Differential evolution of peripheral cytokine levels in symptomatic and asymptomatic responses to experimental influenza virus challenge.

Exposure to influenza virus triggers a complex cascade of events in the human host. In order to understand more clearly the evolution of this intricate response over time, human volunteers were inoculated with influenza A/Wisconsin/67/2005 (H3N2), and then had serial peripheral blood samples drawn and tested for the presence of 25 major human cytokines. Nine of 17 (53%) inoculated subjects developed symptomatic influenza infection. Individuals who will go on to become symptomatic demonstrate increased circulating levels of interleukin (IL)-6, IL-8, IL-15, monocyte chemotactic protein (MCP)-1 and interferon (IFN) gamma-induced protein (IP)-10 as early as 12-29 h post-inoculation (during the presymptomatic phase), whereas challenged patients who remain asymptomatic do not. Overall, the immunological pathways of leucocyte recruitment, Toll-like receptor (TLR)-signalling, innate anti-viral immunity and fever production are all over-represented in symptomatic individuals very early in disease, but are also dynamic and evolve continuously over time. Comparison with simultaneous peripheral blood genomics demonstrates that some inflammatory mediators (MCP-1, IP-10, IL-15) are being expressed actively in circulating cells, while others (IL-6, IL-8, IFN-α and IFN-γ) are probable effectors produced locally at the site of infection. Interestingly, asymptomatic exposed subjects are not quiescent either immunologically or genomically, but instead exhibit early and persistent down-regulation of important inflammatory mediators in the periphery. The host inflammatory response to influenza infection is variable but robust, and evolves over time. These results offer critical insight into pathways driving influenza-related symptomatology and offer the potential to contribute to early detection and differentiation of infected hosts.

Impact of delivery models on understanding genomic risk for type 2 diabetes.

BACKGROUND: Genetic information, typically communicated in-person by genetic counselors, can be challenging to comprehend; delivery of this information online--as is becoming more common--has the potential of increasing these challenges. METHODS: To address the impact of the mode of delivery of genomic risk information, 300 individuals were recruited from the general public and randomized to receive genomic risk information for type 2 diabetes mellitus in-person from a board-certified genetic counselor or online through the testing company's website. RESULTS: Participants were asked to indicate their genomic risk and overall lifetime risk as reported on their test report as well as to interpret their genomic risk (increased, decreased, or same as population). For each question, 59% of participants correctly indicated their risk. Participants who received their results in-person were more likely than those who reviewed their results on-line to correctly interpret their genomic risk (72 vs. 47%, p = 0.0002) and report their actual genomic risk (69 vs. 49%, p = 0.002). CONCLUSIONS: The delivery of personal genomic risk through a trained health professional resulted in significantly higher comprehension. Therefore, if the online delivery of genomic test results is to become more widespread, further evaluation of this method of communication may be needed to ensure the effective presentation of results to promote comprehension.

Personalized medicine in women's obesity prevention and treatment: implications for research, policy and practice.

The prevalence of obesity in America has reached epidemic proportions, and obesity among women is particularly concerning. Severe obesity (body mass index ≥35 kg m(-2) ) is more prevalent in women than men. Further, women have sex-specific risk factors that must be considered when developing preventive and therapeutic interventions. This review presents personalized medicine as a dynamic approach to obesity prevention, management and treatment for women. First, we review obesity as a complex health issue, with contributing sex-specific, demographic, psychosocial, behavioural, environmental, epigenetic and genetic/genomic risk factors. Second, we present personalized medicine as a rapidly advancing field of health care that seeks to quantify these complex risk factors to develop more targeted and effective strategies that can improve disease management and/or better minimize an individual's likelihood of developing obesity. Third, we discuss how personalized medicine can be applied in a clinical setting with current and emerging tools, including health risk assessments, personalized health plans, and strategies for increasing patient engagement. Finally, we discuss the need for additional research, training and policy that can enhance the practice of personalized medicine in women's obesity, including further advancements in the '-omics' sciences, physician training in personalized medicine, and additional development and standardization of innovative targeted therapies and clinical tools.

