Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis.

Consensus diagnostic recommendations to distinguish GORD from eosinophilic oesophagitis (EoE) by response to a trial of proton pump inhibitors (PPIs) unexpectedly uncovered an entity called 'PPI-responsive oesophageal eosinophilia' (PPI-REE). PPI-REE refers to patients with clinical and histological features of EoE that remit with PPI treatment. Recent and evolving evidence, mostly from adults, shows that patients with PPI-REE and patients with EoE at baseline are clinically, endoscopically and histologically indistinguishable and have a significant overlap in terms of features of Th2 immune-mediated inflammation and gene expression. Furthermore, PPI therapy restores oesophageal mucosal integrity, reduces Th2 inflammation and reverses the abnormal gene expression signature in patients with PPI-REE, similar to the effects of topical steroids in patients with EoE. Additionally, recent series have reported that patients with EoE responsive to diet/topical steroids may also achieve remission on PPI therapy. This mounting evidence supports the concept that PPI-REE represents a continuum of the same immunological mechanisms that underlie EoE. Accordingly, it seems counterintuitive to differentiate PPI-REE from EoE based on a differential response to PPI therapy when their phenotypic, molecular, mechanistic and therapeutic features cannot be reliably distinguished. For patients with symptoms and histological features of EoE, it is reasonable to consider PPI therapy not as a diagnostic test, but as a therapeutic agent. Due to its safety profile, ease of administration and high response rates (up to 50%), PPI can be considered a first-line treatment before diet and topical steroids. The reasons why some patients with EoE respond to PPI, while others do not, remain to be elucidated.

Valeur diagnostique du rapport CD103+CD4+/CD4+ pour différencier la sarcoïdose d'autres causes de lymphocytose alvéolaire.

Introduction: CD103 is a specific integrin present on some CD4+ lymphocytes of the mucosal immune system. It has been hypothesized that most CD4+ lymphocytes in pulmonary sarcoidosis do not originate from mucosal sites but from redistribution from the peripheral blood, and therefore do not bear the CD103 integrin. Several studies have suggested that a low CD103+ percentage among bronchoalveolar lavage (BAL) CD4+ lymphocytes discriminates between sarcoidosis and other causes of lymphocytic alveolitis, but contradictory data exist. Methods: We reviewed 1151 consecutive patients with BAL lymphocytosis >10% and flow cytometry performed between 2006 and 2014. 944 cases were excluded due to poor BAL quality (n= 97), unavailable clinical data (n= 760), or unclear diagnosis (n= 87). The remaining 207 patients were grouped into 9 diagnostic categories. To assess the discriminative value of the CD103+CD4+/CD4+ ratio to distinguish sarcoidosis from the other entities, area under ROC curves (AUC) were determined. Results: Sarcoidosis patients (n=53) had a lower CD103+CD4+/CD4+ ratio than the other diagnostic categories. AUC was 62% for sarcoidosis compared to all other patients and 69% for sarcoidosis compared to other interstitial lung diseases. When combining CD103+CD4+/CD4+ and CD4+/CD8+ ratios, AUC increased to 76% and 78% respectively. When applying published cut-offs from 4 previous studies to our population, AUC varied between 54 and 73%. Conclusions: The CD103+CD4+/CD4+ ratio does not accurately discriminate between sarcoidosis and other causes of lymphocytic alveolitis, neither alone nor in combination with CD4+/CD8+ ratio, and is not a relevant marker for the diagnosis of sarcoidosis.

A randomized double-blind control study of early intra-coronary autologous bone marrow cell infusion in acute myocardial infarction: the REGENERATE-AMI clinical trial?.

