Climate change and infectious diseases: What can we expect?

Global climate change, driven by anthropogenic greenhouse gas emissions, is being particularly felt in Canada, with warming generally greater than in the rest of the world. Continued warming will be accompanied by changes in precipitation, which will vary across the country and seasons, and by increasing climate variability and extreme weather events. Climate change will likely drive the emergence of infectious diseases in Canada by northward spread from the United States and introduction from elsewhere in the world via air and sea transport. Diseases endemic to Canada are also likely to re-emerge. This special issue describes key infectious disease risks associated with climate change. These include emergence of tick-borne diseases in addition to Lyme disease, the possible introduction of exotic mosquito-borne diseases such as malaria and dengue, more epidemics of Canada-endemic vector-borne diseases such as West Nile virus, and increased incidence of foodborne illnesses. Risk is likely to be compounded by an aging population affected by chronic diseases, which results in greater sensitivity to infectious diseases. Identifying emerging disease risks is essential to assess our vulnerability, and a starting point to identify where public health effort is required to reduce the vulnerability and exposure of the Canadian population.

Risk assessment strategies for early detection and prediction of infectious disease outbreaks associated with climate change.

A new generation of surveillance strategies is being developed to help detect emerging infections and to identify the increased risks of infectious disease outbreaks that are expected to occur with climate change. These surveillance strategies include event-based surveillance (EBS) systems and risk modelling. The EBS systems use open-source internet data, such as media reports, official reports, and social media (such as Twitter) to detect evidence of an emerging threat, and can be used in conjunction with conventional surveillance systems to enhance early warning of public health threats. More recently, EBS systems include artificial intelligence applications such machine learning and natural language processing to increase the speed, capacity and accuracy of filtering, classifying and analysing health-related internet data. Risk modelling uses statistical and mathematical methods to assess the severity of disease emergence and spread given factors about the host (e.g. number of reported cases), pathogen (e.g. pathogenicity) and environment (e.g. climate suitability for reservoir populations). The types of data in these models are expanding to include health-related information from open-source internet data and information on mobility patterns of humans and goods. This information is helping to identify susceptible populations and predict the pathways from which infections might spread into new areas and new countries. As a powerful addition to traditional surveillance strategies that identify what has already happened, it is anticipated that EBS systems and risk modelling will increasingly be used to inform public health actions to prevent, detect and mitigate the climate change increases in infectious diseases.

Differential insulin sensitivities of glucose, amino acid, and albumin metabolism in elderly men and women.

Regulation of glucose homeostasis by insulin is modified during aging, but whether this alteration is associated with changes in protein metabolism is less defined. Insulin dose responses of whole body glucose, leucine, and albumin metabolism have been investigated using isotopic dilution of D-[6, 6-(2)H(2)]glucose and L-[1-(13)C]leucine in 14 young (Y; 24.0 +/- 0.9 yr; mean +/- SEM, 20.5 +/- 0.4 kg/m(2)) and 12 healthy elderly subjects (E; 69.4 +/- 0.6 yr; 24.6 +/- 0.8 kg/m(2)) using a euglycemic and euaminoacidemic hyperinsulinemic clamp at two insulin infusion rates of 0.2 and 0.5 mU/kg.min (CL1 and CL2, respectively). Despite significantly higher plasma insulin in E than in Y, the glucose disposal rate was lower in E than in Y at both insulin levels, whereas glucose production was normally suppressed. Whole body protein breakdown was less inhibited by insulin in E than in Y at CL1 (-13.5 +/- 1.4% vs. -8.8 +/- 1.3%, Y vs. E, P < 0.05), but not significantly at CL2 (-22.0 +/- 1.4% vs. -18.8 +/- 1.7%, Y vs. E, P = NS). The albumin synthesis rate was identical and stimulated to the same extent by insulin in groups Y and E. Gender affected basal leucine metabolism, but the response to insulin was similar in both groups. In conclusion, decreased insulin action on glucose disposal is associated with a reduced insulin sensitivity for protein breakdown in healthy elderly subjects at low insulin concentrations. Higher insulin levels compensate for a reduced insulin action on protein metabolism in elderly subjects.

Splanchnic and whole-body leucine kinetics in young and elderly men.

