Humans ; Norepinephrine ; Bacterial Infections/drug therapy* ; Immunity, Innate

Humans ; Histamine ; Receptors, Histamine H2 ; Schizophrenia/drug therapy*

Objective The efficacy and safety of pitolisant in the treatment of adult narcolepsy have been confirmed in clinical trials abroad， but there is a lack of data on the application of pitolisant in Chinese patients. The aim of this study is to investigate the efficacy and safety of pitolisant in the treatment of adult narcolepsy in China.Methods A total of 30 subjects were enrolled in this study and were given individualized titration once a day for 8 weeks. Epworth Somnolence Scale （EES） and daily cataplexy rate （DCR） were used as the primary outcome measures，and Clinical Global Impression-Severity scale（CGI-S） and Clinical Global Impression of Change Scale （CGI-C） were used as the secondary outcome measures；safety indicators included adverse event （AE） records and laboratory examination.Results The results showed that there were significant improvements in ESS score and number of cataplexy attacks after medication. At the end of treatment，ESS score was reduced by（7.63±4.79）（P<0.001）. For all subjects， the average daily number of cataplexy attacks was 0.83 at baseline，which was reduced significantly to （0.39±0.82）after 3 weeks of pitolisant treatment and（0.38±0.79）after 5 weeks of pitolisant treatment（P<0.05）. After the treatment ended， the median CGI-S score of excessive daytime sleepiness （EDS） improved from "severe" at baseline to "mild"（P<0.001）， and the CGI-S score of cataplexy improved from "mild" at baseline to "basically normal"（P<0.001）. Most AEs were mild and did not receive any drug treatment， and there were no significant changes in other laboratory markers used to monitor the general condition of the subjects before and after treatment. Conclusion Pitolisant has good efficacy and safety in the treatment of EDS and cataplexy in Chinese adults with narcolepsy.
Narcolepsy ; Histamine ; Cataplexy

Trace amines are endogenous molecules distributed in the central nervous system and peripheral tissues that resemble common biogenic amines in terms of subcellular localization, chemical structure, and metabolism. Trace amine-associated receptor (TAAR) is a kind of evolutionarily conserved G-protein-coupled receptors in vertebrates, in which TAAR1 is a functional regulator of monoamine transmitters such as dopamine and serotonin. TAAR1 is widely considered as a potential therapeutic target for schizophrenia, depression and drug addiction. Moreover, TAAR1 is also expressed in peripheral tissues. The homeostasis imbalance of trace aminergic system can induce over-activation of peripheral immune system and central immune inflammatory response. TAAR1 modulators are becoming potential emerging drugs for the treatment of immune-related illnesses, because they may play a major role in the activation or modulation of immune response.
Animals ; Humans ; Receptors, G-Protein-Coupled/metabolism* ; Biogenic Amines ; Dopamine ; Substance-Related Disorders

OBJECTIVES: Nerve growth factor (NGF) induces neuron transdifferentiation of adrenal medulla chromaffin cells (AMCCs) and consequently downregulates the secretion of epinephrine (EPI), which may be involved in the pathogenesis of bronchial asthma. Mammalian achaete scute-homologous 1 (MASH1), a key regulator of neurogenesis in the nervous system, has been proved to be elevated in AMCCs with neuron transdifferentiation in vivo. This study aims to explore the role of MASH1 in the process of neuron transdifferentiation of AMCCs and the mechanisms. METHODS: Rat AMCCs were isolated and cultured. AMCCs were transfected with siMASH1 or MASH1 overexpression plasmid, then were stimulated with NGF and/or dexamethasone, PD98059 (a MAPK kinase-1 inhibitor) for 48 hours. Morphological changes were observed using light and electron microscope. Phenylethanolamine-N-methyltransferase (PNMT, the key enzyme for epinephrine synthesis) and tyrosine hydroxylase were detected by immunofluorescence. Western blotting was used to test the protein levels of PNMT, MASH1, peripherin (neuronal markers), extracellular regulated protein kinases (ERK), phosphorylated extracellular regulated protein kinases (pERK), and JMJD3. Real-time RT-PCR was applied to analyze the mRNA levels of MASH1 and JMJD3. EPI levels in the cellular supernatant were measured using ELISA. RESULTS: Cells with both tyrosine hydroxylase and PNMT positive by immunofluorescence were proved to be AMCCs. Exposure to NGF, AMCCs exhibited neurite-like processes concomitant with increases in pERK/ERK, peripherin, and MASH1 levels (all P<0.05). Additionally, impairment of endocrine phenotype was proved by a signifcant decrease in the PNMT level and the secretion of EPI from AMCCs (all P<0.01). MASH1 interference reversed the effect of NGF, causing increases in the levels of PNMT and EPI, conversely reduced the peripherin level and cell processes (all P<0.01). MASH1 overexpression significantly increased the number of cell processes and peripherin level, while decreased the levels of PNMT and EPI (all P<0.01). Compared with the NGF group, the levels of MASH1, JMJD3 protein and mRNA in AMCCs in the NGF+PD98059 group were decreased (all P<0.05). After treatment with PD98059 and dexamethasone, the effect of NGF on promoting the transdifferentiation of AMCCs was inhibited, and the number of cell processes and EPI levels were decreased (both P<0.05). In addition, the activity of the pERK/MASH1 pathway activated by NGF was also inhibited. CONCLUSIONS MASH1 is the key factor in neuron transdifferentiation of AMCCs. NGF-induced neuron transdifferentiation is probably mediated via pERK/MASH1 signaling.
Animals ; Rats ; Adrenal Medulla ; Cell Transdifferentiation ; Chromaffin Cells ; Dexamethasone ; Epinephrine/pharmacology* ; Mammals ; Nerve Growth Factor ; Neurons ; Peripherins ; Protein Kinases ; Tyrosine 3-Monooxygenase