Primary care physicians' knowledge of and experience with pharmacogenetic testing.

It is anticipated that as the range of drugs for which pharmacogenetic testing becomes available expands, primary care physicians (PCPs) will become major users of these tests. To assess their training, familiarity, and attitudes toward pharmacogenetic testing in order to identify barriers to uptake that may be addressed at this early stage of test use, we conducted a national survey of a sample of PCPs. Respondents were mostly white (79%), based primarily in community-based primary care (81%) and almost evenly divided between family medicine and internal medicine. The majority of respondents had heard of PGx testing and anticipated that these tests are or would soon become a valuable tool to inform drug response. However, only a minority of respondents (13%) indicated they felt comfortable ordering PGx tests and almost a quarter reported not having any education about pharmacogenetics. Our results indicate that primary care practitioners envision a major role for themselves in the delivery of PGx testing but recognize their lack of adequate knowledge and experience about these tests. Development of effective tools for guiding PCPs in the use of PGx tests should be a high priority.

The oral microbiome in health and disease and the potential impact on personalized dental medicine.

Every human body contains a personalized microbiome that is essential to maintaining health but capable of eliciting disease. The oral microbiome is particularly imperative to health because it can cause both oral and systemic disease. The oral microbiome rests within biofilms throughout the oral cavity, forming an ecosystem that maintains health when in equilibrium. However, certain ecological shifts in the microbiome allow pathogens to manifest and cause disease. Severe forms of oral disease may result in systemic disease at different body sites. Microbiomics and metagenomics are two fields of research that have emerged to identify the presence of specific microbes in the body and understand the nature of the microbiome activity during both health and disease. The analysis of the microbiome and its genomes will pave the way for more effective therapeutic and diagnostic techniques and, ultimately, contribute to the development of personalized medicine and personalized dental medicine.

Genome technologies and personalized dental medicine.

The addition of genomic information to our understanding of oral disease is driving important changes in oral health care. It is anticipated that genome-derived information will promote a deeper understanding of disease etiology and permit earlier diagnosis, allowing for preventative measures prior to disease onset rather than treatment that attempts to repair the diseased state. Advances in genome technologies have fueled expectations for this proactive healthcare approach. Application of genomic testing is expanding and has already begun to find its way into the practice of clinical dentistry. To take full advantage of the information and technologies currently available, it is vital that dental care providers, consumers, and policymakers be aware of genomic approaches to understanding of oral diseases and the application of genomic testing to disease diagnosis and treatment. Ethical, legal, clinical, and educational initiatives are also required to responsibly incorporate genomic information into the practice of dentistry. This article provides an overview of the application of genomic technologies to oral health care and introduces issues that require consideration if we are to realize the full potential of genomics to enable the practice of personalized dental medicine.

Personalized medicine: revolutionizing drug discovery and patient care.

Advances in human genome research are opening the door to a new paradigm for practising medicine that promises to transform healthcare. Personalized medicine, the use of marker-assisted diagnosis and targeted therapies derived from an individual's molecular profile, will impact the way drugs are developed and medicine is practiced. Knowledge of the molecular basis of disease will lead to novel target identification, toxicogenomic markers to screen compounds and improved selection of clinical trial patients, which will fundamentally change the pharmaceutical industry. The traditional linear process of drug discovery and development will be replaced by an integrated and heuristic approach. In addition, patient care will be revolutionized through the use of novel molecular predisposition, screening, diagnostic, prognostic, pharmacogenomic and monitoring markers. Although numerous challenges will need to be met to make personalized medicine a reality, with time, this approach will replace the traditional trial-and-error practice of medicine.

Psychostimulants in preschool children with attention-deficit/hyperactivity disorder: clinical evidence from a developmental disorders institution.

