Suppression of the histologic changes of GVHD by FK 506 in rat small bowel transplantation.
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Biomedical subjects
Publications and source records attributed to T Kiriyama.
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26,27-F6-1,25(OH)2D3 has a higher potency both in vivo and in vitro systems, and longer duration of action in vivo, instead of almost equal binding to 1,25(OH)2D3 receptor and comparatively short serum half-life. To date, the mechanism of higher action is not known, but using these analogues as a mirror we might be able to elucidate the mechanism of action or the metabolism of the kidney hormone, 1,25(OH)2D3.
The fluorine introduced analog of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3 [26,27-F6-1,25-(OH)2D3] is 5-10 times more potent than 1,25-(OH)2D3 in vitamin D-deficient rats and chicks. In this study we established cultures of human bone cells in order to elucidate the mechanisms responsible for the higher activity of this compound. The effects of 26,27-F6-1,25-(OH)2D3 and 26,26,26,27,27,27-hexafluoro-1,23(S),25-trihydroxyvitamin D3[26,27-F6-1,23(S),25-(OH)3D3], the postulated main metabolite of 26,27-F6-1,25-(OH)2D3, were assessed by the response of alkaline phosphatase (ALP) activity. 26,27-F6-1,25-(OH)2D3 increased ALP activity in a dose-related fashion, from a concentration of 10(-11) M and caused a 3-fold elevation at a concentration of 10(-9) M. To achieve the same stimulating effect on ALP activity, the required dose of 26,27-F6-1,25-(OH)2D3 was 100 times less than that of 1,25-(OH)2D3. Analysis of the receptors of these cells revealed that they have specific receptors for 1,25-(OH)2D3, which have a dissociation constant of 0.9 x 10(-10) M. The competitive binding assays of 26,27-F6-1,25-(OH)2D3 on these receptors showed that binding ability of 26,27-F6-1,25-(OH)2D3 is almost the same as that of 1,25-(OH)2D3. Therefore, receptor binding affinity does not account for the higher potency of 26,27-F6-1,25-(OH)2D3. The trihydroxylated compound, 26,27-F6-1,23(S),25-(OH)3D3 revealed almost the same stimulatory activity on ALP activity in these cells. The most likely explanation for the higher activity of 26,27-F6-1,25-(OH)2D3 than 1,25-(OH)2D3 is that 26,27-F6-1,25-(OH)2D3 is metabolized to 26,27-F6-1,23(S),25-(OH)3D3, which has almost the same activity as 26,27-F6-1,25-(OH)2D3 in target tissues, whereas 1,25-(OH)2D3 is degraded to less active metabolites such as 1,24,25-(OH)3D3.
A newly synthesized fluorinated analogue of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3 (26,27-F6-1,25-(OH)2D3) has been compared with 1,25(OH)2D3 as to its biological activity in vitamin D-deficient chicks. One day-old, white Leghorn cockerels were fed a rachitogenic diet for 5 weeks. They were then given vehicle or 32.5, 130 or 325 pmol of 26,27-F6-1,25(OH)2D3 or 1,25(OH)2D3 in a solution of propylenglycol:ethanol (95:5 v/v) sc every day for 2 weeks. Twenty-four hours after the last dose, the animals were sacrificed and their femurs were removed. 26,27-F6-1,25(OH)2D3 was more active than 1,25(OH)2D3 in stimulating growth, healing of rachitic cartilage visualized by soft X-ray radiography, elevation of serum inorganic phosphorus, and mineralization of rachitic bone. These biological differences between two compounds were observed only for the dose of 130 pmol. However, this fluorinated compound has less binding ability than 1,25(OH)2D3 to fetal chick intestinal cytosol receptors. The mechanism of the higher potency of this analogue is still unknown, but its affinity to the 1,25(OH)2D3 receptor does not account for the higher activity. Since 26-hydroxylation can be postulated as the inactivation step in vitamin D metabolism, these results suggest that the reason for increased activity of this fluorinated analogue is most likely its slower metabolism.
