Posted by: kelsijo97 | October 18, 2012

October 2012

A combination of viral, bacterial, and host factors contributes to the severity and overall mortality associated with influenza virus-bacterium superinfections. To date, the virulence associated with the recently identified influenza virus protein PB1-F2 has been largely defined using models of primary influenza virus infection, with only limited assessment in models of Streptococcus pneumoniae superinfection. Specifically, these studies have incorporated isogenic viruses that differ in the PB1-F2 expressed, but there is still knowledge to be gained from evaluation of natural variants derived from a nonhuman host species (swine). Using this rationale, we developed the hypothesis that naturally occurring viruses expressing variants of genes, like the PB1-F2 gene, can be associated with the severity of secondary bacterial infections. To test this hypothesis, we selected viruses expressing variants in PB1-F2 and evaluated outcomes from superinfection with three distinct Gram-positive respiratory pathogens: Streptococcus pneumoniae, Staphylococcus aureus, and Streptococcus pyogenes. Our results demonstrate that the amino acid residues 62L, 66S, 75R, 79R, and 82L, previously proposed as molecular signatures of PB1-F2 virulence for influenza viruses in the setting of bacterial superinfection, are broadly associated with enhanced pathogenicity in swine in a bacterium-specific manner. Furthermore, truncated PB1-F2 proteins can preferentially increase mortality when associated with Streptococcus pyogenes superinfection. These findings support efforts to increase influenza virus surveillance to consider viral genotypes that could be used to predict increased severity of superinfections with specific Gram-positive respiratory pathogens.
Basic Biomedical Sciences, Vermillion Campus.
An, Hunter, W. Hardin, and  Z. H. Wu. (2012). Information Asymmetry and Corporate Liquidity Management: Evidence from Real Estate Investment Trusts. [Article]. Journal of Real Estate Finance and Economics, 45(3), 678-704.
We examine the impact of information asymmetry on a firm’s choice between cash and credit lines for corporate liquidity management using a panel data set from real estate investment trusts (REITs). Information asymmetry, as measured by analyst forecast error and dispersion, is negatively related to the use of lines of credit. Specifically, firms with more severe information asymmetry are less likely to have access to bank credit lines. Concurrently, more transparent firms are more likely to utilize bank credit lines as opposed to cash for liquidity management. The results are robust to alternative information asymmetry proxies and specifications. These findings suggest that information asymmetry plays an important role in corporate liquidity management.
Beacom School of Business
Ghosh, Suvankar, and  Marvin D. Troutt. (2012). Complex compound option models – Can practitioners truly operationalize them? European Journal of Operational Research, 222(3), 542-552.
While there is practitioner interest in real options (RO), there are significant difficulties in practitioner use of complicated RO models, such as compound options pricing models (OPMs) of multistage investments. Drawing upon theories of learning and knowledge, we propose a general framework whereby practitioners can successfully operationalize complex OPMs. From an epistemological perspective, most academic articles on OPMs are essentially propositional knowledge representations that attest to model veracity, and they require a deep background in the analytics of options pricing to comprehend the model which many practitioners lack. A key element of our framework is that the propositional knowledge representation of complex OPMs must be accompanied by a layer of abstraction translating the propositional into procedural knowledge for using the model. Secondly, while this layer of abstraction can be embodied in a software tool for using the OPM, this must be transparently done in order to build trust in the software tool. Thirdly, in the tradition of constructivist learning, using the tool must be illustrated in the context of some contemporary business problem. Finally, a continuous engagement loop must be established which makes routine the application of the RO methodology using this tool. We demonstrate these steps in the context of Geske compound option models for multistage investments. We also show how to apply our tool to the major business problem of enterprise integration. This article therefore provides academics with prescription on fostering practitioner embrace of complex OPMs and practitioners with a tool for operationalizing n-fold compound option models. (C) 2012 Elsevier B.V. All rights reserved.
Beacom School of Business.
Kiesow, A. M., E. M. Monroe, and  Hugh B. Britten. (2012). Genetic structure of the arboreal squirrels (Glaucomys sabrinus and Tamiasciurus hudsonicus) in the North American Black Hills. [Article]. Canadian Journal of Zoology-Revue Canadienne De Zoologie, 90(9), 1191-1200.
