Prolonged antinociceptive effect of poly (DL-lactic acid)-fentanyl composites after their intrathecal injection in rats

We synthesized poly (DL-lactic acid)-fentanyl composites and compared the duration of analgesia after the administration of a single intrathecal dose of these agents in rats. The drug was injected with an intrathecal catheter into the intrathecal space. Fentanyl composites or plain fentanyl in doses of 2.5 or 25 micrograms were administered, respectively. Animals were then tested for analgesia using the tail-flick test. The release rate of fentanyl from fentanyl composites in vitro was also evaluated. The antinociceptive effect of fentanyl composites (25 micrograms) was significantly longer than that of plain fentanyl. Administration of poly (DL-lactic acid) alone did not induce the antinociceptive effect. Four of 7 animals given plain fentanyl (25 micrograms) exhibited temporary respiratory depression, but none of the animals given fentanyl composites showed this response. In vitro experiments demonstrated a slow release of fentanyl from the fentanyl composites. We conclude that the antinociceptive effect of fentanyl can be prolonged when administered as a poly (DL-lactic acid)-fentanyl composite in the intrathecal space with decreased systemic side effects compared with the plain formulation.     

Etidronate (EHDP) Inhibits Osteoclastic-Bone Resorption, Promotes Apoptosis and Disrupts Actin Rings in Isolate-Mature Osteoclasts

Bisphosphonates, therapeutic reagents against tumoral bone diseases (Paget's disease or osteoporosis), are potent inhibitors of bone resorption. The mechanisms by which they directly act on mature osteoclasts remain unclear. Using a recently developed technique for isolation of highly purified mammalian mature osteoclasts, we demonstrated that etidronate [ethane-1-hydroxy-1,1-diphosphonate (EHDP), 1-hydroxy-1,1-ethylidenebisphosphonate], inhibited directly osteoclastic bone-resorbing activity by pit assay. In addition, EHDP also directly induced apoptosis and disrupted actin rings in osteoclasts. The data support previous data on non-purified osteoclasts and results in vivo. Received: 26 June 1997 / Accepted: 27 July 1998     

TMC-171A,B,C and TMC-154, novel polyketide antibiotics produced by Gliocladium sp. TC 1304 and TC 1282

Four new antibiotics, TMC-171A (2), B (3), C (4) and TMC-154 (5) have been isolated from the fermentation of fungal strains Gliocladium sp. TC 1304 and TC 1282, respectively. Spectroscopic and degradation studies have shown that TMC-171s and TMC-154 were new members of the TMC-151 class of antibiotics, unique polyketides modified with a D-mannose and a D-mannitol or a D-arabitol. These compounds showed moderate cytotoxicity to various tumor cell lines.     

Clinical application of intrathecal lidocaine administration in surgery of the descending thoracic aorta

We studied the protective effects of intrathecally administered lidocaine against ischemic spinal cord injury during surgery. Seven patients (mean age 63.7 years, malefemale=61) with descending thoracic aortic aneurysms underwent reconstructive surgery. Following intrathecal lidocaine administration (10 ml), the operation was performed under femorofemoral bypass with an oxygenator. The aorta was cross-clamped at the distal end of the descending thoracic aorta and the proximal end of the lesions. The cross-clamping time was 47.1±23.3 minutes (mean ± SD). The operative procedure was total replacement of the descending thoracic aorta in five cases and patch closure in two. There were no operative deaths but paraparesis developed in two cases of total replacement. Neurological deficit was transient and disappeared in one case. In the other case, with 88 minutes of normothermic aortic cross-clamping, paraparesis gradually improved but was persistent after 7 months of follow-up. Graft anastomosis at the distal aortic arch was time consuming in this case and presumably caused prolonged spinal cord ischemia. Intrathecal administration of lidocaine was likely to reduce ischemic spinal cord injury and increase tolerance of the spinal cord to ischemia caused by prolonged aortic cross-clamping. This method was considered to provide a useful assistance to expand the safety limit of spinal cord ischemia in surgical reconstruction of the descending thoracic aorta requiring aortic occlusion. Tissue protective effects of intrathecal lidocaine administration may be further augmented by combining with deep hypothermia.     

