New antifungal agents for the systemic mycoses

The azoles are the prominent broad spectrum oral antifungal agents in use or under clinical investigation for the systemic mycoses. This class of antifungal agents is represented by the marketed drug ketoconazole (Nizoral) and the experimental triazoles furthest along in clinical trials in the United States, itraconazole and fluconazole. Ketoconazole use is limited by its side effect profile and activity spectrum. Itraconazole appears to be better tolerated and less toxic to liver function, does not cause adrenal suppression and is more active against Aspergillus and Sporothrix schenckii. Fluconazole appears to be a highly promising agent due its highly favorable pharmacokinetic profile; it is water soluble, is well tolerated, is not metabolized to inactive constituents, it has a long half-life and, unlike the other azoles, high cerebrospinal fluid levels are readily attained for consideration in meningeal mycoses. It remains to be determined what place these new triazoles have in managing immunosuppressed patients including those with acquired immune deficiency syndrome known as AIDS. Other experimental antifungal agents, including ambruticin, amphotericin B methyl ester and saramycetin are also described. Sales figures are presented of drugs marketed in the United States for the systemic mycoses and reflect the growing problem of fungal diseases in the population.Presented as part of the Everett S. Beneke Symposium in Mycology, May 27, 1988.     

On the mechanism of formation of N-acetyldopamine quinone methide in insect cuticle

The mechanism of formation of quinone methide from the sclerotizing precursor N-acetyldopamine (NADA) was studied using three different cuticular enzyme systems viz. Sarcophaga bullata larval cuticle, Manduca sexta pharate pupae, and Periplaneta americana presclerotized adult cuticle. All three cuticular samples readily oxidized NADA. During the enzyme-catalyzed oxidation, the majority of NADA oxidized became bound covalently to the cuticle through the side chain with the retention of o-diphenolic function, while a minor amount was recovered as N-acetylnorepinephrine (NANE). Cuticle treated with NADA readily released 2-hydroxy-3′,4′-dihydroxyacetophenone on mild acid hydrolysis confirming the operation of quinone methide sclerotization. Attempts to demonstrate the direct formation of NADA-quinone methide by trapping experiments with N-acetylcysteine surprisingly yielded NADA-quinone-N-acetylcysteine adduct rather than the expected NADA-quinone methide-N-acetylcysteine adduct. These results are indicative of NADA oxidation to NADA-quinone and its subsequent isomerization to NADA-quinone methide. Accordingly, all three cuticular samples exhibited the presence of an isomerase, which catalyzed the conversion of NADA-quinone to NADA-quinone methide as evidenced by the formation of NANE—the water adduct of quinone methide. Thus, in association with phenoloxidase, newly discovered quinone methide isomerase seems to generate quinone methides and provide them for quinone methide sclerotization.     

The structure of the basement membrane of human lymph node high endothelial venules: An ultrastructural, histochemical and immunocytochemical study

Summary The structure of the basement membrane of the high endothelium of reactive human lymph nodes was investigated by techniques selective for carbohydrates (periodic acid-Schiff; critical electrolyte concentration staining with Alcian Blue; lectin histochemistry), specific proteins (immunohistochemistry for laminin and fibronectin) and by conventional techniques of light and transmission electron microscopy. Adjacent small lymphocytes were assigned to B and T cell subsets by use of monoclonal antibodies and they were analysed for non-specific esterase,-glucuronidase,-N-acetylglucaminidase and proteolytic activities. The basement membranes were shown to be distinctive and to contain three layers, of differing laminin, glycosaminoglycan and glycoprotein oligosaccharide content. Certain lymphocytes (probably T) contained enzymes potentially able to degrade some components of these basement membranes.     

Foraging-efficiency-predation-risk trade-off in the grey squirrel

Many animals must often respond to environmental patterns that simulatneously influence both foraging efficiency and predation risk. We noted that grey squirrels (Sciurus carolinensis) sometimes immediately consume food items in areas of relatively great exposure to predators, and at other times carry food items to the safety of a tree prior to consumption. We outlined a hypothesis that the squirrels were somehow trading-off energy intake rate against predation risk. A simple model shows that maximal energetic efficiency is associated with immediate consumption, whereas (under the field conditions studied) carrying items to the safety of trees provides for minimal exposure to predation. Our analysis of the model predicts that the tendency to carry a food item should decrease with distance of food from cover (travel time) and increase with item size (handling time). To test our predictions, we presented free-roaming grey squirrels with patches containing a fixed number of identical food items. We estimated the proportion of items carried to trees before consumption for 12 different combinations of distance to the nearest tree and item size. The results support our hypothesis and indicate that a simple behavioural criterion based solely on foraging rate or time exposed to predators is insufficient to explain the variation in the data.     

