An oral adsorbent, AST-120, combined with a low-protein diet and RAS blocker, for chronic kidney disease

BACKGROUND: A low-protein diet and treatment with renin-angiotensin system (RAS) blockers can delay the progression of chronic kidney disease (CKD). The oral adsorbent AST-120 (Kremezin) has a renoprotective effect by reducing serum levels of uremic toxins. We investigated the influence of AST-120 on the preservation of renal function in patients with CKD. METHODS: Twenty-eight patients were randomized to 2 groups: 15 patients receiving 6.0 g of AST-120 daily for 12 months plus a low-protein diet and RAS blocker therapy (group A) and 13 patients who were not given AST-120 (group B). All of them had shown progressive deterioration of renal function with basal treatment. Mean baseline serum creatinine level (+/- standard deviation) was 2.4 +/- 0.8 mg/dL in group A and 2.7 +/- 0.8 mg/dL in group B. There were no significant differences in background parameters before AST-120 therapy. RESULTS: The change in the estimated glomerular filtration rate (eGFR) was significantly smaller in group A than in group B. The change was also significantly smaller in patients with a baseline serum creatinine <2.4 mg/dL and in patients with rapid progression. After 12 months, the slope of the eGFR curve was significantly less steep compared with baseline in group A (-1.77 vs. -0.52 ml/min per month), but there was no significant change in group B. The slope was also significantly less steep in patients with rapid progression. CONCLUSIONS: Adding AST-120 to a low-protein diet and RAS blocker therapy may delay the deterioration of chronic renal failure, especially in patients with early or rapid progression.     

Fibronectin/integrin system is involved in P2X(4) receptor upregulation in the spinal cord and neuropathic pain after nerve injury

We have previously shown that activation of the ATP-gated ion channel subtype P2X(4) receptors (P2X(4)Rs) in the spinal cord, the expression of which is upregulated in microglia after nerve injury, is necessary for producing neuropathic pain. The upregulation of P2X(4)Rs in microglia is, therefore, a key process in neuropathic pain, but the mechanism remains unknown. Here, we find a fibronectin/integrin-dependent mechanism in the upregulation of P2X(4)Rs. Microglia cultured on dishes coated with fibronectin, an extracellular matrix molecule, expressed a higher level of P2X(4)R protein when compared with those cultured on control dishes. The increase was suppressed by echistatin, a peptide that selectively blocks beta(1) and beta(3)-containing integrins, and with a function-blocking antibody of beta(1) integrin. In in vivo studies, the upregulation of P2X(4)Rs in the spinal cord after spinal nerve injury was significantly suppressed by intrathecal administration of echistatin. Tactile allodynia in response to nerve injury and intrathecal administration of ATP- and fibronectin-stimulated microglia was inhibited by echistatin. Furthermore, intrathecal administration of fibronectin in normal rats increased the level of P2X(4)R protein in the spinal cord and produced tactile allodynia. Moreover, the fibronectin-induced allodynia was not observed in mice lacking P2X(4)R. Taken together with the results of our previous study showing an increase in the spinal fibronectin level after nerve injury, the present results suggest that the fibronectin/integrin system participates in the upregulation of P2X(4)R expression after nerve injury and subsequent neuropathic pain.     

Diabetic retinopathy and coronary artery disease from the cardiac surgeon's perspective

Coronary artery disease is the leading cause of death in diabetics; therefore, the main purpose of managing coronary artery disease in diabetics should be to lengthen life expectancy. Recent evidence demonstrates that the severity of diabetic retinopathy is associated with a graded, increased risk of death from coronary artery disease and myocardial infarction. Recently, we found that the survival benefit of coronary artery bypass grafting over percutaneous coronary intervention is more apparent in patients with diabetic retinopathy than in diabetic patients without it. In this article, we review published studies evaluating the association between diabetic retinopathy and coronary artery disease, and we propose that coronary artery bypass surgery should be the first choice for revascularization of patients with diabetic retinopathy, especially in its early stage. Furthermore, coronary artery disease complicating diabetic retinopathy is often underdiagnosed, and all diabetic retinopathy patients should undergo screening for coronary artery disease followed by coronary artery bypass grafting. Future studies will probably comprise carefully performed cost-effective analyses of treatment effectiveness and prospective randomized studies comparing survival after coronary artery bypass grafting with that of survival after percutaneous coronary intervention, stratified by the stage of retinopathy.     

Vacuum-assisted closure for pediatric post-sternotomy mediastinitis: are low negative pressures sufficient?

We present 3 cases of pediatric post-sternotomy mediastinitis treated by a vacuum-assisted closure (VAC). The patients 2 girls, aged 6 months and 10 months, and a 2-year-old boy. The onset of infection was at 9, 14, and 32 postoperative days. The culture examination detected coagulase-negative Staphylococci strains in 2 cases, and Staphylococcus aureus in 1 case. A VAC was performed at -50 mm Hg for 10, 12, and 7 days. The wounds were closed without vascularized soft tissue. A VAC under a low negative pressure is a useful and safe procedure for the management of pediatric post-sternotomy mediastinitis.     

