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1.  Changes in Gastrointestinal Hormones and Leptin After Roux-en-Y Gastric Bypass Surgery 
Roux-en-Y gastric bypass (RYGB) imparts long-term weight loss, the mechanisms for which are not well understood. Changes in leptin and gastrointestinal (GI) hormones, including glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin, may contribute to the relative success of RYGB compared with conventional weight loss methods. This study evaluated changes in GI hormones and leptin post-RYGB. The study also evaluated whether GI hormones differed after a short-term dose of protein or fat.
GLP-1, PYY, ghrelin, and leptin were assessed in 16 women before RYGB and up to 1 year after RYGB. Plasma was collected before and at several times after a short-term equicaloric dose of protein or fat.
GLP-1 area under the curve (AUC) increased at week 6 and 1 year in the fat beverage (FAT-BEV) group compared with baseline. PYY AUC remained elevated at 1 year in the FAT-BEV group. Ghrelin AUC decreased at week 2, week 6, and 1 year in the protein beverage (PRO-BEV) group compared with baseline. Ghrelin AUC was lower in the PRO-BEV group compared with the FAT-BEV group at week 6. Fasted leptin decreased at all visits in both groups and was lower in the FAT-BEV group compared with the PRO-BEV group at 1 year.
Changes from baseline were evident for all GI hormones and leptin; some differences were evident soon after surgery (ghrelin, leptin), whereas others were maintained long term (GLP-1, PYY, ghrelin, leptin). In response to a short-term stimulus, protein suppressed ghrelin and fat potently stimulated GLP-1 and PYY. Future work in this area is warranted.
PMCID: PMC4284080  PMID: 21378246
obesity; ghrelin; peptide YY; glucagon-like peptide 1; leptin; gastric bypass; gastrointestinal hormones
2.  Primed low-frequency repetitive transcranial magnetic stimulation and constraint-induced movement therapy in pediatric hemiparesis: a randomized trial 
Developmental medicine and child neurology  2013;56(1):10.1111/dmcn.12243.
The aim of this study was to determine the feasibility and efficacy of five treatments of 6Hz primed, low-frequency, repetitive transcranial magnetic stimulation (rTMS) combined with constraint-induced movement therapy (CIMT) to promote recovery of the paretic hand in children with congenital hemiparesis.
Nineteen children with congenital hemiparesis aged between 8 and 17 years (10 males, nine females; mean age 10y 10mo, SD 2y 10mo; Manual Ability Classification Scale levels I-III) underwent five sessions of either real rTMS (n=10) or sham rTMS (n=9) alternated daily with CIMT. CIMT consisted of 13 days of continuous long-arm casting with five skin-check sessions. Each child received a total of 10 hours of one-to-one therapy. The primary outcome measure was the Assisting Hand Assessment (AHA) and the secondary outcome variables were the Canadian Occupational Performance Measure (COPM) and stereognosis. A Wilcoxon signed-rank sum test was used to analyze differences between pre- and post-test scores within the groups. Analysis of covariance was used to compute mean differences between groups adjusting for baseline. Fisher’s exact test was used to compare individual change in AHA raw scores with the smallest detectable difference (SDD) of 4 points.
All participants receiving treatment finished the study. Improvement in AHA differed significantly between groups (p=0.007). No significant differences in the secondary outcome measures were found. Eight out of 10 participants in the rTMS/CIMT group showed improvement greater than the SDD, but only two out of nine in the sham rTMS/CIMT group showed such improvement (p=0.023). No serious adverse events occurred.
Primed, low-frequency rTMS combined with CIMT appears to be safe, feasible, and efficacious in pediatric hemiparesis. Larger clinical trials are now indicated.
PMCID: PMC3864983  PMID: 23962321
3.  Low Bone Mineral Content and Challenges in Interpretation of Dual-Energy X-Ray Absorptiometry in Children With Mucopolysaccharidosis Types I, II, and VI 
Osteoporosis has been described in animal models of mucopolysaccharidosis (MPS). Whether clinically significant osteoporosis is common among children with MPS is unknown. Therefore, cross-sectional data from whole body (WB; excluding head) and lumbar spine (LS) bone mineral density (BMD) compared with sex-, chronologic age–, and ethnicity-matched healthy individuals (Zage), height-for-age (HAZ) Z-score (ZHAZ) and bone mineral content (BMC) measured by dual-energy X-ray absorptiometry (DXA) in 40 children with MPS were analyzed. A subset of these children (n = 24) was matched 1:3 by age and sex to a group of healthy children (n = 72) for comparison of BMC adjusted for Tanner stage, race, lean body mass, height, and bone area. Low BMD Z-score was defined as Z-score of −2 or less. In children with MPS, 15% had low WB Zage and 48% had low LS Zage; 0% and 6% had low WB ZHAZ and low LS ZHAZ, respectively. Adjusted WB BMC was lower in MPS participants (p = 0.009). In conclusion, children with MPS had deficits in WB BMC after adjustments for stature and bone area. HAZ adjustment underestimated bone deficits (i.e., overestimated WB BMD Z-scores) in children with MPS likely owing to their abnormal bone shape. The influence of severe short stature and bone geometry on DXA measurements must be considered in children with MPS to avoid unnecessary exposure to antiresorptive treatments.
