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Chapel Hill, NC, United States

The University of North Carolina at Chapel Hill is a coeducational public research university located in Chapel Hill, North Carolina, United States. North Carolina has been consistently listed among the highest and best ranked universities in the United States and is one of the original eight Public Ivy schools that provide an Ivy League experience for a public schooling price. After being chartered in 1789, the university first began enrolling students in 1795, which allows it to be one of three schools to claim the title of the oldest public university in the United States.The first public institution of higher education in North Carolina, the school opened its doors to students on February 12, 1795. The university offers degrees in over 70 courses of study through fourteen colleges and the College of Arts and science. All undergraduates receive a liberal arts education and have the option to pursue a major within the professional schools of the university or within the College of Arts and science from the time they obtain junior status. Under the leadership of President Kemp Plummer Battle, in 1877 North Carolina became coeducational and began the process of desegregation in 1951 when African-American graduate students were admitted under Chancellor Robert Burton House. In 1952, North Carolina opened its own hospital, UNC Health Care, for research and treatment, and has since specialized in cancer care. The school's students, alumni, and sports teams are known as "Tar Heels".The campus of North Carolina is located in Chapel Hill, North Carolina, a university town. The campus covers a rather small 729 acres over Chapel Hill's downtown area, encompassing places like the Morehead Planetarium and the many stores and shops located on Franklin Street. Students can participate in over 550 officially recognized student organizations. The student-run newspaper The Daily Tar Heel has won national awards for collegiate media, while the student radio station WXYC provided the world's first internet radio broadcast. North Carolina is one of the charter members of the Atlantic Coast Conference, which was founded on June 14, 1953. Competing athletically as the Tar Heels, North Carolina has achieved great success in sports, most notably in men's basketball, women's soccer, and women's field hockey. Wikipedia.


Alperin M.,University of North Carolina at Chapel Hill | Hoehler T.,NASA
Science | Year: 2010

Our understanding of a major methane sink is based on studies of quiescent sediments and dynamic seeps. But do the same processes operate in both environments? Source


Wolberg A.S.,University of North Carolina at Chapel Hill
Haemophilia | Year: 2010

Growing evidence suggests that fibrin network structure and stability are important determinants of haemostasis and thrombosis, with alterations in fibrin structure implicated as a causative mechanism in various haemostatic and thrombotic disorders. In haemophilia, for example, deficiency of factor VIII or IX reduces the rate and peak of thrombin generation and produces coarse fibrin clots that show increased susceptibility to fibrinolysis. More recently, studies have shown significant effects of cellular activity and integrin composition on fibrin network and stability. Platelets support the formation of a dense, stable fibrin network via interactions between the αIIbβ3 integrin and the fibrin network, whereas tissue factor-bearing cells regulate fibrin structure and stability predominantly via procoagulant activity. Highly procoagulant extravascular cells (e.g. fibroblasts and smooth muscle cells) support the formation of dense fibrin networks that resist fibrinolysis, whereas unstimulated intravascular cells (e.g. endothelial cells) produce coarser networks that are susceptible to fibrinolysis. Moreover, cellular contributions produce heterogeneous clots in which fibrin network density and stability decrease with increasing distance from the cell surface. Together, these findings suggest that specific plasma and cellular mechanisms link thrombin generation, clot stability and haemostatic or thrombotic outcome. Understanding these mechanisms may provide new therapeutic targets in the management of bleeding and thrombotic disorders. © 2010 The Author. Journal Compilation © 2010 Blackwell Publishing Ltd. Source


Hayashi P.H.,University of North Carolina at Chapel Hill | Fontana R.J.,University of Michigan
Seminars in Liver Disease | Year: 2014

Patients with idiosyncratic drug-induced liver injury (DILI) can pose substantial diagnostic, prognostic, and therapeutic challenges to the practicing gastroenterologist. The presentation of DILI may vary from asymptomatic liver enzyme elevation to acute liver failure. Although most DILI resolves following drug discontinuation, up to 20% of patients progress to chronic DILI further challenging the clinicians diagnostic and management skills. Also, some medications can lead to advanced fibrosis, encephalopathy, and portal hypertension without significant elevation in liver enzymes during exposure. Finally, there are no objective tests to definitively diagnose DILI. Although causality assessment instruments are available, none are widely accepted or used in clinical practice. Therefore, the diagnosis of DILI depends on thorough and accurate history taking, follow-up of the patient's clinical course and excluding more common causes of liver injury. In this review, we discuss the variable clinical presentations, course, and diagnostic methods used to establish a diagnosis and prognosis in DILI. Copyright © 2014 by Thieme Medical Publishers, Inc. Source


Dorn S.D.,University of North Carolina at Chapel Hill
Clinical Gastroenterology and Hepatology | Year: 2016

Clinicians are required to report their performance on an ever-increasing number of quality measures. However, it is difficult to measure health care quality and it is unclear whether broadly applying accountability measures effectively improves care. This article considers these challenges and includes recommendations that may help gastroenterologists respond to demands for increased quality measurement. © 2016 AGA Institute. Source


Zeisel S.H.,University of North Carolina at Chapel Hill
International Journal of Women's Health | Year: 2013

Women, during pregnancy and lactation, should eat foods that contain adequate amounts of choline. A mother delivers large amounts of choline across the placenta to the fetus, and after birth she delivers large amounts of choline in milk to the infant; this greatly increases the demand on the choline stores of the mother. Adequate intake of dietary choline may be important for optimal fetal outcome (birth defects, brain development) and for maternal liver and placental function. Diets in many low income countries and in approximately one-fourth of women in high income countries, like the United States, may be too low in choline content. Prenatal vitamin supplements do not contain an adequate source of choline. For women who do not eat foods containing milk, meat, eggs, or other choline-rich foods, a diet supplement should be considered. © 2013 Zeisel, publisher and licensee Dove Medical Press Ltd. Source


Shaheen N.J.,University of North Carolina at Chapel Hill
American Journal of Gastroenterology | Year: 2013

Symptoms of gastroesophageal reflux are the only commonly used criterion for endoscopic screening for esophageal adenocarcinoma (EAC). Recent research has elucidated multiple other risk factors for both EAC and Barrett's esophagus (BE). Utilization of these risk factors may allow for the selection of a screening population with a much higher pre-test probability of disease. A recently developed risk-prediction model for BE is a significant step in the right direction; however, further refinements in this model will likely be necessary to optimize utility. Our inability to prognosticate cancer risk in BE does temper enthusiasm for increasing the pool of patients under endoscopic surveillance for BE, and again highlights the need for better, cheaper, and more accurate means of stratifying cancer risk in BE. Source


Garland E.L.,University of Utah | Howard M.O.,University of North Carolina at Chapel Hill
Psychotherapy and Psychosomatics | Year: 2013

Background: Chronic pain involves hypervigilance for pain-related stimuli. Selective attention to pain-related stimuli, known as pain attentional bias (AB), can exacerbate chronic pain, prolong suffering, and undermine quality of life. The aim of this study was to determine if a multimodal mindfulness-oriented intervention could significantly reduce pain AB among chronic pain patients receiving opioid analgesics. Methods: A total of 67 chronic pain patients were randomized to an 8-week Mindfulness-Oriented Recovery Enhancement (MORE) intervention or a social support group intervention and began treatment. A dot probe task was used to measure pain AB. Primary outcomes were pain AB scores for cues presented for 2,000 and 200 ms. Results: Prior to intervention, participants exhibited a significant bias towards pain-related cues presented for 2,000 ms, but no bias for cues presented for 200 ms. A statistically significant time × intervention condition interaction was observed for 2,000 ms pain AB, such that participants in MORE evidenced significantly reduced posttreatment pain AB relative to pretreatment levels, whereas no significant pre-post treatment changes in pain AB were observed for support group participants. Decreases in pain AB were associated with increased perceived control over pain and attenuated reactivity to distressing thoughts and emotions. Conclusion: Study findings provide the first indication that a mindfulness-oriented intervention may reduce pain AB among adults suffering from chronic pain. Given the magnitude of chronic pain in postindustrial societies, coupled with the dramatic escalation in prescription opioid misuse, future studies should evaluate MORE as a nonpharmacological means of addressing factors linked with chronic pain. © 2013 S. Karger AG, Basel. Source


Wolfenden R.,University of North Carolina at Chapel Hill
Cellular and Molecular Life Sciences | Year: 2014

Ever since the publication of Darwin's Origin of Species, questions have been raised about whether enough time has elapsed for living organisms to have reached their present level of complexity by mutation and natural selection. More recently, it has become apparent that life originated very early in Earth's history, and there has been controversy as to whether life originated in a hot or cold environment. This review describes evidence that rising temperature accelerates slow reactions disproportionately, and to a much greater extent than has been generally recognized. Thus, the time that would have been required for primordial chemistry to become established would have been abbreviated profoundly at high temperatures. Moreover, if the catalytic effect of a primitive enzyme (like that of modern enzymes) were to reduce a reaction's heat of activation, then the rate enhancement that it produced would have increased as the surroundings cooled, quite aside from changes arising from mutation (which is itself highly sensitive to temperature). Some nonenzymatic catalysts of slow reactions, including PLP as a catalyst of amino acid decarboxylation, and the CeIV ion as a catalyst of phosphate ester hydrolysis, have been shown to meet that criterion. The work reviewed here suggests that elevated temperatures collapsed the time required for early evolution on Earth, furnishing an appropriate setting for exploring the vast range of chemical possibilities and for the rapid evolution of enzymes from primitive catalysts. © 2014 Springer. Source


Nolin D.A.,University of North Carolina at Chapel Hill
Human Nature | Year: 2010

Exponential random graph modeling (ERGM) is used here to test hypotheses derived from human behavioral ecology about the adaptive nature of human food sharing. Respondents in all (n = 317) households in the fishing and sea-hunting village of Lamalera, Indonesia, were asked to name those households to whom they had more frequently given (and from whom they had more frequently received) food during the preceding sea-hunting season. The responses were used to construct a social network of between-household food-sharing relationships in the village. The results show that kinship, proximity, and reciprocal sharing all strongly increase the probability of giving food to a household. The effects of kinship and distance are relatively independent of each other, although reciprocity is more common among residentially and genealogically close households. The results show support for reciprocal altruism as a motivation for food sharing, while kinship and distance appear to be important partner-choice criteria. © 2010 Springer Science + Business Media, LLC. Source


Clemens J.C.,University of North Carolina at Chapel Hill
Astrophysical Journal Letters | Year: 2010

We present the discovery of photometric variations in the carbon-dominated atmosphere (hot DQ) white dwarf star SDSS J133710.19-002643.6. We find evidence for two low-amplitude, harmonically related periodicities at 169 s and 339 s, making it the fastest and smallest amplitude of the four known hot DQ variables and the only variable whose spectrum suggests the presence of hydrogen. The star's fundamental and harmonic amplitudes are roughly equal, and its pulse shape is similar to the other two members of the class with detected harmonics. Like the other variables, it appears relatively stable in frequency and amplitude.©2010. The American Astronomical Society. All rights reserved. Source


Borras T.,University of North Carolina at Chapel Hill
Journal of Ocular Pharmacology and Therapeutics | Year: 2014

Myocilin is a secreted glaucoma-associated protein, specifically induced by dexamethasone in human trabecular meshwork cells, where it was discovered. Myocilin is expressed in several tissues of the body, but it causes disease only in the eye. The protein contains two domains: an N-terminal region with significant homologies to nonmuscle myosin, and a C-terminal region, which is similar to the olfactomedin proteins. Forty percent of myocilin undergoes an intracellular endoproteolytic cleavage by calpain II, a calcium-dependent cysteine protease, which releases the 2 domains. The protein is known to interact with intracellular and extracellular matrix proteins, and some is released into the extracellular space associated with exosomes. Myocilin mutations are linked to glaucoma and induce elevated intraocular pressure. Most of the glaucoma-causative mutations map to the olfactomedin domain, which appears to be a critical domain for the function of the protein. Myocilin mutants are misfolded, aggregate in the endoplasmic reticulum, and are not secreted. Overexpression of myocilin and of its mutants in primary human trabecular meshwork cells triggers changes in the expression of numerous genes, many of which have been known to be involved in mechanisms important for the physiology and pathology of the tissue. Here we review recent studies from our laboratory and those of others that deal with trabecular meshwork genes, which are altered by the overexpression of wild-type and glaucoma-causative mutant myocilin genes. © 2014, Mary Ann Liebert, Inc. Source


Sartor R.B.,University of North Carolina at Chapel Hill
Alimentary Pharmacology and Therapeutics | Year: 2016

Background Gut microbiota dysbiosis contributes to the pathogenesis of inflammatory bowel diseases (IBD). Although the microbiota's role in IBD pathogenesis, specifically Crohn's disease (CD), provides a rationale for antibiotic treatment, antibiotic use in CD remains controversial. Rifaximin, traditionally identified as a nonsystemic bactericidal antibiotic, may be therapeutically beneficial for inducing CD remission. Aim To examine the role of rifaximin in the management of IBD and its potential mechanisms of action. Methods A literature search using the following strategy: ('inflammatory bowel disease' OR 'Crohn's' OR 'ulcerative'), 'rifaximin' AND ('barrier' OR 'translocation' OR 'adhesion' OR 'internalization' OR 'pregnane X'), AND 'pregnane X' AND ('Crohn's' OR 'ulcerative colitis' OR 'inflammatory bowel disease'). Results In vitro data suggest rifaximin mediates changes in epithelial cell physiology and reduces bacterial attachment and internalisation. In experimental colitis models, rifaximin antagonised the effects of tumour necrosis factor-α on intestinal epithelial cells by activating pregnane X receptor, which inhibits nuclear factor-κB-mediated proinflammatory mediators and induces detoxification genes (e.g. multidrug resistance 1 and cytochrome P450 3A4). Rifaximin also inhibits bacterial translocation into the mesenteric lymph nodes. Conclusion Accumulating evidence suggests that mechanisms of action of rifaximin in IBD may not be limited to direct bactericidal activity; therefore, rifaximin could potentially be redefined as a gut environment modulator. © 2015 John Wiley & Sons Ltd. Source


Wheeler S.B.,University of North Carolina at Chapel Hill
Journal of Adolescent Health | Year: 2010

Purpose: To determine whether higher self-esteem and higher academic performance among youth reduce the likelihood of early sexual intercourse and illegal substance use. Methods: Using data from waves I-III of the National Longitudinal Study of Adolescent Health, this study used multivariate logistic regression, stratified by gender and controlling for known covariates, to examine relationships between self-esteem and academic performance and youth decision-making, specifically self-reported initiation of sexual intercourse and use of illegal substances. Self-esteem was constructed as an ascending scale of 10 Likert-scaled survey items. Academic performance was assessed using the most recent grades from English, Math, Science, and History. Results: Among virginal adolescents, higher self-esteem at baseline had no effect on sexual debut 1 year later. However, higher self-esteem at baseline among females corresponded with a significantly lower likelihood of illegal substance use 1 year later (OR, .96; p = .003). In terms of academic performance at baseline, girls averaging "A" grades as compared with girls averaging "C" grades or lower were significantly less likely to initiate sexual intercourse 1 year later (OR, .52; p = .004). Additionally among girls, being an "A" student or a "B" student was associated with lower odds of illegal substance use, compared with students who averaged "C" grades or lower (p < .01). Among young boys, self-esteem and academic performance were not significantly predictive of illegal substance use. Conclusions: This study suggests that bolstering self-esteem and improving academic performance among young girls may have specific benefits in sexual decision-making and substance-related risk-taking. © 2010 Society for Adolescent Health and Medicine. All rights reserved. Source


Peden D.,University of North Carolina at Chapel Hill | Reed C.E.,Mayo Medical School
Journal of Allergy and Clinical Immunology | Year: 2010

Airborne allergens are the major cause of allergic rhinitis and asthma. Daily exposure comes from indoor sources, chiefly at home but occasionally at schools or offices. Seasonal exposure to outdoor allergens, pollens, and molds is another important source. Exposure to unusual substances at work causes occupational asthma, accounting for about 5% of asthma in adults. Indoor and outdoor air pollutants trigger airway inflammation and increase the severity of asthma. Diesel exhaust particles increase the production of IgE antibodies. Identification and reduction of exposure to allergens is a very important part of the management of respiratory allergic diseases. The first section of this chapter discusses domestic allergens, arthropods (mites and cockroaches), molds, and mammals (pets and mice). Indoor humidity and water damage are important factors in the production of mite and mold allergens, and discarded human food items are important sources of proliferation of cockroaches and mice. Means of identifying and reducing exposure are presented. The second section discusses outdoor allergens: pollens and molds. The particular plants or molds and the amount of exposure to these allergens is determined by the local climate, and local pollen and mold counts are available to determine the time and amount of exposure. Climate change is already having an important effect on the distribution and amount of outdoor allergens. The third section discusses indoor and outdoor air pollution and methods that individuals can take to reduce indoor pollution in addition to eliminating cigarette smoking. The fourth section discusses the diagnosis and management of occupational asthma. © 2010 American Academy of Allergy, Asthma & Immunology. Source


Beam K.S.,University of North Carolina at Chapel Hill
Journal of Perinatology | Year: 2014

Objective:Bronchopulmonary dysplasia (BPD) is the most common cause of pulmonary morbidity in premature infants and is associated with life-long morbidities. Developing drugs for the prevention of BPD would improve public health. We sought to determine characteristics of favorable randomized controlled trials (RCTs) of drugs for BPD prevention.Study Design:We searched MEDLINE and EMBASE from 1992 to 2014 using the MeSH terms 'BPD' and 'respiratory distress syndrome, newborn'. We included a Cochrane Library search to ensure inclusion of all available RCTs. We identified RCTs with BPD as a primary or secondary outcome and determined the definition of BPD used by the study. We determined whether a phase I or phase II study-to determine drug safety, efficacy or optimal dose-was performed before the RCT. Finally, we searched the Cochrane Library for meta-analyses for each drug and used the results of available meta-analyses to define a favorable versus unfavorable RCT.Result:We identified 2026 articles; 47 RCTs met our inclusion criteria encompassing 21 drugs; 5 of the drugs reduced the incidence of BPD. We found data from phase I or II studies for 16 of the drugs, but only 1 demonstrated a reduction of BPD.Conclusion:The majority of the drugs studied in RCTs failed to reduce the incidence of BPD. Performing early-phase studies before phase III trials might provide necessary information on drugs and drug doses capable of preventing BPD, thus informing the development of future RCTs.Journal of Perinatology advance online publication, 10 July 2014; doi:10.1038/jp.2014.126. Source


Abrahams S.W.,University of North Carolina at Chapel Hill
Journal of Human Lactation | Year: 2012

Background: The advent of social networking sites and other online communities presents new opportunities and challenges for the promotion, protection, and support of breastfeeding. This study examines the presence of infant formula marketing on popular US social media sites, using the World Health Organization International Code of Marketing of Breast-milk Substitutes (the Code) as a framework. Methods: We examined to what extent each of 11 infant formula brands that are widely available in the US had established a social media presence in popular social media venues likely to be visited by expectant parents and families with young children. We then examined current marketing practices, using the Code as a basis for ethical marketing. Results: Infant formula manufacturers have established a social media presence primarily through Facebook pages, interactive features on their own Web sites, mobile apps for new and expecting parents, YouTube videos, sponsored reviews on parenting blogs, and other financial relationships with parenting blogs. Violations of the Code as well as promotional practices unforeseen by the Code were identified. These practices included enabling user-generated content that promotes the use of infant formula, financial relationships between manufacturers and bloggers, and creation of mobile apps for use by parents. An additional concern identified for Code enforcement is lack of transparency in social media-based marketing. Conclusion: The use of social media for formula marketing may demand new strategies for monitoring and enforcing the Code in light of emerging challenges, including suggested content for upcoming consideration for World Health Assembly resolutions. © The Author(s) 2012. Source


Kahn R.,University of North Carolina at Chapel Hill
Health Affairs | Year: 2012

Type 2 diabetes prevention studies have shown that the onset of the disease can be delayed or prevented, chiefly by weight loss. But the current efforts to establish community-based lifestyle modification programs will not be very effective in preventing diabetes, largely because most overweight or obese people cannot maintain weight loss over time. A complex environment is driving greater food consumption along with less energy expenditure, making maintenance of weight loss extremely difficult. To improve the likelihood of achieving populationwide success in reducing the obesity pandemic, we need a better understanding of the biological processes that underlie the balance between intake and expenditure of energy. In the meantime, once diabetes develops, we can greatly reduce the likelihood of serious complications through early detection and proper medical management. Source


Servedio M.R.,University of North Carolina at Chapel Hill
Proceedings. Biological sciences / The Royal Society | Year: 2013

Although sexual selection is an important cause of display evolution, in socially monogamous species (e.g. many birds), displays continue after formation of the pair bond. Here, we consider that these displays evolve because they stimulate the partner to increase investment in offspring. Our study is motivated by elaborate mutual displays in species that are largely monomorphic and have long-term pair bonds (e.g. the great crested grebe, Podiceps cristatus) and by many empirical results evidencing that display manipulation affects parental investment. Using population genetic models, we show that a necessary condition for the permanent establishment of mutual displays in the pair bond is that the benefit of investment by the pair is more than twice that resulting from investment by a single individual. Pre-existing biases to respond to displays by increased investment are a necessary component of display evolution. We also consider examples where one sex (e.g. males) stimulates increased investment in offspring by the other sex. Here, display and additional investment cannot evolve permanently, but can increase and linger at high frequency for a long time before loss. We discuss how such transient effects may lead to the evolution of permanent displays as a result of evolution at additional loci. Source


Jensen E.,University of North Carolina at Chapel Hill
Maternal and Child Health Journal | Year: 2012

This research builds on literature that suggests a negative association between participation in the Supplemental Nutrition Program for Women, Infants, and Children (WIC) and breastfeeding. Variation in results at the national, regional, and state level has important policy implications for breastfeeding promotion through WIC. Using the 2007 National Immunization Survey dataset, Chi-square, ANOVA, and adjusted regression modeling techniques assess the relationship between WIC participation and breastfeeding initiation and duration. Adjusted regression models suggest a negative association between WIC participation and breastfeeding initiation rates (OR = 0.67, 95% CI: 0.61, 0.72). Of those who initiated breastfeeding, WIC participation was associated with a mean breastfeeding duration decrease of 0.63 months (95% CI: -0.86, -0.39). At the regional level, 3 of 7 regions showed a negative association between WIC participation and breastfeeding initiation. All of the regions indicated a negative association between WIC participation and breastfeeding duration. Out of 50 states, 13 had a statistically significant reduction in odds of initiation of breastfeeding and 10 had reduced duration of breastfeeding among participants of WIC when compared to non-participants. No state showed a positive association between WIC participation and breastfeeding. Regional and state differences in breastfeeding rates suggest that further research is needed to understand the role of national, regional, and state level policies which may undermine WIC's breastfeeding promotion efforts. Although WIC revised the food packages to create a stronger incentive for breastfeeding, a disincentive for breastfeeding may exist given the higher market value of the formula packages. © Springer Science+Business Media, LLC 2011. Source


Donohue J.F.,University of North Carolina at Chapel Hill | Jain N.,Maricopa Medical Center
Respiratory Medicine | Year: 2013

Until recently, no point-of-care tool was available for assessing the underlying airway inflammation associated with asthma. Fractional exhaled nitric oxide (FeNO) emerged in the last decade as an important biomarker for asthma assessment and management. Evidence also indicates that FeNO is most accurately classified as a marker of T-helper cell type 2 (Th2)-mediated airway inflammation with a high positive and negative predictive value for identifying corticosteroid-responsive airway inflammation. This manuscript evaluates the evidence for FeNO as a predictor of Th2-mediated corticosteroid-responsive airway inflammation and presents the results of a meta-analysis of three adult studies comparing asthma exacerbation rates with FeNO-based versus clinically-based asthma management algorithms, one of which was not included in a 2012 Cochrane meta-analysis. The primary purpose of the updated meta-analysis was to evaluate asthma exacerbation rates. The results demonstrate that the rate of exacerbations was significantly reduced in favor of FeNO-based asthma management (mean treatment difference = -0.27; 95% CI [-0.42, -0.12] as was the relative rate of asthma exacerbations (relative rate = 0.57; 95% CI [0.41, 0.80]). In summary, FeNO has value for identifying patients with airway inflammation who will and will not respond to corticosteroids. Importantly, the use of FeNO in conjunction with clinical parameters is associated with significantly lower asthma exacerbation rates compared with asthma managed using clinical parameters alone. Together these data indicate that FeNO testing has an important role in the assessment and management of adult asthma. Further studies will continue to define the exact role of FeNO testing in adult asthma. © 2013 Elsevier Ltd. All rights reserved. Source


Jones S.M.,University of Arkansas for Medical Sciences | Burks A.W.,University of North Carolina at Chapel Hill
Journal of Allergy and Clinical Immunology | Year: 2013

The field of food allergy is continually changing, with advances in clinical care to better understand the mechanisms of disease and in possible new diagnostics and treatment models. The development of several new guidelines that focus on improving the standardization of the diagnosis and management of food allergy has helped to further guide clinicians in providing optimized care for children and adults with food allergy around the world. Much of this work has been made possible through the collaborative efforts of advocacy organizations, industry, and government with clinicians and researchers in the fields of allergy and immunology. We have been able to advance our understanding of disease mechanisms and to help close gaps in knowledge and resolve misconceptions in the treatment of food allergy. This review will focus on the concepts of a holistic approach to food allergy that is working to improve CARE for subjects with food allergy, including new advances in clinical care, advocacy, research, and education. © 2012 American Academy of Allergy, Asthma & Immunology. Source


Lee K.-H.,University of North Carolina at Chapel Hill
Journal of Natural Products | Year: 2010

Medicinal plants have long been an excellent source of pharmaceutical agents. Accordingly, the long-term objectives of the author's research program are to discover and design new chemotherapeutic agents based on plant-derived compound leads by using a medicinal chemistry approach, which is a combination of chemistry and biology. Different examples of promising bioactive natural products and their synthetic analogues, including sesquiterpene lactones, quassinoids, naphthoquinones, phenylquinolones, dithiophenediones, neo-tanshinlactone, tylophorine, suksdorfin, DCK, and DCP, will be presented with respect to their discovery and preclinical development as potential clinical trial candidates. Research approaches include bioactivity- or mechanism of action-directed isolation and characterization of active compounds, rational drug design-based modification and analogue synthesis, and structure-activity relationship and mechanism of action studies. Current clinical trial agents discovered by the Natural Products Research Laboratories, University of North Carolina include bevirimat (dimethyl succinyl betulinic acid), which is now in phase IIb trials for treating AIDS. Bevirimat is also the first in a new class of HIV drug candidates called "maturation inhibitors". In addition, an etoposide analogue, GL-331, progressed to anticancer phase II clinical trials, and the curcumin analogue JC-9 is in phase II clinical trials for treating acne and in development for trials against prostate cancer. The discovery and development of these clinical trial candidates will also be discussed. © 2010 American Chemical Society and American Society of Pharmacognosy. Source


Algoe S.B.,University of North Carolina at Chapel Hill | Stanton A.L.,University of California at Los Angeles
Emotion | Year: 2012

Theory and evidence suggest that everyday positive emotions may be potent factors in resilience during periods of chronic stress, yet the body of evidence is scant. Even less research focuses on the adaptive functions of specific positive emotions in this critical context. In the current research, 54 women with metastatic breast cancer provided information about their emotional responses to benefits received to test hypotheses regarding the social functions of gratitude. One set of analyses provide support for the hypothesized role of ego-transcendence in feeling gratitude upon receipt of a benefit from another person. As predicted, in a second set of analyses, grateful responding to received benefits predicted an increase in perceived social support over three months only for women low in ambivalence over emotional expression. These findings add to evidence regarding the social causes and consequences of gratitude, supporting a view of gratitude as an other-focused positive emotion that functions to promote high-quality relationships. Discussion focuses on the chronically stressful context as an important testing ground for theory on gratitude and other positive emotions. © 2011 American Psychological Association. Source


Mulcahy J.J.,University of Arizona | Carson III C.C.,University of North Carolina at Chapel Hill
European Urology | Year: 2011

Background: Diabetic patients may be more prone to penile-implant infections than other men. Objective: We sought to determine whether revision surgeries due to infection were less common in diabetic men after implantation of an inflatable penile prosthesis (IPP) impregnated with minocycline and rifampin (M/R) versus a nonimpregnated prosthesis. Design, setting, and participants: Infection-related revisions for M/R-impregnated and nonimpregnated implants were compared during a retrospective review of patient-implant and removal data recorded in the manufacturer's database. The data set included men with diabetes as an etiology of erectile dysfunction and who were implanted with their first IPPs between 2001 and 2008. Intervention: All men received three-piece IPPs. Measurements: The number of first revisions due to infection reported at any time during the study period were summarized for each group. Freedom from infection-related revisions for initial M/R-impregnated implants were compared to nonimpregnated implants with ≤84 mo of follow-up using life-table survival analysis. Infection-free survival was also compared for diabetics versus nondiabetics. Results and limitations: Mean age was 59.1 yr for the 6071 diabetic men in the M/R-impregnated group. The nonimpregnated group included 624 diabetics with a mean age of 57.6 yr. Initial revisions due to infection were reported for 1.47% of M/R-impregnated versus 4.17% of nonimpregnated implants. At 7 yr, the rate of infection-related revisions was significantly lower for M/R-impregnated (1.62%) than for nonimpregnated implants (4.24%; log-rank p < 0.0001). Diabetic men had a significantly higher rate of revisions due to infection at 7 yr (1.88%) than men without diabetes (1.53%; log-rank p = 0.0052). Conclusions: This long-term evidence from the largest known database of diabetic IPP recipients establishes that the use of an antibiotic-impregnated IPP can decrease revisions due to infection. Reducing the incidence of this devastating complication represents a significant medical advance in erectile restoration for diabetic patients. © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. Source


Sheldon G.F.,University of North Carolina at Chapel Hill
Academic Medicine | Year: 2013

In this issue, Kastor discusses the challenges and responsibilities of a contemporary chair of medicine as described in interviews of 44 chairs. As a chair of surgery at the University of North Carolina at Chapel Hill for 17 years, the author of this commentary uses his own experiences to reflect on how the insights presented in Kastor's commentary can apply to department chairs in other specialties. Elements from Kastor's commentary, as well as additional observations from the author's tenure, may be sources of advice to future chairs of any department. The author concludes that, despite a changing health care environment and other significant leadership challenges, being a department chair is a rewarding job with many opportunities to pursue worthwhile objectives. Source


Muenzer J.,University of North Carolina at Chapel Hill
Rheumatology | Year: 2011

The mucopolysaccharidoses (MPSs) are a group of rare, inherited lysosomal storage disorders that are clinically characterized by abnormalities in multiple organ systems and reduced life expectancy. The MPSs are heterogeneous, progressive disorders. Patients typically appear normal at birth, but during early childhood they experience the onset of clinical disease, including skeletal, joint, airway and cardiac involvement, hearing and vision impairment, and mental retardation in the severe forms of MPS I, MPS II and MPS VII and all subtypes of MPS III. There are two treatment options for patients with MPS that are directed at the underlying pathophysiology: haematopoietic stem cell transplantation, which is useful for selected patients, and recombinant i.v. enzyme replacement therapy, which is available for MPS I, II and VI. Early diagnosis and treatment can improve patient outcomes and may reduce the disease burden on patients and caregivers. As skeletal and joint abnormalities are characteristic of many patients with MPS, rheumatologists are positioned to recognize the features of the disease and to facilitate early diagnosis and referral. In this overview, the clinical features of the MPS disorders and a brief review of treatment options will be presented in order to aid the rheumatologist in recognizing the features of these rare genetic disorders. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. Source


Ross MacDonald J.,University of North Carolina at Chapel Hill
Journal of Physics Condensed Matter | Year: 2012

Several important ambiguities in immittance spectroscopy (IS) model data-fitting results are identified and illustrated by means of complex-nonlinear-least-squares (CNLS) fits of experimental and synthetic frequency response data. A well-known intrinsic ambiguity, following from Maxwells electromagnetic equations, arises from the indistinguishability in external measurements of conduction and displacement currents. Usual fit models for either dielectric or conductive-system situations, such as the DavidsonCole one, only involve a strength parameter, a dielectric constant, a characteristic relaxation time, and a fractional exponent and lead to no additional ambiguities. But the situation is different for more powerful and useful general models, such as ordinaryor anomalous diffusion PoissonNernstPlanck ones: PNP and PNPA, used here, whose historical background, current status, and applicability are described and discussed herein. They apply to two different kinds of experimental IS situations and involve several additional, potentially free fit parameters, such as the mobilities of positive and negative charge carriers, and generationrecombination parameters that determine the partial or complete dissociation of a neutral entity of concentration N 0 into positive and negative charge carriers of equal concentration, c 0. Then, several additional ambiguities appear that may require information about the material system involved for their adequate resolution. © 2012 IOP Publishing Ltd. Source


Kahn R.,University of North Carolina at Chapel Hill | Davidson M.B.,Drew University
Diabetes Care | Year: 2014

