How does organophosphorus chemical warfare agent exposure affect respiratory physiology in mice?

In the absence of appropriate medical care, exposure to organophosphorus nerve agents, such as VX, can lead to respiratory failure, and potentially death by asphyxiation. Despite the critical role of respiratory disturbances in organophosphorus-induced toxicity, the nature and underlying mechanisms of respiratory failure remain poorly understood. This study aimed to characterize respiratory alterations by determining their type and duration in mice exposed to a subcutaneous sublethal dose of VX. Respiratory ventilation in Swiss mice was monitored using dual-chamber plethysmography for up to 7 days post-exposure. Cholinesterase activity was assessed via spectrophotometry, and levels of inflammatory biomarkers were quantified using Luminex technology in blood and tissues involved in respiration (diaphragm, lung, and medulla oblongata). Additionally, a histological study was conducted on these tissues to ensure their structural integrity. Ventilatory alterations appeared 20-25 minutes after the injection of 0.9 LD50 VX and increased until the end of the recording, i.e., 40 minutes after intoxication. Concurrent with the occurrence of apnea, increased inspiratory and expiratory times resulted in a significant decrease in respiratory rate in exposed mice compared to controls. Ventilatory amplitude and, consequently, minute volume were reduced, while specific airway resistance significantly increased, indicating bronchoconstriction. These ventilatory effects persisted up to 24 or even 72 hours post-intoxication, resolving on the 7th day. They were correlated with a decrease in acetylcholinesterase activity in the diaphragm, which persisted for up to 72 hours, and with the triggering of an inflammatory reaction in the same tissue. No significant histologic lesions were observed in the examined tissues. The ventilatory alterations observed up to 72 hours post-VX exposure appear to result from a functional failure of the respiratory system rather than tissue damage. This comprehensive characterization contributes to a better understanding of the respiratory effects induced by VX exposure, which is crucial for developing specific medical countermeasures.

Ion channel dysregulation and cellular adaptations to alpha-synuclein in stressful pacemakers of the parkinsonian brainstem.

Parkinson's disease (PD) is diagnosed by its cardinal motor symptoms that are associated with the loss of dopamine neurons in the substantia nigra pars compacta (SNc). However, PD patients suffer from various non-motor symptoms years before diagnosis. These prodromal symptoms are thought to be associated with the appearance of Lewy body pathologies (LBP) in brainstem regions such as the dorsal motor nucleus of the vagus (DMV), the locus coeruleus (LC) and others. The neurons in these regions that are vulnerable to LBP are all slow autonomous pacemaker neurons that exhibit elevated oxidative stress due to their perpetual influx of Ca2+ ions. Aggregation of toxic α-Synuclein (aSyn) - the main constituent of LBP - during the long prodromal period challenges these vulnerable neurons, presumably altering their biophysics and physiology. In contrast to pathophysiology of late stage parkinsonism which is well-documented, little is known about the pathophysiology of the brainstem during prodromal PD. In this review, we discuss ion channel dysregulation associated with aSyn aggregation in brainstem pacemaker neurons and their cellular responses to them. While toxic aSyn elevates oxidative stress in SNc and LC pacemaker neurons and exacerbates their phenotype, DMV neurons mount an adaptive response that mitigates the oxidative stress. Ion channel dysregulation and cellular adaptations may be the drivers of the prodromal symptoms of PD. For example, selective targeting of toxic aSyn to DMV pacemakers, elevates the surface density of K+ channels, which slows their firing rate, resulting in reduced parasympathetic tone to the gastrointestinal tract, which resembles the prodromal PD symptoms of dysphagia and constipation. The divergent responses of SNc & LC vs. DMV pacemaker neurons may explain why the latter outlive the former despite presenting LBPs earlier. Elucidation the brainstem pathophysiology of prodromal PD could pave the way for physiological biomarkers, earlier diagnosis and novel neuroprotective therapies for PD.

