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Abstract: We analyse chronologies of historical flash floods derived from searches of newspaper archives and other sources commencing before 1800 and recent gauged rainfall and stream flow data. Five key examples are chosen to illustrate specific features of flash floods. Pluvial flash floods arise from rainfall before it reaches a watercourse and may cause severe flooding of land and properties far from rivers. River flash floods, like pluvial floods, have the characteristic of rapid speed of response, a principal source of risk to life. Intense rainfall can generate ‘walls of water’ in river courses which can propagate long distances downstream and steepen, without upstream structural failure. Steeply rising wavefronts more commonly occur on steep upland catchments but, where intensities of extreme short period rainfall are sufficient, such wavefronts can also occur on lowland catchments. A definition of flash floods from intense rainfall, relevant to British landscape and climate, is proposed. [ABSTRACT FROM AUTHOR]

River flow is a reflection of the input of moisture and its transformation in storage and transmission over the catchment. In the Upper Indus Basin (UIB), since high altitude climate measurement and observations of glacier mass balance are weak or absent, analysis of trends in magnitude and timing in river flow provides a window on trends and fluctuations in climate and glacier outflow. Trend analysis is carried out using a Mann-Kendall nonparametric trend test on records extending from 1960 to 1998. High level glacial catchments show a falling trend in runoff magnitude and a declining proportion of glacial contribution to the main stem of the Indus. Elsewhere annual flow has predominantly increased with several stations exhibiting statistically significant positive trends. Analysis of timing using spring onset date (SOT) and centre of volume date (CoV) indicated no clear trends -- in direct contrast to what has been observed in Western North America. There is, however, a consistent relationship between CoV and annual runoff volume. A consistently positive correlation was also found between SOT and CoV for all the stations implying that initial snowpack conditions before the onset of runoff influence timing throughout the season. The results of the analysis presented here indicate that the magnitude and timing of streamflow hydrograph is influenced both by the initial snowpack and by seasonally varied trends in temperature. The study contributes to the understanding of the links between climate trends and variability and river runoff and glacier mass balance and runoff. The Upper Indus Basin is predominantly influenced by winter precipitation; similar trend analysis applied to summer monsoon dominated catchments of the Central Himalaya is recommended. [ABSTRACT FROM AUTHOR]

Mountains are essential sources of freshwater for our world, but their role in global water resources could well be significantly altered from anticipated climate change. How well do we understand these changes today, and what are implications for water resources management and for policy? With these questions in mind, a dozen researchers - most of them with experience in collaborating with water managers - from around the world assembled for a workshop in Göschenen, Switzerland on 16-19 September 2009 by invitation of the Mountain Research Initiative (MRI). Their goal was to develop an up-to-date overview of moun tain water resources and climate change and to identify pressing issues with relevance for science and society. This special issue of Hydrology and Earth System Sciences assembles contributions providing insight into climate change and water resources for selected casestudy mountain regions from around the world. The present introductory article is based on analysis of these regions and on the workshop discussions. We will give a brief overview of the subject (Sect. 1), introduce the case-study regions (Sect. 2) and examine the state of knowledge regarding the importance of water supply from mountain areas for water resources in the adjacent lowlands and anticipated climate change impacts (Sect. 3). From there, we will identify research and monitoring needs 20 (Sect. 4), make recommendations for research, water resources management and policy (Sect. 5) and finally draw conclusions (Sect. 6). [ABSTRACT FROM AUTHOR]

Despite substantial evidence that land use and management can enhance flood runoff at a local scale, evidence of increased flood risk based on peak discharges is lacking in catchments greater than 10 km². This analysis is instead based on assessing changes in short-term rates of change in discharge. The influence of land use is demonstrated first on the small Coalburn catchment where changes in rates of rise are closely related to drainage and afforestation. For the larger Axe catchment (288km²), changes in rates of rise are investigated by comparing annual maximum and peaks over a threshold flows for different periods, by comparing rates of rise associated with given daily rainfall and by adapting the method of flow variability analysis for use of rates of change rather than flow itself. All these methods demonstrate significant changes in river flow dynamics which seem to be in parallel with land use changes even when the influence of climate variability from year to year has been taken into account. Rates of change in discharge appear to respond to land use changes and thus provide a potential basis for application to land use management policies. [ABSTRACT FROM AUTHOR]

