[Long-term outcome of EVAHEART I implantable ventricular assist device for the treatment of end stage heart failure: clinical 3-year follow-up results of 15 cases].

Objective: To evaluate the long-term efficacy and safety of the implantable ventricular assist system EVAHEART I in clinical use. Methods: Fifteen consecutive patients with end-stage heart failure who received left ventricular assist device therapy in Fuwai Hospital from January 2018 to December 2021 were enrolled in this study, their clinical data were retrospectively analyzed. Cardiac function, liver and kidney function, New York Heart Association (NYHA) classification, 6-minute walk distance and quality of life were evaluated before implantation and at 1, 6, 12, 24 and 36 months after device implantation. Drive cable infection, hemolysis, cerebrovascular events, mechanical failure, abnormally high-power consumption and abnormal pump flow were recorded during follow up. Results: All 15 patients were male, mean average age was (43.0±7.5) years, including 11 cases of dilated cardiomyopathy, 2 cases of ischemic cardiomyopathy, and 2 cases of valvular heart disease. All patients were hemodynamically stable on more than one intravenous vasoactive drugs, and 3 patients were supported by preoperative intra aortic balloon pump (IABP). Compared with before device implantation, left ventricular end-diastolic dimension (LVEDD) was significantly decreased ((80.93±6.69) mm vs. (63.73±6.31) mm, P<0.05), brain natriuretic peptide (BNP), total bilirubin and creatinine were also significantly decreased ((3 544.85±1 723.77) ng/L vs. (770.80±406.39) ng/L; (21.28±10.51) µmol/L vs. (17.39±7.68) µmol/L; (95.82±34.88) µmol/L vs. (77.32±43.81) µmol/L; P<0.05) at 1 week after device implantation. All patients in this group were in NYHA class Ⅳ before implantation, and 9 patients could recover to NYHA class Ⅲ, 3 to class Ⅱ, and 3 to class Ⅰ at 1 month after operation. All patients recovered to class Ⅰ-Ⅱ at 6 months after operation. The 6-minute walk distance, total quality of life and visual analogue scale were significantly increased and improved at 1 month after implantation compared with those before operation (P<0.05). All patients were implanted with EVAHEART I at speeds between 1 700-1 950 rpm, flow rates between 3.2-4.5 L/min, power consumption of 3-9 W. The 1-year, 2-year, and 3-year survival rates were 100%, 87%, and 80%, respectively. Three patients died of multiple organ failure at 412, 610, and 872 d after surgery, respectively. During long-term device carrying, 3 patients developed drive cable infection on 170, 220, and 475 d after surgery, respectively, and were cured by dressing change. One patient underwent heart transplantation at 155 d after surgery due to bacteremia. Three patients developed transient ischemic attack and 1 patient developed hemorrhagic stroke events, all cured without sequelae. Conclusion: EVAHEART I implantable left heart assist system can effectively treat critically ill patients with end-stage heart failure, can be carried for long-term life and significantly improve the survival rate, with clear clinical efficacy.

[Surgical treatment of heart failure in China: towards the era of artificial heart].

The number of patients with heart failure in China is large, and the proportion of patients with end-stage heart failure continues to increase. The clinical effect of guideline-directed medications therapy for end-stage heart failure is poor. Heart transplantation is the most effective treatment for end-stage heart failure. But it is faced with many limitations such as the shortage of donors. In recent years, the research and development of artificial heart in China has made great progress. Three devices have been approved by the National Medical Products Administration for marketing, and another one is undergoing pre-marketing clinical trial. Since 2017, more than 200 cases of ventricular assist device implantation have been carried out in more than 34 hospitals in China. Among them, 70 patients in Fuwai Hospital, Chinese Academy of Medical Sciences had a 2-year survival rate of 90%. The first patient has survived more than 5 years with the device. More efforts should be put into the training of standardized technical team and quality control. Further research should be carried out in the aspects of pulsatile blood flow pump, fully implanted cable-free device, and improved biomaterial with better blood compatibility.

Joint synovial macrophages as a potential target for intra-articular treatment of osteoarthritis-related pain.

