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Item Usability of Implementing a Tablet-Based Decision Support and Integrated Record-Keeping (DESIRE) Tool in the Nurse Management of Hypertension in Rural Kenya(IOS Press, 2013) Blank, Evan; Tuikong, Nelly; Misoi, Lawrence; Kamano, Jemima; Hutchinson, Claire; Kimaiyo, Sylvester; Fuster, Valentin; Were, Martin; Vedanthan, Rajesh; Medicine, School of MedicineIn sub-Saharan Africa (SSA), cardiovascular disease (CVD) is the leading cause of death among individuals over the age of 30. Hypertension, a major risk factor for CVD, contributes significantly to the CVD burden in SSA. In order to address the human resource challenge of managing hypertension in low- and middle-income countries (LMICs), task-shifting hypertension care from physicians to nurses has been proposed. To support this task-shifting strategy, the Academic Partnership Providing Access to Healthcare (AMPATH) has developed an Android tablet-based electronic Decision Support and Integrated Record-Keeping (DESIRE) tool to record patient data and assist with clinical decision-making. We investigated the usability of the DESIRE tool in the setting of nurse management of hypertension in rural western Kenya through the use of “mock patient” encounters and “think aloud” exercises. Fiftyseven critical incidents were identified and twenty-three design changes were suggested. Optimization of the tool has the potential to broadly impact treatment of non-communicable diseases in LMICs by providing a model of electronic decision-support in task shifting.Item Oral processing effort, appetite and acute energy intake in lean and obese adults(Elsevier, 2013) Mattes, Richard D.; Considine, Robert V.; Medicine, School of MedicineChewing reportedly contributes to satiation and satiety signals. Attempts to document and quantify this have led to small and inconsistent effects. The present trial manipulated oral processing effort though required chewing of gums of different hardness and measured appetitive sensations, energy intake, gastric emptying, GI transit time, and concentrations of glucose, insulin, GLP-1, ghrelin and pancreatic polypeptide. Sixty adults classified by sex and BMI (15 each of lean females, obese females, lean males and obese males) were tested in a randomized, controlled, cross-over trial with three arms. They chewed nothing, soft gum or hard gum for 15 min while sipping grape juice (10% of individual energy needs) containing acetaminophen and lactulose on one day each separated by 7 days. Electromyographic recordings and self-reports were obtained during and after chewing to quantify oral processing effort. Blood was sampled through an indwelling catheter and appetite ratings were obtained at baseline and at 0, 15, 30, 45, 60, 90, 120, 180 and 240 min after chewing initiation. Breath samples were collected at 10 min intervals for the first 2h and at 30 min intervals for the next 2h. No effects of chewing were observed for appetitive sensations or gut peptide concentrations. Energy intake tended to decline in lean and increase in obese participants so that daily energy intake differed significantly between the two groups when chewing either gum, while no difference was observed on the non-chewing day. Serum glucose and insulin were significantly lower at selected time points 90-240 min after chewing compared to baseline and the non-chewing day. These data indicate chewing effort does not affect appetitive sensations or gut peptide secretion, but may exert a small differential effect on acute energy intake in lean and obese individuals and lead to greater post-prandial declines of serum glucose and insulin. The efficacy of gum chewing as a substitute for eating for weight management remains uncertain.Item NAFLD Fibrosis Score – Is it ready for wider use in clinical practice and for clinical trials?