PMCID: PMC3872499  PMID: 23562131
Bone mineral content; bone mineral density; mucopolysaccharidoses; osteoporosis; skeletal dysplasia
4.  Semen Parameters in Fertile US Men: The Study for Future Families 
Andrology  2013;1(6):10.1111/j.2047-2927.2013.00125.x.
Establishing reference norms for semen parameters in fertile men is important for accurate assessment, counseling and treatment of men with male factor infertility. Identifying temporal or geographic variability in semen quality also requires accurate measurement of semen parameters in well-characterized, defined populations of men. The Study for Future Families (SFF) recruited men who were partners of pregnant women attending prenatal clinics in Los Angeles CA, Minneapolis MN, Columbia MO, New York City NY and Iowa City IA. Semen samples were collected on site from 763 men (73% White, 15% Hispanic/Latino, 7% Black and 5% Asian or other ethnic group) using strict quality control and well-defined protocols. Semen volume (by weight), sperm concentration (hemacytometer) and sperm motility were measured at each center. Sperm morphology (both WHO, 1999 strict and WHO, 1987) was determined at a central laboratory. Mean abstinence was 3.2 days. Mean (median; 5th – 95th percentile) values were: semen volume, 3.9 (3.7; 1.5 – 6.8) ml; sperm concentration, 60 (67; 12–192) × 106/ml; total sperm count 209 (240; 32–763) × 106; % motile, 51 (52; 28–67) %; and total motile sperm count, 104 (128; 14–395) × 106, respectively. Values for sperm morphology were 11 (10; 3–20) % and 57 (59; 38–72) % normal forms for WHO, 1999 (strict) and WHO, 1987 criteria, respectively. Black men had significantly lower semen volume, sperm concentration and total motile sperm counts than White and Hispanic/Latino men. Semen parameters were marginally higher in men who achieved pregnancy more quickly but differences were small and not statistically significant. The SFF provides robust estimates of semen parameters in fertile men living in five different geographic locations in the US. Fertile men display wide variation in all of the semen parameters traditionally used to assess fertility potential.
PMCID: PMC3812375  PMID: 24009155
5.  No effect of exercise on urinary 6-sulfatoxymelatonin and catecholamines in young women participating in a 16-week randomized controlled trial 
Women with breast cancer have decreased levels of melatonin or its metabolite in plasma and/or urine.
We measured serum melatonin, urinary 6-sulfatoxymelatonin, catecholamines and cortisol in 141 sedentary young female participants in a clinical trial comparing 150 min/wk aerobic exercise for 4 months to no-exercise controls. Demographics, health surveys, body composition, sleep quality, fitness levels, blood and urine samples were obtained at baseline and 16 weeks.
There were no differences between groups at baseline in demographics, exercise, sleep habits, or study hormones. There were also no significant differences between groups in any of the hormones at 16 weeks.
Sixteen weeks of exercise had minimal effects on melatonin secretion of young women.
There is convincing evidence that exercise protects against breast cancer, but this does not appear to occur through changes in melatonin secretion.
PMCID: PMC3769436  PMID: 23861293
6-sulfatoxymelatonin; cortisol; epinephrine; exercise; randomized controlled trial
6.  Low fat diet with omega-3 fatty acids increases plasma insulin-like growth factor concentration in healthy postmenopausal women1 
The insulin-like growth factor pathway plays a central role in the normal and abnormal growth of tissues; however, nutritional determinants of insulin-like growth factor I (IGF-I) and its binding proteins in normal individuals are not well-defined. Three test diets: high fat diet (HF; 40% energy as fat), low fat diet (LF; 20% energy as fat) and low fat, high omega-3 fatty acids diet (LFn3; 23% energy as fat) were tested in a randomized cross-over designed controlled feeding trial in healthy postmenopausal women. Plasma IGF-I, IGFBP-3, insulin, glucose and ratio of IGF-I:IGFBP-3 concentrations were measured in response to diets. Insulin sensitivity was calculated using the homeostatic model assessment of insulin resistance (HOMA-IR). We hypothesized that IGF-I, insulin and glucose concentrations would decrease and IGF binding protein-3 (IGFBP-3) concentration would increase in response to the low fat diets. 8 weeks of the LFn3 diet increased circulating IGF-I (P < 0.001) and IGFBP-3 (P = 0.01) and the LF diet increased IGFBP-3 (P = 0.04) resulting in trends towards an increased IGF-I:IGFBP-3 ratio with the LFn3 diet and a decreased IGF-I:IGFBP-3 ratio with the LF diet (P = 0.13 for both comparisons). No statistically significant differences were detected between treatments at baseline or 8 weeks for IGF-I, IGFBP-3 or IGFBP-3. Insulin, glucose and HOMA-IR were not altered by the interventions. Low fat diet with high n-3 fatty acids may increase circulating IGF-I concentrations without adversely affecting insulin sensitivity in healthy individuals.