Osteoarthritis is the most common form of joint disease and is one of the leading causes of chronic pain. Given the multi-factorial nature, numerous efforts have been made to clarify the multiple factors impacting the pain symptoms and joint pathology, including synovial macrophages in particular. Accumulating evidence from studies involving human participants and experimental animal models suggests that accumulating macrophages in synovial tissue are implicated in peripherally mediated pain sensitization of affected joints in osteoarthritis. Crosstalk between synovial macrophages and the innervating primary nociceptive neurons is thought to contribute to this facilitated pain processing by the peripheral nervous system. Due to high plasticity and complexity of synovial macrophages in the joint, safe therapies targeting single cells or molecules are currently lacking. Using advanced technologies (such as single-cell RNA sequencing and mass cytometry), studies have shown that diverse subpopulations of synovial macrophages exist in the distinct synovial microenvironments of specific osteoarthritis subtypes. Considerable progress has been made in delineating the molecular mechanisms of various subsets of synovial macrophages in the development of osteoarthritis. To develop a novel intra-articular treatment paradigm targeting synovial macrophages, we have summarized in this review the recent advances in identifying the functional consequences of synovial macrophage sub-populations and understanding of the molecular mechanisms driving macrophage-mediated remodeling.

[The impact of donor-to-recipient gender compatibility on outcomes of haploid hematopoietic stem cell transplantation in patients with hematological malignancies].

Objective: To investigate how gender differences between the donor and the recipient affect the effectiveness of antithymocyte globulin (ATG) and pure peripheral blood stem cell (PBSC) hematopoietic stem cell transplantation (haplo-HSCT) in the treatment of malignant hematological diseases. Methods: From February 2015 to September 2020, 648 hematological malignancies patients underwent myeloablative condition regimen haplo-HSCT treatment at the Bone Marrow Transplant Center of the First Affiliated Hospital of Zhejiang University. The median age was 32 (14-62) years, with 363 males (56.0% ) and 285 females (44.0% ) present. 242 cases of acute lymphoblastic leukemia (ALL) (37.3% ) , 293 cases of acute myeloid leukemia (AML) (45.2% ) , 56 cases of myelodysplastic syndrome (MDS) (8.7% ) , 27 cases of non-Hodgkin's lymphoma (NHL) (4.2% ) , and 30 cases of other hematological malignancies (4.6% ) . Results: ① The 3-year overall survival (OS) , DFS, the incidence of Ⅱ-Ⅳ grade acute graft-versus-host disease (aGVHD) , the incidence of Ⅲ-Ⅳ grade aGVHD, the 3-year incidence of moderate & severe chronic GVHD (cGVHD) , severe cGVHD, the 3-year incidence of relapse, and NRM of the whole group were (73.10±1.90) % , (70.80±1.90) % , (33.96±1.87) % , (13.08±1.33) % , (35.10±2.14) % , (10.66±1.38) % , (19.43±1.67) % , and (9.80±1.24) % , respectively. ②There was no statistically significant difference between the donor-recipient gender match and donor-recipient gender mismatch groups in the 28-day cumulative neutrophil engraftment rate, 28-day cumulative platelet engraftment rate, the incidence of Ⅱ-Ⅳ grade aGVHD, the incidence of Ⅲ-Ⅳ grade aGVHD, 3-year OS, 3-year DFS, the cumulative incidence of relapse, NRM, and incidence of moderate & severe cGVHD, severe cGVHD. ③The 28-day cumulative neutrophil engraftment rate did not differ statistically between the male-female, female-female, male-male, and female-male groups (P=0.148) . The incidence of Ⅱ-Ⅳ grade aGVHD, the incidence of Ⅲ-Ⅳ grade aGVHD, 3-year OS, 3-year DFS, cumulative relapse rate, and NRM, and the incidence of cGVHD were not statistically different among the four groups (P>0.05) . The 28-day cumulative platelet engraftment rate of the female-male group was significantly lower than male-female group, and the female-female group [ (91.45±2.63) % vs. (94.77±1.75) % , P=0.004; (91.45±2.63) % vs. (95.54±2.05) % , P=0.005]. No significant difference existed in the 28-day cumulative platelet engraftment rate between the female-male group and the male-male group [ (91.45±2.63) % vs. (95.08±1.41) % , P=0.284]. ④Among patients ≤35 years old, the 3-year incidence of severe cGVHD patients receiving sister donors and sibling donors were (26.71±5.90) % and (10.33±4.43) % , respectively (P=0.054) . Patients accepting daughter donors and son donors had a 3-year incidence of moderate and severe cGVHD that was 40.07% vs. 27.41% , respectively, among those over 35 (40.07±6.65) % vs. (27.41±4.54) % (P=0.084) . ⑤Female donors to male recipients had a significantly lower 28-day cumulative platelet engraftment rate compared to the other groups [ (91.45±2.63) % vs. (95.08±0.95) % , P=0.037]. ⑥ Female donors to male recipients had a significantly lower 28-day cumulative platelet engraftment rate than the other groups in the ATG-Fresenius (ATG-F) 10 mg/kg group [ (89.29±4.29) % vs. (94.49±1.45) % , P=0.037]. But when compared to the other groups in the Rabbit Antihuman Thymocyte Immunoglobulin (rATG-T) 6 mg/kg group, the 28-day cumulative platelet implantation rate between female donors and male recipients was not significantly different [ (93.44±3.38) % vs. (95.62±1.26) % , P=0.404]. Conclusion: The main clinical outcomes of patients with malignant blood diseases following transplantation are unaffected by the gender combination of the donor and patient in the haplo-HSCT mode based on ATG and PBSC sources. Female donors to male recipients have a lower 28-day cumulative platelet engraftment rate and longer platelet engraftment times.

