Bolzano,Cauchy and the “new analysis” of the early nineteenth century

Summary In this paper I discuss the development of mathematical analysis during the second and third decades of the nineteenth century; and in particular I assert that the well-known correspondence of new ideas to be found in the writings of Bolzano and Cauchy is not a coincidence, but that Cauchy had read one particular paper of Bolzano and drew on its results without acknowledgement. The reasons for this conjecture involve not only the texts in question but also the state of development of mathematical analysis itself, Cauchy both as personality and as mathematician, and the rivalries which were prevalent in Paris at that time.     

Non-host-selective fungal phytotoxins: Biochemical aspects of their mode of action

During the last decade increasing attention has been directed towards the biochemical mechanisms responsible for the biological activity of phytotoxins. Studies on the mode of action of some non-host-selective phytotoxins, some following on from previous observations, have demonstrated a very specific interaction with particular components of the cell machinery, and have suggested the possible use of these phytotoxins as tools for the investigation of important biochemical processes. This review article reports and discusses results of studies carried out in the 1980s with seven non-host-selective fungal toxins: brefeldin A, cercosporin,Cercospora beticola toxin, fusicoccin, ophiobolins, tentoxin, and zinniol. Each of these interferes with the life of the host by interacting with a different biochemical target.     

Self-labeling of human polymorphonuclear leucocyte myeloperoxidase with125iodine

In order to obtain a radioimmunoassay (RIA) technique for the measurement of human plasma myeloperoxidase (MPO), we purified the enzyme from polymorphonuclear granulocytes (neutrophils), and compared three methods of labeling it with¹²⁵Iodine: chloramine T, lactoperoxidase, and an original technique of self labeling based on the ability of the enzyme to oxidize and bind¹²⁵I in the presence of H₂O₂. The chloramine T technique produced a degraded protein, as well shown by a high non-specific binding of tracer to antibody. The lactoperoxidase technique did not succeed in labeling MPO with an adequate specific activity. In contrast, the self-labeling method gave a stable tracer with a specific activity of 23 Ci/gmg MPO (85 MBq), a satisfactory level of immunoreactivity, and a low-specific binding (3%). After labeling, purification of tracer was achieved by gel filtration chromatography in phosphate buffer (0.05 M; pH7) to which 0.1% poly-L-lysine was added. The labeled molecule remained stable for 40 days and could be used for RIA with a polyclonal antibody raised in rabbits.     

Disruption of mitochondrial function as the basis of the trypanocidal effect of trifluoperazine onTrypanosoma cruzi

Summary The tricyclic anti-calmodulin drug trifluoperazine (TFP) inhibited growth and motility of epimastigotes ofTrypanosoma cruzi, at concentrations lower than 100 M, and motility and infectivity of the bloodstream trypomastigote form at 200 M. Electron microscopy of TFP-treated epimastigotes showed that the major effect was at the mitochondrial level, with gross swelling and disorganization. The oligomycin-sensitive, mitochondrial ATPase was completely inhibited by 20 M TFP, and the same drug concentration caused a 60% decrease in intracellular ATP content. The results suggest that the trypanocidal effect of TFP may be related more to mitochondrial damage than to the well-known anticalmodulin effect of the drug.     

The discovery of antidepressants: A winding path

Summary Modern treatment of mental depression started with the availability of monoamine oxidase (MAO) inhibitors and tricyclic antidepressants. These drugs also contributed to the early development of psychopharmacology. Attempts to improve the anti-tuberculous action of the hydrazine derivative isoniazid by developing derivatives thereof led to the synthesis of iproniazid. Its introduction as the first modern antidepressant was based on three unexpected actions of the drug: MAO-inhibition, reversal of reserpine-induced sedation, and the presence of psychostimulation as a clinical side effect in man. However, the initial success of iproniazid and other MAO inhibitors, hydrazides and non-hydrazides, was curtailed by the occurrence of undesirable side effects such as potentiation of the blood-pressure elevating action of food amines. The tricyclic antidepressants were a development of the class of antihistamines, one of which, chlorpromazine, showed neuroleptic activity. A congener of this compound, imipramine, was discovered by clinical observation to have unexpected antidepressant effects. The clinical success of this drug (which is still in use) led to the development of a successful series of other tricyclic and non-tricyclic antidepressants. Progress in the elucidation of possible mechanisms of the action of the tricyclic compounds has helped this development. Recent advances in basic research have also induced a revival of MAO-inhibitors since, due to the discovery of MAO-subtypes, inhibitors with higher specificity and fewer undesirable side effects are now available.