Identification of harmful drinking in subjects who have had their driving license suspended due to alcohol use: a retrospective Italian study.

OBJECTIVE: Early identification of Harmful Drinking (HD) is difficult, and underestimated. The aim of our retrospective study was to investigate the presence of HD in a population of subjects who had their driving license suspended due to driving under the influence of alcohol. MATERIALS AND METHODS: We retrospectively recruited 979 subjects. During the first appointment (T0), clinical and laboratory characteristics of patients were evaluated, and the AUDIT questionnaire was administered. Two groups were then defined: Harmful Drinking (HD) and non-HD, and all subjects underwent a brief interview for 5-10 minutes before being assigned to a group. RESULTS: 95.9% of our sample were identified as non-HD, whereas 4.1% of them were HD; twenty-one (2.1%) of the HD underwent a control appointment (T1), and 17 (1.7%) of them were diagnosed with alcohol use disorder (AUD); there was a statistically significant reduction in mean daily alcohol intake (p<0.009), and in the mean values of the blood markers of HD between T0 and T1 in HD. CONCLUSIONS: The present study shows that 4.1%, and 1.7% of subjects presented a diagnosis of HD and AUD, respectively, and their entry in a protocol of drinking monitoring proved beneficial in reducing alcohol intake. Thus, the implementation of strict surveillance of subjects found driving under the influence of alcohol involving a network of professional figures (from police forces to specialists in alcohol addiction treatment) may help to detect and to treat subjects with HD and AUD, and to monitor their alcohol use over time.

Prediction of in-hospital mortality of patients with SARS-CoV-2 infection by comorbidity indexes: an Italian internal medicine single center study.

OBJECTIVE: Clinical outcomes in patients hospitalized for severe acute respiratory syndrome due to coronavirus (SARS-CoV-2) infection seems to be closely related with burden of comorbidities. A comorbidity score could help in clinical stratification of patients admitted to internal medicine units. Our aim was to assess a novel modified Elixhauser index (mEi) and the Charlson Comorbidity Index (CCI) for predicting in-hospital mortality (IHM) in internal medicine patients with SARS-CoV-2 infection. PATIENTS AND METHODS: This single-center retrospective study enrolled all consecutive patients discharged from internal medicine unit with confirmed SARS-CoV-2 infection. Both the mEi and CCI were easily calculated from administrative data. Comorbidity scores were tested using receiver operating characteristic (ROC) analysis, and the respective area under the curve (AUC). RESULTS: The total sample consisted of 151 individuals, and 30 (19.9%) died during their hospital stay. Deceased subjects were older (82.8±10.8 vs. 63.3±18.1 years; p<0.001) and had a higher burden of comorbidities: the mEi and CCI were 29.9±11 vs. 8.8±9.2 and 4.6±2.6 vs. 1.2±2 (p<0.001), respectively. Only the mEi was independently associated with IHM (OR 1.173), and ROC curves analysis showed that the AUCs were 0.863 and 0.918 for the CCI and for mEi, respectively. CONCLUSIONS: In patients admitted to internal medicine wards with SARS-CoV-2 infection, the mEi showed a better performance in predicting IHM than CCI.

Morning vs. evening administration of antiviral therapy in COVID-19 patients. A preliminary retrospective study in Ferrara, Italy.

