[Association between maternal peri-conceptional exposures and risk of hypospadias and cryptorchidism in offspring].

Objective: To investigate the relationship between maternal exposures to peri-conceptional risk factors and the risk of hypospadias and cryptorchidism in offspring. Methods: Pregnant women who delivered male newborns and participated in the China birth cohort study between February 2018 and December 2020 at the research center of Beijing Obstetrics and Gynecology Hospital, Capital Medical University were selected for the study. All were enrolled at 6-13+6 weeks of their gestation. Baseline risk factor information was collected by questionnaire survey. Information on the outcome of hypospadias and cryptorchidism was obtained by clinical examination at birth and ultrasonography. Logistic regression was used to analyze the Odds Ratio (OR) and 95% Confidence Interval (95%CI) of each factor with respect to the onset of the outcome. Results: A total of 15, 833 pregnant women with an average age of (31.81±3.84) years were included. Among their offsprings, 113 were diagnosed as hypospadias or cryptorchidism (42 hypospadias, 69 cryptorchidism, and 2 both hypospadias and crypterchidism), with an incidence of 7.14‰. The results of multivariate logistic regression analysis showed that mothers with pregnancy history of birth defects (OR=3.01, 95%CI: 1.09-8.35), with preconception Hepatitis B infection (OR=4.74, 95%CI: 1.10-20.42), fetal growth restriction (OR=4.02, 95%CI: 2.10-7.68), multivitamin use since preconception (OR=1.98, 95%CI: 1.12-3.52), and never cook and eat at home (OR=2.17, 95%CI: 1.23-3.82) were risk factors for hypospadias and cryptorchidism (all P<0.05). Conclusions: Obesity in early pregnancy, preconception Hepatitis B infection, pregnancy history of birth defects, fetal growth restriction, multivitamin use before pregnancy, and rarely cook and eat at home were associated with an increased risk of hypospadias or cryptorchidism in their offsprings.

[Association between early pregnancy maternal blood pressure and risk of congenital heart disease in offspring].

Objective: To analyze the association between maternal blood pressure and congenital heart disease (CHD) in offspring. Methods: From February 2018 to December 2020, pregnant women who participated in the China birth cohort study in Beijing Obstetrics and Gynecology Hospital, Shenzhen Maternal and Child Healthcare Hospital and Chengdu Women's and Children's Central Hospital were enrolled in this study. The baseline and follow-up information were collected using an electronic data collection system. Stepwise logistic regression model was used to analyze the association between maternal blood pressure including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and pulse pressure difference (PP) in the first trimester of pregnancy and the risk of CHD in the offspring. A restrictive cubic spline curve was used to draw the dose-response curve between maternal blood pressure and CHD. Results: A total of 55 552 participants were included in this study. Of them, 31 038, 15 375 and 9 139 pregnant women were enrolled in Beijing Obstetrics and Gynecology Hospital, Shenzhen Maternal & Child Healthcare Hospital and Chendu Women's and Children's Central Hospital, respecitively. The age of pregnant women was (31.3±4.0) and the incidence of CHD in the offspring was 0.78% (435/55 552). Multivariable logistic regression model analysis showed that the increase of SBP (OR=1.01, 95%CI: 1.00-1.02), DBP (OR=1.01, 95%CI: 1.00-1.03) and MAP (OR=1.02, 95%CI: 1.00-1.03) in the first trimester were significantly associated with the risk of CHD in the offspring. The restrictive cubic spline analysis showed a positive linear association of SBP (Ptotal<0.001; Pnon-liear=0.315), DBP (Ptotal<0.001; Pnon-liear=0.928) and MAP (Ptotal<0.001; Pnon-liear=0.929) with the risk of CHD in the offspring. Conclusion: Maternal SBP, DBP and MAP in the first trimester of pregnancy were positively associated with the risk of CHD in the offspring.

[Analysis of incidence and associated factors of preterm birth based on pre-pregnancy body mass index stratification].

