Serotonin (5-HT)2A/2C receptor agonist 2,5-dimethoxy-4-iodophenyl-2-aminopropane hydrochloride improves detrusor sphincter dyssynergia by inhibiting L-type voltage-gated calcium channels in spinal cord injured rats.

AIMS: To explore the role of voltage-gated calcium channels (VGCC) in 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-iodophenyl-2-aminopropane hydrochloride's improvement of spinal cord injury (SCI) induced detrusor sphincter dyssynergia and the expressions of the 5-hydroxy tryptamine (5-HT) 2A receptors and VGCCs in lumbosacral cord after SCI. METHODS: Female Sprague-Dawley rats were randomized into normal control group and SCI group (N = 15 each). Cystometrogram (CMG), simultaneous CMG, and external urethral sphincter electromyography (EUS-EMG) were conducted in all groups under urethane anesthesia. Drugs were administered intrathecally during CMG and EUS-EMG. Rats were euthanized and L6-S1 spinal cord were acquired for immunofluorescence. RESULTS: In SCI rats, intrathecal administration of 2,5-dimethoxy-4-iodophenyl-2-aminopropane hydrochloride or L-type VGCC blocker, nifedipine, could significantly increase voiding volume, voiding efficiency, and the number of high-frequency oscillations. They could also prolong EUS bursting activity duration on EUS-EMG. Moreover, the effect of 2,5-dimethoxy-4-iodophenyl-2-aminopropane hydrochloride can be eliminated with the combined administration of L-type VGCC agonist, (±)-Bay K 8644. No significant differences were observed in CMG after intrathecal administration of T-type VGCC blocker TTA-P2. Additionally, immunofluorescence of the lumbosacral cord in control and SCI rats showed that the 5-HT2A receptor and Cav1.2 immunolabeling-positive neurons in the anterior horn of the lumbosacral cord were increased in SCI rats. CONCLUSIONS: Our study demonstrated that 5-HT2A/2C agonist 2,5-dimethoxy-4-iodophenyl-2-aminopropane hydrochloride may improve SCI-induced DSD by inhibiting the L-type voltage-gated calcium channel in lumbosacral cord motoneurons.

The serotonin(5-HT)2A receptor is involved in the hypersensitivity of bladder afferent neurons in cyclophosphamide-induced cystitis.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic bladder inflammation characterized by the main symptoms of urinary frequency, urgency, and pelvic pain. The hypersensitivity of bladder afferent neurons is considered a significant pathophysiologic mechanism in IC/PBS. Serotonin (5-HT, 5-hydroxytryptamine) receptors are known to be involved in the regulation of the micturition reflex and hyperalgesia, but the effect of 5-HT receptors on cystitis remains unknown. In this study, a rat model of interstitial cystitis induced by intraperitoneal injection of cyclophosphamide (CYP) was used to investigate the role of 5-HT receptors on cystitis. The histology and urodynamics exhibited chronic cystitis and overactive bladder in CYP-treated rats. Notably, among 5-HT1A, 5-HT2A and 5-HT7 receptors, the expression of 5-HT2A receptor was significantly increased in bladder afferent neurons in CYP-treated rats. Intrathecal administration of the 5-HT2A receptor antagonist M100907 could alleviate bladder overactivity and hyperalgesia in CYP-induced cystitis rats. Neuronal calcium imaging of bladder afferent neurons revealed increased calcium influx induced by the 5-HT2A receptor agonist or capsaicin in cystitis rats, which could be inhibited by M100907. Moreover, RNA sequencing indicated that differentially expressed genes were enriched in inflammation-related pathways and cellular calcium homeostasis. These findings suggest that the 5-HT2A receptor is involved in the hypersensitivity of bladder afferent neurons in CYP-induced cystitis, and M100907 could alleviate bladder overactivity and hyperalgesia in CYP-induced cystitis by inhibiting neuronal hypersensitivity in the afferent pathways. The 5-HT2A receptor may be a potential therapeutic target for the treatment of IC/BPS.

A retrospective study on the analysis of influencing factors of neutropenia in endometrial cancer with adjuvant chemoradiotherapy.

