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The transcription factor and oncoprotein MYC is a potent driver of many human cancers and can regulate numerous biological activities that contribute to tumorigenesis. How a single transcription factor can regulate such a diverse set of biological programmes is central to the understanding of MYC function in cancer. In this Perspective, we highlight how multiple proteins that interact with MYC enable MYC to regulate several central control points of gene transcription. These include promoter binding, epigenetic modifications, initiation, elongation and post-transcriptional processes. Evidence shows that a combination of multiple protein interactions enables MYC to function as a potent oncoprotein, working together in a 'coalition model', as presented here. Moreover, as MYC depends on its protein interactome for function, we discuss recent research that emphasizes an unprecedented opportunity to target protein interactors to directly impede MYC oncogenesis.

Despite MYC dysregulation in most human cancers, strategies to target this potent oncogenic driver remain an urgent unmet need. Recent evidence shows the PP1 phosphatase and its regulatory subunit PNUTS control MYC phosphorylation, chromatin occupancy, and stability, however the molecular basis remains unclear. Here we demonstrate that MYC interacts directly with PNUTS through the MYC homology Box 0 (MB0), a highly conserved region recently shown to be important for MYC oncogenic activity. By NMR we identified a distinct peptide motif within MB0 that interacts with PNUTS residues 1-148, a functional unit, here termed PNUTS amino-terminal domain (PAD). Using NMR spectroscopy we determined the solution structure of PAD, and characterised its MYC-binding patch. Point mutations of residues at the MYC-PNUTS interface significantly weaken their interaction both in vitro and in vivo, leading to elevated MYC phosphorylation. These data demonstrate that the MB0 region of MYC directly interacts with the PAD of PNUTS, which provides new insight into the control mechanisms of MYC as a regulator of gene transcription and a pervasive cancer driver. Funding: Canadian Institutes of Health Research [FRN156167 to L.Z.P., FDN154328 to C.H.A., FDN143312 to D.W.A.]; Swedish Cancer Society [20 1276 PjF 01 H to M.S.]; Swedish Childhood Cancer Fund [PR2019-0143 project grant to M.S., TJ2018-0103 postdoc award to A.A.]; Swedish Research Council [2018-04390 to M.S., 2016-05369 to B.W.]; Princess Margaret Cancer Centre; Princess Margaret Cancer Foundation; Ontario Ministry of Health; the Structural Genomics Consortium is a registered charity [1097737] that receives funds from Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196]; EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN grant 875510]; Janssen, Merck KGaA (aka EMD in Canada and US); Pfizer; Takeda; NMR access at the ProLinC core facility was funded by Linköping University; the computations were performed on resources provided by the Swedish National Infrastructure for Computing (SNIC) at the National Supercomputer Centre (NSC) in Linköping; L.Z.P. and D.W.A. hold Tier 1 Canada Research Chairs in Molecular Oncology and Membrane Biogenesis, respectively. Funding for open access charge: Canadian Institutes of Health Research.

By identifying MYC protein-protein interactors, we aim to gain a deeper mechanistic understanding of MYC as a regulator of gene transcription and potent oncoprotein. This information can then be used to devise strategies for disrupting critical MYC protein-protein interactions to inhibit MYC-driven tumorigenesis. In this chapter, we discuss four techniques to identify and validate MYC-interacting partners. First, we highlight BioID, a powerful discovery method used to identify high-confidence proximal interactors in living cells. We also discuss bioinformatic prioritization strategies for the BioID-derived MYC-proximal complexes. Next, we discuss how protein interactions can be validated using techniques such as in vivo-in vitro pull-down assays and the proximity ligation assay (PLA). We conclude with an overview of biolayer interferometry (BLI), a quantitative method used to characterize direct interactions between two proteins in vitro. Overall, we highlight the principles of each assay and provide methodology necessary to conduct these experiments and adapt them to the study of interactors of additional proteins of interest.

