Search

Ovarian carcinoma includes a wide variety of entities and appropriate subclassification is one of the chief goals in diagnostic gynecologic pathology. Over the years, several new entities have been added to the list of ovarian carcinomas. Moreover, recent advances in the pathogenesis of newer and “older” types of ovarian carcinoma have allowed for the development of ancillary studies that are important in both the subclassification and prognostication. The surgical pathologist must assimilate these new discoveries in ovarian carcinoma in addition to refining their morphology-based diagnostic skillset. The purpose of this review article is to provide an overview of specific genetic factors, clinical disease states, and microscopic queues that are important in the subclassification of ovarian carcinoma.

Background: Understanding the sensitivity and utility of clinical assessments across different HD stages is important for study/trial endpoint selection and clinical assessment development. The Integrated HD Progression Model (IHDPM) characterizes the complex symptom progression of HD and separates the disease into nine ordered disease states. Objective: To generate a temporal map of discriminatory clinical measures across the IHDPM states. Methods: We applied the IHDPM to all HD individuals in an integrated longitudinal HD dataset derived from four observational studies, obtaining disease state assignment for each study visit. Using large-scale screening, we estimated Cohen's effect sizes to rank the discriminative power of 2,472 clinical measures for separating observations in disease state pairs. Individual trajectories through IHDPM states were examined. Discriminative analyses were limited to individuals with observations in both states of the pairs compared (N = 3,790). Results: Discriminative clinical measures were heterogeneous across the HD life course. UHDRS items were frequently identified as the best state pair discriminators, with UHDRS Motor items - most notably TMS - showing the highest discriminatory power between the early-disease states and early post-transition period states. UHDRS functional items emerged as strong discriminators from the transition period and on. Cognitive assessments showed good discriminative power between all state pairs examined, excepting state 1 vs. 2. Several non-UHDRS assessments were also flagged as excellent state discriminators for specific disease phases (e.g., SF-12). For certain state pairs, single assessment items other than total/summary scores were highlighted as having excellent discriminative power. Conclusion: By providing ranked quantitative scores indicating discriminatory ability of thousands of clinical measures between specific pairs of IHDPM states, our results will aid clinical trial designers select the most effective outcome measures tailored to their study cohort. Our observations may also assist in the development of end points targeting specific phases in the disease life course, through providing specific conceptual foci. [ABSTRACT FROM AUTHOR]

T-large granular lymphocytes (T-LGL) characterized by dim CD5 staining, although not completely understood, have unique roles in the immune system. Expansion of peripheral blood (PB) clonal T-LGL populations is associated with various entities in adults. We have previously demonstrated clonal T-LGL proliferations in pediatric immune dysregulation/inflammatory/proliferative conditions. However, T-LGL populations have not been studied in broader spectrum pathologies. In this study we evaluated sizes and correlates of T-LGL populations in the pediatric and young adult populations with various disease states. Lymphocytes including T-LGL were investigated retrospectively by reviewing PB multiparameter flow cytometric data with various indications over a 4-year period. Associations with clinical, laboratory findings, and T-LGL population sizes were sought. Among 520 cases reviewed, 240 were females and 280 males with a mean age of 9 years (0–33 years); mean T-LGL population constituted 14% (1–67%) in PB T cells. There were significant differences between T-LGL and CD5-bright, regular T cells. T-LGL correlated with CD8 + /DR + (R = 0.570; P < 0.01) and CD8 + /CD11b + (R = 0.597; P < 0.01) expression, indicating activated cytotoxic phenotype. The highest average T-LGL were seen in bone marrow transplant recipients (23.7%), Evans syndrome (23.7%), lymphoma (20.6%), and acute EBV infection (20.4%) cases, all with underlying immune dysregulation pathologies. In pediatric and young adult patients with different clinical conditions, PB T-LGL constitute an average of 14% of the T cells and have a predominantly activated cytotoxic T cell phenotype. Higher relative presence was seen in cases with an immune dysregulation background. These results may serve as a reference for T-LGL research efforts. [ABSTRACT FROM AUTHOR]