[Clinical application value of transthoracic echocardiography during perioperative period in patients undergoing left ventricular assist device implantation].

Objective: To observe the changes of parameters derived from transthoracic echocardiography (TTE) before and after left ventricular assist device (LVAD) implantation, and to evaluate the clinical value of TTE in the perioperative period of LVAD implantation. Methods: This is a retrospective study. The data of patients who underwent LVAD implantation in Fuwai Hospital from January 2018 to December 2020 were analyzed retrospectively. The TTE parameters, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and total bilirubin (TBil) before and 1 month after LVAD implantation were collected and analyzed. Results: A total of 12 male patients undergoing LVAD implantation were included in this study. The mean age was (43.3±8.6) years. The left atrial volume index ((41.4±12.8)ml/m2 vs. (74.9±30.7)ml/m2, P<0.001), left ventricular end-diastolic volume index ((152.1±35.3)ml/m2 vs. (205.5±35.7)ml/m2, P<0.001), left ventricular end-systolic volume index ((112.5±27.9)ml/m2 vs. (155.1±29.1)ml/m2, P<0.001), right atrial diameter index ((23.7±3.5)mm/m2 vs. (27.2±5.8)mm/m2, P=0.023), right ventricular internal diameter at end-diastole ((24.6±2.7)mm vs. (30.0±4.8)mm, P<0.001), tricuspid annular plane systolic excursion ((11.5±2.9)mm vs. (14.6±2.8)mm, P=0.007), systolic pulmonary arterial pressure ((29.2±4.8) mmHg vs. (55.1±19.3) mmHg, P<0.001, 1 mmHg=0.133 kPa) were significantly reduced at 1 month post LVAD implantation as compared to before LVAD implantation. The aortic sinus diameter ((33.8±4.7)mm vs. (31.6±5.1)mm, P=0.007), left ventricular ejection fraction ((26.3±3.0)% vs. (23.8±4.4)%, P=0.016), right ventricular fractional area change ((31.0±8.6)% vs. (23.8±5.5)%, P=0.004) at 1 month post LVAD implantation were significantly higher than before LVAD implantation. The degree of mitral and tricuspid regurgitation decreased, and the inspiratory collapse rate of inferior vena cava increased (all P<0.05). NT-proBNP ((1 418.4±812.6)ng/L vs. (5 097.5±3 940.4)ng/L, P=0.004) and TBil ((12.4±5.4)µmol/L vs. (27.5±14.0)µmol/L, P=0.001) decreased significantly at 1 month post LVAD implantation. Conclusions: TTE results show that LVAD could effectively relieve left ventricular load and improve right ventricular function. TTE can monitor the cardiac structural and functional changes during the perioperative period of LVAD implantation, and provide the imaging evidence for clinical evaluation of the therapeutic effect of LVAD.

LINC01605 regulates proliferation, migration and invasion of colorectal cancer cells via targeting miR-3960/SOX11.

