Adrenergic Research Articles

Intracerebral hemorrhage

Background: Compared to ischemic stroke, intracerebral hemorrhage (ICH) has higher mortality and more severe disability. Asian such as Chinese and Japanese and Mexican Americans, Latin Americans, African Americans, Native Americans have higher incidences than do white Americans. So, ICH is an important cerebrovascular disease in Asia. Summary: ICH accounts for approximately 10-20% of all strokes. The incidence of ICH is higher in low- and middle-income than high-income countries and is estimated 8-15% in western countries like USA, UK and Australia, and 18-24% in Japan, Taiwan and Korea. The ICH incidence increases exponentially with age, and old age especially over 80 years is a major predictor of mortality independent of ICH severity. Females are older at the onset of ICH and have higher clinical severity than males. Modifiable risk factors include blood pressure, smoking, alcohol consumption, lipid profiles, use of anticoagulants, antiplatelet agents and sympathomimetic drugs. Non-modifiable risk factors constitute old age, male gender, Asian ethnicity, cerebral amyloid angiopathy, cerebral microbleed, and chronic kidney disease. Blood pressure is the most important risk factor of ICH. Imaging markers may help predict ICH outcome, which include black hole sign, blend sign, iodine sign, island sign, leakage sign, satellite sign, spot sign, spot-tail sign, swirl sign, and hypodensities. ICH prognostic scoring system such as ICH scoring system and ICH grading scale scoring system in Chinese and Osaka prognostic score and Naples prognostic score has been used to predict ICH outcome. Early minimally invasive removal of ICH can be recommended for lobar ICH of 30–80 mL within 24 hours after onset. Decompressive craniectomy without clot evacuation might benefit ICH patients aged 18–75 years with 30–100 mL at basal ganglia or thalamus. However, clinical studies are needed to investigate the effect of surgery on patients with smaller or larger ICH, ICH in non-lobar locations, and for older patients or patients with preexisting disability. Surgical treatment is usually associated with neurological sequels if survived. For medical treatment, blood pressure lowering should be careful titrated to secure continuous smooth and sustained control and avoid peaks and large variability in systolic blood pressure. Stroke and cancer are the most common causes of death in Asian ICH patients, compared to stroke and cardiac disease in non-Asian patients. Key Messages: The incidence and outcome are different between Asian and non-Asian patients, and more clinical studies are needed to investigate the best management for Asian ICH patients.

Preliminary Characterization of the Vasorelaxant Effect of Thymus atlanticus (Ball) Roussine Using Optical Methods.

Thymus atlanticus (Ball) Roussine is a Moroccan endemic thyme species that is traditionally used as an aromatic and medicinal plant. Several studies have demonstrated its pharmacological significance and therapeutic value. The current study aimed to assess the vasorelaxant effect of the aqueous extract of this species. The contractility of isolated rat aortas was investigated using the multi-well organ bath technique. This method was adapted and validated in our experimental conditions using epinephrine and hydralazine as vasoconstrictive and vasodilator agents, respectively. The application of 10 μM epinephrine induced a clear vasoconstriction of the aorta rings (Lumen reduction = 31.8±0.4%). However, hydralazine induced a dose-dependent relaxation with an EC50 value of 6.1±1.2 mM. For the aqueous extract of T. atlanticus, the aortic rings were precontracted with epinephrine, and then increasing concentrations (0.125-1 mg/mL) of this extract were added cumulatively. The results have indicated T. atlanticus extract to have a significant vasodilatory effect in a dose-dependent manner (EC50 = 0.52±0.03 mg/mL). The findings provide preliminary evidence of the vasorelaxant effect of the aqueous extract of T. atlanticus using a low-cost optical approach. However, the cellular and molecular mechanisms underlying this effect have yet to be revealed.

