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Abstract

Eosinophilic Esophagitis: Stricture Risk and Molecular DiagnosisThe incidence of eosinophilic esophagitis (EoE), a chronic immune-mediated esophageal disorder characterized by esophageal dysfunction, primarily dysphagia leading to food impaction, and eosinophil-predominant inflammation on biopsy, has significantly increased since its initial description over 2 decades ago. In this issue of Gastroenterology (accompanied by an editorial), 2 studies address the diagnosis and natural history of this emerging yet still enigmatic disorder.The diagnosis of EoE currently rests on the histologic analysis of esophageal biopsies in concert with clinical symptoms of esophageal dysfunction. However, esophageal eosinophilia is not specific to EoE. Taking advantage of the discovery of a uniquely conserved gene expression profile in patients with EoE, Wen et al developed a molecular EoE diagnostic panel (EDP) using a quantitative polymerase chain reaction array of 94 representative EoE genes and 2 housekeeping controls to better diagnose EoE. This EDP identified pediatric and adult patients with EoE with high sensitivity (∼96%) and specificity (∼98%; Figure 1). The EDP also discriminated between patients with EoE in remission from normal controls. Furthermore, in patients with <15 eosinophils/high-power field, the EDP identified a subset of patients at risk for developing active EoE. Finally, the EDP distinguished patients with EoE from patients with gastroesophageal reflux disease and nonerosive reflux disease. Comparable results were obtained whether fresh or formalin-fixed paraffin-embedded tissue was used. These findings provide proof of principle for the use of a tissue-based molecular test in the diagnosis of EoE and highlight the advantages of such techniques over histologic analysis.The endoscopic features of EoE have been categorized as either inflammatory, characterized by whitish exudates, edema, and linear furrows, or fibrotic, characterized by rings, strictures, and crepe paper esophagus, although most patients present with an overlap of these features. Schoepfer et al perform a retrospective analysis of the relationship between the duration of untreated disease and the risk of stricture formation in 200 patients with EoE. The median diagnostic delay (time from first symptoms to diagnosis) was 6 years and was longest in patients ≤20 years old, and decreased with increasing age. Inflammatory features were present in 79.5%, fibrotic features in 60%, and strictures in 37.5% of patients at the time of EoE diagnosis. The prevalence of fibrotic features at the time of EoE diagnosis with or without inflammatory features increased with increasing duration of diagnostic delay from 46.5% in patients with a diagnostic delay of ≤2 years compared with 87.5% in patients with a diagnostic delay of >20 years. In addition, the prevalence of esophageal strictures correlated with the presence of fibrotic features and the duration of diagnostic delay, with a prevalence of strictures of 17.2% in patients with a diagnostic delay of ≤2 years compared with 70.8% in patients with a diagnostic delay of >20 years. The duration of diagnostic delay was the only risk factor associated with the presence of strictures at the time of EoE diagnosis. In contrast, the prevalence of inflammatory features alone decreased with increasing duration of diagnostic delay. These findings help to define the natural history of untreated EoE and support measures to reduce the diagnostic delay in patients with this chronic esophageal disorder.See 1230 and 1289; editorial on page 1186.IBS: Emotional Learning and Rome III Criteria ValidationIrritable bowel syndrome (IBS) is commonly seen in gastroenterology practices with a global prevalence of about 20%. It is characterized by abdominal pain with changes in stool consistency and frequency. IBS is a functional bowel disorder whose diagnosis can be established only when other organic gastrointestinal diseases are absent. As a result, patient evaluation commonly employs costly diagnostic interventions such as colonoscopy, esophagoduodenoscopy, and imaging studies. The overlap of IBS symptoms with those of other organic gastrointestinal diseases contributes to the associated high costs of a diagnostic evaluation. Thus, symptom-based criteria have been developed for the purpose of differentiating patients with IBS from those with organic diseases. These have included the Manning, Rome I, Rome II, and Rome III criteria. A missing element underlying many of the criteria is the absence of adequate clinical validation. In this issue of Gastroenterology, Ford et al studied 1848 adult patients from 2 hospitals in Hamilton, Canada. The Rome III questionnaire was applied to the patients, followed by a colonoscopy with biopsies. If the patients' celiac disease serologies were positive, an upper endoscopy was also performed. The criteria used for IBS in this study consisted of lower abdominal pain at least once a week, altered bowel habits, and the absence of evidence for organic disease on endoscopy and pathology.The results indicated that Rome III performed less well than either the Rome I and II criteria (Table 1). All criteria studied to date, however, exhibit positive predictive values of <50%, which underscores the need for developing diagnostic strategies for IBS that are without the risk and expense of current approaches.Table 1Criteria for the Diagnosis