This Month in Gastroenterology

Abstract

NSAIDs and Complications of DiverticulitisDiverticular disease is a highly prevalent age-related anatomical change of the wall of the large intestine, which may lead to complications such as diverticulitis and diverticular bleeding. A number of case control studies have suggested an association between nonsteroidal anti-inflammatory drugs (NSAIDs) and complications of diverticular disease like diverticulitis or bleeding, but the risk estimates vary widely and most of these studies had some methodological limitations.In this issue of Gastroenterology, Strate et al report the results of an analysis of the influence of aspirin and NSAIDs usage on the risk of diverticular disease complications in a large cohort of men enrolled in the Health Professionals Follow-up Study. The Health Professionals Follow-up Study is a prospective cohort of 51,529 male healthcare professionals who were aged 40–75 years at baseline in 1986 and returned a detailed medical and dietary questionnaire. Medical and dietary information have been updated every 2 to 4 years via self-administered questionnaires. From 1990 onwards, men reporting newly diagnosed diverticulosis or diverticulitis were sent supplementary questionnaires, to distinguish between uncomplicated diverticulitis, complications of diverticulitis and diverticular bleeding. Use of aspirin and NSAIDs, including dose regimens, body mass index, dietary habits, and physical activity were obtained from the database. The association between regular use of aspirin and NSAIDs, the type of NSAID, and the dosage, and the incidence of diverticulitis and diverticular bleeding was assessed in uni- and multivariate analysis.Data from a total of 47,210 were available and eligible for analysis. During 859,164 person years of follow-up, 939 incident cases of diverticulitis, and 256 incident cases of diverticular bleeding were registered. Of the participants, 29% reported regular aspirin intake and 5% regular NSAID intake. A significantly higher risk of diverticulitis was found among regular users of NSAIDs (hazard ratio [HR] 1.72; 95% confidence interval [CI], 1.40–2.11), and to a lesser degree among regular users of aspirin (HR 1.25; 95% CI, 1.05–1.47) (Figure 1). Regular NSAID use was most strongly associated with the risk of complicated diverticulitis (HR 2.55; 95% CI, 1.32–4.95), but also with uncomplicated diverticulitis (HR 1.65; 95% CI, 1.32–2.05), while HRs for aspirin did not differ between complicated and uncomplicated disease. For diverticular bleeding, the associations of regular use of NSAIDs and aspirin were similar (HR 1.74; 95% CI, 1.15–2.64 and HR 1.70; 95% CI, 1.21–2.39, respectively). Concurrent use of NSAIDs and aspirin was not associated with a significantly higher risk. A higher risk was associated with almost daily intake, and with moderately high doses of aspirin (2 to 5.9 standard doses of 325 mg per week).This large prospective study in men confirms aspirin and NSAID use are associated with a similarly increased risk of diverticular bleeding, and NSAID use is more strongly associated with diverticulitis than aspirin use. These findings have important clinical and public health implications given the prevalence of diverticular disease particularly in the elderly, where the use of analgesic or anti-inflammatory agents should be considered carefully.Retrospective analysis of the largest series of Wilson disease patients in the literature shows a higher rate of treatment discontinuation, a higher incidence of treatment failure and a higher incidence of the combined event “liver transplation or death” in patients under zinc therapy compared with chelation therapy. Future studies are needed to identify the reasons for this lower treatment response, and prospective multi-center studies are needed to compare different chelating agents. The authors recommend systematic monitoring of the development of new neurological or hepatic symptoms and measurement of liver function tests and urinary copper excretion in Wilson disease patients under zinc salt therapy. If these show unfavourable results, a switch to chelating therapy should be considered.See page 1427.A Novel Method to Assess Oropharyngeal DysphagiaSwallowing dysfunction (oropharyngeal dysphagia) is extremely common both in the pediatric and adult population within a wide range of disorders (developmental, neurological, muscular diseases …). Besides compromising nutritional intake, swallowing dysfunction may also lead to chronic pulmonary aspiration with recurrent pneumonia, progressive lung disease, and even death. The main clinical tools available to study swallow function are videofluoroscopy and manometry, with videofluoroscopy the current gold standard. However, videofluoroscopy is hampered by radiation exposure and manometry lacks accuracy in predicting aspiration risk. Catheter-based intraluminal impedance measurement has emerged in recent years as a technique that can be used to measure bolus transport, for instance in the esophagus, but attempts to