Efforts to reduce the burden of type 2 diabetes include attempts to prevent or delay the onset of the disease. Landmark clinical trials have shown that lifestyle modification programs focused on weight loss can delay the onset of type 2 diabetes in subjects at high risk of developing the disease. Building on this knowledge, many community-based studies have attempted to replicate the trial results and, simultaneously, payers have begun to cover diabetes prevention services. This article focuses on the evidence supporting the premise that community prevention efforts will be successful. Unfortunately, no study has shown that diabetes can be delayed or prevented in a community setting, and efforts to replicate the weight loss achieved in the trials have been mostly disappointing. Furthermore, both the clinical trials and the community-based prevention studies have not shown a beneficial effect on any diabetes-related clinical outcome. While the goal of diabetes prevention is extremely important, the absence of any persuasive evidence for the effectiveness of community programs calls into question whether the use of public funds or national prevention initiatives should be supported at this time. © 2014 by the American Diabetes Association. Source


Flynn M.R.,University of North Carolina at Chapel Hill
Annals of Occupational Hygiene | Year: 2010

A new method for estimating the mean and standard deviation from censored exposure data is presented. The method WMAX treats the censored data as variables in a constrained optimization problem. Values for the censored data are calculated by maximizing the Shapiro-Wilk W statistic subject to the constraint that the values are between 0 and the limit of detection (or other censoring limit). The methodology is illustrated here with the Microsoft Excel Solver tool using real exposure data sets subject to repeated censoring. For the data sets explored here, the WMAX estimates are comparable to those obtained using the restricted maximum likelihood method based on bias as the performance index. Source


Story W.T.,University of North Carolina at Chapel Hill
Health and Place | Year: 2014

This study examines the association between social capital and the utilization of antenatal care, professional delivery care, and childhood immunizations using a multilevel analytic sample of 10,739 women who recently gave birth and 7403 children between one and five years of age in 2293 communities and 22 state-groups from the 2005 India Human Development Survey. Exploratory factor analysis was used to create and validate six social capital measures that were used in multilevel logistic regression models to examine whether each form of social capital had an independent, contextual effect on health care use. Results revealed that social capital operated at the community level in association with all three care-seeking behaviors; however, the results differed based on the type of health care utilized. Specifically, components of social capital that led to heterogeneous bridging ties were positively associated with all three types of health care use, whereas components of social capital that led to strong bonding ties were negatively associated with the use of preventive care, but positively associated with professional delivery care. © 2014 Elsevier Ltd. Source


Despite improvements in automotive safety, motor vehicle collision (MVC)-related facial fractures remain common and represent preventable injuries. This study examines the changing characteristics of facial fractures treated at a regional, level I trauma center, from 2005 to 2010. Methods: We identified all patients with facial fractures admitted to our hospital, from 2005 to 2010, by querying the North Carolina Trauma Registry, using International Classification of Diseases, Ninth Revision codes. Prospectively collected data, sorted by year, were descriptively analyzed for demographics, referral patterns, etiology, anatomic location, and clinical outcomes. Results: Number of patients with facial fractures increased from 201 per year to 263 per year (total n = 1508). Although transport distances remained constant at ∼85 miles, standard deviation increased from 37 to 68 miles. Transport time increased from 87 to 119 minutes. Referrals came from 28 surrounding counties in 2005 and 43 counties in 2010. Regarding etiology, MVCs decreased from 40% to 27%, all-terrain vehicle crashes decreased from 6% to 2%, falls increased from 8% to 19%, and bicycle accidents increased from 3% to 6%. Regarding anatomic location, frontal sinus fractures increased from 8% to 37%, zygomaticomaxillary fractures increased from 9% to 18%, nasoethmoid fractures decreased from 12% to 6%, orbital floor fractures decreased from 6% to 3%, and mandible fractures decreased from 28% to 18%. Single-site fractures increased from 75% to 90%. Length of intensive care unit and hospital stay remained stable at 3 and 7 days, respectively. Conclusions: Despite a decrease in MVC-related facial fractures, the overall increase in facial fractures referred to our trauma center is due to a growing number of patient transfers from rural hospitals, where a paucity of qualified surgeons may exist. Copyright © 2012 by Lippincott Williams & Wilkins. Source


Adams K.F.,University of North Carolina at Chapel Hill
Heart Failure Reviews | Year: 2010

Dramatic advances in molecular biology dominated twentieth century biomedical science and delineated the function of individual genes and molecules in exquisite detail. However, biological processes cannot be fully understood based on the properties of individual genes and molecules alone, since these elements act in concert to enable the specific functions that make for living cells and organisms. The discipline of systems biology provides a novel conceptual framework for understanding biological phenomenon. Systems biology synthesizes information concerning the interactions of genes and molecules and allows characterization of the supramolecular networks and functional modules that represent the most essential aspects of cell organization and physiology. Source


Key N.S.,University of North Carolina at Chapel Hill
Thrombosis Research | Year: 2010

There has recently been intense interest in the clinical measurement of tissue factor (TF)-positive microparticles (MPs) in clinical disease states. This interest has been driven by the demonstration of an putative role for circulating TF-positive MPs in animal models of thrombus propagation. Both immunological and functional assays for MP-TF have been described. While each approach has its own advantages and drawbacks, neither has yet been truly established as the 'gold standard'. Heterogeneity of TF-bearing MPs, such as the variable co-expression of surface phosphatidylserine, may determine not only their procoagulant potential, but also additional properties including rate of clearance from the circulation. © 2009 Elsevier Ltd. All rights reserved. Source


Richardson D.B.,University of North Carolina at Chapel Hill
Occupational and Environmental Medicine | Year: 2010

Objective: To discuss the use of discrete time hazards models for the analysis of occupational and environmental cohort data. Methods: Analytical data structures and regression methods for discrete time hazards models are described. This approach is illustrated via analyses of data from a study of mortality in a cohort of chemical workers exposed to dioxin. Results and conclusions: Analyses employing a discrete time hazards model facilitate examination of observed and expected counts, the calculation of attributable fractions, and empirical description of the estimated hazard rates. In addition, this approach can be used to fit non-multiplicative models, such as the linear hazards ratio model (which has been employed in epidemiological analyses of a variety of environmental and occupational exposures). Source


De Kok I.J.,University of North Carolina at Chapel Hill
The International journal of oral & maxillofacial implants | Year: 2011

The mandibular two-implant overdenture has been shown to be a highly successful treatment. However, overdenture patients who desire a fixed prosthesis may not be satisfied with a removable overdenture. This prospective study sought to compare prosthetic outcomes, patient satisfaction, and survival rates of implants between two-implant-supported overdentures (IODs) and three-implant-supported fixed dentures (ISFDs). Twenty completely edentulous patients were randomly and equally assigned to two groups. New conventional complete dentures were made, and the mandibular denture was used as a surgical guide during implant placement. Implants were placed in one stage, followed by a mandibular denture soft reline (provisional loading). Ball attachments were inserted at 8 weeks, and ISFDs were delivered at 16 weeks. IODs were connected to the attachments at 8 weeks, using each patients's existing denture. The definitive ISFDs were fabricated using computer-aided design/computer-assisted manufacture milled titanium frameworks and acrylic resin base and teeth. Patient satisfaction and panoramic radiographs were investigated at 6 and 12 months. Both treatments had significant and positive effects on patient satisfaction and quality of life. None of the 50 implants placed had failed at 12 months of follow-up; therefore, the implant survival rate was 100%. Prosthetic complications were generally rare and easily manageable. Both the treatment modalities-the ISFD supported by three implants and the IOD supported by two implants-significantly and similarly improved patient satisfaction and oral health-related quality of life, and prosthetic complications were relatively rare for both treatments. Three implants can be used to support a mandibular fixed prosthesis; however, a longer observation period is needed to validate this treatment modality. Source


Margolis D.M.,University of North Carolina at Chapel Hill | Hazuda D.J.,Merck And Co.
Current Opinion in HIV and AIDS | Year: 2013

PURPOSE OF REVIEW: A serious effort has begun to develop therapies that may be capable of eradicating established HIV infection in man. Because of the biological complexity of HIV infection that persists despite potent antiretroviral therapy, it is widely believed that if such therapies can be developed they will involve complex, multimodality approaches. We highlight some of the recent studies in this effort. RECENT FINDINGS: An inhibitor of histone deacetylase has been demonstrated to disrupt latency in man, and new histone deacetylase inhibitors have been identified. Other potential targets, such as histone methyltransferase, protein kinase C, and BRD4, have been recently studied. Model systems, both in primary cells and in animal models, are beginning to be validated. In the clinic, immune-based therapies to aid in the clearance of persistent infection are also being tested. SUMMARY: It is too early to know what combination eradication therapies for HIV infection will look like in the future, but candidate therapies and model systems to perform preclinical validation are beginning to take shape. © 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins. Source


Richardson D.B.,University of North Carolina at Chapel Hill
Epidemiology | Year: 2010

BACKGROUND:: Occupational cohort mortality studies rarely include information on smoking history. Consequently, smoking is often an unmeasured potential confounder in analyses of associations between occupational exposures and lung cancer. Several authors have recommended sensitivity analyses to assess confounding by smoking, which require speculation about the prevalence of smokers in different occupational exposure groups. METHODS:: A method of adjustment for confounding by smoking is proposed in which the target parameter of interest (the log hazard ratio for lung cancer contrasting exposed to unexposed workers, adjusted for smoking) is approximated by the difference between the crude exposure-disease associations for lung cancer and chronic obstructive pulmonary disease. A polytomous logistic regression method is used to derive appropriate confidence intervals. The performance of this adjustment approach is assessed via direct calculations. RESULTS:: Under the scenarios considered, 90% or more of the bias due to confounding by smoking was removed via this adjustment in the absence of smoking data. CONCLUSIONS:: This approach to adjustment for confounding by smoking can be employed without explicitly positing the distribution of smoking with respect to occupational exposure. The approach is easily implemented in analyses of occupational cohort data and should facilitate quantitative assessments of bias due to unmeasured confounding by smoking in occupational studies of lung cancer. Copyright © 2010 by Lippincott Williams & Wilkins. Source


Sandelowski M.,University of North Carolina at Chapel Hill
Nursing Inquiry | Year: 2015

Driven by an impetus to standardize, numerous checklists have been devised to address quality in qualitative research, but these standards and the mindset driving them offer no language with which to speak about taste, or the aesthetic sensibilities that play such a key role in evaluating the goodness of any object. In this article, quality appraisal in qualitative research is considered in the context of taste, that is, in the discernment involved in judging the value of research and in the recognition of the key role reviewer preferences, sensibilities and membership in one or more taste communities play in these judgements. The evaluation of a study is accomplished by evaluating one or more reports from that study, and such reports may be conceived as art forms amenable to the same criteria for appraisal as poems or paintings. Taste implies judgements about the quality of objects and a person's ability to sift through and select from a store of knowledge that knowledge appropriate to judge its value. What binds a community of practitioners (here reviewers of qualitative studies) together is taste-making, or the constant refinements of judgements concerning what constitutes good and bad practice. © 2014 John Wiley & Sons Ltd. Source


Margolis D.M.,University of North Carolina at Chapel Hill
Current HIV/AIDS Reports | Year: 2010

Rarely HIV type 1 establishes proviral latency within the host genome, maintained with little or no viral gene expression. This state has been quantitated in peripheral blood and lymphoid tissues of HIV-infected patients, appearing in the earliest days of infection. These rare cellular reservoirs are unaffected by current antiretroviral therapy and unrecognized by the host immune response, and can regenerate disseminated viremia if therapy is interrupted. Proviral latency may be established when a newly HIV-infected cell exits the cell cycle and returns to the resting state. Rarely, direct infection of resting cells may also occur. Multiple molecular mechanisms appear to underlie the establishment and maintenance of persistent, latent HIV infection, most frequent in the resting central memory CD4+ T cell. Interrupting processes that maintain latency may allow therapeutic attack of this primary form of persistent HIV infection, but a better understanding of relevant mechanisms in vivo is needed. © 2010 Springer Science+Business Media, LLC. Source


Muss H.B.,University of North Carolina at Chapel Hill
The oncologist | Year: 2011

In the U.S., cancer is a disease of aging. The average 65-year-old patient has an anticipated life expectancy of 20 years, and clinicians should take this into account when making breast cancer management decisions. However, older breast cancer patients can present with wide variations in health status, and treatment in older patients should therefore include a careful evaluation of comorbidities, physical function, polypharmacy, and other issues that could potentially impact a patient's ability to undergo chemotherapy without excessive risk. Evaluation tools are under development, including potential molecular markers, to identify which older patients are the best candidates for chemotherapy, as well as those more susceptible to actually developing cancer. Standard chemotherapy regimens are just as effective in older patients as they are in the younger population, and can substantially prolong life expectancy when used in the right patients. This article discusses breast cancer in seniors, including the epidemiology of breast cancer in these patients, the potential impact of comorbidities, and effective adjuvant therapy in selected older patients. Source


Perou C.M.,University of North Carolina at Chapel Hill
The oncologist | Year: 2011

Research focused on the analysis and classification of breast tumors, primarily using DNA microarrays and patterns of gene expression, has resulted in distinct tumor subtypes. Although no knowledge of patient survival or outcomes was used to derive these gene descriptions, these different classes based upon patterns of gene expression have important prognostic implications. Predictive markers in estrogen receptor-negative and triple-negative disease will be particularly important because in the absence of therapy, these tumor subtypes tend to have a poor prognosis. In addition, the claudin-low subgroup has been found to be common within the triple-negative cancers and may have further prognostic and therapeutic implications. Patients with triple-negative breast cancer do benefit from chemotherapy, but better treatment options are needed that are less toxic, reduce the risk of disease progression, and are more targeted to this patient population. Potential treatments include poly (ADP-ribose) polymerase inhibitors, and therapies that target cancer stem cells could also have an important impact in these patients. This article will focus on the molecular stratification of triple-negative breast cancers and the therapeutic implications of these classifications. Source


Ringel-Kulka T.,University of North Carolina at Chapel Hill
American Journal of Gastroenterology | Year: 2015

OBJECTIVES:Dysbiosis leading to abnormal intestinal fermentation has been suggested as a possible etiological mechanism in irritable bowel syndrome (IBS). We aimed to investigate the location and magnitude of altered intestinal bacterial fermentation in IBS and its clinical subtypes.METHODS:IBS patients who satisfied the Rome III criteria (114) and 33 healthy controls (HC) were investigated. Intestinal fermentation was assessed using two surrogate measures: intestinal intraluminal pH and fecal short-chain fatty acids (SCFAs). Intraluminal pH and intestinal transit times were measured in the small and large bowel using a wireless motility capsule (SmartPill) in 47 IBS and 10 HC. Fecal SCFAs including acetate, propionate, butyrate, and lactate were analyzed by capillary gas chromatography in all enrolled subjects. Correlations between intestinal pH, fecal SCFAs, intestinal transit time, and IBS symptom scores were analyzed.RESULTS:Colonic intraluminal pH levels were significantly lower in IBS patients compared with HC (total colonic pH, 6.8 for IBS vs. 7.3 for HC, P=0.042). There were no differences in total and segmental pH levels in the small bowel between IBS patients and HC (6.8 vs. 6.8, P=not significant). The intraluminal colonic pH differences were consistent in all IBS subtypes. Total SCFA level was significantly lower in C-IBS patients than in D-IBS and M-IBS patients and HC. The total SCFA level in all IBS subjects was similar with that of HC. Colonic pH levels correlated positively with colon transit time (CTT) and IBS symptoms severity. Total fecal SCFAs levels correlated negatively with CTT and positively with stool frequency.CONCLUSIONS:Colonic intraluminal pH is decreased, suggesting higher colonic fermentation, in IBS patients compared with HC. Fecal SCFAs are not a sensitive marker to estimate intraluminal bacterial fermentation.Am J Gastroenterol advance online publication, 25 August 2015; doi:10.1038/ajg.2015.220. © 2015 American College of Gastroenterology Source


Powers W.J.,University of North Carolina at Chapel Hill
Stroke | Year: 2010

Nontraumatic intracerebral hemorrhage (ICH) remains a devastating condition with 30-day mortality rates of 35% to 52%. Until the pathophysiology of this condition is better understood, it will not be possible to develop effective therapies. Studies of cerebral blood flow and metabolism in patients with acute ICH show similar abnormalities to those that occur in patients with traumatic brain injury, thus raising the question of whether there are common mechanisms of injury shared by the 2 conditions. In both ICH and traumatic brain injury, there is an early reduction in the cerebral metabolic rate of oxygen without ischemia, mitochondrial dysfunction, and transient focal increases in regional glucose metabolism that occur after a few days. ICH and traumatic brain injury share barotrauma from pressure waves that propagate through the intracranial contents as a common mechanism of brain injury. Recent data demonstrating contralateral hemispheric damage in patients with acute ICH provide further support for this theory of common injury mechanisms. © 2010 American Heart Association, Inc. Source


VanderWeele T.J.,Harvard University | Robinson W.R.,University of North Carolina at Chapel Hill
Epidemiology | Year: 2014

We consider several possible interpretations of the "effect of race" when regressions are run with race as an exposure variable, controlling also for various confounding and mediating variables. When adjustment is made for socioeconomic status early in a person's life, we discuss under what contexts the regression coefficients for race can be interpreted as corresponding to the extent to which a racial inequality would remain if various socioeconomic distributions early in life across racial groups could be equalized. When adjustment is also made for adult socioeconomic status, we note how the overall racial inequality can be decomposed into the portion that would be eliminated by equalizing adult socioeconomic status across racial groups and the portion of the inequality that would remain even if adult socioeconomic status across racial groups were equalized. We also discuss a stronger interpretation of the effect of race (stronger in terms of assumptions) involving the joint effects of race-associated physical phenotype (eg, skin color), parental physical phenotype, genetic background, and cultural context when such variables are thought to be hypothetically manipulable and if adequate control for confounding were possible. We discuss some of the challenges with such an interpretation. Further discussion is given as to how the use of selected populations in examining racial disparities can additionally complicate the interpretation of the effects. Copyright © 2014 by Lippincott Williams & Wilkins. Source


Atieh M.A.,University of North Carolina at Chapel Hill
The International journal of oral & maxillofacial implants | Year: 2012

Dental implant therapy for posterior partial edentulism may utilize short implants. The advantages of short implants include the ability to avoid the additional surgical procedures that would be required to place longer implants. The aim of this study was to systematically review studies concerning dental implants of ≤ 8.5 mm placed in the posterior maxilla and/or mandible to support fixed restorations. English-language articles published between 1992 and May 2011 were identified electronically and by hand search of the PubMed, Embase, and Cochrane libraries. Data were extracted and compared statistically. Forest plots were generated to compare outcomes of short versus long implants. An initial screening of 1,354 studies led to direct evaluation of 401 articles. Of these, 33 met the research criteria: 5 randomized clinical studies; 16 prospective, nonrandomized, noncontrolled studies; 12 retrospective, nonrandomized studies; and 1 study with both prospective and retrospective data. These studies indicated that there is no significant difference in the reported survival of short versus long implants. Failure of 59 of 2,573 short implants at 1 year was recorded, with 71% of them failing before loading. Only 101 short implants were followed for 5 years. The initial survival rate for short implants for posterior partial edentulism is high and not related to implant surface, design, or width. Short implants may constitute a viable alternative to longer implants, which may often require additional augmentation procedures. Source


Kole A.J.,University of North Carolina at Chapel Hill
Cell death & disease | Year: 2013

Neurons completely transform how they regulate cell death over the course of their lifetimes. Developing neurons freely activate cell death pathways to fine-tune the number of neurons that are needed during the precise formation of neural networks. However, the regulatory balance between life and death shifts as neurons mature beyond early development. Mature neurons promote survival at all costs by employing multiple, often redundant, strategies to prevent cell death by apoptosis. This dramatic shift from permitting cell death to ensuring cellular survival is critical, as these post-mitotic cells must provide neuronal circuitry for an organism's entire lifetime. Importantly, as many neurodegenerative diseases afflict adult neuronal populations, the survival mechanisms in mature neurons are likely to be either reversed or circumvented during neurodegeneration. Examining the adaptations for inhibiting apoptosis during neuronal maturation is key to comprehending not just how neurons survive long term, but may also provide insight for understanding how neuronal toxicity in various neurodegenerative diseases may ultimately lead to cell death. Source


Slade G.D.,University of North Carolina at Chapel Hill
Community dentistry and oral epidemiology | Year: 2012

To review population-based research into oral health-related quality of life. Narrative review of selected publications. In the 1970s, there were two incentives to assess nonclinical aspects of health: (i) a desire to understand the impacts of disease on individuals' quality of life; and (ii) a search for population-level measures that might better quantify the impact of health care systems on populations. Dental researchers responded to those incentives, creating dozens of questionnaires that assess individuals' ratings of subjective oral health and quality of life. This has been a boon for clinical dental research, for example, by showing marked improvements in subjective oral health in patients receiving implant-supported dentures. Also, health surveys show poorer subjective oral health among disadvantaged population groups. However, the same measures show only modest benefits of general dental care. Furthermore, several population surveys show that today's young adults, who grew up with widespread exposure to preventive dental programs, have poorer subjective oral health than earlier generations that experienced unprecedented levels of oral disease. Yet to materialize is the hope that 'socio-dental indicators' of subjective oral health might provide a meaningful metric to demonstrate population-level benefits of dental care. A fundamental limitation is that population health is a contextual measure, not merely the aggregated health status of individuals within the population. While researchers have successfully broken with clinical dogma by assessing subjective dimensions of individuals' oral health, they have failed to explicitly ask people to assess the oral health of the community in which they live. © 2012 John Wiley & Sons A/S. Source


Dellon E.S.,University of North Carolina at Chapel Hill
Current Opinion in Gastroenterology | Year: 2012

Purpose of review: To present the clinical, endoscopic, and histologic features of eosinophilic esophagitis (EoE), review the current diagnostic guidelines for EoE, and present an approach for diagnosis of EoE. It will also highlight selected techniques that are under development that may be useful in the future for diagnosis of EoE. Recent findings: Recently updated guidelines emphasize that EoE is a clinicopathologic condition. Specifically, three criteria must be met to diagnose EoE: clinical symptoms of esophageal dysfunction; an esophageal biopsy with a maximum eosinophil count of at least 15 eosinophils per high-power microscopy field, with few exceptions; and exclusion of other possible causes of esophageal eosinophilia, including proton-pump inhibitor responsive esophageal eosinophilia (PPI-REE). A PPI trial is typically required both to assess for PPI-REE and to evaluate for the presence of concomitant gastroesophageal reflux disease. Summary: EoE is a chronic, immune-mediated disorder. Because no single symptom, endoscopic finding, or histopathologic feature is pathognomonic, diagnosis can be challenging. In the future, symptom scores, tissue or serum biomarkers, and genetic testing may play a role in diagnosis, but these methods have yet to be validated and are not yet recommended for routine clinical use. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Viera A.J.,University of North Carolina at Chapel Hill
Journal of the American Board of Family Medicine | Year: 2012

Resistant hypertension (RH) is defined as blood pressure above a goal despite adherence to at least 3 optimally dosed antihypertensive medications of different classes, one of which is a diuretic. Evaluation of possible RH begins with an assessment of adherence to medications. The white-coat effect should be ruled out by out-of-office blood pressure monitoring. Obesity, heavy alcohol intake, and interfering substances all contribute to RH. Dietary sodium restriction is an important part of management. RH may be secondary to problems such as renal disease, obstructive sleep apnea, or aldosteronism, and testing for these conditions should be considered. Adequate diuretic treatment is a key part of therapy. Chlorthalidone is more effective than hydrochlorothiazide in reducing blood pressure because it is more potent and lasts longer. In addition, it may reduce cardiovascular events to a greater extent than hydrochlorothiazide. When glomerular filtration rate is <30 mL/min, a loop diuretic usually is needed. The addition of spironolactone, with careful attention to potassium levels, is an evidence-based strategy for the treatment of RH. Other strategies include use of a vasodilating β-blocker, adding a long-acting nondihydropyridine calcium channel blocker, or adding clonidine. When blood pressure is not coming under control despite 4 or 5 agents, referral to a hypertension specialist may be warranted. Source


Cockrell Skinner A.,University of North Carolina at Chapel Hill
Journal of obesity | Year: 2013

As a public health problem, childhood obesity operates at multiple levels, ranging from individual health behaviors to school and community characteristics to public policies. Examining obesity, particularly childhood obesity, from any single perspective is likely to fail, and systems science methods offer a possible solution. We systematically reviewed studies that examined the causes and/or consequences of obesity from a systems science perspective. The 21 included studies addressed four general areas of systems science in obesity: (1) translating interventions to a large scale, (2) the effect of obesity on other health or economic outcomes, (3) the effect of geography on obesity, and (4) the effect of social networks on obesity. In general, little research addresses obesity from a true, integrated systems science perspective, and the available research infrequently focuses on children. This shortcoming limits the ability of that research to inform public policy. However, we believe that the largely incremental approaches used in current systems science lay a foundation for future work and present a model demonstrating the system of childhood obesity. Systems science perspective and related methods are particularly promising in understanding the link between childhood obesity and adult outcomes. Systems models emphasize the evolution of agents and their interactions; such evolution is particularly salient in the context of a developing child. Source


Knickmeyer R.C.,University of North Carolina at Chapel Hill
Current Opinion in Neurology | Year: 2012

Purpose of review Turner syndrome, which results from the complete or partial loss of a sex chromosome, is associated with a particular pattern of cognitive impairments and strengths and an increased risk for specific neurodevelopmental disorders. This review highlights recent progress in understanding brain structure and function in Turner syndrome and identifies several critical research needs. Recent findings Recent work on social cognition in Turner syndrome has identified a range of difficulties despite a maintained social appetite, a disconnect which could result in distress for affected individuals. Progress has been made in identifying foundational deficits in attention and executive function that could explain visual- spatial and arithmetical impairments. Neuroimaging studies have advanced our understanding of brain development and function through the application of cutting edge analysis techniques. Haploinsufficiency of genes, failure to express parentally imprinted genes, uncovering of X chromosome mutations, and gonadal steroid deficiency may all contribute to altered brain development, but additional work is required to link specific mechanisms to specific phenotypes. Also needed are studies of interventions to assist individuals with Turner syndrome in visual-spatial, mathematical, and social skills. Summary Ultimately a better understanding of brain structure and function in Turner syndrome will generate new therapeutic approaches for this population. © 2012 Wolters Kluwer Health | Lippincott Williams &Wilkins. Source


Ng S.W.,University of North Carolina at Chapel Hill | Dunford E.,The George Institute for Global Health
Obesity Reviews | Year: 2013

Summary: In developed nations and increasingly in the rest of the world, a large proportion of people's diets comes from manufactured food sources and food not produced at home. These types of products are constantly changing and have significant nutrition and health implications for the world's population. However, researchers, public health workers and policy makers face major complexities in understanding what these changes are and their relationships to diet and health outcomes. This paper will describe some of the complexities faced in monitoring and evaluating the nutritional composition of food products and what it means for population health. Importantly, no existing food composition database is able to keep up with the continuous reformulation and introductions and removals of packaged foods and food services. The paper will also discuss opportunities to improve and update the monitoring and evaluation of changes made by each of these key sectors of the modern food supply and how these changes can influence the nutrients purchased or consumed across the globe. The focus will be on the United States with some examples from other developed nations and a discussion of implications for low- and middle-income countries. © 2013 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of the International Association for the Study of Obesity. Source


Dai X.,University of North Carolina at Chapel Hill
Journal of the American Heart Association | Year: 2013

Major advances have been made in the treatment of ST-elevation myocardial infarction (STEMI) in outpatients. In contrast, little is known about outcomes in STEMI that occur in patients hospitalized for a noncardiac condition. This was a retrospective, single-center study of inpatient STEMIs from January 1, 2007, to July 31, 2011. Forty-eight cases were confirmed to be inpatient STEMIs of a total of 139 410 adult discharges. These patients were older and more often female and had higher rates of chronic kidney disease and prior cerebrovascular events compared with 227 patients with outpatient STEMIs treated during the same period. Onset of inpatient STEMI was heralded most frequently by a change in clinical status (60%) and less commonly by patient complaints (33%) or changes on telemetry. Coronary angiography and percutaneous coronary intervention were performed in 71% and 56% of patients, respectively. The median time to obtain ECG (41 [10, 600] versus 5 [2, 10] minutes; P<0.001), ECG to angiography time (91 [26, 209] versus 35 [25, 46] minutes; P<0.001) and ECG to first device activation (FDA) (129 [65, 25] versus 60 [47, 76] minutes; P<0.001) were longer for inpatient versus outpatient STEMI. Survival to discharge was lower for inpatient STEMI (60% versus 96%; P<0.001), and this difference persisted after adjusting for potential confounders. Patients who develop a STEMI while hospitalized for a noncardiac condition are older and more often female, have more comorbidities, have longer ECG-to-FDA times, and are less likely to survive than patients with an outpatient STEMI. Source


Ronnegard L.,Dalarna University | Valdar W.,University of North Carolina at Chapel Hill
Genetics | Year: 2011

Traditional methods for detecting genes that affect complex diseases in humans or animal models, milk production in livestock, or other traits of interest, have asked whether variation in genotype produces a change in that trait's average value. But focusing on differences in the mean ignores differences in variability about that mean. The robustness, or uniformity, of an individual's character is not only of great practical importance in medical genetics and food production but is also of scientific and evolutionary interest (e.g., blood pressure in animal models of heart disease, litter size in pigs, flowering time in plants). We describe a method for detecting major genes controlling the phenotypic variance, referring to these as vQTL. Our method uses a double generalized linear model with linear predictors based on probabilities of line origin. We evaluate our method on simulated F2 and collaborative cross data, and on a real F2 intercross, demonstrating its accuracy and robustness to the presence of ordinary mean-controlling QTL. We also illustrate the connection between vQTL and QTL involved in epistasis, explaining how these concepts overlap. Our method can be applied to a wide range of commonly used experimental crosses and may be extended to genetic association more generally. © 2011 by the Genetics Society of America. Source


Wan Y.Y.,University of North Carolina at Chapel Hill
Trends in Immunology | Year: 2014

GATA3 has conventionally been regarded as a transcription factor that drives the differentiation of T helper (Th) 2 cells. Increasing evidence points to a function for GATA3 beyond controlling Th2 differentiation. GATA3 regulates T cell development, proliferation, and maintenance. Furthermore, recent studies have demonstrated important roles for GATA3 in innate lymphoid cells. Thus, GATA3 emerges as a factor with diverse functions in immune regulation, which are in some cases cell-type specific and in others shared by multiple cell types. Here, I discuss recent discoveries and the current understanding of the functions of GATA3 in immune regulation. © 2014 Elsevier Ltd. Source


Garcia J.V.,University of North Carolina at Chapel Hill
Journal of Clinical Investigation | Year: 2016

HIV persistence in patients undergoing antiretroviral therapy is a major impediment to the cure of HIV/AIDS. The molecular and cellular mechanisms underlying HIV persistence in vivo have not been fully elucidated. This lack of basic knowledge has hindered progress in this area. The in vivo analysis of HIV persistence and the implementation of curative strategies would benefit from animal models that accurately recapitulate key aspects of the human condition. This Review summarizes the contribution that humanized mouse models of HIV infection have made to the field of HIV cure research. Even though these models have been shown to be highly informative in many specific areas, their great potential to serve as excellent platforms for discovery in HIV pathogenesis and treatment has yet to be fully developed. Source


Manning J.S.,University of North Carolina at Chapel Hill
The Journal of clinical psychiatry | Year: 2013

College students with ADHD may need help to overcome symptoms that make studying, organizing and completing projects, and managing their time a challenge. In order to properly treat these patients, clinicians must correctly assess ADHD and comorbid conditions using rating scales and educate patients about their responsibility to reach their treatment goals and to properly use and protect their medication. Patients with past substance use may require treatment options that are less likely to be misused, such as a nonstimulant or long-acting stimulants. Throughout the treatment process, clinicians should continue to monitor symptoms and side effects with regular office visits and random testing, watching for signs of drug misuse. © Copyright 2013 Physicians Postgraduate Press, Inc. Source


Cohen M.S.,University of North Carolina at Chapel Hill
The Journal of infectious diseases | Year: 2010

Acute human immunodeficiency virus (HIV) infection (AHI) can be defined as the time from HIV acquisition until seroconversion. Incident HIV infection is less well defined but comprises the time from the acquisition of HIV (acute infection) through seroconversion (early or primary HIV infection) and the following months until infection has been well established, as characterized by a stable HIV viral load (viral load set point) and evolution of antibodies with increased concentration and affinity for HIV antigens. During AHI, a viral latent pool reservoir develops, the immune system suffers irreparable damage, and the infected (often unsuspecting) host may be most contagious. It has proved very difficult to find individuals with AHI either in longitudinal cohorts of subjects at high risk for acquiring the virus or through cross-sectional screening, and the opportunity for diagnosis is generally missed during this phase. We review the technical strategies for identifying individuals with acute or incident HIV infection. We conclude that further technical advances are essential to allow more widespread detection of patients with AHI and to affect HIV treatment outcomes and transmission prevention. Source


