Catecholamine Release Research Articles

Laparoscopic large adrenal mass resection: why we should be more careful?

BackgroundPheochromocytoma is a rare tumor originating from the adrenal medulla, and surgical removal is the main treatment. We report a case of large size pheochromocytoma that was removed laparoscopically without preoperative blockade of alfa adrenergic receptors.Case presentationA 58-y-old woman was referred to our center with incidentally found 7 cm right adrenal mass. She did not have any history of hypercatecholamine state, and 24 h urine test for catecholamine metabolites was in normal range; we thought there is no need for preoperative catecholamine blockade. She was scheduled for laparoscopic mass resection, and during the operation, there was no significant bleeding and no major hypertension or hypotension crisis. The final pathology report was pheochromocytoma.ConclusionAs the catecholamine release of pheochromocytoma may be periodic and inconsistent, the preoperative test should be repeated especially for large adrenal tumors.

Stress-Induced Diabetes: A Review.

It has long been established that stress has a significant impact on metabolic function. Type 2 diabetes may be initiated by psychological and physical stress. The central and peripheral nervous systems are both involved in the neuroendocrine framework that underlies the underlying processes. The release of catecholamines and a rise in serum glucocorticoid concentrations caused by psychological stress enhance the requirement for insulin and insulin resistance. Experiencing persistent hyperglycemia in people with diabetes may be influenced by stress. Blood sugar levels may rise due to hormones being released in response to stress. Although this has adaptive significance in a healthy patient, in the long run, it can cause insulin resistance and lead to diabetes. Additionally, diabetes may cause abnormalities in the regulation of these stress hormones.

β2-Adrenergic Receptor Signaling Pathway Stimulates the Migration and Invasion of Cancer Cells via Src Activation.

Chronic stress has been reported to stimulate the release of catecholamines, including norepinephrine (NE) and epinephrine (E), which promote cancer progression by activating the adrenergic receptor (AR). Although previous studies showed that β2-AR mediated chronic stress-induced tumor growth and metastasis, the underlying mechanism has not been fully explored. In this study, we aimed to investigate the molecular mechanism by which β2-AR exerts a pro-metastatic function in hepatocarcinoma (HCC) cells and breast cancer (BC) cells. Our results showed that Hep3B human HCC cells and MDA-MB-231 human BC cells exhibited the highest ADRB2 expression among diverse HCC and BC cell lines. NE, E, and isoprenaline (ISO), adrenergic agonists commonly increased the migration and invasion of Hep3B cells and MDA-MB-231 cells. The phosphorylation level of Src was significantly increased by E/NE. Dasatinib, a Src kinase inhibitor, blocked E/NE-induced migration and invasion, indicating that AR agonists enhanced the mobility of cancer cells by activating Src. ADRB2 knockdown attenuated E/NE-induced Src phosphorylation, as well as the metastatic ability of cancer cells, suggesting the essential role of β2-AR. Taken together, our results demonstrate that chronic stress-released catecholamines promoted the migration and invasion of HCC cells and BC cells via β2-AR-mediated Src activation.

Takotsubo Syndrome

Abstract Takotsubo syndrome occurs in 1-2% of patients admitted in the emergency department with suspicion of ST-segment elevation myocardial infarction (STEMI), over 90% being postmenopause women. Psycho-emotional or physical stress is the main trigger that causes the release of catecholamines, with an important role in the pathophysiology of Takotsubo cardiomyopathy. In most cases, supportive and symptomatic treatment is sufficient, with a dynamic follow-up of the left ventricular (LV) function. Usually, a complete recovery occurs in 3-4 weeks. We are presenting the case of a 67-year-old patient with a severe angina attack which occuredafter a major psycho-emotional stress, with an electrocardiographic appearance of an anterior STEMI and echocardiographic apical ballooning, both compatible with Takotsubo syndrome. Coronary angiography showed a muscle bridge with a systolic compression of 75% on the anterior descending artery (ADA). The evolution was marked by the occurrence of cardiogenic shock remitted under treatment, with complete recovery of LV systolic function. The particularity of the case resides in an acute coronary syndrome (ACS) after a psycho-emotional stress associated with a muscular bridge, as well as the appearance of the cardiogenic shock.

6-nitrodopamine is a major endogenous modulator of human vas deferens contractility.

