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1.  Self-Reported Hearing Difficulties Among Adults With Normal Audiograms: The Beaver Dam Offspring Study 
Ear and hearing  2015;36(6):e290-e299.
Clinicians encounter patients who report experiencing hearing difficulty (HD) even when audiometric thresholds fall within normal limits. When there is no evidence of audiometric hearing loss, it generates debate over possible biomedical and psychosocial etiologies. It is possible that self-reported HDs relate to variables within and/or outside the scope of audiology. The purpose of this study is to identify how often, on a population basis, people with normal audiometric thresholds self-report HD and to identify factors associated with such HDs.
This was a cross-sectional investigation of participants in the Beaver Dam Offspring Study. HD was defined as a self-reported HD on a four-item scale despite having pure-tone audiometric thresholds within normal limits (<20 dB HL0.5, 1, 2, 3, 4, 6, 8 kHz bilaterally, at each frequency). Distortion product otoacoustic emissions and word-recognition performance in quiet and with competing messages were also analyzed. In addition to hearing assessments, relevant factors such as sociodemographic and lifestyle factors, environmental exposures, medical history, health-related quality of life, and symptoms of neurological disorders were also examined as possible risk factors. The Center for Epidemiological Studies-Depression was used to probe symptoms associated with depression, and the Medical Outcomes Study Short-Form 36 mental score was used to quantify psychological stress and social and role disability due to emotional problems. The Visual Function Questionnaire-25 and contrast sensitivity test were used to query vision difficulties.
Of the 2783 participants, 686 participants had normal audiometric thresholds. An additional grouping variable was created based on the available scores of HD (four self-report questions), which reduced the total dataset to n = 682 (age range, 21–67 years). The percentage of individuals with normal audiometric thresholds who self-reported HD was 12.0% (82 of 682). The prevalence in the entire cohort was therefore 2.9% (82 of 2783). Performance on audiological tests (distortion product otoacoustic emissions and word-recognition tests) did not differ between the group self-reporting HD and the group reporting no HD. A multivariable model controlling for age and sex identified the following risk factors for HD: lower incomes (odds ratio [OR] $50,000+ = 0.55, 95% confidence interval [CI] = 0.30–1.00), noise exposure through loud hobbies (OR = 1.48, 95% CI = 1.15–1.90), or firearms (OR = 2.07, 95% CI = 1.04–4.16). People reporting HD were more likely to have seen a doctor for hearing loss (OR = 12.93, 95% CI = 3.86–43.33) and report symptoms associated with depression (Center for Epidemiological Studies-Depression [OR = 2.39, 95% CI = 1.03–5.54]), vision difficulties (Visual Function Questionnaire-25 [OR = 0.93, 95% CI = 0.89–0.97]), and neuropathy (e.g., numbness, tingling, and loss of sensation [OR = 1.98, 95% CI = 1.14–3.44]).
The authors used a population approach to identify the prevalence and risk factors associated with self-reported HD among people who perform within normal limits on common clinical tests of auditory function. The percentage of individuals with normal audiometric thresholds who self-reported HD was 12.0%, resulting in an overall prevalence of 2.9%. Auditory and nonauditory risk factors were identified, therefore suggesting that future directions aimed at assessing, preventing, and managing these types of HDs might benefit from information outside the traditional scope of audiology.
PMCID: PMC4824300  PMID: 26164105
Aging; Auditory neuropathy; Central auditory processing disorder; Hidden hearing loss; King-Kopetzky syndrome; Obscure auditory dysfunction; Self-reported hearing loss; Temporal processing disorder
2.  What Drives the Association between Weight Conscious Peer Groups and Disordered Eating? Disentangling Genetic and Environmental Selection from Pure Socialization Effects 
Journal of abnormal psychology  2016;125(3):356-368.
Previous studies suggest strong associations between exposure to weight conscious peer groups and increased levels of disordered eating. This association has been attributed to socialization effects (i.e., membership leads to disordered eating); however, selection effects (i.e., selecting into peer groups based on genetic and/or environmental predispositions toward disordered eating) could contribute to or even account for these associations. The current study was the first to use a co-twin control design to disentangle these types of selection factors from socialization effects. Participants included 610 female twins (ages 8–14) drawn from the Michigan State University Twin Registry. To comprehensively examine a range of eating pathology, several disordered eating attitudes and behaviors (e.g., body dissatisfaction, binge eating) were examined via self-report questionnaires. Questionnaires also were used to assess peer group emphasis on body weight and shape. Replicating previous results, significant individual-level associations were found between membership in weight conscious peer groups and disordered eating. However, co-twin control analyses indicated that these associations were largely due to genetic and/or shared environmental selection factors rather than pure socialization effects. Importantly, results remained unchanged when controlling for pubertal status, suggesting that effects do not vary across developmental stage. Overall, these findings question whether associations between weight conscious peer groups and disordered eating are due entirely to socialization processes. Future studies are needed to identify the specific genetic and/or shared environmental factors that may drive selection into weight conscious peer groups.