OBJECTIVE: This retrospective study aimed to investigate the factors influencing the occurrence of neutropenia in patients with endometrial cancer (EC) following adjuvant chemoradiotherapy (CRT). METHODS: Retrospective analysis of EC patients who underwent adjuvant CRT from January 2012 to June 2023 in the Department of Gynecology and Oncology of the First Affiliated Hospital of Shandong First Medical University. Neutropenia was defined as an Absolute Neutrophil Count (ANC) of peripheral blood neutrophils below 2 × 109/L. Factors affecting neutropenia in EC patients treated with CRT using Generalized Estimating Equation (GEE), and Logistic regression was used to further analyze the effect of adding radiotherapy to different chemotherapy cycles on neutropenia, so that patients receive optimal adjuvant CRT while the risk of neutropenia is appropriately controlled. RESULTS: A total of 144 patients met the inclusion criteria. They underwent 330 cycles of adjuvant chemotherapy, of whom 96 (66.7%) developed neutropenia, which occurred 140 times. The results of one-way GEE analysis showed that before CRT, White Blood Cell (WBC) (OR = 0.827; 95%CI, 0.701-0.976), ANC (OR = 0.749; 95%CI, 0.586-0.957), Absolute Monocyte Count (AMC) (OR = 0.047; 95%CI, 0.008-0.283), Blood Urea Nitrogen (BUN) (OR = 0.857; 95%CI, 0.741-0.991), platinum and docetaxel (platinum/docetaxel) dosing regimen (OR = 2.284; 95%CI, 1.130-4.618) were associated with neutropenia with adjuvant CRT for EC (p < 0.05), results of multifactorial GEE analysis showed that before adjuvant CRT ANC (OR = 0.552; 95%CI, 0.973-2.231), AMC (OR = 0.047; 95%CI, 0.004-0.052), platinum/docetaxel (OR = 2.437; 95%CI, 1.087-5.464) were an independent influence on neutropenia in adjuvant CRT for EC (p < 0.05). Multifactorial Logistic regression shows addition of radiotherapy to the first cycle of chemotherapy (OR = 4.413; 95%CI, 1.238-18.891) was an independent influence of neutropenia (p < 0.05). CONCLUSIONS: Patients with low pre-CRT ANC and AMC, platinum/docetaxel dosing regimens need to be closely monitored during each cycle of CRT. Also, the concurrent addition of radiotherapy should be avoided during the first cycle of chemotherapy.

Effective dose of propofol combined with intravenous esketamine for smooth flexible laryngeal mask airway insertion in two distinct age groups of preschool children.

BACKGROUND: There is limited research on the combined use of propofol and esketamine for anesthesia induction during flexible laryngeal mask airway (FLMA) in pediatric patients, and the effective dosage of propofol for FLMA smooth insertion remains unclear. We explored the effective dose of propofol combined with intravenous esketamine for the smooth insertion of FLMA in two distinct age groups of preschool children. METHODS: This is a prospective, observer-blind, interventional clinical study. Based on age, preschool children scheduled for elective surgery were divided into group A (aged 1-3 years) and group B (aged 3-6 years). Anesthesia induction was started with intravenous administration of esketamine (1.0 mg.kg- 1) followed by propofol administration. The FLMA was inserted 2 min after propofol administration at the target dose. The initial dose of propofol in group A and group B was 3.0 mg.kg- 1 and 2.5 mg.kg- 1, respectively. The target dose of propofol was determined with Dixon's up-and-down method, and the dosing interval of propofol was 0.5 mg.kg- 1. If there was smooth insertion of FLMA in the previous patient, the target dose of propofol for the next patient was reduced by 0.5 mg.kg- 1; otherwise, it was increased by 0.5 mg.kg- 1. The median 50% effective dose (ED50) for propofol was estimated using Dixon's up-and-down method and Probit analysis, while the 95% effective dose (ED95) was estimated through Probit analysis. Vital signs and adverse events during induction were recorded. RESULTS: Each group included 24 pediatric patients. Using Dixon's up-and-down method, the ED50 of propofol combined with esketamine for smooth insertion of FLMA in group A was 2.67 mg.kg- 1 (95%CI: 1.63-3.72), which was higher than that in group B (2.10 mg. kg- 1, 95%CI: 1.36-2.84) (p = 0.04). Using Probit analysis, the ED50 of propofol was calculated as 2.44 (95% CI: 1.02-3.15) mg.kg- 1 in group A and 1.93 (95% CI: 1.39-2.32) mg.kg- 1 in group B. The ED95 of propofol was 3.72 (95%CI: 3.07-15.18) mg.kg- 1 in group A and 2.74 (95%CI: 2.34-5.54) mg.kg- 1 in group B. In Group B, one pediatric patient experienced laryngospasm. CONCLUSION: The effective dose of propofol when combined with intravenous esketamine for smooth insertion of FLMA in children aged 1-3 years is 2.67 mg.kg- 1, which is higher than that in children aged 3-6 years (2.10 mg. kg- 1). TRIAL REGISTRATION: Chinese Clinical Trial Registry Center (Registration Number: ChiCTR2100044317; Registration Date: 2021/03/16).

