BMC Journals

Background: Previous studies in adults have found that a lower resting metabolic rate is a predictor of future body weight gain. Methods: To determine if energy expenditures are reduced in infants born to obese mothers, 21 healthy infants (3.9 +/- 1.9 months) born to lean (n=7, BMI 30) mothers, respectively, participated in this study. Measurements of infant weight, length and skin-fold thicknesses, and mother's weight and height were obtained. Infant energy expenditure was measured for 4-hours using the Enhanced Metabolic Testing Activity Chamber. Metabolic data were extrapolated to 24-hours and adjusted for differences in age and body composition using linear regression analysis (SPSS, version 13) and expressed as kcal/day. Differences between the three groups were determined by one way ANOVA with the Bonferroni Post Hoc test procedure (p

IntroductionEstrogen receptor (ER)-positive breast cancers are considered prognostically more favorable than ER(-) tumors, whereas HER2/neu(+) breast cancers are associated with worse prognosis. The objective of the study was to determine whether ER(+) and ER(-) status related to epigenetic changes in breast cancer-related genes. To evaluate epigenetic differences of tumor-related genes relating to ER and HER2/neu status of primary tumors, we examined the promoter methylation status of eight major breast tumor-related genes' (RASSF1A, CCND2, GSPT1, TWIST, APC, NES1, RARbeta2, and CDH1) promoter CpG islands. Methods: Paired ER(+) (n=65) and ER(-) (n=65) primary breast tumors (n=130) matched for prognostic factors were assessed. DNA was extracted from paraffin-embedded tumors after microdissection, and methylation-specific PCR and capillary array electrophoresis analysis were performed. Results: In early stages of tumor progression (T1 and N0), RASSF1A and CCND2 were significantly (p

Background: DNA sequencing is now emerging as an important component in biomedical studies of diseases like cancer. Short-read, highly parallel sequencing instruments are expected to be used heavily for such projects, but many design specifications have yet to be conclusively established. Perhaps the most fundamental of these is the redundancy required to detect sequence variations, which bears directly upon genomic coverage and the consequent resolving power for discerning somatic mutations. Results: We address the medical sequencing coverage problem via an extension of the standard mathematical theory of haploid coverage. The expected diploid multi-fold coverage, as well as its generalization for aneuploidy are derived and these expressions can be readily evaluated for any project. The resulting theory is used as a scaling law to calibrate performance to that of standard BAC sequencing at 8X to 10X redundancy, i.e. for expected coverages that exceed 99% of the unique sequence. A differential strategy is formalized for tumor/normal studies wherein tumor samples are sequenced more deeply than normal ones. In particular, both tumor alleles should be detected at least twice, while both normal alleles are detected at least once. Our theory predicts these requirements can be met for tumor and normal redundancies of approximately 26X and 21X, respectively. We explain why these values do not differ by a factor of 2, as might intuitively be expected. Future technology developments should prompt even deeper sequencing of tumors, but the 21X value for normal samples is essentially a constant. Conclusions: Given the assumptions of standard coverage theory, our model gives pragmatic estimates for required redundancy. The differential strategy should be an efficient means of identifying potential somatic mutations for further study.

Background: Multifactor Dimensionality Reduction (MDR) has been introduced previously as a non-parametric statistical method for detecting gene-gene interactions. MDR performs a dimensional reduction by assigning multi-locus genotypes to either high- or low-risk groups and measuring the percentage of cases and controls incorrectly labelled by this classification -- the classification error. The combination of variables that produces the lowest classification error is selected as the best or most fit model. The correctly and incorrectly labelled cases and controls can be expressed as a two-way contingency table. We sought to improve the ability of MDR to detect gene-gene interactions by replacing classification error with a different measure to score model quality. Results: In this study, we compare the detection and power of MDR using a variety of measures for two-way contingency table analysis. We simulated 40 genetic models, varying the number of disease loci in the model (2 - 5), allele frequencies of the disease loci (.2/.8 or .4/.6) and the broad-sense heritability of the model (.05 - .3). Overall, detection using NMI was 65.36% across all models, and specific detection was 59.4% versus detection using classification error at 62% and specific detection was 52.2%. Conclusions: Of the 10 measures evaluated, the likelihood ratio and normalized mutual information (NMI) are measures that consistently improve the detection and power of MDR in simulated data over using classification error. These measures also reduce the inclusion of spurious variables in a multi-locus model. Thus, MDR, which has already been demonstrated as a powerful tool for detecting gene-gene interactions, can be improved with the use of alternative fitness functions.

