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1.  Glomerular cell death and inflammation with high-protein diet and diabetes 
Nephrology Dialysis Transplantation  2013;28(7):1711-1720.
Overfeeding amino acids (AAs) increases cellular exposure to advanced glycation end-products (AGEs), a mechanism for protein intake to worsen diabetic kidney disease (DKD). This study assessed receptor for AGE (RAGE)-mediated apoptosis and inflammation in glomerular cells exposed to metabolic stressors characteristic of high-protein diets and/or diabetes in vitro with proof-of-concept appraisal in vivo.
Mouse podocytes and mesangial cells were cultured under control and metabolic stressor conditions: (i) no addition; (ii) increased AAs (4–6-fold >control); (iii) high glucose (HG, 30.5 mM); (iv) AA/HG combination; (v) AGE-bovine serum albumin (AGE-BSA, 300 µg/mL); (vi) BSA (300 µg/mL). RAGE was inhibited by blocking antibody. Diabetic (streptozotocin) and nondiabetic mice (C57BL/6J) consumed diets with protein calories of 20 or 40% (high) for 20 weeks. People with DKD and controls provided 24-h urine samples.
In podocytes and mesangial cells, apoptosis (caspase 3/7 activity and TUNEL) increased in all metabolic stressor conditions. Both inflammatory mediator expression (real-time reverse transcriptase–polymerase chain reaction: serum amyloid A, caspase-4, inducible nitric oxide synthase, and monocyte chemotactic protein-1) and RAGE (immunostaining) also increased. RAGE inhibition prevented apoptosis and inflammation in podocytes. Among mice fed high protein, podocyte number (WT-1 immunostaining) decreased in the diabetic group, and only these diabetic mice developed albuminuria. Protein intake (urea nitrogen) correlated with AGE excretion (carboxymethyllysine) in people with DKD and controls.
High-protein diet and/or diabetes-like conditions increased glomerular cell death and inflammation, responses mediated by RAGEs in podocytes. The concept that high-protein diets exacerbate early indicators of DKD is supported by data from mice and people.
PMCID: PMC3707525  PMID: 23314315
apoptosis; high-protein diet; mesangial cells; podocytes; receptor for advanced glycation end-products
2.  Puberty as a Critical Risk Period for Eating Disorders: A Review of Human and Animal Studies 
Hormones and behavior  2013;64(2):399-410.
Puberty is one of the most frequently discussed risk periods for the development of eating disorders. Prevailing theories propose environmentally mediated sources of risk arising from the psychosocial effects (e.g., increased body dissatisfaction, decreased self-esteem) of pubertal development in girls. However, recent research highlights the potential role of ovarian hormones in phenotypic and genetic risk for eating disorders during puberty. The goal of this paper is to review data from human and animal studies in support of puberty as a critical risk period for eating disorders and evaluate the evidence for hormonal contributions. Data are consistent in suggesting that both pubertal status and pubertal timing significantly impact risk for most eating disorders in girls, such that advanced pubertal development and early pubertal timing are associated with increased rates of eating disorders and their symptoms in both cross-sectional and longitudinal research. Findings in boys have been much less consistent and suggest a smaller role for puberty in risk for eating disorders in boys. Twin and animal studies indicate that at least part of the female-specific risk is due to genetic factors associated with estrogen activation at puberty. In conclusion, data thus far support a role for puberty in risk for eating disorders and highlight the need for additional human and animal studies of hormonal and genetic risk for eating disorders during puberty.
PMCID: PMC3761220  PMID: 23998681
puberty; eating disorders; anorexia nervosa; bulimia nervosa; ovarian hormones; estrogen; twin studies
3.  Development of an artificial placenta V: 70 h veno-venous extracorporeal life support after ventilatory failure in premature lambs 
Journal of pediatric surgery  2013;48(1):145-153.
An artificial placenta would change the paradigm of treating extremely premature infants. We hypothesized that using a veno-venous extracorporeal life support (VV-ECLS) artificial placenta after ventilatory failure would stabilize premature lambs and maintain normal fetal physiologic parameters for 70h.
A near-term neonatal lamb model (130 days; term=145) was used. The right jugular vein (drainage) and umbilical vein (reinfusion) were cannulated with 10–12 Fr cannulas. Lambs were then transitioned to an infant ventilator. After respiratory failure, the endotracheal tube was filled with amniotic fluid, and VV-ECLS total artificial placenta support (TAPS) was initiated. Lambs were maintained on TAPS for 70h.
Six of seven lambs survived for 70h. Mean ventilation time was 57±22min. During ventilation, mean MAP was 51±14mmHg, compared to 44±14mmHg during TAPS (p=0.001). Mean pH and lactate during ventilation were 7.06±0.15 and 5.7±2.3mmol/L, compared to 7.33±0.07 and 2.0±1.8mmol/L during TAPS (p<0.001 for both). pO2 and pCO2 remained within normal fetal parameters during TAPS, and mean carotid blood flow was 25±7.5mL/kg/min. Necropsy showed a patent ductus arteriosus and no intracranial hemorrhage in all animals.
