The objective of this study was to evaluate phytochemicals present in the resin of Garcinia indica (Gamboge). We assessed the phytochemical constituents and antioxidant potential of acetone, methanol, and water extracts of resin. Acetone and methanol extracts contain a high amount of phenolics (183.90 and 182.85 mg GAE (gallic acid equivalent)/g) and flavonoids (72.65 and 71.33 mg QE (quercetin equivalent)/g), respectively, whereas methanol extract had the highest 7.62 mg AE (atropine equivalent)/g of alkaloid. GC-MS analysis of acetone extract identified 15 compounds and the majority of them were terpenoids, and 9,19-cyclo-25,26-epoxyergostan-3-ol,4,4,14-trimethyl-, acetate was the major compound among all terpenoids. Both acetone and methanol extracts showed excellent antioxidant activity as assessed by DPPH, total antioxidant activity, and FRAP assays. This experimental evidence suggests that G. indica resin is an excellent source of bioactive compounds and can be explored for its medicinal applications.

Although not routinely used, cardioneuroablation or modulation of the cardiac autonomic nervous system has been proposed as an alternative approach to treat young individuals with enhanced vagal tone and significant atrioventricular (AV) disturbances.We report the case of a 42-year-old athlete with prolonged ventricular pauses associated with sinus bradycardia and paroxysmal episodes of AV block (maximum of 6.6 s) due to enhanced vagal tone who was admitted to our hospital for pacemaker implantation. Cardiac magnetic resonance and stress test were normal. Although he was asymptomatic, safety concerns regarding possible neurological damage and sudden cardiac death were raised, and he accordingly underwent electrophysiological study (EPS) and cardiac autonomic denervation. Mapping and ablation were anatomically guided and radiofrequency pulses were delivered at empirical sites of ganglionated plexi. Modulation of the parasympathetic system was confirmed through changes in heart rate and AV nodal conduction properties associated with a negative cardiac response to atropine administration.After a follow-up of nine months, follow-up 24-hour Holter revealed an increase in mean heart rate and no AV disturbances, with rare non-significant ventricular pauses, suggesting that this technique may become a safe and efficient procedure in this group of patients.

Cholinergic muscarinic stimulation of vast areas of the limbic brain induced a well-documented polydipsia in laboratory rats. This excessive water-drinking behavior has not received any convincing biological and physiological interpretation for the last 50 years. This review offers such an interpretation and suggests that cholinergically induced drinking response, mostly by carbachol, is associated with activation of the ascending mesolimbic cholinergic system that serves for initiation of emotional aversive arousal of the organism. The ascending cholinergic system originates from the laterodorsal tegmental nucleus, has a diffuse nature, and affects numerous subcortical limbic structures. It is proposed that the carbachol-induced drinking response is related to the state of anxiety and does not serve the regulation of thirst. Instead, the response is anxiety-induced polydipsia that might occur as a soothing procedure that decreases the aversiveness of the negative emotional state induced by carbachol. It is concluded that carbachol-induced water-drinking behavior is a rewarding process that contributes to alleviating the feeling of anxiety by bringing some relief from the cholinergically induced aversive state, and it is a homologue to anxiety-driven polydipsia in humans.

Paxlovid (nirmatrelvir/ritonavir) is a game changer in the fight against COVID-19 due to its ease of administration and significant benefits of reducing progression to severe COVID-19, hospitalization, and death. Cardiac adverse events such as bradycardia and syncope are not known with this medication. We report a case of a 71-year-old patient who developed symptomatic bradycardia, syncopal episodes, and sinus pause after taking Paxlovid. Discontinuing medication and intravenous atropine helped to reverse the bradycardia and symptoms promptly. She did not require a pacemaker. We would like to report this possible association between Paxlovid and bradycardia. Until further information or studies are available, it is advised to promptly discontinue Paxlovid after any evidence of bradycardia and closely monitor for at least 40 hours in a hospital setting. The reported half-life (t 1/2) of the medication is 6.05 ± 1.79 hours and using 8 hours as a reference for the upper limit of t 1/2, around 97 % of the medication should be cleared off in about 40 hours (five half-lives).

