Effect of chronic treatment with 5-HT1 agonist (8-OH-DPAT and RU 24969) and antagonist (isapirone) drugs on the behavioural responses of mice to 5-HT1 and 5-HT2 agonists.

The effects of chronic (14 day) administration to mice of the 5-HT1 agonists 8-hydroxy 2-(di-n-propylamino) tetralin (8-OH-DPAT) and 5-methoxy-3 (1,2,3,6-tetrahydropyridin-4-yl) IH indole (RU 24969) on the hypothermic response to 8-OH-DPAT and the locomotor response to RU 24969 have been examined. Chronic administration of 8-OH-DPAT (5 mg kg-1, s.c.) resulted in an attenuated hypothermic response to this drug given subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) but did not alter the locomotor response to RU 24969. Chronic injection of RU 24969 (3 mg kg-1, i.p.) produced an attenuated locomotor response to this drug given i.p. or i.c.v. but not the hypothermic response to 8-OH-DPAT (0.5 mg kg-1, s.c.). Chronic administration of the putative presynaptic 5-HT1 antagonist isapirone (10 mg kg-1, i.p.) decreased the hypothermic response following 8-OH-DPAT injection but did not alter RU 24969-induced locomotion. Chronic treatment with 8-OH-DPAT (5 mg kg-1, s.c.) produced a modest enhancement of the 5-HT2 receptor-mediated head-twitch behaviour initiated by 5-hydroxytryptophan injection while chronic isapirone decreased this behavioural response. 5-HT2 receptor number in frontal cortex was unaltered by isapirone treatment but markedly decreased (34%) by chronic 8-OH-DPAT. These data suggest that chronic administration of the 5-HT1 agonists induces tolerance in their respective responses but not cross-tolerance, while chronic isapirone may down-regulate the 5-HT1A site in a matter analogous to that seen by 5-HT2 receptors following 5-HT2 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

PCP and sigma receptors in brain are not altered after repeated exposure to PCP in humans

The psychotomimetic effects of phencyclidine (PCP) in humans can persist or reappear months after the drug has been eliminated, suggesting that PCP can induce long-term changes in the brain. The present study examined whether repeated exposure to PCP in a human drug-addicted population was accompanied by alterations in either PCP or sigma binding sites in their postmortem brains as compared to suicide controls. Saturation studies using [3H]TCP and [3H]haloperidol in the presence of spiperone to measure PCP and sigma sites, respectively, revealed no significant differences in the affinity or density of binding sites between these two clinical populations in a variety of brain areas examined. The results suggest that these brain binding sites remain unperturbed in humans despite multiple challenges with PCP. Delayed psychotic episodes following the use of PCP may be attributed to other neurochemical changes that are initiated by interactions of PCP with these two binding sites.     

Infectious keratitis: correlation between corneal and contact lens cultures.

PURPOSE: This article reports a study of the effectiveness of performing contact lens cultures to identify causative organisms of infectious keratitis in patients using extended-wear soft contact lenses (cosmetic or therapeutic). METHODS: Patients' records from the Ocular Microbiology Laboratory of the Department of Ophthalmology, Paulista School of Medicine, from 1976 to 2000, and data of patients with contact lens-related keratitis in which the contact lens had been cultured were collected and reviewed. RESULTS: One hundred thirteen patients were included. Only soft contact lenses had been cultured and 29.2% of them were therapeutic contact lenses. An overall concordance of 84.0% was found between cultures obtained from corneal scrapings and contact lenses, with a higher rate in fungal keratitis (100%) compared to amebic (80.0%) and bacterial (74.5%) keratitis. In cases of concomitant bacterial growth in cultures of scrapings and contact lenses, the same organism was detected in 97.04%. Most cases of bacterial infection were caused by Pseudomonas spp. Among the discordant cases (16%), a microorganism was more likely to be isolated by contact lens culture (94.4%). CONCLUSION: Contact lens cultures may identify the causative organisms in most cases of contact lens-related keratitis. The clinical relevance of positive contact lens cultures in keratitis with negative corneal cultures needs further investigation.     

Aged venous thrombi: radioimmunoimaging with fibrin-specific monoclonal antibody

Radioimmunoimaging of fresh canine venous thrombi with a murine monoclonal antibody specific for human and dog fibrin has been reported. Successful imaging of canine deep venous thrombi 1, 3, and 5 days old at the time of antibody injection is reported. Images were positive in all dogs, and the uptake of fibrin-specific antibody was equivalent to that of fresh thrombi.     

3-[4'-bromo-(1,1'-biphenyl)-4-yl]-N,N-dimethyl-3-(2-thienyl)-2-propen-1-amine: synthesis,cytotoxicity, and leishmanicidal,trypanocidal and antimycobacterial activities

Current therapies for Chagas' disease, leishmaniasis and tuberculosis are unsatisfactory because of the failure rates, significant toxicity and/or drug resistance. In this study, the compound 3-[4'-bromo-(1,1'-biphenyl)-4-yl]-N,N-dimethyl-3-(2-thienyl)-2-propen-1-amine (IV) was synthesized and its trypanocidal, leishmanicidal and antimycobacterial activities were investigated. The cytotoxicity was determined on V79 cells with three endpoints: nucleic acid content, 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide reduction and Neutral Red uptake. This compound was active against different species of mycobacteria and different life cycle stages of Trypanosoma cruzi. In experiments with trypomastigotes performed at 4 degrees C in the presence of blood, the activity was 8.8-fold more active than the standard drug, Crystal Violet. Higher activity was achieved against Leishmania amazonensis, with an ED(50)/24 h of 3.0 +/- 0.3 micro mol/L. The effect against trypanosomatids, which suggests high activity of compound IV against promastigotes of L. amazonensis and amastigotes of T. cruzi, stimulated further studies in vitro with amastigotes interiorized in macrophages and with in vivo models. Our results indicate that mammalian V79 cells are less susceptible to the action of compound IV than promastigotes of L. amazonensis (8.0-13.3-fold) and axenic amastigotes of T. cruzi (3.5-5.9-fold).     

