Roles ofin vitro- andin vivo-administered histamine and serotonin in compound 48/80-induced gastric acid secretion in isolated,perfused rat stomach

In this investigation, an isolated, perfused rat stomach system was used to elucidate the roles of histamine, serotonin, and the action of cimetidine, methysergide, and propranolol in relation to the in vivo and in vitro administration of compound 48/80. While histamine administered both in vivo and in vitro stimulated acid secretion in the perfused rat stomach, serotonin, added in vitro, inhibited histamine-induced gastric acid secretion. Cimetidine, given either in vivo or in vitro, blocked histamine-induced acid secretion, and methysergide, but not propranolol, reversed the serotonin-induced inhibition of histamine-stimulated acid secretion. Compound 48/80, given in vitro, caused gastric acid secretion that was blocked by pretreatment with cimetidine. Administered in vivo, however, compound 48/80 inhibited both basal and histamine-stimulated acid secretion. This inhibition was partially reversed by pretreatment with methysergide. The absence of inhibition of acid secretion by in vitro-administered compound 48/80 may be related to the timing of the serotonin effect. When serotonin was given prior to histamine, it blocked acid secretion, whereas no inhibition occurred when serotonin was administered together with histamine. None of the other agents investigated affected basal acid secretion.     

Gastric mucosal histamine storing cells

Gastric mucosal histamine content, enterochromaffin-like cell density, and mast cell density were studied in 13 subjects under omeprazole therapy, 13 partially gastrectomized subjects with a Billroth II reconstruction, 10 partially gastrectomized subjects with a Roux-en-Y reconstruction, and 9 control subjects. Histamine content was significantly greater both in the subjects with higher gastrinemic levels (omeprazole-treated subjects) and those with more abundant enterogastric reflux (Billroth II subjects) than in controls. Enterochromaffin-like cell density was significantly greater in the omeprazole subjects than in each of the other groups. Mast cell density was significantly greater in Billroth II subjects than in controls. Serum gastrin levels, mucosal histamine content, and enterochromaffin-like cell density were positively correlated. Gastrin was not correlated to mast cell densilty. These results support the existence of different control pathways for enterochromaffin-like and mast cells. Moreover, they suggest that enterochromaffin-like cells and mast cells are involved in the regulation of gastric secretion and in gastric mucosal injury-repair mechanisms, respectively, due to histamine release.     

Invasiveness of fibroblast-like synoviocytes is an individual patient characteristic associated with the rate of joint destruction in patients with rheumatoid arthritis

OBJECTIVE: Rheumatoid arthritis (RA) is characterized by inflammation and destruction of synovial joints. Fibroblast-like synoviocytes (FLS) harvested from synovial tissue of patients with RA can invade normal human cartilage in severe combined immunodeficient (SCID) mice and Matrigel basement membrane matrix in vitro. This study was undertaken to investigate the association of these in vitro characteristics with disease characteristics in patients with RA. METHODS: Synovial tissue samples from 72 RA and 49 osteoarthritis (OA) patients were obtained. Samples of different joints were collected from 7 patients with RA. The FLS invasiveness in Matrigel was studied, and the intraindividual and interindividual differences were compared. From the patients with FLS who exhibited the most extreme differences in in vitro ingrowth (most and least invasive FLS), radiographs of the hands and feet were collected and scored according to the Sharp/van der Heijde method to determine the relationship between in vitro invasion data and estimated yearly joint damage progression. RESULTS: FLS from patients with RA were more invasive than FLS from patients with OA (P < 0.001). The mean intraindividual variation in FLS invasion was much less than the mean interindividual variation (mean +/- SD 1,067 +/- 926 and 3,845 +/- 2,367 for intraindividual and interindividual variation, respectively; P = 0.035), which shows that the level of FLS invasion is a patient characteristic. The mean +/- SEM Sharp score on radiographs of the hands or feet divided by the disease duration was 4.4 +/- 1.1 units per year of disease duration in patients with the least invasive FLS (n = 9), which was much lower compared with the 21.8 +/- 3.1 units per year of disease duration in patients with the most invasive FLS (n = 9) (P < 0.001). CONCLUSION: The ex vivo invasive behavior of FLS from RA patients is associated with the rate of joint destruction and is a patient characteristic, given the much smaller intraindividual than interindividual FLS variation.     

