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We aimed to evaluate the immunodiagnostic values of autoantibodies to a panel of six tumor-associated antigens (TAAs) in the detection of patients with breast cancer. This study determines whether a panel of multiple TAAs would enhance antibody detection and be a useful approach in breast cancer detection and diagnosis. The panel of multiple TAAs was composed of six TAAs including Imp1, p16, Koc, survivin, cyclin B1, and c-myc full-length recombinant proteins. Enzyme-linked immunosorbent assay (ELISA) was used to detect antibodies against these six TAAs in 49 sera from patients with breast cancer, 35 sera from patients with benign breast tumor, and 38 sera from normal individuals. Antibody frequency to any individual TAA in breast cancer was variable and ranged from 12.2 to 18.4 %. With the successive addition of TAAs to a final total of six antigens, there was a stepwise increase of positive antibody reactions reaching a sensitivity of 67.3 % and a specificity of 92.2 % in breast cancer. Positive and negative likelihood ratios were 8.52 and 0.36, respectively, which showed that the clinical diagnostic value of a parallel assay of six TAAs was high. Positive and negative predictive values were, respectively, 91.7 and 68.6 %, indicating that the parallel assay of six TAAs raised the diagnostic accuracy greatly. Agreement rate and kappa value were 78.1 % and 0.57, respectively, which indicated that the observed value of this assay had a middle range of coincidence with the actual value. The data from this study further support our previous hypothesis that the detection of autoantibodies for diagnosis of a certain type of cancer can be enhanced by using a panel of several carefully selected TAAs as target antigens and a panel of multiple TAAs would be a useful approach in the detection and diagnosis of breast cancer.

Roland Brosch and colleagues report whole-genome sequencing of tubercle bacilli with smooth colony morphology, also known as Mycobacterium canetti and/or Mycobacterium prototuberculosis , obtained from humans with tuberculosis from geographically diverse regions. Their comparative genomic analysis with Mycobacterium tuberculosis and other M. tuberculosis complex members identifies extensive recombination and provides insights into the evolution of mycobacteria. The authors also report that tubercle bacilli with smooth colony morphology show reduced persistence and virulence compared to M. tuberculosis strains in infection experiments in mice. Global spread and limited genetic variation are hallmarks of M. tuberculosis , the agent of human tuberculosis. In contrast, Mycobacterium canettii and related tubercle bacilli that also cause human tuberculosis and exhibit unusual smooth colony morphology are restricted to East Africa. Here, we sequenced and analyzed the whole genomes of five representative strains of smooth tubercle bacilli (STB) using Sanger (4–5× coverage), 454/Roche (13–18× coverage) and/or Illumina DNA sequencing (45–105× coverage). We show that STB isolates are highly recombinogenic and evolutionarily early branching, with larger genome sizes, higher rates of genetic variation, fewer molecular scars and distinct CRISPR-Cas systems relative to M. tuberculosis . Despite the differences, all tuberculosis-causing mycobacteria share a highly conserved core genome. Mouse infection experiments showed that STB strains are less persistent and virulent than M. tuberculosis. We conclude that M. tuberculosis emerged from an ancestral STB-like pool of mycobacteria by gain of persistence and virulence mechanisms, and we provide insights into the molecular events involved.