OBJECTIVE: To examine psychostimulant response in preschool children with attention-deficit/hyperactivity disorder (ADHD) in an outpatient child psychiatry clinic (housed within a developmental disorders institution) over 3, 12, and 24 months of treatment. METHOD: A systematic retrospective chart review was conducted for 27 preschool children with ADHD who were started on psychostimulants between the ages of 3 and 5 years, inclusive. Two child and adolescent psychiatrists reviewed each chart independently, using the Clinical Global Impressions (CGI) scale to rate the severity of illness and global improvement and the Side Effects Rating Form to rate side effects. RESULTS: Over 24 months, psychostimulants were stopped in three children (11%) because of side effects and concomitant psychotropic medications were added in seven children (26%). The CGI severity-of-illness ratings showed a significant effect of time over 3, 12, and 24 months of psychostimulant treatment (all p values < .0001). Rate of response was 74% at 3 months and 70% at 12 and 24 months. Side effects were mostly mild and occurred in 63% of the children at 3 months, 41% at 12 months, and 29% at 24 months. CONCLUSIONS: The findings suggest that preschool children with developmental disorders respond to psychostimulants but need close monitoring because of frequent side effects. Inasmuch as the study participants were recruited from a child psychiatry clinic housed within a developmental disorders institution and had a high rate of developmental disorders, the findings may not generalize to other preschool children with ADHD.

Gender differences in exercise-induced changes in sex hormone levels and lipid peroxidation in athletes participating in the Hawaii Ironman triathlon. Ginsburg-gender and exercise-induced lipid peroxidation.

BACKGROUND: Exercise reduces the risk of coronary heart disease in men and women but paradoxically, may promote free-radical formation, lipid peroxidation and vascular tissue injury. In this study, we assessed whether exercise-induced oxidative stress similarly affected men and women who participated in the Hawaii Ironman triathlon. METHODS AND RESULTS: Fifty-seven athletes (38 males) who completed the triathlon (3.9 km swim, 180.2 km bike, 42.2 km run) participated in this study. Blood samples were obtained 2 days before and immediately after the triathlon for the measurement of lipids, antioxidants and sex hormones and for the assessment of the susceptibility of plasma lipids to peroxidation. Lipid changes after exercise were similar for men and women. However, the susceptibility of plasma lipids to peroxidation was reduced by 61% (P < 0.001) in men and only 14% (P = NS) in women postrace. These changes were not associated with the supplemental use or levels of antioxidants. In addition, in men there was an increase of 58% in the antioxidant sex hormone estradiol and a decrease of 58% in testosterone (P < 0.001) postrace. No significant changes were noted for these two hormones in women. CONCLUSIONS: There are significant gender-specific differences in the susceptibility of lipids to peroxidation and in changes in estradiol and testosterone levels as a result of ultra-endurance exercise. These changes may in part explain the salutary effect of exercise on the development of vascular disease.

Atherosclerosis: a cancer of the blood vessels?

A series of molecular pathways have in common a significant role in the pathogenesis and progression of atherosclerosis and cancer. Shared mechanisms implicated for both diseases include oxidative stress and the cellular damage that results from it, toxic metabolites produced by cigarette smoking, and increased dietary fat intake. Atherosclerosis may begin when an injury or infection mutates or transforms a single arterial smooth muscle cell in the progenitor of a proliferative clone, similar to the most widely held carcinogenesis theory. Cell proliferation regulatory pathways have been associated with plaque progression, stenosis, and restenosis after angioplasty and with cancer progression. Alterations in cell adhesion molecules have been linked to plaque formation and thrombosis and to tumor invasion and metastasis. Altered expression of proteases associated with thrombolysis has been implicated in atherosclerotic plaque expansion and hemorrhage and in the invasion and metastasis of malignant neoplasms. Ligand-growth factor receptor interactions have been associated with early atherosclerotic lesions and with cancer development and spread. Nuclear transcription factors have been associated with progression of both diseases. Angiogenesis modulators have been linked to plaque expansion and restenosis of atherosclerotic lesions and to local and metastatic tumor expansion.

Atherosclerosis and cancer: common molecular pathways of disease development and progression.

