Pathophysiological Effects Research Articles

Melatonin's Impact on Cytokine Storm and Modulation of Purinergic Receptors for COVID-19 Prognosis: A Mental Health Perspective.

In 2019, coronavirus disease 2019 (COVID-19) started a global health crisis and was associated with high rates of depression and anxiety. Both mental disorders and COVID-19 exhibit similarities in pathophysiology, characterized by immune system overactivation, involvement of the purinergic system, and oxidative stress, besides additional factors and systems likely contributing to the complexities of these conditions. The purinergic system contributes to the disease-influenced immune response, an essential strategy for controlling pathophysiological effects. In this context, the hormone melatonin emerges as a substance that can modulate the purinergic system and contribute positively to the pathophysiology of SARS-CoV-2 infection and associated mental disorders. Melatonin is a hormone that regulates the body's circadian rhythms, plays an essential role in regulating sleep and mood, and modulates the purinergic system. Recent studies suggest melatonin's anti-inflammatory and antioxidant properties may benefit COVID-19. This review explores melatonin's impact on inflammatory cytokine storm in COVID-19 through purinergic system modulation.

Redefining Calciphylaxis as a Uniquely Bone Forming Subcutaneous C5b-9-Mediated Microvascular Injury Syndrome Associated With Localized Subcutaneous and Systemic Complement Pathway Activation.

Microvascular thrombosis is key to the pathogenesis of calciphylaxis. C5b-9-mediated microvascular injury reflective of complement pathway activation could be a key pathophysiologic event. We conducted a retrospective multicenter study of 24 patients who have had biopsy-supported calciphylaxis from the 2010-2022 data base from Emory where C5b-9 immunohistochemistry (IHC) had not been conducted and the 2019-2023 data base from Cornell where C5b-9 IHC was done as part of the routine calciphylaxis work up. IHC for C5b-9 on lesional biopsy specimens was assessed and correlated with routine light microscopic findings and clinical features. Most of the patients in our study had uremic calciphylaxis associated with obesity, diabetes, dialysis, hypertension, hyperparathyroidism and elevated serum phosphorus. Most patients did not have defined procoagulant and/or hyperviscosity states. The vascular pathology was predominantly limited to the subcutaneous fat and ranged from a calcific intimal arteriopathy to microvascular thrombosis with endothelial injury with or without endothelial calcification. In most cases (ie, in excess of 80%), there was prominent deposition of C5b-9 within the vasculature including the microvasculature and arteries of the fat at least localized to injured vessels suggesting a causal association. In about 40% of cases, there was evidence of systemic complement pathway activation revealed by concurrent dermal microvascular C5b-9 deposition. Calciphylaxis is characterized by subcuticular vascular changes that reflect an interplay between complement triggered endothelial cell injury, resultant vascular thrombosis, and subsequent abluminal calcification. Complement inhibition therapy defines a potential intervention that should be explored.

Biological effects of Maillard reaction products: use of Caenorhabditis elegans as an in vivo model.

Maillard reaction products (MRPs), including melanoidins and volatile odor compounds, are associated with distinct flavors and colors during food processing and cooking. Although MRPs have health benefits, such as antioxidant activity, they are also associated with pathophysiological effects. Several in vivo models, especially rodents, are used to demonstrate physiological effects. Caenorhabditis elegans (C. elegans), an easy to rear free-living nematode with a short lifespan, has been used as a promising in vivo organism for the evaluation of functional properties in food components, including anti-aging, antioxidant, and anti-obesity properties. Furthermore, the high olfactory discrimination of this organism allows for the basic elucidation of behavior and regulation of aging. In this Minireview, I discuss the various attributes of C. elegans that make it a promising in vivo model for studying the biological effects of MRPs.

Heart Failure: A Deficiency of Energy-A Path Yet to Discover and Walk.