Objective: To analyze the incidence of preterm birth based on pre-pregnancy body mass index (BMI) stratification and explore the associated factors of preterm birth among pregnant women at different BMI stratifications. Methods: From February 2018 to December 2020, pregnant women who participated in China Birth Cohort Study (CBCS) and gave birth at Beijing Obstetrics and Gynecology Hospital were enrolled as the study subjects. Electronic Data Capture System and standard structured questionnaires were used to collect data related to pre-pregnancy, pregnancy, and delivery for pregnant women. Pregnant women were divided into the low-weight group, normal-weight group and overweight group based on their pre-pregnancy BMI. A Cox proportional hazards model was used to analyze the associated factors of preterm birth among pregnant women with different BMI before pregnancy. Results: A total of 27 195 singleton pregnant women were included, with a preterm birth rate of 5.08% (1 381/27 195). The preterm birth rates in the low-weight group, normal-weight group and overweight group were 4.29% (138/3 219), 4.63% (852/18 390) and 7.00% (391/5 586) respectively (P<0.001). After adjusting for relevant factors, the Cox proportional hazards model showed that the risk of preterm birth in the overweight group was 1.457 times higher than that in the normal-weight group (95%CI: 1.292-1.643). Preeclampsia-eclampsia (HR=2.701, 95%CI: 1.318-5.537) was the associated factor for preterm birth in the low-weight group. Advanced maternal age (HR=1.232, 95%CI: 1.054-1.441), history of preterm birth (HR=4.647, 95%CI: 3.314-6.515), vaginal bleeding in early pregnancy (HR=1.613, 95%CI: 1.380-1.884), and preeclampsia-eclampsia (HR=3.553, 95%CI: 2.866-4.404) were associated factors for preterm birth in the normal-weight group. Advanced maternal age (HR=1.473, 95%CI: 1.193-1.818), history of preterm birth (HR=3.209, 95%CI: 1.960-5.253), vaginal bleeding in early pregnancy (HR=1.636, 95%CI: 1.301-2.058), preeclampsia-eclampsia (HR=2.873, 95%CI:2.265-3.643), and pre-gestational diabetes mellitus (HR=1.867, 95%CI: 1.283-2.717) were associated factors for preterm birth in the overweight group. Conclusion: Pre-pregnancy overweight is an associated factor for preterm birth, and there are significant differences in the associated factors of preterm birth among pregnant women with different BMI before pregnancy.

[Association between coagulation function indicators and placental abruption among preeclampsia-eclampsia pregnant women].

Objective: To explore the association between coagulation function indicators and placental abruption (PA) in different trimesters of pregnancy among preeclampsia-eclampsia pregnant women. Methods: From February 2018 to December 2020, pregnant women who participated in the China birth cohort study and were diagnosed with preeclampsia, eclampsia and chronic hypertension with superimposed preeclampsia in Beijing Obstetrics and Gynecology Hospital were enrolled in this study. The baseline and follow-up information were collected by questionnaire survey, and the coagulation function indicators in the first and third trimesters were obtained through medical records. The Cox proportional hazards model was used to analyze the association between the coagulation function indicators and PA. A restrictive cubic spline curve was used to draw the dose-response curve between the relevant coagulation function indicators and PA. Results: A total of 1 340 participants were included in this study. The age was (32.50±4.24) and the incidence of PA was 4.4% (59/1 340). After adjusting for relevant factors, Cox proportional hazards model showed that compared with the high-level classification of fibrinogen (FIB), participants within the middle-(HR=3.28, 95%CI: 1.27-8.48) and low-level (HR=3.84, 95%CI: 1.40-10.53) classification during the first trimester and within the low-level classification (HR=4.18, 95%CI: 1.68-10.39) during the third trimester were more likely to experience PA. Compared with the middle-level classification of pro-thrombin time (PT), the risk of PA in the participants within the low-level classification (HR=2.67, 95%CI: 1.48-4.82) was significantly higher in the third trimester. The restrictive cubic spline analysis showed a linear negative association between FIB and PA in the first and third trimesters, while PT and PA showed an approximately L-shaped association. Conclusion: Among pregnant women diagnosed with preeclampsia-eclampsia, the middle-and low-level classification of FIB in the first and third trimesters and the low-level classification of PT in the third trimester could increase the risk of PA.

[Preoperative video distraction alleviates separation anxiety and improves induction compliance of preschool children: a randomized controlled clinical trial].