OBJECTIVE: At the end of 2019, the Novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), spread rapidly from China to the whole world. Circadian rhythms can play crucial role in the complex interplay between viruses and organisms, and temporized schedules (chronotherapy) have been positively tested in several medical diseases. We aimed to compare the possible effects of a morning vs. evening antiviral administration in COVID patients. PATIENTS AND METHODS: We retrospectively evaluated all patients admitted to COVID internal medicine units with confirmed SARS-CoV-2 infection, and treated with darunavir-ritonavir (single daily dose, for seven days). Age, sex, length of stay (LOS), pharmacological treatment, and timing of antiviral administration (morning or evening), were recorded. Outcome indicators were death or LOS, and laboratory parameters, e.g., variations in C-reactive protein (CRP) levels, ratio of arterial oxygen partial pressure (PaO2, mmHg) to fractional inspired oxygen (FiO2) (PaO2/FiO2), and leucocyte count. RESULTS: The total sample consisted of 151 patients, 33 (21.8%) of whom were selected for antiviral treatment. The mean age was 61.8±18.3 years, 17 (51.5%) were male, and the mean LOS was 13.4±8.6 days. Nine patients (27.3%) had their antiviral administration in the morning, and 24 (72.7%) had antiviral administration in the evening. No fatalities occurred. Despite the extremely limited sample size, morning group subjects showed a significant difference in CRP variation, compared to that in evening group subjects (-65.82±33.26 vs. 83.32±304.89, respectively, p<0.032). No significant differences were found for other parameters. CONCLUSIONS: This report is the first study evaluating temporized morning vs. evening antiviral administration in SARS-CoV-2 patients. The morning regimen was associated with a significant reduction in CRP values. Further confirmations with larger and multicenter samples of patients could reveal novel potentially useful insights.

Chronobiology of acute pancreatitis in a single Italian centre.

OBJECTIVE: Seasonal variation may occur in many different diseases hence influencing awareness in clinical practice. This study aimed to establish seasonal variations of acute pancreatitis by using a validated chronobiological analysis. PATIENTS AND METHODS: All cases of acute pancreatitis consecutively observed in fifteen years, i.e., from January 2003 to December 2017, at St. Anna University Hospital of Ferrara, Italy, were included in this study. Accurate statistical and logistic regression analyses were applied to our database. RESULTS: A total number of 1883 consecutive cases of acute pancreatitis were observed. A significant peak was identified in the summer period (p=0.014). Patient stratification, according to age, showed that elderly people had an increased incidence of acute pancreatitis in autumn and summer (being the biliary stone disease the main cause, p=0.011) vs. other seasons (p=0.003). Mortality occurred more prominently in males vs. females, although the latter gender was more prone to acute pancreatitis (p=0.017). CONCLUSIONS: In a single centre of Northern East of Italy, we demonstrated that acute pancreatitis had a clear seasonal variation with a prominent incidence during summer. Various associated factors could contribute to this chronobiological pattern, including gender, age, and biliary stone disease.

Costs of irritable bowel syndrome in European countries with universal healthcare coverage: a meta-analysis.

OBJECTIVE: To provide an overall estimate of the direct, indirect and total costs of irritable bowel syndrome (IBS) for the adult population of the European countries with universal healthcare coverage. MATERIALS AND METHODS: We searched MedLine and Scopus databases (up to September 2018) to identify the European studies that evaluated the economic impact of IBS. Mean annual direct, indirect and total per-capita IBS costs were estimated using random-effect single-group meta-analyses of continuous data. All analyses were stratified by payer category (governments, insurance, societal), and the results were expressed as summary mean and 95% CI. RESULTS: A total of 24 studies were included in the meta-analyses. Only two studies evaluated IBS costs in Italy. The pooled summary of direct IBS per-capita cost, obtained from 23 European datasets (n=15,157), was €1837/year (95% CI: 1480-2195), with large differences across payers (from €1183 to €3358, in countries with publicly-funded and insurance-based health systems, respectively). The mean indirect cost, extracted from 13 datasets (n=3978), was €2314/year (95% CI: 1811-2817), again with wide differences across payers. Finally, the meta-analysis estimating the total annual cost, based upon 11 European datasets (n=2757), yielded a summary estimate of €2889/year (95% CI: 2318-3460) per patient, ranging from €1602 (insurance-based health systems) to €3909 (studies adopting a societal perspective). CONCLUSIONS: Considering a conservative estimate of 2,736,700 Italian adults affected by the syndrome, the minimum costs due to IBS in Italy - likely underestimated - range from 6 to 8 billion euro per year. Given the substantial economic burden for patients, healthcare systems and society, IBS should be included among the priorities of the public health agenda.

Sex and acute oesophageal variceal bleeding-related in-hospital mortality: a 15-year retrospective study.

