Adrenergic Research Articles

(324) History of Priapism Treatment in the 20th Century

Abstract Introduction Priapism, defined as a prolonged erection in the absence of sexual arousal, leads to decreased quality of life, physical health, and increased erectile dysfunction. The modern priapism treatments of vasoconstriction and cavernous aspiration stem from strides made throughout the last century. Objective As a result, we seek to chronicle the history of priapism treatment throughout the 20th century. Methods We reviewed over two dozen academic articles and medical textbooks from 1872 to 1990 with relevant information on priapism treatment. Results In the 19th century, treatment of priapism solely involved symptomatic management with morphine and medicinal leeches. In 1928, Dr. Robert McKay and Dr. John Colston discovered that a thrombotic condition is sufficient to sustain an erection and that removing clots from the penis is sufficient to alleviate the erection. They recommended the newly-discovered anticoagulant heparin as a potential remedy. Dr. Rita Franklin then established in 1940 a positive association between testosterone propionate levels and priapism in eunuchoid men. Priapism therapies improved exponentially beginning in the late 1950s. Dr. H. Stephen Brody conducted the first successful penile aspiration in 1957 by aspirating blood from the base of each corpus cavernosum in a hypotensive patient. This groundbreaking procedure is conducted to this day for patients who do not respond effectively to medication management. Nine years after Dr. Brody’s study in 1966, Dr. Robert Garrett and Dr. Donald Rhamy reported penile flaccidity and sexual satisfaction in five patients who underwent a corpus-saphenous shunt to improve venous drainage. In 1997, Dr. Pierre Bondil and colleagues conducted a novel experiment demonstrating the efficacy of vasoconstrictive alpha agonist agents in decreasing penile blood flow to decrease erections and preserve erectile function. Conclusions The last one hundred years has shown significant innovation in the treatment of priapism. Some of the major developments in the first half of the 20th century included the use of heparin and the establishment of a relationship between testosterone and priapism. The second half of the 20th included treatment still in use today, such as carvenoglandular shunts and vasoconstrictive agents. Therapies from the 20th century will continue to play a vital role in the treatment and research of priapism management. Disclosure No.

(053) Penile Entrapment Due to Metal Constriction Rings: Removal, Recovery and Complications

Abstract Introduction Penile incarceration due to a metal constriction ring is a rare urologic emergency. Improper ring sizing, use of makeshift rings or prolonged length of use can cause penile/penoscrotal entrapment with resulting sequelae including genital ischemia, necrosis, and urinary retention. Metal rings are prone to this exigent situation, as they tend to be denser and thicker than typical constriction rings which presents a challenge for safe removal. Objective We aim to report a multi-institutional experience characterizing the presentation, removal methods, and outcomes after prolonged penile entrapment in patients with metal constriction rings. Methods We performed a retrospective chart review from 2000 to 2023 at participating institutions to identify men presenting with penile incarceration due to metal constriction ring use using the following ICD-10 codes: S30.842A, S30.843, W49.04XA, S31.24X, and T19.4. Operative/procedural tools and duration were recorded from the initial emergency room encounter and follow-up notes were reviewed for any subsequent complications. Results Twelve patients with median age 55 with interquartile range (IQR) of 26 were identified (Table 1). The metal rings varied in size, and most were composed of stainless steel. The length of time the constriction ring was in place before seeking medical attention ranged from 3 hours to 10 days with a median time of 42 hours, (IQR, 60). Removal instruments included a powered drill cutting tool, ring cutter, and bolt cutters. Median operative/procedural time was 90 minutes (IQR, 63). Cool irrigation was used in all cases where powered rotary cutting tool was used in combination with a mechanism to protect the underlying skin such as a metal retractor. Additionally, a barrier such as saline-soaked towels and/or lubricating jelly was used to protect the surrounding skin during operative intervention with a powered tool. Most patients reported full recovery despite prolonged entrapment; however, one patient developed a urethrocutaneous fistula and one patient reported diminished erectile function. Interestingly, one patient with concomitant substance abuse and vasoconstrictive agents use presented with penile skin necrosis requiring concurrent debridement which was further complicated by Fournier’s gangrene 1 month later in the setting of continued substance use and non-adherence to prescribed antibiotics. Conclusions Penile incarceration by metal constriction ring is a rare urologic emergency. This study represents the first multi-institutional and largest investigation evaluating the management of this condition. Manual and powered cutting tools are effective in removing metal constriction rings. If powered tools are employed, irrigation and retractors are necessary to prevent thermal injury. Despite most patients fully recovering after removal, significant complications have been observed. Therefore, prompt management and proper follow-up are recommended. Disclosure No.

