Neuroimmune circuits in the plaque and bone marrow regulate atherosclerosis.

Atherosclerosis remains the leading cause of death globally. Although its focal pathology is atheroma that develops in arterial walls, atherosclerosis is a systemic disease involving contributions by many organs and tissues. It is now established that the immune system causally contributes to all phases of atherosclerosis. Recent and emerging evidence positions the nervous system as a key modulator of inflammatory processes that underly atherosclerosis. This neuro-immune crosstalk, we are learning, is bidirectional, and immune regulated afferent signaling is becoming increasingly recognized in atherosclerosis. Here, we summarize data and concepts that link the immune and nervous systems in atherosclerosis by focusing on two important sites, the arterial vessel and the bone marrow.

Morphometric analysis and functional insights into the serotonergic system of Girardia tigrina (Tricladida, Platyhelminthes).

Using immunocytochemistry, serotonergic nerve elements were documented in the nervous system of the planarian Girardia tigrina. Serotonin-immunopositive components were observed in the brain, ventral, dorsal and longitudinal nerve cords, transverse nerve commissures connecting the nerve cords, and in the nerve plexus. Whole-mount preparations of G. tigrina were analyzed by fluorescent and confocal laser scanning microscopy. An essential quantitative morphometric measurement of serotonin-immunopositive structures was conducted in three body regions (anterior, middle, and posterior) of the planarian. The number of serotonin neurons was maximal in the head region. The ventral nerve cords gradually decreased in thickness from anterior to posterior body ends. Physiological action of exogenously applied serotonin was studied in G. tigrina for the first time. It was found that serotonin (0.1 and 1 µmol L-1) accelerated eye regeneration. The transcriptome sequencing performed for the first time for the planarian G. tigrina revealed the transcripts of the tryptophan hydroxylase (trph), amino acid decarboxylase (aadc) and serotonin transporter (sert) genes. The data obtained indicate the presence of the components of serotonin pathway in G. tigrina. The identified transcripts can take part in serotonin turnover and participate in the realization of biological effects of serotonin in planarians, associated with eyes regeneration and differentiation.

Neurological manifestations in dogs with acute leukemia.

Canine acute leukemia is a rare hematopoietic neoplasm. Neurological abnormalities have been frequently reported in dogs with acute leukemia (AL). However, the description of the presentation and findings are limited. This study aimed to describe the clinical findings in dogs with acute leukemia presenting with neurological signs as their primary complaint. The database of a private referral hospital was searched for cases that presented to the neurological department with neurological deficits and were subsequently diagnosed with acute leukemia. Six cases were included; all had neurological clinical signs and an abnormal neurological examination. All cases had a focal neuroanatomical localisation on neurological examination (brain n = 4; spinal = 2). Out of the four dogs with a complete magnetic resonance imaging (MRI) study, there was an ill-defined infiltrative pattern with abnormal signal intensity in the central nervous system (CNS) in three dogs and the loss of grey and white matter differentiation in the brain (n = 2) and/or spinal cord (n = 2). Other MRI findings included abnormal meningeal enhancement (n = 3), changes affecting spinal nerves and epaxial muscles (n = 2), and lymphadenopathy in the field of view (n = 2). The bone marrow assessment on MRI showed evidence of signal change (n = 3), characterized by a loss of normal fat opacity and an abnormal degree of contrast enhancement. The cerebrospinal fluid (CSF) analysis of the four dogs showed an increased protein level with non-specific pleocytosis and without evidence of malignant cells. Treatment with cytotoxic medication was implemented in two dogs. The dogs diagnosed with acute leukemia had focal neuroanatomical localisation, an infiltrative CNS pattern, and bone marrow remodulation on MRI with an increase in CSF protein and negative cytology analysis.

