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Body dissatisfaction is a well-replicated risk factor for disordered eating, yet not all individuals with body dissatisfaction exhibit disordered eating. This study examined the role of perceptions of social norms on the relationship between body dissatisfaction and disordered eating. Perceptions of descriptive and injunctive peer norms, body dissatisfaction, and disordered eating were examined in a non-clinical sample of college men and women using cross-sectional survey methods. For women, perceptions of the injunctive norms of peer thinness and peer acceptability moderated the relationship between body dissatisfaction and disordered eating with an additive effect; perceptions of the descriptive norm peer prevalence of disordered eating behaviors did not. In men, norms did not moderate the relationship between body dissatisfaction and disordered eating. Endorsement of injunctive norms is associated with reported disordered eating in women with high body dissatisfaction. Norm-based interventions may be best suited for women with high body dissatisfaction., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Mycophenolic acid (MPA) exposure in pediatric patients with kidney transplant receiving body surface area (BSA)-based dosing exhibits large variability. Several genetic variants in glucuronosyltransferases (UGTs) and of multidrug resistance-associated protein 2 (MRP2) have independently been suggested to predict MPA exposure in adult patients with varying results. Here, the combined contribution of these genetic variants to MPA pharmacokinetic variability was investigated in pediatric renal transplant recipients who were on mycophenolic mofetil maintenance therapy., Methods: MPA and MPA-glucuronide concentrations from 32 patients were quantified by high-performance liquid chromatography. MPA exposure (AUC) was estimated using a 4-point abbreviated sampling strategy (predose/trough and 20 minutes, 1 hour, and 3 hours after dose) using a validated pediatric Bayesian estimator. Genotyping was performed for all of the following single nucleotide polymorphisms (SNPs): UGT1A8 830G>A(*3), UGT1A9 98T>C(*3), UGT1A9-440C>T, UGT1A9-2152C>T, UGT1A9-275T>A, UGT2B7-900A>G, and MRP2-24T>C., Results: Recipients heterozygous for MRP2-24T>C who also had UGT1A9-440C>T or UGT2B7-900A>G (n = 4), and MRP2-24T>C-negative recipients having both UGT1A9-440C>T and UGT2B7-900A>G (n = 5) showed a 2.2 and 1.7 times higher dose-dependent and BSA-normalized MPA-AUC compared with carriers of no or only 1 UGT-SNP (P < 0.001 and P = 0.01, respectively) (n = 7). Dose-dependent and BSA-normalized predose MPA concentrations were 3.0 and 2.4 times higher, respectively (P < 0.001). Interindividual variability in peak concentrations could be explained by the presence of the UGT1A9-440C>T genotype (P < 0.05)., Conclusion: Our preliminary study demonstrates that combined UGT1A9-440C>T, UGT2B7-900A>G, and MRP2-24T>C polymorphisms can be important predictors of interindividual variability in MPA exposure in the pediatric population.

Background: Intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial with excellent activity against pathogens associated with intra-abdominal infections. The purpose of this study was to determine the safety and effectiveness of meropenem in young infants with suspected or complicated intra-abdominal infections., Methods: Preterm and term infants <91 days of age with suspected or confirmed intra-abdominal infections hospitalized in 24 neonatal intensive care units were studied in an open-label, multiple-dose study. Adverse events and serious adverse events were collected through 3 and 30 days following the last meropenem dose, respectively. Effectiveness was assessed by 3 criteria: death, bacterial cultures, and presumptive clinical cure score., Results: Of 200 subjects enrolled in the study, 99 (50%) experienced an adverse event, and 34 (17%) had serious adverse events; no adverse events were probably or definitely related to meropenem. The most commonly reported adverse events were sepsis (6%), seizures (5%), elevated conjugated bilirubin (5%), and hypokalemia (5%). Only 2 of the serious adverse events were determined to be possibly related to meropenem (isolated ileal perforation and an episode of fungal sepsis). Effectiveness was evaluable in 192 (96%) subjects, and overall treatment success was 84%., Conclusions: Meropenem was well tolerated in this cohort of critically ill infants, and the majority of infants treated with meropenem met the definition of therapeutic success., Clinical Trials Registration: NCT00621192.

Objective: To establish a short measure of attitudes toward sexual consent in the context of alcohol consumption., Methods: Using a multistage and systematic measurement development process, the investigators developed the Alcohol and Sexual Consent Scale using a sample of college students., Results: The resulting 12-item scale, the Alcohol and Sexual Consent Scale, was examined across a variety of validation measures. The measure is related to alcohol consumption, sexual habits, and sexual victimization and/or perpetration., Conclusions: The Alcohol and Sexual Consent Scale can be used to serve as an outcome measure in sexual assault prevention programming.

Introduction and Hypothesis: This study evaluates potential risk factors for mesh exposure following transvaginal placement of polypropylene mesh for pelvic organ prolapse requiring reoperation., Methods: We performed a case-control study. Cases had mesh exposure requiring surgical revision; controls had no mesh exposures and were chosen for similar surgical date and type of mesh., Results: We identified 48 cases and 48 controls. The adjusted odds ratio of having a bleeding complication at the time of mesh implantation was 7.25 [95% confidence interval (CI) 1.47-35.66], smokers versus nonsmokers was 3.17 (95% CI 0.59-17.12), and being 1 year older was 0.96 (95% CI 0.92-1.0), among women with mesh exposure., Conclusions: We identified bleeding complications at the time of mesh implantation as a risk factor for mesh exposure requiring reoperation. Despite being one of the largest studies on this topic, our data were inconclusive regarding the impact of other possible factors on mesh exposure.

Objective: To assess surgeon practice patterns for antibiotic prophylaxis in gynecologic surgery., Methods: A survey was distributed at the 2011 annual scientific meeting of the Society of Gynecologic Surgeons regarding antibiotic prophylaxis practices., Results: The response rate was 51%. Most surgeons did not use antibiotic prophylaxis for dilation and curettage without products of conception, hysteroscopy, and loop electrocautery excision procedure/cone biopsy. For laparoscopy without graft placement, 45.9% did not use prophylaxis. Prophylaxis was common for hysterectomy. For midurethral slings, 8.2% did not use prophylaxis. When graft material was used in prolapse surgery, at least 93% of surgeons administered some form of antibiotic prophylaxis. Only 70% of respondents prescribe antibiotic prophylaxis for hysterectomy consistent with recommendations from the American College of Obstetricians and Gynecologists, whereas 78% are consistent with specifications from the Joint Commission., Conclusions: Wide variability exists in antibiotic prophylaxis in gynecologic surgery. Surgeon preference or local hospital policies affect choice of prophylaxis less than 14.9% of the time.