Heart failure is a complex syndrome and our understanding and therapeutic approach relies mostly on its phenotypic presentation. Notably, the heart is characterized as the most energy-consuming organ, being both a producer and consumer, in order to satisfy multiple cardiac functions: ion exchange, electromechanical coordination, excitation-contraction coupling, etc. By obtaining further knowledge of the cardiac energy field, we can probably better characterize the basic pathophysiological events occurring in heart disease patients and understand the metabolic substance changes, the relationship between the alteration of energy production/consumption, and hence energetic deficiency not only in the heart as a whole but in every single cardiac territory, which will hopefully provide us with the opportunity to uncover the beginning of the heart failure process. In this respect, using (a) newer imaging techniques, (b) biomedicine, (c) nanotechnology, and (d) artificial intelligence, we can gain a deeper understanding of this complex syndrome. This, in turn, can lead to earlier and more effective therapeutic approaches, ultimately improving human health. To date, the scientific community has not given sufficient attention to the energetic starvation model. In our view, this review aims to encourage scientists and the medical community to conduct studies for a better understanding and treatment of this syndrome.

Intercellular junction-driven stromal cell stacking in a confined 3D microcavity.

Understanding the detailed mechanisms driving fibroblast migration within native tissue settings during pathophysiological events presents a critical research challenge. In this study, we elucidate how stromal cells migrate and contribute to the development of three-dimensional (3D) cellular aggregates within confined microcavities. Integrin α5β1 and β-catenin (β-cat) are central in guiding this collective migration and achieving optimal filling of the microcavity. When β-cat is suppressed, cells tend to migrate more sporadically, leading to less efficient cellular organization. Furthermore, we also detail the pivotal roles of Cx43 and N-cadherin (N-cad) in orchestrating collective migration and in shaping efficient cellular stacking. Suppressing gap junctions, especially Cx43, significantly impacts the extracellular matrix expression, integrin α5 and β1, and other elements in the 3D construct, emphasizing the importance of physicochemical cell-cell interactions. The distribution patterns of N-cad and focal adhesion kinase (FAK) further corroborate the essential roles in forming cell-cell junctions and FAK in establishing the foundational layer that underpins the cell stacking within the microcavity. Interestingly, neither Rho-associated protein kinase (ROCK) nor RhoA significantly alter the cell migration pattern toward microcavity. These findings provide fresh perspectives on fibroblast activities in 3D space, enriching our understanding and offering implications for advancements in wound healing and tissue engineering.

Adverse Effects of Aβ1-42 Oligomers: Impaired Contextual Memory and Altered Intrinsic Properties of CA1 Pyramidal Neurons.

Aβ1-42 (amyloid beta) oligomers, the major neurotoxic culprits in Alzheimer's disease, initiate early pathophysiological events, including neuronal hyperactivity, that underlie aberrant network activity and cognitive impairment. Although several synaptotoxic effects have been extensively studied, neuronal hyperexcitability, which may also contribute to cognitive deficits, is not fully understood. Here, we found several adverse effects of in vivo injection of Aβ1-42 oligomers on contextual memory and intrinsic properties of CA1 pyramidal neurons. Male rats underwent behavioral and electrophysiological studies 1 week after microinjections into the dorsal CA1 region, followed by histological analysis. After 1 week, Aβ1-42 oligomers impaired contextual learning without affecting basic physiological functions and triggered training-induced neuronal excitability. Furthermore, riluzole, a persistent sodium current (INaP) blocker, dose-dependently reduced Aβ1-42 oligomer-induced hyperexcitability. Congo red staining, which detects insoluble amyloid deposits, further identified labeling of CA1 pyramidal neurons while immunohistochemistry with lecanemab, which detects soluble Aβ oligomers, revealed immunoreactivity of both pyramidal and non-pyramidal cells in the target area. Therefore, our study suggests that a single injection of Aβ1-42 oligomers resulted in contextual memory deficits along with concomitant neuronal hyperexcitability and amyloid deposition in the CA1 region after 1 week.

