Liver disease in humans encompasses a wide range of pathological disturbances that can lead to a reduction in liver blood flow, extrahepatic or intrahepatic shunting of blood, hepatocyte dysfunction, quantitative and qualitative changes in serum proteins, and changes in bile flow. Although there are numerous causes of hepatic injury, it appears that the hepatic response to injury is a limited one and that the functional consequences are determined more by the extent of the injury than by the cause. At this time there is no generally available test that can be used to correlate changes in drug absorption and disposition with the degree of hepatic impairment. In this chapter, we summarize the known effects of liver disease on drug disposition and provide some guidance for modification of drug therapy in patients with liver disease. We make the case that more research and collaborative efforts are needed in the field for more precise drug use in these patients.

The Health Sciences and Technology Academy's, (HSTA) goals are to increase college attendance of African American, financially disadvantaged, first generation college and rural Appalachian youth and increase health-care providers and STEM professionals in underserved communities. Students enter in the 9th grade and remain in HSTA four years. They engage in a rigorous academic program within the nurturing environment of small after-school clubs punctuated by yearly summer camps on multiple college campuses. A distinctive piece of HSTA is its students' development of research projects under the mentorship of teachers and researchers that examine and address health issues faced by their communities. The projects help HSTA students to understand the health dynamics in their local community, transforming them into community advocates who address health and social issues at home as they prepare to move on to college and beyond. Substantial in-state tuition waivers inspire 99% of the 3,021 HSTA graduates to attend college versus 56% of WV high school graduates. Approximately 85% of matriculating HSTA students graduate with a four-year degree or higher versus less than 50% of all college entrants. To date, 57% of HSTA students go into health and other STEM majors, much higher than the state and national figures.

Clinical and laboratory data used in national regulatory decisions are legally mandated to meet the written specification detailed under the rubric of "Good Clinical Practice" and "Good Laboratory Practice" (GLP). This chapter is written in two distinct sections that distinguish the two disciplines supporting clinical investigation: the first section "Good Clinical Practice" is written to advise the clinician investigator; it is based on the 1996 International Conference on Harmonization guidelines and incorporates the National Institute of Health regulations as well as Food and Drug Administration (FDA) regulations and guidance documents. The second section "Good Laboratory Practice" is written for the laboratory director with emphasis on specialized laboratory services that have not yet been incorporated into routine clinical practice. It is based on the FDA regulations for GLPs.

Despite the central role of the liver in drug metabolism, surprisingly there is lack of certainty in anticipating the extent of modification of the clearance of a given drug in a given patient. The intent of this review is to provide a conceptual framework in considering the impact of liver disease on drug disposition and reciprocally the impact of drug disposition on liver disease. It is proposed that improved understanding of the situation is gained by considering the issue as a special example of a drug-gene-environment interaction. This requires an integration of knowledge of the drug's properties, knowledge of the gene products involved in its metabolism, and knowledge of the pathophysiology of its disposition. This will enhance the level of predictability of drug disposition and toxicity for a drug of interest in an individual patient. It is our contention that advances in pharmacology, pharmacogenomics, and hepatology, together with concerted interests in the academic, regulatory, and pharmaceutical industry communities provide an ideal immediate environment to move from a qualitative reactive approach to quantitative proactive approach in individualizing patient therapy in liver disease.

Background Advances in smartphones and the wide usage of social networking systems offer opportunities for the development of innovative interventions to promote physical activity. To that end, we developed a persuasive and social mHealth application designed to monitor and motivate users to walk more every day. Objective The objectives of this project were to conduct a focused review on the fundamental characteristics of mHealth for physical activity promotion, to develop an mHealth application that meets such characteristics, and to conduct a feasibility study to deploy the application in everyday life. Methods This project started as an analytical study to review the fundamental characteristics of the technologies used in physical activity monitoring and promotion. Then, it was followed by a technical development of the application. Next, a 4 week deployment was conducted where participants used the application as part of their daily life. A think-aloud method and in-depth semistructured interviews were conducted following the deployment. A qualitative description method was used to thematically analyze the interviews. Feasibility measures included, adherence to the program, user-system interactions, motivation to use, and experience with physical activity and online social interactions. Results There were seven fundamental characteristics of physical activity monitoring and promotion that were identified, which were then used as a foundation to develop the application. There were fourteen participants that enrolled in the application evaluation. The age range was from 24 to 45; body mass index ranged from 18.5 to 42.98, with 4 of the subjects falling into the category “obese”. Half of them were experienced with smartphones, and all were familiar with a social network system. There were thirteen participants that completed the study; one was excluded. Overall, participants gave high scores to almost all of the usability factors examined, with averages of 4.52 out of a 5.00 maximum. Over 29 days, participants used the application for a total of 119,380 minutes (average=7.57 hours/day/participant; SD 1.56). Conclusions Based on the fundamental characteristics, the application was successfully developed. The usability results suggest that the system is usable and user satisfaction was high. Deploying the application was shown to be feasible for the promotion of daily physical activity.

