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Amyloid precursor protein (APP) is endoproteolytically processed by BACE1 and gamma-secretase to release amyloid peptides (Abeta40 and 42) that aggregate to form senile plaques in the brains of patients with Alzheimer's disease (AD). The C-terminus of Abeta40/42 is generated by gamma-secretase, whose activity is dependent upon presenilin (PS 1 or 2). Missense mutations in PS1 (and PS2) occur in patients with early-onset familial AD (FAD), and previous studies in transgenic mice and cultured cell models demonstrated that FAD-PS1 variants shift the ratio of Abeta40 : 42 to favor Abeta42. One hypothesis to explain this outcome is that mutant PS alters the specificity of gamma-secretase to favor production of Abeta42 at the expense of Abeta40. To test this hypothesis in vivo, we studied Abeta40 and 42 levels in a series of transgenic mice that co-express the Swedish mutation of APP (APPswe) with two FAD-PS1 variants that differentially accelerate amyloid pathology in the brain. We demonstrate a direct correlation between the concentration of Abeta42 and the rate of amyloid deposition. We further show that the shift in Abeta42 : 40 ratios associated with the expression of FAD-PS1 variants is due to a specific elevation in the steady-state levels of Abeta42, while maintaining a constant level of Abeta40. These data suggest that PS1 variants do not simply alter the preferred cleavage site for gamma-secretase, but rather that they have more complex effects on the regulation of gamma-secretase and its access to substrates.

Previous studies have shown that the metabotropic glutamate receptor (mGluR)2/3 agonist LY354740 attenuated glutamate release in medial prefrontal cortex (mPFC) induced by the non-competitive N -methyl- d -aspartate (NMDA) receptor antagonist phencyclidine. In the present study we examined the effects of the more potent mGluR2/3 selective agonist LY379268 on ketamine-evoked glutamate and dopamine (DA) release in mPFC of male rats. Subjects were implanted with a unilateral microdialysis probe in the mPFC and were tested 12–24 h after implantation. Ketamine (18 mg/kg, s.c.) evoked a significant release of glutamate and DA, although the glutamate response was slower in onset compared with DA. Pretreatment with either systemic (3 mg/kg s.c.) or local (1 μM, in the probe) LY379268 blocked ketamine-evoked glutamate, but not DA, release. When applied directly to the mPFC via the dialysis probe, ketamine (1 mM in the probe) had no effect on glutamate release but did significantly enhance the release of DA. Application of NMDA (500 μM in the probe), on the other hand, decreased DA while increasing glutamate release. The effect of NMDA on evoking glutamate release was blocked by systemic but not local administration of LY379268. These findings indicate that systemic ketamine increases both glutamate and DA release in mPFC and that the effect on glutamate can be blocked by stimulating mPFC group II mGluR receptors. Local ketamine, on the other hand, does not increase glutamate but does increase DA release. This suggests that ketamine acts outside of the mPFC to enhance glutamate, but within the mPFC to enhance DA release. The origin of the ketamine effect on mPFC glutamate is currently not known.

Objective:To determine the effects of Vicoprofen® and ibuprofen on aerobic performance, agility, and pain after exercise-induced muscle damage.Design:Double-blind randomized, placebo-controlled, repeated-dose clinical trial.Setting:Human-performance and sports-medicine laboratory.Participants:36 healthy men.Methods and Measures:Baseline testing was performed, 72 hours after which subjects performed eccentric exercise to induce muscle damage. They were evaluated for pain 24 hours postdamage and placed randomly into 3 groups: Vicoprofen (VIC), ibuprofen, or placebo (P). Postdamage testing was performed every day for 5 days. Subjects performed an economy run and a t-agility test to determine exercise performance.Results:The drugs had no significant effect on performance throughout the 5-day evaluation period. Pain was lower at days 4 and 5 in the VIC group than in P.Conclusions:It appears that Vicoprofen reduced pain after muscle damage, but the drug interventions did not enhance performance in aerobic and agility tasks.

