Genetic control of HgCl2-induced IgE and autoimmunity by a 117-kb interval on rat chromosome 9 through CD4 CD45RChigh T cells.

Gold or mercury salts trigger a dramatic IgE response and a CD4 T-cell-dependent nephropathy in Brown-Norway (BN), but not in Lewis (LEW) rats. We previously identified the 1.1-Mb Iresp3 (immunoglobin response QTL3) locus on chromosome 9 that controls these gold salt-triggered immune disorders. In the present work, we investigated the genetic control of HgCl(2)-induced immunological disorders and assessed the relative contribution of the CD45RC(high) and CD45RC(low) CD4 T-cell subpopulations in this control. By using interval-specific congenic lines, we narrowed down Iresp3 locus to 117-kb and showed that BN rats congenic for the LEW 117-kb were protected from HgCl(2)-triggered IgE response and nephropathy. This 117-kb interval also controls CD45RC expression by CD4 T cells and the ability of CD45RC(high) CD4 T cells to trigger the autoimmune disorders resulting from HgCl(2) administration. This 117-kb region contains four genes, including Vav1, a strong candidate gene according to its cellular function and exclusive expression in hematopoietic cells. Thus, this study highlights the role of the CD45RC(high) CD4 T-cell subpopulation in the opposite susceptibility of BN and LEW rats to HgCl(2)-triggered immune disorders and identifies a 117-kb interval on chromosome 9 that has a key role in their functions.

Obstacles and solutions for spontaneous reporting of adverse drug reactions in the hospital.

AIM: To describe the opinions of hospital physicians concerning problems regarding the spontaneous reporting of adverse drug reactions (ADRs) and ways to solve them. METHODS: A qualitative study was carried out. Fifteen focus groups were conducted among physicians working in a tertiary teaching hospital. A total of 208 physicians from different medical specialities participated. The focus group discussions were recorded by three different observers and the transcripts of each session were analysed for issues and themes emerging from the text. RESULTS: Four types of obstacles to spontaneous reporting were considered particularly important: (i) problems with the ADR(S) diagnosis; (ii) problems with the usual workload and lack of time; (iii) problems related to the organization and activities of the pharmacovigilance system; (iv) and problems related to potential conflicts. The potential solutions suggested for improving spontaneous reporting were to define the kind of ADR(S) which should be reported, to facilitate an easy contact and quick access to the hospital pharmacovigilance system, to facilitate information and support for reporting and feedback of pharmacovigilance activities. CONCLUSIONS: The perception of the different obstacles by the hospital physicians is an important factor in determining the causes of the underreporting of ADRs and addressing these obstacles could lead to an improvement in spontaneous reporting. A closer relationship between the doctors and the pharmacovigilance centre is suggested as a means of solving these problems. More information is needed to improve the spontaneous reporting of ADR(S) in specialized healthcare.

Effects of phorbol 12,13-diacetate on human isolated bronchus.

Protein kinase C appears to be involved in the regulation of airway contractility. Phorbol 12,13-diacetate (PDA; 0.01-10 microM), a protein kinase C activator, produced a transient relaxation followed by a sustained contraction of human isolated bronchus. Different protein kinase C inhibitors (calphostin C, staurosporine and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine) (H-7), nifedipine (NIF; 1 microM) or incubation with Ca(2+)-free medium, inhibited the spasmogenic response to phorbol, while ouabain (10 microM) suppressed only the initial relaxation. These results indicate that the initial relaxation, in response to PDA, is related to the activation of Na(+)/K(+)-ATPase, while the ensuing contraction depends on extracellular Ca(2+) entry.Incubation with PDA (1-5 microM) depressed the maximal relaxation to theophylline and caffeine obtained at 37 degrees C but augmented the spasmogenic responses to methylxanthines (10 mM) obtained in cooled preparations. These effects do not result apparently from increased extracellular entry of Ca(2+), but instead, from facilitation of the release of Ca(2+) from intracellular stores.

[Safety of meningococcal A and C vaccine. Data from the Spanish drug surveillance system. Meningococcal Vaccine Research Group of the Spanish System of Drug Surveillance]. / Seguridad de la vacuna antimeningocócica A+C. Datos recogidos por el Sistema Español de Farmacovigilancia. Grupo de Investigación sobre la vacuna antimeningocócica del Sistema Español de Farmacogigilancia.