Trigeminocardiac reflex (TCR) can result in bradycardia and even cardiac arrest, and is reversible with elimination of the stimulus. Here, we report the case of a 68-year-old man who experienced cardiac arrest during percutaneous balloon compression for the treatment of trigeminal neuralgia. In this patient, sinus rhythm did not recover after stimulation removal, causing us to successfully perform cardiopulmonary resuscitation (CPR). The patient regained a sinus rhythm and was pretreated with atropine 0.5 mg, allowing the operation to be started again. The operation was completed successfully and the patient experienced no complications. Subsequent heart rate variability (HRV) analysis showed that parasympathetic activity predominated before anesthesia induction and after tracheal intubation. It further elevated during foramen ovale puncture, leading to prolonged asystole. Fortunately, sympathetic activity predominated after atropine was administered, which manifested as an increase in sympathetic activity and a decrease in parasympathetic activity. This could be beneficial for patients with TCR. This case indicates that TCR-related cardiac arrest might not be reversed with stimulus cessation, and atropine played a key role in preventing TCR. Moreover, HRV analysis might be essential for preoperative screening for high-risk patients. We also reviewed the literature for cases of TCR with prolonged asystole.

Eliglustat is an orphan medicine used for long-term treatment of Gaucher disease type 1 (GD1) in adults. GD1 is a genetic condition, in which glucosylceramide builds up in the body, typically in liver, spleen, and bone. Clinical signs and symptoms of the disease are anemia, tiredness, easy bruising, hepatosplenomegaly, bone pain, and fractures. Eliglustat works by blocking glucosylceramide synthase (substrate reduction therapy). This medicine is subject to additional safety monitoring by regulatory authorities in the European Union. Scientific literature on eliglustat overdose is not available. We herein describe successful treatment of a suicidal attempt with massive eliglustat overdose. A 29-year-old female with GD1, a poor metabolizer of cytochrome P450 2D6 on a recommended daily dose of 84 mg of eliglustat, had taken 94 capsules of eliglustat (84 mg per capsule). One hour after ingestion of almost 8 g of eliglustat, the patient suffered from somnolence, severe bradycardia (37 bpm), and hypotension (systolic blood pressure of 70 mm Hg). After intravenous administration of atropine (1 mg) and cafedrine/theoadrenaline (100 mg/5 mg) by the called emergency physician, the patient resolved gradually. She remained 24 h with stable hemodynamics at a nearby intensive care unit. During continuous ECG monitoring, increased frequency of supraventricular ectopic activity and a first-degree atrioventricular block were observed. To our knowledge, this is the first case report on a suicidal attempt with eliglustat.

The perioperative cardiac events may be brought about by a relative imbalance of autonomic activities due to excessive psychological and physical stress. The present case study focuses on the asystole that can occur as a serious cardiac adverse event associated with vasovagal reflex likely to be triggered by venipuncture for securing an intravenous line during dental care. In addition, we describe and discuss herein the management of intravenous sedation for a dental phobic patient who experienced the vasovagal reflex involved in an unexpected transient asystole. The patient with vasovagal reflex episodes in daily life, who had no past medical history relevant to cardiovascular disorders, was scheduled for dental extraction under intravenous sedation. Immediately after peripheral intravenous catheterization, she complained of discomfort and nausea, and a II-lead electrocardiogram revealed asystole following bradycardia associated with vasovagal reflex. Oxygenation and intravenous fluid loading in the supine position with elevation of the lower extremities restored sinus rhythm and normal hemodynamics without the intervention of cardiopulmonary resuscitation. With administration of intravenous atropine and betamethasone as premedication, she was uneventfully treated in stress-free psychosomatic conditions under optimal sedation with midazolam without any signs of cardiovascular disorders. After administration of flumazenil, the patient satisfactorily recovered from sedation without re-sedation. The present case suggests that an asystole associated with vasovagal reflex can be triggered by venipuncture for intravenous catheterization during dental anxiety likely to affect the imbalance between sympathetic and parasympathetic activities.