adapt the method to pharyngeal bolus flow have met with difficulties because of the larger variability and short time interval of the signals.In this issue of Gastroenterology, Omari et al report the results of a study where they evaluated a new analysis method for high resolution manometry and impedance catheter-based measurements of swallow function. The authors studied 20 patients with swallow dysfunction and suspected risk of aspiration who were referred for combined videomanometry of the pharynx and esophagus, and compared the results with those in 10 healthy controls. All subjects were intubated with a solid-state high resolution manometric and impedance catheter. Fluoroscopy images and manometry/impedance data were recorded during ingestion of different volumes of liquid and semi-solid boluses. Fluoroscopic images were scored for the presence of pharyngeal residue and the occurrence of aspiration-penetration. Manometry and impedance recordings were correlated in time with fluoroscopic images and analysed to derive 4 different pharyngeal pressure-flow reflecting bolus passage.A total of 54 swallows in patients were analysed, of which 28 failed to clear the bolus fully, and 14 showed deglutitive aspiration-penetration. In volunteers, 26 swallows were recorded of which 8 showed incomplete bolus clearance; no aspiration-penetration occurred. Clearing swallows in patients with aspiration had a longer flow interval, a higher nadir impedance, a lower peak pressure and a shorter average time delay from nadir impedance to peak pressure than those without inspiration. These 4 variables were combined into a swallow risk index (SRI). The overall median SRI was significantly higher in patients compared with controls. The SRI increased with increasing severity of aspiration score (Figure 2) and logistic regression showed a highly significant correlation between SRI and aspiration (odds ratio [OR] 8.1; 95% confidence interval [CI] 2.0–32.6). Amongst swallows from the patient cohort, the median SRI for swallows during which no aspiration was observed were significantly lower compared to swallows with aspiration (SRI 11.9 [3.9, 21.3] without aspiration vs 66.8 [24.6, 136.8] with aspiration, P<.001).Figure 2Box plot showing median and inter-quartile ranges for first swallow SRI in controls and patients. Patient data are further stratified based on aspiration score. No aspiration = score 1, penetration = score 2–5 and aspiration = score 6–8.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The authors investigated whether the first swallow SRI recorded in an individual patient could predict the presence/absence of aspiration during fluoroscopy. An average first swallow SRI of 15.0 was a perfect threshold for accurate prediction of aspiration in the patient cohort and was also optimal in terms of sensitivity and specificity. The authors developed a swallow risk index, based on the objective calculation of 4 pharyngeal pressure-flow variables, which has the potential to identify individual patients at deglutitive aspiration risk without use of fluoroscopy. This novel methodology, which does not require radiation exposure, has important potential for clinical implementation as a screening tool for aspiration risk, in pediatric as well as adult patients with swallowing disorders.See page 1454.Structural Changes in Gastric Tissue From Patients With Diabetic and Idiopathic GastroparesisGastroparesis, whether diabetic or idiopathic, carries significant morbidity for patients, but changes that occur for its pathogenesis at the tissue level is not fully understood. Most of our understanding regarding cellular structural changes in gastroparetic stomachs comes from animal studies. The Gastroparesis Clinical Research Consortium, established by the National Institutes of Health, obtained full-thickness human stomach biopsies to investigate structural changes at the tissue and cellular levels.In the study by Grover et al, 20 diabetic and 20 idiopathic gastroparetic stomach biopsies were obtained at the time of placement of a gastric stimulator, and compared with 20 age- and gender-matched control (non-gastroparetic) stomach biopsies that were taken at the time of duodenal switch gastric bypass surgery. Histologic changes were noted in 16 of 20 diabetic and in 17 of 20 idiopathic gastroparetics, for 83% of all gastroparetics. Quantification of immunohistochemical staining for components of the enteric nervous system (PGP9.5, nNOS, VIP, substance P, and tyrosine hydroxylase) revealed a 14%–18% decrease in PGP9.5 in gastroparetics, which stains enteric nerves, and no differences in the other markers. The most common abnormality was a decrease in interstitial cells of Cajal (ICC), detected by c-kit staining, and found in half of gastroparetics. Counting ICC cell bodies demonstrated the decrease, with 5.3 cell bodies per microscopic field in controls, compared with 1.1 cell bodies per field in diabetic and 1.6 cell bodies per field in idiopathic gastroparetics. Stains for smooth muscle cells and fibrosis showed no