The essential eukaryotic chaperone Hsp90 regulates the form and function of diverse client proteins, many of which govern thermotolerance, virulence, and drug resistance in fungal species. However, use of Hsp90 inhibitors as antifungal therapeutics has been precluded by human host toxicities and suppression of immune responses. We recently described resorcylate aminopyrazoles (RAPs) as the first class of Hsp90 inhibitors capable of discriminating between fungal (Cryptococcus neoformans, Candida albicans) and human isoforms of Hsp90 in biochemical assays. Here, we report an iterative structure-property optimization toward RAPs capable of inhibiting C. neoformans growth in culture. In addition, we report the first X-ray crystal structures of C. neoformans Hsp90 nucleotide binding domain (NBD), as the apoprotein and in complexes with the non-species-selective Hsp90 inhibitor NVP-AUY922 and three RAPs revealing unique ligand-induced conformational rearrangements, which reaffirm the hypothesis that intrinsic differences in protein flexibility can confer selective inhibition of fungal versus human Hsp90 isoforms.

By identifying MYC protein-protein interactors, we aim to gain a deeper mechanistic understanding of MYC as a regulator of gene transcription and potent oncoprotein. This information can then be used to devise strategies for disrupting critical MYC protein-protein interactions to inhibit MYC-driven tumorigenesis. In this chapter, we discuss four techniques to identify and validate MYC-interacting partners. First, we highlight BioID, a powerful discovery method used to identify high-confidence proximal interactors in living cells. We also discuss bioinformatic prioritization strategies for the BioID-derived MYC-proximal complexes. Next, we discuss how protein interactions can be validated using techniques such as in vivo-in vitro pull-down assays and the proximity ligation assay (PLA). We conclude with an overview of biolayer interferometry (BLI), a quantitative method used to characterize direct interactions between two proteins in vitro. Overall, we highlight the principles of each assay and provide methodology necessary to conduct these experiments and adapt them to the study of interactors of additional proteins of interest.

Objective:Meta-analyses report moderate effects across cognitive remediation (CR) trials in schizophrenia. However, individual responses are variable, with some participants showing no appreciable gain in cognitive performance. Furthermore, reasons for heterogeneous outcome are undetermined. We examine the extent to which CR outcome is attributable to near learning—direct gains in trained cognitive tasks—while also exploring factors influencing far transfer of gains during training to external cognitive measures.Method:Thirty-seven schizophrenia outpatients were classified as CR responders and non-responders according to change in MATRICS Consensus Cognitive Battery composite score following 20 sessions of computer-based training. Metrics of near learning during training, as well as baseline demographic, clinical, cognitive, and electroencephalographic (EEG) measures, were examined as predictors of responder status.Results:Significant post-training improvement in cognitive composite score (Cohen’s d = .41) was observed across the sample, with n = 21 and n = 16 classified as responders and non-responders, respectively. Near learning was evidenced by significant improvement on each training exercise with practice; however, learning did not directly predict responder status. Group-wise comparison of responders and non-responders identified two factors favoring responders: higher EEG individual alpha frequency (IAF) and lower antipsychotic dosing. Tested in moderation analyses, IAF interacted with learning to predict improvement in cognitive outcome.Conclusion:CR outcome in schizophrenia is not directly explained by learning during training and appears to depend on latent factors influencing far transfer of trained abilities. Further understanding of factors influencing transfer of learning is needed to optimize CR efficacy.

Species in the genus Klossiella Smith and Johnson, 1902 are unique among the suborder Adeleorina because they are monoxenous in mammals exclusively, whereas all other reported members of the Adeleorina use invertebrates as definitive hosts. Unlike other coccidia, all members of the Adeleorina undergo syzygy, the association of microgamonts and macrogamonts before maturation to gametes and syngamy. After fertilization, many members of the Adeleorina produce thin-walled polysporocystic oocysts. Despite being biologically similar to other members of the Adeleorina, the phylogenetic placement of the genus Klossiella has been questioned based on its unique host affinity. In the present study, 2 cases of Klossiella equi were reported from the kidneys of horses in Ontario. Details of the life cycle as well as mitochondrial and nuclear 18S ribosomal DNA ( 18S rDNA) sequences were analyzed to provide both morphological and molecular evidence for the phylogenetic placement of K. equi. Initially, various stages of the life cycle were identified in histological slides prepared from the kidney tissue, and DNA was isolated from the infected tissue. Polymerase chain reaction and Sanger sequencing were used to generate a complete mitochondrial genome sequence (6,569 bp) and a partial 18S rDNA sequence (1,443 bp). The K. equi 18S rDNA sequence was aligned with various publicly available apicomplexan 18S rDNA sequences. This alignment was used to generate a phylogenetic tree based on Bayesian inference. Multiple K. equi stages were identified including meronts, microgamonts, and macrogamonts associating in syzygy as well as thin-walled oocysts in various stages of sporogonic development. The 18S rDNA sequence of K. equi positioned within the monophyletic Adeleorina clade. The mitochondrial genome of K. equi contained 3 coding sequences for cytochrome c oxidase I, cytochrome c oxidase III, and cytochrome b as well as various fragmented ribosomal sequences. These components were arranged in a unique order that has not been observed in other apicomplexan mitochondrial genomes sequenced to date. Overall, it was concluded that there were sufficient morphological and molecular data to confirm the placement of K. equi and the genus Klossiella among the Adeleorina. The biological and molecular data obtained from these cases may assist with future studies evaluating the prevalence and life history of this seemingly underreported parasite and better define the impact of K. equi on the health of domestic and wild equids.