Background: With the amount of influenza genome sequence data growing rapidly, researchers need machine assistance in selecting datasets and exploring the data. Enhanced visualization tools are required to represent results of the exploratory analysis on the web in an easy-to-comprehend form and to facilitate convenient information retrieval. Results: We developed an approach to visualize large phylogenetic trees in an aggregated form with a special representation of sub-scale details. The initial aggregated tree representation is built with a level of resolution automatically selected to fit into the available screen space, with terminal groups selected based on sequence similarity. The default aggregated representation can be refined by users interactively. Structure and data variability within terminal groups are displayed using small trees that have the same vertical size as the text annotation of the group. These subscale representations are calculated using systematic sampling from the corresponding terminal group. The aggregated tree containing terminal groups can be annotated using aggregation of structured metadata, such as seasonal distribution, geographic locations, etc.AvailabilityThe algorithms are implemented in JavaScript within the NCBI Influenza Virus Resource [1].

Background: The most common substitution matrices currently used (BLOSUM and PAM) are based on protein sequences with average amino acid distributions, thus they do not represent a fully accurate substitution model for proteins characterized by a biased amino acid composition. This problem has been addressed recently by adjusting existing matrices, however, to date, no empirical approach has been taken to build matrices which offer a substitution model for comparing proteins sharing an amino acid compositional bias. Here, we present a novel procedure to construct series of symmetrical substitution matrices to align proteins from similarly biased Plasmodium proteomes. Results: We generated substitution matrices by selecting from the BLOCKS database those multiple alignments with a compositional bias similar to that of P. falciparum and P. yoelii proteins. A novel "fuzzy" clustering method was adopted to group sequences within these alignments, showing that this method retains more complete information on the amino acid substitutions when compared to hierarchical clustering. We assessed the performance against the BLOSUM62 series and showed that the usage of our matrices results in an improvement in the performance of BLAST database searches, greatly reducing the number of false positive hits. We then demonstrated applications of the use of novel matrices to improve the annotation of homologs between the two Plasmodium species and to classify members of the P. falciparum RIFIN /STEVOR family. Conclusions: We confirmed that in the case of compositionally biased proteins, standard BLOSUM matrices are not suited for optimal alignments, and specific substitution matrices are required. In addition, we showed that the usage of these matrices leads to a reduction of false positive hits, facilitating the automatic annotation process.

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Background: Although breast-feeding accounts for 15-20% of mother-to-child transmission (MTCT) of HIV, it is not prohibited in some developing countries because of the higher mortality associated with not breast-feeding. We assessed the potential impact, on HIV infection and infant mortality, of a recommendation for shorter durations of exclusive breast-feeding (EBF) and poor compliance to these recommendations. Methods: We developed a deterministic mathematical model using primarily parameters from published studies conducted in Uganda or Kenya and took into account non-compliance resulting in mixed-feeding practices. Outcomes included the number of children HIV-infected and/or dead (cumulative mortality) at 2 years following each of 6 scenarios of infant-feeding recommendations in children born to HIV-infected women: Exclusive replacement-feeding (ERF) with 100% compliance, EBF for 6 months with 100% compliance, EBF for 4 months with 100% compliance, ERF with 70% compliance, EBF for 6 months with 85% compliance, EBF for 4 months with 85% compliance. Results: In the base model, reducing the duration of EBF from 6 to 4 months reduced HIV infection by 11.8% while increasing mortality by 0.4%. Mixed-feeding in 15% of the infants increased HIV infection and mortality respectively by 2.1% and 0.5% when EBF for 6 months was recommended; and by 1.7% and 0.3% when EBF for 4 months was recommended. In sensitivity analysis, recommending EBF resulted in the least cumulative mortality when the a) mortality in replacement-fed infants was greater than 50 per 1000 person-years, b) rate of infection in exclusively breast-fed infants was less than 2 per 1000 breast-fed infants per week, c) rate of progression from HIV to AIDS was less than 15 per 1000 infected infants per week, or d) mortality due to HIV/AIDS was less than 200 per 1000 infants with HIV/AIDS per year. Conclusion: Recommending shorter durations of breast-feeding in infants born to HIV-infected women in these settings may substantially reduce infant HIV infection but not mortality. When EBF for shorter durations is recommended, lower mortality could be achieved by a simultaneous reduction in the rate of progression from HIV to AIDS and or HIV/AIDS mortality, achievable by the use of HAART in infants.

