Water scarcity hotspots travel downstream due to human interventions in the 20th and 21st century.

Water scarcity is rapidly increasing in many regions. In a novel, multi-model assessment, we examine how human interventions (HI: land use and land cover change, man-made reservoirs and human water use) affected monthly river water availability and water scarcity over the period 1971-2010. Here we show that HI drastically change the critical dimensions of water scarcity, aggravating water scarcity for 8.8% (7.4-16.5%) of the global population but alleviating it for another 8.3% (6.4-15.8%). Positive impacts of HI mostly occur upstream, whereas HI aggravate water scarcity downstream; HI cause water scarcity to travel downstream. Attribution of water scarcity changes to HI components is complex and varies among the hydrological models. Seasonal variation in impacts and dominant HI components is also substantial. A thorough consideration of the spatially and temporally varying interactions among HI components and of uncertainties is therefore crucial for the success of water scarcity adaptation by HI.

Double-blind, placebo-controlled pilot trial of anthocyanin-rich purple sweet potato beverage on serum hepatic biomarker levels in healthy Caucasians with borderline hepatitis.

The objective is to evaluate the efficacy of anthocyanin-rich purple-fleshed sweet potato (PSP) beverage on the serum levels of gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in healthy Caucasians with borderline hepatitis. Forty healthy Caucasians (41-69 years) consumed three bottles of the PSP beverage (177 mg anthocyanins per 125-ml bottle) or placebo (1.3 mg) per day for 8 weeks. Thirty-nine subjects completed the study and two subjects were excluded from statistical analysis. GGT levels in the PSP group on days 15 and 43 were lower (P=0.077 and 0.038, respectively), AST levels in the PSP group on days 29 and 43 were lower (P=0.010 and 0.045, respectively) and ALT level in the PSP group on day 43 was lower (P=0.037) than in the placebo group. The PSP beverage did not induce clinically relevant changes in other blood and clinical chemistry parameters.

Cytomegalovirus infection after prophylactic valganciclovir therapy post-kidney transplantation: case reports.

This report describes three patients who developed cytomegalovirus infection 4 months after high-risk donor+/recipient-(D+/R-) kidney transplantation, despite treatment with valgancyclovir (VGCV) for 3 months at low dose (450 mg/d).

Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis.

Ras guanyl nucleotide-releasing proteins (RasGRPs) are activators of Ras. Previous studies have indicated the possible involvement of RasGRP1 and RasGRP4 in leukemogenesis. Here, the predominant role of RasGRP1 in T-cell leukemogenesis is clarified. Notably, increased expression of RasGRP1, but not RasGRP4, was frequently observed in human T-cell malignancies. In a mouse bone marrow transplantation model, RasGRP1 exclusively induced T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) after a shorter latency when compared with RasGRP4. Accordingly, Ba/F3 cells transduced with RasGRP1 survived longer under growth factor withdrawal or phorbol ester stimulation than those transduced with RasGRP4, presumably due to the efficient activation of Ras. Intriguingly, NOTCH1 mutations resulting in a gain of function were found in 77% of the RasGRP1-mediated mouse T-ALL samples. In addition, gain-of-function NOTCH1 mutation was found in human T-cell malignancy with elevated expression of RasGRP1. Importantly, RasGRP1 and NOTCH1 signaling cooperated in the progression of T-ALL in the murine model. The leukemogenic advantage of RasGRP1 over RasGRP4 was attenuated by the disruption of a protein kinase C phosphorylation site (RasGRP1(Thr184)) not present on RasGRP4. In conclusion, cooperation between aberrant expression of RasGRP1, a strong activator of Ras, and secondary gain-of-function mutations of NOTCH1 have an important role in T-cell leukemogenesis.

Expression of ADAMTS4 in Ewing's sarcoma.