Gresset A.,University of North Carolina at Chapel Hill
Sub-cellular biochemistry | Year: 2012

The physiological effects of many extracellular neurotransmitters, hormones, growth factors, and other stimuli are mediated by receptor-promoted activation of phospholipase C (PLC) and consequential activation of inositol lipid signaling pathways. These signaling responses include the classically described conversion of phosphatidylinositol(4,5)P(2) to the Ca(2+)-mobilizing second messenger inositol(1,4,5)P(3) and the protein kinase C-activating second messenger diacylglycerol as well as alterations in membrane association or activity of many proteins that harbor phosphoinositide binding domains. The 13 mammalian PLCs elaborate a minimal catalytic core typified by PLC-d to confer multiple modes of regulation of lipase activity. PLC-b isozymes are activated by Gaq- and Gbg-subunits of heterotrimeric G proteins, and activation of PLC-g isozymes occurs through phosphorylation promoted by receptor and non-receptor tyrosine kinases. PLC-e and certain members of the PLC-b and PLC-g subclasses of isozymes are activated by direct binding of small G proteins of the Ras, Rho, and Rac subfamilies of GTPases. Recent high resolution three dimensional structures together with biochemical studies have illustrated that the X/Y linker region of the catalytic core mediates autoinhibition of most if not all PLC isozymes. Activation occurs as a consequence of removal of this autoinhibition. Source


Bautch V.L.,University of North Carolina at Chapel Hill
Cold Spring Harbor Perspectives in Medicine | Year: 2012

VEGF-A signaling is required for almost every aspect of vascular development, and it is a major regulator of vessel morphogenesis and patterning. VEGF-A perturbations are associated with severe vascular defects and lethality, and the pathway is coopted in pathological scenarios, including tumor angiogenesis. This review focuses on the roles of VEGF-A signaling during vessel development and patterning. I review the impact of VEGF-A signaling on endothelial cells in developing vessels, with emphasis on the importance of spatial regulation of several pathway components. I also discuss VEGF-A signaling patterns at the level of the vessel, with a focus on how polarity is set up and maintained in several vessel axes. The role of VEGF-A in patterning vessels relative to tissues and organs is also reviewed, with emphasis on neurovascular patterning and patterning at the embryonic midline. © 2012 Cold Spring Harbor Laboratory Press. Source


Dodson C.,University of North Carolina at Chapel Hill
Personalized Medicine | Year: 2011

Pharmacogenomics has become an area of great potential in the medical community. Therefore, the assessment of the knowledge and attitudes among healthcare professionals is essential. The purpose of this systematic literature review is to explore the knowledge and attitudes of healthcare professionals regarding pharmacogenetic testing with a specific emphasis in oncology. A total of 12 articles were found and reviewed. A majority of the articles reported only on the attitudes of healthcare professionals. Four of the articles reported on both knowledge and attitudes of healthcare professionals concerning pharmacogenetic testing, and one article reported only on the knowledge level of healthcare professionals. This systematic literature review revealed that healthcare professionals generally perceive themselves to have limited knowledge regarding pharmacogenetic testing. In addition, these articles highlighted the overwhelming ethical concerns surrounding pharmacogenomics. However, these articles also revealed that healthcare professionals believed that there were also many advantages regarding the utilization of pharmacogenomics. © 2011 Future Medicine Ltd. Source


Kim W.-Y.,University of Nebraska Medical Center | Snider W.D.,University of North Carolina at Chapel Hill
Frontiers in Molecular Neuroscience | Year: 2011

Glycogen synthase kinase-3 (GSK-3) is central to multiple intracellular pathways including those activated by Wnt/β-catenin, Sonic Hedgehog, Notch, growth factor/RTK, and G protein-coupled receptor signals. All of these signals importantly contribute to neural development. Early attention on GSK-3 signaling in neural development centered on the regulation of neuronal polarity using in vitro paradigms. However, recent creation of appropriate genetic models has demonstrated the importance of GSK-3 to multiple aspects of neural development including neural progenitor self-renewal, neurogenesis, neuronal migration, neural differentiation, and synaptic development. © 2011 Kim and Snider. Source


Fisher E.B.,University of North Carolina at Chapel Hill
Family practice | Year: 2010

Peer support may improve self-management among the millions of people with diabetes around the world. A major challenge to international promotion of peer support is allowing for tailoring to population, cultural, health system and other features of specific settings, while also ensuring congruence with standards for what peer support entails. One strategy to address this challenge was used in the Robert Wood Johnson Foundation Diabetes Initiative. Key functions of self-management-Resources and Supports for Self-Management-were identified. Individual programmes were then encouraged to implement these resources and support in ways that were feasible in their settings and responsive to the needs and perspectives of those they serve. Extending this to peer support, three Key functions are (i) assistance in managing and living with diabetes in daily life; (ii) social and emotional support and (iii) linkage to clinical care. International promotion may be advanced by emphasizing these key functions and then encouraging local variation in the specific ways they are addressed. Similarly, evaluation of the general benefits of peer support across several individual programmes may rest on measurement of implementation of the key functions, participants' reports of receipt of them and common end points. Challenges to promoting peer support include integrating peers amidst others in the health care system, harmonizing peers with family and other social networks, maintaining the engagement of peer supporters and those they assist and preventing training, quality improvement and professionalism from distorting the fundamental benefits of support from a peer. Source


Pinschmidt Jr. R.K.,University of North Carolina at Chapel Hill
Journal of Polymer Science, Part A: Polymer Chemistry | Year: 2010

A sustained effort to develop and commercialize a practical radical addition route to amine functional polymers (AFPs) resulted, after almost 20 years, in the successful completion of a world scale monomer plant to produce N-vinylformamide (NVF). NVF is readily polymerized and its polymers are easily hydrolyzed to reactive and atom economical polyvinylamine (PVAm) or its salts. This highlight touches on work by many companies, but focuses on efforts at Air Products and Chemicals, tracing the origins, rational, challenges, technical and commercial advances, and failures. Practical routes to new AFPs, copolymers, and derivatives across the entire molecular weight range (MW < 103 to >106) were achieved. NVF offers access to multiple water soluble, water dispersible, and nonwater soluble polymer markets, including papermaking additives and coatings, water treatment polymers, enhanced oil recovery polymers, radiation cure monomers, stabilizers, dispersing agents, surfactants, and crosslinkers. Lessons learned along the road to commercializing major new chemical technologies are also highlighted. © 2010 Wiley Periodicals, Inc. Source


Gutin B.,University of North Carolina at Chapel Hill
International Journal of Pediatric Obesity | Year: 2011

It is commonly theorized that some youths become fatter than others simply because they eat too much and exercise too little; i.e., they have an excessive positive energy balance. This theory suggests that obesity prevention efforts should emphasize dietary strategies designed to reduce energy intake, with moderate physical activity (PA) playing a supporting role. However, such interventions have typically been unsuccessful, perhaps because pediatric research that has measured body fatness, rather than weight, has found that the simple energy balance theory is faulty; it is critical to also consider whether the ingested energy is deposited in fat or lean tissue in order to provide a more complete picture of the etiology of pediatric obesity. In some way that is still poorly understood; vigorous PA and mechanical stimulation of the body stimulate stem cells to differentiate into bone and muscle rather than fat, with the result that ingested nutrients tend to be partitioned into lean tissue rather than fat. Thus, active youths tend to ingest more energy than their sedentary peers without increasing the percentage of the body mass that is comprised of fat tissue. Having a high level of both energy expenditure and intake is in accord with the biologic drives of youths because it encourages them to ingest sufficient amounts of the nutrients needed for healthy growth. Thus, public health interventions are likely to be more effective if they devote more attention to increasing PA and less attention to dietary strategies designed to reduce energy intake. © 2011 Informa Healthcare. Source


Rivera M.P.,University of North Carolina at Chapel Hill | Mehta A.C.,Cleveland Clinic | Wahidi M.M.,Duke University
Chest | Year: 2013

Background: Lung cancer is usually suspected in individuals who have an abnormal chest radiograph or have symptoms caused by either local or systemic effects of the tumor. The method of diagnosis of lung cancer depends on the type of lung cancer (small cell lung cancer or non-small cell lung cancer [NSCLC]), the size and location of the primary tumor, the presence of metastasis, and the overall clinical status of the patient. The objective of this study was to determine the test performance characteristics of various modalities for the diagnosis of suspected lung cancer. Methods: To update previous recommendations on techniques available for the initial diagnosis of lung cancer, a systematic search of the MEDLINE, Healthstar, and Cochrane Library databases covering material to July 2011 and print bibliographies was performed to identify studies comparing the results of sputum cytology, conventional bronchoscopy, flexible bronchoscopy (FB), electromagnetic navigation (EMN) bronchoscopy, radial endobronchial ultrasound (R-EBUS)-guided lung biopsy, transthoracic needle aspiration (TTNA) or biopsy, pleural fluid cytology, and pleural biopsy with histologic reference standard diagnoses among at least 50 patients with suspected lung cancer. Recommendations were developed by the writing committee, graded by a standardized method (see the article "Methodology for Development of Guidelines for Lung Cancer" in this guideline), and reviewed by all members of the Lung Cancer Guideline Panel prior to approval by the Thoracic Oncology NetWork, the Guidelines Oversight Committee, and the Board of Regents of the American College of Chest Physicians. Results: Sputum cytology is an acceptable method of establishing the diagnosis of lung cancer, with a pooled sensitivity rate of 66% and a specificity rate of 99%. However, the sensitivity of sputum cytology varies according to the location of the lung cancer. For central, endobronchial lesions, the overall sensitivity of FB for diagnosing lung cancer is 88%. The diagnostic yield of bronchoscopy decreases for peripheral lesions. Peripheral lesions < 2 or > 2 cm in diameter showed a sensitivity of 34% and 63%, respectively. R-EBUS and EMN are emerging technologies for the diagnosis of peripheral lung cancer, with diagnostic yields of 73% and 71%, respectively. The pooled sensitivity of TTNA for the diagnosis of lung cancer was 90%. A trend toward lower sensitivity was noted for lesions < 2 cm in diameter. TTNA is associated with a higher rate of pneumothorax compared with bronchoscopic procedures. In a patient with a malignant pleural effusion, pleural fluid cytology is reported to have a mean sensitivity of about 72%. A definitive diagnosis of metastatic disease to the pleural space can be estalished with a pleural biopsy. The diagnostic yield for closed pleural biopsy ranges from 38% to 47% and from 75% to 88% for image-guided closed biopsy. Thoracoscopic biopsy of the pleura carries the highest diagnostic yield, 95% to 97%. The accuracy in differentiating between small cell and non-small cell cytology for the various diagnostic modalities was 98%, with individual studies ranging from 94% to 100%. The average false-positive and false-negative rates were 9% and 2%, respectively. Although the distinction between small cell and NSCLC by cytology appears to be accurate, NSCLCs are clinically, pathologically, and molecularly heterogeneous tumors. In the past decade, clinical trials have shown us that NSCLCs respond to different therapeutic agents based on histologic phenotypes and molecular characteristics. The physician performing diagnostic procedures on a patient suspected of having lung cancer must ensure that adequate tissue is acquired to perform accurate histologic and molecular characterization of NSCLCs. Conclusions: The sensitivity of bronchoscopy is high for endobronchial disease and poor for peripheral lesions < 2 cm in diameter. The sensitivity of TTNA is excellent for malignant disease, but TTNA has a higher rate of pneumothorax than do bronchoscopic modalities. R-EBUS and EMN bronchoscopy show potential for increasing the diagnostic yield of FB for peripheral lung cancers. Thoracoscopic biopsy of the pleura has the highest diagnostic yield for diagnosis of metastatic pleural effusion in a patient with lung cancer. Adequate tissue acquisition for histologic and molecular characterization of NSCLCs is paramount. Copyright © by the American College of Chest Physicians 2013. Source


Boothroyd R.I.,University of North Carolina at Chapel Hill
Family practice | Year: 2010

INTRODUCTION: Peers for Progress, a global initiative of the American Academy of Family Physicians Foundation, developed out of the World Health Organization (WHO) Consultation on Peer Support Programmes in Diabetes as a strategic approach to promote best practices in peer support for health around the world. Why peer support. People often find themselves on their own to manage complex factors for behaviour change. Peer support can link people sharing experiences to provide the practical, emotional, and ongoing support that is critical to sustained behaviour change. The need. Diabetes is a global epidemic that affects all aspects of people's lives for the rest of their lives. The complexity of self-management requires ongoing support for effective and sustained management. Key principles, strategies, activities. Peers for Progress aims to strengthen evidence of the value of peer support through evaluation grants, encourage recognition of a state-of-the-art in peer support through defining key functions of support that can be tailored and applied globally, and promote peer support through networking with programmes and leaders around the world. CONCLUSIONS: People seeking to prevent or manage health conditions can be a powerful source of support to each other to manage complex behaviors. Peers for Progress has a defined functional framework for peer support's core functions, and is evaluating the scope and impact of peer support interventions based on this framework and a set of consensus evaluation measures. Peers for Progress looks to raise the visibility and applicability of peer support as good health care for all people. Source


Ringel-Kulka T.,University of North Carolina at Chapel Hill
Nutrition in Clinical Practice | Year: 2012

The intestinal microbiota is a functional organ with a variety of important metabolic, trophic, immunologic, and digestive activities. Current data suggest that alterations in the intestinal microbiota may be related to disease conditions. Manipulation of the intestinal microbiota such as with probiotics, prebiotics, and synbiotics may be beneficial in preventing and treating certain disease conditions. This article provides an overview of the evidence gathered through randomized clinical trials, reviews, and meta-analyses on probiotics and prebiotics in commonly studied conditions in the pediatric population. It concludes with current recommendations for their use, noting safety and gaps in clinical evidence. © 2012 American Society for Parenteral and Enteral Nutrition. Source


Davenport M.L.,University of North Carolina at Chapel Hill
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Turner syndrome (TS) occurs in about 1:4000 live births and describes females with a broad constellation of problems associated with loss of an entire sex chromosome or a portion of the X chromosome containing the tip of its short arm. TS is associated with an astounding array of potential abnormalities, most of them thought to be caused by haploinsufficiency of genes that are normally expressed by both X chromosomes. A health care checklist is provided that suggests screening tests at specific ages and intervals for problems such as strabismus, hearing loss, and autoimmune thyroid disease. Four areas of major concern in TS are discussed: growth failure, cardiovascular disease, gonadal failure, and learning disabilities. GH therapy should generally begin as soon as growth failure occurs, allowing for rapid normalization of height. Cardiac imaging, preferably magnetic resonance imaging, should be performed at diagnosis and repeated at 5- to 10-yr intervals to assess for congenital heart abnormalities and the emergence of aortic dilatation, a precursor to aortic dissection. Hypertension should be aggressively treated. For those with gonadal dysgenesis, hormonal replacement therapy should begin at a normal pubertal age and be continued until the age of 50 yr. Transdermal estradiol provides the most physiological replacement. Finally, non-verbal learning disabilities marked by deficits in visual-spatial-organizational skills, complex psychomotor skills, and social skills are common in TS. Neuropsychological testing should be routine and families given support in obtaining appropriate therapy, including special accommodations at school. Copyright © 2010 by The Endocrine Society. Source


Feduccia A.,University of North Carolina at Chapel Hill
Cretaceous Research | Year: 2014

Debate on the magnitude of Cretaceous extinctions and timing of modern bird origins has sharply coalesced over the past two decades into contested models, gradualistic or explosive. Molecular clocks, bolstered by phylogenetic, biogeographic, and vicariance models, support an Early Cretaceous origin for birds and mammals over 100 million years ago. Yet, although numerous new Chinese fossils of archaic ornithurine birds have been discovered in the Jehol Biota of the Early Cretaceous of China, none shows close affinity to modern neornithines; it is not until the latest Cretaceous when some fossils show more advanced ornithurine morphology, and are possibly Neornithes. In contrast to mass survival scenarios, most paleontological evidence appears to support an explosive radiation following the Cretaceous-Paleogene (K-Pg) mass extinction event, closely paralleling the geometry of mammal evolution. Gradualistic models ignore recent evidence of cataclysmic worldwide events following the impact event. How could mass survival of the environmentally sensitive birds have occurred following cosmopolitan environmental destruction, when other terrestrial vertebrates, particularly ectotherms, suffered dramatic loss? Given the paucity and scrappy nature of avian fossils immediately prior to and after the K-Pg boundary, it is prudent to use mammalian and other biotic evolution in the Paleogene as a guidepost for avian evolution. Our continued inability to produce a veracious phylogeny of higher avian taxa is likely related to a Paleogene explosive burst or 'big bang' evolution of bird and mammal evolution, resulting in short ordinal internodes. © 2014 Elsevier Ltd. Source


Mersini-Houghton L.,University of Cambridge | Mersini-Houghton L.,University of North Carolina at Chapel Hill
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2014

Particle creation leading to Hawking radiation is produced by the changing gravitational field of the collapsing star. The two main initial conditions in the far past placed on the quantum field from which particles arise, are the Hartle-Hawking vacuum and the Unruh vacuum. The former leads to a time-symmetric thermal bath of radiation, while the latter to a flux of radiation coming out of the collapsing star. The energy of Hawking radiation in the interior of the collapsing star is negative and equal in magnitude to its value at future infinity. This work investigates the backreaction of Hawking radiation on the interior of a gravitationally collapsing star, in a Hartle-Hawking initial vacuum. It shows that due to the negative energy Hawking radiation in the interior, the collapse of the star stops at a finite radius, before the singularity and the event horizon of a black hole have a chance to form. That is, the star bounces instead of collapsing to a black hole. A trapped surface near the last stage of the star's collapse to its minimum size may still exist temporarily. Its formation depends on the details of collapse. Results for the case of Hawking flux of radiation with the Unruh initial state, will be given in a companion paper II. © 2014 The Author. Source


Fried M.W.,University of North Carolina at Chapel Hill
Liver International | Year: 2011

The ability to achieve a sustained virological response (SVR) to peginterferon (PEG-IFN) and ribavirin (RBV) depends on numerous host and virological factors, as well as adherence to a prescribed treatment regimen. Patients who have failed to achieve a SVR to PEG-IFN and RBV have limited options for retreatment. Emerging data from phase II and phase III clinical trials of direct-acting antiviral agents suggest that new therapeutic regimens will be available for many patients. Treatment with protease inhibitors such as PEG-IFN, RBV, ribavirin. and boceprevir, combined with PEG-IFN and RBV, has been shown to produce high rates of virological response in both prior relapsers and, to a lesser extent, prior non-responders. The benefits of these novel treatment regimens for each individual patient must be weighed against the side effects, costs and potential of developing viral resistance. Regulatory approval of telaprevir and boceprevir is expected to begin in mid-late 2011. © 2011 John Wiley & Sons A/S. Source


Ludlow J.B.,University of North Carolina at Chapel Hill
Dentomaxillofacial Radiology | Year: 2011

Objectives: The dosimetry of the Kodak 9500 cone beam CT (CBCT) unit (Carestream Health, Rochester, NY) was measured before and after installation of copper filtration. Methods: Dosimetry of a pre-production Kodak 9500 CBCT unit was compared with a current production unit with 0.4 mmof added filtration and increased kVp. Thermoluminescent dosimeter 100 chips were placed at 24 locations in a RANDO (radiation analogue dosimetry) head phantom (Nuclear Associates, Hicksville, NY). Small, medium and large adult default exposure settings were used in separate dosimeter runs for large and mediumfield of view (FOV) examinations with both units. Equivalent dose and effective dose were calculated using International Commission on Radiological Protection (ICRP) 1990 and 2007 tissue weights. Results: Estimations of risk using 2007 ICRP calculations increased by an average of 77% for large FOV scans and 125%for the medium FOV scans in comparison with 1990 calculations.With added filtration, effective dose for medium FOV examinations for default settings were: small adult 76 μSv,medium adult 98 μSv, and large adult 166 μSv. Effective doses for large FOVexaminations were: small adult 93 μSv, medium adult 163 μSv, and large adult 260 μSv. Effective dose was reduced by an average of 43% in examinations made with increased filtration and adjusted kVp. Conclusion: The manufacturer's installation of additional filtration with the adjustment of kVp in the Kodak 9500 CBCT unit resulted in significant patient dose reductions for examinations at all adult default settings. © 2011 The British Institute of Radiology. Source


Dellon E.S.,University of North Carolina at Chapel Hill
Current Gastroenterology Reports | Year: 2011

Eosinophilic esophagitis (EoE), a chronic inflammatory condition with a rapidly evolving epidemiology, is now a major cause of esophageal disease. Current guidelines emphasize that EoE is a clinicopathologic condition with the following criteria: clinical symptoms of esophageal dysfunction; at least 15 eosinophils in one high-power field on esophageal biopsy; and lack of responsiveness to high-dose proton-pump inhibition or normal pH monitoring of the distal esophagus. Challenges in diagnosis include lack of standardized esophageal biopsy protocols, variability in how eosinophil counts are determined, variability in the size of microscope high-power fields, and the need to evaluate the differential diagnosis of esophageal eosinophilia. In particular, the complex interplay between esophageal eosinophilia, EoE, and reflux disease remains an area both of controversy and active study. In the future, diagnostic strategies could include symptom scores, tissue or noninvasive biomarkers, and/or genetic expression profiles. © 2011 Springer Science+Business Media, LLC. Source


Loeser R.F.,University of North Carolina at Chapel Hill
Matrix Biology | Year: 2014

The integrin family of cell adhesion receptors plays a major role in mediating interactions between cells and the extracellular matrix. Normal adult articular chondrocytes express α1β1, α3β1, α5β1, α10β1, αVβ1, αVβ3, and αVβ5 integrins, while chondrocytes from osteoarthritic tissue also express α2β1, α4β1, α6β1. These integrins bind a host of cartilage extracellular matrix (ECM) proteins, most notably fibronectin and collagen types II and VI, which provide signals that regulate cell proliferation, survival, differentiation, and matrix remodeling. By initiating signals in response to mechanical forces, chondrocyte integrins also serve as mechanotransducers. When the cartilage matrix is damaged in osteoarthritis, fragments of fibronectin are generated that signal through the α5β1 integrin to activate a pro-inflammatory and pro-catabolic response which, if left unchecked, could contribute to progressive matrix degradation. The cell signaling pathways activated in response to excessive mechanical signals and to fibronectin fragments are being unraveled and may represent useful therapeutic targets for slowing or stopping progressive matrix destruction in arthritis. © 2014. Source


Van Landeghem L.,University of North Carolina at Chapel Hill
American journal of physiology. Gastrointestinal and liver physiology | Year: 2012

Recent identification of intestinal epithelial stem cell (ISC) markers and development of ISC reporter mice permit visualization and isolation of regenerating ISCs after radiation to define their functional and molecular phenotypes. Previous studies in uninjured intestine of Sox9-EGFP reporter mice demonstrate that ISCs express low levels of Sox9-EGFP (Sox9-EGFP Low), whereas enteroendocrine cells (EEC) express high levels of Sox9-EGFP (Sox9-EGFP High). We hypothesized that Sox9-EGFP Low ISCs would expand after radiation, exhibit enhanced proliferative capacities, and adopt a distinct gene expression profile associated with rapid proliferation. Sox9-EGFP mice were given 14 Gy abdominal radiation and studied between days 3 and 9 postradiation. Radiation-induced changes in number, growth, and transcriptome of the different Sox9-EGFP cell populations were determined by histology, flow cytometry, in vitro culture assays, and microarray. Microarray confirmed that nonirradiated Sox9-EGFP Low cells are enriched for Lgr5 mRNA and mRNAs enriched in Lgr5-ISCs and identified additional putative ISC markers. Sox9-EGFP High cells were enriched for EEC markers, as well as Bmi1 and Hopx, which are putative markers of quiescent ISCs. Irradiation caused complete crypt loss, followed by expansion and hyperproliferation of Sox9-EGFP Low cells. From nonirradiated intestine, only Sox9-EGFP Low cells exhibited ISC characteristics of forming organoids in culture, whereas during regeneration both Sox9-EGFP Low and High cells formed organoids. Microarray demonstrated that regenerating Sox9-EGFP High cells exhibited transcriptomic changes linked to p53-signaling and ISC-like functions including DNA repair and reduced oxidative metabolism. These findings support a model in which Sox9-EGFP Low cells represent active ISCs, Sox9-EGFP High cells contain radiation-activatable cells with ISC characteristics, and both participate in crypt regeneration. Source


Nichols C.D.,Louisiana State University Health Sciences Center | Roth B.L.,University of North Carolina at Chapel Hill
Frontiers in Molecular Neuroscience | Year: 2013

Understanding how discreet tissues and neuronal circuits function in relation to the whole organism to regulate physiological processes and behaviors is a fundamental goal of modern biological science. Powerful and important new tools in this discovery process are modified G-protein coupled receptors (GPCRs) known as 'Receptors Activated Solely by Synthetic Ligands (RASSLs),' and 'Designer Receptors Exclusively Activated by a Designer Drug (DREADDs).' Collectively, these are GPCRs modified either through rational design (RASSLs) or directed molecular evolution (DREADDs), that do not respond to native ligand, but functionally respond only to synthetic ligands. Importantly, the utility of these receptors is not limited to examination of the role of GPCR-coupled effector signal transduction pathways. Due to the near ubiquitous expression of GPCRs throughout an organism, this technology, combined with whole animal transgenics to selectively target expression, has the ability to regulate activity of discreet tissues and neuronal circuits through effector pathway modulation to study function and behavior throughout the organism. Advantages over other systems currently used to modify in vivo function include the ability to rapidly, selectively and reversibly manipulate defined signal transduction pathways both in short term and long term studies, and no need for specialized equipment due to convenient systemic treatment with activating ligand. © 2009 Nichols and Roth. Source


Andersen K.L.,University of North Carolina at Chapel Hill
International Journal of Gynecology and Obstetrics | Year: 2012

This study aimed to understand women's pathways of seeking care for postabortion complications in Madhya Pradesh, India. The study recruited 786 women between July and November 2007. Data were collected on service provision, abortion-related complications, care-seeking behavior, knowledge about abortion legality and availability, methods used, symptoms, referral source, and out-of-pocket costs. Women seeking care for complications from induced abortion followed more complex pathways to treatment than women with complications of spontaneous abortion. More complex pathways were associated with higher out-of-pocket costs. Improving community awareness on legal aspects, safe abortion methods, and trained providers are necessary to reduce morbidity associated with unsafe abortion. © 2012 International Federation of Gynecology and Obstetrics. Source


Jani A.J.,University of California at Santa Barbara | Cotter P.A.,University of North Carolina at Chapel Hill
Cell Host and Microbe | Year: 2010

Type VI secretion systems (T6SS) have been studied primarily in the context of pathogenic bacteria-host interactions. Recent data suggest, however, that these versatile secretion systems may also function to promote commensal or mutualistic relationships between bacteria and eukaryotes or to mediate cooperative or competitive interactions between bacteria. © 2010 Elsevier Inc. Source


Peden D.B.,University of North Carolina at Chapel Hill
Immunological Reviews | Year: 2011

Ozone (O3) and endotoxin are common environmental contaminants that cause asthma exacerbation. These pollutants have similar phenotype response characteristics, including induction of neutrophilic inflammation, changes in airway macrophage immunophenotypes, and ability to enhance response to inhaled allergen. Evoked phenotyping studies of volunteers exposed to O3 and endotoxin were used to identify the response characteristics of volunteers to these pollutants. New studies support the hypotheses that similar innate immune and oxidant processes modulate response to these agents. These include TLR4 and inflammasome-mediated signaling and cytokine production. Innate immune responses are also impacted by oxidative stress. It is likely that continued discovery of common molecular processes which modulate response to these pollutants will occur. Understanding the pathways that modulate response to pollutants will also allow for discovery of genetic and epigenetic factors that regulate response to these pollutants and determine risk of disease exacerbation. Additionally, defining the mechanisms of response will allow rational selection of interventions to examine. Interventions focused on inhibition of Toll-like receptor 4 and inflammasome represent promising new approaches to preventing pollutant-induced asthma exacerbations. Such interventions include specific inhibitors of innate immunity and antioxidant therapies designed to counter the effects of pollutants on cell signaling. © 2011 John Wiley & Sons A/S. Source


Northouse L.L.,University of Michigan | Katapodi M.C.,University of Michigan | Song L.,University of North Carolina at Chapel Hill | Zhang L.,University of Michigan | Mood D.W.,Wayne State University
CA Cancer Journal for Clinicians | Year: 2010

Family caregivers of cancer patients receive little preparation, information, or support to perform their caregiving role. However, their psychosocial needs must be addressed so they can maintain their own health and provide the best possible care to the patient. The purpose of this article is to analyze the types of interventions offered to family caregivers of cancer patients, and to determine the effect of these interventions on various caregiver outcomes. Meta-analysis was used to analyze data obtained from 29 randomized clinical trials published from 1983 through March 2009. Three types of interventions were offered to caregivers: psychoeducational, skills training, and therapeutic counseling. Most interventions were delivered jointly to patients and caregivers, but they varied considerably with regard to dose and duration. The majority of caregivers were female (64%) and Caucasian (84%), and ranged in age from 18 to 92 years (mean age, 55 years). Meta-analysis indicated that although these interventions had small to medium effects, they significantly reduced caregiver burden, improved caregivers' ability to cope, increased their self-efficacy, and improved aspects of their quality of life. Various intervention characteristics were also examined as potential moderators. Clinicians need to deliver research-tested interventions to help caregivers and patients cope effectively and maintain their quality of life. © 2010 American Cancer Society, Inc. Source


McMurray R.G.,University of North Carolina at Chapel Hill
BMC Medicine | Year: 2013

The association between physical activity and cardiovascular disease risk factors in children has been the focus of research for over two decades. The majority of this research has focused on children over 10 years of age with little information on very young children. The data recently published in BMC Medicine by Jiménez-Pavón and colleagues suggest that adverse cardiovascular disease (CVD) risk profiles, as indicated by a clustered risk score for the metabolic syndrome, are evident in very young children (two to six years of age), but differ between the sexes. The authors evaluated the relationship of CVD risk profiles and protective levels of moderate-to-vigorous physical activity (MVPA) and concluded that boys aged six years or younger needed >60 minutes of MVPA per day, whereas boys from six to nine years of age needed >80 minutes of MVPA per day; girls in either age group needed approximately 15 minutes less. Therefore, when clinicians recommend physical activity for children they should evaluate " at risk" children on a case-by-case basis rather than using generalized guidelines. Please see related research: http://www.biomedcentral.com/1741-7015/11/172. © 2013 McMurray; licensee BioMed Central Ltd. Source


Parker J.S.,University of North Carolina at Chapel Hill
Nature Medicine | Year: 2016

B cell lymphoma and melanoma harbor recurrent mutations in the gene encoding the EZH2 histone methyltransferase (EZH2), but the carcinogenic role of these mutations is unclear. Here we describe a mouse model in which the most common somatic Ezh2 gain-of-function mutation (EZH2Y646F in human; Ezh2Y641F in mouse) is conditionally expressed. Expression of Ezh2Y641F in mouse B cells or melanocytes caused high-penetrance lymphoma or melanoma, respectively. Overexpression of the anti-apoptotic protein Bcl2, but not the oncoprotein Myc, or loss of the tumor suppressor protein p53 (encoded by Trp53 in mice) further accelerated lymphoma progression. Expression of the mutant Braf but not the mutant Nras oncoprotein further accelerated melanoma progression. Although expression of Ezh2Y641F globally increased the abundance of trimethylated Lys27 of histone H3 (H3K27me3), it also caused a widespread redistribution of this repressive mark, including a loss of H3K27me3 that was associated with increased transcription at many loci. These results suggest that Ezh2Y641F induces lymphoma and melanoma through a vast reorganization of chromatin structure, inducing both repression and activation of polycomb-regulated loci. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source


Popkin B.M.,University of North Carolina at Chapel Hill
Obesity Reviews | Year: 2014

Summary: The China Health and Nutrition Survey (CHNS) is important for its insights into current and future diet, physical activity, and obesity-related changes in China and for understanding underlying processes common across low- and middle-income countries (LMICs). While China modernized later than Latin American countries, many changes seen in China echo those in Latin America and in other LMICs. In general, changes in physical activity and diet behaviours in China have occurred at a faster pace relative to other LMICs. Modernization of the overall Chinese food system has lagged behind most other LMICs, yet the now-rapid changes in the Chinese food system are similar to what has been seen in other LMICs. Further, there is variation in these changes across social and geographic space. The incidence of obesity and non-communicable diseases has increased as the major health burden has shifted towards the poor. This paper examines changes in China and addresses the literature and issues that link these changes with those in other LMICs. In many ways, the detailed 20-year CHNS, with nine repeated measures, provides a remarkable window through which to understand nutrition-related changes in other LMICs. © 2014 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of the International Association for the Study of Obesity. Source


Allen J.D.,University of North Carolina at Chapel Hill
Journal of Experimental Marine Biology and Ecology | Year: 2012