AIMS: Clinical trials suggest that intracoronary delivery of autologous bone marrow-derived cells (BMCs) 1-7 days post-acute myocardial infarction (AMI) may improve left ventricular (LV) function. Earlier time points have not been evaluated. We sought to determine the effect of intracoronary autologous BMC on LV function when delivered within 24 h of successful reperfusion therapy. METHODS AND RESULTS: A multi-centre phase II randomized, double-blind, and placebo-controlled trial. One hundred patients with anterior AMI and significant regional wall motion abnormality were randomized to receive either intracoronary infusion of BMC or placebo (1:1) within 24 h of successful primary percutaneous intervention (PPCI). The primary endpoint was the change in left ventricular ejection fraction (LVEF) between baseline and 1 year as determined by advanced cardiac imaging. At 1 year, although LVEF increased compared with baseline in both groups, the between-group difference favouring BMC was small (2.2%; 95% confidence interval, CI: -0.5 to 5.0; P = 0.10). However, there was a significantly greater myocardial salvage index in the BMC-treated group compared with placebo (0.1%; 95% CI: 0.0-0.20; P = 0.048). Major adverse events were rare in both treatment groups. CONCLUSION: The early infusion of intracoronary BMC following PPCI for patients with AMI and regional wall motion abnormality leads to a small non-significant improvement in LVEF when compared with placebo; however, it may play an important role in infarct remodelling and myocardial salvage. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT00765453 and EudraCT 2007-002144-16.

Molecular Markers of Oral Lichen Planus

Oral lichen planus (OLP) is a chronic inflammatory mucosal disease and is detected in between 0.5% - 2.2% of the population. WHO has defined OLP as a potentially precancerous disorder, representing a generalized state associated with a significantly increased risk of cancer. However, only 0.5 – 2.9% of OLP lesions will progress to cancer. Currently, there are no prognostic markers to identify the lesions at increased risk for malignant transformation. The main aim of these studies was to identify cellular and molecular markers in order to understand the pathogenesis of atrophic OLP and its progression towards malignancy. Selected markers for cell proliferation, adhesion, apoptosis, and lymphocytic infiltration were assessed by immunohistochemistry in addition to static cytometry analyses for DNA content. DNA quantification of epithelial cells in 82 biopsy samples derived from atrophic lichen planus showed altered DNA content in 41% of the samples. DNA content was associated with proliferation activity, topoisomerase IIalpha, desmocollin-1 and infection with human papillomavirus. CD27+ and CD38+ lymphocytes were detected in inflammatory cell infiltrate, indicating an abnormal homing of B cells from blood circulation to tissue. Physiologic cell death, apoptosis, is frequently seen in OLP, but its pathways are unknown. Here it was shown that caspases 2 and 12 were up-regulated in OLP, indicating that intracellular apoptosis, rather than an external causal factor, is triggering apoptosis. However, this thesis could not identify any singular prognostic marker of malignancy in OLP. Thus, every OLP patient should receive regular follow-up care to identify cancer risk patients at an early stage.

Probiotic interventions in infancy: Benefit and Safety Assessment of Extended Applications

Immaturity of the gut barrier system in the newborn has been seen to underlie a number of chronic diseases originating in infancy and manifesting later in life. The gut microbiota and breast milk provide the most important maturing signals for the gut-related immune system and reinforcement of the gut mucosal barrier function. Recently, the composition of the gut microbiota has been proposed to be instrumental in control of host body weight and metabolism as well as the inflammatory state characterizing overweight and obesity. On this basis, inflammatory Western lifestyle diseases, including overweight development, may represent a potential target for probiotic interventions beyond the well documented clinical applications. The purpose of the present undertaking was to study the efficacy and safety of perinatal probiotic intervention. The material comprised two ongoing, prospective, double-blind NAMI (Nutrition, Allergy, Mucosal immunology and Intestinal microbiota) probiotic interventions. In the mother-infant nutrition and probiotic study altogether 256 women were randomized at their first trimester of pregnancy into a dietary intervention and a control group. The intervention group received intensive dietary counselling provided by a nutritionist, and were further randomized at baseline, double-blind, to receive probiotics (Lactobacillus rhamnosus GG and Bifidobacterium lactis) or placebo. The intervention period extended from the first trimester of pregnancy to the end of exclusive breastfeeding. In the allergy prevention study altogether 159 women were randomized, double-blind, to receive probiotics (Lactobacillus rhamnosus GG) or placebo 4 weeks before expected delivery, the intervention extending for 6 months postnatally. Additionally, patient data on all premature infants with very low birth weight (VLBW) treated in the Department of Paediatrics, Turku University Hospital, during the years 1997 - 2008 were utilized. The perinatal probiotic intervention reduced the risk of gestational diabetes mellitus (GDM) in the mothers and perinatal dietary counselling reduced that of fetal overgrowth in GDM-affected pregnancies. Early gut microbiota modulation with probiotics modified the growth pattern of the child by restraining excessive weight gain during the first years of life. The colostrum adiponectin concentration was demonstrated to be dependent on maternal diet and nutritional status during pregnancy. It was also higher in the colostrum received by normal-weight compared to overweight children at the age of 10 years. The early perinatal probiotic intervention and the postnatal probiotic intervention in VLBW infants were shown to be safe. To conclude, the findings in this study provided clinical evidence supporting the involvement of the initial microbial and nutritional environment in metabolic programming of the child. The manipulation of early gut microbial communities with probiotics might offer an applicable strategy to impact individual energy homeostasis and thus to prevent excessive body-weight gain. The results add weight to the hypothesis that interventions aiming to prevent obesity and its metabolic consequences later in life should be initiated as early as during the perinatal period.

