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Background: Extraintestinal Manifestations (EIMs) are a common and potentially debilitating complication of Inflammatory Bowel Diseases (IBD), sometimes requiring additional treatment beyond those used to control intestinal disease. IBD-associated arthritis (IAA), a form of spondyloarthritis, is associated with several factors including disease location, sex, and IBD type. However, much remains unknown about other clinical factors predicting development of EIMs. Our goal was to identify additional factors associated with IAA. Methods: Participants in the LOCATION-IBD cohort were included in this analysis. We performed univariate and multivariate analysis of demographics, clinical data, and patient-reported outcomes data. Results: The LOCATION-IBD cohort included 182 participants with (n = 53) and without (n = 110) joint EIMs and with joint pain of unclear etiology (n = 19). In a multivariate analysis comparing those with and without joint EIMs, female sex (OR = 2.5, p = 0.014), the presence of concomitant autoimmune and inflammatory disorders (OR = 2.5, p = 0.038), and Crohn's disease (OR = 2.9, p = 0.026) were associated with the presence of joint EIMs. Conclusion: This analysis reveals patients with IAA are more likely to have concomitant autoimmune disorders. Further studies are needed to confirm this association, understand the mechanisms underlying the common pathogenesis of these concurrent disorders, and evaluate their impact on the treatment of IAA. [ABSTRACT FROM AUTHOR]

Data are being generated, collected, and aggregated in massive quantities at exponentially increasing rates. This "big data," discussed in depth in the first section of this two-part series, is increasingly important to understand the nuances of the gastrointestinal tract and its complex interactions and networks involving a host of other organ systems and microbes. Creating and using these datasets correctly requires comprehensive training; however, current instruction in the integration, analysis, and interpretation of big data appears to lag far behind data acquisition. While opportunities exist for those interested in acquiring the requisite training, these appear to be underutilized, in part due to widespread ignorance of their existence. Here, to address these gaps in knowledge, we highlight existing big data learning opportunities and propose innovative approaches to attain such training. We offer suggestions at both the undergraduate and graduate medical education levels for prospective clinical and basic investigators. Lastly, we categorize training opportunities that can be selected to fit specific needs and timeframes. [ABSTRACT FROM AUTHOR]

A multitude of federally and industry-funded efforts are underway to generate and collect human, animal, microbial, and other sources of data on an unprecedented scale; the results are commonly referred to as "big data." Often vaguely defined, big data refers to large and complex datasets consisting of myriad datatypes that can be integrated to address complex questions. Big data offers a wealth of information that can be accessed only by those who pose the right questions and have sufficient technical knowhow and analytical skills. The intersection comprised of the gut-brain axis, the intestinal microbiome and multi-ome, and several other interconnected organ systems poses particular challenges and opportunities for those engaged in gastrointestinal and liver research. Unfortunately, there is currently a shortage of clinicians, scientists, and physician-scientists with the training needed to use and analyze big data at the scale necessary for widespread implementation of precision medicine. Here, we review the importance of training in the use of big data, the perils of insufficient training, and potential solutions that exist or can be developed to address the dearth of individuals in GI and hepatology research with the necessary level of big data expertise. [ABSTRACT FROM AUTHOR]

M3 muscarinic receptors (M3R) modulate β-catenin signaling and colon neoplasia. CDC42/RAC guanine nucleotide exchange factor, βPix, binds to β-catenin in colon cancer cells, augmenting β-catenin transcriptional activity. Using in silico, in vitro, and in vivo approaches, we explored whether these actions are regulated by M3R. At the invasive fronts of murine and human colon cancers, we detected co-localized nuclear expression of βPix and β-catenin in stem cells overexpressing M3R. Using immunohistochemistry, immunoprecipitation, proximity ligand, and fluorescent cell sorting assays in human tissues and established and primary human colon cancer cell cultures, we detected time-dependent M3R agonist-induced cytoplasmic and nuclear association of βPix with β-catenin. βPix knockdown attenuated M3R agonist-induced human colon cancer cell proliferation, migration, invasion, and expression of PTGS2, the gene encoding cyclooxygenase-2, a key player in colon neoplasia. Overexpressing βPix dose-dependently augmented β-catenin binding to the transcription factor TCF4. In a murine model of sporadic colon cancer, advanced neoplasia was attenuated in conditional knockout mice with intestinal epithelial cell deficiency of βPix. Expression levels of β-catenin target genes and proteins relevant to colon neoplasia, including c-Myc and Ptgs2, were reduced in colon tumors from βPix-deficient conditional knockout mice. Targeting the M3R/βPix/β-catenin axis may have therapeutic potential. [ABSTRACT FROM AUTHOR]