Ocular fundus changes and association with systemic conditions in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs and systems. Ocular involvement is estimated to manifest in one-third of individuals with SLE, of which lupus retinopathy and choroidopathy represent the severe subtype accompanied by vision impairment. Advancements in multimodal ophthalmic imaging have allowed ophthalmologists to reveal subclinical microvascular and structural changes in fundus of patients with SLE without ocular manifestations. Both ocular manifestations and subclinical fundus damage have been shown to correlate with SLE disease activity and, in some patients, even precede other systemic injuries as the first presentation of SLE. Moreover, ocular fundus might serve as a window into the state of systemic vasculitis in patients with SLE. Given the similarities of the anatomy, physiological and pathological processes shared among ocular fundus, and other vital organ damage in SLE, such as kidney and brain, it is assumed that ocular fundus involvement has implications in the diagnosis and evaluation of other systemic impairments. Therefore, evaluating the fundus characteristics of patients with SLE not only contributes to the early diagnosis and intervention of potential vision damage, but also holds considerate significance for the evaluation of SLE vasculitis state and prediction of other systemic injuries.

Cajal and his love for Nature: a sentimental essence in the legacy of neurosciences.

Santiago Ramón y Cajal (1852-1934) revolutionized the branches of neuroscience in a forceful way, and he did it with extreme delicacy and candor. His scientific writings and drawings are full of allusions to Nature, a fact that demonstrates how he saw, understood and enjoyed it with exquisite sensitivity and pressing emotion. Neuroscience awakened in him the utmost curiosity to delve into the powerful mysteries of the mind, and neurohistology allowed him to satisfy his deepest concerns for fascinating scenarios, a desire not sufficiently fulfilled throughout the fields, mountains and forests of his childhood and youth. Through that wonderful microscopic world Cajal changed the size of the dreamed landscapes but not the dimension of the longed-for adventures. Exploring and entering unknown paths he unraveled some of the greatest enigmas that the nervous system hid, but he would do so with a deep feeling toward the infinite beauty that Nature itself offered him. In short, Nature was the vital axis of Cajal's overwhelming and complex personality, his most genuine essence and the inexhaustible source of inspiration where he poured his imagination and fantasy. He became a vocational adventurer, an insatiable explorer, a talented artist and an exquisite humanist. An eminently romantic soul who knew how to link Nature and Neuroscience with unconditional and perpetual emotionality.

Phosphatidylserine: A comprehensive overview of synthesis, metabolism, and nutrition.

Phosphatidylserine (PtdS) is classified as a glycerophospholipid and a primary anionic phospholipid and is particularly abundant in the inner leaflet of the plasma membrane in neural tissues. It is synthesized from phosphatidylcholine or phosphatidylethanolamine by exchanging the base head group with serine, and this reaction is catalyzed by PtdS synthase-1 and PtdS synthase-2 located in the endoplasmic reticulum. PtdS exposure on the outside surface of the cell is essential for eliminating apoptotic cells and initiating the blood clotting cascade. It is also a precursor of phosphatidylethanolamine, produced by PtdS decarboxylase in bacteria, yeast, and mammalian cells. Furthermore, PtdS acts as a cofactor for several necessary enzymes that participate in signaling pathways. Beyond these functions, several studies indicate that PtdS plays a role in various cerebral functions, including activating membrane signaling pathways, neuroinflammation, neurotransmission, and synaptic refinement associated with the central nervous system (CNS). This review discusses the occurrence of PtdS in nature and biosynthesis via enzymes and genes in plants, yeast, prokaryotes, mammalian cells, and the brain, and enzymatic synthesis through phospholipase D (PLD). Furthermore, we discuss metabolism, its role in the CNS, the fortification of foods, and supplementation for improving some memory functions, the results of which remain unclear. PtdS can be a potentially beneficial addition to foods for kids, seniors, athletes, and others, especially with the rising consumer trend favoring functional foods over conventional pills and capsules. Clinical studies have shown that PtdS is safe and well tolerated by patients.

