32 research outputs found
Identification of Genes for Spontaneous Neuropathic Pain in Mice: Whole Genome and Candidate Gene Approaches
No full textChronic neuropathic pain (NP) affects many people worldwide; causing suffering that is difficult to treat, incurable and not preventable. There is growing hope that pain genetics may identify novel treatment targets. In this dissertation we report on candidate NP genes using a mouse NP model produced by hindpaw denervation. Previous research showed that inbred A/J (A-mice) but not C57BL6/J (B-mice) express highly variable levels of self-mutilation of the denervated hindpaw (`autotomy', a behaviour related to NP). This suggested that genetic and environmental factors interact (GXE) in controlling this variance. Using this NP model in recombinant inbred mice, a region on chromosome-15 (`Pain1') was identified as harbouring autotomy gene(s). Here we report that Csf2rb1, a gene encoding the colony stimulating factor-2Beta1 common receptor of GM-CSF (granulocyte-macrophage colony stimulating factor), and interleukins 3 and 5, is a candidate autotomy gene in Pain1. Up-regulation in Csf2rb1 expression levels in the lumbar spinal cord correlated autotomy levels in denervated A and B mice vs. their na誰ve or sham groups. Csf2rb1-expressing cells were labelled immunohistologically in several CNS structures known to process pain inputs, including spinal dorsal horn, central canal, and select spinal white matter regions, hippocampal dentate gyrus, ventricle linings and periventricular and arcuate hypothalamus nuclei. CSF2RB1 protein levels were increased in spinal cord and brain of denervated A mice expressing autotomy vs. non-autotomizing A and B mice, and vs. their control groups (na誰ve and sham A and B mice). Based on cyto-morphology and co-localization with Vimentin, but not GFAP (astrocytes), OX42 (microglia), NeuN (neurons), MAP2 (neurons), and NG2 (oligodendrocytes) markers, Csf2rb1-expressing cells were identified as ependymal cells/radial glia/tanycytes. Previous studies showed that C3H/HeN mice express significantly more pain behaviour than C3H/HeJ mice in several models. This contrast has been attributed to a mutation in Tlr4 encoding Toll-like receptor-4 in C3H/HeJ mice. We show here that denervated C3H/HeN mice express higher autotomy levels than C3H/HeJ mice. Spinal Csf2rb1 expression levels increased significantly post-denervation in C3H/HeN but not C3H/HeJ mice. Thus, we propose that spontaneous NP behaviour in mice is associated with up-regulated Csf2rb1 and CSF2RB1 levels in the CNS and associated with TLR4 signalling.Ph.D
Identification of Genes for Spontaneous Neuropathic Pain in Mice: Whole Genome and Candidate Gene Approaches
No full textChronic neuropathic pain (NP) affects many people worldwide; causing suffering that is difficult to treat, incurable and not preventable. There is growing hope that pain genetics may identify novel treatment targets. In this dissertation we report on candidate NP genes using a mouse NP model produced by hindpaw denervation. Previous research showed that inbred A/J (A-mice) but not C57BL6/J (B-mice) express highly variable levels of self-mutilation of the denervated hindpaw (`autotomy', a behaviour related to NP). This suggested that genetic and environmental factors interact (GXE) in controlling this variance. Using this NP model in recombinant inbred mice, a region on chromosome-15 (`Pain1') was identified as harbouring autotomy gene(s). Here we report that Csf2rb1, a gene encoding the colony stimulating factor-2Beta1 common receptor of GM-CSF (granulocyte-macrophage colony stimulating factor), and interleukins 3 and 5, is a candidate autotomy gene in Pain1. Up-regulation in Csf2rb1 expression levels in the lumbar spinal cord correlated autotomy levels in denervated A and B mice vs. their na誰ve or sham groups. Csf2rb1-expressing cells were labelled immunohistologically in several CNS structures known to process pain inputs, including spinal dorsal horn, central canal, and select spinal white matter regions, hippocampal dentate gyrus, ventricle linings and periventricular and arcuate hypothalamus nuclei. CSF2RB1 protein levels were increased in spinal cord and brain of denervated A mice expressing autotomy vs. non-autotomizing A and B mice, and vs. their control groups (na誰ve and sham A and B mice). Based on cyto-morphology and co-localization with Vimentin, but not GFAP (astrocytes), OX42 (microglia), NeuN (neurons), MAP2 (neurons), and NG2 (oligodendrocytes) markers, Csf2rb1-expressing cells were identified as ependymal cells/radial glia/tanycytes. Previous studies showed that C3H/HeN mice express significantly more pain behaviour than C3H/HeJ mice in several models. This contrast has been attributed to a mutation in Tlr4 encoding Toll-like receptor-4 in C3H/HeJ mice. We show here that denervated C3H/HeN mice express higher autotomy levels than C3H/HeJ mice. Spinal Csf2rb1 expression levels increased significantly post-denervation in C3H/HeN but not C3H/HeJ mice. Thus, we propose that spontaneous NP behaviour in mice is associated with up-regulated Csf2rb1 and CSF2RB1 levels in the CNS and associated with TLR4 signalling.Ph.D
Smooth Pursuit Eye Movement of Monkeys Naive to Laboratory Setups With Pictures and Artificial Stimuli
No full textWhen animal behavior is studied in a laboratory environment, the animals are often extensively trained to shape their behavior. A crucial question is whether the behavior observed after training is part of the natural repertoire of the animal or represents an outlier in the animal’s natural capabilities. This can be investigated by assessing the extent to which the target behavior is manifested during the initial stages of training and the time course of learning. We explored this issue by examining smooth pursuit eye movements in monkeys naïve to smooth pursuit tasks. We recorded the eye movements of monkeys from the 1st days of training on a step-ramp paradigm. We used bright spots, monkey pictures and scrambled versions of the pictures as moving targets. We found that during the initial stages of training, the pursuit initiation was largest for the monkey pictures and in some direction conditions close to target velocity. When the pursuit initiation was large, the monkeys mostly continued to track the target with smooth pursuit movements while correcting for displacement errors with small saccades. Two weeks of training increased the pursuit eye velocity in all stimulus conditions, whereas further extensive training enhanced pursuit slightly more. The training decreased the coefficient of variation of the eye velocity. Anisotropies that grade pursuit across directions were observed from the 1st day of training and mostly persisted across training. Thus, smooth pursuit in the step-ramp paradigm appears to be part of the natural repertoire of monkeys’ behavior and training adjusts monkeys’ natural predisposed behavior
