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Cell Reports Sep 2023Visual stimuli that deviate from the current context elicit augmented responses in the primary visual cortex (V1). These heightened responses, known as "deviance...
Visual stimuli that deviate from the current context elicit augmented responses in the primary visual cortex (V1). These heightened responses, known as "deviance detection," require local inhibition in the V1 and top-down input from the anterior cingulate area (ACa). Here, we investigated the mechanisms by which the ACa and V1 interact to support deviance detection. Local field potential recordings in mice during an oddball paradigm showed that ACa-V1 synchrony peaks in the theta/alpha band (≈10 Hz). Two-photon imaging in the V1 revealed that mainly pyramidal neurons exhibited deviance detection, while contextually redundant stimuli increased vasoactive intestinal peptide (VIP)-positive interneuron (VIP) activity and decreased somatostatin-positive interneuron (SST) activity. Optogenetic drive of ACa-V1 inputs at 10 Hz activated V1-VIPs but inhibited V1-SSTs, mirroring the dynamics present during the oddball paradigm. Chemogenetic inhibition of V1-VIPs disrupted Aca-V1 synchrony and deviance detection in the V1. These results outline temporal and interneuron-specific mechanisms of top-down modulation that support visual context processing.
Topics: Animals; Mice; Visual Perception; Cerebral Cortex; Pyramidal Cells; Interneurons; Optogenetics; Vasoactive Intestinal Peptide
PubMed: 37708021
DOI: 10.1016/j.celrep.2023.113133 -
Annals of Cardiac Anaesthesia 2023Orthotopic liver transplantation (OLT) is the standard of care for patients suffering from end stage liver disease (ESLD). This is a high-risk procedure with the... (Review)
Review
Orthotopic liver transplantation (OLT) is the standard of care for patients suffering from end stage liver disease (ESLD). This is a high-risk procedure with the potential for hemorrhage, large shifts in preload and afterload, and release of vasoactive mediators that can have profound effects on hemodynamic equilibrium. In addition, patients with ESLD can have preexisting coronary artery disease, cirrhotic cardiomyopathy, porto-pulomary hypertension and imbalanced coagulation. As cardiovascular involvement is invariable and patient are at an appreciable risk of intraoperative cardiac arrest, Trans esophageal echocardiography (TEE) is increasingly becoming a routinely utilized monitor during OLT in patients without contraindications to its use. A comprehensive TEE assessment performed by trained operators provides a wealth of information on baseline cardiac function, while a focused study specific for the ESLD patients can help in prompt diagnosis and treatment of critical events. Future studies utilizing TEE will eventually optimize examination safety, quality, permit patient risk stratification, provide intraoperative guidance, and allow for evaluation of graft vasculature.
Topics: Humans; Liver Transplantation; Echocardiography, Transesophageal; Heart; Cardiovascular Diseases; Blood Coagulation
PubMed: 37861569
DOI: 10.4103/aca.aca_186_22 -
BMJ Supportive & Palliative Care Oct 2023It is estimated that 5% of patients with heart failure (HF) will progress to end-stage disease refractory to medical therapy and might require prolonged hospitalisation...
It is estimated that 5% of patients with heart failure (HF) will progress to end-stage disease refractory to medical therapy and might require prolonged hospitalisation with inotropic support. We present the case of a patient with end-stage HF who was admitted with cardiogenic shock. During his hospitalisation, he required prolonged intravenous vasopressor therapy due to refractory hypotension. He did not qualify for heart transplantation or left ventricular-assist device strategies. Midodrine was started as a last resort attempt to wean off vasopressors. After 5 days of therapy, the patient was weaned entirely off vasopressors and was discharged home for hospice care. By the time of discharge, he was tolerating low-dose carvedilol along with midodrine. We propose midodrine as a reasonable alternative for patients with end-stage HF with reduced ejection fraction and refractory hypotension, who are dependent on intravenous vasoactive drugs and are not candidates for advanced HF therapies.
Topics: Male; Humans; Midodrine; Vasoconstrictor Agents; Hospitalization; Heart Failure; Hypotension
PubMed: 32581003
DOI: 10.1136/bmjspcare-2020-002369 -
The Journal of Allergy and Clinical... Aug 2023Angioedema is generally readily recognizable clinically and is characterized by localized nonpitting edema involving subcutaneous, submucosal, or deep dermal tissue...