(Elsevier, 2013) Gawrieh, Samer; Chalasani, Naga; Medicine, School of MedicineItem ICOS-Expressing Lymphocytes Promote Resolution of CD8-Mediated Lung Injury in a Mouse Model of Lung Rejection(Public Library of Science, 2013-08-13) Wu, Qiang; Gardiner, Gail J.; Berry, Elizabeth; Wagner, Sarah R.; Lu, Tiffany; Clay, Bryan S.; Moore, Tamson V.; Ferreira, Caroline M.; Williams, Jesse W.; Luster, Andrew D.; Medoff, Benjamin D.; Cannon, Judy L.; Sperling, Anne I.; Shilling, Rebecca A.; Medicine, School of MedicineAcute rejection, a common complication of lung transplantation, may promote obliterative bronchiolitis leading to graft failure in lung transplant recipients. During acute rejection episodes, CD8(+) T cells can contribute to lung epithelial injury but the mechanisms promoting and controlling CD8-mediated injury in the lung are not well understood. To study the mechanisms regulating CD8(+) T cell-mediated lung rejection, we used a transgenic model in which adoptively transferred ovalbumin (OVA)-specific cytotoxic T lymphocytes (CTL) induce lung injury in mice expressing an ovalbumin transgene in the small airway epithelium of the lungs (CC10-OVA mice). The lung pathology is similar to findings in humans with acute lung transplant. In the presence of an intact immune response the inflammation resolves by day 30. Using CC10-OVA.RAG(-/-) mice, we found that CD4(+) T cells and ICOS(+/+) T cells were required for protection against lethal lung injury, while neutrophil depletion was not protective. In addition, CD4(+)Foxp3 (+) ICOS(+) T cells were enriched in the lungs of animals surviving lung injury and ICOS(+/+) Tregs promoted survival in animals that received ICOS(-/-) T cells. Direct comparison of ICOS(-/-) Tregs to ICOS(+/+) Tregs found defects in vitro but no differences in the ability of ICOS(-/-) Tregs to protect from lethal lung injury. These data suggest that ICOS affects Treg development but is not necessarily required for Treg effector function.Item Plasma and Whole Blood Clot Strength Measured by Thrombelastography in Patients Treated with Clopidogrel during Acute Coronary Syndromes(Elsevier, 2013) Lu, Deshun; Owens, Janelle; Kreutz, Rolf P.; Medicine, School of MedicineIntroduction: Treatment with clopidogrel, a selective platelet P2Y12 receptor antagonist, reduces risk of recurrent ischemic events in patients with acute coronary syndrome (ACS), by limiting platelet aggregation and activation. Stable whole blood clot formation requires activation of platelets, generation of fibrin and final fibrin crosslinks. In this study we intended to compare plasma and whole blood thrombelastography (TEG) measurements in patients during ACS. Materials and methods: Whole blood and plasma samples from 32 patients with non-ST segment elevation myocardial infarction (NSTEMI) were collected after administration of clopidogrel. Whole blood and plasma fibrin clot strength (MA) were determined by TEG. Platelet aggregation was determined by light transmittance aggregometry (LTA) using adenosine 5'-diphosphate (ADP), thrombin receptor activation peptide (TRAP), or collagen as agonists. Fibrinogen and C-reactive protein (CRP) concentrations were measured by ELISA. Results: Heightened plasma fibrin clot strength was associated with increased platelet reactivity stimulated by ADP (ρ=0.536; p=0.002), TRAP (ρ=0.481; p=0.007), and collagen (ρ=0.538; p=0.01). In contrast to plasma fibrin MA, whole blood MA did not correlate with platelet aggregation. Platelet count was the primary contributor to the difference in thrombin induced whole blood MA and plasma fibrin MA. Increasing levels of CRP were associated with increased plasma fibrin clot strength and platelet reactivity. Conclusions: Our data suggest that inflammation is associated with increased plasma fibrin clot strength and lower platelet inhibition by clopidogrel during ACS. Platelet count is a main contributor to additional contractile force of whole blood TEG as compared to plasma TEG during treatment with clopidogrel.Item Estimating Kidney Function in HIV-Infected Adults in Kenya: Comparison to a Direct Measure of Glomerular Filtration Rate by Iohexol Clearance(Public Library of Science, 2013-08-08) Wyatt, Christina M.; Schwartz, George J.; Ong’or, Willis Owino; Abuya, Joseph; Abraham, Alison G.; Mboku, Charles; M’mene, Loice B.; Koima, Winnie J.; Hotta, Mathew; Maier, Paula; Klotman, Paul E.; Wools-Kaloustian, Kara; Medicine, School of MedicineBackground: More than two-thirds of the world's HIV-positive individuals live in sub-Saharan Africa, where genetic susceptibility to kidney disease is high and resources for kidney disease screening and antiretroviral therapy (ART) toxicity monitoring are limited. Equations to estimate glomerular filtration rate (GFR) from serum creatinine were derived in Western populations and may be less accurate in this population. Methods: We compared results from published GFR estimating equations with a direct measure of GFR by iohexol clearance in 99 HIV-infected, ART-naïve