When the body fosters empathy: The interconnectivity between bodily reactivity, meditation, and embodied abstract concepts.

Empathy is a fundamental social ability that allows humans to infer others' emotions and intentions. Empathy is thought to be rooted in bodily sensations coming from the autonomic nervous system. In parallel, the functionality and perceptions coming from the autonomic nervous system could be improved by practicing activities that involve mind-body interactions, such as meditation. Furthermore, perceptions from the autonomic nervous system are thought to be important in the embodiment of abstract concepts. Consequently, in the current study, we collected data online from 581 participants and explored the associations between levels of empathy and (1) the practice of meditation, music, and sports; (2) the impact of self-report measures on bodily awareness and reactivity; and (3) the embodiment of abstract concepts in interoception. In line with previous studies, Meditators were found to have higher empathy scores than Non-Meditators. In addition, lower levels of autonomic reactivity in organs above the diaphragm were associated with higher empathy. Finally, we also observed that empathy was positively associated with interoceptive components of abstract concepts in those participants with high autonomic reactivity. Taken together, the results suggest that meditation practice and having low autonomic reactivity are associated with empathy, arguably through the downregulation of autonomic responses. Implications for mind-body interaction in meditation and its role in promoting empathy are discussed.

Neuroimmune modulation in liver pathophysiology.

The liver, the largest organ in the human body, plays a multifaceted role in digestion, coagulation, synthesis, metabolism, detoxification, and immune defense. Changes in liver function often coincide with disruptions in both the central and peripheral nervous systems. The intricate interplay between the nervous and immune systems is vital for maintaining tissue balance and combating diseases. Signaling molecules and pathways, including cytokines, inflammatory mediators, neuropeptides, neurotransmitters, chemoreceptors, and neural pathways, facilitate this complex communication. They establish feedback loops among diverse immune cell populations and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems within the liver. In this concise review, we provide an overview of the structural and compositional aspects of the hepatic neural and immune systems. We further explore the molecular mechanisms and pathways that govern neuroimmune communication, highlighting their significance in liver pathology. Finally, we summarize the current clinical implications of therapeutic approaches targeting neuroimmune interactions and present prospects for future research in this area.

Renal autonomic dynamics in hypertension: how can we evaluate sympathetic activity for renal denervation?

This review explores the various pathophysiological factors influencing antihypertensive effects, involving the regulation of vascular resistance, plasma volume, cardiac function, and the autonomic nervous system, emphasizing the interconnected processes regulating blood pressure (BP). The kidney's pivotal role in BP control and its potential contribution to hypertension is complicated but important to understand the effective mechanisms of renal denervation (RDN), which may be a promising treatment for resistant hypertension. Excessive stimulation of the sympathetic nervous system or the renin-angiotensin-aldosterone system (RAAS) can elevate BP through various physiological changes, contributing to chronic hypertension. Renal sympathetic efferent nerve activation leads to elevated norepinephrine levels and subsequent cascading effects on vasoconstriction, renin release, and sodium reabsorption. RDN reduces BP in resistant hypertension by potentially disrupting sensory afferent nerves, decreasing feedback activation to the central nervous system, and reducing efferent sympathetic nerve activity in the heart and other structures. RDN may also modulate central sympathetic outflow and inhibit renal renin-angiotensin system overactivation. While evidence for RDN efficacy in hypertension is increasing, accurate patient selection becomes crucial, considering complex interactions that vary among patients. This review also discusses methods to evaluate autonomic nerve activity from the golden standard to new potential examination for finding out optimization in stimulation parameters or rigorous patient selection based on appropriate biomarkers.

Advice to People with Parkinson's in My Clinic: Orthostatic Hypotension.

