Safety, pharmacokinetics, and food-effect of pivmecillinam after single- and multiple-dose in healthy Chinese subjects: a phase I study.

Urinary tract infection (UTI) is one of the most prevalent bacterial infectious diseases worldwide. However, the resistance of urinary pathogens to other UTI antibiotics such as trimethoprim and trimethoprim/sulphamethoxazole increased. Pivmecillinam is a prodrug of mecillinam, which is effective for the treatment of urinary tract infections. The purpose of this study was to assess the safety, and pharmacokinetics of pivmecillinam and mecillinam after single- and multiple-dose oral administration of pivmecillinam tablets in healthy Chinese subjects. The study also investigated the profile of urinary excretion of mecillinam, as well as the effect of food and gender on the pharmacokinetics of pivmecillinam and mecillinam. This study was a single-center, open-label phase I study carried out in three groups. In total, 34 subjects were included in the study: group 1-food effect study with pivmecillinam 200 mg (n = 12); group 2-single- and multiple-dose study with pivmecillinam 400 mg (n = 12); group 3-single dose study with pivmecillinam 600 mg (n = 10). The plasma and urine concentrations of pivmecillinam and mecillinam were measured, and their pharmacokinetics were calculated. Treatment-emergent adverse events were evaluated and recorded in safety assessments for three groups. No severe adverse events were found in this study. After a single dose of pivmecillinam was taken orally, the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of pivmecillinam increased in a dose-proportional manner, nor did mecillinam. Food had significant effects on Cmax and AUC0-t of pivmecillinam and Cmax of mecillinam. The mean cumulative percentage of urine excretion of mecillinam at 0 to 24 h ranged from 35.5 to 44.0%. Urinary cumulative excretion is relative to the drug dose, but the diet and multiple-dose administration did not affect the urinary cumulative excretion rate. The safety and pharmacokinetics of pivmecillinam and mecillinam after single- (200/400/600 mg) or multiple-dose (400 mg) administration were demonstrated in healthy Chinese subjects. Food affected the pharmacokinetics of pivmecillinam and mecillinam.

LC-MS/MS methods for determination of venetoclax in human plasma and cerebrospinal fluid.

We developed and validated sensitive MS/MS methods for the determination of venetoclax, an oral selective B-cell lymphoma-2 inhibitor, in human plasma and cerebrospinal fluid (CSF). Acetonitrile was used as protein precipitant. The mobile phase was 10 mM ammonium formate consisting of 0.1% formic acid and acetonitrile (40:60, v/v). The analytes were separated on an ACQUITY UPLC HSS T3 column (2.1 × 50 mm, 1.8 µm) in 5 min. An API 4000 mass spectrometer was selected to quantify venetoclax and internal standard using m/z 868.3 → 636.3 and 876.3 → 644.3 under multiple response monitoring mode. In plasma, the calibration curve exhibited good linearity ranging from 20.0 to 5000 ng/mL, whereas in the CSF, the linear range was 0.500-100 ng/mL. The matrix effect of venetoclax and internal standard (venetoclax-d8) was not obvious in both plasma and CSF. The inter- and intra-run accuracy was within ±11.9%, and the inter- and intra-run precision was below 13.6%. Both methods had no carryover, and the recovery was close to 100%. The validated methods were employed to quantify the concentrations of venetoclax in the plasma and CSF of patients diagnosed with chronic lymphocytic leukemia or acute myelogenous leukemia.

Knowledge, attitude, behaviour, and influencing factors of home-based medication safety among community-dwelling older adults with chronic diseases: a cross-sectional study.

