Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor

The accompanying multivariate analysis of the binding profiles of antiparkinson agents revealed contrasting patterns of affinities at diverse classes of monoaminergic receptor. Herein, we characterized efficacies at human (h)D(2SHORT(S)), hD(2LONG(L)), hD(3), and hD(4.4) receptors and at halpha(2A)-, halpha(2B)-, halpha(2C)-, and halpha(1A)-adrenoceptors (ARs). As determined by guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding, no ligand displayed "full" efficacy relative to dopamine (100%) at all "D(2)-like" sites. However, at hD(2S) receptors quinpirole, pramipexole, ropinirole, quinerolane, pergolide, and cabergoline were as efficacious as dopamine (E(max)100%); TL99, talipexole, and apomorphine were highly efficacious (79-92%); piribedil, lisuride, bromocriptine, and terguride showed intermediate efficacy (40-55%); and roxindole displayed low efficacy (11%). For all drugs, efficacies were lower at hD(2L) receptors, with terguride and roxindole acting as antagonists. At hD(3) receptors, efficacies ranged from 33% (roxindole) to 94% (TL99), whereas, for hD(4) receptors, highest efficacies (approximately 70%) were seen for quinerolane, quinpirole, and TL99, whereas piribedil and terguride behaved as antagonists and bromocriptine was inactive. Although efficacies at hD(2S) versus hD(2L) sites were highly correlated (r = 0.79), they correlated only modestly to hD(3)/hD(4) sites (r = 0.44-0.59). In [(35)S]GTPgammaS studies of halpha(2A)-ARs, TL99 (108%), pramipexole (52%), talipexole (51%), pergolide (31%), apomorphine (16%), and quinerolane (11%) were agonists and ropinirole and roxindole were inactive, whereas piribedil and other agents were antagonists. Similar findings were obtained at halpha(2B)- and halpha(2C)-ARs. Using [(3)H]phosphatidylinositol depletion, roxindole, bromocriptine, lisuride, and terguride displayed potent antagonist properties at halpha(1A)-ARs. In conclusion, antiparkinson agents display diverse agonist and antagonist properties at multiple subtypes of D(2)-like receptor and alpha(1)/alpha(2)-AR, actions, which likely contribute to their contrasting functional profiles.     

Recurrent valvular replacement due to exacerbation of Behcet's disease by Streptococcus agalactiae infection

Valvular heart complications in Behcet's disease are rarely reported. Moreover, the risk of dehiscence in postoperative valvular replacement is high in Behcet's disease. We report a case of recurrent aortic prosthetic dehiscence revealing Behcet's disease in a young woman. Each disease exacerbation was concomitant to a Streptococcus agalactiae infection. This infection appears to act as a trigger for Behcet's disease exacerbation. The patient was successfully treated with immunosuppression plus antibiotic therapy.     

Frequent detection of thyroid peroxidase-specific IgG+ memory B cells in blood of patients with autoimmune thyroid disease

Centrocytes in germinal centers on selection differentiate into plasma cells and/or memory B cells. Cells that have acquired autoreactivity by somatic mutation generally fail to undergo positive selection and die by apoptosis. Presence of isotype-switched high-affinity autoantibodies in serum of autoimmune patients suggests that autoreactive plasma cells eventually emerge from a germinal center reaction. Currently, it is still unclear to which extent the same is true for autoreactive memory B cells. To address this question, we have analyzed whether IgG-bearing memory B cells with specificity for thyroid peroxidase (TPO) can be found in blood of patients with autoimmune thyroid disease and in normal blood donors. Autoreactive TPO-specific IgG+ memory B cells were identified using a previously described assay combining two-step immunomagnetic enrichment with flow cytometric detection. Autoreactive IgG+ memory B cells were found in 65% of the patients with autoimmune thyroid disease and in 17% of normal blood donors; 40% of the latter had no detectable TPO-specific IgG in the serum. The specificity of enriched TPO-specific IgG+ memory B cells was confirmed by in vitro proliferation and differentiation into antibody-secreting cells at limiting dilution and analysis of the supernatants for the presence of TPO-specific IgG. Detection of TPO-specific IgG+ memory B cells in most patients with clinically manifested autoimmune thyroid disease and few normal blood donors may argue for a role of circulating memory B cells in onset of disease.     

Generation and use of alternative multimers of peptide/MHC complexes

For many years, the detection of antigen-specific T cells has relied on indirect in vitro assays such as cytokine secretion, proliferation or chromium release assays. Things have dramatically changed during the past few years, thanks to the imagination of several investigators who have developed very elegant strategies to produce multivalent peptide/MHC complexes. One of these strategies has been to produce peptide-loaded monomeric biotinylated MHC molecules, which could be obtained as tetramers upon incubation with tetravalent streptavidin. Although this latter approach has been by far the most popular, this review focuses on other strategies which have also been successful.     