We selected two isolated mammalian populations, the Black Hills northern flying squirrel (Glaucomys sabrinus (Shaw, 1801)) and red squirrel (Tamiasciurus hudsonicus (Erxleben, 1777)), to elucidate their genetic structure. We trapped both squirrels from 2005 to 2007, in three regions of the Black Hills, differing in geology and vegetation, to collect ear samples for genetic analyses. Microsatellite loci (northern flying (9) and red squirrel (13)) were used to examine genetic structure. Data analyses estimated genetic variability, substructure, and gene flow. Northern flying and red squirrel populations have allelic diversity and observed heterozygosity similar to other isolated populations. Each species shows weak substructure from STRUCTURE and GENELAND analyses, suggesting squirrel movements may be inhibited by topography or unsuitable habitat. Recent gene flow estimates from BAYESASS indicate that both species experience some within population gene flow and red squirrels may be more structured than northern flying squirrels because of lower migration rates. Concordant patterns of genetic structure in northern flying and red squirrels indicate that other species’ movements in the Black Hills may be affected by topography and habitat. Because their habitat is isolated in the Black Hills, management practices and conservation measures are recommended to promote viability and survival of each species.
Biology Department.
We demonstrate a direct fabrication of PbS nanocube supercrystals without size-selection pretreatment on the building blocks. Electron microscopic and synchrotron small angle X-ray scattering analyses confirm that nanocubes pack through a tilted face-centered-cubic (fcc) arrangement, that is, face-to-face along the < 110 >(super) direction, resulting in a real packing efficiency of as high as similar to 83%. This new type of superstructure consisting of nanocubes as building blocks, reported here for the first time, is considered the most stable surfactant-capped nanocube superstructure determined by far.
Chemistry Department.
Sun, Haoran, Anjaneyulu Putta, and  Michael Billion. (2012). Arene Trifluoromethylation: An Effective Strategy to Obtain Air-Stable n-Type Organic Semiconductors with Tunable Optoelectronic and Electron Transfer Properties. [Article]. Journal of Physical Chemistry A, 116(30), 8015-8022.
Modulation of organic semiconductor band gap, electron affinities (EA), ionization potentials (IP), and reorganization energies (lambda) associated with charge transfer is critical for its applications. We report here that trifluoromethylation not only increases both IP and EA significantly as expected but also narrows the HOMO-LUMO band gaps and increases considerably the air-stability of arene-based n-type organic semiconductors. The increased air-stability results from relatively high EA energies and a change in oxidation mechanism. Calculated EM and IPs show that trifluoromethylated arenes are excellent candidates for n-type semiconductor materials; though a moderate increase of inner-sphere reorganization energy (lambda(i)) associated with charge transfer is the penalty for the improved performance of the trifluoromethylated compounds. However, since lambda(i) decreases as the pi conjugation increases, a rational design to produce air-stable n-type semiconductor materials with reasonably small lambda(i) is simply to prepare trifluoromethylated arenes with extended pi conjugation. Furthermore, we found that structural isomerization can fine-tune the optoelectronic and electronic transfer properties of the corresponding aromatics.
Chemistry Department.
The lumen degradation of light emitting diodes subject to increasing stress loading is investigated by using a cumulative damage model. The cumulative damage process is taken as a Wiener diffusion process with a drift which depends on two stress loadings. General statistical inferences on the parameters and percentiles of the light emitting diode lifetime distribution are presented based on the cumulative damage measurements, collected from a two-variable constant-stress loading accelerated degradation test. Approximate lower s-confidence bounds of the light emitting diode lighting lifetime percentiles are given using the Fisher information of the maximum-likelihood estimators, and Bonferroni’s inequality. The application of the proposed method is illustrated by a lumen cumulative damage data set of high power light emitting diodes.
Mathematics Department.
Barker, D., D. M. Mei, and  C. Zhang. (2012). Muon-induced background study for an argon-based long baseline neutrino experiment. [Article]. Physical Review D, 86(5), 4001-4001.