OBJECTIVE: We aimed to determine the expression level of long intergenic non-coding ribonucleic acid 1605 (LINC01605) in colorectal cancer (CRC), and to explore the effects of the LINC01605/microRNA (miR)-3960/sex-determining region Y-box 11 (SOX11) regulatory axis on the biological behaviors of CRC cells and the molecular mechanism therein. PATIENTS AND METHODS: Tissue specimens were collected from 38 patients with CRC, and the relative expression level of LINC01605 in the CRC tissues and CRC cells was measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Then, the effects of LINC01605 on the proliferation, apoptosis, invasion and metastasis of CRC cells were observed via in vitro assays [cell counting kit (CCK)-8 assay, flow cytometry and transwell assay]. Besides, the possible miRNAs binding to LINC01605 were predicted by the bioinformatics method, and they were screened and verified using qRT-PCR and Dual-Luciferase reporter gene assay. Finally, the downstream target genes of miR-3960 were predicted by means of bioinformatics, and they were also screened and confirmed via qRT-PCR and Dual-Luciferase reporter gene assay. RESULTS: According to the results of qRT-PCR, the expression of LINC01605 was up-regulated in 31 out of 38 cases of CRC tissue specimens, and its expression in CRC cells was higher than that in normal colorectal cells. The results of in vitro assays revealed that the proliferation, migration and invasion abilities of CRC cells were weakened, with an increased apoptosis rate after interference with LINC01605 expression. Based on the results of qRT-PCR and Dual-Luciferase reporter gene assay, miR-3960 was the target of LINC01605, while SOX11 was the target of miR-3960. Moreover, the expression of miR-3960 rose, but that of SOX11 declined after interference with LINC01605 expression. It was found through Western blotting that the protein expression of SOX11 was lowered after interference with LINC01605 expression. CONCLUSIONS: LINC01605 has an up-regulated expression in CRC, and accelerates the proliferation, migration and metastasis of CRC cells by the miR-3960/SOX11 regulatory axis.

[Clinicopathological features and gene phenotypes of benign metastasizing leiomyoma].

Objective: To study the clinicopathological features, immunophenotypes and MED12 gene status in benign metastasizing leiomyoma (BML). Methods: Nine cases of BML diagnosed at the Affiliated Hospital of Qingdao University from 2012 to 2018 were collected, and the radiologic and histologic features were analyzed. The protein expression of leiomyosarcoma-related driver genes, including RB1, PTEN,ATRX,p16,p53, as well as ER,PR,CD34,FH, and Ki-67 were detected using immunohistochemistry, and the mutation status of MED12 gene exon 2 was detected by Sanger sequencing. Results: All the nine patients with BML were female, and the age range was 48 to 64 years (median 55 years). All patients had history of uterine fibroids. The morphologic features of BML were similar to a benign uterine leiomyoma and did not exhibit malignant characteristics. All cases were positive for ER and PR, and negative for CD34. In addition, RB1, PTEN, ATRX, and FH were positive in all cases (wild type), while p16 showed a focally positive pattern. P53 positive index was less than 5% (wild type), and Ki-67 positive index was less than 1%. Sanger sequencing was done in six BML samples; one sample harbored a nonsense mutation c. 142_144delinsTAA (p.Glu48Ter), and another exhibited a synonymy mutation (c.192C>T, p.Phe64=)and one missense mutation c.196C>T (p.Pro66Ser). Conclusions: The present study suggests that BML is a unique leiomyoma entity that is pathologically and genetically different from leiomyosarcomas and conventional uterine leiomyomas. Evaluating the genetic phenotype of BML, especially the expression of leiomyosarcoma-related driver genes protein and MED12 gene status, may be helpful in understanding the pathogenesis of BML and in its differentiation from leiomyosarcoma.

[Association of platelet/lymphocyte ratio and neutrophil/lymphocyte ratio with protein-energy wasting in maintenance hemodialysis patients].

