Changes in skin blood flow in type 2 diabetes induced by prostacyclin: association with ankle brachial index and plasma thrombomodulin levels

In a previous study, we reported that beraprost sodium (BPS), a stable prostaglandin I(2) (PGI(2)) analog, increases skin blood flow in the feet of both control subjects and patients with type 2 diabetes, and that the flow increase induced by BPS is lower in diabetic patients than in controls. The present study was undertaken to clarify factors associated with smaller increases in skin blood flow in the feet of patients with type 2 diabetes after the administration of BPS, and to investigate the relationship between microalbuminuria and the changes in skin blood flow induced by the PGI(2) analog. We studied 61 patients with type 2 diabetes: 10 received placebo (control) and 51 (31 with normoalbuminuria and 20 with microalbuminuria) received BPS. Using laser Doppler flowmetry, we measured the skin blood flow at the pulp of the right big toe before and 90 minutes after administration of 40 microg BPS, and calculated the change in blood flow, i.e., delta flux (peak flux at 90 minutes - basal flux at 0 minutes). Plasma concentrations of soluble thrombomodulin (TM) were determined using an enzyme immunoassay (EIA) sandwich method. BPS significantly increased skin blood flow in the treatment group compared with the placebo group (P <.01). The delta flux was positively correlated with the value of the ankle brachial index (ABI) (r =.41, P <.0038) and was negatively correlated with plasma TM levels (r = -.53, P <.0001). By multiple regression analysis both the ABI value and the plasma TM level retained a significant influence on delta flux. Furthermore, both the delta flux and the ABI value in patients with microalbuminuria were lower than in patients with normoalbuminuria (P <.05). The results suggest that BPS increases the skin blood flow of the toe of patients with type 2 diabetes and that the increased flow is independently influenced by the value of the ABI and the plasma TM levels; in addition, microalbuminuria is associated with the impairment of vasodilation in the feet in response to BPS.     

Osteopontin is released from the heart into the coronary circulation in patients with a previous anterior wall myocardial infarction.

The present study was designed to clarify whether osteopontin, an extracellular matrix protein, is released from the heart into the coronary circulation in patients with a previous (>3 months) anterior wall myocardial infarction (MI). Using a commercially available enzyme immunoassay kit, plasma concentrations of osteopontin were measured in 30 patients (26 men, 4 women; mean age, 61+/-12 years). Blood samples were obtained from the aortic root and coronary sinus. The difference in the plasma concentrations of osteopontin in the aortic root and coronary sinus, which reflects the cardiac production of osteopontin released into the coronary circulation, was compared with the left ventricular ejection fraction (LVEF) and volumes obtained from contrast left ventriculography. Plasma osteopontin concentrations were significantly higher in the coronary sinus than in the aortic root (672+/-446 vs 610+/-398 ng/ml, p=0.02). The transcardiac gradient of plasma osteopontin concentration correlated negatively with LVEF (r=-0.55, p=0.0005) and positively with left ventricular (LV) end-diastolic (r=0.63, p=0.0001) and end-systolic volume indexes (r=0.79, p<0.0001). This is the first study to show that in patients with a previous anterior wall MI osteopontin is released from the heart into the coronary circulation in proportion to the LV systolic function and volumes, suggesting that this extramatrix protein is associated with post-MI LV remodeling.     

Gastric gastrointestinal stromal tumor smaller than 20 mm with liver metastasis

There have been no reports of gastric gastrointestinal stromal tumors (GISTs) <20 mm with distant metastasis. We report a case of a 15-mm gastric GIST with liver metastasis 1 year after surgical resection of the primary lesion. A 35-year-old man underwent routine esophagogastroduodenoscopy in July 2009. A submucosal tumor (SMT) <20 mm was incidentally detected at the posterior wall of the gastric body. Endoscopic ultrasound (EUS) indicated that it was a gastrointestinal mesenchymal tumor, including GIST, leiomyoma or schwannoma. He did not accept regular follow-up for this gastric SMT, therefore local laparoscopic excision was carried out in October 2009. The final pathological diagnosis after surgery was GIST, 15 mm in size, and a mitotic rate of 7/50 high-power fields, which did not indicate a high metastatic risk. The patient was followed up regularly without adjuvant chemotherapy. At 1 year after surgery, a space-occupying lesion ~15 mm was detected in the left lobe of the liver by abdominal ultrasound, where no mass lesion had been observed before surgery. To make a definite diagnosis of the hepatic mass lesion, EUS-guided fine-needle aspiration was performed, which demonstrated a metastatic liver tumor from a gastric GIST. Although this was a rare case, we should keep in mind that gastric GISTs do have a chance of malignant behavior, even if <20 mm.     

Hydration of surfactant-modified and PEGylated cationic cholesterol-based liposomes and corresponding lipoplexes by monitoring a fluorescent probe and the dielectric relaxation time

For the optimization of plasmid DNA (pDNA)-cationic lipid complexes and lipoplex delivery, proper indexes of the physicochemical properties of lipoplexes are required. In general, the characteristics of lipoplexes are defined by particle size and zeta-potential at various mixing ratios of cationic liposomes and pDNA. In this study, we characterized the hydration level of surfactant-modified and PEGylated cationic cholesterol-based (OH-Chol) liposomes and their lipoplexes by monitoring both the fluorescent probe laurdan and the dielectric relaxation time. Fluorescence measurement using laurdan detected hydration of the headgroup of lipids in surfactant-modified liposomes and PEGylated DOTAP-liposomes, but hardly any fluorescence was detected in PEGylated OH-Chol-liposomes because the PEG layers may extend and cover the fluorescent maker. On the other hand, the measurement of dielectric relaxation time of water molecules revealed total hydration, including hydration of the PEG layer and the headgroup of cationic lipids. Furthermore, we found an inverse correlation between hydration level and cellular uptake of PEGylated lipoplexes (R=0.946). This finding indicated that the dielectric relaxation time of water molecules provides an important indicator of hydration of liposome and lipoplexes along with the fluorescence intensity of laurdan.     