We evaluated rates of transversing muons, muon-induced fast neutrons, and production of (40)Cl and other cosmogenically produced nuclei that pose as potential sources of background to the physics program proposed for an argon-based long baseline neutrino experiment at the Sanford Underground Research Facility, Homestake Mine, in Lead, South Dakota. The Geant4 simulations were carried out with muons and muon-induced neutrons for both the 800 ft level (0.712 km w.e.) and 4850 ft level (4.3 km w.e.). We developed analytic models to independently calculate the (40)Cl production using the measured muon fluxes at different levels of the Homestake Mine. The muon induced (40)Cl production rates through stopped muon capture and the muon-induced neutrons and protons via (n, p) and (p, n) reactions were evaluated. We find that the Monte Carlo simulated production rates of (40)Cl agree well with the predictions from analytic models. A depth-dependent parametrization was developed and benchmarked to the direct analytic models. We conclude that the muon-induced processes will result in large backgrounds to the physics proposed for an argon-based long baseline neutrino experiment at a depth of less than 4.0 km w.e.
Physics Department.
The article discusses a study that was conducted for examining the correlation existing between self-reported history of concussion and exertional heat illness (EHI) symptoms as observed while exercising in heat among college athletes. The results of the study prove that athletes with a history of concussion exhibit higher risks of EHI. The patterns of association and the impacts of both disorders are also analyzed.
Sanford School of Medicine, Sioux Falls Campus.
Anderson, Heather M., Cheryl Miller, Earl Kemp, and  Mark K. Huntington. (2012). Bullous impetigo associated with Abiotrophia defectiva in an immunocompetent adult. [Article]. Journal of Medical Microbiology, 61(7), 1029-1031.
Infection of humans by Abiotrophia defectiva, a nutritionally variant streptococcus, most commonly takes the form of endocarditis, though a variety of other manifestations ranging from central nervous system abscesses to orthopaedic infections have been seen. We report here what we believe is the first case of bullous impetigo associated with this organism.
Sanford School of Medicine, Sioux Falls Campus.
Bergeron, Michael F., R. Bahr, P. Bartsch, L. Bourdon, J. A. L. Calbet, K. H. Carlsen, O. Castagna, J. Gonzalez-Alonso, C. Lundby, R. J. Maughan, G. Millet, M. Mountjoy, S. Racinais, P. Rasmussen, D. G. Singh, A. W. Subudhi, A. J. Young, T. Soligard, and  L. Engebretsen. (2012). International Olympic Committee consensus statement on thermoregulatory and altitude challenges for high-level athletes. [Article]. British Journal of Sports Medicine, 46(11), 770-779.
Challenging environmental conditions, including heat and humidity, cold, and altitude, pose particular risks to the health of Olympic and other high-level athletes. As a further commitment to athlete safety, the International Olympic Committee (IOC) Medical Commission convened a panel of experts to review the scientific evidence base, reach consensus, and underscore practical safety guidelines and new research priorities regarding the unique environmental challenges Olympic and other international-level athletes face. For non-aquatic events, external thermal load is dependent on ambient temperature, humidity, wind speed and solar radiation, while clothing and protective gear can measurably increase thermal strain and prompt premature fatigue. In swimmers, body heat loss is the direct result of convection at a rate that is proportional to the effective water velocity around the swimmer and the temperature difference between the skin and the water. Other cold exposure and conditions, such as during Alpine skiing, biathlon and other sliding sports, facilitate body heat transfer to the environment, potentially leading to hypothermia and/or frostbite; although metabolic heat production during these activities usually increases well above the rate of body heat loss, and protective clothing and limited exposure time in certain events reduces these clinical risks as well. Most athletic events are held at altitudes that pose little to no health risks; and training exposures are typically brief and well-tolerated. While these and other environment-related threats to performance and safety can be lessened or averted by implementing a variety of individual and event preventative measures, more research and evidence-based guidelines and recommendations are needed. In the mean time, the IOC Medical Commission and International Sport Federations have implemented new guidelines and taken additional steps to mitigate risk even further.
Sanford School of Medicine, Sioux Falls Campus.
Introduction: The expression of hundreds of genes is altered in response to left ventricular (LV) remodeling following large transmural myocardial infarction (MI). Thyroid hormone (TH) improves LV remodeling and cardiac performance after MI. However, the molecular basis is unknown. Methods: MI was produced by ligation of the left anterior descending coronary artery in female SD rats. Rats were divided into the following groups: (1) Sham MI, (2) MI, and (3) MI+T4 treatment (T4 pellet 3.3 mg, 60 days release, implanted subcutaneously immediately following MI). Four weeks after surgery, total RNA was isolated from LV non-infarcted areas for microarray analysis using the Illumina RatRef-12 Expression BeadChip Platform. Results: Signals were detected in 13,188 genes (out of 22,523), of which the expression of 154 genes were decreased and the expression of 200 genes were increased in MI rats compared with Sham MI rats (false discovery rate (FDR) < 0.05). Compared to MI rats, T4 treatment decreased expression of 27 genes and increased expression of 28 genes. In particular, 6 genes down- regulated by MI and 12 genes up-regulated by MI were reversed by T4. Most of the 55 genes altered by T4 treatment are in the category of molecular function under binding (24) and biological processes which includes immune system process (9), multi-organism process (5) and biological regulation (19) nonexclusively. Conclusions: These results suggest that altered expression of genes for molecular function and biological process may be involved in the beneficial effects of thyroid hormone treatment following MI in rats.