Life-history models for marine invertebrate animals assume a strong correlation between the size of the egg and the time from fertilization until metamorphosis. This assumption is supported by comparative data across a wide range of phyla. However, the exact form of the relationship between egg size and development time has a strong effect on the predicted outcomes of life-history models and has been the subject of much debate. Comparative data suggest that as egg size increases the effect of egg size reductions on development time will decrease and the effects of size reductions on juvenile size will increase. I used blastomere separations to test the effects of a 50% reduction in egg volume on development time and juvenile size in three species of echinoid echinoderms (Arbacia punctulata, Strongylocentrotus purpuratus, and Dendraster excentricus) that develop from eggs of a range of sizes (80-124 μm). I also manipulated the food level given to developing embryos and larvae to investigate the potential interaction between the effects of egg size reductions and food availability. Larvae from halved zygotes took significantly longer to develop to metamorphosis than their whole size counterparts in all three species. In only one species was I able to detect a significant reduction in juvenile size for offspring developing from halved zygotes. When compared with similar manipulations in species with larger eggs (140-387 μm), egg size reductions have a stronger effect on development time in species with small eggs. As predicted, development time does not change linearly with egg size but instead increases exponentially as egg size is reduced. The relationship between egg size and juvenile size remains unclear. Further investigations into the factors, including egg size, that influence juvenile performance are warranted. © 2012 Elsevier B.V.. Source


Clemmons D.R.,University of North Carolina at Chapel Hill
Current Opinion in Endocrinology, Diabetes and Obesity | Year: 2010

PURPOSE OF REVIEW: This review summarizes the recent published information regarding efficacy and complications of growth hormone replacement therapy. Several recent reports have monitored patients for periods of up to 10 years. Additionally, a consensus conference has been held regarding needed improvements in diagnostic testing and the recommendations of consensus panels regarding diagnostic criteria and laboratory test utilization are summarized. RECENT FINDINGS: Long-term studies show growth hormone can be administered safely and that muscle strength and function as well as lipoprotein abnormalities and low-bone mineral density show sustained improvement over extended periods of time. The complications that occur are generally dose-dependent and once attenuated do not tend to recur. Long-term safety studies regarding improvement in cardiovascular mortality and/or worsening prognosis for patients who develop malignancies are available only in the form of observational studies and randomized controlled long-term trial information is not yet available. The studies reported provide a means for clinicians to ascertain the patients who are likely to derive the greatest benefit from growth hormone when the appropriate diagnostic testing and treatment paradigms are utilized. SUMMARY: The studies that are summarized provide useful information for assessing the response to treatment, selecting patients who are candidates for long-term replacement therapy and for selecting those in whom the need for therapy may need to be reassessed. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Mathurin P.,Lille 2 University of Health and Law | Bataller R.,University of North Carolina at Chapel Hill
Journal of Hepatology | Year: 2015

Alcoholic liver disease (ALD) is the most prevalent cause of advanced liver disease in Europe and is the leading cause of death among adults with excessive alcohol consumption. There is a dose-response relationship between the amount of alcohol consumed and the risk of ALD. The relative risk of cirrhosis increases in subjects who consume more than 25 g/day. The burden of alcohol-attributable liver cirrhosis and liver cancer is high and is entirely preventable. Health agencies should develop population-based policies to reduce the prevalence of harmful and/or hazardous alcohol consumption and foster research in this field to provide new diagnostic and therapeutic tools. Disease progression of patients with ALD is heavily influenced by both genetic and environmental factors. Non-invasive methods for the diagnosis of fibrosis have opened new perspectives in the early detection of advanced ALD in asymptomatic patients. Alcoholic hepatitis, the most severe form of ALD, carries a high short-term mortality (around 30-50% at 3 months). Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis but duration of therapy should be adapted to early response. Liver transplantation is the best option for patients with severe liver dysfunction. However, alcohol relapse after transplantation remains a critical issue and drinking habits of transplanted patients need to be routinely screened. © 2015 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. Source


Chua J.L.,University of North Carolina at Chapel Hill
Medical Anthropology Quarterly | Year: 2012

In the language of the medical file, "complaint" refers to the symptoms and ailments reported by the patient. In this article, I draw on ethnographic fieldwork conducted between 2004 and 2007 in the mental healthcare setting in South India to argue that the typology of "complaint" and the dialogic exchanges involved in its production mark a far wider catchment area for the allegations and grievances that circulate between patient, kin, clinician, and observing anthropologist. I propose the notion of the register of complaint as a hermeneutic for grappling with the emotionally charged, interactional processes of accusation, arbitration, and reportage that drive clinical modes of inquiry and evaluation in the South Indian mental health encounter. Ethnographic case studies suggest that grievance and accusation command both a vital directive force and evidentiary role in the social, moral, and emotional work of psychiatric diagnosis. © 2012 by the American Anthropological Association. Source


Hammond W.P.,University of North Carolina at Chapel Hill
American Journal of Community Psychology | Year: 2010

The current study proposed and tested a conceptual model of medical mistrust in a sample of African American men (N = 216) recruited primarily from barbershops in the Midwest and Southeast regions of the United States. Potential psychosocial correlates were grouped into background factors, masculine role identity/socialization factors, recent healthcare experiences, recent socioenvironmental experiences (e.g., discrimination), and healthcare system outcome expectations (e.g., perceived racism in healthcare). Direct and mediated relationships were assessed. Results from the hierarchical regression analyses suggest that perceived racism in healthcare was the most powerful correlate of medical mistrust even after controlling for other factors. Direct effects were found for age, masculine role identity, recent patient-physician interaction quality, and discrimination experiences. Also, perceived racism in healthcare mediated the relationship between discrimination experiences and medical mistrust. These findings suggest that African American men's mistrust of healthcare organizations is related to personal characteristics, previous negative social/healthcare experiences, and expectations of disparate treatment on the basis of race. These findings also imply that aspects of masculine role identity shape the tone of patient-physician interactions in ways that impede trust building processes. © Society for Community Research and Action 2010. Source


Key N.S.,University of North Carolina at Chapel Hill
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2010

There is a long-standing controversy in the literature as to whether sickle-cell trait (SCT) should be viewed as a benign carrier state or as an intermediate disease phenotype. Because SCT is routinely detected by neonatal screening for sickle-cell disease, it becomes imperative that consensus on this issue be achieved in order to provide the best medical advice to affected individuals. The issue of selective screening in the post-neonatal period was thrust into the limelight recently by the National Collegiate Athletic Association's recommendation that its member colleges and universities test student-athletes to confirm their carrier status if not already known. The stated goal of this recommendation was to prevent exercise-related sudden death in athletes with SCT. We review some of the reported complications of SCT for which new information has emerged, focusing particularly on venous thromboembolism and renal manifestations. Source


Buckley L.B.,University of North Carolina at Chapel Hill
Global Ecology and Biogeography | Year: 2010

Aim: Most predictions of species ranges are based on correlating current species localities to environmental conditions. These correlative models do not explicitly include a species' biology. In contrast, some mechanistic models link traits to energetics and population dynamics to predict species distributions. These models enable one to ask whether considering a species' biology is important for predicting its range. I implement mechanistic models to investigate how a species' morphology, physiology and life history influence its range. Location: North America. Methods: I compare the mechanistic model predictions with those of correlative models for eight species of North American lizards in both current environments and following a uniform 3 °C temperature warming. I then examine the implications of superimposing habitat and elevation requirements on constraints associated with environmental tolerances. Results: In the mechanistic model, species with a narrower thermal range for activity are both predicted and observed to have more restricted distributions. Incorporating constraints on habitat and elevation further restricts species distributions beyond areas that are thermally suitable. While correlative models generally outperform mechanistic models at predicting current distributions, the performance of mechanistic models improves when incorporating additional factors. In response to a 3 °C temperature warming, the northward range shifts predicted by the mechanistic model vary between species according to trait differences and are of a greater extent than those predicted by correlative models. Main conclusions: These findings highlight the importance of species traits for understanding the dynamics of species ranges in changing environments. The analysis demonstrates that mechanistic models may provide an important complement to correlative models for predicting range dynamics, which may underpredict climate-induced range shifts. © 2010 Blackwell Publishing Ltd. Source


Speizer I.S.,University of North Carolina at Chapel Hill
Journal of Interpersonal Violence | Year: 2010

This study examines intimate partner violence (IPV) attitudes and experience among women and men in Uganda to inform IPV-prevention programs in the region. Nationally representative population-based data from women aged 15 to 49 and men aged 15 to 54 were collected between May and October 2006 as part of the Uganda Demographic and Health Survey. The survey included questions on women's and men's attitudes toward wife beating and information on IPV victimization (women) and perpetration (men). More than half of men and nearly three quarters of women have attitudes supportive of wife beating in Uganda. More than half of married women report IPV victimization, and 40% of married men report perpetration. Women and men who reported witnessing their fathers beating their mothers were more likely to report IPV victimization (perpetration for men). Witnessing violence was also associated with positive attitudes toward wife beating among men. IPV-prevention programs need to address the important role of having witnessed wife beating between the mother and the father on men's subsequent attitudes and behaviors. Women who witnessed wife beating are also the most likely to have supportive attitudes and IPV experience, possibly indicating that their relationship expectations are different than women who did not witness violence. Community-based prevention programs targeting men and women are needed in Uganda and elsewhere in sub-Saharan Africa where gender norms that justify IPV prevail. © The Author(s) 2010. Source


Francescangeli O.,Marche Polytechnic University | Samulski E.T.,University of North Carolina at Chapel Hill
Soft Matter | Year: 2010

We present X-ray diffraction evidence for clusters exhibiting a skewed cybotactic supramolecular structure in the nematic phase of the butyloxy-phenyl diester, ODBP-Ph-OC4, a bent core mesogenic diester of the nonlinear diol 2,5-bis-(p-hydroxyphenyl)-1,3,4-oxadiazole (ODBP). The temperature dependence of the off-meridional four-spot pattern shows that the tilt angle in the cybotactic clusters changes with temperature. The correlation lengths exhibit no evidence of critical behavior but there is no underlying smectic C phase in ODBP-Ph-OC4. The tilted cybotactic clusters persist throughout the 85 °C wide nematic phase, and even remain evident in the supercooled nematic. This inherently biaxial supramolecular structure - clusters of stratified and tilted mesogens - embedded in an otherwise translationally disordered nematic host medium may account for the NMR biaxiality observed in nematic phases of ODBP mesogens. © 2010 The Royal Society of Chemistry. Source


Fedoriw A.,University of North Carolina at Chapel Hill
Cold Spring Harbor perspectives in biology | Year: 2012

Epigenetic mechanisms are extensively utilized during mammalian development. Specific patterns of gene expression are established during cell fate decisions, maintained as differentiation progresses, and often augmented as more specialized cell types are required. Much of what is known about these mechanisms comes from the study of two distinct epigenetic phenomena: genomic imprinting and X-chromosome inactivation. In the case of genomic imprinting, alleles are expressed in a parent-of-origin-dependent manner, whereas X-chromosome inactivation in females requires that only one X chromosome is active in each somatic nucleus. As model systems for epigenetic regulation, genomic imprinting and X-chromosome inactivation have identified and elucidated the numerous regulatory mechanisms that function throughout the genome during development. Source


Sullivan P.F.,University of North Carolina at Chapel Hill | Daly M.J.,Harvard University | O'Donovan M.,University of Cardiff
Nature Reviews Genetics | Year: 2012

Psychiatric disorders are among the most intractable enigmas in medicine. In the past 5 years, there has been unprecedented progress on the genetics of many of these conditions. In this Review, we discuss the genetics of nine cardinal psychiatric disorders (namely, Alzheimer's disease, attention-deficit hyperactivity disorder, alcohol dependence, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depressive disorder, nicotine dependence and schizophrenia). Empirical approaches have yielded new hypotheses about aetiology and now provide data on the often debated genetic architectures of these conditions, which have implications for future research strategies. Further study using a balanced portfolio of methods to assess multiple forms of genetic variation is likely to yield many additional new findings. © 2012 Macmillan Publishers Limited. All rights reserved. Source


Ennett S.T.,University of North Carolina at Chapel Hill
Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco | Year: 2010

We apply a social contextual perspective based on Bronfenbrenner's ecology of human development theory to understanding development of youth cigarette smoking. We examine the contributions of family, peer, school, and neighborhood contexts. Context attributes examined were derived from social learning and social control theories. Data are from 6,544 youth who participated in at least one of five waves of data collection between Spring 2002 and Spring 2004, 1,663 randomly selected parents who participated in one or more of three waves of data collection in the same time period; and the U.S. Census. Three-level hierarchical growth models were used to examine the contributions of time-varying measures of the four social contexts to development of smoking from age 11-17 years. Interactions between variables were examined within and between social contexts. Attributes of each social context made independent contributions to adolescent smoking development; there also were significant interactions between variables from different contexts indicating joint contextual effects. Attributes of the social bond moderated exposure to models of smoking within and between the family and peer contexts. Results suggest the value of a social contextual perspective in research on the etiology of youth smoking development as well as the utility of guidance by social learning and social control theories. While all contexts were implicated in adolescent smoking, the family and peer contexts were primarily implicated, with findings suggesting the need for consideration of interactive effects between social learning and social control variables within and between these contexts. Source


Servedio M.R.,University of North Carolina at Chapel Hill
Evolutionary Applications | Year: 2016

Theoretical and empirical research on the evolution of reproductive isolation have both indicated that the effects of sexual selection on speciation with gene flow are quite complex. As part of this special issue on the contributions of women to basic and applied evolutionary biology, I discuss my work on this question in the context of a broader assessment of the patterns of sexual selection that lead to, versus inhibit, the speciation process, as derived from theoretical research. In particular, I focus on how two factors, the geographic context of speciation and the mechanism leading to assortative mating, interact to alter the effect that sexual selection through mate choice has on speciation. I concentrate on two geographic contexts: sympatry and secondary contact between two geographically separated populations that are exchanging migrants and two mechanisms of assortative mating: phenotype matching and separate preferences and traits. I show that both of these factors must be considered for the effects of sexual selection on speciation to be inferred. © 2016 John Wiley & Sons Ltd. Source


Rubenstein J.H.,Veterans Affairs Center for Clinical Management Research | Rubenstein J.H.,University of Michigan | Shaheen N.J.,University of North Carolina at Chapel Hill
Gastroenterology | Year: 2015

Esophageal adenocarcinoma (EAC) is rapidly increasing in incidence in Western cultures. Barrett's esophagus is the presumed precursor lesion for this cancer. Several other risk factors for this cancer have been described, including chronic heartburn, tobacco use, white race, and obesity. Despite these known associations, most patients with EAC present with symptoms of dysphagia from late-stage tumors; only a small number of patients are identified by screening and surveillance programs. Diagnostic analysis of EAC usually commences with upper endoscopy followed by cross-sectional imaging. Endoscopic ultrasonography is useful to assess the local extent of disease as well as the involvement of regional lymph nodes. T1a EAC may be treated endoscopically, and some patients with T1b disease may also benefit from endoscopic therapy. Locally advanced disease is generally managed with esophagectomy, often accompanied by neoadjuvant chemoradiotherapy or chemotherapy. The prognosis is based on tumor stage; patients with T1a tumors have an excellent prognosis, whereas few patients with advanced disease have long-term survival. © 2015 by the AGA Institute. Source


Shaheen N.J.,University of North Carolina at Chapel Hill | Falk G.W.,University of Pennsylvania | Iyer P.G.,Mayo Clinic Minnesota | Gerson L.B.,University of California at San Francisco
American Journal of Gastroenterology | Year: 2016

Barrett's esophagus (BE) is among the most common conditions encountered by the gastroenterologist. In this document, the American College of Gastroenterology updates its guidance for the best practices in caring for these patients. These guidelines continue to endorse screening of high-risk patients for BE; however, routine screening is limited to men with reflux symptoms and multiple other risk factors. Acknowledging recent data on the low risk of malignant progression in patients with nondysplastic BE, endoscopic surveillance intervals are attenuated in this population; patients with nondysplastic BE should undergo endoscopic surveillance no more frequently than every 3-5 years. Neither routine use of biomarker panels nor advanced endoscopic imaging techniques (beyond high-definition endoscopy) is recommended at this time. Endoscopic ablative therapy is recommended for patients with BE and high-grade dysplasia, as well as T1a esophageal adenocarcinoma. Based on recent level 1 evidence, endoscopic ablative therapy is also recommended for patients with BE and low-grade dysplasia, although endoscopic surveillance continues to be an acceptable alternative. Given the relatively common recurrence of BE after ablation, we suggest postablation endoscopic surveillance intervals. Although many of the recommendations provided are based on weak evidence or expert opinion, this document provides a pragmatic framework for the care of the patient with BE. © 2016 by the American College of Gastroenterology. Source


Knies J.L.,Brown University | Kingsolver J.G.,University of North Carolina at Chapel Hill
American Naturalist | Year: 2010

The initial rise of fitness that occurs with increasing temperature is attributed to Arrhenius kinetics, in which rates of reaction increase exponentially with increasing temperature. Models based on Arrhenius typically assume single rate-limiting reactions over some physiological temperature range for which all the ratelimiting enzymes are in 100% active conformation. We test this assumption using data sets for microbes that have measurements of fitness (intrinsic rate of population growth) at many temperatures and over a broad temperature range and for diverse ectotherms that have measurements at fewer temperatures. When measurements are available at many temperatures, strictly Arrhenius kinetics are rejected over the physiological temperature range. However, over a narrower temperature range, we cannot reject strictly Arrhenius kinetics. The temperature range also affects estimates of the temperature dependence of fitness. These results indicate that Arrhenius kinetics only apply over a narrow range of temperatures for ectotherms, complicating attempts to identify general patterns of temperature dependence. © 2010 by The University of Chicago. Source


Dent E.W.,University of Wisconsin - Madison | Gupton S.L.,Massachusetts Institute of Technology | Gupton S.L.,University of North Carolina at Chapel Hill | Gertler F.B.,Massachusetts Institute of Technology
Cold Spring Harbor Perspectives in Biology | Year: 2011

Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. Over the past two decades, our knowledge of the many guidance cues, receptors, and downstream signaling cascades involved in neuronal outgrowth and guidance has increased dramatically. Less is known, however, about how those cascades of information converge and direct appropriate remodeling and interaction of cytoskeletal polymers, the ultimate effectors of movement and guidance. During development, much of the communication that occurs between environmental guidance cues and the cytoskeleton takes place at the growing tip of the axon, the neuronal growth cone. Several articles on this topic focus on the "input" to the growth cone, themyriad of receptor types, and their corresponding cognate ligands. Others investigate the signaling cascades initiated by receptors and propagated by second messenger pathways (i.e., kinases, phosphatases, GTPases). Ultimately, this plethora of information converges on proteins that associate directly with the actin and microtubule cytoskeletons. The role of these cytoskeletal-associated proteins, aswell as the cytoskeleton itself in axon outgrowth and guidance, is the subject of this article. © 2011 Cold Spring Harbor Laboratory Press. Source


Fisher J.A.,University of North Carolina at Chapel Hill
Science Technology and Human Values | Year: 2015

Phase I clinical trials are the first stage of testing new pharmaceuticals in humans. The majority of these studies are conducted under controlled, inpatient conditions using healthy volunteers who are paid for their participation. This article draws on an ethnographic study of six phase I clinics in the United States, including 268 semistructured interviews with research staff and healthy volunteers. In it, I argue that an institutional banalization of risk structures the perceptions of research staff and healthy volunteers participating in the studies. For research staff, there are three mechanisms by which risk becomes banal: a perceived homogeneity of studies, Fordist work regimes, and data-centric discourse. For healthy volunteers, repeat study participation contributes to the institutional banalization of risk both through the process of desensitization to risk and the formation of trust in the clinics. I argue that the institutional banalization of risk also renders invisible ethical concerns about exploitation of underprivileged groups in pharmaceutical research. © The Author(s) 2014. Source


Duronio R.J.,University of North Carolina at Chapel Hill
Genes and Development | Year: 2012

The duration of S phase in early embryos is often short, and then increases as development proceeds because of the appearance of late-replicating regions of the genome. In the April 1, 2012, issue of Genes & Development, Farrell and colleagues (pp. 714-725) demonstrate that the down-regulation of cyclin-dependent kinase 1 (Cdk1) activity triggers the onset of late-replicating DNA and an increase in S-phase length in Drosophila embryos, revealing an unexpected role for Cdk1 in replication control during development. © 2012 by Cold Spring Harbor Laboratory Press. Source


Kelly S.A.,Ohio Wesleyan University | Pomp D.,University of North Carolina at Chapel Hill
Trends in Genetics | Year: 2013

Variation in voluntary exercise behavior is an important determinant of long-term human health. Increased physical activity is used as a preventative measure or therapeutic intervention for disease, and a sedentary lifestyle has generally been viewed as unhealthy. Predisposition to engage in voluntary activity is heritable and induces protective metabolic changes, but its complex genetic/genomic architecture has only recently begun to emerge. We first present a brief historical perspective and summary of the known benefits of voluntary exercise. Second, we describe human and mouse model studies using genomic and transcriptomic approaches to reveal the genetic architecture of exercise. Third, we discuss the merging of genomic information and physiological observations, revealing systems and networks that lead to a more complete mechanistic understanding of how exercise protects against disease pathogenesis. Finally, we explore potential regulation of physical activity through epigenetic mechanisms, including those that persist across multiple generations. © 2013 Elsevier Ltd. Source


Picher M.,University of North Carolina at Chapel Hill
Sub-Cellular Biochemistry | Year: 2011

In the respiratory system, extracellular nucleotides and nucleosides serve as signaling molecules for a wide spectrum of biological functions regulating airway defenses against infection and toxic material. Their concentrations are controlled by a complex network of cell surface enzymes named ectonucleotidases. This highly integrated metabolic network combines the activities of three dephosphorylating ectonucleotidases, namely nucleoside triphosphate diphosphohydrolases (NTPDases), nucleotide pyrophosphatase/phosphodiesterases (NPPs) and alkaline phosphatases (APs). Extracellular nucleotides are also inter-converted by the transphosphorylating activities of ecto adenylate kinase (ectoAK) and nucleoside diphosphokinase (NDPK). Different cell types use specific combinations of ectonucleotidases to regulate local concentrations of P2 receptor agonists (ATP, UTP, ADP and UDP). In addition, they provide AMP for the activity of ecto 50-nucleotidase (ecto 50-NT; CD73), which produces the P1 receptor agonist: adenosine (ADO). Finally, mechanisms are in place to prevent the accumulation of airway ADO, namely adenosine deaminases and nucleoside transporters. This chapter reviews the properties of each enzyme and transporter, and the current knowledge on their distribution and regulation in the airways.   © Springer Science+Business Media B.V. 2011 Source


Willett C.S.,University of North Carolina at Chapel Hill
Journal of Heredity | Year: 2012

The outcome of hybridization can be impacted by environmental conditions, which themselves can contribute to reproductive isolation between taxa. In crosses of genetically divergent populations, hybridization can have both negative and positive impacts on fitness, the balance between which might be tipped by changes in the environment. Genetically divergent populations of the intertidal copepod Tigriopus californicus have been shown to differ in thermal tolerance at high temperatures along a latitudinal gradient. In this study, a series of crosses were made between pairs of genetically divergent populations of T. californicus, and the thermal tolerance of these hybrids was tested. In most cases, the first-generation hybrids had relatively high thermal tolerance and the second-generation hybrids were not generally reduced below the less-tolerant parental population for high temperature tolerance. This pattern contrasts with previous studies from crosses of genetically divergent populations of this copepod, which often shows hybrid breakdown in these second-generation hybrids for other measures of fitness. These results suggest that high temperature stress could either increase the positive impacts of hybridization or decrease the negative impacts of hybridization resulting in lowered hybrid breakdown in these population crosses. © The American Genetic Association. 2011. All rights reserved. Source


McCown T.J.,University of North Carolina at Chapel Hill
Current Gene Therapy | Year: 2011

Adeno-associated virus (AAV) vectors exhibit a number of properties that have made this vector system an excellent choice for both CNS gene therapy and basic neurobiological investigations. In vivo, the preponderance of AAV vector transduction occurs in neurons where it is possible to obtain long-term, stable gene expression with very little accompanying toxicity. Promoter selection, however, significantly influences the pattern and longevity of neuronal transduction distinct from the tropism inherent to AAV vectors. AAV vectors have successfully manipulated CNS function using a wide variety of approaches including expression of foreign genes, expression of endogenous genes, expression of antisense RNA and expression of RNAi. With the discovery and characterization of different AAV serotypes, as well as the creation of novel chimeric serotypes, the potential patterns of in vivo vector transduction have been expanded substantially, offering alternatives to the more studied AAV 2 serotype. Furthermore, the development of specific AAV chimeras offers the potential to further refine targeting strategies. These different AAV serotypes also provide a solution to the immune silencing that proves to be a realistic likelihood given broad exposure of the human population to the AAV 2 serotype. These advantageous CNS properties of AAV vectors have fostered a wide range of clinically relevant applications including Parkinson's disease, lysosomal storage diseases, Canavan's disease, epilepsy, Huntington's disease and ALS. In many cases the proposed therapies have progressed to phase I/II clinical trials. Each individual application, however, presents a unique set of challenges that must be solved in order to attain clinically effective gene therapies. © 2011 Bentham Science Publishers Ltd. Source


Bray G.A.,Louisiana State University | Popkin B.M.,University of North Carolina at Chapel Hill
Diabetes Care | Year: 2014

Sugar-sweetened drinks have been associated with several health problems. In the point narrative as presented below, we provide our opinion and review of the data to date that we need to reconsider consumption of dietary sugar based on the growing concern of obesity and type 2 diabetes. In the counterpoint narrative following our contribution, Drs. Kahn and Sievenpiper provide a defense and suggest that dietary sugar is not the culprit. Data from the National Health and Nutrition Examination Survey and U.S. Department of Agriculture dietary surveys along with commercial Homescan data on household purchases were used to understand changes in sugar and fructose consumption. Meta-analyses and randomized clinical trials were used to evaluate outcomes of beverage and fructose intake. About 75% of all foods and beverages contain added sugar in a large array of forms. Consumption of soft drinks has increased fivefold since 1950. Meta-analyses suggest that consumption of sugar-sweetened beverages (SSBs) is related to the risk of diabetes, the metabolic syndrome, and cardiovascular disease. Drinking two 16-ounce SSBs per day for 6 months induced features of the metabolic syndrome and fatty liver. Randomized controlled trials in children and adults lasting 6 months to 2 years have shown that lowering the intake of soft drinks reduced weight gain. Recent studies suggest a gene-SSB potential relationship. Consumption of calorie-sweetened beverages has continued to increase and plays a role in the epidemic of obesity, the metabolic syndrome, and fatty liver disease. Reducing intake of soft drinks is associated with less weight gain. © 2014 by the American Diabetes Association. Source


Wise E.K.,University of North Carolina at Chapel Hill
Water Resources Research | Year: 2010

Tree ring samples collected near the Snake River headwaters were augmented with preexisting tree ring chronologies to create a 415 year reconstruction of upper Snake River streamflow, extending the short instrumental record and providing the first description of multicentury water supply variability in this river. Results indicate that the region's early 21st century drought is severe even in the context of long-term climatic variability and that the instrumental record is representative of low-flow individual years. In terms of overall magnitude, droughts of the recent past are eclipsed by a sustained low-flow period lasting for over 30 years in the early to mid-1600s. A comparison of reconstructed Snake River flow with streamflow reconstructions of the Colorado, Sacramento, and Verde rivers suggests that changes in the predominance of zonal versus meridional atmospheric flow may have influenced drought patterns in the western United States through time. © 2010 by the American Geophysical Union. Source


Meltzer-Brody S.,University of North Carolina at Chapel Hill
Dialogues in Clinical Neuroscience | Year: 2011

Maternal perinatal mental health has enormous consequences for the well-being of the mother, her baby, and the family. Although it is well documented that perinatal depression is both common and morbid, with a prevalence of 10% to 15% in the general population, there remain many critically important unanswered questions about the pathogenesis of perinatal depression and most effective treatment regimens. Current lines of evidence from both human and animal models implicate hormonal dysregulation, abnormalities in hypothalamic-pituitary-adrenal axis activity, and the contributions of genetics and epigenetics as playing key roles in the development of perinatal reproductive mood disorders. Investigations into both human and animal models of perinatal depression offer much promise for the future identification of the underlying pathophysiology and subsequent early identification and/or prevention and appropriate treatment for women at risk for postpartum depression. Lastly, although it is generally accepted that pregnancy is not protective with regard to new onset or relapse of depression, the way to best treat maternal depression during pregnancy and lactation remains hotly debated. Future research in this area will more clearly elucidate the underlying pathogenesis, the potential long-term impact of perinatal depression on the developing fetus, and how best to counsel pregnant women about the risks of untreated major depressive disorder versus the risks of psychopharmacologic treatment during pregnancy and lactation. © 2011, LLS SAS. Source


Roubey R.A.S.,University of North Carolina at Chapel Hill
Lupus | Year: 2010

Antiphospholipid antibodies (aPL) are best considered as risk factors. aPL are not diagnostic tests and considering them as such can be misleading and may direct attention away from the more important clinical issue of risk modification and management. When considering aPL as risk factors, quantitative aPL tests such enzyme-linked immunosorbent assay (ELISA) for anticardiolipin (aCL) and anti-β2-glycoprotein I (anti-β2GPI) antibodies, should be interpreted carefully. Risk for clinical manifestations appears to be associated with moderate to high levels of these autoantibodies. Lower levels may be statistically abnormal compared with a control population, but may not be associated with the risk of thrombosis or pregnancy loss. Lupus anticoagulants (LA) are generally thought to be more strongly associated with the risk of clinical manifestation of antiphospholipid syndrome (APS) than aCL and anti-β2GPI antibodies. One reason for the stronger association may be related to patients antibody titers. LA assays are not very analytically sensitive, i.e. a relatively high concentration of antibodies is required to prolong the clotting time in these tests. Thus, the presence of LA indicates a high titer of aPL and this, rather than the intrinsic functional characteristics of LA antibodies, may explain the high risk of clinical manifestations associated with LA. © 2010 The Author(s). Source


Jeffers L.,University of North Carolina at Chapel Hill
Advances in dental research | Year: 2011

Viral infections are often associated with salivary gland pathology. Here we review the pathogenesis of HIV-associated salivary gland disease (HIV-SGD), a hallmark of diffuse infiltrative lymphocytosis syndrome. We investigate the presence and contributions of viral diseases to the pathogenesis of salivary gland diseases, particularly HIV-SGD. We have detected BK viral shedding in the saliva of HIV-SGD patients consistent with viral infection and replication, suggesting a role for oral transmission. For further investigation of BKV pathogenesis in salivary glands, an in vitro model of BKV infection is described. Submandibular (HSG) and parotid (HSY) gland salivary cell lines were capable of permissive BKV infection, as determined by BKV gene expression and replication. Analysis of these data collectively suggests the potential for a BKV oral route of transmission and salivary gland pathogenesis within HIV-SGD. Source


Willis M.J.,Cornell University | Willis M.J.,University of North Carolina at Chapel Hill | Herried B.G.,University of Minnesota | Bevis M.G.,Ohio State University | Bell R.E.,Lamont Doherty Earth Observatory
Nature | Year: 2015

In a warming climate, surface meltwater production on large ice sheets is expected to increase. If this water is delivered to the ice sheet base it may have important consequences for ice dynamics. For example, basal water distributed in a diffuse network can decrease basal friction and accelerate ice flow, whereas channelized basal water can move quickly to the ice margin, where it can alter fjord circulation and submarine melt rates. Less certain is whether surface meltwater can be trapped and stored in subglacial lakes beneath large ice sheets. Here we show that a subglacial lake in Greenland drained quickly, as seen in the collapse of the ice surface, and then refilled from surface meltwater input. We use digital elevation models from stereo satellite imagery and airborne measurements to resolve elevation changes during the evolution of the surface and basal hydrologic systems at the Flade Isblink ice cap in northeast Greenland. During the autumn of 2011, a collapse basin about 70 metres deep and about 0.4 cubic kilometres in volume formed near the southern summit of the ice cap as a subglacial lake drained into a nearby fjord. Over the next two years, rapid uplift of the floor of the basin (which is approximately 8.4 square kilometres in area) occurred as surface meltwater flowed into crevasses around the basin margin and refilled the subglacial lake. Our observations show that surface meltwater can be trapped and stored at the bed of an ice sheet. Sensible and latent heat released by this trapped meltwater could soften nearby colder basal ice and alter downstream ice dynamics. Heat transport associated with meltwater trapped in subglacial lakes should be considered when predicting how ice sheet behaviour will change in a warming climate. ©2015 Macmillan Publishers Limited. All rights reserved. Source


Poole C.,University of North Carolina at Chapel Hill
Annals of Epidemiology | Year: 2015