Objective: To explore the effect of video distraction on preoperative separation anxiety and induction compliance of preschool children receiving strabismus surgery under general anesthesia. Methods: In this prospective trial, 80 children aged 3 to 6 years scheduled for strabismus surgery under inhalation anesthesia were randomly allocated to one of two groups, a control group and a video distraction group, with 40 cases in each group. Children in the video distraction group continuously watched videos from waiting in the holding area, separating with parents, entering the operating room and induction of anesthesia, while children in the control group didn't watch videos during the same process. The modified Yale Preoperative Anxiety Scale (mYPAS) of children were recorded upon arriving at the holding area(T1)and separating with parents(T2). Induction Compliance Checklist (ICC) score was recorded when the anesthesia induction was performed. The emergence time, the occurrence rate of adverse events in post-anesthesia care unit (PACU) including nausea and vomiting, laryngospasm, severe cough, hypoxemia and sinus bradycardia, incidence of postoperative adverse reactions such as pain, dizziness, nausea and vomiting and lethargy, the parents' satisfaction of anesthesia were also assessed. Results: There were no significant difference in mYPAS score and the proportion of mYPAS score>30 between 2 groups at T1 (all P>0.05). At T2, the mYPAS score and the proportion of mYPAS score>30 in video distraction group were (34.41±13.23) and 52.50%, which were lower than those in control group (50.64±20.96, 87.50%) with statistically significant difference (all P<0.05). The ICC score of video distraction group was lower than that of the control group, which was (1.83±2.26) vs (4.03±2.99), and the difference was statistically significant (P<0.05). The proportion of children with ICC score=0 in video distraction group was 37.50%, which was higher than that in the control group (12.50%), while the proportion of children with ICC score=4-10 was lower than that of the control group, which was 17.50% vs 45.00%, and the difference was statistically significant (P<0.05). No significant intergroup differences were observed in emergence time, incidence of adverse events in PACU, and incidence of postoperative adverse reactions (P>0.05). The parents' satisfaction of anesthesia in the video distraction group was (9.23±0.89), which was higher than that in the control group (8.63±1.23), with statistically significant (P<0.05). Conclusion: Preoperative video distraction alleviates separation anxiety, improves induction compliance of preschool children receiving strabismus surgery under general anesthesia, and increases the parents' satisfaction of anesthesia.

[Non-muscle myosin heavy chain 9 gene-related disorders with thrombocytopenia: report of two pedigrees and literature review].

Objective: To summarize the clinical characteristics and gene variants of 2 pedigrees of non-muscle myosin heavy chain 9 related diseases (MYH9-RD) in children. Methods: The basic information, clinical features, gene variants and laboratory tests of MYH9-RD patients from 2 pedigrees confirmed in the First Affiliated Hospital of Zhengzhou University in November 2021 and July 2022 were analyzed retrospectively. "Non-muscle myosin heavy chain 9 related disease" "MYH9" and "children" were used as key words to search at Pubmed database, CNKI and Wanfang database up to February 2023. The MYH9-RD gene variant spectrum and clinical data were analyzed and summarized. Results: Proband 1 (male, 11 years old) sought medical attention due to epistaxis, the eldest sister and second sister of proband 1 only showed excessive menstrual bleeding, the skin and mucous membrane of the their mother were prone to ecchymosis after bumping, the uncle of proband 1 had kidney damage, and the maternal grandmother and maternal great-grandmother of proband 1 had a history of cataracts. There were 7 cases of phenotypic abnormalities in this pedigree. High-throughput sequencing showed that the proband 1 MYH9 gene had c.279C>G (p.N93K) missense variant, and family verification analysis showed that the variant was inherited from the mother. A total of 4 patients including proband 1 and family members were diagnosed with MYH9-RD. The proband 2 (female, 1 year old) sought medical attention duo to fever and cough, and the father's physical examination revealed thrombocytopenia. There were 2 cases of phenotypic abnormalities in this pedigree. High-throughput sequencing showed that there was a c.4270G>A (p.D1424N) missense variant in the proband 2 MYH9 gene, and family verification analysis showed that the variant was inherited from the father. A total of 2 patients including proband 2 and his father were diagnosed with MYH9-RD. A total of 99 articles were retrieved, including 32 domestic literatures and 67 foreign literatures. The MYH9-RD cases totaled 149 pedigrees and 197 sporadic patients, including 2 pedigrees in our study. There were 101 cases with complete clinical data, including 62 sporadic cases and 39 pedigrees. There were 56 males and 45 females, with an average age of 6.9 years old. The main clinical manifestations were thrombocytopenia, skin ecchymosis, and epistaxis. Most patients didn't receive special treatment after diagnosis. Six English literatures related to MYH9-RD caused by c.279C>G mutation in MYH9 gene were retrieved. Italy reported the highest number of cases (3 cases). Twelve literatures related to MYH9-RD caused by c.4270G>A mutation in MYH9 gene were retrieved. China reported the highest number of cases (9 cases). Conclusions: The clinical manifestations of patients in the MYH9-RD pedigrees varied greatly. MYH9 gene c.279C>G and c.4270G>A mutations are the cause of MYH9-RD.

