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.

[Outcome of patients in metastatic renal cell carcinoma with or without embolization].

Nineteen cases of metastatic renal cell carcinoma were embolized (embolization group) and 18 cases were not (non-embolization group). The median survival time after nephrectomy for the 14 cases in the embolization group, 23 months, was more favorable than the 11 months obtained for the 13 cases in the non-embolization group. In the case of one organ metastasis, the median survival time was 33 months for 9 cases in the embolization group and 11 months for 10 cases in the non-embolization group, with a remarkable difference in survival time between the two groups. Therefore, the survival rate can be improved by performing nephrectomy after embolization in the case of single organ metastasis. On the other hand, in the case of multiple organ metastasis prolongation of survival time cannot be expected even when embolization is performed with or without nephrectomy.

[Analysis of computed X-ray tomography of the brain in incontinence patients with senile dementia. Relationship between circulatory defect of the brain, brain atrophy and urinary incontinence].

To evaluate the condition of incontinence in patients with senile dementia, we performed computed tomography X-rays to the brain and analyzed the relationship among the circulatory defect of the brain, the brain atrophy and the degree of incontinence. There were 92 patients subjected to this study who were hospitalised due to senile dementia; 74 patients had vascular dementia, 10 patients had senile dementia of Alzheimer type, and 8 patients had the mixed type. (age ranged: 54-95 years; mean: 80.3 years). The degree of incontinence in these patients varied as follows: 18 patients with continence, 16 patients with moderate incontinence, 58 patients with total incontinence. The diagnosis of circulatory defect of the brain was based on computed tomography observation of periventricular lucency (P.V.L.), and the degree of brain atrophy was evaluated based on 4 criteria: the Lateral body ratio, the Huckman number, the Evans ratio, and the enlargement of the subarachnoid space. Among the 92 patients, P.V.L. was present in 31 patients, among them 27 patients suffered from incontinence. There was a significant correlation between P.V.L. and incontinence (p < 0.001). As the incontinence progressively worsened (Continence, Moderate incontinence Total incontinence), the lateral body ratio increased to 24.8, 27.8, 28.6, (p < 0.05). The Huckman number also increased to 18.3, 19.3, 21.3, (p < 0.01), and the evans ratio likewise 29.9, 32.3, 33.7 (p < 0.01). The enlargement of the subarachnoid space was also correlated with the severity of incontinence. We conclude that urinary incontinence originating from senile dementia is connected to brain atrophy and is strongly influenced by the circulatory disorders of the brain.

[A study of the clinical effect of hormone replacement therapy for patients with stress incontinence].

BACKGROUND: Our purpose was to clarify the effect of hormone replacement therapy (H.R.T.) for patients with stress incontinence. METHODS: We investigated 25 postmenopausal women, age 54-73 years, with a leakage volume is less than 15 g/day. In this study 0.625 mg of conjugated estrogen and 2.5 mg of medroxyprogesterone acetate were administrated for a total of 4 months. A clinical evaluation, measurement of volume of leakage per day and urodynamic evaluation (urethral pressure profile) were performed three times at pre administration, and at 2 months and 4 months after administration. RESULTS: Five of the 24 patients (20.8%) were improved significantly both clinically and urodynamically. Six patients (25.0%) improved clinically, and two patients (8.3%) improved urodynamically, the remaining 11 patients (45.8%) showed no change. Side effects occurred in eight cases. In one patient, it was necessary to stop administration due to severe irregular genital bleeding and leukorrhea, and in one patient the dosage was reduced due to swelling of breasts. The side effects of swelling of breasts and genital bleeding were relatively mild in the remaining six patients and they could continue H.R.T. administration. CONCLUSIONS: These results suggest that H.R.T. for patients with stress incontinence is not necessarily superior to the other non surgical methods. However, it may provide an alternative treatment method for incontinence.

[The male reproductive function in patients with spinal cord injury].

Seminal findings and blood hormone levels were studied for evaluating the male reproductive function in patients with spinal cord injury. The patients were divided into 3 groups, namely, 18 patients with complete injury, 5 patients with incomplete injury and 3 patients with dyspermatism. The number of sperms, the rate of movement and rate of deformation were measured for semen obtained by forced ejaculation. The number of sperms was kept at a relatively high level in the three groups, while the rate of movement fell off in all of the three groups. The rate of deformation was highest in the patients with complete injury and lowest in the patients with dyspermatism. As for blood hormone levels, LH, FSH and Testosterone (hereinafter referred to as TES) were determined by the RIA. The cases were classified into those in the acute stage and those in the chronic stage 3 months after sustaining injury for a comparative study. The subjects consisted of 27 cases in the acute stage and 47 cases in the chronic stage. For 8 patients in the acute stage, the blood hormone levels were determined even in the chronic stage and follow-up observations were made on the changes in the levels. The FSH level was low in both stages, while LH and TES tended to increase in the chronic stage. Particularly, the TES level was elevated in all the cases in the follow-up observations made in 8 patients. From the results mentioned above, transient disturbance of the interstitial function is suggested as the mechanism of male gonadal disturbance due to spinal cord injury.