The artificial placenta stabilized premature lambs after ventilatory failure and maintained fetal circulation, hemodynamic stability, gas exchange, and cerebral perfusion for 70h.
PMCID: PMC4076781  PMID: 23331807
Artificial placenta; ECLS; ECMO; Neonatal; Fetal; Respiratory failure
4.  Evocative gene–environment correlation in the mother–child relationship: A twin study of interpersonal processes 
Development and psychopathology  2013;25(1):105-118.
The behavior genetic literature suggests that genetically influenced characteristics of the child elicit specific behaviors from the parent. However, little is known about the processes by which genetically influenced child characteristics evoke parental responses. Interpersonal theory provides a useful framework for identifying reciprocal behavioral processes between children and mothers. The theory posits that, at any given moment, interpersonal behavior varies along the orthogonal dimensions of warmth and control and that the interpersonal behavior of one individual tends to elicit corresponding or contrasting behavior from the other (i.e., warmth elicits warmth, whereas control elicits submission). The current study thus examined these dimensions of interpersonal behavior as they relate to the parent–child relationship in 546 twin families. A computer joystick was used to rate videos of mother–child interactions in real time, yielding information on mother and child levels of warmth and control throughout the interaction. Analyses indicated that maternal control, but not maternal warmth, was influenced by evocative gene–environment correlational processes, such that genetic influences on maternal control and child control were largely overlapping. Moreover, these common genetic influences were present both cross-sectionally and over the course of the interaction. Such findings not only confirm the presence of evocative gene–environment correlational processes in the mother–child relationship but also illuminate at least one of the specific interpersonal behaviors that underlie this evocative process.
PMCID: PMC4052725  PMID: 23398756
5.  Streptococcus pneumoniae Carriage Prevalence in Nepal: Evaluation of a Method for Delayed Transport of Samples from Remote Regions and Implications for Vaccine Implementation 
PLoS ONE  2014;9(6):e98739.
Pneumococcal disease is a significant cause of morbidity and mortality in young children in Nepal, and currently available pneumococcal conjugate vaccines offer moderate coverage of invasive disease isolates.
A prevalence study of children aged 1.5 to 24 months in urban and rural Nepal was conducted. In the urban group, nasopharyngeal swabs (NPS) were transported using silica desiccant packages (SDP) with delayed processing (2 weeks), or skim-milk-tryptone-glucose-glycerin (STGG) with immediate processing (within 8 hours). Pneumococcal nasopharyngeal carriage prevalence, serogroup/type distribution and isolate genotypes (as defined by multilocus sequence typing) were determined.
1101 children were enrolled into the study: 574 in the urban group and 527 in the rural group. Overall carriage prevalence based on culture from specimens transported and stored in STGG was 58.7% (337/574), compared to 40.9% (235/574) in SDP. There was concordance of detection of pneumococcus in 67% of samples. Using the SDP method, pneumococcal carriage prevalence was higher in the rural population (69.2%; 364/526) compared to the urban population (40.9%; 235/574). Serogroup/type distribution varied with geographical location. Over half of the genotypes identified in both the urban and rural pneumococcal populations were novel.
The combination of delayed culture and transport using SDP underestimates the prevalence of pneumococcal carriage; however, in remote areas, this method could still provide a useful estimate of carriage prevalence and serogroup/type distribution. Vaccine impact is unpredictable in a setting with novel genotypes and limited serotype coverage as described here. Consequently, continued surveillance of pneumococcal isolates from carriage and disease in Nepali children following the planned introduction of pneumococcal conjugate vaccines introduction will be essential.
PMCID: PMC4048273  PMID: 24905574
6.  Shading as a Control Method for Invasive European Frogbit (Hydrocharis morsus-ranae L.) 
PLoS ONE  2014;9(6):e98488.
Invasive European frogbit (Hydrocharis morsus-ranae L.) has negative environmental and economic impacts in North American water bodies. It is therefore important to develop effective management tools to control this invasive species. This study investigated shading as a control method for European frogbit in both greenhouse and lake mesocosm experiments. A series of shade treatments (0%, 50%, 60%, 70%, 80%, and 100%) were tested in the greenhouse for three weeks. Results showed that the 100% shade was most effective at controlling European frogbit, and other shade treatments greater than 50% were less effective, reducing frogbit biomass up to 38.2%. There were no differences found in temperature between treatments, but dissolved oxygen decreased as shading increased. A lake mesocosm experiment utilizing 0% shade, 70% shade, and 100% shade treatments was performed in a sheltered inlet of Oneida Lake in New York State for over one month. Resulting European frogbit biomass was significantly (25 times) less in areas treated with the 70% shade and nearly zero with the 100% shade. Shading did not affect temperature but improved DO conditions. Results on the shading effects on submerged macrophytes were not conclusive: no significant differences in changes in species richness and abundance between the three groups at the end of studied period suggested no shading effects; significant differences between the beginning and end communities in the 70% shade and the 100% shade but not in the control group indicated significant impacts of shading. This study is the first one to investigate shading as a control method for European frogbit and it is concluded that a moderately high density shade can effective remove European frogbit likely with minor impacts on the environment. More experiments with larger scales and longer time periods are recommended for further investigation.