ObjectiveInsulin resistance (IR) is an important risk factor for type 2 Diabetes Mellitus (DM2) and cardiovascular disease (CVD). Metabolic Syndrome (MS) is a clustering of metabolic alterations associated to IR; however, there is no international consensus for defining its diagnosis. Our objective was to evaluate the prevalence and characteristics of MS identified by the ATP III and IDF criteria in adults from Talca city. Research and methods- We studied 1007 individuals, aged 18-74, and residents from Talca. MS subjects were defined according to ATP III (three altered factors) and IDF criteria (patients with waist circumference >80/90 cm (W/M) and two others altered factors). Results: The prevalence of metabolic syndrome according to the IDF and ATP III criteria was 36.4% and 29.5%, respectively after adjustment for age and sex. The agreement for both criteria was 89%. The prevalence in men was higher than in women for both MS definitions, although not significant. MS probability increased with age, and the highest risk was in the 57-68 age group (ATP-MS) and 53-72 age group (IDF-MS). Hypertension, high triglycerides and abdominal obesity are the most frequent alterations in MS. Conclusions: MS prevalence in adults was higher when diagnosed with IDF than with ATP criterion; in both, age is directly related with the MS presence. The MS subjects showed higher levels of blood pressure, waist circumference and plasma triglycerides. Considering our results, it is worrisome that one third of our population has a high risk of developing DM2 and CVD in the future.

Background: Gastrointestinal irritability can deter pregnant women from starting or continuing prenatal multivitamin supplementation. In a previous study, suboptimal tolerability was observed among pregnant women taking a large tablet (18 mm x 8 mm x 8 mm) multivitamin with high elemental iron content (60 mg as ferrous fumarate). The objective of the present study was to compare rates of adherence and reported adverse events among pregnant women who were randomized to commence supplementation with a small-tablet prenatal multivitamin, containing either low or high iron content. Methods: Pregnant women who called the Motherisk Program (Hospital for Sick Children, Toronto) and had not started taking or had discontinued any multivitamin due to adverse events were included in this prospective, randomized, open-label, 2-arm study. Women were randomized to take a small-size (16 mm x 9 mm x 4 mm), low elemental iron content (35 mg as ferrous fumarate) multivitamin ('35 mg' group); or a small-size (5 mm radius, 5 mm thickness), high elemental iron content (60 mg as ferrous sulphate) multivitamin ('60 mg' group). Follow-up interviews documented pill intake and adverse events. Rates of adherence and adverse events were compared between groups using chi-squared tests and Kaplan-Meier survival curves. Results: Of 167 randomized women, 92 in the '35 mg' group and 75 in the '60 mg' group were included in the analysis. Despite ideal conditions and regular follow-ups, mean adherence based on pill intake recall, in both groups was approximately 50%. No statistically significant difference was detected in proportions of women who actually started taking either multivitamin. Among those who started, no difference was detected in rates of adherence or reported adverse events. Conclusion: The present results suggest that iron content is not a major determinant of adherence to prenatal multivitamins. Combined with our previous study, tablet size may be the more definitive factor affecting adherence.

