Rescue of the pseudo-vitamin D deficiency rickets phenotype of CYP27B1-deficient mice by treatment with 1,25-dihydroxyvitamin D3: biochemical, histomorphometric, and biomechanical analyses.

The treatment of choice for pseudo-vitamin D deficiency rickets (PDDR), caused by mutations in the 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1; 1alpha-OHase) gene, is replacement therapy with 1,25(OH)2D3. We have previously engineered an animal model of PDDR by targeted inactivation of the 1alpha-OHase gene in mice. Replacement therapy was performed in this model. The 1alpha-OHase-/- mice and heterozygote controls were treated with 500 pg of 1,25(OH)2D/g body weight/day for 2 weeks, followed by 100 pg of 1,25(OH)2D3/g body weight/day for an additional 3 weeks before death at 8 weeks of age. Blood biochemistry analysis revealed that the rescue treatment corrected the hypocalcemia and secondary hyperparathyroidism. The daily injections of 1,25(OH)2D3 induced strong expression of CYP24, the 25-hydroxyvitamin D 24-hydroxylase gene. Bone histology and histomorphometry confirmed that the rickets and osteomalacia were cured. The rescue regimen also restored the biomechanical properties of the bone tissue within normal parameters. These results show that chronic treatment with the active 1,25(OH)2D3 metabolite is effective to rescue the PDDR phenotype of 1alpha-OHase mutant mice.     

White blood cell counts and malaria

White blood cells (WBCs) were counted in 4697 individuals who presented to outpatient malaria clinics in Maesod, Tak Province, Thailand, and Iquitos, Peru, between 28 May and 28 August 1998 and between 17 May and 9 July 1999. At each site and in each year, WBC counts in the Plasmodium falciparum-infected patients were lower than those in the Plasmodium vivax-infected patients, which, in turn, were lower than those in the uninfected patients. In Thailand, one-sixth of the P. falciparum-infected patients had WBC counts of <4000 cells/microL. Leukopenia may confound population studies that estimate parasite densities on the basis of an assumed WBC count of 8000 cells/microL. For instance, in the present study, use of this conventional approach would have overestimated average asexual parasite densities in the P. falciparum-infected patients in Thailand by nearly one-third.     

Factors related to screening of hepatitis C virus in general medicine

Despite the high prevalence of hepatitis C in France ( approximately 1.2%), a large proportion of people infected with hepatitis C virus (HCV) are not known aware of their status. The objective of this study was to investigate the factors related to screening in general medicine. MATERIAL AND METHODS: Three hundred and one general practitioners were interviewed by phone in South-Eastern France about their HCV screening practices, knowledge of the epidemic, of the natural course of the disease, and opinions about health care for people infected with HCV. RESULTS: While general practitioners often offered HCV screening to intravenous drug users, screening for people who had received blood transfusion, and identification of risk factors among patients were not satisfactory. Multivariate analysis showed that certain characteristics in general practitioners were negatively and independently related to the frequency of HCV screening, especially: general practitioners older than 40 (odds-ratio: 3.12), general practitioners who did not care for intravenous drug users (odds-ratio: 2.24) and did not prescribe human immunodeficiency virus tests (odds-ratio: 5.55). Other characteristics such as awareness of the course of hepatitis C and health care were also associated with HCV screening. Conversely knowledge of the size of the epidemic was not related to better HCV screening practices. CONCLUSION: Our study shows that knowledge about the size of the epidemic and the natural history of hepatitis C, HCV screening practices and investigation of risk factors among patients are not satisfactory among South-eastern French general practitioners. Although HCV screening and health care must be improved among intravenous drug users, hepatitis C should not be considered as a disease of injecting drug users only by general practitioners and the population. Efforts should be made so that hepatitis C is recognized as a global public health issue, and training of general practitioners should be improved to investigate risk factors and offer HCV screening instead of merely dramatizing the situation.     

Hydrological droughts in the 21st century,hotspots and uncertainties from a global multimodel ensemble experiment