of IBSSensitivity (95% CI; %)Specificity (95% CI; %)Positive predictive value (95% CI; %)Negative predictive value (95% CI)Positive likelihood ratio (95% CI; %)Negative likelihood ratio (95% CI)Rome III17.4 (13.9–21.5)95.6 (94.4–96.5)49.6 (42.0–58.7)82.1 (80.0–83.6)3.92 (2.85–5.38)0.86 (0.83–0.91)Rome II23.3 (19.4–27.8)94.5 (93.2–95.5)51.7 (44.9–59.5)82.9 (80.8–84.4)4.21 (3.20–5.53)0.81 (0.77–0.86)Rome I24.3 (20.3–28.8)93.9 (92.6–95.0)50.5 (44.0–58.1)83.0 (80.9–84.4)4.01 (3.08–5.22)0.81 (0.76–0.85)Manning13.7 (10.6–17.6)97.1 (96.1–97.8)54.1 (45.3–64.6)81.6 (79.6–83.1)4.66 (3.18–6.82)0.89 (0.85–0.93) Open table in a new tab In a second paper in this issue of Gastroenterology, Labus et al performed a single-center, randomized, double-blind, cross-over trial that evaluated an antagonist of corticotropin-releasing factor receptor 1 (CRF-R1), GW876008, on conditioned fear and extinction learning to abdominal pain. In addition to abdominal pain and changes in bowel habits, IBS is also associated with increased anxiety and sensory sensitivity to stimuli related to their symptoms. Central CRF had previously been implicated in anxiety disorders and IBS. A recent study by the same authors suggested that a CRF-R1 antagonist attenuated the exaggerated brain response to a pain threat in IBS patients. The present study examined 11 IBS patients diagnosed using the Rome II criteria and 15 healthy controls, all women, and compared the CRF-R1 antagonist with a placebo. Functional brain magnetic resonance imaging and skin conductance responses were measured in response to the acquisition and extinction of a conditioned fear response to stimulated abdominal pain. The results showed that GW876008 improved the impaired extinction learning exhibited by IBS patients. The results support a role for impaired CRF signaling in IBS, and provides an avenue for therapeutic development.See pages 1253 and 1262.Acute Kidney Injury and Mortality in Patients With Cirrhosis and InfectionThe development of acute kidney injury (AKI) in patients with cirrhosis, typically precipitated by infection, all too commonly has a devastating outcome. The poor prognosis of type 1 hepatorenal syndrome is well recognized. However, even lesser degrees of renal dysfunction in patients with advanced cirrhosis, in whom serum creatinine may not accurately reflect renal function as a result of muscle wasting, are associated with significant morbidity and mortality. To better define cirrhosis-associated AKI, a rise in the serum creatinine of > 0.3 mg/dL in less than 48 hours or a 50% increase in serum creatinine from a stable baseline value within the last 6 months were recently proposed as criteria. In this issue of Gastroenterology, Wong et al have performed a multicenter prospective study to evaluate the ability of these criteria to predict 30-day mortality in 287 patients with cirrhosis hospitalized for infection and 50 patients in whom infection developed during hospitalization. Urinary tract infections, spontaneous bacterial peritonitis (SBP), and skin infections were the leading infections. AKI developed in 166 patients (49%) with most of these patients (57%) developing a creatinine increase between 0.3-0.5 mg/dL; complete renal recovery occurred only in 59% of these patients. AKI was significantly more likely in patients who developed a second infection during hospitalization. Higher Child-Pugh and MELD scores and lower mean arterial pressures (MAP) on admission were associated with a higher risk for the development of AKI. Death within 30 days of hospitalization was higher in patients with AKI (34% vs 7%), even in patients who completely recovered their renal function, as were transfers to an intensive care setting, requirement for mechanical ventilation, and length of stay. Outcome was worse for patients who developed nosocomial infections compared with those who were admitted with an infection. Independent factors associated with 30-day mortality were AKI outcome (transient, persistent, or progressive), number of organ failures, MELD score, admission MAP, and SBP as the precipitating infection (Table 2). These findings demonstrate the utility of these diagnostic criteria to predict outcome in hospitalized patients with cirrhosis and infection and suggest that early recognition and treatment of AKI and institution of measures to prevent the development of nosocomial infections in this patient population may lead to better outcomes.Table 2Independent Factors Associated With 30-Day Mortality in a Multi-Variate Logistic Regression AnalysisEffectEstimateOR (95% confidence interval)Standard errorWald χ2dfP valueMAP at Admission0.041.04 (1.01, 1.06)0.017.651.0057MELD0.101.10 (1.04, 1.17)0.0311.011.0009SBP Infection0.942.56 (1.06, 6.20)0.454.331.0375Number of Organ Failures1.293.64 (2.37, 5.61)0.2234.611<.0001AKI Outcome22.392<.0001 No AKI vs Persistent/Progressive−0.560.16 (0.07, 0.40)0.28 Transient vs Persistent/Progressive−0.720.14 (0.05, 0.36)0.29Age0.011.01 (0.97, 1.05)0.020.2110.6472 Open table in a new tab See page 1280.Experimental Salmonella Intestinal Infection: Autophagy and TransportersTwo studies presented in this issue of Gastroenterology utilize genetically modified murine models to study the underlying biology of Salmonella infections. The first study by Marchelletta et al focuses on the mechanisms underlying Salmonella-associated diarrhea. Mice normally do not manifest diarrhea with Salmonella infections, presumably because many inbred strains