Interactions between Polyunsaturated Fatty Acids and Probiotics

The prevalence of inflammatory based diseases has increased in industrialized countries over the last decades. For allergic diseases, two primary hypotheses have been proposed to explain this phenomenon, namely the hygiene and dietary evolution based hypothesis. Particularly, the reduced early exposure to microbes and an increase in the amount of polyunsaturated fatty acids (especially n-6 PUFA) in the diet have been discussed. Often, these two factors have been studied independently, even though both factors have been shown to possess potential health benefits and their mode of action to share similar mechanisms. The hypothesis of the present study was that demonstrate that PUFA and probiotics are not separate entities as such but do interact with each other. In the present study, we investigated whether maternal diet and atopic status influence the PUFA composition of breast milk and serum fatty acids of infants, and whether the fatty acid absorption and utilization of infant formula fatty acids is affected by supplementation of infant formula with probiotic bacteria (Lactobacillus GG and Bifidobacterium lactis Bb-12). Moreover, we investigated the mechanisms by which different PUFA influence the physicochemical and functional properties of probiotics as well as functionality of epithelial cells in vitro. We demonstrated a carry-over effect of dietary fatty acids from maternal diet via breast milk into infants’ serum lipid fatty acids. Our data confirmed the previously shown allergy –related PUFA level imbalances, though it did not fully support the impaired desaturation and elongation capacity hypothesis. We also showed that PUFA incorporation into phospholipids of infants was influenced by probiotics in infant formula in a strain dependent manner. Especially,Bifidobacterium lactis Bb-12 in infant formula promoted the utilization of n-3 PUFA. Mechanistically, we demonstrated that probiotics (Lactobacillus GG, Lactobacillus casei Shirota and Lactobacillus bulgaricus) did incorporate and interconvert exogenous free PUFA in the growth medium into bacterial fatty acids strain and PUFA dependently. In general, high concentrations of free PUFA inhibited the growth and mucus adhesion of probiotics, whereas low concentrations of specific long chain PUFA were found to promote the growth and mucus adhesion of Lactobacillus casei Shirota. These effects were paralleled with only minor alterations in hydrophobicity and electron donor – electron acceptor properties of lactobacilli. Furthermore, free PUFA were also demonstrated to alter the adhesion capacity of the intestinal epithelial cells; n-6 PUFA tended to inhibit the Caco-2 adhesion of probiotics, whereas n-3 PUFA had either no or minor effects or even promote the bacterial adhesion (especially Lactobacillus casei Shirota) to PUFA treated Caco-2 cells. The results of this study demonstrate the close and bilateral interactions between dietary PUFA and probiotics. Probiotics were shown to influence the absorption and utilization of dietary PUFA, whereas PUFA were shown to alter the functional properties of both probiotics and mucosal epithelia. These findings suggest that a more thorough understanding of interactions between PUFA and intestinal microbiota is a prerequisite, when the beneficial effects of new functional foods containing probiotics are designed and planned for human intervention studies.

