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2.  Epigenetic control of metastasis-associated protein 1 gene expression by hepatitis B virus X protein during hepatocarcinogenesis 
Oncogenesis  2012;1(9):e25-.
Expression of metastasis-associated protein 1 (MTA1) gene correlates with the degree of invasion and metastasis in hepatocellular carcinoma (HCC). Expression of MTA1 is induced by hepatitis B virus X protein (HBx); however, little is known about the transcriptional regulation of MTA1 gene expression. Here, we report that the 5′-flanking region of the human MTA1 promoter contains two CpG islands. Transient expression of HBx in Chang liver cells increased the methylation of the CpG island1 from 18 to 49% when measured by bisulfite-modified direct sequencing. Chromatin immunoprecipitation showed that HBx recruited DNA methyltransferase 3a (DNMT3a) and DNMT3b to the CpG island1. In silico analysis of CpG island1 predicted the existence of putative p53-binding sequences. p53 was pulled down by a DNA probe encoding the p53-binding sequences but not by the methylated DNA probe. The mouse MTA1 promoter also contains a CpG island encoding a p53-binding sequence of which p53 binding was decreased in the presence of HBx, and the expression of MTA1 and DNMT3 was increased in the liver of HBx-transgenic mice. Comparison of MTA1 and DNMT3a expression in the human normal liver and HCC specimens produced a significant correlation coefficient >0.5 (r=0.5686, P=0.0001) for DNMT3a, and a marginally significant coefficient (r=0.3162, P=0.0103) for DNMT3b. These data show that HBx induces methylation of CpG island in the MTA1 promoter, which interferes with DNA binding of p53 in the specific DNA region. This result may explain the molecular mechanism responsible for the induction of MTA1 gene expression by HBx.
PMCID: PMC3503295  PMID: 23552838
MTA1; p53; HBx; DNA methylation
3.  Apoptosis of skeletal muscle on steroid-induced myopathy in rats. 
Journal of Korean Medical Science  2001;16(4):467-474.
Recently apoptotic cell death has been reported in differentiated skeletal muscle, where apoptosis was generally assumed not to occur. To investigate whether apoptosis may contribute to the steroid-induced myopathy, rats treated with triamcinolone acetonide (TA) for 9 days were sacrificed for detecting apoptosis by in situ end labeling (ISEL) and electron microscopy in the soleus muscles. Immunohistochemical stainings of Fas antigen and p53 protein were performed to examine whether apoptosis-related proteins were present in the myopathy. Muscle fiber necrosis and apoptotic myonuclei appeared in the soleus muscles following administration of TA, while control muscles showed no evidences for apoptosis. Fas antigen was not detected in control muscles, but expressed in the soleus muscles of steroid-induced myopathy. Some of the Fas antigen-expressing muscle fibers were positive for ISEL. p53 protein was not detected in any muscle fibers. These findings indicate that TA can induce apoptosis in differentiated skeletal muscles, and Fas antigen might be partly related to apoptotic muscle death in steroid-induced myopathy.
PMCID: PMC3054783  PMID: 11511793
4.  Congenital cytomegalovirus infection: three autopsy case reports. 
Journal of Korean Medical Science  2000;15(3):337-342.
We report three autopsy cases of congenital cytomegalovirus (CMV) infection in fetuses with a review of literature. The clinical manifestations in these cases of congenital CMV infection include intrauterine fetal death, hydrops fetalis, and CMV pneumonia associated with cardiovascular defect. The pathological characteristics were as follows: 1) the kidney was the most frequently involved organ, followed by lung and liver, 2) CMV inclusions were found predominantly in epithelial cells and to a lesser degree in endothelial cells, 3) intrahepatic bile duct epithelial cells were frequently involved, and 4) inflammatory reaction around CMV inclusions was not prominent in the early stage of pregnancy. Diagnostic confirmation was obtained by in situ hybridization (ISH) using a biotinylated CMV-DNA probe, which demonstrated intranuclear inclusions and sometimes recognized cells that did not show intranuclear inclusion.
PMCID: PMC3054627  PMID: 10895978
5.  Expression of Th1 and Th2 type cytokines responding to HBsAg and HBxAg in chronic hepatitis B patients. 
Journal of Korean Medical Science  1999;14(2):175-181.