Objective: To explore the association of platelet/lymphocyte ratio (PLR) and neutrophil/lymphocyte ratio (NLR) with protein energy wasting (PEW) in maintenance hemodialysis (MHD) patients. Methods: A multicenter cross-sectional study was conducted in eleven hemodialysis centers of Guizhou province from June to August, 2017. Clinical data, physical parameters, body composition data and laboratory values of MHD patients were collected. PLR and NLR were calculated according to routine blood test. All patients were divided into four groups (Q1-Q4) according to the median and quartile of PLR and NLR. Multivariate logistic regression models were applied to analyze the relationships between PLR, NLR and PEW. The comparison of predictive power of PLR and NLR for PEW was evaluated by receiver operating characteristic curve (ROC). Results: A total of 936 MHD patients were enrolled (519 males, 417 females), with a mean age of (55.6±15.6) years. The prevalence of PEW was 46.2% (432/936). Multivariate logistic regression analysis showed that patients in group PLR Q3 and Q4 were 2.07 (95%CI: 1.03-4.13, P=0.014) and 2.73 (95%CI: 1.58-4.74, P<0.001) times more likely to have PEW, compared with those in group PLR Q1 in unadjusted models. PLR was significantly associated with the development of PEW after adjusting age, sex, history of hypertension, diabetes and hemoglobin. Patients in Group PLR Q3 and Q4 were 2.82 times (95%CI: 1.42-5.60, P=0.003) and 2.93 times (95%CI: 1.50-5.73, P=0.002) times more likely to have PEW than those in Group PLR Q1. The ROC showed that only PLR can predict the development of PEW with a diagnostic threshold of 144.09 [area under curve (AUC)=0.61, 95%CI: 0.56-0.66, P<0.001], with a sensitivity and specificity of 61% and 58%, respectively, while the AUC of NLR is 0.55 (P=0.091). Conclusion: For MHD patients, only PLR could be a relevent factor of PEW and it showed the predictive power of PEW rather than NLR.

[Interventional treatment of symptomatic intracranial in-stent restenosis].

Objective: To assess the feasibility and safety of interventional treatment of symptomatic intracranial in-stent restenosis (SISR). Methods: Clinical data of 21 patients with SISR who underwent interventional treatment in the General Hospital of the PLA Rocket Force from January 2012 to May 2018 were retrospectively analyzed. Perioperative complications, angiographic and clinical follow-up results were recorded. Results: The success rate of treatment was 100%, including 21 lesions of SISR (7 at the V4 segment of the vertebral artery, 7 at the basilar artery, 5 at the M1 segment of middle cerebral artery, 2 at the internal carotid artery). The residual stenosis rate was preoperative 84±7, postoperative 30±14 respectively. Balloon angioplasty and stent implantation were performed in 10 patients (48.6%) and 11 patients (52.4%), respectively. After treatment, 1 patient experienced perforating event without neurological sequelae. Of the 11 patients (52.4%) completed angiography follow-up, 3 (3/11, 27.3%) ocurred restenosis and 1 was retreated. During clinical follow-up, 1 patients received intravenous thrombolysis for the symptom of acute cerebral infarction in territory of stenting artery, in-stent restenosis or occlusion was not demonstrated by emergency cerebral angiography. Conclusion: Interventional treatment of SISR is feasible and safe, however, further studies need to warrant the long-term effects.

[Association of low serum parathyroid hormone with protein-energy wasting in maintenance hemodialysis patients].

Objective: To examine the relationship between low serum parathyroid hormone (PTH) and protein-energy wasting (PEW) in patients who underwent maintenance hemodialysis (MHD) treatment. Methods: A cross-sectional study was conducted in MHD patients between June 2015 and August 2017 in 11 MHD centers from Guizhou province. Body composition and physical parameters were measured, clinical data and other related laboratory values were collected according to the medical record system. Participants were assigned to low serum PTH group (PTH<150 ng/L), target PTH group (150 ng/L≤ PTH ≤300 ng/L) and high serum PTH group (PTH>300 ng/L). Multivariate logistic regression analysis was used to analyze the relationship between low serum PTH and risk of PEW, which was diagnosed according to the diagnostic criteria recommened by the International Society of Renal Nutrition and Metabolism (ISRNM). Results: A total of 873 MHD patients (488 males and 385 females) were included in the final analysis, with a mean age of 55.0 (44.0, 67.0) years and a mean hemodialysis duration of 31.0(17.0, 54.0) months. In unadjusted model, low serum PTH group was associated with PEW (OR=2.12, 95% CI: 1.26-3.54, P=0.004), when compared with high serum PTH group. After adjustment for age and sex, low serum PTH group was still significantly associated with PEW (OR=2.09, 95% CI: 1.23-3.52, P=0.006). Further adjustment for diabetes and hypertension, the correlation between low serum PTH group and PEW was still significant (OR=2.02, 95% CI: 1.04-3.90, P=0.037). However, the correlation was not observed in target PTH group and high serum PTH group. Conclusion: Low serum PTH was associated with risk of PEW, regardless of age, sex, history of diabetes and hypertension, and thus it might be a promising indicator of PEW in MHD patients.

