Biomarkers and surrogate end points for fit-for-purpose development and regulatory evaluation of new drugs.

A consistent framework for the acceptance and qualification of biomarkers for regulatory use is needed to facilitate innovative and efficient research and subsequent application of biomarkers in drug development. One key activity is biomarker qualification, a graded, "fit-for-purpose" evidentiary process linking a biomarker with biology and clinical end points. A biomarker consortium model will distribute cost and risk, and drive efficient execution of research and ultimately regulatory acceptance of biomarkers for specific indications.

Analysis of latency in cattle after inoculation with a temperature sensitive mutant of bovine herpesvirus 1 (RLB106).

Calves were inoculated with the bovine herpes virus 1 (BHV-1) vaccine strain (RLB 106), which is a temperature sensitive mutant. The route of inoculation was intranasal instillation or intramuscular (i.m.) injection (flank or neck). As a control, five calves were given placebo by i.m. injection of the neck. Regardless of the infection route, clinical symptoms did not occur. However, BHV-1 neutralizing antibodies were detected after inoculation demonstrating that sero-conversion occurred. At 60 days post-inoculation, dexamethasone was given by i.m. injection to attempt reactivation of RLB 106. Only those calves inoculated by the intranasal route shed virus leading to an increase in BHV-1 specific antibodies. As expected, viral DNA and the latency related-RNA were detected in trigeminal ganglia (TG) of calves inoculated by the intranasal route. In contrast, viral nucleic acid was not detected in TG of calves inoculated by the i.m. route or in calves inoculated with placebo. In cervical ganglia or sacral dorsal root ganglia, viral nucleic acid was not consistently detected. This study provides evidence that efficient latency and reactivation does not occur following i.m. inoculation. Since serum-neutralizing antibodies were detected in all inoculated calves, i.m. inoculation led to sero-conversion.

Population and dwelling unit estimates from space.

"To increase the utility of satellite imagery as a source of cheap and current information for planning and managing cities some problems have to be resolved.... One answer is to adopt interpretation methods that use the increased information in a more detailed scene. This paper reports on attempts to measure the morphological patterns in an urban satellite scene and to use these for image interpretation. The interpretation task addressed is the estimation of residential dwelling units from the patterns discernible in high resolution satellite images of cities. The practical results include dwelling estimates that can be aggregated to any geographical unit of analysis, population estimates for cities and a dwelling density surface that can be categorised into any number of residential land-use classes."

Efficacy of subcutaneous sumatriptan in repeated episodes of migraine.

This double-blind, placebo-controlled, multicenter, crossover study investigated the efficacy and tolerability of sumatriptan administered for up to three separate migraine attacks. One hundred twenty adults received sumatriptan (SC, 6 mg; three attacks) and placebo (one attack). Patients completed questionnaires assessing the impact of migraine on their lives and the performance of sumatriptan relative to their usual acute therapies. Sumatriptan statistically outperformed placebo on all efficacy measures, including pain severity; presence/absence of nausea, vomiting, phonophobia, and photophobia; rescue medication use; and clinical disability. Efficacy was consistently maintained with repeated administration. For all attacks, pain relief 90 minutes postdose occurred in 86% to 90% of sumatriptan-treated patients, compared with 9% to 38% of placebo-treated patients. Sumatriptan was well tolerated, and the frequency and severity of adverse events did not change with repeated administration. Patients' perceptions of sumatriptan were consistent with clinical data demonstrating the drug's high degree of efficacy and tolerability.

The chief scientist reports ... hyperbaric oxygen for multiple sclerosis patients.

An 18-month uncontrolled study of the effects of hyperbaric oxygen therapy was conducted in 97 individuals with multiple sclerosis. Two-thirds of the patients were classified as progressive and one-third as stable. Assessment was based mainly on three aspects of activities of daily living: bladder function, mobility and communication. Bladder function showed a tendency to improve over the 12 month period of treatment but there was no evidence that treatment led to an improvement of mobility or communication. There are several reports of immediate improvement in bladder function, objectively and subjectively determined, in response to hyperbaric oxygen. In one study similar to that reported here, lack of deterioration in bladder function amongst progressive patients over two years, was related to continued hyperbaric oxygen treatment.

Methodological problems in evaluating hyperbaric treatment of multiple sclerosis. A case study.

The paper describes a number of methodological problems experienced in a long-term evaluation of hyperbaric treatment for MS. Among the problems discussed are those relating to the locus and logistics of assessment, the reliability of 'subjective' assessments, the feasibility of 'objective' measurements, the identification of outcome categories and patient drop-out and selectivity.

Principles of a quantitative assay for bacterial endotoxins in blood that uses Limulus lysate and a chromogenic substrate.

Some factors affecting the use of chromogenic substrates with Limulus lysate for assaying bacterial endotoxins in blood have been assessed. It was found that endogenous amidases, which degrade the substrate, could be inactivated by heating serum at 60 degrees C for 15 min. Endotoxin was found not to be removed from serum during clotting. A potent inhibitor of the activated lysate was found to be anti-thrombin II, but specific absorption of anti-thrombin II from plasma reduced only marginally the inhibition of lysate by plasma. The presence of specific antibody to the endotoxin was found not to affect its ability to activate lysate. Inactivation of endotoxin by serum enzymes was biphasic in unheated serum, and most of the activity was destroyed in 3 h at 37 degrees C or in 24 h at 5 degrees C. The relevance of these findings to the objective quantitation of endotoxin activities is discussed.