Phosphate kinetics in patients on chronic hemodialysis

To investigate the phosphate kinetics in hemodialysis (HD), 8 patients in a stable condition, who were receiving HD three times a week for 4 hours per session, were investigated. Plasma phosphate was under 7 mg/dl, and residual renal function had almost disappeared. Dialysate containing phosphate was prepared by adding Na2HPO4 using a micro-infusion pump from the inlet of single pass dialysate in the individual dialysate delivery system. In the first week, Na2HPO4 was not added as the control period. In the second session of the second and third week, Na2HPO4 was added to give a phosphate concentration of 1.0 and 2.0 mmol/l in the dialysate, respectively. Total phosphate mass removal was 777 +/- 46.64 mg in the control period, 403 +/- 67.21 mg in the second week, and -230 +/- 214.8 mg in the third week. Total phosphate mass removal in the second and third week was significantly lower than that of the control period. Plasma phosphate concentration was significantly decreased after the HD compared with before the HD in the control and second week. There was no significant difference in plasma phosphate concentration between the period before HD and at 48 hours in the control and the second week. Plasma phosphate concentration before HD not only depended on phosphate mass removal by HD, but also on other factors. We suggest that dialysate containing phosphate might prevent excessive phosphate removal from non-extracellular compartments during HD.     

Immunomodulation for intestinal transplantation by allograft irradiation, adjunct donor bone marrow infusion, or both

BACKGROUND: The passenger leukocytes in the intestine have a lineage profile that predisposes to graft-versus-host disease (GVHD) in some animal models and have inferior tolerogenic qualities compared with the leukocytes in the liver, other solid organs, and bone marrow. Elimination by ex vivo irradiation of mature lymphoid elements from the bowel allografts is known to eliminate the GVHD risk. We hypothesized that infusion of donor bone marrow cells (BMC) in recipients of irradiated intestine would improve tolerogenesis without increasing the risk of GVHD. METHODS: Orthotopic small intestine transplantation was performed with the GVHD-prone Lewis (LEW)-to-Brown Norway (BN) combination and the reverse GVHD-resistant BN-to-LEW model under a short course of tacrolimus treatment (1 mg/kg/day, days 0-13, 20, 27). Grafts were irradiated ex vivo, using a 137Cs source. In selected experimental groups, donor BMC (2.5 x 10(8)) were infused on the day of small intestine transplantation. RESULTS: The unmodified LEW intestine remained intact, whether transplanted alone or with adjunct donor BMC infusion, but all of the BN recipients died of GVHD after approximately 2 months. Intestinal graft irradiation (10 Gy) effectively prevented the GVHD and prolonged survival to 92.5 days, but all of the BN recipients died with chronic rejection of the LEW grafts, which was prevented by infusion of adjunct donor BMC without causing GVHD. In the GVHD-resistant reverse strain direction (BN-->LEW), all intestinal recipients treated for 27 days with tacrolimus survived > or =150 days without regard for graft irradiation or adjunct BMC, but chronic rejection was severe in the irradiated intestine, moderate in the unaltered graft, and least in the irradiated intestine transplanted with adjunct BMC. Mild arteritis in the 150 day allografts of both strain combinations (i.e., LEW--> BN and BN-->LEW) may have been irradiation associated, but this was prevented when weekly doses of tacrolimus were continued for the duration of the experiment rather than being stopped at 27 days. CONCLUSIONS: Recipients are protected from GVHD by irradiating intestinal allografts, but the resulting leukocyte depletion leads to chronic rejection of the transplanted bowel. The chronic rejection is prevented with adjunct donor BMC without causing GVHD. Although application of the strategy may be limited by the possibility of radiation injury, the results are consistent with the paradigm that we have proposed to explain organ-induced graft acceptance, tolerance, and chronic rejection.     

The expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase associates with angiogenesis in epithelial ovarian cancer

Background The object of this study is to clarify the association of an angiogenic factor, PD-ECGF (platelet-derived endothelial cell growth factor/thymidine phosphorylase), with clinicopathologic factors, in this case tumor angiogenesis, in epithelial ovarian cancers. Methods Tumor specimens were obtained at the time of surgery from the primary lesion in 60 patients with epithelial ovarian cancer. Histologic cell types were assigned to tumors according to the World Health Organization classification: 26 were classified as serous adenocarcinoma, 15 as endometrioid adenocarcinoma, 9 as mucinous adenocarcinoma, 9 as clear cell carcinoma, and 1 as undifferentiated carcinoma. Surgical staging was based on the international Federation of Gynecology and Obstetrics (FIGO) staging system: 16 were stage I, 6 were stage II, 34 were stage III, and 4 were stage IV. Expression of PD-ECGF was evaluated by immunohistochemical staining. Microvessel density was assessed by immunostaining for factor VIII-related antigen in the most neovascularized area. Results Stroma cells stained more strongly than cancer cells (80% vs. 33%). The immunopositivity of PD-ECGF in stroma cells was higher in cases of advanced cancer. Expression of PD-ECGF in mucinous adenocarcinomas was significantly higher than that in serous adenocarcinomas, while PD-ECGF expression in clear cell carcinomas was significantly lower. The microvessel density in the cases with marked PD-ECGF-positive stroma cells was significantly higher than that in the cases with absent/minimal PD-ECGF-positive stroma cells (P<0.05). Conclusion The expression of PD-ECGF may play a crucial role in the promotion of angiogenesis in epithelial ovarian cancers.     

