Bacterial hydrogen peroxide contributes to cerebral hyperemia during early stages of experimental pneumococcal meningitis.

Alterations of blood flow contribute to major clinical complications in invasive infections such as sepsis and bacterial meningitis. As a unique feature streptococci -- in particular, Streptococcus pneumoniae, the most frequent pathogen in bacterial meningitis -- release hydrogen peroxide (H(2)O(2)) because of the absence of functional catalase. In a 6 h rat model of experimental meningitis, we studied the impact of bacterial H(2)O(2) production on regional cerebral blood flow (rCBF) and intracranial pressure (ICP). Compared to wild-type D39 pneumococci, the increase of rCBF was diminished in meningitis induced by the H(2)O(2) defective SpxB(-) mutant (maximum increase, 135% +/- 17% versus 217% +/- 23% of the individual baseline; P<0.01) or after treatment of D39-induced meningitis with H(2)O(2)-degrading catalase or with tetraethylammonium (TEA), a blocker of calcium-sensitive potassium channels, which mediate H(2)O(2)-induced vasodilation. Catalase did not significantly reduce the remaining rCBF increase caused by SpxB(-), supporting the predominant role of bacterial H(2)O(2). We conclude that in addition to host-sided mediators, bacterial-derived H(2)O(2) acts as a potent vasodilator, which accounts for a certain proportion of the early cerebral hyperperfusion in pneumococcal meningitis.     

Leukocyte apoptosis and its significance in sepsis and shock

Sepsis and multiple organ failure continue to be significant problems among trauma, burn, and the critically ill patient population. Thus, a number of laboratories have focused on understanding the role of altered apoptotic cell death in contributing to immune and organ dysfunction seen in sepsis and shock. Immune cells that undergo altered apoptotic changes include neutrophils, macrophages, dendritic cells, as well as various lymphocyte populations. Evidence of epithelial as well as endothelial cell apoptotic changes has also been reported. Although mediators such as steroids, tumor necrosis factor, nitric oxide, C5a, and Fas ligand (FasL) appear to contribute to the apoptotic changes, their effects are tissue- and cell population-selective. As inhibiting Fas-FasL signaling (e.g., gene deficiency, Fas fusion protein, or Fas short interfering RNA administration), caspase inhibition (caspase mimetic peptides), and/or the overexpression of downstream antiapoptotic molecules (e.g., Bcl-2, Akt) improve survival of septic mice, it not only demonstrates the pathological significance of this process but points to novel targets for the treatment of sepsis.     

Heart-focused anxiety,illness beliefs,and behavioral impairment: Comparing healthy heart-anxious patients with cardiac and surgical inpatients

Psychological features and complaints of persons presenting to medical settings with heart-focused anxiety and noncardiac chest pain are poorly understood. Comparing 20 healthy heart-anxious patients to cardiac and surgical inpatients and nonpatient controls, we found that healthy heart-anxious patients (a) were as afraid of chest pain and heart palpitations as inpatients with heart disease, (b) were as incapacitated by symptoms and using medical services as much as both inpatient groups; and (c) reported higher levels of cardiac disease conviction, heart awareness, and behaviors designed to protect their heart than surgical patients and nonpatients. Compared to all other groups, healthy heart-anxious patients reported more panic and other anxiety disorders, hypochondriacal beliefs, physical symptoms, obsessive-compulsive concerns, and negative affect. Following a hyperventilation test, heart-anxious patients also indicated more distressing symptoms and thoughts, and felt less safe and in control than surgical patients and nonpatients. Results support efforts for a timely recognition, diagnosis, and behavioral treatment of persons with heart-focused anxiety.     

Studies on the dispersal of staphylococci

The dispersal of staphylococci during undressing in a cubicle has been investigated. The ability to disperse appears to be largely dependent on the degree of contamination of the skin with staphylococci. There are some major differences in the numbers of bacteria and skin scales disseminated by different groups of people, e.g., patients with skin disease disseminated more than did normal persons. Differences in dissemination between males and females appeared to be largely due to differences in clothing.     