Purpose: Since Doll published the first PAF in 1951, it has been a mainstay. Confusion in terminology abounds with regard to these measures. The ability to estimate all of them in case-control studies as well as in cohort studies is not widely appreciated. Methods: This article reviews and comments on the historical development of the population attributable fraction (PAF), the exposed attributable fraction (EAF), the rate difference (ID), the population rate (or incidence) difference (PID), and the caseload difference (CD). Results: The desire for PAFs to sum to no more than 100% and the interpretation of the complement of a PAF as the proportion of a rate that can be attributed to other causes are shown to stem from the same problem: a failure to recognize the pervasiveness of shared etiologic responsibility among causes. A lack of appreciation that "expected" numbers of cases and deaths are not actually the numbers to be expected when an exposure or intervention appreciably affects person-time denominators for rates, as in the case of smoking and nonnormal body mass, makes many CD estimates inflated. A movement may be gaining momentum to shift away from assuming, often unrealistically, the complete elimination of harmful exposures and toward estimating the effects of realistic interventions. This movement could culminate in a merger of the academic concept of transportability with the applied discipline of risk assessment. Conclusions: A suggestion is offered to pay more attention to absolute measures such as the rate difference, the population rate difference, and the CD, when the latter can be validly estimated and less attention to proportional measures such as the EAF and PAF. © 2015 Elsevier Inc. Source


Garbutt J.C.,University of North Carolina at Chapel Hill
Current Pharmaceutical Design | Year: 2010

Naltrexone, a broad opioid-receptor antagonist, was the first medication since disulfiram to be approved by the United States of America Food and Drug Administration for the treatment of alcohol dependence. In the initial clinical trials in the early 1990s, oral naltrexone, 50 mg, was shown to significantly reduce the risk of relapsing to heavy drinking compared to placebo. These early trials were followed by other trials throughout the world such that by 2010 about 4,000 individuals had been studied. Meta-analyses of these trials revealed that oral naltrexone is effective in reducing relapse to heavy drinking but less effective in enhancing abstinence. The effect size is modest, in the. 15 to. 2 range, which has impacted the adoption of naltrexone use by clinicians. Intramuscular versions of naltrexone active for one month have also shown efficacy. The tolerability of naltrexone is reasonable with the most common side-effect being nausea. Hepatotoxicity with naltrexone has not emerged as a clinical problem at the standard 50 mg dose though at higher doses hepatoxicity is of concern. The length of treatment with naltrexone has not been well studied though many clinicians recommend one year of treatment. Efforts are underway to identify predictors of naltrexone response but, to date, no predictor has achieved clinical utility. It is anticipated that the role of naltrexone and other opioid antagonists in the treatment of alcohol dependence will continue to be refined and that this class of medications will come to be seen as an important option in the clinical care of the patient with alcohol dependence. © 2010 Bentham Science Publishers Ltd. Source


Wang C.,University of Chicago | Wang C.,University of North Carolina at Chapel Hill | Liu D.,University of Chicago | Lin W.,University of Chicago
Journal of the American Chemical Society | Year: 2013

Metal-organic frameworks (MOFs), also known as coordination polymers, represent an interesting class of crystalline molecular materials that are synthesized by combining metal-connecting points and bridging ligands. The modular nature of and mild conditions for MOF synthesis have permitted the rational structural design of numerous MOFs and the incorporation of various functionalities via constituent building blocks. The resulting designer MOFs have shown promise for applications in a number of areas, including gas storage/separation, nonlinear optics/ferroelectricity, catalysis, energy conversion/storage, chemical sensing, biomedical imaging, and drug delivery. The structure-property relationships of MOFs can also be readily established by taking advantage of the knowledge of their detailed atomic structures, which enables fine-tuning of their functionalities for desired applications. Through the combination of molecular synthesis and crystal engineering, MOFs thus present an unprecedented opportunity for the rational and precise design of functional materials. © 2013 American Chemical Society. Source


Nichols T.C.,University of North Carolina at Chapel Hill
Blood | Year: 2013

In this issue of Blood, Chan et al have described mechanisms by which L5, the most electronegative of 5 recognized fractions of low density lipoprotein (LDL), activates both platelets and endothelium in a manner that supports thrombosis and could possibly produce ST-elevation myocardial infarctions (STEMI). © 2013 by The American Society of Hematology. Source


Purpose of review Leukemia relapse remains a significant cause of failure after allogeneic hematopoietic stem cell transplantation (HSCT). Although it is widely accepted that immunological components of the stem cell graft play a critical role in promoting leukemia eradication (graft versus leukemia effect), it is also evident that their efficacy is frequently inadequate and leukemia relapse still occurs. This article reviews recent insights into T cell-based posttransplant immunotherapy approaches aimed at preventing or controlling leukemia relapse. Recent findings Donor lymphocyte infusion with T cells genetically modified with safety switches improves the patient's immune reconstitution while offering appropriate control of graft versus host disease. T lymphocytes engineered with artificial tumor-specific receptors such as abT-cell receptor chains or chimeric antigen receptors are major players in promoting antileukemia effects after allogeneic HSCT. Summary The landscape of adoptive T cell therapies after allogeneic HSCT has seen significant achievements with the introduction of T cell engineering. Gene transfer grants the generation of T cell products characterized by standardizable specificity and functionality. This aspect is critical for scalable and reproducible approaches for application in large clinical studies. The clinical results so far reported are encouraging and multicenter studies conducted by pharmaceutical companies will provide definitive conclusions on the clinical impact of these new methodologies. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source


Synchronized transitions in the polymorph mineralogy of the major reef-building and sediment-producing calcareous marine organisms and abiotic CaCO 3 precipitates (ooids, marine cements) throughout Phanerozoic time are believed to have been caused by tectonically induced variations in the Mg/Ca ratio of seawater (molar Mg/Ca 2Combining double low line aragonite seas", <2Combining double low line calcite seas). Here, I assess the geological evidence in support of secular variation in seawater Mg/Ca and its effects on marine calcifiers, and review a series of recent experiments that investigate the effects of seawater Mg/Ca (1.0-5.2) on extant representatives of calcifying taxa that have experienced variations in this ionic ratio of seawater throughout the geologic past.-Secular variation in seawater Mg/Ca is supported by synchronized secular variations in (1) the ionic composition of fluid inclusions in primary marine halite, (2) the mineralogies of late stage marine evaporites, abiogenic carbonates, and reef-and sediment-forming marine calcifiers, (3) the Mg/Ca ratios of fossil echinoderms, molluscs, rugose corals, and abiogenic carbonates, (4) global rates of tectonism that drive the exchange of Mg2+ and Ca2+ along zones of ocean crust production, and (5) additional proxies of seawater Mg/Ca including Sr/Mg ratios of abiogenic carbonates, Sr/Ca ratios of biogenic carbonates, and Br concentrations in marine halite.-Laboratory experiments have revealed that aragonite-secreting bryopsidalean algae and scleractinian corals and calcite-secreting coccolithophores exhibit higher rates of calcification and growth in experimental seawaters formulated with seawater Mg/Ca ratios that favor their skeletal mineral. These results support the assertion that seawater Mg/Ca played an important role in determining which hypercalcifying marine organisms were the major reef-builders and sediment-producers throughout Earth history. The observation that primary production increased along with calcification within the bryopsidalean and coccolithophorid algae in mineralogically favorable seawater is consistent with the hypothesis that calcification promotes photosynthesis within some species of these algae through the liberation of CO2.-The experiments also revealed that aragonite-secreting bryopsidalean algae and scleractinian corals, and bacterial biofilms that secrete a mixture of aragonite and high Mg calcite, began secreting an increased proportion of their calcium carbonate as the calcite polymorph in the lower-Mg/Ca experimental seawaters. Furthermore, the Mg/Ca ratio of calcite secreted by the coccolithophores, coralline red algae, reef-dwelling animals (crustacea, urchins, calcareous tube worms), bacterial biofilms, scleractinian corals, and bryopsidalean algae declined with reductions in seawater Mg/Ca. Notably, Mg fractionation in autotrophic organisms was more strongly influenced by changes in seawater Mg/Ca than in heterotrophic organisms, a probable consequence of autotrophic organisms inducing a less controlled mode of calcification simply through the removal of CO 2 via photosynthesis.-These results indicate that biomineralogical control can be partially overridden by ambient seawater Mg/Ca and suggest that modern aragonite-secreting organisms may have secreted a mixture of aragonite and low Mg calcite, and that modern high Mg calcite-secreting organisms probably secreted low Mg calcite, in calcite seas of the past. These effects of seawater Mg/Ca on the polymorph mineralogy and calcite Mg/Ca ratio of calcareous skeletons should be accounted for in thermal-chemical reconstructions of seawater that are based upon skeletal Mg/Ca.-Lastly, by identifying how marine calcifiers respond to changes in seawater Mg/Ca and absolute Ca2+ concentration, this work should enhance our interpretation of parallel studies investigating the effects of anthropogenic CO 2-induced ocean acidification on marine calcification. © 2010 Author(s). Source


Martin N.,University of North Carolina at Chapel Hill
Antipode | Year: 2010

Transformations in urban economies are leading to the growth of jobs where labor and employment laws are routinely violated. Workers in these jobs are subject to harsh conditions such as low wages, hazardous work sites, and retaliation for speaking up. Many of these workers are undocumented migrants who are in a weak position to make demands on their employers or to request government assistance. These workers often turn to migrant civil society organizations for help with the multiple conflicts they face at work. Drawing on case studies of nonprofit organizations in Chicago, this paper focuses on the role of such organizations in the social reproduction of the migrant workforce. I posit that such organizations are integral to the functioning of the informal economy because the wide range of programs and services that they provide are essential to the social reproduction of migrant workers. © 2010 The Author Journal compilation © 2010 Editorial Board of Antipode. Source


Anderson M.S.,University of California at San Francisco | Su M.A.,University of North Carolina at Chapel Hill
Current Opinion in Immunology | Year: 2011

In the thymus, developing T cells that react against self-antigens with high affinity are deleted in the process of negative selection. An essential component of this process is the display of self-antigens, including those whose expression are usually restricted to specific tissues, to developing T cells within the thymus. The Autoimmune Regulator (Aire) gene plays a crucial role in the expression of tissue specific self-antigens within the thymus, and disruption of Aire function results in spontaneous autoimmunity in both humans and mice. Recent advances have been made in our understanding of how Aire influences the expression of thousands of tissue-specific antigens in the thymus. Additional roles of Aire, including roles in chemokine and cytokine expression, have also been revealed. Factors important in the differentiation of Aire-expressing medullary thymic epithelial cells have been defined. Finally, the identity of antigen presenting cells in negative selection, including the role of medullary thymic epithelial cells in displaying tissue specific antigens to T cells, has also been clarified. © 2010 Elsevier Ltd. Source


Macdonald J.R.,University of North Carolina at Chapel Hill
Electrochimica Acta | Year: 2014

Two different analyses of impedance data obtained from ultra-pure water allowed to equilibrate with the atmosphere have recently appeared. They both thus show much smaller low-frequency resistances than does ultra-pure water. Different fitting models were used in these analyses and led to appreciably different parameter estimates from their data fits. Their two "pure" water experimental data sets are here analyzed with a Poisson-Nernst-Planck model that incorporates the possibility of dissociation of a neutral species to positive and negative charges of arbitrary mobilities, anomalous diffusion in the interface region, and reaction of mobile ions at the electrodes. Complex-nonlinear-least-squares fitting of these data sets with either charges of a single sign mobile or with those of both signs mobile showed that the one-mobile choice was far superior to the two-mobile one. These results were compared both with newly calculated theoretical ultra-pure water immittance ones and with the results obtained in the earlier two papers, where different Poisson-Nernst-Planck-related fitting models were employed. Both involved the restrictive assumptions of full dissociation and two-mobile behavior with equal mobilities of the positive and negative charges. The dominant mobile charge species present in the equilibrated "pure" water data sets (protons for the ultra-pure water), involved mobile impurity ions, possibly oxygen ones. The Poisson-Nernst-Planck model used here is simpler than the other models, and it led to better fits of the data sets and to more physically significant parameter estimates than did the earlier fits. © 2014 Elsevier Ltd. All rights reserved. Source


Burd C.E.,University of North Carolina at Chapel Hill
PLoS genetics | Year: 2010

Human genome-wide association studies have linked single nucleotide polymorphisms (SNPs) on chromosome 9p21.3 near the INK4/ARF (CDKN2a/b) locus with susceptibility to atherosclerotic vascular disease (ASVD). Although this locus encodes three well-characterized tumor suppressors, p16(INK4a), p15(INK4b), and ARF, the SNPs most strongly associated with ASVD are ∼120 kb from the nearest coding gene within a long non-coding RNA (ncRNA) known as ANRIL (CDKN2BAS). While individuals homozygous for the atherosclerotic risk allele show decreased expression of ANRIL and the coding INK4/ARF transcripts, the mechanism by which such distant genetic variants influence INK4/ARF expression is unknown. Here, using rapid amplification of cDNA ends (RACE) and analysis of next-generation RNA sequencing datasets, we determined the structure and abundance of multiple ANRIL species. Each of these species was present at very low copy numbers in primary and cultured cells; however, only the expression of ANRIL isoforms containing exons proximal to the INK4/ARF locus correlated with the ASVD risk alleles. Surprisingly, RACE also identified transcripts containing non-colinear ANRIL exonic sequences, whose expression also correlated with genotype and INK4/ARF expression. These non-polyadenylated RNAs resisted RNAse R digestion and could be PCR amplified using outward-facing primers, suggesting they represent circular RNA structures that could arise from by-products of mRNA splicing. Next-generation DNA sequencing and splice prediction algorithms identified polymorphisms within the ASVD risk interval that may regulate ANRIL splicing and circular ANRIL (cANRIL) production. These results identify novel circular RNA products emanating from the ANRIL locus and suggest causal variants at 9p21.3 regulate INK4/ARF expression and ASVD risk by modulating ANRIL expression and/or structure. Source


Scotti A.,University of North Carolina at Chapel Hill
Journal of Physical Oceanography | Year: 2015

This paper uses the energetics framework developed by Scotti and White to provide a critical assessment of the widely used Thorpe-scale method, which is used to estimate dissipation and mixing rates in stratified turbulent flows from densitymeasurements along vertical profiles. This study shows that the relevant displacement scale in general is not the rms value of the Thorpe displacement. Rather, the displacement field must be Reynolds decomposed to separate the mean from the turbulent component, and it is the turbulent component that ought to be used to diagnose mixing and dissipation. In general, the energetics ofmixing in an overall stably stratified flow involves potentially complex exchanges among the available potential energy and kinetic energy associated with themean and turbulent components of the flow. The author considers two limiting cases: shear-driven mixing, where mixing comes at the expense of the mean kinetic energy of the flow, and convective-driven mixing, which taps the available potential energy of the mean flow to drive mixing. In shear-driven flows, the rms of the Thorpe displacement, known as the Thorpe scale is shown to be equivalent to the turbulent component of the displacement. In this case, the Thorpe scale approximates the Ozmidov scale, or, which is the same, the Thorpe scale is the appropriate scale to diagnosemixing and dissipation. However,whenmixing is driven by the available potential energy of the mean flow (convective-driven mixing), this study shows that the Thorpe scale is (much) larger than theOzmidov scale.Using the rms of the Thorpe displacement overestimates dissipation and mixing, since the amount of turbulent available potential energy (measured by the turbulent displacement) is only a fraction of the total available potential energy (measured by the Thorpe scale). Corrective measures are discussed that can be used to diagnosemixing from knowledge of the Thorpe displacement. In a companion paper,Mater et al. analyze field data and show that the Thorpe scale can indeed be much larger than the Ozmidov scale. © 2015 American Meteorological Society. Source


Fedoriw A.M.,University of North Carolina at Chapel Hill
G3 (Bethesda, Md.) | Year: 2012

The organization of the genome within the mammalian nucleus is nonrandom, with physiologic processes often concentrated in specific three-dimensional domains. This organization may be functionally related to gene regulation and, as such, may play a role in normal development and human disease processes. However, the mechanisms that participate in nuclear organization are poorly understood. Here, we present data characterizing localization of the imprinted Kcnq1 alleles. We show that nucleolar association of the paternal allele (1) is stimulated during the differentiation of trophoblast stem cells, (ii) is dependent upon the Kcnq1ot1 noncoding RNA, (3) does not require polycomb repressive complex 2, and (4) is not sufficient to preclude transcription of imprinted genes. Although nucleolar positioning has been proposed as a mechanism to related to gene silencing, we find that silencing and perinucleolar localization through the Kcnq1ot1 noncoding RNA are separable events. Source


Peragallo Urrutia R.,University of North Carolina at Chapel Hill
Obstetrics and gynecology | Year: 2013

To estimate the risk of venous thromboembolism, stroke, or myocardial infarction (MI) associated with the use of oral contraceptive pills (OCPs) and to describe how these risks vary by dose or formulation. We searched PubMed, Embase, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for studies published from January 1995 through June 2012 that evaluated the association between OCP use and risk of venous thromboembolism, stroke, or MI. We reviewed 6,476 citations. We included English-language, controlled studies with human participants reporting a quantitative association between exposure to OCPs and outcomes of venous thromboembolism, stroke, or MI. Two investigators independently reviewed articles for inclusion or exclusion; discordant decisions were resolved by team review and consensus. Random-effects meta-analysis was used to generate summary odds ratios (ORs). Fifty studies met inclusion criteria. There were no randomized clinical trials. We found threefold increased odds of venous thromboembolism among current compared with noncurrent OCP users (14 studies; OR 2.97, 95% confidence interval [CI] 2.46-3.59). We found twofold increased odds of ischemic stroke (seven studies; OR 1.90, 95% CI 1.24-2.91). There was no evidence of increased risk of hemorrhagic stroke (four studies; OR 1.03, 95% CI 0.71-1.49) or MI (eight studies; OR 1.34, 95% CI 0.87-2.08). Current use of combined OCPs is associated with increased odds of venous thromboembolism and ischemic stroke but not hemorrhagic stroke or MI. Source


Lord S.T.,University of North Carolina at Chapel Hill
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2011

Fibrin structure and stability have been linked to many thrombotic diseases, including venous thromboembolism. Analysis of the molecular mechanisms that affect fibrin structure and stability became possible when the crystal structure of fibrinogen was solved. Biochemical studies of natural and recombinant variant fibrinogens have examined the interactions that mediate the conversion of soluble fibrinogen to the insoluble fibrin network. These studies identified intermolecular interactions that control fibrin structure, although some critical events remain ambiguous. Studies show that fibrin structure modulates the enzymatic lysis of the fibrin network, so the molecular mechanisms that control structure also control stability. Studies show that the mechanical stability of the fibrin clot depends on the properties of the fibrin monomer, leading investigators to explore the molecular basis of the monomer's mechanical properties. The work summarized here provides insights that might allow the development of pharmaceuticals and treatments to modulate fibrin structure and stability in vivo and thereby prevent or limit thrombotic disease. Copyright © 2011 American Heart Association. All rights reserved. Source


Wetherington C.E.,University of North Carolina at Chapel Hill
Journal of pediatric psychology | Year: 2010

OBJECTIVE: The behavioral ratings of preschoolers who sustained traumatic brain injury (TBI) prior to the age of 2 years and a typically developing group were compared; predictors of behavioral functioning were examined. METHODS: Eighty-two 3-year-olds comprised mild TBI (n = 31), moderate/severe TBI (n = 20), and typically developing (n = 31) groups, with Child Behavior Checklist (CBCL) as the primary outcome measure. RESULTS: Groups differed on the CBCL Withdrawal Scale. No differences emerged in the proportion of children demonstrating clinical elevations, with average mean scores for each group. Exploratory analyses yielded no differences between inflicted, non-inflicted, and typical groups. Glasgow Coma Scale and Self-Report Family Inventory Leadership predicted Externalizing Problems; developmental level predicted Internalizing Problems. CONCLUSIONS: After early TBI, preschoolers did not differ from one another or a matched comparison group in behavioral ratings; however, it may be premature to infer that preschoolers do not evidence behavioral dysfunction after early TBI. Source


Zhang H.,University of North Carolina at Chapel Hill
Journal of Cerebral Blood Flow and Metabolism | Year: 2010

Severity of stroke varies widely among individuals. Whether differences in the extent of the native (preexisting) pial collateral circulation exist and contribute to this variability is unknown. We addressed these questions and probed for potential genetic contributions using morphometric analysis of the collateral circulation in 15 inbred mouse strains recently shown to exhibit wide differences in infarct volume. Morphometrics were determined in the unligated left hemisphere (for native collaterals) and ligated right hemisphere (for remodeled collaterals) 6 days after permanent middle cerebral artery (MCA) occlusion. Variation among strains in native collateral number, diameter, MCA, anterior cerebral artery (ACA), and posterior cerebral artery (PCA) tree territories were, respectively: 56-fold, 3-fold, 42%, 56%, and 61%. Collateral length (P< 0.001) and the number of penetrating arterioles branching from them also varied (P< 0.05). Infarct volume correlated inversely with collateral number (P< 0.0001), diameter (P< 0.0001), and penetrating arteriole number (P0.05) and directly with MCA territory (P0.05). Relative collateral conductance and MCA territory, when factored together, strongly predicted infarct volume (P0.0001). Outward remodeling of collaterals in the ligated hemisphere varied̃ 3-fold. These data show that the extent of the native pial collateral circulation and collateral remodeling after obstruction vary widely with genetic background, and suggest that this variability, due to natural polymorphisms, is a major contributor to variability in infarct volume. & 2010 ISCBFM. Source


Watkins P.B.,University of North Carolina at Chapel Hill
Clinical Pharmacology and Therapeutics | Year: 2011

During a recent review of a new drug application for treatment of a chronic disease, US Food and Drug Administration (FDA) regulators agreed with the sponsors assessment of efficacy. However, it was noted that two subjects receiving active treatment experienced abnormal liver chemistries that possibly, but not definitely, indicated a liver safety liability. The sponsor was told that a prerequisite for approval would be a new clinical trial involving 20,000 patients treated for 1 year, with 10,000 receiving the new drug and 10,000 receiving a comparator treatment. The sponsor is now faced with the substantial costs involved in undertaking such a large study, the loss of patent life during the conduct and analysis of the study, and the prospect of losing in-class market position. If the drug is ultimately approved, this detour will result in costs and potential revenue loss to the sponsor of well over $1 billion. © 2011 American Society for Clinical Pharmacology and Therapeutics. Source


Greenhawt M.J.,University of Michigan | Vickery B.P.,University of North Carolina at Chapel Hill
Journal of Allergy and Clinical Immunology: In Practice | Year: 2015

Food allergen oral immunotherapy (OIT) is an experimental, immune-modifying therapy that may induce clinical desensitization in some patients. OIT is still in early phase clinical research, but some providers may offer OIT as a clinical service. To understand the current practices of allergists who perform OIT, an online survey was sent by e-mail to members of the American Academy of Allergy Asthma & Immunology. Among 442 respondents, 61 reported participating in using OIT (13.8%), including 28 in nonacademic settings. Informed consent for OIT was obtained by 91.3%, institutional review board approval by 47.7% and Investigational New Drug approval by 38.1%. Compared with nonacademic participants, more academic participants used peanut OIT, obtained institutional review board and Investigational New Drug (P < .0001 respectively), and challenged patients before entry (P= .008). More nonacademic providers billed the patient or insurance for reimbursement (P < .0001). Low reported regard for the importance for US Food and Drug Administration approval or a standardized product (increased odds), and a high regard for better safety data (decreased odds) were associated with considering offering OIT as a service. Significant differences exist with OITs that occur in academic versus nonacademic settings. Further assessment is needed regarding the different motivations and practice styles among providers who offer OIT and those who are considering doing so. © 2014 American Academy of Allergy, Asthma & Immunology. Source


Dolan L.,University of North Carolina at Chapel Hill | Goddard P.,Institute for Advanced Study
Journal of High Energy Physics | Year: 2014

A proof is given of the formula, recently proposed by Cachazo, He and Yuan (CHY) for gluon tree amplitudes in pure Yang-Mills theory in arbitrary dimension. The approach is to first establish the corresponding result for massless φ3 theory using the BCFW recurrence relation and then to extend this to the gauge theory case. Additionally, it is shown that the scattering equations introduced by CHY can be generalized to massive particles, enabling the description of tree amplitudes for massive φ3 theory. © 2014 The Author(s). Source


Bloom K.S.,University of North Carolina at Chapel Hill
Annual Review of Genetics | Year: 2014

Centromeres are specialized domains of heterochromatin that provide the foundation for the kinetochore. Centromeric heterochromatin is characterized by specific histone modifications, a centromere-specific histone H3 variant (CENP-A), and the enrichment of cohesin, condensin, and topoisomerase II. Centromere DNA varies orders of magnitude in size from 125 bp (budding yeast) to several megabases (human). In metaphase, sister kinetochores on the surface of replicated chromosomes face away from each other, where they establish microtubule attachment and bi-orientation. Despite the disparity in centromere size, the distance between separated sister kinetochores is remarkably conserved (approximately 1 μm) throughout phylogeny. The centromere functions as a molecular spring that resists microtubule-based extensional forces in mitosis. This review explores the physical properties of DNA in order to understand how the molecular spring is built and how it contributes to the fidelity of chromosome segregation. © 2014 by Annual Reviews. All rights reserved. Source


Ulrich J.N.,University of North Carolina at Chapel Hill
Retina | Year: 2014

PURPOSE:: To evaluate if a single drop of nepafenac can reduce the ocular discomfort after intravitreal injections compared with placebo. METHODS:: One hundred and twenty patients undergoing intravitreal injections of bevacizumab or ranibizumab received a drop of nepafenac or placebo (Systane Ultra) after the injection in a prospective, double-masked, randomized controlled design. Patients rated their pain levels from 0 to 3 (no pain, mild pain, moderate pain, severe pain) at 1 hour, 6 hours, and 24 hours after the procedure. RESULTS:: Statistically significant reduction of postinjection pain with nepafenac was noted 6 hours after the injection when compared with placebo (0.8 ± 0.6 [standard deviation] vs. 1.3 ± 0.8, P < 0.001) with similar trends at 1 hour (1.1 ± 0.7 vs. 1.3 ± 0.7, P = 0.12) and 24 hours (0.3 ± 0.5 vs. 0.5 ± 0.6, P = 0.15). CONCLUSION:: A single drop of nepafenac is effective in reducing discomfort after intravitreal injections. © 2013 Ophthalmic Communications Society, Inc. Source


Moss L.A.,Injury Prevention Research Center | Skelton J.A.,University of North Carolina at Chapel Hill
New England Journal of Medicine | Year: 2015

BACKGROUND The prevalence of severe obesity among children and young adults has increased over the past decade. Although the prevalence of cardiometabolic risk factors is relatively low among children and young adults who are overweight or obese, those with more severe forms of obesity may be at greater risk. METHODS We performed a cross-sectional analysis of data from overweight or obese children and young adults 3 to 19 years of age who were included in the National Health and Nutrition Examination Survey from 1999 through 2012 to assess the prevalence of multiple cardiometabolic risk factors according to the severity of obesity. Weight status was classified on the basis of measured height and weight. We used standard definitions of abnormal values for total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, triglycerides, blood pressure, glycated hemoglobin, and fasting glucose and report the prevalence of abnormal values in children and young adults according to weight status. RESULTS Among 8579 children and young adults with a body-mass index at the 85th percentile or higher (according to the Centers for Disease Control and Prevention growth charts), 46.9% were overweight, 36.4% had class I obesity, 11.9% had class II obesity, and 4.8% had class III obesity. Mean values for some, but not all, cardiometabolic variables were higher with greater severity of obesity in both male and female participants, and the values were higher in male participants than in female participants; for HDL cholesterol, the mean values were lower with greater severity of obesity. Multivariable models that controlled for age, race or ethnic group, and sex showed that the greater the severity of obesity, the higher the risks of a low HDL cholesterol level, high systolic and diastolic blood pressures, and high triglyceride and glycated hemoglobin levels. CONCLUSIONS Severe obesity in children and young adults was associated with an increased prevalence of cardiometabolic risk factors, particularly among boys and young men. © 2015 Massachusetts Medical Society. All rights reserved. Source


Berkowitz M.L.,University of North Carolina at Chapel Hill | Vacha R.,University of Cambridge
Accounts of Chemical Research | Year: 2012

In a sense, life is defined by membranes, because they delineate the barrier between the living cell and its surroundings. Membranes are also essential for regulating the machinery of life throughout many interfaces within the cell's interior. A large number of experimental, computational, and theoretical studies have demonstrated how the properties of water and ionic aqueous solutions change due to the vicinity of membranes and, in turn, how the properties of membranes depend on the presence of aqueous solutions. Consequently, understanding the character of aqueous solutions at their interface with biological membranes is critical to research progress on many fronts.The importance of incorporating a molecular-level description of water into the study of biomembrane surfaces was demonstrated by an examination of the interaction between phospholipid bilayers that can serve as model biological membranes. The results showed that, in addition to well-known forces, such as van der Waals and screened Coulomb, one has to consider a repulsion force due to the removal of water between surfaces. It was also known that physicochemical properties of biological membranes are strongly influenced by the specific character of the ions in the surrounding aqueous solutions because of the observation that different anions produce different effects on muscle twitch tension.In this Account, we describe the interaction of pure water, and also of aqueous ionic solutions, with model membranes. We show that a symbiosis of experimental and computational work over the past few years has resulted in substantial progress in the field. We now better understand the origin of the hydration force, the structural properties of water at the interface with phospholipid bilayers, and the influence of phospholipid headgroups on the dynamics of water. We also improved our knowledge of the ion-specific effect, which is observed at the interface of the phospholipid bilayer and aqueous solution, and its connection with the Hofmeister series.Nevertheless, despite substantial progress, many issues remain unresolved. Thus, for example, we still cannot satisfactorily explain the force of interaction between phospholipid bilayers immersed in aqueous solutions of NaI. Although we try to address many issues here, the scope of the discussion is limited and does not cover such important topics as the influence of ionic solutions on phases of bilayers, the influence of salts on the properties of Langmuir monolayers containing lipid molecules, or the influence of aqueous solutions on bilayers containing mixtures of lipids. We anticipate that the future application of more powerful experimental techniques, in combination with more advanced computational hardware, software, and theory, will produce molecular-level information about these important topics and, more broadly, will further illuminate our understanding of interfaces between aqueous solutions and biological membranes. © 2011 American Chemical Society. Source


Coleman R.A.,University of North Carolina at Chapel Hill | Mashek D.G.,University of Minnesota
Chemical Reviews | Year: 2011

An overview of TAG metabolism as a dynamic process that allows its lipid participants to play numerous inter-related roles within cells is presented. For most synthetic pathways each step is catalyzed by a single enzyme unless specific regulation is required. Yet, in the glycerol-3-phosphate pathway of TAG synthesis, investigators have confirmed four independent GPAT isoforms, three AGPAT isoforms, three PAP isoforms, and two DGAT isoforms. The non-backcrossed mice resist weight gain on a high-fat diet. Their subdermal fat depots are absent, and their gonadal and brown adipose fat pads and adipocytes are smaller. The differences in fat pad size are not solely due to absent GPAT4 activity within the tissue, because although NEM-sensitive GPAT activity in brown adipose is 50% lower than in wild-type brown adipose, gonadal NEM-sensitive GPAT activity is identical. Source


Matute D.R.,University of North Carolina at Chapel Hill
American Naturalist | Year: 2015

Reinforcement is the process by which selection against hybridization leads to an increase in reproductive isolation. The influence of reinforcing selection can be detected when sympatric individuals (those from areas of secondary contact) show a higher degree of prezygotic isolation than allopatric individuals (those from areas outside each other’s range). In areas of secondary contact with Drosophila santomea, Drosophila yakuba females show reinforcement of gametic isolation but not behavioral isolation, despite the fact that both behavioral and gametic isolation evolve in D. yakuba in experimental sympatry. Using behavioral assays and experimental evolution, I studied how both gametic and behavioral isolation are affected by biotic factors that the two species encounter in their natural environment. I show that if D. yakuba females are in environments where D. yakuba, D. santomea, and males from other species coexist, these females cannot fully discern between conspecific and heterospecific males. In such complex environments, gametic but not behavioral isolation evolves. The presence of nonhybridizing species can constrain the effect of reinforcement on behavioral isolation. © 2015 by The University of Chicago. Source


Wilson E.M.,University of North Carolina at Chapel Hill
Asian Journal of Andrology | Year: 2014

A gain-of-function stabilizing somatic mutation in 3?-hydroxysteroid dehydrogenase type 1 (3?HSD1, HSD3B1) was reported in castration-resistant prostate cancer. The A?C nucleotide polymorphism replaced asparagine-367 with threonine (3?HSD1-N367T) as a homozygous somatic mutation in a subset of castration-resistant prostate cancers by loss of heterozygosity of the wild-type allele. Increased stability of 3?HSD1-N367T was assoc i a ted with de c re a s ed ubiquitin-mediated degradation and higher levels of dihydrotestosterone (DHT). Th e studies suggest that genetic instability in castration-resistant prostate cancer favors the more stable 3?HSD1-N367T mutant that contributes to drug resistance. A somatic mutation in a steroid metabolic enzyme required for DHT synthesis provides further support for intratumoral androgen synthesis contributing to prostate cancer progression. Source


