Bupivacaine attenuates contractility by decreasing sensitivity of myofilaments to Ca2+ in rat ventricular muscle

BACKGROUND: Bupivacaine exhibits a cardiodepressant effect, the molecular mechanism(s) of which have yet to be fully understood. Bupivacaine may directly act on contractile proteins and thereby decrease myofibrillar Ca2+ sensitivity. METHODS: Rat ventricular muscle was used. First, the effect of bupivacaine was examined on tetanic contractions in isolated intact myocytes. Next, Triton X-100-treated ventricular trabeculae were used to investigate the effect of bupivacaine on the pCa (= -log [Ca2+ ])-tension relation as well as on maximal Ca2+ -activated tension. Furthermore, to test whether bupivacaine inhibits the pathway downstream from Ca2+ binding to troponin C, tension was elicited in the skinned preparations by lowering the Mg-adenosine triphosphate (MgATP) concentration in the absence of Ca2+. The effect of bupivacaine on the pMgATP (= -log [MgATP])-tension relation was examined. RESULTS: In myocytes, 3 microm bupivacaine significantly (P < 0.01) increased intracellular Ca2+ concentration required for 5% cell shortening from the resting cell length. In skinned preparations, bupivacaine shifted the pCa-tension relation to the lower pCa side; the midpoint of the pCa curve (pCa50) was significantly (P < 0.05) changed by 10 and 100 microm bupivacaine. A highly correlated linear relation (R = 0.81; P< 0.0005) was present between pCa50 and maximal Ca2+ -activated tension. Bupivacaine (10 and 100 microm) significantly (P < 0.05) shifted the midpoint of the pMgATP-tension relation to the higher pMgATP side. CONCLUSIONS: Bupivacaine decreases myofibrillar Ca2+ sensitivity in ventricular muscle, and this is coupled with the compound's inhibitory effect on the pathway beyond Ca2+ binding to troponin C, possibly on the actomyosin interaction. The current results may partly explain the overall cardiodepressant effect of bupivacaine in vivo.     

Platelet-sparing effect of paclitaxel in heavily pretreated ovarian cancer patients

 Carboplatin has proven to be effective in the treatment of patients with recurrent ovarian cancer who have responded to platinum-based first-line chemotherapy. However, thrombocytopenia is a problem in heavily pretreated patients. Paclitaxel has a so-called platelet-sparing effect, but until now it was unknown whether this effect could be obtained in heavily pretreated patients. We treated four patients with recurrent epithelial ovarian cancers who had previously undergone heavy chemotherapy. Because these patients had responded to platinum-based first-line therapy, single carboplatin administration was employed. Although satisfactory tumor marker responses were obtained, thrombocytopenia occurred. When paclitaxel was administered before the carboplatin infusion in the subsequent treatments, the thrombocytopenia became milder. It was concluded that a platelet-sparing effect was also observed in patients who had undergone heavy prior chemotherapy. Received: January 9, 2002 / Accepted: March 29, 2002 Correspondence to:H. Ishikawa     

Brain metastases from esophageal carcinoma: natural history, prognostic factors, and outcome

BACKGROUND: Brain metastases from esophageal carcinoma are extremely rare, and information regarding the natural history, results of treatment, and possible prognostic factors in these patients is limited. METHODS: The records of 36 patients with brain metastases from esophageal carcinoma who were treated between 1986 and 2000 were reviewed. For brain metastases, 12 patients (33%) were treated with surgical resection followed by radiation therapy (S+RT), and the remaining 24 patients were treated with radiation therapy alone. RESULTS: At the initial diagnosis of esophageal carcinoma, the median primary tumor length was 8 cm (range, 2-19 cm), and 26 of 32 available patients (81%) had clinical Stage III-IV tumors according to the International Union Against Cancer 1997 criteria. At time brain metastases appeared, lung metastases were not demonstrated in 25 of 36 patients (69%) who were assessed by chest computed tomography (CT) scans. The overall median survival for all patients was 3.9 months (range, 0.6-36.8 months), and the actuarial survival rates at 12 months and 24 months were 14% and 3%, respectively. In univariate analysis, treatment modality, Karnofsky performance status (KPS), and extracranial disease status each had a statistically significant impact on survival, and, in multivariate analysis, treatment modality and KPS were statistically significant prognostic factors for survival. Five patients (14%) survived more than 1 year, all of whom were treated with S+RT. These five patients had inactive extracranial disease and, four of five patients (80%) had a 90-100% KPS. CONCLUSIONS: Brain metastases from esophageal carcinoma tended to occur in patients with a large primary tumors and/or disease in advanced clinical stages. With the appearance of brain metastases, an absence of lung metastasis frequently was observed on chest CT scans. The prognoses for these patients were generally poor, although selected patients may survive longer with intensive brain tumor treatment.     