OBJECTIVE: The relationship between in-hospital mortality (IHM) and acute oesophageal variceal bleeding (AOEVB) has not been fully assessed. The aim of this study was to establish the association between sex and mortality for patients hospitalized with AOEVB. PATIENTS AND METHODS: We analyzed hospitalizations from the Italian Health Ministry database by identifying all patients discharged with AOEVB from January 2001 to December 2015. A total of 144,943 hospitalizations were for oesophageal varices, but only 24,570 emergency admissions with AOEVB coded as the primary or secondary diagnosis were included for analysis. Factors independently associated with IHM were evaluated by multilevel logistic regression. RESULTS: Approximately half of the population was aged ≥ 65 years, and nearly 10% was diagnosed with hepatocellular carcinoma. Overall, the IHM was 11.8%, with 12.1% in males and 11.3% in females, increasing from 9.2% among subjects aged < 55 years to 18.9% among those aged ≥ 85 years. The crude risk of death was slightly higher among females; however, when age and clinical presentation were considered, female sex was associated with reduced mortality. For liver disease, the risk of death in women was lower only in those with non-alcoholic liver disease (odds ratio= 0.77, 0.66-0.89), but it was similar to that in men for unspecified, cancer and alcoholic liver disease. The risk declined over time and was increased in patients with multiple comorbidities. CONCLUSIONS: AOEVB-related IHM decreased from 2001-2005 to 2011-2015. Factors affecting mortality included liver disease, age, sex, development of hepatocellular carcinoma and comorbidities.

Expression of RAD21 immunoreactivity in myenteric neurons of the human and mouse small intestine.

BACKGROUND: RAD21 is a double-strand-break repair protein and component of the cohesin complex with key roles in cellular functions. A RAD21 loss-of-function mutation was found in cases of chronic intestinal pseudo-obstruction (CIPO) with associated enteric neuronal loss. Analysis of RAD21 expression in the enteric nervous system is lacking, thus we aimed to characterize RAD21 immunoreactivity (IR) in myenteric ganglia. METHODS: Double labeling immunofluorescence in mouse and human jejunum was used to determine colocalization of RAD21 with HuC/D, PGP9.5, neuronal nitric oxide synthase (nNOS), neuropeptide Y (NPY), choline acetyl transferase (ChAT), Kit, platelet-derived growth factor receptor-α (PDGFRα), and glial fibrillary acid protein (GFAP) IRs. RESULTS: A subset of PGP9.5- and HuC/D-IR neuronal cell bodies and nerve fibers in the myenteric plexus of human and mouse small intestine also displayed cytoplasmic RAD21-IR Cytoplasmic RAD21-IR was found in 43% of HuC/D-IR neurons in adult and neonatal mice but did not colocalize with nNOS. A subset of ChAT-positive neurons had cytoplasmic RAD21-IR Punctate RAD21-IR was restricted to the nucleus in most cell types consistent with labeling of the cohesin complex. Cytoplasmic RAD21-IR was not detected in interstitial cells of Cajal, fibroblast-like cells or glia. Subsets of neurons in primary culture exhibited cytoplasmic RAD21-IR Suppression of RAD21 expression by shRNA knockdown abolished RAD21-IR in cultured neurons. CONCLUSIONS: Our data showing cytoplasmic RAD21 expression in enteric neurons provide a basis toward understanding how mutations of this gene may contribute to altered neuronal function/survival thus leading to gut-motor abnormalities.

Enteroendocrine profile of α-transducin and α-gustducin immunoreactive cells in the chicken (Gallus domesticus) gastrointestinal tract.