Bradycardia, renal failure, atrioventricular (AV) nodal disease, shock, and hyperkalemia (BRASH) syndrome is a well-recognized constellation of distinct clinicopathologic entities comprising bradycardia, renal failure, AV nodal disease, shock, and hyperkalemia. Our patient is an 89-year-old female with a past medical history significant for hypertension and diabetes, who was newly started on labetalol and had recent gastroenteritis; she presented to our Emergency Department with bradycardia and shock. Upon presentation, she showed physical signs of volume depletion, and her blood pressure was 50 mmHg systolic and heart rate was 25 beats per minute. The initial electrocardiogram showed an idioventricular rhythm. The laboratory workup revealed hyperkalemia. The patient was given repeated doses of atropine with no significant response. She was resuscitated with isotonic fluids. The patient improved clinically, her blood pressure stabilized, her potassium level, renal function, and heart rate were normalized, and normal sinus rhythm was restored with a narrow QRS complex. A diagnosis of BRASH syndrome was made retrospectively. Overall, the treatment of this syndrome is largely symptomatic. Hemodynamic support with fluid and treatment of hyperkalemia remains the goal of care. The overall prognosis is good if identified early and managed appropriately.

A 63-year-old male was admitted to a district hospital after ingesting ethanol and pirimiphos-methyl (PM) with suicidal intentions. History included alcoholic cirrhosis with alcoholism, adiposity, diabetes with cerebral microangiopathy, chronic renal insufficiency, heparin-induced thrombocytopenia, and status post necrotizing fasciitis. Emergency medical service reported an alert patient without signs of cholinergic crisis; activated charcoal and atropine were administered. Upon hospital arrival, he received fluid resuscitation, activated charcoal, and atropine. He was transferred to a toxicology unit the next day. On admission, he had no cholinergic signs (dry mucous membranes, warm skin, and mydriatic pupils) requiring small atropine doses (0.5 mg per hour). Four hours after admission, he developed bradycardia and respiratory distress, necessitating intubation. He received atropine by continuous infusion for 7 days (248 mg total) and obidoxime (bolus and continuous infusion). PM, pirimiphos-methyl-oxon (PMO), and phosphorylated tyrosine (Tyr) adducts derived from human serum albumin were analyzed in vivo. Cholinesterase status (acetylcholinesterase (AChE), butyrylcholinesterase (BChE), inhibitory activity of patient plasma and reactivatability, and phosphorylated BChE-derived nonapeptides) was measured in vivo. Obidoxime and atropine were monitored. PM and PMO were detectable, PM with maximum concentration ∼24 h post admission (p.a.) and PMO at ∼18 h p.a. Tyr adducts were detectable. AChE in vivo was suppressed on admission, increased continuously after starting obidoxime, and reached maximum activity after ∼30 h. AChE in vivo and reactivatability remained at the same level until the end of monitoring. BChE was already suppressed on admission; termination of the antidote treatment was possible after BChE had recovered to 1/5th of its normal value and extubation was possible after BChE had recovered to 2/5th. While a substantial part of BChE was already aged on admission, aging continued peaking at ∼24 h p.a. After initiating obidoxime treatment, plasma levels increased until obidoxime plasma levels reached a steady state. On admission, plasma atropine level was low; it increased with the start of the continuous infusion. Afterward, the level dropped to a steady state. The clinical course was characterized by bouts of pneumonia, necessitating re-intubation and prolonged ventilation, sepsis, delirium, and a peripheral neuropathy. After psychiatric evaluation, the patient was discharged to a neurological rehabilitation facility after 77 days of hospital care.

