Subcellular Compartmentalization of Cyclic Adenosine Monophosphate in Heart Failure and Inotropic Pharmacology.

Cyclic adenosine monophosphate (cAMP) is a second messenger downstream of many G-protein coupled receptors, including the ß1-adrenoceptor, which is the target of many clinically used inotropic agents. When the Gαs subunit of a heterotrimeric G-protein is activated, it causes a localized elevation of cAMP. The significance of the spatial distribution of the elevation in cAMP is increasingly recognized, as is the disturbance of these microdomains in diseased states. Herein, the spatial compartmentalization of inotropic signaling is explored, including from internalized receptors.

A case of Bartonellosis presenting as a puzzling multisystem disorder complicated by nosocomial COVID-19 infection.

The most commonly considered infection with a Bartonella species is cat-scratch disease caused by Bartonella henselae Here, we discuss a unique case of a 60-year-old man who presented with Bartonella infection complicated by nosocomial COVID-19. He was admitted with a history of chest pain, persistent fever, rash and influenza-like symptoms. Positive Bartonella serology confirmed diagnosis and the patient developed complications of pericardial effusion in addition to COVID-19 infection, requiring non-invasive ventilation and admission to the intensive care unit. We discuss his symptoms, investigations, treatment and outcomes, while also highlighting the challenges of assessing patients presenting with fever of unknown origin during the COVID-19 pandemic.

Biased Agonism: The Future (and Present) of Inotropic Support.

Biased agonism, which is the concept that different ligands activate different downstream signalling partners in different ratios to cause different functional effects, is yet to gain appropriate appreciation in the field of inotropic pharmacology. Biased agonism has already proven to be a clinically translatable technology in analgesic pharmacology, but this development is yet to be translated into inotropes. A better appreciation of bias in clinically used inotropes and a focus on bias when developing novel inotropes has the potential to lead to more targeted, personalized, and cleaner inotropes.

Recommendations for measuring whisker movements and locomotion in mice with sensory, motor and cognitive deficits.

BACKGROUND: Previous studies have measured whisker movements and locomotion to characterise mouse models of neurodegenerative disease. However, these studies have always been completed in isolation, and do not involve standardized procedures for comparisons across multiple mouse models and background strains. NEW METHOD: We present a standard method for conducting whisker movement and locomotion studies, by carrying out qualitative scoring and quantitative measurement of whisker movements from high-speed video footage of mouse models of Amyotrophic Lateral Sclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, Cerebellar Ataxia, Somatosensory Cortex Development and Ischemic stroke. RESULTS: Sex, background strain, source breeder and genotype all affected whisker movements. All mouse models, apart from Parkinson's disease, revealed differences in whisker movements during locomotion. R6/2 CAG250 Huntington's disease mice had the strongest behavioural phenotype. Robo3R3-5-CKO and RIM-DKOSert mouse models have abnormal somatosensory cortex development and revealed significant changes in whisker movements during object exploration. COMPARISON WITH EXISTING METHOD(S): Our results have good agreement with past studies, which indicates the robustness and reliability of measuring whisking. We recommend that differences in whisker movements of mice with motor deficits can be captured in open field arenas, but that mice with impairments to sensory or cognitive functioning should also be filmed investigating objects. Scoring clips qualitatively before tracking will help to structure later analyses. CONCLUSIONS: Studying whisker movements provides a quantitative measure of sensing, motor control and exploration. However, the effect of background strain, sex and age on whisker movements needs to be better understood.

Characterisation of progressive motor deficits in whisker movements in R6/2, Q175 and Hdh knock-in mouse models of Huntington's disease.

BACKGROUND: Motor dysfunction is a major component of the Huntington's disease (HD) phenotype, both in patients and animal models. Motor function in mice is usually measured using tests that involve a novel environment, or require a degree of learning, which creates potential confounds in animals, such as anxiety and/or learning. NEW METHOD: We propose that studying whisker control provides a more naturalistic way to measure motor function in HD mice. To this end we tested three strains of HD mice; R6/2 (CAG250), zQ175 and Hdh (CAG50, 150 and 250) mice. RESULTS: We discovered a clear and progressive whisking deficit in the most severe model, the R6/2 CAG250 mouse. At 10 weeks, R6/2 mice showed an increase in whisking movements, which may be a correlate of the hyperkinesia seen in HD patients. By 18 weeks the R6/2 mice showed a reduction in whisking movements. Hdh Q250 mice showed a hyperkinetic profile at 10 weeks, approximately 4 months before other motor deficits have previously been reported in these mice. Q175 mice showed very little change in whisking behaviour, apart from a transient increase in retraction velocity at 10 weeks. COMPARISONS WITH EXISTING METHODS: Our findings suggest that whisking may be a more sensitive test of motor function in HD mice than more commonly used methods, such as the rotarod. CONCLUSIONS: Our data suggest that whisking deficits represent a novel way of assessing the progression of the motor phenotype, and are early indicators for reversal of phenotype studies, such as drug trials.