changes from controls. The second most common abnormality was an increase in CD45 immunofluorescence, a marker for immune cells, in the myenteric plexus of gastroparetics. More specific stains suggest the cells are macrophages and not B or T cells. With any of the markers, there was no difference between diabetic and idiopathic gastroparetics. Electron microscopy (EM) from diabetic gastroparetic tissue showed some normal ICCs, but also ICCs with intracytoplasmic vacuoles and swollen mitochondria and loss of contact with nerve endings. Nerve endings were very large and often devoid of content (Figure 3). Tissue subjected to EM from idiopathic gastroparetics revealed the nerve endings were either empty or contained sequestered synaptic vessels and lamellar bodies. Glial cell cytoplasm was filled with lysosomes and lipofuscinic bodies, and fibrosis was noted around the nerve structures.Figure 3Transmission EM of the diabetic gastroparesis stomach. (A) An ICC with large vacuoles in the cytoplasm and a discontinuous, thick basal lamina (asterisks). SMC, smooth muscle cell. (B) Smooth muscle cells immersed in a fibrotic stroma and separated, except for small junctional areas, most of which are gap junctions (small asterisks). (C) Nerve bundle surrounded by a very thick basal lamina and numerous collagen fibers. The nerve endings are empty.View Large Image Figure ViewerDownload Hi-res image Download (PPT)The study finds common abnormalities and characterizes the major histologic changes in human diabetic and idiopathic gastroparetic stomachs—loss of ICCs, damaged nerve endings, and increase in immune cell infiltrate—potentially opening up avenues to better study the pathogenesis of gastroparesis.See page 1575.Hepatic Fibrosis Does Not Depend on Plasma or Cellular Fibronectin in the Extracellular MatrixHepatic fibrosis is the end result from liver tissue repair after injury. Activated hepatic stellate cells (HSCs) transdifferentiate and produce cellular type fibronectin, and along with plasma type fibronectin, forms the provisional matrix for a collagen network. It is believed that the fibronectin matrix is required for the collagen network to form. Fibronectin sequesters the pro-fibrotic cytokine, transforming growth factor (TGF)-β in its latent form, and with tissue injury, TGF-β becomes active to drive fibrosis. Without fibronectin in the liver, hepatic fibrosis may not occur.In the study by Moriya et al, liver-specific fibronectin-null (LivFn-null) mice were created through Flox-Cre recombinase mating and under the interferon– and pI-pC–inducible promoter, then treated with carbon tetrachloride to induce liver injury. The fibronectin gene was deleted from both parenchymal and nonparenchymal cells in LivFn-null mice. Despite fibronectin being absent, LivFn-null mice laid down a collagen network after hepatic injury, indicating an alternative mechanism for collagen fibrillogenesis in the absence of fibronectin. Livers from LivFn-null mice demonstrated elevated production of the latent form of TGF-β increasing this profibrotic cytokine's bioavailability to signal through downstream SMADs, and subsequently activate HSCs. TGF-β was the most potent stimulator of fibronectin-null HSCs, which increased its production of the collagen gene Col5a1 mRNA 2.5-fold over control HSCs, and induced type V collagen assembly followed by type III and type I collagen fibril network formation. Livers from LivFn-null mice showed more extensive deposition and assembly of type V collagen. Both livers from LivFn-null and control mice showed the same extent of bridging fibrosis (Figure 4) by 8 weeks after injury, and serum alanine aminotransferase, bilirubin, albumin/globulin ratios, and hepatic hydroxyproline content were no different between groups.Figure 4Sirius red staining of control and liver specific fibronectin-null (LivFn-null) mice in response to chronic liver injury after 8 weeks. Bar = 100 μm.View Large Image Figure ViewerDownload Hi-res image Download (PPT)This study indicates that collagen fibril organization does not require the prior assembly of fibronectin matrix. The absence of fibronectin will not prevent hepatic fibrosis.See page 1653. NSAIDs and Complications of DiverticulitisDiverticular disease is a highly prevalent age-related anatomical change of the wall of the large intestine, which may lead to complications such as diverticulitis and diverticular bleeding. A number of case control studies have suggested an association between nonsteroidal anti-inflammatory drugs (NSAIDs) and complications of diverticular disease like diverticulitis or bleeding, but the risk estimates vary widely and most of these studies had some methodological limitations.In this issue of Gastroenterology, Strate et al report the results of an analysis of the influence of aspirin and NSAIDs usage on the risk of diverticular disease complications in a large cohort of men enrolled in the Health Professionals Follow-up Study. The Health Professionals Follow-up Study is a prospective cohort of 51,529 male healthcare professionals