Identifying vital sign trajectories to predict 28-day mortality of critically ill elderly patients with acute respiratory distress syndrome.

BACKGROUND: The mortality rate of acute respiratory distress syndrome (ARDS) increases with age (≥ 65 years old) in critically ill patients, and it is necessary to prevent mortality in elderly patients with ARDS in the intensive care unit (ICU). Among the potential risk factors, dynamic subphenotypes of respiratory rate (RR), heart rate (HR), and respiratory rate-oxygenation (ROX) and their associations with 28-day mortality have not been clearly explored. METHODS: Based on the eICU Collaborative Research Database (eICU-CRD), this study used a group-based trajectory model to identify longitudinal subphenotypes of RR, HR, and ROX during the first 72 h of ICU stays. A logistic model was used to evaluate the associations of trajectories with 28-day mortality considering the group with the lowest rate of mortality as a reference. Restricted cubic spline was used to quantify linear and nonlinear effects of static RR-related factors during the first 72 h of ICU stays on 28-day mortality. Receiver operating characteristic (ROC) curves were used to assess the prediction models with the Delong test. RESULTS: A total of 938 critically ill elderly patients with ARDS were involved with five and 5 trajectories of RR and HR, respectively. A total of 204 patients fit 4 ROX trajectories. In the subphenotypes of RR, when compared with group 4, the odds ratios (ORs) and 95% confidence intervals (CIs) of group 3 were 2.74 (1.48-5.07) (P = 0.001). Regarding the HR subphenotypes, in comparison to group 1, the ORs and 95% CIs were 2.20 (1.19-4.08) (P = 0.012) for group 2, 2.70 (1.40-5.23) (P = 0.003) for group 3, 2.16 (1.04-4.49) (P = 0.040) for group 5. Low last ROX had a higher mortality risk (P linear = 0.023, P nonlinear = 0.010). Trajectories of RR and HR improved the predictive ability for 28-day mortality (AUC increased by 2.5%, P = 0.020). CONCLUSIONS: For RR and HR, longitudinal subphenotypes are risk factors for 28-day mortality and have additional predictive enrichment, whereas the last ROX during the first 72 h of ICU stays is associated with 28-day mortality. These findings indicate that maintaining the health dynamic subphenotypes of RR and HR in the ICU and elevating static ROX after initial critical care may have potentially beneficial effects on prognosis in critically ill elderly patients with ARDS.

Fabrication of a large computer-generated hologram with high diffraction efficiency and high accuracy by scanning homogenization etching.

The diffraction efficiency, defined as the ratio of diffracted power to incident power, is one of the key working indicators for a computer-generated hologram (CGH). The CGH with high diffraction efficiency could suppress stray light and eliminate ghost images, thus improving interferometric performance in aspherical testing of low-reflectivity or large off-axis distance surfaces. However, the high-efficiency CGH is hard to precisely fabricate by traditional reactive ion etching and focusing ion beam, because it requires high etching depth with a high uniformity and sub-nanometric roughness in the glass, especially in the fabrication of a large CGH with an aperture of up to 300 mm. In this study, fabrication of the above-mentioned CGH was demonstrated via what we believe to be a new method called scanning homogenization etching (SHE), in which the ion source with a Gaussian energy distribution accurately scans the glass surface to realize homogenization etching. Different from controlling dwell time at each etching point, this paper proposes to control the scanning rate to achieve not only uniform but also quantitative depth removal in a single scan. Moreover, the depth errors in deep etching across the whole glass surface can be remarkably reduced due to homogenization effects introduced by multiple scanning etching. Finally, the target etching depth of 692.3 nm with an etching uniformity of 2.2% in the etching of a 300 mm CGH was achieved. The roughness of the etched and unetched area both have Ra values of 0.3 nm. The diffraction efficiency of working order is 39.998%, achieving 98.6% of the theoretical diffraction efficiency. In addition, the SHE is not limited by the aperture of the ion source, so it can achieve even larger diffractive optical elements with high diffraction efficiency and high accuracy.

Risk factors for venous ulceration in patients with varicose veins of lower extremities.

