Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency

Artemisinin and its derivatives (ARTs) are frontline antimalarial drugs. However, ART monotherapy is associated with a high frequency of recrudescent infection, resulting in treatment failure. A subset of parasites is thought to undergo ART-induced latency, but the mechanisms remain unknown. Here, we report that ART treatment results in phosphorylation of the parasite eukaryotic initiation factor-2α (eIF2α), leading to repression of general translation and latency induction. Enhanced phosphorylated eIF2α correlates with high rates of recrudescence following ART, and inhibiting eIF2α dephosphorylation renders parasites less sensitive to ART treatment. ART-induced eIF2α phosphorylation is mediated by the Plasmodium eIF2α kinase, PK4. Overexpression of a PK4 dominant-negative or pharmacological inhibition of PK4 blocks parasites from entering latency and abolishes recrudescence after ART treatment of infected mice. These results show that translational control underlies ART-induced latency and that interference with this stress response may resolve the clinical problem of recrudescent infection

Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study

<p>Background: Randomized controlled trials have shown the importance of tight glucose control in type 1 diabetes (T1DM), but few recent studies have evaluated the risk of cardiovascular disease (CVD) and all-cause mortality among adults with T1DM. We evaluated these risks in adults with T1DM compared with the non-diabetic population in a nationwide study from Scotland and examined control of CVD risk factors in those with T1DM.</p> <p>Methods and Findings: The Scottish Care Information-Diabetes Collaboration database was used to identify all people registered with T1DM and aged ≥20 years in 2005–2007 and to provide risk factor data. Major CVD events and deaths were obtained from the national hospital admissions database and death register. The age-adjusted incidence rate ratio (IRR) for CVD and mortality in T1DM (n = 21,789) versus the non-diabetic population (3.96 million) was estimated using Poisson regression. The age-adjusted IRR for first CVD event associated with T1DM versus the non-diabetic population was higher in women (3.0: 95% CI 2.4–3.8, p<0.001) than men (2.3: 2.0–2.7, p<0.001) while the IRR for all-cause mortality associated with T1DM was comparable at 2.6 (2.2–3.0, p<0.001) in men and 2.7 (2.2–3.4, p<0.001) in women. Between 2005–2007, among individuals with T1DM, 34 of 123 deaths among 10,173 who were <40 years and 37 of 907 deaths among 12,739 who were ≥40 years had an underlying cause of death of coma or diabetic ketoacidosis. Among individuals 60–69 years, approximately three extra deaths per 100 per year occurred among men with T1DM (28.51/1,000 person years at risk), and two per 100 per year for women (17.99/1,000 person years at risk). 28% of those with T1DM were current smokers, 13% achieved target HbA1c of <7% and 37% had very poor (≥9%) glycaemic control. Among those aged ≥40, 37% had blood pressures above even conservative targets (≥140/90 mmHg) and 39% of those ≥40 years were not on a statin. Although many of these risk factors were comparable to those previously reported in other developed countries, CVD and mortality rates may not be generalizable to other countries. Limitations included lack of information on the specific insulin therapy used.</p> <p>Conclusions: Although the relative risks for CVD and total mortality associated with T1DM in this population have declined relative to earlier studies, T1DM continues to be associated with higher CVD and death rates than the non-diabetic population. Risk factor management should be improved to further reduce risk but better treatment approaches for achieving good glycaemic control are badly needed.</p&gt

Increased dietary protein in the second trimester of gestation increases live weight gain and carcass composition in weaner calves to 6 months of age

Genetically similar nulliparous Polled Hereford heifers from a closed pedigree herd were used to evaluate the effects of dietary protein during the first and second trimester of gestation upon fetal, placental and postnatal growth. Heifers were randomly allocated into two groups at 35d post AI (35dpc) to a single bull and fed High (15.7%CP) or Low (5.9%CP) protein in the first trimester (T1). At 90dpc, half of each nutritional treatment group changed to a High or Low protein diet for the second trimester until 180dpc (T2). High protein intake in the second trimester increased birthweight in females (P = 0.05) but there was no effect of treatment upon birthweight when taken over both sexes. Biparietal diameter was significantly increased by high protein in the second trimester with the effect being greater in the female (P = 0.02) but also significant overall (P = 0.05). Placental weight was positively correlated with birth weight, fibroblast volume, and relative blood vessel volume (P < 0.05). Placental fibroblast density was increased and trophoblast volume decreased in the high protein first trimester treatment group (P <0.05). There was a trend for placental weight to be increased by high protein in the second trimester (P = 0.06). Calves from heifers fed the high protein treatment in the second trimester weighed significantly more on all occasions preweaning (at one month (P = 0.0004), 2 mths (P = 0.006), 3 mths (P = 0.002), 4 mths (P = 0.01), 5 mths (P = 41 0.03), 6 mths (P = 0.001)), and grew at a faster rate over the 6 month period. By 6 mths of age the calves from heifers fed high nutrition in the second trimester weighed 33kg heavier than those fed the low diet in the second trimester. These results suggest that dietary protein in early pregnancy alters the development of the bovine placenta and calf growth to weaning