Sanford School of Medicine, Sioux Falls Campus.
Ehli, Erik A., Abdel Abdellaoui, Yueshan Hu, Jouke Jan Hottenga, Mathijs Kattenberg, Toos van Beijsterveldt, Meike Bartels, Robert R. Althoff, Xiangjun Xiao, Paul Scheet, Eco J. de Geus, James J. Hudziak, Dorret I. Boomsma, and  Gareth E. Davies. (2012). De novo and inherited CNVs in MZ twin pairs selected for discordance and concordance on Attention Problems. European journal of human genetics : EJHG, 20(10), 1037-1043.
Copy number variations (CNVs) have been reported to be causal suspects in a variety of psychopathologic traits. We investigate whether de novo and/or inherited CNVs contribute to the risk for Attention Problems (APs) in children. Based on longitudinal phenotyping, 50 concordant and discordant monozygotic (MZ) twin pairs were selected from a sample of 3200 MZ pairs. Two types of de novo CNVs were investigated: (1) CNVs shared by both MZ twins, but not inherited (pre-twinning de novo CNVs), which were detected by comparing copy number (CN) calls between parents and twins and (2) CNVs not shared by co-twins (post-twinning de novo CNVs), which were investigated by comparing the CN calls within MZ pairs. The association between the overall CNV burden and AP was also investigated for CNVs genome-wide, CNVs within genes and CNVs outside of genes. Two de novo CNVs were identified and validated using quantitative PCR: a pre-twinning de novo duplication in a concordant-unaffected twin pair and a post-twinning deletion in the higher scoring twin from a concordant-affected pair. For the overall CNV burden analyses, affected individuals had significantly larger CNVs that overlapped with genes than unaffected individuals (P=0.008). This study suggests that the presence of larger CNVs may increase the risk for AP, because they are more likely to affect genes, and confirms that MZ twins are not always genetically identical.
Sanford School of Medicine, Sioux Falls Campus.
Background The identification of individuals exposed prenatally to alcohol can be challenging, with only those having the characteristic pattern of facial features, central nervous system abnormality, and growth retardation receiving a clinical diagnosis of fetal alcohol syndrome (FAS). Methods Seventeen anthropometric measurements were obtained at 5 and 9years from 125 Cape Town, South African children, studied since birth. The children were divided into 3 groups: FAS or partial FAS (PFAS), heavily exposed nonsyndromal (HE), and non-alcohol-exposed controls (C). Anthropometric measurements were evaluated for mean group differences. Logistic regression models were used to identify the subset of anthropometric measures that best predicted group membership. Anthropometric measurements were examined at the 2 ages in relation to prenatal alcohol exposure obtained prospectively from the mothers during pregnancy. Correlation of these facial measurements with key neurobehavioral outcomes including Wechsler Intelligence Scales for Children-IV IQ and eyeblink conditioning was used to assess their utility as indicators of alcohol-related central nervous system impairment. Results Significant group differences were found for the majority of the anthropometric measures, with means of these measures smaller in the FAS/PFAS compared with HE or C. Upper facial widths, ear length, lower facial depth, and eye widths were consistent predictors distinguishing those exposed to alcohol from those who were not. Using longitudinal data, unique measures were identified that predicted facial anomalies at one age but not the other, suggesting the face changes as the individual matures. And 41% of the FAS/PFAS group met criteria for microtia at both ages. Three of the predictive anthropometric measures were negatively related to measures of prenatal alcohol consumption, and all were positively related to at least 1 neurobehavioral outcome. Conclusions The analysis of longitudinal data identified a common set of predictors, as well as some that are unique at each age. Prenatal alcohol exposure appears to have its primary effect on brain growth, reflected by smaller forehead widths, and may suppress neural crest migration to the branchial arches, reflected by deficits in ear length and mandibular dimensions. These results may improve diagnostic resolution and enhance our understanding of the relation between the face and the neuropsychological deficits that occur.
