Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action

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A longitudinal study of chest radiographic changes of workers in the refractory ceramic fiber industry

STUDY OBJECTIVE: This industry-wide longitudinal study examines chest radiographic changes of workers manufacturing refractory ceramic fibers (RCF). DESIGN: Chest radiographs were obtained every 3 years and were interpreted using the 1980 International Labour Organization classification for pneumoconiosis. Three exposure metrics were calculated: duration and latency in a production job, and cumulative exposure (fiber-months per cubic centimeter). PARTICIPANTS: The radiographic survey included 625 current workers at five manufacturing sites and 383 former workers at two of the five sites. MEASUREMENTS AND RESULTS: Pleural changes were seen in 27 workers (2.7%). Of workers with > 20 years of latency from initial production job or 20 years of duration in a production job, 16 workers (8.0%) and 5 workers (8.1%) demonstrated pleural changes, respectively. Results from the cumulative exposure analysis (> 135 fiber-months per cubic centimeter) demonstrated a significant elevated odds ratio (OR) of 6.0 (95% confidence interval [CI], 1.4 to 31.0). The incidence of irregular opacities at profusion categories > or = 1/0 was similar to other nonspecified dust-exposed worker populations at 1.0%, and showed a nonsignificant elevated OR in regard to cumulative fiber exposure of 4.7 (95% CI, 0.97 to 23.5). CONCLUSIONS: RCF are significantly associated with pleural changes that were predominantly pleural plaques, but have not resulted in a statistically significant increase in interstitial changes.     

BGC20-1531, a novel,potent and selective prostanoid EP4 receptor antagonist: a putative new treatment for migraine headache

Background and purpose:

Prostanoid EP₄ receptor antagonists may have therapeutic utility in the treatment of migraine since EP₄ receptors have been shown to be involved in prostaglandin (PG)E₂-induced cerebral vascular dilatation, which may be an important contributor to migraine pain. This study reports the pharmacological characterization of BGC20-1531, a novel EP₄ receptor antagonist.

Experimental approach:

BGC20-1531 was characterized in radioligand binding and in vitro functional assays employing recombinant and native EP₄ receptors. Changes in canine carotid haemodynamics were used to assess the pharmacodynamic profile of BGC20-1531 in vivo.

Key results:

BGC20-1531 exhibited high affinity at recombinant human EP₄ receptors expressed in cell lines (pK_B 7.6) and native EP₄ receptors in human cerebral and meningeal artery (pK_B 7.6–7.8) but showed no appreciable affinity at a wide range of other receptors (including other prostanoid receptors), channels, transporters and enzymes (pKi < 5). BGC20-1531 competitively antagonized PGE₂-induced vasodilatation of human middle cerebral (pK_B 7.8) and meningeal (pK_B 7.6) arteries in vitro, but had no effect on responses induced by PGE₂ on coronary, pulmonary or renal arteries in vitro. BGC20-1531 (1–10 mg·kg⁻¹ i.v.) caused a dose-dependent antagonism of the PGE₂-induced increase in canine carotid blood flow in vivo.

Conclusions and implications:

BGC20-1531 is a potent and selective antagonist at EP₄ receptors in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation. BGC20-1531 is currently in clinical development for the treatment of migraine headache.     

The imported fire ant: immunopathologic significance

The imported fire ant is a major insect cause of generalized hypersensitivity in the southern United States. The alkaloids in the ant's unique venom also produce substantial morbidity due to local reactions, both toxin- and IgE-mediated. Immunotherapy--with whole body extracts as well as with venom--is given only to patients with systemic reactions.     

Decision making by emergency physicians when assessing cardiac arrest patients on arrival at hospital.

OBJECTIVE: To investigate the factors which influence decision making by experienced emergency physicians when they decide whether to (a) pronounce 'life extinct' in adult patients with non traumatic cardiac arrest while in the ambulance, or (b) bring them into the resuscitation room in the Emergency Department for further assessment/management. DESIGN: Qualitative study involving semi structured interviews and a focus group. SETTING: Accident & Emergency (A&E) departments in the Yorkshire region. PARTICIPANTS: Fifteen emergency physicians (two clinical fellows, nine specialist registrars and four consultants) working in the Yorkshire region. RESULTS: Six main themes were identified that impacted upon the decision making process: the doctor's past experience, ambulance service issues, prehospital care, patient characteristics, presence and views of relatives, and organisational issues. CONCLUSION: The reasoning behind decisions made when a patient arrives at the Emergency Department in cardiac arrest is multifactorial. Strict guidelines would be difficult to construct since individuals vary in the importance they attach to different factors.     

Inactivation of H‐type and L‐type bovine spongiform encephalopathy following recommended autoclave decontamination procedures

The resistance of H‐type and L‐type BSE prions to autoclaving under EU regulation conditions for specified risk material is unknown. We employed transgenic mouse (bovinized line tg1896) bioassay to assess the efficacy of such decontamination on L‐ and H‐type BSE. For each source, titre calculation was based on the comparison of incubation period and attack rate prior to and after decontamination. The infectious titre of L‐type BSE was reduced by at least 9.40 log₁₀ and of H‐type BSE by at least 3.94 log₁₀. In fact, no infectivity was detected for L‐type or H‐type BSE post‐inactivation even at a 10^–1 dilution.     

Multi-envelope HIV vaccine safety and immunogenicity in small animals and chimpanzees

A significant obstacle to HIV vaccine development lies in the remarkable diversity of envelope proteins, the major targets of neutralizing antibody. That envelope diversity must be targeted is dem onstrated by results from nonhuman primate studies in which single-envelope vaccines have protected against homologous, but rarely against heterologous virus challenges. Similarly, in clinical trials, single-envelope vaccines have failed to prevent break-through infections when challenge viruses were inevitably mismatched with the vaccine, To protect humans from infection by any isolate of HIV, we have prepared vaccine cocktails combining multiple envelopes from distinct viral isolates. We have tested several vehicles for vaccine delivery in small animals and have shown that successive immunizations with envelope, presented first as a DNA recombinant, then as a vaccinia virus (VV) recombinant, and finally as purified protein elicited strong neutralizing antibody responses. We have also tested the VV recombinant vaccine in chimpanzees. Pairs of animals received either single- or multi-envelope VV recombinant vaccines administered by the subcutaneous route. Results showed that the multienvelope vaccine was safe, immunogenic, and superior to the single-envelope vaccine ineliciting HIV-specific antibody measurable in a standard clinical, immune assay. The promise of this system has led to the initiation of clinical trials, with which the hypothesis that cocktail vaccines will prevent human HIV infections may ultimately be tested.