The General Neurocognitive Decline in Patients with Methamphetamine Use and Transient Methamphetamine-induced Psychosis Primarily Determined by Oxidative and AGE-RAGE Stress.

BACKGROUND: Chronic Methamphetamine (MA) usage is linked to oxidative and AGE (advanced glycation end products) - RAGE (receptors for AGEs) stress, changes in magnesium, calcium, and copper, increased psychotic symptoms, and neurocognitive deficits. Nevertheless, it is still unclear whether these biological pathways mediate the latter impairments. OBJECTIVE: This study aimed to investigate the relationships between neurocognition, the aforementioned biomarkers, and psychotic symptoms. METHODS: We recruited 67 participants, namely 40 patients diagnosed with MA-substance use and 27 healthy controls, and assessed the Brief Assessment of Cognition in Schizophrenia (BACS), symptoms of psychosis, excitation, and formal thought disorders, oxidative toxicity (computed as the sum of myeloperoxidase (MPO), oxidized high-density lipoprotein (HDL), oxidized low-DL (malondialdehyde), antioxidant defenses (catalase, glutathione peroxidase, total antioxidant capacity, zinc, and HDL), and increased AGEs and RAGEs. RESULTS: We were able to extract one validated latent vector from the Mini-Mental State Examination score and the BACS test results (including executive functions, verbal fluency, and attention), labeled general cognitive decline (G-CoDe). We found that 76.1% of the variance in the G-CoDe was explained by increased oxidative toxicity, lowered antioxidant defenses, number of psychotic episodes, and MA dose. In patients with MA use, MPO was significantly associated with the GCoDe. CONCLUSION: The use of MA induced mild cognitive impairments through MA-induced activation of detrimental outcome pathways, including oxidative and AGE-RAGE stress, and suppression of protective antioxidant pathways. Increased MPO, oxidative, and AGE-RAGE stress are new drug targets to prevent neurocognitive deficits and psychosis due to MA use.

Association of spontaneous coronary artery dissection and takotsubo syndrome: What has been suspected has been found.

There is ample literature revealing an association of SCAD with TTS, while it is not clear whether these 2 pathological entities are mechanistically linked in the sense that the one triggers the other. Considering that physical/emotional stress triggers TTS, it is plausible that stress related to SCAD, could result in the emergence of TTS. Conversely, it has been speculated that the junction between hypercontractile and akinetic/dyskinetic myocardium regions in TTS could lead to a "hinge pivoting point", imparting vascular disruption in coronary arteries, crossing these abutting myocardial planes, in susceptible individuals, causing SCAD.

GBA1-Associated Parkinson's Disease Is a Distinct Entity.

GBA1-associated Parkinson's disease (GBA1-PD) is increasingly recognized as a distinct entity within the spectrum of parkinsonian disorders. This review explores the unique pathophysiological features, clinical progression, and genetic underpinnings that differentiate GBA1-PD from idiopathic Parkinson's disease (iPD). GBA1-PD typically presents with earlier onset and more rapid progression, with a poor response to standard PD medications. It is marked by pronounced cognitive impairment and a higher burden of non-motor symptoms compared to iPD. Additionally, patients with GBA1-PD often exhibit a broader distribution of Lewy bodies within the brain, accentuating neurodegenerative processes. The pathogenesis of GBA1-PD is closely associated with mutations in the GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase). In this review, we discuss two mechanisms by which GBA1 mutations contribute to disease development: 'haploinsufficiency,' where a single functional gene copy fails to produce a sufficient amount of GCase, and 'gain of function,' where the mutated GCase acquires harmful properties that directly impact cellular mechanisms for alpha-synuclein degradation, leading to alpha-synuclein aggregation and neuronal cell damage. Continued research is advancing our understanding of how these mechanisms contribute to the development and progression of GBA1-PD, with the 'gain of function' mechanism appearing to be the most plausible. This review also explores the implications of GBA1 mutations for therapeutic strategies, highlighting the need for early diagnosis and targeted interventions. Currently, small molecular chaperones have shown the most promising clinical results compared to other agents. This synthesis of clinical, pathological, and molecular aspects underscores the assertion that GBA1-PD is a distinct clinical and pathobiological PD phenotype, necessitating specific management and research approaches to better understand and treat this debilitating condition.

