The promise of e-Health – a Canadian perspective

Canadians value their health care system above any other social program. Canada's system of health care faces significant financial and population pressures, relating to cost, access, quality, accountability, and the integration of information and communication technologies (ICTs). The health-system also faces certain unique challenges that include care delivery within a highly decentralised system of financing and accountability, and care delivery to a significant portion of the population sparsely distributed across a landmass of 10 million square kilometres, in areas of extreme climatic conditions. All of these challenges are significant catalysts in the development of technologies that aim to significantly mitigate or eliminate these selfsame challenges.The system is undergoing widespread review, nationally, and within each province and territory, where the bulk of care provision is financed and managed. The challenges are being addressed by national, regional and provincial initiatives in the public, private and not-for-profit sectors.The promise of e-Health lies in the manner and degree to which it can mitigate or resolve these challenges to the health system and build on advancements in ICTs supporting the development of a health infostructure. Canada is actively developing and implementing technological solutions to deliver health information and health care services across the country. These solutions, while exciting and promising, also present new challenges, particularly in regard to acceptable standards, choice of technologies, overcoming traditional jurisdictional boundaries, up-front investment, and privacy and confidentially.Many organisations and governments are working to address these challenges. The Canadian Institute for Health Information (CIHI) will play an increasingly significant role in these initiatives, as the management of health information becomes a more crucial factor in the successful delivery of health care services in the new millennium.     

Nitric oxide — a retrograde messenger for carbon monoxide signaling in ischemic heart

To examine the intracellular signaling mechanism of NO in ischemic myocardium, isolated working rat hearts were made ischemic for 30 min followed by 30 min of reperfusion. A separate group of hearts were pre-perfused with 3 mM L-arginine in the presence or absence of 650 M of protoporphyrin, a heme oxygenase inhibitor for 10 min prior to ischemia. The release of NO was monitored using an on-line amperometric sensor placed into the right atrium. The aortic flow and developed pressure were examined to determine the effects of L-arginine on ischemic/reperfusion injury. Induction for the expression of heme oxygenase was studied by Northern hybridization. For signal transduction experiments, sarcolemmal membranes were radiolabeled by perfusing the isolated hearts with [³H] myoinositol and [¹⁴C] arachidonic acid. Biopsies were processed to determine the isotopic incorporation into various phosphoinositols as well as phosphatidic acid and diacylglycerol. cGMP was assayed by radioimmunoassay and SOD content was determined by enzymatic analysis. The release of NO was diminished following ischemia and reperfusion and was augmented by L-arginine. L-arginine reduced ischemic/reperfusion injury as evidenced by the enhanced myocardial functional recovery. Protoporphyrin modulated the effects of L-arginine. cGMP, which was remained unaffected by ischemia and reperfusion, was stimulated significantly after L-arginine treatment. The NO-mediated augmentation of cGMP was reduced by protoporphyrin suggesting that part of the effects may be mediated by CO generated through the heme oxygenase pathway. Reperfusion of ischemic myocardium resulted in significant accumulation of radiolabeled inositol phosphate, inositol bisphosphate, and inositol triphosphate. Isotopic incorporation of [³H] inositol into phosphatidylinositol, phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-bisphosphate was increased significantly during reperfusion. Reperfusion of the ischemic heart prelabeled with [¹⁴C] arachidonic acid resulted in modest increases in [¹⁴C] diacylglycerol and [¹⁴C] phosphatidic acid. Pretreatment of the heart with L-arginine significantly reversed this enhanced phosphodiesteratic breakdown during ischemia and early reperfusion. However, at the end of the reperfision the inhibitory effect of L-arginine on the phosphodiesterases seems to be reduced. In L-arginine treated hearts, SOD activity was progressively decreased with the duration of reperfusion time. The results suggests for the first time that NO plays a significant role in transmembrane signaling in the ischemic myocardium. This signaling appears to be on- and off- nature, and linked with SOD content of the tissue. The signaling is transmitted via cGMP and opposes the effects of phosphodiesterases by inhibiting the ischemia/reperfusion-induced phosphodiesteratic breakdown. Our results also suggest that NO activates heme oxygenase which further stimulates the production of cGMP presumably by CO signaling. Thus, NO not only potentiates cGMP mediated intracellular signaling, it also functions as a retrograde messenger for CO signaling in heart.     

