Interventions can shift the thermal optimum for parasitic disease transmission

Temperature constrains the transmission of many pathogens. Interventions that target temperature-sensitive life stages, such as vector control measures that kill intermediate hosts, could shift the thermal optimum of transmission, thereby altering seasonal disease dynamics and rendering interventions less effective at certain times of the year and with global climate change. To test these hypotheses, we integrated an epidemiological model of schistosomiasis with empirically determined temperature-dependent traits of the human parasite Schistosoma mansoni and its intermediate snail host (Biomphalaria spp.). We show that transmission risk peaks at 21.7 °C (T_opt), and simulated interventions targeting snails and free-living parasite larvae increased T_opt by up to 1.3 °C because intervention-related mortality overrode thermal constraints on transmission. This T_opt shift suggests that snail control is more effective at lower temperatures, and global climate change will increase schistosomiasis risk in regions that move closer to T_opt. Considering regional transmission phenologies and timing of interventions when local conditions approach T_opt will maximize human health outcomes.

Temperature is important to the transmission of most infectious diseases, but the effects of temperature variability on parasite and host traits and their interactive effects on infection dynamics are poorly understood across many host–parasite systems (1–3). The variable responses of host and parasite traits to altered thermal regimes (i.e., thermal trait variation) could also impact intervention efficacy if the mortality of temperature-sensitive life stages is greater than the relative contribution of natural, temperature-dependent constraints on parasite transmission. For example, anthelminthic drugs decrease parasite transmission but likely have little effect on temperature-dependent transmission dynamics because adult parasites are buffered from environmental temperature in endothermic hosts. In contrast, vector control measures and water sanitation cause vector and parasite mortality, respectively, that is independent of ecophysiological constraints and irrespective of environmental temperature (4–6).If interventions override natural temperature-dependent constraints on transmission, they could cause shifts in the thermal optimum (T_opt) of parasite transmission, which could theoretically alter seasonal disease dynamics and render interventions less effective at certain times of the year and with global warming. This, in turn, would affect risk assessments and intervention planning for various disease systems (7, 8), especially under global climate change. Nevertheless, the hypotheses of intervention-related shifts to the T_opt of transmission and the resulting knock-on effects on disease phenology and intervention efficacy have never been proposed or tested.Human schistosomiasis, which affects more than 200 million people worldwide, is a major source of human morbidity and mortality in sub-Saharan Africa (9) and represents an ideal system to test these hypotheses. Schistosoma mansoni, an important causative parasite species, is transmitted through two aquatic larval stages (Fig. 1). Miracidia infect intermediate snail hosts (Biomphalaria spp.), and cercariae are released from snails to infect humans (10). Because free-living parasite larvae and snails are ectotherms, aquatic transmission is influenced by temperature (11, 12), with warm temperatures decreasing miracidial (13, 14) and cercarial survival (15) and reducing the odds of infection (13, 16). Although several Schistosoma parasite and snail traits are temperature-dependent (17–21), many models assume temperature-invariant transmission (12, 22, 23). Additionally, schistosomiasis interventions either target temperature-sensitive transmission stages, such as molluscicides, snail removal, and water sanitation, or temperature-insensitive stages, such as anthelmintic drugs provided to endothermic hosts. These interventions might impact T_opt differently and thus transmission phenology in areas where S. mansoni is endemic.Open in a separate windowFig. 1.The schistosomiasis transmission cycle spans the endothermic human body and aquatic environment. Parameters representing temperature-dependent traits investigated in this study are highlighted in purple. Parameters pertaining to disease control interventions are highlighted in orange. Parameter definitions are given in the main text and SI Appendix, Table S6.The objectives of this study were to: 1) quantify temperature-dependent S. mansoni and Biomphalaria spp. traits; 2) derive temperature-specific R₀ (i.e., estimated number of secondary cases from one infected human) predictions and thus a T_opt for schistosome transmission; 3) evaluate how R₀ and T_opt are affected by three interventions targeting distinct components of the parasite life cycle; and 4) explore the effects of temperature and interventions on transmission with regard to spatial and temporal surface water temperature variation.We predicted that 1) parasite and snail traits would exhibit unimodal responses to temperature, allowing for the identification of a T_opt for each trait; 2) transmission (i.e., R₀) would decrease in response to all interventions; 3) T_opt of R₀ would only change in response to interventions targeting ectothermic parasite and host life stages; and 4) this in turn would alter transmission phenology in geographically and temporally dependent manners based on the proximity of local conditions to T_opt.     

