Mark Pimentel

Cedars-Sinai Medical Center, Los Ángeles, California, United States

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Publications (152)1031.99 Total impact

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    ABSTRACT: Case-control studies are vital for understanding the pathophysiology of gastrointestinal disease. While the definition of disease is clear, the definition of healthy control is not. This is particularly relevant for functional bowel diseases such as irritable bowel syndrome (IBS). In this study, a systematic review formed the basis for a prospective study evaluating the effectiveness of commonly used techniques for defining healthy controls in IBS. A systematic review of the literature was conducted to identify case-control studies involving functional gastrointestinal disorders. "Lack of Rome criteria", self-description as "healthy" and the bowel disease questionnaire (BDQ) were common methods for identifying healthy controls. These 3 methods were then applied to a cohort of 53 non-patient subjects to determine their validity compared to objective outcome measures (7-day stool diary). "Lack of Rome criteria" and "healthy" self-description were the most common methods for identifying healthy control subjects, but many studies failed to describe the methods used. In the prospective study, more subjects were identified as non-healthy using the BDQ than using either lack of Rome criteria (P=0.01) or "healthy" self-description (P=0.026). Furthermore, stool diaries identified several subjects with abnormal stool form and/or frequency which were not identified using lack of Rome criteria or the "healthy" question. Comparisons revealed no agreement (κ) between the different methods for defining healthy controls. The definitions of healthy controls in studies of functional bowel diseases such as IBS are inconsistent. Since functional symptoms are common, a strict definition of "normal" is needed in this area of research.
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    ABSTRACT: Acute gastroenteritis can precipitate irritable bowel syndrome (IBS) in humans. Cytolethal distending toxin is common to all pathogens causing gastroenteritis. Its active subunit, CdtB, is associated with post-infectious bowel changes in a rat model of Campylobacter jejuni infection, including small intestinal bacterial overgrowth (SIBO). To evaluate the role of host antibodies to CdtB in contributing to post-infectious functional sequelae in this rat model. Ileal tissues from non-IBS human subjects, C. jejuni-infected and control rats were immunostained with antibodies to CdtB, c-Kit, S-100, PGP 9.5 and vinculin. Cytosolic and membrane proteins from mouse enteric neuronal cell lysates were immunoprecipitated with anti-CdtB and analyzed by mass spectrometry. ELISAs were performed on rat cardiac serum using CdtB or vinculin as antigens. Anti-CdtB antibodies bound to a cytosolic protein in interstitial cells of Cajal (ICC) and myenteric ganglia in C. jejuni-infected and naïve rats and human subjects. Mass spectrometry identified vinculin, confirmed by co-localization and ELISAs. Anti-CdtB antibodies were higher in C. jejuni-infected rats (1.27 ± 0.15) than controls (1.76 ± 0.12) (P < 0.05), and rats that developed SIBO (2.01 ± 0.18) vs. rats that did not (1.44 ± 0.11) (P = 0.019). Vinculin expression levels were reduced in C. jejuni-infected rats (0.058 ± 0.053) versus controls (0.087 ± 0.023) (P = 0.0001), with greater reductions in rats with two C. jejuni infections (P = 0.0001) and rats that developed SIBO (P = 0.001). Host anti-CdtB antibodies cross-react with vinculin in ICC and myenteric ganglia, required for normal gut motility. Circulating antibody levels and loss of vinculin expression correlate with number of C. jejuni exposures and SIBO, suggesting that effects on vinculin are important in the effects of C. jejuni infection on the host gut.