OBJECTIVE: Data on meningococcal vaccines safety are scanty. In 1997 several vaccination campaign took place in Spain. Thus, this situation was used to improve our knowledge about the safety profile of this vaccine. METHODS: An inquiry was carried out to the Regional Centers of the Spanish Pharmacovigilance System to know the number of vaccinated people and the type and number of suspected cases of adverse reactions. RESULTS: There were 133 identified cases of suspected adverse reactions associated with meningococcal A and C vaccine until June 1st, 1998. Most of them affected the skin (25,3%) or nervous system (similar proportion). Those of allergic reactions accounted for 35,2%. Two cases were considered as severe, although they were resolved without secuelae. CONCLUSIONS: Serious risks were not detected. The Spanish Pharmacosurveillance System as an epidemiological surveillance resource has been useful to know the safety problems associated with antimeningococcal vaccine in the community.

Effects of cromakalim (BRL 34915) in trachea isolated from actively sensitized guinea-pigs.

The effects of cromakalim were examined in tracheal strips isolated from normal (unsensitized) guinea-pigs and from animals actively sensitized to bovine serum albumin. Sensitized tracheae exhibited hyper-responsiveness to KCl, acetylcholine and histamine. In normal and sensitized tracheae, cromakalim (0.01-10 microM) produced a concentration-related suppression of spontaneous tone. The ability of cromakalim to relax tracheal strips was reduced when tone was raised by KCl (25 mM), acetylcholine (0.1 mM) or histamine (0.1 mM) and lost against KCl (120 mM)-induced spasm. Procaine (5 mM) abolished the relaxant effect of cromakalim whilst tetraethylammonium (8 mM) was without effect. These effects were similar in normal and sensitized tissues. Cromakalim (10 microM) produced minor alterations of the concentration-effect curves of KCl (1-100 mM), acetylcholine (1 nM-1 mM) and histamine (1 nM-1 mM) in normal and sensitized tissues. The results from this pharmacomechanical study do not support the hypothesis that altered properties of cromakalim-sensitive K+ channels underlie the airway hyper-reactivity induced by active sensitization to bovine serum albumin.

The relaxant effects of cromakalim (BRL 34915) on human isolated airway smooth muscle.

Cromakalim (BRL 34915) is a potassium channel opener with therapeutic potential as a bronchodilator in asthma. Cromakalim (0.1-30 mumol/l) inhibited the spontaneous tone of human isolated bronchi in a concentration-related manner being nearly as effective as isoprenaline or theophylline. The order of relaxant potencies (expressed as -log10 IC50 mol/l; mean +/- SEM) was isoprenaline (7.29 +/- 0.27; n = 8) > cromakalim (5.89 +/- 0.12; n = 7) > theophylline (4.07 +/- 0.13; n = 10). In human bronchi where tone had been raised by addition of histamine (0.1 mmol/l), acetylcholine (0.1 mmol/l) or leukotriene D4 (LTD4, 0.1 mumol/l), the relaxant effect of cromakalim was substantially reduced. Cromakalim suppressed the contraction produced by KCl (25 mmol/l) but not that produced by KCl (120 mmol/l). Tetraethylammonium (8 mmol/l) was without effect against the relaxant action of cromakalim but procaine (0.5-5 mmol/l) and glibenclamide (0.3 mumol/l) antagonised it. Cromakalim (10 mumol/l) produced an upward displacement of concentration-effect curves for KCl (1-100 mmol/l), acetylcholine (1 nmol/l-1 mmol/l) and histamine (1 nmol/l-1 mmol/l) but it did not alter the concentration-effect curve for LTD4 (0.1 nmol/l-0.1 mumol/l). When tissues were challenged in the presence of cromakalim (10 mumol/l) with KCl (100 mmol/l), acetylcholine (1 mmol/l) or histamine (1 mmol/l), an enhanced contraction was observed compared to control tissues. This enhancement by cromakalim was absent when tissues were challenged with acetylcholine or histamine in either a Ca(2+)-free medium (plus EGTA 0.1 mmol/l) or in the presence of verapamil (10 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)