Abstract Background This study aimed to obtain health utility parameters among Chinese breast cancer patients in different disease states for subsequent health economics model. In addition, we aimed to explore the feasibility of establishing a breast cancer health utility mapping model in China. Methods Multiple patient-reported health attributes were assessed, including quality of life, which was measured by the Functional Assessment of Cancer Therapy-Breast (FACT-B) instrument; health utility and self-rated health, which were measured by the EuroQol-5 Dimension-5 Level (EQ-5D-5L) questionnaire. Multivariate regression models, including a linear regression model, an ordinal logistic regression model and a Tobit model, were employed to analyze health differences among 446 breast cancer patients. Subgroup analyses were performed to examine differences in multiple dimensions of health derived from the FACT-B and EQ-5D-5L instruments. A mapping function was used to estimate health utility from quality of life. Rank correlation analyses were employed to examine the correlation between estimated and observed health utility values. Results A total of 446 breast cancer patients with different disease states were analyzed. The health utility values of breast cancer patients in the P state (without cancer recurrence and metastasis), R state (with cancer recurrence within a year), S state (with primary and recurrent breast cancer for the second year and above), and M state (metastatic cancer) were 0.81 (SD ± 0.23), 0.90 (SD ± 0.12), 0.78 (SD ± 0.31), and 0.74 (SD ± 0.27), respectively. There were positive correlations between all scores, including every domain of the FACT-B instrument (p

The administered dose of a drug modulates whether patients will experience optimal effectiveness, toxicity including death, or no effect at all. Dosing is particularly important for diseases and/or drugs where the drug can decrease severe morbidity or prolong life. Likewise, dosing is important where the drug can cause death or severe morbidity. Since we believe there are many examples where more precise dosing could benefit patients, it is worthwhile to consider how to prioritize drug–disease targets. One key consideration is the quality of information available from which more precise dosing recommendations can be constructed. When a new more precise dosing scheme is created and differs significantly from the approved label, it is important to consider the level of proof necessary to either change the label and/or change clinical practice. The cost and effort needed to provide this proof should also be considered in prioritizing drug–disease precision dosing targets. Although precision dosing is being promoted and has great promise, it is underutilized in many drugs and disease states. Therefore, we believe it is important to consider how more precise dosing is going to be delivered to high priority patients in a timely manner. If better dosing schemes do not change clinical practice resulting in better patient outcomes, then what is the use? This review paper discusses variables to consider when prioritizing precision dosing candidates while highlighting key examples of precision dosing that have been successfully used to improve patient care.

Disease states such as liver cirrhosis and chronic kidney disease can lead to altered pharmacokinetics (PK) of drugs by influencing drug absorption, blood flow to organs, plasma protein binding, apparent volume of distribution, and drug‐metabolizing enzyme and transporter (DMET) abundance. Narrow therapeutic index drugs are particularly vulnerable to undesired pharmacodynamics (PD) because of the changes in drug PK in disease states. However, systematic clinical evaluation of disease effect on drug PK and PD is not always possible because of the complexity or the cost of clinical studies. Physiologically based PK (PBPK) modeling is emerging as an alternate method to extrapolate drug PK from the healthy population to disease states. These models require information on the effect of disease condition on the activity or tissue abundance of DMET proteins. Although immunoquantification‐based abundance data were available in the literature for a limited number of DMET proteins, the emergence of mass spectrometry‐based quantitative proteomics as a sensitive, robust, and high‐throughput tool has allowed a rapid increase in data availability on tissue DMET abundance in healthy versus disease states, especially in liver tissue. Here, we summarize these data including the available immunoquantification or mRNA levels of DMET proteins (healthy vs disease states) in extrahepatic tissue and discuss the potential applications of DMET abundance data in enhancing the capability of PBPK modeling in predicting drug disposition across disease states. Successful examples of PBPK modeling that integrate differences in DMET proteins between healthy and disease states are discussed. [ABSTRACT FROM AUTHOR]

The administered dose of a drug modulates whether patients will experience optimal effectiveness, toxicity including death, or no effect at all. Dosing is particularly important for diseases and/or drugs where the drug can decrease severe morbidity or prolong life. Likewise, dosing is important where the drug can cause death or severe morbidity. Since we believe there are many examples where more precise dosing could benefit patients, it is worthwhile to consider how to prioritize drug–disease targets. One key consideration is the quality of information available from which more precise dosing recommendations can be constructed. When a new more precise dosing scheme is created and differs significantly from the approved label, it is important to consider the level of proof necessary to either change the label and/or change clinical practice. The cost and effort needed to provide this proof should also be considered in prioritizing drug–disease precision dosing targets. Although precision dosing is being promoted and has great promise, it is underutilized in many drugs and disease states. Therefore, we believe it is important to consider how more precise dosing is going to be delivered to high priority patients in a timely manner. If better dosing schemes do not change clinical practice resulting in better patient outcomes, then what is the use? This review paper discusses variables to consider when prioritizing precision dosing candidates while highlighting key examples of precision dosing that have been successfully used to improve patient care. [ABSTRACT FROM AUTHOR]