The cytokine pattern on viral antigen recognition is believed to exert a profound influence on the resolution of viral infections and viral clearance. This study was initiated to investigate whether a cytokine imbalance oriented toward Th2 type response plays a role in chronic hepatitis B. Cytokine profiles of peripheral blood mononuclear cells associated with chronic hepatitis B were analysed by RT-PCR. Upon HBsAg stimulation, expression of IFN-gamma, IL-2, IL-4, and IL-10 was detected in 41%, 8%, 41%, and 50% of the patients, respectively. Among these cytokines, the expression of IFN-gamma was associated with high levels of serum AST/ALT. However, we could not prove that Th2 type cytokines had a protective effect on hepatocytes. Upon HBxAg stimulation, there was no recognizable association of cytokine patterns with AST/ALT levels. In conclusion, production of a Th1 cytokine, IFN-gamma, by HBsAg-reactive cells was associated with hepatocyte damage in chronic hepatitis B, while no counteracting effect of Th2 cytokines produced by those cells was observed.
PMCID: PMC3054367  PMID: 10331564
6.  Multiple symmetric lipomatosis. 
Multiple symmetric lipomatosis (MSL) is an extremely uncommon disorder. In the medical literatures about 200 cases have been reported. MSL is not associated with other generalized lipomatous disorders, nor are these patient to be necessarily obese. The cause of MSL is unknown. The disorder usually occurs in middle-aged males and there is frequently a history of alcoholism. Some instances of familial occurrence have been reported, but the majority of cases are sporadic. Two cases of MSL are presented.
PMCID: PMC3053672  PMID: 3267365
7.  Computerized quality control of radioimmunoassay in Korea. 
Automated data processing and quality control of radioimmunoassays offer not only increased speed but also a more thorough and statistically rigorous analysis of results. An external quality assessment scheme for serum thyroxine, triiodothyronine and thyroid stimulating hormone (TSH) assays was performed in five nuclear medicine laboratories in Korea to compare with the assay performances of the World Health Organization Radioimmunoassay Program. The required radioimmunoassay kits were supplied through the International Atomic Energy Agency (IAEA). We have determined the weighted root mean squared error, and variance ratio as the indices of standard curve and also the average batch coefficient of variation (ABCV) as the parameters of response error relationship curve and precision profile. There was a good fit for the triiodothyronine assay, but 3 of 5 laboratories showed possible bad fit in the T4 and TSH assay systems. The ABCV was less than 5 percent for the T3 and T4 assay system, however for the TSH system, only 1 laboratory showed the ABCV value of less than 5 percent. We have also calculated the within batch variation (drift) and between laboratory variations.
PMCID: PMC3053655  PMID: 3267360
8.  The Sleep Or Mood Novel Adjunctive therapy (SOMNA) trial: a study protocol for a randomised controlled trial evaluating an internet-delivered cognitive behavioural therapy program for insomnia on outcomes of standard treatment for depression in men 
BMC Psychiatry  2015;15:16.
Insomnia is a significant risk factor for depression onset, can result in more disabling depressive illness, and is a common residual symptom following treatment cessation that can increase the risk of relapse. Internet-based cognitive behavioural therapy for insomnia has demonstrated efficacy and acceptability to men who are less likely than women to seek help in standard care. We aim to evaluate whether internet delivered cognitive behavioural therapy for insomnia as an adjunct to a standard depression therapeutic plan can lead to improved mood outcomes.
Male participants aged 50 years or more, meeting Diagnostic and Statistical Manual of Mental Disorders criteria for current Major Depressive Episode and/or Dysthymia and self-reported insomnia symptoms, will be screened to participate in a single-centre double-blind randomised controlled trial with two parallel groups involving adjunctive internet-delivered cognitive behavioural therapy for insomnia and an internet-based control program. The trial will consist of a nine-week insomnia intervention period with a six-month follow-up period. During the insomnia intervention period participants will have their depression management coordinated by a psychiatrist using standard guideline-based depression treatments. The study will be conducted in urban New South Wales, Australia, where 80 participants from primary and secondary care and direct from the local community will be recruited. The primary outcome is change in the severity of depressive symptoms from baseline to week 12.
This study will provide evidence on whether a widely accessible, evidence-based, internet-delivered cognitive behavioural therapy for insomnia intervention can lead to greater improvements than standard treatment for depression alone, in a group who traditionally do not readily access psychotherapy. The study is designed to establish effect size, feasibility and processes associated with implementing e-health solutions alongside standard clinical care, to warrant undertaking a larger more definitive clinical trial.