Orthostatic hypotension (OH) is the most common manifestation of cardiovascular autonomic dysfunction in Parkinson's disease. In this viewpoint, we discuss five practical questions regarding OH in Parkinson's disease: 1) How common is the problem? 2) Why should people with Parkinson's disease and providers care about OH? 3) What are the symptoms of OH? 4) How to confirm a diagnosis of OH? And 5) How to treat OH? OH is an important non-motor symptom of Parkinson's disease for which we have available treatments to significantly mitigate morbidity and possibly positively impact the disease course.

The risk factors affecting the persistence of corpus callosum splenium lesions.

BACKGROUND: The most compact portion of the corpus callosum (CC) is the corpus splenium (CS). PURPOSE: To evaluate the connection between clinical and demographic features to determine whether neuroimaging findings will be permanent or temporary in CS patients. MATERIAL AND METHODS: We enrolled 93 patients (age range = 18-86 years) with CS lesions. Demographic and clinical information were recorded. We examined the lesions depending on the location. Group 1 (n = 20) had lesions limited to the CS (egg-shaped or round); group 2 (n = 15) had "boomerang sign" lesions; and group 3 (n = 58) had splenium involvement in conditions affecting the whole brain (Boomerang sign+ plus). RESULTS: Group 1 had a lower mean age, shorter disease duration, and fewer persistent lesions than others (P < 0.01, P < 0.001, and P < 0.001, respectively). The mean disease onset age (in years) in group 1 was higher than that of the other groups (P < 0.045). Group 2 had lower potassium (K) (P < 0.003) and red cell distribution width levels (P < 0.029) than the other groups. Age <41.5 years (P < 0.001), age at illness initiation <48.5 years (P < 0.002), disease duration <5.5 months (P < 0.001), and eosinophil level <0.29 uL (P 0.014) all point to temporary lesions. CONCLUSION: Cases with limited CS lesions have younger onset ages, lower disease onset ages, and shorter disease durations. Age, age of disease onset, disease duration, and eosinophil level are risk variables that affect whether CS lesions are permanent or temporary.

Sensory sentinels: Neuroimmune detection and food allergy.

Food allergy is classically characterized by an inappropriate type-2 immune response to allergenic food antigens. However, how allergens are detected and how that detection leads to the initiation of allergic immunity is poorly understood. In addition to the gastrointestinal tract, the barrier epithelium of the skin may also act as a site of food allergen sensitization. These barrier epithelia are densely innervated by sensory neurons, which respond to diverse physical environmental stimuli. Recent findings suggest that sensory neurons can directly detect a broad array of immunogens, including allergens, triggering sensory responses and the release of neuropeptides that influence immune cell function. Reciprocally, immune mediators modulate the activation or responsiveness of sensory neurons, forming neuroimmune feedback loops that may impact allergic immune responses. By utilizing cutaneous allergen exposure as a model, this review explores the pivotal role of sensory neurons in allergen detection and their dynamic bidirectional communication with the immune system, which ultimately orchestrates the type-2 immune response. Furthermore, it sheds light on how peripheral signals are integrated within the central nervous system to coordinate hallmark features of allergic reactions. Drawing from this emerging evidence, we propose that atopy arises from a dysregulated neuroimmune circuit.

Hematopoietic stem cell transplantation leads to biochemical and functional correction in two mouse models of acid ceramidase deficiency.

Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare lysosomal storage disorders caused by deficient acid ceramidase (ACDase) activity. Although both conditions are caused by mutations in the ASAH1 gene, clinical presentations differ considerably. FD patients usually die in childhood while SMA-PME patients can live until adulthood. There is no treatment for FD or SMA-PME. Hematopoietic stem cell transplantation (HSCT) and gene therapy strategies for the treatment of ACDase deficiency are being investigated. We have previously generated and characterized mouse models of both FD and SMA-PME that recapitulate the symptoms described in patients. Here, we show that HSCT improves lifespan, behavior, hematopoietic system anomalies, plasma cytokine levels, and significantly reduces histiocytic infiltration and ceramide accumulation throughout the tissues investigated, including the CNS, in both models of ACDase deficient mice. HSCT was also successful in preventing lesion development and significant demyelination of the spinal cord seen in SMA-PME mice. Importantly, we note that only early and generally pre-symptomatic treatment was effective and kidney impairment was not improved in either model.