Use of Beta-Blockers as a First-Line Treatment for Primary Hypertension

Background: Even though beta-blockers had been used as a first-line therapy for hypertension, since the late 1960s, the Eighth Joint National Committee, JNC 8, decided to recommend them no longer. This decision was based on relatively weak evidence from previous studies, which found that first-line beta-blockers were less effective in reducing stroke and heart failure, the main outcomes of hypertension. Despite the general perception, the most common events caused by hypertension are death and MI, not stroke or heart failure. Therefore, this study aimed to clarify beta-blocker efficacy by incorporating the data from all relevant beta-blocker trials, using the composite outcome of major cardiovascular events. Method: A search was conducted on MEDLINE, PubMed, Embase, and the Cochrane Library, restricted to published, peer-reviewed, human, meta-analysis, and controlled clinical trials. The term words used were “beta-blockers or adrenergic beta antagonists”, “hypertension”, and “death or coronary heart disease or stroke or congestive heart failure or myocardial infarction”. For this research, we selected six randomized controlled trials, and three meta-analyses were also chosen. Results: The results showed that beta-blockers were as effective as other first-line medications in younger hypertensive patients. On the other hand, in the patients aged above 60, the results were mixed. Beta-blockers were more effective than diuretics, but inferior to angiotensin receptor blockers. Also, beta-blockers were as safe and effective as angiotensin-converting enzyme inhibitors in reducing coronary heart disease, myocardial infarction, heart failure, and sudden death. However, beta-blockers were inferior to calcium channel blockers in reducing strokes. Conclusions: Beta-blockers were found to be the most effective in many aspects except for strokes. Further studies are needed to assess beta-blockers’ effectiveness in treating primary hypertension.

A retrospective cohort analysis comparing the effectiveness and safety of perioperative angiotensin II to adrenergic vasopressors as a first-line vasopressor in kidney transplant recipients

BackgroundPerioperative adrenergic vasopressors in kidney transplantation have been linked to negative outcomes and arrhythmias. Synthetic angiotensin II (AT2S) could improve renal hemodynamics, preserve allograft function, and reduce arrhythmias.ObjectiveWe aimed to compare the effectiveness and safety of AT2S to adrenergic vasopressors when used for perioperative hypotension in kidney transplant.MethodsThis single-center, retrospective cohort study included adults with perioperative shock requiring AT2S or adrenergic agents as first-line vasopressors during kidney transplant. The primary outcome was the need for a second continuous infusion vasopressor agents beyond the first-line agent. Secondary outcomes assessed adverse events and early allograft outcomes.ResultsTwenty patients receiving AT2S and 60 patients receiving adrenergic vasopressor agents were included. Intraoperatively, 1 of 20 patients (5%) in the AT2S group needed a second continuous vasopressor compared to 7 of 60 patients (11.7%) who needed a second continuous vasopressor in the adrenergic vasopressor group (P = 0.672). Postoperatively, 1 of 20 patients (5%) in the AT2S group compared to 12 of 60 patients (20%) in the adrenergic vasopressor group required a second vasopressor (P = 0.168). There were significantly fewer arrhythmias (1/20 [5%] vs. 17/60 [28.3%]), P = 0.03) and ischemic complications (0/20 [0%] vs. 11/20 [18.3%], P = 0.031) in patients who received AT2S. There were no differences in immediate, slow, or delayed graft function or in discharge, 1-month, and 3-month glomerular filtration rates (p > 0.05).Conclusion and RelevanceBoth AT2S and adrenergic vasopressors are effective for perioperative hypotension in kidney transplant, with AT2S showing a lower incidence of arrhythmias and ischemic complications.

A systematic review and meta-analysis of efficacy of vasopressin as a vasoconstrictive and uterotonic drug in laparoscopic myomectomy