PMCID: PMC3703097  PMID: 23827131
Diet; Dietary Fat; Omega-3 Fatty Acids; insulin-like growth factor I (IGF-I); IGF binding protein-3 (IGFBP-3); insulin; glucose
7.  Serum 25(OH) Vitamin D Concentration Changes after Roux-en-Y Gastric Bypass Surgery 
Obesity (Silver Spring, Md.)  2013;21(12):10.1002/oby.20464.
To describe serum 25(OH)D changes after Roux-en-Y gastric bypass (RYGB) and to determine if fat mass (FM) loss and vitamin D intake are associated with changes in serum levels.
We investigated the relationship between serum 25(OH)D and 1) FM, 2) weight, 3) % excess weight loss (EWL), and 4) BMI, after controlling for potential confounders using a mixed effects linear model in 20 women before and up to 1-year post-RYGB. Subcutaneous (SAT) and visceral adipose tissue (VAT) vitamin D concentrations at time of RYGB were also evaluated.
Weight and FM decreased 1-year after surgery by 45±1kg and 37±1kg, respectively while 25(OH)D increased by 10±2 ng/mL. Weight, FM, BMI, and %EWL changes were associated with 25(OH)D change. VAT had on average 21% more vitamin D per gram than SAT and concentrations were highly correlated.
Although weight loss may lead to increased serum 25(OH)D after RYGB, low levels remain a concern in some patients 1-year post-surgery. Additional research is needed to clarify the relationship between adipose storage of vitamin D and serum 25(OH)D in obesity, and how that relationship might change after surgery. This could lead to improved clinical management of vitamin D in this ever-growing clinical population.
PMCID: PMC3731401  PMID: 23526677
8.  Identification of a Human Monoclonal Antibody To Replace Equine Diphtheria Antitoxin for Treatment of Diphtheria Intoxication 
Infection and Immunity  2013;81(11):3992-4000.
Diphtheria antitoxin (DAT) has been the cornerstone of the treatment of Corynebacterium diphtheriae infection for more than 100 years. Although the global incidence of diphtheria has declined steadily over the last quarter of the 20th century, the disease remains endemic in many parts of the world, and significant outbreaks still occur. DAT is an equine polyclonal antibody that is not commercially available in the United States and is in short supply globally. A safer, more readily available alternative to DAT would be desirable. In the current study, we obtained human monoclonal antibodies (hMAbs) directly from antibody-secreting cells in the circulation of immunized human volunteers. We isolated a panel of diverse hMAbs that recognized diphtheria toxoid, as well as a variety of recombinant protein fragments of diphtheria toxin. Forty-five unique hMAbs were tested for neutralization of diphtheria toxin in in vitro cytotoxicity assays with a 50% effective concentration of 0.65 ng/ml for the lead candidate hMAb, 315C4. In addition, 25 μg of 315C4 completely protected guinea pigs from intoxication in an in vivo lethality model, yielding an estimated relative potency of 64 IU/mg. In comparison, 1.6 IU of DAT was necessary for full protection from morbidity and mortality in this model. We further established that our lead candidate hMAb binds to the receptor-binding domain of diphtheria toxin and physically blocks the toxin from binding to the putative receptor, heparin-binding epidermal growth factor-like growth factor. The discovery of a specific and potent human neutralizing antibody against diphtheria toxin holds promise as a potential therapeutic.
PMCID: PMC3811848  PMID: 23940209
9.  The Effects of Aerobic Exercise on Estrogen Metabolism in Healthy Premenopausal Women 
It is well accepted that exercise can decrease breast cancer risk. Limited clinical evidence suggests that this risk could be mediated through changes in estrogen metabolism in premenopausal women. Our objective was to investigate the effects of exercise on premenopausal estrogen metabolism pertinent to breast cancer risk.
Sedentary, healthy, young eumenorrheic women were randomized into an intervention of 30 minutes of moderate-to-vigorous aerobic exercise 5 times a week for approximately 16 weeks (n = 212), or into a usual-lifestyle sedentary control group (n = 179). Urinary levels of estrogens (estrone [E1], estradiol, and estriol) and nine estrogen metabolites were measured at baseline and at study end by liquid chromatography/tandem mass spectrometry. The ratios of 2-hydroxyestrone to 16α-hydroxyestrone (2-OHE1/16α-OHE1) and 2-OHE1 to 4-hydroxyestrone (2- OHE1/4-OHE1) were also calculated.
The exercise intervention resulted in significant increases in aerobic fitness and lean body mass, and a significant decrease in percent body fat. For exercisers who completed the study (n = 165), 2-OHE1/16α-OHE1 increased significantly (P = 0.043), while E1 decreased significantly (P = 0.030) in control participants (n = 153). The change from baseline in 2-OHE1/16α-OHE1 was significantly different between groups (P = 0.045), even after adjustment for baseline values.
The exercise intervention resulted in a significant increase in the 2-OHE1/16α-OHE1 ratio, but no differences in other estrogen metabolites or ratios.
Our results suggest that changes in premenopausal estrogen metabolism may be a mechanism by which increased physical activity lowers breast cancer risk.
