How do the macrocyclic lactones kill filarial nematode larvae?

The macrocyclic lactones (MLs) are one of the few classes of drug used in the control of the human filarial infections, onchocerciasis and lymphatic filariasis, and the only one used to prevent heartworm disease in dogs and cats. Despite their importance in preventing filarial diseases, the way in which the MLs work against these parasites is unclear. In vitro measurements of nematode motility have revealed a large discrepancy between the maximum plasma concentrations achieved after drug administration and the amounts required to paralyze worms. Recent evidence has shed new light on the likely functions of the ML target, glutamate-gated chloride channels, in filarial nematodes and supports the hypothesis that the rapid clearance of microfilariae that follows treatment involves the host immune system.     

Physician choices in pulmonary embolism testing

BACKGROUND:Evidence-based guidelines advise excluding pulmonary embolism (PE) diagnosis using d-dimer in patients with a lower probability of PE. Emergency physicians frequently order computed tomography (CT) pulmonary angiography without d-dimer testing or when d-dimer is negative, which exposes patients to more risk than benefit. Our objective was to develop a conceptual framework explaining emergency physicians’ test choices for PE.METHODS:We conducted a qualitative study using in-depth interviews of emergency physicians in Canada. A nonmedical researcher conducted in-person interviews. Participants described how they would test simulated patients with symptoms of possible PE, answered a knowledge test and were interviewed on barriers to using evidence-based PE tests.RESULTS:We interviewed 63 emergency physicians from 9 hospitals in 5 cities, across 3 provinces. We identified 8 domains: anxiety with PE, barriers to using the evidence (time, knowledge and patient), divergent views on evidence-based PE testing, inherent Wells score problems, the drive to obtain CT rather than to diagnose PE, gestalt estimation artificially inflating PE probability, subjective reasoning and cognitive biases supporting deviation from evidence-based tests and use of evidence-based testing to rule out PE in patients who are very unlikely to have PE. Choices for PE testing were influenced by the disease, environment, test qualities, physician and probability of PE.INTERPRETATION:Analysis of structured interviews with emergency physicians provided a conceptual framework to explain how these physicians use tests for suspected PE. The data suggest 8 domains to address when implementing an evidence-based protocol to investigate PE.

Pulmonary embolism (PE) occurs when a blood clot lodges in the pulmonary arteries. If left untreated, the disorder can progress, causing worsening morbidity and may become fatal.¹ Because of the acute nature of this condition, many patients with PE present to the emergency department.Diagnosing and excluding PE using computed tomography pulmonary angiography (CTPA) alone can be problematic because of radiation exposure, anaphylaxis to contrast, misdiagnosis and “overdiagnosis” of inconsequential PE² (leading to unnecessary anticoagulation therapy and psychological distress³). Choosing Wisely^4,5 and the guideline from the American College of Physicians⁶ recommend the use of risk stratification tools, including the Pulmonary Embolism Rule-out Criteria (PERC) clinical decision rule,⁷ the Wells score⁸ and blood concentration of d-dimer. These tools use different predetermined diagnostic algorithms to indicate the need for CTPA.^8–11 Evidence-based guidelines discourage further testing in patients at lower risk who have normal d-dimer levels, where imaging can cause more harm than benefit.^12,13 However, many emergency physicians opt for CTPA as a stand-alone test for PE.^14–17It remains unclear why emergency physicians sometimes do not use validated diagnostic PE tools. Furthermore, implementation of computerized decision support systems has had little success in modifying this behaviour.^18,19 We sought to develop a conceptual framework to describe how Canadian emergency physicians test for PE, and to document the cognitive and contextual barriers to using existing evidence-based diagnostic PE pathways.     

Immunocytochemical identification of enkephalinergic neurons in the hypothalamic magnocellular preoptic nucleus of the goldfish,Carassius auratus

Summary Secretory granule area and glycoprotein concentration of the saliva in the submaxillary gland of rats were measured during various stages of acclimation to heat at 34±1° C. Granule size decreased by 18% during the first five days of heat acclimation (0.025<p<0.05) after which period it increased to reach 118% of the control levels after 28 days (p<0.05). Glycoprotein concentration in the saliva of stimulated glands rose above control levels, reaching a maximum between the 2nd and 5th day of acclimation (p<0.05). It was concluded that the initial decrease in granule size reflects a decrease in glycoprotein content following an increase in salivary flow known to occur at high ambient temperatures. The subsequent increase in granule size is considered an adaptation of the gland to continuous stimulation. The rise in salivary glycoprotein concentration suggests increased efficiency of the secretory mechanism.Supported by the joint research fund of the Hebrew University-Hadassah School of Dental Medicine founded by the Alfa Omega Fraternity and the Hadassah Medical Organization     

Prolactin and insulin are targeted to the regulated pathway in GH4C1 cells, but their storage is differentially regulated

