TORU AIZAWA, MD 4OBJECTIVE -The goal of this study was to know the fate of albuminuria in Japanese patients with type 2 diabetes under tight blood pressure and glycemic control.RESEARCH DESIGN AND METHODS -Patients having normoalbuminuria (urinary albumin excretion Ͻ30 mg/g creatinine, n ϭ 179) or microalbuminuria (albumin excretion 30 -299 mg/g creatinine, n ϭ 94) at baseline have been followed up for 8 years: ratio of men to women was 160/113, the mean age was 58 years, pretreatment HbA 1c (A1C) was 8.8%, and blood pressure was 136/76 mmHg. A1C Ͻ6.5% and blood pressure Ͻ130/80 mmHg were targeted, and the A1C of 6.5 Ϯ 0.7% (mean Ϯ SD) and blood pressure of 127 Ϯ 11/72 Ϯ 6 mmHg have been maintained during the 8 years. Development of microalbuminuria or macroalbuminuria (albumin excretion Ն300 mg/g creatinine) in initially normoalbuminuric patients and progression to macroalbuminuria or regression to normoalbuminuria in initially microalbuminuric patients were assessed at year 8.RESULTS -Development occurred in 27 (15%) of the normoalbuminuric patients and progression and regression in 16 (17%) and 20 (21%), respectively, of the microalbuminuric patients. Significant independent relationships existed between development and higher achieved mean systolic blood pressure (SBP) and regression and lower achieved mean SBP. In the patients with achieved mean SBP Ͻ120 mmHg, development was 3%, progression was 11%, and regression was 44% during 8 years. Prediction for nephropathy by blood pressure and glycemia alone was limited. Nevertheless, albumin excretion at year 8 was positively correlated with achieved mean SBP and baseline albuminuria.CONCLUSIONS -Development and progression were low and regression was high with SBP of 120 mmHg, provided A1C was maintained at 6.5%. Diabetes Care 28:2733-2738, 2005D iabetic nephropathy is now the leading cause of end-stage renal failure in Europe, the U.S., and Japan (1), and the establishment of an effective treatment strategy for diabetic nephropathy is of paramount importance. In particular, early intervention is hoped to bring about 1) the prevention of new development of nephropathy, 2) the prevention of progression of early-phase nephropathy, and 3) the regression of existing nephropathy (1-3). Urinary albumin excretion (UAE) is a marker of earlyphase diabetic nephropathy (1-3), and the amount of UAE correlates with renal pathologic changes in both type 1 and type 2 diabetes (4). Accordingly, many studies have been performed with UAE as a marker of diabetic nephropathy (5-7). The development and progression of nephropathy were improved by glycemic and blood pressure controls as expected (5-8). Antihypertensive therapy and improved glycemic control were independent predictors of the regression from micro-to normoalbuminuria (8). In this study, we analyzed the fate of early-phase diabetic nephropathy as indexed by the change in UAE in Japanese patients with type 2 diabetes over an 8-year period. In particular, the relationship between blood pressure and the state of albuminuria...

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Resistance of cancer cells to chemotherapy is a serious problem for cancer treatment. Such resistance may develop during drug treatment or may be an inherent feature of a particular tumor type. The 170 kDa multidrug resistance 1 (MDR1) P-glycoprotein was the first human ATP-binding cassette (ABC) transporter to be identified and has the ability to mediate multidrug resistance in cancer cells. Multidrug resistance-associated proteins (MRP) including MRP1 and 2 are also involved in multidrug resistance in cancer chemotherapy. These proteins act as ATP-dependent molecular pumps that extrude a number of anticancer drugs from the cells, which results in decreases in their intracellular concentrations. [1][2][3][4] MRP1 was identified in the non-P-glycoprotein multidrugresistant small cell lung cancer cell line H69 after stepwise exposure to doxorubicin. 5,6) MRP1 shows relatively ubiquitous expression, whereas MRP2, which was initially identified as a canalicular organic anion transporter, is restricted mainly to the renal, intestinal and hepatic epithelia. Since there is extensive overlapping of the tissue distributions of Pglycoprotein and MRP2, it is likely that these two proteins play cooperative roles in pharmacological and toxicological protective functions, by mediating the efflux of different (but partially overlapping) sets of substrates. 7,8) P-glycoprotein extrudes large hydrophobic molecules that are uncharged or positively charged, while the members of the MRP family tend to pump out both hydrophobic uncharged molecules and water-soluble anionic compounds. The lung resistance protein (LRP), which is the major component of complex ribonucleoprotein particles called "vaults," was detected in a non-P-glycoprotein lung cancer cell line. 9) Like P-glycoprotein and MRP, LRP expression by tumor cell lines is believed to be associated with resistance to various anticancer drugs, 10) though the molecular function of LRP remains to be fully elucidated.Retinoblastomas are a rare intraocular malignancy occurring in early childhood. They occur in 1 in 15000 to 20000 live births irrespective of ethnicity or gender. The management of retinoblastomas is complex and includes enucleation and non-enucleation (conservative) techniques. 11) Retinoblastomas have traditionally been treated by enucleation of the affected eye and/or a combination of radiation therapy, cryotherapy or focal laser therapy. 11) Though external beam radiotherapy has been a standard treatment for retinoblastomas, it increases the risk of cosmetic deformities and secondary malignant tumors in the field of irradiation. Currently, the most popular conservative technique is primary systemic chemotherapy, which is also called chemoreduction. 12) Chan et al. 13) reported that increased expression of P-glycoprotein was detected in multidrug-resistant retinoblastoma cell lines as well as in the tumors from which the cell lines were derived, while drug-sensitive retinoblastoma cell lines were negative for P-glycoprotein staining. Subsequently, clinical studies...

The quantitative relationship between deleted mitochondrial DNA and the clinical course of patients with Kearns-Sayre syndrome is poorly understood. We investigated this point using tissue samples obtained at age 10 years when the patient was diagnosed as Kearns-Sayre syndrome and at age 20 years when he died of disseminated intravascular coagulation. By long polymerase chain reaction, a shortened mitochondrial genome (8.8 kb; normal, 16.6 kb) was detected in the patient. By quantitative competitive polymerase chain reaction, the percentage of deletion-carrying mitochondrial DNA was not increased as expected and did not differ significantly by tissue type or sampling time or correlate with clinical course. Although we could not demonstrate that the amounts of wild-type mitochondrial DNA decreased with accelerating progression, it was emphasized that such a reduction of mitochondrial DNA in various tissues, including those of the central nervous system, could play a significant pathogenetic role, since only wild-type mitochondrial DNA is functional in patients with large-scale deletions of mitochondrial DNA.

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Xeroderma pigmentosum is an autosomal recessive disease characterized by extreme sensitivity of the skin to ultraviolet light, which results in a high incidence of early skin cancer. We report here the molecular analysis of the xeroderma pigmentosum group A complementing genes of five Japanese patients with group A xeroderma pigmentosum and their families, by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis, and by PCR and non-radioactive single strand conformation polymorphism (SSCP) analysis using the Pharmacia PhastSystem. Four of the five patients were found to be homozygous for a known splicing mutation of intron 3. One patient was found to be heterozygous for the splicing mutation of intron 3 and a known nonsense mutation of exon 6. This nonradioactive PCR-SSCP technique was as useful for the molecular diagnosis of patients with group A xeroderma pigmentosum as was PCR-RFLP analysis.