Lidocaine Increases Intracellular Sodium Concentration through Voltage-dependent Sodium Channels in an Identified Lymnaea Neuron

Background: The local anesthetic lidocaine affects neuronal excitability in the central nervous system; however, the mechanisms of such action remain unclear. The intracellular sodium concentration ([Na+]i) and sodium currents (INa) are related to membrane potential and excitability. Using an identifiable respiratory pacemaker neuron from Lymnaea stagnalis, the authors sought to determine whether lidocaine changes [Na+]i and membrane potential and whether INa is related to these changes.

Methods: Intracellular recording and sodium imaging were used simultaneously to measure membrane potentials and [Na+]i, respectively. Measurements for [Na+]i were made in normal, high-Na+, and Na+-free salines, with membrane hyperpolarization, and with tetrodotoxin pretreatment trials. Furthermore, changes of INa were measured by whole cell patch clamp configuration.

Results: Lidocaine increased [Na+]i in a dose-dependent manner concurrent with a depolarization of the membrane potential. In the presence of high-Na+ saline, [Na+]i increased and the membrane potential was depolarized; the addition of lidocaine further increased [Na+]i, and the membrane potential was further depolarized. In Na+-free saline or in the presence of tetrodotoxin, lidocaine did not change [Na+]i. Similarly, hyperpolarization of the membrane by current injections also prevented the lidocaine-induced increase of [Na+]i. In the patch clamp configuration, membrane depolarization by lidocaine led to an inward sodium influx. A persistent reduction in membrane potential, resulting from lidocaine, brings the cell within the window current of INa where sodium channel activation occurs.     

Association of dietary and genetic factors related to one‐carbon metabolism with global methylation level of leukocyte DNA

Global hypomethylation of leukocyte DNA has been associated with an increased risk of cancer. As dietary and genetic factors related to one‐carbon metabolism may influence both the methylation and synthesis of DNA, we investigated associations between these factors and the global methylation level of peripheral blood leukocyte DNA based on a cross‐sectional study of 384 Japanese women. Dietary intake of folate and vitamins B2, B6, and B12 was assessed with a validated semiquantitative food frequency questionnaire. Five polymorphisms in methylenetetrahydrofolate reductase (MTHFR) ( rs1801133 and rs1801131 ), methionine synthase (MTR) ( rs1805087 ), and methionine synthase reductase (MTRR) ( rs10380 and rs162049 ) were genotyped. Global DNA methylation of leukocyte DNA was quantified using Luminometric Methylation Assay. A linear trend of association between methylation and dietary and genetic factors was evaluated by regression coefficients in a multivariable linear regression model. Mean global methylation level (standard deviation) was 70.2% (3.4) and range was from 59.0% to 81.2%. Global methylation level significantly decreased by 0.36% (95% confidence interval, 0.03–0.69) per quartile category for folate level. Subgroup analysis suggested that alcohol drinking modified the association between folate intake and global methylation level (P_interaction = 0.01). However, no statistically significant association was observed for intake of vitamins B2, B6, and B12, alcohol consumption, or five single nucleotide polymorphisms of MTHFR, MTR, and MTRR. We found that higher folate intake was significantly associated with a lower level of global methylation of leukocyte DNA in a group of healthy Japanese females.     

Second allogeneic transplantation using umbilical cord blood for a patient with relapsed ALK+ anaplastic large cell lymphoma after allogeneic bone marrow transplantation in the era of ALK inhibitors: A case report

Rationale:Anaplastic lymphoma kinase (ALK) + anaplastic large cell lymphoma (ALCL) is considered as a good prognosis lymphoma. However, in an extremely rare subset of patients, ALK+ ALCL with leukemic presentations is known to be chemotherapy-resistant. Although several novel therapies have been tested, the standard therapy for relapsed/refractory ALK+ ALCL has not been established yet.Patient concerns:An 18-year-old female patient who had conventional chemotherapy- and Brentuximab Vedotin (BV)-resistant ALK+ ALCL with leukemic presentation. She was successfully treated with an ALK inhibitor, crizotinib. Crizotinib induced complete remission (CR) and bridged to allogeneic bone marrow transplantation (BMT).Diagnosis:However, her ALCL relapsed on day 60 after BMT and she developed high grade fever and lymphadenopathy.Intervention:Although crizotinib was given to the patient immediately after relapse, she developed grade 3 nausea and could not continue to take it. Then, we gave alectinib to the patient, which promptly induced sustained CR without any further chemotherapy. The patient received second stem cell transplantation using umbilical cord blood with myeloablative regimen in 2^nd CR.Outcomes:The patient has been in CR under maintenance therapy of alectinib for more than 16 months.Lessons:Both ALK inhibitors demonstrated drastic efficacy for our patient who had chemotherapy- and BV-resistant ALK+ ALCL with leukemic presentation. Alectinib showed less gastro-intestinal toxicity than crizotinib and the patient was able to take it even at the relatively early phase of stem cell transplantation.     