A case of cerebellar ataxia showing severe dystonia masquerading as myoclonic jerky movements on arm extension]

A 43-year-old man was admitted to our hospital due to unstable walking, head tilting to the left and difficulty in extending his arm. He was quite healthy until the age of 20 years, when these symptoms appeared and progressed slowly afterward. Due to his unstable walking, he started to use a wheelchair when he was 39 years old. He had no family history of similar disease. On admission, neurological examination revealed spasmodic torticollis, ataxic speech and marked limb and truncal ataxia. Myoclonic jerky flexion of the forearm was induced when he raised and extended his forearm. He also showed mild hyperreflexia in the lower limbs without pathological reflexes. He had weakness and atrophy of the left supraspinatus, infraspinatus, deltoid and biceps brachii muscles and mild superficial sensory impairment in the left axillary nerve territory due to cervical spondylotic radiculopathy of the left C5 root. MRI of the brain demonstrated severe bilateral atrophy of the cerebellar hemispheres and vermis but minimal atrophy of the cerebrum and brainstem. Because surface electromyography revealed continuous discharge with phasic components in the biceps and wrist flexor muscles on extending the upper limbs, the jerky flexion movement of the forearm was considered to be primarily dystonia. Although no giant SEP was observed, a C-response was detected in the long-loop reflex in response to right median nerve stimulation. Nuclear examinations showed diffuse hypoperfusion and decreased glucose metabolism in the cerebellum. Based on these findings, we hypothesized that cerebellar dysfunction may have induced severe dystonic movement resembling myoclonus. We would like to name this complicated involuntary movement an "arm thrust". This is the first case to be reported of sporadic, chronic, progressive cerebellar ataxia accompanied by severe dystonic movement, especially on stretching the forearms, that mimics myoclonic movement.     

Expression of nitric oxide synthases in the anterior horn cells of amyotrophic lateral sclerosis

The authors investigated for a correlation between the expression of nitric oxide synthases (NOSs) with the severity of motor neuronal loss in the anterior horns of patients with amyotrophic lateral sclerosis (ALS). Spinal cords from six patients with ALS and from three normal controls were examined. The sections of cervical, lumbar, and sacral cord including Onuf's nucleus, which are seldom degenerated until the late stage, were stained with three antibodies against NOSs (anti-n-NOS, anti-e-NOS, and anti-i-NOS) using ABC methods. Perikarya of motor neurons in ALS, but not in controls, were immunoreactive against anti-n-NOS and e-NOS. Anti-i-NOS did not recognize the motor neurons of ALS or of controls. The immunoreactivity for n- and e-NOSs was approximately the same in the sections of cervical, lumbar, and sacral cord in ALS. No significant differences in immunoreactivity were observed among the patients with ALS. These results suggest that the expression of NOSs does not immediately affect neuronal loss in ALS.     

Analysis of interfractional set-up errors and intrafractional organ motions during IMRT for head and neck tumors to define an appropriate planning target volume (PTV)- and planning organs at risk volume (PRV)-margins.