who were aged 40–75 years at baseline in 1986 and returned a detailed medical and dietary questionnaire. Medical and dietary information have been updated every 2 to 4 years via self-administered questionnaires. From 1990 onwards, men reporting newly diagnosed diverticulosis or diverticulitis were sent supplementary questionnaires, to distinguish between uncomplicated diverticulitis, complications of diverticulitis and diverticular bleeding. Use of aspirin and NSAIDs, including dose regimens, body mass index, dietary habits, and physical activity were obtained from the database. The association between regular use of aspirin and NSAIDs, the type of NSAID, and the dosage, and the incidence of diverticulitis and diverticular bleeding was assessed in uni- and multivariate analysis.Data from a total of 47,210 were available and eligible for analysis. During 859,164 person years of follow-up, 939 incident cases of diverticulitis, and 256 incident cases of diverticular bleeding were registered. Of the participants, 29% reported regular aspirin intake and 5% regular NSAID intake. A significantly higher risk of diverticulitis was found among regular users of NSAIDs (hazard ratio [HR] 1.72; 95% confidence interval [CI], 1.40–2.11), and to a lesser degree among regular users of aspirin (HR 1.25; 95% CI, 1.05–1.47) (Figure 1). Regular NSAID use was most strongly associated with the risk of complicated diverticulitis (HR 2.55; 95% CI, 1.32–4.95), but also with uncomplicated diverticulitis (HR 1.65; 95% CI, 1.32–2.05), while HRs for aspirin did not differ between complicated and uncomplicated disease. For diverticular bleeding, the associations of regular use of NSAIDs and aspirin were similar (HR 1.74; 95% CI, 1.15–2.64 and HR 1.70; 95% CI, 1.21–2.39, respectively). Concurrent use of NSAIDs and aspirin was not associated with a significantly higher risk. A higher risk was associated with almost daily intake, and with moderately high doses of aspirin (2 to 5.9 standard doses of 325 mg per week).This large prospective study in men confirms aspirin and NSAID use are associated with a similarly increased risk of diverticular bleeding, and NSAID use is more strongly associated with diverticulitis than aspirin use. These findings have important clinical and public health implications given the prevalence of diverticular disease particularly in the elderly, where the use of analgesic or anti-inflammatory agents should be considered carefully.Retrospective analysis of the largest series of Wilson disease patients in the literature shows a higher rate of treatment discontinuation, a higher incidence of treatment failure and a higher incidence of the combined event “liver transplation or death” in patients under zinc therapy compared with chelation therapy. Future studies are needed to identify the reasons for this lower treatment response, and prospective multi-center studies are needed to compare different chelating agents. The authors recommend systematic monitoring of the development of new neurological or hepatic symptoms and measurement of liver function tests and urinary copper excretion in Wilson disease patients under zinc salt therapy. If these show unfavourable results, a switch to chelating therapy should be considered.See page 1427. Diverticular disease is a highly prevalent age-related anatomical change of the wall of the large intestine, which may lead to complications such as diverticulitis and diverticular bleeding. A number of case control studies have suggested an association between nonsteroidal anti-inflammatory drugs (NSAIDs) and complications of diverticular disease like diverticulitis or bleeding, but the risk estimates vary widely and most of these studies had some methodological limitations. In this issue of Gastroenterology, Strate et al report the results of an analysis of the influence of aspirin and NSAIDs usage on the risk of diverticular disease complications in a large cohort of men enrolled in the Health Professionals Follow-up Study. The Health Professionals Follow-up Study is a prospective cohort of 51,529 male healthcare professionals who were aged 40–75 years at baseline in 1986 and returned a detailed medical and dietary questionnaire. Medical and dietary information have been updated every 2 to 4 years via self-administered questionnaires. From 1990 onwards, men reporting newly diagnosed diverticulosis or diverticulitis were sent supplementary questionnaires, to distinguish between uncomplicated diverticulitis, complications of diverticulitis and diverticular bleeding. Use of aspirin and NSAIDs, including dose regimens, body mass index, dietary habits, and physical activity were obtained from the database. The association between regular use of aspirin and NSAIDs, the type of NSAID, and the dosage, and the incidence of diverticulitis and diverticular bleeding was assessed in uni- and multivariate analysis. Data from a total of 47,210 were available and eligible for analysis. During 859,164 person years of follow-up, 939 incident cases of diverticulitis, and 256 incident