[Application of the descending branch of the lateral circumflex femoral artery in the coronary artery bypass grafting operation].

Objective: To investigate the technical method for harvesting and application of the descending branch of the lateral circumflex femoral artery (DBLCFA) in the coronary artery bypass grafting (CABG) operation. Methods: Between December 2016 and April 2017, 19 patients were arranged to use DBLCFA and got CT angiography (CTA) of pelvic and femoral arteries pre-operative at Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Finally, DBLCFA was harvested in 16 patients (including 2 female patients, with a mean age of (47.4±8.5) years) through the anterior thigh incision (13 cases on the left side, 3 cases on the right side). The CABG operations were performed under the cardiopulmonary bypass support (in 10 cases) or under the beating heart condition (in 6 cases), and the DBLCFA conduit was used combining with bilateral internal thoracic artery (in 12 cases), radial artery (in 7 cases) and saphenpous vein (in 3 cases). Results: Due to anatomical variations such as short length and anomalous branch, or due to silent atherosclerosis stenosis of femoral artery, DBLCFA in 3 patients was considered inappropriate for use and was not harvested after CTA examination. In another 16 patients, DBLCFA was safely and quickly harvested and successfully used. On average, 3.4±0.6 anastomosis was built up in CBAG, no adverse effects were exhibited. The length of the harvested DBLCFA was (10.3±1.8) cm, with average lumen diameter of (1.9±0.5) mm. DBLCFA was used as free graft in 15 patients (7 to the first diagonal branch, 6 to the ramus intermedius branch, 1 to the left anterior descending branch and 1 to the second obtuse marginal branch). In 1 patient, the DBLCFA was firstly implanted end-to-side to the internal thoracic artery as a "Y" type composite graft, and then anastomosed to the third obtuse marginal branch. Conclusions: The descending branch of the lateral circumflex femoral artery is an option conduit in CABG. It can be harvested easily and safely. However, pre-operative CTA examination is necessary to exclude the variation and appropriate strategy for graft establishment should be considered during the operation.

[Future directions of cardiovascular surgery in China].

The cardiovascular surgery in China has achieved great progress both on scale and technology though development over the past thirty years. However, the technical predominance of cardiovascular surgery in therapies for some diseases has been weakened, along with developments of new drugs and interventional technology. Besides, the change of doctor-patient relationship result from internet medical information service and less attraction of cardiovascular surgery discipline to talents bring certain challenge to the development of cardiovascular surgery. Currently, cardiovascular surgeons should practice the "patient first" principle, carry out individual customized treatment and precision therapy, absorb the advantages of other subjects like intervention and imaging in order to achieve technological breakthroughs, create new treatment technologies and models with smaller trauma and better outcome, establish heart team to provide patient oriented treatment. Besides, cardiovascular surgeons should improve knowledge system by learning related technology and science, become hybrid doctors of research. Cardiovascular surgeons should pay high attention to critical effect of research on the disciplinary development, carry out question and demand oriented clinical studies, change the medical practice by virtue of research achievements, direct the treatment for cardiovascular diseases, and finally provide better health service and rebuild the predominance of cardiovascular surgery.

Effect of acute/subchronic samarium exposure on the concentration, motility, and morphology of sperm in male mice.

Male ICR mice were orally administered samarium nitrate [Sm(NO3)3] to investigate its effects on sperm concentration and sperm quality. After acute exposure to ≥2880.00 mg/kg Sm(NO3)3 via intragastric gavage, sperm motility and acrosome integrity were decreased, and the sperm malformation percentage was increased (P < 0.05). After subchronic exposure to ≥500.00 mg/L Sm(NO3)3 administered via drinking water for 90 days, relative gonad weight, sperm concentration, and sperm quality significantly decreased (P < 0.05). Sperm malformation also increased after subchronic exposure to Sm, which was found to be the most sensitive index. Sperm head malformation accounted for the largest proportion of all types of sperm malformations evaluated. Of the six different subtypes of head malformation, irregular shape accounted for the largest proportion.

Expression of immediate-early genes in the inferior colliculus and auditory cortex in salicylate-induced tinnitus in rat.