Purpose: The bile salt export pump (BSEP), a key player in hepatic bile acid clearance, has been the center of research on drug-induced cholestasis. However, such studies focus primarily on the direct inhibition of BSEP, often overlooking the potential impact of transcriptional repression. This work aims to explore the disruption of bile acid efflux caused by drug-induced BSEP repression. Methods: BSEP activity was analyzed in human primary hepatocytes (HPH) using a traditional biliary-clearance experiment and a modified efflux assay, which includes a 72-h pretreatment prior to efflux measurement. Relative mRNA and protein expressions were examined by RT-PCR and Western blotting, respectively. Results: Metformin concentration-dependently repressed BSEP expression in HPH. Although metformin did not directly inhibit BSEP activity, longer metformin exposure reduced BSEP transport function in HPH by down-regulating BSEP expression. BSEP repression by metformin was found to be AMP-activated protein kinase-independent. Additional screening of 10 reported cholestatic non-BSEP inhibitors revealed that the anti-cancer drug tamoxifen also markedly repressed BSEP expression and reduced BSEP activity in HPH. Conclusions: Repression of BSEP alone is sufficient to disrupt hepatic bile acid efflux. Metformin and tamoxifen appear to be prototypes of a class of BSEP repressors that may cause drug-induced cholestasis through gene repression instead of direct BSEP inhibition. [ABSTRACT FROM AUTHOR]

In up to 50% of people diagnosed with a common ailment, diarrhea-predominant irritable bowel syndrome, diarrhea results from excess spillage of bile acids into the colon—data emerging over the past decade identified deficient release of a gut hormone, fibroblast growth factor 19 (FGF19), and a consequent lack of feedback suppression of bile acid synthesis as the most common cause. 75Selenium homotaurocholic acid (SeHCAT) testing, considered the most sensitive and specific means of identifying individuals with bile acid diarrhea, is unavailable in many countries, including the United States. Other than SeHCAT, tests to diagnose bile acid diarrhea are cumbersome, non-specific, or insufficiently validated; clinicians commonly rely on a therapeutic trial of bile acid binders. Here, we review bile acid synthesis and transport, the pathogenesis of bile acid diarrhea, the reasons clinicians frequently overlook this disorder, including the limitations of currently available tests, and our efforts to develop a novel 19F magnetic resonance imaging (MRI)-based diagnostic approach. We created 19F-labeled bile acid analogues whose in vitro and in vivo transport mimics that of naturally occurring bile acids. Using dual 1H/19F MRI of the gallbladders of live mice fed 19F-labeled bile acid analogues, we were able to differentiate wild-type mice from strains deficient in intestinal expression of a key bile acid transporter, the apical sodium-dependent bile acid transporter (ASBT), or FGF15, the mouse homologue of FGF19. In addition to reviewing our development of 19F-labeled bile acid analogue-MRI to diagnose bile acid diarrhea, we discuss challenges to its clinical implementation. A major limitation is the paucity of clinical MRI facilities equipped with the appropriate coil and software needed to detect 19F signals. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) accounts for ~9% of all cancers in the Veteran population, a fact which has focused a great deal of the attention of the VA's research and development efforts. A field-based meeting of CRC experts was convened to discuss both challenges and opportunities in precision medicine for CRC. This group, designated as the VA Colorectal Cancer Cell-genomics Consortium (VA4C), discussed advances in CRC biology, biomarkers, and imaging for early detection and prevention. There was also a discussion of precision treatment involving fluorescence-guided surgery, targeted chemotherapies and immunotherapies, and personalized cancer treatment approaches. The overarching goal was to identify modalities that might ultimately lead to personalized cancer diagnosis and treatment. This review summarizes the findings of this VA field-based meeting, in which much of the current knowledge on CRC prescreening and treatment was discussed. It was concluded that there is a need and an opportunity to identify new targets for both the prevention of CRC and the development of effective therapies for advanced disease. Also, developing methods integrating genomic testing with tumoroid-based clinical drug response might lead to more accurate diagnosis and prognostication and more effective personalized treatment of CRC. [ABSTRACT FROM AUTHOR]