PMCID: PMC4824549  PMID: 27043917
selection; socialization; co-twin control; disordered eating; weight conscious peer groups
3.  Zygosity Differences in Height and Body Mass Index of Twins From Infancy to Old Age: A Study of the CODATwins Project 
Jelenkovic, Aline | Yokoyama, Yoshie | Sund, Reijo | Honda, Chika | Bogl, Leonie H. | Aaltonen, Sari | Ji, Fuling | Ning, Feng | Pang, Zengchang | Ordoñana, Juan R. | Sánchez-Romera, Juan F. | Colodro-Conde, Lucia | Burt, S. Alexandra | Klump, Kelly L. | Medland, Sarah E. | Montgomery, Grant W. | Kandler, Christian | McAdams, Tom A. | Eley, Thalia C. | Gregory, Alice M. | Saudino, Kimberly J. | Dubois, Lise | Boivin, Michel | Tarnoki, Adam D. | Tarnoki, David L. | Haworth, Claire M. A. | Plomin, Robert | Öncel, Sevgi Y. | Aliev, Fazil | Stazi, Maria A. | Fagnani, Corrado | D’Ippolito, Cristina | Craig, Jeffrey M. | Saffery, Richard | Siribaddana, Sisira H. | Hotopf, Matthew | Sumathipala, Athula | Rijsdijk, Fruhling | Spector, Timothy | Mangino, Massimo | Lachance, Genevieve | Gatz, Margaret | Butler, David A. | Bayasgalan, Gombojav | Narandalai, Danshiitsoodol | Freitas, Duarte L. | Maia, José Antonio | Harden, K. Paige | Tucker-Drob, Elliot M. | Kim, Bia | Chong, Youngsook | Hong, Changhee | Shin, Hyun Jung | Christensen, Kaare | Skytthe, Axel | Kyvik, Kirsten O. | Derom, Catherine A. | Vlietinck, Robert F. | Loos, Ruth J. F. | Cozen, Wendy | Hwang, Amie E. | Mack, Thomas M. | He, Mingguang | Ding, Xiaohu | Chang, Billy | Silberg, Judy L. | Eaves, Lindon J. | Maes, Hermine H. | Cutler, Tessa L. | Hopper, John L. | Aujard, Kelly | Magnusson, Patrik K. E. | Pedersen, Nancy L. | Dahl Aslan, Anna K. | Song, Yun-Mi | Yang, Sarah | Lee, Kayoung | Baker, Laura A. | Tuvblad, Catherine | Bjerregaard-Andersen, Morten | Beck-Nielsen, Henning | Sodemann, Morten | Heikkilä, Kauko | Tan, Qihua | Zhang, Dongfeng | Swan, Gary E. | Krasnow, Ruth | Jang, Kerry L. | Knafo-Noam, Ariel | Mankuta, David | Abramson, Lior | Lichtenstein, Paul | Krueger, Robert F. | McGue, Matt | Pahlen, Shandell | Tynelius, Per | Duncan, Glen E. | Buchwald, Dedra | Corley, Robin P. | Huibregtse, Brooke M. | Nelson, Tracy L. | Whitfield, Keith E. | Franz, Carol E. | Kremen, William S. | Lyons, Michael J. | Ooki, Syuichi | Brandt, Ingunn | Nilsen, Thomas Sevenius | Inui, Fujio | Watanabe, Mikio | Bartels, Meike | van Beijsterveldt, Toos C. E. M. | Wardle, Jane | Llewellyn, Clare H. | Fisher, Abigail | Rebato, Esther | Martin, Nicholas G. | Iwatani, Yoshinori | Hayakawa, Kazuo | Sung, Joohon | Harris, Jennifer R. | Willemsen, Gonneke | Busjahn, Andreas | Goldberg, Jack H. | Rasmussen, Finn | Hur, Yoon-Mi | Boomsma, Dorret I. | Sørensen, Thorkild I. A. | Kaprio, Jaakko | Silventoinen, Karri
A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
PMCID: PMC4605819  PMID: 26337138
twins; height; BMI; zygosity differences
4.  Preconception Stress, Birth Weight, and Birth Weight Disparities among U.S. Women 
American journal of public health  2014;104(8):e125-e132.
To examine the impact of preconception acute and chronic stressors on offspring birth weight and racial/ethnic birth weight disparities.
We included birth weights for singleton live first (n=3512) and second (n=1901) births to White, Mexican- and other-origin Latina, and Black women reported at Wave IV of the National Longitudinal Study of Adolescent Health (2007-2008; ages 24-32). We generated factor scores for preconception acute and chronic stressors from Wave I (1994-1995; ages 11-19) or III (2001-2002; ages 18-26) for the same cohort of women.
Linear regression models indicated that chronic stressors, but not acute stressors, were inversely associated with birth weight for both first and second births (b= -192; 95% confidence interval [CI]: -270, -113; and b= -180; 95% CI: -315, -45 respectively), and partially explained the disparities in birth weight between the minority racial/ethnic groups and Whites.
Preconception chronic stressors contribute to restricted birth weight and to racial/ethnic birth weight disparities.
PMCID: PMC4103215  PMID: 24922164
5.  Minocycline as a re-purposed anti-Wolbachia macrofilaricide: superiority compared with doxycycline regimens in a murine infection model of human lymphatic filariasis 
Scientific Reports  2016;6:23458.
Lymphatic filariasis and onchocerciasis are parasitic helminth diseases, which cause severe morbidities such as elephantiasis, skin disease and blindness, presenting a major public health burden in endemic communities. The anti-Wolbachia consortium (A·WOL: has identified a number of registered antibiotics that target the endosymbiotic bacterium, Wolbachia, delivering macrofilaricidal activity. Here we use pharmacokinetics/pharmacodynamics (PK/PD) analysis to rationally develop an anti-Wolbachia chemotherapy by linking drug exposure to pharmacological effect. We compare the pharmacokinetics and anti-Wolbachia efficacy in a murine Brugia malayi model of minocycline versus doxycycline. Doxycycline exhibits superior PK in comparison to minocycline resulting in a 3-fold greater exposure in SCID mice. Monte-Carlo simulations confirmed that a bi-daily 25–40 mg/Kg regimen is bioequivalent to a clinically effective 100–200 mg/day dose for these tetracyclines. Pharmacodynamic studies showed that minocycline depletes Wolbachia more effectively than doxycycline (99.51% vs. 90.35%) after 28 day 25 mg/Kg bid regimens with a more potent block in microfilarial production. PK/PD analysis predicts that minocycline would be expected to be 1.7 fold more effective than doxycycline in man despite lower exposure in our infection models. Our findings warrant onward clinical investigations to examine the clinical efficacy of minocycline treatment regimens against lymphatic filariasis and onchocerciasis.
