A series of alkylidene hydrazide derivatives containing an alkoxyaryl moiety was optimized. The resulting hydrazide-ethers were competitive antagonists at the human glucagon receptor. Pharmacokinetic ...experiments showed fast clearance of most of the compounds tested. A representative compound 4-hydroxy-3-cyanobenzoic acid (4-isopropylbenzyloxy-3,5-dimethoxymethylene)hydrazide with an IC
50 value of 20 nM was shown to reduce blood glucose levels in fasted rats.
Further optimization of a series of alkylidene hydrazides having affinity for the human glucagon receptor, representative in vitro metabolism, and pharmacodynamic results are described.
We performed a retrospective review of 34 humerus shaft fractures (HSFs) in children younger than 3 years to determine the frequency of child abuse in young children with this injury. Data were ...obtained from hospital records (including previous and subsequent emergency, clinic, and inpatient notes), radiographs, and county child-protective services. Cases were reviewed independently by four physicians and were classified as probable abuse, probable not abuse, and indeterminate. Only 18% were classified as probable abuse. The history and findings other than the fracture itself were critical in establishing cause. Neither age nor fracture pattern is pathognomonic of abuse, but suspicion should remain high. A detailed history, complete physical examination, and appropriate radiographic investigation are required in every case either to make the diagnosis of abuse or to avoid the trauma of a false accusation.
Examination of the low hematocrit (HCT) deferral rates in whole blood donors based on gender/menstrual status and donation intensity unexpectedly revealed that low HCT deferral rates level off and ...even begin to decrease in frequent donors (>8 donations in 2 years) suggesting that frequent blood donors are a self-selected population possessing either behavioral or biochemical characteristics that allow greater iron absorption than the general population. To define these characteristics, 138 donors (101 male, 37 female, 136 Caucasian) that had donated 13 times in a 2-year period (“superdonors”) completed a questionnaire and had a blood sample analyzed for ferritin, hepcidin and HFE and JAK-2 genotypes. Ferritin was 31.0±20.3 ug/L for males and 25.2±14.8 ug/L for females. Two-thirds of both men and women had ferritin below 30 ug/L indicating that most have reduced iron stores. Average ferritin was ∼15 ug/L higher in donors taking multiple vitamins with iron or iron supplements than in those who did not take them. Hepcidin is an iron regulatory hormone that negatively regulates intestinal iron absorption. Serum hepcidin levels were determined using a liquid chromatography tandem mass spectrometry assay. The normal serum hepcidin concentration using this assay is 8–11 ng/ml Blood 110:1048( 2007). Serum hepcidin was greatly decreased in superdonors (males 2.9±5.4 ng/ml; females 2.8±2.7 ng/ml) and 55 had no detectable hepcidin (<1 ng/ml), suggesting that superdonors absorb maximal amounts of intestinal iron. The C282Y mutation in the HFE gene has been linked to unregulated iron absorption and the development of hemochromatosis. This mutation was analyzed to determine if heterozygosity is present at greater than expected frequency in superdonors. It is present in 21 (15.2%) of the superdonors. This is higher than the reported frequency of 10–12% in Caucasians but did not reach statistical significance. The JAK-2 mutation is strongly associated with polycythemia vera and other myeloproliferative disorders. None of the superdonors had this mutation. In summary, superdonors are able to frequently donate whole blood with a lower than expected frequency of low HCT deferral despite having very low iron stores. Many, but not all, superdonors take either multiple vitamins with iron or an iron supplement that partially accounts for their ability to repeatedly meet the HCT requirement for whole blood donation. A key biochemical characteristic of superdonors that also contributes to their ability to repeatedly donate whole blood is greatly reduced serum hepcidin concentration that allows maximal intestinal iron absorption. Genetic analyses revealed that there is a trend towards an increased prevalence of heterozygosity for the C282Y mutation that may allow some superdonors to efficiently absorb intestinal iron and donate frequently without low HCT deferral, but no evidence for presence of the JAK-2 mutation indicating that undiagnosed polycythemia vera is not a common cause for successful repeated blood donation by superdonors.
Abstract
The radio astronomy satellite HALCA was launched by the Institute of Space and Astronautical Science in 1997 February to participate in Very Long Baseline Interferometry (VLBI) observations ...with arrays of ground radio telescopes. HALCA is the main element of the VLBI Space Observatory Programme (VSOP), a complex international endeavor involving over 25 ground radio telescopes, five tracking stations and three correlators. Simultaneous observations with HALCA's 8 meter diameter radio telescope and ground radio telescopes synthesize a radio telescope over twice the size of the Earth, enabling the highest resolution 1.6 GHz and 5 GHz images to be made.