Leukemia is broadly divided into acute and chronic lymphocytic and myeloid types based on the proportion of blasts, morphology of cells, and expression of specific antigens on neoplastic cells. Classifying leukemia in horses can be challenging if blasts predominate and since few antibodies to identify cell types are available. The objective of this study was to describe in detail the clinical and pathologic features of acute leukemia in horses. Twelve horses ranging from 0.2 to 25.9 years of age were diagnosed with acute leukemia. Six cases were classified as acute lymphocytic leukemia (ALL) based on predominance of blasts, lack of granulocytic or monocytic differentiation, and detection of CD3, CD20, and/or CD79a antigens by immunohistochemistry. Six other cases were classified as acute myeloid leukemia (AML) with myelomonocytic ( n = 4), basophilic ( n = 1), and eosinophilic ( n = 1) differentiation based on > 20% bone marrow blasts and partial leukocytic differentiation. Reactivity with antibodies to Iba-1/AIF-1, CD172a, and CD163 was determined for all cases of AML. Eleven horses had thrombocytopenia, 10 had neutropenia, 8 had anemia, all had blasts on blood films, and none had leukocytosis. Ten horses had increased serum acute phase proteins. Bone marrow cellularity ranged from 30% to 100%, and the proportion of blasts ranged from 80% to 100% and 30% to 60% in ALL and AML, respectively. Horses were severely ill at diagnosis and euthanized within days or weeks. Unique features of acute leukemia in horses compared to other species were variable lymphocyte antigen expression (ALL) and frequent inflammation (ALL and AML).

Objective—To evaluate influence of electrode position on cardioversion energy (CE; energy delivered in the shock at which cardioversion was achieved) during transvenous electrical cardioversion (TVEC) in horses with atrial fibrillation. Animals—37 horses with atrial fibrillation (41 cardioversion events). Procedures—Records were reviewed to identify horses that underwent TVEC for treatment of atrial fibrillation. Signalment and CE were recorded. Electrode positions in the right atrium and pulmonary artery were identified on intraoperative radiographs. An orthogonal coordinate space was created, and electrode y- and z-axis coordinates and shadow lengths were determined. Trigonometric modeling was used to estimate x-axis electrode positions that resulted in observed shadows. Postmortem casts of catheterized horses were used to assess electrode paths and anatomic relationships. Model assumptions were tested by use of these and a theoretical data set. Relationships between signalment, electrode position, and CE were assessed via multivariate analysis. Results—Sex and y-axis differences between electrode positions were significant predictors of CE. Population stratification based on examination of residuals improved model strength; populations differed in z-axis variables and in CE. Decreasing distance between electrodes and pulmonary artery electrode positions ventral to the right atrium were associated with increased CE. Agreement between estimated and actual x-axis coordinates was poor. Conclusions and Clinical Relevance—Optimal electrode positioning can reduce the energy requirement for successful TVEC and may eventually support application of TVEC under short-term IV anesthesia and potentially increase chances of treatment response. Further investigation into these relationships is warranted.