Genetic and Epigenetic Biomarkers Linking Alzheimer's Disease and Age-Related Macular Degeneration.

Alzheimer's disease (AD) represents a prominent neurodegenerative disorder (NDD), accounting for the majority of dementia cases worldwide. In addition to memory deficits, individuals with AD also experience alterations in the visual system. As the retina is an extension of the central nervous system (CNS), the loss in retinal ganglion cells manifests clinically as decreased visual acuity, narrowed visual field, and reduced contrast sensitivity. Among the extensively studied retinal disorders, age-related macular degeneration (AMD) shares numerous aging processes and risk factors with NDDs such as cognitive impairment that occurs in AD. Histopathological investigations have revealed similarities in pathological deposits found in the retina and brain of patients with AD and AMD. Cellular aging processes demonstrate similar associations with organelles and signaling pathways in retinal and brain tissues. Despite these similarities, there are distinct genetic backgrounds underlying these diseases. This review comprehensively explores the genetic similarities and differences between AMD and AD. The purpose of this review is to discuss the parallels and differences between AMD and AD in terms of pathophysiology, genetics, and epigenetics.

Past, Present, and Future of Surgical Treatment of Anomalous Left Coronary Artery from the Pulmonary Artery.

In recent years, with advancements in surgical techniques and the widespread utilization of extracorporeal cardiac assist devices such as extracorporeal membrane oxygenation (ECMO), the treatment outcomes for ALCAPA (Anomalous left coronary artery from the pulmonary artery) have demonstrated significant improvements. However, the surgical indications and methods of ALCAPA, especially the surgical methods of ALCAPA with intramural coronary artery, and whether to treat MR at the same time are still controversial. The long-term prognosis remain discouraging simultaneously, with significant variations in outcomes across different centers. The present review specifically addresses these aforementioned concerns. This article reviews the pathophysiology and classification, diagnosis, indications, surgical strategy and prognosis of ALCAPA. We believe that this review will provide some reference for future researchers and provide new ideas for reducing the adverse prognosis of children with congenital heart disease in future.

CSF proteomic profiles of neurodegeneration biomarkers in Alzheimer's disease.

INTRODUCTION: We aimed to unravel the underlying pathophysiology of the neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics. METHODS: Individuals without dementia were classified as A+ (CSF amyloid beta [Aß]42), T+ (CSF phosphorylated tau181), and N+ or N- based on Ng, NfL, or HCV separately. CSF proteomics were generated and compared between groups using analysis of covariance. RESULTS: Only a few individuals were A+T+Ng-. A+T+Ng+ and A+T+NfL+ showed different proteomic profiles compared to A+T+Ng- and A+T+NfL-, respectively. Both Ng+ and NfL+ were associated with neuroplasticity, though in opposite directions. Compared to A+T+HCV-, A+T+HCV+ showed few proteomic changes, associated with oxidative stress. DISCUSSION: Different N markers are associated with distinct neurodegenerative processes and should not be equated. N markers may differentially complement disease staging beyond amyloid and tau. Our findings suggest that Ng may not be an optimal N marker, given its low incongruency with tau pathophysiology. HIGHLIGHTS: In Alzheimer's disease, neurogranin (Ng)+, neurofilament light (NfL)+, and hippocampal volume (HCV)+ showed differential protein expression in cerebrospinal fluid. Ng+ and NfL+ were associated with neuroplasticity, although in opposite directions. HCV+ showed few proteomic changes, related to oxidative stress. Neurodegeneration (N) markers may differentially refine disease staging beyond amyloid and tau. Ng might not be an optimal N marker, as it relates more closely to tau.

