[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.

[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.

[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.

[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.

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.

Personal beliefs, learned resourcefulness, and adaptive functioning in depressed adults.

Learned resourcefulness and personal beliefs are significant predictors of adaptive functioning. The mediating effect of personal beliefs on the relationship between learned resourcefulness and adaptive functioning was validated in adults with depression. The findings from this study may provide the basis for developing a useful nursing intervention constituting resourcefulness skills with positive personal beliefs to help patients with depression improve their ability to function well in their daily activities. ABSTRACT: Research has shown that patients with depression have difficulty with performing daily tasks and meeting their own personal care needs. According to Beck's cognitive theory of depression, such deficits in adaptive functioning are affected by disturbances in specific personal beliefs that reflect the process of regulating cognitions. Rosenbaum's learned resourcefulness theory proposed that adaptive functioning is influenced by learned resourcefulness, while learned resourcefulness is associated with the process regulating cognitions. This study aims to test the mediating effect of personal beliefs on the relationship between resourcefulness and adaptive functioning. The study involved a cross-sectional design. Participants consisted of 187 adults with depression in southern Taiwan. The data were collected through four instruments: Cognitive Triad Inventory, Self-Control Schedule, modified Community Living Skills Scale, and a demographic questionnaire. Both resourcefulness and personal beliefs were significant predictors of adaptive functioning, and personal beliefs mediated the effect of learned resourcefulness on the adaptive functioning of the adults with depression. The results validate the role played by personal beliefs in effecting learned resourcefulness and adaptive functioning among adults with depression and provide direction for designing nursing interventions that consider personal beliefs when teaching resourcefulness skills to adults with depression.

miR-30d, miR-181a and miR-199a-5p cooperatively suppress the endoplasmic reticulum chaperone and signaling regulator GRP78 in cancer.

GRP78, a major endoplasmic reticulum chaperone and signaling regulator, is commonly overexpressed in cancer. Moreover, induction of GRP78 by a variety of anti-cancer drugs, including histone deacetylase inhibitors, confers chemoresistance to cancer, thereby contributing to tumorigenesis. Thus, therapies aimed at decreasing GRP78 levels, which results in the inhibition of tumor cell proliferation and resensitization of tumor cells to chemotherapeutic drugs may hold promise for cancer treatment. Despite advances in our understanding of GRP78 actions, little is known about endogenous inhibitors controlling its expression. As endogenous regulators, microRNAs (miRNAs) play important roles in modulating gene expression; therefore, we sought to identify miRNA(s) that target GRP78, under the hypothesis that these miRNAs may serve as therapeutic agents. Here, we report that three miRNAs (miR-30d, miR-181a, miR-199a-5p) predicted to target GRP78 are down-regulated in prostate, colon and bladder tumors, and human cancer cell lines. We show that in C42B prostate cancer cells, these miRNAs down-regulate GRP78 and induce apoptosis by directly targeting its 3' untranslated region. Importantly, we demonstrate that the three miRNAs act cooperatively to decrease GRP78 levels, suggesting that multiple miRNAs may be required to efficiently control the expression of some genes. In addition, delivery of multiple miRNAs by either transient transfection or lentivirus transduction increased the sensitivity of cancer cells to the histone deacetylase inhibitor, trichostatin A, in C42B, HCT116 and HL-60 cells. Together, our results indicate that the delivery of co-transcribed miRNAs can efficiently suppress GRP78 levels and GRP78-mediated chemoresistance, and suggest that this strategy holds therapeutic potential.

Special section on machine intelligence approaches to systems biology.

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

Twenty-year follow-up of the Carpentier-Edwards standard porcine bioprosthesis in the Oriental population.