PMCID: PMC4800446  PMID: 26996237
6.  E2F1 in neurons is cleaved by calpain in an NMDA receptor-dependent manner in a model of HIV-induced neurotoxicity 
Journal of neurochemistry  2014;132(6):742-755.
The transcription factor E2F1 activates gene targets required for G1-S phase progression and for apoptosis, and exhibits increased expression levels in neurons in several CNS diseases including HIV encephalitis, Alzheimer disease, and Parkinson Disease. While E2F1 is known to regulate cell viability through activation of caspases, here we present evidence supporting the involvement of E2F1 in NMDA receptor-dependent, HIV-induced neuronal death mediated by calpains. Using an in vitro model of HIV-induced neurotoxicity that is dependent on NMDA receptor and calpain activation, we have shown that cortical neurons lacking functional E2F1 are less susceptible to neuronal death. Additionally, we report that neuronal E2F1 is cleaved by calpain to a stable 55-kiloDalton fragment following NR2B-dependent NMDA receptor stimulation. This cleavage of E2F1 is protein conformation-dependent and involves at least two cleavage events, one at each terminus of the protein. Intriguingly, the stabilized E2F1 cleavage product is produced in postmitotic neurons of all ages, but fails to be stabilized in cycling cells. Finally, we show that a matching E2F1 cleavage product is produced in human fetal neurons, suggesting that calpain cleavage of E2F1 may be produced in human cortical tissue. These results suggest neuronal E2F1 is processed in a novel manner in response to NMDA receptor-mediated toxicity, a mechanism implicated in HAND pathogenesis as well as several other diseases of the CNS.
PMCID: PMC4359652  PMID: 25279448
excitotoxicity; neuron; cell cycle; HAND; neurodegeneration; protease; calpain
7.  The Iminosugar UV-4 is a Broad Inhibitor of Influenza A and B Viruses ex Vivo and in Mice 
Viruses  2016;8(3):71.
Iminosugars that are competitive inhibitors of endoplasmic reticulum (ER) α-glucosidases have been demonstrated to have antiviral activity against a diverse set of viruses. A novel iminosugar, UV-4B, has recently been shown to provide protection against lethal infections with dengue and influenza A (H1N1) viruses in mice. In the current study, the breadth of activity of UV-4B against influenza was examined ex vivo and in vivo. Efficacy of UV-4B against influenza A and B viruses was shown in primary human bronchial epithelial cells, a principal target tissue for influenza. Efficacy of UV-4B against influenza A (H1N1 and H3N2 subtypes) and influenza B was demonstrated using multiple lethal mouse models with readouts including mortality and weight loss. Clinical trials are ongoing to demonstrate safety of UV-4B and future studies to evaluate antiviral activity against influenza in humans are planned.
PMCID: PMC4810261  PMID: 27072420
Iminosugar; UV-4B; influenza; human bronchial epithelial cells; antiviral; mice
8.  Arctic ground squirrel neuronal progenitor cells resist oxygen and glucose deprivation-induced death 
AIM: To investigate the influence of ischemia/reperfusion on arctic ground squirrel (AGS) neuronal progenitor cells (NPCs), we subjected these cultured cells to oxygen and glucose deprivation.
METHODS: AGS NPCs were expanded and differentiated into NPCs and as an ischemia vulnerable control, commercially available human NPCs (hNPCs) were seeded from thawed NPCs. NPCs, identified by expression of TUJ1 were seen at 14-21 d in vitro (DIV). Cultures were exposed to control conditions, hypoxia, oxygen and glucose deprivation or glucose deprivation alone or following return to normal conditions to model reperfusion. Cell viability and death were assessed from loss of ATP as well as from measures of alamarBlue® and lactate dehydrogenase in the media and from counts of TUJ1 positive cells using immunocytochemistry. Dividing cells were identified by expression of Ki67 and phenotyped by double labeling with GFAP, MAP2ab or TUJ1.
RESULTS: We report that when cultured in NeuraLife™, AGS cells remain viable out to 21 DIV, continue to express TUJ1 and begin to express MAP2ab. Viability of hNPCs assessed by fluorescence alamarBlue (arbitrary units) depends on both glucose and oxygen availability [viability of hNPCs after 24 h oxygen glucose deprivation (OGD) with return of oxygen and glucose decreased from 48151 ± 4551 in control cultures to 43481 ± 2413 after OGD, P < 0.05]. By contrast, when AGS NPCs are exposed to the same OGD with reperfusion at 14 DIV, cell viability assessed by alamarBlue increased from 165305 ± 11719 in control cultures to 196054 ± 13977 after OGD. Likewise AGS NPCs recovered ATP (92766 ± 6089 in control and 92907 ± 4290 after modeled reperfusion; arbitrary luminescence units), and doubled in the ratio of TUJ1 expressing neurons to total dividing cells (0.11 ± 0.04 in control cultures vs 0.22 ± 0.2 after modeled reperfusion, P < 0.05). Maintaining AGS NPCs for a longer time in culture lowered resistance to injury, however, did not impair proliferation of NPCs relative to other cell lineages after oxygen deprivation followed by re-oxygenation.
CONCLUSION: Ischemic-like insults decrease viability and increase cell death in cultures of human NPCs. Similar conditions have less affect on cell death and promote proliferation in AGS NPCs.
PMCID: PMC4768121  PMID: 26981205
Neurogenesis; Neuronal progenitor; Hypoxia tolerance; Hibernation
9.  Influenza A Virus Infection, Innate Immunity, and Childhood 
JAMA pediatrics  2015;169(10):956-963.