PMCID: PMC4041761  PMID: 24886916
7.  Item Banks for Alcohol Use from the Patient-Reported Outcomes Measurement Information System (PROMIS): Use, Consequences, and Expectancies 
Drug and alcohol dependence  2012;130(0):167-177.
We report on the development and calibration of item banks for alcohol use, negative and positive consequences of alcohol use, and negative and positive expectancies regarding drinking as part of the Patient-Reported Outcomes Measurement Information System (PROMIS).
Comprehensive literature searches yielded an initial bank of more than 5,000 items from over 200 instruments. After qualitative item analysis (including focus groups and cognitive interviewing), 141 items were included in field testing. Items for alcohol use and consequences were written in a first-person, past-tense format with a 30-day time frame and 5 response options reflecting frequency. Items for expectancies were written in a third-person, present-tense format with no time frame specified and 5 response options reflecting intensity. The calibration sample included 1,407 respondents, 1,000 from the general population (ascertained through an internet panel) and 407 from community treatment programs participating in the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN).
Final banks of 37, 31, 20, 11, and 9 items (108 total items) were calibrated for alcohol use, negative consequences, positive consequences, negative expectancies, and positive expectancies, respectively, using item response theory (IRT). Seven-item static short forms were also developed from each item bank.
Test information curves showed that the PROMIS item banks provided substantial information in a broad range of severity, making them suitable for treatment, observational, and epidemiological research.
PMCID: PMC3596476  PMID: 23206377
alcohol use; alcohol consequences; alcohol expectancies; item response theory; measurement
8.  Lower Mortality for Abdominal Aortic Aneurysm Repair in High Volume Hospitals is Contingent upon Nurse Staffing 
Health services research  2012;48(3):972-991.
To determine whether and to what extent the lower mortality rates for patients undergoing abdominal aortic aneurysm (AAA) repair in high volume hospitals is explained by better nursing.
Data Sources
State hospital discharge data, Multi-State Nursing Care and Patient Safety Survey, and hospital characteristics from the AHA Annual Survey.
Study Design
Cross-sectional analysis of linked patient outcomes for individuals undergoing AAA repair in four states.
Data Collection
Secondary data sources.
Principal Findings
Favorable nursing practice environments and higher hospital volumes of AAA repair are associated with lower mortality and fewer failures-to-rescue in main effects models. Further, nurse staffing interacts with volume such that there is no mortality advantage observed in high volume hospitals with poor nurse staffing. When hospitals have good nurse staffing, patients in low volume hospitals are 3.4 times as likely to die and 2.6 times as likely to die from complications as patients in high volume hospitals (p<0.001).
Nursing is part of the explanation for lower mortality after AAA repair in high volume hospitals. Importantly, lower mortality is not found in high volume hospitals if nurse staffing is poor.
PMCID: PMC3651774  PMID: 23088426
nurse staffing; nurse practice environment; volume-outcomes; abdominal aortic aneurysm
9.  Use of a Low Resistance Compliant Thoracic Artificial Lung in the Pulmonary Artery to Pulmonary Artery Configuration 
The Journal of thoracic and cardiovascular surgery  2013;145(6):10.1016/j.jtcvs.2013.01.020.
Thoracic artificial lungs (TALs) have been proposed as a bridge to transplant in patients with end-stage lung disease. Systemic embolic complications can occur following TAL attachment in the pulmonary artery to left atrium (PA-LA) configuration. Therefore, we evaluated the function of a compliant TAL (cTAL) attached via the proximal PA to distal main PA configuration.
The cTAL was attached to five (63 ± 0.9 kg) sheep in the PA-PA configuration. Device function and animal hemodynamics were assessed at baseline and with approximately 60%, 75%, and 90% of CO diverted to the cTAL. At each condition, dobutamine (0 and 5 mcg · kg−1 · min−1) was used to simulate rest and exercise conditions.
At rest, CO decreased from 6.20 ± 0.53 L/min at baseline to 5.40 ± 0.43, 4.66 ± 0.31, and 4.05 ± 0.27 L/min with 50, 75, and 90% of CO to the cTAL (p<0.01 for each flow diversion vs. baseline). During exercise, CO decreased from 7.85 ± 0.70 L/min at baseline to 7.46 ± 0.55, 6.93 ± 0.51, and 5.96 ± 0.44 L/min (p=0.82, 0.19, and p<0.01 with respect to baseline) with 50, 75, and 90% of CO to the cTAL. The cTAL resistance averaged 0.46 ± 0.02 mmHg/(L/min) and did not vary significantly with cTAL blood flow rate.