[Prognostic analysis of children with Philadelphia chromosome-like acute lymphoblastic leukemia common genes].

Objective: To summarize the clinical data and prognosis of children with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) common genes. Methods: This was a retrospective cohort study.Clinical data of 56 children with Ph-like ALL common gene cases (Ph-like ALL positive group) treated from January 2017 to January 2022 in the First Affiliated Hospital of Zhengzhou University, Henan Children's Hospital, Henan Cancer's Hospital and Henan Provincial People's Hospital were collected, 69 children with other high-risk B cell acute lymphoblastic leukemia (B-ALL) at the same time and the same age were selected as the negative group. The clinical characteristics and prognosis of two groups were analyzed retrospectively. Comparisons between groups were performed using Mann-Whitney U test and χ2 test. Kaplan-Meier method was used for survival curve, Log-Rank test was used for univariate analysis, and the Cox regression model was used for multivariate prognosis analysis. Results: Among 56 Ph-like ALL positive patients, there were 30 males and 26 females, and 15 cases were over 10 years old. There were 69 patients in Ph-like ALL negative group. Compared with the negative group, the children in positive group were older (6.4 (4.2, 11.2) vs. 4.7 (2.8, 8.4) years), and hyperleukocytosis (≥50×109/L) was more common (25% (14/56) vs. 9% (6/69)), the differences were statistically significant (both P<0.05). In the Ph-like ALL positive group, 32 cases were positive for IK6 (1 case was co-expressed with IK6 and EBF1-PDGFRB), 24 cases were IK6-negative, of which 9 cases were CRLF2 positive (including 2 cases with P2RY8-CRLF2, 7 cases with CRLF2 high expression), 5 cases were PDGFRB rearrangement, 4 cases were ABL1 rearrangement, 4 cases were JAK2 rearrangement, 1 case was ABL2 rearrangement and 1 case was EPOR rearrangement. The follow-up time of Ph-like ALL positive group was 22 (12, 40) months, and 32 (20, 45) months for negative group. The 3-year overall survival (OS) rate of positive group was significantly lower than the negative group ((72±7) % vs. (86±5) %, χ2=4.59, P<0.05). Compared with the 24 IK6-negative patients, the 3-year event free survival (EFS) rate of 32 IK6 positive patients was higher, the difference was statistically significant ((88±9) % vs. (65±14) %, χ2=5.37, P<0.05). Multivariate Cox regression analysis showed that the bone marrow minimal residual disease (MRD) not turning negative at the end of first induction (HR=4.12, 95%CI 1.13-15.03) independent prognostic risk factor for patient with Ph-like ALL common genes. Conclusions: Children with Ph-like ALL common genes were older than other high-risk B-ALL patients at diagnosis, with high white blood cells and lower survival rate. The bone marrow MRD not turning negative at the end of first induction were independent prognostic risk factor for children with Ph-like ALL common gene.

[Analysis of 8 cases of asparaginase related cerebral venous sinus thrombosis in children].

Objective: To summarize the clinical features, treatment and prognosis of asparaginase (ASP) related cerebral venous sinus thrombosis (CVST). Methods: Clinical profiles including age, sex, first symptoms, coagulation function, imaging findings, ASP type, treatment and prognosis of eight acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) children with ASP related CVST at the Department of Pediatrics, First Affiliated Hospital of Zhengzhou University from November 2016 to October 2021 were analyzed retrospectively. Results: Eight CVST children were all male, including 6 ALL and 2 LBL, with the onset age ranged from 5 to 15 years, 6 cases occurred in the stage of first induction remission, and the initial symptom were mainly epileptic seizures (7 cases). Magnetic resonance imaging combined magnetic resonance venography (MRV) showed the most common site of venous sinus enlargement was superior sagittal sinus (8 cases). Secondary cerebral hemorrhage was found in 5 cases. D-dimer elevated on the day of onset in all cases. Three patients were treated with intravascular mechanical thrombectomy and thrombolysis combined with anticoagulant therapy, 3 patients were treated with continuous anticoagulant therapy only, 2 patients were not treated with anticoagulant therapy. MRV follow-up for 3 months showed that the thrombi in patients were almost completely absorbed except in 2 patients who were not treated with anticoagulant therapy. Thrombolysis combined with anticoagulant therapy was the fastest way for thrombosis absorption. Among 8 patients, 1 died of early recurrence of ALL, and 7 patients accepted further asparaginase and no CVST recurrence or progression was found. There were no sequelae of nervous system except 1 patient with left upper limb muscle strength impairment. Conclusions: ASP related CVST is more common in older male children and the prognosis is good. ASP related CVST occurred mostly in the stage of first induction remission, and most initial manifestation is epileptic seizure. The superior sagittal region is a common site of thrombus, magnetic resonance imaging combined with MRV is helpful for accurately diagnosis. Timely anticoagulant treatment can improve the prognosis, and mechanical thrombectomy and thrombolysis can quickly recanalize the vessel.