Mixed hemopoietic chimerism has the potential to correct genetic hemological diseases (sickle cell anemia, thalassemia) and eliminate chronic immunosuppressive therapy following organ transplantation. To date, most strategies require either recipient conditioning (gamma-irradiation, depletion of the peripheral immune system) or administration of "mega" doses of bone marrow to facilitate reliable engraftment. Although encouraging, many issues remain that may restrict or prevent clinical application of such strategies. We describe an alternative, nonirradiation based strategy using a single dose of busulfan, costimulation blockade, and T cell-depleted donor bone marrow, which promotes titratable macrochimerism and a reshaping of the T cell repertoire. Chimeras exhibit robust donor-specific tolerance, evidenced by acceptance of fully allogeneic skin grafts and failure to generate donor-specific proliferative responses in an in vivo graft-versus-host disease model of alloreactivity. In this model, donor cell infusion and costimulation blockade without busulfan were insufficient for tolerance induction as donor-specific IFN-gamma-producing T cells re-emerged and skin grafts were rejected at approximately 100 days. When applied to a murine beta-thalassemia model, this approach allows for the normalization of hemologic parameters and replacement of the diseased red cell compartment. Such a protocol may allow for clinical application of mixed chimerism strategies in patients with end-stage organ disease or hemoglobinopathies.

The double-stranded (ds) RNA-dependent protein kinase PKR is considered to play an important role in interferon's (IFN's) response to viral infection. Here, we demonstrate that mice lacking PKR are predisposed to lethal intranasal infection by the usually innocuous vesicular stomatitis virus, and also display increased susceptibility to influenza virus infection. Our data indicate that in normal cells, PKR primarily prevents virus replication by inhibiting the translation of viral mRNAs through phosphorylation of eIF2alpha, while concomitantly assisting in the production of autocrine IFN and the establishment of an antiviral state. These results show that PKR is an essential component of innate immunity that acts early in host defense prior to the onset of IFN counteraction and the acquired immune response.

Noscapine, a phthalideisoquinoline alkaloid derived from opium, has been used as an oral anti-tussive agent and has shown very few toxic effects in animals or humans. Recently, we reported that noscapine binds stoichiometrically to tubulin and promotes microtubule polymerization. Noscapine causes growth arrest of tumor cells in mitosis and induces apoptosis of tumor cells in vitro. Previous experiments also showed that noscapine has potent antitumor activity in mice when administered parenterally or by gastric lavage. Here, we report that the anti-mitotic effect was specific to noscapine since closely related compounds did not inhibit the growth of a lymphoma cell line. In addition, noscapine was shown to be effective in reducing the growth of the lymphoma and increasing the survival of tumor-bearing mice when administered in the drinking water. It is noteworthy that, noscapine showed little or no toxicity to kidney, liver, heart, bone marrow, spleen or small intestine at tumor-suppressive doses. Furthermore, oral noscapine did not inhibit primary immune responses, which are critically dependent upon proliferation of lymphoid cells. Thus, our results indicate that noscapine has the potential to be an effective chemotherapeutic agent for the treatment of human cancer.

