The Henry-Gauer hypothesis: is it still valid?

This proceeding will address the following two issues: 1) Is arginine vasopressin (AVP, previously ADH) regulated by changes in LAP? 2) Is AVP the main modulator of extracellular fluid-volume, and thereby blood volume, control?     

Oxidative stress and vascular disease in diabetes: is the dichotomization of insulin signaling still valid?

The current wisdom indicates that insulin's positive effects, normoglycemia, vasodilation, and anti-inflammation, are mediated by the canonical phosphoinositide 3-kinase (PI3K)/Akt pathway whereas the negative effects are mediated by the mitogen-activated protein kinase (MAPK)/extracellular regulated kinase (ERK) pathway. Much of the intracellular oxidant stress is mediated by the MAPK/ERK pathway which is a downstream signal also for other proatherogenic hormones such as angiotensin II. However, recent evidence links MAPK activation to antioxidant activity and vascular protection. We argue against a dichotomization of insulin signaling also in light of the concept that ERK-MAPK represents a critical node in the intracellular insulin network responsible for several positive effects related not only to vascular function but also to life span.     

Antigen cocktails: valid hypothesis or unsubstantiated hope?

After more than three decades of research into the development of vaccines against parasites, a substantial number of antigens have been identified that, as purified native proteins or recombinant proteins, induce some protection against the target parasite. Very few achieve a degree of efficacy likely to make them candidates for single-antigen vaccines. Therefore, multi-antigen or 'cocktail' vaccines are proposed based on the assumption that such cocktails will show enhanced efficacy. This assumption, although often poorly acknowledged, has become central to much vaccine research. The experimental evidence for it, however, is extremely scarce and contradictory. The efficacy of multicomponent vaccines deserves greater experimental attention than it has received.     

Function of the alternative oxidase: is it still a scavenger?

The alternative oxidase is a respiratory chain protein found in all higher plants, fungi, non-fermentative yeasts and trypanosomes. Its primary structure suggests that it is a new member of the di-iron carboxylate protein family. Recent sequence analysis indicates an evolutionary relationship between primitive members of this protein family and the alternative oxidase, suggesting that its early function was to scavenge di-oxygen. However, modelling of plant growth kinetics suggests a different function.     

Prion hypothesis: the end of the controversy?

Forty-three years have passed since it was first proposed that a protein could be the sole component of the infectious agent responsible for the enigmatic prion diseases. Many discoveries have strongly supported the prion hypothesis, but only recently has this once heretical hypothesis been widely accepted by the scientific community. In the past 3 years, researchers have achieved the 'Holy Grail' demonstration that infectious material can be generated in vitro using completely defined components. These breakthroughs have proven that a misfolded protein is the active component of the infectious agent, and that propagation of the disease and its unique features depend on the self-replication of the infectious folding of the prion protein. In spite of these important discoveries, it remains unclear whether another molecule besides the misfolded prion protein might be an essential element of the infectious agent. Future research promises to reveal many more intriguing features about the rogue prions.     

Vaccines targeting drugs of abuse: is the glass half-empty or half-full?

The advent of vaccines targeting drugs of abuse heralded a fundamentally different approach to treating substance-related disorders. In contrast to traditional pharmacotherapies for drug abuse, vaccines act by sequestering circulating drugs and terminating the drug-induced 'high' without inducing unwanted neuromodulatory effects. Drug-targeting vaccines have entered clinical evaluation, and although these vaccines show promise from a biomedical viewpoint, the ethical and socioeconomic implications of vaccinating patients against drugs of abuse merit discussion within the scientific community.     

Digoxin-like immunoreactivity: is it still worth measuring?

On the assumption that digoxin-like immunoreactivity may represent digitalis-like sodium pump inhibitors in the mammalian body, many investigators have used radioimmunoassay for digoxin to monitor such factors during the past decade. The presence of digoxin-like immunoreactivity has been confirmed by numerous studies using biochemical, immunological or morphological methods. Very recently, ouabain or a very similar substance, which did not cross-react with antidigoxin antibodies, was identified from the human plasma as the long-sought sodium pump inhibitor. However, it is yet to be determined whether sodium pump inhibitory activity in the circulation results from one substance or several. Some researchers still insist on the possible physiological roles of digoxin-like immunoreactivity which may or may not be related to the regulation of sodium pump. These issues are critically reviewed in this article.     

The impact of new emerging drugs in the treatment of multiple myeloma: is there still a role for PBSC transplantation?

High-dose therapy with the rescue of autologous stem cells represents today the standard approach for multiple myeloma patients aged <65 years. Several studies, in fact, have demonstrated the superiority of high-dose therapy with respect to conventional chemotherapy in younger patients. Peripheral blood stem cells (PBSCs) provide a rapid and effective hematopoietic recovery after the administration of supra maximal chemotherapy and mainly for this reason have become the preferred source of stem cells for autologous transplantation. Recently, however, a number of new drugs have appeared in the armamentarium of the hematologist. Among these, thalidomide has been the first antiangiogenetic drug effectively adopted firstly in refractory-relapsed patients and now also as first line treatment with better results respect to VAD or VAD-like regimens. Inhibitors of proteasome, such as bortezomib, and other immunomodulatory agents, such as lenalidomide, have been also studied more recently in myeloma patients. In particular, bortezomib has shown to be very effective as single agent or in combination with high-dose dexamethasone. In this review, we try to define the potential role of these new drugs, how and when they can be included in the therapeutic program designed for younger and older patients, and mostly if and how these new agents could jeopardize the central role of autologous stem cell transplantation in the treatment of multiple myeloma.     