OBJECTIVE: To investigate the effects of umbilical moxibustion therapy on phobic behavior and the contents of norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) in different brain regions of the stress-model rats and explore the potential mechanism of umbilical moxibustion on phobic behavior. METHODS: Among 50 Wistar male rats, 45 rates were selected and randomly divided into a control group, a model group and an umbilical moxibustion group, 15 rats in each one; and the rest 5 rats were used for preparing the model of electric shock. The bystander electroshock method was adopted to prepare phobic stress model in the model group and the umbilical moxibustion group. After modeling, the intervention with umbilical moxibustion started in the umbilical moxibustion group, in which, the ginger-isolated moxibustion was applied at "Shenque" (CV 8), once daily, 2 cones for 20 min each time, for consecutively 21 days. After modeling and intervention completed, the rats in each group were subjected to the open field test to evaluate the state of fear. After intervention, the Morris water maze test and fear conditioning test were performed to evaluate the changes in learning and memory ability and the state of fear. Using high performance liquid chromatography (HPLC), the contents of NE, DA and 5-HT in the hippocampus, prefrontal cortex and hypothalamus were determined. RESULTS: Compared with the control group, the horizontal and vertical activity scores were lower (P<0.01), the number of stool particles was increased (P<0.01), the escape latency was prolonged (P<0.01), the times of target quadrant were reduced (P<0.01), and the freezing time was prolonged (P<0.05) in the rats of the model group. The horizontal and vertical activity scores were increased (P<0.05), the number of stool particles was reduced (P<0.05), the escape latency was shortened (P<0.05, P<0.01), the times of target quadrant were increased (P<0.05), and the freezing time was shortened (P<0.05) in the rats of the umbilical moxibustion group when compared with the model group. The trend search strategy was adopted in the control group and the umbilical moxibustion group, while the random search strategy was used in rats of the model group. Compared with the control group, the contents of NE, DA and 5-HT in the hippocampus, prefrontal cortex and hypothalamus were reduced (P<0.01) in the model group. In the umbilical moxibustion group, the contents of NE, DA and 5-HT in the hippocampus, prefrontal cortex and hypothalamus were increased (P<0.05, P<0.01) when compared with the model group. CONCLUSION Umbilical moxibustion can effectively relieve the state of fear and learning and memory impairment of phobic stress model rats, which may be related to the up-regulation of contents of brain neurotransmitters, i.e. NE, DA, and 5-HT.
Rats ; Male ; Animals ; Moxibustion ; Rats, Sprague-Dawley ; Rats, Wistar ; Serotonin ; Hippocampus ; Dopamine ; Norepinephrine ; Neurotransmitter Agents