To investigate how the CNS copes with load uncertainty in catching, anticipatory postural adjustments (APAs) in one-handed catching of balls of known and unknown weights were compared. Twenty-nine (n = 29) men (mean age = 21.1 years) participated, all of whom had engaged in a sport activity requiring hand-eye coordination. Participants' muscle activity in the biceps brachii, triceps brachii, wrist flexor group, and bilateral erector spinae at L4-5 was recorded using electromyography (EMG) while they caught visually identical balls of four different weights (0.5, 1.33, 2.17, and 3.0 kg). EMG integrals were computed for the 1 s prior to ball drop (pre-drop period), and the interval between ball drop and catch (drop period). Uncertainty about ball weight had no effect on APA activity during the pre-drop period. During the drop period, however, load uncertainty did influence APA activity in the biceps brachii, triceps brachii, and the wrist flexor muscles (i.e., the effect of ball weight on APA magnitude depended on the presence or absence of load knowledge). In the known ball weight condition, participants exhibit greater APA magnitude with increases in ball weight. In contrast, under the unknown ball weight condition, APA magnitude was relatively consistent across ball weights and at a level similar to the APA magnitude for an intermediate weight (i.e., the second heaviest ball of four) in the known weight condition. In catching balls of unknown weights, the CNS appears to scale APA magnitude to afford the greatest chance of catching the ball, regardless of the weight.

Voriconazole is the treatment of choice for invasive aspergillosis and its use is increasing in pediatrics. Minimal pharmacokinetic data exist in young children. We report voriconazole concentrations for 10 children <3 years of age and pharmacokinetic parameters for 1 infant who had therapeutic drug monitoring performed. Trough concentrations were unpredictable based on dose, highlighting the need to follow values during therapy.

Summary: The affordability of high-throughput sequencing has created an unprecedented surge in the use of genomic data in basic, translational and clinical research. The rapid evolution of sequencing technology, coupled with its broad adoption across biology and medicine, necessitates fast, collaborative interdisciplinary discussion. SEQanswers provides a real-time knowledge-sharing resource to address this need, covering experimental and computational aspects of sequencing and sequence analysis. Developers of popular analysis tools are among the >4000 active members, and ~40 peer-reviewed publications have referenced SEQanswers., Availability: The SEQanswers community is freely accessible at http://SEQanswers.com/

Background: Suspected or complicated intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial agent with excellent activity against pathogens associated with intra-abdominal infections in this population. The purpose of this study was to determine the pharmacokinetics (PK) of meropenem in young infants as a basis for optimizing dosing and minimizing adverse events., Methods: Premature and term infants <91 days old hospitalized in 24 neonatal intensive care units were studied. Limited PK sampling was performed following single and multiple doses of meropenem 20 to 30 mg/kg of body weight every 8 to 12 hours based on postnatal and gestational age at birth. Population and individual patient (Bayesian) PK parameters were estimated using NONMEM., Results: In this study, 200 infants were enrolled and received the study drug. Of them, 188 infants with 780 plasma meropenem concentrations were analyzed. Their median (range) gestational age at birth and postnatal age at PK evaluation were 28 (23-40) weeks and 21 (1-92) days, respectively. In the final PK model, meropenem clearance was strongly associated with serum creatinine and postmenstrual age (clearance [L/h/kg] = 0.12*[(0.5/serum creatinine)**0.27]*[(postmenstrual age/32.7)**1.46]). Meropenem concentrations remained >4 μg/mL for 50% of the dose interval and >2 μg/mL for 75% of the dose interval in 96% and 92% of patients, respectively. The estimated penetration of meropenem into the cerebrospinal fluid was 70% (5-148)., Conclusions: Meropenem dosing strategies based on postnatal and gestational age achieved therapeutic drug exposure in almost all infants.

Background and Objective: The primary objective of this study was to characterize the pharmacokinetic profile of pantoprazole delayed-release granules in infants and children aged 1 month to <6 years with gastro-oesophageal reflux disease (GORD). The studies described in this manuscript were conducted to fulfil the requirements of the paediatric written request for pantoprazole by the US FDA., Methods: Two randomized, open-label, multicentre studies were conducted in infants aged 1 month to <12 months (study 1) and children aged 1 year through <6 years (study 2) with GORD. Patients were randomly assigned to either the low-dose pantoprazole group (0.6 mg/kg equivalent) or the high-dose pantoprazole group (1.2 mg/kg equivalent) in a 1 : 1 fashion. Pantoprazole granules were administered approximately 30 minutes before breakfast for at least five consecutive doses. Blood samples were obtained at prespecified intervals. Plasma pantoprazole concentration-time data were analysed by non-compartmental methods. Descriptive statistics were calculated for pharmacokinetic parameters. Patients in study 2 additionally received pantoprazole for 28 days. Safety was monitored throughout., Results: In study 1, 43 patients were randomized; 42 were included in the single-dose pharmacokinetic evaluation (15 females, 27 males; mean postnatal age 6.3 months). In study 2, 17 patients were randomized, and all were included in the single-dose pharmacokinetic evaluation (6 females, 11 males; mean age 3.2 years). In both studies, exposure increased with dose. Mean (standard deviation) maximum (peak) plasma concentration values for the low and high doses were 503 (506) ng/mL and 1318 (1307) ng/mL, respectively, in study 1, and 229 (196) ng/mL and 653 (645) ng/mL, respectively, in study 2. Area under the plasma concentration-time curve values for the low and high doses were 1046 (1043) ng · h/mL and 3602 (3269) ng · h/mL, respectively, in study 1, and 293 (146) ng · h/mL and 2448 (2170) ng · h/mL, respectively, in study 2. There was a trend for increasing clearance with increasing age across the ages 1 month through <6 years. There was no evidence of drug accumulation after multiple doses. On-treatment adverse events (AEs) occurred in 19 of 43 patients in study 1 and in 11 of 17 patients in study 2. Serious AEs occurred in two patients in study 1 (gastroenteritis in one patient and acute gastroenteritis from rotavirus infection resulting in discontinuation of one patient); the serious AEs resolved and were not considered by the investigators to be drug related. No other safety-related discontinuations occurred in either study., Conclusions: Exposure increased with increasing doses of pantoprazole granules, even though wide interindividual variability was observed. Compared with that in adults receiving pantoprazole 40 mg, exposure obtained with the 1.2 mg/kg dose was similar in study 1 and slightly lower in study 2. Pantoprazole was generally well tolerated in infants and children aged 1 month through <6 years with GORD. Trial registration numbers (ClinicalTrials.gov): NCT00259012 (study 1) and NCT00141817 (study 2).

Background: The purpose of this investigation was to model the relationships between developmental assets, life satisfaction, and health-related quality of life (HRQOL) among a stratified, random sample (n = 765, 56% response rate) of college students., Methods: Structural equation modeling techniques were employed to test the relationships using Mplus v4.21; Model evaluations were based on 1) theoretical salience, 2) global fit indices (chi-square goodness of fit, comparative fit index: CFI and Tucker-Lewis Index: TLI), 3) microfit indices (parameter estimates, root mean squared error of approximation: RMSEA and residuals) and 4) parsimony., Results: The model fit the data well: χ2(n = 581, 515) = 1252.23, CFI = .94, TLI = .93 and RMSEA = .05. First, participants who reported increased Family Communication also reported higher levels of life satisfaction. Second, as participants reported having more Non-Parental Role Models, life satisfaction decreased and poor mental HRQOL days increased. Finally increased Future Aspirations was related to increased poor mental HRQOL days. Results were variant across gender., Conclusions: Preliminary results suggest not all developmental assets are related to positive health outcomes among college students, particularly mental health outcomes. While the findings for Family Communication were expected, the findings for Non-Parental Role Models suggest interactions with potential role models in college settings may be naturally less supportive. Future Aspirations findings suggest college students may harbor a greater temporal urgency for the rigors of an increasingly competitive work world. In both cases, these assets appear associated with increased poor mental HRQOL days.