Genotyping of Mycobacterium tuberculosis isolates is a powerful tool for epidemiological control of tuberculosis (TB) and phylogenetic exploration of the pathogen. Standardized PCR-based typing, based on 15 to 24 mycobacterial interspersed repetitive unit-variable number of tandem repeat (MIRU-VNTR) loci combined with spoligotyping, has been shown to have adequate resolution power for tracing TB transmission and to be useful for predicting diverse strain lineages in European settings. Its informative value needs to be tested in high TB-burden countries, where the use of genotyping is often complicated by dominance of geographically specific, genetically homogeneous strain lineages. We tested this genotyping system for molecular epidemiological analysis of 369 M. tuberculosis isolates from 3 regions of Brazil, a high TB-burden country. Deligotyping, targeting 43 large sequence polymorphisms (LSPs), and the MIRU-VNTRplus identification database were used to assess phylogenetic predictions. High congruence between the different typing results consistently revealed the countrywide supremacy of the Latin-American-Mediterranean (LAM) lineage, comprised of three main branches. In addition to an already known RDRio branch, at least one other branch characterized by a phylogenetically informative LAM3 spoligo-signature seems to be globally distributed beyond Brazil. Nevertheless, by distinguishing 321 genotypes in this strain population, combined MIRU-VNTR typing and spoligotyping demonstrated the presence of multiple distinct clones. The use of 15 to 24 loci discriminated 21 to 25% more strains within the LAM lineage, compared to a restricted lineage-specific locus set suggested to be used after SNP analysis. Noteworthy, 23 of the 28 molecular clusters identified were exclusively composed of patient isolates from a same region, consistent with expected patterns of mostly local TB transmission. Standard MIRU-VNTR typing combined with spoligotyping can reveal epidemiologically meaningful clonal diversity behind a dominant M. tuberculosis strain lineage in a high TB-burden country and is useful to explore international phylogenetical ramifications.

PE and PE_(P)GRS are two mycobateria-restricted multigene families encoding membrane associated and secreted proteins that have expanded mainly in the pathogenic species, notably the Mycobacterium tuberculosis complex (MTBC). Several lines of evidence attribute to PE and PE_(P)GRS genes critical roles in mycobacterial pathogenicity. To get more insight into the nature of these genes, we sought to address their evolutionary trajectories in the group of smooth tubercle bacilli (STB), the putative ancestor of the clonal MTBC. By focussing on six polymorphic STB PE/PE_(P)GRS genes, we demonstrate significant incongruence among single gene genealogies and detect strong signals of recombination using various approaches. Coalescent-based estimation of population recombination and mutation rates ([rho] and [theta], respectively) indicates that the two mechanisms are of roughly equal importance in generating diversity ([rho]/[theta] = 1.457), a finding in a marked contrast to house keeping genes (HKG) whose evolution is chiefly brought about by mutation ([rho]/[theta] = 0.012). In comparison to HKG, we found 15 times higher mean rate of nonsynonymous substitutions, with strong evidence of positive selection acting on PE_(P)GRS62 (dN/dS = 1.42), a gene that has previously been shown to be essential for mycobacterial survival in macrophages and granulomas. Imprint of positive selection operating on specific amino acid residues or along branches of PE_(P)GRS62 phylogenetic tree was further demonstrated using maximum likelihood- and covarion-based approaches, respectively. Strikingly, PE_(P)GR62 proved highly conserved in present-day MTBC strains. Overall the data indicate that, in STB, PE/PE_(P)GRS genes have undergone a strong diversification process that is speeded up by recombination, with evidence of positive selection. The finding that positive selection involved an essential PE_(P)GRS gene whose sequence appears to be driven to fixation in present-day MTBC strains lends further support to the critical role of PE/PE_(P)GRS genes in the evolution of mycobacterial pathogenicity.