PMCID: PMC3648856  PMID: 23652373
Aerobic Exercise; Estrogen Metabolism; Randomized Clinical Trial; Breast Cancer Risk
10.  Combined Prospective and Retrospective Correction to Reduce Motion-Induced Image Misalignment and Geometric Distortions in EPI 
Despite rigid-body realignment to compensate for head motion during an echo-planar imaging (EPI) time-series scan, non-rigid image deformations remain due to changes in the effective shim within the brain as the head moves through the B0 field. The current work presents a combined prospective/retrospective solution to reduce both rigid and non-rigid components of this motion-related image misalignment. Prospective rigid-body correction, where the scan-plane orientation is dynamically updated to track with the subject’s head, is performed using an active marker setup. Retrospective distortion correction is then applied to unwarp the remaining non-rigid image deformations caused by motion-induced field changes. Distortion correction relative to a reference time-frame does not require any additional field mapping scans or models, but rather uses the phase information from the EPI time-series itself. This combined method is applied to compensate EPI scans of volunteers performing in-plane and through-plane head motions, resulting in increased image stability beyond what either prospective or retrospective rigid-body correction alone can achieve. The combined method is also assessed in a BOLD fMRI task, resulting in improved Z-score statistics.
PMCID: PMC3402592  PMID: 22499027
geometric distortion correction; unwarp; functional magnetic resonance imaging; fMRI; EPI; prospective real-time motion correction; active marker; RF-coil
11.  Aerobic training reduces systemic oxidative stress in young women with elevated levels of F2-isoprostanes 
Contemporary clinical trials  2012;34(2):212-217.
The purpose of this trial was to determine whether exercise without weight loss would reduce F2-isoprostanes in previously sedentary young women. Participants (N=319) were randomized to four months of 150 min/wk aerobic exercise or a control group. Plasma free F2-isoprostanes were measured by gas chromatography-mass spectrometry. Other assessments included fitness and % body fat. Intervention groups were compared with stratification by quartiles of baseline plasma F2-isoprostane. This stratified comparison was linearly adjusted for baseline plasma F2-isoprostane and we also used baseline plasma F2-isoprostane as a propensity score to balance the intervention. Training resulted in significant improvements in aerobic fitness (0.88 METs) and body fat percent (1%) in exercisers compared to controls (p<0.001). The exercise group had significantly higher mean baseline plasma F2-isoprostanes (79.1 vs 67.9 pg/mL) than the control group in the highest quartile of baseline plasma F2-isoprostanes. Within this highest quartile, exercise led to a greater decline in plasma F2-isoprostanes (−20.2 ± 2.5 pg/mL) than control (−7.4 ± 2.5 pg/mL); with adjustment for baseline plasma F2-isoprostanes and in the balanced groups, this difference was reduced but remained significant. Four months of exercise training resulted in significant reductions of systemic oxidative stress only among previously sedentary young women who were in the highest quartile of plasma F2-isoprostanes at baseline (≥57 pg/mL). Our findings indicate that the benefits of aerobic exercise in reducing systemic oxidative stress may be limited to those who present higher baseline levels of plasma F2-isoprostanes.
PMCID: PMC3593978  PMID: 23178737
F2-isoprostanes; exercise; women; body composition; fitness
12.  Prospective active marker motion correction improves statistical power in BOLD fMRI 
NeuroImage  2012;68:154-161.
Group level statistical maps of blood oxygenation level dependent (BOLD) signals acquired using functional magnetic resonance imaging (fMRI) have become a basic measurement for much of systems, cognitive and social neuroscience. A challenge in making inferences from these statistical maps is the noise and potential confounds that arise from the head motion that occurs within and between acquisition volumes. This motion results in the scan plane being misaligned during acquisition, ultimately leading to reduced statistical power when maps are constructed at the group level. In most cases, an attempt is made to correct for this motion through the use of retrospective analysis methods. In this paper, we use a prospective active marker motion correction (PRAMMO) system that uses radio frequency markers for real-time tracking of motion, enabling on-line slice plane correction. We show that the statistical power of the activation maps is substantially increased using PRAMMO compared to conventional retrospective correction. Analysis of our results indicates that the PRAMMO acquisition reduces the variance without decreasing the signal component of the BOLD (beta). Using PRAMMO could thus improve the overall statistical power of fMRI based BOLD measurements, leading to stronger inferences of the nature of processing in the human brain.
PMCID: PMC3638742  PMID: 23220430
active tracking; radio-frequency markers; echo planar imaging; fMRI; group analysis; prospective motion correction
13.  PFMFind: a system for discovery of peptide homology and function 
Protein Fragment Motif Finder (PFMFind) is a system that enables e cient discovery of relationships between short fragments of protein sequences using similarity search. It supports queries based on amino acid similarity matrices and position specific score matrices (PSSMs) obtained through an iterative procedure. PSSM construction is customisable through plugins written in Python. PFMFind consists of a GUI client, an index for fast similarity search and a relational database for storing search results and sequence annotations. It is written mostly in Python. The components of PFMFind communicate through TCP/IP sockets and can be located on different physical machines. PFMFind is freely available for download (under a GPL licence) from
PMCID: PMC3903583  PMID: 24479118
similarity search; indexing; protein fragments
14.  A trade off between mlo resistance to powdery mildew and increased susceptibility of barley to a newly important disease, Ramularia leaf spot 
Journal of Experimental Botany  2014;65(4):1025-1037.