[Clinical characteristics and prognosis of 83 children with newly treated hepatoblastoma].

Objective: To investigate the clinical features, survival and prognostic risk factors of children with hepatoblastoma (HB). Methods: Clinical data of 83 children with newly treated HB at the Department of Hematology and Oncology, Children's Hospital, the First Affiliated Hospital of Zhengzhou University from January 2012 to October 2019 were analyzed retrospectively. The sex, age, first clinical manifestations, pretreatment extent of disease (PRETEXT) stages, pathological types, initial alpha-fetoprotein (AFP), treatment methods and treatment outcome of all patients were summarized. The children diagnosed before 2018 were treated with "Wuhan Protocol", and those who diagnosed after 2018 were treated with the "Expert Consensus for Multidisciplinary Management of Hepatoblastoma"(CCCG-HB-2016) protocol. Kaplan-Meier survival analysis was used to calculate the survival rate, Log-Rank test was used in univariate analysis, and the Cox regression model was used in multivariate prognosis analysis. Results: Among 83 cases, there were 51 males and 32 females. The age of onset was 25.2 (9.0, 34.0) months old, and 64 cases (77%) were under 3 years old. The most common first clinical manifestation was abdominal mass in 45 cases (54%). There were 8 cases of PRETEXT stage Ⅰ, 43 cases of stage Ⅱ, 20 cases of stage Ⅲ and 12 cases of stage Ⅳ. During the follow-up period of 40 (17, 63) months, the 1-year overall survival (OS) rate and event-free survival (EFS) rate were (84±4) % and (79±5) %, respectively, and 5-year OS rate and EFS rate were (78±5) % and (76±5) %, respectively. Fifty-five cases were treated with "Wuhan Protocol", and the 5-year OS and EFS rate were (73±6) % and (71±6) %, respectively. Twenty-eight cases were treated with CCCG-HB-2016 protocol, and the 5-year OS and EFS rate were (88±7) % and (82±9) %, respectively. Multivariate COX regression analysis showed that AFP did not turn negative after 3 courses of postoperative chemotherapy (HR=9.228, 95%CI 1.017-83.692) and PRETEXT stage Ⅳ (HR=6.587, 95%CI 1.687-25.723) were independent risk factors affecting the prognosis of children with HB. Conclusions: The "Wuhan Protocol" and CCCG-HB-2016 protocol were effective in the treatment of children with HB. AFP did not turn negative after 3 courses of postoperative chemotherapy and PRETEXT stage Ⅳ were independent risk factors affecting the prognosis of children with HB.

Novel long non-coding RNA LBX2-AS1 indicates poor prognosis and promotes cell proliferation and metastasis through Notch signaling in non-small cell lung cancer.

OBJECTIVE: Recent reports have suggested that long non-coding RNA LBX2 antisense RNA 1 (LBX2-AS1) acts as an important regulator in cancer progression. This study aimed to investigate the clinical significance of LBX2-AS1 in non-small cell lung cancer (NSCLC) patients and its biological functions. PATIENTS AND METHODS: The expressions of LBX2-AS1 were examined in 165 paired NSCLC tissues and adjacent normal tissues from NSCLC patients by qRT-PCR. The clinical significance of LBX2-AS1 was determined using a series of statistical methods. The effects of LBX2-AS1 knockdown on NSCLC cell proliferation, migration, and invasion were investigated by CCK-8 assays, colony formation assays, EdU proliferation assays, Wound healing assays, and transwell assays. The promotive roles of LBX2-AS1 on Notch1 signal were determined using RT-PCR and Western blot. RESULTS: We found that LBX2-AS1 was highly expressed in NSCLC tissues and cell lines. The increased levels of LBX2-AS1 were observed to be positively correlated with TNM stage, histological grade, and lymph node metastasis. Furthermore, the Kaplan-Meier survival curves indicated that patients with higher expressions of LBX2-AS1 had unfavorable overall survival. Lost-of-functions assays revealed that the knockdown of LBX2-AS1 in H1299 and A549 cells inhibited cell proliferation, migration, and invasion. Mechanistic studies revealed that the suppression of LBX2-AS1 resulted in the reduced expressions of Notch1, p21, and Hes1, suggesting that LBX2-AS1 might promote the activation of the Notch pathway. CONCLUSIONS: Our study identified a novel NSCLC-related lncRNA LBX2-AS1, which may represent a novel prognostic biomarker and a potential therapeutic target for NSCLC.

