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The trajectory of glomerular filtration rate (GFR) in relation to glomerular hyperfiltration (GHF) has been unknown. It was evaluated retrospectively in 23,982 GHF-free health examinees who were followed for 2−10 yr (mean: 5.1 yr). GFR was estimated by the serum creatinine concentration, and GHF was defined as age- and sex-specific estimated GFR (eGFR) ≥ 95% of the Japanese general population. The temporal profile of eGFR was plotted in a GHF-centered way, which was fitted to a random coefficient linear mixed model. Of the 23,982 subjects, 797 and 23,185 subjects developed or did not develop GHF, respectively, so that they were termed as the GHF(+)and GHF(−)groups. At baseline, median eGFR was significantly elevated in the GHF(+)group compared with in the GHF(−)group: 94.1 versus 77.3 mL/min/1.73 m2( P < 0.001). Elevation of basal eGFR lasted for a mean (SD) of 3.3 (1.9) yr in the GHF(+)group; mean eGFR then rose to the GHF range, which was 108.5 mL/min/1.73 m2. The eGFR decline after the peak was steeper in the GHF(+)group than in the GHF(−)group: −0.984 versus −0.497 mL/min/1.73 m2/yr ( P < 0.001). Baseline eGFR, but no other variable, well predicted incident GHF, with an area under the receiver operating characteristic curve of 0.87 (95% confidence interval: 0.86–0.88). In conclusion, GHF occurs as a chronic, multiphasic phenomenon: initially with a sustained GFR elevation for years, followed by a GFR surge to the GHF range, which was accompanied by accelerated GFR declining.

Aims To compare impact of elevated HbA1c and fasting plasma glucose (FPG) on incident chronic kidney disease (CKD) in a non-diabetic cohort. Methods Data from diabetes- and CKD-free 25,109 health examinees were retrospectively analysed with a mean observation period of 5.3 years. Prediabetes was diagnosed by the ADA and WHO criteria, and CKD by estimated glomerular filtration rate (eGFR) Results For incident CKD (n = 2483), high HbA1c but not FPG was an independent risk: adjusted hazard ratio (AHR, 95%CI) for HbA1c 1% and FPG 1 mmol/L, 1.91 (1.70–2.16) and 0.85 (0.60–1.20), respectively. Prediabetes by the ADA and WHO criteria were both risk for CKD with AHR (95%CI), 1.21 (1.12–1.32) and 1.31 (1.16–1.48), respectively. Prediabetes diagnosed by ‘elevated HbA1c irrespective of FPG’, either by the ADA and the WHO definition, was a risk with AHR (95%CI), 1.48 (1.36–1.61) and 1.51 (1.31–1.74), respectively. In contrast, prediabetes diagnosed by ‘raised FPG irrespective of HbA1c’ was not a CKD risk. Conclusions Elevated HbA1c, but not FPG, identified CKD risk in non-diabetic individuals.

A hypothesis that postchallenge hyperglycemia in subjects with low body weight (BW) may be due, in part, to small glucose volume (GV) was tested. We studied 11,411 nondiabetic subjects with a mean BW of 63.3 kg; 5,282 of them were followed for a mean of 5.3 yr. In another group of 1,537 nondiabetic subjects, insulin sensitivity, secretion, and a product of the two (index of whole body insulin action) were determined. Corrected 2 h-plasma glucose (2hPGcorr) during a 75-g oral glucose tolerance test in subjects with BW ≤ 59 kg was calculated as 2hPGcorr = δPG2h · ECW/[16.1 (males) or 15.3 (females)] + fasting PG (FPG), where δPG2h is plasma glucose increment in 2 h; ECW is extracellular water (surrogate of GV); FPG is fasting plasma glucose; and 16.1 and 15.3 are ECW of men and women, respectively, with BW = 59 kg. Multivariate analyses for BW with adjustment for age, sex, and percent body fat were undertaken. BW was, across its entire range, positively correlated with FPG ( P < 0.01). Whereas BW was correlated with 2hPG and δPG in a skewed J-shape, with inflections at around 60 kg ( P for nonlinearity < 0.01 for each). Nonetheless, in those with BW ≤ 59 kg, insulin sensitivity, secretion, and action were unattenuated, and incident diabetes was less compared with heavier counterparts. BW was linearly correlated with 2hPGcorr, i.e., the J-shape correlation was mitigated by the correction. In conclusion, postchallenge hyperglycemia in low BW subjects is in part due to small GV rather than impaired glucose metabolism.