    Digestive Diseases and Sciences 11/2014; DOI:10.1007/s10620-014-3435-5 · 2.26 Impact Factor
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    ABSTRACT: Gastroesophageal reflux disease (GERD) is commonly reported on esophagram (UGI) studies. The correlation of findings suggestive of GERD on UGI with pH monitoring and high-resolution esophageal manometry (HRM) studies is unclear. We investigate the correlation between reflux on UGI with the findings on pH studies and HRM. Subjects completed a symptom questionnaire before their scheduled study. Data from pH and HRM studies were compared with findings of the UGI. Sixty-five patients were evaluated. Reflux was reported on UGI in 19 of 65 (29.2%). Thirty-six patients had both UGI and pH studies; 22 of 36 (61.1%) had reflux on pH studies. UGI had a false-negative finding in 11 of 20 (55%) with no radiographic evidence of reflux. There was a false-positive finding in five of 16 (31.2%) patients on UGI. There was concordance in 11 of 36 (30.5%). Sixty-three patients had both UGI and HRM; there was positive concordance in eight of 63 (12.7%). Using pH monitoring as the gold standard for GERD, sensitivity was 0.50, specificity 0.64, positive predictive value 0.68, and negative predictive value 0.45 for reflux on UGI. The correlation between reflux reported on UGI and 24-hour pH monitoring is poor. Esophagram (UGI) should be reserved for defining structural defects in the esophagus and not reflux.
    The American surgeon 10/2014; 80(10). · 0.92 Impact Factor
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    P Schoenfeld, M Pimentel
    Alimentary Pharmacology & Therapeutics 07/2014; 40(2):209. DOI:10.1111/apt.12837 · 4.55 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-721. DOI:10.1016/S0016-5085(14)62615-9 · 13.93 Impact Factor
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    ABSTRACT: The antibiotic rifaximin is used to treat non-constipated irritable bowel syndrome (IBS). Methane production is associated with constipation and its severity in constipation-predominant IBS (C-IBS). A previous retrospective study suggested that rifaximin and neomycin was superior to neomycin alone in improving symptoms in methane-positive subjects. To determine the effectiveness of neomycin alone or with rifaximin in improving symptoms in methane-positive C-IBS subjects. A double-blind, randomized, placebo-controlled trial was performed from 2010 to 2013 at three tertiary care centers. Subjects aged 18-65 with C-IBS (Rome II criteria) and breath methane (>3 ppm) meeting the inclusion and exclusion criteria were recruited. Subjects completed a baseline symptom questionnaire rating the severity of abdominal and bowel symptoms on a visual analog scale and were randomized to receive neomycin and placebo or neomycin and rifaximin for 14 days. Symptom severity was assessed by weekly questionnaire for 2 weeks of therapy and 4 additional weeks of follow-up. Thirty-one subjects (16 neomycin and placebo, 15 neomycin and rifaximin) were included in the intention-to-treat analysis. Constipation severity was significantly lower in the neomycin and rifaximin group (28.6 ± 30.8) compared to neomycin alone (61.2 ± 24.1) (P = 0.0042), with greater improvement in constipation (P = 0.007), straining (P = 0.017) and bloating (P = 0.020), but not abdominal pain. In the neomycin and rifaximin group, subjects with methane <3 ppm after treatment reported significantly lower constipation severity (30.5 ± 21.8) than subjects with persistent methane (67.2 ± 32.1) (P = 0.020). Rifaximin plus neomycin is superior to neomycin alone in improving multiple C-IBS symptoms. This effect is predicted by a reduction in breath methane.
    Digestive Diseases and Sciences 05/2014; DOI:10.1007/s10620-014-3157-8 · 2.26 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-679. DOI:10.1016/S0016-5085(14)62469-0 · 13.93 Impact Factor
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    Eric Shah, Mark Pimentel
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    ABSTRACT: Ongoing efforts to improve clinical trial design in irritable bowel syndrome have been hindered by high placebo response rates and ineffective outcome measures. We assessed established strategies to minimize placebo effect as well as the various ap-proaches to placebo effect which can affect trial design. These include genetic markers such as catechol-O-methyltransferase, opioidergic and dopaminergic neurobiologic theory, pre-cebo effect centered on expectancy theory, and side effect unblinding grounded on conditioning theory. We reviewed endpoints used in the study of IBS over the past decade including adequate relief and subjective global relief, emphasizing their weaknesses in fully evaluating the IBS condition, specifically their motility effects based on functional net value and relative benefit-harm based on dropouts due to adverse events. The focus of this review is to highlight ongoing efforts to improve clinical trial design which can lead to better outcomes in a real-world setting.