The enteroendocrine profile and distribution patterns of the taste signaling molecules, α-gustducin (Gαgust) and α-transducin (Gαtran) protein subunits, were studied in the gastrointestinal (GI) tract of the chicken (Gallus domesticus) using double labeling immunohistochemistry. Gαtran or Gαgust immunoreactivity was observed in enteroendocrine cells (EEC) expressing different peptides throughout the entire GI tract with different density. In the proventriculus tubular gland, Gαtran or Gαgust/gastrin (GAS) immunoreactive (-IR) cells were more abundant than Gαtran/or Gαgust containing glucagon-like peptide-1 (GLP-1) or peptide YY (PYY), whereas only few Gαtran or Gαgust cells co-stored ghrelin (GHR) or 5-hydroxytryptamine (5-HT). In the pyloric mucosa, many Gαtran or Gαgust-IR cells co-expressed GAS or GHR, with less Gαtran or Gαgust cells containing GLP-1, PYY, or 5-HT. In the small intestine, a considerable subset of Gαtran or Gαgust-IR cells co-expressed 5-HT in the villi of the duodenum and ileum, PYY in the villi of the jejunum, CCK or GLP-1 in the villi of the ileum, and GHR in the duodenum crypts. In the large intestine, many Gαtran or Gαgust-IR cells contained 5-HT or GLP-1 in the villi of the rectum, whereas some Gαtran/Gαgust-IR cells co-expressed PYY- or CCK-, and few Gαtran/Gαgust-IR cells were positive for GHR-IR. In the cecum, several Gαtran or Gαgust-IR cells were IR for 5-HT. Finally, many Gαtran/Gαgust cells containing 5-HT were observed in the villi and crypts of the cloaca, whereas there were few Gαtran or Gαgust/CCK-IR cells. The demonstration that Gα-subunits are expressed in the chicken GI enteroendocrine system supports the involvement of taste signaling machinery in the chicken chemosensing processes.

Neoplasms and renal transplantation: impact of gender, comorbidity and age on in-hospital mortality. A retrospective study in the region Emilia-Romagna of Italy.

OBJECTIVE: The aim of this retrospective study was to investigate the relationship between cancer, non-immunologic comorbidity, estimated by International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codification, gender and in-hospital mortality (IHM) in a large sample of renal transplant recipients (RTRs) living in the region Emilia-Romagna (RER) of Italy. PATIENTS AND METHODS: We evaluated IHM in RTRs admitted between 2000 and 2013 recorded in the RER database. By using ICD-9-CM codes, the Elixhauser index (EI) was calculated, and cancers were identified and classified as skin cancers (SC), solid organ cancers (SOC) and post-transplant lymphoproliferative disorders (PTLD). IHM was the dependent variable of the multivariate models, while age, gender, EI corrected removing the effect of malignancies (cEI), and different types of cancer were the independent ones. RESULTS: During the examined period, a total of 9,063 admissions in 3,648 RTRs were recorded, of whom 117 died (3.2%). The mean age was 52.9±13.1 years. Cancers were reported in 580 admissions (6.4%), and mean cEI was 3.5±3.4. Deceased RTRs were older, had a higher prevalence of PTLD and SOC, and had a higher cEI than survivors. IHM was independently associated with (in decreasing order) PTLD (OR 12.431, 95%CI 5.834-26.489, p<0.001), SOC (OR 6.804, 95%CI 4.323-10.707, p<0.001), female gender (OR 1.633, 95%CI 1.057-2.523, p=0.006), cEI (OR 1.106, 95%CI 1.068-1.145, p<0.001), and age (OR 1.049, 95%CI 1.031-1.068, p<0.001) CONCLUSIONS: Cancer, in particular SOC and PTLD, is strongly associated with IHM in RTRs. On the other hand, rather surprisingly, female gender exhibited a stronger association with IHM than other more expected factors, such as comorbidity and age.

INPP4B overexpression and c-KIT downregulation in human achalasia.