Special section on machine intelligence approaches to systems biology.

The three papers in this special section focus on machine intelligence approaches to systems biology.

Investigation into the intestinal metabolism of [D-Ala1] peptide T amide: implication for oral drug delivery.

The anti-AIDS drug, [D-Ala1] Peptide T amide (D-ASTTTNYT.NH2) is an octapeptide which competitively inhibits the attachment of HIV to the receptor CD4 molecule on the T-lymphocyte. The objective of the study is to investigate the degradative process of this peptide and its effective enzyme inhibitors. The metabolites of [D-Ala1] Peptide T amide in rabbit brush-border membrane vesicles at pH 6.5 are ASTT, ASTTTN, YT and Y. The sequential time-course study of each metabolite reveals that enkephalinase (EC 3.4.24.11) plays an important role in the hydrolysis of [D-Ala1] Peptide T amide to ASTT. With the addition of an enkephalinase inhibitor, thiorphan, 85% of degradation was inhibited. Aminopeptidase is also involved in its degradative process and 25% of inhibition was observed by amastatin, an aminopeptidase inhibitor. The results show that no significant difference was observed between the in situ and chronical loop perfusion studies and enzyme activities are somewhat inhibited under acidic conditions in both methods. Approx. 90% of the parent peptide remained when rats were perfused with pH 4.0 peptide solution at a flow rate of 0.123 ml/min, while only 60% was recovered when pH 6.5 peptide solution was applied. The addition of amastatin made a quadrupled increase in the amount of parent peptide recovered. A 117-fold increment was observed when thiorphan was added. The dimensionless wall permeability of this peptide was 1.19 +/- 0.16 when pH 4.0 peptide solution was used during chronical loop perfusion study. Therefore, this study suggests that [D-Ala1] Peptide T amide could be absorbed via small intestine where enzymatic degradation s a rate-limiting step for the absorption of this peptide.

Acute effects of urinary bladder distention on the coronary circulation in patients with early atherosclerosis.

OBJECTIVES: We sought to examine whether distention of the urinary bladder, a physiologic stimulus, could induce impaired coronary circulation in patients with early atherosclerosis. BACKGROUND: Distention of the urinary bladder reflexively causes an increase in sympathetic activity. The effect of such distention on the coronary circulation in patients with early atherosclerosis remains unknown. METHODS: To assess the effect of bladder distention on coronary dynamic forces, epicardial and microvascular responses were measured with an intracoronary Doppler flow wire in 40 patients with early atherosclerosis (<50% diameter stenosis). Patients were randomized into two groups according to whether they did not (group 1, n = 20) or did have (group 2, n = 20) pretreatment with an alpha1-adrenergic receptor blocker (oral doxazosin, 2 mg). Coronary flow velocity was monitored by quantitative coronary angiography at baseline, during urinary bladder distention and after intracoronary nitroglycerin injection. RESULTS: Bladder distention significantly decreased the coronary diameter in the stenotic segments (p<0.001), decreased coronary blood flow (p<0.001) and increased coronary resistance (p<0.001), as compared with baseline values, in group 1 patients. In group 2 patients with bladder distention, the angiographic variables did not show significant changes, as compared with baseline values. No significant differences were noted between the groups in the responses of the angiographic variables after nitroglycerin administration. CONCLUSIONS: The present study shows, for the first time, that urinary bladder distention caused vasoconstriction of coronary conduit and resistance vessels involved mechanisms related to alpha1 adrenoceptors. Pretreated administration of doxazosin reversed the changes toward baseline. Vasoconstriction during bladder distention can be relieved after nitroglycerin administration, suggesting an unchanged responsiveness of vascular smooth muscle cells to such distention.

Differential lipogenic effects of cilostazol and pentoxifylline in patients with intermittent claudication: potential role for interleukin-6.