Morphine is a drug commonly administered via the epidural or intrathecal route, and is regarded by many as the 'gold-standard' single-dose neuraxial opioid due to its postoperative analgesic efficacy and prolonged duration of action. However, respiratory depression is a recognized side effect of neuraxial morphine administered in the perioperative setting. We conducted an extensive review of articles published since 1945 that examine respiratory depression or failure associated with perioperative intrathecal or epidural morphine use. Respiratory depression was previously thought to result from the interaction of opioid in the cerebrospinal fluid with ventral medullary opioid receptors. More recently, the preBötzinger complex located in the medulla has been identified as the site responsible for the decrease in respiratory rate following systemic administration of opioids. Neurons in the preBötzinger complex expressing neurokinin-1 receptors are selectively inhibited by opioids, and therefore are the mediators of opioid-induced respiratory depression. Epidural, intrathecal and plasma pharmacokinetics of opioids are complex, vary between neuraxial compartments, and can even differ within the epidural space itself depending upon level of insertion. Caution should be exercised when prescribing systemic opioids (intravenous or oral) in addition to neuraxial morphine as this can compound the potential for early or delayed respiratory depression. There is a wide range of incidences for respiratory depression following neuraxial morphine in a perioperative setting. Disparity of definitions used for the diagnosis of respiratory depression in the literature precludes identification of the exact incidence of this rare event. The optimal neuraxial opioid dose is a balance between the conflicting demands of providing optimal analgesia while minimizing dose-related adverse effects. Dose-response studies show that neuraxial morphine appears to have an analgesic efficacy 'ceiling'. The optimal 'single-shot' intrathecal dose appears to be 0.075-0.15 mg and the ideal 'single-shot' epidural morphine dose is 2.5-3.75 mg. Analgesic efficacy studies have not been adequately powered to show differences in the incidence of clinically significant respiratory depression. Opioid antagonists such as naloxone to prevent or treat opioid-induced respiratory depression have a number of limitations. Researchers have recently focused on non-opioid drugs such as serotonin receptor agonists. Early evidence suggests that ampakine (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid [AMPA]) receptor modulators may be effective at reducing opioid-induced respiratory depression while maintaining analgesia. Sodium/proton exchanger type 3 (NHE3) inhibitors, which act centrally on respiratory pathways, also warrant further study. [PUBLICATION ABSTRACT]

Morphine is a drug commonly administered via the epidural or intrathecal route, and is regarded by many as the ‘gold-standard’ single-dose neuraxial opioid due to its postoperative analgesic efficacy and prolonged duration of action. However, respiratory depression is a recognized side effect of neuraxial morphine administered in the perioperative setting. We conducted an extensive review of articles published since 1945 that examine respiratory depression or failure associated with perioperative intrathecal or epidural morphine use. Respiratory depression was previously thought to result from the interaction of opioid in the cerebrospinal fluid with ventral medullary opioid receptors. More recently, the preBötzinger complex located in the medulla has been identified as the site responsible for the decrease in respiratory rate following systemic administration of opioids. Neurons in the preBötzinger complex expressing neurokinin-1 receptors are selectively inhibited by opioids, and therefore are the mediators of opioid-induced respiratory depression. Epidural, intrathecal and plasma pharmacokinetics of opioids are complex, vary between neuraxial compartments, and can even differ within the epidural space itself depending upon level of insertion. Caution should be exercised when prescribing systemic opioids (intravenous or oral) in addition to neuraxial morphine as this can compound the potential for early or delayed respiratory depression. There is a wide range of incidences for respiratory depression following neuraxial morphine in a perioperative setting. Disparity of definitions used for the diagnosis of respiratory depression in the literature precludes identification of the exact incidence of this rare event. The optimal neuraxial opioid dose is a balance between the conflicting demands of providing optimal analgesia while minimizing dose-related adverse effects. Dose-response studies show that neuraxial morphine appears to have an analgesic efficacy ‘ceiling’. The optimal ‘single-shot’ intrathecal dose appears to be 0.075–0.15mg and the ideal ‘single-shot’ epidural morphine dose is 2.5–3.75mg. Analgesic efficacy studies have not been adequately powered to show differences in the incidence of clinically significant respiratory depression. Opioid antagonists such as naloxone to prevent or treat opioid-induced respiratory depression have a number of limitations. Researchers have recently focused on non-opioid drugs such as serotonin receptor agonists. Early evidence suggests that ampakine (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid [AMPA]) receptor modulators may be effective at reducing opioid-induced respiratory depression while maintaining analgesia. Sodium/proton exchanger type 3 (NHE3) inhibitors, which act centrally on respiratory pathways, also warrant further study.

This is an exploratory case study that explored service-learning experiences and perceptions among Latinas enrolled in a South Texas university. This study also addresses the challenges and benefits that are associated with Latinas and service-learning in higher education as service providers. This study provides a better understanding of Latina students' experiences and perceptions of their involvement in providing services within their Latino community.