Leptin was originally believed to be an exclusively adipocyte-derived hormone regulating appetite and energy balance. It has recently become apparent that leptin is actively expressed in a number of ...other tissues including the CNS and pituitary, as well as brain- and pituitary-derived cell lines. However, the factors controlling leptin expression in cells of neuroectodermal origin are unknown. The mouse leptin gene 5′-flanking DNA contains multiple AP-1 and SRF-1 binding sites as well as a consensus CRE site at −491 to −482 bp. In addition, a number of potential PIT1 and Oct-1 binding sites may contribute to leptin gene transcription in pituitary and brain. We have used leptin promoter-luciferase reporter constructs to examine the regulation of the leptin promoter in 3T3-L1 preadipocytes, C6 glioma cells, and GH3 pituitary cells in response to serum and hormonal stimuli. Cells were transiently transfected with reporter constructs containing either the proximal 500 bp of the leptin promoter (−500-luc) or 6000 bp of the leptin gene 5′ flanking region (−6000-luc). Functional analysis indicates that the leptin promoter is constitutively active in all 3 cell lines. Transcriptional activity was significantly higher with a −500 to +9 promoter than with a construct containing −6000 to +9 bp of 5′ flanking DNA, indicating the presence of repressor elements which may contribute to the tissue-specific regulation of leptin expression. However, qualitatively similar results were observed with both constructs in response to serum and hormonal manipulation. Leptin promoter activity was significantly stimulated by serum in all cell lines, although to varying extents. In contrast, the response of the leptin promoter to insulin, IGF-1 and dibutyryl cAMP was cell-type specific and dependent on the presence or absence of FBS in the culture medium. Insulin, IGF-1 and dibutyryl cAMP each caused an approximately two-fold stimulation of leptin promoter activity in 3T3-L1 cells under serum-free conditions, but had no significant effect in the presence of 10% FBS. In contrast, dibutyryl cAMP markedly stimulated leptin promoter activity (5–8-fold) in C6 or GH3 cells in the presence or absence of FBS, whereas insulin or IGF-1 had minimal effects. These findings support our previous studies on the regulation of leptin steady state mRNA levels in C6 cells and demonstrate tissue-specific differences in the regulation of leptin gene transcription in adipose vs. neuroectodermal tissues.
INTRODUCTION:
Recent studies at sites in northern Australia have reported severe and rapid decline of several native mammal species, notwithstanding an environmental context (small human population ...size, limited habitat loss, substantial reservation extent) that should provide relative conservation security. All of the more speciose taxonomic groups of mammals in northern Australia have some species for which their conservation status has been assessed as threatened, with 53 % of dasyurid, 47 % of macropod and potoroid, 33 % of bandicoot and bilby, 33 % of possum, 30 % of rodent, and 24 % of bat species being assessed as extinct, threatened or near threatened. However, the geographical extent and timing of declines, and their causes, remain poorly resolved, limiting the application of remedial management actions.
MATERIAL AND METHODS:
Focusing on the tropical savannas of northern Australia, this paper reviews disparate recent and ongoing studies that provide information on population trends across a broader geographic scope than the previously reported sites, and examines the conservation status and trends for mammal groups (bats, macropods) not well sampled in previous monitoring studies. It describes some diverse approaches of studies seeking to document conservation status and trends, and of the factors that may be contributing to observed patterns of decline.
RESULTS AND DISCUSSION:
Current trends and potential causal factors for declines . The studies reported demonstrate that the extent and timing of impacts and threats have been variable across the region, although there is a general gradational pattern of earlier and more severe decline from inland lower rainfall areas to higher rainfall coastal regions. Some small isolated areas appear to have retained their mammal species, as have many islands which remain critical refuges. There is now some compelling evidence that predation by feral cats is implicated in the observed decline, with those impacts likely to be exacerbated by prevailing fire regimes (frequent, extensive and intense fire), by reduction in ground vegetation cover due to livestock and, in some areas, by 'control' of dingoes. However the impacts of dingoes may be complex, and are not yet well resolved in this area. The relative impacts of these individual factors vary spatially (with most severe impacts in higher rainfall and more rugged areas) and between different mammal species, with some species responding idiosyncratically: the most notable example is the rapid decline of the northern quoll ( Dasyurus hallucatus ) due to poisoning by the introduced cane toad ( Rhinella marina ), which continues to spread extensively across northern Australia. The impact of disease, if any, remains unresolved.
CONSERVATION MANAGEMENT RESPONSES:
Recovery of the native mammal fauna may be impossible in some areas. However, there are now examples of rapid recovery following threat management. Priority conservation actions include: enhanced biosecurity for important islands, establishment of a network of feral predator exclosures, intensive fire management (aimed at increasing the extent of longer-unburnt habitat and in delivering fine scale patch burning), reduction in feral stock in conservation reserves, and acquisition for conservation purposes of some pastoral lands in areas that are significant for mammal conservation.
Some models of visual cortical development are based on the assumption that the tangential organization of V1 is not determined prior to visual experience. In these models, correlated binocular ...activity is a key element in the formation of visual cortical columns, and when the degree of interocular correlation is reduced the models predict an increase in column spacing. To examine this prediction we measured the spacing of columns, as defined by cytochrome oxidase (CO) blobs, in the visual cortex of monkeys whose binocular vision was either normal or disrupted by a strabismus. The spatial distribution of blobs was examined in seven normal and five strabismic macaques. Tangential sections through the upper layers of the visual cortex were stained to reveal the two-dimensional (2D) pattern of CO blobs. Each blob was localized and their center-to-center spacing, packing arrangement and density were calculated using 2D nearest-neighbor spatial analyses. The mean center-to-center spacing of blobs (590 microm for normally reared and 598 microm for strabismic macaques) and the mean density of blobs (3.67 blobs/mm2 for normally reared and 3.45 blobs/mm2 for strabismic macaques) were not significantly different. In addition, the 2D packing arrangement of the blobs was not affected by strabismus. While it is clear that neural activity plays a key role in the elaboration and refinement of ocular dominance cortical modules, we conclude that it does not determine the spatial period of the pattern of CO blobs. This suggests that aspects of the neural circuitry underlying the columnar architecture of the visual cortex are established prenatally and its fundamental periodicity is not modifiable by experience.
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