Sanford School of Medicine, Sioux Falls Campus.
Objectives. There is limited data regarding physical strain and minimally invasive gynecologic surgery (MIS). We sought to evaluate ergonomic strain among gynecologic oncologists. Methods. An online survey was sent to all physician members of the Society of Gynecologic Oncology in North America in 2010. The survey contained 42 questions and data was analyzed using univariate and bivariate analyses with summary statistics, t-tests, and chi-squared test. Results. There were 260 respondents (31.2%) to the survey. Case mix was 26% benign and 64% oncologic surgery. Over 52% of respondents had been in practice for greater than 11 years and 52% practice in an academic setting. Physical discomfort related to MIS was reported in 88% (216/244) of surgeons with 52% reporting persistent pain. Increased pain symptoms were associated with surgeon’s height, glove size, age and female gender. Patient body mass index (BMI) was associated with pain symptoms in surgeons performing conventional laparoscopic surgery, but not robotic surgery. To decrease pain, surgeons changed positions (78%), limited the number of cases per day (14%), spread cases throughout the week (6%), or limited the total number of cases (3%). Only 29% had received treatment at any time for pain symptoms. Treatment included physical therapy (59%), medical management (28%), surgery (13%), and time off (1%). Only 16% of those with pain symptoms had received formal ergonomic training. Conclusion. Physical strain rates of 88% are far greater than previously reported. Such prevalent occupational strain presents a growing problem in the face of increasing demand for MIS. (C) 2012 Elsevier Inc. All rights reserved.
Sanford School of Medicine, Sioux Falls Campus.
Hu, Y., E. A. Ehli, J. J. Hudziak, and  G. E. Davies. (2012). Berberine and evodiamine influence serotonin transporter (5-HTT) expression via the 5-HTT-linked polymorphic region. The pharmacogenomics journal, 12(5), 372-378.
The aim of this study was to investigate the effect of berberine and evodiamine on serotonin transporter (5-HTT) expression and then test how allelic variations previously identified in the promoter region could modulate that effect in the serotonergic neuronal cell line RN46A. Both berberine and evodiamine, alone and in combination, increased 5-HTT mRNA and protein expression significantly across the various alleles. When tested against the S, XS(11), L(G), L(A), XL(17), and XL(18) alleles, respectively, 100muM berberine increased 5-HTT promoter activities by 67%, 128.7%, 106.9%, 100.4%, 26.2% and 82%, 2muM evodiamine increased 5-HTT promoter activities by 216.7%, 81.6%, 305.6%, 181.5%, 175.3% and 102.2%. Berberine and evodiamine increased 5-HTT promoter activity differently depending on the genetic variation of the 5-HTTLPR polymorphism. This study has provided a convincing example of how herbal compounds influence the expression of one of the most intensively studied psychiatric candidate genes, the serotonin transporter.
Sanford School of Medicine, Sioux Falls Campus.
The p21-activated kinase-1 (PAK1) is implicated in regulation of insulin exocytosis as an effector of Rho GTPases. PAK1 is activated by the onset of glucose-stimulated insulin secretion (GSIS) through phosphorylation of Thr-423, a major activation site by Cdc42 and Rac1. However, the kinase(s) that phosphorylates PAK1 at Thr-423 in islet β-cells remains elusive. The present studies identified SAD-A (synapses of amphids defective), a member of AMP-activated protein kinase-related kinases exclusively expressed in brain and pancreas, as a key regulator of GSIS through activation of PAK1. We show that SAD-A directly binds to PAK1 through its kinase domain. The interaction is mediated by the p21-binding domain (PBD) of PAK1 and requires both kinases in an active conformation. The binding leads to direct phosphorylation of PAK1 at Thr-423 by SAD-A, triggering the onset of GSIS from islet β-cells. Consequently, ablation of PAK1 kinase activity or depletion of PAK1 expression completely abolishes the potentiating effect of SAD-A on GSIS. Consistent with its role in regulating GSIS, overexpression of SAD-A in MIN6 islet β-cells significantly stimulated cytoskeletal remodeling, which is required for insulin exocytosis. Together, the present studies identified a critical role of SAD-A in the activation of PAK1 during the onset of insulin exocytosis.