BACKGROUND: Achalasia is a rare motility disorder characterized by myenteric neuron and interstitial cells of Cajal (ICC) abnormalities leading to deranged/absent peristalsis and lack of relaxation of the lower esophageal sphincter. The mechanisms contributing to neuronal and ICC changes in achalasia are only partially understood. Our goal was to identify novel molecular features occurring in patients with primary achalasia. METHODS: Esophageal full-thickness biopsies from 42 (22 females; age range: 16-82 years) clinically, radiologically, and manometrically characterized patients with primary achalasia were examined and compared to those obtained from 10 subjects (controls) undergoing surgery for uncomplicated esophageal cancer (or upper stomach disorders). Tissue RNA extracted from biopsies of cases and controls was used for library preparation and sequencing. Data analysis was performed with the "edgeR" option of R-Bioconductor. Data were validated by real-time RT-PCR, western blotting and immunohistochemistry. KEY RESULTS: Quantitative transcriptome evaluation and cluster analysis revealed 111 differentially expressed genes, with a P ≤ 10-3 . Nine genes with a P ≤ 10-4 were further validated. CYR61, CTGF, c-KIT, DUSP5, EGR1 were downregulated, whereas AKAP6 and INPP4B were upregulated in patients vs controls. Compared to controls, immunohistochemical analysis revealed a clear increase in INPP4B, whereas c-KIT immunolabeling resulted downregulated. As INPP4B regulates Akt pathway, we used western blot to show that phospho-Akt was significantly reduced in achalasia patients vs controls. CONCLUSIONS & INFERENCES: The identification of altered gene expression, including INPP4B, a regulator of the Akt pathway, highlights novel signaling pathways involved in the neuronal and ICC changes underlying primary achalasia.

Multimodal Surgical Approach for Adult Patients With Chronic Intestinal Pseudo-Obstruction: Clinical and Psychosocial Long-term Outcomes.

BACKGROUND: Clinical and psychosocial outcomes of a multimodal surgical approach for chronic intestinal pseudo-obstruction were analyzed in 24 patients who were followed over a 2- to 12-year period in a single center after surgery or intestinal/multivisceral transplant (CTx). METHODS: The main reasons for surgery were sub-occlusion in surgery and parenteral nutrition-related irreversible complications with chronic intestinal failure in CTx. RESULTS: At the end of follow-up (February 2015), 45.5% of CTx patients were alive: after transplantation, improvement in intestinal function was observed including a tendency toward recovery of oral diet (81.8%) with reduced parenteral nutrition support (36.4%) in the face of significant mortality rates and financial costs (mean, 202.000 euros), frequent hospitalization (mean, 8.8/re-admissions/patient), as well as limited effects on pain or physical wellness. CONCLUSIONS: Through psychological tests, transplant recipients perceived a significant improvement of mental health and emotional state, showing that emotional factors were more affected than were functional/cognitive impairment and social interaction.

Cerebral Mitochondrial Microangiopathy Leads to Leukoencephalopathy in Mitochondrial Neurogastrointestinal Encephalopathy.

BACKGROUND AND PURPOSE: Mitochondrial neurogastrointestinal encephalopathy is a rare disorder due to recessive mutations in the thymidine phosphorylase gene, encoding thymidine phosphorylase protein required for mitochondrial DNA replication. Clinical manifestations include gastrointestinal dysmotility and diffuse asymptomatic leukoencephalopathy. This study aimed to elucidate the mechanisms underlying brain leukoencephalopathy in patients with mitochondrial neurogastrointestinal encephalopathy by correlating multimodal neuroradiologic features to postmortem pathology. MATERIALS AND METHODS: Seven patients underwent brain MR imaging, including single-voxel proton MR spectroscopy and diffusion imaging. Absolute concentrations of metabolites calculated by acquiring unsuppressed water spectra at multiple TEs, along with diffusion metrics based on the tensor model, were compared with those of healthy controls using unpaired t tests in multiple white matters regions. Brain postmortem histologic, immunohistochemical, and molecular analyses were performed in 1 patient. RESULTS: All patients showed bilateral and nearly symmetric cerebral white matter hyperintensities on T2-weighted images, extending to the cerebellar white matter and brain stem in 4. White matter, N-acetylaspartate, creatine, and choline concentrations were significantly reduced compared with those in controls, with a prominent increase in the radial water diffusivity component. At postmortem examination, severe fibrosis of brain vessel smooth muscle was evident, along with mitochondrial DNA replication depletion in brain and vascular smooth-muscle and endothelial cells, without neuronal loss, myelin damage, or gliosis. Prominent periependymal cytochrome C oxidase deficiency was also observed. CONCLUSIONS: Vascular functional and histologic alterations account for leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy. Thymidine toxicity and mitochondrial DNA replication depletion may induce microangiopathy and blood-brain-barrier dysfunction, leading to increased water content in the white matter. Periependymal cytochrome C oxidase deficiency could explain prominent periventricular impairment.

