The amnestic agent anisomycin disrupts intrinsic membrane properties of hippocampal neurons via a loss of cellular energetics.

The nearly axiomatic idea that de novo protein synthesis is necessary for long-term memory consolidation is based heavily on behavioral studies using translational inhibitors such as anisomycin. Although inhibiting protein synthesis has been shown to disrupt the expression of memory, translational inhibitors also have been found to profoundly disrupt basic neurobiological functions, including the suppression of ongoing neural activity in vivo. In the present study, using transverse hippocampal brain slices, we monitored the passive and active membrane properties of hippocampal CA1 pyramidal neurons using intracellular whole cell recordings during a brief ~30-min exposure to fast-bath-perfused anisomycin. Anisomycin suppressed protein synthesis to 46% of control levels as measured using incorporation of radiolabeled amino acids and autoradiography. During its application, anisomycin caused a significant depolarization of the membrane potential, without any changes in apparent input resistance or membrane time constant. Anisomycin-treated neurons also showed significant decreases in firing frequencies and spike amplitudes, and showed increases in spike width across spike trains, without changes in spike threshold. Because these changes indicated a loss of cellular energetics contributing to maintenance of ionic gradients across the membrane, we confirmed that anisomycin impaired mitochondrial function by reduced staining with 2,3,5-triphenyltetrazolium chloride and also impaired cytochrome c oxidase (complex IV) activity as indicated through high-resolution respirometry. These findings emphasize that anisomycin-induced alterations in neural activity and metabolism are a likely consequence of cell-wide translational inhibition. Critical reevaluation of studies using translational inhibitors to promote the protein synthesis dependent idea of long-term memory is absolutely necessary.NEW & NOTEWORTHY Memory consolidation is thought to be dependent on the synthesis of new proteins because translational inhibitors produce amnesia when administered just after learning. However, these agents also disrupt basic neurobiological functions. We show that blocking protein synthesis disrupts basic membrane properties of hippocampal neurons that correspond to induced disruptions of mitochondrial function. It is likely that translational inhibitors cause amnesia through their disruption of neural activity as a result of dysfunction of intracellular energetics.

Temperature-related differences in mitochondrial function among clones of the cladoceran Daphnia pulex.

This study assessed the thermal sensitivity of mitochondrial respiration in the small crustacean Daphnia pulex. More specifically, we wanted to determine if clones that inhabit different latitudes and habitats showed differences in the thermal sensitivity of their mitochondrial function. The experimental design included two clones from temperate environments (Fence from Ontario and Hawrelak from Alberta) and two clones from subarctic environments (A24 from Manitoba and K154 from Quebec). The integrated mitochondrial function was measured with high-resolution respirometry following whole-animal permeabilization. Mitochondrial respiration was performed under six different temperatures (10, 15, 20, 25, 30, and 35°C) in the clone Hawrelak and at two temperatures (10 and 20°C) in the three other clones. In the clone Hawrelak, complexes I and II respiration showed higher sensitivity to temperature variation compared to complex IV respiration. Interestingly, the threshold plot showed no excess capacity of complex IV at 20°C in this clone. The clones showed significant divergence in the ability to oxidize the complex I and complex IV substrates relative to the maximal oxidative phoshorylation capacity of mitochondria. More importantly, some of the clonal divergences were only detected under low assay temperatures, pointing toward the importance of this parameter in comparative studies. Future and more complex studies on clones from wider environmental gradients will help to resolve the link between mitochondrial function and adaptations of organisms to particular conditions, principally temperature.

Remote patient monitoring for chronic heart failure in France: When an innovative funding program (ETAPES) meets an innovative solution (Satelia® Cardio).

