Renal and Blood Pressure Response to a High-Salt Diet in Mice With Reduced Global Expression of the Glucocorticoid Receptor

Salt-sensitive hypertension is common in glucocorticoid excess. Glucocorticoid resistance also presents with hypercortisolemia and hypertension but the relationship between salt intake and blood pressure (BP) is not well defined. GRβgeo/+ mice have global glucocorticoid receptor (GR) haploinsufficiency and increased BP. Here we examined the effect of high salt diet on BP, salt excretion and renal blood flow in GRβgeo/+mice. Basal BP was ∼10 mmHg higher in male GRβgeo/+ mice than in GR+/+ littermates. This modest increase was amplified by ∼10 mmHg following a high-salt diet in GRβgeo/+ mice. High salt reduced urinary aldosterone excretion but increased renal mineralocorticoid receptor expression in both genotypes. Corticosterone, and to a lesser extent deoxycorticosterone, excretion was increased in GRβgeo/+ mice following a high-salt challenge, consistent with enhanced 24 h production. GR+/+ mice increased fractional sodium excretion and reduced renal vascular resistance during the high salt challenge, retaining neutral sodium balance. In contrast, sodium excretion and renal vascular resistance did not adapt to high salt in GRβgeo/+ mice, resulting in transient sodium retention and sustained hypertension. With high-salt diet, Slc12a3 and Scnn1a mRNAs were higher in GRβgeo/+ than controls, and this was reflected in an exaggerated natriuretic response to thiazide and benzamil, inhibitors of NCC and ENaC, respectively. Reduction in GR expression causes salt-sensitivity and an adaptive failure of the renal vasculature and tubule, most likely reflecting sustained mineralocorticoid receptor activation. This provides a mechanistic basis to understand the hypertension associated with loss-of-function polymorphisms in GR in the context of habitually high salt intake

Challenges facing the Family Farm - proceedings of a seminar

The papers put forward should be valuable reference to all farmers in the wheatbelt. to bridge the gap between experts and farmers. My aim in organising this seminar was an attempt to bridge the gap between experts and farmers

Breakpoint characterization of large deletions in EXT1 or EXT2 in 10 Multiple Osteochondromas families

<p>Abstract</p> <p>Background</p> <p>Osteochondromas (cartilage-capped bone tumors) are by far the most commonly treated of all primary benign bone tumors (50%). In 15% of cases, these tumors occur in the context of a hereditary syndrome called multiple osteochondromas (MO), an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped bone tumors at children's metaphyses. MO is caused by various mutations in <it>EXT1 </it>or <it>EXT2</it>, whereby large genomic deletions (single-or multi-exonic) are responsible for up to 8% of MO-cases.</p> <p>Methods</p> <p>Here we report on the first molecular characterization of ten large <it>EXT1</it>- and <it>EXT2</it>-deletions in MO-patients. Deletions were initially indentified using MLPA or FISH analysis and were subsequently characterized using an MO-specific tiling path array, allele-specific PCR-amplification and sequencing analysis.</p> <p>Results</p> <p>Within the set of ten large deletions, the deleted regions ranged from 2.7 to 260 kb. One <it>EXT2 </it>exon 8 deletion was found to be recurrent. All breakpoints were located outside the coding exons of <it>EXT1 </it>and <it>EXT2</it>. Non-allelic homologous recombination (NAHR) mediated by <it>Alu</it>-sequences, microhomology mediated replication dependent recombination (MMRDR) and non-homologous end-joining (NHEJ) were hypothesized as the causal mechanisms in different deletions.</p> <p>Conclusions</p> <p>Molecular characterization of <it>EXT1</it>- and <it>EXT2</it>-deletion breakpoints in MO-patients indicates that NAHR between <it>Alu-</it>sequences as well as NHEJ are causal and that the majority of these deletions are nonrecurring. These observations emphasize once more the huge genetic variability which is characteristic for MO. To our knowledge, this is the first study characterizing large genomic deletions in <it>EXT1 </it>and <it>EXT2</it>.</p