Trial registration
Australian and New Zealand Clinical Trials Registry ACTRN12612000985886.
PMCID: PMC4321324  PMID: 25652579
Depression; Insomnia; Adjunctive; e-health; Cognitive behavioural therapy; Randomised controlled trial; Men
9.  Inspiratory Muscles do not Limit Maximal Incremental Exercise Performance in Healthy Subjects 
We investigated whether the inspiratory muscles affect maximal incremental exercise performance using a placebo-controlled, crossover design. Six cyclists each performed 6 incremental exercise tests. For 3 trials, subjects exercised with proportional assist ventilation (PAV). For the remaining 3 trials, subjects underwent sham respiratory muscle unloading (placebo). Inspiratory muscle pressure (Pmus) was reduced with PAV (−35.9 ± 2.3% vs. placebo; P < 0.05). Furthermore, V̇O2 and perceptions of dyspnea and limb discomfort at submaximal exercise intensities were significantly reduced with PAV. Peak workload, however, was not different between placebo and PAV (324 ± 4 vs. 326 ± 4 W; P > 0.05). Diaphragm fatigue (bilateral phrenic nerve stimulation) did not occur in placebo. In conclusion, substantially unloading the inspiratory muscles did not affect maximal incremental exercise performance. Therefore, our data do not support a role for either inspiratory muscle work or fatigue per se in the limitation of maximal incremental exercise performance.
PMCID: PMC4313890  PMID: 17134946
diaphragm; fatigue; respiratory muscles; dyspnea
10.  miR-203 Induces Oxaliplatin Resistance in Colorectal Cancer Cells by Negatively Regulating ATM Kinase 
Molecular oncology  2013;8(1):83-92.
Chemotherapy for patients with metastatic colorectal cancer (CRC) is the standard of care, but ultimately nearly all patients develop drug resistance. Understanding the mechanisms that lead to resistance to individual chemotherapeutic agents may help identify novel targets and drugs that will, in turn, improve therapy. Oxaliplatin is a common component combination therapeutic regimen for use in patients with metastatic CRC, but is also used as a component of adjuvant therapy for patients at risk for recurrent disease. In this study, unbiased microRNA array screening revealed that the miR-203 microRNA is up-regulated in three of three oxaliplatin-resistant CRC cell lines, and therefore we investigated the role of miR-203 in chemoresistance. Exogenous expression of miR-203 in chemo-naïve CRC cells induced oxaliplatin resistance. Knockdown of miR-203 sensitized chemoresistant CRC cells to oxaliplatin. In silico analysis identified ataxia telangiectasia mutated (ATM), a primary mediator of the DNA damage response, as a potential target of miR-203. ATM mRNA and protein levels were significantly down-regulated in CRC cells with acquired resistance to oxaliplatin. Using TCGA database, we identified a significant reverse correlation of miR-203 and ATM expression in CRC tissues. We validated ATM as a bona fide target of miR-203 in CRC cells. Mutation of the putative miR-203 binding site in the 3′ untranslated region (3’UTR) of the ATM mRNA abolished the inhibitory effect of miR-203 on ATM. Furthermore, stable knockdown of ATM induced resistance to oxaliplatin in chemo-naïve CRC cells. This is the first report of oxaliplatin resistance in CRC cells induced by miR-203-mediated suppression of ATM.
PMCID: PMC4124530  PMID: 24145123
chemoresistance; miR-203; ATM; DNA damage response; oxaliplatin
11.  Effect of By-product Feed-based Silage Feeding on the Performance, Blood Metabolites, and Carcass Characteristics of Hanwoo Steers (a Field Study) 
This study was conducted to determine the effects of feeding by-product feed (BF)-based silage on the performance, blood metabolite parameters, and carcass characteristics of Hanwoo steers. The BF-based silage was composed of 50% spent mushroom substrate, 21% recycled poultry bedding, 15% cut ryegrass straw, 10.8% rice bran, 2% molasses, 0.6% bentonite, and 0.6% microbial additive (on a wet basis), and ensiled for over 5 d. Fifteen steers were allocated to three diets during the growing and fattening periods (3.1 and 9.8 months, respectively): a control diet (concentrate mix and free access to rice straw), a 50% BF-based silage diet (control diet+50% of maximum BF-based silage intake), and a 100% BF-based silage diet (the same amount of concentrate mix and ad libitum BF-based silage). The BF-based silage was fed during the growing and fattening periods, and was replaced with larger particles of rice straw during the finishing period. After 19.6 months of the whole period all the steers were slaughtered. Compared with feeding rice straw, feeding BF-based silage tended (p = 0.10) to increase the average daily gain (27%) and feed efficiency (18%) of the growing steers, caused by increased voluntary feed intake. Feeding BF-based silage had little effect on serum constituents, electrolytes, enzymes, or the blood cell profiles of fattening steers, except for low serum Ca and high blood urea concentrations (p<0.05). Feeding BF-based silage did not affect cold carcass weight, yield traits such as back fat thickness, longissimus muscle area, yield index or yield grade, or quality traits such as meat color, fat color, texture, maturity, marbling score, or quality grade. However, it improved good quality grade (1+ and 1++) appearance rates (60% for the control group vs 100% for the BF-based silage-fed groups). In conclusion, cheap BF-based silage could be successfully used as a good quality roughage source for beef cattle.