Ewing's sarcoma (EWS) is a malignant bone tumor that frequently occurs in teenagers. Genetic mutations which cause EWS have been investigated, and the most frequent one proved to be a fusion gene between EWS gene of chromosome 22 and the FLI1 gene of chromosome 11. However, a limited numbers of useful biological markers for diagnosis of EWS are available. In this study, we identified ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs) as a possible tumor marker for EWS using the retrovirus-mediated signal sequence trap method. ADAMTS4 is a secreted protein of 837 amino acids with a predicted molecular mass of 98-100 kDa. It is a member of metalloprotease family, is expressed mainly in cartilage and brain, and regulates the degradation of aggrecans. ADAMTS4 has been suggested to be involved in arthritic diseases and gliomas. Herein, we show that ADAMTS4 mRNA was expressed in all primary EWS samples and all EWS-derived cell lines examined, while its expression was detected only in small subpopulations of other solid tumors. Furthermore, ADAMTS4 expression was found to be regulated by EWS-FLI1 fusion gene-dependent manner. We also demonstrated that ADAMTS4 protein was highly expressed in tumor samples of the patients with EWS by using immunohistochemistry. These results suggest that ADAMTS4 is a novel tumor marker for EWS.

AID-induced T-lymphoma or B-leukemia/lymphoma in a mouse BMT model.

Activation-induced cytidine deaminase (AID) diversifies immunoglobulin through somatic hypermutation (SHM) and class-switch recombination (CSR). AID-transgenic mice develop T-lymphoma, indicating that constitutive expression of AID leads to tumorigenesis. Here, we transplanted mouse bone marrow cells transduced with AID. Twenty-four of the 32 recipient mice developed T-lymphoma 2-4 months after the transplantation. Surprisingly, unlike AID-transgenic mice, seven recipients developed B-leukemia/lymphoma with longer latencies. None of the mice suffered from myeloid leukemia. When we used nude mice as recipients, they developed only B-leukemia/lymphoma, presumably due to lack of thymus. Analysis of AID mutants suggested that an intact form with SHM activity is required for maximum ability of AID to induce lymphoma. Except for a K-ras active mutant in one case, specific mutations could not be identified in T-lymphoma; however, Notch1 was constitutively activated in most cases. Importantly, truncations of Ebf1 or Pax5 were observed in B-leukemia/lymphoma. In conclusion, this is the first report on the potential of AID overexpression to promote B-cell lymphomagenesis in a mouse model. Aberrant expression of AID in bone marrow cells induced leukemia/lymphoma in a cell-lineage-dependent manner, mainly through its function as a mutator.

Evaluation of miniY-STR multiplex PCR systems for extended 16 Y-STR loci.

We developed three short amplicon Y-chromosomal short tandem repeat (miniY-STR) polymerase chain reaction multiplex systems for 16 Y-STR loci (DYS441, DYS446, DYS462, DYS481, DYS485, DYS495, DYS505, DYS510, DYS511, DYS549, DYS 575, DYS578, DYS593, DYS618, DYS638, and DYS643), using newly designed primer sets. In an assay of 238 Japanese males using the three miniY-STR systems, amplification product lengths ranged from 91 to 151 bp for all 16 Y-STR loci. We identified 212 different haplotypes among the 238 individuals, finding haplotype diversity and discrimination capacity of 0.9974 and 0.8908, respectively. An assay of degraded DNA samples using the three miniY-STR multiplex systems, including artificially degraded samples and degraded forensic casework samples, proved remarkably effective. In conclusion, analyses of miniY-STR multiplex systems will play an important role in forensic applications involving degraded DNA samples for which genotyping using only commercial kits is ill-suited.

Identification of TSC-22 as a potential tumor suppressor that is upregulated by Flt3-D835V but not Flt3-ITD.