Background: Understanding the sensitivity and utility of clinical assessments across different HD stages is important for study/trial endpoint selection and clinical assessment development. The Integrated HD Progression Model (IHDPM) characterizes the complex symptom progression of HD and separates the disease into nine ordered disease states., Objective: To generate a temporal map of discriminatory clinical measures across the IHDPM states., Methods: We applied the IHDPM to all HD individuals in an integrated longitudinal HD dataset derived from four observational studies, obtaining disease state assignment for each study visit. Using large-scale screening, we estimated Cohen's effect sizes to rank the discriminative power of 2,472 clinical measures for separating observations in disease state pairs. Individual trajectories through IHDPM states were examined. Discriminative analyses were limited to individuals with observations in both states of the pairs compared ( N  = 3,790)., Results: Discriminative clinical measures were heterogeneous across the HD life course. UHDRS items were frequently identified as the best state pair discriminators, with UHDRS Motor items - most notably TMS - showing the highest discriminatory power between the early-disease states and early post-transition period states. UHDRS functional items emerged as strong discriminators from the transition period and on. Cognitive assessments showed good discriminative power between all state pairs examined, excepting state 1 vs. 2. Several non-UHDRS assessments were also flagged as excellent state discriminators for specific disease phases (e.g., SF-12). For certain state pairs, single assessment items other than total/summary scores were highlighted as having excellent discriminative power., Conclusion: By providing ranked quantitative scores indicating discriminatory ability of thousands of clinical measures between specific pairs of IHDPM states, our results will aid clinical trial designers select the most effective outcome measures tailored to their study cohort. Our observations may also assist in the development of end points targeting specific phases in the disease life course, through providing specific conceptual foci., Competing Interests: JW, SS, and CS are employed by CHDI Management, Inc., the company that manages the scientific activities of CHDI Foundation, Inc. SD, EE, and JH are employed by IBM Research, which was contracted by CHDI Foundation for this work. ZS was employed by IBM Research during the study., (Copyright © 2024 Sun, Ware, Dey, Eyigoz, Sathe, Sampaio and Hu.)

Chronic kidney disease (CKD) is characterized by the accumulation of uremic solutes; however, little is known about how these solutes affect drug absorption and disposition. The goal of this study is to evaluate the effect of uremic solutes on the organic cation transporter, OCT2, which plays a key role in the renal secretion of many basic drugs. As a second goal, we reviewed the literature to determine whether there was evidence for the effect of CKD on the renal secretion of basic drugs. We first screened 72 uremic solutes as inhibitors of [ 14 C]-labeled metformin uptake by OCT2. Seven were identified as inhibitors and 3 of them were determined to be clinically relevant. Of the 7 solutes, dimethylamine, malondialdehyde, trimethylamine, homocysteine, indoxyl-β-d-glucuronide, and glutathione disulfide were novel OCT2 inhibitors. For 6 drugs that are known OCT2 substrates, both secretory clearance and glomerular filtration rate declined in parallel with progression of CKD from stage 2 to 4, suggesting that selective effects of uremic solutes on net tubular secretion of organic cations do not occur. Further clinical studies are warranted with a broader range of OCT2 substrates to determine whether CKD may differentially affect tubular secretion of drugs especially in patients with advanced CKD. [ABSTRACT FROM AUTHOR]

People living in Africa face a heavy and wide-ranging burden of disease that takes an incalculable toll on social and economic development as well as shortening life expectancy (life expectancy in Tanzania is about 60 vs. about 80 in the United States and Europe. Further, the pharmaceutical market in developing countries is immature and may not support quality medicines. In many cases, a tender system is used, and medicines are bought by the government at the lowest price. In addition to access to medicines, a number of pharmaceutical sciences problems are apparent. The availability of infrastructure and especially standard instruments such as HPLC and X-ray diffraction is minimal. Additionally, there is an important need to increase access to advanced education for men and women in Africa, especially access to state-of-the-art scientific education. Utilizing the mandate of Nelson Mandela, Purdue's conceptual approach has been to utilize education to combat these problems. [ABSTRACT FROM AUTHOR]