Raney: a ubiquitous neurosurgical eponym.

Prior to the 1937 invention of the Raney clip, surgeons relied on hemostatic sutures, pneumatic tourniquets, sequentially applied hemostatic forceps, and the administration of local vasoconstrictive agents to achieve scalp hemostasis. The Raney clip is now the quintessential tool for achieving scalp hemostasis in cranial neurosurgery; with nearly 13.8 million cranial neurosurgical cases per year globally, Raney clips are in high demand and their use is ubiquitous. What is less known, however, is the story of their invention and the related stories of those who bear the Raney name. This paper fills these gaps in neurosurgical history, using information obtained during an extensive series of contemporary interviews and correspondence with the Raney family.

Contractile Effects of Amphetamine, Pseudoephedrine, Nor-pseudoephedrine (Cathine), and Cathinone on Atrial Preparations of Mice and Humans.

Amphetamine derivatives are used worldwide legally or illegally and intoxications may be accompanied by cardiac arrhythmias. Here, we tested contractile effects of cumulative applied (±)-amphetamine, pseudoephedrine, nor-pseudoephedrine (cathine), and cathinone in electrically stimulated (1 Hz) human right atrial preparations (HAP) and mouse left atrial preparations and in spontaneously beating mouse right atrial preparations. In mouse atrial preparations, amphetamine increased force of contraction and beating rate in a concentration- and time-dependent manner, starting at 1 µM in left atrial preparations to 157.1% ± 3.0% and right atrial preparations to 146.6% ± 9.8% at 10 µM, respectively [mean ± standard error of the mean (SEM); n = 5; P < 0.05]. Pseudoephedrine, cathine, or cathinone alone were ineffective in mouse atrial preparations but after pre-incubation with the phosphodiesterase IV inhibitor rolipram (0.1 µM), a positive inotropic effect was noted (mean ± SEM: pseudoephedrine: 112.3% ± 9.8%; cathine: 109.0% ± 4.3%; cathinone: 138.3% ± 21.2%). The effects of all drugs were greatly attenuated by 10 µM cocaine or 10 µM propranolol treatments. However, In HAP, not only amphetamine (to a mean ± SEM of 208% ± 32%) but also pseudoephedrine (to a mean ± SEM of 287% ± 60%), cathine (to a mean ± SEM of 234% ± 52%), and cathinone (to a mean ± SEM of 217% ± 65%) increased force of contraction without the need of phosphodiesterase inhibition. The contractile effects in HAP were attenuated by 10 µM cocaine and antagonized by 10 µM propranolol. We conclude that amphetamine, pseudoephedrine, cathine, and cathinone act probably via release of noradrenaline from cardiac stores as indirect sympathomimetic agents in mouse and more pronounced in human atrial preparations.

Management of iatrogenic airway bleeding with flexible bronchoscopy: Evidence or experience-based?

Iatrogenic bleeding during bronchoscopy may lead to early termination, insufficient sample collection, decreased diagnostic accuracy, and even death. Unlike rigid bronchoscopy, the management of bleeding during flexible fiberoptic bronchoscopy does not allow the use of methods such as cautery, direct pressure, etc. and is usually limited to the application of liquids. The management of endobronchial bleeding usually depends on two main mechanisms: 1) vasoconstriction; 2) enhancing coagulation to form fibrin clots. The data on cold saline, the most widely recognized agent, is based on case reports and the experience of centers, not randomized controlled trials. Vasoconstrictor agents consist of adrenaline, vasopressin analogues, phenylephrine, and xylometazoline hydrochloride. However, there are only a limited number of randomized controlled trials on adrenaline, and information on the remaining substances is limited to retrospective studies, case reports, and expert opinions. The endobronchial administration of tranexamic acid, which inhibits fibrin degradation, has been the subject of very few studies. Despite its documented efficacy, information regarding its dosage, frequency of use, and safety is lacking. Although Ankaferd Blood Stopper, which binds erythrocytes to the vascular endothelium, has been shown to be effective in controlling bleeding related to dental procedures, the gastrointestinal tract, and operations, only one retrospective study found it to be effective against endobronchial bleeding that could not be controlled with cold saline and adrenaline. Although there are a variety of agents that centers use in their routine procedures, there is not yet a consensus on the efficacy, dose, frequency, and safety of any of them.

