Effect of brefelamide on proliferation of 1321N1 human astrocytoma cells induced by glial cell line-derived neurotrophic factor.

Malignant gliomas are highly resistant to chemotherapy and radiation and more effective options for treatment are urgently needed. We reported previously that the aromatic amide brefelamide, which is isolated from methanolic extracts of the cellular slime molds Dictyostelium giganteum and D. brefeldianum, hinders cellular proliferation in a glioma model utilizing 1321N1 human astrocytoma cells. Herein, we examined the mechanisms underlying the inhibition of 1321N1 cell proliferation by brefelamide. Glial cell line-derived neurotrophic factor (GDNF) was found to enhance the rate of proliferation of serum-free cultured 1321N1 cells, but did not affect proliferation in PC12 cells. Brefelamide pretreatment inhibited GDNF-induced cell proliferation and expression of rearranged during transfection (RET). GDNF enhanced the phosphorylation of extracellular signal-regulated kinase (ERK), AKT, and c-jun-N-terminal kinase (JNK); however, brefelamide pretreatment inhibited these effects. Brefelamide also reduced the expression of GDNF mRNA and GDNF secretion. Together, the findings from this study indicate that brefelamide inhibits the proliferation of 1321N1 cell via several mechanisms including reduced GDNF receptor expression and GDNF secretion, and reduced phosphorylation of ERK, AKT, and JNK.

Two brothers with distal arthrogryposis, peculiar facial appearance, cleft palate, short stature, hydronephrosis, retentio testis, and normal intelligence: a new type of distal arthrogryposis?

We report on two brothers, a 22-month-old boy and a 7-month-old boy, with multiple distal arthrogryposis (DA), peculiar facial appearance, cleft palate, short stature, hydronephrosis, retentio testis, and normal intelligence and karyotypes. The parents were cousins once removed. The combination of the clinical manifestations in the patients and the lack of involvement in their parents are incompatible with any known types of DA, and suggest a new type of DA. The parental consanguinity in the family suggests that the disorder is an autosomal recessive condition, although X-linked inheritance is not ruled out.

Isolation and characterization of Aeromonas sp. B-5 capable of decolorizing various dyes.

Aeromonas sp. B-5, which has the ability to decolorize azo dyes, was isolated from soil. Aeromonas sp. B-5 completely decolorized 100 mg/l of Bordeaux S by reductive cleavage of azo bonds under static conditions in 24 h. Though the decolorization of Bordeaux S by Aeromonas sp. B-5 was suppressed under shaking, rapid decolorization was observed when the culture was changed to static conditions after cultivation with shaking. The indigoid dye, Acid blue 74, was decolorized by Aeromonas sp. B-5 under shaking conditions, in contrast to the decolorization of azo dyes.

Effect of benidipine on microvascular remodeling and coronary flow reserve in two-kidney, one clip Goldblatt hypertension.

OBJECTIVE: To determine whether chronic treatment with benidipine, a calcium antagonist, leads not only to regression of left ventricular hypertrophy, but also to an improvement in coronary flow reserve and microvascular remodeling. DESIGN AND METHODS: Two-kidney, one clip Goldblatt hypertensive rats were assigned either to a benidipine-treatment group or to a group without treatment after their kidneys had been clipped for 4 weeks. Benidipine was administered to rats in the treatment group for 6 weeks. At the end of the treatment, the systemic hemodynamics and coronary blood flow were determined in conscious unrestrained rats by using nonradioactive colored microspheres injected through the left atrium. The coronary blood flow was determined in rats of both groups with the rats at rest and after near-maximal vasodilatation induced by carbochrome. For evaluation of the microvascular remodeling capillary density, the wall : lumen ratio of arterioles and perivascular fibrosis were quantified by using an image analyzer after fixation of heart tissue. RESULTS: Benidipine treatment lowered the blood pressure significantly with a decrease in total peripheral resistance, and the left ventricular mass decreased markedly compared with that of untreated hypertensive rats. The coronary flow reserve of the untreated hypertensive rats was lower than that of the controls, but benidipine treatment improved the coronary flow reserve. We found a significant decrease in capillary density, and significant increases in wall : lumen ratio and perivascular fibrosis in untreated hypertensive rats. These changes in microvasculature were improved by benidipine treatment. CONCLUSION: Taken together, these results suggest that benidipine exerts favorable effects as an antihypertensive drug by reversing cardiac hypertrophy and improving the coronary flow reserve and microvascular remodeling.