    Journal of neurogastroenterology and motility 04/2014; 20(2):163-170. DOI:10.5056/jnm.2014.20.2.163 · 2.70 Impact Factor
  • Ali Rezaie, Mark Pimentel
    Gastroenterology 04/2014; DOI:10.1053/j.gastro.2014.04.011 · 12.82 Impact Factor
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    ABSTRACT: Background The efficacy of rifaximin, a nonsystemic, gut-targeted antibiotic for reducing non–constipation-predominant irritable bowel syndrome (non-C IBS) symptoms, has been demonstrated in one phase 2b and two phase 3 randomised, double-blind, placebo-controlled trials, but detailed data about rifaximin safety and tolerability during treatment and subsequent follow-up periods are lacking.AimTo assess and determine the frequency of rifaximin and placebo adverse events (AEs) in phase 2b and phase 3 non-C IBS trials.MethodsA post hoc pooled safety analysis of the phase 2b (rifaximin 275, 550, and 1100 mg twice daily for 2 weeks; 550 mg twice daily for 4 weeks) and phase 3 (rifaximin 550 mg three times daily for 2 weeks) studies was performed. Data on treatment and post-treatment AEs were collected. Patients were followed up for 12 weeks and 10 weeks post-treatment in the phase 2b and phase 3 trials, respectively.ResultsPatients receiving rifaximin (n = 1103) and placebo (n = 829) had a similar incidence of drug-related AEs (12.1% vs. 10.7%), serious AEs (1.5% vs. 2.2%), drug-related AEs resulting in study discontinuation (0.8% vs. 0.8%), gastrointestinal-associated AEs (12.2% vs. 12.2%) and infection-associated AEs (8.5% vs. 9.5%). There were no cases of Clostridium difficile colitis or deaths.Conclusions The safety and tolerability profile of rifaximin during treatment and post-treatment was comparable to placebo. Future research should define the safety and tolerability profile, including risk of C. difficile colitis and microbial antibiotic resistance, with repeated courses of rifaximin in patients with non—constipation-predominant irritable bowel syndrome (ClinicalTrials.gov: NCT00269412, NCT00731679, and NCT00724126).
    Alimentary Pharmacology & Therapeutics 04/2014; 39(10). DOI:10.1111/apt.12735 · 4.55 Impact Factor
  • E. Shah, M. Pimentel
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    ABSTRACT: Background The recent FDA provisional endpoint incorporates a one-tailed measure of improvement for IBS based on the underlying motility complaint. However, motility exists along a spectrum. Patients may experience diarrhoea resulting from therapy for their constipation-predominant IBS (IBS-C) or constipation during treatment for diarrhoea-predominant IBS (IBS-D), but still meet a unidirectional motility-based FDA endpoint. AimTo weigh the reported efficacy of existing therapies based on patient-reported outcomes with negative intestinal side effects in controlled clinical trial data. Methods We analysed the difference between ‘attributable risk’ of efficacy based on number needed to treat (NNT) in the literature and percentage of adverse events (AE) of opposite intestinal complaints in placebo-controlled trials identified through a literature search of IBS trials. This calculation was coined ‘functional net value’ (FNV) or net benefit of the given drug. ResultsFor treating IBS-C, lubiprostone caused diarrhoea in excess of placebo in 3.9% of patients, leading to a FNV of 3.9 percentage units. Linaclotide caused diarrhoea in 15.3% resulting in negative FNV (−1.0 percentage unit). For IBS-D, alosetron and tricyclic anti-depressants caused constipation among a respective 16.9% and 13.0% resulting in a FNV of −3.6 and −0.5 percentage units. Among all therapies, only rifaximin did not cause the adverse event opposite the underlying motility complaint and the drug only had benefit, not detriment. Conclusions Functional net value (FNV) offers a method of evaluating the net benefit of a drug in IBS. Most IBS treatments have a negative effect on IBS that exceeds the benefits.