226 Background: HCC diagnosed at advanced stages has a poor prognosis. Patients who progress on sorafenib have few options. Nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), has demonstrated clinical and survival benefit in a number of tumor types. Here we report updated interim analyses of safety, efficacy, and exploratory biomarkers in patients with advanced HCC treated with nivolumab in the CheckMate 040 study (NCT01658878). Methods: Patients enrolled had advanced HCC with or without hepatitis C or B virus (HCV or HBV) infection. Prior sorafenib was allowed. Phase 1 dose-escalation evaluated nivolumab (0.1–10 mg/kg) Q2W. Phase 2 dose-expansion was initiated in 4 cohorts: sorafenib naïve/intolerant, sorafenib progressors, HCV infected, and HBV infected. All cohorts received nivolumab 3 mg/kg Q2W. The primary endpoint in the dose-escalation phase was safety/tolerability, and the primary endpoint in the dose-expansion phase was objective response rate (ORR) by RECIST v1.1 (central review). Secondary endpoints included duration of response (DOR), disease control rate (DCR), and overall survival (OS). Biomarkers within pre-treatment tumors were assessed. Results: Across dose escalation and expansion phases, 262 patients have been treated. Grade 3/4 treatment-related adverse events occurred in 20%. No maximum tolerated dose was reached during dose escalation (n = 48). The ORR (investigator-assessed) was 20% (95% CI 15–26) in 214 patients treated in the dose expansion phase with a median DoR of 9.9 months; DCR was 64% (95% CI 58–71). Responses were observed across etiologies and regardless of tumor PD-L1 expression. ORRs of 23% (95% CI 13–36) and 21% (95% CI 11–34) were observed in the uninfected sorafenib-naive and -treated patients, respectively. The 9-month overall survival rate in the expansion phase was 74% (95% CI 67–79). Association between immune-cell biomarkers and clinical outcomes will be presented. Conclusions: In this heavily pretreated population, responses to nivolumab were durable with encouraging overall survival. Safety was manageable and consistent with that observed in other solid tumors with no new safety signals. Clinical trial information: NCT01658878.

The music business is a case study in how macro-environmental factors can radically transform an industry. Developments such as digital production and distribution, coupled with social media, crowdfunding, and changing consumer preferences, have dramatically transformed the business model for the recorded music industry in recent years and spurred the development of entrepreneurial business models to enable musicians to survive in their changing environment. As a solo artist and founding member of the musical groups Jefferson Airplane and Hot Tuna, Rock and Roll Hall of Fame musician Jorma (“The Captain”) Kaukonen has recorded albums for major labels such as RCA, Sony, and Columbia, as well as independent labels such as Relix and Red House Records. In this interview, Jorma and his wife and business manager, Vanessa Kaukonen, discuss their experiences as musical entrepreneurs in the digital age, including their founding of the unique Fur Peace Ranch guitar camp in the hills of Appalachia. The entrepreneurial business undertakings of the Kaukonens highlight the potential for entrepreneurial musicians to develop innovative and sustainable business models for surviving in this new world of music.

American College of Cardiology Foundation ### American Heart Association View this table: ACCF/AHA/CDC Consensus Conference Report on Emerging Infectious Diseases and Biological Terrorism Threats—Participants’ Relationships With Industry

A blood culture cohort study investigating issues related to isolation of coagulase-negative staphylococci (CoNS) and other skin microflora is reported. Data were collected over 12 weeks to determine the incidence of significant CoNS bacteremia versus that of pseudobacteremia (contaminants) and to evaluate drug therapy in patients with cultures positive for CoNS. In addition, the effectiveness of 0.2% chlorine peroxide as a bactericidal disinfectant was compared to that of 10% providone iodine. A total of 3,276 cultures of blood from 1,433 patients were evaluated in the study. Eighty-nine cultures were positive for skin flora, with 81 of 89 (91%) involving CoNS. The incidence of significant CoNS bacteremia was 20 of 81 (24.7%), that of indeterminate bacteremia was 10 of 81 (12.3%), and that of contamination was 59 of 81 (72.8%). The incidence of significant bacteremia involving CoNS was double the 10 to 12% rate based on previous estimations at our institutions. In tests with the two bactericidal disinfectants, 22 of 1,639 cultures (1.3%) in the chlorine peroxide group versus 37 of 1,637 (2.3%) in the providone iodine group were considered contaminated ( P = 0.065). Rates of contamination for venipuncture versus catheter collection were not significantly different ( P = 0.46). The overall contamination rate was 59 of 3,276 (1.8%), which is consistent with the lower end of published quality assurance benchmark standards. The low rate was believed to be due to the professional phlebotomy staff in our institutions. There was excellent agreement between retrospective analysis by reviewers, when formal criteria were used, and the attending physicians’ intuitive clinical impressions in the classification of significant bloodstream infections (100% agreement) or contamination (95% agreement). However, physicians still used antimicrobial agents to treat nearly one-half of the patients with contaminated blood cultures, with vancomycin being misused in 34% of patients. In addition, 10% of patients with significant bacteremia were treated with inappropriate agents. There were no significant adverse events or prolonged hospital stays due to the unnecessary use of vancomycin; however, the additional costs of treating patients whose cultures contained CoNS contaminants was estimated to be $1,000 per patient. Measures to limit the unnecessary use of vancomycin (and other agents) are important.