AIM: The 20-year period long-term results of porcine bioprosthetic valve use are limited. In addition, the majority of these reports come from Western countries. Given the scanty information reported in Oriental countries, this study was therefore designed to examine 20-year long-term results in patients who received a Carpentier-Edwards porcine bioprosthetic valve in an effort to contribute further information on the long-term clinical performance of porcine prosthetic valves from a viewpoint of results in the Oriental population. METHODS: From July 1979 to April 2001, 82 patients received valve replacement with a standard Carpentier-Edwards porcine valve. There were 40 men and 42 women with a mean age of 42.3+/-15.1 years (range 16 to 73 years). Follow-up time extended more than 20 years (mean 10.9+/-3.2 years, range 0.5 to 21.5 years ) for a total of 719.5 patient-years. RESULTS: The overall operative mortality was 16.9% (14 of 83 procedures). At 5, 10, 15, and 20 years, the actuarial survival rate of patients was 71.7%, 66.9%, 55.5%, and 44.4%, respectively. Actuarial estimates of freedom from structural valvular deterioration (SVD) at 5, 10, 15, and 17 years were 96.3%, 64.0%, 24.3%, and 24.3%, respectively; from reoperation 96.3%, 64.5%, 24.5%, and 24.5%; from operated valvular endocarditis 96.8%, 92.6%, 92.6%, and 92.6%; and from overall thromboembolism 96.3%, 88.5%, 67.2%, and 52.2%. In normal sinus rhythm, actuarial estimates of freedom from thromboembolism at 5, 10, 15, and 17 years were 100.0%, 100.0%, 81.8%, and 81.8%, respectively. Whereas for those in patients with atrial fibrillation, the estimates of freedom from thromboembolism were 94.5%, 82.4%, 57.7%, and 38.5%. CONCLUSION: This study demonstrates the very satisfactory 20-year period long-term performance of freedom from bleeding events, thromboembolism (except in patients with atrial fibrillation), and valvular endocarditis in Oriental patients undergoing replacement with a porcine valve. However, the remarkable rate of SVD and reoperation ensued at 6 years after bioprosthesis implanted which does not differ from the series reported from Western countries.

Oestrogen attenuates coronary vasoconstriction after angioplasty: role of endothelin-1.

BACKGROUND AND AIMS: There were controversies as to whether endothelin-1 is released after coronary angioplasty. We sought to determine whether endothelin-1 is released after coronary angioplasty and whether oestrogen administration can affect coronary vasomotor tone by reducing endothelin-1 concentrations. METHODS: The study was designed to prospectively investigate 24 consecutive patients scheduled for elective coronary angioplasty. Patients were randomized into two groups according to whether they did not (group 1, n = 12) or did (group 2, n = 12) have intracoronary treatment with oestrogen. Quantitative coronary angiography was monitored at baseline, immediately after successful angioplasty, and 15 min after the last deflation. Blood samples for measuring the levels of endothelin-1 were drawn from the ascending aorta and the coronary sinus simultaneously before angioplasty and 15 min after balloon dilatation. RESULTS: The diameters of the coronary artery at the dilated segments were significantly reduced 15 min after dilation compared with those immediately after dilation in group 1 from 3.20 +/- 0.22 to 2.30 +/- 0.23 mm (P < 0.001), respectively. The vasoconstriction was significantly blunted in group 2. The endothelin-1 levels from the coronary sinus rose significantly, by 29%, 15 min after angioplasty in group 1, which was attenuated after administering oestrogen. Significant correlation was found between the changes of coronary vasomotion of the dilated segment and endothelin-1 levels (r = 0.70, P = 0.01). CONCLUSION: Endothelin-1 is released into the coronary circulation after angioplasty, and this vasoactive substance may contribute to the occurrence of vasoconstriction. The vasoconstriction is attenuated by oestrogen by reducing the endothelin-1 levels. This finding provided a new strategy to treat coronary vasoconstriction after angioplasty.

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.

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.

Differential effects of cilostazol and pentoxifylline on vascular endothelial growth factor in patients with intermittent claudication.