PMCID: PMC4283162  PMID: 25557813
Spent Mushroom Substrate; By-product Feed; Silage; Meat Quality; Steer; Hanwoo
12.  ATP Citrate Lyase Mediates Resistance of Colorectal Cancer Cells to SN38 
Molecular cancer therapeutics  2013;12(12):2782-2791.
Combination chemotherapy is standard for metastatic colorectal cancer (CRC); however, nearly all patients develop drug resistance. Understanding the mechanisms that lead to resistance to individual chemotherapeutic agents may enable identification of novel targets and more effective therapy. Irinotecan is commonly used in first- and second-line therapy for patients with metastatic CRC, with the active metabolite being SN38. Emerging evidence suggests that altered metabolism in cancer cells is fundamentally involved in the development of drug resistance. Using Oncomine and unbiased proteomic profiling, we found that ATP citrate lyase (ACLy), the first-step rate-limiting enzyme for de novo lipogenesis, was upregulated in CRC compared to its levels in normal mucosa and in chemoresistant CRC cells compared to isogenic chemo-naïve CRC cells. Overexpression of exogenous ACLy by lentivirus transduction in chemo-naïve CRC cells led to significant chemoresistance to SN38 but not to 5-fluorouracil or oxaliplatin. Knockdown of ACLy by siRNA or inhibition of its activity by a small-molecule inhibitor sensitized chemo-naïve CRC cells to SN38. Furthermore, ACLy was significantly increased in cancer cells that had acquired resistance to SN38. In contrast to chemo-naïve cells, targeting ACLy alone was not effective in re-sensitizing resistant cells to SN38, due to a compensatory activation of the AKT pathway triggered by ACLy suppression. Combined inhibition of AKT signaling and ACLy successfully re-sensitized SN38-resistant cells to SN38. We conclude that targeting ACLy may improve the therapeutic effects of irinotecan and that simultaneous targeting of ACLy and AKT may be warranted to overcome SN38 resistance.
PMCID: PMC4302275  PMID: 24132143
Chemoresistance; ATP citrate lyase; SN38; irinotecan; colorectal cancer
13.  Probe Lasso: A novel method to rope in differentially methylated regions with 450K DNA methylation data 
The speed and resolution at which we can scour the genome for DNA methylation changes has improved immeasurably in the last 10 years and the advent of the Illumina 450K BeadChip has made epigenome-wide association studies (EWAS) a reality. The resulting datasets are conveniently formatted to allow easy alignment of significant hits to genes and genetic features, however; methods that parse significant hits into discreet differentially methylated regions (DMRs) remain a challenge to implement. In this paper we present details of a novel DMR caller, the Probe Lasso: a flexible window based approach that gathers neighbouring significant-signals to define clear DMR boundaries for subsequent in-depth analysis. The method is implemented in the R package ChAMP (Morris et al., 2014) and returns sets of DMRs according to user-tuned levels of probe filtering (e.g., inclusion of sex chromosomes, polymorphisms) and probe-lasso size distribution. Using a sub-sample of colon cancer- and healthy colon-samples from TCGA we show that Probe Lasso shifts DMR calling away from just probe-dense regions, and calls a range of DMR sizes ranging from tens-of-bases to tens-of-kilobases in scale. Moreover, using TCGA data we show that Probe Lasso leverages more information from the array and highlights a potential role of hypomethylated transcription factor binding motifs not discoverable using a basic, fixed-window approach.