Angioedema is generally readily recognizable clinically and is characterized by localized nonpitting edema involving subcutaneous, submucosal, or deep dermal tissue caused by increased vascular permeability and extravasation of intravascular fluid. It can occur via a variety of mechanisms. A number of clinical conditions (masqueraders) are occasionally mistaken for angioedema. Clinical classification of the various angioedema forms begins with noting the presence or absence of concurrent urticaria or wheals. Pathogenesis can be considered through two broad categories: mast cell-mediated with release of vasoactive mediators causing angioedema usually associated with urticaria or in the context of an anaphylactic reaction; and bradykinin (BK)-driven, in which increased vascular permeability is mediated by BK. BK-mediated angioedema does not occur with urticaria, nor does it respond to antiallergic medications. The various forms of hereditary angioedema are included in this category, requiring specific tests of C4 and C1 inhibitor level and function to confirm the diagnosis. Angiotensin converting enzyme inhibitors, which impair the degradation of BK, account for up to a third of all patients with angioedema presenting to the emergency department. Finally, angioedema may occur by yet unknown mechanisms; under this circumstance, it is difficult to manage.
Topics: Humans; Angioedema; Urticaria; Angioedemas, Hereditary; Complement C1 Inhibitor Protein; Bradykinin; Angiotensin-Converting Enzyme Inhibitors
PubMed: 37343921
DOI: 10.1016/j.jaip.2023.06.022 -
Interdisciplinary Cardiovascular and... Jul 2023
PubMed: 37449899
DOI: 10.1093/icvts/ivad118 -
Neuron Sep 2023Experience-dependent plasticity of synapses modulates information processing in neural circuits and is essential for cognitive functions. The genome, via non-coding...
Experience-dependent plasticity of synapses modulates information processing in neural circuits and is essential for cognitive functions. The genome, via non-coding enhancers, was proposed to control information processing and circuit plasticity by regulating experience-induced transcription of genes that modulate specific sets of synapses. To test this idea, we analyze here the cellular and circuit functions of the genomic mechanisms that control the experience-induced transcription of Igf1 (insulin-like growth factor 1) in vasoactive intestinal peptide (VIP) interneurons (INs) in the visual cortex of adult mice. We find that two sensory-induced enhancers selectively and cooperatively drive the activity-induced transcription of Igf1 to thereby promote GABAergic inputs onto VIP INs and to homeostatically control the ratio between excitation and inhibition (E/I ratio)-in turn, this restricts neural activity in VIP INs and principal excitatory neurons and maintains spatial frequency tuning. Thus, enhancer-mediated activity-induced transcription maintains sensory processing in the adult cortex via homeostatic modulation of E/I ratio.
Topics: Mice; Animals; Neurons; Interneurons; Sensation; Synapses; Genomics; Perception; Neuronal Plasticity
PubMed: 37354902
DOI: 10.1016/j.neuron.2023.05.026 -
IScience Oct 2023The circadian rhythm pacemaker, the suprachiasmatic nucleus (SCN), mediates light entrainment via vasoactive intestinal peptide (VIP) neurons (SCN). Yet, how these...
The circadian rhythm pacemaker, the suprachiasmatic nucleus (SCN), mediates light entrainment via vasoactive intestinal peptide (VIP) neurons (SCN). Yet, how these neurons uniquely respond and connect to intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing melanopsin (Opn4) has not been determined functionally in freely behaving animals. To address this, we first used monosynaptic tracing from SCN neurons in mice and identified two SCN subpopulations. Second, we recorded calcium changes in response to ambient light, at both bulk and single-cell levels, and found two unique activity patterns in response to high- and low-intensity blue light. The activity patterns of both subpopulations could be manipulated by application of an Opn4 antagonist. These results suggest that the two SCN subpopulations connect to two types of Opn4-expressing ipRGCs, likely M1 and M2, but only one is responsive to red light. These findings have important implications for our basic understanding of non-image-forming circadian light processing.