Reactor physics project final report

"September 30, 1970."Statement of responsibility on title-page reads: Editors, M. J. Driscoll, I. Kaplan, D. D. Lanning, N. C. Rasmussen. Contributors: V. K. Agarwala, F. M. Clikeman, M. J. Driscoll, Y. Hukai, L. L. Izzo, I. Kaplan, M. S. Kazimi, D.D. Lanning, T.C. Leung, E.L. McFarland, N.C. Rasmussen, S.S. Seth, G.E. Sullivan, and A.T. SuppleIncludes bibliographical referencesFinal report; January 1, 1968 to September 30, 1970This is the final report in an experimental and theoretical program to develop and apply single- and few-element methods for the determination of reactor lattice parameters. The period covered by the report is January 1, 1968 through September 30, 1970. In addition to summarizing results for the entire contract period, this report also serves as the final annual report; thus, work completed in the period of October 1, 1969 through September 30, 1970 is dealt with in more detail than the earlier work. Methods were developed to measure the heterogeneous parameters 17, [Gamma] [eta] and [Alpha] for single fuel elements immersed in moderator in an exponential tank using foil activation measurements external to the fuel. These methods were applied to clustered fuel rods in D 20 moderator and single fuel rods in H 20 moderator, and the results were extended to and compared with data on complete multi-element lattices reported by other laboratories. Advanced gamma spectrometric methods using Ge(Li) detectors were applied to the analysis of both prompt and fission product decay gammas for the nondestructive analysis of the fuel used in this work. The latter includes both simulated burned fuel containing plutonium and actual burned fuel irradiated to 20,000 MWD/T in the Dresden BWR.U.S. Atomic Energy Commission contract AT (30-1)-394

Peri-conception and first trimester diet modifies reproductive development in bulls

Nutritional perturbation during gestation alters male reproductive development in rodents and sheep. In cattle both the developmental trajectory of the feto–placental unit and its response to dietary perturbations is dissimilar to that of these species. This study examined the effects of dietary protein perturbation during the peri-conception and first trimester periods upon reproductive development in bulls. Nulliparous heifers (n = 360) were individually fed a high- or low-protein diet (HPeri and LPeri) from 60 days before conception. From 24 until 98 days post conception, half of each treatment group changed to the alternative post-conception high- or low-protein diet (HPost and LPost) yielding four treatment groups in a 2 × 2 factorial design. A subset of male fetuses (n = 25) was excised at 98 days post conception and fetal testis development was assessed. Reproductive development of singleton male progeny (n = 40) was assessed until slaughter at 598 days of age, when adult testicular cytology was evaluated. Low peri-conception diet delayed reproductive development: sperm quality was lowered during pubertal development with a concomitant delay in reaching puberty. These effects were subsequent to lower FSH concentrations at 330 and 438 days of age. In the fetus, the low peri-conception diet increased the proportion of seminiferous tubules and decreased blood vessel area in the testis, whereas low first trimester diet increased blood vessel number in the adult testis. We conclude that maternal dietary protein perturbation during conception and early gestation may alter male testis development and delay puberty in bulls

Progress report no. 2

Statement of responsibility on title-page reads: Editors: I.A. Forbes, M.J. Driscoll, N.C. Rasmussen, D.D. Lanning and I. Kaplan; Contributors: S.T. Brewer, G.J. Brown, P.DeLaquil, III, M.J. Driscoll, I.A. Forbes, C.W. Forsberg, E.P. Gyftopoulos, P.L. Hendrick, C.S. Kang, I. Kaplan, J.L. Klucar, D.D. Lanning, T.C. Leung, E.A. Mason, N.R. Ortiz, N.A. Passman, N.C. Rasmussen, I.C. Rickard, V.C. Rogers, G.E. Sullivan, A.T. Supple, and C. P. TzanosIncludes bibliographical referencesProgress report; June 30, 1971U.S. Atomic Energy Commission contract AT(11-1)306

Patients' perspectives on high-tech home care: a qualitative inquiry into the user-friendliness of four technologies