Comparison between small bowel manometric patterns and full-thickness biopsy histopathology in severe intestinal dysmotility.

BACKGROUND: Intestinal manometry is the current standard for direct evaluation of small bowel dysmotility. Patients with abnormal motility can either be diagnosed of pseudo-obstruction when there are radiological findings mimicking mechanical intestinal obstruction or of enteric dysmotility when these findings are absent. The aim of the present study was to prospectively compare small bowel manometric abnormalities with histopathological findings in intestinal full-thickness biopsies in patients with severe dysmotility disorders. METHODS: We investigated 38 patients with intestinal manometry and a subsequent full-thickness intestinal biopsy. Manometric recordings were read by 4 investigators and a diagnostic consensus was obtained in 35 patients. Histopathological analysis, including specific immunohistochemical techniques of small bowel biopsies was performed and compared to manometric readings. KEY RESULTS: Patients with abnormal intestinal manometry had abnormal histopathological findings in 73% of cases. However, manometric patterns did not match with the specific neuromuscular abnormalities. Among patients with a neuropathic manometry pattern and abnormal histopathology, only 23% had an enteric neuropathy, whereas 62% had neuromuscular inflammation, and 15% an enteric myopathy. On the other hand, patients with a myopathic manometry pattern all had abnormal histopathology, however, none of them with signs of enteric myopathy. CONCLUSION & INFERENCES: Small bowel dysmotility detected by intestinal manometry is often associated with abnormal neuromuscular findings in full-thickness biopsies. However, there is no correlation between the specific manometric patterns and the histopathological findings.

Glioplasticity in irritable bowel syndrome.

BACKGROUND: Growing evidence indicates a wide array of cellular remodeling in the mucosal microenvironment during irritable bowel syndrome (IBS), which possibly contributes to pathophysiology and symptom generation. Here, we investigated whether enteric glial cells (EGC) may be altered, and which factors/mechanisms lead to these changes. METHODS: Colonic mucosal biopsies of IBS patients (13 IBS-Constipation [IBS-C]; 10 IBS-Diarrhea [IBS-D]; 11 IBS-Mixed [IBS-M]) and 24 healthy controls (HC) were analyzed. Expression of S100ß and GFAP was measured. Cultured rat EGC were incubated with supernatants from mucosal biopsies, then proliferation and Ca2+ response to ATP were analyzed using flow cytometry and Ca2+ imaging. Histamine and histamine 1-receptor (H1R) involvement in the effects of supernatant upon EGC was analyzed. KEY RESULTS: Compared to HC, the mucosal area immunoreactive for S100ß was significantly reduced in biopsies of IBS patients, independently of the IBS subtype. IBS-C supernatants reduced EGC proliferation and IBS-D and IBS-M supernatants reduced Ca2+ response to ATP in EGC. EGC expressed H1R and the effects of supernatant upon Ca2+ response to ATP in EGC were blocked by pyrilamine and reproduced by histamine via H1R. IBS supernatants reduced mRNA expression of connexin-43. The S100ß-stained area was negatively correlated with the frequency and intensity of pain and bloating. CONCLUSION AND INFERENCES: Changes in EGC occur in IBS, involving mucosal soluble factors. Histamine, via activation of H1R-dependent pathways, partly mediates altered Ca2+ response to ATP in EGC. These changes may contribute to the pathophysiology and the perception of pain and bloating in patients with IBS.

Chronic intestinal pseudo-obstruction: Progress in management?