PMCID: PMC4304833  PMID: 25461817
Differentially methylated regions; DNA methylation; Epigenetics; EWAS; Illumina 450K BeadChip
14.  Glycemic Control in Young Children with Diabetes: The Role of Parental Health Literacy 
Patient education and counseling  2013;94(1):10.1016/j.pec.2013.09.002.
This cross sectional study examined the relationship between parental health literacy (HL), diabetes related numeracy, and parental perceived diabetes self-efficacy on glycemic control in a sample of young children with Type 1 DM.
Seventy primary caregivers of children (age 3–9 years) with Type 1 DM were recruited and surveyed at diabetes outpatient clinic visits. Patients’ medical histories were obtained by medical chart review.
Parental diabetes related numeracy (r = −.52, p <.01), but not reading skills (r = −.25, p = NS) were inversely correlated with the child’s glycemic control (HbA1c). Parental perceived diabetes self-efficacy was also negatively correlated to their child’s HbA1c (r = −.47, p <.01). When numeracy and parental perceived diabetes self-efficacy were included as predictors of HbA1c, the model was significant (F = 12.93, p<.01) with both numeracy (β = − .46, p<.01) and parental perceived diabetes self-efficacy (β = − .36, p=.01) as significant predictors of HbA1c.
Data from this study highlight the importance of considering the role of parental numeracy, in health outcomes for children with Type 1 DM. Practice Implications: Practitioners should assess parental health literacy and consider intervention when needed.
PMCID: PMC3865071  PMID: 24091252
Type 1 diabetes; health literacy; glycemic control; children; parents; numeracy
15.  Pathway connectivity and signaling coordination in the yeast stress-activated signaling network 
Molecular Systems Biology  2014;10(11):759.
Stressed cells coordinate a multi-faceted response spanning many levels of physiology. Yet knowledge of the complete stress-activated regulatory network as well as design principles for signal integration remains incomplete. We developed an experimental and computational approach to integrate available protein interaction data with gene fitness contributions, mutant transcriptome profiles, and phospho-proteome changes in cells responding to salt stress, to infer the salt-responsive signaling network in yeast. The inferred subnetwork presented many novel predictions by implicating new regulators, uncovering unrecognized crosstalk between known pathways, and pointing to previously unknown ‘hubs’ of signal integration. We exploited these predictions to show that Cdc14 phosphatase is a central hub in the network and that modification of RNA polymerase II coordinates induction of stress-defense genes with reduction of growth-related transcripts. We find that the orthologous human network is enriched for cancer-causing genes, underscoring the importance of the subnetwork's predictions in understanding stress biology.
PMCID: PMC4299600  PMID: 25411400
environmental stress; integer programming; proteomics; signal transduction; transcriptomics
16.  Capacity for Physical Activity Predicts Weight Loss After Roux-en-Y Gastric Bypass 
Obesity (Silver Spring, Md.)  2008;17(1):92-99.
Despite its overall excellent outcomes, weight loss after Roux-en-Y gastric bypass (RYGB) is highly variable. We conducted this study to identify clinical predictors of weight loss after RYGB. We reviewed charts from 300 consecutive patients who underwent RYGB from August 1999 to November 2002. Data collected included patient demographics, medical comorbidities, and diet history. Of the 20 variables selected for univariate analysis, 9 with univariate P values ≤ 0.15 were entered into a multivariable regression analysis. Using backward selection, covariates with P < 0.05 were retained. Potential confounders were added back into the model and assessed for effect on all model variables. Complete records were available for 246 of the 300 patients (82%). The patient characteristics were 75% female, 93% white, mean age of 45 years, and mean initial BMI of 52.3 kg/m2. One year after surgery, patients lost an average of 64.8% of their excess weight (s.d. = 20.5%). The multivariable regression analysis revealed that limited physical activity, higher initial BMI, lower educational level, diabetes, and decreased attendance at postoperative appointments had an adverse effect on weight loss after RYGB. A model including these five factors accounts for 41% of the observed variability in weight loss (adjusted r2 = 0.41). In this cohort, higher initial BMI and limited physical activity were the strongest predictors of decreased excess weight loss following RYGB. Limited physical activity may be particularly important because it represents an opportunity for potentially meaningful pre- and postsurgical intervention to maximize weight loss following RYGB.
PMCID: PMC4226065  PMID: 18997674
17.  Family, Community and Clinic Collaboration to Treat Overweight and Obese Children: Stanford GOALS -- a Randomized Controlled Trial of a Three-Year, Multi-Component, Multi-Level, Multi-Setting Intervention 
Contemporary clinical trials  2013;36(2):10.1016/j.cct.2013.09.001.