Postabsorptive factors which can affect systemic drug exposure are assumed to be dependent on the active pharmaceutical ingredient (API), and thus independent of formulation. In contrast, preabsorptive factors, for example, hypochlorhydria, might affect systemic exposure in both an API and a formulation-dependent way. The aim of this study was to evaluate whether the oral absorption of 2 poorly soluble, weakly basic APIs, ketoconazole (KETO) and posaconazole (POSA), would be equally sensitive to changes in dissolution rate under the following dosing conditions—coadministration with water, with food, with carbonated drinks, and in drug-induced hypochlorhydria. The systems-components of validated absorption and PBPK models for KETO and POSA were modified to simulate the above-mentioned clinical scenarios. Virtual bioequivalence studies were then carried out to investigate whether formulation effects on the plasma profile vary with the dosing conditions. The slow precipitation of KETO upon reaching the upper part of the small intestine renders its absorption more sensitive to the completeness of gastric dissolution and thus to the gastric environment than POSA, which is subject to extensive precipitation in response to a pH shift. The virtual bioequivalence studies showed that hypothetical test and reference formulations containing KETO would be bioequivalent only if the microenvironment in the stomach enables complete gastric dissolution. We conclude that physiologically based pharmacokinetic modeling and simulation has excellent potential to address issues close to bedside such as optimizing dosing conditions. By studying virtual populations adapted to various clinical situations, clinical strategies to reduce therapeutic failures can be identified. [ABSTRACT FROM AUTHOR]

The 2016 American College of Clinical Pharmacy ( ACCP) Educational Affairs Committee was charged with updating and contemporizing ACCP's 2009 Pharmacotherapy Didactic Curriculum Toolkit. The toolkit has been designed to guide schools and colleges of pharmacy in developing, maintaining, and modifying their curricula. The 2016 committee reviewed the recent medical literature and other documents to identify disease states that are responsive to drug therapy. Diseases and content topics were organized by organ system, when feasible, and grouped into tiers as defined by practice competency. Tier 1 topics should be taught in a manner that prepares all students to provide collaborative, patient-centered care upon graduation and licensure. Tier 2 topics are generally taught in the professional curriculum, but students may require additional knowledge or skills after graduation (e.g., residency training) to achieve competency in providing direct patient care. Tier 3 topics may not be taught in the professional curriculum; thus, graduates will be required to obtain the necessary knowledge and skills on their own to provide direct patient care, if required in their practice. The 2016 toolkit contains 276 diseases and content topics, of which 87 (32%) are categorized as tier 1, 133 (48%) as tier 2, and 56 (20%) as tier 3. The large number of tier 1 topics will require schools and colleges to use creative pedagogical strategies to achieve the necessary practice competencies. Almost half of the topics (48%) are tier 2, highlighting the importance of postgraduate residency training or equivalent practice experience to competently care for patients with these disorders. The Pharmacotherapy Didactic Curriculum Toolkit will continue to be updated to provide guidance to faculty at schools and colleges of pharmacy as these academic pharmacy institutions regularly evaluate and modify their curricula to keep abreast of scientific advances and associated practice changes. Access the current Pharmacotherapy Didactic Curriculum Toolkit at [ABSTRACT FROM AUTHOR]

Background: There is controversy as to whether use of statistical clustering methods to identify common disease patterns in schizophrenia identifies patterns generalizable across countries. Objective: The goal of this study was to compare disease states identified in a published study (Mohr/Lenert, 2004) considering US patients to disease states in a European cohort (EuroSC) considering English, French, and German patients. Methods: Using methods paralleling those in Mohr/Lenert, we conducted a principal component analysis (PCA) on Positive and Negative Syndrome Scale items in the EuroSC data set (n = 1,208), followed by k-means cluster analyses and a search for an optimal k. The optimal model structure was compared to Mohr/Lenert by assigning discrete severity levels to each cluster in each factor based on the cluster center. A harmonized model was created and patients were assigned to health states using both approaches; agreement rates in state assignment were then calculated. Results: Five factors accounting for 56% of total variance were obtained from PCA. These factors corresponded to positive symptoms (Factor 1), negative symptoms (Factor 2), cognitive impairment (Factor 3), hostility/aggression (Factor 4), and mood disorder (Factor 5) (as in Mohr/Lenert). The optimal number of cluster states was six. The kappa statistic (95% confidence interval) for agreement in state assignment was 0.686 (0.670-0.703). Conclusion: The patterns of schizophrenia effects identified using clustering in two different data sets were reasonably similar. Results suggest the Mohr/Lenert health state model is potentially generalizable to other populations. [ABSTRACT FROM AUTHOR]