Ramularia leaf spot (RLS), caused by the fungus Ramularia collo-cygni, is a serious, recently emerged disease of barley in Europe and other temperate regions. This study investigated the trade off between strong resistance to powdery mildew conferred by mlo mutant alleles and increased susceptibility to RLS. In field trials and seedling tests, the presence of mlo alleles increased severity of RLS. Genetic analysis of a doubled-haploid population identified one quantitative trait locus for susceptibility to RLS, colocalizing with the mlo-11 allele for mildew resistance. The effect of mlo-11 on RLS severity was environmentally sensitive. Analysis of near-isogenic lines of different mlo mutations in various genetic backgrounds confirmed that mlo alleles increased RLS severity in seedlings and adult plants. For mlo resistance to mildew to be fully effective, the genes ROR1 and ROR2 are required. RLS symptoms were significantly reduced on mlo-5 ror double mutants but fungal DNA levels remained as high as in mlo-5 single mutants, implying that ror alleles modify the transition of the fungus from endophytism to necrotrophy. These results indicate that the widespread use of mlo resistance to control mildew may have inadvertently stimulated the emergence of RLS as a major disease of barley.
PMCID: PMC3935564  PMID: 24399175
Biotrophic pathogens; Blumeria graminis; disease resistance; Hordeum vulgare; necrotrophic pathogens; plant breeding; Ramularia collo-cygni; ROR genes.
15.  Behavioral, Virologic, and Immunologic Factors Associated With Acquisition and Severity of Primary Epstein–Barr Virus Infection in University Students 
Background. University students were studied prospectively to determine the incidence of and risk factors for acquisition of primary Epstein–Barr virus (EBV) infection and the virologic and immune correlates of disease severity.
Methods. EBV antibody–negative freshmen participated in monthly surveillance until graduation. If antibodies developed, proximate samples were assayed for viral load by polymerase chain reaction. Lymphocyte and natural killer (NK) cell numbers and activation were measured by flow cytometry, and plasma cytokine levels were measured by a multiplex assay.
Results. Of 546 students screened, 202 (37%) were antibody negative; 143 antibody-negative students were enrolled. During a median of 3 years of observation, 66 subjects experienced primary infection. Of these, 77% had infectious mononucleosis, 12% had atypical symptoms, and 11% were asymptomatic. Subjects reporting deep kissing with or without coitus had the same higher risk of infection than those reporting no kissing (P < .01). Viremia was transient, but median oral shedding was 175 days. Increases were observed in numbers of NK cells and CD8+ T-cells but not in numbers of CD4+ T-cells during acute infection. Severity of illness correlated positively with both blood EBV load (P = .015) and CD8+ lymphocytosis (P = .0003).
Conclusions. Kissing was a significant risk for primary EBV infection. A total of 89% of infections were symptomatic, and blood viral load and CD8+ lymphocytosis correlated with disease severity.
PMCID: PMC3523797  PMID: 23100562
IL-1; S. pneumoniae; coagulation; fibrinogen; innate immunity
16.  Oral Glucose Tolerance Testing in Children with Cystic Fibrosis 
Pediatric diabetes  2010;11(7):10.1111/j.1399-5448.2009.00632.x.
Cystic fibrosis related diabetes is the most common co-morbidity in persons with CF. ISPAD guidelines recommend annual OGTT screening starting at age 10. The OGTT might be recommended in younger children if, as in adults, it provided clinically relevant prognostic information. A database review was performed to determine whether OGTT findings in children with CF predict subsequent clinical course.
A retrospective matched-pair cohort study was based on OGTTs performed 1998–2003. Children age 6–9 were classified as normal glucose tolerance (NGT) or abnormal glucose tolerance (AGT). AGT were matched by age and gender to NGT. Clinical status was assessed at baseline and 5 years later. In a separate investigation, diabetes and prior AGT status of children aged 10–18 were used to assess predictions derived from the cohort study.
In 1998–2003, 39 of 94 children had AGT. Of these, 31 had sufficient follow-up data to be included. Both at baseline and 5 years later there was no significant difference in height, weight, BMI or lung function between AGT and NGT. Diabetes developed in 13 AGT (42%) and one NGT (3%) (odds ratio (OR) 11, p= 0.0009). Age of diabetes onset was 12±1 years in boys and 11±1 in girls, compared to ~23 years in the general CF population. Fifteen current children age 10–18 who had AGT before age 10 have diabetes, close to the prediction of 19.
Abnormal glucose tolerance in children with CF age 6–9 years identifies those at high risk for progression to early onset diabetes.
PMCID: PMC3856892  PMID: 20202149
CFRD; prognosis
17.  Genome-wide association mapping of frost tolerance in barley (Hordeum vulgare L.) 
BMC Genomics  2013;14:424.
Frost tolerance is a key trait with economic and agronomic importance in barley because it is a major component of winter hardiness, and therefore limits the geographical distribution of the crop and the effective transfer of quality traits between spring and winter crop types. Three main frost tolerance QTL (Fr-H1, Fr-H2 and Fr-H3) have been identified from bi-parental genetic mapping but it can be argued that those mapping populations only capture a portion of the genetic diversity of the species. A genetically broad dataset consisting of 184 genotypes, representative of the barley gene pool cultivated in the Mediterranean basin over an extended time period, was genotyped with 1536 SNP markers. Frost tolerance phenotype scores were collected from two trial sites, Foradada (Spain) and Fiorenzuola (Italy) and combined with the genotypic data in genome wide association analyses (GWAS) using Eigenstrat and kinship approaches to account for population structure.