OBJECTIVE: To evaluate the effect of transcutaneous acupoint electrical stimulation (TEAS) at Neiguan (PC 6) on general anesthesia under preserving spontaneous breathing in thoracoscopic lobectomy. METHODS: A total of 66 patients of primary lung cancer undergoing thoracoscopic lobectomy were divided to an observation group (33 cases, 1 case discontinued) and a control group (33 cases). In the observation group, TEAS at Neiguan (PC 6) was used 30 min before anesthesia induction till the end of surgery. The surgery time, maximum value of partial pressure of end-tidal carbon dioxide (P_ETCO₂) and minimum value of oxygen saturation (SpO₂) of the two groups were recorded. The dosage of propofol, sufentanil, remifentanil and dexmedetomidine were analyzed. Separately, before induction (T₀), at the start of surgery (T₁), thoracic exploration (T₂) and lobectomy (T₃), as well as 30 min (T₄) and 60 min (T₅) after lobectomy, the mean arterial pressure (MAP), heart rate (HR), respiratory rate (RR), serum cortisol (Cor) and norepinephrine (NE) were measured. The time of post anesthesia care unit (PACU) stay, ambulation, flatus, chest drainage and the incidence of nausea and vomiting were compared between the two groups. RESULTS: The maximum value of P_ETCO₂, the dosage of propofol and remifentanil in the observation group were lower than those in the control group (P < 0.05, P < 0.01), the minimum value of SpO₂ in the observation group was higher than that of the control group (P < 0.01). At T₁-T₅, the MAP, HR, serum Cor and NE levels in the observation group were all lower than those in the control group (P < 0.05). The ambulation time, the time for the flatus, chest drainage time, and the incidence of nausea and vomiting in the observation group were all lower than those in the control group (P<0.001, P < 0.01). CONCLUSION For the general anesthesia under preserving spontaneous breathing in thoracoscopic surgery, TEAS at Neiguan (PC 6) relieves stress response, reduces opioids dosage and promotes postoperative recovery.
Humans ; Acupuncture Points ; Carbon Dioxide ; Flatulence ; Propofol ; Remifentanil ; Anesthesia, General ; Nausea ; Norepinephrine ; Electric Stimulation

Acetylcholine (ACh) is an important neuromodulator in various cognitive functions. However, it is unclear how ACh influences neural circuit dynamics by altering cellular properties. Here, we investigated how ACh influences reverberatory activity in cultured neuronal networks. We found that ACh suppressed the occurrence of evoked reverberation at low to moderate doses, but to a much lesser extent at high doses. Moreover, high doses of ACh caused a longer duration of evoked reverberation, and a higher occurrence of spontaneous activity. With whole-cell recording from single neurons, we found that ACh inhibited excitatory postsynaptic currents (EPSCs) while elevating neuronal firing in a dose-dependent manner. Furthermore, all ACh-induced cellular and network changes were blocked by muscarinic, but not nicotinic receptor antagonists. With computational modeling, we found that simulated changes in EPSCs and the excitability of single cells mimicking the effects of ACh indeed modulated the evoked network reverberation similar to experimental observations. Thus, ACh modulates network dynamics in a biphasic fashion, probably by inhibiting excitatory synaptic transmission and facilitating neuronal excitability through muscarinic signaling pathways.
Cholinergic Agents/pharmacology* ; Acetylcholine/metabolism* ; Neurons/metabolism* ; Synaptic Transmission/physiology*

OBJECTIVE: To investigate the survival of patients with cardiac arrest and cardiopulmonary resuscitation (CA-CPR), and to analyze the factors influencing survival at 30 days after restoration of spontaneous circulation (ROSC). METHODS: A retrospective cohort study was conducted. Clinical data of 538 patients with CA-CPR admitted to the People's Hospital of Ningxia Hui Autonomous Region from January 2013 to September 2020 were enrolled. The gender, age, underlying disease, cause of CA, type of CA, initial rhythm, presence or absence of endotracheal intubation, defibrillation, use of epinephrine, and 30-day survival rate of patients were collected. The etiology of CA and 30-day survival rate among patients with different ages were compared, as well as the clinical data between patients who survived and died at 30 days after ROSC were also compared. Multivariate Logistic regression was used to analyze the relevant factors affecting the 30-day survival rate of patients. RESULTS: Among 538 patients with CA-CPR, 67 patients with incomplete information were excluded, and 471 patients were enrolled. Among 471 patients, 299 were males and 172 were females. Aged from 0 to 96 years old, 23 patients (4.9%) were < 18 years old, 205 patients (43.5%) were 18 to 64 years old, and 243 patients (51.6%) were ≥ 65 years old. 302 cases (64.1%) achieved ROSC, and 46 patients (9.8%) survived for more than 30 days. The 30-day survival rate of patients aged < 18 years old, 18-64 years old and ≥ 65 years old was 8.7% (2/23), 12.7% (26/205) and 7.4% (18/243), respectively. The main causes of CA in patients younger than 18 years were severe pneumonia (13.1%, 3/23), respiratory failure (13.1%, 3/23), and trauma (13.1%, 3/23). The main causes were acute myocardial infarction (AMI; 24.9%, 51/205), respiratory failure (9.8%, 20/205), and hypoxic brain injury (9.8%, 20/205) in patients aged 18-64 years old, and AMI (24.3%, 59/243) and respiratory failure (13.6%, 33/243) in patients aged ≥ 65 years old. Univariate analysis results revealed that the 30-day survival rate of patients with CA-CPR may be related to the the cause of CA was AMI, initial rhythm was ventricular tachycardia/ventricular fibrillation, endotracheal intubation and epinephrine. Multivariate Logistic regression analysis results showed that CA was caused by AMI [odds ratio (OR) = 0.395, 95% confidence interval (95%CI) was 0.194-0.808, P = 0.011] and endotracheal intubation (OR = 0.423, 95%CI was 0.204-0.877, P = 0.021) was a protective factor for 30 days of survival after ROSC in patients with CA-CPR. CONCLUSIONS The 30-day survival rate of CA-CPR patients was 9.8%. The 30-day survival rate of CA-CPR patients with AMI after ROSC is higher than that of patients with other CA causes, and early endotracheal intubation can improve the prognosis of patients.
Female ; Male ; Humans ; Infant, Newborn ; Infant ; Child, Preschool ; Child ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Retrospective Studies ; Survival Rate ; Heart Arrest ; Hospitals ; Epinephrine ; Ventricular Fibrillation