    Alimentary Pharmacology & Therapeutics 03/2014; 39(9). DOI:10.1111/apt.12692 · 4.55 Impact Factor
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    ABSTRACT: Anaerobic fermentation of the undigested polysaccharide fraction of carbohydrates produces hydrogen in the intestine which is the substrate for methane production by intestinal methanogens. Hydrogen and methane are excreted in the flatus and in breath giving the opportunity to indirectly measure their production using breath testing. Although methane is detected in 30%-50% of the healthy adult population worldwide, its production has been epidemiologically and clinically associated with constipation related diseases, like constipation predominant irritable bowel syndrome and chronic constipation. While a causative relation is not proven yet, there is strong evidence from animal studies that methane delays intestinal transit, possibly acting as a neuromuscular transmitter. This evidence is further supported by the universal finding that methane production (measured by breath test) is associated with delayed transit time in clinical studies. There is also preliminary evidence that antibiotic reduction of methanogens (as evidenced by reduced methane production) predicts the clinical response in terms of symptomatic improvement in patients with constipation predominant irritable bowel syndrome. However, we have not identified yet the mechanism of action of methane on intestinal motility, and since methane production does not account for all constipation associated cases, there is need for high quality clinical trials to examine methane as a biomarker for the diagnosis or as a biomarker that predicts antibiotic treatment response in patients with constipation related disorders.
    Journal of neurogastroenterology and motility 01/2014; 20(1):31-40. DOI:10.5056/jnm.2014.20.1.31 · 2.70 Impact Factor
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    ABSTRACT: Rifaximin, a non-absorbable rifamycin derivative, has published clinical efficacy in the alleviation of symptoms in patients with irritable bowel syndrome (IBS). Small intestinal bacterial overgrowth (SIBO) is associated with the pathogenesis of IBS. This study describes for the first time the antimicrobial effect of rifaximin against SIBO micro-organisms from humans. Fluid was aspirated from the third part of the duodenum from 567 consecutive patients; quantitative cultures diagnosed SIBO in 117 patients (20.6%). A total of 170 aerobic micro-organisms were isolated and the in vitro efficacy of rifaximin was studied by (i) minimum inhibitory concentration (MIC) testing by a microdilution technique and (ii) time-kill assays using bile to simulate the small intestinal environment. At a breakpoint of 32μg/mL, rifaximin inhibited in vitro 85.4% of Escherichia coli, 43.6% of Klebsiella spp., 34.8% of Enterobacter spp., 54.5% of other Enterobacteriaceae spp., 82.6% of non-Enterobacteriaceae Gram-negative spp., 100% of Enterococcus faecalis, 100% of Enterococcus faecium and 100% of Staphylococcus aureus. For the time-kill assays, 11 E. coli, 15 non-E. coli Gram-negative enterobacteria and three E. faecalis isolates were studied. Rifaximin produced a >3log10 decrease in the starting inoculum against most of the tested isolates at 500μg/mL after 24h of growth. The results indicate that rifaximin has a potent effect on specific small bowel flora associated with SIBO. This conclusion should be regarded in light of the considerable time-kill effect at concentrations lower than those achieved in the bowel lumen after administration of conventional doses in humans.
    International journal of antimicrobial agents 01/2014; 43(3). DOI:10.1016/j.ijantimicag.2013.12.008 · 3.03 Impact Factor
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    Eric Shah, Ali Rezaie, Mark Riddle, Mark Pimentel
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    ABSTRACT: Psychological disorders have been associated with irritable bowel syndrome (IBS) for decades in the absence of other objective etiology. However, such associations are also evident in other chronic diseases with more clearly defined pathogenesis such as ulcerative colitis. In this study, we examined the prevalence and severity of psychological disorders among IBS and ulcerative colitis (UC) patients relative to healthy controls.