Cilostazol, a novel oral phosphodiesterase inhibitor, has shown consistent improvement in exercise tolerance in patients with intermittent claudication (IC). In addition to this effect, cilostazol has previously been shown to have beneficial effects on the dyslipidemia, i.e., combination of high triglycerides with low high-density-lipoprotein cholesterol (HDL-C) levels. Interleukin-6 (IL-6) suppresses the activity of lipoprotein lipase, which modulates the metabolism of triglycerides and HDL-C. To determine whether a reduction of IL-6 contributes to the improvement of lipid profiles, we prospectively investigated the effect of cilostazol (n=16, 100 mg, twice daily) on the changes of lipid profiles and on the association with the changes of IL-6 compared with those of pentoxifylline (n=16, 400 mg, bid) in patients with IC. After eight weeks of administration of cilostazol to patients with IC, walking distances were increased, associated with a 29% decrease in plasma triglycerides and a 13% increase in HDL-C. No significant changes of lipid profiles in the pentoxifylline and placebo groups were observed although a similar improvement in walking distances was achieved in the pentoxifylline group. IL-6 levels were significantly reduced in patients receiving cilostazol as compared with those receiving placebo or pentoxifylline. The cilostazol-induced changes in the IL-6 were positively related to those of triglycerides in the cilostazol group (r=0.63, P<0.05) and negatively related to those of HDL-C (r=-0.55, P<0.05). These findings suggest that in addition to consistent improvement of exercise tolerance, cilostazol may improve lipid profiles by reducing IL-6 release. However, pentoxifylline did not affect lipid profiles although a similar improvement of maximal walking distance (MWD) was achieved.

Effect of pravastatin on myocardial protection during coronary angioplasty and the role of adenosine.

Pravastatin has been shown, in an experimental model of ischemia reperfusion, to increase adenosine levels, which exert a potent and protective effect on the heart. The purpose of this study was to investigate whether pravastatin can provide cardioprotection by increased production of adenosine in patients undergoing coronary angioplasty, a clinical model of ischemia reperfusion. Thirty-five hyperlipidemic patients who underwent elective angioplasty for a major epicardial coronary artery were randomly allocated to either 3-month pravastatin or placebo before catheterization. In the placebo group, the mean ST-segment shift during the second balloon inflation was similar that observed during the first inflation, whereas in the preconditioned patients, the shift was significantly less, which is consistent with ischemic preconditioning. In the pravastatin-treated patients, the changes of ST-segment shift were similar between the first and second balloon inflations. In contrast, the patients who received aminophylline developed higher ST-segment shifts during the first and second inflations than those in the pravastatin-treated group alone. Measurements of chest pain score and myocardial lactate extraction ratios during inflation mirrored those of the ST-segment shift. The present study demonstrates that administration of pravastatin results in a significant gain in tolerance to ischemia during angioplasty. The effect of pravastatin was abolished by aminophylline, suggesting that the cardioprotective effect of pravastatin may result from activation of adenosine receptors.

Effects of pravastatin on left ventricular mass in patients with hyperlipidemia and essential hypertension.

Left ventricular (LV) mass is a powerful predictor for future cardiovascular events. Epidemiologic studies have shown that hyperlipidemia is associated with higher LV mass. The effects of statin therapy for hyperlipidemia on LV mass have not been studied. To determine the effects of statin therapy on LV mass, we prospectively studied 3 groups of age and body surface area-matched patients: group 1 (n = 20), patients with systemic hypertension and hyperlipidemia treated with pravastatin plus anti-hypertensive drugs; group 2 (n = 20), patients with hypertension and hyperlipidemia treated with hypertensive agents and diet control alone; and group 3 (n = 20), hypertensive patients with normolipidemia treated with antihypertensive agents. A group of controls without hypertension or hyperlipidemia was used for comparison. Echocardiograms were recorded at baseline and after 6-month therapy. All hypertensive groups showed significant decreases in LV mass index after treatment. Group 1 had the greatest decrease in LV mass and it was significantly higher than in groups 2 and 3. Multivariate analysis revealed that regression of LV mass was significantly correlated only with the use of statins and sex (p = 0.005 and 0.01, respectively, R(2) = 0.47). Linear regression analysis in group 1 showed a significant correlation between changes in arterial compliance and LV mass regression (r = 0.57, p = 0.01). Thus, the addition of a statin may have an additional effect on reducing LV mass, independent of lipid-lowering effects.