Transforming growth factor-beta (TGF-beta)-stimulated clone-22 (TSC-22) was originally isolated as a TGF-beta-inducible gene. In this study, we identified TSC-22 as a potential leukemia suppressor. Two types of FMS-like tyrosine kinase-3 (Flt3) mutations are frequently found in acute myeloid leukemia: Flt3-ITD harboring an internal tandem duplication in the juxtamembrane domain associated with poor prognosis and Flt3-TKD harboring a point mutation in the kinase domain. Comparison of gene expression profiles between Flt3-ITD- and Flt3-TKD-transduced Ba/F3 cells revealed that constitutive activation of Flt3 by Flt3-TKD, but not Flt3-ITD, upregulated the expression of TSC-22. Importantly, treatment with an Flt3 inhibitor PKC412 or an Flt3 small interfering RNA decreased the expression level of TSC-22 in Flt3-TKD-transduced cells. Forced expression of TSC-22 suppressed the growth and accelerated the differentiation of several leukemia cell lines into monocytes, in particular, in combination with differentiation-inducing reagents. On the other hand, a dominant-negative form of TSC-22 accelerated the growth of Flt3-TKD-transduced 32Dcl.3 cells. Collectively, these results suggest that TSC-22 is a possible target of leukemia therapy.

Serum matrix metalloproteinase-3 levels correlate with disease activity in relapsing-remitting multiple sclerosis.

BACKGROUND: Adhesion molecules and matrix metalloproteinases (MMPs) are known to be relevant to the ongoing development and disappearance of areas of demyelination in the white matter of the CNS of multiple sclerosis (MS) patients. This study examined whether serum matrix metalloproteinase-3 (MMP-3) levels correlate with disease activity in MS. METHODS: Serum MMP-3 levels in 47 consecutive patients with relapsing-remitting MS were measured by immunoassay every 4 weeks over a 15 month period. RESULTS: During the study period, 48 clinical relapses occurred. Serum MMP-3 levels within 1 month of relapse were significantly higher than during the remission phase. Sequential analysis showed that serum MMP-3 levels had increased transiently at the time of clinical relapse but returned to the normal range within a month. CONCLUSIONS: Circulatory MMP-3 levels are correlated with disease activity in relapsing-remitting MS. This may contribute to the breakdown of the blood-brain barrier at the time of relapse.

Virtual water trade and world water resources.

Global virtual water trade was quantitatively estimated and evaluated. The basic idea of how to estimate unit requirement of water resources to produce each commodity is introduced and values for major agricultural and stock products are presented. The concept of virtual water and the quantitative estimates can help in assessing a more realistic water scarcity index in each country, projecting future water demand for food supply, increasing public awareness on water, and identifying the processes wasting water in the production. Really required water in exporting countries is generally smaller than virtually required water in importing countries, reflecting the comparative advantage of water use efficiency, and it is estimated to be 680 km3/y for 2000. On the contrary the virtually required water for the same year is estimated to be 1,130 km3/y, and the difference of 450 km3/y is virtually saved by global trade. However, solely virtual water should not be used for any decision making since the idea of virtual water implies only the usage and influence of water and no concerns on social, cultural, and environmental implications. Virtual water trade also does not consider other limiting factors than water.

Ethanol production from starch by immobilized Aspergillus awamori and Saccharomyces pastorianus using cellulose carriers.

A simultaneous saccharification and fermentation (SSF) process was investigated to produce ethanol using two kinds of cellulose carriers that were respectively suitable for immobilization of Aspergillus awamori and Saccharomyces pastorianus. The maximum ethanol concentration attained by the batch operation was 25.5 g l(-1). Under suitable conditions, both cellulose carriers with immobilized cells could be reused efficiently for three cycles. The total amount of ethanol production was 66.0 g (per 1 l working volume) after the repeated operation. Ethanol productivity mainly depends on a saccharification process. There is a limit in durability in the repeated batch operation, and it is important to maintain high activity of the fungus in order to produce ethanol efficiently.

Effects of angiotensin II type 1 receptor antagonist (candesartan) in preventing fatal ventricular arrhythmias in dogs during acute myocardial ischemia and reperfusion.