BACKGROUND AND PURPOSE: To analyze the interfractional set-up errors and intrafractional organ motions and to define appropriate planning target volume (PTV)- and planning organs at risk volume (PRV)-margins in intensity-modulated radiotherapy (IMRT) for head and neck tumors. PATIENTS AND METHODS: Twenty-two patients with head and neck or brain tumors who were treated with IMRT were enrolled. The set-up errors were defined as the displacements of the coordinates of bony landmarks on the beam films from those on the simulation films. The organ motions were determined as the displacements of the coordinates of the landmarks on the images recorded every 3 min for 15 min on the X-ray simulator from those on the initial image. RESULTS: The standard deviations (SDs) of the systematic set-up errors (Sigma-INTER) and organ motions (Sigma-intra) distributed with a range of 0.7-1.3 and 0.2-0.8 mm, respectively. The average of the SDs of the random set-up errors (sigma-INTER) and organ motions (sigma-intra) ranged from 0.7 to 1.6 mm and from 0.3 to 0.6 mm, respectively. Appropriate PTV-margins and PRV-margins for all the landmarks ranged from 2.0 to 3.6 mm and from 1.8 to 2.4 mm, respectively. CONCLUSIONS: We have adopted a PTV-margin of 5mm and a PRV-margin of 3mm for head and neck IMRT at our department.     

Prolonged blastomere movement induced by the delay of pronuclear fading and first cell division adversely affects pregnancy outcomes after fresh embryo transfer on Day 2: a time-lapse study

Research question

What is the incidence, origin and clinical significance of blastomere movement after the first cell division in the human embryo?

Potentiation of Growth-inhibitory Activity of 9-β-d-Arabinofuranosyladenine by 2'-Deoxycoformycin in Human Cultured Cell Lines Derived from Leukemias and Lymphomas

Growth-inhibitory activity of 2'-deoxycoformycin (DCF) and 9-β-D-arabinofuranosyladenine (Ara-A) used either singly or in combination was assessed in 30 human cultured cell lines (seven T-cell, nine B-cell, five non-T, non-B, and nine myeloid cell lines) derived from leukemias and lymphomas. DCF had little activity even at 100 μM any of the cell lines, while Ara-A had an obvious inhibitory effect on them, especially on non-T, non-B cell lines at 10 μM or less. Lymphoid cell lines were apparently more sensitive to the combined use of Ara-A and DCF than myeloid cell lines. DCF potentiated the antiproliferative activity of Ara-A not only in T-cell lines with high adenosine deaminase (ADA) activity, but also in some other cell lines with low ADA activity. DCF was stable in the culture medium, but Ara-A in the medium containing cultured cells was rapidly inactivated. DCF completely inhibited the inactivation of Ara-A in the medium containing P12/ICH or NALM-6, but not in the medium containing Daudi. This suggests that there is some unknown mechanism(s) of inactivation of Ara-A other than ADA in Daudi, which was insensitive to Ara-A in the presence of 1 μM DCF. The capacity of DCF to inhibit degradation of Ara-A in the medium containing these cultured cells correlated with the level of Ara-A sensitivity potentiated by DCF. In all seven T-cell lines, seven of the nine B-cell lines, all five non-T, non-B cell lines, and only three of nine myeloid cell lines, the IC50 value for Ara-A decreased to 5 μM or less in the presence of 1 μM DCF. These results suggest that the combination of DCF and Ara-A may be effective against various types of lymphoid malignancies and some myeloid leukemias.     

Surgical management of inflammatory granuloma which developed following subcutaneous injection of leuprorelin acetate: a case report

A case of granuloma which developed following a subcutaneous injection of leuprorelin acetate is presented. A prominent induration developed at the site of injection with a three-month type preparation, and radical retropubic prostatectomy and simultaneous excision of the granulomas were requested by the patient since they were large, infectious and painful. Our experience may indicate the necessity of conversion from leuprorelin acetate to other drugs (e.g., goserelin acetate, castration) if a local induration, caused by a subcutaneous injection of leuprorelin acetate, has developed to a large granuloma.