Since reduced antithrombin III (AT III) activity are associated with increased risk of thromboembolism, we have determined it in 39 patients with prostatic carcinoma. Pre-treatment levels were determined in 24 patients, 6 additional patients with prostatic carcinoma on estrogen treatment and 9 patients on chlormadinone acetate (CMA) therapy. In 12 of 24 patients we studied AT III levels before and after estrogen therapy was initiated. A significant decrease in AT III activity of 23.5% was found after one month on estrogen treatment, the patients on low doses of estrogen. Recovery of the levels of AT III was found after 6 months treatment even in in 5 of 6 patients who had shown depression of AT III levels initially. CMA treatment did not cause its depression. AT III levels was not connected with the stage of the disease or age of the patient.
Adjuvant chemotherapy mainly consisting of cisplatin, adriamycin and mitomycin C was administered to 17 patients after cystectomy for bladder tumor (chemotherapy group). Seventeen concurrently treated patients did not receive adjuvant chemotherapy (control group). From the comparison of survival curves of these two groups, the following results were obtained. 1) Survival curves of the patients in all stages did not differ significantly between chemotherapy and control groups. 2) Among patients in stage pT3, pT4 and/or N+, survival of the chemotherapy group seemed to have some advantage over that of the control group, but the survival curves did not differ significantly between these two groups. 3) Among patients in N+, survival of the chemotherapy group was far better than that of the usual cases. Review of the literature on adjuvant chemotherapy after cystectomy for bladder tumor revealed the necessity of randomized study to determine whether adjuvant chemotherapy is effective.
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A case of paratesticular rhabdomyosarcoma is presented. An 18-year-old male was admitted with the complaint of giant scrotal swelling and abdominal fullness on September 5, 1986. Left radical orchiectomy was performed with the pathologic diagnosis of alveolar rhabdomyosarcoma. The tumor was paratesticular in location and had invaded a spermatic cord. Radiological examination showed a gross metastatic mass in retroperitoneal lymph nodes, supraclavicular lymph nodes and Douglas pouch. The patient received induction chemotherapy containing vincristine, actinomycin-D, cyclophosphamide, bleomycin, CDDP and VP-16. After 3 courses, he had no mass in Douglas pouch and supraclavicular lesion. He received retroperitoneal lymph node dissection for residual retroperitoneal mass, and postoperative radiotherapy was given. However, recurrent disease was developed in the paraaortic region with malignant ascites. He was treated with salvage chemotherapy, had without any significant effect. He died of liver dysfunction due to progressive mass in hepatic hilum. A review of the current approach of paratesticular rhabdomyosarcoma with the usefulness of combination chemotherapy is given.
A 51-year-old man was admitted with the complaint of left scrotal swelling (11 x 5 x 5 cm). He had undergone left nephrectomy and removal of tumor thrombus in inferior vena cava due to renal cell carcinoma. Nine months after the nephrectomy, left scrotal enlargement was noticed. Left high orchiectomy was performed on January 20, 1988. A clear cell carcinoma was present in spermatic cord and pampiniform plexus histologically but testis and epididymis were intact. Renal cell carcinoma seemed to disseminate retrograde through the spermatic vein to spermatic cord. The metastatic tumor of spermatic cord from renal cell carcinoma is very rare and this case is the fifth case in the Japanese literature.
Surgical excision of the indurated penile plaque and tunica vaginalis autografting was done in 3 patients. Preoperatively, their chief complaints had not been impotence but penile angulation or pain. Postoperatively, all of them improved and erectile failure was not seen, although hypesthesia of glans developed in all patients. One patient complained of impotence. The patients had been followed from 2 months to 9 months. As prosthesis is not prevailing in Japan and tunica vaginalis is easy to procure and handle, tunica vaginalis autografting is recommended.
Cisplatin was administered to 11 patients as a continuous infusion, 25 mg/m2/day for 1 to 4 days. Total and filterable platinum in plasma were monitored for 12 courses and a pharmacokinetic study was carried out in 7 patients by computerized nonlinear least-squares analysis. Following interruption of the infusion, the decrease of plasma filterable platinum was biphasic, with initial and terminal half-life of 21.6 +/- 11.4 min and 31.7 +/- 27.1 hr. Filterable platinum was still detectable in plasma 24 hours after the end of infusion. The total AUC exposure of filterable platinum for 24 hrs, 48 hrs and 96 hrs infusion were 3.67 micrograms.hr/ml, 13.68 micrograms.hr/ml and 14.75 micrograms.hr/ml, which were at least 3-fold higher than that observed for the short-term infusion of equal dose in literature. Gastrointestinal toxicity was evaluated and compared with short-term infusion of equal dose. In the continuous-infusion patients, the reduction of vomiting was observed but the duration of nausea was not shortened.