Tinnitus could be associated with neuronal hyperactivity in the auditory center. As a neuronal activity marker, immediate-early gene (IEG) expression is considered part of a general neuronal response to natural stimuli. Some IEGs, especially the activity-dependent cytoskeletal protein (Arc) and the early growth response gene-1 (Egr-1), appear to be highly correlated with sensory-evoked neuronal activity. We hypothesize, therefore, an increase of Arc and Egr-1 will be observed in a tinnitus model. In our study, we used the gap prepulse inhibition of acoustic startle (GPIAS) paradigm to confirm that salicylate induces tinnitus-like behavior in rats. However, expression of the Arc gene and Egr-1 gene were decreased in the inferior colliculus (IC) and auditory cortex (AC), in contradiction of our hypothesis. Expression of N-methyl d-aspartate receptor subunit 2B (NR2B) was increased and all of these changes returned to normal 14 days after treatment with salicylate ceased. These data revealed long-time administration of salicylate induced tinnitus markedly but reversibly and caused neural plasticity changes in the IC and the AC. Decreased expression of Arc and Egr-1 might be involved with instability of synaptic plasticity in tinnitus.

Association between methylenetetrahydrofolate reductase polymorphisms and the relapse of acute lymphoblastic leukemia: a meta-analysis.

Relapse is a threat in patients treated for acute lymphoblastic leukemia (ALL). Methylenetetrahydrofolate reductase (MTHFR) activity may affect the sensitivity of patients to folate-based chemotherapeutic drugs, thus influencing the relapse risk. Two polymorphisms of the gene encoding MTHFR, C677T and A1298C, alter MTHFR enzyme activity and may be associated with ALL relapse. The aim of this meta-analysis was to clarify the correlation between the C677T and A1298C polymorphisms and ALL relapse. To this end, data were collected from studies of the association between these two polymorphisms and ALL relapse. Analysis of the data revealed a serious contradiction among the results. A recessive model demonstrated that the ALL relapse risk was significantly increased in carriers of the 677 TT genotype, especially for pediatric ALL, but was unaffected by the A1298C polymorphism. These findings confirm that the MTHFR C677T polymorphism could be considered as a good marker of the pediatric ALL relapse risk.

COX-2 and fatty acid amide hydrolase can regulate the time course of depolarization-induced suppression of excitation.

BACKGROUND AND PURPOSE: Depolarization-induced suppression of inhibition (DSI) and excitation (DSE) are two forms of cannabinoid CB(1) receptor-mediated inhibition of synaptic transmission, whose durations are regulated by endocannabinoid (eCB) degradation. We have recently shown that in cultured hippocampal neurons monoacylglycerol lipase (MGL) controls the duration of DSE, while DSI duration is determined by both MGL and COX-2. This latter result suggests that DSE might be attenuated, and excitatory transmission enhanced, during inflammation and in other settings where COX-2 expression is up-regulated. EXPERIMENTAL APPROACH: To investigate whether it is possible to control the duration of eCB-mediated synaptic plasticity by varied expression of eCB-degrading enzymes, we transfected excitatory autaptic hippocampal neurons with putative 2-AG metabolizing enzymes: COX-2, fatty acid amide hydrolase (FAAH), α/ß hydrolase domain 6 (ABHD6), α/ß hydrolase domain 12 (ABHD12) or MGL. KEY RESULTS: We found that overexpression of either COX-2 or FAAH shortens the duration of DSE while ABHD6 or ABHD12 do not. In contrast, genetic deletion (MGL(-/-)) and overexpression of MGL both radically altered eCB-mediated synaptic plasticity. CONCLUSIONS AND IMPLICATIONS: We conclude that both FAAH and COX-2 can be trafficked to neuronal sites where they are able to degrade eCBs to modulate DSE duration and, by extension, net endocannabinoid signalling at a given synapse. The results for COX-2, which is often up-regulated under pathological conditions, are of particular note in that they offer a mechanism by which up-regulated COX-2 may promote neuronal excitation by suppressing DSE while enhancing conversion of 2-AG to PGE(2) -glycerol ester under pathological conditions.

Complementary synaptic distribution of enzymes responsible for synthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in the human hippocampus.