The field of environmental research has benefited greatly from the concept of biomarkers, which originally expanded our thinking by opening the "black box" between environmental exposures and manifestations of disease and dysfunction in exposed populations, as laid out in a highly influential article published in 1987 by an expert committee convened by the National Research Council. Advances in biomedical research now challenge us to revise this concept to include the microbiome as a critical stage in the progression from exposure to outcome. Incorporating the microbiome into the basic 1987 model can spur new advances and understanding in environmental health. The human microbiome as a whole comprises the majority of cells and genes of the super-organism (host and microbiome). Site-specific microbiomes are the first to encounter xenobiotics, prior to absorption across gut, skin, or respiratory system. A growing literature indicates that these microbial communities may participate in biotransformation and thus constitute a compartment to add to the original biomarker schematic. In addition, these microbiomes interact with the "niche" in which they are located and thus transduce responses to and from the host organism. Incorporating the microbiome into the environmental health paradigm will enlarge our concepts of susceptibility as well as the interactions between xenobiotics and other factors that influence the status and function of these barrier systems. This article reviews the complexities of host:microbiome responses to xenobiotics in terms of redefining toxicokinetics and susceptibility. Our challenge is to consider these multiple interactions between and within the microbiome, the immune system, and other systems of the host in terms of exposure to exogenous agents, including environmental toxicants. [ABSTRACT FROM AUTHOR]

Pathophysiological changes are associated with alterations in the expression and function of numerous ADME-related proteins. We have previously demonstrated that the membrane localization of ATP-binding cassette ( ABC) transporters in liver was decreased without change of total expression levels in adjuvant-induced arthritis ( AA) in rats. Ezrin/radixin/moesin ( ERM) proteins are involved in localization of some ABC transporters in canalicular membrane. The m RNA levels of radixin decreased significantly in liver but not kidney, small intestine, and brain. The m RNA levels of ezrin and moesin did not change in AA. The membrane localization of radixin was reduced in liver of AA and the ratios of activated radixin (p-radixin) to total radixin were decreased in AA, although the protein levels of radixin did not change in homogenate and membrane protein. To clarify whether AA affects the linker functions of ERM proteins, we examined the interactions between ERM proteins and ABC transporters. The interactions between radixin and ABC transporters were decreased in AA. In vitro studies using human hepatoma Hep G2 cells showed that interleukin-1β decreased the m RNA levels of radixin and colocalization of radixin and Mrp2. Our results show that the decreased radixin functions affect the interaction between radixin and ABC transporters in inflammation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:4058-4065, 2014 [ABSTRACT FROM AUTHOR]

Aim As a consequence of the improved survival of patients and of cost-effectiveness requirements for new treatments, health-related quality of life ( HRQoL) issues have gained increasing attention in colorectal cancer ( CRC). This cross-sectional study assesses HRQoL in several health states of CRC and explores factors influencing HRQoL. Method Five hundred and eight Finnish CRC patients (aged 26-96 years; colon cancer 56%; women 47%) assessed their HRQoL using generic 15D and EQ-5D and cancer-specific EORTC QLQ-C30 questionnaires. Patients were divided into five groups: primary treatment, rehabilitation, remission, metastatic disease and palliative care. The patients' HRQoL was compared with population reference values. Multivariate modelling was used to find factors associated with HRQoL scores. Results The HRQoL of CRC patients is fairly good and comparable with that of the standardized general population except for those under palliative care. The mean 15D score of patients in the primary treatment group was 0.889 (95% CI 0.869-0.914), in rehabilitation 0.877 (0.855-0.907), in remission 0.886 (0.875-0.903), in metastatic disease 0.860 (0.844-0.878) and in palliative care 0.758 (0.716-0.808). The respective EQ-5D scores were 0.760 (0.699-0.823), 0.835 (0.777-0.881), 0.850 (0.828-0.882), 0.820 (0.783-0.858) and 0.643 (0.546-0.747). Multivariate analysis showed that fatigue, pain, age and financial difficulties had a marked negative impact on HRQoL. Conclusion The mean HRQoL scores of CRC patients varied considerably depending on the HRQoL instrument used, but remained surprisingly good up to the palliative stage. In addition to age- and cancer-related symptoms, financial difficulties also had a clear negative impact on HRQoL, which needs to be taken into consideration when supporting patient HRQoL. [ABSTRACT FROM AUTHOR]