Fatal arrhythmias may be prevented by long-term oral administration of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 (AT 1 ) receptor antagonists. However, there have been no studies evaluating the electrophysiologic changes that occur with the acute administration of AT 1 receptor antagonists during acute myocardial ischemia and reperfusion. This study aimed to evaluate the ability of candesartan to prevent fatal arrhythmias during acute myocardial ischemia and reperfusion. The left anterior descending (LAD) coronary artery was ligated for 10 min and then reperfused for 10 min in 45 adult mongrel dogs. Candesartan (1 mg/kg) or saline was administered intravenously 10 min before ligation of the LAD coronary artery (candesartan group [n = 20] and control group [n = 25], respectively). Changes in ventricular effective refractory period (ERP) and intramyocardial conduction time (ICT) in the risk area were compared during LAD occlusion and reperfusion. Ischemia-induced shortening of ERP was inhibited in the candesartan group compared with the control. There was a 4.7 +/- 5.8% increase in ERP in the candesartan group, compared with a 11.5 +/- 6.3% shortening in the control group (p < 0.01). Prolongation of ICT was inhibited in the candesartan group compared with the control group during both ischemia and reperfusion (maximal prolongation of ICT: 0.1 +/- 3.0% vs. 37.7 +/- 9.6%, respectively; p < 0.01). Incidence of ventricular fibrillation was lower in the candesartan group than in the control group (25% [5/20] vs. 72% [18/25], respectively; p < 0.01). Candesartan suppresses changes in ERP and ICT during acute myocardial ischemia and reperfusion, suggesting that candesartan can prevent the development of fatal arrhythmias.

Acute lethal injury of lung and liver in mice transplanted with ex vivo-expanded CTLs.

Clinical application of cytotoxic T lymphocytes (CTL) induced in vitro is extensively used for the treatment of viral infection and malignant diseases. We produced anti H-2d CTL in vitro from C57BL/6 (B6) splenocytes presensitized with (B6 x DBA/2) F1 (BDF1) splenocytes to establish a model system of CTL therapy. The specificity and cytotoxic activity were high enough (E/T ratio 1:1 = 38.8%) to induce graft versus host reaction. Though the total number of B6 splenocytes decreased by 0.27 during the 4 days of culture, the number of CD8+ lymphocytes increased 1.3-fold. When more than 5 x 10(6) cells of H-2d-reactive CTL were transplanted into BDF1 mice, mice died within 2 days postinduction. This lethal effect was not seen in the mice induced with ConA-stimulated T cells. Histological examination of the lungs and liver revealed massive infiltration of neutrophils in alveoli and the necrosis of hepatocytes. Therefore, this protocol was shown to be effective to produce alloantigen-specific CTLs and applicable to in vitro manipulation such as retrovirus-mediated gene transfer.

Altered expression of HES-1, BETA2/NeuroD, and PDX-1 is involved in impaired insulin synthesis induced by glucocorticoids in HIT-T15 cells.

Expression of the insulin gene is highly specific to pancreatic beta cells and is upregulated mainly by PDX-1 and BETA2/NeuroD depending on the extracellular glucose concentration. However, its downregulation has not been well studied. Reporter gene analyses using pancreatic HIT-T15 cells revealed that the glucose-dependent insulin promoter activity was blocked by glucocorticoids, dexamethasone (DEX) and hydrocortisone, in a dose-dependent manner. After the addition of DEX (20 nM) to HIT-T15 cells, a decrease of insulin mRNA was observed at 12-24 h, followed by a decline of insulin protein at 48 h. Expressions of PDX-1 and BETA2/NeuroD decreased within 2 h. HES-1, a potent negative regulator of bHLH-type transcription factors, was found to be expressed in HIT-T15 cells, and its expression was increased 6 h after the addition of DEX. Overexpression of HES-1 suppressed the insulin promoter activity in a dose-dependent manner. These results suggest that glucocorticoids impair insulin synthesis in HIT-T15 cells by decreasing PDX-1 and BETA2/NeuroD and that enhancement of HES-1 expression is involved in this regulation.

Relationship of androgens to muscle size and bone mineral density in women with polycystic ovary syndrome.