Sanford School of Medicine, Sioux Falls Campus.
Kenyon, DenYelle Baete, and  Jessica D. Hanson. (2012). Incorporating Traditional Culture Into Positive Youth Development Programs With American Indian/Alaska Native Youth. [Article]. Child Development Perspectives, 6(3), 272-279.
The majority of research and programs for American Indian/Alaska Native (AI/AN) youth focus on negative health behaviors and risks, ignoring the positive attributes that traditional AI/AN culture can provide. Therefore, it is critical to highlight the importance of incorporating traditional AI/AN worldviews and values into youth programming and health interventions. Accordingly, this article provides (a) a brief overview of AI/AN culture and historical policies and practices, (b) a description of the positive youth development (PYD) framework with a focus on research and programs that include AI/AN youth, (c) details on the strengths of AI/AN culture and how they can be incorporated into programming for AI/AN youth, and (d) examples of exemplary PYD programs for AI/AN youth.
Sanford School of Medicine, Sioux Falls Campus.
Kovacs, Attila D., A. Saje, A. Wong, S. Ramji, J. D. Cooper, and  David A. Pearce. (2012). Age-dependent therapeutic effect of memantine in a mouse model of juvenile Batten disease. [Article]. Neuropharmacology, 63(5), 769-775.
Currently there is no treatment for juvenile Batten disease, a fatal childhood neurodegenerative disorder caused by mutations in the CLN3 gene. The Cln3-knockout (Cln3(Delta ex1-6)) mouse model recapitulates several features of the human disorder. Cln3(Delta ex1-6) mice, similarly to juvenile Batten disease patients, have a motor coordination deficit detectable as early as postnatal day 14. Previous studies demonstrated that acute attenuation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor activity by the non-competitive AMPA antagonist, EGIS-8332, in both 1- and 6-7-month-old Cln3(Delta ex1-6) mice results in improvement in motor coordination. Here we show that acute inhibition of N-methyl-D-aspartate (NMDA)-type glutamate receptors by memantine (1 and 5 mg/kg i.p.) had no effect on the impaired motor coordination of one-month-old Cln3(Delta ex1-6) mice. At a later stage of the disease, in 6-7-month-old Cln3(Delta ex1-6) mice, memantine induced a delayed but extended (8 days) improvement of motor skills similarly to that observed previously with EGIS-8332 treatment. An age-dependent therapeutic effect of memantine implies that the pathomechanism in juvenile Batten disease changes during disease progression. In contrast to acute treatment, repeated administration of memantine or EGIS-8332 (1 mg/kg, once a week for 4 weeks) to 6-month-old Cln3(Delta ex1-6) mice had no beneficial effect on motor coordination. Moreover, repeated treatments did not impact microglial activation or the survival of vulnerable neuron populations. Memantine did not affect astrocytosis in the cortex. EGIS-8332, however, decreased astrocytic activation in the somatosensory barrelfield cortex. Acute inhibition of NMDA receptors can induce a prolonged therapeutic effect, identifying NMDA receptors as a new therapeutic target for juvenile Batten disease. (C) 2012 Elsevier Ltd. All rights reserved.
Sanford School of Medicine, Sioux Falls Campus.
Rapamycin/interleukin-2 (IL-2) combination treatment of NOD mice effectively treats autoimmune diabetes. We performed a phase 1 clinical trial to test the safety and immunologic effects of rapamycin/IL-2 combination therapy in type 1 diabetic (T1D) patients. Nine T1D subjects were treated with 2-4 mg/day rapamycin orally for 3 months and 4.5 x 10(6) IU IL-2 s.c. three times per week for 1 month. beta-Cell function was monitored by measuring C-peptide. Immunologic changes were monitored using flow cytometry and serum analyses. Regulatory T cells (Tregs) increased within the first month of therapy, yet clinical and metabolic data demonstrated a transient worsening in all subjects. The increase in Tregs was transient, paralleling IL-2 treatment, whereas the response of Tregs to IL-2, as measured by STAT5 phosphorylation, increased and persisted after treatment. No differences were observed in effector T-cell subset frequencies, but an increase in natural killer cells and eosinophils occurred with IL-2 therapy. Rapainycin/IL-2 therapy, as given in this phase 1 study, resulted in transient beta-cell dysfunction despite an increase in Tregs. Such results highlight the difficulties in translating therapies to the clinic and emphasize the importance of broadly interrogating the immune system to evaluate the effects of therapy. Diabetes 61:2340-2348, 2012
Sanford School of Medicine, Sioux Falls Campus.