Background: Syphilis spirochete Treponema pallidum ssp. pallidum remains the enigmatic pathogen, since no virulence factors have been identified and the pathogenesis of the disease is poorly understood. Increasing rates of new syphilis cases per year have been observed recently. Results: The genome of the SS14 strain was sequenced to high accuracy by an oligonucleotide array strategy requiring hybridization to only three arrays (Comparative Genome Sequencing, CGS). Gaps in the resulting sequence were filled with targeted dideoxy-terminators (DDT) sequencing and the sequence was confirmed by whole genome fingerprinting (WGF). When compared to the Nichols strain, 327 single nucleotide substitutions (224 transitions, 103 transversions), 14 deletions, and 18 insertions were found. On the proteome level, the highest frequency of amino acid-altering substitution polymorphisms was in novel genes, while the lowest was in housekeeping genes, as expected by their evolutionary conservation. Evidence was also found for hypervariable regions and multiple regions showing intrastrain heterogeneity in the T. pallidum chromosome. Conclusions: The observed genetic changes do not have influence on the ability of Treponema pallidum to cause syphilitic infection, since both SS14 and Nichols are virulent in rabbit. However, this is the first assessment of the degree of variation between the two syphilis pathogens and paves the way for phylogenetic studies of this fascinating organism.

Background: The histone-like Hlp protein is emerging as a key component in mycobacterial pathogenesis, being involved in the initial events of host colonization by interacting with laminin and glycosaminoglycans (GAGs). In the present study, nuclear magnetic resonance (NMR) was used to map the binding site(s) of Hlp to heparan sulfate and identify the nature of the amino acid residues directly involved in this interaction. Results: The capacity of a panel of 30 mer synthetic peptides covering the full length of Hlp to bind to heparin/heparan sulfate was analyzed by solid phase assays, NMR, and affinity chromatography. An additional active region between the residues Gly46 and Ala60 was defined at the N-terminal domain of Hlp, expanding the previously defined heparin-binding site between Thr31 and Phe50. Additionally, the C-terminus, rich in Lys residues, was confirmed as another heparan sulfate binding region. The amino acids in Hlp identified as mediators in the interaction with heparan sulfate were Arg, Val, Ile, Lys, Phe, and Thr. Conclusions: Our data indicate that Hlp interacts with heparan sulfate through two distinct regions of the protein. Both heparan sulfate-binding regions here defined are preserved in all mycobacterial Hlp homologues that have been sequenced, suggesting important but possibly divergent roles for this surface-exposed protein in both pathogenic and saprophic species.

Background: Recent attempts to diminish nickel use in most industrial products have led to an increasing utilization of alternative metal compounds for destinations such as the alloys used in orthopaedics, jewellery and dentistry. The present study was undertaken with the aim to evaluate the potential for an allergic response to nickel, palladium and rhodium on the basis of antigen-specific induction of inflammatory/regulatory cytokines, and to characterize, according to the cytokine profiles, the nature of simultaneous positive patch tests elicited in vivo. Peripheral blood mononuclear cells (PBMC) from 40 patients with different patch test results were kept in short term cultures in the presence of optimized concentrations of NiSO4 x 6H2O, PdCl2 and Rh(CH3COO)2. The production of IFN-gamma and IL-10 elicited by metal compounds were analyzed by the ELISpot assay. Results: We found a specific IFN-gamma response by PBMC upon in vitro stimulation with nickel or palladium in well recognized allergic individuals. All controls with a negative patch test to a metal salt showed an in vitro IL-10 response and not IFN-gamma production when challenged with the same compound. Interestingly, all subjects with positive patch test to both nickel and palladium (group 3) showed an in vitro response characterized by the release of IFN-gamma after nickel stimulation and production of IL-10 in response to palladium. Conclusion: These results strongly suggest that the different cytokine profiles elicited in vitro reflect different immune responses which may lead to the control of the allergic responses or to symptomatic allergic contact dermatitis. The development of sensitive and specific in vitro assays based on the determination of the cytokine profiles in response to contact allergens may have important diagnostic and prognostic implications and may prove extremely useful in complementing the diagnostic limits of traditional patch testing.