Introduction: Remote patient monitoring (RPM) is a telehealth activity to collect and analyze patient health or medical data. Its use has expanded in the past decade and has improved medical outcomes and care management of non-communicable chronic diseases. However, implementation of RPM into routine clinical activities has been limited. The objective of this study was to describe the French funding program for RPM (known as ETAPES) and one of the RPM solution providers (Satelia®) dedicated to chronic heart failure (CHF). Methods: A descriptive assessment of both the ETAPES funding program and Satelia® RPM solution was conducted. Data were collected from official legal documents and information that was publicly available online from the French Ministry of Health. Results and Discussion: ETAPES was formally created in 2016 based on previous legislation pertaining to the national health insurance funding strategy. However, it only started to operate in 2018. Patients with CHF were only eligible if they were at medium or high risk of re-hospitalization with a New York Heart Association (NYHA) score superior or equal to two and a BNP>100 pg/ml or NT pro BNP>1000 pg/ml. Medical monitoring was supported through the therapeutic education of a patient on the RPM model of care with a minimum of three training sessions during the first six months. The use of Satelia® Cardio is noteworthy since it relies only on symptomatic monitoring through which the patient manually reports their information by answering a simple questionnaire on a regular basis and does not rely on any connected devices. Conclusion: Innovative funding programs and solutions for RPM need real-world evaluation in the future.

Mitochondria in the human heart.

The heart relies mainly on mitochondrial metabolism to provide the energy needed for pumping blood to oxygenate the organs of the body. The study of mitochondrial function in the human heart faces many obstacles and elucidation of the role of mitochondria in cardiac diseases has relied mainly on studies with animal models. Cardiac diseases are the leading cause of mortality worldwide. With the emergence of new therapies to treat and prevent heart disease, some aiming at metabolic modulation, a need for acquiring a better understanding of mitochondrial function in the human heart becomes apparent. Our review is aimed at specific evaluation of the human heart in terms of (1) methods to understand mitochondrial function, with particular emphasis on integrated function, (2) data on the role of mitochondrial dysfunction in cardiovascular disease, and (3) possible applications of this knowledge in the treatment of patients with cardiac disease.

Does membrane fatty acid composition modulate mitochondrial functions and their thermal sensitivities?

We investigated the effect of modifying fatty acid modification of heart mitochondrial membranes by dietary intervention on the functions and thermal sensitivity of electron transport system complexes embedded in the inner mitochondrial membrane. Four groups of rats were fed diets differing in their fat (coconut, olive or fish oil) and antioxidant (fish oil with or without probucol) contents. After 16 weeks of feeding, the coconut and olive oil groups had lower long-chain n-3 polyunsaturated fatty acids contents and a lower unsaturation index compared to both fish oil groups. These differences in fatty acid composition were not related to any differences in the mitochondrial respiration rate induced at Complexes I, II or IV, or to differences in their thermal sensitivity. The coconut oil group showed a lower mitochondrial affinity for pyruvate at 5 degrees C (k(mapp)=6.4+/-1.8) compared to any other groups (k(mapp)=3.8+/-0.5; 4.7+/-0.8; 3.6+/-1.1, for olive, fish oil and fish oil and probucol groups, respectively). At least in rat heart, our results do not support a major impact of the fatty acid composition of the mitochondrial membrane on the function of mitochondrial enzymatic complexes or on their temperature sensitivity.

[Aortic atheroma: not a sensitive indicators for coronary artery disease in patients with mitral valve disease]. / L'athérome aortique: indicateur peu sensible de coronaropathie dans les valvulopathies mitrales.