Nine-year surveillance of methicillin-resistant Staphylococcus aureus in a hospital suggests instability of mecA DNA region in an epidemic strain

The distributions of the antibiotic resistance patterns in a population of Staphylococcus aureus isolates from a teaching hospital were studied over a 9-year period. The results indicate the existence of successive major epidemic methicillin-resistant strains and the emergence of a methicillin-susceptible strain with an unusual resistance pattern. Our findings suggest that this methicillin-susceptible S. aureus strain could be derived from the dominant gentamicin-susceptible methicillin-resistant S. aureus strain with the loss of a 40-kb DNA fragment.     

Kaposi's sarcoma herpesvirus and HIV-1 seroprevalences in prostitutes in Djibouti

Kaposi's sarcoma herpesvirus (KSHV) is linked causally to Kaposi's sarcoma. Epidemiological studies have shown that KSHV transmission can occur during sex among homosexual men, but heterosexual transmission seems to be very rare in KSHV low prevalence countries. A seroepidemiological study was conducted to determine whether KSHV is transmitted sexually between heterosexuals in an endemic country. Sera from 282 subjects of African origin living in Djibouti were tested for antibodies to KSHV and HIV-1. Among the 282 individuals, 43 were female prostitutes working in the streets (group 1), 123 were female prostitutes working in luxury bars (group 2), 41 were non-prostitute females (group 3), and 75 were non-prostitute males (group 4). KSHV seroprevalence was 26, 20, 17, and 36% in groups 1, 2, 3, and 4, respectively. The seroprevalence of KSHV is not different between street or bar prostitutes and non-prostitute females (OR = 1.67; P = 0.34 and OR = 1.18; P = 0.73). These results suggest that in this endemic country commercial sex work does not seem to be a risk factor for KSHV infection and provides evidence against heterosexual transmission of KSHV in the female population studied.     

Phospholipid scramblase,a new effector of FcepsilonRI signaling in mast cells

The signaling network of the high-affinity receptor for IgE in mast cells involves tyrosine phosphorylation of a number of proteins. Here we report evidence that phospholipid scramblase, a protein involved in the distribution of phospholipids between the two leaflets of the plasma membrane, is a target for tyrosine kinases in this signal. The implication of this observation is briefly discussed.     

Benign paroxysmal positional vertigo in patients with Ménière's disease treated with intratympanic gentamycin

OBJECTIVES: To analyze the incidence and characteristics of benign paroxysmal positional vertigo (BPPV) in patients with Ménière's disease who did not respond to medical treatment and to whom intratympanic gentamycin treatment was proposed. STUDY DESIGN: This is a retrospective analysis of the patients in our database. A complete otoneurologic bedside examination of each patient, including assessment of positional nystagmus, was performed at the time of diagnosis and during the follow-up. RESULTS: Nine of 90 patients with Ménière's disease also had BPPV, which manifested in different ways. In 3 patients, BPPV preceded the onset of Ménière's symptomatology in the same ear; in 1, BPPV manifested after treatment for Meniere's disease had ended and the patient was in complete control of the spontaneous spells of vertigo; in 5 cases, recurrences of both Meniere's disease and the positioning symptomatology coincided. Treatment for each condition was conducted independently and favorable results were obtained after long-term follow-up when Meniere's disease and BPPV did not coincide simultaneously. In the group manifesting symptoms of both disorders at the same time, gentamycin treatment with the Canalith Repositioning Procedure and/or Semont maneuver partially resolved the symptoms. CONCLUSIONS: In the context of Ménière's disease, the sequence of appearance of BPPV relative to the spontaneous episodes must be taken into account when planning the treatment for each of the disorders, which should be considered independently. This pattern could also influence the prognosis for each disorder.     

Antiproliferative effect of thalidomide alone and combined with carmustine against C6 rat glioma

Thalidomide could have therapeutic applications in neoplasms and in other diseases, particularly those of autoimmune origin. The objective of this study was to investigate the effect of various doses of thalidomide on the growth of C6 glioma in rats, and to determine its effects on parameters of cell proliferation and angiogenesis. Additionally, we investigated a potential enhancement of the antitumoral action of thalidomide when combined with a low dose of the antineoplastic carmustine. C6 glioma cells were implanted subcutaneously in Wistar rats. A highly malignant glioma developed in 80% of animals. When the tumour reached 2.0 cm diameter thalidomide was administered at doses of 100, 200 or 400 mg/kg/day. When given at a dose of 400 mg/kg/day thalidomide significantly reduced the tumour volume, the mitotic index and cell proliferation but not the vascular density. The combination of thalidomide plus carmustine increased the inhibitory effect on tumoral growth. Our results indicate that thalidomide is effective against malignant glioma; apparently by an antiproliferative effect, rather than by inhibition of angiogenesis; when combined with carmustine it could increase the response of glioma to antineoplastic treatment.