Healthcare Provider Burnout: Red Flag for a Rising Epidemic.

This article aims to broaden the understanding of burnout in healthcare providers, its causes, and its reduction strategies. The objectives are to raise awareness, facilitate early intervention, and, ultimately, improve the overall well-being of healthcare providers and the quality of patient care. The study investigated healthcare-provision-associated burnout, an often-unrecognized syndrome affecting professionals worldwide, and its prevalence. It also examined the impact of burnout on patient outcomes, safety, and provider health and well-being. Here, we delve into the triad of burnout attributes: emotional exhaustion, depersonalization, and decreased personal accomplishment. Specific causes, such as work-life balance, workplace environment, and communication/teamwork, are investigated. The existing literature and studies we report explore the pathophysiological effects of burnout, including its impact on health, sleep patterns, and the alarming correlation with suicide. The prevalence of burnout among healthcare providers is between 30% and 50%. Burnout is a significant factor contributing to poor patient outcomes and threatening patient safety. Furthermore, burnout can induce physical symptoms, including psychological, cardiovascular, and gastrointestinal disorders. We emphasize the importance of identifying and preventing burnout to maintain the overall integrity of healthcare providers and eliminate vulnerabilities for harm to their patients. Burnout awareness should be a priority from the early stages of healthcare providers' careers because it is crucial for maintaining their well-being, preventing medical errors, and sustaining high-quality patient care. The identification and prevention of burnout are deemed vital not only for the well-being of healthcare providers but also to safeguard against potential harm to patients. This article calls for increased awareness of burnout, its underlying causes, and the implementation of effective reduction strategies in the healthcare profession.

Liposomes and Their Therapeutic Applications in Enhancing Psoriasis and Breast Cancer Treatments.

Psoriasis and breast cancer are two examples of diseases where associated inflammatory pathways within the body's immune system are implicated. Psoriasis is a complex, chronic and incurable inflammatory skin disorder that is primarily recognized by thick, scaly plaques on the skin. The most noticeable pathophysiological effect of psoriasis is the abnormal proliferation of keratinocytes. Breast cancer is currently the most diagnosed cancer and the leading cause of cancer-related death among women globally. While treatments targeting the primary tumor have significantly improved, preventing metastasis with systemic treatments is less effective. Nanocarriers such as liposomes and lipid nanoparticles have emerged as promising drug delivery systems for drug targeting and specificity. Advances in technologies and drug combinations have emerged to develop more efficient lipid nanocarriers to include more than one drug in combinational therapy to enhance treatment outcomes and/or relief symptoms for better patients' quality of life. Although there are FDA-approved liposomes with anti-cancer drugs for breast cancer, there are still unmet clinical needs to reduce the side effects associated with those nanomedicines. Hence, combinational nano-therapy may eliminate some of the issues and challenges. Furthermore, there are no nanomedicines yet clinically available for psoriasis. Hence, this review will focus on liposomes encapsulated single and/or combinational therapy to augment treatment outcomes with an emphasis on the effectiveness of combinational therapy within liposomal-based nanoparticulate drug delivery systems to tackle psoriasis and breast cancer. This review will also include an overview of both diseases, challenges in delivering drug therapy and the roles of nanomedicines as well as psoriasis and breast cancer models used for testing therapeutic interventions to pave the way for effective in vivo testing prior to the clinical trials.

Artificial gravity: an effective countermeasure for microgravity-induced headward fluid shift?

