High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation.

Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 50 mg/kg/day i.v. day -6; plus fludarabine 30-40 mg/m²/day i.v. on days -6 to -2 and TBI 200 cGy on day -1. F-ara-A pharmacokinetics were carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC((0-∞))) was 5.0 μg h/mL (2.0-11.0), clearance 15.3 L/h (6.2-36.6), C(min) 55 ng/mL (17-166) and concentration on day(zero) 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced OS. Patients with an AUC((0-∞)) greater than 6.5 μg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT

The development of the size–weight illusion in children coincides with the development of nonverbal cognition rather than motor skills

This is the final version. Available on open access from Elsevier via the DOI in this recordWe examined how the strength of the size–weight illusion develops with age in typically developing children. To this end, we recruited children aged 5–12 years and quantified the degree to which they experienced the illusion. We hypothesized that the strength of the illusion would increase with age. The results supported this hypothesis. We also measured abilities in manual dexterity, receptive language, and abstract reasoning to determine whether changes in illusion strength were associated with these factors. Manual dexterity and receptive language did not correlate with illusion strength. Conversely, illusion strength and abstract reasoning were tightly coupled with each other. Multiple regression further revealed that age, manual dexterity, and receptive language did not contribute more to the variance in illusion strength beyond children's abilities in abstract reasoning. Taken together, the effects of age on the size–weight illusion appear to be explained by the development of nonverbal cognition. These findings not only inform the literature on child development but also have implications for theoretical explanations on the size–weight illusion. We suggest that the illusion has a strong acquired component to it and that it is strengthened by children's reasoning skills and perhaps an understanding of the world that develops with age.Australian Research Counci

Management of chronic lateral instability due to lateral collateral ligament deficiency after total knee arthroplasty: a case report

<p>Abstract</p> <p>Introduction</p> <p>Lateral instability following total knee arthroplasty (TKA) is a rare condition with limited report of treatment options. The objective of this case presentation is to demonstrate the outcomes of different surgical procedures performed in a single patient with lateral collateral ligament (LCL) deficiency.</p> <p>Case presentation</p> <p>We present a case of chronic lateral instability due to LCL deficiency after primary TKA in a 47-year-old Caucasian woman with an obesity problem. Multiple treatment options have been performed in order to manage this problem, including the following: ligament reconstruction; combined ligament reconstruction and constrained implant; and rotating-hinge knee prosthesis that was the most recent surgery. All ligament reconstruction procedures failed within one year. The varus-valgus constrained prosthesis provided stability for six years.</p> <p>Conclusions</p> <p>Ligament reconstruction alone cannot provide enough stability for the treatment of chronic lateral instability in patients with obesity problems and LCL deficiency. When the reconstruction fails, a salvage procedure with rotating-hinge knee is still available.</p

Childhood Atopic Diseases and Early Life Circumstances: An Ecological Study in Cuba

Background: Children are especially vulnerable during periods of resource shortage such as economic embargoes. They are likely to suffer most from poor nutrition, infectious diseases, and other ensuing short-term threats. Moreover, early life circumstances can have important consequences for long-term health. We examined the relationship between early childhood exposure to the Cuban economic situation in the nineties and the occurrence of atopic diseases later in childhood. Methodology/Principal Findings: A cross-sectional study of 1321 primary schoolchildren aged 4-14 was conducted in two Cuban municipalities. Asthma, allergic rhinoconjunctivitis and atopic dermatitis were diagnosed using the International Study of Asthma and Allergies in Childhood questionnaire. Children were divided into three groups of exposure to the economic situation in the nineties according to birth date: (1) unexposed; (2) exposed during infancy; (3) exposed during infancy and early childhood. Associations were assessed using multiple logistic regression models. Exposure during infancy had a significant inverse association with the occurrence of asthma (OR 0.56, 95% CI 0.33-0.94) and allergic rhinoconjunctivitis (OR 0.46, 95% CI 0.25-0.85). The associations were stronger after longer exposure, i.e. during infancy and early childhood, for asthma (OR 0.40, 95% CI 0.17-0.95) and allergic rhinoconjunctivitis (OR 0.29, 95% CI 0.11-0.77). No significant associations were found for atopic dermatitis. Conclusions/Significance: Exposure to the economic situation in the nineties during infancy and early childhood was inversely associated with asthma and allergic rhinoconjunctivitis occurrence later in childhood. We hypothesize that factors related to this period, such as infectious diseases and undernutrition, may have an attenuating effect on atopic disease development. The exact cause and underlying mechanisms need to be further elucidated

Large scale analytic calculations in quantum field theories

We present a survey on the mathematical structure of zero- and single scale quantities and the associated calculation methods and function spaces in higher order perturbative calculations in relativistic renormalizable quantum field theories.Comment: 25 pages Latex, 1 style fil

Outbreaks of virulent diarrheagenic Escherichia coli - are we in control?