Young children are at increased risk for valproic acid (VPA) hepatotoxicity. Urinary organic acid profiles, as a surrogate of mitochondrial function, were obtained in children 1.9 to 17.3 years of age (n = 52) who were undergoing treatment with VPA for seizure disorders. Age-matched patients receiving treatment with carbamazepine (CBZ; n = 50) and healthy children not undergoing treatment (n = 22) served as controls. Age-related changes in organic acid profiles were observed in all three groups. Although the untreated and CBZ control groups were indistinguishable from each other with respect to the principal-component analysis (PCA) score plots of the subjects, a distinct boundary was apparent between the VPA and each of the control groups. Interindividual variability was observed in the VPA-induced alterations in endogenous pathways corresponding to branched-chain amino acid metabolism and oxidative stress. The data suggest that more detailed metabolomic analysis may provide novel insights into biological mechanisms and predictive biomarkers for children at highest risk for serious toxicity.

Children with gastroesophageal reflux disease (GERD) may benefit from gastric acid suppression with proton pump inhibitors such as pantoprazole. Effective treatment with pantoprazole requires correct dosing and understanding of the drug's kinetic profile in children. The aim of these studies was to characterize the pharmacokinetic (PK) profile of single and multiple doses of pantoprazole delayed-release tablets in pediatric patients with GERD aged 6 to 11 years (study 1) and 12 to 16 years (study 2). Patients were randomly assigned to receive pantoprazole 20 or 40 mg once daily. Plasma pantoprazole concentrations were obtained at intervals through 12 hours after the single dose and at 2 and 4 hours after multiple doses for PK evaluation. PK parameters were derived by standard noncompartmental methods and examined as a function of both drug dose and patient age. Safety was also monitored. Pantoprazole PK was dose independent (when dose normalized) and similar to PK reported from adult studies. There was no evidence of accumulation with multiple dosing or reports of serious drug-associated adverse events. In children aged 6 to 16 years with GERD, currently available pantoprazole delayed-release tablets can be used to provide systemic exposure similar to that in adults.

Evolution hinges on the ability of organisms to adapt to their environment. A key regulator of adaptability is mutation rate, which must be balanced to maintain genome fidelity while permitting sufficient plasticity to cope with environmental changes. Multiple mechanisms govern an organism's mutation rate. Constitutive mechanisms include mutator alleles that drive global, permanent increases in mutation rates, but these changes are confined to the subpopulation that carries the mutator allele. Other mechanisms focus mutagenesis in time and space to improve the chances that adaptive mutations can spread through the population. For example, environmental stress can induce mechanisms that transiently relax the fidelity of DNA repair to bring about a temporary increase in mutation rates during times when an organism experiences a reduced fitness for its surroundings, as has been demonstrated for double-strand break repair in Escherichia coli. Still, other mechanisms control the spatial distribution of mutations by directing changes to especially mutable sequences in the genome. In eukaryotic cells, for example, the stress-sensitive chaperone Hsp90 can regulate the length of trinucleotide repeats to fine-tune gene function and can regulate the mobility of transposable elements to enable larger functional changes. Here, we review the regulation of mutation rate, with special emphasis on the roles of tandem repeats and environmental stress in genome evolution., (Copyright © 2012 S. Karger AG, Basel.)

The current study examined the ability of the transtheoretical model (TTM) to describe and predict alcohol consumption-related behaviors. Data from 321 first-year students were collected on the first day of classes and the week before finals. Three structural models consistent with the TTM were evaluated and tested. The three models fit the data well and indicated that stage of change was a good predictor of alcohol consumption-related behaviors, current and future, and change in alcohol consumption-related behaviors. These results suggest that interventions aimed at first-year students that concentrate on stage of change and the cons of alcohol use may be effective.

In previous studies, number of sexual partners and sexual assertiveness were examined as independent risk factors for sexual victimization among college women. Using a sample of 335 college women, this study examined the interaction of number of sexual partners and sexual assertiveness on verbal sexual coercion and rape. Approximately 32% of the sample reported unwanted sexual intercourse, 6.9% (n = 23) experienced verbal sexual coercion, 17.9% (n = 60) experienced rape, and 7.2% (n = 24) experienced both. As number of sexual partners increased, instances of verbal sexual coercion increased for women low in relational sexual assertiveness but not for women high in relational sexual assertiveness. A similar relationship was not found for rape. Among women who experienced both verbal sexual coercion and rape, increases in number of partners in the context of low refusal and relational assertiveness were associated with increases in verbal sexual coercion and rape. Findings suggest sexual assertiveness is related to fewer experiences of sexual coercion.

High-throughput Structural Genomics yields many new protein structures without known molecular function. This study aims to uncover these missing annotations by globally comparing select functional residues across the structural proteome. First, Evolutionary Trace Annotation, or ETA, identifies which proteins have local evolutionary and structural features in common; next, these proteins are linked together into a proteomic network of ETA similarities; then, starting from proteins with known functions, competing functional labels diffuse link-by-link over the entire network. Every node is thus assigned a likelihood z-score for every function, and the most significant one at each node wins and defines its annotation. In high-throughput controls, this competitive diffusion process recovered enzyme activity annotations with 99% and 97% accuracy at half-coverage for the third and fourth Enzyme Commission (EC) levels, respectively. This corresponds to false positive rates 4-fold lower than nearest-neighbor and 5-fold lower than sequence-based annotations. In practice, experimental validation of the predicted carboxylesterase activity in a protein from Staphylococcus aureus illustrated the effectiveness of this approach in the context of an increasingly drug-resistant microbe. This study further links molecular function to a small number of evolutionarily important residues recognizable by Evolutionary Tracing and it points to the specificity and sensitivity of functional annotation by competitive global network diffusion. A web server is at http://mammoth.bcm.tmc.edu/networks.

The FT-microwave spectrum of germylcyclohexane, c-C(6)H(11)GeH(3), has been recorded, and more than 40 transitions for the (70)Ge, (72)Ge, and (74)Ge isotopomers (isotopologues) have been assigned for the chair-equatorial conformer. The heavy atom adjusted r(0) structural parameters have been determined [distances, C(gamma)-C(delta) = 1.533(3) A, C(gamma)-C(beta) = 1.532(3) A, C(alpha)-C(beta) = 1.540(3) A, C(alpha)-Ge = 1.957(3) A; angles, angleC(gamma)C(delta)C(beta) = 111.2(5) degrees , angleGeC(alpha)C(beta) = 111.1(5) degrees , with the dihedral angle angleC(gamma)C(delta)C(beta)C(alpha) = 55.6(10) degrees ]. Raman and/or infrared spectra of gas, liquid, and solid germylcyclohexane have been recorded. The temperature dependency of the Raman spectrum of the conformer pair 712 (equatorial)/683 (axial) cm(-1) gives an enthalpy difference of 453 +/- 38 cm(-1) (1.30 +/- 0.11 kcal/mol) with the chair-equatorial conformer the more stable form. At ambient temperature, the abundance of the axial conformer is 11 +/- 1%. Substituent effects on the enthalpy difference and structure of monosubstituted cyclohexanes are discussed for a number of molecules.