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    ABSTRACT: Clinical trial design is challenging in irritable bowel syndrome (IBS) due in part to a high placebo effect. We postulated that the mere presence of an adverse event (AE) may unmask patients in clinical trials who are assigned to the active agent, and this may lead to higher reported efficacy. We evaluated therapies receiving at least a Grade 1B from the American College of Gastroenterology Task Force for IBS or which passed recent phase III clinical trials. Therapies with AE data derived from less than 50 patients in each study arm were excluded. Statistically significant excess AE were identified, risk difference was calculated for each AE, and incidence of AE in the treatment arm was reported. We examined the relationship of attributable drug benefit, defined as the reciprocal of number-needed-to-treat found in literature, with various measures of AE incidence. Attributable drug benefit correlated significantly with average AE risk difference, calculated as treatment arm AE incidence minus placebo arm AE incidence (R(2) = 0.70, p = 0.039), and also with highest treatment arm AE incidence (R(2) = 0.70, p = 0.038) for each therapy. There were also trends toward correlation with average treatment arm AE incidence (R(2) = 0.54, p = 0.096) and highest AE risk difference (R(2) = 0.63, p = 0.059) for each therapy. Our study suggests that higher AE incidence on active therapy is associated with more beneficial patient-reported outcomes in IBS clinical trials. This raises the issue of spontaneous unblinding.
    Neurogastroenterology and Motility 12/2013; DOI:10.1111/nmo.12289 · 2.94 Impact Factor
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    ABSTRACT: Humans are host to trillions of microbial colonizers that contribute significantly to human health and disease. Advances in sequencing and other technologies have facilitated dramatic advances in our knowledge of the types and number of organisms colonizing different areas of the body, and while our knowledge of the roles played by the different bacteria, fungi, and archaea has increased dramatically, there remains much to uncover. The microbes that colonize the human gut contribute to vitamin biosynthesis, immune modulation, and the breakdown of otherwise indigestible foods for nutrient harvest. Bacteria and archaea produce various gases as by-products of fermentation, and it is becoming increasingly understood that these gases have both direct and indirect effects on the gut, and may also be used as diagnostic markers, e.g., hydrogen production as measured by breath testing can be used to diagnose bacterial overgrowth. In this article, we review the roles and effects of hydrogen (H2), methane (CH4) and hydrogen sulfide (H2S) in the human gut.
    Current Gastroenterology Reports 12/2013; 15(12):356. DOI:10.1007/s11894-013-0356-y
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    ABSTRACT: In high-resolution manometry lower esophageal sphincter pressure (LESP) is measured relative to intragastric pressure, however Gastric Marker™ (GM) location used to determine resting LESP is not well established with hiatal hernia (HH). We test the hypothesis that measured resting LESP varies with HH based on GM location. Subjects with HH ≥ 2 cm were included. The eSleeve™ was adjusted to span only the LES, excluding the crural diaphragm (CD). Resting LESP was determined by placing the GM below and above the CD (in the position yielding the highest resting LESP). Resting pressure across the lower esophageal sphincter (LES) to CD and pressure in the HH relative to subdiaphragmatic intragastric pressure were also measured. HH ≥ 2 cm was present in 98 patients (mean length 2.7 cm). LESP decreased when GM was moved from below the CD into the HH: respiratory minimum LESP 7.5 ± 1.1 to 3.6 ± 0.9 mmHg; P < 0.001, mean LESP 17.7 ± 1.3 to 13.7 ± 1.1 mmHg; P < 0.001. When the eSleeve encompassed the LES and CD, the respiratory minimum pressure was 12.2 ± 0.9 mmHg and mean pressure was 23.9 ± 1.0 mmHg pressure (P < 0.001 for both). Pressure in the hernia pouch was greater than intragastric pressure: respiratory minimum 3.0 ± 0.7 mmHg and mean 9.0 ± 0.8 mmHg (P < 0.001 for both). pH studies showed a trend toward an association between abnormal distal esophagus acid exposure and lower resting LESP. GM placement in the HH produces lower resting LESPs. This may provide a more physiologic representation of LESP in HH.
    Journal of neurogastroenterology and motility 10/2013; 19(4):479-84. DOI:10.5056/jnm.2013.19.4.479 · 2.70 Impact Factor
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    ABSTRACT: Gastrointestinal tract (GIT) involvement in systemic sclerosis (scleroderma, SSc) is the most common internal complication. This review discusses the outcome measures to capture GIT involvement in clinical care and trials. Patient-reported outcome measures have been validated (UCLA Scleroderma Clinical Trial Consortium GIT 2.0 and NIH PROMIS scales) in SSc-GIT. Multiple objective measures are available to assess mucosal involvement and motility in GIT. However, these need to be validated in SSc for trials. GIT is a common cause of morbidity and has negative impact on quality of life in SSc. Recommendations are given for trial design and evaluation of GIT involvement in SSc.