Whole-body and splanchnic protein metabolism were determined in six young (mean age: 22.7 y) and six old (68.2 y) men before and during a standardized meal (41.8 kJ/kg) containing 15.6% protein, by using a combination of intravenous ([13C]leucine) and oral ([2H3]leucine) tracers. In the postabsorptive state, leucine flux and oxidation were similar in both groups when corrected for lean body mass (mean +/- SEM: 1.80 +/- 0.09 compared with 1.79 +/- 0.07 mumol.kg-1.min-1 and 0.55 +/- 0.02 compared with 0.49 +/- 0.04 mumol.kg-1.min-1 for young and old men, respectively, NS). The pattern of response to the meal was also similar in young and old men: increased flux and oxidation, decreased protein breakdown, and unchanged protein synthesis. Splanchnic extraction of dietary leucine was twice as high in elderly men (50 +/- 11% compared with 23 +/- 2%, P < 0.05), was inversely related to plasma leucine concentration (r = -0.771, P < 0.01), and was positively related to body mass index (r = 0.861, P < 0.001). In conclusion, in elderly men there is higher leucine extraction by the gut, liver, or both during feeding, which could lead to a lower peripheral availability of dietary leucine.

Assessment of drugs by functional imaging of thallium-201 distribution in the dog.

The effect of drugs on thallium-201 biodistribution in the body has been studied in dogs using a new functional imaging method. The calculation is based upon the comparison of the activities of the two scintigraphic images obtained after two successive injections of thallium-201 separated by an interval of at least 10 min, during which some drug of interest can be administered. This imaging technique was applied in control dogs (n = 6) and in animals treated with dipyridamole (n = 7) or grisorixin (n = 7). As expected, these two vasoactive drugs increased mainly the myocardial uptake, whereas smaller variations were noted in the other organs studied: liver, kidney, lungs, and skeletal muscles. Thus this method should allow a rapid and reliable noninvasive assessment of cardiovascular drugs with thallium-201.

Myocardial imaging in dogs treated with grisorixin: relationship between thallium-201 uptake and coronary blood flow.

Thallium-201 myocardial imaging was performed in dogs after pretreatment with grisorixin, which appeared to increase the myocardial uptake of Tl-201. This effect of grisorixin was found to be dose dependent, with an optimal dose of 60 microgram/kg. The myocardial-to-background ratio, which was 1.92 in the control dogs, rose to 4.45. The increase in the absolute myocardial uptake was demonstrated in guinea pigs that received Tl-201 after similar pretreatment with grisorixin. In the animals treated with 500 microgram/kg, the uptake of Tl-201 by the heart was 35% over the control value. With 60 microgram/kg grisorixin, the coronary blood flow increased from 40 to 176 ml/min 5 min after the injection. This dose, optimal for imaging, induced the maximum vasodilator effect with only a very slight concomitant increase in the left-ventricular pressure and myocardial contractility. Above 60 microgram/kg, grisorixin appeared to be a potent inotropic agent, whereas below this dose it showed only coronary vasodilator properties. Some evidence for an ionophore effect of this compound was found in dogs pretreated with 60 microgram/kg. In these the radionuclide was injected when the coronary vasodilatation had become insignificant, but a significant improvement of the M/B ratio was still evident.

Hexakis (2-methoxy isobutylisonitrile) technetium-99m and thallium-201 chloride: uptake and release in cultured myocardial cells.

Hexakis (2-methoxy isobutylisonitrile) technetium-99m [(99mTc]MIBI), a new tracer of myocardial blood flow, was compared with 201TI CI in cultures of myocardial cells of newborn rats. The kinetics of uptake and release of both tracers were assessed in basal conditions and in the presence of 5 mM cyanide, an inhibitor of the respiratory chain, 0.1 mM iodoacetate, an inhibitor of glycolysis, 10 microM ouabain, an inhibitor of the Na-K ATPase, or with various pH values. The amplitude and frequency of contractions of the cells were also monitored in the same conditions. Results show that the washin and washout kinetics of [99mTc]MIBI are slower than 201TI(T1/2) of the washout curves were, respectively, of 28 min and 6 min). The kinetics of release of both tracers were not influenced by any of the inhibitors. There was a strong effect of the pH on the 201TI uptake only. Moreover 201TI uptake was decreased by 34% in the presence of cyanide plus iodoacetate. Otherwise the uptakes of 201TI and [99mTc]MIBI were not decreased by any of the drugs. The cellular contractility was significantly diminished by cyanide and it was abolished by cyanide plus iodoacetate. It is concluded that (a) impaired contractility can be associated with normal 201TI and [99mTc]MIBI kinetics in myocardial cells in culture, (b) that 201TI uptake may depend on the level of ATP devoted to the maintenance of membrane integrity, (c) that [99mTc]MIBI shows slower kinetics but is less sensitive to metabolic inhibitors than 201TI.