Reconstruction of right ventricular outflow tract with stentless xenografts in Ross procedure

To investigate whether the use of a stentless porcine aortic xenograft can be an alternative for right ventricular outflow tract (RVOT) reconstruction during the Ross procedure, 9 patients underwent the Ross procedure and RVOT reconstruction with a stentless xenograft since January 2000. After the aortic valve was replaced with a pulmonary autograft, a stentless xenograft with a xeno- pericardial roll was implanted in the RVOT. One patient required subsequent aortic valve replacement because of severe regurgitation of the pulmonary autograft. All patients recovered well from the operation. The right ventricle-pulmonary arterial pressure gradient was 18 +/- 7 mm Hg at discharge and was not significantly increased during the 2-year follow-up period. Although 1 patient died of ventricular arrhythmia 5 months after, his cardiac function was normal, and transpulmonary valve pressure was 19 mm Hg in the follow-up. The other 7 patients are currently in New York Heart Association functional Class I. Although long-term follow-up is required to explain the durability, the stentless xenograft with a pericardial roll is considered to be an alternative for reconstruction of the RVOT within 2 years after the Ross procedure.     

Glucose attenuating local anesthetic-induced hemolysis

BACKGROUND: The effect of glucose on local anesthetic-induced neural damage has not been fully studied. We examined the effect of glucose on hemolysis induced by local anesthetics. METHODS: The mean EC50 values (the local anesthetic level that causes destruction of half of the red blood cells in vitro) of lidocaine HCl, tetracaine HCl and dibucaine HCl were determined with 0% and 7.5% glucose contained in Krebs solution at pH 6.4. RESULTS: The mean EC50 values of lidocaine HCl, tetracaine HCl, and dibucaine HCl in 0%-glucose Krebs solution were 6.51%, 0.45%, 0.17%, respectively, which increased significantly to 7.05%, 0.64% and 0.23%, in 7.5% glucose Krebs solution at pH 6.4. CONCLUSIONS: Glucose may have a protective role in local anesthetic-induced neural damage.     

Para-aortic lymph node metastasis in relation to serum CA 125 levels and nuclear grade in endometrial carcinoma

BACKGROUND: To investigate the relationship between preoperative serum CA 125 levels and para-aortic lymph node (PAN) metastasis as determined by systematic pelvic and para-aortic lymph node dissection in endometrial carcinoma. METHODS: This study included 180 patients (n = 55, premenopausal; n = 125, postmenopausal) with endometrial carcinoma treated by complete surgical staging. Cut-off values of preoperative serum CA 125 levels for PAN metastasis were determined by receiver characteristic curve (ROC) analysis. Logistic regression analysis was used to determine independent predictors for PAN metastasis. RESULTS: The median serum CA 125 levels of patients with PAN metastasis were significantly higher than the levels of those with no metastasis in both premenopausal and postmenopausal groups. Based on ROC analysis, we could determine four cut-off values (70 and 210 U/mL for premenopausal patients, 20 and 60 U/mL for postmenopausal patients) and categorize the serum CA 125 levels into low, moderate and high groups. By logistic regression analysis, the CA 125 level and nuclear grade were found to be significant predictors of PAN metastasis, respectively. Using this model, the patients were stratified into three risk groups. The probabilities of PAN metastasis for patients in the low-risk, intermediate-risk and high-risk groups were less than 2%, 2-25% and more than 50%, respectively. CONCLUSIONS: Serum CA 125 levels and nuclear grade are important risk factors for PAN metastasis in endometrial carcinoma.     