[A case of anti-glomerular basement membrane antibody (AGBMA) nephritis associated with myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)].

A 68-year-old patient visited our hospital, because of progressive renal failure. Laboratory data were serum creatinine 13.3 mg/dl, BUN 74.3 mg/dl, AGBMA 134U, MPO-ANCA 37% and CIC 1.6 g/dl. Hemodialysis was performed on admission and renal biopsy was conducted. Though the histological findings showed fibrocellular crescents and global sclerosis in many glomeruli, renal function was gradually ameliorated by administration of prednisolone (40 mg/day) and cyclophosphamide (50 mg/day). After 3 weeks of therapy, hemodialysis was withdrawn temporarily. Because of the complication of pneumocystis carini, prednisolone and cyclophosphamide were discontinued, and maintenance hemodialysis was resumed. In spite of progressed histological findings, hemodialysis was withdrawn at least temporarily through the use of pharmacological therapy. Thus, the presence of ANCA may indicate a relatively good prognosis of AGBMA nephritis.

Effects of intra-atrial injection of colored microspheres on systemic hemodynamics and regional blood flow in rats.

The hemodynamic effects of various numbers of colored nonradioactive microspheres (CMS) and those of accumulation of CMS caused by multiple sequential injection were evaluated in 51 Sprague-Dawley male rats. CMS (15 microns) were injected into the left atrium. Regional blood flow and cardiac output were evaluated using the reference blood sample technique. Ficoll-70 was given after each blood sample withdrawal as a fluid replacement. A bolus injection of < or = 1,000,000 CMS caused no significant hemodynamic disturbances. Amounts of 500,000 CMS can be repeatedly injected up to four times (cumulative dose of 2,000,000 CMS) without producing any adverse hemodynamic effects. The values of cardiac output obtained with the CMS technique were correlated well (r = 0.971, P < 0.0001) with those obtained with electromagnetic flow probes. An excellent reproducibility of organ blood flow was observed after four sequential injections of 500,000 CMS. This study establishes the limits of CMS that can be injected into the rat without inducing hemodynamic changes and also suggests that the CMS technique can be employed to evaluate cardiac output and regional blood flow precisely and repeatedly.

[A case of metastatic splenic tumor treated with intra-arterial immunochemotherapy to induce endogenous LAK cell].

The patient was an 82-year-old female with a 32-month clinical course after right hemicolectomy for ascending colon cancer. Serum carcino embryonic antigen (S-CEA) increased about 38 ng/ml, and metastatic spleen tumor was recognized by abdominal CT and MRI. To induce endogenous LAK, intra-arterial immunochemotherapy with cyclophosphamide (CPM) and OK-432 was performed. Three days after CPM administration, peripheral white blood cells decreased. Recovery from this CPM side effect was achieved with granulocyte colony-stimulating factor (G-CSF). LAK activity of peripheral blood lymphocytes increased from 3% to 17%. Then intra-arterial immunochemotherapy was continued for 7 months, after which the tumor size increased but the S-CEA level remained under 40 ng/ml.

Dilated cardiomyopathy in a patient receiving continuous ambulatory peritoneal dialysis.

We describe a unique case of a 10 year old girl with dilated cardiomyopathy who has been receiving continuous ambulatory peritoneal dialysis. She responded to treatment with a beta 1-agonist. We note that electrocardiography and echocardiography are effective for early recognition of the onset of dilated cardiomyopathy and that a thallium scan should be performed to assess the severity of dilated cardiomyopathy in patients with chronic renal insufficiency.

[Effect of prostaglandin E1 on peripheral body temperature in pediatric patients after open heart surgery].

The effect of prostaglandin E1 was studied to examine if it works favorably for peripheral circulation in pediatric patients after cardiac surgery. Dose of 0.1 mcg.kg-1.min-1 increased temperature of dorsal pedis significantly. Difference of temperature of dorsalis pedis and that of rectum was significantly smaller than that in control group. A significant increase in heart rate and a decrease in systolic arterial pressure produced no clinical side effects. We conclude that prostaglandin E1 is a useful and safe vasodilator for circulatory management of pediatric patients after cardiac surgery.

[Effect of endoscopic local injection of OK-432 on regional lymph nodes in gastric cancer patients].