Background: Lower serum Cr levels in women as compared to men result in underestimation of renal dysfunction and lower model for end-stage liver disease-sodium scores leading to reduced access to liver transplantation in women compared to men with comparable hepatic dysfunction.Aim: The aim of this study was to determine the gender differences in serum Cr, cystatin C, and other endogenous glomerular filtration rate (GFR) biomarkers, measured and estimated GFR, Cr clearance, and Cr production rates.Methods: We measured GFR by iothalamate plasma clearance in 103 patients with cirrhosis and assessed gender differences in GFR, Cr clearance and production rate, serum Cr, cystatin C and other endogenous GFR biomarkers including beta-trace protein, beta-2 microglobulin, and dimethylarginines.Results: Comparison of men and women showed significantly lower values for mean serum Cr (0.97 vs. 0.82 mg/dl, P = 0.023), and Cr production rate (13.37 vs. 11.02 mg/kg/day, P = 0.022). In contrast to the serum Cr and Cr production rate, men and women exhibited no significant differences in the means of serum cystatin C and other GFR biomarkers, measured GFR, GFR estimated using Cr–cystatin C GFR equation for cirrhosis, measured and estimated Cr clearances. After controlling for age, race, weight, height, and GFR, female gender remained associated with lower serum Cr levels (P = 0.003). Serum cystatin C levels were not associated with gender, age, race, weight, height, C-reactive protein, and history of hypothyroidism.Conclusions: Our results suggest that cystatin C and endogenous GFR biomarkers other than Cr, measured GFR, GFR estimated by Cr–cystatin C GFR equation for cirrhosis, measured and estimated Cr clearance minimized between-gender biases in accounting for renal function in patients with cirrhosis. Therefore, serum cystatin C should be measured as a complementary test to serum Cr when renal function is assessed in patients with cirrhosis, particularly in women and those with sarcopenia. [ABSTRACT FROM AUTHOR]

Purpose: To synthesize a trifluorinated bile acid that can be used for F magnetic resonance imaging (MRI) of bile acid enterohepatic circulation, characterize its in vitro transporter affinity, stability, and F-MRI signal, and assess its ability to concentrate in the gallbladder of C57BL/6 mice. Methods: Target compound CA-lys-TFA was synthesized and tested for affinity toward the apical sodium dependent bile acid transporter (hASBT) and the Na+/taurocholate cotransporting polypeptide (hNTCP). In a pilot study, fasted mice were gavaged with vehicle control, 150 mg/kg or 300 mg/kg CA-lys-TFA. CA-lys-TFA in gallbladder, liver and plasma at t = 5 h was quantified. Additionally, a 24-h time course (24 mice across eight time points) was studied using 50 mg/kg CA-lys-TFA. Results: CA-lys-TFA was a potent substrate of hASBT (Kt = 39.4 μM, normalized Vmax = 0.853) and hNTCP (Kt = 8.99 μM, normalized Vmax = 0.281). F MRI phantom imaging showed linear signal-concentration dependence. In vivo studies showed that rapid accumulation of CA-lys-TFA in the gallbladder was maximal within 4-7 h. Conclusions: These findings suggest that CA-lys-TFA, a fluorinated non-radioactive bile acid analogue, has potential for use in MRI to measure in vivo bile acid transport and diagnose bile acid malabsorption and other conditions associated with impaired bile acid transport. [ABSTRACT FROM AUTHOR]

