Effects of the vertically transmitted microsporidian Facilispora margolisi and the parasiticide emamectin benzoate on salmon lice (Lepeophtheirus salmonis)

Abstract Background Microsporidia are highly specialized, parasitic fungi that infect a wide range of eukaryotic hosts from all major taxa. Infections cause a variety of damaging effects on host physiology from increased stress to death. The microsporidian Facilispora margolisi infects the Pacific salmon louse (Lepeophtheirus salmonis oncorhynchi), an economically and ecologically important ectoparasitic copepod that can impact wild and cultured salmonids. Results Vertical transmission of F. margolisi was demonstrated by using PCR and in situ hybridization to identify and localize microsporidia in female L. salmonis and their offspring. Spores and developmental structures of F. margolisi were identified in 77% of F1 generation copepods derived from infected females while offspring from uninfected females all tested negative for the microsporidia. The transcriptomic response of the salmon louse to F. margolisi was profiled at both the copepodid larval stage and the pre-adult stage using microarray technology. Infected copepodids differentially expressed 577 transcripts related to stress, ATP generation and structural components of muscle and cuticle. The infection also impacted the response of the copepodid to the parasiticide emamectin benzoate (EMB) at a low dose of 1.0 ppb for 24 h. A set of 48 transcripts putatively involved in feeding and host immunomodulation were up to 8-fold underexpressed in the F. margolisi infected copepodids treated with EMB compared with controls or either stressor alone. Additionally, these infected lice treated with EMB also overexpressed 101 transcripts involved in stress resistance and signalling compared to the other groups. In contrast, infected pre-adult lice did not display a stress response, suggesting a decrease in microsporidian virulence associated with lice maturity. Furthermore, copepodid infectivity and moulting was not affected by the microsporidian infection. Conclusions This study demonstrated that F. margolisi is transmitted vertically between salmon louse generations and that biological impacts of infection differ depending on the stage of the copepod host. The infection caused significant perturbations of larval transcriptomes and therefore must be considered in future studies in which impacts to host development and environmental factors are assessed. Fitness impacts are probably minor, although the interaction between pesticide exposure and microsporidian infection merits further study

Stimulation of cardiac sympathetic nerve activity by central angiotensinergic mechanisms in conscious sheep

Central actions of angiotensin play an important role in cardiovascular control and have been implicated in the pathogenesis of hypertension and heart failure. One feature of centrally or peripherally administered angiotensin is that the bradycardia in response to an acute pressor effect is blunted. It is unknown whether after central angiotensin this is due partly to increased cardiac sympathetic nerve activity (CSNA). We recorded CSNA and arterial pressure in conscious sheep, at least 3 days after electrode implantation. The effects of intracerebroventricular infusions of ANG II ( 3 nmol/h for 30 min) and artificial cerebrospinal fluid (CSF) ( 1 ml/h) were determined. The response to intracerebroventricular hypertonic saline (0.6 M NaCl in CSF at 1 ml/h) was examined as there is evidence that hypertonic saline acts via angiotensinergic pathways. Intracerebroventricular angiotensin increased CSNA by 23 +/- 7% (P < 0.001) and mean arterial pressure (MAP) by 7.6 +/- 1.2 mmHg (P < 0.001) but did not significantly change heart rate (n = 5). During intracerebroventricular ANG II the reflex relation between CSNA and diastolic blood pressure was significantly shifted to the right (P < 0.01). Intracerebroventricular hypertonic saline increased CSNA (+9.4 +/- 6.6%, P < 0.05) and MAP but did not alter heart rate. The responses to angiotensin and hypertonic saline were prevented by intracerebroventricular losartan (1 mg/h). In conclusion, in conscious sheep angiotensin acts within the brain to increase CSNA, despite increased MAP. The increase in CSNA may account partly for the lack of bradycardia in response to the increased arterial pressure. The responses to angiotensin and hypertonic saline were losartan sensitive, indicating they were mediated by angiotensin AT-1 receptors

Disparate Effects of Diabetes and Hyperlipidemia on Experimental Kidney Disease.

It is well established that diabetes is the major cause of chronic kidney disease worldwide. Both hyperglycemia, and more recently, advanced glycation endproducts, have been shown to play critical roles in the development of kidney disease. Moreover, the renin-angiotensin system along with growth factors and cytokines have also been shown to contribute to the onset and progression of diabetic kidney disease; however, the role of lipids in this context is poorly characterized. The current study aimed to compare the effect of 20 weeks of streptozotocin-induced diabetes or western diet feeding on kidney disease in two different mouse strains, C57BL/6 mice and hyperlipidemic apolipoprotein (apo) E knockout (KO) mice. Mice were fed a chow diet (control), a western diet (21% fat, 0.15% cholesterol) or were induced with streptozotocin-diabetes (55 mg/kg/day for 5 days) then fed a chow diet and followed for 20 weeks. The induction of diabetes was associated with a 3-fold elevation in glycated hemoglobin and an increase in kidney to body weight ratio regardless of strain (p < 0.0001). ApoE deficiency significantly increased plasma cholesterol and triglyceride levels and feeding of a western diet exacerbated these effects. Despite this, urinary albumin excretion (UAE) was elevated in diabetic mice to a similar extent in both strains (p < 0.0001) but no effect was seen with a western diet in either strain. Diabetes was also associated with extracellular matrix accumulation in both strains, and western diet feeding to a lesser extent in apoE KO mice. Consistent with this, an increase in renal mRNA expression of the fibrotic marker, fibronectin, was observed in diabetic C57BL/6 mice (p < 0.0001). In summary, these studies demonstrate disparate effects of diabetes and hyperlipidemia on kidney injury, with features of the diabetic milieu other than lipids suggested to play a more prominent role in driving renal pathology

Climate change and public health: An evaluation framework for local government.