Interferon (IFN) mediates its antiviral effects by inducing a number of responsive genes, including the double-stranded RNA (dsRNA)-dependent protein kinase, PKR. Here we report that inducible overexpression of functional PKR in murine fibroblasts sensitized cells to apoptosis induced by influenza virus, while in contrast, cells expressing a dominant-negative variant of PKR were completely resistant. We determined that the mechanism of influenza virus-induced apoptosis involved death signaling through FADD/caspase-8 activation, while other viruses such as vesicular stomatitis virus (VSV) and Sindbis virus (SNV) did not significantly provoke PKR-mediated apoptosis but did induce cytolysis of fibroblasts via activation of caspase-9. Significantly, treatment with IFN-alpha/beta greatly sensitized the fibroblasts to FADD-dependent apoptosis in response to dsRNA treatment or influenza virus infection but completely protected the cells against VSV and SNV replication in the absence of any cellular destruction. The mechanism by which IFN increases the cells' susceptibility to lysis by dsRNA or certain virus infection is by priming cells to FADD-dependent apoptosis, possibly by regulating the activity of the death-induced signaling complex (DISC). Conversely, IFN is also able to prevent the replication of viruses such as VSV that avoid triggering FADD-mediated DISC activity, by noncytopathic mechanisms, thus preventing destruction of the cell.

We have previously demonstrated that high levels of allogeneic, donor-derived mouse haemopoietic progenitor cells engraft following in utero transplantation in NOD/SCID mice. To evaluate whether the fetal NOD/SCID haemopoietic microenvironment supports the growth and development of human fetal haemopoietic progenitor cells, we injected fetal liver mononuclear cells (FL) or fetal bone marrow (FBM) derived CD34+ cells into NOD/SCID mice on day 13/14 of gestation. At 8 weeks of age 12% of FBM recipients and 10% of FL recipients were found to have been successfully engrafted with CD45+ human cells. CD45+ cells were present in the BM of all chimaeric animals; 5/6 recipients showed engraftment of the spleen, and 4/6 recipients had circulating human cells in the peripheral blood (PB). The highest levels of donor cells were found in the BM, with up to 15% of the nucleated cells expressing human specific antigens. Multilineage human haemopoietic engraftment, including B cells (CD19), myelomonocytic cells (CD13/33) and haemopoietic progenitor cells (CD34), was detected in the BM of chimaeric mice. In contrast, no human CD3+ cells were detected in any of the tissues evaluated. When the absolute number of engrafted human cells in the PB, BM and spleens of chimaeric mice was determined, a mean 16-fold expansion of human donor cells was observed. Although multilineage engraftment occurs in these fetal recipients, both the frequency and the levels of engraftment are lower than those previously reported when human cells are transplanted into adult NOD/SCID recipients.

Substantial barriers exist to the engraftment of hematopoietic cells in mice after in utero transplantation. Although high levels of donor-derived hematopoiesis have been reported in SCID mice, the majority of chimeric recipients exhibit decreasing levels of donor cells over time. To directly test whether the natural killer cell and macrophage activity of the recipients represents a barrier to sustained engraftment, fetal NOD/SCID mice were injected on day 13.5 of gestation with an enriched congenic hematopoietic progenitor cell population. Forty-four percent of pups showed the presence of Ly5.1+ donor cells 4 weeks after transplantation. The mean number of donor-derived nucleated cells in the peripheral blood (PB) was 30%. Although the majority of circulating donor cells were lymphocytes, up to 15% expressed myelomonocytic markers. Serial PB samples from individual mice indicated that the percentage of circulating donor cells increased from 17% to 55% between 4 and 24 weeks. At 6 months posttransplantation, an increased frequency of multilineage, donor-derived cells was also observed in the bone marrow (BM) and the spleen of chimeric recipients. The engraftment of pluripotent hematopoietic stem cells was evaluated by transplanting BM from chimeric mice into irradiated congenic recipients. Irradiated secondary recipients also exhibited multilineage donor-derived hematopoiesis in the PB, BM, and spleen for up to 6 months. These results show that the in utero transplantation of lineage-depleted BM cells into NOD/SCID recipients produces a high frequency of sustained engraftment of allogeneic hematopoietic stem cells.