The aim of this case-control study was to explore the potential risk factors for venous ulceration in patients with varicose veins of lower extremities and to establish a simplified diagnostic score model. Seventy subjects with varicose veins of lower extremities and venous ulceration were compared with 1164 controls with varicose veins of lower extremities and no history of venous ulceration. Stepwise multivariate logistic regression analysis was used to identify the risk factors for venous ulceration. The steps in developing the diagnostic score model were based on the Framingham Heart study. The area under the receiver operating characteristic curve (AUC) was calculated to assess the diagnostic ability of the diagnostic score model. Multivariate analysis showed that men, overweight, obesity, longer duration varicose veins, deep venous valve insufficiency, low lymphocyte counts, and high fibrinogen content were independently associated with an increased risk of venous ulceration. The AUC for the diagnostic score model was 0.75, which indicated good discriminatory ability. Special attention should be paid to the high-risk group of patients with lower extremity varicose veins. The diagnostic score model might be a useful screening tool for clinicians, policy makers, and patients.

Molecular understanding of anthocyanin biosynthesis activated by PAP1 and regulated by 2, 4-dichlorophenoxyacetic acid in engineered red Artemisia annua cells.

MAIN CONCLUSION: Eight promoters were cloned, from which AC and G-box cis-elements were identified. PAP1 enhanced the promoter activity. 2,4-D reduced the anthocyanin biosynthesis via downregulating the expression of the PAP1 transgene. Artemisia annua is an effective antimalarial medicinal crop. We have established anthocyanin-producing red cell cultures from this plant with the overexpression of Production of Anthocyanin Pigment 1 (PAP1) encoding a R2R3MYB transcription factor. To understand the molecular mechanism by which PAP1 activated the entire anthocyanin pathway, we mined the genomic sequences of A. annua and obtained eight promoters of the anthocyanin pathway genes. Sequence analysis identified four types of AC cis-elements from six promoters, the MYB response elements (MRE) bound by PAP1. In addition, six promoters were determined to have at least one G-box cis-element. Eight promoters were cloned for activity analysis. Dual luciferase assays showed that PAP1 significantly enhanced the promoting activity of seven promoters, indicating that PAP1 turned on the biosynthesis of anthocyanins via the activation of these pathway gene expression. To understand how 2,4-dichlorophenoxyacetic acid (2,4-D), an auxin, regulates the PAP1-activated anthocyanin biosynthesis, five different concentrations (0, 0.05, 0.5, 2.5, and 5 µM) were tested to characterize anthocyanin production and profiles. The resulting data showed that the concentrations tested decreased the fresh weight of callus growth, anthocyanin levels, and the production of anthocyanins per Petri dish. HPLC-qTOF-MS/MS-based profiling showed that these concentrations did not alter anthocyanin profiles. Real-time RT-PCR was completed to characterize the expression PAP1 and four representative pathway genes. The results showed that the five concentrations reduced the expression levels of the constitutive PAP1 transgene and three pathway genes significantly and eliminated the expression of the chalcone synthase gene either significantly or slightly. These data indicate that the constitutive PAP1 expression depends on gradients added in the medium. Based on these findings, the regulation of 2,4-D is discussed for anthocyanin engineering in red cells of A. annua.

Multicomponent prediction of 2-year mortality and amputation in patients with diabetic foot using a random survival forest model: Uric acid, alanine transaminase, urine protein and platelet as important predictors.

The current methods for the prediction of mortality and amputation for inpatients with diabetic foot (DF) use only conventional, simple variables, which limits their performance. Here, we used a random survival forest (RSF) model and multicomponent variables to improve the prediction of mortality and amputation for these patients. We performed a retrospective cohort study of 175 inpatients with DF who were recruited between 2014 and 2021. Thirty-one predictors in six categories were considered as potential covariates. Seventy percent (n = 122) of the participants were randomly selected to constitute a training set, and 30% (n = 53) were assigned to a testing set. The RSF model was used to screen appropriate variables for their value as predictors of 2-year all-cause mortality and amputation, and a multicomponent prediction model was established. Model performance was evaluated using the area under the curve (AUC) and the Hosmer-Lemeshow test. The AUCs were compared using the Delong test. Seventeen variables were selected to predict mortality and 23 were selected to predict amputation. Uric acid and alanine transaminase were the top two most useful variables for the prediction of mortality, whereas urine protein and platelet were the top variables for the prediction of amputation. The AUCs were 0.913 and 0.851 for the prediction of mortality for the training and testing sets, respectively; and the equivalent AUCs were 0.963 and 0.893 for the prediction of amputation. There were no significant differences between the AUCs for the training and testing sets for both the mortality and amputation models. These models showed a good degree of fit. Thus, the RSF model can predict mortality and amputation in inpatients with DF. This multicomponent prediction model could help clinicians consider predictors of different dimensions to effectively prevent DF from clinical outcomes .