Shiga toxin-producing Escherichia coli (STEC) are the most virulent diarrheagenic E. coli known to date. They can be spread with alarming ease via food as exemplified by a large sprout-borne outbreak of STEC O104:H4 in 2011 that was centered in northern Germany and affected several countries. Effective control of such outbreaks is an important public health task and necessitates early outbreak detection, fast identification of the outbreak vehicle and immediate removal of the suspected food from the market, flanked by consumer advice and measures to prevent secondary spread

A Whole Virus Pandemic Influenza H1N1 Vaccine Is Highly Immunogenic and Protective in Active Immunization and Passive Protection Mouse Models

The recent emergence and rapid spread of a novel swine-derived H1N1 influenza virus has resulted in the first influenza pandemic of this century. Monovalent vaccines have undergone preclinical and clinical development prior to initiation of mass immunization campaigns. We have carried out a series of immunogenicity and protection studies following active immunization of mice, which indicate that a whole virus, nonadjuvanted vaccine is immunogenic at low doses and protects against live virus challenge. The immunogenicity in this model was comparable to that of a whole virus H5N1 vaccine, which had previously been demonstrated to induce high levels of seroprotection in clinical studies. The efficacy of the H1N1 pandemic vaccine in protecting against live virus challenge was also seen to be equivalent to that of the H5N1 vaccine. The protective efficacy of the H1N1 vaccine was also confirmed using a severe combined immunodeficient (SCID) mouse model. It was demonstrated that mouse and guinea pig immune sera elicited following active H1N1 vaccination resulted in 100% protection of SCID mice following passive transfer of immune sera and lethal challenge. The immune responses to a whole virus pandemic H1N1 and a split seasonal H1N1 vaccine were also compared in this study. It was demonstrated that the whole virus vaccine induced a balanced Th-1 and Th-2 response in mice, whereas the split vaccine induced mainly a Th-2 response and only minimal levels of Th-1 responses. These data supported the initiation of clinical studies with the same low doses of whole virus vaccine that had previously been demonstrated to be immunogenic in clinical studies with a whole virus H5N1 vaccine

Despotism and Risk of Infanticide Influence Grizzly Bear Den-Site Selection

Given documented social dominance and intraspecific predation in bear populations, the ideal despotic distribution model and sex hypothesis of sexual segregation predict adult female grizzly bears (Ursus arctos) will avoid areas occupied by adult males to reduce risk of infanticide. Under ideal despotic distribution, juveniles should similarly avoid adult males to reduce predation risk. Den-site selection and use is an important component of grizzly bear ecology and may be influenced by multiple factors, including risk from conspecifics. To test the role of predation risk and the sex hypothesis of sexual segregation, we compared adult female (n = 142), adult male (n = 36), and juvenile (n = 35) den locations in Denali National Park and Preserve, Alaska, USA. We measured elevation, aspect, slope, and dominant land cover for each den site, and used maximum entropy modeling to determine which variables best predicted den sites. We identified the global model as the best-fitting model for adult female (area under curve (AUC) = 0.926) and elevation as the best predictive variable for adult male (AUC = 0.880) den sites. The model containing land cover and elevation best-predicted juvenile (AUC = 0.841) den sites. Adult females spatially segregated from adult males, with dens characterized by higher elevations ( = 1,412 m, SE = 52) and steeper slopes ( = 21.9°, SE = 1.1) than adult male (elevation:  = 1,209 m, SE = 76; slope:  = 15.6°, SE = 1.9) den sites. Juveniles used a broad range of landscape attributes but did not avoid adult male denning areas. Observed spatial segregation by adult females supports the sex hypothesis of sexual segregation and we suggest is a mechanism to reduce risk of infanticide. Den site selection of adult males is likely related to distribution of food resources during spring

Integrating BRAF/MEK inhibitors into combination therapy for melanoma

The discovery of BRAF mutations in melanoma has not yet translated into clinical success, suggesting that BRAF/MEK inhibitors will need to be combined with other agents. In the current review, we discuss other pathways likely to be important for melanoma progression and suggest possible drug combinations for future clinical testing

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