Use of a cTAL may be feasible in the PA-PA setting if cTAL blood flow is held at < 75% of CO. To ensure a drop in CO < 10%, a cTAL flow rate < 60% of CO is advised.
PMCID: PMC3653992  PMID: 23402692
10.  The dysregulated cluster in personality profiling research: Longitudinal stability and associations with bulimic behaviors and correlates 
Journal of personality disorders  2013;27(3):10.1521/pedi_2013_27_091.
Among cluster analytic studies of the personality profiles associated with bulimia nervosa, a group of individuals characterized by emotional lability and behavioral dysregulation (i.e., a dysregulated cluster) has emerged most consistently. However, previous studies have all been cross-sectional and mostly used clinical samples. This study aimed to replicate associations between the dysregulated personality cluster and bulimic symptoms and related characteristics using a longitudinal, population-based sample. Participants were females assessed at ages 17 and 25 from the Minnesota Twin Family Study, clustered based on their personality traits. The Dysregulated cluster was successfully identified at both time points and was more stable across time than either the Resilient or Sensation Seeking clusters. Rates of bulimic symptoms and related behaviors (e.g., alcohol use problems) were also highest in the dysregulated group. Findings suggest that the dysregulated cluster is a relatively stable and robust profile that is associated with bulimic symptoms.
PMCID: PMC3887551  PMID: 23398096
personality cluster; bulimic behaviors; stability
11.  Relationship of vitamin D, HIV, HIV treatment and lipid levels in the Women’s Interagency HIV study (WIHS) of HIV-infected and un-infected women in the US 
Relationships between vitamin D, lipids, HIV infection, and HIV treatment (±ART) were investigated with Women’s Interagency HIV Study data (n=1758 middle-aged women) using multivariable regression. 63 % had vitamin D deficiency. Median 25-OH vitamin D was highest in HIV-infected +ART-treated women (17 ng/mL, p<0.001), but the same in HIV-uninfected or HIV-infected without ART (14 ng/mL). Vitamin D levels were lower if ART included efavirenz (15 vs 19 ng/mL, p<0.001). The most common lipid abnormality was high triglycerides (≥200 mg/dL) in HIV-infected +ART, (13%, vs 7% of HIV-infected without ART and 5% of HIV-uninfected (p<0.001) with a positive relationship between 25-OH-D and triglycerides (95% confidence interval 0.32 to 1.69, p<.01). No relationships between 25-OH-D and cholesterol were detected. Vitamin D deficiency is common irrespective of HIV status but influenced by HIV treatment. Similarly, vitamin D levels were positively related to triglycerides only in ART treated HIV infected, and unrelated to cholesterol.
PMCID: PMC4016117  PMID: 24668135
Vitamin D; lipids; HIV infected; HIV uninfected; 25-OH vitamin D; cholesterol; LDL-cholesterol; triglycerides; lipids; WIHS
12.  Habituation of Arctic ground squirrels (Urocitellus parryii) to handling and movement during torpor to prevent artificial arousal 
Hibernation is a unique physiological adaptation characterized by periods of torpor that consist of repeated, reversible, and dramatic reductions of body temperature, metabolism, and blood flow. External and internal triggers can induce arousal from torpor in the hibernator. Studies of hibernating animals often require that animals be handled or moved prior to sampling or euthanasia but this movement can induce changes in the hibernation status of the animal. In fact, it has been demonstrated that movement of animals while they are hibernating is sufficient to induce an artificial arousal, which can detrimentally alter experimental findings obtained from animals assumed to be torpid. Therefore, we assessed a method to induce habituation of torpid hibernators to handling and movement to reduce inadvertent arousals. A platform rocker was used to mimic motion experienced during transfer of an animal and changes in respiratory rate (RR) were used to assess responsiveness of torpid Arctic ground squirrels (AGS, Urocitellus parryii). We found that movement alone did not induce a change in RR, however, exposure to handling induced an increase in RR in almost all AGS. This change in RR was markedly reduced with increased exposures, and all AGS exhibited a change in RR ≤ 1 by the end of the study. AGS habituated faster mid-season compared to early in the season, which mirrors other assessments of seasonal variation of torpor depth. However, AGS regained responsiveness when they were not exposed to daily handling. While AGS continued to undergo natural arousals during the study, occurrence of a full arousal was neither necessary for becoming habituated nor detrimental to the time required for habituation. These data suggest that even when torpid, AGS are able to undergo mechanosensory habituation, one of the simplest forms of learning, and provides a reliable way to reduce the sensitivity of torpid animals to handling.