Clinical and experimental evidence demonstrates that endocannabinoids play either beneficial or adverse roles in many neurological and psychiatric disorders. Their medical significance may be best explained by the emerging concept that endocannabinoids are essential modulators of synaptic transmission throughout the central nervous system. However, the precise molecular architecture of the endocannabinoid signaling machinery in the human brain remains elusive. To address this issue, we investigated the synaptic distribution of metabolic enzymes for the most abundant endocannabinoid molecule, 2-arachidonoylglycerol (2-AG), in the postmortem human hippocampus. Immunostaining for diacylglycerol lipase-α (DGL-α), the main synthesizing enzyme of 2-AG, resulted in a laminar pattern corresponding to the termination zones of glutamatergic pathways. The highest density of DGL-α-immunostaining was observed in strata radiatum and oriens of the cornu ammonis and in the inner third of stratum moleculare of the dentate gyrus. At higher magnification, DGL-α-immunopositive puncta were distributed throughout the neuropil outlining the immunonegative main dendrites of pyramidal and granule cells. Electron microscopic analysis revealed that this pattern was due to the accumulation of DGL-α in dendritic spine heads. Similar DGL-α-immunostaining pattern was also found in hippocampi of wild-type, but not of DGL-α knockout mice. Using two independent antibodies developed against monoacylglycerol lipase (MGL), the predominant enzyme inactivating 2-AG, immunostaining also revealed a laminar and punctate staining pattern. However, as observed previously in rodent hippocampus, MGL was enriched in axon terminals instead of postsynaptic structures at the ultrastructural level. Taken together, these findings demonstrate the post- and presynaptic segregation of primary enzymes responsible for synthesis and elimination of 2-AG, respectively, in the human hippocampus. Thus, molecular architecture of the endocannabinoid signaling machinery supports retrograde regulation of synaptic activity, and its similar blueprint in rodents and humans further indicates that 2-AG's physiological role as a negative feed-back signal is an evolutionarily conserved feature of excitatory synapses.

An assessment of teicoplanin use and monitoring serum levels in a Chinese teaching hospital.

OBJECTIVE: To validate a high performance liquid chromatography (HPLC) method for serum teicoplanin measurement and use the method for clinical monitoring of teicoplanin levels to analyze the clinical application of teicoplanin. METHODS: 55 patient profiles were collected and analyzed for the clinical teicoplanin application. 10 critically ill patients of the 55 cases were monitored for teicoplanin trough concentration using the HPLC method. RESULTS: The modified HPLC method exhibited excellent linearity, with correlation coefficient r = 0.9995. The intra-day and inter-day coefficients of variation were less than 10%. The lower limit of detection of teicoplanin was 5.63 mg/l. The recovery of teicoplanin was above 90%. Of the 55 patients in this study, there were 42 patients without load-dosing. There were only 29 patients treated with teicoplanin documented Gram-positive infections by etiological diagnoses. In the 10 patients with teicoplanin serum trough concentration monitoring, all cases received a loading dose of 400 mg every 12 h for 3 doses, and the mean trough concentration of teicoplanin was 10.82 ± 4.51 mg/l. The mean trough levels were 13.04 ± 6.23 mg/l in 4 patients with microbiological eradication and improvement of symptoms of diseases and 9.34 ± 2.61 mg/l in 6 patients with persistence of previous clinical infectious symptoms, respectively. CONCLUSION: The modified HPLC method is robust, highly reproducible and suited to monitor the concentration of teicoplanin. In critically ill Chinese patients, we should consider more appropriate loading doses and evaluate the relationship between teicoplanin trough concentration and the efficacy using microbiological and clinical parameters.

Design and performance testing of an axial-flow ventricular assist device developed at the Fu Wai Hospital in Beijing.

PURPOSE: Various ventricular assist devices (VADs) have been developed for clinical use in recent years. The aim of a multidisciplinary research team at the Fuwai Hospital of the Peking Union Medical College is to design and develop an axial flow left ventricular assist device (LVAD) for adults. METHODS: Using Computational Fluid Dynamics (CFD), the inflow characteristics of the axial flow pump were analyzed. After CFD analysis, the axial pump was fabricated using a 5-axis, computer numerical control (CNC) milling machine. Performances of the pump both in vitro and in vivo were tested. RESULTS: This VAD, which was developed after numerous CFD analyses for the flow characteristics of the pump, is 58.5 mm long, 30 mm wide and weighs 120 g. The pump can deliver 5 lpm for pressures of 100 mmHg over 8500 rpm. The NIH value was 0.01 g/100 L. The hemolysis, which was evaluated in an in vivo test, was a bit higher than the normal value, but remained within an acceptable range. CONCLUSIONS: Performance of the pump in vitro and in vivo was considered sufficient for an LVAD. Further design improvements are being undertaken in terms of hemolysis and thrombosis to improve the biocompatibility of the pump.