Although many elite sporting events occur in climate-controlled venues, some athletes train and compete in environments that can potentially pose a risk to the athlete’s health. In particular, athletes in aquatics, track and field, tennis, football and triathlon can be exposed to extreme heat during competition or while training. The International Federations responsible for these sports are aware of these health risks and have implemented measures to help protect the health of their athletes. This review paper outlines the sport-specific environmental health risks and the safety standards implemented to safeguard athlete health.
Sanford School of Medicine, Sioux Falls Campus.
Purpose. A pre-post analysis of an antimicrobial stewardship program (ASP) involving the use of data-mining software to prospectively identify cases for ASP intervention was conducted. Methods. The investigators evaluated clinical outcomes and cost metrics before and after implementation of the ASP, which entailed daily physician review of summary reports on all adult inpatients receiving antimicrobial therapy. The primary outcome measures were annual antimicrobial expenditures and rates of infections due to common nosocomial pathogens; secondary outcome measures included patient survival and length of stay (LOS) in cases involving the indicator diagnoses of pneumonia and abdominal sepsis. Results. Antimicrobial expenditures, which had increased by an average of 14.4% annually in the years preceding ASP implementation, decreased by 9.75% in the first year of the program and remained relatively stable in subsequent years, with overall cumulative cost savings estimated at $1.7 million. Rates of nosocomial infections involving Clostridium difficile, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci all decreased after ASP implementation. A pre-post comparison of survival and LOS in patients with pneumonia (n = 2186) or abdominal sepsis (n = 225) showed no significant differences in those outcomes in either patient group, possibly due to the hospital’s initiation of other, concurrent infection-control programs during the study period. Conclusion. A prospective collaborative ASP employed automated reports to efficiently identify key data for ASP review. After ASP implementation, antimicrobial expenditures and rates of nosocomial infections caused by resistant pathogens dropped without significant changes in patient survival, LOS, and readmissions for the two studied illness categories. Am J Health-Syst Pharm. 2012; 69:1500-8
Sanford School of Medicine, Sioux Falls Campus.
Background Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC) exhibits distinct patterns worldwide, but its prevalence has not been extensively evaluated in Korea. The E7 oncogene-mediated carcinogenesis and its meaning are yet to be uncovered for oropharyngeal SCCs. Methods In a Korean oropharyngeal SCC cohort, epidemiological indicators, HPV, and G1 cell cycle marker expressions were correlated with survival. Results Among 93 surgically treated patients with oropharyngeal SCCs, 49.5% were HPV+, which were significantly younger, and predominantly nonsmoking. They demonstrated better survival than HPV- (94% vs 60%). Patients who were HPV+ with oropharyngeal SCCs expressed higher p16, cyclin-dependent kinase 4 (cdk4), and lower pRb. The p16 (hazard ratio [HR] 2.39), pRb (HR 2.13), and CCND1 (HR 2.09) correlated with survival. Notably, combined markers like p16/cdk4 ratio (HR 2.47) and cdk4+CCND1 sum (HR 2.65) were more significantly correlated. Conclusion Incidence of HPV-related oropharyngeal SCC in Korea is similar to U.S.-European data. HPV presence correlates with improved survival. Expression ratios of G1 markers may predict survival of oropharyngeal SCCs better than each marker alone. (c) 2011 Wiley Periodicals, Inc. Head Neck, 2011
Sanford School of Medicine, Sioux Falls Campus.
Red blood cell (RBC) fatty acid (FA) patterns have been shown to predict risk for cardiovascular and other chronic diseases. As part of a project analyzing RBC samples from the Women’s Health Initiative Memory Study (WHIMS) we observed implausibly low levels of highly unsaturated fatty acids (HUFA) suggestive of degradation. This was hypothesized to be due to short term storage (< 1 month) at -20 A degrees C during sample aliquoting. The purpose of this study was to measure the extent of degradation that occurs under these conditions, and then to use regression calibration equations with multiple imputations to correct the biases. Samples from the Women’s Health Initiative that had always been stored at -80 A degrees C were obtained and subjected to similar conditions as the WHIMS samples. General linear mixed models were used to develop bias-corrected calibration equations for each fatty acid. Sample degradation occurred at -20 A degrees C with the average HUFA loss of 3.5 to 5.9 % per week depending on aliquot size (250 and 80 A mu L, respectively). Using the ratio of HUFA to saturated fatty acids (HUFA/SAT) as a marker of degradation, this bias-correction method raised the HUFA/SAT from 0.70 to 0.81, which was similar to that (0.78) seen in another large study with optimal processing. In summary, RBC samples should always be stored at -80 A degrees C. The FA compositions of the degraded RBC samples from WHIMS were rehabilitated by application of regression calibration equations and multiple imputations, and these imputed datasets should be used in all future WHIMS studies.