Formulation Development and Evaluation of Highly Oxidative Degradative Drug Molecule Injectable Dosage form by Lyophilisation Techniques

Adrenaline (ADR) It is lifesaving and is the only first-line drug for the treatment of anaphylaxis. Adrenaline (ADR) is the endogenous catecholamine with potent alpha- and beta-adrenergic stimulating properties. Alpha-adrenergic action increases systemic and pulmonary vascular resistance, increasing both systolic and diastolic blood pressure. Adrenaline is released in the bloodstream, which increases heartbeat, muscle strength, blood pressure, and glucose metabolism. Oxidation degradation of the medicinal product is the main route of degradation. Affects chemical and physical changes in drugs during the formulation development process. Physicochemical changes in the product can affect both the safety and efficacy of the drug product. Main product development strategy to develop, a stable, freeze-dried product of epinephrine for injection. The stability of adrenaline injection is of paramount objective as it is classified as a catechol compound that is sensitive to oxidation to o-quinone and therefore can react further to form highly colored compounds. Adrenergic drugs further react to form adrenochrome, a highly colored indole derivative. The rate of this reaction increased with pH, temperature and presence of the metal ions. Aqueous solutions of adrenergic agonists decompose rapidly when exposed to air, light, or heat, turning pink due to oxidation to adrenochrome and brown due to melanin formation. Due to its strong oxidizing properties and easy decomposition in aqueous solutions. To achieve this, the aqueous solutions of adrenergic agonists decompose rapidly when exposed to air, light, or heat, turning pink due to oxidation to adrenochrome and brown due to melanin formation. Due to its strong oxidizing properties and easy decomposition in aqueous solutions.

Age-related structural and functional changes of the intracardiac nervous system

BackgroundAlthough aging is known to be associated with an increased incidence of both atrial and ventricular arrhythmias, there is limited knowledge about how Schwann cells (SC) and the intracardiac nervous system (iCNS) remodel with age. Here we investigate the differences in cardiac SC, parasympathetic nerve fibers, and muscarinic acetylcholine receptor M2 (M2R) expression in young and old mice. Additionally, we examine age-related changes in cardiac responses to sympathomimetic and parasympathomimetic drugs. Methods and resultsLower SC density, lower SC proliferation and fewer parasympathetic nerve fibers were observed in cardiac and, as a control sciatic nerves from old (20–24 months) compared to young mice (2–3 months). In old mice, chondroitin sulfate proteoglycan 4 (CSPG4) was increased in sciatic but not cardiac nerves. Expression of M2R was lower in ventricular myocardium and ventricular conduction system from old mice compared to young mice, while no significant difference was seen in M2R expression in sino-atrial or atrio-ventricular node pacemaker tissue. Heart rate was slower and PQ intervals were longer in Langendorff-perfused hearts from old mice. Ventricular tachycardia and fibrillation were more frequently observed in response to carbachol administration in hearts from old mice versus those from young mice. ConclusionsOn the background of reduced presence of SC and parasympathetic nerve fibers, and of lower M2R expression in ventricular cardiomyocytes and conduction system of aged hearts, the propensity of ventricular arrhythmogenesis upon parasympathomimetic drug application is increased. Whether this is caused by an increase in heterogeneity of iCNS structure and function remains to be elucidated.

Comparing Efficacy and Safety Aspects of 2% Lidocaine Hydrochloride Combination with 1:80.000 Added Epinephrine Solution versus the Most Commonly Used 2% Lidocaine Hydrochloride Solution in Surgical Procedures on Human Fingers and Toes

The effective management of pain and hemostasis is a pivotal concern in surgical procedures performed on human fingers and toes. The anatomical intricacies and limited tissue volume demand a meticulous approach to ensure both the safety of the patient and the successful outcome of the surgery. The use of vasoconstrictor agents, such as epinephrine, to provide clear surgical field and better surgical outcome further complicates the landscape. While epinephrine is a valuable adjunct to local anesthesia due to its hemostatic properties and ability to prolong anesthetic effects, its application in procedures on fingers and toes necessitates a deep understanding of potential risks and complications. This literature review delves into the comparative analysis of two widely employed local anesthetic solutions which are the 2% lidocaine hydrochloride solution and the 2% lidocaine hydrochloride solution combined with 1:80,000 epinephrine, with specific aim to comprehensively evaluate the efficacy and safety aspects of both local anesthetic solutions. Lidocaine solution alone offers effective pain relief with minimal systemic risks but might lack the extended duration and hemostasis benefits of epinephrine. The lidocaine-epinephrine combination solution provides prolonged anesthesia and reduced bleeding, but clinicians must balance these advantages with the potential for ischemic events and delayed wound healing. Close monitoring, precise dosing, and careful patient selection are paramount in ensuring successful outcomes while minimizing complications.

