Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction

BACKGROUND: Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart. METHODS AND RESULTS: We used a tetracycline-responsive binary transgene system based on the α-myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardium supports adaptation after MI. In sham-operated mice, transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion and preserved systolic and diastolic function. After coronary artery ligation, transgenic FGF9 enhanced hypertrophy of the noninfarcted left ventricular myocardium with increased microvessel density, reduced interstitial fibrosis, attenuated fetal gene expression, and improved systolic function. Heart failure mortality after MI was markedly reduced by transgenic FGF9, whereas rupture rates were not affected. Adenoviral FGF9 gene transfer after MI similarly promoted left ventricular hypertrophy with improved systolic function and reduced heart failure mortality. Mechanistically, FGF9 stimulated proliferation and network formation of endothelial cells but induced no direct hypertrophic effects in neonatal or adult rat cardiomyocytes in vitro. FGF9-stimulated endothelial cell supernatants, however, induced cardiomyocyte hypertrophy via paracrine release of bone morphogenetic protein 6. In accord with this observation, expression of bone morphogenetic protein 6 and phosphorylation of its downstream targets SMAD1/5 were increased in the myocardium of FGF9 transgenic mice. CONCLUSIONS: Conditional expression of FGF9 promotes myocardial vascularization and hypertrophy with enhanced systolic function and reduced heart failure mortality after MI. These observations suggest a previously unrecognized therapeutic potential for FGF9 after MI.

Sequential variations of phytoplankton growth and mortality in an NPZ model: a remote-sensing-based assessment

Radiometric data in the visible domain acquired by satellite remote sensing have proven to be powerful for monitoring the states of the ocean, both physical and biological. With the help of these data it is possible to understand certain variations in biological responses of marine phytoplankton on ecological time scales. Here, we implement a sequential data-assimilation technique to estimate from a conventional nutrient–phytoplankton–zooplankton (NPZ) model the time variations of observed and unobserved variables. In addition, we estimate the time evolution of two biological parameters, namely, the specific growth rate and specific mortality of phytoplankton. Our study demonstrates that: (i) the series of time-varying estimates of specific growth rate obtained by sequential data assimilation improves the fitting of the NPZ model to the satellite-derived time series: the model trajectories are closer to the observations than those obtained by implementing static values of the parameter; (ii) the estimates of unobserved variables, i.e., nutrient and zooplankton, obtained from an NPZ model by implementation of a pre-defined parameter evolution can be different from those obtained on applying the sequences of parameters estimated by assimilation; and (iii) the maximum estimated specific growth rate of phytoplankton in the study area is more sensitive to the sea-surface temperature than would be predicted by temperature-dependent functions reported previously. The overall results of the study are potentially useful for enhancing our understanding of the biological response of phytoplankton in a changing environment.

Early treatment with intranasal neostigmine reduces mortality in a mouse model of Naja naja (Indian Cobra) envenomation

Objective. Most snakebite deaths occur prior to hospital arrival; yet inexpensive, effective, and easy to administer out-of-hospital treatments do not exist. Acetylcholinesterase inhibitors can be therapeutic in neurotoxic envenomations when administered intravenously, but nasally delivered drugs could facilitate prehospital therapy for these patients. We tested the feasibility of this idea in experimentally envenomed mice. Methods. Mice received intraperitoneal injections of Naja naja venom 2.5 to 10 times the estimated LD50 and then received 5

Improving the health forecasting alert system for cold weather and heat-waves in England: a proof-of-concept using temperature-mortality relationships