Background The Affordable Care Act of 2010 identifies "patient experience of care" as one of five domains of excellent care. We hypothesized that there are specific demographic factors associated with higher or lower physician satisfaction (PS) scores in trauma patients. Methods Press-Ganey PS scores for September 2004 to December 2010 were compared with trauma variables and the association of a mean PS greater than or equal to 75 (high score) or less than or equal to 50 (low score). Those variables that proved significant on univariate analysis were subjected to multivariate logistic regression analysis. Significance was at p Results There were 12,196 admissions, of whom 1,631 (13.4%) returned patient satisfaction survey. A total of 1,174 patients (75.5%) returned a high PS (≥75), and 126 patients (8.1%) returned a low PS (≤50). In the multiple logistic regression analysis, 65 years or older (odds ratio [OR], 1.7), having had a surgical procedure (OR, 1.6), and having a positive impression of the hospital care (OR, 7.0) proved significant for a high PS. Those patients who scored a low PS were significantly more likely to be younger (18-29 years: OR, 2.4; 30-64 years: OR, 1.8), to have not had surgery (OR, 2.2), had an Injury Severity Score (ISS) of 16 or lower (OR, 2.6), had a complication of care (OR, 4.4), and rated the hospital care as poor (OR, 9.2). Conclusion A trauma patient who is satisfied with his or her physician care is one who is 65 years or older, requires surgery, and is predominantly satisfied with other aspects of their hospital care. Unsatisfied patients are younger, are nonoperative, had lower ISS, had a complication of care, and rated their hospital care as poor. Understanding the specific characteristics of Press-Ganey results for trauma patients will allow trauma surgeons and their hospital partners to develop strategies to improve patients' satisfaction with their trauma surgeon's care. Level of evidence Epidemiologic study, level III; therapeutic study, level IV.

Mobile devices pose a challenge for most faculty members in higher education as they view the device as disruptive and in competition with the work to be completed in the classroom. The goal of this chapter is to examine the implementation of HTC tablet devices and the changing roles of the faculty instructor and learners when using this device in an undergraduate business management course in a business college and a graduate course in early childhood in a college of education in a large Midwestern university. The chapter describes the classroom setting, instructor and student perspectives of the implementation, and the use of the tablet both in class and out of class as well as the barriers associated with tablet use when embedded in a higher education course.

4012Background: For pts with advanced HCC on sorafenib (sor), overall survival (OS) is 11 mo; median OS with best supportive care (BSC) post-sor failure is 7–8 mo.Safety and preliminary antitumor e...

TPS4147Background: HCC is the fifth most prevalent cancer globally and the second-leading cause of cancer-related deaths. The high mortality rate is typically due to the late stage of disease at di...

4078Background: HCC tumors are associated with chronic inflammation that can promote an immunosuppressive environment; anti-PD-1 therapy may counter this inhibition. Nivo, a fully human IgG4 monocl...