Aortic atheroma detected by transoesophageal echocardiography has been reported to be a good prognostic marker for coronary disease on angiography. The value of this detection in valvular heart disease would be to avoid preoperative coronary angiography in asymptomatic patients. The aim of this study was to assess the prognostic value of aortic atheroma in a population with a low prevalence of coronary artery disease in whom transoesophageal echocardiography was systematically performed. In addition, calcification of the aortic knuckle, a marker of atherosclerosis, was analysed by simple chest X-ray. One hundred and ninety two patients (103 men, 89 women; mean age: 63.1 +/- 15 years), operated for mitral valve replacement, underwent transoesophageal echocardiography, angiography, within 6 months, and chest X-ray. The cardiovascular risk factors, presence of aortic atherome, angiographic coronary artery disease and aortic calcification were studied. Aortic atheroma was observed in 72 patients (37.5%), usually in the descending thoracic aorta (73.6%). Coronary stenosis was observed in 36 patients (18.7%). On univariate analysis, aortic atherome predicted coronary stenosis with a sensitivity of 53%, specificity of 66% and positive predictive value of 26% and negative predictive value of 86%, compared with chest X-ray: 71%, 65%, 33% and 90%, respectively. In multivariate analysis, only hypercholesterolaemia, smoking and age predicted the presence of coronary artery disease. The presence of aortic atheroma was not predictive (p = 0.3). The authors conclude that aortic atheroma does not predict the presence of coronary artery disease in a patient population with mitral valve disease and a low prevalence of coronary artery disease. Simple chest X-ray has almost the same diagnostic value. The association of these two investigations does not give sufficient negative predictive values to avoid coronary angiography.

Phenotypic flexibility of digestive system in Atlantic cod (Gadus morhua).

This study examined the restoration of the digestive capacity of Atlantic cod (Gadus morhua Linnaeus) following a long period of food deprivation. Fifty cod (48 cm, 1 kg) were food-deprived for 68 days and then fed in excess with capelin (Mallotus villosus Müller) on alternate days. Ten fish were sampled after 0, 2, 6, 14 and 28 days and the mass of the pyloric caeca, intestine and carcass determined. Two metabolic enzymes (cytochrome c oxidase and citrate synthase) were assayed in white muscle, pyloric caeca and intestine, and trypsin activity was measured in the pyloric caeca. A delay of 14 days was required before body mass started to increase markedly, whereas most of the increase in mass of both the pyloric caeca and intestine relative to fish length occurred earlier in the experiment. By day 14, the activities of trypsin and citrate synthase in the pyloric caeca as well as citrate synthase in the intestine had reached maxima. The growth of the digestive tissues and restoration of their metabolic capacities thus occur early upon refeeding and are likely required for recovery growth to take place. The phenotypic flexibility of the cod digestive system is therefore remarkable: increases in trypsin activity and size of pyloric caeca resulted in a combined 29-fold increase in digestive capacity of the fish during the refeeding period. Our study suggests that Atlantic cod are able to cope with marked fluctuations in food availability in their environment by making a rapid adjustment of their digestive capacity as soon as food availability increases.

The impact of the thermal sensitivity of cytochrome c oxidase on the respiration rate of Arctic charr red muscle mitochondria. pierre_blier@uqar.qc.ca.

To assess if cytochrome c oxidase could determine the response of mitochondrial respiration to changes in environmental temperature in ectotherms, we performed KCN titration of the respiration rate and cytochrome c oxidase activity in mitochondria from Arctic charr (Salvelinusfontinalis) muscle at four different temperatures (1 degrees C, 6 degrees C, 12 degrees C, and 18 degrees C). Our data showed an excess of cytochrome c oxidase activity over the mitochondrial state 3 respiration rate. Mitochondrial oxygen consumption rates reached approximately 12% of the cytochrome c oxidase maximal capacity at every temperature. Also, following titration, the mitochondrial respiration rate significantly decreased when KCN reached concentrations that inhibit almost 90% of the cytochrome c oxidase activity. This strongly supports the idea that the thermal sensitivity of the maximal mitochondrial respiration rate cannot be dictated by the effect of temperature on cytochrome c oxidase catalytic capacity. Furthermore, the strong similarity of the Q10s of mitochondrial respiration and cytochrome c oxidase activity suggests a functional or structural link between the two. The functional link could be coevolution of parts of the mitochondrial system to maintain optimal functions in most of the temperature range encountered by organisms.