Microbial stimuli and atmospheric particulate matter (PM) interact to amplify the release of inflammatory and immune-modulating cytokines. The basis of this interaction, however, is not known. Cultured human lung fibroblasts (HLF) were used to determine whether various protein kinase pathways were involved in the release of IL-6 following combined exposure to the PM-derived metal, Ni, and M. fermentans-derived macrophage-activating lipopeptide 2 (MALP-2), a toll-like receptor 2 agonist. Synergistic release of IL-6 by MALP-2 and NiSO4 was obvious after 8h of co-stimulation and correlated with a late phase accumulation of IL-6 mRNA. Ni and MALP-2, alone or together, all led to rapid and transient phosphorylations of ERK(1/2) and JNK/SAPK of similar magnitude. p38 phosphorylation, however, was observed only after prolonged treatment of cells with both stimuli together. A constitutive level of PI3K-dependent Akt phosphorylation remained unchanged by Ni and/or MALP-2 exposure. IL-6 induced by Ni/MALP-2 co-exposure was partially dependent on activity of HIF-1alpha and COX-2 as shown by targeted knockdown using siRNA. IL-6 release in response to Ni/MALP-2 was partially sensitive to pharmacological inhibition of ERK(1/2), p38, and PI3K signaling. The protein kinase inhibitors had minimal or no effects on Ni/MALP-2-induced accumulation of HIF-1alpha protein, however, COX-2 expression and, more markedly PGE(2) production, were suppressed by LY294002, SB203580, and U0126. Thus, Ni/MALP-2 interactions involve multiple protein kinase pathways (ERK(1/2), p38, and PI3K) that modulate events downstream from the early accumulation of HIF-1alpha to promote IL-6 gene expression directly or secondarily, through COX-2-derived autocrine products like PGE(2)., (2010 Elsevier Inc. All rights reserved.)

Inhaled glucocorticoid (GC) therapy is a vital part of the management of chronic asthma. GCs are metabolized by members of the cytochrome P450 3A family in both liver and lung, but the enzymes are differentially expressed. Selective inhibition of one or more P450 3A enzymes could substantially modify target and systemic concentrations of GCs. In this study, we have evaluated the mechanism-based inactivation of P450 3A4, 3A5, and 3A7 enzymes by GCs. Among the five major inhaled GCs approved for clinical use in the United States, fluticasone propionate (FLT) was the most potent mechanism-based inactivator of P450 3A5, the predominant P450 enzyme in the lung. FLT inactivated P450 3A5 in a time- and concentration-dependent manner with K(I), k(inact), and partition ratio of 16 muM, 0.027 min(-1), and 3, respectively. In contrast, FLT minimally inactivated P450 3A4 and did not inactivate 3A7, even with a concentration of 100 muM. The inactivation of P450 3A5 by FLT was irreversible because dialysis did not restore enzyme activity. In addition, the exogenous nucleophilic scavenger GSH did not attenuate inactivation. The prosthetic heme of P450 3A5 was not modified by FLT. The loss of P450 3A5 activity in lung cells could substantially decrease the metabolism of FLT, which would increase the effective FLT concentration at its target site, the respiratory epithelium. Also, inactivation of lung P450 3A5 could increase the absorption of inhaled FLT, which could lead to high systemic concentrations and adverse effects, such as life-threatening adrenal crises or cataracts that have been documented in children receiving high doses of inhaled GCs.

Protein functional sites control most biological processes and are important targets for drug design and protein engineering. To characterize them, the evolutionary trace (ET) ranks the relative importance of residues according to their evolutionary variations. Generally, top-ranked residues cluster spatially to define evolutionary hotspots that predict functional sites in structures. Here, various functions that measure the physical continuity of ET ranks among neighboring residues in the structure, or in the sequence, are shown to inform sequence selection and to improve functional site resolution. This is shown first, in 110 proteins, for which the overlap between top-ranked residues and actual functional sites rose by 8% in significance. Then, on a structural proteomic scale, optimized ET led to better 3D structure-function motifs (3D templates) and, in turn, to enzyme function prediction by the Evolutionary Trace Annotation (ETA) method with better sensitivity of (40% to 53%) and positive predictive value (93% to 94%). This suggests that the similarity of evolutionary importance among neighboring residues in the sequence and in the structure is a universal feature of protein evolution. In practice, this yields a tool for optimizing sequence selections for comparative analysis and, via ET, for better predictions of functional site and function. This should prove useful for the efficient mutational redesign of protein function and for pharmaceutical targeting.

Purpose: The pharmacokinetic profile of pantoprazole granules was assessed in neonates and preterm infants with gastroesophageal reflux disease (GERD) in a multicenter, randomized, open-label trial., Methods: Patients were randomly assigned to either the pantoprazole 1.25 mg (approx. 0.6 mg/kg) or 2.5 mg (approx. 1.2-mg/kg) group and treated for > or =5 consecutive days. Blood was sampled either at 0, 2, 8, and 18 h postdose or at 0, 1, 4, and 12 h postdose on day 1 and at 3 and 6 h postdose after > or =5 consecutive doses. Cytochrome P450 2C19 (CYP2C19) and CYP3A4 genotypes were determined. Safety was monitored. Population pharmacokinetics (popPK) analyses were conducted using nonlinear mixed-effects modeling., Results: The popPK modeling of the pantoprazole 1.25 mg and 2.5 mg groups obtained mean (+/-standard deviation) estimates for the area under the plasma concentration versus time curve (AUC) of 3.54 (+/-2.82) and 7.27 (+/-5.30) microg h/mL, respectively, and mean estimates for half-life of 3.1 (+/-1.5) and 2.7 (+/-1.1) h, respectively. Pantoprazole did not accumulate following multiple-dose administration. The two patients with the CYP2C19 poor metabolizer genotype had a substantially higher AUC than extensive metabolizers. No safety-related discontinuations occurred., Conclusions: In preterm infants and neonates, pantoprazole granules were generally well tolerated, mean exposures with pantoprazole 2.5 mg were slightly higher than that in adults who received 40 mg. While the half-life was longer, accumulation did not occur.