BACKGROUND: Older adults with chronic diseases require long-term medication. However, due to lack of drug knowledge and hypomnesia, older adults with chronic diseases are prone to adverse drug events and increased medical costs. This study aimed to explore the status and influencing factors of home-based medication safety among community-dwelling older adults with chronic diseases in China to provide a basis for follow-up to conduct targeted health education. METHODS: Overall, 427 community-dwelling older adults with chronic diseases participated in this study. The Knowledge, Attitude, and Behaviour of Medication Safety among Older Adults with Chronic Diseases Questionnaire was used to assess their home-based medication safety. Multivariate linear regression was used to identify the factors influencing knowledge, attitude, and behaviour regarding medication safety. RESULTS: The average score of home-based medication safety among older adults with chronic diseases was 68.26 ± 8.96, indicating that they had a moderate grasp of medication safety. The scoring rate of each subscale was ranked from high to low as follows: behaviour (84.51%), knowledge (63.33%), and attitude (47.39%). Stepwise linear regression analysis showed that medication safety knowledge, attitudes, and behaviours were significantly associated with higher monthly income, adverse drug events, and taking medicine several times a day (p < 0.05). Additional influencing factors included having fewer chronic diseases, being female, higher educational attainment, taking medicines multiple kinds a day, better self-care ability, and non-hospitalisation for chronic illnesses (p < 0.05). CONCLUSION: Medical staff and community workers should pay attention to the drug safety of older adults with different characteristics and mobilise their enthusiasm for participation to improve their medication self-management ability. TRIAL REGISTRATION: Chinese Clinical Trial Register: ChiCTR2200060987 ; reg. date: 15/06/2022.

Relationships between children-related factors, basic psychological need satisfaction, and multiple happiness among urban empty-nesters in China: a structural equation modeling.

BACKGROUND: Aging and empty-nesting in China are becoming more and more serious. Empty-nesters refer to older adults who were not living with their children, were living alone, or were living independently with their spouses. The mental health of empty-nesters needs timely attention. Satisfying the needs of older adults is primarily dependent on their children. Therefore, this study aimed to explore relationships between children-related factors, basic psychological need satisfaction, and multiple happiness among urban empty-nesters in China. METHODS: This study employs the Children-related Factors Questionnaire (CFQ), the Chinese Version of the Basic Psychological Need Satisfaction (BPNS) Scale, and the Multiple Happiness Questionnaire (MHQ) to explore children-related factors, basic psychological need satisfaction and multiple happiness of urban empty-nesters in Fuzhou, China. A total of 507 samples were recruited by cluster sampling. RESULTS: Factors that affect BPNS include physical condition, the number of children, satisfaction with children's marriage, employment and income, retirement, gender, monthly personal income, and self-care have statistical differences (P < 0.05). Factors that affect MHQ include physical condition, the number of children, satisfaction with children's marriage, employment and income, gender, monthly personal income, living status, and self-care have statistical significances (P < 0.05). Structural equation model results showed that BPNS directly impacted MHQ, and factors about children indirectly affect MHQ through BPNS. The mediating role of BPNS in the relationship between children-related factors and MHQ. CONCLUSION: We should encourage our children to spend more time with the empty-nesters and communicate with them, which could help them relieve their negative emotions, satisfy their psychological needs, and improve their well-being. TRIAL REGISTRATION: Reg date: 20/08/2021; No. ChiCTR2100050175.

Exploring urban empty-nesters' using WeChat influencing factors and quality of life: A qualitative descriptive study.

OBJECTIVE: To explore urban empty-nesters using WeChat influencing factors and experiences of improving their quality of life. METHODS: 14 registered empty-nesters who had used WeChat in Fuzhou communities were recruited via convenience and purposive sampling methods with a qualitative descriptive design. Data were collected through individual, semi-structured, and face-to-face interviews and analyzed according to content analysis. RESULTS: The research revealed two primary themes with associated sub-themes: 1) influencing factors of using WeChat, and 2) quality of life experiences. DISCUSSIONS: Physiological factors, education level, and social support were using WeChat influencing factors by urban empty-nesters. WeChat is a convenient channel to improve empty-nesters' daily lives and a practical platform to meet empty-nesters' needs. Identifying these experiences could help older adults, especially empty-nesters' accept the era of intelligence and provide inspiration and reference for the increasingly normalized empty nest life.