To test the effects of a three-year, community-based, multi-component, multi-level, multi-setting (MMM) approach for treating overweight and obese children.
Two-arm, parallel group, randomized controlled trial with measures at baseline, 12, 24, and 36 months after randomization.
Seven through eleven year old, overweight and obese children (BMI ≥ 85th percentile) and their parents/caregivers recruited from community locations in low-income, primarily Latino neighborhoods in Northern California.
Families are randomized to the MMM intervention versus a community health education active-placebo comparison intervention. Interventions last for three years for each participant. The MMM intervention includes a community-based after school team sports program designed specifically for overweight and obese children, a home-based family intervention to reduce screen time, alter the home food/eating environment, and promote self-regulatory skills for eating and activity behavior change, and a primary care behavioral counseling intervention linked to the community and home interventions. The active-placebo comparison intervention includes semi-annual health education home visits, monthly health education newsletters for children and for parents/guardians, and a series of community-based health education events for families.
Main Outcome Measure
Body mass index trajectory over the three-year study. Secondary outcome measures include waist circumference, triceps skinfold thickness, accelerometer-measured physical activity, 24-hour dietary recalls, screen time and other sedentary behaviors, blood pressure, fasting lipids, glucose, insulin, hemoglobin A1c, C-reactive protein, alanine aminotransferase, and psychosocial measures.
The Stanford GOALS trial is testing the efficacy of a novel community-based multi-component, multi-level, multi-setting treatment for childhood overweight and obesity in low-income, Latino families.
PMCID: PMC3844020  PMID: 24028942
children; overweight; obesity; treatment; community; family
18.  Hoffa’s fat pad tumours: What do we know about them? 
International Orthopaedics  2013;37(11):2225-2229.
We report on a group of patients with tumours in the Hoffa’s fat pad (HFP), their clinical presentation, histological type and treatment, including two synovial sarcomas with their clinical follow-up, which have not been described previously in the literature.
We performed a retrospective review of our prospectively collected database of 25 cases of HFP tumours with at least six months follow-up.
The gender, age at presentation (over and under 16 years of age), clinical features, history of trauma, treatment chosen, and complications were recorded. The mean age of the patients was 32 years (three to 47). Six patients were under 16 years old. Pain was the most common symptom, present in 92 % (n = 23/25). The final diagnoses included 23 (92 %) benign tumours and two (8 %) malignant tumours. The most common benign tumour was pigmented villonodular synovitis (PVNS) (48 % n = 12). The two malignant tumours were synovial sarcomas and both presented in patients under 16 years old.
Hoffa’s fat pad tumours are an uncommon and rarely diagnosed group of lesions that can be misinterpreted as any knee pathology. Although the majority of HFP tumours are benign, malignant tumours should be considered in the differential diagnosis for the paediatric population.
PMCID: PMC3824884  PMID: 24000088
Hoffa’s fat pad; Knee; Tumours; PVNS; Malignant tumours; Synovial sarcomas
19.  Optimizing Intramuscular Adaptations to Aerobic Exercise: Effects of Carbohydrate Restriction and Protein Supplementation on Mitochondrial Biogenesis12 
Advances in Nutrition  2013;4(6):657-664.
Mitochondrial biogenesis is a critical metabolic adaptation to aerobic exercise training that results in enhanced mitochondrial size, content, number, and activity. Recent evidence has shown that dietary manipulation can further enhance mitochondrial adaptations to aerobic exercise training, which may delay skeletal muscle fatigue and enhance exercise performance. Specifically, studies have demonstrated that combining carbohydrate restriction (endogenous and exogenous) with a single bout of aerobic exercise potentiates the beneficial effects of exercise on markers of mitochondrial biogenesis. Additionally, studies have demonstrated that high-quality protein supplementation enhances anabolic skeletal muscle intracellular signaling and mitochondrial protein synthesis following a single bout of aerobic exercise. Mitochondrial biogenesis is stimulated by complex intracellular signaling pathways that appear to be primarily regulated by 5′AMP-activated protein kinase and p38 mitogen-activated protein kinase mediated through proliferator-activated γ receptor co-activator 1 α activation, resulting in increased mitochondrial DNA expression and enhanced skeletal muscle oxidative capacity. However, the mechanisms by which concomitant carbohydrate restriction and dietary protein supplementation modulates mitochondrial adaptations to aerobic exercise training remains unclear. This review summarizes intracellular regulation of mitochondrial biogenesis and the effects of carbohydrate restriction and protein supplementation on mitochondrial adaptations to aerobic exercise.