Aim To clarify the natural course of prediabetes and develop predictive models for conversion to diabetes. Methods A retrospective longitudinal study of 2105 adults with prediabetes was carried out with a mean observation period of 4.7years. Models were developed using multivariate logistic regression analysis and verified by 10-fold cross-validation. The relationship between [final BMI minus baseline BMI] (δBMI) and incident diabetes was analyzed post hoc by comparing the diabetes conversion rate for low ( 2 ) and high δBMI (≥ −0.31kg/m 2 ) subjects after matching the two groups for the covariates. Results Diabetes developed in 252 (2.5%/year), and positive family history, male sex, higher systolic blood pressure, plasma glucose (fasting and 1h- and 2h-values during 75g OGTT), hemoglobin A1c (HbA1c) and alanine aminotransferase were significant, independent predictors for the conversion. By using a risk score (RS) that took account of all these variables, incident diabetes was predicted with an area under the ROC curve (95% CI) of 0.80 (0.70–0.87) and a specificity of prediction of 61.8% at 80% sensitivity. On division of the participants into high- ( n =248), intermediate- ( n =336) and low-risk ( n =1521) populations, the conversion rates were 40.1%, 18.5% and 5.9%, respectively. The conversion rate was lower in subjects with low than high δBMI (9.2% vs 14.4%, p =0.003). Conclusions Prediabetes conversion to diabetes could be predicted with accuracy, and weight reduction during the observation was associated with lowered conversion rate.

The quantitative impact of weight gain on prediabetic glucose dysregulation remains unknown; only one study quantitated the impact of weight loss. We quantified the impact of weight gain on the evolution and regression of prediabetes (PDM).In 4234 subjects without diabetes, using logistic regression analysis with a 4.8-year follow-up period, we analyzed the relationship between (1) δBMI (BMIMean (±s.d.) δBMI was 0.17 (±1.3) kg/mIn Japanese adults, an increase in the BMI by even 1 kg/m

To clarify if prediabetes defined by the International Expert Committee (PrediabetesIEC) and/or the American Diabetes Society (PrediabetesADA) is a risk for incident glomerular hyperfiltration (GH). 24,524 health examinees without diabetes, chronic kidney disease (CKD), GH and antihypertensive treatment at baseline, and repeated examinations at least twice during a mean of 5.3 years were retrospectively analysed. Diabetes was defined as fasting plasma glucose (FPG) ≥ 7.0 mmol/L and/or HbA1c ≥ 47 mmol/mol, CKD by estimated glomerular filtration rate (eGFR)

To develop diabetes risk score (RS) based on the current definition of diabetes, we retrospectively analyzed consecutive 4,159 health examinees who were non-diabetic at baseline. Diabetes, diagnosed by fasting plasma glucose (FPG) ≥7.0 mmol/L, 2hPG ≥11.1 mmol/L and/or HbA1c ≥6.5% (48 mmol/mol), developed in 279 of them during the mean period of 4.9 years. A full RS (RSFull), a RS without 2hPG (RS-2hPG) and a non-invasive RS (RSNI) were created on the basis of multivariate Cox proportional model by weighted grading based on hazard ratio in half the persons assigned. The RSs were verified in the remaining half of the participants. Positive family history (FH), male sex, smoking and higher age, systolic blood pressure (SBP), FPG, 2hPG and HbA1c were independent predictors for RSFull. For RS-2hPG, 7 independent predictors, exclusive of 2hPG and smoking but inclusive of elevated triglycerides (TG) comparing to RSFull, were selected. FH, male sex, and higher age, SBP and HbA1c were independent predictors in RSNI. In the validation cohort, C-statistic (95%CI) of RSFull, RS-2hPG and RSNI were 0.80 (0.76-0.84), 0.75 (0.70-0.78) and 0.68 (0.63-0.72), respectively, which were significantly different from each other (P

Risk profile for incident chronic kidney disease (CKD) in Japanese subjects has not been established. Our aim was to identify risk factors for CKD in Japanese.Consecutive 171 536 health examinees (median age 49 years and estimated glomerular filtration rate (eGFR) 78.2 mL/min per 1.73 mIn the Derivation cohort, CKD developed in 1002 (5.8%) subjects. Seven variables such as lower eGFR, male gender, higher uric acid concentration, lower red cell count and higher age and systolic blood pressure were identified as significant risks for CKD, with lowered eGFR being an overwhelmingly strong risk: adjusted hazard ratio for those with the baseline eGFR70 mL/min per 1.73 mSeven risk factors for incident CKD were identified in Japanese health examinees. However, lowered baseline eGFR outweighed other risks to the degree that eGFR alone was suffice for CKD prediction.