Síndrome de chilaiditi associada a megaduodeno e megacólon transverso

Chilaiditi syndrome is a rare abnormality, uncommon in children, whith an incidence increasing with the age, ranging from 0.025% to 0.28% in the general population usually affecting males. The patients are usually asymptomatics and the syndrome is incidently discover through radiologic exams. However, abdominal pain and distention, nauseas, vomits and changes in intestinal habits, and even intestinal obstruction can occur. The authors report a case of a patient with Chilaiditi's syndrome associated to megastomach, megaduodenum and megacolon.

Neurobiology of pathological gambling. Brain imaging and epidemiological studies

Pathological gambling, a form of behavioral addiction, refers to maladaptive, compulsive gambling behavior severely interfering with an individual’s normal life. The prevalence of pathological gambling has been estimated to be 1–2% in western societies. The reward deficiency hypothesis of addiction assumes that individuals that have, or are prone, to addictions have blunted mesolimbic dopamine reward signaling, which leads to compulsive reward seeking in an attempt to compensate for the malfunctioning brain reward network. In this research project, the effects of gambling were measured using brain [11C] raclopride PET during slot machine gambling and possible brain structural changes associated with pathological gambling using MRI. The subjects included pathological gamblers and healthy volunteers. In addition, impulse control disorders associated with Parkinson’s disease were investigated by using brain [18F]fluorodopa PET and conducting an epidemiological survey. The results demonstrate mesolimbic dopamine release during gambling in both pathological gamblers and healthy volunteers. Striatal dopamine was released irrespective of the gambling outcome, whether the subjects won or not. There was no difference in gambling induced dopamine release between pathological gamblers and control subjects, although the magnitude of the dopamine release correlated with gambling related symptom severity in pathological gamblers. The results also show that pathological gambling is associated with extensive abnormality of brain white matter integrity, as measured with diffusion tensor imaging, similar to substance-addictions. In Parkinson’s disease patients with impulse control disorders, enhanced brain [18F] fluorodopa uptake in the medial orbitofrontal cortex was observed, indicating increased presynaptic monoamine function in this region, which is known to influence signaling in the mesolimbic system and reward processing. Finally, a large epidemiological survey in Finnish Parkinson’s disease patients showed that compulsive behaviors are very common in Parkinson disease and they are strongly associated with depression. These findings demonstrate the role of dopamine in pathological gambling, without support for the concept of reward deficiency syndrome.

Duplicação uretral em homem adulto

Urethral duplication is a rare congenital anomaly. The clinical presentation and treatment varies because of the different anatomical patterns of this abnormality. We report a case of this entity in the adult male patient. The clinical, radiological and endoscopic findings, as well as the treatment are discussed.

Tobacco experimental model to induce urinary bladder neoplasms

OBJECTIVE: to develop an experimental model of exposure to tobacco burning (cigarette) products to assess the effects of its chronic use in relation to cancers of the bladder. METHODS: the animals were chronically exposed to the burning tobacco products in a semi-open chamber to simulate smoking. Thirty young Wistar rats were divided into two groups: one with 20 animals simulating smoking for six months, and ten not exposed control animals for the same period. After exposure by inhalation of cigarette smoke, animals were euthanized and subjected to histopathological study of the bladder wall. RESULTS: no tumor was found but mild and non significant alterations. The studies of hemo-oximetry (carboxyhemoglobin and methemoglobin) and the concentration of carbon dioxide (CO2) confirm that the animals were exposed to high concentrations of tobacco smoke and its derivatives. CONCLUSION: no bladder mucosal neoplasia was found in the pathological study of animals. The developed experimental models were highly efficient, practical and easy to use and can be used in other similar studies to determine the harmful effects caused by smoking.