Infection with influenza A virus is responsible for considerable morbidity and mortality in children worldwide. While it is apparent that adequate activation of the innate immune system is essential for pathogen clearance and host survival, an excessive inflammatory response to infection is detrimental to the young host. A review of the literature indicates that innate immune responses change throughout childhood. Whether these changes are genetically programmed or triggered by environmental cues is unknown. The objectives of this review are to summarize the role of innate immunity in influenza A virus infection in the young child and to highlight possible differences between children and adults that may make children more susceptible to severe influenza A infection. A better understanding of age-related differences in innate immune signaling will be essential to improve care for this high-risk population.
PMCID: PMC4765914  PMID: 26237589
10.  Differences Between Early and Late Readmissions Among Medical Patients, A Cohort Study 
Annals of internal medicine  2015;162(11):741-749.
Early and late readmissions may have different causal factors and thus require different strategies for prevention.
Determine whether predictors of readmission change within the 30-day window post-discharge.
Retrospective cohort study
Academic medical center
Medicine discharges, 1/1/2009-12/31/2010
(1) Factors related to the index hospitalization: acute illness burden, inpatient care process factors, and clinical indicators of instability at discharge; (2) Unrelated factors: chronic illness burden, and social determinants of health.
(1) Early readmissions, 0-7d post-discharge; (2) Late readmissions, 8-30d post-discharge.
13,334 discharges, representing 8,078 patients were included in the analysis, 1,046 readmissions (7.8%) occurred in the early period and 1,586 readmissions (11.9%) occurred in the late period. Early readmissions were associated with markers of acute illness burden, including length of hospital stay (Odds Ratio(OR) 1.02, 95%CI 1.00-1.03), and whether a rapid response team assessment was called (OR1.48, 95%CI 1.15-1.89); some markers of chronic illness burden, including being on a medication that indicates organ failure (OR1.19 95%CI 1.02-1.40); and some social determinants of health, including barriers to learning (OR 1.18 95%CI 1.01-1.38); and were less likely if a patient was discharged from the hospital between 800AM-1259 PM (OR0.76, 95%CI 0.58-0.99). Late readmissions were associated with markers of chronic illness burden, including being on a medication that indicated organ failure (OR1.27, 95%CI 1.10-1.46) or hemodialysis (OR1.75, 95%CI 1.29-2.37); and social determinants of health, including barriers to learning (OR1.22, 95%CI 1.07-1.40), and having unsupplemented Medicare or Medicaid (OR1.20, 95%CI 1.04-1.38).
Single center, only ascertains readmissions at our institution
The 30 days following hospital discharge may not be homogeneous. Causal factors and readmission prevention strategies may be different for the early vs. late periods.
Primary Funding Source
Health Resources and Services Administration training grant [T32 HP12706].
PMCID: PMC4747330  PMID: 26030632
11.  Reconstruction of an Entire Thumb Metacarpal: A Case Report 
This case report discusses the reconstruction of an entire thumb metacarpal after a diagnosis of giant cell tumor of bone. The patient underwent excision of the entire thumb metacarpal, followed by interposition of a tricortical iliac crest bone graft and metacarpophalangeal and carpometacarpal joint arthrodeses. This option allowed salvage of the patient’s native thumb with functional use as a stable post to which she can pinch and grasp objects. At 9 months postoperatively, there was no evidence of recurrence.
PMCID: PMC4778881  PMID: 27014539
12.  Age Differences in Prenatal Testosterone's Protective Effects on Disordered Eating Symptoms: Developmental Windows of Expression? 
Behavioral neuroscience  2015;129(1):18-36.
Prenatal testosterone exposure may be protective against disordered eating. However, prior studies have produced mixed results. Developmental differences in prenatal testosterone's protective effects on disordered eating may explain these discrepancies. Indeed, studies have differed in the age of participants assessed, with data supporting prenatal testosterone effects on disordered eating in early adolescent and young adult samples but not in late adolescence. The present series of studies are the first to investigate age differences in prenatal testosterone's protective effects on disordered eating. Two indirect markers of higher prenatal testosterone were examined: 1) lower finger-length ratios [index (2D)/ring (4D) finger] (Study 1), and 2) lower disordered eating in females from opposite-sex twin pairs (who are thought to be exposed to higher prenatal testosterone from their male co-twin) relative to female controls (Study 2). Participants were twins from the Michigan State University Twin Registry (Study 1: n = 409; Study 2: n = 1,538) in early adolescence, late adolescence, or young adulthood. Disordered eating was assessed with well-validated questionnaires. Finger-length ratios were measured from hand scans, using electronic computer calipers. Findings were consistent across both studies. Higher prenatal testosterone (lower 2D:4D; females from opposite-sex twin pairs vs. controls) predicted lower disordered eating in early adolescence and young adulthood only. Prenatal testosterone-disordered eating associations were not observed during late adolescence. Results point to the possibility of developmental windows of expression for prenatal testosterone's protective effects on disordered eating and suggest that prior discrepant results may reflect age differences across samples.
PMCID: PMC4317713  PMID: 25621790
disordered eating; eating disorder; sex difference; testosterone; hormones; 2D:4D
13.  A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells12 
Neoplasia (New York, N.Y.)  2016;18(1):60-70.