cases of diverticular bleeding were registered. Of the participants, 29% reported regular aspirin intake and 5% regular NSAID intake. A significantly higher risk of diverticulitis was found among regular users of NSAIDs (hazard ratio [HR] 1.72; 95% confidence interval [CI], 1.40–2.11), and to a lesser degree among regular users of aspirin (HR 1.25; 95% CI, 1.05–1.47) (Figure 1). Regular NSAID use was most strongly associated with the risk of complicated diverticulitis (HR 2.55; 95% CI, 1.32–4.95), but also with uncomplicated diverticulitis (HR 1.65; 95% CI, 1.32–2.05), while HRs for aspirin did not differ between complicated and uncomplicated disease. For diverticular bleeding, the associations of regular use of NSAIDs and aspirin were similar (HR 1.74; 95% CI, 1.15–2.64 and HR 1.70; 95% CI, 1.21–2.39, respectively). Concurrent use of NSAIDs and aspirin was not associated with a significantly higher risk. A higher risk was associated with almost daily intake, and with moderately high doses of aspirin (2 to 5.9 standard doses of 325 mg per week). This large prospective study in men confirms aspirin and NSAID use are associated with a similarly increased risk of diverticular bleeding, and NSAID use is more strongly associated with diverticulitis than aspirin use. These findings have important clinical and public health implications given the prevalence of diverticular disease particularly in the elderly, where the use of analgesic or anti-inflammatory agents should be considered carefully. Retrospective analysis of the largest series of Wilson disease patients in the literature shows a higher rate of treatment discontinuation, a higher incidence of treatment failure and a higher incidence of the combined event “liver transplation or death” in patients under zinc therapy compared with chelation therapy. Future studies are needed to identify the reasons for this lower treatment response, and prospective multi-center studies are needed to compare different chelating agents. The authors recommend systematic monitoring of the development of new neurological or hepatic symptoms and measurement of liver function tests and urinary copper excretion in Wilson disease patients under zinc salt therapy. If these show unfavourable results, a switch to chelating therapy should be considered. See page 1427. A Novel Method to Assess Oropharyngeal DysphagiaSwallowing dysfunction (oropharyngeal dysphagia) is extremely common both in the pediatric and adult population within a wide range of disorders (developmental, neurological, muscular diseases …). Besides compromising nutritional intake, swallowing dysfunction may also lead to chronic pulmonary aspiration with recurrent pneumonia, progressive lung disease, and even death. The main clinical tools available to study swallow function are videofluoroscopy and manometry, with videofluoroscopy the current gold standard. However, videofluoroscopy is hampered by radiation exposure and manometry lacks accuracy in predicting aspiration risk. Catheter-based intraluminal impedance measurement has emerged in recent years as a technique that can be used to measure bolus transport, for instance in the esophagus, but attempts to adapt the method to pharyngeal bolus flow have met with difficulties because of the larger variability and short time interval of the signals.In this issue of Gastroenterology, Omari et al report the results of a study where they evaluated a new analysis method for high resolution manometry and impedance catheter-based measurements of swallow function. The authors studied 20 patients with swallow dysfunction and suspected risk of aspiration who were referred for combined videomanometry of the pharynx and esophagus, and compared the results with those in 10 healthy controls. All subjects were intubated with a solid-state high resolution manometric and impedance catheter. Fluoroscopy images and manometry/impedance data were recorded during ingestion of different volumes of liquid and semi-solid boluses. Fluoroscopic images were scored for the presence of pharyngeal residue and the occurrence of aspiration-penetration. Manometry and impedance recordings were correlated in time with fluoroscopic images and analysed to derive 4 different pharyngeal pressure-flow reflecting bolus passage.A total of 54 swallows in patients were analysed, of which 28 failed to clear the bolus fully, and 14 showed deglutitive aspiration-penetration. In volunteers, 26 swallows were recorded of which 8 showed incomplete bolus clearance; no aspiration-penetration occurred. Clearing swallows in patients with aspiration had a longer flow interval, a higher nadir impedance, a lower peak pressure and a shorter average time delay from nadir impedance to peak pressure than those without inspiration. These 4 variables were combined into a swallow risk index (SRI). The overall median SRI was significantly higher in patients compared with controls. The SRI increased with increasing severity of aspiration score (Figure 2) and logistic regression showed a highly significant correlation