Between June, 1984 and May, 1988, 22 cases of renal injury were treated. There were 13 males and 9 females. The most frequent causes were traffic accidents (13 cases) and the next were falls (7 cases). Associated injuries were seen in 9 cases, including bone fractures, head injuries, liver lacerations, hemothorax and splenic laceration. Out of the 22 patients, there were 13 cases of renal contusion, 6 cases of renal laceration, 1 case of renal rupture and 2 cases of pedicle injury. Evaluation was made by IVP, CT, arteriography and so on. Arteriography was the most useful method whether immediate surgery should be done or not. Three cases were treated surgically (2 nephrectomies for rupture and pedicle injury, 1 drainage for laceration). The other cases were treated conservatively and no complications have been seen.
Between June, 1983 and December, 1988, 40 patients with primary bladder tumor underwent total cystectomy. Of the 40 patients, 33 (82.5%) were treated by total cystectomy at first presentation. Only 7 patients (17.5%) had prior history of bladder tumors. The mean time from the onset of symptoms to consultation was 11.5 months. In 68.5% of the evaluable 35 patients, gross hematuria was the first symptom. In 74.4% of the 39 evaluable patients, preoperative urine cytology was positive. If class III (suspicious) was included, the positive urine cytology rate was 82.1%. The operative mortality rate was 15%. Early complications occurred in 52.5% of the 40 patients. Late complications occurred in 35.3% of the 34 patients. The 1-, 2- and 3-year actual survival rates of the 40 patients were 69.6%, 65.5% and 65.5% respectively. The 2-year survival rate according to pathologic stage was 14.3% for patients in pT4, 43.8% in pT3b, 75% in pT3a, 100% in pT2, 78.8% in pT1 and 100% in pT0 + pTis. Of the 28 patients who underwent pelvic lymphadenectomy, 8 (28.6%) had positive nodes, including 1 of 1 (100%) in pT4, 5 of 7 (71.4%) in pT3b, 1 of 6 (16.7%) in pT3a, 1 of 4 (25%) in pT2 and 0 of 10 (0%) in pT1 + pT0 + pTis. The prognosis of the 7 patients who had prior history of bladder tumor was poor. The selection of initial therapy and the clinical follow-up should be done carefully.
We report a case of bilateral synchronous renal cancers for which only right radical nephrectomy was performed at another hospital. Five years later we performed partial nephrectomy (enucleation) for the left renal cancer. By computed tomographic scans we studied the radiological change of this tumor which occurred during a five-year period. We found a slow doubling time of this tumor. Three years after enucleation, tumor recurrence was noticed and we performed left partial nephrectomy with a normal parenchymal margin. We reviewed the literature about enucleation of renal cancer.
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In a histological study of 17 prostates excised in toto for stages B and C primary carcinoma, we found one focus of well differentiated carcinoma in each of six prostates, which, in addition to these foci, had large tumors of invasive prostatic carcinoma. In four of the six prostates, the foci were located near but separate from the main tumor, and in the remaining two they were invaded by the main tumor. These findings strongly suggest that prostatic carcinoma is multifocal in origin and that focal well differentiated carcinomas are different in biological behavior from invasive poorly differentiated carcinomas.
Effects of four mucopolysaccharides and dextran sulphate on penicillin-induced lysis of Staphylococcus aureus FDA 209P were studied. Heparin and dextran sulphate inhibited lysis, whereas hyaluronic acid enhanced it. Chondroitin sulphates A and C had no effect. Incubation of S. aureus suspended in 0.03 M phosphate buffer (pH 7.0) with dextran sulphate inhibited autolysis of the bacteria, whereas incubation with hyaluronic acid enhanced autolysis. Both extracellular and cell-associated autolysin activities of S. aureus were suppressed by dextran sulphate and high concentrations of heparin. The addition of hyaluronic acid enhanced autolysin activity. The release of lipoteichoic acid (LTA), a modulator of autolysin activity, from penicillin-treated bacteria was inhibited by heparin and dextran sulphate. However, hyaluronic acid had no effect on release of LTA. These results suggest that inhibition of penicillin-induced lysis of S. aureus by heparin results mainly from inhibition of LTA release while dextran sulphate inhibits both autolysin activity and LTA release. Hyaluronic acid appears to enhance penicillin-induced lysis through activation of the autolysins.