Cilostazol is a new phosphodiesterase inhibitor with anti-platelet and vasodilatory properties. Cilostazol and pentoxifylline are the only two drugs that have been approved for the treatment of patients with intermittent claudication. However, the mechanisms by which exercise tolerance is improved remain unclear. Vascular endothelial growth factor (VEGF) is a potent endothelial mitogen that results in angiogenesis when overexpressed in human subjects. To assess the potential role of VEGF in the improvement in exercise tolerance, we investigated plasma levels of VEGF in 50 patients with intermittent claudication who were allocated randomly to groups receiving cilostazol (n=17), pentoxifylline (n=17) or placebo (n=16). Patients given either cilostazol or pentoxifylline showed a significant improvements in maximal walking distance compared with the placebo group (34 m and 33 m respectively, compared with 5 m; both P<0.05). Neither cilostazol nor pentoxifylline increased the ankle-brachial index after treatment. Circulating VEGF levels were increased (from 116+/-29 to 169+/-45 pg/ml; P=0.002), and the levels of VEGF were correlated significantly with exercise tolerance in a positive direction (r=0.88, P=0.004), in those patients treated with cilostazol that did not have diabetes mellitus. In contrast, VEGF levels remained stable after the administration of pentoxifylline. These findings suggest that VEGF may contribute to the cilostazol-related improvement in exercise tolerance in non-diabetic patients. However, pentoxifylline did not affect VEGF levels, although a similar improvement in maximal walking distance was achieved. Thus the mechanisms involved in the pentoxifylline-treated group were different from those in the cilostazol-treated group, and require further study.

Effect of hydroxyzine on the transport of etoposide in rat small intestine.

Etoposide, an anti-neoplastic agent and a substrate of P-glycoprotein (P-gp), exhibits variable oral bioavailability. P-gp, the multidrug resistance gene (mdr1) product, has been considered as an absorption barrier against intestinal drug absorption. Terfenadine, an antihistamine, has been shown to be a P-gp inhibitor. The current study was designed to assess the effect of hydroxyzine, an antihistamine, on the transport of etoposide in the small intestine. Everted rat gut sacs were used to determine the absorption and exsorption of etoposide under different conditions, as rhodamine 123 was chosen to evaluate the role of P-gp in the drug interaction. The results showed that the transport of etoposide was significantly increased from the luminal site to the serosal site in the jejunum by 2- and 4-fold after 90 min in the presence of hydroxyzine and quinidine, respectively. A similar trend was observed in the ileal sacs. This in vitro exsorption study also demonstrated that hydroxyzine could reduce the efflux of etoposide to the luminal site in either jejunum or ileum. The effect of hydroxyzine on the pharmacokinetics of etoposide differed by the in vivo route of administration, thus assuming clinical importance for chemotherapeutic treatment.

Distension of urinary bladder induces exaggerated coronary constriction in smokers with early atherosclerosis.

Distension of the urinary bladder causes an increase in efferent sympathetic activity, which can precipitate myocardial ischemia. Smoking has been shown to modulate activities of afferent nerves from the distended urinary bladder and to impair endothelial function in response to sympathetic activation. To assess the effect of bladder distension on coronary dynamics in smokers, we measured epicardial and microvascular responses in 24 patients with early atherosclerosis (< 50% diameter stenosis). Patients were classified into habitual smokers (group 1, n = 14) and nonsmokers (group 2, n = 10). Habitual smokers were randomized into two subgroups on the basis of the use of doxazosin, as follows: subgroup 1A (n = 7), without administration of doxazosin before catheterization; subgroup 1B (n = 7), with dosing doxazosin. In response to bladder distension (mean intravesical pressure 21.5 mmHg), bladder distension significantly decreased coronary diameter at the stenotic segments, coronary blood flow, and increased coronary resistance compared with baseline values, in subgroup 1A patients. In subgroup 1B patients during bladder distension, coronary diameter, coronary blood flow, and coronary resistance did not show significant changes compared with baseline values. There were significant differences of coronary diameter at the stenotic segments, coronary blood flow, and of changes of coronary vascular resistance between subgroup 1A and group 2 during bladder distension, despite similar changes in rate-pressure product. The present study showed that urinary bladder distension caused an abnormal vasomotor response of epicardial vasoconstriction and a concomitant increased coronary resistance, which leads to reduction in coronary blood flow in patients with early atherosclerosis. Smoking may further impair the response, implying that smoking has exaggerated response to sympathetic stimulation of conduit and resistance vessels. The abnormal response was abolished by pretreated administration of doxazosin, suggesting that the involved mechanisms are related to alpha(1)-adrenoceptors.

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.

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.