Activation of the adenosine A1 receptor in the lumbosacral spinal cord improves bladder overactivity in rats with cystitis induced by cyclophosphamide.

PURPOSE: To investigate the effect of intrathecal administration of CCPA, an adenosine A1 receptor agonist, on voiding function in rats with cystitis induced by cyclophosphamide (CYP). METHODS: Thirty 8-week-old Sprague Dawley rats were randomly divided into a control group (n = 15) and a cystitis group (n = 15). Cystitis was induced by a single intraperitoneal injection of CYP (200 mg/kg, dissolved in physiological saline) in rats. Control rats were injected intraperitoneally with physiological saline. The PE10 catheter reached the level of L6-S1 spinal cord through L3-4 intervertebral space for intrathecal injection. Forty-eight hours after intraperitoneal injection, urodynamic tests were conducted to observe the effect of intrathecal administration of 10% dimethylsulfoxide (vehicle) and 1 nmol CCPA on micturition parameters, including basal pressure (BP), threshold pressure (TP), maximal voiding pressure (MVP), intercontraction interval (ICI), voided volume (VV), residual volume (RV), bladder capacity (BC), and voiding efficiency (VE). Histological changes of the bladder of cystitis rats were studied through hematoxylin-eosin staining (HE staining). Moreover, Western blot and immunofluorescence were used to study the expression of adenosine A1 receptor in the L6-S1 dorsal spinal cord in both groups of rats. RESULTS: HE staining revealed submucosal hemorrhage, edema, and inflammatory cell infiltration in the bladder wall of cystitis rats. The urodynamic test showed significant increase in BP, TP, MVP and RV in cystitis rats, while ICI, VV, BC and VE decreased significantly, indicating bladder overactivity. CCPA inhibited the micturition reflex in both control and cystitis rats, and significantly increased TP, ICI, VV, BC, and VE, but had no significant effect on BP, MVP and RV. Western blot and immunofluorescence showed that there was no significant difference in the expression of adenosine A1 receptor in the L6-S1 dorsal spinal cord between the control and cystitis rats. CONCLUSION: The findings of this study suggest that intrathecal administration of the adenosine A1 receptor agonist CCPA alleviates CYP-induced bladder overactivity. Furthermore, our results indicate that the adenosine A1 receptor in the lumbosacral spinal cord may be a promising target for treatment of bladder overactivity.

Associations between antipsychotics and the risk of incident cardiovascular diseases in individuals with schizophrenia: a nested case-control study.

BACKGROUND: The association between antipsychotics and cardiovascular diseases (CVDs) remains significant yet unestablished, especially in Chinese populations. OBJECTIVE: To investigate the risk of CVDs associated with antipsychotics among Chinese individuals with schizophrenia. METHODS: We conducted a nested case-control study on individuals diagnosed with schizophrenia in Shandong, China. The case group included individuals diagnosed with incident CVDs between 2012 and 2020. Each case was randomly matched with up to three controls. We used weighted logistic regression models to assess the risk of CVDs associated with antipsychotics and restricted cubic spline analysis to explore the dose-response relationship. FINDINGS: In total, 2493 cases and 7478 matched controls were included in the analysis. Compared with non-users, any antipsychotics use was associated with higher risk of any CVDs (weighted OR=1.54, 95% CI 1.32 to 1.79), with the risk mainly driven by ischaemic heart diseases (weighted OR=2.26, 95% CI 1.71 to 2.99). Treatments with haloperidol, aripiprazole, quetiapine, olanzapine, risperidone, sulpiride and chlorpromazine were associated with increased risk of CVDs. A non-linear dose-response relationship between dosage of antipsychotics and risk of CVDs was observed, with a sharp increase in risk in the beginning and then flattening out with higher doses. CONCLUSIONS: Use of antipsychotics was associated with increased risk of incident CVDs among individuals with schizophrenia, and the risk varied substantially among different antipsychotics and specific CVDs. CLINICAL IMPLICATIONS: Clinicians should consider the cardiovascular risk of antipsychotics and choose the appropriate type and dose of drugs in the treatment of schizophrenia.

Metabolic engineering of the anthocyanin biosynthetic pathway in Artemisia annua and relation to the expression of the artemisinin biosynthetic pathway.