possess a mutant Nramp1 gene, which compromises host defenses and leads to rapid and overwhelming infections. The authors consequently utilized mice that express the wild-type Nramp1 gene, which resulted in Salmonella-associated diarrhea.The authors explored the mechanisms responsible for the ensuing diarrhea using colonic tissue mounted in Ussing chambers that enabled measurements of ion transport across the intestinal epithelium. Their analysis revealed defects in ion transport that would contribute to decreases in intestinal absorption. A second approach examined the subcellular distribution of ion channels using confocal immunofluorescence microscopy, and demonstrated altered location and expression of several transporters. With respect to the underlying causes, higher levels of intestinal proliferation were observed and believed to contribute to the reduction of ion channel expression and function. The authors proposed that treatments that restore intestinal absorption be developed for Salmonella gastroenteritis.A second paper by Conway et al explored the role of autophagy as a host defense for intestinal Salmonella infection. Autophagy is a process responsible for the intracellular degradation of subcellular organelles and other cellular constituents, presumably as a nutrient and energy source during periods of deprivation or stress. It typically entails the formation of a membrane-bound autophagosome that subsequently fuses with lysosomes, which result in degradation of the contents by lysosomal hydrolases. Autophagy has also been linked with immunity in lower organisms such as Caenorhabditis elegans and Dictyostelium discoideum, where the intracellular degradation of microorganisms such as Salmonella has been observed. In this issue of Gastroenterology, Conway et al explore autophagy's role in vivo with Salmonella-infected murine intestines. This was achieved by generating knockout mouse in which a gene essential for autophagy, Atg16l1, was conditionally deleted in the intestine. The authors established that Salmonella infection in controls results in autophagy-associated proteins co-localizing with the bacteria. In contrast, intestinal epithelial cells without Atg16l1 did not demonstrate such co-localization. Infected Atg16l1 knockout mice also exhibited increased inflammation and extension of the Salmonella into the spleen and mesenteric lymph nodes (Figure 2). The authors concluded that Atg16l1 knockout mice are deficient in their ability to process Salmonella within autophagosomes, which supports hypotheses that autophagy serves a role in host defense against microbial organisms in vivo. Likewise, the identification and application of a drug, trifluoperazine, that enhances autophagy resulted in enhanced bacterial clearance.Figure 2Cecal histology with and without Salmonella infection in wild-type and Atg16l1 knockout mice.View Large Image Figure ViewerDownload Hi-res image Download (PPT)See pages 1347 and 1358. Eosinophilic Esophagitis: Stricture Risk and Molecular DiagnosisThe incidence of eosinophilic esophagitis (EoE), a chronic immune-mediated esophageal disorder characterized by esophageal dysfunction, primarily dysphagia leading to food impaction, and eosinophil-predominant inflammation on biopsy, has significantly increased since its initial description over 2 decades ago. In this issue of Gastroenterology (accompanied by an editorial), 2 studies address the diagnosis and natural history of this emerging yet still enigmatic disorder.The diagnosis of EoE currently rests on the histologic analysis of esophageal biopsies in concert with clinical symptoms of esophageal dysfunction. However, esophageal eosinophilia is not specific to EoE. Taking advantage of the discovery of a uniquely conserved gene expression profile in patients with EoE, Wen et al developed a molecular EoE diagnostic panel (EDP) using a quantitative polymerase chain reaction array of 94 representative EoE genes and 2 housekeeping controls to better diagnose EoE. This EDP identified pediatric and adult patients with EoE with high sensitivity (∼96%) and specificity (∼98%; Figure 1). The EDP also discriminated between patients with EoE in remission from normal controls. Furthermore, in patients with <15 eosinophils/high-power field, the EDP identified a subset of patients at risk for developing active EoE. Finally, the EDP distinguished patients with EoE from patients with gastroesophageal reflux disease and nonerosive reflux disease. Comparable results were obtained whether fresh or formalin-fixed paraffin-embedded tissue was used. These findings provide proof of principle for the use of a tissue-based molecular test in the diagnosis of EoE and highlight the advantages of such techniques over histologic analysis.The endoscopic features of EoE have been categorized as either inflammatory, characterized by whitish exudates, edema, and linear furrows, or fibrotic, characterized by rings, strictures, and crepe paper esophagus, although most patients present with an overlap of these features. Schoepfer et al perform a retrospective analysis of the relationship between the duration of untreated disease and the risk of stricture formation in 200 patients with EoE. The median diagnostic delay (time from first symptoms to diagnosis) was 6 years and was longest in patients ≤20 years old, and decreased with increasing age. Inflammatory features were present in 79.5%, fibrotic features in 60%, and strictures in 37.5% of patients at the