PMCID: PMC4023073  PMID: 24847278
habituation; handling and movement; hibernation; Urocitellus parryii; Arctic ground squirrel
13.  Accelerated Resolution Therapy for treatment of pain secondary to symptoms of combat-related posttraumatic stress disorder 
European Journal of Psychotraumatology  2014;5:10.3402/ejpt.v5.24066.
As many as 70% of veterans with chronic pain treated within the US Veterans Administration (VA) system may have posttraumatic stress disorder (PTSD), and conversely, up to 80% of those with PTSD may have pain. We describe pain experienced by US service members and veterans with symptoms of PTSD, and report on the effect of Accelerated Resolution Therapy (ART), a new, brief exposure-based therapy, on acute pain reduction secondary to treatment of symptoms of PTSD.
A randomized controlled trial of ART versus an attention control (AC) regimen was conducted among 45 US service members/veterans with symptoms of combat-related PTSD. Participants received a mean of 3.7 sessions of ART.
Mean age was 41.0 + 12.4 years and 20% were female. Most veterans (93%) reported pain. The majority (78%) used descriptive terms indicative of neuropathic pain, with 29% reporting symptoms of a concussion or feeling dazed. Mean pre-/post-change on the Pain Outcomes Questionnaire (POQ) was −16.9±16.6 in the ART group versus −0.7±14.2 in the AC group (p=0.0006). Among POQ subscales, treatment effects with ART were reported for pain intensity (effect size = 1.81, p=0.006), pain-related impairment in mobility (effect size = 0.69, p=0.01), and negative affect (effect size = 1.01, p=0.001).
Veterans with symptoms of combat-related PTSD have a high prevalence of significant pain, including neuropathic pain. Brief treatment of symptoms of combat-related PTSD among veterans by use of ART appears to acutely reduce concomitant pain.
PMCID: PMC4014659  PMID: 24959325
Psychological trauma; PTSD; pain; exposure therapy; psychotherapy; imagery rescripting; prevalence; clinical trials; eye movements; combat
14.  The Emergence of Sex Differences in Risk for Disordered Eating Attitudes During Puberty: A Role for Prenatal Testosterone Exposure 
Journal of abnormal psychology  2013;122(2):420-432.
Research suggests that prenatal testosterone exposure may masculinize (i.e., lower) disordered eating (DE) attitudes and behaviors and influence the lower prevalence of eating disorders in males versus females. How or when these effects become prominent remains unknown, although puberty may be a critical developmental period. In animals, the masculinizing effects of early testosterone exposure become expressed during puberty when gonadal hormones activate sex-typical behaviors, including eating behaviors. This study examined whether the masculinizing effects of prenatal testosterone exposure on DE attitudes emerge during puberty in 394 twins from opposite-sex and same-sex pairs. Twin type (opposite sex vs. same sex) was used as a proxy for level of prenatal testosterone exposure because females from opposite-sex twin pairs are thought to be exposed to testosterone in utero from their male co-twin. Consistent with animal data, there were no differences in levels of DE attitudes between opposite-sex and same-sex twins during pre-early puberty. However, during mid-late puberty, females from opposite-sex twin pairs (i.e., females with a male co-twin) exhibited more masculinized (i.e., lower) DE attitudes than females from same-sex twin pairs (i.e., females with a female co-twin), independent of several “third variables” (e.g., body mass index [BMI], anxiety). Findings suggest that prenatal testosterone exposure may decrease DE attitudes and at least partially underlie sex differences in risk for DE attitudes after mid-puberty.
PMCID: PMC4011635  PMID: 23713501
disordered eating; eating disorder; puberty; sex difference; testosterone
17.  Risk of Substance Abuse and Dependence Among Young Adult Sexual Minority Groups Using a Multidimensional Measure of Sexual Orientation 
Public Health Reports  2013;128(3):144-152.
We examined associations between two definitions of sexual minority status (SMS) and substance abuse and/or dependence among young adults in a national population.
A total of 14,152 respondents (7,529 women and 6,623 men) interviewed during wave four of the National Longitudinal Study of Adolescent Health were included in the study (age range: 24–32 years). We used two definitions of SMS based on self-reported attraction, behavior, and identity: 1-indicator SMS (endorsing any dimension) and 3-indicator SMS (endorsing all dimensions). Outcomes included nicotine dependence as well as ≥3 signs of substance dependence, any sign of substance abuse, and lifetime diagnosis of abuse or dependence for alcohol, marijuana, and a composite measure of other drugs. Weighted logistic regression models were fit to estimate the odds of each outcome for each of the sexual minority groups (compared with the heterosexual majority), controlling for sociodemographic covariates.