OBJECTIVE: To investigate the correlation between early-stage blood pressure indexes and prognosis in sepsis patients. METHODS: A retrospective cohort study was conducted on the medical records of patients diagnosed with sepsis from 2001 to 2012 in the Medical Information Mart for Intensive Care-III (MIMIC-III) database. Patients were divided into survival group and death group according to the 28-day prognosis. General data of patients and heart rate (HR) and blood pressure at admission to ICU and within 24 hours after admission were collected. The blood pressure indexes including the maximum, median and mean value of systolic index, diastolic index and mean arterial pressure (MAP) index were calculated. The data were randomly divided into training set and validation set (4 : 1). Univariate Logistic regression analysis was used to screen covariates, and multivariate Logistic stepwise regression models were further developed. Model 1 (including HR, blood pressure, and blood pressure index related variables with P < 0.1 and other variables with P < 0.05) and Model 2 (including HR, blood pressure, and blood pressure index related variables with P < 0.1) were developed respectively. The receiver operator characteristic curve (ROC curve), precision recall curve (PRC) and decision curve analysis (DCA) curve were used to evaluate the quality of the two models, and the influencing factors of the prognosis of sepsis patients were analyzed. Finally, nomogram model was developed according to the better model and effectiveness of it was evaluated. RESULTS: A total of 11 559 sepsis patients were included in the study, with 10 012 patients in the survival group and 1 547 patients in the death group. There were significant differences in age, survival time, Elixhauser comorbidity score and other 46 variables between the two groups (all P < 0.05). Thirty-seven variables were preliminarily screened by univariate Logistic regression analysis. After multivariate Logistic stepwise regression model screening, among the indicators related to HR, blood pressure and blood pressure index, the HR at admission to ICU [odds ratio (OR) = 0.992, 95% confidence interval (95%CI) was 0.988-0.997] and the maximum HR (OR = 1.006, 95%CI was 1.001-1.011), maximum MAP index (OR = 1.620, 95%CI was 1.244-2.126), mean diastolic index (OR = 0.283, 95%CI was 0.091-0.856), median systolic index (OR = 2.149, 95%CI was 0.805-4.461), median diastolic index (OR = 3.986, 95%CI was 1.376-11.758) were selected (all P < 0.1). There were 14 other variables with P < 0.05, including age, Elixhauser comorbidity score, continuous renal replacement therapy (CRRT), use of ventilator, sedation and analgesia, norepinephrine, norepinephrine, highest serum creatinine (SCr), maximum blood urea nitrogen (BUN), highest prothrombin time (PT), highest activated partial thromboplastin time (APTT), lowest platelet count (PLT), highest white blood cell count (WBC), minimum hemoglobin (Hb). The ROC curve showed that the area under the curve (AUC) of Model 1 and Model 2 were 0.769 and 0.637, respectively, indicating that model 1 had higher prediction accuracy. The PRC curve showed that the AUC of Model 1 and Model 2 were 0.381 and 0.240, respectively, indicating that Model 1 had a better effect. The DCA curve showed that when the threshold was 0-0.8 (the probability of death was 0-80%), the net benefit rate of Model 1 was higher than that of Model 2. The calibration curve showed that the prediction effect of the nomogram model developed according to Model 1 was in good agreement with the actual outcome. The Bootstrap verification results showed that the nomogram model was consistent with the above results and had good prediction effects. CONCLUSIONS The nomogram model constructed has good prediction effects on the 28-day prognosis in sepsis patients, and the blood pressure indexes are important predictors in the model.
Humans ; Cohort Studies ; Retrospective Studies ; Blood Pressure ; Intensive Care Units ; ROC Curve ; Sepsis/diagnosis* ; Prognosis ; Critical Care ; Norepinephrine