By design, structural genomics (SG) solves many structures that cannot be assigned function based on homology to known proteins. Alternative function annotation methods are therefore needed and this study focuses on function prediction with three-dimensional (3D) templates: small structural motifs built of just a few functionally critical residues. Although experimentally proven functional residues are scarce, we show here that Evolutionary Trace (ET) rankings of residue importance are sufficient to build 3D templates, match them, and then assign Gene Ontology (GO) functions in enzymes and non-enzymes alike. In a high-specificity mode, this Evolutionary Trace Annotation (ETA) method covered half (53%) of the 2384 annotated SG protein controls. Three-quarters (76%) of predictions were both correct and complete. The positive predictive value for all GO depths (all-depth PPV) was 84%, and it rose to 94% over GO depths 1-3 (depth 3 PPV). In a high-sensitivity mode, coverage rose significantly (84%), while accuracy fell moderately: 68% of predictions were both correct and complete, all-depth PPV was 75%, and depth 3 PPV was 86%. These data concur with prior mutational experiments showing that ET rank information identifies key functional determinants in proteins. In practice, ETA predicted functions in 42% of 3461 unannotated SG proteins. In 529 cases--including 280 non-enzymes and 21 for metal ion ligands--the expected accuracy is 84% at any GO depth and 94% down to GO depth 3, while for the remaining 931 the expected accuracies are 60% and 71%, respectively. Thus, local structural comparisons of evolutionarily important residues can help decipher protein functions to known reliability levels and without prior assumption on functional mechanisms. ETA is available at http://mammoth.bcm.tmc.edu/eta., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

The lack of study of medications in pediatric patients has been recognized since the 1960s, when Shirkey described children as "therapeutic orphans." In 1968, only 25% of approved drugs included adequate pediatric prescribing information on the label. This did not begin to improve until the 1990s, with the 1997 US Food and Drug Administration (FDA) Modernization Act, the Best Pharmaceuticals for Children Acts, and the Pediatric Research Equity Acts. By 2009, more than 300 labeling changes improved pediatric prescribing information, but newborns were seldom included.

This study investigated the interrelationships among trauma exposure, PTSD, and mental health problems in a sample of 289 adolescents (199 male, 90 female) detained in a juvenile correctional facility. Mean differences were found in that females scored higher than males on measures of interpersonal trauma exposure and symptoms of both simple and complex PTSD. Females also endorsed more mental health problems in the areas of depression/anxiety, somatic complaints, and suicidal ideation. For all youth, trauma exposure, PTSD, and mental health problems were correlated. Results of structural equation modeling were consistent with the hypothesis that PTSD mediates the relationship between interpersonal trauma and mental health problems for all youth, although the results were stronger for females.

Background: Young infants are susceptible to developmental factors influencing the pharmacokinetics of drugs. Fluconazole is increasingly used to prevent and treat invasive candidiasis in infants. Dosing guidance remains empiric and variable because limited pharmacokinetic data exist., Methods: Our population pharmacokinetic model derived from 357 fluconazole plasma concentrations from 55 infants (23-40 week gestation) illustrates expected changes in fluconazole clearance based upon gestational age, postnatal age, weight, and creatinine. We used a Monte Carlo simulation approach based on parametric description of a patient population's pharmacokinetic response to fluconazole to predict fluconazole exposure (median: 10th and 90th percentile population variability range) after 3, 6, and 12 mg/kg dosing., Results: For the treatment of invasive candidiasis, a dose of at least 12 mg/kg/d in the first 90 days after birth is needed to achieve an area under the concentration curve (AUC) of >400 mg*h/L and an AUC/minimum inhibitory concentration (MIC) >50 for Candida species with MIC <8 microg/mL in > or =90% of <30 week gestation infants and 80% of 30 to 40 week gestation infants. The more preterm infants achieve a higher median AUC (682 mg*hr/L) compared with more mature infants (520 mg*hr/L). For early prevention of candidiasis in 23 to 29 week infants, a dose of 3 or 6 mg/kg twice weekly during the first 42 days of life is equivalent to an AUC of 50 and 100 mg*hr/L, respectively, and maintains fluconazole concentrations > or =2 or 4 microg/mL, respectively, for half of the dosing interval. For late prevention, the 6 mg/kg dose every 72 hours provides similar exposure to 3 mg/kg daily dose. Infants with serum creatinine > or =1.3 mg/dL have delayed drug clearance and dose adjustment is indicated if creatinine does not improve within 96 hours., Conclusions: A therapeutic concentration of fluconazole in premature infants with invasive candidiasis requires dosing substantially greater than commonly recommended in most reference texts. To prevent invasive candidiasis, twice weekly prophylaxis regimens can provide adequate exposure when unit specific MICs are taken into account.

Objectives: The Vanderbilt Evidence-based Practice Center systematically reviewed evidence on treatment of overactive bladder (OAB), urge urinary incontinence, and related symptoms. We focused on prevalence and incidence, treatment outcomes, comparisons of treatments, modifiers of outcomes, and costs., Data: We searched PubMed, MEDLINE, EMBASE, and CINAHL., Review Methods: We included studies published in English from January 1966 to October 2008. We excluded studies with fewer than 50 participants, fewer than 75 percent women, or lack of relevance to OAB. Of 232 included publications, 20 were good quality, 145 were fair, and 67 poor. We calculated weighted averages of outcome effects and conducted a mixed-effects meta-analysis to investigate outcomes of pharmacologic treatments across studies., Results: OAB affects more than 10 to 15 percent of adult women, with 5 to 10 percent experiencing urge urinary incontinence (UUI) monthly or more often. Six available medications are effective in short term studies: estimates from meta-analysis models suggest extended release forms (taken once a day) reduce UUI by 1.78 (95 percent confidence interval (CI): 1.61, 1.94) episodes per day, and voids by 2.24 (95 percent CI: 2.03, 2.46) per day. Immediate release forms (taken twice or more a day) reduce UUI by 1.46 (95 percent CI: 1.28, 1.64), and voids by 2.17 (95 percent CI: 1.81, 2.54). As context, placebo reduces UUI episodes by 1.08 (95 percent CI: 0.86, 1.30), and voids by 1.48 (95 percent CI: 1.19, 1.71) per day. No one drug was definitively superior to others, including comparison of newer more selective agents to older antimuscarinics. Current evidence is insufficient to guide choice of other therapies including sacral neuromodulation, instillation of oxybutynin, and injections of botulinum toxin. Acupuncture was the sole complementary and alternative medicine treatment, among reflexology and hypnosis, with early evidence of benefit. The strength of the evidence is insufficient to fully inform choice of these treatments. Select behavioral interventions were associated with symptom improvements comparable to medications. Limited evidence suggests no clear benefit from adding behavioral interventions at the time of initiation of pharmacologic treatment., Conclusions: OAB and associated symptoms are common. Treatment effects are modest. Quality of life and treatment satisfaction measures suggest such improvements can be important to women. The amount of high quality literature available is meager for helping guide women's choices. Gaps include weak or absent data about long-term followup, poorly characterized and potentially concerning harms, information about best choices to minimize side effects, and study of how combinations of approaches may best be used. This is problematic since the condition is chronic and a single treatment modality is unlikely to fully resolve symptoms for most women.

