New therapeutic approach for impaired arteriogenesis in diabetic mouse hindlimb ischemia.

BACKGROUND: The combined treatment of sustained-release basic fibroblast growth factor (Sr-bFGF) and a 5-hydroxytryptamine(2A) blocker, sarpogrelate, was evaluated to see whether it reversed the impaired collateral circulation in diabetic (DM) mouse hindlimb ischemia. METHOD AND RESULTS: Diabetic and normal mice with ischemic hindlimb were randomly assigned to 1 of 5 experimental groups (no treatment, sarpogrelate 50 mg . kg(-1) . day(-1), 20 microg or 50 microg Sr-bFGF and a combined treatment of 20 microg Sr-bFGF and sarpogrelate), and treated for 4 weeks. Tissue blood perfusion (TBP), vascular density (angiogenesis) and the number of mature vessels (arteriogenesis) were checked by the use of standard methods. Although angiogenesis was comparable (161+/-14 vs 154+/-12 vessels/mm(2)), the laser Doppler perfusion image index (LDPII) (0.43+/-0.11 (SD) vs 0.63+/-0.08, p<0.05) and arteriogenesis (8+/-3 vs 12+/-4 vessels/mm(2), p<0.05) were significantly lower in DM mice than those in normal mice. The dose of Sr-bFGF for the sufficient number of mature vessels (>or=45 vessels/mm(2)) and LDPII (>or=0.9) was 20 microg for the normal mice, and 50 microg for the DM mice, which was reduced with the aid of sarpogrelate. Conclusions A combined therapy of Sr-bFGF and sarpogrelate is effective for neovascularization to reverse the impaired arteriogenesis and TBP in DM mice.     

The change in renal replacement therapy on acute renal failure in a general intensive care unit in a university hospital and its clinical efficacy: a Japanese experience

The aim of our study was to examine renal replacement therapies (RRT) that have been used for acute renal failure (ARF) in our intensive care unit (ICU) patients and to compare their outcomes. Sixteen patients who underwent intermittent hemodialysis (IHD), 14 patients who underwent continuous hemofiltration (CHF) in combination with IHD (CHF + IHD), and 38 patients who underwent continuous hemodiafiltration (CHDF) were evaluated. Regarding the effects of blood purification on hemodynamics and renal function, the percentage increase in blood pressure and percent rapid increase in urinary output were the greatest in the CHDF group. The hourly urinary output after the start of initial blood purification increased only in the CHDF group. The survival rate was significantly higher in the CHDF group. These results suggest that CHDF should be the first-line therapy for patients with ARF and that we are moving in the right direction regarding the application of RRT to treat ARF in ICU patients.     

Successful therapy with argatroban for superior mesenteric vein thrombosis in a patient with congenital antithrombin deficiency

A 38-year-old woman was admitted with superior mesenteric vein (SMV) thrombosis, which was refractory to anticoagulation therapy. The plasma antithrombin activity was decreased and hardly compensated by concentrated antithrombin preparation due to high consumption rate. However, successful anticoagulation was achieved by administration of direct thrombin inhibitor, argatroban. Family studies of antithrombin activity revealed that she had type I congenital antithrombin deficiency. A novel heterozygous mutation in the gene for antithrombin (single nucleotide T insertion at 7916 and 7917, Glu 272 to stop in exon 4) was identified. Argatroban administration would be effective in the treatment of congenital antithrombin deficiency with SMV thrombosis.     

Two-staged hepato-pancreatoduodenectomy and interventional pancreaticojejunostomy

Two-staged pancreatoduodenectomy, including exteriorization of the pancreatic juice and second-look pancreaticojejunostomy, has been recommended for high-risk patients to avoid pancreatic leakage, which often causes intra-abdominal hemorrhage. We present a new technique of interventional pancreaticojejunostomy under both fluoroscopy and endoscopy without second-look laparotomy. A 77-year-old woman with local recurrence and liver metastasis from colon cancer underwent hepato-pancreatoduodenectomy with the external drainage of pancreatic juice via the pancreatic duct tube without pancreaticojejunostomy. Two months later, the jejunum was punctured with the insertion of a 5-F needle-knife into the pancreatic fistula during endoscopic observation of jejunal lumen, followed by the insertion of two 0.35-inch guidewires into the jejunum and the pancreatic fistula. Finally, a 10-Fr stenting tube was placed between the jejunum and the pancreatic fistula. No complications developed.     

Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast

It is well known that sex steroids play important roles in the development of invasive ductal carcinoma (IDC) of the human breast. However, biological significance of sex steroids remains largely unclear in ductal carcinoma in situ (DCIS), regarded as a precursor lesion of IDC, which is partly due to the fact that the intratumoral concentration of sex steroids has not been examined in DCIS. Therefore, in this study, we first examined the intratumoral concentrations of estradiol and 5alpha-dihydrotestosterone (DHT) using liquid chromatography/electrospray tandem mass spectrometry in DCIS. Intratumoral concentrations of both estradiol and DHT were threefold higher in DCIS than non-neoplastic breast tissues and estrogen-producing enzymes (aromatase, steroid sulfatase, and 17beta-hydroxysteroid dehydrogenase type 1 (17betaHSD1)), and androgen-producing enzymes (17betaHSD5 and 5alpha-reductase type 1 (5alphaRed1)) were abundantly expressed in DCIS by real-time PCR and immunohistochemical analyses. The intratumoral concentration of DHT was significantly lower in IDC than DCIS, while the expression of aromatase mRNA in carcinoma cells and intratumoral stromal cells was significantly higher in IDC than those in DCIS. Immunohistochemistry for sex steroid-producing enzymes in DCIS demonstrated that 5alphaRed1 immunoreactivity was positively correlated with Ki-67 labeling index and histological grade and was also associated with an increased risk of recurrence in patients with DCIS examined. Results of our study suggest that intratumoral concentrations of estradiol and DHT are increased in DCIS, which is possibly due to intratumoral production of these steroids. Therefore, estradiol and DHT may play important roles in the development of DCIS of the human breast.     

Analysis of the T cell receptor V beta repertoire in 2,4,6-trinitrobenzenesulfonic acid induced colitis in mice

The aim of this study was to analyze which types of T cells are at work and the specific nature of their response, using a mouse 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced colitis model. The response of T cells to TNBS was analyzed by anti-TNBS mixed-lymphocyte reaction. T cell clones were established by limiting dilution. Phenotypes and T cell receptor (TCR) V beta of T cells were analyzed by flow cytometry. Colitis was induced by administration of TNBS enemas, and lamina propria lymphocytes were isolated and analyzed. The proliferative responses to TNBS of spleen T cells were partially inhibited by the addition of antimouse CD4 or CD8 antibodies to the mixed-lymphocyte culture. Conversely, these were inhibited by the addition of both antibodies. Flow cytometric analysis showed that TCR V beta 14 T cells specifically increased in the CD8+ T cell population. We established CD8+ TCR V beta 14 T cell clones which were TNBS reactive and self-restricted. Investigation using lamina propria lymphocytes in TNBS-induced colitis revealed that the rate of CD8+ TCR V beta 14 T cells changed with histological inflammatory activity which also attained a peak on day 5 following enema administration. Both CD4+ and CD8+ T cell subsets responded to TNBS, and the rate of CD8+ TCR V beta 14 T cells changed with histological inflammatory activity in TNBS-induced colitis.     

Assessment of the viability and treatment response of bone metastases in patients with metastatic castration-resistant prostate cancer using choline PET/CT

This study aimed to evaluate the clinical use of choline-PET/CT for discriminating viable progressive osteoblastic bone metastasis from benign osteoblastic change induced by the treatment effect and evaluating the response of bone metastasis to treatment in metastatic castration-resistant prostate cancer (mCRPC) patients. Thirty patients with mCRPC underwent a total of 56 ¹¹C-choline-PET/CT scans for restaging, because 4 patients received 1 scan and 26 had 2 scans. Using 2 (pre- and post-treatment) ¹¹C-choline-PET/CT examinations per patient, treatment response was assessed according to European Organization for Research and Treatment of Cancer (EORTC) criteria in 20 situations, in which only bony metastases were observed on ¹¹C-choline-PET/CT scans. Viable bone metastases and osteoblastic change induced by the treatment effect were identified in 53 (94.6%) and 29 (51.8%) of 56 ¹¹C-choline-PET/CT scans, respectively. In 27 cases (48.2%), ¹¹C-choline-PET/CT scans could discriminate the 2 entities. The mean SUVmax of the metastatic bony lesions was 5.82 ± 3.21, 5.95 ± 3.96, 6.73 ± 5.04, and 7.91 ± 3.25 for the osteoblastic, osteolytic, mixed, and invisible types, respectively. Of the 20 situations analyzed, CMR, PMR, SMD, and PMD, as determined by the EORTC, were seen in 1, 2, 3, and 14 cases, respectively. Of the 13 patients with increasing PSA trend, all 13 showed PMD. Of the 2 patients with PSA response of <50%, both 2 showed SMD. Of the 5 patients with PSA response of ≥50%, 1 showed CMR, 2 showed PMR, 1 showed SMD, and 1 showed PMD. Choline-PET/CT is very useful to discriminate viable progressive osteoblastic bone metastasis from osteoblastic change, and assess treatment response of bone metastases in mCRPC.     

Factors associated with frailty in Japanese patients with rheumatoid arthritis: results from the Institute of Rheumatology Rheumatoid Arthritis cohort study

Clinical Rheumatology - This study aimed to evaluate the prevalence of, and the factors associated with, frailty in Japanese patients with rheumatoid arthritis (RA). Patients with RA enrolled in...