QT PRODACT: evaluation of the potential of compounds to cause QT interval prolongation by action potential assays using guinea-pig papillary muscles

Certain compounds that prolong QT interval in humans have little or no effect on action-potential (AP) duration used traditionally, but they inhibit rapidly-activated-delayed-rectifier potassium currents (IKr) and/or human ether-a-go-go-related gene (hERG) currents. In this study using isolated guinea-pig papillary muscles, we investigated whether new parameters in AP assays can detect the inhibitory effects of various compounds on IKr and/or hERG currents with high sensitivity. The difference in AP duration between 60% and 30% repolarization, 90% and 60% repolarization, and 90% and 30% repolarization (APD30-60, APD60-90, and APD30-90, respectively) were calculated as the new parameters. All the 15 IKr and/or hERG current inhibitors that have been reported (9 compounds) or not reported (6 compounds) to inhibit calcium currents prolonged APD30-60, APD60-90, and/or APD30-90; and 8 of the 15 inhibitors prolonged APD30-60, APD60-90, and/or APD30-90 more potently than APD90. The APD30-60, APD60-90, and APD30-90 measurements revealed no difference in sensitivity when evaluating the effects of the IKr and/or hERG current inhibitors on the three parameters. On the other hand, compounds with little or no effect on hERG currents had no effect on APD30-60, APD60-90, or APD30-90. Therefore, it is concluded that in AP assays using isolated guinea-pig papillary muscles, APD30-60, APD60-90, and APD30-90 are useful indexes for evaluating the inhibitory effects of compounds including mixed ion-channel blockers on IKr and/or hERG currents.     

Immunosuppression by morphine-induced lymphocyte apoptosis: is it a real issue?

Morphine has been an optimal choice for cancer pain management. However, several recent studies suggested that morphine induces apoptosis in human peripheral blood lymphocytes (PBLs), raising a serious concern about the use of opioid-based analgesic strategies. In this study, therefore, we aimed to evaluate whether morphine induced apoptosis in cultured human PBLs. Apoptotic events were assessed by flow-cytometrical detection of surface phosphatidylserine and nuclear fragmentation, as well as Fas, Bcl-2, and Caspase-3 activity in PBLs gated on a light-scatter basis. Peripheral blood mononuclear cells isolated from healthy subjects were cultured with etoposide, morphine, or vehicle (medium) for 48 h. During co-culture with etoposide, apo-ptosis was significantly induced in PBLs, and the cells did not survive for 48 h. In comparison, morphine had no effect on the expression rate of any of the detected molecules, suggesting that no apparent apoptotic processes were induced during the incubation. Furthermore, co-incubation with a Fas-specific antibody did not increase apoptotic cell rates in the morphine cultures. These results do not support the hypothesis that morphine directly modulates PBL apoptosis resulting in immunosuppression. We believe that the choice of opioids for optimal pain relief should not be discouraged until further studies clarify this issue. IMPLICATIONS: Recent reports that morphine potentially induces apoptosis in human lymphocytes in vitro have raised a concern about the use of opioid-based analgesic strategies. Regarding this issue, we present rather contradictory findings that morphine has no effects on the cell expression of various apoptosis-related molecules in cultured human lymphocytes.     

A case of prostatic stromal tumor of uncertain malignant potential

Sarcomas and related proliferative lesions of specialized prostatic stroma are rare. Lesions have been classified into prostatic stromal tumor of uncertain malignant potential (P-STUMP) and prostatic stromal sarcoma based on the degree of stromal cellularity, presence of mitotic figures, necrosis, and stromal overgrowth. STUMPs are considered neoplastic, based on the observations that they may diffusely infiltrate the prostate gland and extend into adjacent tissues, and often recur. Although most cases of STUMPs do not behave in an aggressive fashion, occasional cases have been documented to recur rapidly after resection and a minority have progressed to stromal sarcoma. Here we describe a case of P-STUMP. A 57-year-old male went to his family doctor because of pollakisuria. Digital examination revealed abnormal findings in the prostate, then he was referred to our medical center. The mass was palpable in the left lobe of the prostate; it was elastic hard, surface smooth, about 2 cm in diameter. Serum PSA was elevated slightly (5.42 mg /dl). We diagnosed firstly leiomyosarcoma by transrectal ultra sound guided needle biopsy of the prostate. Then we performed radical prostatectomy. Finally we made the pathological diagnosis of P-STUMP. After 11 months, there is no sign of metastasis or recurrence.     