Room temperature photolysis of aminoborylene complexes, [(CO)(5)M=B=N(SiMe(3))(2)] (1: M = Cr, 2: Mo) in the presence of a series of alkynes and diynes, 1,2-bis(4-methoxyphenyl)ethyne, 1,2-bis(4-(trifluoromethyl)phenyl)ethyne, 1,4-diphenylbuta-1,3-diyne, 1,4-bis(4-methoxyphenyl)buta-1,3-diyne, 1,4-bis(trimethylsilylethynyl)benzene and 2,5-bis(4-N,N-dimethylaminophenylethynyl)thiophene led to the isolation of novel mono and bis-bis-(trimethylsilyl)aminoborirenes in high yields, that is [(RC=CR)(mu-BN(SiMe(3))(2)], (3: R = C(6)H(4)-4-OMe and 4: R = C(6)H(4)-4-CF(3)); [{(mu-BN(SiMe(3))(2)(RC=C-)}(2)], (5: R = C(6)H(5) and 6: R = C(6)H(4)-4-OMe); [1,4-bis-{(mu-BN(SiMe(3))(2)(SiMe(3)C=C)}benzene], 7 and [2,5-bis-{(mu-BN(SiMe(3))(2) ((C(6)H(4)NMe(2))C=C)}-thiophene], 8. All borirenes were isolated as light yellow, air and moisture sensitive solids. The new borirenes have been characterized in solution by (1)H, (11)B, (13)C NMR spectroscopy and elemental analysis and the structural types were unequivocally established by crystallographic analysis of compounds 6 and 7. DFT calculations were performed to evaluate the extent of pi-conjugation between the electrons of the carbon backbone and the empty p(z) orbital of the boron atom, and TD-DFT calculations were carried out to examine the nature of the electronic transitions.

Summary: The Evolutionary Trace Annotation (ETA) Server predicts enzymatic activity. ETA starts with a structure of unknown function, such as those from structural genomics, and with no prior knowledge of its mechanism uses the phylogenetic Evolutionary Trace (ET) method to extract key functional residues and propose a function-associated 3D motif, called a 3D template. ETA then searches previously annotated structures for geometric template matches that suggest molecular and thus functional mimicry. In order to maximize the predictive value of these matches, ETA next applies distinctive specificity filters -- evolutionary similarity, function plurality and match reciprocity. In large scale controls on enzymes, prediction coverage is 43% but the positive predictive value rises to 92%, thus minimizing false annotations. Users may modify any search parameter, including the template. ETA thus expands the ET suite for protein structure annotation, and can contribute to the annotation efforts of metaservers., Availability: The ETA Server is a web application available at (http://mammoth.bcm.tmc.edu/eta/).

Objective: To compare the risk of ureteral compromise and of recurrent vault prolapse following vaginal vs. laparoscopic uterosacral vault suspension at the time of vaginal hysterectomy., Study Design: In this retrospective, cohort study, uterosacral ligament suspension was performed using either a vaginal or laparoscopic approach. The primary outcome was intraoperative ureteral compromise; secondary outcomes were postoperative anatomic result and recurrent prolapse. The Canadian Task Force Classification was II-2., Results: One hundred eighteen patients were included: 96 patients in the vaginal group and 22 patients in the laparoscopic group. Ureteral compromise was identified intraoperatively in 4 (4.2%) cases in the vaginal group; no ureteral compromise was observed in the laparoscopic group (p = 0.33). Failure at the apex, defined as stage > or = II for point C, was seen in 6.3% of patients in the vaginal group as compared with 0% in the laparoscopic group; this difference did not achieve statistical significance. Similarly, trends toward lower recurrent symptomatic vault prolapse (10% vs. 0%), any symptomatic prolapse recurrence (12.5% vs. 4.6%), and higher postoperative Pelvic Organ Prolapse Quantification point C were observed in the laparoscopic group (p > 0.05 for all)., Conclusion: Laparoscopic uterosacral vault suspension following vaginal hysterectomy is a safe alternative to the vaginal approach.

The present study utilized a mixed retrospective and prospective design with an 8-month follow-up period to test a model of revictimization that included multiple childhood (i.e., child sexual, physical, and emotional abuse) and situational variables (i.e., substance use, sexual behavior) for predicting rape among 276 college women. It was of particular interest to determine whether traumatic responses (e.g., posttraumatic symptomatology or risky behavior) increased vulnerability for revictimization. During the 8-month follow-up period, 9% of participants were raped; 88% of assaults involved substance use by the victim. Posttraumatic stress disorder (PTSD) symptomatology predicted rape, substance use, and sexual behavior. Substance use, but not sexual behavior, mediated the relation between PTSD symptomatology and rape during the follow-up period. Sexual behavior indirectly impacted risk for rape via substance use. Results suggest that college women with PTSD symptomatology may be at greater risk for rape if they use substances to reduce distress.

A multicenter, double-blind, randomized, placebo-controlled trial was conducted to evaluate the efficacy and safety of intravenous (IV) ibuprofen (L-lysine) for the early closure of nonsymptomatic patent ductus arteriosus (PDA) within 72 hours of birth in extremely low-birth-weight (ELBW) infants with evidence of ductal shunting by echocardiogram. Eleven sites enrolled 136 infants with nonsymptomatic early PDA (gestational age < 30 weeks; body weight 500 to 1000 g) to receive a 3-day course (10 mg/kg, 5 mg/kg, and 5 mg/kg) of IV ibuprofen ( N = 68) or placebo ( N = 68). Cardiac echocardiogram was performed on study days 1 and 14, and with rescue. Infants were followed to 36 weeks postconceptional age. Patient demographics, mean (standard deviation), were similar between ibuprofen and placebo: birth weight: 798.5 g (128.7) versus 797.3 g (132.8); gestational age: 26.1 weeks (1.3) versus 26.2 weeks (1.4); and age at first dose: 1.5 days (0.7). The intent-to-treat analysis of the primary endpoint, subjects rescued, died, or dropped through study day 14, was 21/68 (30.9%) with ibuprofen and 36/68 (52.9%) for placebo ( P = 0.005). Death, intraventricular hemorrhage, necrotizing enterocolitis, daily fluid intake/output, liver function, bronchopulmonary dysplasia, and retinopathy of prematurity did not differ. A trend toward decreased periventricular leukomalacia by ibuprofen was noted. IV ibuprofen was effective and safe in the early closure of PDA in preterm neonates.

The purpose of this investigation was to assess the reliability and validity of eight developmental asset measures among a stratified, random sample (N = 540) of college students to guide health promotion efforts. The sample was randomly split to produce exploratory and confirmatory samples for factor analysis using principal axis factoring and varimax rotation and structural equation modeling techniques. Items were retained on factors if they had high loadings greater than .40 and were not complex. Concurrent validity was examined among substance use (including alcohol and tobacco) and sexual risk-taking variables. Exploratory and confirmatory samples did not differ on demographics. Parallel analysis confirmed the eight theorized constructs. Exploratory factor loadings were greater than .40. Concurrently, validity analyses were in the predicted direction. Cronbach alphas were .70 or greater with the exception of the Future Aspirations asset. Preliminary analyses support the reliability and validity of measuring developmental assets among emerging adults. Implications and potential uses are discussed.