Abstract Introduction: Laparoscopic myomectomy is a commonly performed operation with fast recovery and excellent results. However, haemorrhagic nature of the operation mandates us to use variety of vasoconstrictive and uterotonic agents. Amongst which, one of them is vasopressin. It is a synthetic antidiuretic hormone analogue which has been in common use as a vasoconstrictive agent in various surgical procedures including laparoscopic myomectomy. Methods: A meta-analysis of randomised controlled trials published from 2013 to 2023 (10 years) comparing the use of vasopressin against other drug or placebo or different doses of vasopressin was performed. The outcome measures were intraoperative blood loss, need for blood transfusion, difference in the haemoglobin (Hb) and haematocrit (Hct). Results: We identified 176 articles through the study search, amongst which 12 articles were included for the meta-analysis. There was a significant heterogeneity in the studies with moderate risk of bias in eight studies and low risk of bias in four studies. Compared to placebo, vasopressin showed significantly lower odds need of blood transfusion (odds ratio [OR] 0.28, 95% confidence interval [CI]: 0.13–0.61, P = 0.002) and significantly lower pre–post fall in Hb (OR −3.12, 95% CI: −4.63–−1.60, P < 0.0001). However, there was no statistically significant difference in intraoperative blood loss (OR −0.56 (95% CI: −2.04–0.92, P = 0.46) and pre–post fall in Hct (OR −0.94, 95% CI: −1.96–0.07, P > 0.05). Compared to other drug (epinephrine, misoprostol and octreotide acetate), vasopressin showed no significant superiority in controlling blood loss (P > 0.05). Even the two doses of vasopressin (dilute vs. concentrated) showed no statistically significant difference between surgical blood loss and need for blood transfusion (P > 0.05). Conclusion: Vasopressin is an efficacious drug to be used for controlling blood loss, decreasing blood transfusion requirement and maintaining Hb and Hct during laparoscopic myomectomy.

Renal Medulla in Hypertension.

Studies have found that blood flow to the renal medulla is an important determinant of pressure-natriuresis and the long-term regulation of arterial pressure. First, a brief review of methods developed enabling the study of the medullary circulation is presented. Second, studies performed in rats are presented showing medullary blood flow plays a vital role in the pressure-natriuresis relationship and thereby in hypertension. Third, it is shown that chronic reduction of medullary blood flow results in hypertension and that enhancement of medullary blood flow reduces hypertension hereditary models of both salt-sensitive rats and salt-resistant forms of hypertension. The key role that medullary nitric oxide production plays in protecting this region from ischemic injury associated with circulating vasoconstrictor agents and reactive oxygen species is presented. The studies cited are largely the work of my students, research fellows, and colleagues with whom I have performed these studies dating from the late 1980s to more recent years.

Low-grade systemic inflammation in patients with long COVID: The role of imbalance of endotoxin-releasing systems and vasoconstrictor markers

Background. Currently, the pathophysiological mechanisms of acute damage to organs and systems caused by coronavirus infection have been studied quite fully, but the mechanisms underlying the clinical manifestations of long COVID have not yet been accurately described. The mechanisms of persistence of a number of symptoms in patients who have had COVID-19 and the role of systemic inflammation and endotoxemia markers in it remain a understudied aspect and a promising direction for further studying.The aim of the study. To assess the markers of systemic inflammation, endotoxin-releasing systems, intestinal permeability and endothelial dysfunction in patients with long COVID at the stage of health resort treatment.Methods. The study included 32 patients who had recovered from coronavirus infection and were undergoing health resort treatment in the pulmonology department of the I.M. Sechenov Academic Research Institute for Physical Therapy, Medical Climatology and Rehabilitation. We also selected a control group (n = 20). All patients underwent peripheral blood analysis to detect the levels of markers of systemic inflammation, endotoxin-releasing systems, intestinal permeability, endothelial dysfunction and vasoconstrictor agents: C-reactive protein (CRP), lipopolysaccharide-binding protein (LPB), tissue-type plasminogen activator (tPA), zonulin, bactericidal/ permeability-increasing protein (BPI), vasopressors of angiotensin 2 and endothelin (EDN1).Results. Patients who had recovered from coronavirus infection had a statistically significant increase in the levels of CRP (3.4 [2.56; 4.0] mg/l), LBP (18.46 [14.0; 25.5] ng/ml), tPA (0.07 [0.02; 0.32] ng/ml), angiotensin 2 (133.3 [63.0; 503.7] pg/ml) and a decrease in the level of BPI (1576 [276; 3588] pg/ml) (p < 0.05).Conclusion. A statistically significant increase in markers of systemic inflammation, endotoxinemia, and vasoconstrictor agents in patients with long COVID indicates an imbalance in endotoxin-binding and endotoxin-releasing systems in patients who have had coronavirus infection. Further study of the described markers is necessary to improve approaches to long-term personalized therapy for this category of patients.