Bibliometric and visual analysis of intraoperative hypotension from 2004 to 2022.

Intraoperative hypotension (IOH) is a common complication occurring in surgical practice. This study aims to comprehensively review the collaboration and impact of countries, institutions, authors, journals, keywords, and critical papers on intraoperative hypotension from the perspective of bibliometric, and to evaluate the evolution of knowledge structure clustering and identify research hotspots and emerging topics. Articles and reviews related to IOH published from 2004 to 2022 were retrieved from the Web of Science Core Collection. Bibliometric analyses and visualization were conducted on Excel, CiteSpace, VOSviewer, and Bibliometrix (R-Tool of R-Studio). A total of 1,784 articles and reviews were included from 2004 to 2022. The number of articles on IOH gradually increased in the past few years, and peaked in 2021. These publications were chiefly from 1,938 institutions in 40 countries, led by America and China in publications. Sessler Daniel I published the most papers and enjoyed the highest number of citations. Analysis of the journals with the most outputs showed that most journals concentrated on perioperative medicine and clinical anesthesiology. Delirium, acute kidney injury and vasoconstrictor agents are the current and developing research hotspots. The keywords "Acute kidney injury", "postoperative complication", "machine learning", "risk factors" and "hemodynamic instability" may also become new trends and focuses of the near future research. This study uses bibliometrics and visualization methods to comprehensively review the research on intraoperative hypotension, which is helpful for scholars to better understand the dynamic evolution of IOH and provide directions for future research.

Long-term risk of cardiovascular side-effects following attention-deficit hyperactivity disorder treatment with sympathomimetic amines

Abstract Background In recent years, patients diagnosed with attention-deficit/hyperactivity disorder (ADHD) has risen markedly, and treatment with sympathomimetic amines has proven effective in mitigating symptoms. However, due to sympathomimetic amines’ amplifying effect on heart rate and blood pressure, long-term cardiovascular drug-safety should be scrutinized. Purpose We investigated long-term risk of heart failure, acute coronary syndrome, and stroke associated with long-term sympathomimetic amine treatment. Methods Using nationwide Danish registers, we identified all patients &amp;gt;18 years of age initiated on sympathomimetic amines (methylphenidate, atomoxetine, lisdexamphetamine, or dexamphetamine) during 1998–2020. Follow-up began one year after patients’ first claimed prescription for patients without known history of heart failure, acute coronary syndrome, or stroke. Exposure was defined according to claimed prescriptions of sympathomimetic amines within 180 days prior to follow-up start and categorized as "discontinued", "low dosage", or "high dosage". Outcomes were heart failure, acute coronary syndrome, stroke, and a composite of all outcomes. We reported standardized 10-year absolute risk (AR) with 95% confidence intervals (CI) and risk ratios (RR) from fitted multivariable cause-specific Cox models with competing risk of death, comparing patients according to their exposure. Similar analyses were conducted at landmarks 1, 2, 3, 4, and 5 years after initial follow-up start where only patients still in treatment at the previous landmark were eligible. Results At follow-up start, 27,724 (36%) patients (42% female, median age: 29 [interquartile range (IQR) 23–41]) had discontinued treatment, 37,772 (49%) patients (47% female, median age: 31 [IQR 24–40]) were categorized as low dosage, and 11,924 (15%) patients (45% female, median age: 30 [IQR 23–41]) as high dosage. Comparing high dosage with discontinuation, there was a significant association with elevated 10-year absolute risk of heart failure (RR 1.7 [95% CI 1.2–2.2], numbers needed to harm [NNH]: 188), stroke (RR 1.3 [95% CI 1.0–1.6], NNH: 190), and the composite outcome (RR 1.4 [95% CI 1.1–1.6], NNH: 93), but not with acute coronary syndrome (RR 1.2 [95% CI 0.8–1.5]) (Figure 1). Comparing high dosage with low dosage, RRs of 1.4 (95% CI 1.0–1.9), 1.0 (95% CI 0.7–1.3), 1.2 (95% CI 1.0–1.5), and 1.2 (95% CI 1.1–1.4) were correspondingly found for the association with 10-year absolute risk of heart failure, acute coronary syndrome, stroke, and the composite outcome (Figure 1). Comparing low dosage with discontinuation, no significant associations were found (Figure 1). Landmark analyses yielded comparable results (Figure 2). Conclusion Effective and well-indicated treatment for ADHD is key; but a possible association with elevated cardiovascular risk in a young patient group should emphasize the need for risk factor mitigation and shared decision making based on available evidence.Figure 1Figure 2