Rat isolated vas deferens releases 6-nitrodopamine (6-ND), and the spasmogenic activity of this novel catecholamine is significantly reduced by tricyclic compounds such as amitriptyline, desipramine, and carbamazepine and by antagonists of the α1 -adrenergic receptors such as doxazosin, tamsulosin, and prazosin. To investigate the liberation of 6-ND by human epididymal vas deferens (HEVDs) and its pharmacological actions. The in vitro liberation of 6-ND, dopamine, noradrenaline, and adrenaline from human vas deferens was evaluated by LC-MS/MS. The contractile effect of the catecholamines in HEVDs was investigated in vitro. The action of tricyclic antidepressants was evaluated on the spasmogenic activity ellicited by the catecholamines and by the electric-field stimulation (EFS). The tissue was also incubated with the inhibitor of nitric oxide (NO) synthase L-NAME and the release of catecholamines and the contractile response to EFS were assessed. 6-ND is the major catecholamine released from human vas deferens and its synthesis/release is inhibited by NO inhibition. The spasmogenic activity elicited by EFS in the human vas deferens was blocked by tricyclic antidepressants only at concentrations that selectively antagonize 6-ND induced contractions of the human vas deferens, without affecting the spasmogenic activity induced by dopamine, noradrenaline, and adrenaline in this tissue. Incubation of the vas deferens with L-NAME reduced both the 6-ND release and the contractions induced by EFS. 6-ND should be considered a major endogenous modulator of human vas deferens contractility and possibly plays a pivotal role in the emission process of ejaculation. It offers a novel and shared mechanism of action for tricyclic antidepressants and α1 -adrenergic receptor antagonists.

COMPARISON OF NTG VS DEXMEDETOMIDINE FOR CONTROL OF HAEMODYNAMIC RESPONSE IN PATIENTS DURING EMERGENCE FROM ANAESTHESIA AND EXTUBATION FOLLOWING LAPAROSCOPY

Endotracheal intubation as well as extubation are associated with various cardiovascular and airway responses leading to increase in heart rate (tachycardia), hypertension (HTN), cardiac arrhythmias, myocardial ischemia (MI), coughing, agitation, bronchospasm, increased bleeding, raised intracranial tension etc. Pneumoperitoneum creation in laparoscopic surgeries, leads to adverse changes in various systems of human body including cardiovascular, respiratory and acid base balance system. Various factors which leads to haemodynamic changes in patient are release of catecholamine, carbon di-oxide absorption, vasopressin release and position of the patient. NTG generate NO (Nitric oxide) which causes vasodilatation in vascular smooth muscle leading to decrease in blood pressure. It also relaxes the respiratory tract smooth muscle and hence it is preferred by anaesthesiologist to prevent laryngospasm. Dexmedetomidine is an 2-adrenoreceptor agonist used to facilitate the extubation after surgeries. Dexmedetomidine used in the intraoperative period causes decrease in serum catecholamine levels by 90%, which in turn blunts the haemodynamic response to laryngoscopy, tracheal intubation, pneumo-peritoneum and extubation. So we did the comparative study between IV dexmedetomidine and IV NTG on hemodynamic response during extubation in laparoscopic surgeries. To study and compare the effect of intravenous nitro-glycerine (NTG) with dexmedetomidine in patients undergoing laparoscopic surgery and during recovery in terms of haemodynamic response during tracheal extubation, airway reexes during tracheal extubation by using extubation quality score, sedation by using Ramsay Sedation Scale & side effects of drug. 60 patients of ASA grade 1 and 2 undergoing laparoscopic surgery were divided into two groups of thirty each. GROUP D (n=30) will receive Dexmedetomidine infusion at the rate of 0.75 mics/kg over 10 minutes and GROUP N (n=30) will receive NTG infusion at the rate of 2 mics/kg over 10 minutes .patients were assessed on the basis of ramsay sedation scale , extubation quality scale and vas scale every 1, 3, 5, 10 and 15 minutes. When both the groups were compared it was found out there was statistically signicant difference in dexmedetomidine group as compared to NTG in terms of decrease in HR , BP, SBP , DBP, MAP , extubation quality score , ramsay sedation scale, and VAS scale .there was no overall complication in both groups. In conclusion, the Dexmedetomidine at a dose of 0.75µg/kg body weight as compared to NTG ( 2 µg/kg body weight )when administered as infusion over 10 minutes, before tracheal extubation attenuates the airway reexes and hemodynamic responses effectively during emergence from anaesthesia providing smooth extubation. It provide adequate sedation, maintaining patient's arousability and delay the need for analgesia in the post-operative period.