Sympathetic response following unannounced loss of balance during walking in young adults - laboratory study.

BACKGROUND: An unannounced balance loss during walking, i.e., balance perturbation, is a stressful event that changes the activity of the Sympathetic Nervous System (SNS). We examined SNS response to unannounced balance perturbation during walking, simulating real-life conditions of balance loss. RESEARCH QUESTION: Do laboratory-induced unannounced balance losses during walking cause a sympathetic response, and if so - does it habituate after a series of perturbations? METHODS: 34 young adults underwent a series of six successive unannounced balance perturbations while walking on a treadmill. Sympathetic activity was monitored continuously using Electrodermal Activity and compared before and immediately after each unannounced perturbation. RESULTS: All perturbations elicited a significant increase in Electrodermal Activity (p<0.001), indicating a phasic increase in the sympathetic drive. The relative phasic increase of Electrodermal Activity caused by the first perturbation was significantly higher than the last perturbation (p<0.05). Three types of Electrodermal Activity behavior were observed: Steady level tonic SNS activity, increased SNS activity, and decreased SNS activity. SIGNIFICANCE: Balance loss during walking triggers phasic SNS response, this response habituates after a series of unannounced balance perturbations. In addition, three distinct patterns of tonic sympathetic activity may imply variations in the ability of the SNS response to habituate across individuals.

Diagnostic uncertainty of steroid-modified Marburg's variant of multiple sclerosis even at autopsy: A case suggesting lymphoma and related myelin loss.

MS (multiple sclerosis) has specific criteria to avoid misdiagnosis. However, the Marburg variant of MS is so fulminant that initial axonal damage and other atypical observations have been allowed in past reports. We present a 74-year-old autopsy case with a vanishing tumor after steroids and radiation therapy, which was pathologically diagnosed as a Marburg variant with initial axonal loss. The case displayed radiological lymphoma-like observations: mass effects protruding to the lateral ventricle, fused extension from the choroid plexus to white matter with C opening sign, a growing lesion from the skull dura mater, high in diffusion-weighted imaging and low in apparent diffusion coefficient on magnetic resonance imaging (MRI) suggesting high cell density lymphoma. In addition, clinical manifestations were atypical for MS: upper limb monoplegia without ipsilateral lower limb involvement, pleocytosis over 50 cells/µL, and class 3 cytological abnormality in cerebrospinal fluid. However, at autopsy following steroids and radiation therapy, there were no lymphoma-like lesions, such as mass effects, fused extensive lesions, masses on the skull dura mater, or high cell density lesions. Instead, there were only myelin losses corresponding to the MRI lesions, highlighting the potential for contamination by other diseases in steroid-modified Marburg's variant of multiple sclerosis, possibly due to lymphoma, even at autopsy.

Enhanced AAV transduction across preclinical CNS models: A comparative study in human brain organoids with cross-species evaluations.

Viral vectors based on recombinant adeno-associated virus (rAAV) have become the most widely used system for therapeutic gene delivery in the central nervous system (CNS). Despite clinical safety and efficacy in neurological applications, a barrier to adoption of the current generation of vectors lies in their limited efficiency, resulting in limited transduction of CNS target cells. To address this limitation, researchers have bioengineered fit-for-purpose AAVs with improved CNS tropism and tissue penetration. While the preclinical assessment of these novel AAVs is primarily conducted in animal models, human induced pluripotent stem cell (hiPSC)-derived organoids offer a unique opportunity to functionally evaluate novel AAV variants in a human context. In this study, we performed a comprehensive and unbiased evaluation of a large number of wild-type and bioengineered AAV capsids for their transduction efficiency in hiPSC-derived brain organoids. We demonstrate that efficient AAV transduction observed in organoids was recapitulated in vivo in both mouse and non-human primate models after cerebrospinal fluid (CSF) delivery. In summary, our study showcases the use of brain organoid systems for the pre-screening of novel AAV vectors. Additionally, we report data for novel AAV variants that exhibit improved CNS transduction efficiency when delivered via the CSF in in vivo preclinical models.

