Serendipity and Vision: Two Methods for Discovery Comments on Nickles

Thomas Nickles challenges my thesis that innovative discoveries can be based on deliberately chosen problems and research strategies. He suggests that all significant innovation can be seen as such only in retrospect and that its generation must be serendipitous. Here I argue in response that significant innovations can and do often arise from self conscious critical appraisal of orthodox practice combined with regulated though speculative abductive argumentation to alternative explanatory schemata. Orthodox practice is not based upon monolithic systems of belief about the subject of inquiry. Rather major domains of scientific practice often are approached from different conceptualizations that provide grounds for critical dialectic and consilient empirical information. Abductive arguments that meet appropriate conditions of likelihood, probability and analogy are an important means of justifying allocating resources to innovative practices that have yet to produce products that can rival those of established orthodoxy.     

Clinical effectiveness of biologics in clinical practice

TNF inhibitors are currently considered both effective and cost-effective in patients with active rheumatoid arthritis (RA), particularly in patients who have not responded fully to methotrexate. There is substantial doubt about the cost-effectiveness of TNF inhibitors as initial treatment for active RA. New data from the National Data Bank for Rheumatic Diseases now question the current consensus in methotrexate failures. The data suggest that in routine clinical practice TNF inhibitors provide only modest incremental benefits over best conventional therapy. If confirmed, these observational studies suggest that the economic argument underpinning the widespread use of TNF inhibitors in established RA is unsustainable.     

Dependence of cytoplasmic calcium transients on the membrane potential in isolated nerve endings of the guinea pig

The relation of changes in internal, free Ca2+, measured with arsenazo III, to the membrane potential, measured with the cyanine dye di-S-C2(5) or 86Rb+ distribution ratio, was studied in isolated guinea pig cortical nerve endings. Depolarization of the plasma membrane with veratridine or gramicidin as well as addition of ionophore A23187 led to an increase in cytosolic Ca2+. Only the response to veratridine was inhibited by tetrodotoxin. The dependence of the depolarization-induced increase in intraterminal, free Ca2+ on the membrane potential between about -50 to 0 mV was sigmoidal. A maximal increase in cytosolic Ca2+ was reached when the membrane potential was depolarized from the resting level, about -64 mV, to about -40 mV. These results show that in isolated nerve endings the activation of voltage-sensitive Ca2+ channels concomitantly leads to an increase in cytosolic, free Ca2+. Comparison of the results of the present study with the previous electrophysiological observations indicate that Ca2+ channels in synaptosomes, presynaptic nerve terminals of the squid giant synapse and cardiac cells have essentially similar voltage dependency.     

Radioiodinated surface proteins of rabbit trophectoderm cells

Summary We have previously used surface iodination to discriminate between the protein patterns of epithelial cell surfaces in uteri of rabbits receptive (Day 6.5) or nonreceptive (Day 4) to nidation (Ricketts et al. 1984). In this paper, we describe application of the same technique to the trophoblastic surface of rabbit blastocysts collected on the same days of pregnancy. Analysis of labelled proteins by polyacrylamide-gel electrophoresis under denaturing conditions did not reveal qualitative differences between the two days of pregnancy. Scanning densitometry was used to quantitate the area under each protein peak on an autoradiogram; these areas were used as variables in statistical analysis of the protein pattern of individual animals. Quantitative differences between the protein patterns of the two surfaces were detected by canonical variate analysis of the pattern of relative areas of labelled protein peaks. In proteins separated on 7.5% gels, this statistical analysis correctly assigned blastocysts from 8 out of 10 animals to one of two groups according to day of pregnancy. The discrimination was not statistically significant, however, in protein patterns on 12.5% gels, used to give better separation in the lower range of molecular weights. The same analysis in the uterus unequivocally separated the surface iodination patterns from these same days of pregnancy. Thus the changes detected by surface iodination appear to be less pronounced on the trophectoderm than on the uterine epithelium in relation to the time of ovoimplantation.     

Pollen-based biome reconstruction for southern Europe and Africa 18,000 yr bp

Pollen data from 18,000 ¹⁴C yr bp were compiled in order to reconstruct biome distributions at the last glacial maximum in southern Europe and Africa. Biome reconstructions were made using the objective biomization method applied to pollen counts using a complete list of dryland taxa wherever possible. Consistent and major differences from present‐day biomes are shown. Forest and xerophytic woods/scrub were replaced by steppe, both in the Mediterranean region and in southern Africa, except in south‐western Cape Province where fynbos (xerophytic scrub) persisted. Sites in the tropical highlands, characterized today by evergreen forest, were dominated by steppe and/or xerophytic vegetation (cf. today’s Ericaceous belt and Afroalpine grassland) at the last glacial maximum. Available data from the tropical lowlands are sparse but suggest that the modern tropical rain forest was largely replaced by tropical seasonal forest while the modern seasonal or dry forests were encroached on by savanna or steppe. Montane forest elements descended to lower elevations than today.