A woman who underwent transobturator sling surgery for urinary incontinence experienced early vaginal mesh erosion, and underwent a partial sling removal. Several months later, she developed recurrent right thigh and groin abscesses and necrotizing fasciitis. The source of the infection, a retained segment of mesh in the obturator space, was identified only after several operative procedures and referrals. This case illustrates several of the areas of concern with the introduction of new surgical materials and techniques.

Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 . (weight/1)(0.75) . (BGA/26)(1.739) . (PNA/2)(0.237) . serum creatinine (SCRT)(-4.896) (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 . (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

The aim of this study was to evaluate whether multichannel urodynamic testing changes a physician's treatment recommendations when managing women with urinary incontinence. In this prospective reader study, four fellowship-trained urogynecologists reviewed 39 abstracted cases of urinary incontinence on two occasions: first without and subsequently with urodynamic data. Treatment recommendations were made for each case after each review. The probability of urodynamic data modifying treatment recommendations was estimated for each reader and for the population of readers using a random effects logistic regression to account for reader variability. The overall probability that urodynamic data would change treatment was 26.9% (95% confidence interval (CI), 18.6%, 37.2%) for medical treatments and 45.5% (95% CI, 37.8%, 53.4%) for surgical treatments. Reader-to-reader differences accounted for 3% and <1% of the total variance for medical and surgical treatments, respectively. Multichannel urodynamic evaluations are significantly associated with changes in medical and surgical treatment recommendations in a referral population.

Although a growing body of scholarly work explores the unique utility and therapeutic uses of psychological assessment, less work has focused specifically on feedback, with few studies that have explored empirically the underlying processes that may describe the role of feedback in a successful assessment. The purpose of this project was to add to the discourse on this topic by engaging in an empirical study exploring assessee and assessor experiences of significant events in psychological assessment feedback. The methodology is qualitative and modeled after significant events research in the study of psychotherapy process. I analyze the accounts of 6 assessment clients and 6 assessment clinicians regarding key events in their experience of feedback.

The Egr2/Krox20 transactivator is required for activation of many myelin-associated genes during peripheral nerve myelination by Schwann cells. However, recent work has indicated that Egr2 not only activates genes required for peripheral nerve myelination but may also be involved in gene repression. The NAB (NGFI-A/Egr-binding) corepressors interact with Egr2 and are required for proper coordination of myelin formation. Therefore, NAB proteins could mediate repression of some Egr2 target genes, although direct repression by Egr2 or NAB proteins during myelination has not been demonstrated. To define the physiological role of NAB corepression in gene repression by Egr2, we tested whether the Egr2.NAB complex directly repressed specific target genes. A screen for NAB-regulated genes identified several (including Id2, Id4, and Rad) that declined during the course of peripheral nerve myelination. In vivo chromatin immunoprecipitation analysis of the myelinating sciatic nerve was used to show developmental association of both Egr2 and NAB2 on the Id2, Id4, and Rad promoters as they were repressed during the myelination process. In addition, NAB2 represses transcription by interaction with the chromodomain helicase DNA-binding protein 4 (CHD4) subunit of the nucleosome remodeling and deacetylase chromatin remodeling complex, and we demonstrate that CHD4 occupies NAB-repressed promoters in a developmentally regulated manner in vivo. These results illustrate a novel aspect of genetic regulation of peripheral nerve myelination by showing that Egr2 directly represses genes during myelination in conjunction with NAB corepressors. Furthermore, repression of Id2 was found to augment activation of Mpz (myelin protein zero) expression.

Stress urinary incontinence (SUI) is a common disorder that does not require treatment unless bothersome to the patient. The evaluation includes a thorough history and physical in order to evaluate for other bladder and pelvic floor disorders. Multichannel urodynamics are not necessary for the diagnosis of SUI, but may be helpful when choosing among appropriate treatment options and for patient counseling. Behavioral and physical therapies are appropriate first-line treatments and should be discussed with all patients, even those desiring surgical treatment. Conservative treatments include the use of pessaries to improve urethral support. Multiple surgical options exist. While mid-urethral slings are commonly used today, there is a still a role for traditional pubovaginal slings and the Burch retropubic urethropexy.

Function prediction frequently relies on comparing genes or gene products to search for relevant similarities. Because the number of protein structures with unknown function is mushrooming, however, we asked here whether such comparisons could be improved by focusing narrowly on the key functional features of protein structures, as defined by the Evolutionary Trace (ET). Therefore a series of algorithms was built to (a) extract local motifs (3D templates) from protein structures based on ET ranking of residue importance; (b) to assess their geometric and evolutionary similarity to other structures; and (c) to transfer enzyme annotation whenever a plurality was reached across matches. Whereas a prototype had only been 80% accurate and was not scalable, here a speedy new matching algorithm enabled large-scale searches for reciprocal matches and thus raised annotation specificity to 100% in both positive and negative controls of 49 enzymes and 50 non-enzymes, respectively-in one case even identifying an annotation error-while maintaining sensitivity ( approximately 60%). Critically, this Evolutionary Trace Annotation (ETA) pipeline requires no prior knowledge of functional mechanisms. It could thus be applied in a large-scale retrospective study of 1218 structural genomics enzymes and reached 92% accuracy. Likewise, it was applied to all 2935 unannotated structural genomics proteins and predicted enzymatic functions in 320 cases: 258 on first pass and 62 more on second pass. Controls and initial analyses suggest that these predictions are reliable. Thus the large-scale evolutionary integration of sequence-structure-function data, here through reciprocal identification of local, functionally important structural features, may contribute significantly to de-orphaning the structural proteome.

Background: Structural genomics projects such as the Protein Structure Initiative (PSI) yield many new structures, but often these have no known molecular functions. One approach to recover this information is to use 3D templates - structure-function motifs that consist of a few functionally critical amino acids and may suggest functional similarity when geometrically matched to other structures. Since experimentally determined functional sites are not common enough to define 3D templates on a large scale, this work tests a computational strategy to select relevant residues for 3D templates., Results: Based on evolutionary information and heuristics, an Evolutionary Trace Annotation (ETA) pipeline built templates for 98 enzymes, half taken from the PSI, and sought matches in a non-redundant structure database. On average each template matched 2.7 distinct proteins, of which 2.0 share the first three Enzyme Commission digits as the template's enzyme of origin. In many cases (61%) a single most likely function could be predicted as the annotation with the most matches, and in these cases such a plurality vote identified the correct function with 87% accuracy. ETA was also found to be complementary to sequence homology-based annotations. When matches are required to both geometrically match the 3D template and to be sequence homologs found by BLAST or PSI-BLAST, the annotation accuracy is greater than either method alone, especially in the region of lower sequence identity where homology-based annotations are least reliable., Conclusion: These data suggest that knowledge of evolutionarily important residues improves functional annotation among distant enzyme homologs. Since, unlike other 3D template approaches, the ETA method bypasses the need for experimental knowledge of the catalytic mechanism, it should prove a useful, large scale, and general adjunct to combine with other methods to decipher protein function in the structural proteome.

