Rationale and Design of the Multicenter Trial on Japan Working Group on the Effects of Angiotensin Receptor Blockers Selection (Azilsartan vs. Candesartan) on Diastolic Function in the Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE Trial

Background

Previous studies suggest that the pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterized not only by high ventricular stiffness, but also by vascular stiffness. Azilsartan has higher vascular affinity compared with other angiotensin II receptor blockers (ARBs), which were proven to have no beneficial effects on clinical outcomes in patients with HFpEF in earlier clinical trials. We aimed to test the hypothesis that azilsartan may improve left ventricular diastolic function in HFpEF patients with hypertension in this trial.

Methods

The Effects of Angiotensin Receptor Blockers on Diastolic Function in Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE trial is a multicenter, randomized, open-labeled, and assessor(s)-blinded, active controlled using candesartan, parallel-group clinical trial, to compare changes in left ventricular (LV) diastolic dysfunction between HFpEF patients with hypertension who have received candesartan or azilsartan for 48 weeks. The primary endpoint is the change in early diastolic wave height/early diastolic mitral annulus velocity (E/e’) assessed by echocardiography from the baseline to the end of the study (48 weeks). A total of 190 patients will be recruited into the study.

Conclusions

The design of the J-TASTE trial will provide data on whether differences between the effects of the two tested drugs on LV diastolic function exist in HFpEF patients with hypertension and will improve understanding of the pathophysiological role of vascular stiffness on diastolic function.

     

Immune thrombocytopenic purpura associated with rheumatoid arthritis: case report

A 54-year-old Japanese woman was diagnosed with rheumatoid arthritis (RA) in 1995 on the basis of symmetric effusive polyarthritis, morning stiffness, and strongly positive rheumatoid factor. She had received low-dose prednisolone, indomethacin, methotrexate (MTX), and cyclophosphamide (CPA), at least, over 4 years before the current admission and showed partial improvement of polyarthralgia. In November 2002, she suddenly developed thrombocytopenia (platelet count was 0.3×10⁴ mm^–3) with purpura and was diagnosed with immune thrombocytopenic purpura (ITP). As she had refractory ITP, the administration of pulsed high-dose dexamethasone (DEX) therapy was started, resulting in the complete remission of ITP. The present paper reports that pulsed high-dose DEX therapy was useful for the treatment of refractory ITP associated with RA.     

Glucosamine enhances platelet-derived growth factor-induced DNA synthesis via phosphatidylinositol 3-kinase pathway in rat aortic smooth muscle cells

Vascular smooth muscle cells play a key role in the development of atherosclerosis. Culture of vascular smooth muscle A10 cells with high glucose for 4 weeks enhanced platelet-derived growth factor (PDGF)-induced BrdU incorporation. Since a long period of high glucose incubation was required for the effect, and it was inhibited by co-incubation with azaserine, the role of hexosamine biosynthesis in the development of atherosclerosis in diabetes was studied in A10 cells. Addition of glucosamine to the culture media enhanced PDGF-stimulated BrdU incorporation, and PDGF-induced tyrosine phosphorylation of the PDGF beta-receptor was increased by glucosamine treatment. Of the subsequent intracellular signaling pathways, PDGF-induced PDGF beta-receptor association with PLC gamma was not affected, whereas tyrosine phosphorylation of Shc, subsequent association of Shc with Grb2, and MAP kinase activation were relatively decreased. In contrast, PDGF-induced PDGF beta-receptor association with the p85 regulatory subunit of PI3-kinase and PI3-kinase activation were increased by 20% (P<0.01) and 36% (P<0.01), respectively. The intracellular signaling molecules responsible for the glucosamine effect were further examined using pharmacological inhibitors. Pretreatment with PLC inhibitor (U73122) had negligible effects, and MEK1 inhibitor (PD98059) showed only a slight inhibitory effect on the PDGF-induced BrdU incorporation. In contrast, pretreatment with PI3-kinase inhibitor (LY294002) significantly inhibited glucosamine enhancement of PDGF-induced BrdU incorporation. These findings suggest that glucosamine is involved in the development of atherosclerosis by enhancing PDGF-induced mitogenesis specifically via the PI3-kinase pathway.     