Recently, a series of shared molecular pathways have emerged that have in common a significant role in the pathogenesis and progression of both atherosclerosis and cancer. Oxidative stress and the cellular damage that results from it have been implicated in a wide variety of disease processes including atherogenesis and neoplasia. Toxic metabolites produced by cigarette smoking and increased dietary fat intake are implicated in the pathogenesis of both diseases. It has been hypothesized that atherosclerosis may begin when an injury or infection mutates or transforms a single arterial smooth muscle cell in the progenitor of a proliferative clone similar to the most widely held theory of carcinogenesis. Cell proliferation regulatory pathways including genes involved in the GIS checkpoint (p53, pRb, p15, p16, and cyclins A, D, E, and cdk 2,4) have been associated with plaque progression, stenosis and restenosis after angioplasty as well as in cancer progression. Alterations in cell adhesion molecules (integrins, cadherin-catenins) have been linked to plaque formation and thrombosis as well as to tumor invasion and metastasis. Altered expression of proteases associated with thrombolysis has been implicated in atherosclerotic plaque expansion and hemorrhage and in the invasion and metastasis of malignancy. Ligand-growth factor receptor interactions (tyrosine kinases) have been associated with early atherosclerotic lesions as well as cancer development and spread. Nuclear transcription factors such as NFkappaB have been associated with progression of both diseases. Angiogenesis modulators have recently been linked to plaque expansion and restenosis of atherosclerotic lesions as well as local and metastatic tumor expansion. Common disease treatments, such as the use of growth factor inhibitors and radiation treatment, established anticancer treatments, were recently introduced into atherosclerosis therapeutic strategies to prevent restenosis after angioplasty and endarterectomy. In conclusion, a series of molecular pathways of disease development and progression common to atherosclerosis and cancer support that the world's two most common diseases are far more closely aligned than previously believed and that emerging anti-inflammatory and antiproliferative therapeutic strategies may ultimately be efficacious in both conditions.

Gender role orientation and fearfulness in children with anxiety disorders.

Research on gender differences in children's fears has generally shown that girls are more fearful than boys. A common hypothesis offered for this finding is that gender role orientations or expectations may be operating. However, this hypothesis has not been directly investigated in child samples. The present study examined the relation between a self-report measure of gender role orientation (i.e., masculinity/femininity) and the intensity of self-reported fears in a clinic sample of children (N = 66; ages 6-11; 41 boys and 25 girls) with anxiety disorders. Results revealed that masculinity was negatively related to overall levels of fearfulness as well as specific fears of failure and criticism, medical fears, and fears of the unknown. In contrast, no relation was found between femininity and fearfulness. These findings suggest that gender role orientation, especially masculinity, may play a role in the development and/or maintenance of fearfulness in children.

Treating anxiety disorders in children with group cognitive-behaviorial therapy: a randomized clinical trial.

A randomized clinical trial evaluated the therapeutic efficacy of group cognitive-behavioral therapy (GCBT) versus a wait-list control (WLC) condition to treat anxiety disorders in children. Results indicated that GCBT, with concurrent parent sessions, was highly efficacious in producing and maintaining treatment gains. Children in GCBT showed substantial improvement on all the main outcome measures, and these gains were maintained at 3-, 6-, and 12-month follow-ups. Children in the WLC condition did not show improvements from the pre- to the postwait assessment point. These findings are discussed in terms of the need to continue to advance the development of practical, as well as conceptual, knowledge of efficacious treatment for anxiety disorders in children.

The treatment of anxiety disorders in children and adolescents.