Hofbauer cells morphology and density in placentas from normal and pathological gestations

PURPOSE: In placentas from uncomplicated pregnancies, Hofbauer cells either disappear or become scanty after the fourth to fifth month of gestation. Immunohistochemistry though, reveals that a high percentage of stromal cells belong to Hofbauer cells. The aim of this study was to investigate the changes in morphology and density of Hofbauer cells in placentas from normal and pathological pregnancies. METHODS: Seventy placentas were examined: 16 specimens from normal term pregnancies, 10 from first trimester's miscarriages, 26 from cases diagnosed with chromosomal abnormality of the fetus, and placental tissue specimens complicated with intrauterine growth restriction (eight) or gestational diabetes mellitus (10). A histological study of hematoxylin-eosin (HE) sections was performed and immunohistochemical study was performed using the markers: CD 68, Lysozyme, A1 Antichymotrypsine, CK-7, vimentin, and Ki-67. RESULTS: In normal term pregnancies, HE study revealed Hofbauer cells in 37.5% of cases while immunohistochemistry revealed in 87.5% of cases. In first trimester's miscarriages and in cases with prenatal diagnosis of fetal chromosomal abnormalities, both basic and immunohistochemical study were positive for Hofbauer cells. In pregnancies complicated with intrauterine growth restriction or gestational diabetes mellitus, a positive immunoreaction was observed in 100 and 70% of cases, respectively. CONCLUSIONS: Hofbauer cells are present in placental villi during pregnancy, but with progressively reducing density. The most specific marker for their detection seems to be A1 Antichymotrypsine. It is remarkable that no mitotic activity of Hofbauer cells was noticed in our study, as the marker of cellular multiplication Ki-67 was negative in all examined specimens.

Gastric ulcers in pigs affected with postweaning multisystemic wasting syndrome

Samples of gastric lymph nodes and the stomachs from 24 pigs selected from herds affected by postweaning multisystemic wasting syndrome (PMWS) and sudden death associated with gastric ulcers were studied. Pigs were selected on the basis of unthriftiness, decreased feed intake, and wasting. The stomachs were opened, inverted, and classified into 0-3 score according the severity of the gross lesions present in pars oesophagica (non-glandulargastric mucosa). Selected samples were processed for paraffin embedding and stained with hematoxylin and eosin. Immunohistochemistry using anti-PCV2 (porcine circovírus type 2) antibody, anti-Helicobacter pylori antibody and a wide-spectrum anti-cytokeratin antibody was performed. Gross changes in pars oesophagea were classified according to the severity of lesions as score 3, 2, and 1 in 8, 6, 5 stomachs respectivelly. Microscopically, hyperplastic lymphoid follicles, lymphohistiocytic inflammatory infiltrates and focci of necrosis in the gastric mucosa were common findings. Large amounts of PCV2 antigen were observed in the cytoplasm and nuclei from intralesional cells and debris from the gastric glandular mucosal zone; however, in the fundus, anti-PCV2 immunostaining was restricted to the surface mucosal cells and foveolar compartment. All gastric lymph nodes were positive for PCV2 antigen. Anti-H. pylori immunostaining was seen in eleven cases, mainly in the antrum, on the mucosal surface and foveolar compartment. The association of the anti-PCV2 immunostaining with the glandular mucus-producing cells suggests a role for PCV2 as an additional factor for the swine ulcer development.

Distribution of collagen types I, III, and IV in gastric tissue of marmosets (Callithrix spp., Callitrichidae: Primates)

Extracellular matrix (ECM) components such as fibrillar collagens play a fundamental role in wound repair and have also been studied in association with the gastric ulcer healing process in gastroenterology. Nevertheless, there have been no studies in the literature to date regarding the description and characterization of ECM components, neither in normal nor in injured gastric tissue of primate species. The objective of this study was to investigate the expression of gastric collagen types I, III, and IV in marmosets (Callithrix sp.). Histological specimens from the stomach of 6 Callithrix jacchus, 12 C. kuhli, and 12 C. geoffroyi were evaluated. The specimens were immunostained with anti-types I and III collagen polyclonal antibodies and anti-type IV collagen monoclonal antibody. Collagen types I and III were detected in the submucosa and lamina propria between the mucosal glands while collagen type IV was detected in the muscularis mucosae, muscular layers, blood vessels, and gastric mucosa between the mucosal glands. It is hoped that these findings can contribute to future studies on the gastric extracellular matrix components in primates and to comparative studies in the area of gastroenterology.