time of EoE diagnosis. The prevalence of fibrotic features at the time of EoE diagnosis with or without inflammatory features increased with increasing duration of diagnostic delay from 46.5% in patients with a diagnostic delay of ≤2 years compared with 87.5% in patients with a diagnostic delay of >20 years. In addition, the prevalence of esophageal strictures correlated with the presence of fibrotic features and the duration of diagnostic delay, with a prevalence of strictures of 17.2% in patients with a diagnostic delay of ≤2 years compared with 70.8% in patients with a diagnostic delay of >20 years. The duration of diagnostic delay was the only risk factor associated with the presence of strictures at the time of EoE diagnosis. In contrast, the prevalence of inflammatory features alone decreased with increasing duration of diagnostic delay. These findings help to define the natural history of untreated EoE and support measures to reduce the diagnostic delay in patients with this chronic esophageal disorder.See 1230 and 1289; editorial on page 1186. The incidence of eosinophilic esophagitis (EoE), a chronic immune-mediated esophageal disorder characterized by esophageal dysfunction, primarily dysphagia leading to food impaction, and eosinophil-predominant inflammation on biopsy, has significantly increased since its initial description over 2 decades ago. In this issue of Gastroenterology (accompanied by an editorial), 2 studies address the diagnosis and natural history of this emerging yet still enigmatic disorder. The diagnosis of EoE currently rests on the histologic analysis of esophageal biopsies in concert with clinical symptoms of esophageal dysfunction. However, esophageal eosinophilia is not specific to EoE. Taking advantage of the discovery of a uniquely conserved gene expression profile in patients with EoE, Wen et al developed a molecular EoE diagnostic panel (EDP) using a quantitative polymerase chain reaction array of 94 representative EoE genes and 2 housekeeping controls to better diagnose EoE. This EDP identified pediatric and adult patients with EoE with high sensitivity (∼96%) and specificity (∼98%; Figure 1). The EDP also discriminated between patients with EoE in remission from normal controls. Furthermore, in patients with <15 eosinophils/high-power field, the EDP identified a subset of patients at risk for developing active EoE. Finally, the EDP distinguished patients with EoE from patients with gastroesophageal reflux disease and nonerosive reflux disease. Comparable results were obtained whether fresh or formalin-fixed paraffin-embedded tissue was used. These findings provide proof of principle for the use of a tissue-based molecular test in the diagnosis of EoE and highlight the advantages of such techniques over histologic analysis. The endoscopic features of EoE have been categorized as either inflammatory, characterized by whitish exudates, edema, and linear furrows, or fibrotic, characterized by rings, strictures, and crepe paper esophagus, although most patients present with an overlap of these features. Schoepfer et al perform a retrospective analysis of the relationship between the duration of untreated disease and the risk of stricture formation in 200 patients with EoE. The median diagnostic delay (time from first symptoms to diagnosis) was 6 years and was longest in patients ≤20 years old, and decreased with increasing age. Inflammatory features were present in 79.5%, fibrotic features in 60%, and strictures in 37.5% of patients at the time of EoE diagnosis. The prevalence of fibrotic features at the time of EoE diagnosis with or without inflammatory features increased with increasing duration of diagnostic delay from 46.5% in patients with a diagnostic delay of ≤2 years compared with 87.5% in patients with a diagnostic delay of >20 years. In addition, the prevalence of esophageal strictures correlated with the presence of fibrotic features and the duration of diagnostic delay, with a prevalence of strictures of 17.2% in patients with a diagnostic delay of ≤2 years compared with 70.8% in patients with a diagnostic delay of >20 years. The duration of diagnostic delay was the only risk factor associated with the presence of strictures at the time of EoE diagnosis. In contrast, the prevalence of inflammatory features alone decreased with increasing duration of diagnostic delay. These findings help to define the natural history of untreated EoE and support measures to reduce the diagnostic delay in patients with this chronic esophageal disorder. See 1230 and 1289; editorial on page 1186. IBS: Emotional Learning and Rome III Criteria ValidationIrritable bowel syndrome (IBS) is commonly seen in gastroenterology practices with a global prevalence of about 20%. It is characterized by abdominal pain with changes in stool consistency and frequency. IBS is a functional bowel disorder whose diagnosis can be established only when other organic gastrointestinal diseases are absent. As a result, patient evaluation commonly employs costly diagnostic interventions such as colonoscopy, esophagoduodenoscopy, and imaging studies. The overlap of IBS symptoms with those of other organic gastrointestinal diseases contributes to the associated high costs of a diagnostic evaluation. Thus, symptom-based criteria have been developed for the purpose of differentiating patients with IBS from those with organic diseases. These have included the Manning, Rome I, Rome II, and Rome III criteria. A