Chronic intestinal pseudo-obstruction (CIPO) is a severe form of gastrointestinal dysmotility (often due to derangement of the innervation/smooth muscle/interstitial cells of Cajal) with recurrent episodes of intestinal subocclusion mimicking a mechanical obstruction. Because of its complexity and heterogeneity, CIPO is often misdiagnosed or remains unrecognized until advanced stages. Management is a critical aspect in CIPO patient care. So far, most prokinetic drugs have not proven efficacy in restoring intestinal propulsion, thus nutritional support, fluid/electrolyte replacement, and antibiotics are the mainstay of treatment. In this issue of the journal, Ohkubo et al showed promising data indicating that percutaneous endoscopic gastro-jejunostomy (PEG-J) can be proposed as a measure for intestinal decompression, thereby improving CIPO-associated abdominal symptoms, including pain. In addition to a concise update of clinical and diagnostic features, the present minireview tackles management options, with a major emphasis on PEG-J, for CIPO patients.

Localization of the 5-hydroxytryptamine 4 receptor in equine enteric neurons and extrinsic sensory fibers.

BACKGROUND: Serotonin plays a pivotal role in regulating gut motility, visceral sensitivity, and fluid secretion via specific receptors. Among these receptors, 5-HT4 exerts a prominent control on gut motor function. Although the prokinetic effect exerted by 5-HT4 agonists is well known, the cellular sites of 5-HT4 expression remain poorly understood in large mammals, e.g., horses. In this study, we evaluated the distribution of 5-HT4 in the horse intestine and in foals with enteric aganglionosis, reminiscent of human Hirschsprung's disease. METHODS: The intestine and spinal ganglia were obtained from three healthy horses and two foals with hereditary ileocolonic aganglionosis. Tissues were processed for immunohistochemistry using a specific antibody to 5-HT4 and a variety of neuronal markers. Myenteric and submucosal plexus 5-HT4 -immunoreactive (IR) neurons were quantified as relative percentage (mean±SD) to the total number of neurons counted. Furthermore, the density of 5-HT4 -IR nerve fibers was evaluated in the mucosa and tunica muscularis. KEY RESULTS: The 5-HT4 immunoreactivity was localized to large percentages of myenteric neurons ranging from 28±9% (descending colon) to 63±19% (ileum), and submucosal neurons ranging from 54±6% (ileum) to 68±14% (duodenum). The 5-HT4 -immunoreactivity was co-expressed by some substance P-IR (SP-IR) spinal ganglion neurons and extrinsic sensory fibers of aganglionic foals. CONCLUSIONS & INFERENCES: The presence of 5-HT4 in many enteric and extrinsic sensory neurons and nerve fibers provides solid morphological evidence of the cellular sites of 5-HT4 expression in horses. The evidence of SP-IR sensory neurons positive for 5-HT4 suggests its role in visceral sensitivity.

Downregulation of neuronal vasoactive intestinal polypeptide in Parkinson's disease and chronic constipation.

BACKGROUND: Chronic constipation (CC) is a common and severe gastrointestinal complaint in Parkinson's disease (PD), but its pathogenesis remains poorly understood. This study evaluated functionally distinct submucosal neurons in relation to colonic motility and anorectal function in PD patients with constipation (PD/CC) vs both CC and controls. METHODS: Twenty-nine PD/CC and 10 Rome III-defined CC patients were enrolled. Twenty asymptomatic age-sex matched subjects served as controls. Colonic transit time measurement and conventional anorectal manometry were evaluated in PD/CC and CC patients. Colonoscopy was performed in all three groups. Colonic submucosal whole mounts from PD/CC, CC, and controls were processed for immunohistochemistry with antibodies for vasoactive intestinal polypeptide (VIP) and peripheral choline acetyltransferase, markers for functionally distinct submucosal neurons. The mRNA expression of VIP and its receptors were also assessed. KEY RESULTS: Four subgroups of PD/CC patients were identified: delayed colonic transit plus altered anorectal manometry (65%); delayed colonic transit (13%); altered manometric pattern (13%); and no transit and manometric impairment (9%). There were no differences in the number of neurons/ganglion between PD/CC vs CC or vs controls. A reduced number of submucosal neurons containing VIP immunoreactivity was found in PD/CC vs controls (P<.05). VIP, VIPR1, and VIPR2 mRNA expression was significantly reduced in PD/CC vs CC and controls (P<.05). CONCLUSIONS AND INFERENCES: Colonic motor and rectal sensory functions are impaired in most PD/CC patients. These abnormalities are associated with a decreased VIP expression in submucosal neurons. Both sensory-motor abnormalities and neurally mediated motor and secretory mechanisms are likely to contribute to PD/CC pathophysiology.