PE and PE_PGRS are two mycobateria-restricted multigene families encoding membrane associated and secreted proteins that have expanded mainly in the pathogenic species, notably the Mycobacterium tuberculosis complex (MTBC). Several lines of evidence attribute to PE and PE_PGRS genes critical roles in mycobacterial pathogenicity. To get more insight into the nature of these genes, we sought to address their evolutionary trajectories in the group of smooth tubercle bacilli (STB), the putative ancestor of the clonal MTBC. By focussing on six polymorphic STB PE/PE_PGRS genes, we demonstrate significant incongruence among single gene genealogies and detect strong signals of recombination using various approaches. Coalescent-based estimation of population recombination and mutation rates (ρ and θ, respectively) indicates that the two mechanisms are of roughly equal importance in generating diversity (ρ/θ = 1.457), a finding in a marked contrast to house keeping genes (HKG) whose evolution is chiefly brought about by mutation (ρ/θ = 0.012). In comparison to HKG, we found 15 times higher mean rate of nonsynonymous substitutions, with strong evidence of positive selection acting on PE_PGRS62 (dN/dS = 1.42), a gene that has previously been shown to be essential for mycobacterial survival in macrophages and granulomas. Imprint of positive selection operating on specific amino acid residues or along branches of PE_PGRS62 phylogenetic tree was further demonstrated using maximum likelihood- and covarion-based approaches, respectively. Strikingly, PE_PGR62 proved highly conserved in present-day MTBC strains. Overall the data indicate that, in STB, PE/PE_PGRS genes have undergone a strong diversification process that is speeded up by recombination, with evidence of positive selection. The finding that positive selection involved an essential PE_PGRS gene whose sequence appears to be driven to fixation in present-day MTBC strains lends further support to the critical role of PE/PE_PGRS genes in the evolution of mycobacterial pathogenicity.

The contribution of horizontal gene transfer (HGT) to the evolution of Mycobacterium tuberculosis--the main causal agent of tuberculosis in humans--and closely related members of the M. tuberculosis complex remains poorly understood. Using a combination of genome-wide parametric analyses, we have identified 48 M. tuberculosis chromosomal regions with atypical characteristics, potentially due to HGT. These specific regions account for 4.5% of the genome (199 kb) and include 256 genes. Many display features typical of the genomic islands found in other bacteria, including residual material from mobile genetic elements, flanking direct repeats, insertion in the vicinity of tRNA sequences, and genes with putative or documented virulence functions. Southern blotting analysis of nine of these 48 regions confirmed their presence in \"Mycobacterium prototuberculosis,\" the ancestral species of the M. tuberculosis complex. Finally, our results strongly suggest that the ancestor of the tubercle bacilli was an environmental bacillus that exchanged genetic material with other bacterial species, including Proteobacteria in particular, present in its surroundings. This study describes a rational approach to searching for mycobacterial virulence genes, and highlights the importance of dissecting gene transfer networks to improve our understanding of mycobacterial pathogenicity and evolution. [PUBLICATION ABSTRACT]

Global spread and genetic monomorphism are hallmarks of Mycobacterium tuberculosis, the agent of human tuberculosis. In contrast, Mycobacterium canettii, and related tubercle bacilli that also cause human tuberculosis and exhibit unusual smooth colony morphology, are restricted to East-Africa. Here, we sequenced and analyzed the genomes of five representative strains of smooth tubercle bacilli (STB) using Sanger (4-5x coverage), 454/Roche (13-18x coverage) and/or Illumina DNA sequencing (45-105x coverage). We show that STB are highly recombinogenic and evolutionary early-branching, with larger genome sizes, 25-fold more SNPs, fewer molecular scars and distinct CRISPR-Cas systems relative to M. tuberculosis. Despite the differences, all tuberculosis-causing mycobacteria share a highly conserved core genome. Mouse-infection experiments revealed that STB are less persistent and virulent than M. tuberculosis. We conclude that M. tuberculosis emerged from an ancestral, STB-like pool of mycobacteria by gain of persistence and virulence mechanisms and we provide genome-wide insights into the molecular events involved.