Ensuring the health of street-involved children is a growing public health challenge. These children are vulnerable, neglected, and rarely a priority for basic service providers and governments. Sizable populations of street-involved children are present in major urban areas worldwide and current trends in urbanization suggest these populations will grow in the coming years. Although migration offers employment and training opportunities, the health and wellbeing of children is negatively impacted by their interactions with the streets. However, systemic barriers may also prevent these children from achieving an adequate health status. The situation of street-involved children in Ghana, West Africa will be discussed. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3619-3622, 2012 [ABSTRACT FROM AUTHOR]

Abstract: Aldehyde dehydrogenases (ALDHs) represent large family members of NAD(P)+-dependent dehydrogenases responsible for the irreversible metabolism of many endogenous and exogenous aldehydes to the corresponding acids. Among 19 ALDH isozymes, mitochondrial ALDH2 is a low K m enzyme responsible for the metabolism of acetaldehyde and lipid peroxides such as malondialdehyde and 4-hydroxynonenal, both of which are highly reactive and toxic. Consequently, inhibition of ALDH2 would lead to elevated levels of acetaldehyde and other reactive lipid peroxides following ethanol intake and/or exposure to toxic chemicals. In addition, many East Asian people with a dominant negative mutation in ALDH2 gene possess a decreased ALDH2 activity with increased risks for various types of cancer, myocardial infarct, alcoholic liver disease, and other pathological conditions. The aim of this review is to briefly describe the multiple post-translational modifications of mitochondrial ALDH2, as an example, after exposure to toxic chemicals or under different disease states and their pathophysiological roles in promoting alcohol/drug-mediated tissue damage. We also briefly mention exciting preclinical translational research opportunities to identify small molecule activators of ALDH2 and its isozymes as potentially therapeutic/preventive agents against various disease states where the expression or activity of ALDH enzymes is altered or inactivated. [Copyright &y& Elsevier]

Vitamin C functions in enzyme activation, oxidative stress reduction, and immune function. There is considerable evidence that vitamin C protects against respiratory tract infections and reduces risk for cardiovascular disease and some cancers. Current trials are examining the efficacy of intravenous vitamin C as cancer therapy. Many experts believe that the recommended intakes for vitamin C (45 to 90 mg daily) are several orders of magnitude too low to support optimal vitamin C functionality. Also, there is a misperception that vitamin C deficiency disease (scurvy) is largely historical and rarely observed in developed nations. Physical symptoms of scurvy include swelling of the lower extremities, bleeding gums, fatigue, and hemorrhaging, as well as psychological problems, including depression, hysteria, and social introversion. The long-term safety of vitamin C supplementation seems evident as large investigations have noted reduced risk of mortality in vitamin C supplementing populations and in those with elevated plasma vitamin C concentrations. [ABSTRACT FROM PUBLISHER]

Thermoanalytical methods have found increasing application in medicine due to the improved sensitivity and usability of the available instrumentation. Studies have identified important findings applied to medicine, including information on the thermal properties of the skin and the effect of insertion into body cavities of implants and prosthetics. These studies have explored the thermal stability of various materials to provide insight into drug penetration in order to design drug delivery systems, which are not only safe but capable of delivering improved and predictable therapeutic outcomes for patients. Differential scanning calorimetry (DSC) has also been applied to the study of disease states such as diabetes, where changes in the collagen structure of the skin, which may lead to long-term complications in these patients, can be detected. Although these results may at this stage not have significant clinical implications, they do provide medical researchers with a starting point for future investigations. The application of these techniques has been further extended to examinations of body systems and other disease states. The key for the future will be the ability of these techniques not only to provide information on alterations in these biological systems, but also to determine whether these alterations are clinically relevant. [ABSTRACT FROM AUTHOR]