Long-duration spaceflight is associated with pathophysiological changes in the intracranial compartment hypothetically linked to microgravity-induced headward fluid shift. This study aimed to determine whether daily artificial gravity (AG) sessions can mitigate these effects, supporting its application as a countermeasure to spaceflight. Twenty-four healthy adult volunteers (16 men) were exposed to 60 days of 6° head-down tilt bed rest (HDTBR) as a ground-based analog of chronic headward fluid shift. Subjects were divided equally into three groups: no AG (control), daily 30-min intermittent AG (iAG), and daily 30-min continuous (cAG). Internal carotid artery (ICA) stroke volume (ICASV), ICA resistive index (ICARI), ICA flow rate (ICAFR), aqueductal cerebral spinal fluid flow velocity (CSFV), and intracranial volumetrics were quantified at 3 T. MRI was performed at baseline, 14 and 52 days into HDTBR, and 3 days after HDTBR (recovery). A mixed model approach was used with intervention and time as the fixed effect factors and the subject as the random effect factor. Compared with baseline, HDTBR was characterized by expansion of lateral ventricular, white matter, gray matter, and brain + total intracranial cerebral spinal fluid volumes, increased CSFv, decreased ICASV, and decreased ICAFR by 52 days into HBTBR (All Ps < 0.05). ICARI was only increased 14 days into HDTBR (P < 0.05). Neither iAG nor cAG significantly affected measurements compared with HDTBR alone, indicating that 30 min of daily exposure was insufficient to mitigate the intracranial effects of headward fluid shift. Greater AG session exposure time, gravitational force, or both are suggested for future countermeasure research.NEW & NOTEWORTHY Brief exposure to continuous or intermittent artificial gravity via short-arm centrifugation was insufficient in mitigating the intracranial pathophysiological effects of the headward fluid shift simulated during head-down tilt bed rest (HDTBR). Our results suggest that greater centrifugation session duration, gravitational force, or both may be required to prevent the development of spaceflight-associated neuro-ocular syndrome and should be considered in future ground-based countermeasure studies.

Simulated ischaemia/reperfusion impairs trophoblast function through divergent oxidative stress- and MMP-9-dependent mechanisms.

Early-onset pre-eclampsia is believed to arise from defective placentation in the 1st trimester, leading to placental ischaemia/reperfusion (I/R) and oxidative stress. However, our current understanding of the effects of I/R and oxidative stress on trophoblast function is ambiguous in part due to studies exposing trophoblasts to hypoxia instead of I/R, and which report conflicting results. Here we present a model of simulated ischaemia/reperfusion (SI/R) to recapitulate the pathophysiological events of early-onset PE, by exposing 1st trimester cytotrophoblast HTR-8/SVneo cells to a simulated ischaemia buffer followed by reperfusion. We examined different ischaemia and reperfusion times and observed that 1h ischaemia and 24h reperfusion induced an increase in reactive oxygen species (ROS) production (p < 0.0001) and oxygen consumption rate (p < 0.01). SI/R-exposed trophoblast cells exhibited deficits in migration, proliferation and invasion (p < 0.01). While the deficits in migration and proliferation were rescued by antioxidants, suggesting a ROS-dependent mechanism, the loss of invasion was not affected by antioxidants, which suggests a divergent ROS-independent pathway. In line with this, we observed a decrease in MMP-9, the key regulatory enzyme necessary for trophoblast invasion (p < 0.01), which was similarly unaffected by antioxidants, and pharmacological inhibition of MMP-9 replicated the phenotype of deficient invasion (p < 0.01). Collectively, these data demonstrate that I/R impairs trophoblast migration and proliferation via a ROS-dependent mechanism, and invasion via a ROS-independent loss of MMP-9, disambiguating the role of oxidative stress and providing insights into the response of trophoblasts to I/R in the context of early-onset PE.

Molecular Pathophysiology of Parathyroid Tumorigenesis-The Lesson from a Rare Disease: The "MEN1 Model".

