Genetic susceptibility to psoriasis: an emerging picture

Psoriasis is recognized as a complex disease for which multiple genetic and non-genetic factors influence susceptibility. The major susceptibility locus resides in the MHC class I region and, until relatively recently, evidence for non-MHC loci was inconsistent. Like many common diseases, knowledge of the genetic basis of this condition has been advanced dramatically in recent times with the advent of genome-wide association studies using single nucleotide polymorphisms. Here, we give an overview of current knowledge of genetic risk factors for psoriasis and consider emerging studies that may further add to our understanding of the genetic basis of the disease

Elevated blood pressure, heart rate and body temperature in mice lacking the XL alpha s protein of the Gnas locus is due to increased sympathetic tone

NEW FINDINGS: What is the central question of this study? Previously, we showed that Gnasxl knock-out mice are lean and hypermetabolic, with increased sympathetic stimulation of adipose tissue. Do these mice also display elevated sympathetic cardiovascular tone? Is the brain glucagon-like peptide-1 system involved? What is the main finding and its importance? Gnasxl knock-outs have increased blood pressure, heart rate and body temperature. Heart rate variability analysis suggests an elevated sympathetic tone. The sympatholytic reserpine had stronger effects on blood pressure, heart rate and heart rate variability in knock-out compared with wild-type mice. Stimulation of the glucagon-like peptide-1 system inhibited parasympathetic tone to a similar extent in both genotypes, with a stronger associated increase in heart rate in knock-outs. Deficiency of Gnasxl increases sympathetic cardiovascular tone. Imbalances of energy homeostasis are often associated with cardiovascular complications. Previous work has shown that Gnasxl-deficient mice have a lean and hypermetabolic phenotype, with increased sympathetic stimulation of adipose tissue. The Gnasxl transcript from the imprinted Gnas locus encodes the trimeric G-protein subunit XLαs, which is expressed in brain regions that regulate energy homeostasis and sympathetic nervous system (SNS) activity. To determine whether Gnasxl knock-out (KO) mice display additional SNS-related phenotypes, we have now investigated the cardiovascular system. The Gnasxl KO mice were ∼20 mmHg hypertensive in comparison to wild-type (WT) littermates (P≤ 0.05) and hypersensitive to the sympatholytic drug reserpine. Using telemetry, we detected an increased waking heart rate in conscious KOs (630 ± 10 versus 584 ± 12 beats min(−1), KO versus WT, P≤ 0.05). Body temperature was also elevated (38.1 ± 0.3 versus 36.9 ± 0.4°C, KO versus WT, P≤ 0.05). To investigate autonomic nervous system influences, we used heart rate variability analyses. We empirically defined frequency power bands using atropine and reserpine and verified high-frequency (HF) power and low-frequency (LF) LF/HF power ratio to be indicators of parasympathetic and sympathetic activity, respectively. The LF/HF power ratio was greater in KOs and more sensitive to reserpine than in WTs, consistent with elevated SNS activity. In contrast, atropine and exendin-4, a centrally acting agonist of the glucagon-like peptide-1 receptor, which influences cardiovascular physiology and metabolism, reduced HF power equally in both genotypes. This was associated with a greater increase in heart rate in KOs. Mild stress had a blunted effect on the LF/HF ratio in KOs consistent with elevated basal sympathetic activity. We conclude that XLαs is required for the inhibition of sympathetic outflow towards cardiovascular and metabolically relevant tissues

Rigid motion revisited: rigid quasilocal frames

We introduce the notion of a rigid quasilocal frame (RQF) as a geometrically natural way to define a "system" in general relativity. An RQF is defined as a two-parameter family of timelike worldlines comprising the worldtube boundary of the history of a finite spatial volume, with the rigidity conditions that the congruence of worldlines is expansion-free (constant size) and shear-free (constant shape). This definition of a system is anticipated to yield simple, exact geometrical insights into the problem of motion in general relativity. It begins by answering the questions what is in motion (a rigid two-dimensional system boundary), and what motions of this rigid boundary are possible. Nearly a century ago Herglotz and Noether showed that a three-parameter family of timelike worldlines in Minkowski space satisfying Born's 1909 rigidity conditions has only three degrees of freedom instead of the six we are familiar with from Newtonian mechanics. We argue that in fact we can implement Born's notion of rigid motion in both flat spacetime (this paper) and arbitrary curved spacetimes containing sources (subsequent papers) - with precisely the expected three translational and three rotational degrees of freedom - provided the system is defined quasilocally as the two-dimensional set of points comprising the boundary of a finite spatial volume, rather than the three-dimensional set of points within the volume.Comment: 10 pages (two column), 24 pages (preprint), 1 figur

