Effect of heparin on tissue binding activity of fibroblast growth factor and heparin-binding epidermal growth factor in experimental colitis in rats

There have been several reports implying a benefit for heparin therapy in patients with refractory ulcerative colitis. Although this effect has been attributed to the anti-inflammatory properties of heparin, other mechanisms have not been excluded. Heparin is a potent modulator of receptor binding of growth factors such as fibroblast growth factor (FGF), vascular endothelial growth factor, and heparin-binding epidermal growth factor (HB-EGF), that play a role in wound repair. We examined the effect of heparin on the functional levels of FGF and HB-EGF in a model of experimental colitis. Fifty-six Wistar rats were divided into four groups: group 1 was the control group, group 2 received s.c. heparin 50 units/kg/d, group 3 underwent induction of 3% iodoacetamide colitis, and group 4 underwent induction of colitis and heparin treatment. Rats were killed and evaluated for severity of colitis by macroscopic and microscopic colitis scores, area of inflammation, and myeloperoxidase levels. FGF and HB-EGF levels were functionally assessed in colonic tissue in each group. Heparin therapy resulted in significant improvement in macroscopic and microscopic features of colitis (p < 0.05), accompanied by a partial reduction in myeloperoxidase levels. FGF receptor binding activity was identical in groups 1 and 2 but increased more than 3-fold after colitis induction in group 3 (p < 0.05). Treatment with heparin caused a significant decrease in FGF concentration. Levels of HB-EGF binding activity were similar in groups 1 and 2 and decreased in group 3 (p < 0.01). Heparin caused a significant increase in HB-EGF content in group 4 (p < 0.05). Levels of growth factors are altered differently in experimental colitis. Colonic FGF binding activity increases with colitis, whereas HB-EGF binding decreases with colitis. These trends were reversed by heparin, concomitant with a clinical and pathologic improvement in colitis. We suggest that one mechanism of heparin-mediated improvement in colitis may involve tissue healing associated with changes in functional levels of colonic growth factors.     

Excessive daytime sleepiness and risk of occupational injuries in non-shift daytime workers

STUDY OBJECTIVES: Only a few studies have examined the possible association between excessive daytime sleepiness (EDS) and risk of occupational injuries, and most of them were based on self-reports. This study tested this association in daytime workers using injury data taken from organizational archives. DESIGN: A retrospective and prospective study. It covered injury occurrence during two years prior to a sleep disorder assessment/education procedure and injury occurrence in the following year. The workers were given the assessment results and, when applicable, a letter to the treating physician. SETTING: Eight industrial plants. Lectures and discussions on sleep disorders, treatment, and implications to safety and quality of life were conducted with small groups who completed the sleep assessment questionnaire beforehand. The workers completed the sleep assessment questionnaire prior to the lecture/discussion. PARTICIPANTS: 532 non-shift daytime workers. INTERVENTIONS: N/A. MEASURES AND RESULTS: A battery of questionnaires to assess EDS (by the Epworth Sleepiness Scale), suspected sleep disorders, sleep habits, and job and environmental conditions. Of the workers studied 22.6% had EDS. Most of those (96.3%) indicated that they had experienced this propensity for the past two years or more and 56% of them had experienced it for 10 years or more. Logistic regression analysis indicated that during the two-year period prior to the procedure, EDS was associated with an increased risk of sustaining a work injury (OR=2.23, 95% CI 1.30-3.81), even after controlling for possible confounders, including factory category, job and environmental conditions. In the year after the procedure, the injury rate decreased by one-third in the workers with EDS but remained unchanged in the workers without EDS. Consequently, the association between EDS and injury was no longer significant (OR=1.42, 95% CI 0.71-2.85). CONCLUSION: EDS is a prevalent phenomenon in non-shift daytime workers. Workers with EDS had over two-fold higher risk of sustaining an occupational injury. Providing workers with the assessment results and of the implications of EDS for safety may explain the decrease in occupational injuries upon follow-up. This decrease might have occurred either because of workers taking steps to reduce EDS and/or adopting safety behaviors.     

Unique overlap in the prerequisites for thrombin inhibition and oral bioavailability resulting in potent oral antithrombotics

Despite intense research over the last 10 years, aided by the availability of X-ray structures of enzyme-inhibitor complexes, only very few truly orally active thrombin inhibitors have been found. We conducted a comprehensive study starting with peptide transition state analogues (TSA). Both hydrophobic nonpeptide analogues as well as hydrophilic peptidic analogues were synthesized. The bioavailability in rats and dogs could be drastically altered depending on the overall charge distribution in the molecule. Compound 27, a tripeptide TSA inhibitor of thrombin, showed an oral bioavailability of 32% in rats and 71% in dogs, elimination half-lives being 58 and 108 min, respectively. The thrombin inhibition constant of compound 27 was 1.1 nM, and in an in vivo arterial flow model, the ED(50) was 5.4 nmol/kg.min, comparable to known non-TSA inhibitors. A molecular design was found that combines antithrombotic efficiency with oral bioavailability at low dosages.     