between SRI and aspiration (odds ratio [OR] 8.1; 95% confidence interval [CI] 2.0–32.6). Amongst swallows from the patient cohort, the median SRI for swallows during which no aspiration was observed were significantly lower compared to swallows with aspiration (SRI 11.9 [3.9, 21.3] without aspiration vs 66.8 [24.6, 136.8] with aspiration, P<.001).The authors investigated whether the first swallow SRI recorded in an individual patient could predict the presence/absence of aspiration during fluoroscopy. An average first swallow SRI of 15.0 was a perfect threshold for accurate prediction of aspiration in the patient cohort and was also optimal in terms of sensitivity and specificity. The authors developed a swallow risk index, based on the objective calculation of 4 pharyngeal pressure-flow variables, which has the potential to identify individual patients at deglutitive aspiration risk without use of fluoroscopy. This novel methodology, which does not require radiation exposure, has important potential for clinical implementation as a screening tool for aspiration risk, in pediatric as well as adult patients with swallowing disorders.See page 1454. Swallowing dysfunction (oropharyngeal dysphagia) is extremely common both in the pediatric and adult population within a wide range of disorders (developmental, neurological, muscular diseases …). Besides compromising nutritional intake, swallowing dysfunction may also lead to chronic pulmonary aspiration with recurrent pneumonia, progressive lung disease, and even death. The main clinical tools available to study swallow function are videofluoroscopy and manometry, with videofluoroscopy the current gold standard. However, videofluoroscopy is hampered by radiation exposure and manometry lacks accuracy in predicting aspiration risk. Catheter-based intraluminal impedance measurement has emerged in recent years as a technique that can be used to measure bolus transport, for instance in the esophagus, but attempts to adapt the method to pharyngeal bolus flow have met with difficulties because of the larger variability and short time interval of the signals. In this issue of Gastroenterology, Omari et al report the results of a study where they evaluated a new analysis method for high resolution manometry and impedance catheter-based measurements of swallow function. The authors studied 20 patients with swallow dysfunction and suspected risk of aspiration who were referred for combined videomanometry of the pharynx and esophagus, and compared the results with those in 10 healthy controls. All subjects were intubated with a solid-state high resolution manometric and impedance catheter. Fluoroscopy images and manometry/impedance data were recorded during ingestion of different volumes of liquid and semi-solid boluses. Fluoroscopic images were scored for the presence of pharyngeal residue and the occurrence of aspiration-penetration. Manometry and impedance recordings were correlated in time with fluoroscopic images and analysed to derive 4 different pharyngeal pressure-flow reflecting bolus passage. A total of 54 swallows in patients were analysed, of which 28 failed to clear the bolus fully, and 14 showed deglutitive aspiration-penetration. In volunteers, 26 swallows were recorded of which 8 showed incomplete bolus clearance; no aspiration-penetration occurred. Clearing swallows in patients with aspiration had a longer flow interval, a higher nadir impedance, a lower peak pressure and a shorter average time delay from nadir impedance to peak pressure than those without inspiration. These 4 variables were combined into a swallow risk index (SRI). The overall median SRI was significantly higher in patients compared with controls. The SRI increased with increasing severity of aspiration score (Figure 2) and logistic regression showed a highly significant correlation between SRI and aspiration (odds ratio [OR] 8.1; 95% confidence interval [CI] 2.0–32.6). Amongst swallows from the patient cohort, the median SRI for swallows during which no aspiration was observed were significantly lower compared to swallows with aspiration (SRI 11.9 [3.9, 21.3] without aspiration vs 66.8 [24.6, 136.8] with aspiration, P<.001). The authors investigated whether the first swallow SRI recorded in an individual patient could predict the presence/absence of aspiration during fluoroscopy. An average first swallow SRI of 15.0 was a perfect threshold for accurate prediction of aspiration in the patient cohort and was also optimal in terms of sensitivity and specificity. The authors developed a swallow risk index, based on the objective calculation of 4 pharyngeal pressure-flow variables, which has the potential to identify individual patients at deglutitive aspiration risk without use of fluoroscopy. This novel methodology, which does not require radiation exposure, has important potential for clinical implementation as a screening tool for aspiration risk, in pediatric as well as adult patients with swallowing disorders. See page 1454. Structural Changes in Gastric Tissue From