BACKGROUND:It has been reported that the prevalence of kidney dysfunction may be increased in patients exposed to tobacco with airflow obstruction. We hypothesized that kidney dysfunction would associate with emphysema rather than with airflow obstruction measured by the FEV₁.METHODS:Five hundred eight current and former smokers completed a chest CT scan, pulmonary function tests, medical questionnaires, and measurement of serum creatinine. Glomerular filtration rates (eGFRs) were estimated using the method of the Chronic Kidney Disease Epidemiology Collaboration. Quantitative determinants of emphysema and airway dimension were measured from multidetector chest CT scans.RESULTS:The mean age was 66 ± 7 years, and mean eGFR was 101 ± 22 mL/min/1.73 m². Univariate and multivariate analysis showed a significant association between radiographically measured emphysema and eGFR: Participants with 10% more emphysema had an eGFR that was lower by 4.4 mL/min/1.73 m² (P = .01), independent of airflow obstruction (FEV₁), age, sex, race, height, BMI, diabetes mellitus, hypertension, coronary artery disease, patient-reported dyspnea, pack-years of smoking, and current smoking. There was no association between eGFR and either FEV₁ or quantitative CT scan measures of airway dimension.CONCLUSIONS:More severe emphysema, rather than airflow obstruction, is associated with kidney dysfunction in tobacco smokers, independent of common risk factors for kidney disease. This finding adds to recent observations of associations between emphysema and comorbidities of COPD, including osteoporosis and lung cancer, which are independent of the traditional measure of reduced FEV₁. The mechanisms and clinical implications of kidney dysfunction in patients with emphysema need further investigation.

Topics in the Prevention, Treatment and Complications of Type 2 Diabetes 310 perception.(Patton, 1990) Our tenant is that evolutionary adaptation faced with cycles of feast and famine has led to multiple, often subtle biological mechanisms for energy conservation, that are strengthened by social cultural behaviors of nurturing, sharing and preparing for future fasts.With the 21 st c e n t u r y a d v a n c e s o f f o o d d i s t r i b u t i o n a n d refinement, the continuous availability of high energy foods and more sedentary lifestyles now render us maladapted to this new environment.We propose that this clash of perception is best addressed by enhancing learning skills in the community to consider each approach, and develop a new way forward.(Ausubel, 1962) Applying these learning skills to focus on a dialogue, between biological and cultural urges and knowledge of future risk, is required to create sustained changes in behavior that we know can work.From this prospective, success or failure of any obesity intervention in the long haul will be require to 'shift in cultures experience as the basis of reality' (referred to by the Zanders' quotation above) (Zander & Zander, 2002) as the essential ingredient for transformational change.We describe an innovative strategy to create such a transformational change by directly addressing this primary root cause.We provide an educational forum through familyoriented learning rather than health care teaching.This strategy is being tested in a rural Appalachian community in the US that is stable, but geographically and economically isolated.It is at the epicenter of the US epidemic, with some of the highest obesity rates yet recorded.(Pancoska et al., 2009) Within this community, the primary target chosen for intervention is the adolescent with a secondary beneficiary being the adolescents' family.The benefits for this concept extend beyond the question of obesity alone, and offer a transformational model for community self-help and self improvement.Our belief is that even though the infrastructure support for our new paradigm is substantial, it addresses the depth of sophistication needed to create sustained change.Elements of the program are generalizable and could be augmented by changes in local and national policies to improve for the interface between education and health care that could benefit affected communities.In this chapter, we described the evolution and goals of the CAIRN program for rural Appalachia, (Figure 1) and point out the role of some of the multiple key players involved.For any program of this level of sophistication, the individual development will be different, and the key players to influence development will vary in the resources and ideas they contribute; however, it will be the key players who will influence the details of what is developed.We suggest that the common critical elements are community willingness to actively participate, the extensive need for voluntary input from as varied a resource base as possible, the need for help from academia and building a multisource funding base for organization and infrastructure. The Setting: A community network of science clubs for adolescents in rural AppalachiaRural Appalachia, although one of the most scenically beautiful regions of the US with its extended mountain range, is also one of the poorest in the country.The only state entirely in Appalachia, West Virginia (WV), the Mountain State, was initially settled by a wave of Scottish-Irish early immigrants looking for homestead farming.Its later wave of African-American and Caucasian migration came with the railroads to work coal mines.Those who remained despite the later depression are the communities for this sparsely populated www.intechopen.com