Pseudoephedrine-Induced Risks of Posterior Reversible Encephalopathy Syndrome and Reversible Cerebral Vasoconstriction Syndrome

Abstract Background Pseudoephedrine is a sympathomimetic drug used as a nasal/sinus decongestant in common cold remedies. Objective The purpose of this review article is to discuss the pseudoephedrine-associated posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS), which have been reported to the Medicines and Healthcare products Regulatory Agency (MHRA) of United Kingdom and Pharmacovigilance Risk Assessment Committee (PRAC) and Committee for Medicinal Products for Human Use (CHMP) of European Medicines Agency (EMA). Methods The aim is to review the literature pertinent to PRES and RCVS linked to the use of pseudoephedrine; the literature was searched in databases such as Medline/PubMed/PMC, Google Scholar, Science Direct, Ebsco, Scopus, Web of Science, Embase, and reference lists. Results The review by MHRA of the United Kingdom and PRAC and CHMP of EMA, all available evidence, including postmarketing safety data, and a few case reports, have confirmed the rare risk of PRES and RCVS associated with the use of pseudoephedrine. Conclusion Health care professionals should be aware of pseudoephedrine-associated PRES and RCVS. Patients with severe or uncontrolled hypertension or those with severe acute or chronic renal disease should avoid using products containing pseudoephedrine.

Global burden of ADHD medication-associated cardiovascular disease, 1967–2023: A comparative analysis using the WHO pharmacovigilance database

BackgroundDespite the widespread use of attention-deficit hyperactivity disorder (ADHD) medications and their known sympathomimetic effects on the cardiovascular system, cardiovascular risk assessment of these medications using comprehensive global data is limited. This study investigated the association between individual ADHD medications and cardiovascular disease (CVD) using global pharmacovigilance data. MethodsReports from the World Health Organization international pharmacovigilance database were utilized (1967–2023; total reports, n=131,255,418). Reporting odds ratios (ROR), and information components (IC) were calculated to evaluate the association between each medication and specific CVDs. ResultsWe identified 13,344 CVD cases related to ADHD medications out of 146,489 cases of all reports on ADHD medications. Cumulative reports on ADHD medications have shown a steady increase, notably in adults since 2010. ADHD medications were associated with a higher risk of CVD overall (ROR [95 % CI], 1.60 [1.58–1.63]; IC [IC0.25], 0.63 [0.60]), with a higher association observed in females than in males. Among specific CVDs, all drugs were associated with an increased risk of torsade de pointes/QT prolongation, cardiomyopathy, and myocardial infarction. Conversely, heart failure, stroke, and cardiac death/shock were exclusively associated with amphetamines. Lisdexamfetamine showed a weaker association with all CVDs compared to amphetamines, and methylphenidate exhibited the lowest overall association with CVD. Atomoxetine had the second-highest association with torsade de pointes/QT prolongation. ConclusionsThe associations between CVDs and ADHD medications vary, with amphetamines posing a higher risk, while lisdexamfetamine and methylphenidate exhibit better safety profiles.

Study of Avicennan unani drug saad kufi (Cyperus scariosus R.Br) for cardiac activity on isolated Langendorff rat heart

Cardioprotective Unani drug, Saad Kufi (Cyperus scariosus R.Br.), mentioned by the intellectual colossus Ibn Sina (Avicenna) a thousand years back in his book, “Kitab al-Adviya al-Qalbia” and still widely used by Unani physicians, was selected for experimental study. The main objective of the study was to explore the trial drug ex vivo for validation, hemodynamic elucidation, and molecular mechanism identification for the improvement of Unani therapeutics and to identify a safe and effective novel cardiovascular drug for mainstream medicine. Five doses of 50% ethanolic extract of the physiochemically standardized root were studied in a normal rat heart, on a semi-automated Langendorff apparatus supported with an advanced data acquisition system, perfused with carbogenated non-recirculating Kreb’s-Hensleit solution, at constant flow mode, by continuous recording. The effect of 6 repetitions (n = 6) of each dose was studied with the following parameters on the Lab chart pro version: heart rate, left ventricular developed pressure, cardiac work, and coronary pressure. The significance of the difference was determined by the student’s “t” test. Results of all doses of Saad Kufi showed a significant increase in the above parameters. The maximum increase was observed by Dose III. It could be concluded that Unani’s clinical use of Saad Kufi (C. scariosus R.Br) as cardioprotective was validated and higher doses were indicated to be clinically optimal. Hemodynamically and molecular mechanism-wise, it is indicated to be a sympathomimetic or inotropic-like agent and possibly a direct vasodilator. Since existing long-term treatment of heart failure is not done by cardiac stimulants or positive inotropic and chronotropic agents, the possible future clinical demonstration of therapeutic improvement in heart failure will bring Saad Kufi as a novel drug in mainstream medicine.

