A new experimental approach in endothelium-dependent pharmacological investigations on isolated porcine coronary arteries mounted for impedance planimetry.

1. The aim of this study was to investigate whether the balloon-based impedance planimetry technique could be a useful tool in endothelium-dependent investigations. 2. Porcine large coronary arteries contracted with prostaglandin F2alpha (PGF2alpha, 10 microM) did not relax to bradykinin (0.1 nM - 0.1 microM), but did relax to sodium nitroprusside (SNP, 10 microM). However, after eversion of the segments, bradykinin induced relaxations with pD2 values and maximal responses of 8.78+/-0.09 and 75+/-2% (n=6), respectively. 3. Incubation with captopril (1 microM) did not reveal a relaxation to bradykinin in the normal vessel configuration and had no influence on the concentration-relaxation relationship in everted segments. 4. Lowering the luminal pressure in contracted segments from 131+/-5 mmHg (isometric, n=5) to 60 mmHg (isobaric, n=5) did not facilitate the action of bradykinin. 5. Eversion of segments did not influence the concentration-response relationship for K+ (4.7 - 125 mM), PGF2alpha (0.3 - 30 microM), and SNP (30 nM - 30 microM), although the time-courses of responses were faster when the agents were added from the intimal compared to the adventitial side of the preparation. 6. In the same everted segment contracted with PGF2alpha, the concentration-response relationship for bradykinin was not different under isometric and isobaric conditions. 7. These results indicate that, (1) reduced endothelium-dependent relaxations to adventitially administered substances can be ascribed to a diffusion barrier in the vessel wall, while enzymatic degradation, luminal pressure and precontractile responses seem not to play a role, (2) impedance planimetry applied to everted cylindrical segments could be a useful experimental approach in pharmacological studies of endothelium-dependent responses under isobaric and isometric conditions.     

Differential patterns of circulating adhesion molecules in children with bronchial asthma and acute bronchiolitis

The object of the study was to assess the levels of circulating forms of the cellular adhesion molecules ICAM-I, VCAM-1, E-selectin, L-selectin and P-selectin in young children with asthma and acute bronchiolitis. Thirty-nine children aged 12 to 84 months with mild or moderate asthma were studied at admission for acute asthma (n = 15) or in a stable phase (n = 24). Ten of the children with acute asthma were seen again after one month. Twenty-two children aged 1 to 17 months with acute bronchiolitis and nine non-atopic controls were also included in the study. In children with acute asthma, the mean concentration of circulating soluble ICAM-1 (SICAM-I) was increased compared to children with stable asthma (mean 442 μg/l versus 363 μg/l; p < 0.001) and to controls (363 μg/l; p < 0.05). The levels of SICAM-1 remained high at follow up. In children with stable asthma, the mean serum concentration of soluble L-selectin (sL-selectin) (2080 μg/l) was significantly higher than in the controls (1664 μg/l; p < 0.05). The levels of circulating cellular adhesion molecules were similar in atopic and non-atopic asthmatics. Children with acute bronchiolitis had increased serum levels of soluble VCAM-1 (sVCAM-I) (1637 μg/l versus 1019 μg/l in the controls; p < 0.01) and sL-selectin (2041 μg/l versus 1664 μg/l in the controls; p < 0.05). There was no difference between the levels of circulating cellular adhesion molecules in children with respiratory syncytial virus (RSV) positive and RSV negative bronchiolitis. Soluble E-selectin (sE-se-lectin) and soluble P-selectin (sP-selectin) in serum were not significantly increased in any of the groups studied. In conclusion, our data suggest differential patterns of circulating cellular adhesion molecules in young children with acute asthma, stable asthma, and acute bronchiolitis, which may reflect differences in the underlying inflammatory processes in these obstructive pulmonary diseases.     

Osteonecrosis of the jaws by long term therapy with bisphosphonates]

For several decades bisphosphonates have been used to reduce skeletal related events in patients with both osteoporosis or bone metastases. Under long term application, besides the known therapy side effects, a new clinical picture has been described within the last few years. This is osteonecrosis of the jaws, which is characterized by its difficulty in treatment. Besides exposed jaw bone, the start of the disease usually lacks any symptoms. The typical clinical symptoms then are foetor ex ore, swelling, exsudation, loosening of teeth, pain or paresthesia. Later oro-antral/nasal or oro-cutaneous fistula can develop. The X-ray shows persisting tooth sockets after extractions and later cloudy radio-lucency, sequestra or fractures. The patient exposed to bisphosphonate can be grouped according to the risk for osteonecrosis: high risk patients with intravenous bisphosphonate therapy and additional chemo-, radiation or corticoid therapy--predominantly patients with a malignant underlying disease and bone metastases low risk patients with an oral bisphosphonate therapy without additional chemo-, radiation or corticoid therapy--preferably patients with non-corticoid-induced osteoporosis. Before starting a bisphosphonate therapy possible causes of infection should be treated and risk of injuries to the mucosa should be reduced according to the individual risk profile. This is supplemented by information of the patient about the risk of necrosis and the possibilities for prevention. Regular dental recall under bisphophonate therapy is emphasised for early recognition of possible problems. Prophylaxis is recommended for the prevention of periodontal infection combined with a follow up of removable denture for possible ulcera. Generally, conservative treatment measures are preferred to surgical ones. Inevitable operations are carried out non-traumatically using broad spectrum antibiotic prophylaxis until the day of suture removal (not before day 10). Long term follow up examinations are recommended.Patients with dental implants inserted before a bisphophonate therapy should be subject to intensive recall examinations. For patients undergoing or following a bisphosphonate therapy the indication for dental implants should be as strict as for patients following head and neck radiation therapy. In the present for patients with osteonecrosis, even after healing, dental implants are regarded as contra-indication. Therapy of the necrosis often requires general anaesthesia, hospitalisation, naso-gastral feeding tube and intravenous, systemic antiinfective treatment. The necrosis is removed completely and a tension free wound closure with vascularised tissue is intended. A literature review shows the metabolic effect of biphosphonates, the known pathogenesis of the bisphosphonate-induced jaw necrosis. It is essential to develop interdisciplinary communication, aiming at a joint care for this group of concerned patients and involving not only those medical disciplines, which order and use bisphosphonates, but especially dentists and maxillofacial surgeons.     