West Nile Virus Genetic Diversity is Maintained during Transmission by Culex pipiens quinquefasciatus Mosquitoes

Due to error-prone replication, RNA viruses exist within hosts as a heterogeneous population of non-identical, but related viral variants. These populations may undergo bottlenecks during transmission that stochastically reduce variability leading to fitness declines. Such bottlenecks have been documented for several single-host RNA viruses, but their role in the population biology of obligate two-host viruses such as arthropod-borne viruses (arboviruses) in vivo is unclear, but of central importance in understanding arbovirus persistence and emergence. Therefore, we tracked the composition of West Nile virus (WNV; Flaviviridae, Flavivirus) populations during infection of the vector mosquito, Culex pipiens quinquefasciatus to determine whether WNV populations undergo bottlenecks during transmission by this host. Quantitative, qualitative and phylogenetic analyses of WNV sequences in mosquito midguts, hemolymph and saliva failed to document reductions in genetic diversity during mosquito infection. Further, migration analysis of individual viral variants revealed that while there was some evidence of compartmentalization, anatomical barriers do not impose genetic bottlenecks on WNV populations. Together, these data suggest that the complexity of WNV populations are not significantly diminished during the extrinsic incubation period of mosquitoes

Global Surveillance of Emerging Influenza Virus Genotypes by Mass Spectrometry

Effective influenza surveillance requires new methods capable of rapid and inexpensive genomic analysis of evolving viral species for pandemic preparedness, to understand the evolution of circulating viral species, and for vaccine strain selection. We have developed one such approach based on previously described broad-range reverse transcription PCR/electrospray ionization mass spectrometry (RT-PCR/ESI-MS) technology.Analysis of base compositions of RT-PCR amplicons from influenza core gene segments (PB1, PB2, PA, M, NS, NP) are used to provide sub-species identification and infer influenza virus H and N subtypes. Using this approach, we detected and correctly identified 92 mammalian and avian influenza isolates, representing 30 different H and N types, including 29 avian H5N1 isolates. Further, direct analysis of 656 human clinical respiratory specimens collected over a seven-year period (1999-2006) showed correct identification of the viral species and subtypes with >97% sensitivity and specificity. Base composition derived clusters inferred from this analysis showed 100% concordance to previously established clades. Ongoing surveillance of samples from the recent influenza virus seasons (2005-2006) showed evidence for emergence and establishment of new genotypes of circulating H3N2 strains worldwide. Mixed viral quasispecies were found in approximately 1% of these recent samples providing a view into viral evolution.Thus, rapid RT-PCR/ESI-MS analysis can be used to simultaneously identify all species of influenza viruses with clade-level resolution, identify mixed viral populations and monitor global spread and emergence of novel viral genotypes. This high-throughput method promises to become an integral component of influenza surveillance

Age evaluation and causation of rock-slope failures along the western margin of the Antrim Lava Group (ALG), Northern Ireland, based on cosmogenic isotope (36Cl) surface exposure dating.

The temporal pattern of postglacial rock-slope failure in a glaciated upland area of Ireland (the western margin of the Antrim Lava Group) was evaluated using both 36Cl exposure dating of surface boulders on run-out debris and 14C dating of basal organic soils from depressions on the debris. The majority of the 36Cl ages (~ 21–15 ka) indicate that major failures occurred during or immediately following local deglaciation (~ 18–17 ka). Other ages (~ 14–9 ka) suggest some later, smaller-scale failures during the Lateglacial and/or early Holocene. The 14C ages (2.36–0.15 cal ka BP) indicate the very late onset of organic accumulation and do not provide close limiting age constraints. Rock-slope failure during or immediately following local deglaciation was probably in response to some combination of glacial debuttressing, slope steepening and paraglacial stress release. Later failures may have been triggered by seismic activity associated with glacio-isostatic crustal uplift and/or permafrost degradation consequent upon climate change. The 36Cl ages support the findings of previous studies that show the deglacial - Lateglacial period in northwest Ireland and Scotland to have been one of enhanced rock-slope failure