Five year study of prenatal testing for Huntington''s disease: demand, attitudes, and psychological assessment.

Adult predictive and prenatal testing programmes for Huntington's disease (HD) in Canada have been available since 1986. However, the demand for prenatal testing and the reasons why some people choose not to have the prenatal test for this late onset disorder have not been well documented. In addition, the knowledge and attitudes of adult predictive testing candidates and their partners about prenatal testing are not well known nor are the psychological effects of prenatal testing well understood. As of September 1991, 425 subjects had entered the Canadian Collaborative Study of Predictive Testing and, of these, 47 subjects or their partners had become pregnant. Of this group, 14 (30%) couples requested prenatal testing, 24 (51%) couples did not want prenatal testing, and nine (19%) at risk subjects had already received a decreased risk through adult predictive testing and, therefore, were not eligible for the prenatal test. Of the 14 couples who initially requested prenatal testing, seven withdrew. Thus, demand for the prenatal test by eligible candidates was 7/38 or 18%, which is much lower than the 32 to 65% expected based on early survey data. The most frequently cited reason for declining prenatal testing was the hope that a cure would be found in time for their children. While the majority of adult predictive testing candidates (71%) in our study had accurate information about definitive prenatal testing, many (63%) did not have a correct understanding of exclusion prenatal testing. Although no serious adverse events such as suicide planning or admission to psychiatric hospital have occurred, a particular need for careful counselling was identified for those at risk candidates and their partners who have one prenatal test and feel compelled to use the test again in future pregnancies. Even though prenatal testing for HD is not requested as often originally expected, it still remains a desired option for some at risk persons and their partners.     

Blood coagulation and fibrinolysis after long-duration treadmill exercise controlled by individual anaerobic threshold

For rehabilitation training it is recommended that the intensity of exercise should be clearly below the individual anaerobic threshold (IAT). We investigated blood coagulation, particularly endogenous thrombin potential (ETP) and fibrinolysis following a standardized treadmill (TR) ergometer test at 90% IAT for 60–120 min. Sixteen healthy male non-smokers underwent the TR test. Blood samples were taken after a 30-min rest, immediately after exercise, and 2 h after exercise completion. Extrinsic and intrinsic total (TTP_ex+in) and endogenous (ETP_ex+in) thrombin potential, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), plasmin-2-antiplasmin complex (PAP), D-dimer, tissue plasminogen activator antigen and activity (tPA-AG and tPA-ACT) and plasminogen activator inhibitor type 1 antigen and activity (PAI-1-AG and PAI-1-ACT) were measured. Immediately after TR, F1+2, TAT and TTP_ex+in were increased (P<0.05) while ETP_ex+in remained unchanged. In contrast, PAP, D-dimer, tPA-AG, tPA-ACT (P<0.05) were distinctly enhanced while PAI-1-ACT was decreased (P<0.05) immediately after exercise. The changes in tPA-AG, tPA-ACT, and PAI-1-ACT were reversed to nearly baseline while the enhancement in PAP and D-dimer was prolonged by more than 2 h after exercise. Long-duration exercise between 60 and 120 min controlled by IAT (90%) on a TR ergometer only implicates a small increase in thrombin generation markers and total (free and ₂-macroglubulin-bound thrombin), but not in endogenous (free) thrombin potential alone. In contrast, fibrinolysis is distinctly increased after this type of exercise. Endurance exercise with an intensity below 90% IAT and a duration below 2 h generates a more favourable condition for fibrinolysis than for blood coagulation in healthy young subjects. Data are given as mean (SD).     

The behaviour of strains of the virus of foot-and-mouth disease in pig,calf, ox and lamb kidney tissue cultures

Summary Strains of the virus of foot-and-mouth disease obtained from different hosts and tissue cultures were tested in tissue cultures of pig, calf, ox and lamb kidneys for their ability to multiply and produce cytopathogenic effects. It was found that whereas cattle and kidney strains of the virus multiplied well in the cultures with cytopathogenic effect, mouse and egg adapted strains did not multiply or show cytopathogenic effect to the same extent especially in the ox and calf kidneys, and this could be correlated with their behaviour in cattle, pigs and cattle tongue epithelium tissue cultures. With all the strains used it was found possible to produce plaques on pig kidney monolayers, but the size and shape of the plaque varied as well as the relation of plaque titre to the titre in mice. The plaque size and plaque population from different sources were compared, and it was found that the relative number of the different plaque sizes varied with the source of the virus and changed in passage in the different systems. The possible significance of these findings in relation to vaccine preparation and adaptation of the virus is discussed.Part of the work described represents the kidney tissue culture side of experiments on attenuated strains of the virus of foot-and-mouth disease. We are grateful to our colleagues at Pirbright for the supply of virus strains and the results of many cattle, egg and mouse titrations.We would also like to thank MissP. Tremayne-Smitli, Mr.W. Chapman and Mr.D. Maskell for their excellent assistance in this work.     

Efficient maturation and cytokine production of neonatal DCs requires combined proinflammatory signals

Specific functional properties of dendritic cells (DCs) have been suspected as being responsible for the impaired specific immune responses observed in human neonates. To analyze stimulatory requirements for the critical transition from immature, antigen-processing DCs to mature, antigen-presenting DCs, we investigated the effect of different proinflammatory mediators and antigens on phenotype and cytokine secretion of human neonatal DCs derived from hematopoietic progenitor cells (HPCs). Whereas single proinflammatory mediators were unable to induce the maturation of neonatal DCs, various combinations of IFNgamma, CD40L, TNFalpha, LPS and antigens, induced the maturation of neonatal DCs documented by up-regulation of HLA-DR, CD83 and CD86. Combinations of proinflammatory mediators also increased cytokine secretion by neonatal DCs. Especially combined stimulation with LPS and IFNgamma proved to be very efficient in inducing maturation and cytokine synthesis of neonatal DCs. In conclusion, neonatal DCs can be stimulated to express maturation as well as costimulatory surface molecules. However, induction of maturation requires combined stimulation with multiple proinflammatory signals.     

Surface modification of poly(ether urethane urea) with modified dehydroepiandrosterone for improved in vivo biostability

In this study, a fatty acid urethane derivative of dehydroepiandrosterone (DHEA) was synthesized and evaluated as a polyurethane additive to increase long-term biostability. The modification was hypothesized to reduce the water solubility of the DHEA and physically anchor the additive in the polyurethane during implantation. Polyurethane film weight loss in water as a function of time was studied to determine the polymer retention of the modified DHEA. The polyurethane film with unmodified DHEA had significant weight loss in the first day (10%) that was previously correlated to rapid leaching of the additive. The polyurethane film with modified DHEA had significantly less weight loss at all time points indicating improved polymer retention. The effect of the modified DHEA additive on the biostability of a poly(ether urethane urea) was examined after 5 weeks of subcutaneous implantation in Sprague-Dawley rats. Optical micrographs and infrared analysis of the specimens indicated that the modified DHEA bloomed to the surface of the film forming a crystalline surface layer approximately 10-15 microns thick. After explantation, this surface layer was intact without measurable differences in surface chemistry as monitored by attenuated total reflectance-Fourier transform infrared spectroscopy. There was no evidence of degradation of the polyurethane underneath the modified DHEA surface layer as compared with the polyurethane control. We have concluded that the modified DHEA self-assembled into a protective surface coating that inhibited degradation of the polyurethane. The roughness of the modified DHEA surface layer prevented adherent cell analysis to determine if the additive retained the ability to down-regulate macrophage activity. Subsequent studies will investigate the ability of surface-modifying additives to modulate cellular respiratory bursts in addition to the formation of an impermeable barrier. This bimodal approach to improving biostability holds great promise in the field of polyurethane biomaterials.