Accuracy of Seven Different Tests for the Diagnosis of Helicobacter pylori Infection and the Impact of H2-Receptor Antagonists on Test Results

Background: In this study we compared the accuracy of seven diagnostic tests in diagnosing Helicobacter pylori infection. Methods: Over 1 year 351 consecutive dyspeptic patients were tested for H. pylori infection by means of antral biopsy specimens for the rapid urease test (RUT), culture, microscopy (acridine stain), and the laboratory urease test (LUT) and, in addition, with ¹⁴C urea breath test (UBT), IgG serology, and IgA serology (Orion Diagnostica Pyloriset New EIA-G and New EIA-A). The criterion for H. pylori infection was a minimum of three positive tests. Before being tested, 38% of the patients had used an H₂-receptor antagonist (H₂RA). Results: Two-hundred and twenty-four patients (64%) were H. pylori-positive. The sensitivity and specificity of the tests were as follows (percentages): RUT, 85, 99; culture, 93, 100; microscopy, 81, 98; LUT, 80, 100; UBT, 95, 95; IgG serology, 99, 91; and IgA serology, 88, 91. The accuracy of the RUT and LUT was reduced in patients receiving HRA therapy (P = 0.04 and 0.01, respectively). Conclusions: Culture, UBT, and IgG serology were all superior to the other four tests in diagnosing H. pylori infection. Invasive urease-based tests were less accurate in patients receiving HRAs.     

Hydrosonography of the Small Intestine: Comparison with Radiologic Barium Study

Background: Transabdominal ultrasonography of the small intestine is hampered by luminal gas. We have developed a new sonographic method (hydrosonography) that largely eliminates the gas problem and have compared this method with radiologic barium study. Methods: Fifty-six patients admitted for X-ray examination of the small bowel because of abdominal pain, diarrhoea, weight loss and/or known inflammatory bowel disease were examined. To remove luminal gas before performing transabdominal ultrasonography, 2 l of polyethylene glycol solution was inserted through a nasojejunal tube by means of a peristaltic pump. Wall thickness, peristalsis, luminal narrowing, prestenotic dilatation, and extraintestinal complications were recorded. Results: On ultrasonography we were able to visualize the terminal part of the ileum in 98% of the patients. Perfect agreement between hydrosonography and barium studies was seen in 50 of 55 patients. However, 44 patients had normal findings on both examinations. The sensitivity and specificity of hydrosonography were 64% and 100%, respectively. The positive predictive value was 100%. For X-ray examination sensitivity and specificity were 91% and 100%, respectively. Four patients with minor mucosal abnormalities or pathologic findings in the upper part of the small intestine accounted for the relatively low overall sensitivity found for hydrosonography compared with roentgenography. However, important extraintestinal complications were disclosed by ultrasound. Conclusions: Hydrosonography of the small bowel is a new, convenient, and reliable method for examining the lower part of the small intestine. However, it cannot replace barium studies in patients with mucosal abnormalities, especially in the upper part of the small bowel.     

Global reconstruction of the human metabolic network based on genomic and bibliomic data

Metabolism is a vital cellular process, and its malfunction is a major contributor to human disease. Metabolic networks are complex and highly interconnected, and thus systems-level computational approaches are required to elucidate and understand metabolic genotype-phenotype relationships. We have manually reconstructed the global human metabolic network based on Build 35 of the genome annotation and a comprehensive evaluation of >50 years of legacy data (i.e., bibliomic data). Herein we describe the reconstruction process and demonstrate how the resulting genome-scale (or global) network can be used (i) for the discovery of missing information, (ii) for the formulation of an in silico model, and (iii) as a structured context for analyzing high-throughput biological data sets. Our comprehensive evaluation of the literature revealed many gaps in the current understanding of human metabolism that require future experimental investigation. Mathematical analysis of network structure elucidated the implications of intracellular compartmentalization and the potential use of correlated reaction sets for alternative drug target identification. Integrated analysis of high-throughput data sets within the context of the reconstruction enabled a global assessment of functional metabolic states. These results highlight some of the applications enabled by the reconstructed human metabolic network. The establishment of this network represents an important step toward genome-scale human systems biology.     

Endoluminal isoproterenol irrigation decreases renal pelvic pressure during flexible ureterorenoscopy: a clinical randomized, controlled study

Objectives

Irrigation during ureterorenoscopic procedures causes increased pelvic pressure (PP), which may lead to intrarenal backflow with potential harmful consequences. This study aims to investigate PP response to intraluminal administration of isoproterenol (β-agonist; ISO) during flexible ureterorenoscopy.