Antimalarial chemotherapy: young guns or back to the future?

The burgeoning global problem of malaria is largely due to the emergence of parasite resistance to our limited armamentarium of antimalarial drugs. The recognition of this impending disaster at the international level and the engagement of the pharmaceutical industry promise a more optimistic future for antimalarial drug development. This is particularly exciting when considering the advances in our understanding of parasite biology, which are currently being fuelled by the malaria genome project. This article discusses recent developments in the area of antimalarial drug discovery and evaluation. New advances, based on traditional antimalarial drug classes including the quinolines, peroxides and antifolates (‘back to the future’), are discussed, followed by a presentation of some novel targets (‘young guns’) that have been shown to be good candidates for chemotherapeutic attack.     

The insulin-receptor interaction: is the kinetic approach for inferring negative-cooperative site-site interactions valid?

The dissociation of insulin from its receptor is reportedly enhanced when the dissociation is induced by dilution in the presence of insulin. This experiment is frequently conducted when curvilinear Scatchard plots of insulin binding are observed in order to infer negative cooperative site-site interactions amongst insulin receptors. However, when insulin binding to purified liver plasma membranes was measured at 15 degrees C in 50 mM Tris, pH 7.5 containing 0.1% bovine serum albumin and 100 U/ml bacitracin, the insulin binding data was characterised by a linear Scatchard plot and a Hill plot with a slope equal to unity. Thus, under the conditions of this binding assay, insulin apparently bound to a single non-interacting class of homogeneous binding sites. But, despite the apparent absence of cooperative interactions under these specific conditions, the dissociation of receptor-bound insulin was still enhanced when the dissociation of insulin from its receptor was induced by dilution in the presence of insulin. This result cast serious doubt on the validity of inferring negative-cooperative site-site interactions amongst insulin receptors based solely on the observation that the dissociation of receptor-bound insulin is enhanced by dilution in the presence of insulin.     

Cardiac adrenoceptors at low temperature: what is the experimental evidence for the adrenoceptor interconversion hypothesis?

Isolated heart preparations of frog and rat were used to test the validity of the adrenoceptor interconversion hypothesis. This hypothesis claims that low temperature converts the inotropic beta-adrenoceptors in isolated frog and rat heart to alpha-adrenoceptors. The present results do not support the adrenoceptor interconversion hypothesis. In the isolated frog ventricle, lowering the temperature from 24 C to 14 C did not significantly alter the inotropic potency of the sympathomimetic drugs isoprenaline, epinephrine, and phenylephrine and did not reduce the potency of the beta-adrenoceptor blocking drug propranolol as an epinephrine antagonist. In the isolated rat left atrium, lowering the temperature from 31 C to 17-19 C did not significantly change the inotropic potency of isoprenaline, norepinephrine and phenylephrine, did not diminish the potency of propranolol, and did not increase the potency of the alpha-adrenoceptor blocking drug phentolamine.--Benfey, B. G. Cardiac adrenoceptors at low temperature; what is the experimental evidence for the adrenoceptor interconversion hypothesis?     

Life cycle abbreviation in trematode parasites and the developmental time hypothesis: is the clock ticking?

The typical multi‐host life cycle of many parasites, although conferring several advantages, presents the parasites with a highly hazardous transmission route. As a consequence, parasites have evolved various adaptations increasing their chances of transmission between the different hosts of the life cycle. Some trematode species like the opecoelid Coitocaecum parvum have adopted a more drastic alternative strategy whereby the definitive host is facultatively dropped from the cycle, resulting in a shorter, hence easier to complete, life cycle. Like other species capable of abbreviating their life cycle, C. parvum does so through progenetic development within its intermediate host. Laboratory‐reared C. parvum can modulate their developmental strategy inside the second intermediate host according to current transmission opportunities, though this ability is not apparent in natural C. parvum populations. Here we show that this difference is likely due to the time C. parvum individuals spend in their intermediate hosts in the natural environment. Although transmission opportunities, i.e. chemical cues of the presence of definitive hosts, promoted the adoption of a truncated life cycle in the early stages of infection, individuals that remained in their amphipod host for a relatively long time had a similar probability of adopting progenesis and the abbreviated cycle, regardless of the presence or absence of chemical cues from the predator definitive host. These results support the developmental time hypothesis which states that parasites capable of facultative life cycle abbreviation should eventually adopt progenesis regardless of transmission opportunities, and provide further evidence of the adaptive plasticity of parasite transmission strategies.     

RNA nanomedicines: the next generation drugs?

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Cervical cancer screening: are the 1989 recommendations still valid? National Workshop on Screening for Cancer of the Cervix.

Although screening for cervical cancer has been shown to be effective in reducing the morbidity and mortality associated with this disease, and despite many attempts to encourage the development of provincial programs, as of 1995 no province had a comprehensive screening program for cervical cancer. Participants at the Interchange ''95 workshop, held in Ottawa in November 1995, reviewed the recommendations of the 1989 National Workshop on Screening for Cancer of the Cervix and identified factors that have impeded their implementation. Participants discussed the need for comprehensive information systems, quality control and strategies to increase recruitment of unscreened and underscreened women. They concluded that the formation of a Cervical Cancer Prevention Network involving key stakeholders will facilitate the development and implementation of provincial programs to ensure optimal screening. They agreed that, in the interim, recommendations for practising physicians should remain as they were following the 1989 workshop.