Species in the genus Klossiella Smith and Johnson, 1902 are unique among the suborder Adeleorina because they are monoxenous in mammals exclusively, whereas all other reported members of the Adeleorina use invertebrates as definitive hosts. Unlike other coccidia, all members of the Adeleorina undergo syzygy, the association of microgamonts and macrogamonts before maturation to gametes and syngamy. After fertilization, many members of the Adeleorina produce thin-walled polysporocystic oocysts. Despite being biologically similar to other members of the Adeleorina, the phylogenetic placement of the genus Klossiella has been questioned based on its unique host affinity. In the present study, 2 cases of Klossiella equi were reported from the kidneys of horses in Ontario. Details of the life cycle as well as mitochondrial and nuclear 18S ribosomal DNA (18S rDNA) sequences were analyzed to provide both morphological and molecular evidence for the phylogenetic placement of K.equi. Initially, various stages of the life cycle were identified in histological slides prepared from the kidney tissue, and DNA was isolated from the infected tissue. Polymerase chain reaction and Sanger sequencing were used to generate a complete mitochondrial genome sequence (6,569 bp) and a partial 18S rDNA sequence (1,443 bp). The K. equi 18S rDNA sequence was aligned with various publicly available apicomplexan 18S rDNA sequences. This alignment was used to generate a phylogenetic tree based on Bayesian inference. Multiple K. equi stages were identified including meronts, microgamonts, and macrogamonts associating in syzygy as well as thin-walled oocysts in various stages of sporogonic development. The 18S rDNA sequence of K. equi positioned within the monophyletic Adeleorina clade. The mitochondrial genome of K. equi contained 3 coding sequences for cytochrome c oxidase I, cytochrome c oxidase III, and cytochrome b as well as various fragmented ribosomal sequences. These components were arranged in a unique order that has not been observed in other apicomplexan mitochondrial genomes sequenced to date. Overall, it was concluded that there were sufficient morphological and molecular data to confirm the placement of K. equi and the genus Klossiella among the Adeleorina. The biological and molecular data obtained from these cases may assist with future studies evaluating the prevalence and life history of this seemingly underreported parasite and better define the impact of K. equi on the health of domestic and wild equids.

Liver kinase B1 (LKB1) is a tumor-suppressing protein that is involved in the regulation of muscle metabolism and growth by phosphorylating and activating AMP-activated protein kinase (AMPK) family members. Here we report the development of a myopathic phenotype in skeletal and cardiac muscle-specific LKB1 knockout (mLKB1-KO) mice. The myopathic phenotype becomes overtly apparent at 30–50 wk of age and is characterized by decreased body weight and a proportional reduction in fast-twitch skeletal muscle weight. The ability to ambulate is compromised with an often complete loss of hindlimb function. Skeletal muscle atrophy is associated with a 50–75% reduction in mammalian target of rapamycin pathway phosphorylation, as well as lower peroxisome proliferator-activated receptor-α coactivator-1 content and cAMP response element binding protein phosphorylation (43 and 40% lower in mLKB1-KO mice, respectively). Maximum in situ specific force production is not affected, but fatigue is exaggerated, and relaxation kinetics are slowed in the myopathic mice. The increased fatigue is associated with a 30–78% decrease in mitochondrial protein content, a shift away from type IIA/D toward type IIB muscle fibers, and a tendency ( P = 0.07) for decreased capillarity in mLKB1-KO muscles. Hearts from myopathic mLKB1-KO mice exhibit grossly dilated atria, suggesting cardiac insufficiency and heart failure, which likely contributes to the phenotype. These findings indicate that LKB1 plays a critical role in the maintenance of both skeletal and cardiac function.

Ciprofloxacin is a fluoroquinolone antimicrobial used extensively in human medicine. It is available in oral and i.v. preparations and is used widely in human medicine for the treatment of urinary, lower respiratory tract, skin, bone and joint infections (Lettieri et al. 1992). It is not labelled for use in horses and there have been no published studies reporting its therapeutic use in this species. This report describes a possible association of oral ciprofloxacin administration with the development of colitis in 4 Standardbred horses.

The purpose of this study is to explore the relationship between customer satisfaction, service quality, and the repurchase intention dimension of consumer loyalty within higher education. The influence of switching costs as a mediating variable is also examined. The setting for the study is the online learning facet of the higher education market. While the relationship between satisfaction, service quality, and loyalty are well known, there is a gap in the literature examining this relationship within higher education. A new research framework is proposed to illustrate the relationship between the independent, mediating, and the dependent variables, and five propositions are put forth.