RATIONALE:Studies demonstrating an association between chronic obstructive pulmonary disease and low bone mineral density (BMD) implicate factors distinct from treatments and severity of lung disease in the pathogenesis of osteoporosis. Whereas emphysema has been independently associated with vascular disease and other comorbidities, its association with BMD has not been well studied.OBJECTIVES:We explored the associations of BMD with computed tomography (CT) measures of emphysema and other risk factors in current and former smokers.METHODS:One hundred ninety subjects completed a CT scan, pulmonary function testing, questionnaires, and dual x-ray absorptiometry measurements of hip and lumbar spine BMD. Subjects were classified as having normal BMD, osteopenia, or osteoporosis. Demographic, physiologic, and radiographic characteristics were compared and the association of BMD with radiographic emphysema, airflow obstruction, and osteoporosis risk factors was assessed.MEASUREMENTS AND MAIN RESULTS:No difference existed in age, tobacco exposure, oral steroid use, or physical activity across BMD categories. Both osteopenia and osteoporosis were associated with the presence of airflow obstruction, inhaled corticosteroid use, and female sex, and demonstrated a significant relationship with the presence of visual emphysema (P = 0.0003). Quantitative emphysema, but not CT-measured indices of airway wall thickness, was inversely associated with BMD. Visual emphysema alone was a significant predictor of osteopenia/osteoporosis (odds ratio = 2.55; 95% confidence interval, 1.24-5.25) in a model including obstruction severity, age, sex, and inhaled and oral steroid use.CONCLUSIONS:Radiographic emphysema is a strong, independent predictor of low BMD in current and former smokers. This relationship suggests a common mechanistic link between emphysema and osteopenia/osteoporosis.

Objective To use cost-utility analysis as an application of the Marginal Utility Theory whereby optimal drug use in terms of optimal drug cost and volume is estimated based on the diminishing marginal utility conditions.Methods Data were collected between 2003 and 2005 from the billing system of two large hospitals that belong to the University of Pittsburgh Medical Center. Domains of interest were stored and correlated in a multidimensional, highly structured Drug Use and Management System (DRUMS) developed by the Center for Clinical Pharmacology at the University of Pittsburgh. Optimal in-hospital drug use is achieved when there are equal marginal rates of substitution between in-hospital drug use and therapeutic outcome subject to diminishing marginal utility conditions.Key findings Patient disposition after hospitalization and length of stay appeared to be reliable indicators of patient therapeutic outcome. Drug cost and volume were over-extended in patients with a length of stay exceeding 20 days and disposition into long-term care, implying over-utilization and/or over-prescribing of drugs. All categories of length of stay and disposition were investigated; they each present a different potential for cost-utility optimization.Conclusion We recommend that entrepreneurial hospital strategists adopt knowledge systems such as DRUMS to analyse aggregate data, and use cost utility as a tool for aggregate in-hospital drug use analyses.