SMS women were more likely than exclusively heterosexual women to experience substance abuse and dependence, regardless of substance or SMS definition. In adjusted models for women, 3-indicator SMS was most strongly associated with abuse/dependence (adjusted odds ratio [AOR] range: 2.74–5.17) except for ≥3 signs of cannabis dependence, where 1-indicator SMS had the strongest association (AOR=3.35). For men, the 1-indicator SMS group had higher odds of nicotine dependence (AOR=1.35) and the 3-indicator SMS group had higher odds of ≥3 signs of alcohol dependence (AOR=1.64).
Young adult female sexual minority groups, regardless of how defined, are at a higher risk than their heterosexual peers of developing alcohol, drug, or tobacco abuse and dependence.
PMCID: PMC3610066  PMID: 23633729
18.  Exploring the Relationship between Negative Urgency and Dysregulated Eating: Etiologic Associations and the Role of Negative Affect 
Journal of abnormal psychology  2013;122(2):433-444.
Negative urgency (i.e., the tendency to engage in rash action in response to negative affect) has emerged as a critical personality trait contributing to individual differences in binge eating. However, studies investigating the extent to which genetic and/or environmental influences underlie the effects of negative urgency on binge eating are lacking. Moreover, it remains unclear whether negative urgency-binge eating associations are simply due to the well-established role of negative affect in the development/maintenance of binge eating. The current study addresses these gaps by examining phenotypic and etiologic associations between negative urgency, negative affect, and dysregulated eating (i.e., binge eating, emotional eating) in a sample of 222 same-sex female twin pairs from the Michigan State Twin Registry. Negative urgency was significantly associated with both dysregulated eating symptoms, even after controlling for the effects of negative affect. Genetic factors accounted for the majority (62–77%) of this phenotypic association, although a significant proportion of this genetic covariation was due to genetic influences in common with negative affect. Non-shared environmental factors accounted for a relatively smaller (23–38%) proportion of the association, but these non-shared environmental effects were independent of negative affect. Findings suggest that the presence of emotion-based rash action, combined with high levels of negative affect, may significantly increase genetic risk for dysregulated eating.
PMCID: PMC3759363  PMID: 23356217
binge eating; emotional eating; impulsivity; negative urgency; negative affect; twin study
19.  Assessment of the Impact of Pattern of Cocaine Dosing Schedule During Conditioning and Reconditioning on Magnitude of Cocaine CPP, Extinction, and Reinstatement 
Psychopharmacology  2012;227(1):109-116.
Rationale and Objective
We sought to examine the impact of differing cocaine administration schedules and dosing on the magnitude of cocaine conditioned place preference (CPP), extinction, and stress- and cocaine-induced reinstatement of CPP.
First, in C57Bl/6J mice, we investigated whether total cocaine administration or pattern of drug exposure could influence the magnitude of cocaine CPP by conditioning mice with a fixed-low dose (FL; 7.5 mg/kg; 30 mg/kg total), a fixed-high dose (FH; 16 mg/kg; 64 mg/kg total), or an ascending dosing schedule (Asc; 2, 4, 8, and 16 mg/kg; 30 mg/kg). Next, we investigated if cocaine or saline is more effective at extinguishing preference by reconditioning mice with either a descending dosing schedule (Desc; 8, 4, 2, and 1 mg/kg) or saline. Finally, we examined if prior conditioning and re-conditioning history alters stress (~2-3 minutes forced swim test) or cocaine (3.5 mg/kg)-induced and reinstatement.
We replicated and extended findings by Itzhak and Anderson (2011) demonstrating Asc conditioning produces a greater CPP than either the FL or FH conditioning schedules. The magnitude of extinction expressed was similar in the Desc reconditioned and saline groups. Moreover, only the saline, and not the Desc reconditioned mice, showed stress and cocaine-induced reinstatement of CPP.
Our results suggest that the schedule of cocaine administration during conditioning and reconditioning can have a significant influence on the magnitude of CPP and extinction of preference, and the ability of cocaine or a stressor to reinstate CPP.
PMCID: PMC3624037  PMID: 23269522
Addiction; cocaine; stress; reward; schedule; dose; pattern; Conditioned Place preference (CPP); reinstatement; extinction
20.  Regulator of G Protein Signaling 2 (RGS2) and RGS4 Form Distinct G Protein-Dependent Complexes with Protease Activated-Receptor 1 (PAR1) in Live Cells 
PLoS ONE  2014;9(4):e95355.