Background: Transvenous electrical cardioversion (TVEC) has been developed for treatment of atrial fibrillation (AF) in horses. The relationship among patient variables, treatment response, and outcome in a typical referral population has not been evaluated. Hypothesis: Patient variables such as age, sex, weight, and duration of arrhythmia affect prognosis for response to treatment and the energy level at which cardioversion occurs. Animals: TVEC was applied to 72 episodes of lone AF in 63 client-owned performance horses, with the majority (54) being Standardbred racehorses. Methods: Catheterization of the right atrium (RA) and pulmonary artery (PA) through the jugular vein was used for electrode placement before horses were placed under general anesthesia. Biphasic, truncated exponential shock waves were delivered at incremental energy levels until cardioversion was achieved or a maximum single-energy level of 300 J was reached (cumulative energy 50–1,960 J). A multivariate model was constructed to evaluate influence of patient factors on cardioversion energy. Results: Cardioversion was achieved in 71 of 72 episodes (62 of 63 horses) at a mean energy of 165.43 ± 8.75 J. Cardioversion energy was higher for females than for males, and for interaction terms, weight was negatively related to energy in females and positively related in males. Age was positively related to cardioversion energy in females. No relationship was identified between duration of arrhythmia before treatment and prognosis for response or cardioversion energy. Conclusions and Clinical Importance: TVEC is highly effective in the treatment of lone AF in horses. Although age and sex influence cardioversion energy level, duration of arrhythmia does not.

Objective—To describe management of anesthesia for transvenous electrical cardioversion (TVEC) in horses and report perianesthetic complications. Design—Retrospective case series. Animals—62 horses with atrial fibrillation and without underlying cardiac disease and 60 horses without atrial fibrillation. Procedures—Medical records of horses with atrial fibrillation anesthetized for TVEC were reviewed, as were records of horses without atrial fibrillation anesthetized for magnetic resonance imaging (MRI). The TVEC group horses were compared with MRI group horses for incidence of intraoperative bradycardia and use of inotropic drugs. Data obtained included patient signalment, weight, duration of anesthesia, heart rate and arterial blood pressure during anesthesia, anesthetic drugs administered, mode of ventilation, perioperative complications, and quality of recovery. Results—The TVEC group horses were > 1 year of age and were predominantly Standardbreds. The TVEC group horses underwent a total of 76 anesthetic episodes. For 40 (52.6%) anesthetic episodes, horses received xylazine only for premedication, and for 26 (34.2%) anesthetic episodes, horses received xylazine and butorphanol. Induction of anesthesia consisted of ketamine administration in various combinations with diazepam and guaifenesin for 74 (97.4%) anesthetic episodes and ketamine alone for 2 (2.6%). Bradycardia in horses was encountered during 15 of 76 (19.7%) anesthetic episodes. Minor signs of possible postanesthetic myopathy occurred following 6 (7.9%) anesthetic episodes. No significant difference was found between TVEC and MRI group horses regarding incidence of bradycardia and inotropic drug administration. Conclusions and Clinical Relevance—Short-duration anesthesia for TVEC of atrial fibrillation in horses without underlying cardiac disease was a safe procedure.

Electrical cardioversion of atrial fibrillation is a well-established technique for restoration of sinus rhythm in humans. While transthoracic cardioversion is more commonly used, transvenous electrical cardioversion (TVEC) has been reported as having higher efficacy at substantially lower energy levels. In horses, treatment of atrial fibrillation has essentially been limited to the administration of quinidine salts either orally or intravenously. TVEC provides an alternative to quinidine salts, especially for those animals in which quinidine is neither effective nor tolerated. The present report details this technique in horses, discusses possible complications of the procedure, and provides guidance for successful outcome. Still and video images are used to illustrate details with regard to TVEC techniques in horses. Please view supplemental material for the videos.

A Synchrotron Radiation Detector measures synchrotron radiation emitted by high energetic particles in the earth magnetic field. This allows to identify cosmic ray electrons and positrons with energies in the TeV region. One possibility for such a detector outside the atmosphere uses YAP crystals to measure synchrotron photons with energies in the keV range. As such a detector can not distinguish between photons and electrons, the main problems are the diffuse cosmic ray gamma background and low energetic electrons in the vicinity of the earth. While the intensity of the diffuse gamma rays is known quite well, there exists limited knowledge about keV-electrons in low earth orbits. To measure these electrons a Prototype Synchrotron Radiation Detector (PSRD) was flown with Space Shuttle mission STS-108 (Dec.2001) and preliminary analysis of the data show very favorable results.