Kenyan adults. Iohexol concentration was measured from dried blood spots on filter paper. The bias ratio (mean of the ratio of estimated to measured GFR) and accuracy (percentage of estimates within 30% of the measured GFR) were calculated. Results: The median age was 35 years, and 60% were women. The majority had asymptomatic HIV, with median CD4+ cell count of 355 cells/mm(3). Median measured GFR was 115 mL/min/1.73 m(2). Overall accuracy was highest for the Chronic Kidney Disease Epidemiology Consortium (CKD-EPI) equation. Consistent with a prior report, bias and accuracy were improved by eliminating the coefficient for black race (85% of estimates within 30% of measured GFR). Accuracy of all equations was poor in participants with GFR 60-90 mL/min/1.73 m(2) (<65% of estimates within 30% of measured GFR), although this subgroup was too small to reach definitive conclusions. Conclusions: Overall accuracy was highest for the CKD-EPI equation. Eliminating the coefficient for race further improved performance. Future studies are needed to determine the most accurate GFR estimate for use in individuals with GFR <90 mL/min/1.73 m(2), in whom accurate estimation of kidney function is important to guide drug dosing. Direct measurement of GFR by iohexol clearance using a filter paper based assay is feasible for research purposes in resource-limited settings, and could be used to develop more accurate GFR estimates in African populations.Item Amiodarone Inhibits Apamin-Sensitive Potassium Currents(Public Library of Science, 2013-07-29) Turker, Isik; Yu, Chih-Chieh; Chang, Po-Cheng; Chen, Zhenhui; Sohma, Yoshiro; Lin, Shien-Fong; Chen, Peng-Sheng; Ai, Tomohiko; Medicine, School of MedicineBackground: Apamin sensitive potassium current (I KAS), carried by the type 2 small conductance Ca(2+)-activated potassium (SK2) channels, plays an important role in post-shock action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (VF) in failing ventricles. Objective: To test the hypothesis that amiodarone inhibits I KAS in human embryonic kidney 293 (HEK-293) cells. Methods: We used the patch-clamp technique to study I KAS in HEK-293 cells transiently expressing human SK2 before and after amiodarone administration. Results: Amiodarone inhibited IKAS in a dose-dependent manner (IC50, 2.67 ± 0.25 µM with 1 µM intrapipette Ca(2+)). Maximal inhibition was observed with 50 µM amiodarone which inhibited 85.6 ± 3.1% of IKAS induced with 1 µM intrapipette Ca(2+) (n = 3). IKAS inhibition by amiodarone was not voltage-dependent, but was Ca(2+)-dependent: 30 µM amiodarone inhibited 81.5±1.9% of I KAS induced with 1 µM Ca(2+) (n = 4), and 16.4±4.9% with 250 nM Ca(2+) (n = 5). Desethylamiodarone, a major metabolite of amiodarone, also exerts voltage-independent but Ca(2+) dependent inhibition of I KAS. Conclusion: Both amiodarone and desethylamiodarone inhibit I KAS at therapeutic concentrations. The inhibition is independent of time and voltage, but is dependent on the intracellular Ca(2+) concentration. SK2 current inhibition may in part underlie amiodarone's effects in preventing electrical storm in failing ventricles.Item Characterization of synergistic anti-cancer effects of docosahexaenoic acid and curcumin on DMBA-induced mammary tumorigenesis in mice(Springer Nature, 2013-09-13) Siddiqui, Rafat A.; Harvey, Kevin A.; Walker, Candace; Altenburg, Jeffrey; Xu, Zhidong; Terry, Colin; Camarillo, Ignacio; Jones-Hall, Yava; Mariash, Cary; Medicine, School of MedicineBackground: The major obstacles to the successful use of individual nutritional compounds as preventive or therapeutic agents are their efficacy and bioavailability. One approach to overcoming this problem is to use combinations of nutrients to induce synergistic effects. The objective of this research was to investigate the synergistic effects of two dietary components: docosahexaenoic acid (DHA), an omega-3 fatty acid present in cold-water fish, and curcumin (CCM), an herbal nutrient present in turmeric, in an in vivo model of DMBA-induced mammary tumorigenesis in mice. Methods: We used the carcinogen DMBA to induce breast tumors in SENCAR mice on control, CCM, DHA, or DHA + CCM diets. Appearance and tumor progression were monitored daily. The tumors were harvested 15 days following their first appearance for morphological and immunohistological analysis. Western analysis was performed to determine expression of maspin and survivin in the