Advanced-phase chronic myeloid leukemia patients treated with imatinib often relapse due to point mutations in the Abl kinase domain. We herein examine the in vitro and in vivo effects of a Bcr-Abl/Lyn dual tyrosine kinase inhibitor, NS-187, on seven mutated Bcr-Abl proteins. NS-187 inhibited both Tyr393-phosphorylated and Tyr393-unphosphorylated Abl, resulting in significant in vitro growth inhibition of cells expressing six of seven mutated Bcr-Abl kinases, though not T315I. Furthermore, NS-187 prolonged the survival of mice injected with leukemic cells expressing all mutated Bcr-Abl tested except T315I, and its efficacy correlated well with its in vitro effects.

Although the Abelson (Abl) tyrosine kinase inhibitor imatinib mesylate has improved the treatment of breakpoint cluster region–Abl (Bcr-Abl)–positive leukemia, resistance is often reported in patients with advanced-stage disease. Although several Src inhibitors are more effective than imatinib and simultaneously inhibit Lyn, whose overexpression is associated with imatinib resistance, these inhibitors are less specific than imatinib. We have identified a specific dual Abl-Lyn inhibitor, NS-187 (elsewhere described as CNS-9), which is 25 to 55 times more potent than imatinib in vitro. NS-187 is also at least 10 times as effective as imatinib in suppressing the growth of Bcr-Abl–bearing tumors and markedly extends the survival of mice bearing such tumors. The inhibitory effect of NS-187 extends to 12 of 13 Bcr-Abl proteins with mutations in their kinase domain but not to T315I. NS-187 also inhibits Lyn without affecting the phosphorylation of Src, Blk, or Yes. These results suggest that NS-187 may be a potentially valuable novel agent to combat imatinib-resistant Philadelphia-positive (Ph+) leukemia.

NS-9 is a complex of polyinosinic-polycytidylic acid and a novel cationic liposome, LIC-101. The complex has strong cytotoxic activity against tumor cells derived from epithelial or fibroblastic cells. We have investigated the mechanism of the cytotoxic activity of NS-9 using knockdown cells in which the expression of proteins of interest was inhibited by RNA interference. NS-9 showed strong cytotoxic activity against knockdown cells with reduced expression of double-stranded RNA-dependent protein kinase, RNase L, or IFN-α/β receptor, but showed no cytotoxic activity against IFN regulatory factor-3 (IRF3) knockdown cells. In IRF3-knockdown cells, NS-9 also did not induce either the DNA fragmentation or the rRNA degradation observed in negative control cells. We conclude that IRF3 plays a crucial role in the cytotoxic activity of NS-9 against tumor cells, whereas RNA-dependent protein kinase, RNase L, or type I IFNs are not important for its activity.

Purpose: The RNA interference effect is an alternative to antisense DNA as an experimental method of down-regulating a specific target protein. Although the RNA interference effect, which is mediated by small interfering RNA (siRNA) or micro-RNA, has potential application to human therapy, the hydrodynamic method usually used for rapid administration of oligonucleotides is unsuitable for use in humans. In this study, we have investigated the antitumor activity of a synthetic siRNA, B717, which is sequence specific for the human bcl-2 oncogene, complexed with a novel cationic liposome, LIC-101. Experimental Design: In a mouse model of liver metastasis, we administered B717/LIC-101 by bolus intravenous injection, adjusting the rate and volume of administration to what is feasible in human therapy. In a mouse model bearing prostate cancer in which the cells were inoculated under the skin, B717/LIC-101 was administered subcutaneously around the tumor. Results: The B717/LIC-101 complex inhibited the expression of bcl-2 protein and the growth of tumor cell lines in vitro in a sequence-specific manner in the concentration range of 3 to 100 nmol/L. Furthermore, the complex had a strong antitumor activity when administered intravenously in the mouse model of liver metastasis. B717 (siRNA) was shown to be delivered to tumor cells in the mouse liver, but only when complexed with LIC-101. The complex also inhibited tumor cell growth in the mouse model bearing prostate cancer. Conclusions: By combining siRNA with our cationic liposome, we overcame the difficulty of administering siRNA to animals in ways that can be applied in human therapy. Although our siRNA/liposome complex is not yet in clinical trials, it is expected to provide a novel siRNA therapy for cancer patients.