PubMed: 37766975
DOI: 10.1016/j.isci.2023.107865 -
Pathologie (Heidelberg, Germany) Jul 2024The complement cascade comprises a variety of soluble and cell surface proteins and is an important component of the innate immune system. When the cascade is triggered... (Review)
Review
The complement cascade comprises a variety of soluble and cell surface proteins and is an important component of the innate immune system. When the cascade is triggered by any of the three activation pathways, the complement system rapidly produces large amounts of protein fragments that are potent mediators of inflammatory, vasoactive, and metabolic responses. All activation pathways lead to the terminal complement cascade with the formation of the membrane attack complex, which lyses cells by forming membrane pores. Although the complement system is essential for pathogen defense and homeostasis, excessive or uncontrolled activation can lead to tissue damage. Recent research shows that the complement system is activated in almost all kidney diseases, even those not traditionally considered immune-mediated. In directly complement-mediated kidney diseases, complement factors or regulators are defective, afunctional or inactivated by antibodies. In many other renal diseases, the complement system is activated secondarily as a result of renal damage and is therefore involved in the pathogenesis of the disease, but is not the trigger. The detection of complement deposits is also used to diagnose kidney disease. This review describes the structure of the complement system and the effects of its dysregulation as a cause and modulator of renal disease.
Topics: Humans; Complement System Proteins; Complement Activation; Kidney Diseases; Kidney; Immunity, Innate; Complement Membrane Attack Complex
PubMed: 38578365
DOI: 10.1007/s00292-024-01320-x -
International Journal of Molecular... Jul 2023Migraine is a common condition with disabling attacks that burdens people in the prime of their working lives. Despite years of research into migraine pathophysiology... (Review)
Review
Migraine is a common condition with disabling attacks that burdens people in the prime of their working lives. Despite years of research into migraine pathophysiology and therapeutics, much remains to be learned about the mechanisms at play in this complex neurovascular condition. Additionally, there remains a relative paucity of specific and targeted therapies available. Many sufferers remain underserved by currently available broad action preventive strategies, which are also complicated by poor tolerance and adverse effects. The development of preclinical migraine models in the laboratory, and the advances in human experimental migraine provocation, have led to the identification of key molecules likely involved in the molecular circuity of migraine, and have provided novel therapeutic targets. Importantly, the identification that vasoconstriction is neither necessary nor required for headache abortion has changed the landscape of migraine treatment and has broadened the therapy targets for patients with vascular risk factors or vascular disease. These targets include nitric oxide synthase (NOS) and several neuropeptides that are involved in migraine. The ability of NO donors and infusion of some of these peptides into humans to trigger typical migraine-like attacks has supported the development of targeted therapies against these molecules. Some of these, such as those targeting calcitonin gene-related peptide (CGRP), have already reached clinical practice and are displaying a positive outcome in migraineurs for the better by offering targeted efficacy without significant adverse effects. Others, such as those targeting pituitary adenylate cyclase activating polypeptide (PACAP), are showing promise and are likely to enter phase 3 clinical trials in the near future. Understanding these nitrergic and peptidergic mechanisms in migraine and their interactions is likely to lead to further therapeutic strategies for migraine in the future.
Topics: Humans; Migraine Disorders; Headache; Pituitary Adenylate Cyclase-Activating Polypeptide; Calcitonin Gene-Related Peptide; Nitric Oxide Synthase
PubMed: 37569369
DOI: 10.3390/ijms241511993 -
Current Research in Physiology 2024Chronic kidney disease (CKD) is a progressive and long-term condition marked by a gradual decline in kidney function. CKD is prevalent among those with conditions such... (Review)
Review
Chronic kidney disease (CKD) is a progressive and long-term condition marked by a gradual decline in kidney function. CKD is prevalent among those with conditions such as diabetes mellitus, hypertension, and glomerulonephritis. Affecting over 10% of the global population, CKD stands as a significant cause of morbidity and mortality. Despite substantial advances in understanding CKD pathophysiology and management, there is still a need to explore novel mechanisms and potential therapeutic targets. Urotensin II (UII), a potent vasoactive peptide, has garnered attention for its possible role in the development and progression of CKD. The UII system consists of endogenous ligands UII and UII-related peptide (URP) and their receptor, UT. URP pathophysiology is understudied, but alterations in tissue expression levels of UII and UT and blood or urinary UII concentrations have been linked to cardiovascular and kidney dysfunctions, including systemic hypertension, chronic heart failure, glomerulonephritis, and diabetes. UII gene polymorphisms are associated with increased risk of diabetes. Pharmacological inhibition or genetic ablation of UT mitigated kidney and cardiovascular disease in rodents, making the UII system a potential target for slowing CKD progression. However, a deeper understanding of the UII system's cellular mechanisms in renal and extrarenal organs is essential for comprehending its role in CKD pathophysiology. This review explores the evolving connections between the UII system and CKD, addressing potential mechanisms, therapeutic implications, controversies, and unexplored concepts.
PubMed: 38779598
DOI: 10.1016/j.crphys.2024.100126