Heightened auditory sensitivity and atypical processing of sounds by the brain are common in autism. Functional studies that measure brain activity suggest abnormal neural response to sounds, yet the development underlying atypical sound processing in autism is unknown. We examined the growth of the first cortical area of the brain to process sound, the primary auditory cortex, also known as Heschl’s gyrus. Volume of Heschl’s gyrus gray and white matter was measured using structural MRI in 40 children and adolescents with autism and 17 typically developing participants. Up to three time points of volumetric brain data, collected on average every 2.5 years, were examined from individuals 3-12 years of age at their first scan. Our study is the first to examine volumetric changes during childhood and adolescence in Heschl’s gyrus longitudinally, or in the same individuals over time. Consistent with previous studies using only one time point of data, no differences between the participant groups were found in Heschl’s gyrus gray matter volume. However, reduced longitudinal growth of Heschl’s gyrus gray matter volume was found in the right hemisphere in autism. Reduced longitudinal white matter growth in the left hemisphere was found in the right-handed autism participants. Atypical growth of Heschl’s gyrus white matter volume was found bilaterally in the autism individuals with a history of delayed onset of spoken language. Heightened reported sensitivity to sounds, obtained from the Sensory Profile, was associated with reduced gray matter volume growth in the right hemisphere. Our longitudinal analyses revealed dynamic gray and white matter changes in Heschl’s gyrus throughout childhood and adolescence in both typical development and autism.

The first American missionary to Burma, Adoniram Judson was born on August 9, 1788 in Malden, Massachusetts. Adoniram demonstrated remarkable abilities even while very young. His mother taught him to read in one week when he was only 3 years old. When he was 10 he learned navigation from a retired sea captain; and he could read classical Greek by the time he was 12. Keywords: Judson, Adoniram (1788–1850); andover theological seminary; outpouring of spiritual interest; reaching people with the gospel

A Baptist theologian who resisted Hyper-Calvinism in favor of an evangelical position, Fuller was born in Wicken, Cambridgeshire, England on February 6, 1754. His parents were farmers by trade and raised their gifted son in the Soham Particular Baptist Church. The Soham Particular Baptist Church was known for its “hyper” or “high” Calvinism. That is, the church was opposed to evangelism in an open and indiscriminate manner, as it was believed to undermine the sovereignty of God. This variety of Hyper-Calvinism so stressed the sovereignty of God that it was believed that non-Christians would be saved apart from any means and without the involvement of any mortal. Hence, any attempt to carry the gospel to other lands was deemed to undermine God's salvific purpose in the world. Keywords: Fuller, Andrew (1754–1815); baptist theologian, resisting hyper-calvinism; soham particular baptist church; the gospel worthy of all acceptation; fuller, wrestling with gravity of sin; trusting fully in christ; fully rejecting, hyper-calvinism of his upbringing; adopting, evangelical form of calvinism

John Owen was perhaps the most prolific and influential English Puritan. Following the time of the Protestant Reformation, the Puritans sought to continue spiritual renewal and reformation within the Church of England and the Elizabethan settlement. Spanning from roughly 1564 to 1642 (dates given by Richard Baxter and Thomas Fuller; see Cumming 1965: 288), the Puritans pursued a goal of “completing” the English Reformation by reshaping Anglican worship, introducing church discipline in local parishes, establishing a new level of righteousness in political, domestic, and economic fields, and converting everyone to a “vigorous evangelical faith” (Packer 1990: 28). Among the Puritans, John Owen, known as “the Calvin of England” (this designation was first coined by Ambrose Barns; see Toon 1971: 173), was arguably the greatest (Toon 1971). Keywords: Owen, John (1616–1683); prolific and influential english puritan; puritans, spiritual renewal and reformation

We show that the leading $SU(3)$-breaking corrections to the $\Delta S = 1$ $f_1$ vector form factors of hyperons are $O(m_s)$ and $O(m_s^{3/2})$, and are expected to be $\sim 20$--$30\%$ by dimensional analysis. This is consistent with the Ademollo--Gatto theorem, in a sense that we explain. We compute the $O(m_s)$ corrections and a subset of the $O(m_s^{3/2})$ corrections using an effective lagrangian in which the baryons are treated as heavy particles. All of these corrections are surprisingly small, $\sim 5\%$; combining them, we obtain $\sim 5$--$10\%$ corrections. The pattern of corrections is very different than that predicted by quark models., Comment: 11 pages, one figure available by FAX, LBL-33435. Changes: axial-->vector in listing title (!), minor clarifications in text; results are completely unchanged