Objectives In this study a prototype of a new health forecasting alert system is developed, which is aligned to the approach used in the Met Office’s (MO) National Severe Weather Warning Service (NSWWS). This is in order to improve information available to responders in the health and social care system by linking temperatures more directly to risks of mortality, and developing a system more coherent with other weather alerts. The prototype is compared to the current system in the Cold Weather and Heatwave plans via a case-study approach to verify its potential advantages and shortcomings. Method The prototype health forecasting alert system introduces an “impact vs likelihood matrix” for the health impacts of hot and cold temperatures which is similar to those used operationally for other weather hazards as part of the NSWWS. The impact axis of this matrix is based on existing epidemiological evidence, which shows an increasing relative risk of death at extremes of outdoor temperature beyond a threshold which can be identified epidemiologically. The likelihood axis is based on a probability measure associated with the temperature forecast. The new method is tested for two case studies (one during summer 2013, one during winter 2013), and compared to the performance of the current alert system. Conclusions The prototype shows some clear improvements over the current alert system. It allows for a much greater degree of flexibility, provides more detailed regional information about the health risks associated with periods of extreme temperatures, and is more coherent with other weather alerts which may make it easier for front line responders to use. It will require validation and engagement with stakeholders before it can be considered for use.

An upgrade on the rabbit model of anthracycline-induced cardiomyopathy: shorter protocol, reduced mortality, and higher incidence of overt dilated cardiomyopathy

Current protocols of anthracycline-induced cardiomyopathy in rabbits present with high premature mortality and nephrotoxicity, thus rendering them unsuitable for studies requiring long-term functional evaluation of myocardial function (e.g., stem cell therapy). We compared two previously described protocols to an in-house developed protocol in three groups: Group DOX2 received doxorubicin 2 mg/kg/week (8 weeks); Group DAU3 received daunorubicin 3 mg/kg/week (10 weeks); and Group DAU4 received daunorubicin 4 mg/kg/week (6 weeks). A cohort of rabbits received saline (control). Results of blood tests, cardiac troponin I, echocardiography, and histopathology were analysed. Whilst DOX2 and DAU3 rabbits showed high premature mortality (50% and 33%, resp.), DAU4 rabbits showed 7.6% premature mortality. None of DOX2 rabbits developed overt dilated cardiomyopathy; 66% of DAU3 rabbits developed overt dilated cardiomyopathy and quickly progressed to severe congestive heart failure. Interestingly, 92% of DAU4 rabbits showed overt dilated cardiomyopathy and 67% developed congestive heart failure exhibiting stable disease. DOX2 and DAU3 rabbits showed alterations of renal function, with DAU3 also exhibiting hepatic function compromise. Thus, a shortened protocol of anthracycline-induced cardiomyopathy as in DAU4 group results in high incidence of overt dilated cardiomyopathy, which insidiously progressed to congestive heart failure, associated to reduced systemic compromise and very low premature mortality.

A low mortality, high morbidity reduced intensity status epilepticus (RISE) model of epilepsy and epileptogenesis in the rat

Animal models of acquired epilepsies aim to provide researchers with tools for use in understanding the processes underlying the acquisition, development and establishment of the disorder. Typically, following a systemic or local insult, vulnerable brain regions undergo a process leading to the development, over time, of spontaneous recurrent seizures. Many such models make use of a period of intense seizure activity or status epilepticus, and this may be associated with high mortality and/or global damage to large areas of the brain. These undesirable elements have driven improvements in the design of chronic epilepsy models, for example the lithium-pilocarpine epileptogenesis model. Here, we present an optimised model of chronic epilepsy that reduces mortality to 1% whilst retaining features of high epileptogenicity and development of spontaneous seizures. Using local field potential recordings from hippocampus in vitro as a probe, we show that the model does not result in significant loss of neuronal network function in area CA3 and, instead, subtle alterations in network dynamics appear during a process of epileptogenesis, which eventually leads to a chronic seizure state. The model’s features of very low mortality and high morbidity in the absence of global neuronal damage offer the chance to explore the processes underlying epileptogenesis in detail, in a population of animals not defined by their resistance to seizures, whilst acknowledging and being driven by the 3Rs (Replacement, Refinement and Reduction of animal use in scientific procedures) principles.