Characterizing Relationships between T-cell Inflammation and Outcomes in Patients with High-Risk Neuroblastoma According to Mesenchymal and Adrenergic Signatures.

Adrenergic (ADRN) and mesenchymal (MES) lineages are distinct biologic cell types in neuroblastoma. We defined ADRN and MES specific genes and found that high-risk, ADRN tumors harboring elevated T-cell inflammation signatures had superior overall survival. Our findings bolster support for further developing immunotherapy-based approaches for children with high-risk neuroblastoma.

Cell state plasticity in neuroblastoma

Evolving evidence indicates that tumor cells can transdifferentiate between distinct transcriptionally-determined cell states with changes in resultant phenotypes, a phenomenon known as cellular plasticity. These transitions are not driven by genetic mutations and typically in contrast to normal developmental processes, may proceed bidirectionally. Here, we review the role of cellular plasticity in the aggressive childhood solid tumor, neuroblastoma. We discuss the detection of two cell states, termed mesenchymal (MES) and adrenergic (ADRN), their properties and the transcriptional circuitries that control them, their relation to the normal embryogenesis of the sympathetic nervous system and their potential role in drug resistance, escape from therapy and development of relapse.

New method for rapid detection and simultaneous determination of prohibited adrenergic drugs in sports using thin layer chromatography and image processing

This study presents a new method for simultaneous determination of fenoterol, procaterol, clenbuterol, terbutaline and isoprenaline drugs using thin-layer chromatography assisted by image analysis (HPTLC-IA) combined with sensitive detection modes. Separation of the selected drugs was obtained using HPTLC Silica gel 60 F254 plates and mixture of isopropyl alcohol, ethyl acetate and ammonia (20:25:1.5 v/v/v) as mobile phase. UV detection mode combined with the use of 2,2-diphenyl-1-picrylhydrazyl (DPPH•) and 2,2'-azino-bis (3-ethylbenzothiazoline)-6-sulfonic acid (ABTS+•) radicals were applied for the first time for sensible detection of the separated drugs. Grey, green, red and blue scales respectively were selected for image analysis and accurate quantification of spot area. According to the obtained result, the use of DPPH• and ABTS+• reagents revealed a higher sensitivity in detection and accurate quantification of the analyzed drugs. Lower limit of detection (LOD = 0.07 ± 0.03 µg/spot; 0.09 ± 0.03 µg/spot and 0.10 ± 0.04 µg/spot) was obtained for fenoterol, procaterol and terbutaline using the ABTS+• radical and red scale selection for image processing. With the exception of isoprenaline, the proposed HPTLC-IA method showed a good separation of fenoterol, procaterol, clenbuterol and terbutaline drugs from other compounds in urine samples. Good recovery was obtained for these drugs in spiked urine samples.

Beta2-Adrenergic Suppression of Neuroinflammation in Treatment of Parkinsonism, with Relevance for Neurodegenerative and Neoplastic Disorders.

There is a preliminary record suggesting that β2-adrenergic agonists may have therapeutic value in Parkinson's disease; recent studies have proposed a possible role of these agents in suppressing the formation of α-synuclein protein, a component of Lewy bodies. The present study focuses on the importance of the prototypical β2-adrenergic agonist epinephrine in relation to the incidence of Parkinson's disease in humans, and its further investigation via synthetic selective β2-receptor agonists, such as levalbuterol. Levalbuterol exerts significant anti-inflammatory activity, a property that may suppress cytokine-mediated degeneration of dopaminergic neurons and progression of Parkinsonism. In a completely novel finding, epinephrine and certain other adrenergic agents modeled in the Harvard/MIT Broad Institute genomic database, CLUE, demonstrated strong associations with the gene-expression signatures of anti-inflammatory glucocorticoids. This prompted in vivo confirmation in mice engrafted with human peripheral blood mononuclear cells (PBMCs). Upon toxic activation with mononuclear antibodies, levalbuterol inhibited (1) the release of the eosinophil attractant chemokine eotaxin-1, which is implicated in CNS and peripheral inflammatory disorders, (2) elaboration of the tumor-promoting angiogenic factor VEGFa, and (3) release of the pro-inflammatory cytokine IL-13 from activated PBMCs. These observations suggest possible translation to Parkinson's disease, other neurodegenerative syndromes, and malignancies, via several mechanisms.