The effects of OK-432, a streptococcal preparation, administered intratumorally (OK-432 i.t.) on the change of lymphocyte subsets of regional lymph nodes were investigated in 26 gastric cancer patients. The results were as follows: 1) In the proximal lymph nodes, both non-metastatic and metastatic lymph nodes, and the proportion of CD3+ cells were slightly increased. 2) In the proximal lymph nodes without metastasis, the proportion of CD4+2H4+ cells and CD4+4B4- cells was increased about 10%. 3) In 4 of 15 patients who had metastatic lymph nodes macroscopic changes of the tumor and necrosis of metastatic lymph nodes by OK-432 i.t. were observed. In these lymph nodes CD8-CD11+ cells increased over 40%. These data suggested that the lymph node lymphocyte reaction by OK-432 i.t. may differ between metastatic lymph nodes and non-metastatic lymph nodes.

Evaluation of masticatory function following orthognathic surgical correction of mandibular prognathism.

Masticatory function was examined in 17 patients with mandibular prognathism before and after bilateral sagittal splitting osteotomy of the mandibular rami. Masticatory efficiency was measured by means of a spectrophotometer, using adenosine triphosphate (ATP) granules, the biting force and occlusal contact area. Masticatory functions showed a tendency to gradual improvement postoperatively. Concerning masticatory efficiency, mean values of absorbance of ATP granules in patients with mandibular prognathism were inferior to those of subjects who possess a normal occlusion, even 12 months after operation.

Massive cardiac involvement of adult T-cell leukemia/lymphoma. An autopsy case.

We describe an unusual autopsy case of adult T-cell leukemia/lymphoma with massive cardiac involvement. The patient was admitted to the hospital with symptoms of fever and cervical lymph node enlargement, which improved following treatment with vincristine sulfate, cyclophosphamide (Endoxan), prednisolone sodium succinate, and doxorubicin hydrochloride (Adriamycin). He was then followed up in the outpatient clinic, but was readmitted to the hospital with palpitations and dyspnea. Cardiomegaly developed rapidly, and the patient died of congestive heart failure 3 months after readmission. The heart was massively enlarged at autopsy. The heart, including adhered surrounding tissue, weighed 1600 g. The myocardium was found to be replaced by massive infiltration of atypical lymphoid cells. Cardiac involvement by adult T-cell leukemia/lymphoma may result from extension or retrograde flow through cardiac lymphatics from the destroyed mediastinal lymphatic system.

[Reversal of high-dose fentanyl anesthesia by naloxone: analysis of factors attenuating respiratory and hemodynamic responses to naloxone].

The respiratory and hemodynamic responses to postoperative reversal by naloxone of high-dose fentanyl anesthesia were studied in 101 patients after open heart surgery. Respiratory and hemodynamic changes after drip infusion of naloxone were minimum. Change of systolic blood pressure (BPs), mean blood pressure (BPm), CVP and PO2 were statistically significant. BPs increased for 3.8 +/- 14.0 mmHg, BPm increased for 1.6 +/- 8.2 mmHg. CVP decreased for 0.4 +/- 2.1 mmHg, and PO2 decreased for 8.6 +/- 3.4 mmHg. Severe side effect was not observed. Multi-factorial analysis revealed that the abrupt recovery of consciousness from anesthesia and acidosis were the most important factors that attenuate hemodynamic response to naloxone.

In vitro and in vivo antibacterial activities of AT-4140, a new broad-spectrum quinolone.

AT-4140, 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-3,5- dimethyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid, showed broad and potent antibacterial activity. Its MICs for 90% of the strains tested were 0.1 to 0.78 micrograms/ml against gram-positive organisms, such as members of the genera Staphylococcus, Streptococcus, and Enterococcus, and 0.0125 to 1.56 micrograms/ml against gram-negative organisms, such as members of the family Enterobacteriaceae and the genera Pseudomonas, Branhamella, Campylobacter, Haemophilus, and Neisseria. Its MICs were 0.025 to 0.78 micrograms/ml against glucose nonfermenters, such as members of the genera Xanthomonas, Acinetobacter, Alcaligenes, Moraxella, Flavobacterium, and Brucella; 0.2 to 0.78 micrograms/ml against anaerobes, such as Clostridium perfringens and Bacteroides fragilis; 0.0125 to 0.05 micrograms/ml against Legionella spp.; 0.0125 to 0.2 micrograms/ml against Mycoplasma spp.; 0.031 to 0.063 micrograms/ml against Chlamydia spp.; and 0.1 to 0.3 micrograms/ml against Mycobacterium spp. The potencies of AT-4140 against gram-negative organisms were comparable to those of ciprofloxacin and higher than those of ofloxacin, enoxacin, and norfloxacin. The potencies of AT-4140 against gram-positive organisms, glucose nonfermenters, anaerobes, Mycoplasma spp., Chlamydia spp., and Mycobacterium spp. were generally higher than those of the quinolones with which AT-4140 was compared. AT-4140 showed good oral efficacy against systemic infections with Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Escherichia coli, and Pseudomonas aeruginosa in mice. Its efficacy was better when a daily dose was given once than when it was given in two doses. Good efficacies of the orally administered drug were also observed in pulmonary, dermal, and urinary tract infection models in mice. The in vivo efficacies of AT-4140 were equal to or better than those of ciprofloxacin, ofloxacin, enoxacin, and norfloxacin.