RNA-binding proteins in bone pathophysiology.

Bone remodelling is a highly regulated process that maintains mineral homeostasis and preserves bone integrity. During this process, intricate communication among all bone cells is required. Indeed, adapt to changing functional situations in the bone, the resorption activity of osteoclasts is tightly balanced with the bone formation activity of osteoblasts. Recent studies have reported that RNA Binding Proteins (RBPs) are involved in bone cell activity regulation. RBPs are critical effectors of gene expression and essential regulators of cell fate decision, due to their ability to bind and regulate the activity of cellular RNAs. Thus, a better understanding of these regulation mechanisms at molecular and cellular levels could generate new knowledge on the pathophysiologic conditions of bone. In this Review, we provide an overview of the basic properties and functions of selected RBPs, focusing on their physiological and pathological roles in the bone.

USP7 upregulated by TGF-ß1 promotes ferroptosis via inhibiting LATS1-YAP axis in sepsis-induced acute lung injury.

Our work aimed to investigate the interactive roles of transforming growth factor ß1 (TGF-ß1), ubiquitin-specific-processing protease 7 (USP7), and Yes-associated protein (YAP) in ferroptosis during sepsis-secondary acute lung injury (ALI). Our study demonstrated that ferroptosis was aggravated by TGF-ß1 in both cellular and animal models of acute lung injury. Additionally, YAP upregulated glutathione peroxidase 4 (GPX4) and SLC7A11 by regulating the binding of TEAD4 to GPX4/SLC7A11 promoters. Furthermore, large tumor suppressor kinase 1 (LATS1) knockdown resulted in YAP expression stimulation, while USP7 downregulated YAP via deubiquitinating and stabilizing LATS1/2. YAP overexpression or USP7/LATS1 silencing reduced ferroptosis process, which regulated YAP through a feedback loop. However, TGF-ß1 annulled the repression of ferroptosis by YAP overexpression or LATS1/USP7 knockdown. By elucidating the molecular interactions between TGF-ß1, USP7, LATS1/2, and YAP, we identified a new regulatory axis of ferroptosis in sepsis-secondary ALI. Our study sheds light on the pathophysiology of ferroptosis and proposes a potential therapeutic approach for sepsis-induced ALI.

"Inflamed" depression: A review of the interactions between depression and inflammation and current anti-inflammatory strategies for depression.

Depression is a common mental disorder, the effective treatment of which remains a challenging issue worldwide. The clinical pathogenesis of depression has been deeply explored, leading to the formulation of various pathogenic hypotheses. Among these, the monoamine neurotransmitter hypothesis holds a prominent position, yet it has significant limitations as more than one-third of patients do not respond to conventional treatments targeting monoamine transmission disturbances. Over the past few decades, a growing body of research has highlighted the link between inflammation and depression as a potential key factor in the pathophysiology of depression. In this review, we first summarize the relationship between inflammation and depression, with a focus on the pathophysiological changes mediated by inflammation in depression. The mechanisms linking inflammation to depression as well as multiple anti-inflammatory strategies are also discussed, and their efficacy and safety are assessed. This review broadens the perspective on specific aspects of using anti-inflammatory strategies for treating depression, laying the groundwork for advancing precision medicine for individuals suffering from "inflamed" depression.

Misconceptions about trigger finger: a scoping review. Definition, pathophysiology, site of lesion, etiology. Trigger finger solving a maze.

Trigger finger (TF) is a disorder characterized by snapping or locking a finger. It has a prevalence of greater than 3% in the general population; however, this estimate could be increased to 5% up to 20% in diabetic patients. Some unreal ambiguity about definition, pathophysiology, site of lesion, and etiology are found among researchers and clinicians, leading to a lack of understanding of all aspects of the disease and improper management as many clinicians proceed to anti-inflammatory medications or steroids injection without in-depth patient evaluation. Original articles cited up to 2022, found through a Google search using the specified keywords, have been used in this review. Close-access articles were accessed through our researcher account with the Egyptian Knowledge Bank. In this review, we will focus on pathophysiology to present all possible findings and etiology to represent all risk factors and associated diseases to assess and confirm a diagnosis and the exact location of pathology hence better treatment modalities and reducing the recurrence of the pathology.