Diffuse intrinsic pontine glioma (DIPG) is a rare and incurable brain tumor that arises predominately in children and involves the pons, a structure that along with the midbrain and medulla makes up the brainstem. We have previously developed genetically engineered mouse models of brainstem glioma using the RCAS/Tv-a system by targeting PDGF-B overexpression, p53 loss, and H3.3K27M mutation to Nestin-expressing brainstem progenitor cells of the neonatal mouse. Here we describe a novel mouse model targeting these same genetic alterations to Pax3-expressing cells, which in the neonatal mouse pons consist of a Pax3 +/Nestin +/Sox2 + population lining the fourth ventricle and a Pax3 +/NeuN + parenchymal population. Injection of RCAS-PDGF-B into the brainstem of Pax3-Tv-a mice at postnatal day 3 results in 40% of mice developing asymptomatic low-grade glioma. A mixture of low- and high-grade glioma results from injection of Pax3-Tv-a;p53fl/fl mice with RCAS-PDGF-B and RCAS-Cre, with or without RCAS-H3.3K27M. These tumors are Ki67 +, Nestin +, Olig2 +, and largely GFAP − and can arise anywhere within the brainstem, including the classic DIPG location of the ventral pons. Expression of the H3.3K27M mutation reduces overall H3K27me3 as compared with tumors without the mutation, similar to what has been previously shown in human and mouse tumors. Thus, we have generated a novel genetically engineered mouse model of DIPG, which faithfully recapitulates the human disease and represents a novel platform with which to study the biology and treatment of this deadly disease.
PMCID: PMC4735629  PMID: 26806352
Clinics in perinatology  2015;42(2):243-viii.
Neonatologists often have the unique opportunity to be the first to identify abnormalities in the neonate. In this review, multiple anomalies and physical features are discussed along with the potential associated genetic syndromes. The anomalies and physical features that are discussed include birth parameters, aplasia cutis congenita, holoprosencephaly, asymmetric crying facies, preauricular ear tags and pits, cleft lip with or without cleft palate, esophageal atresia/tracheoesophageal fistula, congenital heart defects, ventral wall defects, and polydactyly.
PMCID: PMC4707958  PMID: 26042903
Aplasia cutis congenita; holoprosencephaly; asymmetric crying facies; preauricular tags; cleft lip with or without cleft palate; congenital heart defects; ventral wall defects; polydactyly
15.  Do Non-shared Environmental Influences Persist over Time? An Examination of Days and Minutes 
Behavior genetics  2014;45(1):24-34.
Non-shared environmental influences show only minimal stability over time prior to adulthood. The long assessment lags (typically 3-5 years) that characterize most longitudinal twin studies, however, make it difficult to interpret these results. To more rigorously evaluate non-shared environmental stability prior to adulthood, we fitted biometric correlated factors models to 1) seven consecutive days of self-reported negative and positive affect in 239 twin pairs aged 16-25 years and 2) seven consecutive minutes of observer rated warmth and control in 687 twin pairs aged 6-10 years. We then empirically examined patterns of etiologic stability over time using a mixed effects analog to the one-way ANOVA. Genetic and shared environmental correlations were found to be highly stable over both days and minutes. By contrast, non-shared environmental correlations decreased monotonically with increasing lag length, and moreover, were small-to moderate in magnitude when examining intervals longer than a few minutes. Such findings imply that the non-shared environment may be comprised primarily of transient and idiosyncratic effects prior to adulthood.
PMCID: PMC4289645  PMID: 25262214
non-shared environment; stability; genetic
16.  Human Papillomavirus Vaccine Initiation among 9–13-Year-Olds in the United States 
Preventive medicine reports  2015;2:892-898.
The quadrivalent and 9-valent human papillomavirus (HPV) vaccines are licensed for administration among 9–26-year-old males and females, with routine vaccination recommended for 11–12-year-olds. Despite the availability of the vaccine at younger ages, few studies have explored vaccine uptake prior to age 13, and national HPV vaccination surveillance data is limited to 13–17-year-olds. Our objective was to examine rates and predictors of HPV vaccine initiation among 9–13-year-olds in the United States.
A national sample of mothers of 9–13-year-olds in the United States (N=2,446) completed a 2014 Web-based survey assessing socio-demographic characteristics, child’s HPV vaccination history, provider communication regarding the vaccine, and other attitudes and behaviors pertaining to vaccination and healthcare utilization. The main outcome measure was child’s initiation of the HPV vaccine (i.e., receipt of one or more doses).
Approximately 35% of the full sample and 27.5% of the 9–10-year-olds had initiated HPV vaccination. Females were more likely than males to have initiated HPV vaccination by the age of 13 but not by younger ages. Strength of health provider recommendation regarding HPV vaccination was a particularly salient predictor of vaccine initiation.
Approximately a third of children may be initiating the HPV vaccine series before or during the targeted age range for routine administration of the vaccine. Because coverage remains below national targets, further research aimed at increasing vaccination during early adolescence is needed. Improving providers’ communication with parents about the HPV vaccine may be one potential mechanism for increasing vaccine coverage.
PMCID: PMC4652326  PMID: 26594616
early adolescence; healthcare providers; immunization
17.  Adolescent Peer Networks and the Potential for the Diffusion of Intervention Effects 
Many evaluation studies assess the direct effect of an intervention on individuals, but there is an increasing interest in clarifying how interventions can impact larger social settings. One process that can lead to these setting-level effects is diffusion, in which intervention effects spread from participants to non-participants. Diffusion may be particularly important when intervention participation rates are low, as they often are in universal family-based prevention programs. We drew on socialization and diffusion theories to articulate how features of peer networks may promote the diffusion of intervention effects. Then, we tested the measurement properties of 10 social network analytic (SNA) measures of diffusion potential. Data were from 42 networks (n = 5,784 students) involved in the PROSPER intervention trial. All families of 6th grade students were invited to participate in a family-based substance use prevention program, and 17% of the families attended at least one session. We identified two dimensions of network structure – social integration and location of intervention participants in their peer network – that might promote diffusion. Analyses demonstrated that these SNA measures varied across networks and were distinct from traditional analytic measures that do not require social network analysis (i.e., participation rate, how representative participants are of the broader population). Importantly, several SNA measures and the global network index predicted diffusion over and above the effect of participation rate and representativeness. We conclude by recommending which SNA measures may be the most promising for studying how networks promote the diffusion of intervention effects and lead to setting-level effects.