Background: The Biopsychosocial Model aims to integrate the biological, psychological and social components of illness, but integration is difficult in practice, particularly when patients consult with medically unexplained physical symptoms or functional illness. DiscussionThis Biopsychosocial Model was developed from General Systems Theory, which describes nature as a dynamic order of interacting parts and processes, from molecular to societal. Despite such conceptual progress, the biological, psychological, social and spiritual components of illness are seldom managed as an integrated whole in conventional medical practice. This is because the biomedical model can be easier to use, clinicians often have difficulty relinquishing a disease-centred approach to diagnosis, and either dismiss illness when pathology has been excluded, or explain all undifferentiated illness in terms of psychosocial factors. By contrast, traditional and complementary treatment systems describe reversible functional disturbances, and appear better at integrating the different components of illness. Conventional medicine retains the advantage of scientific method and an expanding evidence base, but needs to more effectively integrate psychosocial factors into assessment and management, notably of 'functional' illness. As an aid to integration, pathology characterised by structural change in tissues and organs is contrasted with dysfunction arising from disordered physiology or psychology that may occur independent of pathological change. SummaryWe propose a classification of illness that includes orthogonal dimensions of pathology and dysfunction to support a broadly based clinical approach to patients; adoption of which may lead to fewer inappropriate investigations and secondary care referrals and greater use of cognitive behavioural techniques, particularly when managing functional illness.

Background: Inherited genetic factors such as E-cadherin (CDH1) promoter variants are believed to influence the risk towards sporadic diffuse gastric cancer (DGC). Recently, a new regulatory region essential for CDH1 transcription has been identified in CDH1 intron 2. Methods: We genotyped all known polymorphisms located within conserved sequences of CDH1 intron 2 (rs10673765, rs9932686, rs1125557, rs9282650, rs9931853) in an Italian population consisting of 134 DGC cases and 100 healthy controls (55 patient relatives and 45 unrelated, matched individuals). The influence of individual variants on DGC risk was assessed using chi2-tests and logistic regression. The relative contribution of alleles was estimated by haplotype analysis. Results: We observed a significant (pA variant (rs1125557) with DGC risk. Odds ratios were 4.55 (95%CI=2.09-9.93) and 1.38 (95%CI=0.75-2.55) for AA and GA carriers, respectively. When adjusted for age, sex, smoking status, alcohol intake and H.pylori infection, the risk estimates remained largely significant for AA carriers. Haplotype analysis suggested the 163+37235A-allele contributes to disease risk independently of the other variants studied. Conclusions: The CDH1 163+37235G>A polymorphism may represent a novel susceptibility variant for sporadic DGC if confirmed in other populations. Considering the broad expression of E-cadherin in epithelia, this exploratory study encourages further evaluation of the 163+37235A-allele as a susceptibility variant in other carcinomas.

IntroductionAlthough per capita crime has generally fallen over the period which coincides with the obesity epidemic, it has not fallen uniformly across communities. It also has not fallen enough to allay fears on the part of parents. Over the past 30 years, technological changes have made the indoor alternatives to playing outside, where children are more vulnerable to criminal activity, more enjoyable (cable TV, video games, and the internet) and comfortable (the spread of air conditioning to low income neighborhoods). We determined whether indoor sedentary behavior patterns are associated with community crime statistics. 4th graders in the U.S. are typically 9 or 10 years old. Methods: We used data from the 2004-2005 Texas School Physical Activity and Nutrition (SPAN) survey linked with U.S. Department of Justice, Office of Justice Programs, Bureau of Justice Statistics data for the years 2000 through 2005 (http://bjsdata.ojp.usdoj.gov/dataonline/Search/Crime/Crime.cfm) and Texas State data on sexual offenders (https://records.txdps.state.tx.us/DPS WEB/Sor/index.aspx). The probability-based sample included a total of 7,907 children in grade four. Multistage probability sampling weights were used. The dependent variables included were hours of TV watching, video game playing, computer use and total indoor sedentary behavior after school. Incremental Relative Rates were computed for community crime rates including robberies, all violent crimes, murders, assaults, property crimes, rapes, burglaries, larcenies and motor vehicle thefts as well as for sexual offenders living in the neighborhood. The neighborhood refers to the areas where the students at each school live. In the case of sexual offenders, sexual offenders per capita are estimated using the per capita rate in the zip code of the school attended; all other crime statistics are estimated by the crimes per capita in the police department jurisdiction covering the school attended. After controlling for sex, age, and African-American and Hispanic, cross-sectional associations were determined using multivariate Poisson regression. Results: 4th grade boys were more likely to play video games in communities with increased per 100 population rates of larceny and burglary as well as in communities with increased per capita sexual offenders; 4th grade girls were more likely to watch television in communities with increased per capita sexual offenders. While 4th grade girls were more likely to watch TV in communities with increased per capita sex offenders, they were less likely to use computers. Per capita sexual offenders were negatively related to computer use amongst 4th grade girls. Conclusion: By combining community crime and cross-sectional individual level data on indoor sedentary behavior, we found that there is an association between community crimes/sex offender rates and certain types of indoor sedentary behavior. The development of technologies in recent decades which makes supervising children easier indoors, where children are much less vulnerable to crime, may be contributing to the epidemic of childhood obesity.