Cellular and humoral sensitivity to gluten fractions in patients with treated nontropical sprue

The presence of circulating antibodies and lymphocyte response to gliadin and fraction III were measured in three groups of 12 patients each. Group I consisted of patients with nontropical sprue maintained on a gluten-free diet; Group II contained patients with other gastrointestinal diseases manifesting malabsorption and Group III was composed of normal controls. Rabbits immunized to both antigens provided positive controls for each method of antibody determination. Results agree with those previously reported in that negligible antibody titers were present to either antigen in normals, patients with other forms of malabsorption or patients with nontropical sprue maintained, for some time, on a gluten-free diet. Lymphocyte stimulation failed to occur with either gluten fraction although the hyporesponsiveness to phytohemagglutinin, previously reported by others, was not observed. Further studies are needed in patients with nontropical sprue following controlled antigenic challenge. Antibody levels in jejunal fluid should also be studied. Until such studies are carried out, evaluation of immunologic factors in the pathogenesis of nontropical sprue will be incomplete.     

Reduction of treatment delay in patients with ST-elevation myocardial infarction: impact of pre-hospital diagnosis and direct referral to primary percutaneous intervention.

We were interested to read the paper by Terkelsen et al.¹ describingpre-hospital identification, by physicians, of patients suitablefor     

PRIORITY SETTING IN GLOBAL HEALTH: TOWARDS A MINIMUM DALY VALUE

Rational and analytic healthcare decision making employed by many national healthcare‐funding bodies could also be expected from global health donors. Cost effectiveness analysis of healthcare investment options presents the effectiveness of a particular action in proportion to the resources required, and cost effectiveness thresholds, while somewhat arbitrary, define the level at which the investment can be considered value for money. Currently, cost effectiveness thresholds reflect the national budget context or willingness‐to‐pay, which is problematic when making cross‐country comparisons. Defining a global minimum monetary value for the disability adjusted life year (DALY) would in effect set a global baseline cost effectiveness threshold. A global minimum DALY value would reflect a universal minimum value on human health, irrespective of a national provider's willingness or ability to pay. A minimum DALY value and associated threshold has both limitations and flaws but is justified on similar grounds to the Millennium Development Goals or the absolute poverty threshold and has the potential to radically improve transparency and efficiency of priority setting in global health. Copyright © 2013 John Wiley & Sons, Ltd.     