Background: Myelination of peripheral nerves by Schwann cells requires not only the Egr2/Krox-20 transactivator, but also the NGFI-A/Egr-binding (NAB) corepressors, which modulate activity of Egr2. Previous work has shown that axon-dependent expression of Egr2 is mediated by neuregulin stimulation, and NAB corepressors are co-regulated with Egr2 expression in peripheral nerve development. NAB corepressors have also been implicated in macrophage development, cardiac hypertrophy, prostate carcinogenesis, and feedback regulation involved in hindbrain development., Results: To test the mechanism of NAB regulation in Schwann cells, transfection assays revealed that both Nab1 and Nab2 promoters are activated by Egr2 expression. Furthermore, direct binding of Egr2 at these promoters was demonstrated in vivo by chromatin immunoprecipitation analysis of myelinating sciatic nerve, and binding of Egr2 to the Nab2 promoter was stimulated by neuregulin in primary Schwann cells. Although Egr2 expression activates the Nab2 promoter more highly than Nab1, we surprisingly found that only Nab1 - but not Nab2 - expression levels were reduced in sciatic nerve from Egr2 null mice. Analysis of the Nab2 promoter showed that it is also activated by ETS proteins (Ets2 and Etv1/ER81) and is bound by Ets2 in vivo., Conclusion: Overall, these results indicate that induction of Nab2 expression in Schwann cells involves not only Egr2, but also ETS proteins that are activated by neuregulin stimulation. Although Nab1 and Nab2 play partially redundant roles, regulation of Nab2 expression by ETS factors explains several observations regarding regulation of NAB genes. Finally, these data suggest that NAB proteins are not only feedback inhibitors of Egr2, but rather that co-induction of Egr2 and NAB genes is involved in forming an Egr2/NAB complex that is crucial for regulation of gene expression.

Objective: The aim of this study was to describe the long-term objective and subjective outcomes after vaginal paravaginal repair with AlloDerm graft (LifeCell, Branchburg, NJ)., Study Design: Thirty-three women with either recurrent stage II or primary or recurrent stage III-IV anterior vaginal wall prolapse underwent a vaginal paravaginal repair with AlloDerm graft between November 1998 and April 2002. Postoperative follow-up was obtained on an annual basis. Objective failure was defined as a stage II or greater anterior wall defect. Descriptive statistics were performed., Results: Long-term follow-up was obtained on 24/33 subjects (72.7%). The mean length of follow-up for the 24 women was 52.0 months (range, 18-86 months). Fourteen of the 24 subjects (58.3%) had recurrent stage II prolapse in the anterior compartment, of which only 4 of 14 (28.6%) were symptomatic., Conclusions: Long-term evaluation of vaginal paravaginal repairs with AlloDerm graft reveals good subjective success, despite a moderate rate of objective failure within the first 24 months.

Myelination in the PNS is accompanied by a large induction of the myelin protein zero (Mpz) gene to produce the most abundant component in peripheral myelin. Analyses of knockout mice have shown that the EGR2/Krox20 and SOX10 transcription factors are required for Mpz expression. Our recent work has shown that the dominant EGR2 mutations associated with human peripheral neuropathies cause disruption of EGR2/SOX10 synergy at specific sites, including a conserved enhancer element in the first intron of the Mpz gene. Further investigation of Egr2/Sox10 interactions reveals that activation of the Mpz intron element by Egr2 requires both Sox10-binding sites. In addition, both Egr1 and Egr3 cooperate with Sox10 to activate this element, which indicates that this capacity is conserved among Egr family members. Finally, a conserved composite structure of Egr2/Sox10-binding sites in the genes encoding Mpz, myelin-associated glycoprotein and myelin basic protein genes was used to screen for similar modules in other myelin genes, revealing a potential regulatory element in the periaxin gene. Overall, these results elucidate a working model for developmental regulation of Mpz expression, several facets of which extend to regulation of other peripheral myelin genes.

To systematically review the literature and to quantitatively compare outcomes and complications following retropubic vs transobturator approach to midurethral slings. We searched PUBMED, OVID, EMBASE, CINAHL, POPLINE, Web of Science, Cochrane Collaboration resources, TRIP, Global Health databases, and abstracts from relevant meetings from 1990 to 2006. We included all studies that compared retropubic and transobturator approaches to midurethral slings and that defined outcomes. We used random-effects models to estimate pooled odds ratios and 95% confidence intervals for objective and subjective failure, complications, and de novo irritative voiding symptoms. Six randomized trials and 11 cohort studies compared transobturator and retropubic approaches to midurethral slings. There was insufficient evidence to support if one approach leads to better objective outcomes. We found no difference in subjective failure between the 2 approaches after pooling data from randomized trials (pooled odds ratio OR 0.85, confidence interval 95% CI 0.38-1.92). The transobturator approach was associated with a decreased risk of complications (pooled OR 0.40, 95% CI 0.19-0.83]). The transobturator approach to midurethral slings is associated with a lower risk of complications; however, it is still unclear if one approach results in superior objective or subjective outcomes.

Dominant mutations in the early growth response 2 (Egr2/Krox20) transactivator, a critical regulator of peripheral myelin development, have been associated with peripheral myelinopathies. These dominant mutants interfere with the expression of genes required for myelination by Schwann cells, including that for the most abundant peripheral myelin protein, Myelin protein zero (Mpz). In this study, we show that Egr2 mutants specifically affect an Egr2-responsive element within the Mpz first intron that also contains binding sites for the transcription factor Sox10. Furthermore, Egr2 activation through this element is impaired by mutation of the Sox10 binding sites. Using chromatin immunoprecipitation assays, we found that Egr2 and Sox10 bind to this element in myelinating sciatic nerve and that a dominant Egr2 mutant does not perturb Egr2 binding but rather attenuates binding of Sox10 to the Mpz intron element. Sox10 binding at other sites of Egr2/Sox10 synergy, including a novel site in the Myelin-associated glycoprotein (Mag) gene, is also reduced by the dominant Egr2 mutant. These results provide the first demonstration of binding of Egr2/Sox10 to adjacent sites in vivo and also demonstrate that neuropathy-associated Egr2 mutants antagonize binding of Sox10 at specific sites, thereby disrupting genetic control of the myelination program.

The purpose of this study is to compare the reliability and predictability of transtheoretical model (TTM) constructs when applied to minority and White women at risk for HIV. Participants consisted of 332 women, including Blacks, Asians, Hispanics, Native Americans, other non-Whites, and Whites. The results supported the reliability and validity of the TTM variables for minority women as well as for White women. Hierarchical multiple regressions demonstrated that TTM variables were able to predict over and above demographic variables. Structural equation models indicate strong support for a mediational model in which the pros and cons predict condom stage of change and unprotected sex though the mediation of self-efficacy. This study provides strong support for TTM scales applied to minority as well as White women at risk for HIV. The authors discuss how these variables might be incorporated into interventions aimed at increasing condom use in minority women.