Coexpression of inducible NO synthase and soluble guanylyl cyclase in colonic enterocytes: a pathophysiologic signaling pathway for the initiation of diarrhea by gram-negative bacteria?

Infectious diarrhea is often caused by the exotoxins of gram-negative bacteria such as Escherichia coli. However, these organisms also contain lipopolysaccharide (LPS) endotoxin. LPS induces nitric oxide synthase II (NOS II, inducible NOS) in various types of cells. We now demonstrate by RNase protection analysis, Western blot, and immunohistochemistry that the expression of NOS II mRNA and protein is markedly induced in colonic enterocytes of mice that ingest LPS with their drinking water. Using the same techniques, significant levels of soluble guanylyl cyclase (GC-S), the effector enzyme of NO, were found constitutively expressed in the mucosa. This creates a pathophysiologic autocrine pathway producing increased levels of cyclic GMP and leading to hypersecretion and diarrhea. In fact, the LPS-induced diarrhea developed in parallel with the NOS II induction. Diarrhea could be controlled with orally administered dexamethasone, which prevented the LPS-stimulated induction of NOS II (RNase protection analysis and Western blot). Diarrhea was also blocked by oral aminoguanidine, an inhibitor of NOS II activity. These data suggest that in addition to the known heat-labile and heat-stable exotoxins, gram-negative bacteria may induce diarrhea through the release of endotoxins that induce a NOS II-GC-S autocrine pathway in mucosal epithelium.     

Intravascular ultrasound elastography

Asthma, a chronic disease of the respiratory tract, affects approximately five percent of the U.S. population, including almost five million children. Childhood asthma has been identified as the leading cause of school absences. This study was to examined efficacy of a school-based program to prevent exacerbation of asthma symptoms and manage asthma in school children using measured doses of an inhaled anti-inflammatory medication. The sample consisted of 22 African-American children in one inner-city elementary school in Dallas, Texas, ages 5-12 years with confirmed diagnoses of asthma. For three months, each child came to the school clinic two times per day for medication administration and measurement of respiratory peak flow rates. Data were collected for a number of variables including bronchodilator use, school absences, self-report of asthma symptoms, and number of visits to the physician. During the study, mean peak flow rates improved approximately 15%, and bronchodilator use decreased 66%. Improvement also was evident in several other areas.     

A formal structure for discrete event simulation. Part II: Object-oriented software implementation for manufacturing systems

This paper describes the development of a prototype object-oriented software system for discrete event simulation and the embedded decision processes of a system being modeled based on previously defined formalism [1] and the Smalltalk programming language. The paper addresses the modular and structured representations of physical and logical entities of a manufacturing system for simulation modeling in the form of reusable software objects. The software takes advantage of the natural link between object-oriented programming and simulation and utilizes inheritance and other features of object-oriented programming to achieve modular yet uniform representation at every level of the model. After giving a brief overview of the object-oriented modeling environment and the relationships between software objects and formalism constructs, a small number of object classes and their operations are summarized. The intelligent entities of the formalism utilize a knowledge-based non-programmed decision mechanism implemented in Smalltalk.     

Assisted circulation to the right ventricle through pulmonary counterpulsation using a biological method

The association between asthma exacerbations and use of antiasthmatics has been studied with a drug dispensing database. Exacerbations were identified through use of oral corticosteroids and the risk was determined for each medication. use of fenoterol and oral xanthines increases the frequency of exacerbations, but a channelling phenomenon is not excluded. This method could be used in the study of treatment combinations or new treatments, facilitating the monitoring of asthmatic populations. A second study collects ambulatory drug use data (POM and OTC drugs) of elderly patients. These data are analysed for the distribution of several variables, such as concomitant use of several medications of the same therapeutic class. As an example, about 15 per cent of NSAIDs users also use aspirin, exposing themselves to increased risk for gastrointestinal effects. These studies illustrate the use of drug dispensing databases in monitoring populations at risk and assessing treatment quality.     

The sequelae of the intraspecific isolation of adult rats (right-handed, left-handed and ambidextrous animals)

We studied the influence of social isolation at the age of 2 months on zoosocial behaviour of mixed-bred male rats with different paw preference. Paw preference was determined in the test of reaching for food in the horizontal tube. The level of aggression but not sociability was found to increase significantly in dextral and ambidextrous late isolants. In sinistrals the increase of sociability but not aggression was observed. Analysis of probabilistic ethological structure of aggressive behaviour showed its validity and revealed the appearance of pathological aggression as a result of isolation in all groups of animals. Being connected with a disfunction of the regulating role of the right brain hemisphere this feature of aggressive behaviour is most pronounced in dextrals and ambidextrals.     

On the recording of sample times and parameter estimation from repeated measures pharmacokinetic data

A pharmacokinetic screen has been advocated for the characterization of the population pharmacokinetics of drugs during Phase 3 clinical trials. A common perception encountered in the collection of such data is that the accuracy of sampling times relative to dose is inadequate. A prospective simulation study was carried out to evaluate the effect of error in the recording of sampling times on the accuracy and precision of population parameter estimates from repeated measures pharmacokinetic data. A two-compartment model with intravenous bolus input(s) (single and multiple doses) was assumed. Random and systematic error in sampling times ranging from 5-50% using profile (block) randomized design were introduced. Sampling times were simulated in EXCEL while concentration data simulation and analysis were done in NONMEM. The effect of error in sampling times was studied at levels of variability ranging from 15-45% for a drug assumed to be dosed at its elimination half-life. One hundred replicate data sets of 100 subjects each were simulated for each case. Although estimates of clearance (CL) and variability in clearance were robust for most of the sampling time errors, there was an increase in bias and imprecision in overall parameter estimation as intersubject variability was increased. If there is interest in parameters other than CL, then the design of prospective population studies should include procedures for minimizing the error in the recording of sample times relative to dosing history.     

A family with a syndrome of ectopia lentis, spontaneous filtering blebs, and craniofacial dysmorphism

Six members of a family presented with a syndrome of mild facial dysmorphism, subluxation of the crystalline lenses, variable degrees of angle closure by iridocorneal adhesions, and patchy areas of iris atrophy. Three nonoperated eyes of two patients had spontaneous filtering blebs that presented as avascular cystic elevations of the superior conjunctiva. Systemic workup of all patients was negative for evidence of diseases known to be associated with dislocated lenses. The pedigree is most compatible with autosomal recessive inheritance with pseudodominance.