Central obesity is detrimental to anti-inflammatory, phenotype, and exhaustion markers in mononuclear cells - A cross-sectional study

To investigate the role of central obesity on immunometabolic response in peripheral blood mononuclear cells (PBMCs) from normal weight and overweight/obese young men. Eighteen individuals were classified as normal weight (NW; n=9 - age: 25±5 and BMI: 21.4±1.7) and overweight/obese (OW; n=9 - age: 29±7 and BMI: 29.2±2.7). The body composition was evaluated by dual-energy x-ray absorptiometry (DXA), waist circumference, and visceral and subcutaneous fat depots by ultrasound. Physical activity levels, metabolic parameters, immune phenotypic characterization, cytokine production by lipopolysaccharide (LPS) -stimulated whole blood cells and LPS or phorbol 12-myristate 13-acetate (PMA)-stimulated PBMC, and mitochondrial respiration in PBMCs were evaluated. Expression of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma (PPAR-γ), nuclear factor-kappa B (NF-κB), toll-like receptor 4 (TLR-4), hypoxia-inducible factor-1 alpha (HIF-1α), and adrenergic receptor beta 1 and 2 (AR-β1 and β2) genes were evaluated in cultured PBMC using quantitative real-time polymerase chain reaction (qRT-PCR). Individuals with overweight/obese (OW) presented higher glucose (P=0.009) and leptin (P=0.010) than individuals with normal weight (NW). PBMCs of OW under stimulation with LPS presented a lower production of interleukin-10 (IL-10) (P=0.011) and macrophage inflammatory protein-1alpha (MIP-1α) (P=0.048) than NW. Mitochondrial respiration rates were not different between NW and OW subjects. Cultured PBMCs in LPS-stimulated condition indicated higher gene expression of AR-β2 in OW, while PMA-stimulated PBMCs presented lower expression of AMPK (P=0.002) and higher expression of NF-κB (P=<0.0001) than NW. OW presented higher numbers of CD3+CD4+ T cells (P=0.009) and higher expression of programmed cell death protein 1 (PD-1) in CD8+ T cells (P=0.001) than NW. Central obesity promoted reductions in interleukin 10 production response and increase in AR-β2 expressions in mitogen-stimulated PBMCs. Furthermore, central obesity altered the phenotype of PBMCs, also increasing the expression of PD-1 exhaustion markers in young adults.

New-Onset Atrial Fibrillation in the Critically Ill COVID-19 Patients Hospitalized in the Intensive Care Unit.

New-onset atrial fibrillation (NOAF) is the most frequently encountered cardiac arrhythmia observed in patients with COVID-19 infection, particularly in Intensive Care Unit (ICU) patients. The purpose of the present review is to delve into the occurrence of NOAF in COVID-19 and thoroughly review recent, pertinent data. However, the causality behind this connection has yet to be thoroughly explored. The proposed mechanisms that could contribute to the development of AF in these patients include myocardial damage resulting from direct virus-induced cardiac injury, potentially leading to perimyocarditis; a cytokine crisis and heightened inflammatory response; hypoxemia due to acute respiratory distress; disturbances in acid-base and electrolyte levels; as well as the frequent use of adrenergic drugs in critically ill patients. Additionally, secondary bacterial sepsis and septic shock have been suggested as primary causes of NOAF in ICU patients. This notion gains strength from the observation of a similar prevalence of NOAF in septic non-COVID ICU patients with ARDS. It is plausible that both myocardial involvement from SARS-CoV-2 and secondary sepsis play pivotal roles in the onset of arrhythmia in ICU patients. Nonetheless, there exists a significant variation in the prevalence of NOAF among studies focused on severe COVID-19 cases with ARDS. This discrepancy could be attributed to the inclusion of mixed populations with varying degrees of illness severity, encompassing not only patients in general wards but also those admitted to the ICU, whether intubated or not. Furthermore, the occurrence of NOAF is linked to increased morbidity and mortality. However, it remains to be determined whether NOAF independently influences outcomes in critically ill COVID-19 ICU patients or if it merely reflects the disease's severity. Lastly, the management of NOAF in these patients has not been extensively studied. Nevertheless, the current guidelines for NOAF in non-COVID ICU patients appear to be effective, while accounting for the specific drugs used in COVID-19 treatment that may prolong the QT interval (although drugs like lopinavir/ritonavir, hydrochlorothiazide, and azithromycin have been discontinued) or induce bradycardia (e.g., remdesivir).