An integrated map of the genome of the tubercle bacillus, Mycobacterium tuberculosis H37Rv, and comparison with Mycobacterium leprae.

An integrated map of the genome of the tubercle bacillus, Mycobacterium tuberculosis, was constructed by using a twin-pronged approach. Pulsed-field gel electrophoretic analysis enabled cleavage sites for Asn I and Dra I to be positioned on the 4.4-Mb circular chromosome, while, in parallel, clones from two cosmid libraries were ordered into contigs by means of fingerprinting and hybridization mapping. The resultant contig map was readily correlated with the physical map of the genome via the landmarked restriction sites. Over 165 genes and markers were localized on the integrated map, thus enabling comparisons with the leprosy bacillus, Mycobacterium leprae, to be undertaken. Mycobacterial genomes appear to have evolved as mosaic structures since extended segments with conserved gene order and organization are interspersed with different flanking regions. Repetitive sequences and insertion elements are highly abundant in M. tuberculosis, but the distribution of IS6110 is apparently nonrandom.     

ACE inhibitors for the treatment of myocardial ischemia?

Summary Apart from their established use in the treatment of hypertension and heat failure, ACE inhibitors have been suggested to exert anti-ischemic effects. This article reviews the mechanisms of systemic and intracardiac angiotensin formation, as well as its interaction with the bradykinin, the prostaglandin, and the sympathetic nervous system. While high doses of angiotensin can precipitate myocardial ischemia, experimental data on a potential beneficial effect of ACE inhibitors on ischemic myocardial blood flow and function are inconsistent and controversial. Pooling the few available clinical data, several ACE inhibitors may attenuate myocardial ischemia at rest and during exercise. However, a significant fraction of patients does not benefit or even deteriorates. Recent experimental studies suggest a beneficial role of ACE inhibitors in attenuating reperfusion arrhythmias and postinfarction left ventricular remodeling. Unless the mechanisms and determinants of potential anti-ischemic actions of ACE inhibitors can be better defined, their use for treatment of myocardial ischemia cannot be recommended at present.     

No confirmation for a causal role of volume-regulated chloride channels in ischemic preconditioning in rabbits

Volume-regulated chloride channels have recently been proposed to be end-effectors in ischemic preconditioning. The present study attempted to confirm this hypothesis by looking both at cardioprotection and channel activity. In isolated rabbit cardiomyocytes, hypo-osmotic stress (167 mosm/l) induced a current with a magnitude of 2-5 pA/pF at 60 mV. That current could be blocked by the selective chloride channel blockers 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) or indanyloxyacetic acid 94 (IAA-94), but only at 100 microM and 1 m M respectively. Lower concentrations were not effective. Because the channel-blocking concentrations were toxic in isolated perfused rabbit hearts, as evidenced by cessation of cardiac contraction and massive infarction, neither agent could be tested against preconditioning's anti-infarct effect. NPPB and IAA-94 at 1 microM and 10 microM, respectively (the doses used in a previous report), did not affect coronary flow, heart rate and developed pressure, and also did not prevent the infarct size reduction of ischemic preconditioning with 5 min global ischemia/10 min reperfusion preceding 30 min of regional ischemia and 120 min of reperfusion [11. 4(+/-3.6) and (11.1(+/-3.7)% infarction of risk area, respectively]. The volume-regulated chloride and organic osmolyte channel blocker 4, 4;-diisothiocyanostilbene-2,2;-disulfonic acid (DIDS) at 100 microM blocked the hypo-osmotically induced current in myocytes, but again could not be used, since it induced total cessation of cardiac contraction and reduced infarct size in non-preconditioned hearts. Our data do not confirm a prior study on a causal role for volume-regulated chloride channels in the protection of ischemic preconditioning. This hypothesis remains to be adequately tested.     