The International College of Psychosomatic Medicine – a personal history

This is a history of the International College of Psychosomatic Medicine from 1970 to the present.     

Biomechanical highlights — the personal miscellany of a decade

Developments of the past decade, primarily in biomechanics, are characterized through personal recollections. Topics covered include pressure treatment of hypertrophic scars, laser eradication of tattoos, amputation stump and artificial limb interactions, elbow arthoplasty, disability rehabilitation and training for sports performance, functional electrical stimulation and joint goniometry. The review is prefaced by comments on the present day context and resource environment of bioengineering research and ends by discussing the anticipated advent of health maintenance orientated community care as the activity of first priority for the future.     

Electronegativity—a perspective

Electronegativity is a very useful concept but it is not a physical observable; it cannot be determined experimentally. Most practicing chemists view it as the electron-attracting power of an atom in a molecule. Various formulations of electronegativity have been proposed on this basis, and predictions made using different formulations generally agree reasonably well with each other and with chemical experience. A quite different approach, loosely linked to density functional theory, is based on a ground-state free atom or molecule, and equates electronegativity to the negative of an electronic chemical potential. A problem that is encountered with this approach is the differentiation of a noncontinuous function. We show that this approach leads to some results that are not chemically valid. A formulation of atomic electronegativity that does prove to be effective is to express it as the average local ionization energy on an outer contour of the atom’s electronic density.     

The morphological interpretation of epiascidiate leaves —An historical perspective—

Epiascidiate leaves are those foliar organs whose adaxial (ventral) side is the inside of a tube. Such tubular leaves are found in Nepenthaceae, Sarraceniaceae, Cephalotaceae, and Lentibulariaceae. Throughout botanical history these leaves have received considerable attention because of their bizarre morphology and problems of interpretation. This paper documents the attempts of the last 150 years to correctly understand their organographic nature. All epiascidiate foliar organs are structurally similar in their early ontogeny, each forms a distinctive adaxial outgrowth (Querzone), and the diverse morphologies of the mature organs seem to be modifications upon a similar primordial ground plan. Typologically these leaves are directly related to peltate leaves and phyllodes (non-petiolar,sensu Boke). Except for certain, highly speculative,de novo theories, such as the “foliar runner” theory of Croizat, all misinterpretations of the nature of epiascidiate leaves are directly attribuable to earlier errors in ascertaining the organography of typologically related leaf forms. Accordingly, the sympodial tubular leaf (Roth) is rejected, as is the petiolar nature of tubular leaves (de Candolle). The typological relationships of these leaves to unifacial foliar organs (Troll) seems well substantiated from both an organographic and a histogenetic viewpoint. The peltate carpel theory (?elakovský; Troll) is, in reality, an epiascidiate carpel theory. The idea of a fundamentally tubular carpel seems correct from both a typological and phylogenetic standpoint. To comprehend the various contradictory interpretations which have been used to explain morphologically complex problems, as well as to understand the genesis of morphological theories, it is necessary to acquire an accurate historical perspective of the subject.     

The first protein ever synthesized in vitro—a personal reminiscence of the total synthesis of crystalline insulin

<正>The total synthesis of crystalline bovine insulin started in 1958 was fully accomplished in 1965. This formidable task was a collaboration of the Institute of Biochemistry in Shanghai,     