Anxiety disorders are the most common psychiatric conditions in the pediatric population, with prevalence estimates ranging from 5-18%. Children and adolescents with excessive anxiety often meet diagnostic criteria for a number of disorders within the DSM-IV. Unfortunately, the current diagnostic system is controversial because of high rates of symptom overlap, comorbidity with other psychiatric disorders, and lack of biological markers that would support a more empirical anxiety nosology. Treatment strategies for pediatric anxiety disorders have important historical roots. Several controlled studies of cognitive-behavioral therapy (CBT) demonstrate efficacy for pediatric anxiety disorders. In contrast, no controlled psychopharmacology studies have demonstrated efficacy in children and adolescents with anxiety disorders, except obsessive-compulsive disorder; however, several large, methodologically sound psychopharmacotherapy trials are underway for pediatric anxiety disorders. This update will review the current status of psychosocial and psychopharmacologic treatment of pediatric anxiety disorders. In addition, a brief discussion of nosology, epidemiology, and developmental course of anxiety is included. Preliminary psychopharmacology treatment and CBT treatment algorithms are presented for pediatric anxiety disorders, based on the best available data. Recommendations for future research directions are also discussed.

Contingency management, self-control, and education support in the treatment of childhood phobic disorders: a randomized clinical trial.

This study evaluated the relative efficacy of an exposure-based contingency management (CM) treatment condition and an exposure-based cognitive self-control (SC) treatment condition relative to an education support (ES) control condition for treating children with phobic disorders. Eighty-one children and their parents completed a 10-week treatment program in which children and parents were seen in separate treatment sessions with the therapist, followed by a brief conjoint meeting. Children in both the CM and SC conditions showed substantial improvement on all of the outcome measures. These gains were maintained at 3-, 6-, and 12-month follow-ups. Interestingly, children in the ES condition also showed comparable improvements at posttreatment and at 3-, 6-, and 12-month follow-ups. Implications of the findings are discussed with respect to knowledge development and clinical practice.

Factor structure of the childhood anxiety sensitivity index.

We developed various factor models of the Childhood Anxiety Sensitivity Index [Silverman, W. K., Fleisig, W., Rabian, B. & Peterson, R. A. (1991). Childhood anxiety sensitivity index. Journal of Clinical Child Psychology, 20, 162-168] and tested the goodness of fit of the models in an independent sample. Of primary interest was to examine the question that characterized the factor analytic studies conducted on the adult version of the anxiety sensitivity index, i.e. the ASI [Reiss, S., Peterson, R. A., Gursky, D. M. & McNally, R. J. (1986). Anxiety sensitivity, anxiety frequency and the prediction of fearfulness. Behaviour Research and Therapy, 24, 1-8]: is anxiety sensitivity in children a unidimensional construct, an orthogonal multidimensional construct, or a hierarchical construct? Two independent samples (a clinic sample and a nonclinical sample) were used for development and replication of the factor models. The clinic sample consisted of 258 children (105 girls and 153 boys) who presented to a child anxiety disorders specialty clinic. The unselected, nonclinic sample consisted of 249 children (122 girls and 127 boys) enrolled in an elementary school. The results provided strong empirical support for a hierarchical multidimensional model with either three or four first-order factors. The two factors that emerged that appeared to be robust were Physical Concerns and Mental Incapacitation Concerns. What remains unresolved is whether Control of anxiety symptoms and Social Concerns are to be differentiated (as in the hierarchical model with four first-order factors) or not (as in the hierarchical model with three first-order factors). In addition to discussing this issue, the convergence of the present study's findings with past findings obtained with the ASI is discussed.

Acute changes in serum lipids and lipoprotein subclasses in triathletes as assessed by proton nuclear magnetic resonance spectroscopy.

Exercise is associated with changes in lipids that may protect against coronary heart disease (CHD). In this study of 28 triathletes, we analyzed acute changes in serum lipid and lipoprotein concentrations after completion of the 1995 World Championship Hawaii Ironman Triathlon. With standard laboratory assays, we demonstrate significant decreases in total cholesterol, VLDL cholesterol, ApoB100, and Lp(a). Total HDL cholesterol increased significantly immediately after the race. With a novel proton NMR spectroscopy assay, we demonstrate that smaller diameter LDL particles, corresponding to small, dense LDL, declined by 62%. Moreover, larger HDL subclasses, whose levels are inversely associated with CHD, increased significantly by 11%. Smaller HDL subclasses, which have been directly associated with CHD in some studies, acutely decreased by 16%. Therefore, exercise not only acutely induces changes in lipoprotein concentrations among the standard species in a manner that favorably affects CHD risk, but also induces favorable changes in specific lipoprotein subclass size distribution that also may alter CHD risk independently of the total lipoprotein serum concentration.