The Prototype Synchrotron Radiation Detector (PSRD) is a small-scale experiment designed to measure the rate of low-energy charged particles and photons in near the Earth's orbit. It is a precursor to the Synchrotron Radiation Detector (SRD), a proposed addition to the upgraded version of the Alpha Magnetic Spectrometer (AMS-02). The SRD will use the Earth's magnetic field to identify the charge sign of electrons and positrons with energies above 1 TeV by detecting the synchrotron radiation they emit in this field. The differential energy spectrum of these particles is astrophysically interesting and not well covered by the remaining components of AMS-02. Precise measurements of this spectrum offer the possibility to gain information on the acceleration mechanism and characteristics of all cosmic rays in our galactic neighbourhood. The SRD will discriminate against protons as they radiate only weakly. Both the number and energy of the synchrotron photons that the SRD needs to detect are small. The identification is complicated by the presence of a large particle and photon background. Existing measurements of these backgrounds are insufficient for the construction of the large-scale SRD, so a measurement in space was indispensable. The PSRD was designed to fly as a Space Shuttle secondary payload, within the Shuttle Small Payloads Project. The flight on board the Space Shuttle Endeavour took place from 5 to 17 December 2001. The scientific goal, hardware and the flight of the PSRD are described in this report.

A 2-week-old Toggenburg kid was evaluated for persistent diarrhea and poor body condition. The herd had high morbidity and mortality associated with diarrhea in neonatal kids. Lactose intolerance was diagnosed on the basis of results of a lactose tolerance test and glucose absorption test. Clinically normal herdmates were used as control animals. The kid responded to lactase supplementation. Cryptosporidium organisms were detected in feces of several affected kids during episodes of acute diarrhea. Lactose intolerance was presumed to have developed secondary to intestinal cryptosporidiosis.

A measurement of the cosmic ray positron fraction e+ / (e+ + e-) in the energy range of 1-30 GeV is presented. The measurement is based on data taken by the AMS-01 experiment during its 10 day Space Shuttle flight in June 1998. A proton background suppression on the order of 106 is reached by identifying converted bremsstrahlung photons emitted from positrons., Physics Letters B, 646 (4), ISSN:0370-2693, ISSN:0031-9163, ISSN:1873-2445

To assess evidence for genetic contributions to atrial fibrillation (AF) in the Standardbred horse.Equine referrals to the Ontario Veterinary College Health Sciences Centre (OVCHSC) for 1985-2009, and age and gait matched breed registry controls.Breeds presenting ≥ 5 times annually were tabulated (admission year and diagnosis; total 40,039; AF 396; no AF 39,643), and breed and year effects examined. Heritability and inbreeding coefficients were determined for Standardbred AF cases and racing contemporaries, and odds ratios for AF were calculated for frequently occurring sires.Year and breed effects on diagnosis were highly significant (Chi-Square 212.85, p0.0001, and 304.25, p0.0001, respectively). Year effect on diagnosis by breed was significant from 1997, and due to Standardbred admissions each year. Quarterhorses were significantly less likely to present with AF (OR 0.0578-0.6048), Standardbreds were more likely (OR 4.3874-10.9006). Heritability of AF on the underlying scale (h²(u)) was estimated at 29.6 ± 3.9% and on the observed binomial scale (h²(o)), at 9.6%. For horses born in 1994 or later, h²(u) was 31.1 ± 4.3% and h²(o), 10.1%. Of 22 first generation sires appearing ≥ 10 times in the case/control file, seven pacing and one trotting sire produced affected horses more frequently than expected (OR 2.66-66.32). Inbreeding was not a factor.There is genetic liability to AF in Standardbred horses, likely due to more than single genes with simple Mendelian inheritance. Genomic studies are required.