Clinical and forensic aspects of potassium iodide: Suddenly in high demand across Europe due to fears of radiation poisoning from a nuclear attack in Ukraine.

Potassium iodide has demonstrated several therapeutic applications over time, being the choice for shielding the thyroid during radiation emergencies involving radioiodine release. Amidst the ongoing military conflict between Ukraine and Russia and the growing concern regarding the potential deployment of nuclear weapons, there has been a surge in the demand for potassium iodide across Europe. This work aimed to comprehensively review the current knowledge regarding the pharmacology, physiology, adverse effects, the protective role in reducing the risk of thyroid cancer and recommendations for potassium iodide use during radiation emergencies. Evidence on adverse effects is scarce, as potassium iodide is generally well-tolerated. Guidelines for thyroid blocking with potassium iodide during radiation emergencies suggest that, among populations vulnerable to radioiodine exposure, the benefits of potassium iodide outweigh the risks of adverse effects. Controversial topics surrounding the utilization of potassium iodide in radiation emergencies include the prophylaxis in iodine-deficient regions and following the detonation of dirty bombs, whether granule formulations versus tablets should be used and mental health concerns. Although the rise in demand seems to be a justified security measure, it is essential to recognize that potassium iodide protects the thyroid from radioiodine and does not impact the body's absorption of other radioactive materials or defend against external radiation exposure.

Participation of Arterial Ischemia in Positional-Related Symptoms among Patients Referred for Thoracic Outlet Syndrome.

Objectives: The coexistence of arterial compression with neurogenic thoracic outlet syndrome (TOS) is associated with a better post-surgical outcome. Forearm transcutaneous oxygen pressure (TcpO2) using the minimal decrease from rest of oxygen pressure (DROPmin) can provide an objective estimation of forearm ischemia in TOS. We hypothesized that a linear relationship exists between the prevalence of symptoms (PREVs) and DROPmin during 90° abduction external rotation (AER) provocative maneuvers. Thereafter, we aimed to estimate the proportion of TOS for which arterial participation is present. Methods: Starting in 2019, we simultaneously recorded forearm TcpO2 recordings (PF6000 Perimed®) and the presence/absence of ipsilateral symptoms during two consecutive 30 s AER maneuvers for all patients with suspected TOS. We retrospectively analyzed the relationship between the prevalence of symptoms and DROPmin results. We estimated the number of cases where ischemia likely played a role in the symptoms, assuming that the relationship should start from zero in the absence of ischemia and increase linearly to a plateau of 100% for the most severe ischemia. Results: We obtained 2560 TcpO2 results in 646 subjects (69% females). The correlation between PREVs and DROPmin was 0.443 (p < 0.001). From these results, we estimated the arterial participation in TOS symptoms to be 22.2% of our 1669 symptomatic upper limbs. Conclusions: TcpO2 appears to be an interesting tool to argue for an arterial role in symptoms in TOS. Arterial participation is frequent in TOS. Whether DROPmin could predict treatment outcomes better than the sole presence of compression is an interesting direction for the future.

Distinguishing pathophysiological features of heart failure with reduced and preserved ejection fraction: A comparative analysis of two mouse models.