Upfront autologous stem-cell transplantation with melphalan,cyclophosphamide, etoposide,and dexamethasone (LEED) in patients with newly diagnosed primary central nervous system lymphoma

Treatment of primary central nervous system lymphoma (PCNSL) improved in recent years. However, the high neurotoxicity and low survival rates associated with this condition remain unresolved. We report 13 consecutive patients with PCNSL for whom upfront melphalan, cyclophosphamide, etoposide, and dexamethasone (known as LEED) followed by autologous stem-cell transplantation (ASCT) was planned at the Anjo Kosei Hospital. All patients were pathologically diagnosed with diffuse large B-cell lymphoma and were negative for human immunodeficiency virus. All patients were to receive three cycles of high-dose methotrexate-based induction chemotherapy, two cycles of high-dose AraC-based chemotherapy, and LEED followed by ASCT. All 13 patients achieved a partial response, and the 3-year overall survival (OS) rate was 76.2 %. Seven of the 13 patients were alive at the last follow-up, without any adverse events, including neurotoxicity. Six of the 13 (46.2 %) patients underwent ASCT and the 3-year OS rate was 80.0 %. Although this study included only a limited number of patients, these preliminary signs of efficacy and tolerability merit further consideration. To make further improvements in survival, the rate of patients undergoing ASCT should be increased. Other prospective studies involving greater numbers of patients are required to confirm these findings.     

Isolated Cerebral Vasculitis in the Unilateral Middle Cerebral Artery in a Case with SLE

A 47-year-old woman, who was diagnosed to have systemic lupus erythematosus (SLE), was admitted because she suffered a severe ischemic stroke three weeks after experiencing a transient attack of aphasia. Diffusion-weighted MRI revealed high intensity at the borderzone of the middle cerebral artery (MCA), while the proximal portion of the left MCA was occluded with its vascular wall enhanced by gadolinium. Intravenous methylprednisolone and heparin were administrated without any symptomatic benefit. She developed severe right hemiparesis with aphasia. Isolated cerebral vasculitis in the large vessel has been rarely reported in SLE patients. The presence of an enhanced vascular wall in the MRI with gadolinium could support the diagnosis.     

New and better protocols for a short-term Caco-2 cell culture system

The aim of the present study was to develop new and better protocols for a short-term Caco-2 cell culture system for use in rapid screening of intestinal drug absorption. Caco-2 cells were cultured according to several protocols for short-term cell culture to obtain monolayers. The effects of serum (fetal bovine serum, FBS) in the culture medium and of the period of cell culture on the barrier function and transporter activities of the monolayers were examined. The barrier function was estimated both from the transepithelial electrical resistance (TEER) and the permeability of [(14)C]mannitol. Transporter activities were monitored by measuring the permeability of [(14)C]glycylsarcosine for oligopeptide transporter (PepT1) and of rhodamine 123 for P-glycoprotein (P-gp). Caco-2 monolayers obtained by 3-day culture in the BIOCOAT HTS Caco-2 Assay System, developed by Becton Dickinson Bioscience, showed much higher permeability to hydrophilic compounds, such as mannitol, compared with those obtained by the standard 21-day culture system, due to the leaky structure of cell junctions. The newly developed 3-day protocol, which includes 10% FBS in the culture medium during the first day of culture, markedly enhanced TEER and lowered mannitol permeability of the monolayers. This protocol allowed us to better determine the rank order of permeability of compounds, giving results equivalent to those in the 21-day culture system. The longer culture period gave tighter monolayers, and the maximum value of TEER was obtained with 5 days in culture. However, after 5 days in culture, the integrity of monolayers decreased gradually. The highest activities of transporters, PepT1 and P-gp, in monolayers were obtained at days 5 or 6 of culture by the new protocol with FBS-containing medium. These results indicate that by a simple modification of the short-term culture protocol, it is possible to obtain Caco-2 monolayers with better barrier properties and higher activity of transporters that are equivalent to those found in the 21-day Caco-2 culture system.     

A case of intrascrotal schwannoma

A 70-year-old male was admitted to our hospital with the chief complaint of a left intrascrotal mass. A painless, solid and elastic-hard mass was palpable in the left scrotum. The testis, epididymis and spermatic cord could not be palpated separately from the mass. Tumor resection was performed. The tumor was 13 x 7.5 x 3.0 cm in size and 285 g in weight. Histological diagnosis was schwannoma. To our knowledge, the case was considered as the sixth reported in Japan.     

A case of carcinosarcoma of the urinary bladder

We report a case of carcinosarcoma of the urinary bladder. A 68-year-old man visited our hospital with complaints of asymptomatic macroscopic hematuria, cold sweat and general malaise. Excretory urography revealed a filling defect in the left wall of the bladder, and subsequent cystoscopy revealed a non-papillary sessile tumor. The tumor was transurethrally resected and its histology showed carcinosarcoma which was characteristics of a mixture of transitional cell carcinoma with spindle cell sarcoma. The patient underwent total cystectomy and his bladder was reconstructed with the ileum. Nevertheless, he died of multiple organ metastases 3 months after the surgery.