Most of the global healthcare issues facing us—from expanding access to care, to providing medical and dental care in the aftermath of disasters—are far too complex for any single sector to successfully solve. Industry, the healthcare profession, government, academia and non-governmental organizations (NGOs) are all limited in their scope and their ability to effectively address the necessary challenges of these multifaceted issues. It is only though public–private partnerships, in which the participants contribute resources and skills for which they individually are best suited, that true progress can be made in affecting change. In addition, every effort should be made to expand the pool of participants for these partnerships, including small and mid-sized organizations that may be inclined to help, but lack the experience or the infrastructure to initiate programs on their own. As the largest distributor of healthcare products and services to office-based practitioners in the combined North American and European markets, Henry Schein, Inc., is uniquely positioned to use its association with thousands of healthcare product manufacturers and its day-to-day relationships with more than 550,000 healthcare practices around the world to catalyze awareness of and support for important healthcare issues. Through Henry Schein's model for giving, the Company has been successful in forging new partnerships among industry, the healthcare profession, government, academia and NGOs, and in expanding existing ones to help meet the healthcare challenges facing us all. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5084–5088, 2008 [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to describe the health related quality of life (HRQoL) in different breast cancer disease states using preference-based measures.Material and Methods: A total of 361 consecutive breast cancer patients attending the breast cancer outpatient clinic at Karolinska University hospital Solna for outpatient visits between April and May 2005 were included in the study. The EQ-5D self classifier and a direct Time Trade Off (TTO) question were used to estimate the HRQoL in different breast cancer disease states.Results: Patients in their first year after a primary breast cancer had a mean EQ-5D index value of 0.696 (95% confidence interval (CI): 0.634-0.747)). Patients in their first year after a recurrence had a mean EQ-5D index value of 0.779 (CI: 0.700-0.849). Patients who had not had a primary breast cancer diagnosis or a recurrence during the previous year had a mean EQ-5D index value of 0.779 (CI: 0.745-0.811). Patients with metastatic disease reported the lowest HRQoL values, and had a mean EQ-5D index value of 0.685 (CI: 0.620-0.735). The main driver behind the reduction in HRQoL was pain and discomfort as well as anxiety and depression. TTO values were higher for all diseases states compared to the EQ-5D index values.Conclusion: This study shows that breast cancer is associated with a reduction in HRQoL. This effect is most pronounced for patients with metastatic disease. [ABSTRACT FROM AUTHOR]

Dehydroepiandrosterone sulfate (DHEAS) is a 19-carbon steroid, situated along the steroid metabolic pathway. It is the most abundant circulating steroid hormone in the body and can be converted to either androgens or estrogens. Their physiological and pathological functions have not yet been fully identified. Serum DHEAS concentrations peak at around age 25 years and then decline steadily over the following decades. Due to its long half-life and high concentration in the blood, the levels of DHEAS remain the same 24 h a day. This makes DHEAS a very interesting new diagnostic tool for both scientific research and clinical diagnostics. Moreover, circulating concentrations of DHEAS can be changed by many factors, such as endogenous production, hormone supplementation, many kinds of drugs, and many types of disease states. As research moves forward to better understand the relationships of DHEAS with health and disease, it is essential that studies should be designed to control for the influence of many factors on serum DHEAS concentrations. [Copyright &y& Elsevier]

During pathologic conditions such as meningitis and traumatic brain injury the function of the blood–brain barrier (BBB) is disturbed. In the present study we examined the cerebral pharmacokinetic pattern of morphine in the intact brain and during experimentally induced meningitis using a pig model. Secondly, the use of intracerebral microdialysis as a potential tool for monitoring damage in the BBB by studying the pharmacokinetics of morphine is addressed. Six pigs were studied under general anaesthesia. One occipital and two frontal microdialysis probes and one pressure transducer were inserted into the brain tissue. Another probe was placed into the jugularis interna. Morphine 1 mg kg−1 was administered as a 10-min infusion, and morphine concentrations were then measured for 3 h. Meningitis was subsequently induced by injecting lipopoly-saccharide into the cisterna magna. When meningitis was established, the morphine experiment was repeated. The unbound area under the concentration-time curve (AUCu) ratio of morphine in brain to blood was 0.47 (0.19) during the control period, and 0.95 (0.20) ( P < 0.001) during meningitis. The increase in the brain/blood AUCu ratio during meningitis implies decreased active efflux and increased passive diffusion of morphine over the BBB. The half-life of morphine in brain was longer than in blood during both periods, and was unaffected by meningitis. This study demonstrates that the morphine exposure to the brain is significantly increased during meningitis as compared with the control situation. [ABSTRACT FROM AUTHOR]