BACKGROUND: Despite increased emphasis on endoscopic performance indicators, e.g., cecal intubation rates, limited data from actual clinical practice have been published. OBJECTIVES: Retrospective database review to determine the rate and documentation of cecal intubation during colonoscopy at the University of Maryland Medical Center. METHODS: We reviewed 5,477 consecutive colonoscopies performed by 10 faculty gastroenterologists at a University hospital over a 6-yr period (March 1, 1999 to February 28, 2005). Unadjusted cecal intubation rates were analyzed as were rates that were adjusted based on the U.S. Multi-Society Task Force on Colorectal Cancer recommendations. We analyzed trends in overall and individual cecal intubation rates, circumstances that impact these rates, and the quality of documentation of cecal intubation. RESULTS: The overall adjusted cecal intubation rate for the entire 6 yr was 90.3%, and increased over the study period with the highest adjusted rate (93.7%) in the most recent year studied. There was no correlation between cecal intubation rate and patient age, gastroenterology fellow involvement, or endoscopist experience and number of procedures/year. In contrast, colon cancer screening, male gender, outpatient colonoscopy, and adequate bowel preparation predicted a higher cecal intubation rate. Written and photographic documentation of cecal intubation improved significantly after 2002. CONCLUSIONS: Our analysis revealed cecal intubation and documentation rates that meet current guidelines, and identified factors that may cause substantial variance in these rates depending on the nature of the practice. The present analysis confirms that computerized databases can be used to assess individual and group cecal intubation and documentation rates on an annual basis, and to make these data available to the public. [ABSTRACT FROM AUTHOR]

Gastrointestinal opportunistic infections, primarily oral and esophageal candidiasis, are common in persons infected with the human immunodeficiency virus (HIV) and contribute significantly to morbidity and mortality. Research early in the AIDS epidemic established a strong association between the presence of oral and esophageal candidiasis in patients complaining of odynophagia, demonstrated the diagnostic efficacy of a therapeutic trial with anti-fungal medicines, and defined the indications for endoscopy in HIV-infected persons with upper gastrointestinal complaints. Resulting diagnostic and treatment strategies with anti-fungal agents were very effective in preventing and treating mycotic infections of the gastrointestinal tract. Now, robust data from the United States and Europe indicate that recent advances in the development and use of highly active anti-retroviral therapy (HAART) are associated with a striking decline in the prevalence of oro-esophageal candidiasis in HIV-infected persons. In addition to developing more effective, safer antiviral agents, an HIV vaccine, and other novel approaches to combating this illness, a major challenge is to provide HAART to those without access to these life-saving drugs. (Am J Gastroenterol 2005;100:1–4) [ABSTRACT FROM AUTHOR]

BACKGROUND: Increasingly, primary care (PC) physicians will be the first to encounter patients with hepatitis C virus (HCV) infection.AIM: To determine opinions and practices of PC residents regarding HCV.METHODS: We administered a one-page questionnaire to 180 PC residents at five U.S. training programs.RESULTS: Respondents were distributed equally across postgraduate year, 83% were U.S. graduates, and 44% had seen>11 (HCV) patients in the past year. Residents tested for HCV in persons with: increased transaminases (83%), history of blood transfusion (46%), multiple tattoos (57%),+ANCA (16%), and alcohol abuse (31%). Sixteen percent of respondents tested all patients. Forty-one percent would vaccinate HCV patients for hepatitis A and 65% for hepatitis B while only 19% and 78% knew the respective vaccination schedules. Although no vaccine is available, 66% recommended vaccination for HCV. Only 37% and 29%, respectively, reported HCV genotype 1 as most common and most resistant to treatment. Fifty-three percent recommend liver biopsy before treating HCV. Only 52% reportedα-interferon (IFN) with ribavirin as initial treatment for HCV while 28% recommend ribavirin or lamivudine alone or combinations of IFN and lamivudine or amantadine. As contraindications to treatment, 33% reported AIDS with PCP infection, 19% coronary artery disease, and 19% suicidal ideation. Sixty-nine percent felt that there was insufficient information on HCV.CONCLUSIONS: Many PC residents lack adequate knowledge of recommended guidelines for the management of HCV. Many test for HCV in inappropriate situations, are unclear regarding available vaccines and their administration, and are uncertain about current treatment. Education of PC residents on guidelines for detection and management of HCV must be improved.(Am J Gastroenterol 2004;99:1720-1725) [ABSTRACT FROM AUTHOR]