Small rock-slope failures conditioned by Holocene permafrost degradation:a new approach and conceptual model based on Schmidt-hammer exposure-age dating, Jotunheimen, southern Norway

Rock-slope failures (RSFs) constitute significant natural hazards but the geophysical processes which control their timing are poorly understood. However, robust chronologies can provide valuable information on the environmental controls on RSF occurrence: information which can inform models of RSF activity in response to climatic forcing. This paper uses Schmidt-hammer exposure-age dating (SHD) of boulder deposits to construct a detailed regional Holocene chronology of the frequency and magnitude of small rock-slope failures (SRSFs) in Jotunheimen, Norway. By focusing on the depositional fans of SRSFs (≤ 103 m3), rather than on the corresponding features of massive RSFs (~108 m3), 92 single-event RSFs are targeted for chronology building. A weighted SHD age-frequency distribution and probability density function analysis indicate four centennial- to millennial-scale periods of enhanced SRSF frequency, with a dominant mode at ~4.5 ka. Using change detection and discreet Meyer wavelet analysis, in combination with existing permafrost depth models, we propose that enhanced SRSF activity was primarily controlled by permafrost degradation. Long-term relative change in permafrost depth provides a compelling explanation for the high-magnitude departures from the SRSF background rate and accounts for (i1) the timing of peak SRSF frequency, (2ii) the significant lag (~2.2 ka) between the Holocene Thermal Maximum and the SRSF frequency peak, and (3iii) the marked decline in frequency in the late-Holocene. This interpretation is supported by geomorphological evidence, as the spatial distribution of SRSFs is strongly correlated with the aspect-dependent lower altitudinal limit of mountain permafrost in cliff faces. Results are indicative of a causal relationship between episodes of relatively warm climate, permafrost degradation and the transition to a seasonal-freezing climatic regime. This study highlights permafrost degradation as a conditioning factor for cliff collapse, and hence the importance of paraperiglacial processes; a result with implications for slope instability in glacial and periglacial environments under global warming scenarios

Glucocorticoids and renal sodium transport:implications for hypertension and salt-sensitivity

The clinical manifestations of glucocorticoid excess include central obesity, hyperglycaemia, dyslipidaemia, electrolyte abnormalities and hypertension. A century on from Cushing's original case study, these cardinal features are prevalent in industrialized nations. Hypertension is the major modifiable risk factor for cardiovascular and renal disease and reflects underlying abnormalities of Na(+) homeostasis. Aldosterone is a master regulator of renal Na(+) transport but here we argue that glucocorticoids are also influential, particularly during moderate excess. The hypothalamic–pituitary–adrenal axis can affect renal Na(+) homeostasis on multiple levels, systemically by increasing mineralocorticoid synthesis and locally by actions on both the mineralocorticoid and glucocorticoid receptors, both of which are expressed in the kidney. The kidney also expresses both of the 11β-hydroxysteroid dehydrogenase (11βHSD) enzymes. The intrarenal generation of active glucocorticoid by 11βHSD1 stimulates Na(+) reabsorption; failure to downregulate the enzyme during adaption to high dietary salt causes salt-sensitive hypertension. The deactivation of glucocorticoid by 11βHSD2 underpins the regulatory dominance for Na(+) transport of mineralocorticoids and defines the ‘aldosterone-sensitive distal nephron’. In summary, glucocorticoids can stimulate renal transport processes conventionally attributed to the renin–angiotensin–aldosterone system. Importantly, Na(+) and volume homeostasis do not exert negative feedback on the hypothalamic–pituitary–adrenal axis. These actions are therefore clinically relevant and may contribute to the pathogenesis of hypertension in conditions associated with elevated glucocorticoid levels, such as the metabolic syndrome and chronic stress

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations