Novel nonpeptide CCK-B antagonists: design and development of quinazolinone derivatives as potent, selective, and orally active CCK-B antagonists

We have designed a novel series of CCK-B receptor antagonists by combining key pharmacophores, an arylurea moiety of 1 and a quinazolinone ring of 3, from two known series. Our earlier studies showed that compounds with methylene linkers in our "target" produced moderate binding affinity and selectivity for CCK-B receptors, whereas its higher and lower homologues resulted in loss of affinity. Introduction of -NH- as a linker dramatically enhanced binding affinity and selectivity for CCK-B receptors, thus providing several compounds with single-digit nanomolar binding affinity and excellent selectivity. Analogous to the earlier studies of the series of quinazolinone derivatives 3, we also found 3-isopropoxyphenyl as a preferred substitution on the N-3 quinazolinone. Electron-withdrawing substitutions on the urea terminal phenyl ring enhanced the CCK-B potency. Representative compounds of this series were tested in the functional assay and showed pure antagonist profiles. Compounds 51 and 61 were orally active in the elevated rat X-maze test. These compounds were also evaluated for their pharmacokinetic profile. The absolute oral bioavailability of compound 61 was 22% in rats.     

Abuse against women in rural Minnesota

Several botanicals, including Crataegus oxycantha, Terminalia arjuna, Inula racemosa, and Astragalus membranaceus, have been found to have therapeutic benefit for the treatment of cardiovascular disease. Crataegus oxycantha has been used traditionally as a cardiac tonic and current uses include treatment for angina, hypertension, arrhythmias, and congestive heart failure. Animal studies have also indicated that Crataegus extracts may also have potential use as anti-ischemic and lipid-lowering agents. The bark of the Terminalia arjuna tree has a long history of use as a cardiac tonic as well, and has been indicated in the treatment of coronary artery disease, heart failure, hypercholesterolemia and for relief of anginal pain. Additionally, it has been found to have antibacterial and antimutagenic properties. Inula racemosa, also known as Pushkarmoola, is another traditional Ayurvedic botanical that has potential cardioprotective benefit. In human trials, a combination of Inula racemosa and Commiphora mukul was shown to be superior to nitroglycerin in reducing the chest pain and dyspnea associated with angina. Astragalus membranaceus, a Chinese herb, is often used as a "Qi tonifier" and has been studied for its therapeutic benefit in treatment of ischemic heart disease, myocardial infarction, heart failure, and relief of anginal pain. Clinical studies have indicated that its in vitro antioxidant activity is the mechanism by which it affords its cardioprotective benefit.     

Helicobacter pylori infection, gastric acid secretion, and infant growth

BACKGROUND: Helicobacter pylori infection is very common in Gambian infants and children, who are also at risk of chronic diarrhoea and undernutrition. Acute H. pylori infection is associated with depressed gastric acid secretion, and loss of the gastric acid barrier may predispose to enteric infections. METHODS: In a prospective study a noninvasive test of gastric acid output (measurement of change in urine acid output before and after a feed) was performed on a population of Gambian infants at high risk of H. pylori infection. The 13C urea breath tests was used to measure the prevalence of H. pylori infection and growth was measured by serial anthropometry. RESULTS: In 101 infants aged 3 to 12 months, there was a significant relation between H. pylori infection and depressed urine acid output in those aged 6 months, during weaning when growth failure and malnutrition begin. Those infants with sustained H. pylori infection grew less well than those without. CONCLUSIONS: We speculate that H. pylori, acquired in infancy, could be a "key that opens the door" to enteric infection in childhood, leading to recurrent diarrhoea, malnutrition, and growth failure.     

Medical surveillance of the lead exposed worker. Current guidelines

1. The "lead standards" established by OSHA for general industry in 1978 and the construction industry in 1993 require employers and clinicians to follow very specific guidelines for protecting lead exposed workers. Depending on the level of exposure, medical surveillance may be legally required. 2. Lead affects multiple body systems and can cause permanent damage. Low level exposures that in the past were thought safe are now considered hazardous as new information emerges about the toxicity of lead. 3. Lead poisoning, if undetected, often results in misdiagnosis and costly care. Adults are exposed to lead in many different workplace settings. All clinicians caring for lead exposed workers need to be informed about the health effects of lead, employer and physician responsibilities, and worker rights. 4. Occupational and environmental health nurses can help identify workers at risk and prevent lead poisoning by education and early intervention through collaboration with the workers, the employer, the company physician, and other health and safety professionals.     

Clinical utility of pH paper versus pH meter in the measurement of critical gastric pH in stress ulcer prophylaxis

OBJECTIVE: To evaluate the clinical utility of measuring gastric pH with a pH meter vs. pH paper in critical care patients. DESIGN: Prospective comparison of gastric pH measurements, using both pH meter and pH paper. SETTING: Surgical intensive care unit (ICU) at a rural Midwestern university medical center. PATIENTS: Fifty-one patients who received therapy for prophylaxis of stress ulcers in the surgical ICU. INTERVENTIONS: Therapy for stress ulcer prophylaxis was monitored. MEASUREMENTS AND MAIN RESULTS: The pH of 985 gastric samples, taken from 51 patients, was measured with both pH meter and pH paper. The pH meter and pH paper measures demonstrated a concordance correlation coefficient of .896. The mean difference between the two measures (pH paper - pH meter) was estimated to be between -0.4 and 1.4, suggesting a positive bias for the paper. The prevalence of events representing clinically relevant differences between the pH meter and pH paper in the measurement of the same gastric sample was calculated. The frequency with which each of the events occurred consecutively (or, in one case, two nearly consecutive events on the same day) was also calculated. Bias in a clinically relevant range was estimated. A set of "probability profiles" was constructed. CONCLUSIONS: A hand-held pH meter and pH paper are not interchangeable measures of gastric pH. The pH paper exhibits an appreciable positive bias compared with a hand-held pH meter in the clinically relevant range of 2 to 6. More research is needed to determine if that bias affects treatment outcomes. We recommend the use of a pH meter for patients who demonstrate pH readings of < or = 4, consecutive with readings of < or = 5.     

