Reduction of cell proliferative activities of gastric stump adenomatous hyperplasias after bile reflux diversion in rats

Previously we reported the majority of lesions induced by bilereflux, in the absence of chemical carcinogens, in the rat remnantstomach to consist primarily of gastric type and secondarilyof intestinal type cells, and that they are reversible afterdiversion of bile reflux. The present study was designed toevaluate changes in proliferative activities in cells of eachtype under these conditions. The frequency of adenomatous hyperplasia(AH) induced in the gastric stump mucosa by duodenal contentreflux after Billroth II partial gastrectomy (BII) increaseduntil the 54th week of the experiment. Roux-en-Y (RY) surgicalprocedure which prevents duodenal reflux performed at the 24thor 36th week after BII led to a decrease in AH. Cell contentof the lesions was analyzed using routine H&E staining,immunohistochemical staining for pepsinogen isoenzyme 1 andhistochemical procedures for mucins (paradoxical concanavalinA, galactose oxidase Schiff and sialidase galactose oxidaseSchiff reactions) and proliferation in each compartment evaluatedby an immunohistochemical method using bromodeoxyuridine (BrdU)and a monoclonal antibody against BrdU. At the 54th week thenumber of BrdU-labeled cells per normal pyloric column was significantly(P < 0.05) increased to 10.63/pit after the BII operation,while it diminished to 5.23/pit after RY diversion, this beingthe same level as with the RY procedure alone. AH maintaineda high rate of BrdU incorporation at 12.7% after BII operation,which was also significantly reduced (P < 0.01) to 7.0% bythe RY surgery. The intestinal type cell showed highest (22.2%),the surface mucous type cell showed the next (16.5%) and thepyloric gland type cell showed lowest (5.2%) BrdU labeling indicesafter BII operation. All the cell types in AH showed similarproportional decreases in BrdU incorporation after RY diversion.Thus surgical intervention reverses the cell proliferation causedby bile reflux in the gastric stump.     

Investigation of under-ascertainment in epidemiological studies based in general practice

BACKGROUND: One of the aims of the Study of Infectious Intestinal Disease (IID) in England is to estimate the incidence of IID presenting to general practice. This sub-study aims to estimate and correct the degree of under-ascertainment in the national study. METHODS: Cases of presumed IID which presented to general practice in the national study had been ascertained by their GP. In 26 general practices, cases with computerized diagnoses suggestive of IID were identified retrospectively. Cases which fulfilled the case definition of IID and should have been ascertained to the coordinating centre but were not, represented the under-ascertainment. Logistic regression modelling was used to identify independent factors which influenced under-ascertainment. RESULTS: The records of 2021 patients were examined, 1514 were eligible and should have been ascertained but only 974 (64%) were. There was variation in ascertainment between the practices (30% to 93%). Patient-related factors independently associated with ascertainment were: i) vomiting only as opposed to diarrhoea with and without vomiting (OR 0.37) and ii) consultation in the surgery as opposed to at home (OR 2.18). Practice-related factors independently associated with ascertainment were: i) participation in the enumeration study component (OR 1.78), ii) a larger number of partners (OR 0.3 for 7-8 partners); iii) rural location (OR 2.27) and iv) previous research experience (OR 1.92). Predicted ascertainment percentages were calculated according to practice characteristics. CONCLUSION: Under-ascertainment of IID was substantial (36%) and non-random and had to be corrected. Practice characteristics influencing variation in ascertainment were identified and a multivariate model developed to identify adjustment factors which could be applied to individual practices. Researchers need to be aware of factors which influence ascertainment in acute epidemiological studies based in general practice.     

Postnatal depression and infant growth and development in low income countries: a cohort study from Goa, India.

BACKGROUND: Postnatal depression is a recognised cause of delayed cognitive development in infants in developed countries. Being underweight is common in South Asia. AIMS: To determine whether postnatal depression contributes to poor growth and development outcomes in Goa, India. METHODS: Cohort study for growth outcomes with nested case-control study for developmental outcomes. A total of 171 babies were weighed and measured at 6-8 weeks following birth. The following measures were used: Edinburgh Postnatal Depression Scale for maternal mood, and sociodemographic and infant health variables. Outcome measures were: weight (<5th centile), length (<5th centile), and Developmental Assessment Scale for Indian Infants scores at six months. RESULTS: Postnatal depression was a strong, and independent, predictor of low weight and length and was significantly associated with adverse mental development quotient scores. CONCLUSIONS: This study provides evidence for the first time that postnatal depression, a potentially treatable disorder, is a cause of poor growth and development in South Asia.     

Induction of CYP1A in the beagle dog by an inhibitor of kinase insert domain-containing receptor: differential effects in vitro and in vivo on mRNA and functional activity.

Compound I [3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2-one] is a potent inhibitor of human kinase insert domain-containing receptor (KDR kinase), which is under investigation for the treatment of cancer. Bile duct-cannulated male beagle dogs were administered 6 mg/kg compound I q.d. for 14 days. There was an approximately 2.5-fold decrease in the mean plasma area under the curve of I on days 7 and 14 (approximately 11.3 microM . h), relative to day 1 (28.2 microM . h). In the dog, compound I was eliminated by metabolism, with a major pathway being aromatic hydroxylation and subsequent sulfation to form the metabolite M3. Metabolic profiling suggested that the pathway leading to the formation of the sulfated conjugate M3 was induced upon multiple dosing of I. Studies conducted in vitro suggested that CYP1A1/2 was responsible for the formation of the hydroxylated metabolite, which is sulfated to yield M3. Additional studies confirmed induction of CYP1A protein and activity in the livers of dogs treated with I. However, studies in a dog hepatocyte model of induction showed a surprising decrease both in CYP1A mRNA and enzymatic activity in the presence of I, emphasizing the need to consider the results from a variety of in vitro and in vivo studies in deriving an understanding of the metabolic fate of a drug candidate. It is concluded that the autoinduction observed after multiple treatments with compound I occurs since compound I is both an inducer and a substrate for dog CYP1A.     

