Leishmaniasis--current chemotherapy and recent advances in the search for novel drugs

The chemotherapy currently available for leishmaniasis is far from satisfactory. Resistance to the pentavalent antimonials, which have been the recommended drugs for the treatment of both visceral (VL) and cutaneous leishmaniasis (CL) for >50 years, is now widespread in India. Although new drugs have become available in recent years for the treatment of VL, including AmBisome^®, the excellent but highly expensive liposomal formulation of amphotericin B, and the oral drug miltefosine, which has now been registered in India, treatment problems remain. Parenteral and topical formulations of the aminoglycoside paromomycin offer potential treatments for VL and CL, respectively. The search for new drugs continues, with bisphosphonates, for example, risedronate and pamidronate, and plant derivatives such as licochalcone A and quinoline alkaloids being reported to have activity against experimental animal infections. The immunomodulator imiquimod has proved to be an adjunct for CL therapy. Many potential drug targets have been identified in biochemical and molecular studies, and some have been validated. Attempts to exploit these targets are in progress.     

Structure-activity relationships of antileishmanial and antimalarial chalcones

A series of oxygenated chalcones which have been evaluated earlier for antimalarial activity (Plasmodium falciparum K1) were tested for antileishmanial activity against Leishmania donovani amastigotes. A comparison of structure-activity relationships reveal that different physicochemical and structural requirements exist for these two activities. Antileishmanial activity is associated with less lipophilic chalcones, in particular those with 4'-hydroxyl-substituted B rings and hetero/polyaromatic A rings. In contrast, chalcones with good antimalarial activity have alkoxylated B rings and electron-deficient A rings. Visualization of the steric and electrostatic fields generated from comparative molecular field analysis (CoMFA) indicate that the ring A of chalcones make a more significant contribution to antileishmanial activity while both rings A and B are important for antimalarial activity. Despite different requirements, two alkoxylated chalcones (8, 19) were identified which combined good antimalarial and antileishmanial activities.     

Oxazolinone derivative of leucine for GC-MS: a sensitive and robust method for stable isotope kinetic studies of lipoproteins

Stable isotope labeled amino acids are commonly used as endogenous tracers to study the metabolism of lipoproteins. The determination of isotopic enrichment of particular amino acids in apolipoproteins is carried out by gas chromatography mass spectrometry (GC-MS). This report describes a robust and sensitive derivative for analysis of d3-leucine by GC-MS and its utility in studying the metabolism of human lipoproteins. The trifluoromethyloxazolinone (oxazolinone) derivative of leucine was formed in a rapid single step procedure using a mixture of trifluoroacetic anhydride (TFAA) and trifluoroacetic acid (TFA). Analysis of the oxazolinone by negative ion chemical ionization GC-MS gave excellent sensitivity and precision, which enabled accurate determination of low levels of isotopic enrichment from small amounts of protein. For example, enrichments between 0.05% and 100% in 100 pg leucine can be measured with a coefficient of variation of <3%. To demonstrate the utility of this procedure, we measured d3-leucine enrichment in apolipoprotein B (apoB) isolated from VLDL and LDL as well as apoA-I isolated from HDL by gel electrophoresis and western blotting. The derivatization procedure gave excellent enrichment data from a single intravenous bolus dose of 5 mg/kg, from which the fractional catabolic rate and production rate of the lipoproteins were calculated. In conclusion, the oxazolinone derivative provides a robust and simple procedure for the sensitive analysis of isotopic enrichment for metabolic studies of human lipoproteins.     

Mate Choice in Female Red-necked Pademelons,Thylogale thetis (Marsupialia: Macropodoidea)

Changes in the behaviour of captive female red-necked pademelons, Thylogale thetis, before, during and after oestrus were observed relative to the location of potential male mates. A penned female was presented with four adjacent, individually caged males representing the size classes large, medium, small and subadult. The female's behaviour was videotaped for 8–9 d spanning oestrous (3 d), post-oestrous (3 d) and normal (3 d) sessions of time. Changes in the activity, orientation and location of six penned females, relative to the caged males, were transcribed from videotape. A model of female pademelon behaviour pattern was developed. Results suggest that the females spent a significantly greater amount of time directly in front of the largest available male, relative to the other three smaller males during the oestrous period only, and that a significant proportion of this time was spent involved in active behaviours (grooming and locomotion, compared with inactive behaviours of sitting and scan/sniffing). Although there was a significant preference for females to orientate their bodies away from the location of the males, they faced the males significantly more during oestrus than any other session. Furthermore, the females faced the large male significantly more frequently than any other male. This study provides evidence for mate choice by female red-necked pademelons.     

A grid-net technique for the analysis of fish positions within free-ranging shoals

The design and operation of a grid-net are described, which allows the capture of entire shoals of wild fish and preserves information about the two-dimensional structure of shoals and the spatial positions of individual fish within the shoal. This simple technique facilitates investigation of several aspects of individual differences in fish shoaling behaviour in the wild for the first time.     