Clinical phase III study on TAP-144-SR, an LH-RH agonist depot formulation, in patients with prostatic cancer

A randomized controlled phase III clinical trial comparing TAP-144-SR (TAP) and diethylstilbestrol diphosphate was conducted for patients with prostatic cancer. Patients with Stage B, C, or D disease, who were previously untreated, were enrolled. TAP-144-SR 3.75 mg was administered subcutaneously at 4-week intervals for 12 weeks (a total of 3 injections) in the TAP-144-SR group, while 100 mg of diethylstilbestrol diphosphate was administered orally three times a day (before meals) for 12 weeks in the control group. A total of 141 patients were enrolled using a centralized telephone registration system. Four of these patients were ineligible, and there were 3 drop-outs who never received drugs because they withdrew their consents to participate in the trial. These 7 were excluded from the evaluation, and as a result, 134 patients (66 in the TAP group and 68 in the control group) were evaluable in safety and efficacy. Between the two groups, there were no significant differences in patient characteristics, except the age distribution. Clinical response rates (CR+PR) in evaluable patients according to the criteria of Japanese Prostatic Cancer Study Group were 54.5% in the TAP group and 47.1% in the control group. In addition, the rates according to the criteria for Evaluating the Direct Response to Chemotherapy in Solid Carcinomas and NPCP criteria were 7.6% in the TAP group and 8.8% in the control group and 18.2% in the TAP group and 20.6% in the control group, respectively. Using any of the three criteria, there were no significant differences in response rate between the two groups. The incidence of side effects was 64.1% in the TAP group and 95.4% in the control group; the incidence being significantly higher in the control group (p less than 0.001; chi 2-test). Therefore, the overall safety was significantly greater in the TAP group than in the control group (p less than 0.001; chi 2-test). On the basis of the efficacy and safety the clinical usefulness rate of TAP-144-SR was significantly higher than that of diethylstilbestrol diphosphate (p = 0.038; U-test). In conclusion, TAP-144-SR was confirmed to be more useful than diethylstilbestrol diphosphate as a standard drug for hormonal therapy of prostatic cancer.     

Chronological variation of adrenal surgery for the past 28 years--experience with 140 adrenal operations

The author experienced 140 adrenal operations from April, 1958 to March, 1986. Surgery was performed in 54 cases of primary aldosteronism (adenoma - 52, hyperplasia - 2), 46 cases of Cushing's syndrome (carcinoma - 3, adenoma - 22, primary nodular hyperplasia - 1, hyperplasia - 20), 26 cases of pheochromocytoma (tumor - 25, hyperplasia - 1) and 11 other adrenal tumors. During the study period of 28 years, remarkable strides have been made in the image diagnostic procedures such as RI scinti-scan, ultrasonography and CT and the hormonal assay. The effect of this progress appeared mainly in the cases after 1972. Therefore, the 140 adrenal operations were studied by dividing the period into the early 14 and the late 14 years. During the period of the early 14 years, 77 operations were carried out, while 63 were performed in the late period. The decreased number of operations during the late 14 years was due to the fact that Cushing's disease came to be treated mostly by transsphenoidal hypophysectomy. Surgical approaches to the adrenal gland are usually classified as anterior transperitoneal and extraperitoneal including translumbar and posterior incisions. In the former period, the transperitoneal approach was indicated in 40 operations, while the extraperitoneal approach was indicated in 37. On the other hand, 53 operations were performed by the extraperitoneal procedure with only 10 transperitoneal surgical interventions in the latter period. The decreased frequency of the transperitoneal surgery in the latter period was considered due to improved preoperative techniques to localize the adrenal lesion. Operative and postoperative complications such as spleen injury, delayed wound healing and intestinal paralysis were compared with regards to the transperitoneal and extraperitoneal approaches. More complications were noted in the transperitoneal approach.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cyclosporine induced nephrotoxicity and renal blood flow]

To elucidate the relationship between cyclosporine (Cs) nephrotoxicity and renal blood flow (RBF), we carried our experiments using rats. Adult male Wistar strain rats each weighing about 100 g were used. Rats were divided into 2 groups; the Cs group (Cs 50 mg/kg/day was intraperitoneally given for 10 consecutive days) and the control group (normal saline solution for 10 consecutive days). The renal cortical blood flow was measured in each group by electrolytic hydrogen gas clearance method. We also carried out renal angiography with barium sulfate (BaSO4). Then we measured blood vessel area/renal sagittal section area ratio and the diameter of interlobar arteries. The Cs group showed a significant decrease of renal cortical blood flow compared with the control group. On the other hand there was no significant change in renal angiogram. In conclusion, Cs decreased renal cortical blood flow. We suppose that vascular resistance increased following afferent arteriolopathy caused by Cs administration.