Primary hyperparathyroidism represents the third most prevalent endocrine disease in the general population, consisting of an excessive secretion of parathyroid hormone from one or, more frequently, more of the parathyroid glands, leading to a dysregulation of calcium homeostasis. Schematically, its development occurs primarily by pathophysiological events with genetic mutation, at the germline and/or somatic level, that favor the neoplastic transformation of parathyroid cells and promote their aberrant proliferation, and mutations determining the shift in the PTH "set-point", thus interfering with the normal pathways of PTH secretion and leading to a "resetting" of Ca2+-dependent PTH secretion or to a secretion of PTH insensitive to changes in extracellular Ca2+ levels. Familial syndromic and non-syndromic forms of primary hyperparathyroidism are responsible for approximately 2-5% of primary hyperparathyroidism cases and most of them are inherited forms. The history of the genetic/molecular studies of parathyroid tumorigenesis associated with multiple endocrine neoplasia type 1 syndrome (MEN1) represents an interesting model to understand genetic-epigenetic-molecular aspects underlying the pathophysiology of primary hyperparathyroidism, both in relation to syndromic and non-syndromic forms. This minireview aims to take a quick and simplified look at the MEN1-associated parathyroid tumorigenesis, focusing on the molecular underlying mechanisms. Clinical, epidemiological, and observational studies, as well as specific guidelines, molecular genetics studies, and reviews, have been considered. Only studies submitted to PubMed in the English language were included, without time constraints.

Integrating observational and modelled data to advance the understanding of heat stress effects on pregnant subsistence farmers in the gambia

Studies on the effect of heat stress on pregnant women are scarce, particularly in highly vulnerable populations. To support the risk assessment of pregnant subsistence farmers in the West Kiang district, The Gambia we conducted a study on the pathophysiological effects of extreme heat stress and assessed the applicability of heat stress indices. From ERA5 climate reanalysis we added location-specific modelled solar radiation to datasets of a previous observational cohort study involving on-site measurements of 92 women working in the heat. Associations between physiological and environmental variables were assessed through Pearson correlation coefficient analysis, mixed effect linear models with random intercepts per participant and confirmatory composite analysis. We found Pearson correlations between r-values of 0 and 0.54, as well as independent effects of environmental variables on skin- and tympanic temperature, but not on heart rate, within a confidence interval of 98%. Pregnant women experienced stronger pathophysiological effects from heat stress in their third rather than in their second trimester. Environmental heat stress significantly altered maternal heat strain, particularly under humid conditions above a 50% relative humidity threshold, demonstrating interactive effects. Based on our results, we recommend including heat stress indices (e.g. UTCI or WBGT) in local heat-health warning systems.

Breaking muscle: neurotoxic and myotoxic effects of Central American snake venoms and the relative efficacies of antivenom and varespladib

BackgroundThe snake genera Atropoides, Cerrophidion, and Metlapilcoatlus form a clade of neotropical pit vipers distributed across Mexico and Central America. This study evaluated the myotoxic and neurotoxic effects of nine species of Atropoides, Cerrophidion, and Metlapilcoatlus, and the neutralising efficacy of the ICP antivenom from Costa Rica against these effects, in the chick biventer cervicis nerve-muscle preparation. Given the prominence of PLA2s within the venom proteomes of these species, we also aimed to determine the neutralising potency of the PLA2 inhibitor, varespladib.ResultsAll venoms showed myotoxic and potential neurotoxic effects, with differential intra-genera and inter-genera potency. This variation was also seen in the antivenom ability to neutralise the muscle damaging pathophysiological effects observed. Variation was also seen in the relative response to the PLA2 inhibitor varespladib. While the myotoxic effects of M. mexicanus and M. nummifer venoms were effectively neutralised by varespladib, indicating myotoxicity is PLA2 mediated, those of C. godmani and M. olmec venoms were not, revealing that the myotoxicity is driven by non-PLA2 toxin types.ConclusionsThis study characterises the myotoxic and neurotoxic venom activity, as well as neutralisation of venom effects from the Atropoides, Cerrophidion, and Metlapilcoatlus clade of American crotalids. Our findings contribute significant clinical and evolutionary knowledge to a clade of poorly researched snakes. In addition, these results provide a platform for future research into the reciprocal interaction between ecological niche specialisation and venom evolution, as well as highlighting the need to test purified toxins to accurately evaluate the potential effects observed in these venoms.

