A nullimorphic ERLIN2 mutation defines a complicated hereditary spastic paraplegia locus (SPG18)

Hereditary Spastic Paraplegia (HSP) is a clinically and genetically heterogeneous group of neurological disorders that are characterized by progressive spasticity of the lower extremities. We describe an extended consanguineous Saudi family in which HSP is linked to SPG18, a previously reported autosomal recessive locus, and show that it is associated with a nullimorphic deletion of ERLIN2, a component of endoplasmic reticulum associated degradation. This finding adds to the growing diversity of cellular functions that are now known to be involved in the maintenance of the corticospinal tract neurons

The "Ram Effect": A "Non-Classical" Mechanism for Inducing LH Surges in Sheep

During spring sheep do not normally ovulate but exposure to a ram can induce ovulation. In some ewes an LH surge is induced immediately after exposure to a ram thus raising questions about the control of this precocious LH surge. Our first aim was to determine the plasma concentrations of oestradiol (E2) E2 in anoestrous ewes before and after the "ram effect" in ewes that had a "precocious" LH surge (starting within 6 hours), a "normal" surge (between 6 and 28h) and "late» surge (not detected by 56h). In another experiment we tested if a small increase in circulating E2 could induce an LH surge in anoestrus ewes. The concentration of E2 significantly was not different at the time of ram introduction among ewes with the three types of LH surge. "Precocious" LH surges were not preceded by a large increase in E2 unlike "normal" surges and small elevations of circulating E2 alone were unable to induce LH surges. These results show that the "precocious" LH surge was not the result of E2 positive feedback. Our second aim was to test if noradrenaline (NA) is involved in the LH response to the "ram effect". Using double labelling for Fos and tyrosine hydroxylase (TH) we showed that exposure of anoestrous ewes to a ram induced a higher density of cells positive for both in the A1 nucleus and the Locus Coeruleus complex compared to unstimulated controls. Finally, the administration by retrodialysis into the preoptic area, of NA increased the proportion of ewes with an LH response to ram odor whereas treatment with the α1 antagonist Prazosin decreased the LH pulse frequency and amplitude induced by a sexually active ram. Collectively these results suggest that in anoestrous ewes NA is involved in ram-induced LH secretion as observed in other induced ovulators

An Exploratory Study of Primary Care Physician Decision Making Regarding Total Joint Arthroplasty

BACKGROUND: For patients to experience the benefits of total joint arthroplasty (TJA), primary care physicians (PCPs) ought to know when to refer a patient for TJA and/or optimize nonsurgical treatment options for osteoarthritis (OA). OBJECTIVE: To evaluate the ability of physicians to make clinical treatment decisions. DESIGN AND PARTICIPANTS: A survey, using ten clinical vignettes, of PCPs in Indiana. MEASUREMENTS: A test score (range 0 to 10) was computed based on the number of correct answers consistent with published explicit appropriateness criteria for TJA. We also collected demographic characteristics and physicians’ perceived success rate of TJA in terms of pain relief and functional improvement. RESULTS: There were 149 PCPs (response rate = 61%) who participated. The mean test score was 6.5 ± 1.5. Only 17% correctly identified the published success rate of TJA (i.e., ≥90%). In multivariate analysis, the only physician-related variables associated with test score were ethnicity, board status, and perceived success rate of TJA. Physicians who were white (P = .001), board-certified (P = .04), and perceived a higher success rate of TJA (P = .004) had higher test scores. CONCLUSIONS: PCP knowledge with respect to guideline-concordant care for OA could be improved, specifically in deciding when to consider TJA versus optimizing nonsurgical options. Moreover, the perception of the success rate of TJA may influence a clinician’s decision making

Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer.

Inhibitors against the p110δ isoform of phosphoinositide-3-OH kinase (PI(3)K) have shown remarkable therapeutic efficacy in some human leukaemias. As p110δ is primarily expressed in leukocytes, drugs against p110δ have not been considered for the treatment of solid tumours. Here we report that p110δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. We demonstrate that p110δ inactivation in regulatory T cells unleashes CD8(+) cytotoxic T cells and induces tumour regression. Thus, p110δ inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology

Deformation-related volcanism in the Pacific Ocean linked to the Hawaiian-Emperor bend

Ocean islands, seamounts and volcanic ridges are thought to form above mantle plumes. Yet, this mechanism cannot explain many volcanic features on the Pacific Ocean floor and some might instead be caused by cracks in the oceanic crust linked to the reorganization of plate motions. A distinctive bend in the Hawaiian–Emperor volcanic chain has been linked to changes in the direction of motion of the Pacific Plate, movement of the Hawaiian plume, or a combination of both. However, these links are uncertain because there is no independent record that precisely dates tectonic events that affected the Pacific Plate. Here we analyse the geochemical characteristics of lava samples collected from the Musicians Ridges, lines of volcanic seamounts formed close to the Hawaiian–Emperor bend. We find that the geochemical signature of these lavas is unlike typical ocean island basalts and instead resembles mid-ocean ridge basalts. We infer that the seamounts are unrelated to mantle plume activity and instead formed in an extensional setting, due to deformation of the Pacific Plate. 40Ar/39Ar dating reveals that the Musicians Ridges formed during two time windows that bracket the time of formation of the Hawaiian–Emperor bend, 53–52 and 48–47 million years ago. We conclude that the Hawaiian–Emperor bend was formed by plate–mantle reorganization, potentially triggered by a series of subduction events at the Pacific Plate margins

The potential monetary benefits of reclaiming hazardous waste sites in the Campania region: an economic evaluation