Abstract 18837: Association of Urinary Catecholamines and Their Metabolites With the Use of Electronic and Combustible Cigarettes

Nicotine, present in combustible cigarettes, is a strong sympathomimetic drug, and many of the cardiovascular and metabolic effects of smoking have been linked to increases in catecholamine production. However, it is not known whether vaping also leads to an increased catecholamine formation. Therefore, we measured the urinary catecholamines and their metabolites associated with vaping and smoking, or no tobacco use. Healthy adults 18-45 yoa who use tobacco products were asked to vape for every 30sec for 10min, smoke 1 cigarette, or inhale through a straw (sham) prior to providing urine samples three times: before tobacco use (T0), one hour (T1), and two hours (T2) after tobacco exposure. Catecholamines and their metabolites were measured in urine samples containing internal standards analyzed on a LC/MS/MS. Participants were categorized by the product used at the study visit: combustible cigarettes (n=70), e-cigarette (n=171), or sham use of a straw (n=82). Log transformed catecholamines and metabolites, normalized to urinary creatinine, were compared among each tobacco use group. Generalized linear models were used to estimate the associations between the outcomes and tobacco product use at each time point, adjusting for age, race and sex seen in table 1. At T0, smoking was associated with lower metanephrine, 5-hydroxindole-3-acetic acid, and vanillymandelic acid. At T1, after vaping normetanephrine and 3-methoxytyramine, epinephrine and homovanillic acid were higher. After smoking, norepinephrine, dopamine, normetnephrine, epinephrine and homovanillic acid were higher at T1. Whereas at T2 there was lower 5-hydroxindole-3-acetic acid in e-cigarette users. Our findings that both vaping and smoking are associated with increased urinary catecholamines or their metabolites, suggesting that the use of either product could elevate CVD risk due to repeated sympathetic stimulation. Catecholamines could be useful as a biomarker of harm for tobacco use.

Abstract 110: Autoangiogenesis Secondary to Chronic Cocaine Use Mimicking Moya‐Moya

Introduction We present the case of a young male presenting with syncope who was found to have incidental hypodensities on computed tomography (CT) of his head, with magnetic resonance imaging (MRI) concerning for Moya‐Moya related occlusion of the right internal carotid artery, but with digital subtraction angiography (DSA) showing extensive autoangiogenesis and collateralization from all other intracranial vascular territories, without Moya‐Moya related changes. This presumably developed as reactive changes to severe chronic cocaine use. Methods We present a case from a tertiary care center in the borough of Manhattan, New York City, USA. All information is deidentified and exempt from IRB approval. Results A 36‐year‐old man with history significant for asthma, active smoker status, and active cocaine use, presented for loss of consciousness. The patient reported 3 days of upper respiratory symptoms and decreased oral intake with subsequent loss of consciousness immediately preceded by lightheadedness and nausea, and without any post‐event confusion, lacerations, or incontinence. Neurologic history is significant for right upper extremity weakness from 9/2022‐12/2022 that self‐resolved and was believed to be a peripheral nerve pathology. Admission exam without focal deficits. Admission CT of his head showed multifocal confluent hypodensities in the subcortical right frontal lobe. CT Angiogram of head and neck showed severe narrowing at right Internal Carotid Artery (ICA) terminus and right M1 segment with lenticulostriate arterial collateralization, severe bilateral A1 stenosis with distal Anterior Cerebral Artery (ACA) flow suggestive of chronic collateralization, and significant right Posterior Cerebral Artery (PCA) collateralization. Given concern for Moya‐Moya disease, MRI of the brain was obtained and despite no acute infarct, MRI was significant for multifocal white matter T2/FLAIR hyperintensities with the largest in the right frontal lobe. The patient subsequently underwent digital subtraction angiography (DSA) to assess collaterals and stratify for possible need for future encephaloduroarteriosynangiosis (EDAS). DSA showed significant auto‐angiogenesis between numerous vascular territories, including recruitment of right Posterior Cerebral Artery and External Carotid Artery branches to perfuse the territory of the severe right ICA terminus steno‐occlusive disease. With minimal anterograde flow into the right Anterior Choroidal Artery and none to the right Middle Cerebral Artery (MCA), the characteristic Moya‐Moya appearance was not appreciated on DSA given minimal anigogenesis around the right ICA occlusion site. Rather, distal perfusion of the R ICA territory was dependent on collaterals from the right PCA, right ACA via the Anterior Communicating Artery, angiogenesis between the right Anterior Falcine Artery and R ACA, and angiogenesis between the right MCA and ACA/MCA cortical branches. These proliferative changes involved all cranial vascular territories, including those without steno‐occlusive disease. Conclusion Acute cocaine use is associated with increased risk of acute ischemic stroke[1], due in part to its sympathomimetic effects causing vasospasm and to its arrhythmic properties[2]. Neuroadaptation after chronic cocaine use is less well understood though rat models suggest that as cerebral ischemia develops from chronic cocaine use, the HIF‐VEGF pathway is activated to promote angiogenesis to restore local blood flow[3]. We present this case as evidence of a similar angiogenic physiologic response in humans to minimize the microvascular ischemic injury from chronic cocaine use.