Mycobacterium ulcerans is the causative agent of the debilitating skin disease Buruli ulcer, which is most prevalent in Western and Central Africa. M. ulcerans shares98% DNA sequence identity with Mycobacterium marinum, however, M. marinum produces granulomatous, but not ulcerative, lesions in humans and animals. Here we report the differential expression of a small heat shock protein (Hsp18) between strains of M. ulcerans (Hsp18(+) ) and M. marinum (Hsp18(-) ) and describe the molecular basis for this difference. We show by gene deletion and GFP reporter assays in M. marinum that a divergently transcribed gene called hspR_2, immediately upstream of hsp18, encodes a MerR-like regulatory protein that represses hsp18 transcription while promoting its own expression. Naturally occurring mutations within a 70 bp segment of the 144 bp hspR_2-hsp18 intergenic region among M. ulcerans strains inhibit hspR_2 transcription and explain the Hsp18(+) phenotype. We also propose a biological role for Hsp18, as we show that this protein significantly enhances bacterial attachment or aggregation during biofilm formation. This study has uncovered a new member of the MerR family of transcriptional regulators and suggests that upregulation of hsp18 expression was an important pathoadaptive response in the evolution of M. ulcerans from a M. marinum-like ancestor.

This article compares professionalism education from the vantage points of three different disciplines: medicine, law, and business. In particular, it asks how each of these professions conceives of "professionalism," and how these different conceptions affect what is taught to graduate students. The object of professionalism education differs among these three disciplines, as do the specific challenges to professionalism and professionalism education. The article offers examples of how professionalism is taught in medicine, law, and business, and what each profession might learn from the others in developing their professionalism education and pedagogy.

Infants with complex congenital heart disease are at increased risk for malnutrition and poor weight gain. At our institution, infants who undergo Stage I Norwood operation are discharged with a home surveillance (HomeSurv) program which includes weight monitoring. To evaluate the impact of home surveillance on interstage growth, a current cohort of patients enrolled in Home Surv (n=18) was compared to a cohort discharged immediately prior to the implementation of the Home Surv program (n=20). The cohorts were compared using parametric and non-parametric methods as appropriate. Results: Infants underwent Stage I at a median age of 3.5 days (range 1–26), and at a mean weight 3.0 ± 0.4 kg., 26 with a modified Blalock-Taussig shunt and 12 with a right ventricular-to-pulmonary artery shunt. There were 26 males and 12 females. There were no significant differences between the groups with and without HomeSurv with respect to Stage I age, sex, Stage I weight, or shunt type. Stage I discharge weights were similar between the two cohorts (p=0.23) and there was no significant difference in Stage I hospital length of stay (p=0.10). Mean age at Stage II was 5.1 mos in the HomeSurv group and 4.9 mos in the pre-HomeSurv group, (p = 0.63). Mean weight at Stage II was higher in the HomeSurv group, but not statistically significant (5.9 kg vs 5.5 kg, p=0.30). However, weight gain >15 gms/day post Stage I discharge (our minimum weight gain threshold) was achieved by 89% of infants with Home Surv in comparison to 60% of the pre-HomeSurv group, p

In this study, we describe the use of intravital microscopy in a transgenic mouse model expressing yellow fluorescent protein (YFP) under the control of a monocyte specific promoter c-fms (CD115) to track and quantify specific leukocyte subsets. Flow cytometry on peripheral and bone marrow leukocytes revealed that YFP was predominantly expressed by CD11a(+), CD11b(+), and CD14(+) monocytes. In the bone marrow, 67+/-4% of Ly6C(high) F4/80(+) cells were YFP(high) while 55+/-1% of Ly6C(low) F4/80(+) cells were YFP(low) supporting the use of c-fms(YFP) expression as a marker of monocyte lineage. 70+/-7% of CD11b(+) F4/80(+) Ly6C(+) ("triple positive") cells expressed YFP. To assess leukocyte-endothelial interactions in YFP(+) cells in c-fms(YFP+) mice, we evaluated leukocyte adhesion, rolling and local shear stress responses in the cremasteric endothelium 4 h following administration of TNFalpha. TNFalpha resulted in a five-fold increase in adhesion of YFP(+) cells to the endothelium and provided superior discriminative ability in assessing rolling and adhesion events when compared with bright field microscopy. Additionally, when compared with Rhodamine-6G labeled leukocytes or GFP(+) cells in mice transplanted with green fluorescent protein (GFP) positive bone marrow, the level of detail observed in the c-fms(YFP+) was greater, with both GFP(+) and YFP(+) cells demonstrating superior signal to noise compared to bright field microscopy. A weak positive linear correlation between wall shear stress and YFP(+) cell adhesion (r(2)=0.20, p

This is a report of work-in-progress on a multi-user sketching tool. The intent behind the project is to produce a simple tool for use in multi-user design and brainstorming sessions. The tool, xsketch, is intended to function across existing internetwork facilities and run on a variety of platforms. This paper covers the requirements and design goals for the tool. Details of a prototype implementation are given along with a list of known problems, shortcomings, and possible extensions.