    Current opinion in rheumatology 09/2013; DOI:10.1097/01.bor.0000434668.32150.e5 · 5.07 Impact Factor
  • Amit H Sachdev, Mark Pimentel
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    ABSTRACT: Small intestinal bacterial overgrowth (SIBO) is defined as the presence of an abnormally high number of coliform bacteria in the small bowel. It is associated with a broad range of predisposing small intestinal motility disorders and with surgical procedures that result in bowel stasis. The most common symptoms associated with SIBO include diarrhea, flatulence, abdominal pain and bloating. Quantitative culture of small bowel contents and a variety of indirect tests have been used over the years in an attempt to facilitate the diagnosis of SIBO. The indirect tests include breath tests and biochemical tests based on bacterial metabolism of a variety of substrates. Unfortunately, there is no single valid test for SIBO, and the accuracy of all current tests remains limited due to the failure of culture to be a gold standard and the lack of standardization of the normal bowel flora in the small intestine. Currently, the ideal approach to treat SIBO is to treat the underlying disease, eradicate overgrowth, and address nutritional deficiencies that may be associated with the development of SIBO.
    09/2013; 4(5):223-31. DOI:10.1177/2040622313496126
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    ABSTRACT: Lymphocytic esophagitis (LE) is a newly described entity characterized histopathologically by peripapillary lymphocytosis (PL) without significant granulocytes (neutrophils and eosinophils). In an initial study, a significant portion of patients with LE had Crohn's disease (CD). A subsequent study revealed LE in one quarter of children with CD. The aim of this study was to test the hypothesis that LE is associated with adult inflammatory bowel disease (IBD) and assess the disease variables that link LE and IBD. Random esophageal biopsies from consecutive adults with CD, ulcerative colitis (UC), or indeterminate colitis (IC) were evaluated. The numbers of lymphocytes, eosinophils, and neutrophils were counted from 3 high-power fields (HPF) in each specimen. Four of 47 patients (8.5%; 3/30 CD, 1/15 UC, and 0/2 IC) had PL (esophageal biopsies with ≥50 lymphocytes/HPF; mean, 100.5±31.1/HPF). A significant number of granulocytes were seen in biopsies from 3 of the 4 patients with PL, leaving 1 who met criteria for LE (PL without significant granulocytes). PL was associated with a higher erythrocyte sedimentation rate (90.3±17.6 mm/hr vs 24.5±3.6 mm/hr; P<.001) and C-reactive protein level (5.5±2.2 mg/dL vs 1.0±0.2 mg/dL; P<.001), with risk ratios of 2.06 (95% confidence interval [CI], 1.45-2.93; P=.031) and 3.56 (95% CI, 2.04-6.19; P=.033), respectively, for elevated values. All patients with PL had a relapsing CD course. The mean Harvey-Bradshaw index (HBI) was higher in these patients (8.5±0.6 vs 4.3±0.7; P=.026), with a risk ratio of 4.78 for moderate-to-severe disease (95% CI, 2.67-8.54; P=.004). We found a less frequent association between IBD and LE than was previously reported. This may be due to differences between pediatric and adult IBD. Alternatively, it may be methodologic because, unlike in previous reports, we evaluated consecutive patients with IBD. PL was associated with elevated inflammatory markers and HBI. These observations suggest that PL may be a marker of disease activity in IBD.
    Gastroenterology and Hepatology 08/2013; 9(8):505-11.

Publication Stats

3k Citations
1,031.99 Total Impact Points

Institutions

  • 2000–2014
    • Cedars-Sinai Medical Center
      • • Cedars Sinai Medical Center
      • • Department of Medicine
      Los Ángeles, California, United States
  • 2001–2013
    • University of California, Los Angeles
      Los Ángeles, California, United States
  • 2010
    • University of Newcastle
      Newcastle, New South Wales, Australia
  • 2007
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      Torrance, California, United States
  • 2005
    • University of Southern California
      • Division of Gastrointestinal and Liver Diseases
      Los Angeles, CA, United States