Epidermal growth factor (EGF)-responsive stem cells have been identified in the murine central nervous system. These cells can be isolated from the brain and maintained in an undifferentiated state in vitro in the presence of EGF. After removing EGF, the cells cease mitosis and can be induced to differentiate into neurons, astrocytes, and oligodendrocytes. We demonstrate that when the undifferentiated stem cells (nestin-positive) are injected into the myelin-deficient rat spinal cord, they respond to cues within the mutant CNS and differentiate into myelinating oligodendrocytes, in contrast to their behavior in vitro, where they mainly form astrocytes. The cells provide a valuable model system for the study of the development of early oligodendrocytes from multipotent neural stem cells. Because these cells are influenced to divide using growth factors, rather than oncogenes, and because they appear to make appropriate lineage decisions when transplanted into a mutant environment, they may provide an excellent source of cells for a variety of future therapies using cellular transplantation.

There is a lack of effective means of promoting remyelination of the central nervous system (CNS) in humans with chronic demyelinating disease. We have investigated the ability of transplanted glia to myelinate areas of the CNS equivalent to focal demyelinated lesions in multiple sclerosis (MS). In these studies we show that transplantation of oligodendrocytes or their progenitors into the CNS of a neonatal or adult canine myelin mutant results in repair of large areas similar in size to many MS plaques. Progenitor or pre-progenitor cells of the oligodendrocyte lineage have the greatest capacity for myelination following grafting, although cells of neonatal origin may also be used. Such an approach may therefore have therapeutic value in the repair of focal lesions in human myelin disease.

Evaluation of glial cell migration following transplantation can be difficult as the force of the injection itself may cause the cells to become immediately dispersed. In this study we evaluated the extent of spread of cells after injection of 1 microliter of a dissociated cell suspension (50,000 cells/microliter) into the dorsal columns of the thoracolumbar spinal cord in the neonatal myelin-deficient (md) rat. Spinal cords were examined at 0, 4, and 24 h after injection to determine the dispersion of cells away from the initial site of deposition. Examination of skip-serial sections collected at 50-microns intervals rostral and caudal to the site of transplantation showed that the injection could result in a spread of transplanted cells up to 1,600 microns. Migration should therefore be defined as the detection of cells beyond the rostral-caudal boundaries defined by the injection deposition. Cell dispersion should be taken into account when evaluating the results of migration in previous and future experiments concerning glial cell transplantation.

This study examined the ability of freshly prepared and cryopreserved canine oligodendrocytes to myelinate axons following transplantation into the myelin deficient (md) rat. The effects of immunosuppression, and the age of the donor tissue, were also examined. Canine glial cells, dissociated from the spinal cords at E50, P2, P20, P28, and P50, were transplanted into the spinal cords of myelin-deficient rats as single cell suspensions. Both cryopreserved (E50 and P28) and freshly dissociated tissue (P2, P20, and P50) were able to form myelin within 13 days of transplantation. Cells from younger donors (< P20) myelinated more md axons than those from older donors. In those rats which received xenografts and which were treated with cyclosporin A there was markedly less cellular infiltration than in untreated animals. For comparison with these xenografts, fresh and cryopreserved adult rat glia were also transplanted. Eight days after transplantation, myelination by allografts of cryopreserved rat glia was qualitatively similar to that produced by freshly prepared cells. These results show that oligodendrocytes transplanted as xenografts are capable of myelinating rat axons, and that cryopreserved glia retain their capacity to myelinate in vivo.

Previous work has shown that transplanted dissociated glial cells derived from neonatal rats can myelinate areas of the myelin deficient (md) rat spinal cord. In the present studies we have examined the ability of adult glial cells, either as suspension of mixed glial cells or as 01 positive oligodendrocytes purified by cell sorting, to myelinate md rat axons following transplantation. Mixed glial cell preparations from adult rats myelinated large areas of either, dorsal, lateral or ventral columns. These areas contained clumped, transplanted oligodendrocytes. In addition, preparations containing over 90% 01 positive oligodendrocytes were also capable of myelinating large numbers of axons upon transplantation. These results suggest that adult oligodendrocytes may play an important role in remyelination of the adult CNS.