Structure-activity relationship studies leading to the discovery of novel mGlu5 receptor antagonists are described. These compounds show high in vitro potency, have good in vivo receptor occupancy, and a reasonable intravenous pharmacokinetic profile.

In modern government and aerospace industry institutions the necessity of controlling current year costs often leads to high mobility in the technical workforce, "one-deep" technical capabilities, and minimal mentoring for young engineers. Thus, formal recording, use, and teaching of lessons learned are especially important in the maintenance and improvement of current knowledge and development of new technologies, regardless of the discipline area. Within the NASA Technical Standards Program Website http://standards.nasa.gov there is a menu item entitled "Lessons Learned/Best Practices". It contains links to a large number of engineering and technical disciplines related data sets that contain a wealth of lessons learned information based on past experiences. This paper has provided a small sample of lessons learned relative to the atmospheric and space environment. There are many more whose subsequent applications have improved our knowledge of the atmosphere and space environment, and the application of this knowledge to the engineering and operations for a variety of aerospace programs.

Alterations in expression of adhesion molecules are important in the trafficking of hematopoietic progenitors and probably in the mobilization process. Relatively little and conflicting data are currently available on the differences in expression between good and poor mobilizing patients.In this study, the expression of eight adhesion molecules on the collected CD34+ cells from 36 patients undergoing mobilization was determined.Good mobilizing patients, defined as those who collected their target in one apheresis procedure, had significantly fewer cells that expressed CD11a (LFA-1) and CD54 (ICAM-1) and borderline fewer that expressed CD11c, CD49d (VLA-4), and CD49d (VLA-5). No differences were detected in CD11b (Mac-1), CD15s (sLe(x)), or CD62L (L-selectin). Linear regression analysis identified number of prior chemotherapy courses and expression of CD11a (LFA-1) as independent predictive factors for mobilization efficiency. Good and poor mobilizing patients had approximately the same number of total CD34+ cells collected and little difference in times to engraftment.CD11a (LFA-1) expression inversely correlates with mobilization efficiency. Elucidation of the mechanism(s) underlying these observations will require further study.

OBJECTIVE: To prospectively examine the influence of hamstring-to-quadriceps (H:Q) ratio and structural abnormalities on the prevalence of overuse knee injuries among female collegiate athletes. DESIGN AND SETTING: We used chi-square 2 x 2 contingency tables and the Fischer exact test to examine associations among H:Q ratios, structural abnormalities, and overuse knee injuries. SUBJECTS: Fifty-three apparently healthy women (age = 19.4 +/- 1.3 years, height = 167.6 +/- 10.1 cm, mass = 65.0 +/- 10.0 kg) from National Collegiate Athletic Association Division I women's field hockey (n = 23), soccer (n = 20), and basketball teams (n = 10) volunteered. MEASUREMENTS: The H:Q ratio was determined from a preseason isokinetic test on a Biodex system at 60 degrees /s and 300 degrees /s. We measured athletes for genu recurvatum and Q-angles with a 14-in (35.56-cm) goniometer. Iliotibial band flexibility was assessed via the Ober test. RESULTS: Ten overuse knee injuries (iliotibial band friction syndromes = 5, patellar tendinitis = 3, patellofemoral syndrome = 1, pes anserine tendinitis = 1) occurred in 9 athletes. The H:Q ratio below the normal range at 300 degrees /s (P = 0.047) was associated with overuse knee injuries, as was the presence of genu recurvatum (P = 0.004). In addition, athletes possessing lower H:Q ratios at 300 degrees /s and genu recurvatum incurred more overuse knee injuries than athletes without these abnormalities (P = 0.001). CONCLUSIONS: The presence of genu recurvatum and an H: Q ratio below normal range was associated with an increased prevalence of overuse knee injuries among female collegiate athletes. Further investigation is needed to clarify which preseason screening procedures may identify collegiate athletes who are susceptible to overuse knee injuries.