Genomics and proteomics have made it possible to define molecular physiology in exquisite detail, when tissues are accessible for sampling. However, many tissues are not accessible for human diagnostic evaluations or experimental studies, creating the need for surrogates that afford insight into exposures and effects in such tissues. Surrogate tissue analysis (STA) incorporating contemporary genomic and proteomic technologies may be useful in determining toxicant exposure and effect, or disease state, in target tissues at the pre- or early clinical stage. We present here a discussion of STA based on presentations given at the Society of Toxicology''s 2003 annual meeting''s “Innovations in Applied Toxicology” symposium. Speakers at the symposium (Box 1) discussed various potential applications of STA, including the use of peripheral blood lymphocytes (PBLs) as a source of genetic biomarkers to monitor radiation exposure; the use of gene expression analysis of PBLs and hair follicles as a means to monitor the impact of toxicants on inaccessible organs; the characterization of disease-associated gene signatures in peripheral blood mononuclear cells (PBMCs) of renal cell carcinoma (RCC) patients; the use of sperm RNA to determine genetic and environmental effects on sperm development in the testis; and the use of serum protein profiles to monitor the development and progression of various cancers. Also discussed are some of the challenges that must be overcome if the utility of STA is to be proven, and thus permit researchers to move this concept from the laboratory to the clinical environment. [Copyright &y& Elsevier]

The detection and identification of pathogens is often painstaking due to the low abundance of diseased cells in clinical samples. The genomic sequences of the pathogen can be amplified through methods such as the polymerase chain reaction and nucleic acid sequence-based amplification, but the nucleic acid targets are often lost among other unintended products of amplification. Novel nucleic acid probes known as molecular beacons have been developed allowing for the rapid and specific detection of genetic markers of a disease. Molecular beacons are hairpin-forming oligonucleotides labelled at one end with a quencher and at the other end with a fluorescent reporter dye. In the absence of target, the fluorescence is quenched. In the presence of target, the hairpin structure opens upon beacon/target hybridisation, resulting in the restoration of fluorescence. The ability to transduce target recognition into a fluorescence signal with high signal-to-background ratio, coupled with an improved specificity, has allowed molecular beacons to enjoy a wide range of biological and biomedical applications. Here, we describe the basic features of molecular beacons, review their applications in disease detection and diagnosis and discuss some of the issues and challenges of in vivo studies. The aim of this paper is to foster the development of new molecular beacon-based assays and to stimulate the application of this technology in laboratory and clinical studies of health and disease. [ABSTRACT FROM PUBLISHER]

Objectives: To assess the impact of visceral leishmaniasis (VL) on the concentration of amphotericin B (AmB) recovered in the liver and spleen following either intravenous (AmBisome®) or oral (iCo-009) AmB administration to mice. [ABSTRACT FROM PUBLISHER]

• Selected organofluorine-containing blockbuster drugs were profiled. • General aspects of the biological properties of these compounds were briefly introduced. • The synthetic methods for preparation of these organofluorine-containing drugs were presented. The role of organo-fluorine compounds in modern health, food and energy related industries is widely-appreciated. The unique properties that fluorine imparts to organic molecules, stemming from its high electronegativity and stability when bound to carbon, finds it increasingly being used in the development of new bioactivities. Around 25 % of the current blockbuster drugs contain fluorine and this number is increasing to well above 30 % for recent FDA approvals. In this Review we highlight a selection of the most successful organo-fluorine drugs, that have achieved blockbuster status, namely, sitagliptin (diabetes), sofosbuvir (hepatitis C), emtricitabine (HIV), glecaprevir/pibrentasvir (hepatitis C), elvitegravir (HIV), dolutegravir (HIV), bictegravir (HIV), efavirenz (HIV), enzalutamide (prostate cancer), aubagio (immunomodulatory) and paliperidone palmitate (schizophrenia). For each compound we discuss their discovery, their relevant disease state and how they are made, emphasizing the source of fluorine-containing moieties, and where known, their mode of action. [ABSTRACT FROM AUTHOR]

The chromatographic separation processes for many molecules in solute bands by stationary phase-mobile phase separation can be compared to ordering disease severity. The common features of chromatographic processes and machine-disease diagnosis-doctor's advice is the separation (classification) of components (individual disease states), both of which show irreversibility of time evolution; however, the former is caused by linear non-equilibrium thermodynamics and latter by nonlinear non-equilibrium thermodynamics (dissipative structure). When the scientific view is extended from drug detection and preparation to evidence-based medicine (EBM), discrete mathematics (axiomatic set theory and probability measure), and artificial intelligence (AI) cloud computing, the convection-diffusion equation and irreversibility in non-equilibrium thermodynamics form a common and core essence of mathematical physics that crosses fields of chromatographic separation and intelligent medicine. It is of profound scientific and practical significance to construct and develop a unified and all-encompassing mathematical framework by incorporating the generality and characteristics of the two subjects.