Objective : To study the responsiveness of peripheral blood mononuclear cells to lipopolysaccharide (LPS) after severe trauma and its regulatory mechanisms. Materials and Methods : The release of proinflammatory reacting cytokines (tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, interferon (IFN)-γ) into whole blood from 12 patients on day 1, 5, 10, and 14 after severe trauma (Injury Severity Score, 39.3 ± 2.8 points) and 10 healthy volunteers was studied after stimulation with LPS, concanavalin A, phorbol myristate acetate (PMA), and the addition of recombinant IFN-γ. Main Results : Trauma caused a significant reduction of LPS and concanavalin A induced release of inflammation activating cytokines into whole blood, including IFN-γ. However, the diminished release of proinflammatory cytokines could be increased with recombinant IFN-γ or even attenuated after stimulation of peripheral blood mononuclear cells with the protein kinase C activator PMA. Conclusions : Trauma leads to reduced responsiveness of blood monocytes to LPS and a decreased secretion of proinflammatory reacting lymphokines. Because activation of the protein kinase C pathway with PMA or the addition of IFN-γ significantly increased cytokine response, endotoxin tolerance is not caused by inhibition of protein synthesis, but to disturbances in the signal transduction pathway and its regulating mediators.

Norplant's long duration of action may result in users being less motivated than non-users to return for reproductive health care appointments. This study determined compliance with scheduled return appointments among adolescents using Norplant and those using other methods of contraception.We retrospectively reviewed the records of all teenagers (ageor = 18 years) who received Norplant between June 1991 and August 1993, as well as those of a comparison group of adolescents, matched for age and race, using other methods of contraception. Subjects receiving Norplant were given appointments for a two-week and an annual examination. Comparison subjects were given only an appointment for an annual examination. Norplant users not returning within 5 weeks or any subject not presenting within 12 months for an annual examination, were considered non-compliant.Eighty-eight adolescents received Norplant during the study period and the records of 85 were available for review. Only 48 of the 85 Norplant users returned for scheduled two-week check-up, while 18 of 43 subjects who had Norplant at least 12 months were compliant with annual examinations. The compliance rate with annual examinations among the 89 subjects not using Norplant was 38%, not dissimilar from that of the Norplant group.These data demonstrate that compliance with return appointments for reproductive health care among adolescent Norplant users is poor but not significantly worse than that of non-users of Norplant. Strategies promoting the benefits of return visits need to be improved for adolescents receiving contraception.Although the long-term protection from pregnancy conferred by Norplant use makes this a potentially effective method for adolescents, there are concerns that teenagers with implants will not be motivated to return for routine reproductive health examinations. To assess this possibility, compliance with scheduled return clinic appointments among 85 Norplant acceptors aged 18 years and younger and 89 age- and race-matched controls was compared through retrospective review of records at a community-based family planning clinic in North Carolina. Only 14 Norplant acceptors returned to have the insertion site examined within five weeks of insertion; another seven appeared for the initial examination after a reminder was mailed, yielding a 25% compliance rate. In terms of the annual examination, 18 of the 43 subjects who had used Norplant for at least 12 months and 34 of the 89 controls were compliant. There was no significant difference in this compliance rate between cases (41.9%) and users of other methods (38.2%). Among cases, the records showed that appointment compliance after Norplant insertion was not significantly lower than it had been among these women when they were using other methods. Only three Norplant acceptors discontinued the method, indicating a high degree of user satisfaction. Although these findings indicate that Norplant use does not increase the risk of poor compliance with reproductive health care, they indicate a need to convince teenagers of the benefits of such care, especially for the detection of sexually transmitted diseases.

A 6-hour-old alpaca was presented for evaluation of respiratory difficulty. As part of routine surveillance, methicillin-resistant Staphylococcus aureus (MRSA) was identified from a nasal swab taken upon admission to the hospital. No signs of MRSA infection were noted. The MRSA strain recovered was a human epidemic clone that has been associated with horses. Methicillin-resistant S. aureus colonization can occur in camelids, and the potential animal and public health risks require consideration.

An 82-cm fragment of nasogastric tube was removed from the stomach of an adult horse under standing sedation by use of an endoscope and electrocautery snare. This is the first report of successful non-surgical removal of a nasogastric tube fragment from the stomach of a horse.

Scholars have shown that maintaining an intrapreneurial culture contributes to superior firm performance (Parboteeah, 2000) and attracting better qualified job applicants (Olmsted, 2005). Yet, there remains a need for more research “regarding the successes or failures of large companies that systematically instill corporate entrepreneurship” (Thornberry, 2003 p. 332). While an increasing number of scholars have examined the benefits and challenges of creating and maintaining an intrapreneurial culture, there remains a need to examine intrapreneurship from an intrapreneur’s perspective. This article is an exploratory study which qualitatively, through the use of informational interviews, explores how experienced intrapreneurs within the Information Technology (IT) field view intrapreneurial opportunities and how management practices explicitly and/or implicitly effect intrapreneurial perceptions.