[Bone disorder in long-term survival after gastrectomy with reference to bone mineral content].

To investigate post-gastrectomy metabolic bone disorder, the radial bone mineral content (BMC) was measured with 125I-photon absorptiometry in 131 long-term survivors, the postoperative periods ranged 3 to 30 years. Sixty-eight patients (52 per cent) showed abnormally low BMC levels compared with healthy controls. The 43 patients with total gastrectomy manifested a higher incidence of decreased BMC levels than did the other 88 patients with partial gastrectomy. In females, patients subjected to the Billroth II procedure manifested low BMC values. The extent of the decline in BMC was much higher in females than in males, and higher in totally gastrectomized patients than in partial gastrectomy group. At more than 10 years postoperatively many patients manifested markedly low BMC levels; in totally gastrectomized patients this finding was made at less than 5 years postoperatively. A significant correlation was found between the extent of the decreased BMC levels and the postoperative periods. Of the patients with decreased BMC values, 30 per cent of them gave histories of osseous symptom after gastrectomy, however, 70 per cent of patients were asymptomatic. Based on the results, in long-term survival treated by total or partial gastrectomy, many patients present an osteopenic status, however, the number of those with clinically manifested bone disease such as osteomalacia may be low.

Bone disorder following partial and total gastrectomy with reference to bone mineral content.

To study post-gastrectomy metabolic bone disorders, we measured the radial bone mineral content (BMC), serum levels of calcium, inorganic phosphorus, alkaline phosphatase, and 25-hydroxyvitamin D(25-OH-D) in 59 patients with partial- and 39 patients with total gastrectomy. Total gastrectomy patients manifested a higher incidence of decreased BMC levels than did partial gastrectomy patients (56 per cent vs. 25 per cent). Patients subjected to the Billroth II procedure, especially females, manifested abnormally low BMC values. The decline in BMC was age-related; it was pronounced in females. At 10 years postoperatively, many of the partial gastrectomy patients manifested markedly low BMC levels; in totally gastrectomized patients this finding was made at less than 5 years postoperatively. Approximately 30 per cent of our patients showed abnormalities in serum minerals, alkaline phosphatase or 25-OH-D.

In vitro and in vivo antibacterial activity of AT-2266.

AT-2266 [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carbo xylic acid] showed a broad spectrum of antibacterial activity against gram-positive and gram-negative microorganisms, including Pseudomonas aeruginosa. The in vitro antibacterial activity of AT-2266 was in general comparable to that of norfloxacin, but much higher than that of pipemidic or nalidixic acid. The 90% minimal inhibitory concentrations (MIC90s) of AT-2266 for P. aeruginosa resistant to gentamicin (MIC range, 25 to greater than 200 microgram/ml) and Enterobacteriaceae resistant to nalidixic acid (25 to greater than 1,600 micrograms/ml) were 3.13 and 12.5 micrograms/ml, respectively. The to nalidixic acid (25 to 1,600 micrograms/ml) were 3.13 and 12.5 micrograms/ml, respectively. The MICs of AT-2266 were only slightly affected by the addition of horse serum or sodium cholate, by the pH of the medium, and by inoculum size. AT-2266 was sodium cholate, by the pH of the medium, and by inoculum size. AT-2266 was bactericidal at concentrations near its MIC value. The 50% effective doses of AT-2266 after oral administration against systemic infections in mice were about 1/2 those of norfloxacin, about 1/10 those of pipemidic acid, and between 1/20 and 1/40 those of nalidixic acid.