missing element underlying many of the criteria is the absence of adequate clinical validation. In this issue of Gastroenterology, Ford et al studied 1848 adult patients from 2 hospitals in Hamilton, Canada. The Rome III questionnaire was applied to the patients, followed by a colonoscopy with biopsies. If the patients' celiac disease serologies were positive, an upper endoscopy was also performed. The criteria used for IBS in this study consisted of lower abdominal pain at least once a week, altered bowel habits, and the absence of evidence for organic disease on endoscopy and pathology.The results indicated that Rome III performed less well than either the Rome I and II criteria (Table 1). All criteria studied to date, however, exhibit positive predictive values of <50%, which underscores the need for developing diagnostic strategies for IBS that are without the risk and expense of current approaches.Table 1Criteria for the Diagnosis of IBSSensitivity (95% CI; %)Specificity (95% CI; %)Positive predictive value (95% CI; %)Negative predictive value (95% CI)Positive likelihood ratio (95% CI; %)Negative likelihood ratio (95% CI)Rome III17.4 (13.9–21.5)95.6 (94.4–96.5)49.6 (42.0–58.7)82.1 (80.0–83.6)3.92 (2.85–5.38)0.86 (0.83–0.91)Rome II23.3 (19.4–27.8)94.5 (93.2–95.5)51.7 (44.9–59.5)82.9 (80.8–84.4)4.21 (3.20–5.53)0.81 (0.77–0.86)Rome I24.3 (20.3–28.8)93.9 (92.6–95.0)50.5 (44.0–58.1)83.0 (80.9–84.4)4.01 (3.08–5.22)0.81 (0.76–0.85)Manning13.7 (10.6–17.6)97.1 (96.1–97.8)54.1 (45.3–64.6)81.6 (79.6–83.1)4.66 (3.18–6.82)0.89 (0.85–0.93) Open table in a new tab In a second paper in this issue of Gastroenterology, Labus et al performed a single-center, randomized, double-blind, cross-over trial that evaluated an antagonist of corticotropin-releasing factor receptor 1 (CRF-R1), GW876008, on conditioned fear and extinction learning to abdominal pain. In addition to abdominal pain and changes in bowel habits, IBS is also associated with increased anxiety and sensory sensitivity to stimuli related to their symptoms. Central CRF had previously been implicated in anxiety disorders and IBS. A recent study by the same authors suggested that a CRF-R1 antagonist attenuated the exaggerated brain response to a pain threat in IBS patients. The present study examined 11 IBS patients diagnosed using the Rome II criteria and 15 healthy controls, all women, and compared the CRF-R1 antagonist with a placebo. Functional brain magnetic resonance imaging and skin conductance responses were measured in response to the acquisition and extinction of a conditioned fear response to stimulated abdominal pain. The results showed that GW876008 improved the impaired extinction learning exhibited by IBS patients. The results support a role for impaired CRF signaling in IBS, and provides an avenue for therapeutic development.See pages 1253 and 1262. Irritable bowel syndrome (IBS) is commonly seen in gastroenterology practices with a global prevalence of about 20%. It is characterized by abdominal pain with changes in stool consistency and frequency. IBS is a functional bowel disorder whose diagnosis can be established only when other organic gastrointestinal diseases are absent. As a result, patient evaluation commonly employs costly diagnostic interventions such as colonoscopy, esophagoduodenoscopy, and imaging studies. The overlap of IBS symptoms with those of other organic gastrointestinal diseases contributes to the associated high costs of a diagnostic evaluation. Thus, symptom-based criteria have been developed for the purpose of differentiating patients with IBS from those with organic diseases. These have included the Manning, Rome I, Rome II, and Rome III criteria. A missing element underlying many of the criteria is the absence of adequate clinical validation. In this issue of Gastroenterology, Ford et al studied 1848 adult patients from 2 hospitals in Hamilton, Canada. The Rome III questionnaire was applied to the patients, followed by a colonoscopy with biopsies. If the patients' celiac disease serologies were positive, an upper endoscopy was also performed. The criteria used for IBS in this study consisted of lower abdominal pain at least once a week, altered bowel habits, and the absence of evidence for organic disease on endoscopy and pathology. The results indicated that Rome III performed less well than either the Rome I and II criteria (Table 1). All criteria studied to date, however, exhibit positive predictive values of <50%, which underscores the need for developing diagnostic strategies for IBS that are without the risk and expense of current approaches. In a second paper in this issue of Gastroenterology, Labus et al performed a single-center, randomized, double-blind, cross-over trial that evaluated an antagonist of corticotropin-releasing factor receptor 1 (CRF-R1), GW876008, on conditioned fear and extinction learning to abdominal pain. In addition to abdominal pain and changes in bowel habits, IBS is also associated with increased anxiety and sensory sensitivity to stimuli related to their symptoms. Central CRF had previously been implicated in anxiety disorders and IBS. A recent study by the same authors suggested that a CRF-R1 antagonist attenuated the exaggerated brain response to a pain threat in IBS patients. The present study examined 11 IBS patients diagnosed using the Rome II criteria and 15 healthy controls, all women, and compared the CRF-R1 antagonist with a placebo. Functional brain magnetic resonance imaging