CT features of primary liver leiomyosarcoma / 中华消化外科杂志

Objective:To investigate the computed tomography (CT) features of primary liver leiomyosarcoma (PHLMS).Methods:The retrospective and descriptive study was conducted. The clinical and imaging data of 10 patients with PHLMS who were admitted to 4 medical centers including 3 cases in Wenzhou Central Hospital, 3 cases in the Second Affiliated Hospital of Wenzhou Medical University, 2 cases in Wenzhou People's Hospital and 2 cases in Yueqing People's Hospital from January 2011 to December 2020 were collected. There were 5 males and 5 females, aged from 41 to 83 years, with a median age of 55 years. All 10 patients underwent abdominal CT examination. Observation indicators: (1) CT features; (2) treatment and pathological examination; (3) follow-up and survival. Follow-up using postoperative outpatient or inpatient examination to detect patient survival was conducted. Patients underwent imaging examination to detect tumor recurrence. Follow-up was up to December 2020. Measurement data with skewed distribution were represented as M (range). Count data were described as absolute numbers. Results:(1) CT features: results of CT examination showed that each of the 10 patients had only one single tumor, including 3 cases with tumor on the left lobe of liver and 7 cases with tumor on the right lobe of liver. The tumor diameter of the 10 patients was 8.0 cm(range, 4.5-13.5 cm). Results of plain CT scan of 10 patients showed that 7 cases had tumor in expansive growth as round or oval, with clear boundaries and the tumor parenchyma showing low-density signals and patchy lower density area can be seen in the center, and 3 cases had tumor in infiltrative growth as patchy, with unclear boundaries and the tumor parenchyma showing iso-density signals. The CT scan value of 10 patients was 40 HU(range, 23-47 HU). Results of enhanced CT scan at arterial phase of the 7 cases with tumor in expansive growth showed that 3 cases undergoing tumor parenchyma with uneven mild enhancement signals, 3 cases undergoing tumor parenchyma with uneven moderate enhancement signals and 1 case undergoing tumor parenchyma with uneven significant enhancement signal. The CT scan value of 7 cases was 68 HU(range, 62-88 HU). Results of enhanced CT scan at arterial phase of the 3 cases with tumor in infiltrative growth showed that the peripheral region had high signal than the central region. The CT scan value of 3 cases was 73 HU(range, 67-90 HU). Results of enhanced CT scan at portal vein phase in the 7 cases with tumor in expansive growth showed that the tumor parenchyma showing continuous and progressive mild and moderate enhancement with uneven density, and the CT scan value was 63 HU(range, 55-78 HU). Of the 7 cases, 3 cases showed the enhancement range of tumor parenchyma with the trend of fusion and filling, and 4 cases showed small patchy or nodular enhancement and grid like enhancement in the center and periphery of the tumor. Results of enhanced CT scan at portal vein phase in the 3 cases with tumor in infiltrative growth showed that the enhancement withdrew, the density was uneven, and the CT scan value was 58 HU(range, 50-62 HU). Results of enhanced CT scan at delayed phase in 10 patients showed that the enhancement in the tumor withdrew slowly, and the CT scan value was 53 HU(range, 50-60 HU). Of the 10 patients, 4 cases showed decreased density of enhanced nodules around the tumor and 6 cases showed partially fused and filled to the center of tumor with no enhancement in the necrotic part. (2) Treatment and pathological examination: all 10 patients underwent completed tumor resection successfully, and no metastasis was found in liver or the hilar region. Results of postoperative pathological examination showed that each of the 10 patients had only one single visible tumor with tumor diameter of 8.0 cm(range, 4.5?13.5 cm). Of the 10 patients, 7 cases had tumor with complete or incomplete pseudocapsule with clear boundary and 3 cases had tumor without pseudocapsule and the boundary was unclear. All 10 patients had tumor with hard parenchyma and the section was mostly gray and fish like. Among them, patchy or punctate necrosis was seen in 7 cases, small patchy or punctate hemorrhage was seen in 3 cases, and small patchy calcification was seen in 2 cases. Microscopically, the tumor tissue was crisscross, the tumor cells were in spindle shaped, the nuclei were in round, oval, blunt at both ends or in thin rod like, with obvious heteromorphism, large and deeply staining, and obviously division. Immunohistochemical staining showed positive staining of smooth muscle actin, desmin and vimentin. (3) Follow-up and survival: all 10 patients were followed up postoperatively for 6 to 130 months, with a median follow-up time of 55 months. The overall survival time of 10 patients were 10 to 120 months, with a median overall survival time of 46 months. Of the 10 patients, 2 cases died of tumor recurrence and distant metastasis 10 and 11 months after operation, respectively and 8 cases survived >12 months.Conclusions:Results of plain CT scan of PHLMS show clear or unclear cysts and solid masses with uneven density. Results of enhancement CT scan of PHLMS show persistent uneven enhancement in tumor parenchyma and the surrounding area.