Effects of Pre-pregnancy Obesity,Race/Ethnicity and Prematurity

To investigate the association between maternal pre-pregnancy obesity, race/ethnicity and prematurity. Retrospective cohort study of maternal deliveries at a single regional center from 2009 to 2010 time period (n = 11,711). Generalized linear models were used for the analysis to estimate an adjusted odds ratio with 95 % confidence interval of the association between maternal pre-pregnancy obesity, race/ethnicity and prematurity. Analysis controlled for diabetes, chronic hypertension, previous preterm birth, smoking and insurance status. The demographics of the study population were as follows, race/ethnicity had predominance in the White/Non-Hispanic population with 60.1 %, followed by the Black/Non-Hispanic population 24.2 %, the Hispanic population with 10.3 % and the Asian population with 5.4 %. Maternal pre-pregnancy weight showed that the population with a normal body mass index (BMI) was 49.4 %, followed by the population being overweight with 26.2 %, and last, the population which was obese with 24.4 %. Maternal obesity increased the odds of prematurity in the White/Non-Hispanic, Hispanic and Asian population (aOR 1.40, CI 1.12–1.75; aOR 2.20, CI 1.23–3.95; aOR 3.07, CI 1.16–8.13, respectively). Although the Black/Non-Hispanic population prematurity rate remains higher than the other race/ethnicity populations, the Black/Non-Hispanic population did not have an increased odds of prematurity in obese mothers (OR 0.87; CI 0.68–1.19). Unlike White/Non-Hispanic, Asian and Hispanic mothers, normal pre-pregnancy BMI in Black/Non-Hispanic mothers was not associated with lower odds for prematurity. The odds for mothers of the White/Non-Hispanic, Hispanic and Asian populations, for delivering a premature infant, were significantly increased when obese. Analysis controlled for chronic hypertension, diabetes, insurance status, prior preterm birth and smoking. Obesity is a risk factor for prematurity in the White/Non-Hispanic, Asian and Hispanic population, but not for the Black/Non-Hispanic population. The design and evaluation of weight-based maternal health programs that aggregate race/ethnicity may not be sufficient. The optimal method to address maternal pre-pregnancy and intra-pregnancy weight-related health disorders may need to be stratified along race/ethnicity adjusted strategies and goals. However, a more global preventative strategy that encompasses the social determinants of health may be needed to reduce the higher rates of prematurity among the Black/Non-Hispanic population.     

Recognising Autism Spectrum Disorders in Primary Care: Perspectives of Speech and Language Therapists

Understanding the process of recognising autism spectrum disorders (ASD) in children is important, both for achieving timely identification of children's difficulties and for ensuring positive experiences for families. Professionals working in primary care services are suitably positioned to identify children requiring referral for diagnostic assessment of ASD through their early contact with children and their families. Speech and language therapists (SLTs) in particular are well situated to recognise ASD, as concerns regarding communication development are frequently raised by parents of children who later go on to receive an ASD diagnosis. This small-scale qualitative study aimed to explore primary care SLTs' experiences of recognising potential ASD in children. Five SLTs working in primary care services in the Republic of Ireland participated in semi-structured interviews. Thematic analysis of the data revealed that participants were concerned with two key events: firstly, accurately recognising potential ASD in children; and secondly, discussing the possibility of ASD with parents. The SLTs' experiences of these events were found to be influenced by both individual and wider organisational factors. The findings are discussed in the context of the current literature on ASD identification and implications for practice are considered.     

Phase-II metabolism limits the antiproliferative activity of urolithins in human colon cancer cells

Purpose

Urolithins, gut microbiota metabolites derived from ellagic acid and ellagitannins, reach micromolar concentrations in the colon lumen where can have anti-inflammatory and anticancer effects. The antiproliferative activity of urolithins (Uro-A, Uro-B, Uro-C and Uro-D) and their most relevant in vivo glucuronides were evaluated in three human colon cancer cell lines (Caco-2, SW480 and HT-29).

Methods

Cell proliferation was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide and Trypan blue exclusion assays. Cell cycle was evaluated by flow cytometry and urolithins metabolism by HPLC–MS/MS.

Results

Urolithins inhibited cell proliferation and cell cycle progression in a time- and dose-dependent manner and arrested the cells at S and G2/M phases, depending on the urolithin. Uro-A exerted the highest antiproliferative activity, followed by Uro-C, Uro-D and Uro-B. Unlike Caco-2 and SW480 cells, HT-29 cells partially overcame the effects after 48 h, which was related to the complete glucuronidation of urolithins. Uro-A or Uro-B glucuronides did not affect cell cycle and showed lower antiproliferative activity than their aglycone counterparts. Uro-A or Uro-B plus inhibitors of drug efflux ABC transporters partially prevented the glucuronidation of urolithins in HT-29 cells which became more sensitive.

Conclusions

Uro-A, Uro-B, Uro-C and Uro-D exerted different antiproliferative effects depending on the colon cancer cell line. We also report here, for the first time, the role of ABC transporters and Phase-II metabolism in HT-29 cells as a mechanism of cancer resistance against urolithins due to their conversion to glucuronide conjugates that exerted lower antiproliferative activity.