Respiratory management during endotracheal placement of the Dumon stent for tracheobronchial stenosis

BACKGROUND: Endotracheal stenting at the stenotic area of the trachea or bronchus is less invasive and beneficial for patients, compared with conventional surgical treatment. METHODS: We investigated intraoperative respiratory managements for 26 patients (65+/-14 years-old) with Dumon type stent in a retrospective manner. SpO2 over 90% was an index for the intraoperative respiratory managements. RESULTS: Nine of the 26 subjects were emergency cases. Four of the 26 patients had been preoperatively under controlled respiration (CR) with an endotracheal tube, while the remaining 22 had been left under spontaneous respiration (SR). The lung cancer (10 patients) was the most frequent causative disease, followed by tracheo-broncheal invasion of the esophageal cancer (6 patients). Preoperative PaO2 in 8 of the SR group was under 70 mmHg. When SR was preserved during subsequent operation, intravenous anesthesia using propofol and fentanyl was given in combination with surface local anesthesia. I-type stent was used for 17 patients with tracheal or bronchial stenosis and Y-type stent for 9 with carina stenosis. As to the respiratory management during stenting, SR was preserved in 14 patients, CR including jet ventilation under the use of a muscle relaxant was performed in 8 patients and percutaneous cardiopulmonary support (PCPS) was used in 4 patients. In one SR patients, SR was switched to emergency PCPS on the way because of airway obstruction. In another SR patient with successful bronchial stenting, the collapsed lung was rapidly re-expanded by using jet ventilation, causing multi-embolism to the vital organs including the heart and the brain. Traumatic complications on bucking were not seen even under the condition of SR. Postoperatively, 21 of the 26 patients were transferred to ICU without endotracheal intubation. CONCLUSIONS: In a case in which severe respiratory insufficiency or airway bleeding is anticipated, PCPS on standby is necessary for safety assurance.     

The effects of hyperventilation upon spinal dorsal horn neuronal single-unit activities under nitrous oxide anesthesia

BACKGROUND: The purpose of this study is to investigate the effects of hyperventilation upon spinal dorsal horn neuronal single-unit activities under nitrous oxide anesthesia. METHODS: Eight decerebrated spinal cats with laminectomy were maintained with oxygen and pancuronium bromide. Following the control period of normocapnia, 50% nitrous oxide was administered for 30 minutes after a hypocapnia period of 20-25 mmHg for 20 minutes. The recoveries of activities followed with normocapnia and pure oxygen administration. The changes of spontaneous and evoked activities by the pinching were investigated every 5 minutes after control study. RESULTS: Inhalation of 50% nitrous oxide suppressed the WDR neuronal activities and with hyperventilation the suppressions significantly increased. CONCLUSIONS: These results were compatible with clinical reports on the effectiveness of hyperventilation as a maintenance method under N2O anesthesia.     

Left coronary ostial stenosis caused by syphilitic aortitis

We report 2 cases of cardiovascular disease related to end-stage syphilitic infection, which is now relatively rare. A 49-year-old man (case 1), and a 45-year-old man (case 2) were admitted to our hospital for angina pectoris. Cardiac catheterization showed severe aortic regurgitation and left coronary ostial stenosis. Active syphilis was detected in both cases by routine blood examination on admission. Oral ampicillin was started immediately to treat the syphilis; however, during the course of treatment, acute heart failure developed in both patients. We performed emergency aortic valve replacement and coronary artery bypass grafting. Intraoperatively, the orifice of the left coronary artery was almost occluded, and retrograde perfusion of cardioplegia was needed to induce cardiac arrest. Both patients recovered uneventfully. When treating patients with antibiotics for syphilitic disease, it is important to prepare for the possibility of urgent surgery.     

Alendronate inhibits bone resorption at the bone-screw interface

In the current study, we investigated whether the systemic administration of alendronate, a third-generation bisphosphonate, suppressed the loosening of screws at the bone-screw interface. We systemically administered alendronate to rats fitted with external fixators. External fixators with two half pins were applied to the right femurs of rats, and alendronate was administrated once a week during a 5-week postoperative period. Radiographic, histologic, and immunohistochemical findings subsequently were analyzed. Treatment with alendronate reduced the width of the fibrous loosening membrane and the number of osteoclasts at the bone-screw interface. These findings indicate that systemic treatment with alendronate exerts an inhibitory effect on local bone resorption at the bone-screw interface.     