and skin conductance responses were measured in response to the acquisition and extinction of a conditioned fear response to stimulated abdominal pain. The results showed that GW876008 improved the impaired extinction learning exhibited by IBS patients. The results support a role for impaired CRF signaling in IBS, and provides an avenue for therapeutic development. See pages 1253 and 1262. Acute Kidney Injury and Mortality in Patients With Cirrhosis and InfectionThe development of acute kidney injury (AKI) in patients with cirrhosis, typically precipitated by infection, all too commonly has a devastating outcome. The poor prognosis of type 1 hepatorenal syndrome is well recognized. However, even lesser degrees of renal dysfunction in patients with advanced cirrhosis, in whom serum creatinine may not accurately reflect renal function as a result of muscle wasting, are associated with significant morbidity and mortality. To better define cirrhosis-associated AKI, a rise in the serum creatinine of > 0.3 mg/dL in less than 48 hours or a 50% increase in serum creatinine from a stable baseline value within the last 6 months were recently proposed as criteria. In this issue of Gastroenterology, Wong et al have performed a multicenter prospective study to evaluate the ability of these criteria to predict 30-day mortality in 287 patients with cirrhosis hospitalized for infection and 50 patients in whom infection developed during hospitalization. Urinary tract infections, spontaneous bacterial peritonitis (SBP), and skin infections were the leading infections. AKI developed in 166 patients (49%) with most of these patients (57%) developing a creatinine increase between 0.3-0.5 mg/dL; complete renal recovery occurred only in 59% of these patients. AKI was significantly more likely in patients who developed a second infection during hospitalization. Higher Child-Pugh and MELD scores and lower mean arterial pressures (MAP) on admission were associated with a higher risk for the development of AKI. Death within 30 days of hospitalization was higher in patients with AKI (34% vs 7%), even in patients who completely recovered their renal function, as were transfers to an intensive care setting, requirement for mechanical ventilation, and length of stay. Outcome was worse for patients who developed nosocomial infections compared with those who were admitted with an infection. Independent factors associated with 30-day mortality were AKI outcome (transient, persistent, or progressive), number of organ failures, MELD score, admission MAP, and SBP as the precipitating infection (Table 2). These findings demonstrate the utility of these diagnostic criteria to predict outcome in hospitalized patients with cirrhosis and infection and suggest that early recognition and treatment of AKI and institution of measures to prevent the development of nosocomial infections in this patient population may lead to better outcomes.Table 2Independent Factors Associated With 30-Day Mortality in a Multi-Variate Logistic Regression AnalysisEffectEstimateOR (95% confidence interval)Standard errorWald χ2dfP valueMAP at Admission0.041.04 (1.01, 1.06)0.017.651.0057MELD0.101.10 (1.04, 1.17)0.0311.011.0009SBP Infection0.942.56 (1.06, 6.20)0.454.331.0375Number of Organ Failures1.293.64 (2.37, 5.61)0.2234.611<.0001AKI Outcome22.392<.0001 No AKI vs Persistent/Progressive−0.560.16 (0.07, 0.40)0.28 Transient vs Persistent/Progressive−0.720.14 (0.05, 0.36)0.29Age0.011.01 (0.97, 1.05)0.020.2110.6472 Open table in a new tab See page 1280. The development of acute kidney injury (AKI) in patients with cirrhosis, typically precipitated by infection, all too commonly has a devastating outcome. The poor prognosis of type 1 hepatorenal syndrome is well recognized. However, even lesser degrees of renal dysfunction in patients with advanced cirrhosis, in whom serum creatinine may not accurately reflect renal function as a result of muscle wasting, are associated with significant morbidity and mortality. To better define cirrhosis-associated AKI, a rise in the serum creatinine of > 0.3 mg/dL in less than 48 hours or a 50% increase in serum creatinine from a stable baseline value within the last 6 months were recently proposed as criteria. In this issue of Gastroenterology, Wong et al have performed a multicenter prospective study to evaluate the ability of these criteria to predict 30-day mortality in 287 patients with cirrhosis hospitalized for infection and 50 patients in whom infection developed during hospitalization. Urinary tract infections, spontaneous bacterial peritonitis (SBP), and skin infections were the leading infections. AKI developed in 166 patients (49%) with most of these patients (57%) developing a creatinine increase between 0.3-0.5 mg/dL; complete renal recovery occurred only in 59% of these patients. AKI was significantly more likely in patients who developed a second infection during hospitalization. Higher Child-Pugh and MELD scores and lower mean arterial pressures (MAP) on admission were associated with a higher risk for the development of AKI. Death within 30 days of hospitalization was higher in patients with AKI (34% vs 7%), even in patients who completely recovered their renal function, as were transfers to an intensive care setting, requirement for mechanical ventilation, and length of stay. Outcome was worse for patients who developed nosocomial infections compared with those who were admitted with an infection. Independent factors associated