Myocardial imaging in dogs with thallium-201 and the ionophore grisorixin.

The effect of grisorixin, a monocarboxylic ionophore, upon the myocardium-to-background ratio in thallium-201 scintigrams has been studied in 20 dogs. Three sequences of injection and two doses of the ionophore have been used. A significant improvement was obtained when grisorixin was injected 10 min before thallium-201 and at a submaximal dose; the myocardium-to-background ratio was at least twice that of the controls during the first 20 min following the tracer injection.

Effects of grisorixin on the distribution of thallium-201 and on the oxidative metabolism in cultured myocardial cells.

Previous experiments in the dog and guinea-pig have shown that grisorixin, a monocarboxylic ionophore, can significantly increase the coronary blood flow and the myocardial uptake of 201Tl, as well as have a stimulant effect on the heart. In this study, cultures of myocardial cells were used in order to isolate the cells from the vascular and extracardiac influences so that any ionophorous effect on 201Tl could be evidenced. The effects of grisorixin on the oxidative metabolism were simultaneously studied. The technique described by Harary was used to prepare the cultures. The activity of the 14CCO2 produced by oxidation of [14C]glucose and [14C]octanoate added to the medium of culture and the intra/extracellular ratio of 201Tl concentrations (Tl i/e) were measured. In the controls (n = 8), the Tl i/e was 40 +/- 10 while it was 17 +/- 6 (p less than 0.05) in the cells that received 201Tl and grisorixin at the same time (n = 4), and 19 +/- 5 (p less than 0.05) in the flasks where 201Tl was injected after grisorixin (n = 7). A significant decrease of the [14C]octanoate oxidation was found in the flasks treated with grisorixin (n = 4, -50 +/- 16%, p less than 0.01) while the [14C]glucose oxidation was not significantly lowered (n = 3; -11 +/- 12%). The conclusion is that grisorixin decreases both the intracellular concentration of 201Tl and the fatty-acids oxidation in cultured myocardial cells. The beneficial effects previously observed in vivo were probably the consequence of the strong coronary dilatation and of an indirect stimulation.

Uptake of technetium-99m-teboroxime in cultured myocardial cells: comparison with thallium-201 and technetium-99m-sestamibi.

The effects of metabolic inhibition on the uptake of 99mTc-teboroxime were assessed in cultured myocardial cells and compared with 201Tl and 99mTc-sestamibi. Metabolic impairment was induced by cyanide (CN), a blocker of the mitochondrial respiratory chain, iodoacetate (IAA), an inhibitor of the glycolytic pathway, and ouabain, an inhibitor of Na(+)-K+ sarcolemmal ATPase. Cellular viability was appreciated by the trypan blue exclusion method. The effects of low temperature and of cellular death resulting from osmotic lysis were also assessed. Net cellular uptake of the radiotracers and the amount of proteins in the culture dishes were measured. All experiments were performed in parallel with control conditions and the results were expressed relatively to the control values. Teboroxime uptake was clearly decreased at low temperature (29.6% +/- 2.2% at 0 degree C, p < 0.001), while metabolic inhibition or osmotic lysis had no definite effect. The uptake of 201Tl and sestamibi was severely diminished in the presence of a mixture of 5 mM CN and 0.1 mM IAA, but 201Tl was less resistant than sestamibi (13.7% +/- 0.3% and 73.5% +/- 3.3%, respectively, after 1 hr of preincubation, p < 0.001 for both). Uptake of both tracers was very low in the presence of dead cells (12.1% +/- 1.3% for 201Tl and 4.1% +/- 0.2% for sestamibi, p < 0.001 for both). Ouabain had a detrimental effect only on 201Tl uptake at doses higher than 100 microM. Of these three currently available coronary blood flow imaging agents, teboroxime shows the lowest sensitivity to metabolic impairment.

Comparison of verapamil and bepridil, two slow channel inhibitors, in protection against calcium-induced arrhythmias.