An historical perspective of the discovery of titin filaments –Part 2

In 2017, a Special Issue of Biophysical Reviews was devoted to “Titin and Its Binding Partners. The issue contained a review: “An historical perspective of the discovery of titin filaments” by dos Remedios and Gilmour that was intended to be a history of the discovery of the giant protein titin, previously named connectin. The review took readers back to the earliest discovery of the so-called third filament component of skeletal and cardiac muscle sarcomeres and ended in 1969. Recently, my colleague Shin’ichi Ishiwata gently reminded me of two papers published in 1990 and 1993 that were unwittingly omitted from the original historical perspective. In the first paper (J Cell Biol 110:53–62, 1990), Funatsu et al. examined the elastic filaments in skeletal muscle using a combination of light and electron microscopy, but they also measured resting as well as passive stiffness mechanical measurements to establish that connectin (titin) is responsible for both stiffness and fiber tension. In the second paper (J Cell Biol 120:711–724, 1993), Funatsu et al. used permeabilised cardiac muscle myocytes (from rabbit papillary muscles) and focussed on filament ultrastructure using either freeze-substitution or deep-etched replica methods to visualise connectin/titin filaments in fibers with and without actin and myosin filaments.     

Three decades in transport business: studies of metabolite transport in chloroplasts – a personal perspective

This article gives an historical overview of our group's research on various metabolite translocators of chloroplasts, such as the translocators for phosphorylated intermediates of the Calvin–Benson cycle and of glycolysis, of ADP and ATP, of dicarboxylates, of pyruvate and of hexoses; how it began and where it led to. Wherever appropriate, references will be made to research in other laboratories. This revised version was published online in June 2006 with corrections to the Cover Date.     

Mechanics of a molecular mousetrap—nucleation-limited innate immune signaling

Innate immune responses, such as cell death and inflammatory signaling, are typically switch-like in nature. They also involve “prion-like” self-templating polymerization of one or more signaling proteins into massive macromolecular assemblies known as signalosomes. Despite the wealth of atomic-resolution structural information on signalosomes, how the constituent polymers nucleate and whether the switch-like nature of that event at the molecular scale relates to the digital nature of innate immune signaling at the cellular scale remains unknown. In this perspective, we review current knowledge of innate immune signalosome assembly, with an emphasis on structural constraints that allow the proteins to accumulate in inactive soluble forms poised for abrupt polymerization. We propose that structurally encoded nucleation barriers to protein polymerization kinetically regulate the corresponding pathways, which allows for extremely sensitive, rapid, and decisive signaling upon pathogen detection. We discuss how nucleation barriers satisfy the rigorous on-demand functions of the innate immune system but also predispose the system to precocious activation that may contribute to progressive age-associated inflammation.     

Chlorophyll a fluorescence induction: a personal perspective of the thermal phase, the J–I–P rise

The fast (up to 1?s) chlorophyll (Chl) a fluorescence induction (FI) curve, measured under saturating continuous light, has a photochemical phase, the O-J rise, related mainly to the reduction of Q(A), the primary electron acceptor plastoquinone of Photosystem II (PSII); here, the fluorescence rise depends strongly on the number of photons absorbed. This is followed by a thermal phase, the J-I-P rise, which disappears at subfreezing temperatures. According to the mainstream interpretation of the fast FI, the variable fluorescence originates from PSII antenna, and the oxidized Q(A) is the most important quencher influencing the O-J-I-P curve. As the reaction centers of PSII are gradually closed by the photochemical reduction of Q(A), Chl fluorescence, F, rises from the O level (the minimal level) to the P level (the peak); yet, the relationship between F and [Q(A) (-)] is not linear, due to the presence of other quenchers and modifiers. Several alternative theories have been proposed, which give different interpretations of the O-J-I-P transient. The main idea in these alternative theories is that in saturating light, Q(A) is almost completely reduced already at the end of the photochemical phase O-J, but the fluorescence yield is lower than its maximum value due to the presence of either a second quencher besides Q(A), or there is an another process quenching the fluorescence; in the second quencher hypothesis, this quencher is consumed (or the process of quenching the fluorescence is reversed) during the thermal phase J-I-P. In this review, we discuss these theories. Based on our critical examination, that includes pros and cons of each theory, as well mathematical modeling, we conclude that the mainstream interpretation of the O-J-I-P transient is the most credible one, as none of the alternative ideas provide adequate explanation or experimental proof for the almost complete reduction of Q(A) at the end of the O-J phase, and for the origin of the fluorescence rise during the thermal phase. However, we suggest that some of the factors influencing the fluorescence yield that have been proposed in these newer theories, as e.g., the membrane potential ΔΨ, as suggested by Vredenberg and his associates, can potentially contribute to modulate the O-J-I-P transient in parallel with the reduction of Q(A), through changes at the PSII antenna and/or at the reaction center, or, possibly, through the control of the oxidation-reduction of the PQ-pool, including proton transfer into the lumen, as suggested by Rubin and his associates. We present in this review our personal perspective mainly on our understanding of the thermal phase, the J-I-P rise during Chl a FI in plants and algae.     