Central nervous injury risk factors after endovascular repair of a thoracic aortic aneurysm with type B aortic dissection.

BACKGROUND: Aortic dissection is the deadliest disease of the cardiovascular system. Type B aortic dissection accounts for 30%-60% of aortic dissections and is mainly treated by endovascular repair of thoracic endovascular aneurysm repair (TEVAR). However, patients are prone to various complications after surgery, with central nervous system injury being the most common, which seriously affects their prognosis and increases the risk of disability and death. Therefore, exploring the risk factors of central nervous system injury after TEVAR can provide a basis for its prevention and control. AIM: To investigate the risk factors for central nervous system injury after the repair of a thoracic endovascular aneurysm with type B aortic dissection. METHODS: We enrolled 306 patients with type B aortic dissection who underwent TEVAR at our hospital between December 2019 and October 2022. The patients were categorized into injury (n = 159) and non-injury (n = 147) groups based on central nervous system injury following surgery. The risk factors for central nervous system injury after TEVAR for type B aortic dissection were screened by comparing the two groups. Multivariate logistic regression analysis was performed. RESULTS: The Association between age, history of hypertension, blood pH value, surgery, mechanical ventilation, intensive care unit stay, postoperative recovery times on the first day after surgery, and arterial partial pressure of oxygen on the first day after surgery differed substantially (P < 0.05). Multivariate logistic regression analysis indicated that age, surgery time, history of hypertension, duration of mechanical ventilation, and intensive care unit stay were independent risk factors for central nervous system injury after TEVAR of type B aortic dissection (P < 0.05). CONCLUSION: For high-risk patients with central nervous system injury after TEVAR of type B aortic dissection, early intervention measures should be implemented to lower the risk of neurological discomfort following surgery in high-risk patients with central nervous system injury after TEVAR for type B aortic dissection.

Unveiling the biological effects of radio-frequency and extremely-low frequency electromagnetic fields on the central nervous system performance.

Introduction: Radiofrequency electromagnetic radiation (RF-EMR) and extremely low-frequency electromagnetic fields (ELF-EMF) have emerged as noteworthy sources of environmental pollution in the contemporary era. The potential biological impacts of RF-EMR and ELF-EMF exposure on human organs, particularly the central nervous system (CNS), have garnered considerable attention in numerous research studies. Methods: This article presents a comprehensive yet summarized review of the research on the explicit/implicit effects of RF-EMR and ELF-EMF exposure on CNS performance. Results: Exposure to RF-EMR can potentially exert adverse effects on the performance of CNS by inducing changes in the permeability of the blood-brain barrier (BBB), neurotransmitter levels, calcium channel regulation, myelin protein structure, the antioxidant defense system, and metabolic processes. However, it is noteworthy that certain reports have suggested that RF-EMR exposure may confer cognitive benefits for various conditions and disorders. ELF-EMF exposure has been associated with the enhancement of CNS performance, marked by improved memory retention, enhanced learning ability, and potential mitigation of neurodegenerative diseases. Nevertheless, it is essential to acknowledge that ELF-EMF exposure has also been linked to the induction of anxiety states, oxidative stress, and alterations in hormonal regulation. Moreover, ELF-EMR exposure alters hippocampal function, notch signaling pathways, the antioxidant defense system, and synaptic activities. Conclusion: The RF-EMR and ELF-EMF exposures exhibit both beneficial and adverse effects. Nevertheless, the precise conditions and circumstances under which detrimental or beneficial effects manifest (either individually or simultaneously) remain uncertain.