Besides their known physiological actions, bile acids are signaling molecules that alter cell function by interacting with muscarinic and nuclear receptors. Bile acid interaction with nuclear receptors modulates bile acid and cholesterol metabolism, whereas the potential consequences of muscarinic receptor activation are much broader. This review examines recent discoveries regarding bile acid interaction with muscarinic receptors. Selective and functional bile acid interaction has been reported with M3 receptors expressed in guinea pig gastric chief cells, human colon cancer cells, and transfected Chinese hamster ovary cells. Interaction of bile acids with chief cells may contribute to mucosal damage and other pathophysiological consequences of bile reflux. Bile acid-induced stimulation of muscarinic receptors on colon cancer cells may contribute to cellular proliferation and neoplasia. Potential consequences of bile acid interaction with muscarinic receptors on gastrointestinal myocytes, biliary epithelium, vascular endothelium and dermal neurons are discussed. Elucidation of molecular mechanisms underlying interaction of bile acids with muscarinic receptors may suggest new treatments for conditions that result from such interactions. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the seroprevalence of Helicobacter pylori and risk factors for infection in gastrointestinal endoscopy personnel and those caring for developmentally disabled individuals. We administered a structured, one-page questionnaire. Helicobacter pylori status was determined serologically. In all, 107 health-care workers participated. Direct patient contact, exposure to gastrointestinal secretions, history of peptic ulcer, and acid-suppressing medicine use were more frequent among those who worked with the developmentally disabled. Seroprevalence of Helicobacter pylori was 24% in endoscopy personnel and 47% among those who cared for the developmentally disabled (P = 0.02). Bed-sharing with a sibling during childhood, working with the developmentally disabled, and direct patient contact were associated with Helicobacter pylori infection; exposure to patients' gastrointestinal secretions was not. We conclude that those caring for developmentally disabled individuals have a higher risk of occupational acquisition of Helicobacter pylori infection than endoscopy personnel. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Primary care physicians have imperfect understanding of current colorectal cancer screening guidelines and recommendations. Furthermore, compliance with colorectal cancer screening by internal medicine residents has been demonstrated to be poor. We sought to identify whether current trainees in internal medicine had adequate understanding of colorectal cancer screening and surveillance and test utilization. METHODS: We applied a structured questionnaire about colorectal cancer screening and the use of fecal occult blood tests to 168 internal medicine residents at four accredited programs in the U.S. They were also asked for recommendations about six hypothetical patients who may have been candidates for screening or surveillance. RESULTS: Seventy-one percent identified 50 yr as the currently recommended age to commence screening in an average-risk individual; 64.3% would begin screening with fecal occult blood testing and flexible sigmoidoscopy and 4.8% with colonoscopy. Most perform fecal occult blood testing on stool obtained at digital rectal exam and without prior dietary restrictions. Many use fecal occult blood testing for indications other than colorectal cancer screening. Only 29% recommended colonoscopy to evaluate a positive fecal occult blood test. Most residents plan to be screened for colorectal neoplasia at the appropriate age; significantly more opted for colonoscopy than recommended it for their patients. CONCLUSIONS: Internal medicine residents have many misperceptions regarding colorectal cancer screening and the utility of the fecal occult blood test. Educational efforts should be directed at internal medicine residents, many of whom plan careers in primary care, where most colorectal cancer screening is currently performed. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Despite recently published national guidelines, many physicians have only limited knowledge about Helicobacter pylori infection. We conducted this study to assess internal medicine residents' knowledge about H. pylori. METHODS: Two hundred and nineteen residents in seven accredited internal medicine training programs completed a self-administered questionnaire on personal demographics and practices related to testing for--and treating--H. pylori infection. RESULTS: Noon conferences (82%), ward teaching (66%), journals (70%), and sponsored symposia (27%) were their major sources of H. pylori-related information. Forty-eight percent had used office-based tests for the infection. Testing for (and treatment of) Helicobacter pylori infection was recommended by 97% (97%) for newly diagnosed duodenal ulcer, but by only 61% (63%) for a past history of duodenal ulcer. Many recommended testing in unproven conditions and might not have offered treatment to an infected patient. A proton pump inhibitor-based triple-drug regimen was the treatment of first choice of 55%; 20% recommended proton pump inhibitor-based dual regimens. Sixty-six percent and 80%, respectively, underestimated the rates of resistance to clarithromycin and metronidazole. In the absence of gastro-intestinal symptoms, 22% would have ordered Helicobacter pylori testing but only 33% of these would undergo treatment if positive. CONCLUSIONS: Internal medicine residents usually test for Helicobacter pylori infection in appropriate conditions, but may not always treat the infection when the result is positive. Most use efficacious treatment regimens although many have inaccurate knowledge of resistance rates, which may adversely influence prescribing. Education should focus on practical issues surrounding Helicobacter pylori testing and treatment such as those contained in the American College of Gastroenterology's 1998 practice guidelines. [ABSTRACT FROM AUTHOR]