Patients With Diabetic and Idiopathic GastroparesisGastroparesis, whether diabetic or idiopathic, carries significant morbidity for patients, but changes that occur for its pathogenesis at the tissue level is not fully understood. Most of our understanding regarding cellular structural changes in gastroparetic stomachs comes from animal studies. The Gastroparesis Clinical Research Consortium, established by the National Institutes of Health, obtained full-thickness human stomach biopsies to investigate structural changes at the tissue and cellular levels.In the study by Grover et al, 20 diabetic and 20 idiopathic gastroparetic stomach biopsies were obtained at the time of placement of a gastric stimulator, and compared with 20 age- and gender-matched control (non-gastroparetic) stomach biopsies that were taken at the time of duodenal switch gastric bypass surgery. Histologic changes were noted in 16 of 20 diabetic and in 17 of 20 idiopathic gastroparetics, for 83% of all gastroparetics. Quantification of immunohistochemical staining for components of the enteric nervous system (PGP9.5, nNOS, VIP, substance P, and tyrosine hydroxylase) revealed a 14%–18% decrease in PGP9.5 in gastroparetics, which stains enteric nerves, and no differences in the other markers. The most common abnormality was a decrease in interstitial cells of Cajal (ICC), detected by c-kit staining, and found in half of gastroparetics. Counting ICC cell bodies demonstrated the decrease, with 5.3 cell bodies per microscopic field in controls, compared with 1.1 cell bodies per field in diabetic and 1.6 cell bodies per field in idiopathic gastroparetics. Stains for smooth muscle cells and fibrosis showed no changes from controls. The second most common abnormality was an increase in CD45 immunofluorescence, a marker for immune cells, in the myenteric plexus of gastroparetics. More specific stains suggest the cells are macrophages and not B or T cells. With any of the markers, there was no difference between diabetic and idiopathic gastroparetics. Electron microscopy (EM) from diabetic gastroparetic tissue showed some normal ICCs, but also ICCs with intracytoplasmic vacuoles and swollen mitochondria and loss of contact with nerve endings. Nerve endings were very large and often devoid of content (Figure 3). Tissue subjected to EM from idiopathic gastroparetics revealed the nerve endings were either empty or contained sequestered synaptic vessels and lamellar bodies. Glial cell cytoplasm was filled with lysosomes and lipofuscinic bodies, and fibrosis was noted around the nerve structures.The study finds common abnormalities and characterizes the major histologic changes in human diabetic and idiopathic gastroparetic stomachs—loss of ICCs, damaged nerve endings, and increase in immune cell infiltrate—potentially opening up avenues to better study the pathogenesis of gastroparesis.See page 1575. Gastroparesis, whether diabetic or idiopathic, carries significant morbidity for patients, but changes that occur for its pathogenesis at the tissue level is not fully understood. Most of our understanding regarding cellular structural changes in gastroparetic stomachs comes from animal studies. The Gastroparesis Clinical Research Consortium, established by the National Institutes of Health, obtained full-thickness human stomach biopsies to investigate structural changes at the tissue and cellular levels. In the study by Grover et al, 20 diabetic and 20 idiopathic gastroparetic stomach biopsies were obtained at the time of placement of a gastric stimulator, and compared with 20 age- and gender-matched control (non-gastroparetic) stomach biopsies that were taken at the time of duodenal switch gastric bypass surgery. Histologic changes were noted in 16 of 20 diabetic and in 17 of 20 idiopathic gastroparetics, for 83% of all gastroparetics. Quantification of immunohistochemical staining for components of the enteric nervous system (PGP9.5, nNOS, VIP, substance P, and tyrosine hydroxylase) revealed a 14%–18% decrease in PGP9.5 in gastroparetics, which stains enteric nerves, and no differences in the other markers. The most common abnormality was a decrease in interstitial cells of Cajal (ICC), detected by c-kit staining, and found in half of gastroparetics. Counting ICC cell bodies demonstrated the decrease, with 5.3 cell bodies per microscopic field in controls, compared with 1.1 cell bodies per field in diabetic and 1.6 cell bodies per field in idiopathic gastroparetics. Stains for smooth muscle cells and fibrosis showed no changes from controls. The second most common abnormality was an increase in CD45 immunofluorescence, a marker for immune cells, in the myenteric plexus of gastroparetics. More specific stains suggest the cells are macrophages and not B or T cells. With any of the markers, there was no difference between diabetic and idiopathic gastroparetics. Electron microscopy (EM) from diabetic gastroparetic tissue showed some normal ICCs, but also ICCs with intracytoplasmic vacuoles and swollen mitochondria and loss of contact with