Effect of estrogen on ventricular repolarization in menopausal patients with syndrome X and effects of nicorandil.

Syndrome X may exhibit myocardial ischemia and is associated with estrogen deficiency. We sought to assess the possible role of estrogen in modulating the characteristics of ventricular repolarization by measurement of QT interval and QT dispersion in patients with syndrome X. We prospectively used 12-lead electrocardiograms and echocardiograms to study 52 consecutive menopausal patients with syndrome X (group subdivided into subgroup 1a, 32 patients who received nicorandil, an adenosine triphosphate-sensitive potassium ion channel opener; subgroup 1b, 20 patients without dosing nicorandil). For comparisons, a control group consisted of age-matched and echocardiographic left ventricular mass index-matched 20 healthy menopausal women. Baseline QT intervals and QT dispersion were similar between the 2 groups (subgroup 1a and controls). After administration of estrogen, there was significant prolongation of maximal QTc intervals and reduction in QT or QTc dispersion compared with baseline in patients with syndrome X. The changes returned to baseline after nicorandil administration. Control subjects had no changes with administration of estrogen. Thus, estrogen modulates characteristics of ventricular repolarization, which appears to be mediated by blocking adenosine triphosphate-sensitive potassium ion channel. The effects of estrogen on QT intervals may be different between menopausal women with or without syndrome X.

Usefulness of transdermal scopolamine for vasovagal syncope.

We studied short-term effectiveness of transdermal scopolamine in a group of patients with unexplained syncope provoked during head-up tilt testing. This double-blind randomized trial of transdermal scopolamine demonstrated no significant effect of preventing vasovagal syncope.

Increased ventricular repolarization inhomogeneity during postural changes in patients with syndrome X.

The interlead variation in QT interval (QT dispersion) can be used to assess regional inhomogeneity of ventricular repolarization under a variety of conditions, including stress. Patients with syndrome X may have increased sympathetic activity that could change QT interval regionally and give rise to an increase in QT dispersion under exercise testing. To test the hypothesis, 26 consecutive patients with syndrome X (group 1) were studied. Two additional groups matched in terms of age, sex, and left ventricular mass index consisting of 26 nonconsecutive patients with coronary artery disease (group 2) and 20 normal subjects (group 3) were studied for comparison. Standing induced a significantly higher increase of heart rate in group 1 than in groups 2 and 3 (7.5+/-6.0 vs 4.0+/-6.3 and 1.1+/-3.6 beats/min; p = 0.05 and 0.003, respectively). There were significant differences in QT dispersion between groups 1 and 2 on upright standing (48+/-12 vs 34+/-14 ms, p = 0.0003), but not at baseline (33+/-14 vs 38+/-11 ms, p = NS) or at peak exercise (38+/-9 vs 38+/-9 ms, p = NS). Results did not change when QTc dispersion was substituted for QT dispersion. From a conditional multivariate logistic regression analysis, the only independent predictor of occurrence of syndrome X on upright standing was QTc dispersion (odds ratio = 1.255, p = 0.01). Electrocardiographic QTc dispersion provides important clinical information. Patients with syndrome X had a higher increase of heart rate and QTc dispersion in response to standing from the supine position compared with patients with coronary artery disease and normal subjects.

Relation of systemic arterial pulse pressure to coronary atherosclerosis in patients with mitral stenosis.

The relation of a wide systemic arterial pulse pressure to coronary atherosclerosis has not been fully defined. One hundred fifty-nine patients > 40 years old with symptomatic mitral stenosis (MS) who received routine coronary angiography were classified into 2 groups according to the presence of > or = 50% diameter narrowing of > or = 1 coronary artery (n = 48) or no significant disease (n = 111). Pulse pressure was determined both by noninvasive sphygmomanometer and invasive catheterization methods. There were no significant differences in risk factors of coronary artery disease (CAD) or the severity of MS between the 2 groups. From multivariate logistic regression analysis, independent predictors of development of CAD in MS were age (standardized coefficient beta = 1.3437, p = 0.0025), gender (beta = 0.0107, p = 0.0105), mean blood pressure (beta = 1.1839, p = 0.0105), and pulse pressure (beta = 1.3157, p = 0.0008). A wide pulse pressure (> or = 60 mm Hg) correlated with the presence of angiographically significant CAD with a sensitivity and specificity of 88% and 77%. The negative predictive value was 93%. Pulse pressure assessed by sphygmomanometry provided important clinical information. A wide pulse pressure in patients with MS was associated with a high incidence of CAD.