Initial Treatment of Cerebral Hemorrhage:Determining the Cause without Preconceived Notions

In Japan, cerebral hemorrhage accounts for 19.5% of stroke patients, and its prognosis is poorer than that of cerebral infarction, with a mortality rate of 14.6%. In the initial treatment of cerebral hemorrhage, the airway, respiration, and circulation should be stabilized, and the intracranial pressure and body temperature should be controlled. Hypertensive cerebral hemorrhage is the most common cause; however, the cause should be carefully examined, and the treatment method should be selected according to the degree of urgency. Cerebral hemorrhage patients undergoing antithrombotic therapy show poor outcomes owing to increased hematoma. Therefore, antithrombotic drugs should be discontinued immediately. Blood products and neutralizing drugs should be administered in response to the administration of antithrombotic drugs. In young individuals, cerebrovascular disorders may be caused by the abuse of sympathomimetic drugs, such as stimulants and cocaine. Whether individuals or their family members are using illegal drugs should be confirmed.

Inquiring about the link between urotensin-II and coronary collateral development in coronary artery patients with and without diabetes

Aims: Coronary collateral circulation consists of vascular channels activated to maintain perfusion in major epicardial coronary arteries in severe stenosis or occlusion. Yet, coronary collateral development (CCD) in diabetic patients was previously proven to be poor. Urotesin-II (U-II) is famous for being the most potent vasoconstrictor agent, and plasma levels are known to elevate in diabetic patients and play an important role in diabetic complications. In this study, we inquired about the link between U-II levels and the development of coronary collaterals between diabetic and non-diabetic patients with coronary artery disease (CAD).&#x0D; Methods: We recruited 31 diabetic and 30 non-diabetic patients with 95% or more coronary artery stenosis or occlusion and considered Rentrop’s classification for grading collaterals. In this sense, while Rentrop grades 0-1 are regarded as poor CCD, Rentrop grades 2-3 correspond to well-developed collaterals. Moreover, we compared the patients’ serum levels of U-II by the degree of CCD.&#x0D; Results: The findings revealed that demographic characteristics did not significantly differ between the groups (p &gt;0.05). Although CCD seemed worse in diabetic patients than those without diabetes (DM), the finding was not statistically significant. However, the diabetic patients had significantly higher U-II levels than non-diabetic patients (388.1±314.2 vs. 229.8±216.9, p=0.026). Despite not being significant, U-II levels were higher in patients with poor CCD than those with well-developed collaterals in the non-diabetic group (370.6±298; 178.6±158.3, p=0.2). In the diabetic group, on the other hand, U-II levels were significantly higher in patients with poor CCD and significantly lower in patients with good CCD (582.7±316.4 and 180.4±121.6, respectively; p

Adrenergic and mesenchymal signatures are identifiable in cell-free DNA and correlate with metastatic disease burden in children with neuroblastoma.

Cell-free DNA (cfDNA) profiles of 5-hydroxymethylcytosine (5-hmC), an epigenetic marker of open chromatin and active gene expression, are correlated with metastatic disease burden in patients with neuroblastoma. Neuroblastoma tumors are comprised of adrenergic (ADRN) and mesenchymal (MES) cells, and the relative abundance of each in tumor biopsies has prognostic implications. We hypothesized that ADRN and MES-specific signatures could be quantified in cfDNA 5-hmC profiles and would augment the detection of metastatic burden in patients with neuroblastoma. We previously performed an integrative analysis to identify ADRN and MES-specific genes (n=373 and n=159, respectively). Purified DNA from cell lines was serial diluted with healthy donor cfDNA. Using Gene Set Variation Analysis (GSVA), ADRN and MES signatures were optimized. We then quantified signature scores, and our prior neuroblastoma signature, in cfDNA from 84 samples from 46 high-risk patients including 21 patients with serial samples. Samples from patients with higher metastatic burden had increased GSVA scores for both ADRN and MES gene signatures (p<.001). While ADRN and MES signature scores tracked together in serially collected samples, we identified instances of patients with increases in either MES or ADRN score at relapse. While it is feasible to identify ADRN and MES signatures using 5-hmC profiles of cfDNA from neuroblastoma patients and correlate these signatures to metastatic burden, additional data are needed to determine the optimal strategies for clinical implementation. Prospective evaluation in larger cohorts is ongoing.