PMCID: PMC4119091  PMID: 24482140
Diffusion; Peer Networks; Family Interventions; Substance Use Prevention Programs; Adolescence
18.  Statin Use is Associated with Improved Survival in Patients Undergoing Surgery for Renal Cell Carcinoma 
Urologic oncology  2014;33(1):21.e11-21.e17.
To determine whether statin use at time of surgery is associated with survival following nephrectomy or partial nephrectomy for renal cell carcinoma (RCC). Statins are thought to exhibit a protective effect on cancer incidence and possibly cancer survival in a number of malignancies; to date, no studies have shown an independent association between statin use and mortality in RCC.
A retrospective cohort study of 916 patients who underwent radical or partial nephrectomy for RCC from 2000–2010 at a single institution was performed. Primary outcomes were overall (OS) and disease-specific survival (DSS). Univariable survival analyses were performed using the Kaplan-Meier and log-rank methods. Multivariable analysis was performed using a Cox proportional hazards model. The predictive discrimination of the models was assessed with Harrell’s c-index.
Median follow-up of the entire cohort was 42.5 months. The three-year OS estimate was 83.1% (95%CI, 77.6–87.3%) for statin users and 77.3% (95%CI, 73.7–80.6%) for non-statin users (p=0.53). Three-year DSS was 90.9% (95%CI, 86.3–94.0%) for statin users and 83.5% (95%CI, 80.1–86.3%) for non-statin users (p=0.015). After controlling for age, ASA class, pT stage, pN stage, metastatic status, pre-operative anemia and corrected hypercalcemia, and blood type, statin use at time of surgery was independently associated with improved OS (HR 0.62, 95%CI 0.43–0.90; p=0.011) and DSS (HR 0.48, 95%CI 0.28–0.83; p=0.009). The multivariable model for DSS had excellent predictive discrimination with a c-index of 0.91.
These data suggest that statin usage at time of surgery is independently associated with improved OS and DSS in patients undergoing surgery for RCC.
PMCID: PMC4274038  PMID: 25456998
Statins; nephrectomy; partial nephrectomy; renal cell carcinoma
19.  Health Disparities Among Young Adult Sexual Minorities in the US 
Emerging research suggests that young adult sexual minorities (identifying as lesbian, gay, or bisexual or engaging in same-sex attractions or behaviors) experience poorer health than their majority counterparts, but many measures of health inequity remain unexamined in population-based research.
To describe a wide range of health status and healthcare access characteristics of sexual minorities in comparison with those of the majority population in a national sample of U.S. young adults.
Binary and multinomial logistic regression analyses of Wave IV data (2008) from the National Longitudinal Study of Adolescent Health (participants aged 24–32 years, n=13,088) were conducted. Health measures were self-rated health; diagnosis of any of several physical or mental illnesses or sexually transmitted infections; measured body mass index; depression classified from self-reported symptoms; use of antidepressant and anxiolytic medication; uninsured; forgone care; and receipt of physical, dental, and psychological services. Analyses were conducted in 2012–2013.
Sexual minority women had elevated odds of most adverse health conditions and lower odds of receiving a physical or dental examination. Sexual minority men had elevated odds of fewer adverse health conditions.
Young adult sexual minorities are at higher risk of poor physical and mental health. The results highlight the multidimensionality of sexual minority status and respond to calls for greater understanding of the health of this population.
PMCID: PMC4274226  PMID: 25241194
20.  Localisation-based imaging of malarial antigens during erythrocyte entry reaffirms a role for AMA1 but not MTRAP in invasion 
Journal of Cell Science  2016;129(1):228-242.
Microscopy-based localisation of proteins during malaria parasite (Plasmodium) invasion of the erythrocyte is widely used for tentative assignment of protein function. To date, however, imaging has been limited by the rarity of invasion events and the poor resolution available, given the micron size of the parasite, which leads to a lack of quantitative measures for definitive localisation. Here, using computational image analysis we have attempted to assign relative protein localisation during invasion using wide-field deconvolution microscopy. By incorporating three-dimensional information we present a detailed assessment of known parasite effectors predicted to function during entry but as yet untested or for which data are equivocal. Our method, termed longitudinal intensity profiling, resolves confusion surrounding the localisation of apical membrane antigen 1 (AMA1) at the merozoite–erythrocyte junction and predicts that the merozoite thrombospondin-related anonymous protein (MTRAP) is unlikely to play a direct role in the mechanics of entry, an observation supported with additional biochemical evidence. This approach sets a benchmark for imaging of complex micron-scale events and cautions against simplistic interpretations of small numbers of representative images for the assignment of protein function or prioritisation of candidates as therapeutic targets.
Highlighted Article: Here we develop a high-definition imaging approach to dissect and assign function to proteins involved in the rapid process of malaria parasite invasion of the human erythrocyte.