Williams S.E.,University of North Carolina at Chapel Hill | Fuchs E.,Rockefeller University
Current Opinion in Cell Biology | Year: 2013

During development, the establishment of proper tissue architecture depends upon the coordinated control of cell divisions not only in space and time, but also direction. Execution of an oriented cell division requires establishment of an axis of polarity and alignment of the mitotic spindle along this axis. Frequently, the cleavage plane also segregates fate determinants, either unequally or equally between daughter cells, the outcome of which is either an asymmetric or symmetric division, respectively. The last few years have witnessed tremendous growth in understanding both the extrinsic and intrinsic cues that position the mitotic spindle, the varied mechanisms in which the spindle orientation machinery is controlled in diverse organisms and organ systems, and the manner in which the division axis influences the signaling pathways that direct cell fate choices. © 2013 Elsevier Ltd. Source


Dolan L.,University of North Carolina at Chapel Hill | Goddard P.,Institute for Advanced Study
Journal of High Energy Physics | Year: 2014

The scattering equations, recently proposed by Cachazo, He and Yuan as providing a kinematic basis for describing tree amplitudes for massless particles in arbitrary space-time dimension (including scalars, gauge bosons and gravitons), are reformulated in polynomial form. The scattering equations for N particles are shown to be equivalent to a Möbius invariant system of N - 3 equations, h ̃ m = 0, 2 ≤ m ≤ N - 2, in N variables, where h ̃ m is a homogeneous polynomial of degree m, with the exceptional property of being linear in each variable taken separately. Fixing the Möbius invariance appropriately, yields polynomial equations h m = 0, 1 ≤ m ≤ N - 3, in N - 3 variables, where h m has degree m. The linearity of the equations in the individual variables facilitates computation, e.g. the elimination of variables to obtain single variable equations determining the solutions. Expressions are given for the tree amplitudes in terms of the h ̃ m and h m. The extension to the massive case for scalar particles is described and the special case of four dimensional space-time is discussed. © 2014 The Author(s). Source


Liu J.,University of North Carolina at Chapel Hill | Linhardt R.J.,Rensselaer Polytechnic Institute
Natural Product Reports | Year: 2014

Heparan sulfate is a polysaccharide that plays essential physiological functions in the animal kingdom. Heparin, a highly sulfated form of heparan sulfate, is a widely prescribed anticoagulant drug worldwide. The heparan sulfate and heparin isolated from natural sources are highly heterogeneous mixtures differing in their polysaccharide chain lengths and sulfation patterns. The access to structurally defined heparan sulfate and heparin is critical to probe the contribution of specific sulfated saccharide structures to the biological functions as well as for the development of the next generation of heparin-based anticoagulant drugs. The synthesis of heparan sulfate and heparin, using a purely chemical approach, has proven extremely difficult, especially for targets larger than octasaccharides having a high degree of site-specific sulfation. A new chemoenzymatic method has emerged as an effective alternative approach. This method uses recombinant heparan sulfate biosynthetic enzymes combined with unnatural uridine diphosphate-monosaccharide donors. Recent examples demonstrate the successful synthesis of ultra-low molecular weight heparin, low-molecular weight heparin and bioengineered heparin with unprecedented efficiency. The new method provides an opportunity to develop improved heparin-based therapeutics. © The Royal Society of Chemistry 2014. Source


THREE DOCETAXEL (DX) LIPID CONJUGATES: 2'-lauroyl-docetaxel (C12-DX), 2'-stearoyl-docetaxel (C18-DX), and 2'-behenoyl-docetaxel (C22-DX) were synthesized to enhance drug loading, entrapment, and retention in liquid oil-filled lipid nanoparticles (NPs). The three conjugates showed ten-fold higher solubility in the liquid oil phase Miglyol 808 than DX. To further increase the drug entrapment efficiency in NPs, orthogonal design was performed. The optimized formulation was composed of Miglyol 808, Brij 78, and Vitamin E tocopheryl polyethylene glycol succinate (TPGS). The conjugates were successfully entrapped in the reduced-surfactant NPs with entrapment efficiencies of about 50%-60% as measured by gel permeation chromatography (GPC) at a final concentration of 0.5 mg/mL. All three conjugates showed 45% initial burst release in 100% mouse plasma. Whereas C12-DX showed another 40% release over the next 8 hours, C18-DX and C22-DX in NPs showed no additional release after the initial burst of drug. All conjugates showed significantly lower cytotoxicity than DX in human DU-145 prostate cancer cells. The half maximal inhibitory concentration values (IC(50)) of free conjugates and conjugate NPs were comparable except for C22-DX, which was nontoxic in the tested concentration range and showed only vehicle toxicity when entrapped in NPs. In vivo, the total area under the curve (AUC(0-∞)) values of all DX conjugate NPs were significantly greater than that of Taxotere, demonstrating prolonged retention of drug in the blood. The AUC(0-∞) value of DX in Taxotere was 8.3-fold, 358.0-fold, and 454.5-fold lower than that of NP-formulated C12-DX, C18-DX, and C22-DX, respectively. The results of these studies strongly support the idea that the physical/chemical properties of DX conjugates may be fine-tuned to influence the affinity and retention of DX in oil-filled lipid NPs, which leads to very different pharmacokinetic profiles and blood exposure of an otherwise potent chemo-therapeutic agent. These studies and methodologies may allow for improved and more potent nanoparticle-based formulations. Source


Adair L.S.,University of North Carolina at Chapel Hill
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2012

Aims: The purpose of this paper is to provide a general framework for thinking about pathways and potential mechanisms through which complementary feeding may influence the risk of developing non-communicable diseases (NCDs). Data synthesis: To provide a context for the lack of clear and consistent evidence relating complementary feeding to NCD risk, methodological challenges faced in trying to develop an evidence base are described. Potential pathways through which complementary feeding may influence obesity-related NCD risk are described and illustrated with examples. Conclusions: Numerous aspects of complementary feeding, including diet composition as well as patterns of feeding have the potential to influence the early development of obesity, which in turn predicts later obesity and NCD risk. Specific dietary exposures during the period of complementary feeding also have the potential to program future disease risk through pathways that are independent of adiposity. These factors all require consideration when making recommendations for optimal complementary feeding practices aimed at prevention of future NCDs. © 2012 Elsevier B.V. Source


Lee A.M.,University of North Carolina at Chapel Hill
Disability and Rehabilitation | Year: 2011

Purpose. Researchers in early childhood conducting secondary data analysis face a number of challenges shared by other early childhood professionals, including needs for efficient, descriptive language to convey characteristics of individuals' functioning to varied audiences. These professionals may benefit from a systematic approach for organising and sharing data which can describe children as functioning wholes with skills across many domains. This study explored the ability of the International Classification of Functioning, Disability and Health for Children and Youth (ICF-CY) to address these needs by considering its utility to adequately organise and describe constructs of child functioning in an existing data set. Methods. Variables from a large data set were mapped to chapters of the ICF-CY Activities/Participation component. Factor analysis with a split-half approach was utilised to explore the relative structural integrity of chapter structure as a mechanism for generating a profile of constructs of child functioning. Results. All variables mapped to chapters of the ICF-CY Activities/Participation component. The factor analyses indicated that variables, which mapped to the same chapter tended to load to the same factor, with the exception of items describing child communication which loaded to all factors. Results further suggested the overlapping nature of children's skills, such that skills in one area likely impact functioning in other functioning domains. Conclusion. The ICF-CY provides adequate depth and breadth for use in conceptualising new questions and information in existing data sets. Findings suggest the structure of the ICF-CY Activities/Participation chapters could be used for generating meaningful profiles of human functioning across salient domains. © 2011 Informa UK, Ltd. Source


Zolotor A.J.,University of North Carolina at Chapel Hill
Pediatric Clinics of North America | Year: 2014

Corporal punishment is used for discipline in most homes in the United States. It is also associated with a long list of adverse developmental, behavioral, and health-related consequences. Primary care providers, as trusted sources for parenting information, have an opportunity to engage parents in discussions about discipline as early as infancy. These discussions should focus on building parents' skills in the use of other behavioral techniques, limiting (or eliminating) the use of corporal punishment and identifying additional resources as needed. © 2014 Elsevier Inc. Source


Ching J.K.S.,University of North Carolina at Chapel Hill
Urban Climate | Year: 2013

Environmental issues and impacts to society will be exacerbated with increased population, diminishing resources and climate changes. Current models available for weather, climate and air quality applications are powerful state-of-science modeling systems can be employed to address the impact of these issues. This paper reviews a selected subset of such systems, considered representative of community-based publically available modeling systems and focus on their utilization for urban applications. Special attention is required given the complex and high degree of spatial inhomogeneity of the underlying surface areas. Such applications optimally require relatively fine grid meshes and scale appropriate science description for the varied and complex land surface atmospheric processes commensurate to the fine scale land surface variability structure. This article provides a brief review and perspective on means and science parameterizations for urban focused modeling in these major modeling systems. Several issues, limitations as well as innovative opportunities specific to the optimal operations of these urban systems, with focus on fine mesh size and data needs are identified and discussed. © 2013 Elsevier Ltd. Source


Bergmeier W.,University of North Carolina at Chapel Hill
Cold Spring Harbor perspectives in biology | Year: 2012

The adhesion and aggregation of platelets during hemostasis and thrombosis represents one of the best-understood examples of cell-matrix adhesion. Platelets are exposed to a wide variety of extracellular matrix (ECM) proteins once blood vessels are damaged and basement membranes and interstitial ECM are exposed. Platelet adhesion to these ECM proteins involves ECM receptors familiar in other contexts, such as integrins. The major platelet-specific integrin, αIIbβ3, is the best-understood ECM receptor and exhibits the most tightly regulated switch between inactive and active states. Once activated, αIIbβ3 binds many different ECM proteins, including fibrinogen, its major ligand. In addition to αIIbβ3, there are other integrins expressed at lower levels on platelets and responsible for adhesion to additional ECM proteins. There are also some important nonintegrin ECM receptors, GPIb-V-IX and GPVI, which are specific to platelets. These receptors play major roles in platelet adhesion and in the activation of the integrins and of other platelet responses, such as cytoskeletal organization and exocytosis of additional ECM ligands and autoactivators of the platelets. Source


Stuebe A.M.,University of North Carolina at Chapel Hill
Seminars in Perinatology | Year: 2015

In mammalian physiology, lactation follows pregnancy. Disruption of this physiology is associated with long-term adverse maternal health outcomes, including higher risks of later-life obesity, type 2 diabetes, metabolic syndrome, hypertension, and cardiovascular disease. Multiple mechanisms likely contribute to these associations, including the metabolic demands of breastfeeding, modulation of stress reactivity, and confounding by other health behaviors. At the same time, evidence suggests that maternal metabolic health entering pregnancy affects lactation performance. In this paradigm, adverse lactation outcomes may be a marker for underlying maternal disease risk. Understanding these relationships has important clinical and policy implications for women's health. © 2015 Elsevier Inc. Source


Bors P.A.,University of North Carolina at Chapel Hill
American Journal of Preventive Medicine | Year: 2012

The Active Living by Design (ALbD) National Program Office (NPO) developed an evaluation system to track progress of 25 community partnerships, funded by the Robert Wood Johnson Foundation (RWJF). Between June 2004 and October 2008, partnerships documented their actions and accomplishments through ALbD's online Progress Reporting System (PRS) database. All entries were verified and analyzed by the NPO. Results from the PRS suggest that the ALbD partnerships were successful fundraisers, leveraging $256 million from grants, policy decisions, in-kind and direct sources. The partnerships also documented newspaper coverage, TV, and radio air time and they developed physical activity programs such as exercise clubs and "walking school buses." Partnerships were adept at influencing decision makers to create or rewrite policies and improve built environments. Selected policy examples included, but were not limited to, approvals for capital improvements, street design standards, and development ordinances. Partnerships also contributed to the completion and approval of influential planning products, such as comprehensive land use, neighborhood, and roadway corridor plans. The most common built-environment changes were street improvements for safer pedestrian and bicycle travel, including new crosswalks, bicycle facilities, and sidewalks. The ALbD community partnerships' accomplishments and challenges contribute to knowledge and best practices in the active living field. Five years after their grant began, RWJF's initial investment showed substantial and measurable results. © 2012 American Journal of Preventive Medicine. Source


The genome sequences of several giant marine sulfur-oxidizing bacteria present evidence of a possible post-transcriptional regulatory network that may have been transmitted to or from two distantly related bacteria lineages. The draft genome of a Cand. "Maribeggiatoa" filament from the Guaymas Basin (Gulf of California, Mexico) seafloor contains 169 sets of TAACTGA direct repeats and one indirect repeat, with two to six copies per set. Related heptamers are rarely or never found as direct repeats. TAACTGA direct repeats are also found in some other Beggiatoaceae, Thiocystis violascens, a range of Cyanobacteria, and five Bacteroidetes. This phylogenetic distribution suggests they may have been transmitted horizontally, but no mechanism is evident. There is no correlation between total TAACTGA occurrences and repeats per genome. In most species the repeat units are relatively short, but longer arrays of up to 43 copies are found in several Bacteroidetes and Cyanobacteria. The majority of TAACTGA repeats in the Cand. "Maribeggiatoa" Orange Guaymas (BOGUAY) genome are within several nucleotides upstream of a putative start codon, suggesting they may be binding sites for a post-transcriptional regulator. Candidates include members of the ribosomal protein S1, Csp (cold shock protein), and Csr (carbon storage regulator) families. No pattern was evident in the predicted functions of the open reading frames (ORFs) downstream of repeats, but some encode presumably essential products such as ribosomal proteins. Among these is an ORF encoding a possible alternate or modified RNA polymerase beta prime subunit, predicted to have the expected subunit interaction domains but lacking most catalytic residues. A similar ORF was found in the Thioploca ingrica draft genome, but in no others. In both species they are immediately upstream of putative sensor kinase genes with nearly identical domain structures. In the marine Beggiatoaceae, a role for the TAACTGA repeats in translational regulation is suggested. More speculatively, the putative alternate RNA polymerase subunit could be a negative transcriptional regulator. © 2015 MacGregor. Source


Frantz D.J.,University of North Carolina at Chapel Hill
Current Gastroenterology Reports | Year: 2012

Approximately one in three Americans is obese. Current society guidelines recommend bariatric surgery after conservative measures at weight loss have failed. The frequency of bariatric surgeries has increased significantly over the past decade. While considered both safe and effective, bariatric surgery presents a distinct set of risks. This review focuses on the neurological complications of bariatric surgery. Injuries have been reported at all levels of the nervous system, including the central, peripheral, and enteric nervous system. Injury can be classified according to time of presentation and location. The two main mechanisms of nerve injury are from mechanical injury or as a consequence of malnutrition. Encephalopathy, peripheral neuropathies, myelopathies, and radiculoneuropathies have all been reported. Mechanical injuries likely occur from mechanical compression. Malnutrition injuries result from multimicronutrient deficiencies. The most likely candidates are vitamin B12, folate, zinc, thiamin, copper, vitamin A, and vitamin E deficiencies. © Springer Science+Business Media, LLC 2012. Source


Watson R.A.,University of North Carolina at Chapel Hill
Journal of Surgical Education | Year: 2014

Objective This study was used to test the feasibility of using additive fabrication techniques 3-dimensional (3D) printing to create personalized/patient-specific hepatic 3D physical models from clinical radiology studies for surgical resident education. Design Patient-specific imaging data from either computed tomography or magnetic resonance imaging scans, in Digital Imaging and Communications in Medicine format, were rendered and manipulated with computer software, translating the medical imaging data sets into useful 3D geometry files in stereo lithography format for 3D printing. A commercial third party was used to print the 3D models in laser sintered nylon, which provided access to expensive, industrial-grade, high-resolution 3-D printers at a low cost. Results Multiple patient-specific preoperative 3D physical models were printed of portal and hepatic venous anatomy at a cost of less than $100 per model. Conclusion Current 3D printing techniques can be used to create low-cost personalized/patient-specific hepatic 3D models from clinical radiology studies for surgical resident education. Source


Culton D.A.,University of North Carolina at Chapel Hill
Journal of Investigative Dermatology | Year: 2015

There are two major clinical subsets of pemphigus vulgaris (PV)—mucosal PV (mPV) and mucocutaneous PV (mcPV). The mPV subset exhibits anti-human desmoglein (Dsg) 3 autoantibodies that fail to recognize murine Dsg3 (mDsg3); thus, passive transfer experiments of mPV IgG into wild-type (WT) mice have been unsuccessful at inducing disease. We therefore generated a fully humanized Dsg3 (hDSG3) murine model utilizing a hDsg3 transgenic animal crossed to the mDsg3 knockout line. Expression of hDsg3 in the mucosa rescues the mDsg3 knockout phenotype. Well-characterized mPV sera bind mucosal epithelia from the hDsg3 mice, but not mucosal tissues from WT mice, as detected by indirect immunofluorescence (IF). The majority of mPV sera preferentially recognize hDsg3 compared with mDsg3 by immunoprecipitation as well. Passive transfer of mPV IgG into adult hDsg3 mice, but not WT mice, induces suprabasilar acantholysis in mucosal tissues, thus confirming the pathogenicity of mPV anti-hDsg3 IgG in vivo. Human anti-hDsg3 antibodies are detected in perilesional mucosa as well as in sera of recipient mice by IF. These findings suggest that the Dsg3 epitopes targeted by pathogenic mPV IgG are human specific. This hDsg3 mouse model will be invaluable in studying the clinical transition from mPV to mcPV.Journal of Investigative Dermatology advance online publication, 26 March 2015; doi:10.1038/jid.2015.54. © 2015 The Society for Investigative Dermatology, Inc Source


Margolis D.M.,University of North Carolina at Chapel Hill
AIDS Research and Human Retroviruses | Year: 2011

Despite the success of antiretroviral therapy (ART) in decreasing mortality for HIV-1-infected patients, ART has not cured the disease. A persistent viral reservoir in the T cells of HIV patients receiving potent ART is a significant barrier preventing eradication of HIV infection. We will briefly review what is known about the mechanisms that establish and maintain persistent HIV infection despite ART, to create a framework in which to consider approaches to the clearance or eradication of infection ("cure"), or to allow clinical stability in the absence of ART ("functional cure"). With regard to eradication therapies, it could be said that as a field our position is analogous to that of ART early in the HIV pandemic. As then we must now simultaneously develop and optimize platforms and paradigms for the discovery and testing of eradication therapies, and begin to advance candidate therapies toward human testing. © Copyright 2011, Mary Ann Liebert, Inc. Source


Casazza B.A.,University of North Carolina at Chapel Hill
American Family Physician | Year: 2012

Acute low back pain is one of the most common reasons for adults to see a family physician. Although most patients recover quickly with minimal treatment, proper evaluation is imperative to identify rare cases of serious underlying pathology. Certain red flags should prompt aggressive treatment or referral to a spine specialist, whereas others are less concerning. Serious red flags include significant trauma related to age (i.e., injury related to a fall from a height or motor vehicle crash in a young patient, or from a minor fall or heavy lifting in a patient with osteoporosis or possible osteoporosis), major or progressive motor or sensory deficit, new-onset bowel or bladder incontinence or urinary retention, loss of anal sphincter tone, saddle anesthesia, history of cancer metastatic to bone, and suspected spinal infection. Without clinical signs of serious pathology, diagnostic imaging and laboratory testing often are not required. Although there are numerous treatments for nonspecific acute low back pain, most have little evidence of benefit. Patient education and medications such as nonsteroidal anti-inflammatory drugs, acetaminophen, and muscle relaxants are beneficial. Bed rest should be avoided if possible. Exercises directed by a physical therapist, such as the McKenzie method and spine stabilization exercises, may decrease recurrent pain and need for health care services. Spinal manipulation and chiropractic techniques are no more effective than established medical treatments, and adding them to established treatments does not improve outcomes. No substantial benefit has been shown with oral steroids, acupuncture, massage, traction, lumbar supports, or regular exercise programs. © 2012 American Academy of Family Physicians. Source


Kahn R.,University of North Carolina at Chapel Hill | Sievenpiper J.L.,Knowledge Factor | Sievenpiper J.L.,McMaster University
Diabetes Care | Year: 2014

In the preceding point narrative, Drs. Bray and Popkin provide their opinion and review data that suggest to them that we need to reconsider the consumption of dietary sugar based on the growing concern of obesity and type 2 diabetes. In the counterpoint narrative below, we argue that there is no clear or convincing evidence that any dietary or added sugar has a unique or detrimental impact relative to any other source of calories on the development of obesity or diabetes. Sugar is purely a highly palatable source of energy; because it has no other property that appears to contribute to our nutritional well-being, it is not an essential food for most of us. For those who wish to reduce energy consumption, ingesting less sugar is a good place to start. However, doing so does not automatically portend any clinical benefit. © 2014 by the American Diabetes Association. Source


Meehana T.D.,University of Wisconsin - Madison | Hurlbert A.H.,University of North Carolina at Chapel Hill | Gratton C.,University of Wisconsin - Madison
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Mandates for biofuel and renewable electricity are creating incentives for biomass production in agricultural landscapes of the Upper Midwest. Different bioenergy crops are expected to vary in their effects on biodiversity and ecosystem services. Here, we use data from the North American Breeding Bird Survey to forecast the impact of potential bioenergy crops on avian species richness and the number of bird species of conservation concern in Midwestern landscapes. Our analysis suggests that expanded production of annual bioenergy crops (e.g., corn and soybeans) on marginal land will lead to declines in avian richness between 7% and 65% across 20% of the region, and will make managing at-risk species more challenging. In contrast, replacement of annual with diverse perennial bioenergy crops (e.g., mixed grasses and forbs) is expected to bring increases in avian richness between 12% and 207% across 20% of the region, and possibly aid the recovery of several species of conservation concern. Source


Pickles R.J.,University of North Carolina at Chapel Hill | DeVincenzo J.P.,University of Memphis
Journal of Pathology | Year: 2015

Infants and young children with acute onset of wheezing and reduced respiratory airflows are often diagnosed with obstruction and inflammation of the small bronchiolar airways, ie bronchiolitis. The most common aetological agents causing bronchiolitis in young children are the respiratory viruses, and of the commonly encountered respiratory viruses, respiratory syncytial virus (RSV) has a propensity for causing bronchiolitis. Indeed, RSV bronchiolitis remains the major reason why previously healthy infants are admitted to hospital. Why RSV infection is such a predominant cause of bronchiolitis is the subject of this review. By reviewing the available histopathology of RSV bronchiolitis, both in humans and relevant animal models, we identify hallmark features of RSV infection of the distal airways and focus attention on the consequences of columnar cell cytopathology occurring in the bronchioles, which directly impacts the development of bronchiolar obstruction, inflammation and disease. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Source


MacDonald J.R.,University of North Carolina at Chapel Hill
Journal of Physical Chemistry C | Year: 2013

This feature article highlights work done by the author and others since 1953 on the Poisson-Nernst-Planck (PNP) continuum model for analyzing and fitting wide-range immittance-spectroscopy (IS) frequency-response data for unsupported materials with diffusing mobile charge species present. The small-signal PNP approach, one relevant for analyzing data involving ordinary or anomalous diffusion, is particularly important because it leads to estimates of the values of far more physically significant parameters than do other available IS fitting models. Unfortunately, its virtues were not well appreciated until recently, and it has thus not been used as widely as it should be. The present work aims at remedying this lack by providing a thorough description of the strengths and weaknesses of the model, its response possibilities, and its broad applicability. It deals with a neutral species that can fully or partially dissociate into positive and negative charged species of equal concentrations but arbitrary mobilities. The full model, including bulk, mobility, generation-recombination, electrode reaction, and adsorption parameters, is first described, and some of its simplified response functions are presented. It is also incorporated in the free LEVMW complex-nonlinear- least-squares fitting program, making all of its features available for analyzing experimental IS data sets. After a detailed review of relevant theoretical and experimental published work involving the PNP approach, exact graphical responses are presented of progressively more complicated PNP models mostly involving charge of only one sign mobile for all four IS immittance levels. Then it is shown to what degree the various PNP-model responses can be fitted within usual experimental error limits by other more common, but less physically germane continuum, discrete, and empirical models. The positive results of such fitting greatly expand the range of usefulness and applicability of the PNP models. Fits of exact and noisy IS Randles-circuit data sets involving a finite-length Warburg part are compared with those involving different PNP models, and the finite-length-Warburg complex-plane response is discussed and compared with that of the interface part of the PNP response. Finally, some other PNP full and interface response possibilities are discussed and illustrated, and results are presented that involve specific adsorption and adsorption-reaction electrode processes of physical interest to such fields as biology, corrosion, and energy storage. Since a composite PNP fitting model with charges of both signs mobile is shown to exactly fit both exact data sets derived from the ordinary Randles circuit and ones generalized to include additional low- or high-frequency relaxation behavior, its scope and utility for fitting and interpreting experimental data should make it the preferred alternative to most fitting circuits that involve both ordinary resistive and capacitive parameters as well as distributed elements such as finite-length Warburg ones. © 2013 American Chemical Society. Source


Shabalin A.A.,University of North Carolina at Chapel Hill
Bioinformatics | Year: 2012

Motivation: Expression quantitative trait loci (eQTL) analysis links variations in gene expression levels to genotypes. For modern datasets, eQTL analysis is a computationally intensive task as it involves testing for association of billions of transcript-SNP (single-nucleotide polymorphism) pair. The heavy computational burden makes eQTL analysis less popular and sometimes forces analysts to restrict their attention to just a small subset of transcript-SNP pairs. As more transcripts and SNPs get interrogated over a growing number of samples, the demand for faster tools for eQTL analysis grows stronger.Results: We have developed a new software for computationally efficient eQTL analysis called Matrix eQTL. In tests on large datasets, it was 2-3 orders of magnitude faster than existing popular tools for QTL/eQTL analysis, while finding the same eQTLs. The fast performance is achieved by special preprocessing and expressing the most computationally intensive part of the algorithm in terms of large matrix operations. Matrix eQTL supports additive linear and ANOVA models with covariates, including models with correlated and heteroskedastic errors. The issue of multiple testing is addressed by calculating false discovery rate; this can be done separately for cis- and trans-eQTLs. © The Author 2012. Published by Oxford University Press. All rights reserved. Source


Hoegh-Guldberg O.,University of Queensland | Bruno J.F.,University of Queensland | Bruno J.F.,University of North Carolina at Chapel Hill
Science | Year: 2010

Marine ecosystems are centrally important to the biology of the planet, yet a comprehensive understanding of how anthropogenic climate change is affecting them has been poorly developed. Recent studies indicate that rapidly rising greenhouse gas concentrations are driving ocean systems toward conditions not seen for millions of years, with an associated risk of fundamental and irreversible ecological transformation. The impacts of anthropogenic climate change so far include decreased ocean productivity, altered food web dynamics, reduced abundance of habitat-forming species, shifting species distributions, and a greater incidence of disease. Although there is considerable uncertainty about the spatial and temporal details, climate change is clearly and fundamentally altering ocean ecosystems. Further change will continue to create enormous challenges and costs for societies worldwide, particularly those in developing countries. Copyright Science 2010 by the American Association for the Advancement of Science; all rights reserved. Source


Wise E.K.,University of North Carolina at Chapel Hill
International Journal of Climatology | Year: 2015

Proxy-based reconstructions of the Pacific Decadal Oscillation (PDO) are essential for understanding pre-instrumental variability in this low-frequency oscillation. Multiple reconstructions of the PDO exist but demonstrate weak coherence prior to the 20th century. Analyses of atmospheric moisture and pressure patterns in teleconnected tree-ring sites used for the reconstructions indicate that terrestrial climate impact patterns associated with northern Pacific conditions have been spatially variable over the instrumental period. Tropical Pacific and Northern Hemisphere climate modes influence these surface patterns and are reflected in the PDO reconstructions. Divergence prior to the 20th century calibration period may be due to time-dependent nonlinearities in the PDO and changes in the influence of the El Niño-Southern Oscillation system over time. © 2014 Royal Meteorological Society. Source


Johnson G.L.,University of North Carolina at Chapel Hill
ACS Chemical Biology | Year: 2011

The mitogen-activated protein kinase (MAPK) signaling network is integrated into most, if not all, defined homeostatic and regulatory responses of eukaryotic cells. A systematic experimental and computational approach has been used to identify more than 2,000 protein interactions related to functions and regulation of the MAPK signaling network. This discovery process provides a rich data and reagent resource for defining complexities of protein networks involving MAPKs and control of cellular physiology. © 2011 American Chemical Society. Source


Kaza N.,University of North Carolina at Chapel Hill
Energy Policy | Year: 2010

Residential energy consumption accounts for 22% of the total energy consumption in the US. However, the impacts of local planning policies, such as increasing density and changing the housing type mix, on residential energy consumption are not well understood. Using Residential Energy Consumption Survey Data from the Energy Information Administration, quantile regression analysis was used to tease out the effects of various factors on entire distribution on the energy consumption spectrum instead of focusing on the conditional average. Results show that while housing size matters for space conditioning, housing type has a more nuanced impact. Self-reported neighborhood density does not seem to have any impact on energy use. Furthermore, the effects of these factors at the tails of the energy use distribution are substantially different than the average, in some cases differing by a factor of six. Some, not all, types of multifamily housing offer almost as much savings as reduction in housing area by 100m2, compared to single family houses. © 2010 Elsevier Ltd. Source


A common adaptation in angiosperms is the deposition of hydrophilic mucilage into the apoplast of seed coat epidermal cells during the course of their differentiation. Upon imbibition, seed mucilage, composed mainly of carbohydrates (i.e. pectins, hemicelluloses and glycans) expands rapidly, encapsulating the seed and aiding in seed dispersal and germination. The FEI1/FEI2 receptor-like kinases and the SOS5 extracellular GPI-anchored protein were previously shown to act on a pathway regulating cellulose biosynthesis during Arabidopsis root elongation. In the highlighted study, we demonstrated that FEI2 and SOS5 regulate the production of the cellulosic rays deposited across the inner adherent-layer of seed mucilage. Mutations in either fei2 or sos5 disrupted the formation of rays, which was associated with an increase in the soluble, outer layer of pectin mucilage and accompanied by a reduction in the inner adherent-layer. Mutations in CELLULOSE SYNTHASE 5 also led to reduced rays and mal-partitioning of the pectic component of seed mucilage, further establishing a structural role for cellulose in seed mucilage. Here, we show that FEI2 expressed from a CaMV 35S promoter complemented both root and seed mucilage defects of the fei1 fei2 double mutant. In contrast, expression of FEI1 from a 35S promoter complemented the root, but not the seed phenotype of the fei1 fei2 double mutant, suggesting that unlike in the root, FEI2 plays a unique and non-redundant role in the regulation of cellulose synthesis in seed mucilage. Altogether, these data suggest a novel role for cellulose in anchoring the pectic component of seed mucilage to the seed surface and indicate that the FEI2 protein has a function distinct from that of FEI1, despite the high sequence similarity of these RLKs. Source


Smith S.H.,University of North Carolina at Chapel Hill
Transactions of the Institute of British Geographers | Year: 2013

Young Ladakhis have grown up along disputed borders between Pakistan and China in India's Jammu and Kashmir State. During their lifetimes, conflict in Kashmir and in their hometowns (between the Buddhist majority and Muslim minority) has highlighted the region's geopolitical vulnerability; in words overheard in the schoolyard and kitchen, religion is always already political and territorial. This article traces how young Muslim and Buddhist Ladakhis in Ladakh's Leh District are constituted as a category and site of territorial potential, and how the young people I spoke with navigate and elude this positioning. Their grandparents married across religious lines and their parents used family planning enthusiastically, but these practices are now political problems. Youth alternate between cynicism and hopeful visions of the future. Meanwhile, parents see education in distant urban centres as a path to a desired 'modernity', but also as a dangerous site where unruly love, lack of supervision and immorality might compromise religious identity. Building on geographies of young people and religion, and on anthropologies of the future, this research draws on two youth projects, a survey and interviews. I suggest that parents, political actors and religious leaders conceive of the young as crucial to the constitution of future territories. This makes their bodies a site of intense anxiety and regulation, as well as hope and potential. Beyond this case study, I offer the concept of generational vertigo, a mixture of apprehension and anticipation regarding the future, and suggest that attending to how and why this vertigo is manifest provides a way to think through relationships between young people, time and territory. The future is located in the volatile bodies of young people; hence the desire to defend territory and shape the future is manifest in attempts to manage the potential of these bodies. © 2012 The Author. Transactions of the Institute of British Geographers © 2012 Royal Geographical Society (with the Institute of British Geographers). Source


Davies Jonathan T.,McGill University | Buckley L.B.,University of North Carolina at Chapel Hill
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