Catecholamine Derivatives: Natural Occurrence, Structural Diversity, and Biological Activity.

Catecholamines (CAs) are aromatic amines containing a 3,4-dihydroxyphenyl nucleus and an amine side chain. Representative CAs included the endogenous neurotransmitters epinephrine, norepinephrine, and dopamine. CAs and their derivatives are good resources for the development of sympathomimetic or central nervous system drugs, while they also provide ligands important for G-protein coupled receptor (GPCR) research. CAs are of broad interest in the fields of chemical, biological, medical, and material sciences due to their high adhesive capacities, chemical reactivities, metal-chelating abilities, redox activities, excellent biocompatibilities, and ease of degradability. Herein, we summarize CAs derivatives isolated and identified from microorganisms, plants, insects, and marine invertebrates in recent decades, alongside their wide range of reported biological activities. The aim of this review is to provide an overview of the structural and biological diversities of CAs, the regularity of their natural occurrences, and insights toward future research and development pertinent to this important class of naturally occurring compounds.

Hemodynamic changes following injection of local anesthesia with vasoconstrictor agent in controlled hypertensive patients

Local anesthesia is considered the most commonly used in dentistry. Vasoconstrictors are added to its composition to maximize its advantages. However, it is considered a tourniquet and acts on beta 1 and 2 receptors. This causes augmentation of heart rate and blood pressure. This study aimed to evaluate the safety of vasoconstrictors during simple tooth extraction in controlled hypertensive patients by monitoring the changes in blood pressure, heart rate and oxygen saturation. A prospective clinical study was carried out in a control group (normotensive patients n=60) and study group (hypertensive patients) (n=60). The following hemodynamic parameters (blood pressure [diastolic and systolic], heart rate and oxygen saturation) were monitored at four different time points (before infiltration of local anesthesia (R1), after 3 minutes of local anesthesia (R2), immediately after extraction (R3) and 25 minutes after local anesthesia infiltration (R4). One carpule of local anesthesia for each patient was provided in the form of lidocaine 2% with adrenaline as vasoconstrictor 1/100,000; (3) Results: Mean heart rate increased from one to four beats per minute in all groups, but the increment was lesser in hypertensive group. The increase of systolic blood pressure in hypertensive patients during (R2, R3 and R4) was significantly lower than in the normotensive group (p&lt;0.001). The diastolic blood pressure reading fell in the hypertensive group more than in the normotensive group during (R2, R3 and R4). No changes in oxygen saturation were recorded between both groups; (4) Conclusions: no adverse effects in well-controlled hypertensive patients were seen during simple tooth extraction. One carpule of local anesthesia with 1\100,000 adrenaline does not induce blood pressure augmentation in hypertension patients included in this study. The changes in heart rate were within the safe limits. Keywords: local anesthesia, adrenaline, vasoconstrictors, hypertensive patients, hemodynamic changes.

Enhancing cardiomyocytes contraction force measuring in drug testing: Integration of a highly sensitive single-crystal silicon strain sensor into SU-8 cantilevers

The development of efficient tools for predicting drug-induced cardiotoxicity in the preclinical phase would greatly benefit the drug development process. This study presents an SU-8 cantilever integrated with a single-crystal silicon strain sensor to enhance force sensitivity in toxicity screening methods based on changes in the contraction force of cardiomyocytes. The proposed cantilever device enables real-time measurements of cardiomyocytes contraction force with high sensitivity, thereby facilitating the assessment of drug cardiotoxicity. The experimental results obtained herein demonstrate the responsiveness of the proposed platform in detecting forces smaller than 0.02 μN with a force sensitivity that is nearly 17 times higher than those of conventional metal-based strain sensors. Moreover, the integration of strain sensors demonstrates the potential for manufacturing cantilever arrays that can be used in high-throughput screening applications. The developed methodology successfully facilitates in vitro culturing of cardiomyocytes and allows for continuous monitoring of their contraction force. The practical applicability of the proposed platform is further validated through cardiotoxicity analysis. The cultured cardiomyocytes are treated with two cardiovascular drugs, namely verapamil (an L-type calcium channel blocker) and isoproterenol (a sympathomimetic drug targeting β1 and β2 adrenergic receptors), to analyze the drug induced effects in the cardiomyocytes.