JAK2-V617F mutation analysis of granulocytes and platelets from patients with chronic myeloproliferative disorders: advantage of studying platelets

There have been conflicting reports over the JAK2-V617F mutation status of platelets in chronic myeloproliferative diseases (CMPDs). The aim of this study was to analyse JAK2-V617F status, not only in granulocytes but also in platelets. The JAK2-V617F mutation was analysed in both granulocytes and platelets in 115 patients with CMPDs using direct sequencing. JAK2-V617F was detected in granulocytes from 71 of those patients, all 71 of whom also had platelet JAK2-V617F expression. The remaining 44 patients showed negative JAK2-V617F expression on granulocytes, but positive JAK2-V617F expression was detected on the platelets from nine of the 33 essential thrombocythaemia (ET) patients, one of the eight polycythaemia vera patients, and two of the three primary myelofibrosis patients. When ET patients were divided into three groups according to granulocyte and platelet JAK2-V617F status (both-positive, platelets-only positive and both-negative), the both-positive and platelets-only positive groups shared the clinical features of higher white blood cell count and frequent thrombosis. These results suggest that analysis of platelets is a more sensitive approach for detecting JAK2-V617F in CMPD patients than analysis of granulocytes. They also suggest that previous reports of the incidence of JAK2-V617F in CMPD patients, obtained using only analysis of granulocytes, could be underestimations.     

Sonodynamic therapy of cancer using a novel porphyrin derivative, DCPH-P-Na(I), which is devoid of photosensitivity

To improve the efficacy of sonodynamic therapy of cancer using photosensitizers, we developed a novel porphyrin derivative designated DCPH-P-Na(I) and investigated its photochemical characteristics and sonotoxicity on tumor cells. DCPH-P-Na(I) exhibited a minimum fluorescent emission by excitation with light, compared with a strong emission from ATX-70, which is known to reveal both photo- and sonotoxicity. According to this observation, when human tumor cells were exposed to light in the presence of DCPH-P-Na(I) in vitro, the least phototoxicity was observed, in contrast to the strong phototoxicity of ATX-70. However, DCPH-P-Na(I) exhibited a potent sonotoxicity on tumor cells by irradiation with ultrasound in vitro. This sonotoxicity was reduced by the addition of L-histidine, but not D-mannitol, thus suggesting that singlet oxygen may be responsible for the sonotoxicity of DCPH-P-Na(I). DCPH-P-Na(I) demonstrated significant sonotoxicity against a variety of cancer cell lines derived from different tissues. In addition, in a mouse xenograft model, a potent growth inhibition of the tumor was observed using sonication after the administration of DCPH-P-Na(I) to the mouse. These results suggest that sonodynamic therapy with DCPH-P-Na(I) may therefore be a useful clinical treatment for cancers located deep in the human body without inducing skin sensitivity, which tends to be a major side-effect of photosensitizers.     

Soy-derived isoflavones inhibit the growth of adult T-cell leukemia cells in vitro and in vivo

Adult T-cell leukemia occurs in human T-lymphotropic virus type I-infected individuals and is endemic to the south-western area of Kyushu in Japan. In this communication, we examined the effect of soy isoflavones on the growth of adult T-cell leukemia cells in vitro and in vivo . In the in vitro study, daidzein and genistein but not glycitein significantly inhibited the proliferation of ED-40515 and Hut102 cells in a dose-dependent manner. Among the isoflavones studied, genistein had the highest growth-inhibitory effect; however, genistein did not exert an apparent growth-inhibitory effect on Jurkat and Molt-4 cells, which were non-adult T-cell leukemia cells. Genistein prevented the G₁/S or G₂/M transition at 3 and 10 or 30 µM, respectively. Genistein upregulated p21 protein expression together with p53 accumulation. In addition, treatment with 30 µM genistein strongly induced phosphorylation of checkpoint kinase (CHK) 2 and p53 at serines 15, 20 and 37. Caffeine, an inhibitor of ataxia-telangiectasia mutated protein kinase, alleviated the genistein-induced p53 and CHK2 phosphorylation, suggesting the involvement of DNA damage at 30 µM. However, marked phosphorylation of CHK2 and p53 could not be detected at 3 and 10 µM genistein. These data indicate that genistein has biphasic growth-inhibitory properties. The in vivo studies demonstrated that soy-derived isoflavones significantly inhibit ED-40515 cell growth and infiltration into various organs in non-obese diabetic severe combined-immunodeficiency common γ-chain knockout mice. Taken together, it is evident that soy isoflavones might serve as a promising compound for the treatment of adult T-cell leukemia. ( Cancer Sci 2007; 98: 1740–1746)     

Chemically synthesized sugar-cholestanols possess a preferential anticancer activity involving promising therapeutic potential against human esophageal cancer

The understanding of the cell signaling pathways and the molecular events leading to cell death of cancer cells will provide in-depth perspective into the identification and development of potent anticancer agents. A balance between cell proliferation and cell death has been raised as a rational target for the management of malignant tumors. In the present study, the authors demonstrated that chemically synthesized sugar-cholestanols consisting of GlcNAcbeta-, Galbeta- and GlcNAcbeta1,3Galbeta-cholestanols exerted a strong inhibiting activity against cell proliferation of esophageal cancer cells, but cholestanol itself did not show such an activity against the same cancer cells at all. In addition to their predominant role as an antiproliferation agent, evidence based on the molecular analyses suggested that sugar-cholestanols played a regulatory role in multiple signal transduction pathways inducing apoptosis through both the death signal-extrinsic and the mitochondria-intrinsic pathways. Sugar-cholestanols seemed to be more susceptible to esophageal cancer cells than to non-cancerous esophageal cells at the very early event of their exposure and, further, to suppress specifically the expression of vascular endothelial growth factor. Taken together, these novel functions of sugar-cholestanols indicate that they could have promising therapeutic potential against human esophageal cancer.