OBJECTIVE: To investigate the relationship of androgens to regional muscle size and bone mineral density (BMD) in women with polycystic ovary syndrome (PCOS). METHODS: Seventy-one amenorrheic and right-side dominant women with PCOS (mean age +/- standard deviation 28.1 +/- 6.7 years) were enrolled. Baseline characteristics included age, height, weight, and body mass index (BMI). Regional BMD and lean mass were measured by whole-body scanning with dual-energy x-ray absorptiometry. Serum levels of testosterone, dehydroepiandrosterone sulfate (DHEAS), and androstenedione were measured by radioimmunoassay. Correlations between regional BMD and variables were investigated using a Pearson correlation test and multiple regression analysis. RESULTS: Serum testosterone levels correlated significantly with lean mass of the left arm, right arm, trunk, left leg, and right leg (r =.34, P <.05 to r =.50, P <.01). Regional lean mass correlated significantly with respective regional BMD (r =.30, P <.05 to r =.68, P <.001). These relationships remained significant after adjusting for age, height, and weight. Serum testosterone levels were not correlated with BMD of the bilateral arms and lumbar spine. Although serum testosterone levels correlated with leg BMD (r =.34, P <.05 to r =.45, P <.01), significance did not persist after adjusting for respective regional lean mass. CONCLUSION: Testosterone influences regional BMD through increasing regional muscle mass in women with polycystic ovary syndrome.

[Severe chronic pain with allodynia in Parkinson's disease: a case report].

We report a 61-year-old man with Parkinson's disease, who had a 3-year history of severe chronic pain with allodynia in the lower extremities prior to motor symptoms. He always had tingling pain around the ankles, and tactile sensation induced severe burning pain expanding to the toes and thighs, so his pain was considered to be allodynia. Pain and motor symptoms were ameliorated by L-dopa therapy and exacerbated by withdrawal of L-dopa. Pain is known to occur in Parkinson's disease, but severe pain rarely occurs. To our knowledge, allodynia, which is usually recognized in causalgia or reflex sympathetic dystrophy, has never been reported in Parkinson's disease. Patients with Parkinson's disease may complain severe causalgia-like pain as an initial symptom.

Muscarinic receptor binding characteristics in rat tissues after oral administration of oxybutynin and propiverine.

Ex vivo muscarinic receptor binding of oxybutynin and propiverine, the most commonly used anticholinergic agents for the treatment in patients with urinary incontinence, was investigated in rat tissues. The oral administration of oxybutynin (50.8 and 127 micromol/kg) caused a significant increase in the apparent dissociation constant (Kd) for specific (-)-[3H]QNB binding in the rat bladder, prostate, submaxillary gland, heart and cerebral cortex, compared with each of the control values. Also, in the submaxillary gland of these rats, there was a reduction in the maximal number of binding sites (Bmax) for (-)-[3H]QNB binding. Similarly, oral administration of propiverine at doses of 74.3-297 micromol/kg brought about a significant increase in the Kd values for (-)-[3H]QNB binding in rat tissues including the bladder, and greater increase in Kd values was seen in the rat prostate, heart and submaxillary gland. On the other hand, oral administration of propiverine, unlike oxybutynin, resulted in very little reduction in the Bmax valules for (-)-[3H]QNB binding in the submaxillary gland. In conclusion, the present study has shown that oxybutynin and propiverine, after oral administration, bind significantly to muscarinic receptors in tissues such as the bladder, which is the target organ for the treatment of urinary incontinence, and that oxybutynin appears to exhibit long-term binding to muscarinic receptors in the salivary gland.

Effect of cilnidipine on left ventricular diastolic function in hypertensive patients as assessed by pulsed Doppler echocardiography and pulsed tissue Doppler imaging.