Protease-activated receptor 1 (PAR1) is a G-protein coupled receptor (GPCR) that is activated by natural proteases to regulate many physiological actions. We previously reported that PAR1 couples to Gi, Gq and G12 to activate linked signaling pathways. Regulators of G protein signaling (RGS) proteins serve as GTPase activating proteins to inhibit GPCR/G protein signaling. Some RGS proteins interact directly with certain GPCRs to modulate their signals, though cellular mechanisms dictating selective RGS/GPCR coupling are poorly understood. Here, using bioluminescence resonance energy transfer (BRET), we tested whether RGS2 and RGS4 bind to PAR1 in live COS-7 cells to regulate PAR1/Gα-mediated signaling. We report that PAR1 selectively interacts with either RGS2 or RGS4 in a G protein-dependent manner. Very little BRET activity is observed between PAR1-Venus (PAR1-Ven) and either RGS2-Luciferase (RGS2-Luc) or RGS4-Luc in the absence of Gα. However, in the presence of specific Gα subunits, BRET activity was markedly enhanced between PAR1-RGS2 by Gαq/11, and PAR1-RGS4 by Gαo, but not by other Gα subunits. Gαq/11-YFP/RGS2-Luc BRET activity is promoted by PAR1 and is markedly enhanced by agonist (TFLLR) stimulation. However, PAR1-Ven/RGS-Luc BRET activity was blocked by a PAR1 mutant (R205A) that eliminates PAR1-Gq/11 coupling. The purified intracellular third loop of PAR1 binds directly to purified His-RGS2 or His-RGS4. In cells, RGS2 and RGS4 inhibited PAR1/Gα-mediated calcium and MAPK/ERK signaling, respectively, but not RhoA signaling. Our findings indicate that RGS2 and RGS4 interact directly with PAR1 in Gα-dependent manner to modulate PAR1/Gα-mediated signaling, and highlight a cellular mechanism for selective GPCR/G protein/RGS coupling.
PMCID: PMC3990635  PMID: 24743392
21.  Monocyte and macrophage-targeted NADPH oxidase mediates antifungal host defense and regulation of acute inflammation in mice 
Chronic granulomatous disease, an inherited disorder of the NADPH oxidase in which phagocytes are defective in the generation of superoxide anion and downstream reactive oxidant species, is characterized by severe bacterial and fungal infections and excessive inflammation. Although NADPH oxidase isoforms exist in several lineages, reactive oxidant generation is greatest in neutrophils, where NADPH oxidase has been deemed vital for pathogen killing. In contrast, the function and importance of NADPH oxidase in macrophages are less clear. Therefore, we evaluated susceptibility to pulmonary aspergillosis in globally NADPH oxidase-deficient mice versus transgenic mice with monocyte/macrophage-targeted NADPH oxidase activity. We found that the lethal inoculum was more than 100-fold greater in transgenic versus globally NADPH oxidase-deficient mice. Consistent with these in vivo results, NADPH oxidase in mouse alveolar macrophages limited germination of phagocytosed Aspergillus fumigatus spores. Finally, globally NADPH oxidase-deficient mice developed exuberant neutrophilic lung inflammation and pro-inflammatory cytokine responses to zymosan, a fungal cell wall-derived product composed principally of particulate beta-glucans, whereas inflammation in transgenic and wildtype mice was mild and transient. Together, our studies identify a central role for monocyte/macrophage NADPH oxidase in controlling fungal infection and in limiting acute lung inflammation.
PMCID: PMC3622122  PMID: 23509361
Chronic Granulomatous Disease; NADPH oxidase; macrophage; Aspergillus
22.  Resistance to Systemic Inflammation and Multi Organ Damage after Global Ischemia/Reperfusion in the Arctic Ground Squirrel 
PLoS ONE  2014;9(4):e94225.
Cardiac arrest (CA) and hemorrhagic shock (HS) are two clinically relevant situations where the body undergoes global ischemia as blood pressure drops below the threshold necessary for adequate organ perfusion. Resistance to ischemia/reperfusion (I/R) injury is a characteristic of hibernating mammals. The present study sought to determine if arctic ground squirrels (AGS) are protected from systemic inflammation and multi organ damage after CA- or HS-induced global I/R and if, for HS, this protection is dependent upon their hibernation season.
For CA, rats and summer euthermic AGS (AGS-EU) were asphyxiated for 8 min, inducing CA. For HS, rats, AGS-EU, and winter interbout arousal AGS (AGS-IBA) were subject to HS by withdrawing blood to a mean arterial pressure of 35 mmHg and maintaining that pressure for 20 min before reperfusion with Ringers. For both I/R models, body temperature (Tb) was kept at 36.5–37.5°C. After reperfusion, animals were monitored for seven days (CA) or 3 hrs (HS) then tissues and blood were collected for histopathology, clinical chemistries, and cytokine level analysis (HS only). For the HS studies, additional groups of rats and AGS were monitored for three days after HS to access survival and physiological impairment.
Rats had increased serum markers of liver damage one hour after CA while AGS did not. For HS, AGS survived 72 hours after I/R whereas rats did not survive overnight. Additionally, only rats displayed an inflammatory response after HS. AGS maintained a positive base excess, whereas the base excess in rats was negative during and after hemorrhage.
Regardless of season, AGS are resistant to organ damage, systemic inflammation, and multi organ damage after systemic I/R and this resistance is not dependent on their ability to become decrease Tb during insult but may stem from an altered acid/base and metabolic response during I/R.