The discovery of long-acting saligenin β₂ adrenergic receptor agonists incorporating a urea group

A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a urea moiety on the terminal right-hand side phenyl ring of (R)-salmeterol is presented. Urea 9j had long duration of action in vitro on guinea pig trachea, and also in vivo similar to that of salmeterol. It had lower oral absorption and bioavailability than salmeterol in both rat and dog. It had a turnover ratio similar to salmeterol, with no evidence for formation of any aniline metabolites in human liver microsomes and hepatocytes. However no crystalline salts suitable for inhaled delivery were identified.     

The world from a cat’s perspective – statistics of natural videos

The mammalian visual system is one of the most intensively investigated sensory systems. However, our knowledge of the typical input it is operating on is surprisingly limited. To address this issue, we seek to learn about the natural visual environment and the world as seen by a cat. With a CCD camera attached to their head, cats explore several outdoor environments and videos of natural stimuli are recorded from the animals perspective. The statistical analysis of these videos reveals several remarkable properties. First, we find an anisotropy of oriented contours with an enhanced occurrence of horizontal orientations, earlier described in the oblique effect as a predominance of the two cardinal orientations. Second, contrast is not elevated in the center of the images, suggesting different mechanisms of fixation point selection as compared to humans. Third, analyzing a sequence of images we find that the precise position of contours varies faster than their orientation. Finally, collinear contours prevail over parallel shifted contours, matching recent physiological and anatomical results. These findings demonstrate the rich structure of natural visual stimuli and its direct relation to extensively studied anatomical and physiological issues.     

The mandible — a measure of the nasopharynx

This investigation aims to ascertain the statistically significant correlation between the individual dimensions of the pharynx and those of the mandible, a bone most commonly found in anthropological finds and whose dimensions can be easily ascertained by radiography in clinical medicine. Further, this study establishes a method for projecting the dimensions of the nasopharynx and associated parts of the skull base from the dimensions of the mandible. Such projections can be useful in anthropological and forensic investigation and in clinical conditions such as sleep apnea. Portion of this material was presented as a platform paper at the NATO Advanced Study Institute on the “Origin of Languages” in Cortona, Italy, July 8–22, 1988.     

Structure–function of the cytochrome b6f lipoprotein complex: a scientific odyssey and personal perspective

Photosynthesis Research - Structure–function studies of the cytochrome b6f complex, the central hetero-oligomeric membrane protein complex in the electron transport chain of oxygenic...     

The discovery of Rubisco activase – yet another story of serendipity

A brief history of Rubisco (ribulose bisphosphate carboxylase oxygenase) research and the events leading to the discovery and initial characterization of Rubisco activase are described. Key to the discovery was the chance isolation of a novel Arabidopsis photosynthesis mutant. The characteristics of the mutant suggested that activation of Rubisco was not a spontaneous process in vivo, but involved a heritable factor. The search for the putative factor by 2D electrophoresis identified two polypeptides, genetically linked to Rubisco activation, that were missing in chloroplasts from the mutant. An assay for the activity of these polypeptides, which were given the name Rubisco activase, was developed after realizing the importance of including ribulose bisphosphate (RuBP) in the assay. The requirement for ATP and the subsequent identification of activase as an ATPase came about fortuitously, the result of a RuBP preparation that was contaminated with adenine nucleotides. Finally, the ability of activase to relieve inhibition of the endogenous Rubisco inhibitor, 2-carboxyarabinitol 1-phosphate, provided an early indication of the mechanism by which activase regulates Rubisco. This revised version was published online in June 2006 with corrections to the Cover Date.