Novel miRNA-inducing drugs enable differentiation of retinoic acid-resistant neuroblastoma cells.

Tumor cell heterogeneity in neuroblastoma, a pediatric cancer arising from neural crest-derived progenitor cells, poses a significant clinical challenge. In particular, unlike adrenergic (ADRN) neuroblastoma cells, mesenchymal (MES) cells are resistant to chemotherapy and retinoid therapy and thereby significantly contribute to relapses and treatment failures. Previous research suggested that overexpression or activation of miR-124, a neurogenic microRNA with tumor suppressor activity, can induce the differentiation of retinoic acid-resistant neuroblastoma cells. Leveraging our established screen for miRNA-modulatory small molecules, we validated PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, as a robust inducer of miR-124. A combination of PP121 and BDNF-activating bufalin synergistically arrests proliferation, induces differentiation, and maintains the differentiated state of MES SK-N-AS cells for 8 weeks. RNA-seq and deconvolution analyses revealed a collapse of the ADRN core regulatory circuitry (CRC) and the emergence of novel CRCs associated with chromaffin cells and Schwann cell precursors. Using a similar protocol, we differentiated and maintained MES neuroblastoma GI-ME-N and SH-EP cell lines, as well as glioblastoma LN-229 and U-251 cell lines, for over 16 weeks. In conclusion, our novel protocol suggests a promising treatment for therapy-resistant cancers of the nervous system. Moreover, these long-lived, differentiated cells provide valuable models for studying mechanisms underlying differentiation, maturation, and senescence.

Pathophysiology and pregnancy outcomes of ascites in preeclampsia-a scoping review.

Preeclampsia is a multisystem disorder associated with defective trophoblast invasion, maternal syndrome, and capillary endothelial leak. The presence of ascites/third space fluid accumulation increases the risk of maternal morbidity and mortality. The current criteria/guidelines of preeclampsia do not establish the presence of ascites as a marker of severity or recognize the timing and need for early delivery despite associated complications. Medline and Embase databases were searched to identify relevant literature, reported up to December 2023, regarding the pathophysiology, pregnancy outcome, and management of preeclampsia complicated with ascites. A total of 5 studies on pathophysiology and eight on pregnancy outcomes met the inclusion criteria, with 41 case reports on ascites in preeclampsia. The etiopathogenesis for the development of ascites in preeclampsia includes endothelial damage, capillary hyperpermeability, release of vasoconstrictive agents, reduced intravascular oncotic pressure, and raised intraabdominal pressure. The presence of ascites represents the extreme form of microvascular damage, which also correlates with the raised sFlt-1 levels in this condition. The adverse pregnancy outcomes include increased risk of congestive heart failure, eclampsia, renal failure, disseminated intravascular coagulation, acute respiratory distress syndrome, and maternal death. The presence of ascites in preeclampsia is associated with the deterioration of the maternal condition. Hence, it is indicative of preeclampsia with severe features and requires vigilant monitoring, and prompt delivery may be considered.

Lineage-dependence of the neuroblastoma surfaceome defines tumor cell state-dependent and independent immunotherapeutic targets.

Neuroblastoma is a heterogeneous disease with adrenergic (ADRN)- and therapy resistant mesenchymal (MES)-like cells driven by distinct transcription factor networks. Here, we investigate the expression of immunotherapeutic targets in each neuroblastoma subtype and propose pan-neuroblastoma and cell state specific targetable cell-surface proteins. We characterized cell lines, patient-derived xenografts, and patient samples as ADRN-dominant or MES- dominant to define subtype-specific and pan-neuroblastoma gene sets. Targets were validated with ChIP- sequencing, immunoblotting, and flow cytometry in neuroblastoma cell lines and isogenic ADRN-to-MES transition cell line models. Finally, we evaluated the activity of MES-specific agents in vivo and in vitro . Most immunotherapeutic targets being developed for neuroblastoma showed significantly higher expression in the ADRN subtype with limited expression in MES-like tumor cells. In contrast, CD276 (B7-H3) and L1CAM maintained expression across both ADRN and MES states. We identified several receptor tyrosine kinases (RTKs) enriched in MES-dominant samples and showed that AXL targeting with ADCT-601 was potently cytotoxic in MES-dominant cell lines and showed specific anti-tumor activity in a MES cell line-derived xenograft. Immunotherapeutic strategies for neuroblastoma must address the potential of epigenetic downregulation of antigen density as a mechanism for immune evasion. We identified several RTKs as candidate MES-specific immunotherapeutic target proteins for the elimination of therapy-resistant cells. We hypothesize that the phenomena of immune escape will be less likely when targeting pan-neuroblastoma cell surface proteins such as B7-H3 and L1CAM, and/or dual targeting strategies that consider both the ADRN- and MES-cell states. Cellular plasticity influences the abundance of immunotherapeutic targets.Subtype-specific targets may be susceptible to epigenetically-mediated downregulation.Immunotherapeutic targets in development, B7-H3 and L1CAM, show "pan-subtype" expression. Neuroblastoma is a lethal childhood malignancy that shows cellular plasticity in response to anti-cancer therapies. Several plasma membrane proteins are being developed as immunotherapeutic targets in this disease. Here we define which cell surface proteins are susceptible to epigenetically regulated downregulation during an adrenergic to mesenchymal cell state switch and propose immunotherapeutic strategies to anticipate and circumvent acquired immunotherapeutic resistance.

A case report of mephentermine dependence with mephentermine-induced psychosis

Abstract: Mephentermine is a cardiac stimulant with sympathomimetic effects which can be abused for bodybuilding. Athletes usually consume mephentermine at the advice of their trainers or peers to increase their stamina to exercise. The most common adverse effects experienced by the users were dependence and psychosis, which developed among chronic users. We report a case of a 37-year-old male, a gym trainer with mephentermine use who presented with schizophrenia-like psychosis.

Levels of circulating angiotensin-converting enzyme 2 are affected by acute exercise and correlate with markers of physical fitness in male athletes.

While under physiological conditions angiotensin-converting enzyme 2 (ACE2) is an antagonist of vasoconstrictive agents in the renin-angiotensin-aldosterone system (RAAS), in the context of SARS coronavirus 2 (SARS-CoV-2) ACE2 serves as the gateway into cells. Furthermore, RAAS has previously been shown to be influenced by exercise training and is suggested to be involved in skeletal muscle mass maintenance. Given this connection, the investigation of circulating ACE2 plasma protein concentration before and following acute and chronic endurance and resistance exercise could increase the understanding of the implications of the exposure of athletes to SARS-CoV-2. Therefore, this study investigated levels of circulating ACE2 in lifelong high-level trained endurance and resistance athletes and control subjects in response to either acute endurance or resistance exercise. Results show no baseline differences in absolute ACE2 concentration between groups, but a strong negative correlation with levels of fitness and positive correlation with BMI in control subjects. Furthermore, acute endurance exercise significantly increased ACE2 levels across all groups, but only in the strength group in response to resistance exercise. This indicates that circulating ACE2 plasma levels are influenced by levels of fitness and health, and that acute endurance exercise has a stronger effect on plasma ACE2 levels than resistance exercise.

Reversible Cerebral Vasoconstriction Syndrome during Cesarean Section Complicated by Seizure Activity, Intraparenchymal and Subarachnoid Hemorrhage

