Updated model of group A Streptococcus M proteins based on a comprehensive worldwide study

Group A Streptococcus (GAS) M protein is an important virulence factor and potential vaccine antigen, and constitutes the basis for strain typing (emm-typing). Although >200 emm-types are characterized, structural data were obtained from only a limited number of emm-types. We aim to evaluate the sequence diversity of near-full-length M proteins from worldwide sources and analyse their structure, sequence conservation and classification. GAS isolates recovered from throughout the world during the last two decades underwent emm-typing and complete emm gene sequencing. Predicted amino acid sequence analyses, secondary structure predictions and vaccine epitope mapping were performed using MUSCLE and Geneious software. A total of 1086 isolates from 31 countries were analysed, representing 175 emm-types. emm-type is predictive of the whole protein structure, independent of geographical origin or clinical association. Findings of an emm-type paired with multiple, highly divergent central regions were not observed. M protein sequence length, the presence or absence of sequence repeats and predicted secondary structure were assessed in the context of the latest vaccine developments. Based on these global data, the M6 protein model is updated to a three representative M protein (M5, M80 and M77) model, to aid in epidemiological analysis, vaccine development and M protein-related pathogenesis studies.     

Enhanced solar photothermal effect of PANi fabrics with plasmonic nanostructures

The photothermal energy conversion in hanging and floating polyaniline (PANi)-cotton fabrics is investigated using a model based on the heat diffusion equation. Perfect absorption and anti-reflection of wet hanging PANi-cotton fabrics cause quick transfer of total incident light into water confining nearly 100% of the sunlight. As a result, a hanging membrane is found to have more attractive properties than a floating above water fabric. We find, however, that the photothermal properties of a floating PANi-cotton membrane can greatly be enhanced by dispersing TiN nanoparticles in the water below the fabric. The calculated temperature gradients for TiN nanoparticle solutions show that the absorbed energy grows with increasing the nanoparticle density and that the photothermal process occurs mostly near the surface. The collective heating effects depend on the size and density of nanoparticles, which can further be used to modulate the photothermal process.

The photothermal energy conversion in hanging and floating polyaniline (PANi)-cotton fabrics is investigated using a model based on the heat diffusion equation.     

In vitro activities and spectrum of lascufloxacin（KRP-AM1977）against anaerobes

The in vitro antibacterial spectra and activities of five antimicrobial agents, including lascufloxacin (LSFX) and two quinolones, were investigated against 69 species of anaerobes in 31 genera and 188 strains in 9 genera, respectively.In this study, minimum inhibitory concentrations (MICs) of lascufloxacin against the reference strains associated with respiratory and head and neck infections. LSFX inhibited the growth of 33 gram-positive and gram-negative reference strains at ≤0.015–2 μg/mL, except for Leptotrichia buccalis. MICs ranges of LSFX against the clinical isolates of 44 Porphyromonas spp., 45 Prevotella spp., 25 Fusobacterium spp., 7 Leptotrichia spp., 25 Parvimonas micra, 25 other gram-positive anaerobic cocci, and 17 Veillonella spp., were ≤0.015–4, 0.125–4, 0.06–0.5, 2, 0.25–16, ≤0.015–2, ≤0.015–16 μg/mL, respectively.LSFX demonstrated potent antibacterial efficacy against a wide range of species isolated from specimens involved in respiratory as well as head and neck infections.     

Indicators of early research productivity among primary care fellows

OBJECTIVE: Little is known about the impact of fellowship training in primary care on subsequent research productivity. Our goal was to identify characteristics of research fellows and their training associated with subsequent publications and research funding. DESIGN: Mail survey in 1998. SETTING AND PARTICIPANTS: 1988-1997 graduates of 25 National Research Service Award primary care research fellowships in the United States. OUTCOME MEASURES: 1) Publishing 1 or more papers per year since the beginning of fellowship, or 2) serving as principal investigator (PI) on a federal or non-federal grant. RESULTS: One hundred forty-six of two hundred fifteen program graduates (68%) completed the survey. The median age was 38 years, and 51% were male. Thirty-two percent had published 1 or more papers per year, and 44% were PIs. Male gender (odds ratio [OR], 3.6; 95% confidence interval [95% CI], 1.4 to 9.2), self-reported allocation of 40% or more of fellowship time to research (OR, 4.4; 95% CI, 1.8 to 11.2), and having an influential mentor during fellowship (OR, 5.0; 95% CI, 1.5 to 17.2) were independently associated with publishing 1 or more papers per year. Fellows with funding as a PI were also more likely to have an influential mentor (OR, 3.0; 95% CI, 1.3 to 7.2). CONCLUSION: Primary care fellows who had influential mentors were more productive in research early after fellowship. Awareness of the indicators of early research success can inform the policies of agencies that fund research training and the curricula of training programs themselves.     