The ability of tuboplastic microsurgery to restore electrical continuity across an anastomosis site was investigated in the rabbit. Three to six weeks following transection and end-to-end anastomosis of the tubal ampulla or isthmus, the pattern of electrical activity adjacent to and across the anastomosis site was examined. Recordings were made in vitro using arrays of closely spaced suction electrodes 68 to 72 hours after an ovulating dose of human chorionic gonadotropin. The pattern of electrical activity across anastomosis sites was not significantly different from corresponding portions of unoperated control oviducts. Microsurgical anastomosis restored electrical continuity between anastomosed segments in both the ampulla and isthmus.

Collagenase was used to dissociate rat skeletal muscle (gastrocnemius) into its constituent cells, from which a myocyte fraction enriched in striated muscle cells, and a non-myocyte fraction containing cells of connective tissue and vascular origin, were prepared. The activities of amine oxidase enzymes and alkaline phosphatase (AP) were then assayed in these fractions, and also in homogenates prepared from corresponding samples of non-dissociated tissue. The specific activities of the semicarbazide-sensitive amine oxidase (SSAO) and AP were considerably higher (30 to 35-fold) in non-myocyte than in myocyte fractions. AP is generally considered to be present predominantly in vascular cells of skeletal muscle, with little, if any, in skeletal muscle cells themselves. Thus, the results obtained may indicate a similar localization for SSAO activity. Support for this came from histochemical studies, which showed staining for SSAO primarily over the walls of larger blood vessels in the muscle. Unlike SSAO and AP, were marked differences in MAO-A activity between myocyte and non-myocyte fractions were not found, suggesting that MAO-A is more probably a constituent of cells within both fractions.

Fertility, ovum transport, and ciliary activity were examined in 35 rabbits after either unilateral microsurgical reversal or double transection (surgical controls) of 1 cm. segments of distal, middle, or proximal ampulla. Fertility was also examined following similar segmental reversal at the level of the distal and proximal isthmus in eight additional rabbits. Reversal of 1 cm. segments of distal, middle, or proximal ampulla effectively prevented pregnancy. In contrast, control animals that underwent double transection without reversal experienced unaltered fertility. Reversal of 1 cm. segments of distal or proximal isthmus was also consistent with normal fertility. Ova placed on the fimbrial surface of oviducts that had undergone ampullary segmental reversal were arrested at the distal anastomosis of the reversed segment. When mechanically displaced into the reversed segment, such ova were transported toward the ovary and were again arrested at the distal anastomosis. Transampullary transport of ova was normal in doubly transected controls. Ova were transported across both anastomosis sites to the ampullary isthmic junction. Studies of ciliary activity confirmed that cilia within reversed segments of ampulla beat in the ovarian direction, counter to that in the rest of the oviduct. Direction of ciliary beat remained unaltered in surgical controls. These experiments demonstrate a critical role of tubal cilia in ovum transport through the rabbit ampulla. In contrast, other mechanisms control ovum transport into and through the tubal isthmus.

Regeneration was induced in rabbit vagus nerves by a crush injury. Fourteen and 50 days later [35S]methionine-radiolabelled, fast axonally transported proteins were separated by one- and two-dimensional electrophoresis. Quantitative densitometric analysis of fluorographs from one-dimensional separations showed increases in the radiolabelling of fast transported proteins of 45 and 20 kDa, and a decrease in the radiolabelling of a 26 kDa protein 14 days after crush injury, which were confirmed by two-dimensional separations. These increases were maintained at 50 days post-crush. The proteins have similar molecular weights and isoelectric points to two growth-associated proteins known to have important roles in growth and regeneration.