with 30-day mortality were AKI outcome (transient, persistent, or progressive), number of organ failures, MELD score, admission MAP, and SBP as the precipitating infection (Table 2). These findings demonstrate the utility of these diagnostic criteria to predict outcome in hospitalized patients with cirrhosis and infection and suggest that early recognition and treatment of AKI and institution of measures to prevent the development of nosocomial infections in this patient population may lead to better outcomes. See page 1280. Experimental Salmonella Intestinal Infection: Autophagy and TransportersTwo studies presented in this issue of Gastroenterology utilize genetically modified murine models to study the underlying biology of Salmonella infections. The first study by Marchelletta et al focuses on the mechanisms underlying Salmonella-associated diarrhea. Mice normally do not manifest diarrhea with Salmonella infections, presumably because many inbred strains possess a mutant Nramp1 gene, which compromises host defenses and leads to rapid and overwhelming infections. The authors consequently utilized mice that express the wild-type Nramp1 gene, which resulted in Salmonella-associated diarrhea.The authors explored the mechanisms responsible for the ensuing diarrhea using colonic tissue mounted in Ussing chambers that enabled measurements of ion transport across the intestinal epithelium. Their analysis revealed defects in ion transport that would contribute to decreases in intestinal absorption. A second approach examined the subcellular distribution of ion channels using confocal immunofluorescence microscopy, and demonstrated altered location and expression of several transporters. With respect to the underlying causes, higher levels of intestinal proliferation were observed and believed to contribute to the reduction of ion channel expression and function. The authors proposed that treatments that restore intestinal absorption be developed for Salmonella gastroenteritis.A second paper by Conway et al explored the role of autophagy as a host defense for intestinal Salmonella infection. Autophagy is a process responsible for the intracellular degradation of subcellular organelles and other cellular constituents, presumably as a nutrient and energy source during periods of deprivation or stress. It typically entails the formation of a membrane-bound autophagosome that subsequently fuses with lysosomes, which result in degradation of the contents by lysosomal hydrolases. Autophagy has also been linked with immunity in lower organisms such as Caenorhabditis elegans and Dictyostelium discoideum, where the intracellular degradation of microorganisms such as Salmonella has been observed. In this issue of Gastroenterology, Conway et al explore autophagy's role in vivo with Salmonella-infected murine intestines. This was achieved by generating knockout mouse in which a gene essential for autophagy, Atg16l1, was conditionally deleted in the intestine. The authors established that Salmonella infection in controls results in autophagy-associated proteins co-localizing with the bacteria. In contrast, intestinal epithelial cells without Atg16l1 did not demonstrate such co-localization. Infected Atg16l1 knockout mice also exhibited increased inflammation and extension of the Salmonella into the spleen and mesenteric lymph nodes (Figure 2). The authors concluded that Atg16l1 knockout mice are deficient in their ability to process Salmonella within autophagosomes, which supports hypotheses that autophagy serves a role in host defense against microbial organisms in vivo. Likewise, the identification and application of a drug, trifluoperazine, that enhances autophagy resulted in enhanced bacterial clearance.See pages 1347 and 1358. Two studies presented in this issue of Gastroenterology utilize genetically modified murine models to study the underlying biology of Salmonella infections. The first study by Marchelletta et al focuses on the mechanisms underlying Salmonella-associated diarrhea. Mice normally do not manifest diarrhea with Salmonella infections, presumably because many inbred strains possess a mutant Nramp1 gene, which compromises host defenses and leads to rapid and overwhelming infections. The authors consequently utilized mice that express the wild-type Nramp1 gene, which resulted in Salmonella-associated diarrhea. The authors explored the mechanisms responsible for the ensuing diarrhea using colonic tissue mounted in Ussing chambers that enabled measurements of ion transport across the intestinal epithelium. Their analysis revealed defects in ion transport that would contribute to decreases in intestinal absorption. A second approach examined the subcellular distribution of ion channels using confocal immunofluorescence microscopy, and demonstrated altered location and expression of several transporters. With respect to the underlying causes, higher levels of intestinal proliferation were observed and believed to contribute to the reduction of ion channel expression and function. The authors proposed that treatments that restore intestinal absorption be developed for Salmonella gastroenteritis. A second paper by Conway et al explored the role of autophagy as a host defense for intestinal Salmonella infection. Autophagy is a process responsible for the intracellular degradation of subcellular organelles and other cellular constituents, presumably as a nutrient and energy source during periods of deprivation