Brain fog in neuropathic postural tachycardia syndrome may be associated with autonomic hyperarousal and improves after water drinking.

BackgroundBrain fog is a common and highly disturbing symptom for patients with neuropathic postural tachycardia syndrome (POTS). Cognitive deficits have been measured exclusively in the upright body position and mainly comprised impairments of higher cognitive functions. The cause of brain fog is still unclear today. This study aimed to investigate whether increased autonomic activation might be an underlying mechanism for the occurrence of brain fog in neuropathic POTS. We therefore investigated cognitive function in patients with neuropathic POTS and a healthy control group depending on body position and in relation to catecholamine release as a sensitive indicator of acute stress. The second aim was to test the effect of water intake on cardiovascular regulation, orthostatic symptoms, cognitive function and catecholamine release.MethodsThirteen patients with neuropathic POTS and 15 healthy control subjects were included. All participants completed a total of four rounds of cognitive testing: two before and two after the intake of 500 ml still water, each first in the supine position and then during head-up tilt. At the end of each cognitive test, a blood sample was collected for determination of plasma catecholamines. After each head-up tilt phase participants were asked to rate their current symptoms on a visual analogue scale.ResultsWorking memory performance in the upright body position was impaired in patients, which was associated with self-reported symptom severity. Patients had elevated plasma norepinephrine independent of body position and water intake that increased excessively in the upright body position. The excessive increase of plasma norepinephrine was related to heart rate and symptom severity. Water intake in patients decreased norepinephrine concentrations and heart rate, and improved symptoms as well as cognitive performance.ConclusionBrain fog and symptom severity in neuropathic POTS are paralleled by an excessive norepinephrine secretion. Bolus water drinking down-regulates norepinephrine secretion and improves general symptom severity including brain fog.

Canine phaeochromocytoma: diagnosis and surgical management

Although pheochromocytomas are uncommon in dogs, awareness of this type of adrenal tumour is important because of the life-threatening consequences related to their functionality. Pheochromocytomas may periodically produce catecholamines, accounting for many of the intermittent clinical signs seen, the inconsistent nature of which can make pheochromocytomas challenging to diagnose. The treatment of choice is surgical excision and optimal outcome relies on careful perioperative medical management to decrease the anaesthetic risk associated with paroxysmal release of catecholamines during surgical manipulation. Both surgical and anaesthetic management can be extremely challenging in cases of pheochromocytoma. However, in cases in which metastasis has not occurred, good survival times are achievable.

Effect of single bolus dose of intravenous magnesium sulfate in attenuating hemodynamic stress response to laryngoscopy and nasotracheal intubation in maxillofacial surgeries

Background: Nasotracheal intubation alters respiratory and cardiovascular physiology by reflex response mediated by both sympathetic and parasympathetic nervous systems and by the physical presence of the nasotracheal tube. Hypertension and tachycardia are the most common responses to intubation mediated by sympathetic efferent through cardio accelerator nerve and sympathetic chain ganglia. MgSO4 inhibits catecholamine release from adrenergic nerve endings and adrenal medulla resulting in attenuation of stress response. Aims and Objectives: In this study, we observed the effects of MgSO4 on the hemodynamic stress response. Materials and Methods: This prospective randomized controlled study was conducted on 60 patients after approval of the Institutional Ethics and Scientific Review committee over the period of 1 year. They were divided into two groups, Group M (MgSO4 group) received 40 mg/kg of intravenous magnesium sulfate in 100 ml normal saline and Group C (control group) received normal saline 10 min before induction. Hemodynamic parameters (HR, SBP, DBP, and MAP) were recorded at baseline, just before induction and at 1, 3, 5, 10, 15, and 30 min after intubation and every 15 min till the end of surgery. Results: After conducting this study, we observed that heart rates at 1, 3, 5, and 10 were significantly lower in the M group as compared to the C group (P<0.05). Systolic, diastolic, and mean blood pressure were also reduced significantly in the M group as compared to the C group (P<0.05). Conclusion: Magnesium sulfate when used at the dose of 40 mg/kg attenuates the hemodynamic stress response during laryngoscopy and nasotracheal intubation.