A comparative life history study of immature Amblyseius fallacis,Amblyseius andersoni,Typhlodromus occidentalis and Typhlodromus pyri (Acari: Phytoseiidae) with a review of larval feeding patterns in the family

Survival, developmental time, activity, feeding rates, and other biological aspects of immatures of Amblyseius fallacis, Amblyseius andersoni, Typhlodromus occidentalis and Typhlodromus pyri were examined in the laboratory in small arenas (2×2 cm) with different egg densities (0, 5, 10, 20 per 12 h) of the twospotted spider mite, Tetranychus urticae (Koch), at 25±1°C, ≈80% RH, and 16L: 8D photoperiod. Egg survival was high (86–100%) in all four species. Larval survival was similarly high except for T. occidentalis which all died in the absence of food. Survival rates of protonymphs and deutonymphs were also high except that up to 50% of A. andersoni died at 5 prey eggs per 1/2 day. Developmental time did not vary significantly with prey density and was similar for males and females in the oligophagous predators (A. fallacis and T. occidentalis), but was longer at lower prey densities and in females than males in the polyphagous predators (A. andersoni and T. pyri). In general, the time allocated to three active instars (=stases) decreased in the order: A. andersoni (81%), T. pyri (78%), A. fallacis (69%), and T. occidentalis (64%). The polyphagous predator species had a shorter larval stage and much longer deutonymphal stage than the oligophagous species. The proportion of time allocated to the protonymphal stage was the least variable among the four species. The interspecific differences in walking activities also appeared greater in larval and deutonymphal stages than in the protonymphal stage. The larvae of the two oligophagous predators (A. fallacis and T. occidentalis, walking activity averaging 36–49%) were more active than the two polyphagous predators (A. andersoni and T. pyri), which spent 80% or more time resting. In deutonymphs, walking activity increased in the order: T. occidentalis (14%), A. andersoni (27%), A. fallacis (43%) and T. pyri (59%). Larvae were more active during the first half of their life than the latter half. In general, most life history traits of immature A. andersoni, T. pyri, A. fallacis, and T. occidentalis are not associated with their phylogenetic relatedness or size, but with the feeding specialization of the predator species. Larval feeding patterns in Phytoseiidae are reviewed and a hypothesis about the evolution of larval feeding behavior in Phytoseiidae is proposed.     

Walking,feeding and intraspecific interaction of larvae of Metaseiulus occidentalis,Typhlodromus pyri,Neoseiulus fallacis and Amblyseius andersoni held with and without eggs of Tetranychus urticae

Larvae of Metaseiulus occidentalis (Nesbitt), Typhlodromus pyri Scheuten, Neoseiulus fallacis (Garman) and Amblyseius andersoni Chant exhibited different activity levels when held on apple leaf or on tile arenas and given or not given eggs of Tetranychus urticae Koch and water (tiles only). M. occidentalis larvae held without prey exhibited high levels of walking (includes searching) during 24 hours of evaluation, whereas M. occidentalis larvae held with prey fed quickly and then became less active. Fed larvae of M. occidentalis were less active on leaves than tile. Larvae of T. pyri on leaves had a very low frequency of walking, almost never fed and quickly assumed a resting position during development. While much less active than M. occidentalis, fed and unfed T. pyri larvae walked more on tiles than leaves before resting. Larvae of N. fallacis and A. andersoni fed at low rates and were similarly active on tiles and leaves. Free water increased walking by M. occidentalis, A. andersoni and T. pyri on tile but not N. fallacis. M. occidentalis larvae interacted 5–7 times more often than larvae of the other three species. Cannibalism or scavenging was rarely seen and then only for M. occidentalis larvae. Larvae of all four mites walked, fed and interacted much more in the first 12 hours than the second 12 hours of tests, except unfed M. occidentalis. Unfed M. occidentalis larvae did not molt to protonymphs but unfed larvae of the other three species did. Unfed and fed protonymphs of all four species walked more at 4 hours after molting than larvae at 12–24 hours. Unfed and fed protonymphs of T. pyri or A. andersoni had similar walking frequencies, but unfed protonymphs of N. fallacis were more active than fed ones. Trends in larval activities are discussed relative to the life history of each species.     

Nuclear medicine in district general hospitals.

Nuclear medicine is a recognised clinical specialty both nationally and internationally. Compared with other countries, it is inadequately developed in Britain, particularly in district general hospitals. To create clinical radioisotope services at district level physicians or radiologists with experience in nuclear medicine need to be trained and appointed. Such appointments would allow facilities to evolve that would provide either a comprehensive nuclear medicine service formed around a physician or an imaging service based on a radiologist. Such units would improve the care of patients at a reasonable recurring cost of 15 pounds--30 pounds per investigation.