Objective: To investigate the bronchoscopy resource allocation and technology application in county-level hospitals in China. Methods: A cross-sectional survey was conducted. In 2021, 12 provinces were sampled from all provinces in China according to the regional Gross Domestic Product (GDP) and the number of counties, in which a total of 291 county-level hospitals were randomly enrolled. Two county-level hospitals which carried out bronchoscopy technology in each province were randomly sampled to investigate the status of bronchoscopy resources, technical application, decontamination and anesthesia by using questionnaires. Independent sample t test or two related sample nonparametric test were used for comparison between groups. Spearman correlation analysis was used to explore the correlation. Bilateral P<0.05 was considered statistically significant. Results: According to the sampling results, it was estimated that in the county-level hospitals, the proportion of those performing bronchoscopy was 11.4% (9.9%, 13.8%), which was significantly correlated with the population in the province (r=0.64, P=0.025) and the regional GDP (r=0.65, P=0.025).The 24 county-level hospitals interviewed were equipped with (1.6±1.0) bronchoscopes on average, and the number of hospitals with electronic bronchoscopes and fiberoptic bronchoscopes was 22 (91.7%) and 6 (25.0%), respectively. Six (25.0%) hospitals performed bronchoscopy every working day. Twelve (50.0%) hospitals had relatively permanent physicians and nurses. All operating doctors had received special training. There was a significant increase in the number of bronchoscopy cases per hospital in 2020 compared to 2019 [140(70, 335) vs. 100(29, 254), P=0.001]. All hospitals used standard cleaning and sterilization workbenches, cleaning agents and disinfectants. Surface anesthesia was available in 24 hospitals, and bronchoscopy techniques under sedation and analgesia were performed in 10 (41.7%) hospitals. Atropine was still used to prevent airway secretions in 2 (8.3%) hospitals,although not recommended by guidelines. Conclusions: There was a large gap between the current status of bronchoscopy technology in county-level hospitals and the standards of the National Health Commission, together with regional disparities. Bronchoscopist training in the standardization and the decontamination work met the requirements. In some hospitals, the use of complementary medicines was not standardized or the sedatives were not given routinely according to the guidelines. We should promote the popularization and standardization of bronchoscopy technology, and strengthen the allocation of related resources in China's county hospitals.

Hesperidin (HSP) is a major flavanone glycoside in citrus fruits, including sweet oranges and lemons. It demonstrates numerous pharmacological activities, such as antihypertensive effects and cardiac and kidney tissue protection. However, its effect on modulating renal function has yet to be properly explored. Female and male Wistar spontaneously hypertensive rats (SHR) were used to test the effect of HSP on renal function. The rats were divided into different groups, treated orally, and placed in metabolic cages for urine collection for 8 h. HSP, at doses of 0.3-3 mg/kg, led to an increase in urine volume in both female and male SHR. This effect was associated with increased Na+ elimination (3 mg/kg) without causing any change in K+ excretion or pH and conductivity values. When given HSP in combination with hydrochlorothiazide (HCTZ) or amiloride (AMLR), urine volume and Na+ elimination were significantly increased compared to the group that received only HSP. In relation to K+ excretion, the depleting effect of HCTZ and the sparing of AMLR prevailed in both groups. Pre-treatment with a non-selective cholinergic receptor antagonist, atropine, partially prevented HSP-induced diuresis and natriuresis in male SHR, but this effect was not demonstrated with the non-selective inhibitor of the enzyme cyclooxygenase, indomethacin. This study shows the diuretic action of HSP in hypertensive rats, an activity probably associated with the cholinergic pathway. Although various biological actions have already been defined for HSP, this pioneering research reveals its potential as a diuretic medicine.