PMCID: PMC3823511  PMID: 24228194
20.  Association between medical home characteristics and staff professional experiences in pediatric practices 
Archives of Public Health  2014;72(1):36.
The patient-centered medical home (PCMH) model has been touted as a potential way to improve primary care. As more PCMH projects are undertaken it is critical to understand professional experiences as staff are key in implementing and maintaining the necessary changes. A paucity of information on staff experiences is available, and our study aims to fill that critical gap in the literature.
Eligible pediatric practices were invited to participate in the Florida Pediatric Medical Home Demonstration Project out which 20 practices were selected. Eligibility criteria included a minimum of 100 children with special health care needs and participation in Medicaid, a Medicaid health plan, or Florida KidCare. Survey data were collected from staff working in these 20 pediatric practices across Florida. Ware’s seven-point scale assessed satisfaction and burnout was measured using the six-point Maslach scale. The Medical Home Index measured the practice’s medical home characteristics. Descriptive and multivariate analyses were conducted. In total, 170 staff members completed the survey and the response rate was 42.6%.
Staff members reported high job satisfaction (mean 5.54; SD 1.26) and average burnout. Multivariate analyses suggest that care coordination is positively associated (b = 0.75) and community outreach is negatively associated (b = -0.18) with job satisfaction. Quality improvement and organizational capacity are positively associated with increased staff burnout (OR = 1.37, 5.89, respectively). Chronic condition and data management are associated with lower burnout (OR = 0.05 and 0.20, respectively). Across all models adaptive reserve, or the ability to make and sustain change, is associated with higher job satisfaction and lower staff burnout.
Staff experiences in the transition to becoming a PCMH are important. Although our study is cross-sectional, it provides some insight about how medical home, staff and practice characteristics are associated with job satisfaction and burnout. Many PCMH initiatives include facilitation and it should assist staff on how to adapt to change. Unless staff needs are addressed a PCMH may be threatened by fatigue, burnout, and low morale.
PMCID: PMC4216343  PMID: 25364502
Medical home; Pediatrics; CHIPRA; Staff; Survey
21.  Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable non-squamous non-small cell lung cancers 
Bevacizumab improves survival in patients with advanced non-small cell lung cancer (NSCLC). This phase II clinical trial assessed the effects of the addition of bevacizumab to neoadjuvant chemotherapy in resectable non-squamous NSCLC.
Patients with resectable stage IB-IIIA non-squamous NSCLC were treated with bevacizumab followed by imaging 2 weeks later to assess single agent effect. They then received 2 cycles of bevacizumab with 4 cycles of cisplatin and docetaxel followed by surgical resection. Resected patients were eligible for adjuvant bevacizumab. The primary endpoint was the rate of pathological downstaging (decrease from pretreatment clinical stage to post-treatment pathological stage). Secondary endpoints included overall survival, safety and radiologic response.
Fifty patients were enrolled. Thirty-four (68%) were clinical stage IIIA. All 3 doses of neoadjuvant bevacizumab were delivered to 40/50 patients. Six (12%) patients discontinued due to bevacizumab-related adverse events. The rate of downstaging (38%), response to chemotherapy (45%), and perioperative complications (12%) were comparable to historical data. No partial responses were observed to single-agent bevacizumab but 18% developed new intratumoral cavitation with a trend toward improved pathologic response (57% vs. 21%, p=0.07). A major pathologic response (≥90% treatment effect) was associated with survival at 3 years (100% vs. 49%, p=0.01). No patients with KRAS-mutant NSCLC (0/10) had a pathologic response as compared with 11/31 with wild-type KRAS.
While preoperative bevacizumab plus chemotherapy was feasible, it did not improve downstaging in unselected patients. New cavitation after single-agent bevacizumab is a potential biomarker. Alternative strategies are needed for KRAS-mutant tumors.
PMCID: PMC4191830  PMID: 23857398
23.  A Randomized Controlled Trial of an Internet Intervention for Adults with Insomnia: Effects on Comorbid Psychological and Fatigue Symptoms 
Journal of clinical psychology  2013;69(10):1078-1093.