Diagnosis and Prevention of Hypersensitivity Reactions to Iodinated Contrast Media

Iodinated contrast media (ICM) have become one of the major causes of drug hypersensitivity reactions (HSRs) related to increasing numbers of ICM-based radiological imaging procedures. Strategies for diagnosing and preventing ICM-induced HSRs have not been uniformly standardized yet. However, advances have been made based on the results of recent research. A previous history of hypersensitivity to ICM is the most significant risk factor for developing HSR by ICM. Avoidance of culprit agents and premedication is the main strategy to prevent recurrences of HSRs in high-risk patients. In addition, we strongly recommend identifying sensitized ICM using skin tests to determine immunoglobulin E-mediated or delayed-type allergy and to guide the choice of an alternative contrast agent. ICM provocation test procedures have been established and are helpful in selected cases. In this paper, we review how to evaluate patients who have experienced immediate or delayed HSRs caused by ICM to minimize the risk of recurrence and discuss unmet needs that require further research.     

Influence of Test Specimen Geometry on Probability of Failure of Composites Based on Weibull Weakest Link Theory

This paper presents an analytical model that quantifies the stress ratio between two test specimens for the same probability of failure based on the Weibull weakest link theory. The model takes into account the test specimen geometry, i.e., its shape and volume, and the related non-constant stress state along the specimen. The proposed model is a valuable tool for quantifying the effect of a change of specimen geometry on the probability of failure. This is essential to distinguish size scaling from the actual improvement in measured strength when specimen geometry is optimized, aiming for failure in the gauge section. For unidirectional carbon fibre composites with Weibull modulus m in the range 10–40, it can be calculated by the model that strength measured with a straight-sided specimen will be 1–2% lower than the strength measured with a specific waisted butterfly-shaped specimen solely due to the difference in test specimen shape and volume.     

The changing of the guards : Can family doctors contain worker absenteeism?

Using administrative data from Norway, we examine the extent to which family doctors influence their clients’ propensity to claim sick-pay. The analysis exploits exogenous switches of family doctors occurring when physicians quit, retire, or for other reasons sell their patient lists. We find that family doctors have significant influence on their clients’ absence behavior, particularly on absence duration. Their influence is stronger in geographical areas with weaker competition between physicians. We conclude that it is possible for family doctors to contain sick-pay expenditures to some extent, and that there is a considerable variation in the way they perform this task.     

Work-related stressors and occurrence of adverse events in an ED

ObjectiveThe purpose of this study was to investigate the relationship between 12 work-related stressors and the occurrence of adverse events in an emergency department (ED).MethodsNurses and physicians, working in an ED at a Danish regional hospital, filled out a questionnaire on occurrence and emotional impact of 12 work-related stressors after each shift during a 4-week period. The questionnaire also instructed the participants to describe any adverse events that they were involved in during the shift.ResultsTwo hundred fourteen adverse events were reported during the 979 studied shifts. During the same period, only 27 adverse events were reported to the mandatory national reporting system, and only 10 of these were duplicates. A high variability of stressors and emotional impact among the different groups of participants was found. Linear regression analysis showed an association between involvement in adverse events and the occurrence and emotional impact of stressors across groups, whereas no significant association was found for age, seniority, shift type, or length.ConclusionThe study showed an association between the occurrence and impact of 12 work-related stressors and involvement in adverse events across the groups of participants. Furthermore, the study showed that most adverse events were not reported to the mandatory national reporting system.     

Photodynamic therapy with photofrin reduces invasiveness of malignant human glioma cells

. In this study we investigated the influence of Photofrin-based photodynamic therapy (PDT) on the migration of two human glioma cell lines in vitro. U87 and U25ln tumour cells were treated with Photofrin at various doses and subjected to a fixed optical (632 nm) dose of 100 mJ/cm². Photofrin cytotoxicity was determined using MTT and colony forming assays. Using a matrigel artificial basement membrane migration assay, we demonstrated that low doses of subcytotoxic PDT treatment, such as PDT with 2.5 μg/ml Photofrin on U87 cells and 1 μg/ml on U25ln cells, significantly (p<0.001) inhibited in vitro migration of both cell lines. Furthermore, in a qualitative spheroid confrontation assay, subcytotoxic PDT of co-cultures between tumour spheroids and brain aggregates resulted in an absence of progressive tumour invasion and destruction of the brain aggregate. In conclusion, our data indicate that low-dose subcytotoxic PDT with Photofrin significantly inhibits invasiveness of U87 and U25ln cells. Paper received 8 May 2002; accepted after revision 19 June 2002. Correspondence to: Michael Chopp, PhD, Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA. Tel: 313-916-3936; Fax: 313-916-1318; e-mail: chopp@neuro.hfh.edu