Comparison of Oliceridine to Remifentanil for Optimal Analgesia in Mechanical Ventilation (CO-ROAM): Study Protocol for a Multicenter Randomized Controlled Trial.

Critically ill patients often endure pain, a distressing experience that can trigger diverse pathophysiological consequences. While remifentanil, with its rapid kinetics, is commonly used for analgesia in intensive care units (ICU), it frequently leads to opioid-related adverse effects. A promising alternative has emerged in oliceridine, a novel G protein-biased μ-opioid receptor agonist. This new drug offers the potential for effective pain relief with fewer side effects. However, its efficacy and safety profile in mechanically ventilated ICU patients remain to be fully elucidated. This is a multicenter, prospective, randomized, single-blind, active-controlled trial conducted across 24 ICUs in China. A total of 292 mechanically ventilated patients requiring analgesia and sedation will be randomly assigned in a 1:1 ratio to either the oliceridine or remifentanil group. The oliceridine group will receive oliceridine (2-20μg/kg/h), while the remifentanil group will receive remifentanil (1.5-12μg/kg/h). Both groups will receive propofol for sedation if necessary. The target for analgesia is Critical-Care Pain Observation Tool (CPOT)<3, and for sedation is Richmond Agitation-Sedation Scale (RASS) -2 to 0. The primary outcome will be the percentage of time within target analgesia during study drug administration. Secondary outcomes will include gastrointestinal dysfunction, respiratory depression, sedative usage, mechanical ventilation duration, ICU stay length, extubation failure rate, etc. TRIAL REGISTRATION: NCT06454292. Registered on June 11, 2024.

The IL-4-IL-4Rα axis modulates olfactory neuroimmune signaling to induce loss of smell.

IL-4 and IL-13 have non-redundant effects in olfaction, with loss of smell in mice evoked only by intranasal administration of IL-4, but not IL-13. IL-4-evoked pathophysiological effects on olfaction is independent of compromised structural integrity of the olfactory neuroepithelium. IL-4-IL-4Rα signaling modulates neuronal crosstalk with immune cells, suggesting a functional link between olfactory impairment and neuroinflammation. Abbreviations: IL, interleukin; KO, knock-out; wk, week; WT, wild-type.

Impaired Endothelium-Dependent Vasodilation and Increased Levels of Soluble Fms-like Tyrosine Kinase-1 Induced by Reduced Uterine Perfusion Pressure in Pregnant Rats: Evidence of Protective Effects with Sodium Nitrite Treatment in Preeclampsia.

Preeclampsia (PE) is a hypertensive disorder of pregnancy and is associated with increases in soluble fms-like tyrosine kinase-1 (sFlt-1) and reductions in nitric oxide (NO) levels. Placental ischemia and hypoxia are hypothesized as initial pathophysiological events of PE. Nitrite (NO metabolite) may be recycled back to NO in ischemic and hypoxic tissues. Therefore, this study examined the sodium nitrite effects in an experimental model of PE. Pregnant rats received saline (Preg group) or sodium nitrite (Preg + Na-Nitrite group). Pregnant rats submitted to the placental ischemia received saline (RUPP group) or sodium nitrite (RUPP + Na-Nitrite group). Blood pressure, placental and fetal weights, and the number of pups were recorded. Plasma levels of NO metabolites and sFlt-1 were also determined. Vascular and endothelial functions were also measured. Blood pressure, placental and fetal weights, the number of pups, NO metabolites, sFlt-1 levels, vascular contraction, and endothelium-dependent vasodilation in the RUPP + Na-Nitrite rats were brought to levels comparable to those in Preg rats. In conclusion, sodium nitrite may counteract the reductions in NO and increases in sFlt-1 levels induced by the placental ischemia model of PE, thus suggesting that increased blood pressure and vascular and endothelial dysfunctions may be attenuated by sodium nitrite-derived NO.