Heart failure (HF) is a heterogeneous condition that can be categorized according to the left ventricular ejection fraction (EF) into HF with reduced (HFrEF) or preserved (HFpEF) EF. Although HFrEF and HFpEF share some common clinical manifestations, the mechanisms underlying each phenotype are often found to be distinct. Identifying shared and divergent pathophysiological features might expand our insights on HF pathophysiology and assist the search for therapies for each HF subtype. In this study, we evaluated and contrasted two new murine models of non-ischaemic HFrEF and cardiometabolic HFpEF in terms of myocardial structure, left ventricular function, gene expression, cardiomyocyte calcium handling, mitochondrial polarization and protein acetylation in a head-to-head fashion. We found that in conditions of similar haemodynamic stress, the HFrEF myocardium underwent a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation was greater in the HFpEF myocardium. We observed opposing features on calcium release, which was diminished in the HFrEF cardiomyocyte but enhanced in the HFpEF cardiomyocyte. Mitochondria were less polarized in both HFrEF and HFpEF cardiomyocytes, reflecting similarly impaired metabolic capacity. Hyperacetylation of cardiac proteins was observed in both models, but it was more accentuated in the HFpEF heart. Despite shared features, unique triggering mechanisms (neurohormonal overactivation in HFrEF vs. inflammation in HFpEF) appear to determine the distinct phenotypes of HF. The findings of the present research stress the need for further exploration of the differential mechanisms underlying each HF subtype, because they might require specific therapeutic interventions. KEY POINTS: The mechanisms underlying heart failure with either reduced (HFrEF) or preserved (HFpEF) ejection fraction are often found to be different. Previous studies comparing pathophysiological traits between HFrEF and HFpEF have been conducted on animals of different ages and strains. The present research contrasted two age-matched mouse models of non-ischaemic HFrEF and cardiometabolic HFpEF to uncover divergent and shared features. We found that upon similar haemodynamic stress, the HFrEF heart experienced a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation appeared to be greater in the HFpEF myocardium. Calcium release was diminished in the HFrEF cardiomyocyte and enhanced in the HFpEF cardiomyocyte. Mitochondria were comparably less polarized in both HFrEF and HFpEF myocytes. Hyperacetylation of proteins was common to both models, but stronger in the HFpEF heart. Casting light on common and distinguishing features might ease the quest for phenotype-specific therapies for heart failure patients.

Circulating biomarkers of kidney angiomyolipoma and cysts in tuberous sclerosis complex patients.

Patients with tuberous sclerosis complex (TSC) develop multi-organ disease manifestations, with kidney angiomyolipomas (AML) and cysts being one of the most common and deadly. Early and regular AML/cyst detection and monitoring are vital to lower TSC patient morbidity and mortality. However, the current standard of care involves imaging-based methods that are not designed for rapid screening, posing challenges for early detection. To identify potential diagnostic screening biomarkers of AML/cysts, we performed global untargeted metabolomics in blood samples from 283 kidney AML/cyst-positive or -negative TSC patients using mass spectrometry. We identified 7 highly sensitive chemical features, including octanoic acid, that predict kidney AML/cysts in TSC patients. Patients with elevated octanoic acid have lower levels of very long-chain fatty acids (VLCFAs), suggesting that dysregulated peroxisome activity leads to overproduction of octanoic acid via VLCFA oxidation. These data highlight AML/cysts blood biomarkers for TSC patients and offers valuable metabolic insights into the disease.

Cannabidiol in experimental cerebral ischemia.

The absence of blood flow in cerebral ischemic conditions triggers a multitude of intricate pathophysiological mechanisms, including excitotoxicity, oxidative stress, neuroinflammation, disruption of the blood-brain barrier and white matter disarrangement. Despite numerous experimental studies conducted in preclinical settings, existing treatments for cerebral ischemia (CI), such as mechanical and pharmacological therapies, remain constrained and often entail significant side effects. Therefore, there is an imperative to explore innovative strategies for addressing CI outcomes. Cannabidiol (CBD), the most abundant non-psychotomimetic compound derived from Cannabis sativa, is a pleiotropic substance that interacts with diverse molecular targets and has the potential to influence various pathophysiological processes, thereby contributing to enhanced outcomes in CI. This chapter provides a comprehensive overview of the primary effects of CBD in in vitro and diverse animal models of CI and delves into some of its plausible mechanisms of neuroprotection.