GWAS analyses identified twelve and seven positive SNP associations at Foradada and Fiorenzuola, respectively, using Eigenstrat and six and four, respectively, using kinship. Linkage disequilibrium analyses of the significant SNP associations showed they are genetically independent. In the kinship analysis, two of the significant SNP associations were tightly linked to the Fr-H2 and HvBmy loci on chromosomes 5H and 4HL, respectively. The other significant kinship associations were located in genomic regions that have not previously been associated with cold stress.
Haplotype analysis revealed that most of the significant SNP loci are fixed in the winter or facultative types, while they are freely segregating within the un-adapted spring barley genepool. Although there is a major interest in detecting new variation to improve frost tolerance of available winter and facultative types, from a GWAS perspective, working within the un-adapted spring germplasm pool is an attractive alternative strategy which would minimize statistical issues, simplify the interpretation of the data and identify phenology independent genetic determinants of frost tolerance.
PMCID: PMC3701572  PMID: 23802597
GWAS; Frost tolerance; Barley
18.  Cognitive ability and educational level in relation to concussion: a population study of young men 
BMJ Open  2013;3(3):e002321.
To investigate the association of concussion with cognitive ability (CA) and educational level (EL).
Epidemiological—cross-linkage of national computer registers.
130 420 young men appearing before the Danish draft board during the period 2006–2010.
Primary and secondary outcome measures
CA test scores, EL and occurrence of concussion during the period 2004–2009, treated either in an A&E unit or upon admission to a hospital ward.
The 3067 men who had suffered a concussion had lower CAs (mean=96.5, SD=15, 95% CI 95.0 to 97.0) than the total cohort and they were lower for 1452 who were admitted to a hospital ward (mean CA=95.8, SD=15, 95% CI 95.1 to 96.6) than for 1615 who were treated only at an A&E unit (mean CA=97.1, SD=15, 95% CI 96.3 to 98.0). Multiple logistic regressions revealed that the effects for EL were stronger than those for CA. Among 127 353 men not sustaining a concussion, 48% attended a ‘gymnasium’ (sixth-form college), among men treated for a concussion at an A&E unit, this falls to 36% and among men hospitalised for a concussion to 30%. Transfer to a gymnasium, if it happens, almost invariably does so before the 18th birthday. Among 701 men suffering a concussion and admitted to a hospital department after this date, only 26% (n=182) were previously transferred to a gymnasium. Among the 804 men treated at an A&E unit after their 18th birthday, 33% (n=265) had done so. These two percentages are significantly below the corresponding non-concussed population (48%).
Taken together, the results suggest that lower CA and, in particular, lower EL are risk factors for sustaining a concussion, the risk increasing with the severity of the injury.
PMCID: PMC3612768  PMID: 23474792
Epidemiology; Trauma Management
19.  Mutualistic Co-evolution of Type III Effector Genes in Sinorhizobium fredii and Bradyrhizobium japonicum 
PLoS Pathogens  2013;9(2):e1003204.
Two diametric paradigms have been proposed to model the molecular co-evolution of microbial mutualists and their eukaryotic hosts. In one, mutualist and host exhibit an antagonistic arms race and each partner evolves rapidly to maximize their own fitness from the interaction at potential expense of the other. In the opposing model, conflicts between mutualist and host are largely resolved and the interaction is characterized by evolutionary stasis. We tested these opposing frameworks in two lineages of mutualistic rhizobia, Sinorhizobium fredii and Bradyrhizobium japonicum. To examine genes demonstrably important for host-interactions we coupled the mining of genome sequences to a comprehensive functional screen for type III effector genes, which are necessary for many Gram-negative pathogens to infect their hosts. We demonstrate that the rhizobial type III effector genes exhibit a surprisingly high degree of conservation in content and sequence that is in contrast to those of a well characterized plant pathogenic species. This type III effector gene conservation is particularly striking in the context of the relatively high genome-wide diversity of rhizobia. The evolution of rhizobial type III effectors is inconsistent with the molecular arms race paradigm. Instead, our results reveal that these loci are relatively static in rhizobial lineages and suggest that fitness conflicts between rhizobia mutualists and their host plants have been largely resolved.
Author Summary
Rhizobia are an important group of bacteria that can enter into mutually beneficial symbiotic interactions with legume plants to fix atmospheric nitrogen. However, in order to do so, a complex dialog involving the exchange of chemical and molecular signals must occur between partners. Some species of beneficial rhizobia employ a type III secretion system, a well-characterized virulence mechanism used by pathogens to inject bacterial-encoded type III effector proteins directly into host cells to coerce the host into accommodating the microbe. In this study, we generated draft genome sequences and employed computational as well as experimental methods to identify type III effectors from eight strains representing Sinorhizobium fredii and Bradyrhizobium japonicum. We demonstrate that the type III effector genes of these rhizobial species are highly conserved in content with little diversity between strains. This work is an important step towards understanding the roles for type III secretion systems and their effectors in mutualistic interactions.