Positive inotropic effects of epigallocatechin-3-gallate (EGCG) involve activation of Na+/H+ and Na+/Ca2+ exchangers

BACKGROUND: There is evidence that the tea catechin epigallocatechin-3-gallate (EGCG) modulates myocardial contractility. However, the underlying mechanisms remain to be determined. AIMS: To study potential signalling pathways involved in EGCG-induced contractile parameters. METHODS AND RESULTS: EGCG increased fractional shortening in rat cardiac myocytes and enhanced intracellular systolic Ca2+ concentrations. In isolated rat hearts, perfusion with EGCG resulted in significant, dose-dependent increase in peak systolic left ventricular pressure, as well as in contraction and relaxation velocities. Heart rate did not change. Inhibition of the beta1-receptor with metoprolol had no influence on the contractile effects of EGCG. Furthermore, levels of cAMP and phosphorylation of phospholamban did not change with EGCG, indicating that the beta-receptor pathway is not involved. The L-type Ca2+ channel inhibitors, nifedipine and gallopamil, failed to modulate EGCG-induced increase in contractility. However, the myocardial effects and intracellular calcium transients stimulated by EGCG were significantly reduced by the antagonist of the Na+/H+ exchanger (NHE) methyl-N-isobutyl amiloride (MIA), and by blocking of the reverse mode of the Na+/Ca2+ exchanger (NCX) by KB-R7943. CONCLUSION: These results indicate that Ca2+-dependent positive inotropic and lusitropic effects of EGCG are mediated in part via activation of the Na+/H+ exchanger and the reverse mode of the Na+/Ca2+ exchanger in the rat myocardium.     

Regional differences of myocardial infarct development and ischemic preconditioning

The spatial and temporal development of myocardial infarction depends on the area at risk (AAR), the severity and duration of blood flow reduction (energy supply) as well as on heart rate and regional wall function (energy demand). Both supply and demand can vary within the AAR of a given heart, potentially resulting in differences in infarct development. We therefore retrospectively analyzed infarct size (IS, %AAR, TTC) in 24 anesthetized pigs in vivo following 90 min hypoperfusion and 120 min reperfusion of the LAD coronary artery, which supplies parts of the LV septum (LVS) and anterior free wall (LVAFW). The total LAD perfusion territory averaged 49.8 +/- 14.2 (SD) g (49.2 +/- 8.4% of LV); 61.4 +/- 8.1% of the AAR was LVAFW. IS within the LVS was 25.3 +/- 15.1%, while IS within the LVAFW was 16.6 +/-10.1% (p<0.05). While ischemic blood flow (radiolabeled microspheres) did not differ between LVS (0.05 +/- 0.02 ml/min/g) and LVAFW (0.05 +/- 0.03 ml/min/g), perivascular connective tissue (56 +/- 9 vs. 38+/-7 microm(2), p < 0.05) and the capillary-to-myocyte distance (1.65 +/- 0.23 vs. 1.18 +/- 0.23 mm, p < 0.05) were larger in LVS than in LVAFW. Interestingly, IS in LVS (9.3 +/- 9.6%, n = 24) and LVAFW (9.2 +/- 9.1%) were reduced to the same absolute extent by ischemic preconditioning with one cycle of 10 min ischemia and 15 min reperfusion, suggesting that a similar regional difference exists also in the protection afforded by ischemic preconditioning. The mechanism(s) for that remain(s) to be established. CONCLUSION : In pigs, regional differences in infarct development and protection from it exist in the LAD perfusion territory, which are independent of ischemic blood flow but apparently related to pre-existing structural differences.     

Steps toward the percutaneous replacement of atrioventricular valves an experimental study

OBJECTIVES: The goal of this study was to develop a device for percutaneous replacement of the tricuspid valve in animals. BACKGROUND: Percutaneous valve replacement has recently been introduced, and early clinical experience has been reported. To date, this technique is limited to the replacement of pulmonary and aortic valves in selected patients. METHODS: A newly designed nitinol stent, forming two large disks separated by a cylinder with a diameter of 18 mm, was specially designed for the purpose of this study. An 18-mm bovine valve was mounted in the central part of the stent, and a polytetrafluoroethylene membrane was sutured onto the ventricular disk. Eight ewes were equally divided into two groups (group 1, acute study; group 2, killed at one month). RESULTS: Seven of eight devices were successfully delivered in the desired position. In one animal, the device was trapped in tricuspid cordae, leading to its incomplete opening. A significant paravalvular leak was noticed in one animal of group 2. Mean right atrial pressure increased from 5 to 7 mm Hg and did not change during the follow-up. At autopsy, examination confirmed the good position of devices in successfully implanted animals. CONCLUSIONS: Implantation of a semi-lunar valve in the tricuspid position is possible in ewes through a transcatheter approach. A disk-based nitinol stent is needed to allow valve implantation in the atrioventricular position. These studies open new perspectives into tricuspid as well as mitral valve replacement.     

VE/VCO2 slope and oxygen uptake efficiency slope in patients with coronary artery disease and intermediate peakVO2.

BACKGROUND: Peak exercise oxygen uptake (peakVO2) is a widely used prognosticator. Novel spirometric parameters, less affected by submaximal performance, such as the rate of increase of minute ventilation per unit decrease of carbon dioxide production (VE/VCO2 slope) and the oxygen uptake efficiency slope (OUES) have recently been introduced. AIM: To evaluate the discriminative value of OUES, as compared to VE/VCO2 slope in patients with coronary artery disease (CAD) and intermediate peakVO2 values. METHODS AND RESULTS: Bicycle spiroergometry was applied in 214 patients with CAD (age 67+/-8 years, 85% men). OUES was strongly related to peakVO2 (r=0.79). New York Heart Association (NYHA) class, 6-min walking distance, N-terminal pro-brain natriuretic peptide (NT-proBNP), inflammatory markers, left ventricular (LV) volumes and ejection fraction were evaluated. NT-proBNP levels predicted independently VE/VCO2-slope and OUES. Patients with intermediate peakVO2 (12-18 ml/kg per min) and increased VE/VCO2-slope (> or = 35) had higher NYHA class, lower walking distance, higher NT-proBNP levels and higher LV volumes as compared to patients with a similar peakVO2 but lower VE/VCO2-slope. Similar findings were found for patients with intermediate peakVO2 and high OUES/kg (median value>15.3). CONCLUSION: In CAD patients, OUES was strongly correlated with peakVO2. Both VE/VCO2 slope and OUES were independently associated with NT-proBNP levels. Both VE/VCO2 slope and OUES/kg were able to identify a subgroup of patients with an intermediate peakVO2 that was characterized by advanced remodelling and a higher degree of neurohumoral activation.     

Hematopoietic stem cell transplantation prevents diabetes in NOD mice but does not contribute to significant islet cell regeneration once disease is established

The treatment of type I diabetes by islet cell transplantation, while promising, remains restricted due to the incomplete efficacy and toxicity associated with current immunosuppression, and by limited organ availability. Given reports suggesting bone marrow derived stem cell plasticity, we sought to determine whether such cells could give rise to pancreatic islet cells in vivo. In the context of autoimmune diabetes, we transplanted unfractionated bone marrow from beta-gal trangenic donor mice into NOD mice prior to, at, and two weeks beyond the onset of disease. Successful bone marrow engraftment before diabetes onset prevented disease in all mice and for 1 year after transplant. However, despite obtaining full hematopoietic engraftment in over 50 transplanted mice, only one mouse became insulin independent, and no beta-Gal positive islets were detected in any of the mice. To test whether tolerance to islets was achieved, we injected islets obtained from the same allogeneic donor strain as the hematopoietic cells into 4 transplant recipients, and 2 had a reversion of their diabetes. Thus allogeneic bone marrow transplantation prevents autoimmune diabetes and tolerizes the recipient to donor islet grants, even in diabetic animals, yet the capacity of bone marrow derived cells to differentiate into functional islet cells, at least without additional manipulation, is limited in our model.