MAIN CONCLUSION: Four types of cells were engineered from Artemisia annua to produce approximately 17 anthocyanins, four of which were elucidated structurally. All of them expressed the artemisinin pathway. Artemisia annua is the only medicinal crop to produce artemisinin for the treatment of malignant malaria. Unfortunately, hundreds of thousands of people still lose their life every year due to the lack of sufficient artemisinin. Artemisinin is considered to result from the spontaneous autoxidation of dihydroartemisinic acid in the presence of reactive oxygen species (ROS) in an oxidative condition of glandular trichomes (GTs); however, whether increasing antioxidative compounds can inhibit artemisinin biosynthesis in plant cells is unknown. Anthocyanins are potent antioxidants that can remove ROS in plant cells. To date, no anthocyanins have been structurally elucidated from A. annua. In this study, we had two goals: (1) to engineer anthocyanins in A. annua cells and (2) to understand the artemisinin biosynthesis in anthocyanin-producing cells. Arabidopsis Production of Anthocyanin Pigment 1 was used to engineer four types of transgenic anthocyanin-producing A. annua (TAPA1-4) cells. Three wild-type cell types were developed as controls. TAPA1 cells produced the highest contents of total anthocyanins. LC-MS analysis detected 17 anthocyanin or anthocyanidin compounds. Crystallization, LC/MS/MS, and NMR analyses identified cyanidin, pelargonidin, one cyanin, and one pelargonin. An integrative analysis characterized that four types of TAPA cells expressed the artemisinin pathway and TAPA1 cells produced the highest artemisinin and artemisinic acid. The contents of arteannuin B were similar in seven cell types. These data showed that the engineering of anthocyanins does not eliminate the biosynthesis of artemisinin in cells. These data allow us to propose a new hypothesis that enzymes catalyze the formation of artemisinin from dihydroartemisinic acid in non-GT cells. These findings show a new platform to increase artemisinin production via non-GT cells of A. annua.

The potential involvement of MRP5 pump in urethral dysfunction in streptozotocin-induced diabetic rats.

PURPOSE: To examine the effects of i.v. administration of MK-571, a MRP4/5 pump inhibitor, on urethral function in the urethane-anesthetized rat, and the changes of urethral multidrug resistance protein 5 (MRP5) pump in streptozotocin (STZ)-induced diabetes mellitus (DM) rats. METHODS: Isovolumetric cystometry and urethral perfusion pressure (UPP) measurements were carried out in normal control (NC) group and 8week DM groups under urethane anesthesia. When stable rhythmic bladder contractions were showed, UPP parameters were recorded after successive administration of various dose of MK-571. Additionally, urethral cyclic guanosine monophosphate (cGMP) protein level was evaluated by ELISA, and changes of MRP5 pump and neurogenic nitric oxide synthase (nNOs) in the urethra were examined with immunohistochemical staining and Western blot analysis. RESULTS: In NC group, UPPnadir was significantly decreased but UPP change increased after administration of MK-571, while no significant differences in UPP parameters were observed in 8-week DM group. Furthermore, urethral MRP5 protein level was up-regulated, whereas urethral cGMP and nNOS protein levels were down-regulated in 8-week DM group. CONCLUSIONS: MK-571 could not restore NO-mediated urethral relaxation dysfunction in DM rats, which may be attributed to the up-regulation of urethral MRP5 pump, and thus decrease of intracellular cGMP concentration in the urethra. These novel results would be useful for a better understanding of DM-related lower urinary tract dysfunction LUT (LUTD). Also, they could be helpful to study the importance of MRP pumps in the control of urethral relaxation mechanisms under physiological and pathological states.

Multi-trajectories of systolic and diastolic hypertension and coronary heart disease in middle-aged and older adults.

Objective: This study aimed to investigate multi-trajectories of systolic and diastolic hypertension and assess their association with the risk of coronary heart disease (CHD) in middle-aged and older Chinese adults. Methods: The study cohort comprised 4,102 individuals aged 40-75 years with records of at least four systolic blood pressure (SBP) and diastolic blood pressure (DBP). A group-based multi-trajectory model was adopted to identify multi-trajectories of systolic and diastolic hypertension, followed by a logistic model to assess the independent associations between these trajectories and CHD risk. The multinomial logistic model was used to evaluate the impact of baseline covariates on trajectory groups. Results: Six distinct trajectories for systolic and diastolic hypertension were identified which represent distinct stages of hypertension and were characterized as low-stable, low-increasing, medium-decreasing, medium-increasing-decreasing, isolated systolic hypertension phase, and high-decreasing. Compared with the low-stable group, the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 2.23 (1.34-3.70) for the medium-increasing-decreasing group and 1.87 (1.12-3.11) for the high-decreasing group after adjustment for baseline covariates. Compared with the low-increasing group, the ORs and 95% CIs were 1.88 (1.06-3.31) for the medium-increasing-decreasing group. Age, gender, drinking, body mass index (BMI), triglyceride (TG), and fasting plasma glucose (FPG) were independent predictors for trajectory groups 4 and 6. Conclusion: Novel, clinically defined multi-trajectories of systolic and diastolic hypertension were identified. Middle-aged and older adults with medium-increasing-decreasing or high-decreasing blood pressure trajectories are potentially critical periods for the development of CHD. Preventing adverse changes in hypertension status and reducing the high risk of CHD is necessary for people in distinct trajectory groups.