PMCID: PMC3585131  PMID: 23468637
20.  Quantitative Patterns of Azathioprine Adherence After Renal Transplantation 
Transplantation  2009;87(5):711-718.
Renal transplant recipients regularly fail to take their prescribed immunosuppressive medications, frequently leading to adverse outcomes.
Medication vials incorporating electronic monitor circuits in their caps compiled prospective data files on the azathioprine dosing patterns of 180 adult renal transplant recipients monitored up to 4 years. These patients were followed for a mean of 8.7 years posttransplantation.
Patients were divided into three groups by the medication doses missed during the first 6 months posttransplant. These initial dosing patterns remained remarkably consistent up to 4 years. Patients (n=47) missing the most doses (≥5%) experienced earlier and more frequent acute rejection episodes (P=0.025). This group also demonstrated significantly longer interdose intervals (P=0.005), with more frequent (P<0.001) and longer (P<0.001) “drug holidays.” A patient subgroup with early declining medication adherence (n=23) experienced dramatically poorer outcomes, with significantly increased acute rejection (P<0.001), chronic rejection (P=0.034), graft loss before death (P<0.001), and death (P=0.04). In all tertiles there was a trend toward missing more medication over time.
Excellent posttransplant medication adherence is critical to improved outcomes. Individual dosing patterns are established early after hospital discharge and remain remarkably consistent, despite gradual erosion in adherence over time. The later consequences of medication nonadherence, especially early declines in adherence, include increased frequencies of rejection, graft loss, and death.
PMCID: PMC3580890  PMID: 19295316
Transplantation; Medication; Adherence; Compliance; Rejection
21.  Wellness Partners: Design and Evaluation of a Web-Based Physical Activity Diary with Social Gaming Features for Adults 
JMIR Research Protocols  2013;2(1):e10.
The United States is currently in an age of obesity and inactivity despite increasing public awareness and scientific knowledge of detrimental long-term health effects of this lifestyle. Behavior-tracking diaries offer an effective strategy for physical activity adherence and weight management. Furthermore, Web-based physical activity diaries can engage meaningful partners in people’s social networks through fun online gaming interactions and generate motivational mechanisms for effective behavioral change and positive health outcomes.
Wellness Partners (WP) is a Web-based intervention in the form of a physical activity diary with social networking and game features. Two versions were designed and developed for the purpose of this study—“Diary” only and “Diary+Game”. The objectives of this study included pilot testing the research process of this intervention design, implementation, evaluation, and exploring the effectiveness of social gaming features on adult participants’ physical activity and anthropometric measures.
We conducted a field experiment with randomized crossover design. Assessments occurred at baseline, first follow-up (FU, 5-8 weeks after using one version of WP), and second FU (5-8 weeks of using the other version of WP). In the control condition, participants started with the “Diary” version of WP while in the experimental condition, participants started with the “Diary+Game” version of WP. A total of 54 adults (egos) ages 44-88, and their family and friends (alters) ages 17-69 participated in the study in ego-network groups. Both egos and their alters completed online surveys about their exercise habits. In addition, egos completed anthropometric measurements of BMI, fat percentage, and fat mass by bioimpedance.
From October 2009 to May 2010, flyers, emails, and Web advertisements yielded 335 volunteers who were screened. Rolling recruitment resulted in enrollment of 142 qualified participants in 54 ego-network groups, which were randomly assigned to a study condition. The final analytic sample included 87 individuals from 41 groups. Data were collected from December 2009 to August 2010, and data analysis was completed in 2011. Overall, the participants were given access to the intervention for 10-13 weeks. Statistical analysis suggested an increase in self-reported exercise frequency (mean days per week) from baseline (2.57, SD 1.92) to first FU (3.21, SD 1.74) in both conditions. Stronger effects were seen in the condition where Diary+Game was played first, especially in network groups with larger age variation between the alters and egos. Overall, the decrease in egos’ BMI was statistically significant from baseline to first FU, with greater decrease for those in the Diary+Game first condition (-0.26 vs -0.16 in the Diary first condition).
The Wellness Partners program increased physical activity among participants and resulted in health benefits among the egos. Web-based diary interventions designed with social gaming features hold potential to promote active lifestyles for middle-age adults and people in their social networks.
PMCID: PMC3628151  PMID: 23611986
physical activity; social networking; diary; game; Web-based intervention; behavior change intervention
Hypertension  2011;58(6):1001-1007.