nerve endings. Nerve endings were very large and often devoid of content (Figure 3). Tissue subjected to EM from idiopathic gastroparetics revealed the nerve endings were either empty or contained sequestered synaptic vessels and lamellar bodies. Glial cell cytoplasm was filled with lysosomes and lipofuscinic bodies, and fibrosis was noted around the nerve structures. The study finds common abnormalities and characterizes the major histologic changes in human diabetic and idiopathic gastroparetic stomachs—loss of ICCs, damaged nerve endings, and increase in immune cell infiltrate—potentially opening up avenues to better study the pathogenesis of gastroparesis. See page 1575. Hepatic Fibrosis Does Not Depend on Plasma or Cellular Fibronectin in the Extracellular MatrixHepatic fibrosis is the end result from liver tissue repair after injury. Activated hepatic stellate cells (HSCs) transdifferentiate and produce cellular type fibronectin, and along with plasma type fibronectin, forms the provisional matrix for a collagen network. It is believed that the fibronectin matrix is required for the collagen network to form. Fibronectin sequesters the pro-fibrotic cytokine, transforming growth factor (TGF)-β in its latent form, and with tissue injury, TGF-β becomes active to drive fibrosis. Without fibronectin in the liver, hepatic fibrosis may not occur.In the study by Moriya et al, liver-specific fibronectin-null (LivFn-null) mice were created through Flox-Cre recombinase mating and under the interferon– and pI-pC–inducible promoter, then treated with carbon tetrachloride to induce liver injury. The fibronectin gene was deleted from both parenchymal and nonparenchymal cells in LivFn-null mice. Despite fibronectin being absent, LivFn-null mice laid down a collagen network after hepatic injury, indicating an alternative mechanism for collagen fibrillogenesis in the absence of fibronectin. Livers from LivFn-null mice demonstrated elevated production of the latent form of TGF-β increasing this profibrotic cytokine's bioavailability to signal through downstream SMADs, and subsequently activate HSCs. TGF-β was the most potent stimulator of fibronectin-null HSCs, which increased its production of the collagen gene Col5a1 mRNA 2.5-fold over control HSCs, and induced type V collagen assembly followed by type III and type I collagen fibril network formation. Livers from LivFn-null mice showed more extensive deposition and assembly of type V collagen. Both livers from LivFn-null and control mice showed the same extent of bridging fibrosis (Figure 4) by 8 weeks after injury, and serum alanine aminotransferase, bilirubin, albumin/globulin ratios, and hepatic hydroxyproline content were no different between groups.This study indicates that collagen fibril organization does not require the prior assembly of fibronectin matrix. The absence of fibronectin will not prevent hepatic fibrosis.See page 1653. Hepatic fibrosis is the end result from liver tissue repair after injury. Activated hepatic stellate cells (HSCs) transdifferentiate and produce cellular type fibronectin, and along with plasma type fibronectin, forms the provisional matrix for a collagen network. It is believed that the fibronectin matrix is required for the collagen network to form. Fibronectin sequesters the pro-fibrotic cytokine, transforming growth factor (TGF)-β in its latent form, and with tissue injury, TGF-β becomes active to drive fibrosis. Without fibronectin in the liver, hepatic fibrosis may not occur. In the study by Moriya et al, liver-specific fibronectin-null (LivFn-null) mice were created through Flox-Cre recombinase mating and under the interferon– and pI-pC–inducible promoter, then treated with carbon tetrachloride to induce liver injury. The fibronectin gene was deleted from both parenchymal and nonparenchymal cells in LivFn-null mice. Despite fibronectin being absent, LivFn-null mice laid down a collagen network after hepatic injury, indicating an alternative mechanism for collagen fibrillogenesis in the absence of fibronectin. Livers from LivFn-null mice demonstrated elevated production of the latent form of TGF-β increasing this profibrotic cytokine's bioavailability to signal through downstream SMADs, and subsequently activate HSCs. TGF-β was the most potent stimulator of fibronectin-null HSCs, which increased its production of the collagen gene Col5a1 mRNA 2.5-fold over control HSCs, and induced type V collagen assembly followed by type III and type I collagen fibril network formation. Livers from LivFn-null mice showed more extensive deposition and assembly of type V collagen. Both livers from LivFn-null and control mice showed the same extent of bridging fibrosis (Figure 4) by 8 weeks after injury, and serum alanine aminotransferase, bilirubin, albumin/globulin ratios, and hepatic hydroxyproline content were no different between groups. This study indicates that collagen fibril organization does not require the prior assembly of fibronectin matrix. The absence of fibronectin will not prevent hepatic fibrosis. See page 1653.