Integration of three-dimensional corticospinal tractography into treatment planning for gamma knife surgery

OBJECT: In the radiosurgical treatment of critically located lesions, the effort to minimize the risk of complication is essential. In this study the integration of diffusion-tensor (DT) imaging-based tractography was clinically applied to treatment planning for gamma knife surgery (GKS). METHODS: Seven patients with cerebral arteriovenous malformations located adjacent to the corticospinal tract (CST) underwent this technique. Data provided by DT imaging were acquired before the frame was affixed to the patient's head and the CST of the DT tractography was created using our original software. Stereotactic three-dimensional imaging studies were obtained after frame fixation and then coregistered with the data from DT tractography. After image fusion of the two studies, the combined images were transported to a GKS treatment-planning workstation. The spatial relationship between the dose distribution and the CST was clearly demonstrated within the 2 hours it took to complete the entire imaging process. The univariate logistic regression analysis of transient or permanent motor complications revealed a significant independent correlation with the volume of the CST that received 25 Gy or more and with a maximum dose to the CST (p < 0.05). CONCLUSIONS: The integration of DT tractography into the GKS treatment planning was highly useful in confirming the dose to the CST during treatment planning.     

Hepatic CCR7lowCD62LlowCD45RClow allograft dendritic cells migrate to the splenic red pulp in immunologically unresponsive rats

Donor dendritic cells (DC) migrate into the recipient spleen after hepatic transplantation. Immunological unresponsiveness to rat hepatic allografts can be induced by prior donor-specific blood transfusion (DST). We investigated homing receptor phenotype and splenic distribution of donor DC after allografting and DST. Immunostaining revealed OX62+ cells in the splenic red pulp of animals receiving pre-transplant DST but only in the white pulp of untreated animals. Most OX62 cells were positive for OX76. There were two subsets of DC in the spleen, CD45RChighOX62+ and CD45RClowOX62+ cells. RT-PCR revealed that CD45RClowOX62+ cells expressed interleukin (IL)-10, while CD45RChighOX62+ cells expressed IL-2 and low levels of IL-10 mRNA. CD45RChighOX62+ cells strongly expressed CCR5 and CCR7, compared with weak expression in CD45RClowOX62+ cells. The Epstein-Barr virus-induced molecule 1 (EBI-1) ligand chemokine (ELC/MIP3beta) was expressed mainly within the splenic white pulp. Mucosal vascular addressin-cell adhesion molecule-1 (MAdCAM-1) was expressed in the marginal zone and white pulp, but expression of splenic MAdCAM-1 was down-regulated in DST-treated animals. L-selectin (CD62L), the ligand for MAdCAM-1, was strongly expressed on CD45RChighOX62+ cells but not on CD45RClowOX62+ cells. In conclusion, differential splenic migration of CCR5lowCCR7lowCD62Llow CD45RClow DC expressing Th2-type cytokines is associated with immunological unresponsiveness to rat hepatic allografts.     

Visceral pleural invasion is an invasive and aggressive indicator of non-small cell lung cancer

OBJECTIVE: Although visceral pleural invasion by non-small cell lung cancer is considered a poor-prognostic factor, further information is lacking, especially in relation to other clinicopathologic prognostic factors. We assessed the relationship between visceral pleural invasion and other clinicopathologic characteristics and evaluated its significance as a prognostic factor. METHODS: We reviewed 1074 patients with surgically resected T1/2 non-small cell lung cancer for their clinicopathologic characteristics and prognoses. The patients were divided into 2 groups according to visceral pleural invasion status (visceral pleural invasion group and non-visceral pleural invasion group). Both groups were compared with regard to age, sex, histology, tumor size, tumor differentiation, lymph node involvement, lymphatic invasion, vascular invasion, scar grade, nuclear atypia, mitotic index, serum carcinoembryonic antigen level, and survival. Univariate and multivariate analyses were conducted. RESULTS: Visceral pleural invasion was identified in 288 (26.8%) of the resected specimens. Survival was 76.0% at 5 years and 53.2% at 10 years in the non-visceral pleural invasion group and was 49.8% at 5 years and 37.0% at 10 years in the visceral pleural invasion group. The difference between groups was highly significant ( P < .0001). Visceral pleural invasion was also significantly associated with a higher frequency of lymph node involvement. However, regardless of N status (N0 or N1/2), there was a significant difference in survival when the visceral pleura was invaded. Visceral pleural invasion was observed significantly more frequently in tumors with factors indicative of tumor aggressiveness/invasiveness: moderate/poor differentiation, lymphatic invasion, vascular invasion, high scar grade, high nuclear atypia grade, high mitotic index, and high serum carcinoembryonic antigen level. By multivariate analysis, visceral pleural invasion proved to be a significant independent predictor of poor prognosis in non-small-cell lung cancer patients with or without lymph node involvement. CONCLUSIONS: Visceral pleural invasion is a significant poor-prognostic factor, regardless of N status. Our analyses indicated that visceral pleural invasion is an independent indicator of non-small cell lung cancer invasiveness and aggressiveness.