Heavy metal contamination of the Nigerian environment from e-waste management: A systematic review of exposure pathway and attendant pathophysiological implications

Nigerian environment has become a depository of worrisome levels of toxicants including heavy metals. Electrical and electronic equipment which leads to the generation of e-waste is one of the considerable sources of environmental contaminants in Nigeria. This systematic review deployed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) method to analyze various empirical and quantitative outputs on heavy metal components of e-waste management sites in Nigeria and investigated the distribution of heavy metals in several environmental matrices such as soil, water, surface dust, plant and blood of e-waste scavengers. Also, the probable environmental multi-transformation that ultimately potentiates the susceptibility of humans to the pathophysiological effects and genetic related disorders of exposure to heavy metal component of e-waste was discussed. The relative abundance of metals in soils due to inappropriate e-waste handling is given as follow: Fe>Cu>Pb>Zn>Mn>Co>Cr>Ni>As>Cd, in underground and surface water: Zn>Fe>Cu>Cr>Mn>Pb>Hg>Ni>Co>Cd>As; in surface dusts: Fe>Zn>Pb>Cu>Mn>Cr>Ni>Cd>Co; in plants: Pb>Cu>Mn>Zn>Ni>Cr>Cd obtained from the Nigerian environment. Moreso, the estimated abundance of heavy metals in the blood of e-waste scavengers is Nigeria is given as Cr>Cd>Hg>Zn>As>Pb>Cu>Mn>Fe. Conclusively, this study does not only show that various matrices of Nigerian environment is contaminated with heavy metal but also that the pattern of abundance differ in the environment and in biological systems with the latter having the abundance of Pb, Cr and Cd and the former having the abundance of Cu, Zn and Fe.

From Venom to Vein: Factor VII Activation as a Major Pathophysiological Target for Procoagulant Australian Elapid Snake Venoms.

Australian elapid snake venoms are uniquely procoagulant, utilizing blood clotting enzyme Factor Xa (FXa) as a toxin, which evolved as a basal trait in this clade. The subsequent recruitment of Factor Va (FVa) as a toxin occurred in the last common ancestor of taipans (Oxyuranus species) and brown snakes (Pseudonaja species). Factor II (prothrombin) activation has been stated as the primary mechanism for the lethal coagulopathy, but this hypothesis has never been tested. The additional activation of Factor VII (FVII) by Oxyuranus/Pseudonaja venoms has historically been considered as a minor, unimportant novelty. This study aimed to investigate the significance of toxic FVII activation relative to prothrombin activation by testing a wide taxonomical range of Australian elapid species with procoagulant venoms. The activation of FVII or prothrombin, with and without the Factor Va as a cofactor, was assessed, along with the structural changes involved in these processes. All procoagulant species could activate FVII, establishing this as a basal trait. In contrast, only some lineages could activate prothrombin, indicating that this is a derived trait. For species able to activate both zymogens, Factor VII was consistently more strongly activated than prothrombin. FVa was revealed as an essential cofactor for FVII activation, a mechanism previously undocumented. Species lacking FVa in their venom utilized endogenous plasma FVa to exert this activity. The ability of the human FXa:FVa complex to activate FVII was also revealed as a new feedback loop in the endogenous clotting cascade. Toxin sequence analyses identified structural changes essential for the derived trait of prothrombin activation. This study presents a paradigm shift in understanding how elapid venoms activate coagulation factors, highlighting the critical role of FVII activation in the pathophysiological effects upon the coagulation cascade produced by Australian elapid snake venoms. It also documented the novel use of Factor Va as a cofactor for FVII activation for both venom and endogenous forms of FXa. These findings are crucial for developing better antivenoms and treatments for snakebite victims and have broader implications for drug design and the treatment of coagulation disorders. The research also advances the evolutionary biology knowledge of snake venoms.