The efficiency of drug metabolism by a single enzyme can be measured as the fractional metabolic clearance which can be used as a measure of whole body activity for that enzyme. Measurement of activity of multiple enzymes simultaneously is feasible using a cocktail approach, however, analytical approach using different assays for drug probes can be cumbersome. A quantitative ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) based method for the rapid measurement of six cytochrome P450 (CYP) probe drugs and their relevant metabolites is described. The six specific probe substrates/metabolites are caffeine/paraxanthine (CYP1A2), flurbiprofen/4'-hydroxyflurbiprofen (CYP2C9), mephenytoin/4'-hydroxymephenytoin (CYP2C19), debrisoquine/4-hydroxydebrisoquine (CYP2D6), chlorzoxazone/6'-hydroxychlorzoxazone (CYP2E1) and dapsone/N-monoacetyldapsone (NAT2). These probes were quantified by stable isotope dilution from plasma and urine. The present workflow provides a robust, fast and sensitive assay for the "Pittsburgh cocktail", and has been successfully applied to a clinical phenotyping study of liver disease. A representative group of 17 controls and patients with chronic liver disease were administered orally caffeine (100 mg), chlorzoxazone (250 mg), debrisoquine (10 mg), mephenytoin (100 mg), flurbiprofen (50 mg) and dapsone (100 mg). Urine (0 through 8 h) and plasma (4 and 8 h) samples were analyzed for drug/metabolite amounts by stable isotope dilution UPLC-MS/MS. The phenotypic activity of drug metabolizing enzymes was investigated with 17 patient samples. Selected reaction monitoring (SRM) was optimized for each drug and metabolite. In the method developed, analytes were resolved by reversed-phase by development of a gradient using a water/methanol solvent system. SRM of each analyte was performed in duplicate on a triple quadrupole mass spectrometer utilizing an 8 min analytical method each, one with the source operating in the positive mode and one in the negative mode, using the same solvent system. This method enabled quantification of each drug (caffeine, chlorzoxazone, debrisoquine, mephenytoin, flurbiprofen, and dapsone) and its resulting primary metabolite in urine or plasma in patient samples. The method developed and the data herein demonstrate a robust quantitative assay to examine changes in CYP enzymes both independently or as part of a cocktail. The clinical use of a combination of probe drugs with UPLC-MS/MS is a highly efficient tool for the assessment of CYP enzyme activity in liver disease.

Abstract Background: HCC is a complex disease with tumor growth replacing adjacent liver. Our initial hypothesis was that tumor traits and loss of liver function are independent processes. We examined this, seeking evidence of coherent discrete structure with respect to survival. Methods: NPS was used to analyze 970 patients with biopsy-proven, non-surgical HCC, all followed prospectively until death. We assumed stochasticity with respect to timing of diagnosis and ambiguity of each variable with respect to survival and used a combination of k-partite graph-based analysis with statistical processing of pairwise dependencies of clinical data ordered by survival, each characterized by the mean of clinical parameters of the 100 patients with the closest survival, for 678 survivals. Results: NPS clearly identified heterogeneity, with 3 distinctive phenotypes based on coherence of multiple variables. Each had different survival ranges with trends of collinear relationships between bilirubin, AFP, alkaline phosphatase, SGOT and GGTP. In patients >70 years, the larger the tumor the higher the biochemical values, with the trends decreasing with longer survival. Above 80 years, bilirubin and AFP were normal, with long survival, 330-1250 days. There were 2 groups of younger patients (<55 years). One, with 30-45 days survival, had a similar profile to the older group. In the other, with 90-330 days survival, the profile was for multiple small tumors to trend with biochemical values. A striking finding was the close correlation in trends for AFP against bilirubin, alkaline phosphatase, GGTP or SGOT values, suggesting that liver damage parameters and tumor parameters were not independent factors, but might be inter-twined, especially in older patients. Conclusions: This NPS analysis does not support the hypothesis that tumor growth and cirrhotic damage are independent, but are intertwined processes. Furthermore, we have evidence based on coherence between variables that the growth rates for unifocal tumors of equivalent size are faster in the young than in the elderly. NPS provides useful insights to design future genomic studies to compare different phenotypes and understand the different pathophysiological processes involved. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2010.

Background and Aim:A large proportion of hepatocellular carcinoma (HCC) patients do not secrete elevated levels of the tumor marker alpha-fetoprotein (AFP). There is little published guide to prognostic features of this patient subset.Methods:We interrogated a large HCC database in which all patients had been followed until death, to examine which features might be prognostically useful.Results:We found 413 biopsy-proven unresectable HCC patients with low serum AFP values. Serum gamma glutamyl transpeptidase (GGTP) levels were one of the most significant factors for survival. This dichotomization into low and high GGTP levels separated the patients into distinctive survival ranges. Patients with GGTP levels < 110 U/100 mL and small tumors had longest survival > 795 days. Patients with GGTP >= 110 U/mL and large tumors with the presence of portal vein thrombosis had the shortest survival range of 300-560 days.Conclusions:Serum levels of the onco-fetal protein GGTP represent a useful prognostic parameter in HCC patients with low AFP levels.

A large cohort of unresectable and untransplantable biopsy-proven HCC patients was rank-ordered for survival. Non-random clustering by age was noted, with 3 sub-cohorts of younger patients with survival in the range of 90-360 days. One sub-cohort had a predominance of females. Tumor numbers were well monitored by serum AFP, but tumor mass was better monitored by serum GGTP. In contrast to the older patients, the probability of hepatitis appeared to have a major impact on their survival and these patients tended to have larger numbers of smaller tumors, consistent with the idea of a hepatitis-mediated carcinogenic field defect.