A case of emphysematous pyelonephritis improved with conservative therapy--indication for conservative therapy

A 51-year-old female patient was hospitalized in our department with high fever and left flank pain. Laboratory examination showed leukocytosis, increase of C-reactive protein (CRP), hyperglycemia and renal insufficiency. Enterobacter aerogenes grew out of the cultured urine. The radiograph and computerized tomographic (CT) scan revealed streaky gas in the destroyed left renal parenchyma with perirenal gas. She was diagnosed with left emphysematous pyelonephritis. Antibiotics therapy, treatment for sepsis and disseminated intravesicular coagulation was initiated resulting in mitigation of inflammation. High blood glucose initially required insulin therapy, but finally returned to normal levels through administration of oral antidiabetics. Although leukocytosis and low grade fever continued, the patient was discharged on day 53 with a negative CRP. CT scan indicated that the emphysematous change was localized after three months and almost resolved after four months. Renal scintigram indicated the residual function of the affected kidney. Because of the possibility of residual renal function and the cure by conservative therapy alone, the conservative therapy is preferred when the initial treatment is effective.     

Possible origin of suprasellar arachnoid cysts: neuroimaging and neurosurgical observations in nine cases

OBJECT: In this study the authors identify and investigate two new classifications of suprasellar arachnoid cysts. METHODS: The authors used computerized tomography cisternography, magnetic resonance (MR) imaging, and neuroendoscopy to investigate nine cases of suprasellar arachnoid cysts. A communicating cyst with early filling and early clearance of a radioopaque tracer was found in seven of nine cases; a communicating cyst with delayed filling and delayed clearance of the tracer was observed in one case; and a noncommunicating cyst was observed in the other. The MR findings indicated a variation in the position of the basilar artery (BA) bifurcation in relation to the ventral surface of the midbrain. A distance existed between the BA bifurcation and the ventral surface of the midbrain in a communicating cyst with early filling, whereas the BA bifurcation was posteriorly displaced in a communicating cyst with delayed filling and also in a noncommunicating cyst, leaving little space between the bifurcation and the ventral surface of the midbrain. Endoscopic observation revealed, in the case of communicating cysts with early filling and early clearance of tracer, that the BA bifurcation is located inside the cyst with no overlying membrane, whereas in a noncommunicating cyst, the BA and its branches can be observed through the transparent membrane of the lesion. CONCLUSIONS: The authors postulate two different types of suprasellar arachnoid cysts: a noncommunicating intraarachnoid cyst of the diencephalic membrane of Liliequist and a communicating cyst that is a cystic dilation of the interpeduncular cistern.     

Heme oxygenase-1 (Hsp32) is involved in the protection of small intestine by whole body mild hyperthermia from ischemia/reperfusion injury in rat.

AIM: The aim of the present study was to explore whether heme oxygenase-1 (HO-1) is involved in the hyperthermia-provided protection of the small intestine from ischemia/reperfusion injury in rats. METHODS: Intestinal damage was induced in male Sprague-Dawley rats by clamping both the superior mesenteric artery and the celiac trunk for 30 min, followed by reperfusion. Whole-body hyperthermia was induced in anesthetized rats by placement in a temperature-controlled water bath. Whole-body hyperthermia to a core temperature of 42-43 degrees C for 15 min was followed by passive cooling. We started the hyperthermic treatment 6 h before the vascular clamping. The severity of the mucosal injury was evaluated by several biochemical markers and histological findings. Hyperthermia-induced heat-shock proteins were detected by Western blotting. We also investigated the effect of zinc protoporphyrin IX (an HO-1 inhibitor) on the protective effect of hyperthermia. RESULTS: The rats, which were killed after ischemia/reperfusion, had severe intestinal inflammation. Hyperthermia significantly induced the production of Hsp70 and HO-1 in intestinal mucosa and significantly reduced ischemia/reperfusion-induced mucosal injury. The combination of zinc protoporphyrin IX with hyperthermia extinguished the protective effects of hyperthermia on ischemia/reperfusion injury. CONCLUSION: Hyperthermia protects against ischemia/reperfusion injury in rat small intestine through the expression of heat-shock proteins, especially HO-1.