In humans, infestation with Strongyloides stercoralis most commonly involves the upper small intestine. We describe a 65-yr-old woman who presented with abdominal pain, weight loss, and hypoalbuminemia, and was found at colonoscopy to have patchy erythema with aphthoid ulcers scattered throughout the large intestine proximal to the splenic flexure. Biopsy of involved areas and examination of the colonic effluent revealed S. stercoralis larvae. Previous reports of colonic involvement with this nematode, and the differential diagnosis of aphthoid ulcers, a newly described lesion associated with S. stercoralis infestation, are discussed. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor regarding the use of thalidomide in patients with hepatitis C.

In humans, acquired copper deficiency anemia is rare. This report describes a 58-yr-old man with metal pica, especially coins, who presented with symptomatic anemia. His workup led to the diagnosis of zinc-induced copper deficiency. We believe that, in this man. leaching of zinc from pennies explained the clinical and laboratory findings. This case demonstrates that health care workers should consider the possibility of zinc-induced copper deficiency when confronted with patients with unexplained anemia who have ingested coins or other zinc-containing metals. [ABSTRACT FROM AUTHOR]

Cholinergic nervous system regulates liver injury. However, the role of M1 muscarinic receptors (M1R) in modulating chronic liver injury is uncertain. To address this gap in knowledge we treated M1R-deficient and WT mice with azoxymethane (AOM) for six weeks and assessed liver injury responses 14 weeks after the last dose of AOM. Compared to AOM-treated WT mice, M1R-deficient mice had attenuated liver nodularity, fibrosis and ductular proliferation, α-SMA staining, and expression of α1 collagen, Tgfβ-R, Pdgf-R, Mmp-2, Timp-1 and Timp-2. In hepatocytes, these findings were associated with reductions of cleaved caspase-3 staining and Tnf-α expression. In response to AOM treatment, M1R-deficient mice mounted a vigorous anti-oxidant response by upregulating Gclc and Nqo1 expression, and attenuating peroxynitrite generation. M1R-deficient mouse livers had increased expression of Trail-R2, a promotor of stellate cell apoptosis; dual staining for TUNNEL and α-SMA revealed increased stellate cells apoptosis in livers from M1R-deficient mice compared to those from WT. Finally, pharmacological inhibition of M1R reduced H2O2-induced hepatocyte apoptosis in vitro. These results indicate that following liver injury, anti-oxidant response in M1R-deficient mice attenuates hepatocyte apoptosis and reduces stellate cell activation, thereby diminishing fibrosis. Therefore, targeting M1R expression and activation in chronic liver injury may provide therapeutic benefit. [ABSTRACT FROM AUTHOR]

Offers observation on the epidemiology of esophageal infections in AIDS. Reason there was significant reluctance on the part of endoscopic personnel, including physicians, to perform endoscopy on AIDS patients; Discussion of surrogate markers for esophageal candidiasis that might obviate the need for upper endoscopy without jeopardizing patient care; Examination of the relationship of oropharyngeal lesions to esophageal findings in several hundred HIV-infected patients seen at Grady Memorial Hospital over a 5-year interval; Role of endoscopic diagnosis in patients with infectious ulcers of the esophagus.

A response by Florence Aslinia and colleagues to a letter to the editor about their article on the various types of endoscopes for colonoscopy is presented.

An abstract of the article "A Survey of IM Residents' and GI Fellows' Knowledge Regarding Evaluation of Abnormal Liver Tests" by Megan M. Dunnigan, Vivek Raj and Jean-Pierre Raufman is presented.