CD14 receptor occupancy in severe sepsis: results of a phase I clinical trial with a recombinant chimeric CD14 monoclonal antibody (IC14)

OBJECTIVE: Binding of bacterial cell wall components to CD14 and co-receptors on myeloid cells results in cellular activation and production of proinflammatory mediators. A recombinant anti-CD14 monoclonal antibody (IC14) has been shown to decrease lipopolysaccharide-induced responses in animal and human models of endotoxemia. This study was performed to evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical pharmacology of IC14 in patients with severe sepsis. DESIGN: Randomized, double-blind, placebo-controlled, dose-ranging, multiple-center trial. SETTING: Six medical and surgical intensive care units located in Germany and The Netherlands. PATIENTS: Forty patients with severe sepsis. INTERVENTIONS: IC14 was administered intravenously to eight patients/cohort as single (1 mg/kg or 4 mg/kg) or multiple doses (4 mg/kg daily for 4 days, or 4 mg/kg on day 1 followed by 2 mg/kg daily for 3 days). A placebo group (two patients/cohort) was also included. MEASUREMENTS AND MAIN RESULTS: The overall incidence and types of adverse events were similar among treatment groups. One patient in the group receiving multiple-dose IC14 4 mg/kg daily for 4 days experienced an anaphylactic reaction after receiving the first dose of study drug. IC14 did not induce antibody formation or increase the incidence of secondary bacterial infection. A mean IC14 serum concentration of approximately 1 microg/mL was required to achieve 50% of maximum membrane-bound CD14 receptor occupancy on peripheral blood monocytes. The pattern of proinflammatory and anti-inflammatory cytokines, chemokine, soluble receptor, soluble E-selectin, and acute phase proteins in response to treatment was highly variable by patient and IC14 treatment group. CONCLUSIONS: Single and multiple doses of IC14 were generally well tolerated and did not induce antibody formation or increase the incidence of secondary bacterial infection. The results suggest that CD14 blockade with IC14 warrants further clinical investigation to determine its ability to attenuate the proinflammatory response due to infection.     

ABO compatibility can influence the results of platelet transfusion. Results of a randomized trial

Sixty consecutive patients with untreated acute leukemia alternately received either ABO-matched or ABO-mismatched random-donor platelet transfusions prepared from pooled platelet concentrate stored for 1 to 3 days. Patients were assigned randomly to receive matched or mismatched platelets as their first transfusion, and the first four transfusions were analyzed. In 40 evaluable patients, there was no significant difference (paired t test) between the 10-minute posttransfusion corrected count increments (CCI) of the initial transfusions of matched and mismatched platelets. In contrast, the second matched transfusion was significantly better than the second mismatched transfusion. This effect of ABO compatibility was particularly pronounced in a subset of patients. Six patients in whom mismatched transfusions were consistently inferior to matched transfusions had either a significant increase in anti-A or -B isoagglutinin titers following the first transfusion or elevated titers before or at the conclusion of the study. Conversely, in five patients in whom there was no apparent effect of ABO mismatching, only one had an increase in isoagglutinin titer. Platelet survival was not altered as the ratio of 18-hour to 10-minute posttransfusion CCl was 0.6 for both matched and mismatched platelet transfusions. These data demonstrate that ABO compatibility can affect the results of random-donor platelet transfusions and that patients who experience poor increments from ABO-mismatched platelets may benefit from a trial of ABO-compatible platelets before the initiation of HLA-matched platelet transfusion.     

PRIMARY MENINGOCOCCAL CONJUNCTIVITIS IN CHILDREN

SUMMARY Four cases of primary meningococcal conjunctivitis in children are reported. This represents an incidence of 2% of patients presenting with conjunctivitis to a paediatric A&E department. All were initially treated with topical chloramphenicol, followed by systemic rifampicin once the diagnosis had been established. No ocular or systemic complications developed, nor recolonisation of the conjunctiva or colonisation of the nasopharynx at follow-up (1–2 years).     

MASSIVE LOWER GASTROINTESTINAL HAEMORRHAGE SECONDARY TO METASTATIC SQUAMOUS CELL CARCINOMA OF THE LUNG

SUMMARY Clinically significant symptoms due to gastrointestinal metastases from primary lung cancers is rare. A case of life-threatening lower gastrointestinal haemorrhage secondary to metastatic squamous cell carcinoma of the lung is reported. Previous reports of such metastases are reviewed, with reference to management and prognosis. After resection of colonic metastases from squamous cell lung cancer, survival is similar to that for primary disease. It is suggested that patients with known or suspected squamous cell lung cancer presenting with lower gastrointestinal symptoms be managed as aggressively as those with no previous history of disease.