The Impact of Mental Stress on Cardiovascular Health-Part II.

Endothelial dysfunction is one of the earliest manifestations of atherosclerosis, contributing to its development and progression. Mental stress induces endothelial dysfunction through increased activity of the sympathetic nervous system, release of corticotropin-releasing hormone from the hypothalamus, inhibition of nitric oxide (NO) synthesis by cortisol, and increased levels of pro-inflammatory cytokines. Mental-stress-induced increased output of the sympathetic nervous system and concomitant withdrawal of the parasympathetic inflammatory reflex results in systemic inflammation and activation of a neural–hematopoietic–arterial axis. This includes the brainstem and subcortical regions network, bone marrow activation, release of leukocytes into the circulation and their migration to the arterial wall and atherosclerotic plaques. Low-grade, sterile inflammation is involved in all steps of atherogenesis, from coronary plaque formation to destabilisation and rupture. Increased sympathetic tone may cause arterial smooth-muscle-cell proliferation, resulting in vascular hypertrophy, thus contributing to the development of hypertension. Emotional events also cause instability of cardiac repolarisation due to brain lateralised imbalance of cardiac autonomic nervous stimulation, which may lead to asymmetric repolarisation and arrhythmia. Acute emotional stress can also provoke severe catecholamine release, leading to direct myocyte injury due to calcium overload, known as myocytolysis, coronary microvascular vasoconstriction, and an increase in left ventricular afterload. These changes can trigger a heart failure syndrome mimicking acute myocardial infarction, characterised by transient left ventricular dysfunction and apical ballooning, known as stress (Takotsubo) cardiomyopathy. Women are more prone than men to develop mental-stress-induced myocardial ischemia (MSIMI), probably reflecting gender differences in brain activation patterns during mental stress. Although guidelines on CV prevention recognise psychosocial factors as risk modifiers to improve risk prediction and decision making, the evidence that their assessment and treatment will prevent CAD needs further evaluation.

Pediatric Metastatic Pheochromocytoma and Paraganglioma: Clinical Presentation and Diagnosis, Genetics, and Therapeutic Approaches

Although pediatric pheochromocytomas and paragangliomas (PPGLs) are rare, they have important differences compared to those in adults. Unfortunately, without timely diagnosis and management, these tumors have a potentially devastating impact on pediatric patients. Pediatric PPGLs are more often extra-adrenal, multifocal/metastatic, and recurrent, likely due to these tumors being more commonly due to a genetic predisposition than in adults. This genetic risk results in disease manifestations at an earlier age giving these tumors time to advance before detection. In spite of these problematic features, advances in the molecular and biochemical characterization of PPGLs have heralded an age of increasingly personalized medicine. An understanding of the genetic basis for an individual patient’s tumor provides insight into its natural history and can guide clinicians in management of this challenging disease. In pediatric PPGLs, mutations in genes related to pseudohypoxia are most commonly seen, including the von Hippel-Lindau gene (VHL) and succinate dehydrogenase subunit (SDHx) genes, with the highest risk for metastatic disease associated with variants in SDHB and SDHA. Such pathogenic variants are associated with a noradrenergic biochemical phenotype with resultant sustained catecholamine release and therefore persistent symptoms. This is in contrast to paroxysmal symptoms (e.g., episodic hypertension, palpitations, and diaphoresis/flushing) as seen in the adrenergic, or epinephrine-predominant, biochemical phenotype (due to episodic catecholamine release) that is commonly observed in adults. Additionally, PPGLs in children more often present with signs and symptoms of catecholamine excess. Therefore, children, adolescents, and young adults present differently from older adults (e.g., the prototypical presentation of palpitations, perspiration, and pounding headaches in the setting of an isolated adrenal mass). These presentations are a direct result of genetic determinants and highlight the need for pediatricians to recognize these differences in order to expedite appropriate evaluations, including genetic testing. Identification and familiarity with causative genes inform surveillance and treatment strategies to improve outcomes in pediatric patients with PPGL.

G Protein-Coupled Receptors-Receptors With New Tricks Up Their Sleeves.

G Protein-Coupled Receptors-Receptors With New Tricks Up Their Sleeves.

The effect of mild dynamic exercise on the electromechanical systole of heart in non-athlete, healthy first year medical students of Bengal as a predictive biomarker of arrhythmia

Introduction and Aim: Measurement of Systolic Time Intervals (STIs) is a non-invasive and convenient way of assessing left ventricular electro-mechanical activity. In this study, we assessed effect of mild dynamic exercise on QT, QS2, QT/QS2 ratio, QS2-Index among healthy young first year students at a government medical college of West Bengal, India and compared the same among girls and boys. Materials and Methods: IX-TA-220 multichannel recorder was used to record Electrocardiogram, Phonocardiogram and Carotid pulse tracing among 180 subjects before and after 1 minute of mild exercise with Harvard's Step of 30 cm height with metronome rhythm of 120 beats per minute. Results were analyzed by Microsoft Excel and comparison of each parameter between boys and girls were done using SPSS software in two hemodynamic states. P-value <0.05 was taken as statistically significant. Results: Post exercise mean QT and QS2 shortened and their ratio QT/QS2 increased. There was a statistically significant difference between pre-exercise and post-exercise mean QT, QT/QS2 ratio, QS2 index and significant differences were observed between mean values of the boys and girls. Conclusion: With hemodynamic changes as in exercise, due to sympathetic stimulation & catecholamine release, both QT andQS2 should reduce as all the phases of systole shorten but if QT does not reduce in comparison to QS2 it may lead to arrhythmia in future. Hence QT/QS2 can be a useful pro-arrhythmic biomarker and may complement ECG and Echocardiography in borderline cases.

Comparision of intravenous magnesium sulphate and lignocaine in attenuation of pressor response to laryngoscopy and endotracheal intubation

Endotracheal intubation and laryngoscopy are noxious stimuli and provoke cardiovascular and autonomic responses because of sympathoadrenal stimulation. Attenuation of significant increases in heart rate and blood pressure decreases the risk of complications.Various pharmacological and non-pharmacological methods have been tried to attenuate hemodynamic response to laryngoscopy and endotracheal intubation. None of the approaches have proved to be ideal.In view of it present study was undertaken to evaluate and compare effects of intravenous magnesium sulphate 30mg/kg and lignocaine 2mg/kg in attenuation of pressor response to laryngoscopy and endotracheal intubation.Prospective randomized controlled study was conducted in which 60 American society of Anesthesiologist 1 patients, aged 18-60yrs, undergoing elective surgery under general anesthesia were selected. Patients were randomized into 2 groups: Group 1 with thirty patients who received MgSO4 30mg/kg and Group 2 with thirty patients who received lignocaine 2 mg/kg intravenous bolus. Anesthesia was induced using premedication glycopyrolate, midazolam, ondansetron injection Fentanyl was administered as analgesic agent. Study drug Injection mgso4 was administered 90sec before induction with injection propofol as induction agent followed by injection succinylscoline to facilitate intubation. Laryngoscopy and intubation response in both groups were studied by recording Heart Rate (HR), blood pressure (BP), at baseline,after administering drug, at laryngoscopy, after intubation, 1min,3min,5minsafter intubation.Study revealed that Group 1 patients had significant decreasing trend in HR and MAP recorded till 5mins after intubation. Mgso4 has vasodilator properties and significantly suppresses release of catecholamines and hence can attenuate stress response to laryngoscopy and endotracheal intubation better than lignocaine.

Takotsubo can also occur during minimally invasive treatment of paraganglioma liver metastasis!

Pheochromocytomas and paragangliomas are catecholamines’ producing tumors with metastatic potential. In expert centers, new techniques have been developed, especially for the management of metastases in interventional radiology. However, during any therapeutic procedure, there is a risk of release of catecholamines. Intraoperative complications are poorly documented during interventional radiology. This case reports a cardiac decompensation during the management of liver metastasis of a paraganglioma by chemoembolization and cryotherapy. The main message of this case study is that cardiovascular events can occur also during interventional radiology management. These procedures require education and close collaboration between the radiologist and the anaesthetiologist.

Inhibition of Sympathetic Activation by Delivering Calcium Channel Blockers from a 3D Printed Scaffold to Promote Bone Defect Repair.

Enhancing osteogenesis by promoting neural network reconstruction and neuropeptide release is considered to be an attractive strategy for repairing of critical size bone defects. However, traumatic bone defects often activate the damaged sympathetic nervous system (SNS) in the defect area and release excessive catecholamine to hinder bone defect repair. Herein, a 3D printed scaffold loaded with the calcium channel blocker-nifedipine is proposed to reduce the concentration of catecholamine present in the bone defect region and to accelerate bone healing. To this end, nifedipine-loaded ethosome and laponite are added into a mixed solution containing sodium alginate, methacrylated gelatin, and bone mesenchymal stem cells (BMSCs) to prepare a cell-laden scaffold using 3D bioprinting. The released nifedipine is able to close the calcium channels of nerve cells, thereby blocking sympathetic activation and ultimately inhibiting the release of catecholamine by sympathetic nerve cells, which further promotes the osteogenic differentiation and migration of BMSCs, inhibits osteoclastogenesis in vitro, and effectively improves bone regeneration in a rat critical-size calvarial defect model. Therefore, the results suggest that sustained release of nifedipine from the scaffold can effectively block SNS activation, providing promising strategies for future treatment of bone defects.

Paraganglioma of the urinary bladder initially diagnosed as gastrointestinal stromal tumor requiring combined resection of the rectum: a case report

BackgroundParaganglioma of the urinary bladder (Pub) is rare and presents with clinical symptoms caused by catecholamine production and release. The typical symptoms of Pub are hypertension, macroscopic hematuria, and a hypertensive crisis during micturition. The average size of detected Pubs is approximately 3 cm. Herein, we report a case of a large Pub in which the symptoms were masked by oral medication, precise preoperative diagnosis was difficult, and intraoperative confirmation of tumoral adhesion to the rectum resulted in hypertensive attacks during surgery.Case presentationA 64-year-old Japanese male with a history of hypertension and arrhythmia controlled with oral medication presented with a large tumor in the pelvic region, detected on examination for weight loss, with no clinical symptoms. Computed tomography and magnetic resonance imaging revealed a tumor measuring 77 mm in diameter in the posterior wall of the urinary bladder. The border with the rectum was unclear, and the tumor showed heterogeneous enhancement in the solid part with an enhancing hypodense lesion. Cystoscopy revealed compression of the bladder trigone by external masses; however, no tumor was visible in the lumen. Endoscopic ultrasonography-guided fine-needle aspiration revealed CD34-positive spindle-shaped cells in the fibrous tissue, suggestive of a mesenchymal neoplasm. The tumor was suspected to be a gastrointestinal stromal tumor, and surgery was performed. After laparotomy, we suspected that the tumor had invaded the rectum, and total cystectomy and anterior resection of the rectum were performed. Histologically, the tumor cells had granular or clear amphophilic cytoplasm with an oval nucleus and nests of cells delimited by connective tissue and vascular septations. Immunohistochemically, the tumor was positive for chromogranin A, CD56, and synaptophysin, and a diagnosis of paraganglioma of the urinary bladder was confirmed. There was no tumor recurrence at the 7-month follow-up.ConclusionThis case highlights the importance of careful examination of pelvic tumors, including endocrine testing, for detecting paraganglioma of the urinary bladder in patients with a history of hypertension or arrhythmia.

Supportive management of patients with pheochromocytoma/paraganglioma undergoing noninvasive treatment.

Many publications review perioperative management of pheochromocytomas/paragangliomas (PPGLs); however, a large population, including 10-20% of metastatic PPGL patients, have inoperable disease. This has necessitated the development of noninvasive treatments (e.g., radio/chemotherapy), which, in affording disease-modification, have led to an ever-growing population of surviving patients with inoperable PPGL. These patients experience debilitating symptoms arising from discomforts related to the masses themselves (e.g., pain from osseous metastasis) and symptoms from tumoral catecholamine production and release. Unfortunately, management of these conditions is not yet well-defined. Adding further insult-to-injury, these noninvasive treatments can trigger catecholamine release, worsening catecholamine-induced symptoms. Herein, we detail these ailments and their management, especially while patients receive these noninvasive treatments. Improved diagnostic evaluations have allowed for earlier detection of PPGL, prolonging survival in patients with inoperable PPGLs. Accordingly, noninvasive treatment strategies have rapidly evolved alongside state-of- the-art theranostics and genetic testing, which inform ongoing management and therapeutic response. While treatments afford improved survival, there must be a corresponding attention to quality-of-life. This is ensured by employing supportive management, which mitigates debilitating symptoms. This is best accomplished with a multidisciplinary approach and familiarity with genetic and biochemical determinants which guide patient education and management.