PMCID: PMC4732298  PMID: 26604223
Plasmodium falciparum; Merozoite; Erythrocyte invasion; Tight junction; Deconvolution
21.  Species-Level Variability in Extracellular Production Rates of Reactive Oxygen Species by Diatoms 
Biological production and decay of the reactive oxygen species (ROS) hydrogen peroxide (H2O2) and superoxide (O2-) likely have significant effects on the cycling of trace metals and carbon in marine systems. In this study, extracellular production rates of H2O2 and O2- were determined for five species of marine diatoms in the presence and absence of light. Production of both ROS was measured in parallel by suspending cells on filters and measuring the ROS downstream using chemiluminescence probes. In addition, the ability of these organisms to break down O2- and H2O2 was examined by measuring recovery of O2- and H2O2 added to the influent medium. O2- production rates ranged from undetectable to 7.3 × 10−16 mol cell−1 h−1, while H2O2 production rates ranged from undetectable to 3.4 × 10−16 mol cell−1 h−1. Results suggest that extracellular ROS production occurs through a variety of pathways even amongst organisms of the same genus. Thalassiosira spp. produced more O2- in light than dark, even when the organisms were killed, indicating that O2- is produced via a passive photochemical process on the cell surface. The ratio of H2O2 to O2- production rates was consistent with production of H2O2 solely through dismutation of O2- for T. oceanica, while T. pseudonana made much more H2O2 than O2-. T. weissflogii only produced H2O2 when stressed or killed. P. tricornutum cells did not make cell-associated ROS, but did secrete H2O2-producing substances into the growth medium. In all organisms, recovery rates for killed cultures (94–100% H2O2; 10–80% O2-) were consistently higher than those for live cultures (65–95% H2O2; 10–50% O2-). While recovery rates for killed cultures in H2O2 indicate that nearly all H2O2 was degraded by active cell processes, O2- decay appeared to occur via a combination of active and passive processes. Overall, this study shows that the rates and pathways for ROS production and decay vary greatly among diatom species, even between those that are closely related, and as a function of light conditions.
PMCID: PMC4812844  PMID: 27066475
reactive oxygen species; superoxide; hydrogen peroxide; diatoms; culture
22.  The CODAtwins project: the cohort description of COllaborative project of Development of Anthropometrical measures in Twins to study macro-environmental variation in genetic and environmental effects on anthropometric traits 
Silventoinen, Karri | Jelenkovic, Aline | Sund, Reijo | Honda, Chika | Aaltonen, Sari | Yokoyama, Yoshie | Tarnoki, Adam D | Tarnoki, David L | Ning, Feng | Ji, Fuling | Pang, Zengchang | Ordoñana, Juan R | Sánchez-Romera, Juan F | Colodro-Conde, Lucia | Burt, S Alexandra | Klump, Kelly L | Medland, Sarah E | Montgomery, Grant W | Kandler, Christian | McAdams, Tom A | Eley, Thalia C | Gregory, Alice M | Saudino, Kimberly J | Dubois, Lise | Boivin, Michel | Haworth, Claire MA | Plomin, Robert | Öncel, Sevgi Y | Aliev, Fazil | Stazi, Maria A | Fagnani, Corrado | D'Ippolito, Cristina | Craig, Jeffrey M | Saffery, Richard | Siribaddana, Sisira H | Hotopf, Matthew | Sumathipala, Athula | Spector, Timothy | Mangino, Massimo | Lachance, Genevieve | Gatz, Margaret | Butler, David A | Bayasgalan, Gombojav | Narandalai, Danshiitsoodol | Freitas, Duarte L | Maia, José Antonio | Harden, K Paige | Tucker-Drob, Elliot M | Christensen, Kaare | Skytthe, Axel | Kyvik, Kirsten O | Hong, Changhee | Chong, Youngsook | Derom, Catherine A | Vlietinck, Robert F | Loos, Ruth JF | Cozen, Wendy | Hwang, Amie E | Mack, Thomas M | He, Mingguang | Ding, Xiaohu | Chang, Billy | Silberg, Judy L | Eaves, Lindon J | Maes, Hermine H | Cutler, Tessa L | Hopper, John L | Aujard, Kelly | Magnusson, Patrik KE | Pedersen, Nancy L | Dahl-Aslan, Anna K | Song, Yun-Mi | Yang, Sarah | Lee, Kayoung | Baker, Laura A | Tuvblad, Catherine | Bjerregaard-Andersen, Morten | Beck-Nielsen, Henning | Sodemann, Morten | Heikkilä, Kauko | Tan, Qihua | Zhang, Dongfeng | Swan, Gary E | Krasnow, Ruth | Jang, Kerry L | Knafo-Noam, Ariel | Mankuta, David | Abramson, Lior | Lichtenstein, Paul | Krueger, Robert F | McGue, Matt | Pahlen, Shandell | Tynelius, Per | Duncan, Glen E | Buchwald, Dedra | Corley, Robin P | Huibregtse, Brooke M | Nelson, Tracy L | Whitfield, Keith E | Franz, Carol E | Kremen, William S | Lyons, Michael J | Ooki, Syuichi | Brandt, Ingunn | Nilsen, Thomas Sevenius | Inui, Fujio | Watanabe, Mikio | Bartels, Meike | van Beijsterveldt, Toos CEM | Wardle, Jane | Llewellyn, Clare H | Fisher, Abigail | Rebato, Esther | Martin, Nicholas G | Iwatani, Yoshinori | Hayakawa, Kazuo | Rasmussen, Finn | Sung, Joohon | Harris, Jennifer R | Willemsen, Gonneke | Busjahn, Andreas | Goldberg, Jack H | Boomsma, Dorret I | Hur, Yoon-Mi | Sørensen, Thorkild IA | Kaprio, Jaakko
For over one hundred years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically 1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and 2) to study the effects of birth related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects including both monozygotic and dizygotic twins using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.
PMCID: PMC4696543  PMID: 26014041
23.  The thioredoxin system in breast cancer cell invasion and migration 
Redox Biology  2015;8:68-78.