Experimental poisoning by Baccharis megapotamica var. weirii in buffalo

Five male 6-8 month-old Murrah buffalo calves were orally dosed with the fresh aerial parts of Baccharis megapotamica var. weirii at doses of 1, 3, 4, 5 and 10g/kg body weight (bw) (~1-10mg macrocyclic trichothecenes/kg/bw). The B. megapotamica used for the experiment was harvested on a farm where a recent spontaneous outbreak of poisoning caused by such plant had occurred. Clinical signs appeared 4-20 hours and 4 buffaloes died 18-49 hours after the ingestion of the plant. Clinical signs were apathy, anorexia, and watery diarrhea, fever, colic, drooling, muscle tremors, restlessness, laborious breathing and ruminal atony, and dehydration. The most consistent gross findings were restricted to the gastrointestinal (GI) tract consisted of varying degrees of edema and reddening of the mucosa of the forestomach. Histopathological findings consisted of varying degrees of necrosis of the epithelial lining of the forestomach and of lymphocytes within lymphoid organs and aggregates. Fibrin thrombi were consistently found in sub-mucosal vessels of the forestomach and in the lumen of hepatic sinusoids. It is suggested that dehydration, septicemia and disseminated intravascular coagulation participate in the pathogenesis of the intoxication and play a role as a cause of death. A subsample of B. megapotamica var. weirii was frozen-dried and ground and analyzed using UHPLC (Ultra High Performance Liquid Chromatography) with high resolution Time of Flight mass spectrometry and tandem mass spectrometry, it was shown that the plant material contained at least 51 different macrocyclic trichothecenes at a total level of 1.1-1.2mg/g. About 15-20% of the total trichothecenes contents was found to be monosaccharide conjugates, with two thirds of these being glucose conjugates and one third constituted by six aldopentose conjugates (probably xylose), which has never been reported in the literature.

Distribution of immune response cells in the pelvic urethra and the prepuce of rams

The pathogens of the reproductive system in the male can penetrate and establish by ascending route, from to the prepuce to the urethra, accessory glands, epididymis and testicles. The aim of this paper is determine the distribution and number of cells involved in the immune response in prepuce and pelvic urethra of rams, without apparent clinical alterations in testicle, epididymis and prepuce. The distribution of some of the cells involved in the immune response at the level of the prepuce and the pelvic urethra was quantified in four one-year-old rams seronegative for B. ovis and A. seminis and without apparent lesions in the testicles, the epididymis, and the prepuce. At the moment of slaughter, samples were taken from the preputial fornix and the pelvic urethra and placed in 10% formalin and under freezing conditions. CD4, CD8, WC1, CD45RO, CD14 and CD1b cells were demonstrated by immunohistochemistry, and immunoglobulin-containing cells (ICC) of the IgA, IgG and IgM classes were demonstrated by immunofluorescence. The labeled cells present in the mucosa of both organs were counted with an image analyzer. The total number of cells was compared between both tissues and differentially between the epithelium and the connective tissue of the mucosa. Significant differences were found in the total number of CD4, CD45RO, and WC1 lymphocytes, in CD14 macrophages, and CD1b dendritic cells, with mean values being greater in the fornix than in the urethra (p<0.05) in all cases. Only dendritic cells were found in the prepuce. No differences were found in the number of CD8 lymphocytes between both organs. The ratio between each cell type in the connective and the intraepithelial tissues and between organs was 10/1 for CD4 in the fornix (p<0.05), against 7/1 in the urethra (p<0.05), while CD8 had a 1/1 distribution in both mucosae. The WC1 ratio was 5/1 in both mucosae (p<0.05). CD45RO labeling was 19/1 in the prepuce (p<0.05) and 1/1 in the urethra. IgA-containing cells did not show differences in the total number of cells in both tissues. In the urethra, no IgG-containing cells were observed and IgM-containing cells were scarce; in contrast, both cell types were present in the prepuce, in amounts greater than in the urethra (p<0.05). IgA-, IgG-, and IgM-containing cells were located in both organs in the mucosal connective tissue. The presence of antigen-presenting cells, macrophages, and dendritic cells, as well as of lymphocytes CD4, CD8 TCR γδ (WC1), IgA-, IgG and IgM positive cells, and CD45RO cells suggests that both mucosae may behave as inductive and effector sites for the mucosal immune response.