Two molecular forms of gonadotropin-releasing hormone (GnRH-I and GnRH-II) are expressed by two separate populations of cells in the rhesus macaque hypothalamus

Gonadotropin-releasing hormone represents the primary neuroendocrine link between the brain and the reproductive axis, and at least two distinct molecular forms of this decapeptide (GnRH-I and GnRH-II) are known to be expressed in the forebrain of rhesus macaques (Macaca mulatta). Although the distribution pattern of the two corresponding mRNAs is largely dissimilar, their expression appears to show some overlap in specific regions of the hypothalamus; this raises the possibility that some cells express both molecular forms of GnRH. To resolve this issue, double-label histochemistry was performed on hypothalamic sections from six male rhesus macaques, using a monoclonal antibody to GnRH-I and a riboprobe to monkey GnRH-II mRNA. In total, more than 2000 GnRH neurons were examined but in no instance were GnRH-I peptide and GnRH-II mRNA found to be coexpressed. This finding emphasizes that GnRH-I and GnRH-II are synthesized by two distinct populations of hypothalamic neurons, and suggests that they may be regulated by different neuroendocrine pathways.     

Evidence for dual effects of nitric oxide in the forced swimming test and in the tail suspension test in mice

L-Arginine (L-Arg), a substrate for nitric oxide synthase (NOS) at a dose of 250-500 mg/kg, i.p., significantly reduced the duration of immobility both in the forced swimming test (FST) and in the tail suspension test (TST), two models of depression in mice, without changing locomotion in an open field. Paradoxically, a similar effect was observed with the administration of N(G)-nitro-L-arginine (L-NNA) (0.3-10 mg/kg, i.p.), an inhibitor of NOS. However, higher doses of L-Arg (750-1000 mg/kg) and L-NNA (30 mg/kg) did not produce any anti-immobility effect in FST and TST. The inactive isomers D-Arg (100-1000 mg/kg, i.p.) and D-NNA (0.3-30 mg/kg, i.p.) did not affect immobility duration in either the FST and TST. Preadministration of L-NNA (30 mg/kg, i.p.), but not of D-NNA completely blocked the anti-immobility effect of L-Arg (500 mg/kg, i.p.) in the FST. Similarly, L-Arg (750 mg/kg, i.p.), but not D-Arg blocked the anti-immobility effect of L-NNA (3 mg/kg, i.p.) in the FST. The results indicate that either the synthesis of NO or the inhibition of its synthesis may produce antidepressant-like effects when assessed in the FST and TST. The physiological meaning of this finding is still obscure, but it could indicate that NO has a dual role in the modulation of depression.     

IMRT for breast. a planning study.

BACKGROUND AND PURPOSE: To evaluate the performance of ten different treatment-planning systems when intensity modulated (IMRT) plans are designed for breast treatments that include the irradiation of the internal mammary chain. PATIENTS AND METHODS: A dataset of five patients (CT images and volumes of interest) was distributed to design IMRT plans on the ten systems. To minimise biases, the same geometry and clinical planning aims were imposed on the individual plans. Results were analysed in terms of dose distributions and dose volume histograms. RESULTS AND CONCLUSIONS: For target coverage, the volume receiving more than 95% of the prescribed dose ranged from 77% (OTP) to 91% (Eclipse and Pinnacle), the volume receiving more than 107% ranged from 3.3% (Hyperion) to 23.2% (OTP). The mean dose to ipsilateral lung ranged from 13 Gy (Eclipse) to 18 Gy (OTP). The volume of the contralateral breast receiving more than 10 Gy ranged from 3% (Pinnacle) to 26% (Precise). The volume of heart receiving more than 20 Gy ranged from 7% (Eclipse) to 47% (Precise), the maximum significant dose to heart ranged from approximately 27 Gy (XiO) to approximately 49 Gy (Precise). The maximum significant dose to healthy tissue ranged from approximately 51 Gy (Eclipse) to approximately 62 Gy (OTP). It was also possible to show that the treatment geometry proposed here enables to minimise contralateral breast irradiation while keeping minimal ipsilateral lung (or heart) involvement and satisfactory target coverage.     

Anti-inflammatory effects of fructose-1,6-bisphosphate on carrageenan-induced pleurisy in rat.

In the present study, we evaluated the effect of fructose-1,6-bisphosphate (FBP), a high energy intermediate metabolite of glycolysis, in an acute model of lung injury. Injection of carrageenan into the pleural cavity of rats elicited an acute inflammation response characterized by a fluid accumulation in the pleural cavity which contained a large number of polymorphonuclear neutrophils. FBP (500mg/kg) attenuated the inflammation parameters: exudate volume, total leukocytes and the number of polymorphonuclear leukocytes, but the protein concentration in the exudate was not significantly affected by treatment with FBP. The precise site and mechanism of the anti-inflammatory effect was not addressed, considering the diverse pharmacological actions of FBP. This drug has anti-inflammatory actions suggesting that it may represent a novel strategy for the modulation of inflammatory response.