7206 Perioperative Management of Pheochromocytoma: The Mayo Clinic Florida Experience

Abstract Disclosure: A. Verma: None. F. Elli: None. S. Rao: None. M. Smith: None. A. Shapiro: None. C. Moshe: None. R. Chadha: None. Introduction: Pheochromocytomas are rare, neuroendocrine tumors derived from chromaffin cells of the neural crest, typically within the adrenal medulla. The pathophysiologic effect of primary concern is the uncontrolled release of catecholamines into the bloodstream, which carry risk for episodic hypertension, palpitations, and life-threatening crises. Preoperative preparation with drugs that block adrenergic receptors is utilized to improve hemodynamic oscillation force and surgical outcomes. Widely used premedication include alpha-blockers, beta-blockers, and calcium channel blockers. Despite adequate pretreatment, hemodynamic instability continues to evoke massive risk. The objective of this study was to assess the incidence of intraoperative hypertensive episodes in patients undergoing robotic assisted laparoscopic adrenalectomy. Methods: This study is an observational retrospective analysis of patients who underwent elective laparoscopic robotic-assisted adrenalectomies from February 2019 to April 2023. 17 patients total patients were included. Preoperative information included age, BMI, ASA physical classification, preoperative blockade regiment, and urine metanephrines. Intraoperative information included operation duration, tumor size, intraoperative anti-hypertensives, and hypertensive spikes defined as a SBP greater than 175 mmHg for 5 consecutive minutes. Data analysis was performed to obtain frequency counts (%), means (standard deviations), and median (range) as appropriate. Results: The mean age at the time of surgery was 57.12 ± 17.2 years. The majority of patients (76%) were ASA status class III. 7 of the 17 patients did not have active pheochromocytoma based on symptomatology, the incidental diagnoses being made by imaging and workup. The average tumor diameter was 3.90 ± 1.8, with a range of 2.0 - 8.0. Mean operative time was 153.76 ± 53.9 minutes. Preoperative urinary metanephrines were observed to have a mean of 1,248.44 ± 2,866.9 pg/mL. In terms of preoperative preparation, 65% of patients received Doxazosin, and 29% of patients received an alternative anti-hypertensive. Yet, 64.7% of patients were found to have at least 1 intraoperative hypertensive spike Conclusion: Despite premedication with anti-hypertensives, a significant percentage of patients experienced intraoperative hemodynamic instability. This emphasizes the importance of anesthesiologist preparation for intraoperative hypertension management to aggressively prevent hypertensive crises. In addition, it questions the routine use of alpha blockade for all cases preoperatively as has been suggested in certain studies, and whether or not it should be driven by other patient characteristics. Presentation: 6/1/2024

Induction of subject-ventilator asynchrony by variation of respiratory parameters in a lung injury model in pigs

BackgroundSubject-ventilator asynchrony (SVA) was shown to be associated with negative clinical outcomes. To elucidate pathophysiology pathways and effects of SVA on lung tissue histology a reproducible animal model of artificially induced asynchrony was developed and evaluated.MethodsAlterations in ventilator parameters were used to induce the three main types of asynchrony: ineffective efforts (IE), auto-triggering (AT), and double-triggering (DT). Airway flow and pressure, as well as oesophageal pressure waveforms, were recorded, asynchrony cycles were manually classified and the asynchrony index (AIX) was calculated. Bench tests were conducted on an active lung simulator with ventilator settings altered cycle by cycle. The developed algorithm was evaluated in three pilot experiments and a study in pigs ventilated for twelve hours with AIX = 25%.ResultsIE and AT were induced reliably and fail-safe by end-expiratory hold and adjustment of respiratory rate, respectively. DT was provoked using airway pressure ramp prolongation, however not controlled specifically in the pilots. In the subsequent study, an AIX = 28.8% [24.0%-34.4%] was induced and maintained over twelve hours.ConclusionsThe method allows to reproducibly induce and maintain three clinically relevant types of SVA observed in ventilated patients and may thus serve as a useful tool for future investigations on cellular and inflammatory effects of asynchrony.