Tackling Complexity in High Performance Computing Applications

We present a software framework that supports the specification of user-definable configuration options in HPC applications independently of the application code itself. Such options include model parameter values, the selection of numerical algorithm, target platform etc. and additional constraints that prevent invalid combinations of options from being made. Such constraints, which are capable of describing complex cross-domain dependencies, are often crucial to the correct functioning of the application and are typically either completely absent from the code or a hard to recover from it. The framework uses a combination of functional workflows and constraint solvers. Application workflows are built from a combination of functional components: higher-order co-ordination forms and first-order data processing components which can be either concrete or abstract, i.e. without a specified implementation at the outset. A repository provides alternative implementations for these abstract components. A constraint solver, written in Prolog, guides a user in making valid choices of parameters, implementations, machines etc. for any given context. Partial designs can be stored and shared providing a systematic means of handling application use and maintenance. We describe our methodology and illustrate its application in two classes of application: a data intensive commercial video transcoding example and a numerically intensive incompressible Navier–Stokes solver.     

油田输油管线热水加热炉失效原因分析

通过对加热炉流管失效部件的宏观和金相检查分析，充分证明该部分炉管的失效是由于在严得超温下工作所引起的，提出了引起对流管超温的可能原因和解决炉管超温的应对措施。     

电容传感器的敏感探头

本文论述了电容传感器几种适用的敏感探头:圆筒内表面探头、圆柱外表面探头、平面探头、同轴圆柱探头的结构原理与电容量的计算方法,并指出各自的适用范围。     

Steam‐air blown bubbling fluidized bed biomass gasification (BFBBG): Multi‐scale models and experimental validation

During fluidized bed biomass gasification, complex gas‐solid mixing patterns and numerous chemical and physical phenomena make identification of optimal operating conditions challenging. In this work, a parametric experimental campaign was carried out alongside the development of a coupled reactor network model which successfully integrates the individually validated sub‐models to predict steady‐state reactor performance metrics and outputs. The experiments utilized an integrated gasification system consisting of an externally‐heated, bench‐scale, 4‐in., 5 kWth, fluidized bed steam/air blown gasifier fed with woody biomass equipped with a molecular beam mass spectrometer to directly measure tar species. The operating temperature (750–850°C) and air/fuel equivalence ratio (ER = 0–0.157) were independently varied to isolate their effects. Elevating temperature is shown to improve the char gasification rate and reduce tar concentrations. Air strongly impacts the composition of tar, accelerating the conversion of lighter polycyclic‐aromatic hydrocarbons into soot precursors, while also improving the overall carbon conversion. © 2016 American Institute of Chemical Engineers AIChE J, 63: 1543–1565, 2017     

The Iowa radon lung cancer study--phase I: Residential radon gas exposure and lung cancer

Exposure to high concentrations of radon (222Rn) progeny produces lung cancer in both underground miners and experimentally-exposed laboratory animals. The goal of the study was to determine whether or not residential radon exposure exhibits a statistically significant association with lung cancer in a state with high residential radon concentrations. A population-based, case-control epidemiologic study was conducted examining the relationship between residential radon gas exposure and lung cancer in Iowa females who occupied their current home for at least 20 years. The study included 413 incident lung cancer cases and 614 age-frequency-matched controls. Participant information was obtained by a mailed-out questionnaire with face-to-face follow-up. Radon dosimetry assessment consisted of five components: (1) on-site residential assessment survey; (2) on-site radon measurements; (3) regional outdoor radon measurements; (4) assessment of subjects' exposure when in another building; and (5) linkage of historic subject mobility with residential, outdoor, and other building radon concentrations. Histologic review was performed for 96% of the cases. Approximately 60% of the basement radon concentrations and 30% of the first floor radon concentrations of study participants' homes exceeded the US Environmental Protection Agency action level of 150 Bq m(-3) (4 pCi l(-1)). Large areas of western Iowa had outdoor radon concentrations comparable to the national average indoor value of 55 Bq m(-3) (1.5 pCi l(-1)). Excess odds of 0.24 (95% CI = -0.05-0.92) and 0.49 (95% CI = 0.03-1.84) per 11 WLM(5-19) were calculated using the continuous radon exposure estimates for all cases and live cases, respectively. Slightly higher excess odds of 0.50 (95% CI = 0.004-1.80) and 0.83 (CI = 0.11-3.34) per 11 WLM(5-19) were noted for the categorical radon exposure estimates for all cases and the live cases. A positive association between cumulative radon gas exposure and lung cancer was demonstrated using both categorical and continuous analyses. The risk estimates obtained in this study indicate that cumulative radon exposure presents an important environmental health hazard.