The variety of isotopes in cosmic rays allows us to study different aspects of the processes that cosmic rays undergo between the time they are produced and the time of their arrival in the heliosphere. In this paper, we present measurements of the isotopic ratios [superscript 2]H/[superscript 4]He, [superscript 3]He/[superscript 4]He, [superscript 6]Li/[superscript 7]Li, [superscript 7]Be/([superscript 9]Be+[superscript 10]Be), and [superscript 10]B/[superscript 11]B in the range 0.2-1.4 GeV of kinetic energy per nucleon. The measurements are based on the data collected by the Alpha Magnetic Spectrometer, AMS-01, during the STS-91 flight in 1998 June., United States. Dept. of Energy, Massachusetts Institute of Technology

Due to the interrelationship between entrepreneurship and marketing, entrepreneurship faculty must have a good understanding of the major academic contributions of scholars in the area of marketing. This paper critically examines twenty classic marketing journal articles that have contributed significantly to the development of marketing theory literature and the advancement of marketing as a social science.

Case Description—4 racehorses were examined because of markedly abnormal behavior following administration of fluphenazine decanoate. Clinical Findings—Clinical signs included restlessness, agitation, profuse sweating, hypermetria, aimless circling, intense pawing and striking with the thoracic limbs, and rhythmic swinging of the head and neck alternating with episodes of severe stupor. Fluphenazine was detected in serum or plasma from all 4 horses. The dose of fluphenazine decanoate administered to 3 of the 4 horses was within the range (25 to 50 mg) routinely administered to adult humans. Treatment and Outcome—In 2 horses, there was no response to IV administration of diphenhydramine hydrochloride, but the abnormal behavior in these 2 horses appeared to resolve following administration of benztropine mesylate, and both horses returned to racing. The other 2 horses responded to diphenhydramine administration. One returned to racing. The other was euthanized because of severe neurologic signs, respiratory failure, and acute renal failure. Clinical Relevance—Findings indicate that adverse extrapyramidal effects may occur in horses given fluphenazine decanoate. These effects appear to be unpredictable and may be severe and life threatening. Use of fluphenazine decanoate as an anxiolytic in performance horses is not permitted in many racing and horse show jurisdictions, and analytic procedures are now available to detect the presence of fluphenazine in serum or plasma.

An inflammatory aural polyp was identified in a 1-year-old standardbred filly, which presented with otorrhea and head rubbing. The polyp was removed by traction-avulsion, and the filly showed no subsequent signs of otorrhea. Aural polyps have not been reported in horses, but they are commonly seen in companion animals and humans.

Objective—To determine clinical signs, diagnostic findings, outcome, and prognostic factors in dogs treated surgically for massive hepatocellular carcinoma (HCC) and compare survival times of surgically and conservatively treated dogs. Design—Retrospective study. Animals—48 dogs. Procedure—Medical records were examined for clinical signs, diagnostic and surgical findings, and postoperative outcome. Dogs were allocated into surgery and nonsurgery groups depending on whether curative- intent liver lobectomy was performed. Data from the surgical and nonsurgical groups were analyzed to identify prognostic factors and determine and compare rates of tumor control and survival time. Results—42 dogs were treated surgically, and 6 were managed conservatively. In the surgery group, intraoperative mortality rate was 4.8% with no local recurrence, metastatic rate was 4.8%, and median survival time was > 1,460 days (range, 1 to 1,460 days). High alanine aminotransferase and aspartate aminotransferase activities were associated with poor prognosis. Median survival time for the nonsurgery group was 270 days (range, 0 to 415 days), which was significantly less than that of surgically treated dogs. Conclusions and Clinical Relevance—Liver lobectomy is recommended for dogs with massive HCC because tumor-related mortality rate was 15.4 times higher in dogs in the nonsurgery group, compared with the surgery group. Tumor control was excellent after surgical resection with no local recurrence and a low metastatic rate. Prognostic factors were identified, but their clinical relevance was uncertain because only 9.5% of dogs in the surgery group died as a result of their disease. (J Am Vet Med Assoc 2004;225:1225–1230)