A single center study of colorectal cancer screening for Lynch syndrome / 中华医学遗传学杂志

OBJECTIVE@#To determine the ratio of deficient mismatch repair (dMMR) proteins and Lynch syndrome among patients undergoing colorectal cancer resection.@*METHODS@#From June 2014 to May 2016, immunohistochemistry for mismatch repair proteins including mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and PMS1 homolog 2 (PMS2) were carried out on 207 surgically resected specimens. Samples with lost expression of MMR proteins underwent genetic testing.@*RESULTS@#Loss of expression of MMR proteins were found among 21 patients and accounted for 10.14% of the colorectal cancers. dMMR was more common in patients ≤50 years old, or with proximal tumor at splenic flexure and mucinous adenocarcinoma. Ten patients underwent genetic testing, with three pathogenic mutations (MSH6 c.3013C>T, MLH1 c.199G>A and a novel MSH6 c.584delT) and four ambiguous mutations identified. At least 1.4% of the colorectal cancers were diagnosed as Lynch syndrome.@*CONCLUSION@#Routine screening for Lynch syndrome among patients with colorectal cancer with MMR protein immunohistochemistry as preliminary screening method and MMR gene sequencing as diagnostic method is effective and feasible. It can reduce missed diagnosis of Lynch syndrome and bring lifelong benefit to patients and their families.

Effect of Guiluerxianjiao on behaviors and HPA axis function in a rat model of post-traumatic stress disorder / 中国药理学通报

To investigate the effects of Guiluerx-ianjiao (GLEXJ) on the change of behaviors and HPA axis function in a rat model of post-traumatic stress disorder ( PTSD ). Methods Single-prolonged stress (SPS) was used to establish the model of PTSD. The level of locomotor activities and anxiety behaviors were assessed by open field test and elevated plus maze test. The hypothalamic-pituitary-adrenal fast negative feedback function was assessed by dexamethasone suppression test. The contents of both plasma CORT and ACTH were measured by ELISA. Results On day 8 after SPS, model group showed enhanced HPA fast negative feedback and continued to day 22. The anxiety level of model group increased on day 8 and lasted on day 29. While on day 29, locomotor activities decreased and plasma CORT content increased. When continuously treated by GLEXJ for 14 days, the enhanced HPA axis negative feedback function was significantly inhibited in GLEXJ group. After 21 days of continuous administration, locomotor activities increased. In addition, the level of anxiety and CORT content were down-regulated in GLEXJ group. Conclusions GLEXJ could mitigate behavior disorder in a rat model of PTSD, which may be related to regulating HPA axis dysfunction.