Detection of Lyman-alpha Emitting Galaxies at Redshift z=4.55

Studies of the formation and early history of galaxies have been hampered by the difficulties inherent in detecting faint galaxy populations at high redshift. As a consequence, observations at the highest redshifts (3.5 < z < 5) have been restricted to objects that are intrinsically bright. These include quasars, radio galaxies, and some Ly alpha-emitting objects that are very close to (within ~10 kpc) -- and appear to be physically associated with -- quasars. But the extremely energetic processes which make these objects easy to detect also make them unrepresentative of normal (field) galaxies. Here we report the discovery using Keck spectroscopic observations of two Ly alpha-emitting galaxies at redshift z = 4.55, which are sufficiently far from the nearest quasar (~700 kpc) that radiation from the quasar is unlikely to provide the excitation source of the Ly alpha emission. Instead, these galaxies appear to be undergoing their first burst of star formation, at a time when the Universe was less than one billion years old.Comment: 8 pages, 1 landscape table, and 3 PostScript figures. Uses aaspp4.sty, flushrt.sty, aj_pt4.sty, overcite.sty (style macros available from xxx.lanl.gov) Figure 1 is bitmapped to 100 dpi. The original PostScript version of Fig. 1 is available via anonymous ftp to ftp://hubble.ifa.hawaii.edu/pub/preprints To appear in Natur

Effects of Monobutyl and Di(n-butyl) Phthalate in Vitro on Steroidogenesis and Leydig Cell Aggregation in Fetal Testis Explants from the Rat: Comparison with Effects in Vivo in the Fetal Rat and Neonatal Marmoset and in Vitro in the Human

BACKGROUND: Certain phthalates can impair Leydig cell distribution and steroidogenesis in the fetal rat in utero, but it is unknown whether similar effects might occur in the human. OBJECTIVES: Our aim in this study was to investigate the effects of di(n-butyl) phthalate (DBP), or its metabolite monobutyl phthalate (MBP), on testosterone production and Leydig cell aggregation (LCA) in fetal testis explants from the rat and human, and to compare the results with in vivo findings for DBP-exposed rats. We also wanted to determine if DBP/MBP affects testosterone production in vivo in the neonatal male marmoset. METHODS: Fetal testis explants obtained from the rat [gestation day (GD)19.5] and from the human (15–19 weeks of gestation) were cultured for 24–48 hr with or without human chorionic gonadotropin (hCG) or 22R-hydroxycholesterol (22R-OH), and with or without DBP/MBP. Pregnant rats and neonatal male marmosets were dosed with 500 mg/kg/day DBP or MBP. RESULTS: Exposure of rats in utero to DBP (500 mg/kg/day) for 48 hr before GD21.5 induced major suppression of intratesticular testosterone levels and cytochrome P450 side chain cleavage enzyme (P450scc) expression; this short-term treatment induced LCA, but was less marked than longer term (GD13.5–20.5) DBP treatment. In vitro, MBP (10(−3) M) did not affect basal or 22R-OH-stimulated testosterone production by fetal rat testis explants but slightly attenuated hCG-stimulated steroidogenesis; MBP induced minor LCA in vitro. None of these parameters were affected in human fetal testis explants cultured with 10(−3) M MBP for up to 48 hr. Because the in vivo effects of DBP/MBP were not reproduced in vitro in the rat, the absence of MBP effects in vitro on fetal human testes is inconclusive. In newborn (Day 2–7) marmosets, administration of a single dose of 500 mg/kg MBP significantly (p = 0.019) suppressed blood testosterone levels 5 hr later. Similar treatment of newborn co-twin male marmosets for 14 days resulted in increased Leydig cell volume per testis (p = 0.011), compared with co-twin controls; this is consistent with MBP-induced inhibition of steroidogenesis followed by compensatory Leydig cell hyperplasia/hypertrophy. CONCLUSIONS: These findings suggest that MBP/DBP suppresses steroidogenesis by fetal-type Leydig cells in primates as in rodents, but this cannot be studied in vitro

In vitro bioactivity of titanium-doped bioglass

Previous studies have suggested that incorporating relatively small quantities of titanium dioxide into bioactive glasses may result in an increase in bioactivity and hydroxyapatite formation. The present work therefore investigated the in vitro bioactivity of a titanium doped bioglass and compared the results with 45S5 bioglass. Apatite formation was evaluated for bioglass and Ti-bioglass in the presence and absence of foetal calf serum. Scanning electron microscopy (SEM) images were used to evaluate the surface development and energy dispersive X-ray measurements provided information on the elemental ratios. X-ray diffraction spectra confirmed the presence of apatite formation. Cell viability was assessed for bone marrow stromal cells under direct and indirect contact conditions and cell adhesion was assessed using SEM

Cellular and Hormonal Disruption of Fetal Testis Development in Sheep Reared on Pasture Treated with Sewage Sludge