Tumor cells have evolved to express immunosuppressive molecules allowing their evasion from the host's immune system. These molecules include programmed death ligands 1 and 2 (PD-L1 and PD-L2). Cancer cells can also produce acetylcholine (ACh), which plays a role in tumor development. Moreover, tumor innervation can stimulate vascularization leading to tumor growth and metastasis. The effects of atropine and muscarinic receptor 3 (M3R) blocker, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), on cancer growth and spread were evaluated in vitro using murine colon cancer cell line, CT-26, and in vivo in an orthotopic mouse model of colorectal cancer. In the in vitro model, atropine and 4-DAMP significantly inhibited CT-26 cell proliferation in a dose dependent manner and induced apoptosis. Atropine attenuated immunosuppressive markers and M3R via inhibition of EGFR/AKT/ERK signaling pathways. However, 4-DAMP showed no effect on the expression of PD-L1, PD-L2, and choline acetyltransferase (ChAT) on CT-26 cells but attenuated M3R by suppressing the phosphorylation of AKT and ERK. Blocking of M3R in vivo decreased tumor growth and expression of immunosuppressive, cholinergic, and angiogenic markers through inhibition of AKT and ERK, leading to an improved immune response against cancer. The expression of immunosuppressive and cholinergic markers may hold potential in determining prognosis and treatment regimens for colorectal cancer patients. This study's results demonstrate that blocking M3R has pronounced antitumor effects via several mechanisms, including inhibition of immunosuppressive molecules, enhancement of antitumor immune response, and suppression of tumor angiogenesis via suppression of the AKT/ERK signaling pathway. These findings suggest a crosstalk between the cholinergic and immune systems during cancer development. In addition, the cholinergic system influences cancer evasion from the host's immunity.

Small teleosts have recently been established as models of human diseases. However, measuring heart rate by electrocardiography is highly invasive for small fish and not widely used. The physiological nature and function of vertebrate autonomic nervous system (ANS) modulation of the heart has traditionally been investigated in larvae, transparent but with an immature ANS, or in anesthetized adults, whose ANS activity may possibly be disturbed under anesthesia. Here, we defined the frequency characteristics of heart rate variability (HRV) modulated by the ANS from observations of heart movement in high-speed movie images and changes in ANS regulation under environmental stimulation in unanesthetized adult medaka (Oryzias latipes). The HRV was significantly reduced by atropine (1 mM) in the 0.25-0.65 Hz and by propranolol (100 μM) at 0.65-1.25 Hz range, suggesting that HRV in adult medaka is modulated by both the parasympathetic and sympathetic nervous systems within these frequency ranges. Such modulations of HRV by the ANS in adult medaka were remarkably suppressed under anesthesia and continuous exposure to light suppressed HRV only in the 0.25-0.65 Hz range, indicating parasympathetic withdrawal. Furthermore, pre-hatching embryos did not show HRV and the power of HRV developed as fish grew. These results strongly suggest that ANS modulation of the heart in adult medaka is frequency-dependent phenomenon, and that the impact of long-term environmental stimuli on ANS activities, in addition to development of ANS activities, can be precisely evaluated in medaka using the presented method.

The aberration of programmed cell death including cell death associated with autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis can be observed in the development and progression of doxorubicin-induced cardiotoxicity (DIC). Vagus nerve stimulation (VNS) has been shown to exert cardioprotection against cardiomyocyte death through the release of the neurotransmitter acetylcholine (ACh) under a variety of pathological conditions. However, the roles of VNS and its underlying mechanisms against DIC have never been investigated. Forty adults male Wistar rats were divided into 5 experimental groups: (i) control without VNS (CSham) group, (ii) doxorubicin (3 mg/kg/day, i.p.) without VNS (DSham) group, (iii) doxorubicin + VNS (DVNS) group, (iv) doxorubicin + VNS + mAChR antagonist (atropine; 1 mg/kg/day, ip, DVNS + Atro) group, and (v) doxorubicin + VNS + nAChR antagonist (mecamylamine; 7.5 mg/kg/day, ip, DVNS + Mec) group. Our results showed that doxorubicin insult led to left ventricular (LV) dysfunction through impaired cardiac autonomic balance, decreased mitochondrial function, imbalanced mitochondrial dynamics, and exacerbated cardiomyocyte death including autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis. However, VNS treatment improved cardiac mitochondrial and autonomic functions, and suppressed excessive autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis, leading to improved LV function. Consistent with this, ACh effectively improved cell viability and suppressed cell cytotoxicity in doxorubicin-treated H9c2 cells. In contrast, either inhibitors of muscarinic (mAChR) or nicotinic acetylcholine receptor (nAChR) completely abrogated the favorable effects mediated by VNS and acetylcholine. These findings suggest that VNS exerts cardioprotective effects against doxorubicin-induced cardiomyocyte death via activation of both mAChR and nAChR.