Methods

Twelve patients admitted for retrograde intrarenal stone surgery (RIRS) were included. Patients were randomized to (1) irrigation with saline (n = 6) or (2) irrigation with ISO 0.1 μg/mL (n = 6). Irrigation rate was standardized to 8 mL/min. A ureteral catheter was retrogradely placed in the renal pelvis for PP measurements. PP, heart rate (HR), and mean arterial pressure (MAP) were also measured.

Results

Baseline PP was 12.1 ± 4 mm Hg in the saline group and 10.3 ± 4 mm Hg in the ISO group (p = 0.44).In the saline group, PP increased to a mean 33 ± 12 mm Hg during ureterorenoscopy. In the ISO group, PP was a mean 19 ± 3 mm Hg (p = 0.029).During endoscopy, PP peaks as high as 328 mm Hg were noted during saline irrigation. The number of pressure peaks above 50 mm Hg was minimized dramatically during ISO irrigation (p = 0.035). No systemic side effects to ISO irrigation were observed.

Conclusion

For the first time, a randomized, controlled human study demonstrates that pharmacologic modulation of the ureter is possible during upper urinary tract endoscopy. The ability to relax ureteral tone during endoscopy may have clinical advantages.     

Substrate specificities of g protein-coupled receptor kinase-2 and -3 at cardiac myocyte receptors provide basis for distinct roles in regulation of myocardial function

The closely related G protein-coupled receptor kinases GRK2 and GRK3 are both expressed in cardiac myocytes. Although GRK2 has been extensively investigated in terms of regulation of cardiac beta-adrenergic receptors, the substrate specificities of the two GRK isoforms at G protein-coupled receptors (GPCR) are poorly understood. In this study, the substrate specificities of GRK2 and GRK3 at GPCRs that control cardiac myocyte function were determined in fully differentiated adult cardiac myocytes. Concentration-effect relationships of GRK2, GRK3, and their respective competitive inhibitors, GRK2ct and GRK3ct, at endogenous endothelin, alpha(1)-adrenergic, and beta(1)-adrenergic receptor-generated responses in cardiac myocytes were achieved by adenovirus gene transduction. GRK3 and GRK3ct were highly potent and efficient at the endothelin receptors (IC(50) for GRK3, 5 +/- 0.7 pmol/mg of protein; EC(50) for GRK3ct, 2 +/- 0.2 pmol/mg of protein). The alpha(1)-adrenergic receptor was also a preferred substrate of GRK3 (IC(50),7 +/- 0.4 pmol/mg of protein). GRK2 lacked efficacy at both endothelin and alpha(1)-adrenergic receptors despite massive overexpression. On the contrary, both GRK2ct and GRK3ct enhanced beta(1)-adrenergic receptor-induced cAMP production with comparable potencies. However, the potency of GRK3ct at beta(1)-adrenergic receptors was at least 20-fold lower than that at endothelin receptors. In conclusion, this study demonstrates distinct substrate specificities of GRK2 and GRK3 at different GPCRs in fully differentiated adult cardiac myocytes. As inferred from the above findings, GRK2 may play its primary role in regulation of cardiac contractility and chronotropy by controlling beta(1)-adrenergic receptors, whereas GRK3 may play important roles in regulation of cardiac growth and hypertrophy by selectively controlling endothelin and alpha(1)-adrenergic receptors.     

Synthesis and structure-activity relationship for a novel class of potent and selective carbamate-based inhibitors of hormone selective lipase with acute in vivo antilipolytic effects

Hormone-sensitive lipase (HSL) is an intracellular enzyme that has a central role in the regulation of fatty acid metabolism. The enzyme, therefore, is a potentially interesting pharmacological target for the treatment of insulin resistance and dyslipidemic disorders. Based on a high throughput screening, a carbamate based HSL inhibitor was identified and optimized into the selective HSL inhibitors 4-hydroxymethyl-piperidine-1-carboxylic acid 4-(5-trifluoromethylpyridin-2-yloxy)-phenyl ester (13f) and 4-hydroxy-piperidine-1-carboxylic acid 4-(5-trifluoromethylpyridin-2-yloxy)-phenyl ester (13g), with IC50 values of 110 and 500 nM, respectively. Both inhibitors were active in acute antilipolytic experiments in vivo and none of the inhibitors inhibited the cytochrome P450 (CYP) isoforms 2D6, 3A4, and 1A2.