuppressive drugs and biological agents the risk of opportunistic infection and the reactivation of latent infection including tuberculosis and hepatitis B, are also higher in IBD patients. Screening and prevention of infection, timely vaccination and the education of the patient is paramount before initiating immunosuppressive drugs. The role of the physician lies not only in the diagnosis and management of IBD but also in the ability to prevent, recognize and treat infections.

Statements of the Malaysian Society of Gastroenterology & Hepatology and the National Heart Association of Malaysia task force 2012 working party on the use of antiplatelet therapy and proton pump inhibitors in the prevention of gastrointestinal bleeding.

The working party statements aim to provide evidence and guidelines to practising doctors on the use of antiplatelet therapy and proton pump inhibitors (PPIs) in patients with cardiovascular risk as well as those at risk of gastrointestinal (GI) bleeding. Balancing the GI and cardiovascular risk and benefits of antiplatelet therapy and PPIs may sometimes pose a significant challenge to doctors. Concomitant use of anti-secretory medications has been shown to reduce the risk of GI bleeding but concerns have been raised on the potential interaction of PPIs and clopidogrel. Many new data have emerged on this topic but some can be confusing and at times controversial. These statements examined the supporting evidence in four main areas: rationale for antiplatelet therapy, risk factors of GI bleeding, PPI-clopidogrel interactions and timing for recommencing antiplatelet therapy after GI bleeding, and made appropriate recommendations.

Endoscopic submucosal dissection for colonic lesions: why and how should we do it?

Endoscopic submucosal dissection (ESD) is a safe and effective alternative to surgery for large non-polypoid colonic lesions and early colorectal carcinoma. In this article, we discuss the development, efficacy and safety of ESD. As the incidence of colorectal cancer is rapidly increasing in Asia, we advocate standardization of ESD program, including patient selection, hardware prerequisites, and training of operators.