Acute coronary syndrome screening in patients presenting with arteriosclerosis in health check-ups: a case-control study.

OBJECTIVES: This research aimed to develop a simple and effective acute coronary syndrome (ACS) screening model in order to intervene early and focus on prevention in patients presenting with arteriosclerosis. DESIGN: A case-control study. SETTING: The study used a cross-sectional survey to collect data from 2243 patients who completed anonymous electronic medical record (EMR) data and coronary angiography was gathered at a hospital in Shandong Province between December 2013 and April 2016. PARTICIPANTS: Adults 18 years old and above diagnosed as ACS or non-ACS according to the records in hospital EMR database, and with completed basic information (age and sex). PREDICTORS: 54 laboratory biomarkers and demographic factors (age and sex). STATISTICAL ANALYSIS: A dataset without missing data of all patients' laboratory indicators and demographic factors was divided into training set and validation set after being balanced. After the training set balanced, area under the curve of random forest (AUCRF) and least absolute shrinkage and selection operator (LASSO) regression were used for feature extraction. Then two set random forest models were established with the different feature sets, and the process of comparison and analysis was made to evaluate models for the optimal model including sensitivity, accuracy and AUC receiver operating characteristic curves with the internal validation set. MAIN OUTCOME MEASURES: To establish an ACS screening model. RESULTS: An RF model with 31 features selected by LASSO with an AUC of 0.616 (95% CI 0.650 to 0.772), a sensitivity of 0.832 and an accuracy of 0.714 in the validation set. The other RF model with 27 features selected by AUCRF with an AUC of 0.621 (95% CI 0.664 to 0.785), a sensitivity of 0.849 and an accuracy of 0.728 in the validation set. CONCLUSIONS: The established ACS screening model with 27 clinical features provides a better performance for practical solution in predicting ACS.

Modeling and suppressing the wavefront degeneration in a CGH interferometric null test.

The computer-generated hologram (CGH) enables the ultra-high accuracy of surface measurement but causes the wavefront degeneration in the optical system. In this article, we give a high-accuracy analytical simulation of the wavefront degeneration in null test by the elliptical Gaussian model. We propose an analytical expression of instrumental transfer function (ITF) for the CGH null test without knowing the phase distribution of CGH, which gives an efficient instruction to suppress the wavefront degeneration. The ITF of the interferometric null test for a ∅3m aspheric mirror can be optimized from 0 to 0.65 at 0.4 Nyquist frequency.

Improvement of urethral dysfunction by 5-HT1A receptor agonist NLX-112 in diabetic rats.

OBJECTIVE: To examine the effects of the selective 5-HT1A receptor agonist, NLX-112, on urethral function in streptozotocin-induced diabetic rats. MATERIALS AND METHODS: Female Sprague-Dawley rats (n = 32) were divided into two groups: rats with type 1 diabetes mellitus (T1DM) and age-matched normal control rats (NC). T1DM was induced by intraperitoneal injection of streptozotocin (65 mg/kg). Isovolumetric cystometry and urethral perfusion pressure (UPP) were evaluated 10 weeks postinjection in rats (n = 9 per group). The selective 5-HT1A receptor antagonist, WAY-100635 maleate salt, was administered after NLX-112 hydrochloride dose-response curve was generated (intravenously). The remaining rats were used for immunofluorescence and Western blot assays. RESULTS: Compared to controls, type 1 diabetic rats (T1D rats) had lower maximal intravesical pressure (IP max) and UPP changes. In T1D rats, NLX-112 hydrochloride (0.003-1.0 mg/kg) induced dose-dependent decreases in UPP nadir, IP max, high-frequency oscillations (HFOs) rate; and increases in UPP change and HFOs amplitude. WAY-100635 maleate salt (0.3 mg/kg) partially or completely reversed the NLX-112-induced changes. Immunofluorescence revealed that 5-HT1A receptors were found in the L6-S1 spinal cord dorsolateral nucleus, but the expression was significantly higher in the T1D rats. Additionally, Western blot showed there were significantly more 5-HT1A receptors in the ventral L6-S1 spinal cord of T1D rats. CONCLUSIONS: Urethral dysfunction in T1D rats was improved by NLX-112. 5-HT1A receptors were upregulated in the dorsolateral nucleus of L6-S1 spinal cord in T1D rats. These findings suggest that NLX-112 may constitute a novel therapeutic strategy to treat diabetic urethral dysfunction.