Insomnia is frequently comorbid with other medical and psychological disorders. This secondary data analysis investigated whether an Internet-delivered cognitive behavioral therapy for insomnia (CBT-I) intervention could also reduce comorbid psychological and fatigue symptoms.
Data from a pilot randomized controlled trial (RCT) testing the efficacy of Internet-delivered CBT-I relative to a waitlist control was used to examine changes in symptoms of depression, anxiety, mental health quality of life (QOL), and fatigue.
Group by time interactions from repeated measures analyses revealed significant post intervention improvements in Internet participants (n = 22) relative to control participants (n = 22) on all psychological symptoms, mental health QOL, and fatigue. A small post hoc subsample of Internet participants with mild or moderate depression also showed large effect size changes in these constructs (depression, anxiety, mental health QOL, and fatigue).
Internet-delivered CBT-I appears to not only improve sleep but also reduce comorbid psychological and fatigue symptoms.
PMCID: PMC4078738  PMID: 24014057
insomnia; eHealth; depression; anxiety; fatigue; Internet; online; CBT; CBT-I; cognitive behavioral therapy; web
24.  Effect of maternal coffee, smoking and drinking behavior on adult son's semen quality: prospective evidence from the Child Health and Development Studies 
Fetal exposure to caffeine is associated with adverse pregnancy outcomes. Animal and human studies suggest that caffeine may have effects on the developing reproductive system. Here we report on mothers' smoking, coffee and alcohol use, recorded during pregnancy, and semen quality in sons in the age group of 38–47 years. Subjects were a subset of the Child Health and Development Studies, a pregnancy cohort enrolled between 1959 and 1967 in the Kaiser Foundation Health Plan near Oakland, California. In 2005, adult sons participated in a follow-up study (n = 338) and semen samples were donated by 196 participants. Samples were analyzed for sperm concentration, motility and morphology according to the National Cooperative Reproductive Medicine Network (Fertile Male Study) Protocol. Mean sperm concentration was reduced by approximately 16 million sperms for sons with high prenatal exposure (5 cups of maternal coffee use per day) compared with unexposed sons (P-value for decreasing trend = 0.09), which translates to a proportionate reduction of 25%. Mean percent motile sperm decreased by approximately 7 points (P-value = 0.04), a proportionate decline of 13%, and mean percent sperm with normal morphology decreased by approximately 2 points (P-value = 0.01), a proportionate decline of 25%. Maternal cigarette and alcohol use were not associated with son's semen quality. Adjusting for son's contemporary coffee, alcohol and cigarette use did not explain the maternal associations. Findings for son's coffee intake and father's prenatal coffee, cigarette and alcohol use were non-significant and inconclusive. These results contribute to the evidence that maternal coffee use during pregnancy may impair the reproductive development of the male fetus.
PMCID: PMC4181836  PMID: 25140488
coffee; prenatal exposure; sperm concentration; sperm motility; sperm morphology
25.  Deciphering the complex three-way interaction between the non-integrin laminin receptor, galectin-3 and Neisseria meningitidis 
Open Biology  2014;4(10):140053.
The non-integrin laminin receptor (LAMR1/RPSA) and galectin-3 (Gal-3) are multi-functional host molecules with roles in diverse pathological processes, particularly of infectious or oncogenic origins. Using bimolecular fluorescence complementation and confocal imaging, we demonstrate that the two proteins homo- and heterodimerize, and that each isotype forms a distinct cell surface population. We present evidence that the 37 kDa form of LAMR1 (37LRP) is the precursor of the previously described 67 kDa laminin receptor (67LR), whereas the heterodimer represents an entity that is distinct from this molecule. Site-directed mutagenesis confirmed that the single cysteine (C173) of Gal-3 or lysine (K166) of LAMR1 are critical for heterodimerization. Recombinant Gal-3, expressed in normally Gal-3-deficient N2a cells, dimerized with endogenous LAMR1 and led to a significantly increased number of internalized bacteria (Neisseria meningitidis), confirming the role of Gal-3 in bacterial invasion. Contact-dependent cross-linking determined that, in common with LAMR1, Gal-3 binds the meningococcal secretin PilQ, in addition to the major pilin PilE. This study adds significant new mechanistic insights into the bacterial–host cell interaction by clarifying the nature, role and bacterial ligands of LAMR1 and Gal-3 isotypes during colonization.
PMCID: PMC4221890  PMID: 25274119
LAMR1; RPSA; galectin-3; 37LRP; 67LR; Neisseria meningitidis

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