Dopamine D4 Receptor Gene Associated with the Frontal-Striatal-Cerebellar Loop in Children with ADHD: A Resting-State fMRI Study / 神经科学通报·英文版

Attention deficit hyperactivity disorder (ADHD) is a common childhood neuropsychiatric disorder that has been linked to the dopaminergic system. This study aimed to investigate the effects of regulation of the dopamine D4 receptor (DRD4) on functional brain activity during the resting state in ADHD children using the methods of regional homogeneity (ReHo) and functional connectivity (FC). Resting-state functional magnetic resonance imaging data were analyzed in 49 children with ADHD. All participants were classified as either carriers of the DRD4 4-repeat/4-repeat (4R/4R) allele (n = 30) or the DRD4 2-repeat (2R) allele (n = 19). The results showed that participants with the DRD4 2R allele had decreased ReHo bilaterally in the posterior lobes of the cerebellum, while ReHo was increased in the left angular gyrus. Compared with participants carrying the DRD4 4R/4R allele, those with the DRD4 2R allele showed decreased FC to the left angular gyrus in the left striatum, right inferior frontal gyrus, and bilateral lobes of the cerebellum. The increased FC regions included the left superior frontal gyrus, medial frontal gyrus, and rectus gyrus. These data suggest that the DRD4 polymorphisms are associated with localized brain activity and specific functional connections, including abnormality in the frontal-striatal-cerebellar loop. Our study not only enhances the understanding of the correlation between the cerebellar lobes and ADHD, but also provides an imaging basis for explaining the neural mechanisms underlying ADHD in children.

Study on relationship between the abnormalities in the area behind the heart and fetal defects / 中华超声影像学杂志

Objective To investigate the relationship between the abnormalities in the area behind the heart in the four-chamber view and fetal defects, the clinical significance of assessment of area behind the heart in fetal screening.Methods 7062 fetuses were scanned.Area behind the heart in the four-chamber view and anatomical survey were detected.Results Fifty-three cases (0.8％, 53/7062) with abnormal sonographic findings in the area behind the heart in the four-chamber view were detected prenatally.Thirtyseven cases were confirmed by autopsy postnatally.Among these cases, 73.0％ (27/37) had heterotaxy syndrome,8.1％(3/37) had situs inversus totalis,18.9％ (7/37) had heart defects.Conclusions There is close relationship between the abnormalities in the area behind the heart and the fetal defects.This can be used as an effective and simple indicator in screening situs inversus and cardiovascular abnomalities.

Expression of matrix metalloproteinase-2,cysteine rich protein61 and CD25 In esophageal carcinoma and their significance / 中国医师进修杂志

ObjectiveTo determine the expression of matrix metalloproteinase-2 (MMP-2),cysteine rich protein 61 (Cyr61) and CD25 in esophageal carcinoma and investigate their clinical significance.MethodThe expression of MMP-2, Cyr61 and CD25 in 68 cases of esophageal tumor tissues (esophageal carcinoma group ) and part-cancer( para-cancer group ) and 68 cases of reflux esophagitis (control group ) was detected by immunohistochemical method and the results were statistically analysed. ResultsThe positive expression rates of MMP-2,Cyr61 and CD25 were 82.35％(56/68), 73.53％(50/68) and 89.71％(61/68)respectively in esophageal carcinoma group,there were significant differences compared with those in paracancer group and control group(P ＜ 0.05) ; while there was no significantdifference between para-cancer group and control group (P ＞ 0.05 ). The positive expression rates of MMP-2, Cyr61 and CD25 in esophageal carcinoma group in different T stage, N stage and M stage all had statisticall differences (P ＜ 0.05),while there was no significant difference in different degree of differentiation (P ＞ 0.05 ). ConclusionMMP-2,Cyr61 and CD25 is highly expressed in esophageal carcinoma,there is some significance for understanding the occurrence, development and prognosis of esophageal carcinoma.