Phylogenetic diversity (PD) captures the shared ancestry of species, and is increasingly being recognized as a valuable conservation currency. Regionally, PD frequently covaries closely with species richness; however, variation in speciation and extinction rates and/or the biogeographic history of lineages can result in significant deviation. Locally, these differences may be pronounced. Rapid recent speciation or high temporal turnover of lineages can result in low PD but high richness. In contrast, rare dispersal events, for example, between biomes, can elevate PD but have only small impact on richness. To date, environmental predictors of species richness have been well studied but global models explaining variation in PD are lacking. Here, we contrast the global distribution of PD versus species richness for terrestrial mammals. We show that an environmental model of lineage diversification can predict well the discrepancy in the distribution of these two variables in some places, for example, South America and Africa but not others, such as Southeast Asia. When we have information on multiple diversity indices, conservation efforts directed towards maximizing one currency or another (e.g. species richness versus PD) should also consider the underlying processes that have shaped their distributions. © 2011 The Royal Society. Source


Unemo M.,Orebro University | Nicholas R.A.,University of North Carolina at Chapel Hill
Future Microbiology | Year: 2012

The new superbug Neisseria gonorrhoeae has retained resistance to antimicrobials previously recommended for first-line treatment and has now demonstrated its capacity to develop resistance to the extended-spectrum cephalosporin, ceftriaxone, the last remaining option for first-line empiric treatment of gonorrhea. An era of untreatable gonorrhea may be approaching, which represents an exceedingly serious public health problem. Herein, we review the evolution, origin and spread of antimicrobial resistance and resistance determinants (with a focus on extended-spectrum cephalosporins) in N. gonorrhoeae, detail the current situation regarding verified treatment failures with extended-spectrum cephalosporins and future treatment options, and highlight essential actions to meet the large public health challenge that arises with the possible emergence of untreatable gonorrhea. Essential actions include: implementing action/response plans globally and nationally; enhancing surveillance of gonococcal antimicrobial resistance, treatment failures and antimicrobial use/misuse; and improving prevention, early diagnosis and treatment of gonorrhea. Novel treatment strategies, antimicrobials (or other compounds) and, ideally, a vaccine must be developed. © 2012 Future Medicine Ltd. Source


Zeisel S.H.,University of North Carolina at Chapel Hill
Journal of Nutrition | Year: 2011

As it becomes evident that single nucleotide polymorphisms (SNPs) in humans can create metabolic inefficiencies, it is reasonable to ask if such SNPs influence dietary requirements. Epidemiologic studies that examine SNPs relative to risks for diseases are common, but there are few examples of clinically sized nutrition studies that examine how SNPs influence metabolism. Studies on how SNPs influence the dietary requirement for choline provide a model for how we might begin examining the effects of SNPs on nutritional phenotypes using clinically sized studies (clinical nutrigenomics). Most men and postmenopausal women develop liver or muscle dysfunction when deprived of dietary choline. More than one-half of premenopausal women may be resistant to choline deficiency-induced organ dysfunction, because estrogen induces the gene [phosphatidylethanolamine-N-methyltransferase (PEMT)] that catalyzes endogenous synthesis of phosphatidylcholine, which can subsequently yield choline. Those premenopausal women that do require a dietary source of choline have a SNP in PEMT, making them unresponsive to estrogen induction of PEMT. It is important to recognize differences in dietary requirements for choline in women, because during pregnancy, maternal dietary choline modulates fetal brain development in rodent models. Because choline metabolism and folate metabolism intersect at the methylation of homocysteine, manipulations that limit folate availability also increase the use of choline as a methyl donor. People with a SNPs in MTHFD1 (a gene of folate metabolism that controls the use of folate as a methyl donor) are more likely to develop organ dysfunction when deprived of choline; their dietary requirement is increased because of increased need for choline as a methyl donor. © 2011 American Society for Nutrition. Source


Whisman M.A.,University of Colorado at Boulder | Baucom D.H.,University of North Carolina at Chapel Hill
Clinical Child and Family Psychology Review | Year: 2012

Relationship functioning and individual mental health and well-being are strongly associated with one another. In this article, we first review the cross-sectional and longitudinal associations between relationship discord and various types of psychopathology, We then review findings suggesting that relationship discord is associated with poorer outcome for individual-based treatments for psychopathology and that, generally, relationship discord does not improve following individual-based treatments for psychopathology. Finally, we present a model for conceptualizing work with couples in which one partner has a psychiatric disorder and review the efficacy of couple-based interventions in the treatment for psychiatric disorders, with a focus on substance-related, mood, and anxiety disorders. © 2011 Springer Science+Business Media, LLC. Source


Blackburn J.T.,University of North Carolina at Chapel Hill
Medicine and Science in Sports and Exercise | Year: 2016

PURPOSE: Chronic quadriceps dysfunction has been implicated as a contributor to knee osteoarthritis (OA) development following anterior cruciate ligament reconstruction (ACLR). This dysfunction potentially leads to impulsive/high rate loading during gait, thus accelerating cartilage degradation. The purpose of this study was to examine relationships between several indices of quadriceps function and gait biomechanics linked to knee OA development in individuals with ACLR. METHODS: Gait biomechanics and quadriceps function were assessed in 39 individuals with ACLR. Indices of quadriceps function included isometric peak torque and rate of torque development (RTD), isokinetic peak torque and power, and the central activation ratio (CAR). Gait biomechanics included the peak vertical ground reaction force and loading rate, and the heelstrike transient (HST) magnitude and loading rate. RESULTS: Isometric peak torque was not associated with any of the gait biomechanical variables. However, greater RTD was associated with lesser peak vGRF linear (r = -0.490, p = 0.003) and instantaneous (r = -0.352, p = 0.031) loading rates, as well as a lesser HST magnitude (r = -0.312, p = 0.049) and instantaneous loading rate (r = -0.355, p = 0.029). Greater CAR was associated with greater HST instantaneous (r = 0.311, p = 0.050) and linear (r = 0.328, p = 0.033) loading rates. Isokinetic peak torque and power not associated with any of the biomechanical variables. CONCLUSION: Poor quadriceps function, especially RTD, is associated with gait kinetics linked to cartilage degradation in individuals with ACLR. These results highlight the likely role of chronic quadriceps dysfunction in OA development following ACLR and the need to emphasize improving quadriceps function as a primary rehabilitation goal. © 2016 American College of Sports Medicine Source


Guerry J.D.,University of North Carolina at Chapel Hill | Hastings P.D.,University of California at Davis
Clinical Child and Family Psychology Review | Year: 2011

Dysregulation of the Hypothalamic-pituitary-adrenal (HPA) axis in adults with major depressive disorder is among the most consistent and robust biological findings in psychiatry. Given the importance of the adolescent transition to the development and recurrence of depressive phenomena over the lifespan, it is important to have an integrative perspective on research investigating the various components of HPA axis functioning among depressed young people. The present narrative review synthesizes evidence from the following five categories of studies conducted with children and adolescents: (1) those examining the HPA system's response to the dexamethasone suppression test (DST); (2) those assessing basal HPA axis functioning; (3) those administering corticotropin-releasing hormone (CRH) challenge; (4) those incorporating psychological probes of the HPA axis; and (5) those examining HPA axis functioning in children of depressed mothers. Evidence is generally consistent with models of developmental psychopathology that hypothesize that atypical HPA axis functioning precedes the emergence of clinical levels of depression and that the HPA axis becomes increasingly dysregulated from child to adult manifestations of depression. Multidisciplinary approaches and longitudinal research designs that extend across development are needed to more clearly and usefully elucidate the role of the HPA axis in depression. © 2011 The Author(s). Source


Baird D.D.,U.S. National Institutes of Health | Steiner A.Z.,University of North Carolina at Chapel Hill
American Journal of Epidemiology | Year: 2012

The objective of the present commentary is to suggest that epidemiologists explore the use of anti-Müllerian hormone (AMH) as a new measurement tool in fecundability studies. The authors briefly summarize the advantages and limitations of the 3 current approaches to studies of fecundability. All 3 approaches involve the collection of time-to-pregnancy or attempt-time data, and most are limited to participants who plan their pregnancies. AMH is produced by ovarian follicles during their early growth stages and is measured clinically to assess ovarian reserve (the number of remaining oocytes). Unlike time to pregnancy, serum AMH level can be assessed regardless of pregnancy-attempt status. Measurements are not significantly affected by phase of the menstrual cycle, oral contraceptive use, or early pregnancy. The authors suggest that AMH measurement can be a valuable addition to traditionally designed fecundability studies. In addition, this hormone should be investigated as an independent measure of fecundability in studies that focus on exposures hypothesized to target the ovary. © 2012 The Author. Source


Suzuki A.,University of North Carolina at Chapel Hill
Nature Chemical Biology | Year: 2016

Protein kinase signaling along the kinetochore–centromere axis is crucial to assure mitotic fidelity, yet the details of its spatial coordination are obscure. Here, we examined how pools of human Polo-like kinase 1 (Plk1) within this axis control signaling events to elicit mitotic functions. To do this, we restricted active Plk1 to discrete subcompartments within the kinetochore–centromere axis using chemical genetics and decoded functional and phosphoproteomic signatures of each. We observe distinct phosphoproteomic and functional roles, suggesting that Plk1 exists and functions in discrete pools along this axis. Deep within the centromere, Plk1 operates to assure proper chromosome alignment and segregation. Thus, Plk1 at the kinetochore is a conglomerate of an observable bulk pool coupled with additional functional pools below the threshold of microscopic detection or resolution. Although complex, this multiplicity of locales provides an opportunity to decouple functional and phosphoproteomic signatures for a comprehensive understanding of Plk1's kinetochore functions. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source


Cotten S.W.,University of North Carolina at Chapel Hill
Nature protocols | Year: 2011

mRNA display is a powerful yet challenging in vitro selection technique that can be used to identify proteins with desired properties from both natural proteome and combinatorial polypeptide libraries. The physical conjugation between a protein and its own RNA presents unique challenges in manipulating the displayed proteins at a low nanomolar scale in an RNase-free environment. The following protocol outlines the generation of cDNA libraries derived from natural organisms as well as the steps required for generation of mRNA-protein fusion molecules, in vitro functional selection and regeneration of the selected cDNA library. The selection procedures for the identification of protease substrates and Ca(2+)-dependent calmodulin-binding proteins from natural cDNA libraries are presented as examples. The method can be generally applied to the identification of protein sequences with desired properties from various natural proteome libraries. One round of mRNA display-based selection can be accomplished in ~7 d. Source


Jaspers I.,University of North Carolina at Chapel Hill
Annals of the American Thoracic Society | Year: 2014

It is well established that exposure to cigarette smoke (CS), through active smoking and through exposure to secondhand smoke, has immunosuppressive effects, yet how this might affect the microbiome is not known. In this manuscript we focus on the effects of CS on innate host defense response, with particular emphasis on the role of epithelial cells and mucosal immune responses in the nose and the potential effects on the microbiome. The studies described here briefly summarize the effects of CS on specific innate immune cells, such as neutrophils, macrophages/monocytes, natural killer cells, and dendritic cells. A detailed description of how CS affects epithelial cells and why we consider this to be a central defect in the overall immunosuppressive effects of CS in the lung is provided. We summarize data on the role of the "epimmunome" in the context of CS exposure, including the effects on soluble mediator production, such as cytokines, chemokines, and antimicrobial defense mediators. Separate emphasis is put on the expression of ligands on epithelial cells, which directly interact with receptors on immune cells, and the effects of CS on these interactions. We introduce the nose and nasal mucosa as a model to study the effects of CS exposure on host defense responses and changes in the microbiome in humans in vivo. Understanding the dynamics of a healthy microbiome and how CS affects this balance is important to uncovering the mechanisms of CS-induced disease. Copyright © 2014 by the American Thoracic Society. Source


Heckman J.J.,University of North Carolina at Chapel Hill | Heckman J.J.,Jefferson Lab
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2015

M5-branes probing an ADE singularity lead to 6D SCFTs with (1, 0) supersymmetry. On the tensor branch, the M5-branes specify domain walls of a 7D Super Yang-Mills theory with gauge group G of ADE-type, thus providing conformal matter for a broad class of generalized quiver theories. Additionally, these theories have G×. G flavor symmetry, and a corresponding Higgs branch. In this Note we use the F-theory realization of these theories to calculate the scaling dimension of the operator parameterizing seven-brane recombination, i.e. motion of the stack of M5-branes off of the orbifold singularity. In all cases with an interacting fixed point, we find that this operator has scaling dimension at least six, and defines a marginal irrelevant deformation. © 2015. Source


O'Connell T.D.,University of Minnesota | Jensen B.C.,University of North Carolina at Chapel Hill | Baker A.J.,University of California at San Francisco | Simpson P.C.,University of California at San Francisco
Pharmacological Reviews | Year: 2014

Adrenergic receptors (AR) are G-protein-coupled receptors (GPCRs) that have a crucial role in cardiac physiology in health and disease. Alpha1-ARs signal through Gαq, and signaling through Gq, for example, by endothelin and angiotensin receptors, is thought to be detrimental to the heart. In contrast, cardiac alpha1-ARs mediate important protective and adaptive functions in the heart, although alpha1-ARs are only a minor fraction of total cardiac ARs. Cardiac alpha1-ARs activate pleiotropic downstream signaling to prevent pathologic remodeling in heart failure. Mechanisms defined in animal and cell models include activation of adaptive hypertrophy, prevention of cardiac myocyte death, augmentation of contractility, and induction of ischemic preconditioning. Surprisingly, at the molecular level, alpha1-ARs localize to and signal at the nucleus in cardiac myocytes, and, unlike most GPCRs, activate "inside-out" signaling to cause cardioprotection. Contrary to past opinion, human cardiac alpha1-AR expression is similar to that in the mouse, where alpha1-AR effects are seen most convincingly in knockout models. Human clinical studies show that alpha1-blockade worsens heart failure in hypertension and does not improve outcomes in heart failure, implying a cardioprotective role for human alpha1-ARs. In summary, these findings identify novel functional and mechanistic aspects of cardiac alpha1-AR function and suggest that activation of cardiac alpha1-AR might be a viable therapeutic strategy in heart failure. Source


Heitsch F.,University of North Carolina at Chapel Hill
Astrophysical Journal | Year: 2013

Two aspects of filamentary molecular cloud evolution are addressed: (1) exploring analytically the role of the environment for the evolution of filaments demonstrates that considering them in isolation (i.e., just addressing the fragmentation stability) will result in unphysical conclusions about the filament's properties. Accretion can also explain the observed decorrelation between FWHM and peak column density. (2) Free-fall accretion onto finite filaments can lead to the characteristic "fans" of infrared-dark clouds around star-forming regions. The fans may form due to tidal forces mostly arising at the ends of the filaments, consistent with numerical models and earlier analytical studies. © 2013. The American Astronomical Society. All rights reserved. Source


Zeisel S.H.,University of North Carolina at Chapel Hill
Clinical Chemistry and Laboratory Medicine | Year: 2013

There are multiple identified mechanisms involved in energy metabolism, insulin resistance and adiposity, but there are here-to-fore unsuspected metabolic factors that also influence these processes. Studies in animal models suggest important links between choline/1-carbon metabolism and energy homeostasis. Rodents fed choline deficient diets become hypermetabolic. Mice with deletions in one of several different genes of choline metabolism have phenotypes that include increased metabolic rate, decreased body fat/lean mass ratio, increased insulin sensitivity, decreased ATP production by mitochondria, or decreased weight gain on a high fat diet. In addition, farmers have recognized that the addition of a metabolite of choline (betaine) to cattle and swine feed reduces body fat/lean mass ratio. Choline dietary intake in humans varies over a > three-fold range, and genetic variation exists that modifies individual requirements for this nutrient. Although there are some epidemiologic studies in humans suggesting a link between choline/1-carbon metabolism and energy metabolism, there have been no controlled studies in humans that were specifically designed to examine this relationship. Source


Heitsch F.,University of North Carolina at Chapel Hill
Astrophysical Journal | Year: 2013

Two aspects of the evolution of externally pressurized, hydrostatic filaments are discussed. (1) The free-fall accretion of gas onto such a filament will lead to filament parameters (specifically, FWHM-column-density relations) inconsistent with the observations of Arzoumanian et al., except for two cases: for low-mass, isothermal filaments, agreement is found as in the analysis by Fischera & Martin. Magnetized cases, for which the field scales weakly with the density as Bn 1/2, also reproduce observed parameters. (2) Realistically, the filaments will be embedded not only in gas of non-zero pressure, but also of non-zero density. Thus, the appearance of sheet-embedded filaments is explored. Generating a grid of filament models and comparing the resulting column density ratios and profile shapes with observations suggests that the three-dimensional filament profiles are intrinsically flatter than isothermal, beyond projection and evolution effects. © 2013. The American Astronomical Society. All rights reserved. Source


Weiner B.J.,University of North Carolina at Chapel Hill
Medical care research and review : MCRR | Year: 2011

Over the past 10 years, the field of health services and management research has seen renewed interest in the use of qualitative research methods. This article examines the volume and characteristics of qualitative research articles published in nine major health services and management journals between 1998 and 2008. Qualitative research articles comprise 9% of research articles published in these journals. Although the publication rate of qualitative research articles has not kept pace with that of quantitative research articles, citation analysis suggests that qualitative research articles contribute comparably to the field's knowledge base. A wide range of policy and management topics has been examined using qualitative methods. Case study designs, interviews, and documentary sources were the most frequently used methods. Half of qualitative research articles provided little or no detail about key aspects the study's methods. Implications are discussed and recommendations are offered for promoting the publication of qualitative research. Source


Popkin B.M.,University of North Carolina at Chapel Hill
Physiology and Behavior | Year: 2010

Total beverage intake patterns have changed greatly over the past half century. The present research was conducted to evaluate historic and current patterns of beverage consumption of adults and children in the U.S. Data were drawn from food balance surveys along with two-day beverage intake averages and were weighted to be nationally representative. A marked slow continuous shift downward in total milk intake with a shift toward an increased proportion of reduced fat milk was determined. The biggest shifts in beverage consumption among children aged 2 to18 were an increase in sugar-sweetened beverages (SSBs) (from 87 to 154. kcal/d), a smaller increase in juices (+. 21. kcal/d), and a decrease in milk consumption (-91 kcal/d). Data among adults aged 19 and older indicated that SSB intake has more than doubled. Water intake was highly variable, with a marked increase in bottled water intake but no clear trend in total water intake. Overall trends by age were presented and indicated that age-related beverage intake, both in ounces and kcal/day, decreased sharply for adults aged 60 and older. Kcal/d values ranged from a low of 283 for those over age 60 to a peak of 533 for those aged 19 to39 to 367 for 2 to 6. year olds. The consumer shift toward increased levels of SSBs and alcohol, limited amounts of reduced fat milk along with a continued consumption of whole milk, and increased juice intake represent issues to address from a public health perspective. © 2010 Elsevier Inc. Source


White M.K.,Temple University | Pagano J.S.,University of North Carolina at Chapel Hill | Khalili K.,Temple University
Clinical Microbiology Reviews | Year: 2014

About a fifth of all human cancers worldwide are caused by infectious agents. In 12% of cancers, seven different viruses have been causally linked to human oncogenesis: Epstein-Barr virus, hepatitis B virus, human papillomavirus, human T-cell lymphotropic virus, hepatitis C virus, Kaposi's sarcoma herpesvirus, and Merkel cell polyomavirus. Here, we review the many molecular mechanisms of oncogenesis that have been discovered over the decades of study of these viruses. We discuss how viruses can act at different stages in the complex multistep process of carcinogenesis. Early events include their involvement in mutagenic events associated with tumor initiation such as viral integration and insertional mutagenesis as well as viral promotion of DNA damage. Also involved in tumor progression is the dysregulation of cellular processes by viral proteins, and we describe how this has been investigated by studies in cell culture and in experimental animals and by molecular cellular approaches. Also important are the molecular mechanisms whereby viruses interact with the immune system and the immune evasion strategies that have evolved. © 2014, American Society for Microbiology. All Rights Reserved. Source


Dellon E.S.,University of North Carolina at Chapel Hill
Gastroenterology Clinics of North America | Year: 2014

In this article, the epidemiology of eosinophilic esophagitis (EoE) is reviewed. Demographic features and natural history are described, the prevalence and incidence of EoE are highlighted, and risk factors for EoE are discussed. EoE can occur at any age, there is a male predominance, it is more common in whites, and there is a strong association with atopic diseases. EoE is chronic, relapses are frequent, and persistent inflammation increases the risk of fibrostenotic complications. The prevalence is currently estimated at 0.5-1 in 1000, and EoE is now the most common cause of food impaction. The incidence of EoE is approximately 1/10,000 new cases per year, and the increase in incidence is outpacing increases in recognition and endoscopy volume, but the reasons for this evolving epidemiology are not yet fully delineated. © 2014 Elsevier Inc. Source


Carson C.C.,University of North Carolina at Chapel Hill | Levine L.A.,Rush University Medical Center
BJU International | Year: 2014

The aims of the present review were to assess the literature on published outcomes and complications associated with surgical treatments for Peyronie's disease (PD) and to assist clinicians in the effective management of PD by increasing understanding and awareness of the outcomes associated with current surgical treatment options. A PubMed literature search was conducted to identify relevant, peer-reviewed clinical and review articles published between January 1980 and October 2013 related to outcomes of surgical correction of PD. Search terms for this non-systematic review included 'Peyronie's disease', 'outcomes', 'complications', 'erectile dysfunction or ED', 'patient expectation', and 'patient satisfaction'; search terms were searched separately and in combination. Case studies and editorials were excluded, primary manuscripts and reviews were included, and bibliographies of articles of interest were reviewed and key references were obtained. Assessment of the study design, methodology, clinical relevance and impact on the surgical outcomes of PD was performed on the sixty-one articles that were selected and analysed. Currently, there are several investigational minimally invasive and non-surgical treatment options for PD; however, surgical treatment remains the standard of care for patients with stable disease and disabling deformity or drug-resistant erectile dysfunction. Each of the different surgical procedures that are used for treatment of PD, including tunical shortening, tunical lengthening (plaque incisions or partial excision and grafting), and use of inflatable penile prostheses, carries its own advantages and disadvantages in terms of potential complications and postoperative satisfaction. Because of the variety of ways that PD may present in affected patients, no single, standard, surgical treatment for this disorder has prevailed and multiple variations of each type of procedure may exist. Surgical outcomes of the most commonly used procedures are not substantially different; therefore, the appropriateness of each treatment option may often depend on disease and patient characteristics (e.g. deformity and erectile function). Surgical algorithms have been published to guide surgeons and patients through the selection of surgical procedures in the absence of conclusive, long-term outcome data. Accumulating data on outcomes associated with established procedures, modifications to these procedures, and new surgical techniques and materials may serve to further guide practice and refine evidence-based selection of the surgical approach. © 2013 The Authors. BJU International © 2013 BJU International. Source


Kaza N.,University of North Carolina at Chapel Hill
Landscape and Urban Planning | Year: 2013

The hallmark of development in the United States has been sprawling urbanisation. However, most of the analyses about urbanisation have focused on specific regions or metropolitan areas. This study provides a comprehensive overview of the changing urban landscape patterns between 2001 and 2006. Using the land cover data from the US Geological Survey for these 2 years, I characterise the landscape metrics for each county in the continental United States. The changes in these metrics are correlated with the drivers of urbanisation including socioeconomic variables. Uneven and heterogeneous patterns of growth in a country this large are not surprising. However, the metrics reveal that while urban counties are becoming less fragmented, some rural counties in the Southern and Western United States are experiencing significant leapfrog development. © 2012 Elsevier B.V. Source


Arnosti C.,University of North Carolina at Chapel Hill
Annual Review of Marine Science | Year: 2011

Extracellular enzymes initiate microbial remineralization of organic matter by hydrolyzing substrates to sizes sufficiently small to be transported across cell membranes. As much of marine primary productivity is processed by heterotrophic microbes, the substrate specificities of extracellular enzymes, the rates at which they function in seawater and sediments, and factors controlling their production, distribution, and active lifetimes, are central to carbon cycling in marine systems. In this review, these topics are considered from biochemical, microbial/molecular biological, and geochemical perspectives. Our understanding of the capabilities and limitations of heterotrophic microbial communities has been greatly advanced in recent years, in part through genetic and genomic approaches. New methods to measure enzyme activities in the field are needed to keep pace with these advances and to pursue intriguing evidence that patterns of enzyme activities in different environments are linked to differences in microbial community composition that may profoundly affect the marine carbon cycle. Copyright © 2011 by Annual Reviews. All rights reserved. Source


Wiley R.H.,University of North Carolina at Chapel Hill
Biological Reviews | Year: 2013

Recognition of conspecifics occurs when individuals classify sets of conspecifics based on sensory input from them and associate these sets with different responses. Classification of conspecifics can vary in specificity (the number of individuals included in a set) and multiplicity (the number of sets differentiated). In other words, the information transmitted varies in complexity. Although recognition of conspecifics has been reported in a wide variety of organisms, few reports have addressed the specificity or multiplicity of this capability. This review discusses examples of these patterns, the mechanisms that can produce them, and the evolution of these mechanisms. Individual recognition is one end of a spectrum of specificity, and binary classification of conspecifics is one end of a spectrum of multiplicity. In some cases, recognition requires no more than simple forms of learning, such as habituation, yet results in individually specific recognition. In other cases, recognition of individuals involves complex associations of multiple cues with multiple previous experiences in particular contexts. Complex mechanisms for recognition are expected to evolve only when simpler mechanisms do not provide sufficient specificity and multiplicity to obtain the available advantages. In particular, the evolution of cooperation and deception is always promoted by specificity and multiplicity in recognition. Nevertheless, there is only one demonstration that recognition of specific individuals contributes to cooperation in animals other than primates. Human capacities for individual recognition probably have a central role in the evolution of complex forms of human cooperation and deception. Although relatively little studied, this capability probably rivals cognitive abilities for language. © 2012 Cambridge Philosophical Society. Source


Sartor R.B.,University of North Carolina at Chapel Hill
Mucosal Immunology | Year: 2011

Co-evolution with an extremely complex commensal enteric microbiota has helped shape mammalian mucosal immune responses. A yet incompletely defined subset of intestinal bacteria is required to stimulate chronic, immune-mediated intestinal inflammation, including human Crohn's disease, and intestinal microbiota composition is altered in a characteristic manner by the inflammatory response to create a dysbiotic relationship of protective vs. aggressive bacteria. We pose a number of questions regarding host interactions with the enteric microbiota, including influences of inflammation, host genetics, early environmental exposure, and diet on microbial composition and function, and conversely, the effect of bacterial metabolism, enteric fungi and viruses, and endogenous protective bacterial species on host immune and inflammatory responses. These questions are designed to stimulate research that will promote a better understanding of host-microbial interactions in the intestine and promote targeted novel therapeutic interventions. © 2011 Society for Mucosal Immunology. Source


Evans J.P.,University of North Carolina at Chapel Hill | Meslin E.M.,Indiana University | Marteau T.M.,Kings College London | Caulfield T.,University of Alberta
Science | Year: 2011

Unrealistic expectations and uncritical translation of genetic discoveries may undermine other promising approaches to preventing disease and improving health. Source


Labbok M.H.,University of North Carolina at Chapel Hill
Breastfeeding Medicine | Year: 2012

Background: The World Health Organization (WHO)/UNICEF Baby-Friendly Hospital Initiative (BFHI) was developed to support the implementation of the Ten Steps for Successful Breastfeeding. The purpose of this study is to assess trends in the numbers facilities ever-designated "Baby-Friendly," to consider uptake of the new WHO/UNICEF BFHI materials, and to consider implications for future breastfeeding support. Materials and Methods: The national contacts from the 2006-2007 UNICEF BFHI update were recontacted, as were WHO and UNICEF officers worldwide, to ascertain the number of hospitals ever-designated "Baby-Friendly," presence of a government breastfeeding oversight committee, use of the new BFHI materials and, if yes, use of the new maternity or human immunodeficiency virus (HIV) materials. Results: Seventy countries reporting in 2010-2011 and the updates from an additional 61 reporting in 2006-2007 (n=131, or 66% of the 198 countries) confirm that there are at least 21,328 ever-designated facilities. This is 27.5% of maternities worldwide: 8.5% of those in industrialized countries and 31% in less developed settings. In 2010, government committees were reported by 18 countries, and 34 reported using the new BFHI materials: 14 reported using the maternity care and 11 reported using the HIV materials. Conclusions: Rates of increase in the number of ever-certified "Baby-Friendly" hospitals vary by region and show some chronological correlation with trends in breastfeeding rates. Although it is not possible to attribute this increase to the BFHI alone, there is ongoing interest in Ten Steps implementation and in BFHI. The continued growth may reflect the dedication of ministries of health and national BFHI groups, as well as increasing recognition that the Ten Steps are effective quality improvement practices that increase breastfeeding and synergize with community interventions and other program efforts. With renewed interest in maternal/neonatal health, revitalization of support for Ten Steps and their effective institutionalization in maternity practices should be considered. Future updates are planned to assess ongoing progress and impact, and ongoing updates from national committees are welcome. © 2012, Mary Ann Liebert, Inc. Source


Deans A.R.,North Carolina State University | Yoder M.J.,North Carolina State University | Balhoff J.P.,National Evolutionary Synthesis Center | Balhoff J.P.,University of North Carolina at Chapel Hill
Trends in Ecology and Evolution | Year: 2012

Taxonomists are arguably the most active annotators of the natural world, collecting and publishing millions of phenotype data annually through descriptions of new taxa. By formalizing these data, preferably as they are collected, taxonomists stand to contribute a data set with research potential that rivals or even surpasses genomics. Over a decade of electronic innovation and debate has initiated a revolution in the way that the biodiversity is described. Here, we opine that a new generation of semantically based digital scaffolding, presently in various stages of completeness, and a commitment by taxonomists and their colleagues to undertake this transformation, are required to complete the taxonomic revolution and critically broaden the relevance of its products. © 2011 Elsevier Ltd. Source


Dudley A.C.,University of North Carolina at Chapel Hill
Cold Spring Harbor perspectives in medicine | Year: 2012

The vascular endothelium is a dynamic cellular "organ" that controls passage of nutrients into tissues, maintains the flow of blood, and regulates the trafficking of leukocytes. In tumors, factors such as hypoxia and chronic growth factor stimulation result in endothelial dysfunction. For example, tumor blood vessels have irregular diameters; they are fragile, leaky, and blood flow is abnormal. There is now good evidence that these abnormalities in the tumor endothelium contribute to tumor growth and metastasis. Thus, determining the biological basis underlying these abnormalities is critical for understanding the pathophysiology of tumor progression and facilitating the design and delivery of effective antiangiogenic therapies. Source


Jobin C.,University of North Carolina at Chapel Hill
Cancer Discovery | Year: 2013

At a simplistic level, colorectal cancer arises from mutations in various proto-oncogenes and tumor suppressor genes. Aside from genetically inherited factors, environmental, lifestyle, and dietary habits have all been identified as risk agents promoting mutational events leading to the development of colorectal cancer. This "In Focus" presents evidence that the intestinal endogenous bacterial community represents a risk factor for the development of colorectal cancer. © 2013 American Association for Cancer Research. Source


Nolin D.A.,University of North Carolina at Chapel Hill
Human Nature | Year: 2011

This paper presents a comparison of social kinship (patrilineage) and biological kinship (genetic relatedness) in predicting cooperative relationships in two different economic contexts in the fishing and whaling village of Lamalera, Indonesia. A previous analysis (Alvard, Human Nature 14:129-163, 2003) of boat crew affiliation data collected in the village in 1999 found that social kinship (patrilineage) was a better predictor of crew affiliation than was genetic kinship. A replication of this analysis using similar data collected in 2006 finds the same pattern: lineage is a better predictor than genetic kinship of crew affiliation, and the two together explain little additional variance over that explained by lineage alone. However, an analogous test on food-sharing relationships finds the opposite pattern: biological kinship is a better predictor of food-sharing relationships than is social kinship. The difference between these two cooperative contexts is interpreted in terms of kin preferences that shape partner choice, and the relative autonomy with which individuals can seek to satisfy those preferences. Drawing on stable matching theory, it is suggested that unilineal descent may serve as a stable compromise among multiple individuals' incongruent partner preferences, with patriliny favored over matriliny in the crew-formation context because it leads to higher mean degrees of relatedness among male cooperators. In the context of food-sharing, kin preferences can be pursued relatively autonomously, without the necessity of coordinating preferences with those of other households through the institution of lineage. © 2011 Springer Science + Business Media, LLC. Source


Erinosho T.,University of North Carolina at Chapel Hill
Journal of the American Dietetic Association | Year: 2011

Early childhood is a critical time to establish nutrition habits to prevent obesity. At least half of US children spend time in care outside of the home, where little is known about their dietary intakes and nutrition environment. The purpose of this study was to evaluate nutrition practices of group child-care centers in New York City and to assess whether dietary intakes of children at these centers meet nutrition recommendations. In 2005 and 2006, student research assistants administered surveys to directors of 40 child-care centers in three underserved communities (Central Brooklyn, East/Central Harlem, South Bronx) and in Manhattan, gathered menus, and observed beverages and foods consumed by 240 3- and 4-year-old children. Almost all centers provided beverages and foods recommended by national guidelines, including reduced-fat milk, 100% fruit juice, and whole grains. Some centers also provided higher-fat milk and sugar-sweetened beverages, but no centers provided soda. Drinking water was available in classrooms at only half of the centers. From observations at meal and snack times between 8 AM to 2 PM, <50% of children ate at least half of the daily recommended intake for each of five main food groups, with only 17% of children eating at least half of the daily recommended intake for vegetables and only 5% of children eating at least half of the daily recommended intake for vitamin E. Although many centers provided healthful beverages and foods to children, further efforts are needed to make water available as a beverage throughout the day and to improve dietary intakes, especially of vegetables and vitamin E-containing foods. Copyright © 2011 American Dietetic Association. Published by Elsevier Inc. All rights reserved. Source