tumor tissues. Characterization of tumor growth was analyzed using appropriate statistical methods. Otherwise all other results are reported as mean ± SD and analyzed with one-way ANOVA and Tukey's post hoc procedure. Results: Analysis of gene microarray data indicates that combined treatment with DHA + CCM altered the profile of "PAM50" genes in the SK-BR-3 cell line from an ER⁻/Her-2⁺ to that resembling a "normal-like" phenotype. The in vivo studies demonstrated that DHA + CCM treatment reduced the incidence of breast tumors, delayed tumor initiation, and reduced progression of tumor growth. Dietary treatment had no effect on breast size development, but tumors from mice on a control diet (untreated) were less differentiated than tumors from mice fed CCM or DHA + CCM diets. The synergistic effects also led to increased expression of the pro-apoptotic protein, maspin, but reduced expression of the anti-apoptotic protein, survivin. Conclusions: The SK-BR-3 cells and DMBA-induced tumors, both with an ER⁻ and Her-2⁺ phenotype, were affected by the synergistic interaction of DHA and CCM. This suggests that the specific breast cancer phenotype is an important factor for predicting efficacy of these nutraceuticals. The combination of DHA and CCM is potentially a dietary supplemental treatment for some breast cancers, likely dependent upon the molecular phenotype of the cancer.Item Dataglove measurement of joint angles in sign language handshapes(John Benjamins, 2012) Eccarius, Petra; Bour, Rebecca; Scheidt, Robert A.; Medicine, School of MedicineIn sign language research, we understand little about articulatory factors involved in shaping phonemic boundaries or the amount (and articulatory nature) of acceptable phonetic variation between handshapes. To date, there exists no comprehensive analysis of handshape based on the quantitative measurement of joint angles during sign production. The purpose of our work is to develop a methodology for collecting and visualizing quantitative handshape data in an attempt to better understand how handshapes are produced at a phonetic level. In this pursuit, we seek to quantify the flexion and abduction angles of the finger joints using a commercial data glove (CyberGlove; Immersion Inc.). We present calibration procedures used to convert raw glove signals into joint angles. We then implement those procedures and evaluate their ability to accurately predict joint angle. Finally, we provide examples of how our recording techniques might inform current research questions.Item DNA Detection and Seroprevalence of Human Papillomavirus in a Cohort of Adolescent Women(BMJ, 2014) Ermel, Aaron C.; Shew, Marcia L.; Weaver, Bree A.; Qadadri, Brahim; Denski, Cheryl; Tu, Wanzhu; Tong, Yan; Fortenberry, J. D.; Brown, Darron R.; Medicine, School of MedicineObjectives: Human papillomavirus (HPV) infections are common in adolescent women, while the rare cancerous sequelae of HPV infections do not generally occur until the 4th or 5th decades of life. This prospective study of a cohort of adolescent women was performed to further our knowledge of the natural history of incident and prevalent HPV infections. Methods: Self-vaginal swabs collected from high-risk, unvaccinated adolescent women in a longitudinal study were analysed for HPV DNA. Sera were collected at enrolment and later tested for HPV antibodies. Statistical analysis was performed to determine the HPV genotype distribution and duration of detection, and to determine rates of seropositivity and seroconversion for HPV types represented in the assays. Results: 146 subjects (mean enrolment age=15.4 years; mean duration of follow-up=5.8 years) had samples adequate for analysis of HPV detection, and 95 of these subjects had paired sera available. The cumulative prevalence for high-risk and low-risk HPV types was 95.9% and 91.1%, respectively. HPV types 6, 11, 16 and 18 (HPV types represented in the quadrivalent vaccine) were found at some point in 40.4%, 6.2%, 48% and 24% of participants, respectively. Serological data confirmed exposure to these vaccine-covered types, as well as to other high-risk HPV types. Conclusions: In this cohort of adolescent women, high- and low-risk HPV types were frequently detected, and serological data confirmed exposure in most subjects. The high-prevalence HPV types represented in the quadrivalent HPV vaccine further support vaccination of women at an age well before sexual debut.