A de novo regulation design shows an effectiveness in altering plant secondary metabolism.

Introduction: Transcription factors (TFs) and cis-regulatory elements (CREs) control gene transcripts involved in various biological processes. We hypothesize that TFs and CREs can be effective molecular tools for De Novo regulation designs to engineer plants. Objectives: We selected two Arabidopsis TF types and two tobacco CRE types to design a De Novo regulation and evaluated its effectiveness in plant engineering. Methods: G-box and MYB recognition elements (MREs) were identified in four Nicotiana tabacum JAZs (NtJAZs) promoters. MRE-like and G-box like elements were identified in one nicotine pathway gene promoter. TF screening led to select Arabidopsis Production of Anthocyanin Pigment 1 (PAP1/MYB) and Transparent Testa 8 (TT8/bHLH). Two NtJAZ and two nicotine pathway gene promoters were cloned from commercial Narrow Leaf Madole (NL) and KY171 (KY) tobacco cultivars. Electrophoretic mobility shift assay (EMSA), cross-linked chromatin immunoprecipitation (ChIP), and dual-luciferase assays were performed to test the promoter binding and activation by PAP1 (P), TT8 (T), PAP1/TT8 together, and the PAP1/TT8/Transparent Testa Glabra 1 (TTG1) complex. A DNA cassette was designed and then synthesized for stacking and expressing PAP1 and TT8 together. Three years of field trials were performed by following industrial and GMO protocols. Gene expression and metabolic profiling were completed to characterize plant secondary metabolism. Results: PAP1, TT8, PAP1/TT8, and the PAP1/TT8/TTG1 complex bound to and activated NtJAZ promoters but did not bind to nicotine pathway gene promoters. The engineered red P + T plants significantly upregulated four NtJAZs but downregulated the tobacco alkaloid biosynthesis. Field trials showed significant reduction of five tobacco alkaloids and four carcinogenic tobacco specific nitrosamines in most or all cured leaves of engineered P + T and PAP1 genotypes. Conclusion: G-boxes, MREs, and two TF types are appropriate molecular tools for a De Novo regulation design to create a novel distant-pathway cross regulation for altering plant secondary metabolism.

Dynamic trajectory of platelet counts after the first cycle of induction chemotherapy in AML patients.

BACKGROUND: Platelet counts varied over time after induction chemotherapy. We aimed to investigate the different trajectories of platelet counts after the first cycle of induction chemotherapy in patients newly diagnosed with acute myeloid leukemia. METHODS AND RESULTS: In total, 149 individuals were included in this study. We identified four distinct trajectories using a group-based trajectory model: low- stability group (n = 27, 18.12%), low-level decrease-medium elevation group (n = 42, 28.19%), low-level decrease-high elevation group (n = 60, 40.27%), and high-level decrease-medium elevation group (n = 20, 13.42%). The baseline characteristics of the high-level decrease-medium elevation group included higher platelet count, lower white blood cell count, lower percentage of bone marrow blasts, and lower rates of complete remission after the first cycle of induction chemotherapy. Compared with the low-stability group, the hazard ratios were 0.32 (95% confidence interval, 0.15-0.68) for the low-level decrease-medium elevation group, 0.31 (95% confidence interval, 0.15-0.63) for the low-level decrease-high elevation group, and 0.35 (95% confidence interval, 0.13-0.89) for the high-level decrease-medium elevation group after adjustment for age and gender by Cox proportional hazard regression. Compared with the low-stability group, the hazard ratios were 0.33 (95% confidence interval, 0.14-0.77) for the low-level decrease-medium elevation group and 0.31 (95% confidence interval, 0.14-0.67) for the low-level decrease-high elevation group after adjustment for age, gender, white blood cell count, and bone marrow blasts. These associations persisted after adjusting for age, gender, white blood cell count, bone marrow blasts, and platelet count. CONCLUSION: The dynamic trajectory of platelet counts after the first cycle of induction chemotherapy is a significant predictor of all-cause mortality in patients with acute myeloid leukemia. Timely intervention should be considered for the low-stability group. The low-level decrease-medium elevation and low-level decrease-high elevation groups were independent protective factors for all-cause mortality.