Chronic intestinal pseudo-obstruction in children and adults: diagnosis and therapeutic options.

BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) represents the most severe form of gastrointestinal dysmotility with debilitating and potentially lethal consequences. Symptoms can be non-specific, and result in this condition being diagnosed incorrectly or too late with consequences for morbidity and even mortality. PURPOSE: The present article aims to provide pediatric and adult gastroenterologists with an up to date review about clinical features, diagnosis and therapeutic options for CIPO. Although pediatric and adult CIPO share many clinical aspects distinctive features can be identified. There is no single diagnostic test or pathognomonic finding of CIPO, thus a stepwise approach including radiology, endoscopy, laboratory, manometry, and histopathology should be considered in the diagnostic work-up. Treatment of patients with CIPO is challenging and requires a multidisciplinary effort with participation of appropriately experienced gastroenterologists, pathologists, dieticians, surgeons, psychologists, and other subspecialists based on the presence of comorbidities. Current treatment options invariably involve surgery and specialized nutritional support, especially in children. Medical therapies are mainly aimed to avoid complications such as sepsis or intestinal bacterial overgrowth and, where possible, restore intestinal propulsion. More efficacious therapeutic options are eagerly awaited for such difficult patients.

Distribution of α-transducin and α-gustducin immunoreactive cells in the chicken (Gallus domesticus) gastrointestinal tract.

The expression and distribution patterns of the taste signaling molecules, α-gustducin (Gαgust) and α-transducin (Gαtran) G-protein subunits, were studied in the gastrointestinal tract of the chicken (Gallus domesticus) using the immunohistochemical method. Gαgust and Gαtran immunoreactive (-IR) cells were observed in the mucosal layer of all examined segments, except the esophagus, crop, and the saccus cranialis of the gizzard. The highest numbers of Gαgust and Gαtran-IR cells were found in the proventriculus glands and along the villi of the pyloric, duodenum, and rectal mucosa. Gαgust and Gαtran-IR cells located in the villi of the jejunum, ileum, and cloaca were much less numerous, while only a few Gαgust and Gαtran-IR cells were detected in the mucosa of the proventriculus and cecum. In the crypts, IR cells were observed in the small and large intestine as well as in the cloaca. Gαgust and Gαtran-IR cells displayed elongated ("bottle-" or "pear-like") or rounded shape. The demonstration of Gαgust and Gαtran expression provides evidence for taste receptor mediated mucosal chemosensitivity in the chicken gastrointestinal tract.

Enteroendocrine cells: a review of their role in brain-gut communication.

BACKGROUND: Specialized endoderm-derived epithelial cells, that is, enteroendocrine cells (EECs), are widely distributed throughout the gastrointestinal (GI) tract. Enteroendocrine cells form the largest endocrine organ in the body and play a key role in the control of GI secretion and motility, the regulation of food intake, postprandial glucose levels and metabolism. EECs sense luminal content and release signaling molecules that can enter the circulation to act as classic hormones on distant targets, act locally on neighboring cells and on distinct neuronal pathways including enteric and extrinsic neurons. Recent studies have shed light on EEC sensory transmission by showing direct connections between EECs and the nervous system via axon-like processes that form a well-defined neuroepithelial circuits through which EECs can directly communicate with the neurons innervating the GI tract to initiate appropriate functional responses. PURPOSE: This review will highlight the role played by the EECs in the complex and integrated sensory information responses, and discuss the new findings regarding EECs in the brain-gut axis bidirectional communication.