PMCID: PMC3984146  PMID: 24728042
23.  Physical Activity and Excess Weight in Pregnancy Have Independent and Unique Effects on Delivery and Perinatal Outcomes 
PLoS ONE  2014;9(4):e94532.
This study examines the effect of low daily physical activity levels and overweight/obesity in pregnancy on delivery and perinatal outcomes.
A prospective cohort study combining manually collected postnatal notes with anonymised data linkage. A total of 466 women sampled from the Growing Up in Wales: Environments for Healthy Living study. Women completed a questionnaire and were included in the study if they had an available Body mass index (BMI) (collected at 12 weeks gestation from antenatal records) and/or a physical activity score during pregnancy (7-day Actigraph reading). The full statistical model included the following potential confounding factors: maternal age, parity and smoking status. Main outcome measures included induction rates, duration of labour, mode of delivery, infant health and duration of hospital stay.
Mothers with lower physical activity levels were more likely to have an instrumental delivery (including forceps, ventouse and elective and emergency caesarean) in comparison to mothers with higher activity levels (adjusted OR:1.72(95%CI: 1.05 to 2.9)). Overweight/obese mothers were more likely to require an induction (adjusted OR:1.93 (95%CI 1.14 to 3.26), have a macrosomic baby (adjusted OR:1.96 (95%CI 1.08 to 3.56) and a longer hospital stay after delivery (adjusted OR:2.69 (95%CI 1.11 to 6.47).
The type of delivery was associated with maternal physical activity level and not BMI. Perinatal outcomes (large for gestational age only) were determined by maternal BMI.
PMCID: PMC3983184  PMID: 24722411
24.  Non-invasive monitoring of BMP-2 retention and bone formation in composites for bone tissue engineering using SPECT/CT and scintillation probes 
Non-invasive imaging can provide essential information for the optimization of new drug delivery-based bone regeneration strategies to repair damaged or impaired bone tissue. This study investigates the applicability of nuclear medicine and radiological techniques to monitor growth factor retention profiles and subsequent effects on bone formation. Recombinant human bone morphogenetic protein-2 (BMP-2, 6.5 μg/scaffold) was incorporated into a sustained release vehicle consisting of poly(lactic-co-glycolic acid) microspheres embedded in a poly(propylene fumarate) scaffold surrounded by a gelatin hydrogel and implanted subcutaneously and in 5-mm segmental femoral defects in 9 rats for a period of 56 days. To determine the pharmacokinetic profile, BMP-2 was radiolabeled with 125I and the local retention of 125I-BMP-2 was measured by single photon emission computed tomography (SPECT), scintillation probes and ex vivo scintillation analysis. Bone formation was monitored by micro-computed tomography (μCT). The scaffolds released BMP-2 in a sustained fashion over the 56-day implantation period. A good correlation between the SPECT and scintillation probe measurements was found and there were no significant differences between the non-invasive and ex-vivo counting method after 8 weeks of follow up. SPECT analysis of the total body and thyroid counts showed a limited accumulation of 125I within the body. Ectopic bone formation was induced in the scaffolds and the femur defects healed completely. In vivo μCT imaging detected the first signs of bone formation at days 14 and 28 for the orthotopic and ectopic implants, respectively, and provided a detailed profile of the bone formation rate. Overall, this study clearly demonstrates the benefit of applying non-invasive techniques in drug delivery-based bone regeneration strategies by providing detailed and reliable profiles of the growth factor retention and bone formation at different implantation sites in a limited number of animals.
PMCID: PMC3974410  PMID: 19105972
Drug delivery; Controlled release; Bone morphogenetic protein-2; Single photon emission computed; tomography; Scintillation probes; Micro-computed tomography
25.  Ovarian Hormones and Emotional Eating Associations across the Menstrual Cycle: An Examination of the Potential Moderating Effects of Body Mass Index and Dietary Restraint 
Associations between within-person changes in ovarian hormones and dysregulated eating (binge eating, emotional eating) have been observed across the menstrual cycle. However, studies have not examined moderators that may contribute to differential associations between individuals. We investigated body-weight regulation variables (body mass index (BMI), dietary restraint) that have theoretical relevance by virtue of their associations with both phenotypes.
Women (N = 196) provided emotional eating ratings and saliva samples for 45 days. BMI and restraint were assessed at three time-points and averaged.
Results showed significant estradiol × progesterone interactions in the prediction of within-subject changes in emotional eating. Neither BMI nor restraint moderated these relationships, although a trend-level dietary restraint × estradiol interaction was observed where estradiol’s effects were enhanced in high restraint scorers.
Findings confirm a role for hormones in changes in emotional eating and suggest that restraint might enhance hormone effects in severe groups.
PMCID: PMC3600109  PMID: 23315657

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