Assessment of hemolysis related quantities in a microaxial blood pump by computational fluid dynamics

A computational assessment or even quantification of shear induced hemolysis in the predesign phase of artificial organs (e.g., cardiac assist devices) would largely decrease efforts and costs of design and development. In this article, a general approach of hemolysis analysis by means of computational fluid dynamics (CFD) is discussed. A validated computational model of a microaxial blood pump is used for detailed analysis of shear stress distribution. Several methods are presented that allow for a qualitative assessment of shear stress distribution and related exposure times using a Lagrangian approach and mass distribution in combination with shear stress analysis. The results show that CFD offers a convenient tool for the general assessment of shear-induced hemolysis. The determination of critical regions and an estimation of the amount of blood subject to potential damage in relation to the total mass flow are shown to be feasible. However, awareness of limitations and potential flaws in CFD based hemolysis assessments is crucial.     

Age-related changes in upper airway muscles morphological and oxidative properties

Obstructive sleep apnea (OSA) is a common disorder of the middle aged and elderly. It results from the decrease in upper airway muscle (UAM) tone that occurs during sleep. It is unclear whether age-related changes in UAM could constitute a contributory mechanism to the increased prevalence of OSA with increasing age, and previous papers evaluating the effects of aging on UAM in rats reported conflicting results. In the present study, we compared, in four age groups of Wistar rats (6–24 months), fiber-type distribution, mean cross-sectional fiber area and succinate dehydrogenase optical density of dilating and non-dilating UAM, and the diaphragm. Succinate dehydrogenase optical density, a marker of oxidative capacity, decreased significantly after the age of 6 months in all muscles (except for the sternohyoid), particularly in the genioglossus, the main tongue protrudor. In this muscle, we also found a significant decrease in type IIa and an increase in IIb fibers after the age of 18 months. Age-related changes in fiber-type distribution in other muscles were mostly insignificant. Dilating UAM could not be distinguished from their non-dilating neighboring muscles by their histochemical properties or aging-related changes. The aging-related changes observed in the present study may decrease UAM endurance, particularly that of the main tongue protrudor, the genioglossus.     

CLINICAL ASSISTED REPRODUCTION: Improvement of IVF Outcome in Poor Responders by Discontinuation of GnRH Analogue During the Gonadotropin Stimulation Phase—A Function of Improved Embryo Quality

Purpose: To assess the efficacy of a protocol involving the discontinuation of the GnRH analogue at the mid-phase of ovarian stimulation for IVF in patients with a previous poor response.Methods: Prospective case-control evaluation compared with same patient's previous performance. Thirty-six patients enrolled in an IVF program were treated in two consecutive cycles. The first with a standardized protocol utilizing mid-luteal administration of Nafarelin (N) 600 mcg/d continued throughout the stimulation phase with human menopausal gonadotropin (hMG) until follicles of 20 mm were identified by transvaginal ultrasound (Standard group). Patients with a poor response in the Standard cycle were treated in the subsequent cycle with N and hMG initially in a similar manner, then N was stopped after 5 days of hMG stimulation (N-stop group). All clinical and laboratory aspects of treatment were done in a similar fashion in both cycles, each patient acting as her own control.Results: Results were analyzed by paired t test. The change in each parameter in the N-stop cycle was expressed as the percent change as compared with the standard protocol cycle for each patient. Peak estradiol (E2) and number of aspirated oocytes were increased in the N-stop cycle (+16.9% and +28%, respectively), but insignificantly so. The percent of cleaving embryos was significantly increased by 27.9% (p = 0.03) in the N-stop cycle, as embryo morphology was improved by 22% (p = 0.02). The efficacy of gonadotropin treatment was enhanced in the N-stop cycle, as expressed by a 32.5% increase in oocytes retrieved per hMG ampoule administered (p = 0.04). Three cycles of 36 were cancelled during the N-stop cycle, whereas only one was cancelled in the standard protocol cycle. Of the 36 patients, 7 conceived in the N-stop protocol and 5 are ongoing pregnancies.Conclusion: Discontinuation of GnRH-a during ovarian stimulation for IVF has a beneficial, but not statistically significant, effect on both E2 and oocyte production. Embryo cleavage rates and morphology were significantly improved, this may be due to improved oocyte quality, which may have been responsible for achieving pregnancies. The efficacy of gonadotropin treatment was enhanced when GnRH-a was discontinued. These results hint that GnRH-a may have a direct negative effect on folliculogenesis and oocytes, which is apparent especially in poor responder patients.     

Acute respiratory distress syndrome in children with malignancy—Can we predict outcome?

Purpose: The purpose of this study was to delineate early respiratory predictors of mortality in children with hemato-oncology malignancy who developed acute respiratory distress syndrome (ARDS). Materials and Methods: We conducted a retrospective chart review of children with malignant and ARDS who needed mechanical ventilation and were admitted to a pediatric intensive care unit from January 1987 to January 1997. Results: Seventeen children with ARDS and malignancy aged 10.5 ± 5.1 years were identified. Six of the 17 children (35.3%) survived. Sepsis syndrome was present in 70.6% of all the children. Peak inspiratory pressure, positive end-expiratory pressure (PEEP), and ventilation index values could distinguish outcome by day 3. A significant relationship between respiratory data and outcome related to efficiency of oxygenation, as determined by PaO₂/FIO₂ and P(A-a)O₂, was present from day 8 after onset of mechanical ventilation. Conclusions: Peak inspiratory pressure, PEEP, and ventilation index values could distinguish survivors from nonsurvivors by day 3. This may assist in early application of supportive nonconventional therapies in children with malignancy and ARDS. Copyright © 2001 by W.B. Saunders Company