[A clinical study of decreased bone density in the patients treated with long-term luteinizing hormone releasing hormone analogue (LHRH-a)--the risk of iatrogenic osteoporosis due to treatment of carcinoma of prostate].

BACKGROUND: It is well known that androgens play an important role in bone metabolism and male hypogonadism induce osteoporosis. Luteinizing hormone-releasing hormone analogue (LHRH-a) which is essential for conservative therapy of prostatic carcinoma (CaP) ultimately reduces circulating testosterone to castration levels. The purpose of this study was to determine the risk of decrease of bone mineral density in men receiving LHRH-a for CaP. PATIENTS AND METHODS: Fifty-three man with CaP aged 63 to 95 years (mean 75.5 years) were included in this study. Seven patients received LHRH-a with estrogen drug, forty-six patients received LHRH-a with or without anti androgen drug. To estimate patient's bone density we use the second metacarpal bone density using a microdensitometry method. RESULTS: Blood level of sex hormone of the forty-six patients who were received LHRH-a without estrogen, was the same as that of castration. Patients who were treated more than twelve months had less bone density than patients who were treated less than eleven months. As the duration of medical castration period was prolonged, patients bone density were reduced. Whereas seven patients who received estrogen drug did not find a decrease of bone density regardless of duration of treatment period. CONCLUSIONS: Hypogonadism induced LHRH-a also reduce bone density, so there is a risk of iatrogenic osteoporosis caused by therapy for CaP with LHRH-a. Patients with osteoporosis easily suffer from a much complicated and pernicious bone fracture, so we should measure bone density of male patients same as female treated with LHRH-a for a long-term.

[A case of sudden gross hematuria caused by an iliac artery-ureteral fistula].

A 51-year-old male patient, who had been treated for nonspecific angitis with pulselessness in the upper extremities, was found to have stenosis of the left common iliac artery. Patch grafting was performed for the stenotic lesion of the artery. Sixteen months after the operation, the patient developed a sudden massive hematuria for which he was immediately admitted. He required blood transfusions and bed rest. Pyelography and arteriography revealed almost complete impairment of the left kidney function. During subsequent left retrograde ureterography , the patient again developed massive hematuria and fell in shock. The ureterogram revealed left hydronephrosis and the adhesive left ureter to the site of the patch graft. Extraluminal outflow of contrast medium into the artery was also noted. These findings were considered to indicate the hematuria being an extravasation of blood from an arterio-ureteral fistula formed in the patch graft region. An emergency operation was performed. Contamination was avoided by construction of the femoro-femoral arterial bypass graft to the left lower extremity, prior to the radical removal of the potentially infected fistula and left kidney. The surgical procedures have saved the patient and his lower extremities.

[The role of preoperative embolization in renal cell carcinoma].

In 84 cases of renal cell carcinoma, the effect of embolization was assessed by dividing the patients into two groups: those having undergone (42 cases) or not having undergone (42 cases) embolization. A 16% decrease in tumor volume following embolization using an MMC-micro capsule was noted. In patients without metastasis at nephrectomy, a tendency was observed for the incidence of postoperative metastasis to be lower with more favorable survival for the group with embolization than that without. On the other hand, among cases with metastasis at nephrectomy, there were more patients who survived for a longer period in the embolization group.

[An autopsy case of double cancer (Hepatocellular carcinoma and mixed germ cell tumor of the testis)--significance of alpha-fetoprotein and human chorionic gonadotropin as tumor markers].

A 43-year-old male suffering from liver cirrhosis was admitted with complaints of general malaise and anorexia. Admission laboratory data evidenced high levels of serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG). Histopathologically, the resected left testis and supraclavicular enlarged lymph nodes revealed mixed germ cell tumor. After castration, the serum HCG level normalized, but AFP continued to increase. Autopsy findings did not unequivocally show mixed germ cell tumor, however, massive type hepatocellular carcinoma was present. These findings suggest that the hepatocellular carcinoma produced AFP, while the mixed germ cell tumor produced HCG.