Sanford School of Medicine, Sioux Falls Campus.
BACKGROUND AND OBJECTIVES: Although advance directives (AD) allow patients a voice during their end-of-life care, less than 20% of US individuals have one. We investigated how physicians, both attendings and residents, of the Sioux Falls Family Medicine Residency Program (SFFMRP) were addressing AD and code status with our geriatric population, which has an increased need for advance directive implementation secondary to declining health. METHODS: We used a retrospective design, in which a random sampling of charts was performed. The setting was the SFFMRP and associated facilities Participants included a chart review of 121 patients over age 65 seen by a SFFMRP physician within the past year. Percentages were calculated looking at overall outcomes, living situation, age, and resident versus attending involvement. Statistical significance was evaluated using Chi square analysis. RESULTS: Overall, 44% of all individuals examined had an advanced directive (80.6% of nursing home (NH) patients, 76% of assisted living (AL) patients, and 21% of independent living patients). Evaluating code status, 55% of all individuals had a known code status (100% of NH patients, 92% of AL patients, and 25% of independent living patients). No significant difference was found when comparing attending versus resident physicians’ patient groups. CONCLUSIONS: SFFMRP geriatric patients are more likely than the national population to have an AD, but more than half of patients still have no known documentation in place. The living situation of a patient significantly affects whether an AD or known code status is present, indicating that focus should be placed on independent living patients completing these documents.
Sanford School of Medicine, Sioux Falls Campus.
Wieking, B. G., D. W. Vermeer, W. C. Spanos, K. M. Lee, P. Vermeer, W. T. Lee, Y. Xu, E. S. Gabitzsch, S. Balcaitis, J. P. Balint, Jr., F. R. Jones, and  J. H. Lee. (2012). A non-oncogenic HPV 16 E6/E7 vaccine enhances treatment of HPV expressing tumors. Cancer gene therapy, 19(10), 667-674.
Human papillomaviruses (HPVs) are the causative factor for >90% of cervical cancers and 25% of head and neck cancers. The incidence of HPV positive (+) head and neck squamous cell carcinomas has greatly increased in the last 30 years. E6 and E7 are the two key viral oncoproteins that induce and propagate cellular transformation. An immune response generated during cisplatin/radiation therapy improves tumor clearance of HPV(+) cancers. Augmenting this induced response during therapy with an adenoviral HPV16 E6/E7 vaccine improves long-term survival in pre-clinical models. Here, we describe the generation of an HPV16 E6/E7 construct, which contains mutations that render E6/E7 non-oncogenic, while preserving antigenicity. These mutations do not allow E6/E7 to degrade p53, pRb, PTPN13, or activate telomerase. Non-oncogenic E6/E7 (E6(Delta)/E7(Delta)) expressed as a stable integrant, or in the [E1-, E2b-] adenovirus, lacks the ability to transform human cells while retaining the ability to induce an HPV-specific immune response. Moreover, E6(Delta)/E7(Delta) plus chemotherapy/radiation statistically enhances clearance of established HPV(+) cancer in vivo.
Sanford School of Medicine, Sioux Falls Campus.
Flynn, Stephen V., Kelly Duncan, and  Maribeth F. Jorgensen. (2012). An Emergent Phenomenon of American Indian Postsecondary Transition and Retention. [Article]. Journal of Counseling & Development, 90(4), 437-449.
This study examined 21 American Indian students’ postsecondary transition and retention experiences through a phenomenological methodology. Postsecondary transition is the process of leaving home and adjusting to postsecondary education. Postsecondary retention is achieving success and remaining at a university for at least 6 months. Data sources included individual interviews, journal analysis, and document analysis. The 10 emergent themes described an interconnected phenomenon centered on institutional, social, and interpersonal dimensions.
School of Education.

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