or stress. It typically entails the formation of a membrane-bound autophagosome that subsequently fuses with lysosomes, which result in degradation of the contents by lysosomal hydrolases. Autophagy has also been linked with immunity in lower organisms such as Caenorhabditis elegans and Dictyostelium discoideum, where the intracellular degradation of microorganisms such as Salmonella has been observed. In this issue of Gastroenterology, Conway et al explore autophagy's role in vivo with Salmonella-infected murine intestines. This was achieved by generating knockout mouse in which a gene essential for autophagy, Atg16l1, was conditionally deleted in the intestine. The authors established that Salmonella infection in controls results in autophagy-associated proteins co-localizing with the bacteria. In contrast, intestinal epithelial cells without Atg16l1 did not demonstrate such co-localization. Infected Atg16l1 knockout mice also exhibited increased inflammation and extension of the Salmonella into the spleen and mesenteric lymph nodes (Figure 2). The authors concluded that Atg16l1 knockout mice are deficient in their ability to process Salmonella within autophagosomes, which supports hypotheses that autophagy serves a role in host defense against microbial organisms in vivo. Likewise, the identification and application of a drug, trifluoperazine, that enhances autophagy resulted in enhanced bacterial clearance. See pages 1347 and 1358. Delay in Diagnosis of Eosinophilic Esophagitis Increases Risk for Stricture Formation in a Time-Dependent MannerGastroenterologyVol. 145Issue 6PreviewDevelopment of strictures is a major concern for patients with eosinophilic esophagitis (EoE). At diagnosis, EoE can present with an inflammatory phenotype (characterized by whitish exudates, furrows, and edema), a stricturing phenotype (characterized by rings and stenosis), or a combination of these. Little is known about progression of stricture formation; we evaluated stricture development over time in the absence of treatment and investigated risk factors for stricture formation. Full-Text PDF Validation of the Rome III Criteria for the Diagnosis of Irritable Bowel Syndrome in Secondary CareGastroenterologyVol. 145Issue 6PreviewThere are few validation studies of existing diagnostic criteria for irritable bowel syndrome (IBS). We conducted a validation study of the Rome and Manning criteria in secondary care. Full-Text PDF Atg16l1 is Required for Autophagy in Intestinal Epithelial Cells and Protection of Mice From Salmonella InfectionGastroenterologyVol. 145Issue 6PreviewIntestinal epithelial cells aid in mucosal defense by providing a physical barrier against entry of pathogenic bacteria and secreting antimicrobial peptides (AMPs). Autophagy is an important component of immune homeostasis. However, little is known about its role in specific cell types during bacterial infection in vivo. We investigated the role of autophagy in the response of intestinal epithelial and antigen-presenting cells to Salmonella infection in mice. Full-Text PDF Impaired Emotional Learning and Involvement of the Corticotropin-Releasing Factor Signaling System in Patients With Irritable Bowel SyndromeGastroenterologyVol. 145Issue 6PreviewAlterations in central corticotropin-releasing factor signaling pathways have been implicated in the pathophysiology of anxiety disorders and irritable bowel syndrome (IBS). We aimed to characterize the effects of the corticotropin-releasing factor receptor 1 (CRF-R1) antagonist, GW876008 , on brain and skin conductance responses during acquisition and extinction of conditioned fear to the threat of abdominal pain in subjects with IBS and healthy individuals (controls). Full-Text PDF New Consensus Definition of Acute Kidney Injury Accurately Predicts 30-Day Mortality in Patients With Cirrhosis and InfectionGastroenterologyVol. 145Issue 6PreviewParticipants at a consensus conference proposed defining cirrhosis-associated acute kidney injury (AKI) based on a >50% increase in serum creatinine level from the stable baseline value in <6 months or an increase of ≥0.3 mg/dL in <48 hours. We performed a prospective study to evaluate the ability of these criteria to predict mortality within 30 days of hospitalization among patients with cirrhosis and infection. Full-Text PDF Molecular Diagnosis of Eosinophilic Esophagitis by Gene Expression ProfilingGastroenterologyVol. 145Issue 6PreviewGene expression profiling provides an opportunity for definitive diagnosis but has not yet been well applied to inflammatory diseases. Here we describe an approach for diagnosis of an emerging form of esophagitis, eosinophilic esophagitis (EoE), which is currently diagnosed by histology and clinical symptoms. Full-Text PDF Altered Expression and Localization of Ion Transporters Contribute to Diarrhea in Mice With Salmonella-Induced EnteritisGastroenterologyVol. 145Issue 6PreviewSalmonella enterica serovar Typhimurium is an enteropathogen that causes self-limiting diarrhea in healthy individuals, but poses a significant health threat to vulnerable populations. Our understanding of the pathogenesis of Salmonella-induced diarrhea has been hampered by the lack of a suitable mouse model. After a dose of oral kanamycin, Salmonella-infected congenic BALB/c.D2NrampG169 mice, which carry a wild-type Nramp1 gene, develop clear manifestations of diarrhea. We used this model to elucidate the pathophysiology of Salmonella-induced diarrhea. Full-Text PDF