BACKGROUND: Evaluating the economic benefit of reducing negative health outcomes resulting from waste management is of pivotal importance for designing an effective waste policy that takes into account the health consequences for the populations exposed to environmental hazards. Despite the high level of Italian and international media interest in the problem of hazardous waste in Campania little has been done to reclaim the land and the waterways contaminated by hazardous waste. OBJECTIVE: This study aims to reduce the uncertainty about health damage due to waste exposure by providing for the first time a monetary valuation of health benefits arising from the reclamation of hazardous waste dumps in Campania. METHODS: First the criteria by which the landfills in the Campania region, in particular in the two provinces of Naples and Caserta, have been classified are described. Then, the annual cases of premature death and fatal cases of cancers attributable to waste exposure are quantified. Finally, the present value of the health benefits from the reclamation of polluted land is estimated for each of the health outcomes (premature mortality, fatal cancer and premature mortality adjusted for the cancer premium). Due to the uncertainty about the time frame of the benefits arising from reclamation, the latency of the effects of toxic waste on human health and the lack of context specific estimates of the Value of Preventing a Fatality (VPF), extensive sensitivity analyses are performed. RESULTS: There are estimated to be 848 cases of premature mortality and 403 cases of fatal cancer per year as a consequence of exposure to toxic waste. The present value of the benefit of reducing the number of waste associated deaths after adjusting for a cancer premium is euro11.6 billion. This value ranges from euro5.4 to euro20.0 billion assuming a time frame for benefits of 10 and 50 years respectively. CONCLUSION: This study suggests that there is a strong economic argument for both reclaiming the land contaminated with hazardous waste in the two provinces of Naples and Caserta and increasing the control of the territory in order to avoid the creation of new illegal dump sites

Perturbation of lipids and glucose metabolism associated with previous 2,4-D exposure: a cross-sectional study of NHANES III data, 1988-1994

<p>Abstract</p> <p>Background</p> <p>Results from previous population studies showed that mortality rates from acute myocardial infarction and type-2 diabetes during the 1980s and 1990s in rural, agricultural counties of Minnesota, Montana, North and South Dakota, were higher in counties with a higher level of spring wheat farming than in counties with lower levels of this crop. Spring wheat, one of the major field crops in these four states, was treated for 85% or more of its acreage with chlorophenoxy herbicides. In the current study NHANES III data were reviewed for associations of 2,4-dichlorophenoxy acetic acid (2,4-D) exposure, one of the most frequently used chlorophenoxy herbicides, with risk factors that are linked to the pathogenesis of acute myocardial infarction and type-2 diabetes, such as dyslipidemia and impaired glucose metabolism.</p> <p>Methods</p> <p>To investigate the toxicity pattern of chlorophenoxy herbicides, effects of a previous 2,4-D exposure were assessed by comparing levels of lipids, glucose metabolism, and thyroid stimulating hormone in healthy adult NHANES III subjects with urinary 2,4-D above and below the level of detection, using linear regression analysis. The analyses were conducted for all available subjects and for two susceptible subpopulations characterized by high glycosylated hemoglobin (upper 50^thpercentile) and low thyroxine (lower 50^thpercentile).</p> <p>Results</p> <p>Presence of urinary 2,4-D was associated with a decrease of HDL levels: 8.6% in the unadjusted data (p-value = 0.006), 4.8% in the adjusted data (p-value = 0.08), and 9% in the adjusted data for the susceptible subpopulation with low thyroxine (p-value = 0.02). An effect modification of the inverse triglycerides-HDL relation was observed in association with 2,4-D. Among subjects with low HDL, urinary 2,4-D was associated with increased levels of triglycerides, insulin, C-peptide, and thyroid stimulating hormone, especially in the susceptible subpopulations. In contrast, subjects with high HDL did not experience adverse 2,4-D associated effects.</p> <p>Conclusions</p> <p>The results indicate that exposure to 2,4-D was associated with changes in biomarkers that, based on the published literature, have been linked to risk factors for acute myocardial infarction and type-2 diabetes.</p

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector

This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}$and correspond to an integrated luminosity of$4.6\;{\rm f}{{{\rm b}}^{-1}}$. The measurement is performed by reconstructing the boosted W or Z bosons in single jets. The reconstructed jet mass is used to identify the W and Z bosons, and a jet substructure method based on energy cluster information in the jet centre-of-mass frame is used to suppress the large multi-jet background. The cross-section for events with a hadronically decaying W or Z boson, with transverse momentum${{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}$and pseudorapidity$|\eta |\lt 1.9$, is measured to be${{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques

Search for direct pair production of the top squark in all-hadronic final states in proton-proton collisions at s√=8 TeV with the ATLAS detector

The results of a search for direct pair production of the scalar partner to the top quark using an integrated luminosity of 20.1fb−1 of proton–proton collision data at √s = 8 TeV recorded with the ATLAS detector at the LHC are reported. The top squark is assumed to decay via t˜→tχ˜01 or t˜→ bχ˜±1 →bW(∗)χ˜01 , where χ˜01 (χ˜±1 ) denotes the lightest neutralino (chargino) in supersymmetric models. The search targets a fully-hadronic final state in events with four or more jets and large missing transverse momentum. No significant excess over the Standard Model background prediction is observed, and exclusion limits are reported in terms of the top squark and neutralino masses and as a function of the branching fraction of t˜ → tχ˜01 . For a branching fraction of 100%, top squark masses in the range 270–645 GeV are excluded for χ˜01 masses below 30 GeV. For a branching fraction of 50% to either t˜ → tχ˜01 or t˜ → bχ˜±1 , and assuming the χ˜±1 mass to be twice the χ˜01 mass, top squark masses in the range 250–550 GeV are excluded for χ˜01 masses below 60 GeV