The selectivity of isoprinosine, NPT 15392, avridine and cyclophosphamide on multiple immune responses in rats

Multiple concomitant immune responses were assessed in individual rats following treatment with the immunoenhancing drugs, isoprinosine (5 or 50 mg/kg), NPT 15392 (0.1 or 1.0 mg/kg) and avridine (1 or 25 mg/kg), or the immunosuppressant, cyclophosphamide (75 mg/kg). Immune responses assessed in each rat were specific antibody synthesis, delayed-type hypersensitivity (DTH), natural killer cell (NKC) cytotoxicity and production of three immunoregulatory cytokines, interleukin 1 (IL1), interleukin 2 (IL2) and prostaglandin E2 (PGE2). Spleen and thymus weights and numbers of splenocytes and resident peritoneal cells were also recorded. Rats treated with isoprinosine had dose-related, significant increases in spleen weights and DTH reactions. Rats treated with NPT 15392 had significantly enhanced DTH reactions at the 0.1 mg/kg dose. Rats treated with the 25 mg/kg dose of avridine had significantly increased spleen weights, DTH reactions and NKC cytotoxicity. The effect of avridine treatment on DTH reactions and IL1 and IL2 production was inverse to the dose administered, while the NKC response was directly related to the dose. Thymus weights, antibody production and PGE2 synthesis were not significantly altered in rats treated with isoprinosine, NPT 15392 or avridine. Cyclophosphamide-treated rats had significantly reduced spleen and thymus weights, antibody synthesis, DTH reactions, NKC cytotoxicity and IL2 production, but IL1 and PGE2 synthesis were significantly elevated. It can be concluded that isoprinosine, NPT 15392 and avridine act as general immunostimulants in the rat, with avridine having the greatest effect under these experimental conditions. It also appears that these drugs are differentially immunoselective in the rat and this effect is at least partially related to the dose administered. These results could be of significance in the selective therapeutic manipulation of different arms of the immune system. Also, enhanced production of PGE2 following cyclophosphamide treatment may contribute to the immunosuppressive effects of this drug.     

Clinical and epidemiological aspects of human bocavirus infection

Human bocavirus was recently described as a novel member of the Parvoviridae to infect humans. Based on accumulating clinical and epidemiological data the virus is currently being associated with respiratory infections in young children and infants and is furthermore discussed as causative agent of gastrointestinal illness.     

Liquid and ion transport by fetal airway and lung epithelia of mice deficient in sodium-potassium-2-chloride transporter

Chloride (Cl(-)) movement across fetal lung epithelia is thought to be mediated by the sodium-potassium-2-Cl(-) cotransporter NKCC1. We studied the role of NKCC1 in Cl(-) and liquid secretion in late-gestation NKCC-null (-/-) and littermate control fetal mouse lung. NKCC -/- mice had decreased lung water compared with littermate controls (wet/dry: control, 8.01 +/- 0.09; NKCC -/-, 7.06 +/- 0.14). Liquid secretion by 17-d NKCC -/- distal lung explants was similar to control explants. Bumetanide inhibited basal liquid secretion in control but not NKCC -/- explants (expansion over 48 h: control, 35 +/- 4%; NKCC -/- 46 +/- 7%). Treatment with 4,4'-diisothiocyanto-stilbene-2,2'-disulfonic acid (DIDS) decreased liquid secretion in both control and NKCC -/- explants. Basal transepithelial potential difference (PD) of control tracheal explants was higher than that of NKCC -/- (control, -13.7 +/- 0.5 mV; NKCC -/-, -11.6 +/- 0.6 mV). Amiloride (10(-)(4) M) inhibited basal PD to the same extent in control and NKCC -/- mice. Terbutaline-stimulated hyperpolarization was less in NKCC -/- than in control tracheas (DeltaPD: control, -10.8 +/- 1.33 mV; NKCC -/-, -6.1 +/- 0.7 mV) and was inhibited by DIDS and acetazolamide in NKCC -/- but not wild-type explants. We conclude that NKCC is rate-limiting for transcellular Cl(-) transport, and that alternative anion transport mechanisms can sustain liquid production at near-normal levels in the fetal NKCC -/- mouse lung.     

Genetic ablation of FLRT3 reveals a novel morphogenetic function for the anterior visceral endoderm in suppressing mesoderm differentiation

During early mouse development, the anterior visceral endoderm (AVE) secretes inhibitor and activator signals that are essential for establishing the anterior–posterior (AP) axis of the embryo and for restricting mesoderm formation to the posterior epiblast in the primitive streak (PS) region. Here we show that AVE cells have an additional morphogenetic function. These cells express the transmembrane protein FLRT3. Genetic ablation of FLRT3 did not affect the signaling functions of the AVE according to the normal expression pattern of Nodal and Wnt and the establishment of a proper AP patterning in the epiblast. However, FLRT3^−/− embryos showed a highly disorganized basement membrane (BM) in the AVE region. Subsequently, adjacent anterior epiblast cells displayed an epithelial-to-mesenchymal transition (EMT)-like process characterized by the loss of cell polarity, cell ingression, and the up-regulation of the EMT and the mesodermal marker genes Eomes, Brachyury/T, and FGF8. These results suggest that the AVE acts as a morphogenetic boundary to prevent EMT and mesoderm induction in the anterior epiblast by maintaining the integrity of the BM. We propose that this novel function cooperates with the signaling activities of the AVE to restrict EMT and mesoderm induction to the posterior epiblast.     

Influence of the histamine control on skin reactivity in skin testing

We investigated the effect of the histamine control (1 mg/ml) on the results of skin prick and intradermal testing with bee and wasp venom. Skin tests were done on the patients' forearms: on the right arm the histamine control and the bee venom dilutions, on the left arm the wasp venom dilutions only, at distances of 4-5 cm. In intradermal testing 11 (9%) of 122 patients showed a positive wheal and flare reaction to the bee venom solution positioned next to the histamine control. The subsequent solutions in higher concentrations did not produce any skin reactions. The results of intradermal testing with bee venom did not occur in intradermal testing with wasp venom or in skin prick testing with both allergens. Our results show clearly that in skin prick tests a distance of 4-5 cm is sufficient to avoid false positive skin reactions. However, using the same distance in intradermal testing showed that histamine affects the skin reactions produced by adjacent allergen solutions. Therefore false positive results may occur.     

Superantigen activation and kinetics of cytokines in the Long-Evans rat.

This study was conducted to identify and quantify, over time, selected cytokine responses in Long-Evans rats that were exposed to staphylococcus enterotoxin B (SEB). The kinetics of selected cytokines [interleukin-2 (IL-2), IL-6, interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF)] and phenotype and cell cycle analysis of T lymphocytes were determined in Long-Evans rats administered a single intraperitoneal (i.p.) dose of either 50 microg or 500 microg of SEB. Rats injected with 50 microg SEB had significantly elevated levels of IL-2, IL-6 and IFN-gamma in their serum 2 hr post-injection. IL-2 serum levels were significantly elevated at 2 hr and returned to near control values by 12 hr while both IL-6 and IFN-gamma peaked at 6 hr but remained significantly increased at 24 hr post SEB exposure. A 500 microg dose of SEB did not further enhance these cytokine responses. When spleen cells were collected for culture 2 hr after rats were injected i.p. with 50 microg SEB and cocultured with SEB, TNF and IL-6 levels were significantly increased after 2 hr incubation, while IL-2 and IL-6 were significantly elevated at 6 hr. Production of all these cytokines in spleen cell cultures continued to increase over the 24 hr sampled. Peritoneal cells were collected for culture either at 1 hr or 2 hr after injection of either 50 microg or 500 microg of SEB. IL-6 was significantly increased after 1 hr in culture while TNF was significantly increased by 2 hr regardless of whether the cells were harvested 1 or 2 hr after SEB injection. The greatest response for both IL-6 and TNF occurred when cells from animals injected with 50 microg SEB were restimulated in vitro with SEB. The peak levels for IL-6 were at 12 hr post SEB exposure while TNF peaked at 6 hr. The percentage of CD4+ cells was significantly increased at 48 hr and 72 hr post SEB (50 microg) administration while the percentage of CD8+ cells remained similar to control values for the 168-hr test period. A similar pattern was observed in cell cycling where the CD4+ cells proliferated up to 2 days post SEB injection and then were significantly suppressed at day 3. The CD8+ cells were comparable to control values. These studies demonstrate that the cytokine responses in Long-Evans rats exposed to a superantigen are somewhat similar to those that occur in mice and humans, e.g. a rapid short increase in the production of IFN-gamma and TNF that was accompanied by an increase in the production of IL-2. Additional responses noted in this species, however, were a marked increase in IL-6 production, as well as an early increase in the number and cycling of CD4+ cells followed by a down-regulation of these events. These activities occurred in the absence of notable histopathological alteration of lymphoid organs. The results indicate that the Long-Evans rat is an acceptable animal model to investigate the pathogenesis of superantigen-induced disease and that IL-6 may be an active mediator of this process.     

Running training and co-ordination between breathing and running rhythms during aerobic and anaerobic conditions in humans

The study was carried out on ten triathletes, six sprinters and ten subjects not trained in running (controls) to assess the effects of training history on the co-ordination between breathing and running rhythms during running on a treadmill. Three exercise intensities were used: 50%, 80% and 110% of the subject's anaerobic threshold (AT). All three intensities were performed twice: once with spontaneous breathing and once with breathing intentionally co-ordinated to the running rhythm. Heart rate, respiratory parameters and leg movements were continuously recorded. Blood lactate concentrations were measured discontinuously. The degree of co-ordination between running and breathing was quantified as the percentage of inspirations and/or expirations starting during the same phase of step. The results showed that the degree of both spontaneous and intended co-ordination at aerobic exercise intensities was in all three groups the same and increased in all groups with increasing intensity from 50% to 80% of AT; further increase of intensity to 110% of AT was associated with a significant decrease of co-ordination in controls and sprinters, whereas triathletes were able to maintain the same high degree of co-ordination as at 80% of AT. It was concluded that running training of either type at aerobic work loads had no effect on the co-ordination between running and breathing rhythms. At anaerobic intensities, however, the degree of co-ordination between running and breathing rhythms was higher in the endurance trained athletes than in the sprinters or in the untrained subjects. The degree of co-ordination increased with increasing regularity of breathing. The ability to increase intentionally the degree of co-ordination by paced breathing was independent of running training and was lowest at anaerobic exercise intensities.     

Offshore telemedicine emergency service: a 1-year experience

Journal of Public Health - Offshore wind energy is a fast growing market. Accordingly, a correspondingly large number of employees are working at the wind farms. Owing to the harsh operating...     

Complete genomic screen in Parkinson disease: evidence for multiple genes.

CONTEXT: The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD. OBJECTIVE: To identify genetic risk factors for idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status. MAIN OUTCOME MEASURES: Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis. RESULTS: Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. CONCLUSIONS: Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.