Musashi2 sustains the mixed-lineage leukemia–driven stem cell regulatory program

Leukemia stem cells (LSCs) are found in most aggressive myeloid diseases and contribute to therapeutic resistance. Leukemia cells exhibit a dysregulated developmental program as the result of genetic and epigenetic alterations. Overexpression of the RNA-binding protein Musashi2 (MSI2) has been previously shown to predict poor survival in leukemia. Here, we demonstrated that conditional deletion of Msi2 in the hematopoietic compartment results in delayed leukemogenesis, reduced disease burden, and a loss of LSC function in a murine leukemia model. Gene expression profiling of these Msi2-deficient animals revealed a loss of the hematopoietic/leukemic stem cell self-renewal program and an increase in the differentiation program. In acute myeloid leukemia patients, the presence of a gene signature that was similar to that observed in Msi2-deficent murine LSCs correlated with improved survival. We determined that MSI2 directly maintains the mixed-lineage leukemia (MLL) self-renewal program by interacting with and retaining efficient translation of Hoxa9, Myc, and Ikzf2 mRNAs. Moreover, depletion of MLL target Ikzf2 in LSCs reduced colony formation, decreased proliferation, and increased apoptosis. Our data provide evidence that MSI2 controls efficient translation of the oncogenic LSC self-renewal program and suggest MSI2 as a potential therapeutic target for myeloid leukemia.     

Health literacy and diabetic foot ulcer healing

The adherence by patients to diabetic foot ulcer therapy is often difficult. The goal of this study was to begin to understand how a patient's health literacy affects their foot ulcer management decisions. Initially using a cross‐sectional study design, we evaluated diabetics with foot ulcers within 4 weeks of being asked to participate in a longitudinal study. We assessed health literacy using measures of general health literacy, diabetes health literacy, diabetes self‐efficacy, and diabetes numeracy. Individuals enrolled in the study had higher health literacy based on the Short Test of Functional Health Literacy in Adults [33.8 (SD 2.3) versus 27.3 (SD 9.6); p = 0.009] as compared to individuals who previously declined an invitation to enroll in the study. Furthermore, patients with lower Short Test of Functional Health Literacy in Adults scores had larger (p = 0.04) and older (p = 0.125) wounds (markers for poorer prognosis). Other measures of literacy showed similar results. In conclusion, those with diminished health literacy were less likely to enroll in an investigational study and had wounds that were less likely to heal.     

Usefulness of transthoracic echocardiography in demonstrating coronary blood flow after coronary artery bypass grafting

In this pilot study, we used transthoracic echocardiography to measure coronary sinus blood flow in 15 patients before and after coronary artery bypass grafting. Coronary sinus blood flow before and after revascularization was 274 +/- 95 and 451 +/- 102 ml/min, respectively (p <0.001). This finding is consistent with those previously demonstrated by invasive techniques.     

Effect of antituberculosis drug resistance on response to treatment and outcome in adults with tuberculous meningitis

BACKGROUND: Tuberculous meningitis (TBM) caused by Mycobacterium tuberculosis resistant to 1 or more antituberculosis drugs is an increasingly common clinical problem, although the impact on outcome is uncertain. METHODS: We performed a prospective study of 180 Vietnamese adults admitted consecutively for TBM. M. tuberculosis was cultured from the cerebrospinal fluid (CSF) of all patients and was tested for susceptibility to first-line antituberculosis drugs. Presenting clinical features, time to CSF bacterial clearance, clinical response to treatment, and 9-month morbidity and mortality were compared between adults infected with susceptible and those infected with drug-resistant organisms. RESULTS: Of 180 isolates, 72 (40.0%) were resistant to at least 1 antituberculosis drug, and 10 (5.6%) were resistant to at least isoniazid and rifampicin. Isoniazid and/or streptomycin resistance was associated with slower CSF bacterial clearance but not with any differences in clinical response or outcome. Combined isoniazid and rifampicin resistance was strongly predictive of death (relative risk of death, 11.63 [95% confidence interval, 5.21-26.32]) and was independently associated with human immunodeficiency virus infection. CONCLUSIONS: Isoniazid and/or streptomycin resistance probably has no detrimental effect on the outcome of TBM when patients are treated with first-line antituberculosis drugs, but combined isoniazid and rifampicin resistance is strongly predictive of death.     

Evaluation of Gallium Citrate Formulations against a Multidrug-Resistant Strain of Klebsiella pneumoniae in a Murine Wound Model of Infection

Skin and soft tissue infections (SSTIs) are a common occurrence in health care facilities with a heightened risk for immunocompromised patients. Klebsiella pneumoniae has been increasingly implicated as the bacterial agent responsible for SSTIs, and treatment can be challenging as more strains become multidrug resistant (MDR). Therefore, new treatments are needed to counter this bacterial pathogen. Gallium complexes exhibit antimicrobial activity and are currently being evaluated as potential treatment for bacterial infections. In this study, we tested a topical formulation containing gallium citrate (GaCi) for the treatment of wounds infected with K. pneumoniae. First, the MIC against K. pneumoniae ranged from 0.125 to 2.0 μg/ml GaCi. After this in vitro efficacy was established, two topical formulations with GaCi (0.1% [wt/vol] and 0.3% [wt/vol]) were tested in a murine wound model of MDR K. pneumoniae infection. Gross pathology and histopathology revealed K. pneumoniae-infected wounds appeared to close faster with GaCi treatment and were accompanied by reduced inflammation compared to those of untreated controls. Similarly, quantitative indications of infection remediation, such as reduced weight loss and wound area, suggested that treatment improved outcomes compared to those of untreated controls. Bacterial burdens were measured 1 and 3 days following inoculation, and a 0.5 to 1.5 log reduction of CFU was observed. Lastly, upon scanning electron microscopy analysis, GaCi treatment appeared to prevent biofilm formation on dressings compared to those of untreated controls. These results suggest that with more preclinical testing, a topical application of GaCi may be a promising alternative treatment strategy for K. pneumoniae SSTI.