Multivariate analysis of histopathologic prognostic factors for invasive cervical cancer treated with radical hysterectomy and systematic retroperitoneal lymphadenectomy

BACKGROUND: The aim of this study was to identify the independent histopathologic prognostic factors for patients with cervical carcinoma treated with radical hysterectomy including paraaortic lymphadenectomy. METHODS: A total of 187 patients with stage IB to IIB cervical carcinomas treated with radical hysterectomy and systematic retroperitoneal lymphadenectomy were retrospectively analyzed. The median follow-up period was 83 months. Cox regression analysis was used to select independent prognostic factors. RESULTS: Using multivariate Cox regression analysis, lymph node (LN) status (negative vs. metastasis to pelvic nodes except for common iliac nodes vs. common iliac/paraaortic node metastasis), histopathologic parametrial invasion, lymph-vascular space invasion (LVSI), and histology of pure adenocarcinoma were found to be independently related to patients' poor survival. For patients who had a tumor histologically confined to the uterus and have neither parametrial invasion nor lymph node metastasis, LVSI was the most important prognostic factor, and histologic type, depth of cervical stromal invasion, and tumor size were not related to survival. The survival of patients with a tumor extending to parametrium or pelvic lymph node(s) was adversely affected by histology of pure adenocarcinoma. When the tumor extended to common iliac or paraaortic nodes, patients' survival became quite poor irrespective of LVSI or histologic type of pure adenocarcinoma. Patients' prognosis could be stratified into low risk (patients with a tumor confined to the uterus not associated with LVSI: n = 80), intermediate risk (patients with a tumor confined to the uterus associated with positive LVSI, and patients with squamous/adenosquamous carcinoma associated with pelvic lymph node metastasis or parametrial invasion: n = 86), and high risk (patients with pure adenocarcinoma associated with pelvic lymph node metastasis or parametrial invasion, and patients with common iliac/paraaortic node metastasis: n = 21) with an estimated 5-year survival rate of 100 +/- 0 (mean +/- SE)%, 85.5 +/- 3.9%, and 25.1 +/- 9.7%, respectively. CONCLUSIONS: LN status, parametrial invasion, LVSI, and histology of pure adenocarcinoma are important histopathologic prognostic factors of cervical carcinoma treated with radical hysterectomy and systematic retroperitoneal lymphadenectomy. Prognosis for patients with cervical carcinoma may be stratified by combined analysis of these histopathologic prognostic factors. Postoperative therapy needs to be individualized according to these prognostic factors and validated for its efficacy using randomized clinical trials.     

Thromboprophylaxis with low molecular weight heparin in thrombophilia-complicated pregnancy

We treated three thrombophilia-complicated pregnant women (two antiphospholipid antibody syndrome, one protein C deficiency) with low molecular weight heparin (dalteparin). All three pregnancies including one twin pregnancy ended in live births without a decrease in bone mineral density. This treatment modality was effective and safe preventing thrombosis during their pregnancies.     

System-engineered cartilage using poly(N-isopropylacrylamide)-grafted gelatin as in situ-formable scaffold: in vivo performance

Our previous study showed that cartilaginous tissue can be engineered in vitro with articular chondrocytes and poly(N-isopropylacrylamide)-grafted gelatin. This short-term in vivo study for cartilage repair was performed to screen a candidate method for a long-term study. In our previous in vitro study, however, two potential problems with the tissue-engineered cartilage were identified: (1). leakage of the transplant due to temperature decline and (2). concave deformation of transplant due to compressive loading. To solve these problems, we investigated in this study the usefulness of suturing with two different covering materials (periosteum or collagen film) and preculturing an engineered tissue for 2 weeks. PNIPAAm-gelatin-based engineered cartilage samples were evaluated at 5 weeks after operation by gross and microscopic examination. Leakage occurred only in specimens without precultured tissue and with a collagen film. Minimal surface deformation occurred in all specimens with precultured tissue. The score on gross examination showed that transplants with precultured tissue acquired a higher score than did the others. Histological evaluation showed a minimal foreign-body response of PNIPAAm-gelatin in all specimens and higher maturity as a cartilaginous tissue in specimens with precultured tissue. These results indicate that transplantation with precultured tissue may be a suitable method for a long-term in vivo study.