Chlorthalidone (CTD) reduces 24-hour blood pressure more effectively than hydrochlorothiazide (HCTZ), but whether this influences electrocardiographic left ventricular hypertrophy (LVH) is uncertain. One source of comparative data is the Multiple Risk Factor Intervention Trial (MRFIT), which randomly assigned 8,012 hypertensive men to special intervention (SI) or usual care (UC). SI participants could use CTD or HCTZ initially; previous analyses have grouped clinics by their main diuretic used (C-clinics: CTD; H-clinics: HCTZ). After 48 months, SI participants receiving HCTZ were recommended to switch to CTD, in part, because higher mortality was observed for SI compared to UC participants in H-clinics, while the opposite was found in C-clinics. In this analysis, we examined change in continuous measures of electrocardiographic LVH using both an ecologic analysis by previously-reported C- or H-clinic groupings, and an individual participant analysis where use of CTD or HCTZ by SI participants was considered and updated annually. Through 48 months, differences between SI and UC in LVH were larger for C-clinics compared to H-clinics (Sokolow-Lyon: −93.9 vs −54.9 μV, P=0.049; Cornell voltage: −68.1 vs −35.9 μV, P=0.019; Cornell voltage product: −4.6 vs −2.2 μV/ms, P=0.071; left ventricular mass: −4.4 vs −2.8 gm, P=0.002). At the individual participant level, Sokolow-Lyon and left ventricular mass were significantly lower for SI men receiving CTD compared to HCTZ through 48 months and 84 months of follow-up. Our findings on LVH support the idea that greater blood pressure reduction with CTD than HCTZ may have led to differences in mortality observed in MRFIT.
PMCID: PMC3245686  PMID: 22025372
hydrochlorothiazide; chlorthalidone; left ventricular hypertrophy; hypertension; blood pressure; electrocardiography
23.  Microalbuminuria in Patients With Cystic Fibrosis 
Diabetes Care  2011;34(7):1526-1528.
We previously found that microalbuminuria (MA) is present in 14% of patients with long-standing cystic fibrosis–related diabetes (CFRD). However, others have reported much higher rates of MA in CF patients with and without diabetes (32–67%), suggesting this test is not sufficiently specific for diabetic nephropathy screening in CF. We investigated transient (TMA) and persistent (PMA) microalbuminuria in CF patients to resolve these contradictory findings.
We reviewed 1,449 outpatient urinary albumin measurements from 467 patients aged ≥10 years, which were collected over a decade. TMA was defined as a single episode of MA that subsequently was resolved. PMA was defined as two consecutive or two out of three consecutive measurements in the MA range.
The prevalence of TMA that subsequently was resolved in CF patients was similar to the general population. It was found in 7.6% of patients, including 5% of youth (aged 10–17 years) and 9% of adults. PMA was found in 6.1% of the overall CF population, including 2% of youth and 8% of adults. The odds of PMA were increased sevenfold in patients with CFRD (95% CI 2.5–20, P = 0.0002) and 48-fold in patients with both CFRD and organ transplant (95% CI 13–177, P < 0.0001). The five patients with PMA in the absence of CFRD or transplant included two youths with presumed benign orthostatic MA and three adults with hypertension.
The spot urine albumin-to-creatinine ratio is specific enough to be a valid screening test for diabetic kidney disease in CFRD.
PMCID: PMC3120207  PMID: 21562324
24.  “Echo-Planar Imaging with Prospective Slice-by-Slice Motion Correction using Active Markers” 
Head motion is a fundamental problem in functional MRI, and is often a limiting factor in its clinical implementation. This work presents a rigid-body motion correction strategy for echo-planar imaging (EPI) sequences that uses micro radio-frequency coil “active markers” for real-time, slice-by-slice prospective correction. Before the acquisition of each EPI-slice, a short tracking pulse-sequence measures the positions of three active markers integrated into a headband worn by the subject; the rigid-body transformation that realigns these markers to their initial positions is then fed back to dynamically update the scan-plane, maintaining it at a fixed orientation relative to the head. Using this method, prospectively-corrected EPI time-series are acquired on volunteers performing in-plane and through-plane head motions, with results demonstrating increased image stability over conventional retrospective image-realignment. Implications of this improvement for BOLD fMRI applications is assessed, as well as the benefit of non-rigid-body distortion-correction to reduce the remaining signal variation.
PMCID: PMC3122130  PMID: 21695720
functional magnetic resonance imaging; fMRI; EPI; motion correction; prospective; real-time; active marker; device tracking; RF-coil; micro-coil; geometric distortion
25.  Enhanced recovery program in total hip arthroplasty 
Indian Journal of Orthopaedics  2012;46(4):407-412.
Enhanced recovery program (ERP) was implemented to optimize the hospital stay in total hip arthroplasty. This study assessed the effects of optimizing preoperative and perioperative care using enhanced recovery (ER) on patients undergoing Total hip arthroplasty.
Materials and Methods:
We compared a prospective group of 64 patients on the ER program with a historic cohort of 63 patients that received conventional care (non ER).
ER patients were discharged earliest from hospital [mean length of stay (LOS) 5.3 days, median 4; P < 0.001] as compared to a mean of 8.3 days among non ER patients. Comparison based on American Association of Anesthesiologists (ASA) grades, preoperative hemoglobin, and body mass index (BMI) revealed that patients with ASA grade 3, preoperative hemoglobin of <14 g/dl, and BMI >30 on ER program spent shorter time in hospital as compared to the non ER's conventionally treated patients with more favorable physiological parameters of ASA grade 1 and 2, preoperative hemoglobin of >14 g/dl, and BMI <30.
The ER protocol is universally beneficial and confers an advantage regardless of the patients’ preoperative condition.
PMCID: PMC3421930  PMID: 22912515
Enhanced recovery program; length of stay; total hip arthroplasty

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