Intestinal non-Hodgkin's lymphoma (NHL), especially the T-cell type, is well known to be associated with celiac disease (CD), an enteropathic disorder with a propensity for certain racial and genetic backgrounds. CD is typically characterized by gastrointestinal (GI) symptoms, anti-transglutaminase antibodies in the sera, and microscopical findings of the intestinal mucosa, which resolve with a gluten-free diet (GFD). In Asian populations, including the Japanese, CD and the associated NHL have been supposed to be quite rare, and studies concerning the frequency of CD or its relationship with NHL are scarce. We describe a Japanese middle-aged man with intestinal diffuse large B-cell lymphoma associated with CD. Following multi-combined chemotherapy, the patient's lymphoma has been in a state of complete response, and his GI symptoms have improved with a GFD. This case suggests that the possibility of CD and its association with intestinal NHL should be kept in mind, even in Asian populations.

Background & Aims The interferon (IFN) system plays a critical role in innate antiviral response. We presume that targeted induction of IFN in human liver shows robust antiviral effects on hepatitis C virus (HCV) and hepatitis B virus (HBV). Methods This study used chimeric mice harboring humanized livers and infected with HCV or HBV. This mouse model permitted simultaneous analysis of immune responses by human and mouse hepatocytes in the same liver and exploration of the mechanism of antiviral effect against these viruses. Targeted expression of IFN was induced by treating the animals with a complex comprising a hepatotropic cationic liposome and a synthetic double-stranded RNA analog, pIC (LIC-pIC). Viral replication, IFN gene expression, IFN protein production, and IFN antiviral activity were analyzed (for type I, II and III IFNs) in the livers and sera of these humanized chimeric mice. Results Following treatment with LIC-pIC, the humanized livers of chimeric mice exhibited increased expression (at the mRNA and protein level) of human IFN-λs, resulting in strong antiviral effect on HBV and HCV. Similar increases were not seen for human IFN-α or IFN-β in these animals. Strong induction of IFN-λs by LIC-pIC occurred only in human hepatocytes, and not in mouse hepatocytes nor in human cell lines derived from other (non-hepatic) tissues. LIC-pIC-induced IFN-λ production was mediated by the immune sensor adaptor molecules mitochondrial antiviral signaling protein (MAVS) and Toll/IL-1R domain-containing adaptor molecule-1 (TICAM-1), suggesting dual recognition of LIC-pIC by both sensor adaptor pathways. Conclusions These findings demonstrate that the expression and function of various IFNs differ depending on the animal species and tissues under investigation. Chimeric mice harboring humanized livers demonstrate that IFN-λs play an important role in the defense against human hepatic virus infection.

We report two patients with diffuse large B-cell lymphoma with isolated oculomotor nerve palsy. This was the initial manifestation of lymphoma in one patient but in a second, the palsy appeared as a part of a generalized recurrence of lymphoma. In addition, we reviewed the clinical findings of 12 previously reported patients. Isolated oculomotor nerve palsy was most frequently associated with the large B-cell lymphoma cell type, and was not frequently associated with periorbital pain. The pupil was spared in half the patients irrespective of infiltration of the oculomotor nerve. MRI and cerebrospinal fluid cytological examinations are helpful in determining invasion of lymphoma to the oculomotor nerve, cavernous sinus, and surrounding leptomeninges.

A 48-year-old woman with Caroli's disease accompanied by hepatolithiasis, choledocholithiasis, and cholangiocarcinoma is reported. Magnetic resonance imaging was useful for the diagnosis of the cholangiocarcinoma. The relationship between cholangiocarcinoma and hepatolithiasis, choledocholithiasis, and chronic cholangitis in Caroli's disease is discussed.