Verapamil and bepridil share the common property of antagonizing the slow inward calcium-mediated current, but bepridil has some additional antiarrhythmic properties. The efficacy of these two compounds against CaCl2-induced arrhythmias has been compared in rats. CaCl2 was administered i.v. by continuous infusion until death (25 mg X kg-1 X min-1 or 40 mg X kg-1 X min-1) or by bolus injection (160 mg X kg-1). Bepridil (5, 10 mg X kg-1) or verapamil (2.5, 5 mg X kg-1) were injected 10 min before CaCl2. Bepridil (10 mg X kg-1) or verapamil (5 mg X kg-1) prolong the survival time during CaCl2 infusion. After pretreatment, the injection of 160 mg X kg-1 CaCl2 is less toxic: 25% of animals are protected by bepridil (5 mg X kg-1), 41% by bepridil (10 mg X kg-1) or verapamil (5 mg X kg-1). At death the myocardial Ca2+ level is not different in controls and pretreated animals, thus, the ratio myocardial Ca2+/total injected Ca2+ is significantly lowered by bepridil (10 mg X kg-1) or verapamil (5 mg X kg-1). The efficacy of the two drugs on this model appears related solely to inhibition of slow inward current despite the additional antiarrhythmic profile of bepridil.

Grisorixin, an ionophorous antibiotic of the nigericin group. II. Chemical and structural study of grisorixin and some derivatives.

Grisorixin, a polycyclic polyether antibiotic of the nigericin group, showed ionophorous properties. The conformations of crystallized grisorixin and its metallic salts are very similar and are compared in this paper. The physico-chemical properties of the salts are described. The chemical oxidation of grisorixin methyl ester allowed us to isolate several oxidation products whose structures are described.

Alborixin, a new antibiotic ionophore: isolation, structure, physical and chemical properties.

Alborixin, a polycyclic polyether ionophorous antibiotic, active against Gram-positive bacteria and fungi, was isolated from cultures of a strain of Streptomyces albus. The isolation, structure and physiochemical properties of this antibiotic are reported. Some derivatives have been prepared and their structures and properties are also described in this paper.

Grisorixin, an ionophorous antibiotic of the nigericin group. I. Fermentation, isolation, biological properties and structure.

Grisorixin is an ionophorous antibiotic of the nigericin group isolated from cultures of a strain of Streptomyces griseus. It shows activity against Gram-positive bacteria and fungi but is also very toxic. The isolation and purification procedures are reported. Its structure and physico-chemical properties are also described.

Comparative effects of ionophores grisorixin, alborixin and two derivatives on K+ glutamate efflux in rat liver mitochondria.

The alkali cations discrimination on a liquid membrane electrodes system, was determined for the carboxylic ionophores grisorixin, alborixin and two derivatives, dihydrogrisorixin and hexahydroalborixin. The two antibiotics exhibited a great perference for K+. Dihydrogrisorixin again showed the selectivity curve of a carboxylic ionophore, but with a discrimination power lowered compared with grisorixin. Hexahydroalborixin had lost all the complexing properties of the natural molecule. The selectivity scales measured for cations, were directly correlated with the K+ and glutamate effluxes measured in rat liver mitochondria. The chemical modifications of the natural structures of grisorixin and alborixin resulted in a drastic reduction of their ionophoric properties. The loss of K+-glutamate might occur in two steps, the efflux of K+ catalysed by the ionophores then causing a loss of negative charges in the form of glutamate.

Relationship between 201Tl uptake and oxidative metabolism in cultured myocardial cells.

The uptake of thallium-201 (201Tl) by myocardial cells in cultures was assessed in the presence of 10(-3) M potassium cyanide (KCN), an inhibitor of mitochondrial respiration, and 10(-4) M dinitrophenol (DNP), an uncoupler of oxidative phosphorylation. The cultures were incubated with 14C-glucose or 14C-octanoate, allowing the measurement of the oxidative metabolism and beta-oxidation from the production of 14CO2. The results demonstrated a moderate decrease in the ratio between the intra/extracellular concentration of 201Tl (Tl i/e) in the presence of KCN (28.9 +/- 8.1 versus 35.6 +/- 9.7 in the controls, n.s.) and no change with DNP (37.6 +/- 9.7). Glycolysis and fatty acid oxidation were lowered with KCN (-28 +/- 15 and -45 +/- 22% respectively, p less than 0.05 in both cases) and were non significantly increased with DNP (+37 +/- 23 and +10 +/- 52% respectively). These results show that 201Tl intracellular uptake is not related directly, but is not totally independent of glycolysis and fatty acid oxidation.