PRL storage in GH4C1 cells, rat pituitary tumor cells, can be induced by treatment with a combination of estradiol, epidermal growth factor, and bovine insulin. This increase in storage is characterized by a preferential increase in intracellular PRL compared with secreted PRL and a 50-fold increase in the number of secretory granules. Treatment with the combined hormones stimulates PRL synthesis approximately 6-fold, but this effect is not sufficient to increase PRL storage, because epidermal growth factor alone increases PRL synthesis to the same extent without affecting storage. The cDNA for human proinsulin down-stream of the RSV-LTR promoter was transfected into GH4C1 cells to determine whether storage of another protein known to be targeted to the regulated pathway would also increase with hormone treatment. Proinsulin and PRL release were stimulated over the same time course and to the same peak height, compared to basal release, by both KCl and TRH, indicating that proinsulin is targeted to the regulated pathway in GH4C1 cells. There was little intracellular processing of proinsulin to insulin. Proinsulin synthesis increased 3.9-fold with the combined treatment, assessed by accumulation of proinsulin immunoreactivity in the medium and increases at the mRNA level. Treatment with the combined hormones did not cause the preferential increase in intracellular proinsulin that occurred with PRL; the increase in intracellular proinsulin could be accounted for primarily by effects on synthesis. These results suggest that storage of the two hormones can be differentially regulated.     

Role of the α1β1 integrin complex in collagen gel contraction in vitro by fibroblasts

Matrix remodeling, critical to embryonic morphogenesis and wound healing, is dependent on the expression of matrix components, their receptors, and matrix proteases. The collagen gel assay has provided an effective model for the examination of the functional role(s) of each of these groups of molecules in matrix remodeling. Previous investigations have indicated that collagen gel contraction involves the β1 integrin family of matrix receptors and is stimulated by several growth factors, including TGF-β, PDGF, and angiotensin II. In particular, collagen gel remodeling by human cells involves the α2β1 and, to a lesser extent the α1β1 integrin complexes. The present studies were undertaken to determine the role of the α1 integrin chain, a collagen/laminin receptor, in collagen gel contration by rodent and avian fibroblasts. A high degree of correlation was found between the expression of the α1β1 integrin complex and the relative ability of cells to contract collagen gels. Further studies using antibodies and antisense oligonucleotides against the α1 integrin indicated a significant role for this integrin chain in contraction of collagen gels by rat cardiac fibroblasts. In addition, antibodies to the α1 integrin chain inhibited migration of these fibroblasts on a collagen substratum, suggesting that at least one role of this integrin is in migration of cells in collagen gels. These results indicate that the α1β integrin complex plays a significant role in cellular interactions with interstital collagen that are involved in matrix remodeling such as is seen during morphogenesis and wound healing. © 1995 Wiley-Liss, Inc.     

Screening Global Positioning System Location Data for Errors Using Animal Movement Characteristics

Abstract: Animal locations estimated by Global Positioning System (GPS) inherently contain errors. Screening procedures used to remove large positional errors often trade data accuracy for data loss. We developed a simple screening method that identifies locations arising from unrealistic movement patterns. When applied to a large data set of moose (Alces alces) locations, our method identified virtually all known errors with minimal loss of data. Thus, our method for screening GPS data improves the quality of data sets and increases the value of such data for research and management.     

Epitope mapping of two isoforms of a trans Golgi network specific integral membrane protein TGN38/41.

TGN38/41 is an integral membrane protein predominantly located in the trans Golgi network (TGN) of rat (NRK) cells. We have used a cDNA expression system to map the epitopes recognised by a panel of antibodies raised to TGN38/41 as a preliminary step in the accurate identification of the region(s) of the molecule responsible for its correct intracellular location. These studies have confirmed the predicted topology of the molecule, and have identified a region in the cytoplasmic domain which is immunologically (and hence potentially functionally) conserved between species.     

Host‐plant genotype mediates supply and demand of animal food in an omnivorous insect

1. Omnivorous predators can protect plants from herbivores, but may also consume plant material themselves. Omnivores and their purely herbivorous prey have previously been thought to respond similarly to host‐plant quality. However, different responses of omnivores and herbivores to their shared host plants may influence the fitness, trophic identity, and population dynamics of the omnivores. 2. The aim of the present study was to show that an omnivorous heteropteran (Anthocoris nemorum L.) and two strictly herbivorous prey species respond differently to different genotypes of their shared host plant, Salix. Some plant genotypes were sub‐optimal for the omnivore, although suitable for the herbivores, and vice versa. 3. The contrasting patterns of plant suitability for the omnivore and the herbivores highlight an interaction between plant genotype and omnivores' access to animal food. Plant genotypes that were sub‐optimal for the omnivore when herbivores were experimentally excluded became the best host plants when herbivores were present, as in the latter situation additional prey became available. By contrast, the quality of plant genotypes that were intrinsically suitable for omnivores, did not improve when herbivores were present as these plant genotypes were intrinsically sub‐optimal for herbivores, thus providing omnivores with almost no additional animal food. 4. The differential responses of omnivores and their prey to the same host‐plant genotypes should allow omnivores to colonise sub‐optimal host plants in their capacity as predators, and to colonise more suitable host plants in their capacity as herbivores. It may thus be difficult for Salix to escape herbivory entirely, as it will rarely be unsuitable for both omnivores and pure herbivores at the same time.