Buckley L.B.,University of North Carolina at Chapel Hill
Annals of the New York Academy of Sciences | Year: 2013

Forecasts of the ecological impacts of climate change are generally focused on direct impacts to individual species. Theory and case studies suggest that indirect effects associated with species interactions may alter these direct responses. How can we tractably predict in which cases indirect effects are likely to be important and appropriately model the interaction of abiotic and biotic drivers? One viable strategy is to characterize partitioning between species along thermal, temporal, and spatial niche axes. The partitioning can be informed by assessing functional traits. Mechanistic models can then be applied to predict how climate change will alter niche partitioning. I illustrate this approach by asking whether competition has altered the responses of Caribbean Anolis lizards to recent warming and find that forested habitat has become more suitable for a warm-adapted, open species, and less suitable for a cool-adapted forest inhabitant. Competition may result in competitive displacement of the cool-adapted species as the warm-adapted species moves into the forest. Species interactions may accentuate abundance and distribution shifts predicted in response to climate change along the elevation gradient. © 2013 New York Academy of Sciences. Source


In recent years, microRNAs (miRNA) have emerged as important posttranscriptional regulators of gene expression in a wide variety of biological pathways. Since the discovery of the liver-specific miRNA-122 (miR-122) and its critical role in hepatic function, numerous additional miRNAs have been implicated in lipid metabolism. It is now apparent that lipid homeostasis is governed in part by an intricate web of miRNA activity. miRNAs are thought to confer robustness against environmental changes, such as diet modifications. Therefore, naturally occurring genetic variation that perturbs miRNA expression and/or function is likely to contribute to interindividual variability in lipid phenotypes. Although the field is still in its infancy, this review describes the growing evidence for miRNA-related genetic variation as etiological factors in lipid disorders. Specific examples, including a variant in a miRNA transcriptional control element that leads to dyslipidemia as well as a variant in a miRNA target site that modulates the effect of diet on plasma lipid levels, are discussed. Finally, the utility of recent systems genetics approaches to uncover hidden miRNA-related genetic associations with lipid disorders are considered, thereby illuminating the needles in the genetic haystack. Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc. Source


O'Daniel J.M.,Illumina | Lee K.,University of North Carolina at Chapel Hill
Cancer Journal (United States) | Year: 2012

The incorporation of whole-genome and whole-exome sequencing into clinical practice will undoubtedly change the way genetic counselors and other clinicians approach genetic testing. Enabling the analysis of essentially all human genes in one comprehensive test, this new technology can result in reduced testing cost and time to diagnosis. Another consequence of this broad scope, however, is the increased amount, complexity, and variety of results a clinician may need to discuss with a patient. The purpose of this article is to review the technology and outline some of the benefits and challenges of whole-genome and whole-exome sequencing in hereditary cancer practice. Copyright © 2012 by Lippincott Williams & Wilkins. Source


Overstreet D.H.,University of North Carolina at Chapel Hill
Methods in Molecular Biology | Year: 2012

Animal models and preclinical tests have played large roles in the development of antidepressant drugs and are likely to continue to play important roles. In the present communication, the main animal models of depression have been described and reviewed. These models include the Flinders sensitive line (FSL) rat, the Wistar Kyoto (WKY) rat, the fawn-hooded (FH) rat, and the learned helpless (LH) rat. In addition, the materials used to assess the behavior of these rats, including swim tanks, drinking tubes, and an open field apparatus, have been discussed. Finally, the methods used in collecting the relevant behaviors in the animal models are described. These include the procedures used in the forced swim test and chronic mild stress protocols, including the sucrose preference test. It is concluded that the behavioral tests used to infer depressed-like behavior in rats will continue to provide useful data if the appropriate animals and proper methods are used. © 2012 Springer Science+Business Media, LLC. Source


Baron J.A.,University of North Carolina at Chapel Hill
Nature Reviews Cancer | Year: 2012

Recent research has raised hopes for impressively accurate screening for cancer with molecular biomarkers. These molecular markers will probably be more sensitive and specific than older screening modalities, as well as easier to use. In this Essay, I argue that these sensitive screening tests might be clinically valuable-but that they will present unique issues in implementation and interpretation. These issues are likely to affect the way clinicians conduct screening and the way that they make diagnoses in individuals who screen positive for cancer. © 2012 Macmillan Publishers Limited. All rights reserved. Source


Mueser K.T.,Boston University | Deavers F.,University of Central Florida | Penn D.L.,University of North Carolina at Chapel Hill | Cassisi J.E.,University of Central Florida
Annual Review of Clinical Psychology | Year: 2013

The current state of the literature regarding psychosocial treatments for schizophrenia is reviewed within the frameworks of the recovery model of mental health and the expanded stress-vulnerability model. Interventions targeting specific domains of functioning, age groups, stages of illness, and human service system gaps are classified as evidence-based practices or promising practices according to the extent to which their efficacy is currently supported by meta-analyses and individual randomized controlled trials (RCTs). Evidence-based practices include assertive community treatment (ACT), cognitive behavior therapy (CBT) for psychosis, cognitive remediation, family psychoeducation, illness self-management training, social skills training, and supported employment. Promising practices include cognitive adaptive therapy, CBT for posttraumatic stress disorder, first-episode psychosis intervention, healthy lifestyle interventions, integrated treatment for co-occurring disorders, interventions targeting older individuals, peer support services, physical disease management, prodromal stage intervention, social cognition training, supported education, and supported housing. Implications and future directions are discussed. Copyright © 2013 by Annual Reviews. Source


The process of HIV-1 genomic RNA (gRNA) encapsidation is governed by a number of viral encoded components, most notably the Gag protein and gRNA cis elements in the canonical packaging signal (ψ). Also implicated in encapsidation are cis determinants in the R, U5, and PBS (primer binding site) from the 5' untranslated region (UTR). Although conventionally associated with nuclear export of HIV-1 RNA, there is a burgeoning role for the Rev/RRE in the encapsidation process. Pleiotropic effects exhibited by these cis and trans viral components may confound the ability to examine their independent, and combined, impact on encapsidation of RNA into HIV-1 viral particles in their innate viral context. We systematically reconstructed the HIV-1 packaging system in the context of a heterologous murine leukemia virus (MLV) vector RNA to elucidate a mechanism in which the Rev/RRE system is central to achieving efficient and specific encapsidation into HIV-1 viral particles. We show for the first time that the Rev/RRE system can augment RNA encapsidation independent of all cis elements from the 5' UTR (R, U5, PBS, and ψ). Incorporation of all the 5' UTR cis elements did not enhance RNA encapsidation in the absence of the Rev/RRE system. In fact, we demonstrate that the Rev/RRE system is required for specific and efficient encapsidation commonly associated with the canonical packaging signal. The mechanism of Rev/RRE-mediated encapsidation is not a general phenomenon, since the combination of the Rev/RRE system and 5' UTR cis elements did not enhance encapsidation into MLV-derived viral particles. Lastly, we show that heterologous MLV RNAs conform to transduction properties commonly associated with HIV-1 viral particles, including in vivo transduction of non-dividing cells (i.e. mouse neurons); however, the cDNA forms are episomes predominantly in the 1-LTR circle form. Premised on encapsidation of a heterologous RNA into HIV-1 viral particles, our findings define a functional HIV-1 packaging system as comprising the 5' UTR cis elements, Gag, and the Rev/RRE system, in which the Rev/RRE system is required to make the RNA amenable to the ensuing interaction between Gag and the canonical packaging signal for subsequent encapsidation. Source


Kenakin T.,University of North Carolina at Chapel Hill
Molecular Pharmacology | Year: 2015

The ability of agonists to selectively activate some but not all signaling pathways linked to pleiotropically signaling receptors has opened the possibility of obtaining molecules that emphasize beneficial signals, de-emphasize harmful signals, and concomitantly deemphasize harmful signals while blocking the harmful signals produced by endogenous agonists. The detection and quantification of biased effects is straightforward, but two important factors should be considered in the evaluation of biased effects in drug discovery. The first is that efficacy, and not bias, determines whether a given agonist signal will be observed; bias only dictates the relative concentrations at which agonist signals will appear when they do appear. Therefore, a Cartesian coordinate system plotting relative efficacy (on a scale of Log relative Intrinsic Activities) as the ordinates and Log(bias) as the abscissae is proposed as a useful tool in evaluating possible biased molecules for progression in discovery programs. Second, it should be considered that the current scales quantifying bias limit this property to the allosteric vector (ligand/receptor/coupling protein complex) and that whole-cell processing of this signal can completely change measured bias from in vitro predictions. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics. Source


Moll S.,University of North Carolina at Chapel Hill
Journal of Thrombosis and Thrombolysis | Year: 2015

No consensus exists as to who should be tested for thrombophilia, mainly due to the lack of good quality clinical outcome data in relationship to presence or absence of a given thrombophilia. Testing may be considered if (a) finding a thrombophilia predicts recurrent thrombosis and, thus, influences length of anticoagulation treatment decisions; (b) identifying a thrombophilia has implications on management of asymptomatic family members who are carriers of the detected thrombophilia; (c) a patient wishes to better understand why a thrombotic event occurred. Testing may be helpful in patients with venous thromboembolism at intermediate risk of recurrence in whom the finding of a strong thrombophilia can be one of the arguments for long-term anticoagulation - the “risk-of-recurrence-triangle” may be a useful aid in this decision process. Patients whose venous thromboembolism was provoked by a major transient risk factor should not be tested for thrombophilia. Thrombophilia tests should only be ordered by health care professionals who can provide the “4P”: (a) appropriately select which patient to test, (b) provide pre-test counseling, (c) properly interpret the test results, and (d) provide education and advice to the patient. If testing is embarked on in patients with venous thromboembolism, it is advisable to be done at the time of decision making whether to stop or continue anticoagulation, i.e. typically after 3 months of anticoagulant therapy. Thrombophilia testing is best not done at the time of an acute thrombotic event and while a patient is on an anticoagulant. © 2015, Springer Science+Business Media New York. Source


Durrance C.P.,University of North Carolina at Chapel Hill
Economic Inquiry | Year: 2013

In 2006, the Food and Drug Administration (FDA) approved access to emergency contraception through pharmacies without a prescription. Several states, however, had previously allowed pharmacy access to emergency contraception. In particular, Washington State was the first state to implement such a program in 1998. If emergency contraception is used as a substitute for a surgical abortion, then pharmacy access could reduce unintended pregnancy. Pharmacy access, however, could lead to an increase in risk taking, especially among teens or young adults, and hence lead to increased rates of sexually transmitted diseases. In this article, we use county-level data as well as specific timing of changes in pharmacy access to consider the intended and unintended consequences of pharmacy access to emergency contraception in Washington. The results indicate that while county-level access to emergency contraception was unrelated to trends in sexually transmitted diseases (STDs) and abortions before access changed, access afterwards led to a statistically significant increase in STD rates (gonorrhea rates), both overall and for females. We do not find, however, an impact of pharmacy access on abortion or birth rates. These results are robust to several specification tests (including use of Oregon counties as additional control counties) as well as several falsification tests. © 2012 Western Economic Association International. Source


Steenkamp J.-B.E.M.,University of North Carolina at Chapel Hill | Geyskens I.,University of Tilburg
Marketing Science | Year: 2014

Although store brands (SBs) are becoming increasingly important across the world, their success varies dramatically across consumer packaged goods categories and countries. The purpose of this paper is to provide insight into how such differences in SB success originate. Using a unique data set that combines scanner data for a three- to five-year period with consumer survey data (nD201987) for scores of food, household care, and personal care categories from 23 countries around the world, we identify cross-national regularities as to the role of nine manufacturer and retailer factors in explaining SB market share. For each manufacturer and retailer factor, we determine whether it can be part of a global integration strategy, whether it can be included in a local adaptation strategy, or whether it is a candidate for worldwide learning. Our findings have important implications for national brand manufacturers and retailers. © 2014 INFORMS. Source


Sethupathy P.,University of North Carolina at Chapel Hill
Current Genomics | Year: 2013

Cellular gene expression is governed by a complex, multi-faceted network of regulatory interactions. In the last decade, microRNAs (miRNAs) have emerged as critical components of this network. miRNAs are small, non-coding RNA molecules that serve as post-transcriptional regulators of gene expression. Although there has been substantive progress in our understanding of miRNA-mediated gene regulation, the mechanisms that control the expression of the miRNAs themselves are less well understood. Identifying the factors that control miRNA expression will be critical for further characterizing miRNA function in normal physiology and pathobiology. We describe recent progress in the efforts to map genomic regions that control miRNA transcription (such as promoters). In particular, we highlight the utility of large-scale "-omic" data, such as those made available by the ENCODE and the NIH Roadmap Epigenomics consortiums, for the discovery of transcriptional control elements that govern miRNA expression. Finally, we discuss how integrative analysis of complementary genetic datasets, such as the NHGRI Genome Wide Association Studies Catalog, can predict novel roles for transcriptional mis-regulation of miRNAs in complex disease etiology. © 2013 Bentham Science Publishers. Source


Furey T.S.,University of North Carolina at Chapel Hill
Nature Reviews Genetics | Year: 2012

Chromatin immunoprecipitation experiments followed by sequencing (ChIP-seq) detect protein-DNA binding events and chemical modifications of histone proteins. Challenges in the standard ChIP-seq protocol have motivated recent enhancements in this approach, such as reducing the number of cells that are required and increasing the resolution. Complementary experimental approaches-for example, DNaseI hypersensitive site mapping and analysis of chromatin interactions that are mediated by particular proteins-provide additional information about DNA-binding proteins and their function. These data are now being used to identify variability in the functions of DNA-binding proteins across genomes and individuals. In this Review, I describe the latest advances in methods to detect and functionally characterize DNA-bound proteins. © 2012 Macmillan Publishers Limited. All rights reserved. Source


Pedersen C.A.,University of North Carolina at Chapel Hill
Brain Research | Year: 2014

Beginning in 1979 with the first report that central administration of oxytocin stimulates maternal behavior in virgin rats, decades of animal research and more recent human studies have demonstrated that oxytocin has many pro-social effects. These many findings suggest that oxytocin may be an effective treatment for social deficits that are hallmark features of disorders such as autism and schizophrenia. Effects in preclinical animal models also imply that oxytocin may be an efficacious pharmacotherapy in a wide range of psychiatric disorders including psychoses and addictions. To date, 3 small clinical trials found that daily intranasal oxytocin treatment for 2-8 weeks significantly reduced psychotic symptoms in schizophrenia. Two of these trials also found improvement in social cognition or neurocognition, areas in which patients have significant deficiencies that do not respond to conventional antipsychotic treatment and contribute to disability. In another small trial, intranasal oxytocin potently blocked alcohol withdrawal. After reviewing the rationale for these trials, they are described in more detail. Questions are then asked followed by discussions of the large gaps in our knowledge about brain oxytocin systems in humans. The hope is to highlight important directions for future investigations of the role of oxytocin in the pathophysiology of psychotic disorders and addictions and to extend clinical research in these areas. Heretofore unrecognized roles for which oxytocin may have been selected during the evolution of placental mammalian maternal-infant and other social attachments are considered as possible origins of oxytocin antipsychotic and antiaddiction effects.This article is part of a Special Issue entitled Oxytocin and Social Behav. © 2014 Elsevier B.V. All rights reserved. Source


Sinnett S.E.,University of North Carolina at Chapel Hill | Brenman J.E.,Neuroscience Center
Pharmacology and Therapeutics | Year: 2014

AMP-activated protein kinase (AMPK) is a promising therapeutic target for cancer, type II diabetes, and other illnesses characterized by abnormal energy utilization. During the last decade, numerous labs have published a range of methods for identifying novel AMPK modulators. The current understanding of AMPK structure and regulation, however, has propelled a paradigm shift in which many researchers now consider ADP to be an additional regulatory nucleotide of AMPK. How can the AMPK community apply this new understanding of AMPK signaling to translational research? Recent insights into AMPK structure, regulation, and holoenzyme-sensitive signaling may provide the hindsight needed to clearly evaluate the strengths and weaknesses of past AMPK drug discovery efforts. Improving future strategies for AMPK drug discovery will require pairing the current understanding of AMPK signaling with improved experimental designs. © 2014 Elsevier Inc. Source


Ting J.,University of North Carolina at Chapel Hill
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society | Year: 2010

Overall and age-specific cervical cytological and histological abnormalities prevalence data across geographical regions, in conjunction with human papillomavirus vaccination status, will be important for the future evaluation of HPV prophylactic vaccine effectiveness. A systematic review was conducted to summarize worldwide data on the prevalence of high- and low-grade squamous intraepithelial lesions, and cervical intraepithelial neoplasia (CIN) 2/3 or 1. More than 12,400,000 women were included in 103 studies. Most studies were from Europe and Middle East (40%) or North America (14%), 14% were from Asia, 17% from Central and South America, and 15% from Africa. Age-specific data were limited from Asia, Central and South America, and Africa. Screening techniques and study exclusion criteria varied, depending on region and population surveyed. Age trends of high-grade cervical lesions seemed to peak at a relatively younger age in North America (<30 years), compared with 25 to 40 years in Europe and Middle East, Africa, Asia, and Central and South America. Age patterns of low-grade lesions generally declined after a peak in the younger age groups (20-30 years). Age-specific CIN 1 and CIN 2/3 prevalence were lower compared with low- and high-grade squamous intraepithelial lesions from the same studies, respectively. Variation in the age patterns of high-grade lesions across regions is likely attributable to differences in age at screening initiation, frequency, coverage, and rates of follow-up of women with cervical abnormalities. Observed age patterns of low-grade lesions are generally consistent to those of human papillomavirus infection in women worldwide. Potential factors contributing to variations in the burden of cytological and histological abnormalities across studies include subjectivity in evaluating cytological slides and discrepancies in the processing, referral rates, and diagnostic interpretation of colposcopically directed biopsy. Source


Chen Y.,National Tsing Hua University | Gao D.-Y.,National Tsing Hua University | Huang L.,University of North Carolina at Chapel Hill
Advanced Drug Delivery Reviews | Year: 2015

MicroRNAs (miRNAs), small non-coding RNAs, can regulate post-transcriptional gene expressions and silence a broad set of target genes. miRNAs, aberrantly expressed in cancer cells, play an important role in modulating gene expressions, thereby regulating downstream signaling pathways and affecting cancer formation and progression. Oncogenes or tumor suppressor genes regulated by miRNAs mediate cell cycle progression, metabolism, cell death, angiogenesis, metastasis and immunosuppression in cancer. Recently, miRNAs have emerged as therapeutic targets or tools and biomarkers for diagnosis and therapy monitoring in cancer. Since miRNAs can regulate multiple cancer-related genes simultaneously, using miRNAs as a therapeutic approach plays an important role in cancer therapy. However, one of the major challenges of miRNA-based cancer therapy is to achieve specific, efficient and safe systemic delivery of therapeutic miRNAs in vivo. This review discusses the key challenges to the development of the carriers for miRNA-based therapy and explores current strategies to systemically deliver miRNAs to cancer without induction of toxicity. © 2014 Elsevier B.V. Source


Watson R.A.,University of North Carolina at Chapel Hill
Academic Medicine | Year: 2014

Purpose: To test the hypothesis that machine learning algorithms increase the predictive power to classify surgical expertise using surgeons' hand motion patterns. Method: In 2012 at the University of North Carolina at Chapel Hill, 14 surgical attendings and 10 first- and second-year surgical residents each performed two bench model venous anastomoses. During the simulated tasks, the participants wore an inertial measurement unit on the dorsum of their dominant (right) hand to capture their hand motion patterns. The pattern from each bench model task performed was preprocessed into a symbolic time series and labeled as expert (attending) or novice (resident). The labeled hand motion patterns were processed and used to train a Support Vector Machine (SVM) classification algorithm. The trained algorithm was then tested for discriminative/predictive power against unlabeled (blinded) hand motion patterns from tasks not used in the training. The Lempel-Ziv (LZ) complexity metric was also measured from each hand motion pattern, with an optimal threshold calculated to separately classify the patterns. Results: The LZ metric classified unlabeled (blinded) hand motion patterns into expert and novice groups with an accuracy of 70% (sensitivity 64%, specificity 80%). The SVM algorithm had an accuracy of 83% (sensitivity 86%, specificity 80%). Conclusions: The results confirmed the hypothesis. The SVM algorithm increased the predictive power to classify blinded surgical hand motion patterns into expert versus novice groups. With further development, the system used in this study could become a viable tool for low-cost, objective assessment of procedural proficiency in a competency-based curriculum. Source


Erickcek A.L.,University of North Carolina at Chapel Hill
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2015

The evolution of the Universe between inflation and the onset of big bang nucleosynthesis is difficult to probe and largely unconstrained. This ignorance profoundly limits our understanding of dark matter: we cannot calculate its thermal relic abundance without knowing when the Universe became radiation dominated. Fortunately, small-scale density perturbations provide a probe of the early Universe that could break this degeneracy. If dark matter is a thermal relic, density perturbations that enter the horizon during an early matter-dominated era grow linearly with the scale factor prior to reheating. The resulting abundance of substructure boosts the annihilation rate by several orders of magnitude, which can compensate for the smaller annihilation cross sections that are required to generate the observed dark matter density in these scenarios. In particular, thermal relics with masses less than a TeV that thermally and kinetically decouple prior to reheating may already be ruled out by Fermi-LAT observations of dwarf spheroidal galaxies. Although these constraints are subject to uncertainties regarding the internal structure of the microhalos that form from the enhanced perturbations, they open up the possibility of using gamma-ray observations to learn about the reheating of the Universe. © 2015 American Physical Society. Source


Key N.S.,University of North Carolina at Chapel Hill
Hematology | Year: 2014

Currently available evidence supports the contention that elevated levels of factor XI (fXI) are associated with a greater risk of venous thromboembolism and ischemic stroke, but, less convincingly, with myocardial infarction. Conversely, reduced plasma levels of fXI seem to offer some protection from venous thromboembolism and stroke, but not myocardial infarction. Factor XI-deficient patients are at risk for certain types of bleeding, particularly posttraumatic hemorrhage on mucosal surfaces where there is a high endogenous fibrinolytic activity. In contrast, the situation with fXII in human thrombosis remains enigmatic. Deficiency of fXII is clearly not associated with any bleeding risk, but neither does it seem to be protective against thrombosis. The longstanding debate as to whether partial fXII deficiency represents a risk factor for thrombosis remains unresolved, with seemingly conflicting results depending on study design, type of assay used, and analyte evaluated. The possibility that elevated fXII levels represent a risk factor for thrombosis is not borne out in the literature. Source


Smith S.C.,University of North Carolina at Chapel Hill | Grundy S.M.,University of Texas Southwestern Medical Center
Journal of the American College of Cardiology | Year: 2014

The American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Practice Guidelines recently issued the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. This new guideline endorses a paradigm shift in strategies for reducing atherosclerotic cardiovascular disease (ASCVD) events by lowering blood cholesterol. Whereas previous guidelines focused on therapy to decrease low-density lipoprotein and non-high-density lipoprotein cholesterol to specific target levels, the new guideline instead proposes implementation of cholesterol-lowering treatment using evidenced-based intensity of statin therapy without such targets. The guideline also provides a new risk estimator for primary prevention decisions, including stroke outcomes and data on African Americans, which will significantly increase the number of patients recommended for outcome-related benefits of cholesterol-lowering therapy. The first section of this paper reviews the process by which the task force developed the new evidence-based guideline, the major findings and recommendations, and their implications. The second section primarily focuses on the question of how much low-density lipoprotein cholesterol should be lowered and on additional considerations in risk assessment. © 2014 by the American College of Cardiology Foundation. Source


Wang H.,University of North Carolina at Chapel Hill
Nature Methods | Year: 2016

LOVTRAP is an optogenetic approach for reversible light-induced protein dissociation using protein A fragments that bind to the LOV domain only in the dark, with tunable kinetics and a >150-fold change in the dissociation constant (Kd). By reversibly sequestering proteins at mitochondria, we precisely modulated the proteins' access to the cell edge, demonstrating a naturally occurring 3-mHz cell-edge oscillation driven by interactions of Vav2, Rac1, and PI3K proteins. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source


Martin K.R.,University of North Carolina at Chapel Hill
Arthritis care & research | Year: 2010

To examine the association between 4 aspects of perceived neighborhood environment (aesthetics, walkability, safety, and social cohesion) and health status outcomes in a cohort of North Carolinians with self-reported arthritis after adjustment for individual and neighborhood socioeconomic status covariates. In a telephone survey, 696 participants self-reported ≥1 types of arthritis or rheumatic conditions. Outcomes measured were physical and mental functioning (Short Form 12 health survey version 2 physical component and mental component summary [MCS]), functional disability (Health Assessment Questionnaire), and depressive symptomatology (Center for Epidemiologic Studies Depression Scale scores <16 versus ≥16). Multivariate regression and multivariate logistic regression analyses were conducted using Stata, version 11. Results from separate adjusted models indicated that measures of associations for perceived neighborhood characteristics were statistically significant (P ≤ 0.001 to P = 0.017) for each health status outcome (except walkability and MCS) after adjusting for covariates. Final adjusted models included all 4 perceived neighborhood characteristics simultaneously. A 1-point increase in perceiving worse neighborhood aesthetics predicted lower mental health (B = -1.81, P = 0.034). Individuals had increased odds of depressive symptoms if they perceived lower neighborhood safety (odds ratio [OR] 1.36, 95% confidence interval [95% CI] 1.04-1.78; P = 0.023) and lower neighborhood social cohesion (OR 1.42, 95% CI 1.03-1.96; P = 0.030). Study findings indicate that an individual's perception of neighborhood environment characteristics, especially aesthetics, safety, and social cohesion, is predictive of health outcomes among adults with self-reported arthritis, even after adjusting for key variables. Future studies interested in examining the role that community characteristics play on disability and mental health in individuals with arthritis might consider further examination of perceived neighborhood environment. Copyright © 2010 by the American College of Rheumatology. Source


Head K.J.,University of Kentucky | Noar S.M.,University of North Carolina at Chapel Hill
Health Psychology Review | Year: 2014

This paper explores the question: what are barriers to health behaviour theory development and modification, and what potential solutions can be proposed? Using the reasoned action approach (RAA) as a case study, four areas of theory development were examined: (1) the theoretical domain of a theory; (2) tension between generalisability and utility, (3) criteria for adding/removing variables in a theory, and (4) organisational tracking of theoretical developments and formal changes to theory. Based on a discussion of these four issues, recommendations for theory development are presented, including: (1) the theoretical domain for theories such as RAA should be clarified; (2) when there is tension between generalisability and utility, utility should be given preference given the applied nature of the health behaviour field; (3) variables should be formally removed/amended/added to a theory based on their performance across multiple studies and (4) organisations and researchers with a stake in particular health areas may be best suited for tracking the literature on behaviour-specific theories and making refinements to theory, based on a consensus approach. Overall, enhancing research in this area can provide important insights for more accurately understanding health behaviours and thus producing work that leads to more effective health behaviour change interventions. © 2013 Taylor & Francis. Source


Janzen W.P.,University of North Carolina at Chapel Hill
Chemistry and Biology | Year: 2014

Screening, high-throughput screening, and ultra-high-throughput screening are all really just points on a spectrum that represent differing applications of the same process: the creation of biologically relevant assays that are relevant, reproducible, reliable, and robust. Whether the discovery program is developing a pharmaceutical, an academic probe, cosmetics, pesticides, or a toxicity monitoring assay, the development of a screen focuses on generating a method that will reliably deliver reproducible results over a period of weeks, months, or years and that will generate consistent results for every test along the way. This review provides both historical perspective on how this unique scientific discipline evolved and commentary on the current state of the art technologies and techniques. © 2014 Elsevier Ltd All rights reserved. Source


Mutations in fukutin-related protein (FKRP) gene cause a wide spectrum of disease phenotypes including the mild limb-girdle muscular dystrophy 2I (LGMD2I), the severe Walker-Warburg syndrome, and muscle-eye-brain disease. FKRP deficiency results in α-dystroglycan (α-DG) hypoglycosylation in the muscle and heart, which is a biochemical hallmark of dystroglycanopathies. To study gene replacement therapy, we generated and characterized a new mouse model of LGMD2I harboring the human mutation leucine 276 to isoleucine (L276I) in the mouse alleles. The homozygous knock-in mice (L276IKI) mimic the classic late onset phenotype of LGMD2I in both skeletal and cardiac muscles. Systemic delivery of human FKRP gene by AAV9 vector in the L276IKI mice, at either neonatal age or at the age of 9 months, rendered body wide FKRP expression and restored glycosylation of α-DG in both skeletal and cardiac muscles. FKRP gene therapy ameliorated dystrophic pathology and cardiomyopathy such as muscle degeneration, fibrosis, and myofiber membrane leakage, resulting in restoration of muscle and heart contractile functions. Thus, these results demonstrated that the treatment based on FKRP gene replacement was effective.Molecular Therapy (2014); doi:10.1038/mt.2014.141. Source


Amorim L.D.A.F.,Federal University of Bahia | Cai J.,University of North Carolina at Chapel Hill
International Journal of Epidemiology | Year: 2015

In many biomedical studies, the event of interest can occur more than once in a participant. These events are termed recurrent events. However, the majority of analyses focus only on time to the first event, ignoring the subsequent events. Several statistical models have been proposed for analysing multiple events. In this paper we explore and illustrate several modelling techniques for analysis of recurrent time-to-event data, including conditional models for multivariate survival data (AG, PWP-TT and PWP-GT), marginal means/ rates models, frailty and multi-state models. We also provide a tutorial for analysing such type of data, with three widely used statistical software programmes. Different approaches and software are illustrated using data from a bladder cancer project and from a study on lower respiratory tract infection in children in Brazil. Finally, we make recommendations for modelling strategy selection for analysis of recurrent event data. © The Author 2014. Source


Orlando R.C.,University of North Carolina at Chapel Hill
Best Practice and Research: Clinical Gastroenterology | Year: 2010

Heartburn is the most common and characteristic symptom of gastroesophageal reflux disease. It ultimately results from contact of refluxed gastric acid with nociceptors within the esophageal mucosa and transmission of this peripheral signal to the central nervous system for cognition. Healthy esophageal epithelium provides an effective barrier between refluxed gastric acid and esophageal nociceptors; but this barrier is vulnerable to attack and damage, particularly by acidic gastric contents. How gastric acid is countered by defensive elements within the esophageal mucosa is a major focus of this discussion. When the defense is successful, the subject is asymptomatic and when unsuccessful, the subject experiences heartburn. Those with heartburn commonly fall into one of three endoscopic types: nonerosive reflux disease, erosive esophagitis and Barrett's esophagus. Although what determines endoscopic type remains unknown; it is proposed herein that inflammation plays a key, modulating role. © 2010 Elsevier Ltd. All rights reserved. Source


Goldstein A.O.,University of North Carolina at Chapel Hill
Annals of Family Medicine | Year: 2015

Once a year, Stuart, a long-haul truck driver, visited a physician to get a signature on the forms that allowed him to continue driving his 18-wheeler. Over 8 years, he had never seen the same physician twice, in large part because of a lack of health insurance. Upon seeing him for the first time, I assured him that we could make financial arrangements, and he subsequently became my continuity patient. Two years later, we both looked forward to his impending 65th birthday, allowing Medicare to ease his fiscal health care burdens. His unexpected death made me ponder how a lack of access to affordable health care profoundly affects patients and their clinicians. © 2015, Annals of Family Medicine, Inc. All rights reserved. Source


Saver R.S.,University of North Carolina at Chapel Hill
Chest | Year: 2014

Under brand new rules implementing the Physician Payments Sunshine Act (Sunshine Act), a wide range of fi nancial relationships, including many research-related payments, between industry, physicians, and teaching hospitals will be publicly disclosed through comprehensive, standardized payment reporting. The Sunshine Act represents the latest in a series of regulatory attempts to address fi nancial confl icts of interest that may bias research conduct and threaten subject safety. This article summarizes the major aspects of the Sunshine Act affecting medical research, how it interacts with existing laws and policies, and identifi es important unresolved issues and implementation challenges that still lie ahead with the rollout of the legislation underway. The Sunshine Act primarily depends on disclosure as a regulatory tool. As such, its long-term impact remains open to question. Disclosure in this context may have limited utility given, among other reasons, uncertainty about who the intended recipients are and their ability to use the information effectively. Apart from the insuffi ciency of transparency, this article further explores how proportionality, fairness, and accountability considerations make optimal regulation of fi nancial confl icts in medical research quite challenging. © 2014 American College of Chest Physicians. Source