Ganglionated Plexus Ablation Procedures to Treat Vasovagal Syncope
No full textVasovagal syncope (VVS) refers to a heterogeneous group of conditions whereby the cardiovascular reflexes normally controlling the circulation are interrupted irregularly in response to a trigger, resulting in vasodilation, bradycardia, or both. VVS affects one-third of the population at least once in their lifetime or by the age of 60, reduces the quality of life, and may cause disability affecting certain routines. It poses a considerable economic burden on society, and, despite its prevalence, there is currently no proven pharmacological treatment for preventing VVS. The novel procedure of ganglionated plexus (GP) ablation has emerged rapidly in the past two decades, and has been proven successful in treating syncope. Several parameters influence the success rate of GP ablation, including specific ablation sites, localization and surgical techniques, method of access, and the integration of other interventions. This review aims to provide an overview of the existing literature on the physiological aspects and clinical effectiveness of GP ablation in the treatment of VVS. Specifically, we explore the association between GPs and VVS and examine the impact of GP ablation procedures as reported in human clinical trials. Our objective is to shed light on the therapeutic significance of GP ablation in eliminating VVS and restoring normal sinus rhythm, particularly among young adults affected by this condition
Increased glucose uptake promotes oxidative stress and PKC-δ activation in adipocytes of obese, insulin-resistant mice
No full textDevelopment of a codon optimization strategy using the efor RED reporter gene as a test case
No full textContemporary Pillars of Heart Failure with Reduced Ejection Fraction Medical Therapy
No full textHeart failure with reduced ejection fraction (HFrEF) is a clinical condition associated with cardiac contractility impairment. HFrEF is a significant public health issue with a high morbidity and mortality burden. Pathological left ventricular (LV) remodeling and progressive dilatation are hallmarks of HFrEF pathogenesis, ultimately leading to adverse clinical outcomes. Therefore, cardiac remodeling attenuation has become a treatment goal and a standard of care over the last three decades. Guideline-directed medical therapy mainly targeting the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS) has led to improved survival and a reduction in HF hospitalization in this population. More recently, novel pharmacological therapies targeting other pathways implicated in the pathophysiology of HFrEF have emerged at an exciting rate, with landmark clinical trials demonstrating additive clinical benefits in patients with HFrEF. Among these novel therapies, angiotensin receptor–neprilysin inhibitors (ARNI), sodium–glucose cotransporter-2 inhibitors (SGLT2i), vericiguat (a novel oral guanylate cyclase stimulator), and omecamtiv mecarbil (a selective cardiac myosin activator) have shown improved clinical benefit when added to the traditional standard-of-care medical therapy in HFrEF. These new comprehensive data have led to a remarkable change in the medical therapy paradigm in the setting of HFrEF. This article will review the pivotal studies involving these novel agents and present a suggestive paradigm of pharmacological therapy representing the 2021 European Society of Cardiology (ESC) guidelines for the treatment of chronic HFrEF
Exploring the Mechanisms Underlying the Cardiotoxic Effects of Immune Checkpoint Inhibitor Therapies
No full textAdaptive immune response modulation has taken a central position in cancer therapy in recent decades. Treatment with immune checkpoint inhibitors (ICIs) is now indicated in many cancer types with exceptional results. The two major inhibitory pathways involved are cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1). Unfortunately, immune activation is not tumor-specific, and as a result, most patients will experience some form of adverse reaction. Most immune-related adverse events (IRAEs) involve the skin and gastrointestinal (GI) tract; however, any organ can be involved. Cardiotoxicity ranges from arrhythmias to life-threatening myocarditis with very high mortality rates. To date, most treatments of ICI cardiotoxicity include immune suppression, which is also not cardiac-specific and may result in hampering of tumor clearance. Understanding the mechanisms behind immune activation in the heart is crucial for the development of specific treatments. Histological data and other models have shown mainly CD4 and CD8 infiltration during ICI-induced cardiotoxicity. Inhibition of CTLA4 seems to result in the proliferation of more diverse T0cell populations, some of which with autoantigen recognition. Inhibition of PD-1 interaction with PD ligand 1/2 (PD-L1/PD-L2) results in release from inhibition of exhausted self-recognizing T cells. However, CTLA4, PD-1, and their ligands are expressed on a wide range of cells, indicating a much more intricate mechanism. This is further complicated by the identification of multiple co-stimulatory and co-inhibitory signals, as well as the association of myocarditis with antibody-driven myasthenia gravis and myositis IRAEs. In this review, we focus on the recent advances in unraveling the complexity of the mechanisms driving ICI cardiotoxicity and discuss novel therapeutic strategies for directly targeting specific underlying mechanisms to reduce IRAEs and improve outcomes