The association between rheumatoid arthritis (RA) and malignancies has received increased attention in recent years. Reports suggesting that tumor necrosis factor blockers might elevate the risk of malignancy in RA patients have prompted researchers to look at the incidence of malignancies in all RA patients. In a recent issue of Arthritis Research & Therapy, Smitten and colleagues suggest that previous reports of a standardized incidence ratio close to one for malignancies in RA may reflect an increased risk for some site-specific malignancies and a reduced risk for others. Here we discuss these findings and suggest what issues could be addressed in future studies.

Background: QuantiFERON(R)TB Gold (QFT) is a promising blood test for tuberculosis infection but with few data so far from immigrant screening. The aim of this study was to compare results of QFT and tuberculin skin test (TST) among newly arrived asylum seekers in Norway and to assess the role of QFT in routine diagnostic screening for latent tuberculosis infection. Methods: The 1000 asylum seekers (age > 18 years) enrolled in the study were voluntarily recruited from 2813 consecutive asylum seekers arriving at the national reception centre from September 2005 to June 2006. Participation included a QFT test and a questionnaire in addition to the mandatory TST and chest X-ray. Results and Discussion: Among 912 asylum seekers with valid test results, 29% (264) had a positive QFT test whereas 50% (460) tested positive with TST (indurations > 6 mm), indicating a high proportion of latent infection within this group. Among the TST positive participants 50 % were QFT negative, whereas 7% of the TST negative participants were QFT positive. There was a significant association between increase in size of TST result and the likelihood of being QFT positive. Agreement between the tests was 71-79 % depending on the chosen TST cut-off and it was higher for non-vaccinated individuals. Conclusions: By using QFT in routine screening, further follow-up could be avoided in 43% of the asylum seekers who would have been referred if based only on a positive TST (> 6 mm). The proportion of individuals referred will be the same whether QFT replaces TST or is used as a supplement to confirm a positive TST, but the number tested will vary greatly. All three screening approaches would identify the same proportion (88-89%) of asylum seekers with a positive QFT and/or a TST > 15 mm, but different groups will be missed.

Background: Explaining public-goods cooperation is a challenge for evolutionary biology. However, cooperation is expected to more readily evolve if it imposes a smaller cost. Such costs of cooperation are expected to decline with increasing resource supply, an ecological parameter that varies widely in nature. We experimentally tested the effect of resource supply on the evolution of cooperation using two well-studied bacterial public-good traits: biofilm formation by Pseudomonas fluorescens and siderophore production by Pseudomonas aeruginosa. Results: The frequency of cooperative bacteria increased with resource supply in the context of both bacterial public-good traits. In both cases this was due to decreasing costs of investment into public-goods cooperation with increasing resource supply. Conclusions: Our empirical tests with bacteria suggest that public-goods cooperation is likely to increase with increasing resource supply due to reduced costs of cooperation, confirming that resource supply is an important factor in the evolution of cooperation.