The purpose of this study was to evaluate whether experimental exposure of pregnant sheep to a mixture of environmental chemicals added to pasture as sewage sludge (n = 9 treated animals) exerted effects on fetal testis development or function; application of sewage sludge was undertaken so as to maximize exposure of the ewes to its contents. Control ewes (n = 9) were reared on pasture treated with an equivalent amount of inorganic nitrogenous fertilizer. Treatment had no effect on body weight of ewes, but it reduced body weight by 12–15% in male (n = 12) and female (n = 8) fetuses on gestation day 110. In treated male fetuses (n = 11), testis weight was significantly reduced (32%), as were the numbers of Sertoli cells (34% reduction), Leydig cells (37% reduction), and gonocytes (44% reduction), compared with control fetuses (n = 8). Fetal blood levels of testosterone and inhibin A were also reduced (36% and 38%, respectively) in treated compared with control fetuses, whereas blood levels of luteinizing hormone and follicle-stimulating hormone were unchanged. Based on immunoexpression of anti-Müllerian hormone, cytochrome P450 side chain cleavage enzyme, and Leydig cell cytoplasmic volume, we conclude that the hormone changes in treated male fetuses probably result from the reduction in somatic cell numbers. This reduction could result from fetal growth restriction in male fetuses and/or from the lowered testosterone action; reduced immunoexpression of α-smooth muscle actin in peritubular cells and of androgen receptor in testes of treated animals supports the latter possibility. These findings indicate that exposure of the developing male sheep fetus to real-world mixtures of environmental chemicals can result in major attenuation of testicular development and hormonal function, which may have consequences in adulthood

Grain-Size Analysis of the Late Pleistocene Sediments in the Corinth Rift: Insights into Strait Influenced Hydrodynamics and Provenance of an Active Rift Basin

Under embargo until: 2023-12-08Grain-size analysis of the sediments in borehole M0079A, which is located in the Corinth Rift, was used to explore hydrodynamic conditions and provenance in the Late Pleistcene Corinth Rift. Grain-size populations that were sensitive to the sedimentary environments were characterized by frequency distribution, particle size-standard deviation, and probability cumulative curves. Our results indicate the grain-size population component in the range 0.15-0.25 μm may be used as a sensitive proxy for hyperpycnal flows, which have commonly been triggered by river floods from the southern margin of the rift since ca. 0.593-0.613 Ma. The high-density plumes derived from the longer rivers of the southern rift that were prevalent before ca. 0.593-0.613 Ma. When sediment is supplied as hemipelagic deposition, the proportion of the total grain-size population that is in the 0.3-0.5 μm range becomes an index for suspension fall-out deposits. The core shows coarser sediments during the marine periods and this may be linked to the current circulation related to the Ishtmia Strait opening. The study thus illustrates how the establishment of interbasinal straits can influence the details of sedimentary hydrodynamics in the deep- water axis of an adjacent depocenter.acceptedVersio

Survival enhancing indications for coronary artery bypass graft surgery in California

<p>Abstract</p> <p>Background</p> <p>Coronary artery bypass graft (CABG) surgery is performed because of anticipated survival benefit, improvement in quality of life, or both. We performed this study to explore variations in clinical indications for CABG surgery among California hospitals and surgeons.</p> <p>Methods</p> <p>Using California CABG Outcomes Reporting Program data, we classified all isolated CABG cases in 2003–2004 as having "probable survival enhancing indications (SEIs)", "possible SEIs" or "non-SEIs." Patient and hospital characteristics associated with SEIs were examined.</p> <p>Results</p> <p>While 82.9% of CABG were performed for probable SEIs, the range extended from 68% to 96% among hospitals and 51% to 100% among surgeons. SEI rates were higher among patients aged ≥ 65 compared with those aged 18–64 (Adjusted Odds Ratio [AOR] > 1.29 for age groups 65–69, 70–74 and ≥ 75; all p < 0.001), among Asians and Native Americans compared with Caucasians (AOR 1.22 and 1.15, p < 0.001); and among patients with hypertension, peripheral vascular disease, diabetes, cerebrovascular disease and congestive heart failure compared to patients without these conditions (AOR > 1.09, all p < 0.001). Variations in indications for surgery were more strongly related to patient mix than to surgeon or hospital effects (intraclass correlation [ICC] = 0.04 for hospital; ICC = 0.01 for surgeon).</p> <p>Conclusion</p> <p>California hospitals and surgeons vary in their distribution of indications for CABG surgery. Further research is required to identify the roles of market factors, referral patterns, patient preferences, and local clinical culture in producing the observed variations.</p

Exposure Assessment in the National Children’s Study: Introduction

The science of exposure assessment is relatively new and evolving rapidly with the advancement of sophisticated methods for specific measurements at the picogram per gram level or lower in a variety of environmental and biologic matrices. Without this measurement capability, environmental health studies rely on questionnaires or other indirect means as the primary method to assess individual exposures. Although we use indirect methods, they are seldom used as stand-alone tools. Analyses of environmental and biologic samples have allowed us to get more precise data on exposure pathways, from sources to concentrations, to routes, to exposure, to doses. They also often allow a better estimation of the absorbed dose and its relation to potential adverse health outcomes in individuals and in populations. Here, we make note of various environmental agents and how best to assess exposure to them in the National Children’s Study—a longitudinal epidemiologic study of children’s health. Criteria for the analytical method of choice are discussed with particular emphasis on the need for long-term quality control and quality assurance measures