0800 Dozing off is a problem, as is a toe falling off - Methylphenidate induced Raynaud’s phenomenon

Abstract Introduction Narcolepsy is a clinical syndrome characterized by a constellation of symptoms including excessive daytime sleepiness, cataplexy, sleep paralysis and sleep hallucinations. Stimulants are commonly used to treat hypersomolence associated with narcolepsy. Common adverse reactions reviewed with patients prior to initiation of amphetamines include decreased appetite, nausea, xerostomia, headache, insomnia, tachycardia and hypertension. A relatively rare concern with stimulants is development of peripheral vasculopathy including Raynaud’s phenomenon. Report of Cases: A 25-year-old female with past medical history of anxiety, depression and obstructive sleep apnea in childhood was treated with tonsillectomy and adenoidectomy. Over the years, she continued to have persistent hypersomnolence, auditory hypnogogic hallucinations with no symptoms of sleep paralysis or cataplexy. She had a polysomnography (PSG) along with multiple sleep latency test (MSLT). PSG did not show evidence of sleep apnea with an AHI of 0.96 per hour. MSLT confirmed the diagnosis of Narcolepsy, Type 2, with a mean sleep onset latency of 3.6 minutes and five sleep-onset REM periods (SOREMPs). She was started on 400mg daily of Modafinil and 20mg daily of Methylphenidate. After a month of using methylphenidate, she noticed purplish discoloration of her digits, sometimes with exposure to cold, other times with no obvious triggers, consistent with development of Raynaud’s phenomenon. The proposed mechanism is that use of methylphenidate causes excessive release of catecholamines due to inhibition of the reuptake of dopamine and norepinephrine, leading to peripheral vasoconstriction. As the patient’s hypersomnolence persisted, she was started on sodium oxybate and the dosage of methylphenidate was decreased to 10mg daily and eventually discontinued. With reduction in the dosage and discontinuation of methylphenidate, symptoms of Raynaud’s phenomenon improved. Conclusion Dose-related peripheral vasculopathy including Raynaud’s phenomenon has been reported in several case reports with the use of methylphenidate. Awareness of this relatively rare adverse effect is imperative among sleep physicians as it could cause significant delay in the diagnosis, management of Raynaud’s phenomenon and its complications including critical digital ischemia and gangrene. Dose adjustments and discontinuation of methylphenidate should be considered in the treatment course of the patients with such concern. Support (If Any)

Full-fusion and kiss-and-run in chromaffin cells controlled by irreversible vesicle size-dependent fusion pore transitions

Exocytosis operates through two distinct modes. Full-fusion leads to rapid expulsion of the entire content of a vesicle; kiss-and-run leads to slow and partial expulsion. These two modes have important biological consequences for endocrine regulation and synaptic transmission. Amperometry recordings of catecholamine release from chromaffin cells reveal single-vesicle fusion events corresponding to both of these modes, but classification is often difficult. This study introduces a new method of analyzing amperometry data to improve this classification. The ratio of the average amplitude to the peak amplitude differs between full-fusion and kiss-and-run, and the probability distribution of this ratio is well fitted by a double-Gaussian. Kiss-and-run events identified by this method have fusion pores with kinetic properties different from pores associated with full-fusion. They have slower transition rates and lifetime distributions indicative of irreversible transitions. The total-charge of an amperometric spike is expected to scale with vesicle volume during a full-fusion event. The cube root of this quantity should therefore scale with diameter, but the distribution of this quantity differs from the distribution of vesicle diameter seen in the electron microscope. Fusion pore lifetimes associated with full-fusion depend on vesicle size, and this makes the choice of mode size dependent. The fusion pore thus bifurcates after opening, and vesicle size influences this choice. The secretory vesicle protein synaptophysin influences the size dependence of fusion pore lifetime and the choice of release mode. Incorporating vesicle size into an analysis of release mode reconciled the kinetics of fusion pores, as well as the distributions of vesicle diameter and catecholamine content. Thus, the initial fusion pore emerges as a critical focus in endocrine regulation. By modulating the size-dependence of the mode of exocytosis, changes in the molecular makeup of the exocytotic apparatus can impact the shape and size of an amperometric event, and the speed and composition of secretion.