Metastasis is the most life threatening aspect of breast cancer. It is a multi-step process involving invasion and migration of primary tumor cells with a subsequent colonization of these cells at a secondary location. The aim of the present study was to investigate the role of thioredoxin (Trx1) in the invasion and migration of breast cancer cells and to assess the strength of the association between high levels of Trx1 and thioredoxin reductase (TrxR1) expression with breast cancer patient survival. Our results indicate that the expression of both Trx1 and TrxR1 are statistically significantly increased in breast cancer patient cells compared with paired normal breast tissue from the same patient. Over-expression of Trx1 in MDA-MB-231 breast cancer cell lines enhanced cell invasion in in vitro assays while expression of a redox inactive mutant form of Trx1 (designated 1SS) or the antisense mRNA inhibited cell invasion. Addition of exogenous Trx1 also enhanced cell invasion, while addition of a specific monoclonal antibody that inhibits Trx1 redox function decreased cell invasion. Over-expression of intracellular Trx1 did not increase cell migration but expression of intracellular 1SS inhibited migration. Addition of exogenous Trx1 enhanced cell migration while 1SS had no effect. Treatment with auranofin inhibited TrxR activity, cell migration and clonogenic activity of MDA-MB-231 cells, while increasing reactive oxygen species (ROS) levels. Analysis of 25 independent cohorts with 5910 patients showed that Trx1 and TrxR1 were both associated with a poor patient prognosis in terms of overall survival, distant metastasis free survival and disease free survival. Therefore, targeting the Trx system with auranofin or other specific inhibitors may provide improved breast cancer patient outcomes through inhibition of cancer invasion and migration.
Graphical abstract
•Over expression of thioredoxin in MDA-MB-231 cells enhanced cell invasion in vitro.•Thioredoxin inhibition reduced cell invasion and migration of MDA-MB-231 cells.•Addition of thioredoxin enhanced migration of MDA-MB-231 cells in vitro.•Auranofin treatment inhibited MDA-MB-231 cell migration and clonogenic activity.•High Trx1 and TrxR1 expression is associated with a poor breast cancer prognosis.
PMCID: PMC4712318  PMID: 26760912
ATL, adult T-cell leukemia; CI, confidence interval; FBS, fetal bovine serum; DFS, disease free survival; DMFS, distant-metastasis free survival; DTNB, 5,5′-Dithio-Bis (2-Nitrobenzoic Acid); DTT, dithiothreitol; GFP, green fluorescent protein; H2DCF-DA, 2′,7′-dichlorodihydrofluorescein diacetate; HR, hazard ratio; HUVEC, human umbilical vein endothelial cells; MMP, matrix metalloproteinase; MTT, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; OS, overall survival; RFU, relative fluorescence units; ROS, reactive oxygen species; TCGA, the cancer genome atlas; TIMP, tissue inhibitor of metalloproteinase; TNB, 2-nitro-5-thiobenzoate anion; TPM, transcripts per million; Trx, thioredoxin; TrxR, thioredoxin reductase; TXNIP, thioredoxin interacting protein; VEGF, vascular endothelial growth factor; Thioredoxin; Breast cancer; Cell invasion; Cell migration; Patient survival; Auranofin
24.  Neonatal mitochondrial abnormalities due to PINK1 deficiency: Proteomics reveals early changes relevant to Parkinson׳s disease 
Data in Brief  2015;6:428-432.
Parkinson׳s disease (PD), the second most common neurodegenerative disorder, affects roughly 7–10 million people worldwide. A wide array of research has suggested that PD has a mitochondrial component and that mitochondrial dysfunction occurs well in advance of the clinical manifestation of the disease. Previous work by our lab has categorized the mitochondrial disorder associated with Parkinson׳s disease in a PINK1 knockout rat model. This model develops Parkinson׳s disease in a spontaneous, predictable manner. Our findings demonstrated PINK1-deficient rats at 4 months of age had mitochondrial proteomic and functional abnormalities before the onset of Parkinsonian symptoms (6 months) such as the movement disorder, loss of midbrain dopaminergic neurons, or the progressive degeneration present at 9 months. With this in mind, our group investigated the PINK1 knockout genetic rat model at postnatal day 10 to determine if the observed alterations at 4 months were present at an earlier time point. Using a proteomic analysis of brain mitochondria, we identified significant mitochondrial proteomic alterations in the absence of mitochondrial functional changes suggesting the observed alterations are part of the mitochondrial pathways leading to PD. Specifically, we identified differentially expressed proteins in the PINK1 knockout rat involved in glycolysis, the tricarboxylic acid cycle, and fatty acid metabolism demonstrating abnormalities occur well in advance of the manifestation of clinical symptoms. Additionally, 13 of the differentially expressed proteins have been previously identified in older PINK1 knockout animals as differentially regulated suggesting these proteins may be viable markers of the PD pathology, and further, the abnormally regulated pathways could be targeted for therapeutic interventions. All raw data can be found in Supplementary Table 1.
PMCID: PMC4710791  PMID: 26866053
25.  What Factors Are Related to Success on Conditional Release/Discharge? Findings from the New Orleans Forensic Aftercare Clinic: 2002–2013 
Behavioral sciences & the law  2014;32(5):641-658.
The present study investigated the empirically based factors that predicted success on conditional release among a sample of individuals conditionally discharged in Louisiana. Not guilty by reason of insanity acquittees and individuals on conditional release/discharge for incompetency to stand trial were included in the study. Success on conditional release was defined as maintenance of conditional release during the study period. Recidivism (arrest on new charges) and incidents were empirically evaluated. Success on conditional release was maintained in over 70% of individuals. Recidivism was low, with only five arrests on new charges. Success on conditional release was predicted by financial resources, not having a personality disorder, and having fewer total incidents in the program. After controlling for the influence of other variables, having an incident on conditional release was predicted by a substance use diagnosis and being released from jail. Individuals conditionally released from jail showed fewer number of days to first incident (67 vs. 575 days) compared with individuals discharged from the hospital. These data provide support for the successful management of forensic patients in the community via conditional release, although they highlight specific factors that should be considered when developing community-based release programming. Conditional release programs should consider empirical factors in the development of risk assessment and risk management approaches to improve successful maintenance of community-based forensic treatment alternatives.
PMCID: PMC4667809  PMID: 25328070

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