In the present study, we examined the antinociceptive and anti-inflammatory activities of a guanylhydrazone derivative, (E)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-guanylhydrazone hydrochloride (LQM10), in mice. The antinociceptive effect was determined by assessing behavioural responses in different pain models, while anti-inflammatory activity was examined in carrageenan-induced pleurisy. Intraperitoneal LQM10 administration reduced the acetic acid-induced nociceptive behaviour, a phenomenon that was unaltered by pretreatment with yohimbine, atropine, naloxone or glibenclamide. In the formalin assay, LQM10 reduced nociceptive behaviour only in the second phase, indicating an inhibitory effect on inflammatory pain. LQM10 did not alter the pain latency in the hot plate assay and did not impact the locomotor activity of mice in the rotarod assay. In the carrageenan-induced pleurisy assay, LQM10 treatment inhibited critical events involved in inflammatory responses, namely, leucocyte recruitment, plasma leakage and increased inflammatory mediators (tumour necrosis factor Like Properties of Chalchones and Flavonoid Derivatives [TNF]-α and interleukin [IL]-1β) in the pleural exudate. Overall, these results indicate that LQM10 exhibits antinociceptive effects associated with peripheral mechanisms and anti-inflammatory activity mediated via a reduction in leucocyte migration and proinflammatory mediators, rendering this compound a promising candidate for treating pain and inflammatory process.

The effects of cycloplegia on ocular biological parameters in children have been extensively studied, but few studies have compared these parameters between different refractive states, ages, and sexes. Therefore, the purpose of this study was to investigate the changes in ocular biometry before and after cycloplegia in different groups based on dioptre, age and sex. We examined a total of 2049 participants in this cross-sectional study. A comprehensive eye examination was conducted before cycloplegia. Cycloplegia was implemented with the application of atropine or tropicamide. Ocular biological parameters were evaluated after cycloplegia, including axial length (AL), mean keratometry (K), flat keratometry (K1), steep keratometry (K2), central corneal thickness (CCT), anterior chamber depth (ACD) and white-to-white (WTW) distance. All the participants were categorized based on dioptre, age and sex. Statistical analysis was performed with paired t tests and Wilcoxon signed-rank tests. Regarding dioptre, AL was found to be increased significantly in the Fs, Ast and FA (p < 0.05) postcycloplegia groups. We observed significant increases in K, K1, K2 and ACD in the Fs group (p < 0.05) after cycloplegia. Regarding age, we found significant increases in AL, CCT and ACD in group 1 (p < 0.05), but AL decreased significantly in groups 2 and 3 (p < 0.05) postcycloplegia. There were no significant changes found in K, K1 and K2 in the three groups after cycloplegia (p > 0.05). Regarding sex, AL and WTW were found to decrease significantly among males and increase significantly among females (p < 0.05) postcycloplegia, while K, K1 and K2 showed the opposite trends. This study showed that there were differences in some ocular biological parameters after cycloplegia across different groups; in particular, there were significant differences in AL, CCT and ACD. Attention should be devoted to the influence of cycloplegia in clinical work.