The highly potent, selective, and brain-penetrant metabotropic glutamate subtype 5 (mGlu5) receptor antagonists 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (47) and 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (48) are reported. Compound 47 is active in the rat fear-potentiated startle (FPS) model of anxiety with ED(50) = 5.4 mg/kg (po) when dosed acutely. In this model the anxiolytic effects of 47 rapidly tolerate on repeated dosing.

This paper will present a brief history of the role of service in higher education, and demonstrate its effectiveness as a full partner to teacher education. We then focus on service-learning in teacher education and how it has enjoyed a strong resurgence in the last 15 years. Finally, we offer a rationale for and a model of service-learning in the northwest region of the US, supported and endorsed by the Northwest Center for Service Learning in Teacher Education.

2-Methyl-6-(phenylethynyl)pyridine (3), a potent noncompetitive mGlu5 receptor antagonist widely used to characterize the pharmacology of mGlu5 receptors, suffers from a number of shortcomings as a therapeutic agent, including off-target activity and poor aqueous solubility. Seeking to improve the properties of 3 led to the synthesis of compound 9, a highly selective mGlu5 receptor antagonist that is 5-fold more potent than 3 in the rat fear-potentiated startle model of anxiety.

It's critical that your athletics department and institution empower your sports medicine staff and physicians to make all medical decisions based on their professional judgment about what's best for the long-term well-being of each student-athlete. In fact, case law establishes the team physician as having the final say in student-athlete medical clearance.

This article examines the role of gambling as an addictive disorder experienced by athletes, both college and professional. Gambling may often be seen as a comorbid factor with other addictions and with depression among athletes. The focus on addictions among athletes has gained considerable attention among sports medicine clinicians. Diagnostic indicators, risk and protective factors, and a stage model of addiction among athletes are addressed. An algorithm and pathway of care for athletes with an addictive disorder is offered as are recommendations that sports physicians, sports medicine specialists, coaches and counsellors need to address athletes who have an addictive disorder.

Dosage imbalance for chromosome 21 in Down syndrome and mutations in the amyloid precursor protein (APP) and presenilin-1 (PS-1 ) genes in early-onset familial Alzheimer's disease (FAD) result in elevated production and deposition of amyloid-β (Aβ) peptides1, particularly the 42 amino acid form, Aβ1–42. One difficulty in studying the generation and deposition of Aβ, neuritic abnormalities, synaptic dysfunction, neuronal cell death and dementia that occurs in Alzheimer's disease (AD) is the paucity of small animal models. To examine effects of the FAD mutations in vivo, we transferred yeast artificial chromosomes (YACs) containing the entire genomic copy of human APP and/or PS-1 genes harboring FAD mutations into transgenic mice2,3. We now document that a mutant APP YAC transgenic mouse develops Aβ deposits and that this deposition is accelerated when the animals are mated to homozygosity and/or to mutant PS-1 YAC transgenic mice.

German Unification and the Union of Europe discusses some of the most interesting questions in the study of comparative politics and international relations. The book studies the sources of continuity and change in German policy toward the European Union, set in the context of the competing pulls of integration into the EU, and unification of East and West Germany. Employing a framework of analysis premised on the interaction of interests, institutions and ideas, the book asks: how has the domestic politics of unification influenced German policy toward Europe? why has continuity reigned in some areas, whereas in others significant changes, sometimes reversals, have been registered? what are the implications of this checkered pattern of outcomes for Germany and for Europe? Jeffrey Anderson's book focusses on the political economy issues (such as trade, internal market, energy, and industrial policy) which represent key components of both German domestic politics and Germany's relationship with Europe. Awarded the DAAD 2000 Prize for Distinguished Scholarship in German Studies: Politics and Foreign Policy.