Characterization of a cholesterol response element (CRE) in the promoter of the cholesteryl ester transfer protein gene: functional role of the transcription factors SREBP-1a, -2, and YY1.

Cholesteryl ester transfer protein (CETP) is expressed in human adipocytes, where it acts to promote selective uptake of HDL-CE (Benoist, F., M. McDonnell, P. Lau, R. Milne, and R. McPherson. 1997. J. Biol. Chem. 272: 23572;-23577). In contrast to other major sterol-responsive genes such as 3-hydroxy-3-methylglutaryl coenzyme A reductase CETP expression is up-regulated rather than down-regulated in response to cholesterol. To define elements involved in cholesterol-mediated up-regulation of CETP gene expression, deletion derivatives of the CETP promoter were cloned into a luciferase reporter construct and transfected into the human liposarcoma cell line SW872, cultured in the presence or absence of lipoproteins. A fragment associated with a positive cholesterol response was identified between nucleotides -361 and -138 (relative to the initiation site of transcription) of the promoter. This region contains a tandem repeat of a sequence known to mediate sterol dependent regulation of the hamster HMG-CoA reductase gene. We have putatively denoted this region, the cholesterol response element (CRE). Using gel mobility shift assays we demonstrate that both YY1 and SREBP-1 interact with the CRE of CETP. Furthermore, in transient co-transfection experiments, both YY1 and SREBP-1a were found to trans-activate, in a dose-dependent manner, the luciferase activity of constructs harboring the CRE. We also demonstrate that SREBP-2, is able to trans-activate a luciferase construct harboring the CRE although much less effectively as compared to SREBP-1. Finally, functional analysis of the CRE confirms its regulatory role in modulating CETP gene expression through its interaction with YY1 and SREBP-1a.

Cardiac troponin T and I, echocardiographic [correction of electrocardiographic] wall motion analyses, and ejection fractions in athletes participating in the Hawaii Ironman Triathlon.

Cardiac troponin T (cTnT) and troponin I (cTnI) are highly sensitive and specific for detecting myocardial damage even in the presence of skeletal muscle injury. In this study, we assessed whether ultraendurance exercise induced cardiomyocyte injury using plasma cTnT and cTnI measurements, quantitative echocardiographic wall-motion analysis, and ejection fraction measurement in athletes who participated in the Hawaii Ironman Triathlon. Twenty-three athletes (11 men) who completed the triathlon (3.9 km swim, 180.2 km bike, and 42.2 km run) participated in this study. Blood samples were obtained 2 days before and immediately after the triathlon for the determination of cTnT (Enzymun, Roche Diagnostics) and cTnI (Dade Behring) concentrations. Quantitative echocardiographic wall motion analysis and ejection fraction were obtained on 12 of the 23 participants before and immediately after the race. No subject had detectable cTnT or cTnI or abnormal echo score before the race. Following the race, 2 subjects (9%) had marked increases in both cTnT (0.15 and 0.33 microg/L) and cTnI (2.09 and 4.44 microg/L). Four additional subjects (17%) had moderate increases in cTnT (0.04 to 0.05 microg/L) but no detectable cTnI. Race time correlated inversely with cTnT (r = -0.65, p <0.01). Mean change in the number of abnormal echo segments after the race was 6.5 in those with a marked increase in cTnT and cTnI, 2.3 in those with a moderate increase in cTnT, and 1.7 in those with no increase. Ejection fraction decreased by an average of 24% after the race (p <0.002). Thus, ultraendurance exercise may cause myocardial damage as indicated by biochemical cardiac-specific markers and echocardiography. The cellular nature of this damage and whether it is transient or permanent is unclear at present.