BACKGROUND: The delivery of technology-enhanced home care is growing in most industrialized countries. The objective of our study was to document, from the patient's perspective, how the level of user-friendliness of medical technology influences its integration into the private and social lives of patients. Understanding what makes a technology user-friendly should help improve the design of home care services. METHODS: Four home care interventions that are frequently used and vary in their technical and clinical features were selected: Antibiotic intravenous therapy, parenteral nutrition, peritoneal dialysis and oxygen therapy. Our qualitative study relied on the triangulation of three sources of data: 1) interviews with patients (n = 16); 2) interviews with carers (n = 6); and 3) direct observation of nursing visits of a different set of patients (n = 16). Participants of varying socioeconomic status were recruited through primary care organizations and hospitals that deliver home care within 100 km of Montreal, the largest urban area in the province of Quebec, Canada. RESULTS: The four interventions have both a negative and positive effect on patients' lives. These technologies were rarely perceived as user-friendly, and user-acceptance was closely linked to user-competence. Compared with acute I.V. patients, who tended to be passive, chronic patients seemed keener to master technical aspects. While some of the technical and human barriers were managed well in the home setting, engaging in the social world was more problematic. Most patients found it difficult to maintain a regular job because of the high frequency of treatment, while some carers found their autonomy and social lives restricted. Patients also tended to withdraw from social activities because of social stigmatization and technical barriers. CONCLUSIONS: While technology contributes to improving the patients' health, it also imposes significant constraints on their lives. Policies aimed at developing home care must clearly integrate principles and resources supporting the appropriate use of technology. Close monitoring of patients should be part of all technology-enhanced home care programs

Transverse-energy distributions at midrapidity in pp++pp, dd++Au, and Au++Au collisions at sNN=62.4\sqrt{s_{_{NN}}}=62.4--200~GeV and implications for particle-production models

Measurements of the midrapidity transverse energy distribution, d\Et/d\eta, are presented for $p$$+$$p$, $d$$+$Au, and Au$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV and additionally for Au$+$Au collisions at $\sqrt{s_{_{NN}}}=62.4$ and 130 GeV. The d\Et/d\eta distributions are first compared with the number of nucleon participants $N_{\rm part}$, number of binary collisions $N_{\rm coll}$, and number of constituent-quark participants $N_{qp}$ calculated from a Glauber model based on the nuclear geometry. For Au$+$Au, \mean{d\Et/d\eta}/N_{\rm part} increases with $N_{\rm part}$, while \mean{d\Et/d\eta}/N_{qp} is approximately constant for all three energies. This indicates that the two component ansatz, $dE_{T}/d\eta \propto (1-x) N_{\rm part}/2 + x N_{\rm coll}$, which has been used to represent $E_T$ distributions, is simply a proxy for $N_{qp}$, and that the $N_{\rm coll}$ term does not represent a hard-scattering component in $E_T$ distributions. The $dE_{T}/d\eta$ distributions of Au$+$Au and $d$$+$Au are then calculated from the measured $p$$+$$p$ $E_T$ distribution using two models that both reproduce the Au$+$Au data. However, while the number-of-constituent-quark-participant model agrees well with the $d$$+$Au data, the additive-quark model does not.Comment: 391 authors, 24 pages, 19 figures, and 15 Tables. Submitted to Phys. Rev. C. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are publicly available at http://www.phenix.bnl.gov/papers.htm

High-pT pi^zero Production with Respect to the Reaction Plane in Au + Au Collisions at sqrt(s_NN) = 200 GeV

Measurements of the azimuthal anisotropy of high-\pT neutral pion neutral pion production in Au+Au collisions at sqrt(s_NN) = 200 GeV by the PHENIX experiment are presented. The data included in this paper were collected during the 2004 RHIC running period and represent approximately an order of magnitude increase in the number of analyzed events relative to previously published results. Azimuthal angle distributions of pi^0s detected in the PHENIX electromagnetic calorimeters are measured relative to the reaction plane determined event-by-event using the forward and backward beam-beam counters. Amplitudes of the second Fourier component (v_2) of the angular distributions are presented as a function of pi^0 transverse momentum p_T for different bins in collision centrality. Measured reaction plane dependent pi^0 yields are used to determine the azimuthal dependence of the pi^0 suppression as a function of p_T, R_AA (Delta phi,p_T). A jet-quenching motivated geometric analysis is presented that attempts to simultaneously describe the centrality dependence and reaction plane angle dependence of the pi^0 suppression in terms of the path lengths of hypothetical parent partons in the medium. This set of results allows for a detailed examination of the influence of geometry in the collision region, and of the interplay between collective flow and jet-quenching effects along the azimuthal axis.Comment: 344 authors, 35 pages text, RevTeX-4, 24 figures, 8 tables. Submitted to Physical Review