OBJECTIVES: To develop and pilot an evaluation framework for assessing the engagement of local government public health teams in England on climate change and sustainability. These teams are uniquely positioned to address local health impacts of climate change and promote health co-benefits of mitigation. No statutory framework currently exists to support their engagement in this agenda. STUDY DESIGN: Literature review and two cross sectional surveys. METHODS: A group of public health professionals conducted a literature review and agreed on criteria based on statutory responsibilities and remit of these teams, available information, and opportunities for local government action. With the resulting framework, this group evaluated all 11 local governments in the East of England region, and then conducted a follow-up survey to assess the framework's impact and acceptability. RESULTS: An evaluation framework was developed with 21 criteria in two sections. The first assessed overall local government action and leadership in climate change and sustainability, to understand the context in which the public health team was situated. The second assessed the climate change related actions undertaken by the public health team.All 11 local governments in the East of England region completed the evaluation. Results indicated inconsistencies in local public health team action on and engagement with climate change and health. Ten local governments completed the follow-up survey on acceptability and impact, reporting that the evaluation was easy to complete. Seven out of ten respondents found that the evaluation had influenced change or reflection within their organisation, for example through identifying gaps and prompting more collaboration between teams. CONCLUSIONS: This evaluation framework is a useful and acceptable tool to assess local government public health engagement and leadership on climate change and sustainability. If used more widely, it could help to support public health teams to advance much-needed action in this area

Empagliflozin modulates renal sympathetic and heart rate baroreflexes in a rabbit model of diabetes

AIMS/HYPOTHESIS: We determined whether empagliflozin altered renal sympathetic nerve activity (RSNA) and baroreflexes in a diabetes model in conscious rabbits. METHODS: Diabetes was induced by alloxan, and RSNA, mean arterial pressure (MAP) and heart rate were measured before and after 1 week of treatment with empagliflozin, insulin, the diuretic acetazolamide or the ACE inhibitor perindopril, or no treatment, in conscious rabbits. RESULTS: Four weeks after alloxan administration, blood glucose was threefold and MAP 9% higher than non-diabetic controls (p < 0.05). One week of treatment with empagliflozin produced a stable fall in blood glucose (-43%) and increased water intake (+49%) but did not change RSNA, MAP or heart rate compared with untreated diabetic rabbits. The maximum RSNA to hypotension was augmented by 75% (p < 0.01) in diabetic rabbits but the heart rate baroreflex was unaltered. Empagliflozin and acetazolamide reduced the augmentation of the RSNA baroreflex (p < 0.05) to be similar to the non-diabetic group. Noradrenaline (norepinephrine) spillover was similar in untreated diabetic and non-diabetic rabbits but twofold greater in empagliflozin- and acetazolamide-treated rabbits (p < 0.05). CONCLUSIONS/INTERPRETATION: As empagliflozin can restore diabetes-induced augmented sympathetic reflexes, this may be beneficial in diabetic patients. A similar action of the diuretic acetazolamide suggests that the mechanism may involve increased sodium and water excretion. Graphical abstract

Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes

OBJECTIVE: Activation of the receptor for advanced glycation end products (RAGE) in diabetic vasculature is considered to be a key mediator of atherogenesis. This study examines the effects of deletion of RAGE on the development of atherosclerosis in the diabetic apoE(-/-) model of accelerated atherosclerosis. RESEARCH DESIGN AND METHODS: ApoE(-/-) and RAGE(-/-)/apoE(-/-) double knockout mice were rendered diabetic with streptozotocin and followed for 20 weeks, at which time plaque accumulation was assessed by en face analysis. RESULTS: Although diabetic apoE(-/-) mice showed increased plaque accumulation (14.9 +/- 1.7%), diabetic RAGE(-/-)/apoE(-/-) mice had significantly reduced atherosclerotic plaque area (4.9 +/- 0.4%) to levels not significantly different from control apoE(-/-) mice (4.3 +/- 0.4%). These beneficial effects on the vasculature were associated with attenuation of leukocyte recruitment; decreased expression of proinflammatory mediators, including the nuclear factor-kappaB subunit p65, VCAM-1, and MCP-1; and reduced oxidative stress, as reflected by staining for nitrotyrosine and reduced expression of various NADPH oxidase subunits, gp91phox, p47phox, and rac-1. Both RAGE and RAGE ligands, including S100A8/A9, high mobility group box 1 (HMGB1), and the advanced glycation end product (AGE) carboxymethyllysine were increased in plaques from diabetic apoE(-/-) mice. Furthermore, the accumulation of AGEs and other ligands to RAGE was reduced in diabetic RAGE(-/-)/apoE(-/-) mice. CONCLUSIONS: This study provides evidence for RAGE playing a central role in the development of accelerated atherosclerosis associated with diabetes. These findings emphasize the potential utility of strategies targeting RAGE activation in the prevention and treatment of diabetic macrovascular complications