TPS3111 Background: Pts with advanced HCC have limited treatment options. Sorafenib, the current standard of care, achieves only modest overall survival improvements. There is a clear etiologic association between HCC and prior/concurrent hepatitis B (HBV) or C (HCV) infection. Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation when bound by ligands including PD-L1/L2. PD-L1 overexpression has been noted on HCC tumors, and PD-1/PD-L1 interaction may contribute to viral hepatitis induced T-cell exhaustion. Nivolumab, a PD-1 receptor blocking antibody, has shown efficacy against various solid tumor types in Ph 1 trials. We hypothesized that blockade of PD-1/PD-L1 interaction could enhance T-cell activation and mediate antitumor and/or antiviral activity in HCC pts. We describe a phase I, dose-escalation study of nivolumab in advanced HCC pts. Methods: Successive pt cohorts with histologically confirmed advanced HCC with/without HBV or HCV infection (N=72 max) will be treated on 3 distinct arms with IV nivolumab at 0.3, 1 and 3.0 mg/kg (uninfected or HCV-infected pts) or 0.1, 0.3, 1 and 3.0 mg/kg (HBV-infected pts) every 2 weeks using a 3+3 escalation scheme. Pts must have progressive disease or intolerance after ≥1 line of therapy or have refused sorafenib treatment, and a Child-Pugh class A. HBV-infected pts must be receiving antiviral therapy (viral DNA

4133 Background: Due to the small anatomic size, multiplicity of epitheliums, and suboptimal diagnostics determining the site of origin of PAA is a challenge. We investigated the ability of a 92-gene RT-PCR assay (CancerTYPE ID) to categorize PAA and to prognostically stratify ampullary adenocarcinomas. Methods: 171 PAA patients who underwent pancreaticoduodenectomies were included; samples were histopathologically verified for tumor subtype determination: pancreatic (PAN), extrahepatic biliary (EB), ampullary (AMP), or duodenal (DOUD). Blinded FFPE tumor sections underwent molecular testing. Analytical sets were an initial 45 PAA set evaluating concordance to histopathological tumor types and prognostic performance, and a second set of 126 AMP and DOUD adenocarcinoma for validation of prognostic performance. Results: Of the initial 45 patient cohort, molecular classification of 43 (96%) evaluable samples (13 AMP, 10 PAN, 10 EB, 10 DOUD) showed 91% concordance: AMP [5 intestinal (int), 7 pancreaticobiliary (pb)], PAN [10 pb], DOUD [3 int, 7 gastroesophageal (ge)], EB [7 pb]. The 92-gene assay was prognostic with a median OS of 70 m for ge/int cases vs. 32 m for pb cases, P=0.05. Discordant classifications were ge for 1 AMP and 2 EB samples, and ovary for 1 EB case. Previous unsupervised RNA hierarchical clustering (Overman GI ASCO 2011 a161) of all 13 AMP cases had identified two prognostic groups (a good-prognosis int-like and a poor-prognosis pb-like), which were identical to the 92-gene classification for 12 of the 13 cases. Conclusions: In the initial cohort of 45 patients, the 92-gene assay demonstrated diagnostic utility for molecular site-of-origin classification of PAA; evaluation of the remaining 126 ampullary and duodenal cases will be presented. Results support exploration of this approach for the management of metastatic PAA (in which pathologic review of a primary resection specimen is not an option). Molecular classification of ampullary adenocarcinomas into intestinal and pancreaticobiliary subgroups is prognostically relevant; these and the gastric-like molecular profile of duodenal adenocarcinomas may have therapeutic implications.

To describe growth patterns in infants with single ventricle physiology and determine factors influencing growth.Data from 230 subjects enrolled in the Pediatric Heart Network Infant Single Ventricle Enalapril Trial were used to assess factors influencing change in weight-for-age z-score (z) from study enrollment (0.7 ± 0.4 months) to pre-superior cavopulmonary connection (SCPC; 5.1 ± 1.8 months, period 1) and pre-SCPC to final study visit (14.1 ± 0.9 months, period 2). Predictor variables included patient characteristics, feeding regimen, clinical center, and medical factors during neonatal (period 1) and SCPC hospitalizations (period 2). Univariate regression analysis was performed, followed by backward stepwise regression and bootstrapping reliability to inform a final multivariable model.Weights were available for 197 of 230 subjects for period 1 and 173 of 197 subjects for period 2. For period 1, greater gestational age, younger age at study enrollment, tube feeding at neonatal hospitalization discharge, and clinical center were associated with a greater negative z (poorer growth) in multivariable modeling (adjusted R(2) = 0.39, P.001). For period 2, younger age at SCPC and greater daily caloric intake were associated with greater positive z (better growth; R(2) = 0.10, P = .002).Aggressive nutritional support and earlier SCPC are modifiable factors associated with a favorable change in weight-for-age z-score.