An information-theory analysis of task specialization among worker honey bees performing hive duties

Worker honey bees (Apis mellifera) performing field duties are known to possess individual task specializations. However, little evidence has been forthcoming about individual specializations among the younger pre-foraging worker bees performing hive duties. This paper reports results obtained from behavioural observations of worker bees in seven hives. An information-theory analysis of these data reveals that the divergence from independence (D₂) of worker bee identity and behavioural pattern performed has a low value in all of the experimental hives. Young worker bees performing hive duties therefore do not possess detectable individual specializations. Environmental and life-history considerations that may account for this difference in behaviour between field and hive worker bees are discussed.     

Digestion of prey in foraminifera is not anomalous: A correlation of light microscopic, cytochemical, and hvem technics to study phagotrophy in two allogromiids

Correlative light, high-voltage electron and conventional electron microscopic methods were used to investigate digestion in two allogromiid foraminiferans, Allogromia sp., strain NF, and A. laticollaris Arnold. Microscopic observations showed that bacterial prey are phagocytosed by reticulopodia and are transported to the allogromiid cell body within blister-like phagosomes. Larger prey (algae, diatoms) are transported along the reticulopodial surface and are either stored extrathalamously or phagocytosed at the oral opening (peduncle). Studies of allogromiids optimally fixed and labeled with an extracellular-space label (colloidal thorium) showed that phagocytosed prey are completely enclosed by a plasma membrane envelope; this finding was corroborated by a serial-section three-dimensional reconstruction of the oral zone of one allogromiid. Cytochemical staining for acid phosphatase showed that lysosomes are absent from reticulopods but abundant in the cell body, particularly in the oral zone cytoplasm. We conclude that digestion in allogromiid foraminiferans is accomplished by a vacuole-based digestive apparatus and not by extracellular digestion within a lacunary system, as has been suggested in earlier studies.     

Canadian survey of thyroid cancer

We report the results of a multicentre retrospective chart review of 2214 patients with thyroid cancer registered at 13 radiotherapy centres between 1958 and 1978. The data analysed included sex, age at the time of diagnosis, pathological diagnosis, extent of disease before treatment, types of treatment and their complications, and the rates of recurrence and survival up to 24 years after diagnosis. Although papillary cancers were most common, anaplastic and miscellaneous tumours were more frequent than expected, which reflects the type of patients referred by endocrinologists and surgeons to radiotherapy centres. There were marked differences in patterns of referral to the centres. Some patients with papillary and follicular thyroid cancers died of these cancers up to 20 years after diagnosis. The clinical manifestations, treatment and outcome of the rarer types of thyroid malignant tumours were of particular interest. The influence of age at the time of diagnosis on survival rates for patients with papillary or follicular thyroid cancer was highly significant, indicating much more aggressive behaviour of these cancers in older patients, particularly those beyond the age of 60 years. A more detailed analysis of tumour subtypes should provide new information on their natural history and lead to better management.     

Fluorescent inhibitors of a cell surface protease used to locate leukaemia cells in kidney sections

Guanidinobenzoatase is a trypsin-like protease on the surface of cells capable of migration, for example leukaemia cells. We have used a number of fluorescent probes that are competitive inhibitors of guanidinobenzoatase to locate leukaemia cells in resin sections of kidney tissue obtained from leukaemic rats. We have demonstrated how this competitive inhibition system can be used to direct desired molecules (such as cytotoxic drugs) to these cells and to monitor the arrival of such compounds at the active site of guanidinobenzoatase. The principles developed in this study could equally well be applied to other enzymes on other cells provided suitable competitive inhibitors were designed. The presence of an enzyme on the surface of a cell can be used to direct molecules to that cell provided that these molecules contain a functional group that acts as an inhibitor for the chosen enzyme.