Increasing concentrations of greenhouse gases in the atmosphere are expected to modify the global water cycle with significant consequences for terrestrial hydrology. We assess the impact of climate change on hydrological droughts in a multimodel experiment including seven global impact models (GIMs) driven by bias-corrected climate from five global climate models under four representative concentration pathways (RCPs). Drought severity is defined as the fraction of land under drought conditions. Results show a likely increase in the global severity of hydrological drought at the end of the 21st century, with systematically greater increases for RCPs describing stronger radiative forcings. Under RCP8.5, droughts exceeding 40% of analyzed land area are projected by nearly half of the simulations. This increase in drought severity has a strong signal-to-noise ratio at the global scale, and Southern Europe, the Middle East, the Southeast United States, Chile, and South West Australia are identified as possible hotspots for future water security issues. The uncertainty due to GIMs is greater than that from global climate models, particularly if including a GIM that accounts for the dynamic response of plants to CO₂ and climate, as this model simulates little or no increase in drought frequency. Our study demonstrates that different representations of terrestrial water-cycle processes in GIMs are responsible for a much larger uncertainty in the response of hydrological drought to climate change than previously thought. When assessing the impact of climate change on hydrology, it is therefore critical to consider a diverse range of GIMs to better capture the uncertainty.The global water cycle is expected to change over the 21st century due to the combined effects of climate change and increasing human intervention. In a warmer world, the water-holding capacity of the atmosphere will increase, resulting in a change in the frequency of precipitation extremes, increased evaporation and dry periods (1), and intensification of droughts (2). This process is represented by most global climate models (GCMs) by increased summer dryness and winter wetness over large areas of continental mid to high latitudes in the Northern Hemisphere (3), associated with a reduction in water availability at continental (4, 5) and global scales (6, 7). Because such changes have potentially very serious implications in some regions of the world, identifying areas where there is agreement in the direction and magnitude of changes in drought characteristics (hotspots) in response to climate change is essential information for water resource management aimed at ensuring water security in a changing climate.Most GCMs, however, are not able to reproduce the fine-scale processes governing terrestrial hydrology (and hence runoff) and suffer from systematic biases (8). As land-atmospheric feedbacks are not yet fully understood and reproduced by global models (9), and because full coupling of GCMs and global impact models (GIMs) is not straightforward, GIMs forced by data from GCMs have been used as tools to quantify the impact of changed climate on the water cycle and droughts (10), despite by definition ignoring important feedbacks and their possible modification with climate change (11). GIMs vary in the types of processes represented and the parameterisations used. Some GIMs, particularly those designed to quantify water resources, calculate only the water balance (12) whereas others consider coupled water and energy balances, sometimes also representing the dynamic response of plants to changes in atmospheric CO₂ and climate (13). Until recently, the uncertainty in the simulation of the terrestrial water cycle related to the choice of a particular GIM had not been investigated. However, the Water Model Intercomparison Project (WaterMIP) (14) highlighted that simulated hydrological averages can vary substantially between GIMs, even when driven with the same bias-corrected climatic forcing (14, 15), and uncertainty in future projection due to GIMs can be as large as that from GCMs in some regions (16, 17). Although in the climate-to-impact modeling chain much effort has been directed to better understand the uncertainty due to GCMs, studies of the impact of climate change on water availability and drought have often been based on one or a few GIMs, potentially underestimating the overall uncertainty.This study focuses on identifying regions where the impact of climate change on hydrological drought (henceforth simply “drought”) shows a strong signal of change between the end of the 20th and 21st centuries. We define drought as occurring when total runoff is less than a given threshold. Drought represents the time-integrated effect of several interlinked processes and stores, including precipitation, evaporation, and soil moisture storage (10); because some of these processes are represented by GCMs and some by GIMs, it is vital to quantify the relative uncertainty introduced by both GCMs and GIMs when assessing climate change impacts.We use outputs from the Inter-Sectoral Impact Model Intercomparison Project (ISI-MIP) multimodel ensemble (MME) experiment (18) of 35 members [for representative concentration pathways (RCPs) 2.6 and 8.5; only 27 members available for RCP4.5 and 6.0] in which GIMs of different types were driven by bias-corrected (8) climate from state-of-the-art CMIP5 GCMs (19). These GIMs describe the terrestrial water cycle at global scale and include current understanding of hydrological systems (20). Note that statistical bias correction can influence the signal of runoff changes but that this effect generally remains smaller than uncertainty from GCMs and GIMs (21). The simulations we use did not consider water management or changes of land use so they represent the effects of climate change alone. We quantify changes in the space-time variability of drought that are projected to occur under four RCPs that span a wide range of radiative forcing (22) (Methods). We also evaluate the uncertainty associated with both GCMs and GIMs so as to identify hotspots of change where we have more confidence in the projections of future drought severity.     

Synthesis, mode of action, and biological activities of rebeccamycin bromo derivatives.

Bromo analogues of the natural metabolite rebeccamycin with and without a methyl substituent on the imide nitrogen were synthesized. The effects of the drugs on protein kinase C, the binding to DNA, and the effect on topoisomerase I were determined. The drugs' uptake and their antiproliferative activities against P388 leukemia cells sensitive and resistant to camptothecin, their antimicrobial activity against a Gram-positive bacterium (B. cereus), and their anti-HIV-1 activity were measured and compared to those of the chlorinated and dechlorinated analogues. Dibrominated imide 5 shows a remarkable activity against topoisomerase I, affecting both the kinase and DNA cleavage activity of the enzyme. The marked cytotoxic potency of this compound depends essentially on its capacity to inhibit topoisomerase I.