Study on relation between the fetal abdominal great vessels anormalities and heterotaxy / 中华超声影像学杂志

Objective To investigate the relation between anormalities of fetal abdominal great vessels and heterotaxy, the clinical significance of screening fetal heterotaxy by the abnormalities of fetal abdominal great vessels. Methods 6532 fetuses from our hospital were scanned and the fetuses with abdominal great vessels abnormalities were included. Parameters of fetal growth, abdominal great vessels and anatomical survey were detected. Results Forty-five cases (0.7%) of fetal abdominal great vessels abnormalities were detected prenatally. Forty-two cases were confirmed postnatally, including 35 cases of heterotaxy syndrome and 7 cases of situs inversus totalis and 3 cases missed. The incidences of the abnormal fetus,heterotaxy syndrome and situs inversus totalis of the fetuses with abnormal abdominal great vessels were higher than that of the fetuses with normal abdominal great vessels, the differences were statistically significant( P＜ 0.001). The incidence of both type Ⅰ and type Ⅱ of the heterotaxy syndrome were significantly higher than that of type Ⅳ (P＜0.001). There was a high incidence of left isomerism in abnormal type Ⅰ and of right isomerism in abnormal type Ⅱ , the differences were statistically significant (P＜ 0.001). Conclusions Abnormal great vessels abnormalities have strong relations to heterotaxy and situs inversus which can be used as effective and simple indicator in screening heterotaxy syndrome.

A role for p38 mitogen-activated protein kinase and c-myc in endothelin-dependent rat aortic smooth muscle cell proliferation.

We have demonstrated recently that endothelin (ET) stimulates rat aortic smooth muscle cell proliferation through an extracellular signal-regulated kinase (ERK)-dependent mechanism. Approximately 70% of ET-dependent [3H]-thymidine incorporation in these cells signals through this system. In the present study, we show that the residual mitogenic activity requires an intact p38 mitogen-activated protein kinase (p38 MAPK) system and increased c-myc gene expression. ET increased [3H]-thymidine incorporation in rat aortic smooth muscle cells approximately 5-fold. p38 MAPK inhibition with SB203580 or ERK/ERK kinase inhibition with PD98059 each effected approximately 70% inhibition in ET-dependent DNA synthesis, whereas the combination led to nearly complete blockade of the ET effect. ET also increased c-myc RNA levels and c-Myc protein levels in these cells. The increment in c-Myc expression was blocked by SB203580 but not by PD98059. Use of antisense oligonucleotides directed against the translation start site of the c-myc transcript, but not scrambled oligonucleotide sequence, resulted in approximately 60% decrease in ET-dependent [3H]-thymidine incorporation. The combination of antisense c-myc and PD98059 resulted in near complete inhibition of ET-dependent DNA synthesis. Both ET and c-Myc increased expression and promoter activity of E2F, a transcription factor that has been linked to enhanced cell cycle activity. The ET-dependent increment in E2F promoter activity was suppressed after treatment with SB203580 or antisense c-myc but not by PD98059 or a scrambled oligonucleotide sequence. Collectively, these findings demonstrate that ET uses 2 complementary signal transduction cascades (ERK and p38 MAPK) to control proliferative activity of vascular smooth muscle cells.

p38 mitogen-activated Protein Kinase in Vascular Smooth Muscle Cells Proliferation in SHR / 中华高血压杂志

Objective To investigate the role of p38 mitogen-activated protein kinase(p38MAPK) pathway in the proliferation of SHR vascular smooth muscle cells(VSMC) induced by angiotensin Ⅱ(Ang Ⅱ) and platelet-derived growth factor-BB(PDGF-BB).Methods VSMC were obtained from SHR thoracic aorta.DNA synthesis was quantified by measuring [3H]-thymidine incorporation.The p38MAPK activity was evaluated by immunobloting technique with phospho-p38MAPK antibody.Results 1) Ang Ⅱ(10-8-10-6 mol/L),PDGF(3-30 ng/L) dose-dependently increased the proliferation activity of VSMC([3H]-TdR incorporation).Ang Ⅱ(10-7 mol/L) or PDGF(10 ng/L) significantly increased [3H]-TdR incorporation rate in VSMCs(Ang Ⅱ:11 588?1322 vs control 2546?207 counts/min,P