Body of the Abstract: (1) To report a rare case of Reversible Cerebral Vasoconstriction Syndrome (RCVS) and associated intraparenchymal and subarachnoid hemorrhage following induction of spinal anesthesia in an uncomplicated, elective C-section (2) To discuss its potentially life threatening or well-being altering effects (3) To review the pathophysiology, diagnosis and potential treatments of the syndrome. Introduction: Reversible cerebral vasoconstriction syndrome (RCVS) is a rare condition defined clinically by symptoms of a severe recurrent headache described as a thunderclap headache, cerebral vasoconstriction of at least two different arteries on imaging, and resolution of vasoconstriction within three months. Complications include non-aneurysmal subarachnoid hemorrhage, seizure, stroke, and intracerebral hemorrhage. More than half of cases of RCVS occur postpartum or after use of vasoactive substances such as adrenergic or serotonergic drugs. Triggers include illicit drugs, eclampsia, or strenuous physical or sexual activity. As RCVS most commonly occurs during the postpartum period, it is extremely rare to encounter RCVS during the antepartum or peripartum periods. There has been only one other reported case of RCVS while undergoing spinal anesthesia for a C-section. Presented is a patient diagnosed with RCVS after spinal anesthesia during an elective C-section subsequently complicated by seizure, intracerebral and subarachnoid hemorrhage. Case Presentation: A 32-yearold G2 now P2002 patient presented at 39 6/7 weeks gestational age for elective primary C-section for a history of delivery complications with the first pregnancy. Medical history was unremarkable. First pregnancy labor epidural analgesia was uncomplicated. Spinal anesthesia induction was uneventful. Shortly thereafter, dizziness was reported and hypotension and bradycardia (P 42, BP 76/41) developed. Treatment included IV Ephedrine and Glycopyrrolate. Frontal headache developed. The patient then developed a tonic-clonic seizure with gaze deviation and upper limb rigidity lasting 45 seconds. An oral airway was placed for respiratory assistance with 100% oxygen. The patient became alert five minutes later. Vital signs: BP 168/98 P 122.C-section was performed. After incision, the patient had a second tonic-clonic seizure lasting 30 seconds. Midazolam was given. A healthy baby was delivered with Apgars of 7 and 9. The C-section was otherwise uncomplicated. Postoperatively, the patient was alert with stable vital signs. The neurologic exam was intact. The CT showed a 1.9 x 3.8 x 1.2 cm intraparenchymal hemorrhage-right frontal lobe with a subarachnoid hemorrhage in both the right frontal lobe and right sylvian fissure. Exam was normal. Headache continued. Tertiary care facility transfer was arranged. Tertiary care evaluation with 24-hour EEG monitoring, CT angiography (CTA) and CT venogram showed no evidence of venous sinus or cortical vein thrombosis. Magnetic resonance imaging (MRI) and transcranial doppler showed vasospasm diagnostic of RCVS. Subsequent CTA showed vasospasm of three branches of the carotid artery. Hospital discharge occurred on day 6. Six-month neurological follow-up showed resolution of hemorrhage and minimal residual symptoms. Discussion: Literature review discovered only one other case of RCVS with induction of regional anesthesia. To our knowledge the associated seizure activity coupled with intraparenchymal/subarachnoid hemorrhages has not been previously reported. RCVS, an extremely rare phenomenon is estimated to occur in 0.26% of headache patients; is more frequent in middle aged women and may have variable triggering factors. It may be associated with antidepressants, illicit drugs or sympathomimetic meds. Pregnancy and vasoconstrictive meds are risk factors with an occurrence rate of 5%. The pathophysiology is unknown but felt to be due to impaired cerebral vessel autoregulation. It is hypothesized that other factors and substances including endothelial dysfunction, pro and antiangiogenic factors, serotonin, cytokines and vascular endothelial growth factor may play some role. While MRI and doppler imaging may be of assistance, CTA is most useful for diagnosis. Since static imaging alone does not confirm the diagnosis, most cases likely go undiagnosed. Rarely, complications of RCVS include stroke, seizure, cerebral hemorrhage and Posterior Reversible Encephalopathy Syndrome. There is no prophylactic or therapeutic treatment proven effective for RCVS. Recommendations include symptomatic treatment of the headache, blood pressure, and delivery if eclampsia is suspected. Calcium channel blockers are often used for vasodilatory effects, although they have not been proven to improve symptoms or outcome in RCVS. Conclusion: RCVS is a very rarely occurring vascular disorder occasionally seen postpartum. This is the first reported case of associated seizure activity and resultant intraparenchymal and subarachnoid hemorrhage occurring after induction of spinal anesthesia for an uncomplicated C-section. It demonstrates the need for awareness of this disorder as well as knowledgeable hemodynamic anesthesia management specific to its unique features. The RCVS diagnostic and management challenges dictate that case collection and research be continued.