The purpose of the present study was to examine the mechanisms of improvement in left ventricular (LV) diastolic function in hypertensive patients treated with cilnidipine, a new and unique calcium antagonist that has both L-type and N-type voltage-dependent calcium channel blocking actions, using pulsed Doppler echocardiography and pulsed tissue Doppler imaging. The study comprised 35 untreated patients with essential hypertension (19 men and 16 women; mean age 65+/-10 years). The peak early diastolic and atrial systolic transmitral flow velocities (E and A, respectively) and their ratio (E/A), and the peak early diastolic and atrial systolic motion velocities (Ew and Aw, respectively) of the LV posterior wall and their ratio (Ew/Aw) were determined in all patients before and after 1, 3 and 6 months on cilnidipine (10 mg/day). One month: Systolic and diastolic blood pressures were significantly decreased. E and E/A were significantly increased, whereas there were no significant changes in Ew and Ew/Aw. Three months: Ew and Ew/Aw were significantly increased compared to those before and 1 month after cilnidipine. Six months: E and E/A were significantly increased compared with before and 3 months after cilnidipine, and Ew and Ew/Aw were significantly increased compared with before cilnidipine. Moreover, the LV mass index was significantly decreased compared to that before cilnidipine. In summary, changes in LV diastolic performance in patients with essential hypertension following cilnidipine treatment were biphasic with an initial increase in early diastolic transmitral flow velocity and a later increase in early diastolic LV wall motion velocity. The initial and later changes can be related to an acute change in afterload and a later improvement in LV relaxation.

alpha-Glucosidase inhibitory action of natural acylated anthocyanins. 1. Survey of natural pigments with potent inhibitory activity.

alpha-Glucosidase (AGH) inhibitory study by natural anthocyanin extracts was done. As the result of a free AGH assay system, 12 anthocyanin extracts were found to have a potent AGH inhibitory activity; in particular, Pharbitis nil (SOA) extract showed the strongest maltase inhibitory activity, with an IC(50) value of 0.35 mg/mL, as great as that of Ipomoea batatas (YGM) extract (IC(50) = 0.36 mg/mL). Interestingly, neither extract inhibited the sucrase activity at all. For the immobilized assay system, which may reflect the pharmacokinetics of AGH at the small intestine, SOA and YGM extracts gave more potent maltase inhibitory activities than those of the free AGH assay, with IC(50) values of 0.17 and 0.26 mg/mL, respectively. Both extracts also inhibited alpha-amylase action, indicating that anthocyanins would have a potential function to suppress the increase in postprandial glucose level from starch.

alpha-Glucosidase inhibitory action of natural acylated anthocyanins. 2. alpha-Glucosidase inhibition by isolated acylated anthocyanins.

Four diacylated pelargonidin (Pg: SOA-4 and SOA-6), cyanidin (Cy: YGM-3), and peonidin (Pn: YGM-6) 3-sophoroside-5-glucosides isolated from the red flowers of the morning glory, Pharbitis nil cv. Scarlett O'Hara (SOA), and the storage roots of purple sweet potato, Ipomoea batatas cv. Ayamurasaki (YGM), were subjected to an alpha-glucosidase (AGH) inhibitory assay, in which the assay was performed with the immobilized AGH (iAGH) system to mimic the membrane-bound AGH at the small intestine. As a result, the acylated anthocyanins showed strong maltase inhibitory activities with IC(50) values of <200 microM, whereas no sucrase inhibition was observed. Of these, SOA-4 [Pg 3-O-(2-O-(6-O-(E-3-O-(beta-D-glucopyranosyl)caffeyl)-beta-D-glucopyranosyl)-6-O-E-caffeyl-beta-D-glucopyranoside)-5-O-beta-D-glucopyranoside] possessed the most potent maltase inhibitory activity (IC(50) = 60 microM). As a result of a marked reduction of iAGH inhibitory activity by deacylating the anthocyanins, that is, Pg (or Cy or Pn) sophoroside-5-glucoside, acylation of anthocyanin with caffeic (Caf) or ferulic (Fer) acid was found to be important in the expression of iAGH (maltase) inhibition. In addition, the result that Pg-based anthocyanins showed the most potent maltase inhibition, with an IC(50) value of 4.6 mM, and the effect being in the descending order of potency of Pg > Pn/Cy strongly suggested that no replacement at the 3'(5')-position of the aglycon B-ring may be essential for inhibiting iAGH action.