Empirical scoring functions. II. The testing of an empirical scoring function for the prediction of ligand-receptor binding affinities and the use of Bayesian regression to improve the quality of the model

This paper tests the performance of a simple empirical scoring function on a set of candidate designs produced by a de novo design package. The scoring function calculates approximate ligand-receptor binding affinities given a putative binding geometry. To our knowledge this is the first substantial test of an empirical scoring function of this type on a set of molecular designs which were then subsequently synthesised and assayed. The performance illustrates that the methods used to construct the scoring function and the reliance on plausible, yet potentially false, binding modes can lead to significant over-prediction of binding affinity in bad cases. This is anticipated on theoretical grounds and provides caveats on the reliance which can be placed when using the scoring function as a screen in the choice of molecular designs. To improve the predictability of the scoring function and to understand experimental results, it is important to perform subsequent Quantitative Structure-Activity Relationship (QSAR) studies. In this paper, Bayesian regression is performed to improve the predictability of the scoring function in the light of the assay results. Bayesian regression provides a rigorous mathematical framework for the incorporation of prior information, in this case information from the original training set, into a regression on the assay results of the candidate molecular designs. The results indicate that Bayesian regression is a useful and practical technique when relevant prior knowledge is available and that the constraints embodied in the prior information can be used to improve the robustness and accuracy of regression models. We believe this to be the first application of Bayesian regression to QSAR analysis in chemistry.     

Analysis of suckling-induced changes in adenohypophyseal prolactin concentration in the lactating rat by three assay methods

Suckling-induced changes in adenohypophyseal prolactin (PRL) concentrations in lactating rats were measured in two experiments by three assays: a disc electrophoretic assay (DEA), a bioassay (BA) and a radioimmunoassay (RIA). Substantial discrepancies among the three assays were found in the absolute amounts of pituitary PRL measured and in the changes in adenohypophyseal PRL concentration that were recorded between suckling intervals. The results indicate that in dynamic states of secretory activity the correspondence among BA, RIA and DEA estimates of pituitary PRL concentration is poor.     

Observations on the A2 England influenza epidemic: a clinicopathological study

A clinicopathological study of the 1972-1973 A2 England influenza epidemic is presented. In fatal cases early necrosis of myofibrils was present in those patients who died within 24 hours of the onset of the influenza symptoms. At 5 days gross changes were present. These were largely resolved by the eighteenth day of illness. In 42 patients treated at home, transient ECG changes were found in 18 cases. These included ST-segment deviation, T-wave inversion, flattening of the T wave, sinus bradycardia, sinus tachycardia, nodal rhythm, and atrial fibrillation. Permanent changes were observed in one patient and in an additional patient admitted to hospital with permanent A-V block.     

Caroli's disease with intrahepatic gall-stones and salmonella infection

At operation for small bowel intussusception, a 26-year-old man was found to have an enlarged liver and spleen. Subsequent investigations suggested bile passage infection associated with numerous intrahepatic gall-stones but symptomatic cholangitis did not present until 5 months later. Retrograde cholangiography showed cavernous ectasia of the bile ducts which contained gall-stones.     

Surgical management of necrotizing scleritis

We successfully used autogenous periosteum to reinforce the weakened sclera of two patients with necrotizing scleritis. One of these patients previously had an onlay scleral graft made from homologous banked sclera, which had subsequently melted. Autogenous periosteum is suggested as an alternative to banked sclera for scleral reinforcement.