Selected acute phase CSF factors in ischemic stroke: findings and prognostic value

<p>Abstract</p> <p>Background</p> <p>Study aimed at investigation of pathogenic role and prognostic value of several selected cerebrospinal fluid acute phase factors that can reflect the severity of ischemic brain damage.</p> <p>Methods</p> <p>Ninety five acute ischemic stroke patients were investigated. Ischemic region visualized at the twenty fourth hour by conventional Magnetic Resonance Imaging. Stroke severity evaluated by National Institute Health Stroke Scale. One month outcome of disease was assessed by Barthel Index. Cerebrospinal fluid was taken at the sixth hour of stroke onset. CSF pro- and anti-inflammatory cytokines were studied by Enzyme Linked Immunosorbent Assay. Nitric Oxide and Lipoperoxide radical were measured by Electron Paramagnetic Resonance. CSF Nitrate levels were detected using the Griess reagent. Statistics performed by SPSS-11.0.</p> <p><b>Results</b></p> <p>At the sixth hour of stroke onset, cerebrospinal fluid cytokine levels were elevated in patients against controls. Severe stroke patients had increased interleukin-6 content compared to less severe strokes (P < 0.05). Cerebrospinal fluid Electron Paramagnetic Resonance signal of nitric oxide was increased in patients against controls. Severe stroke group had an elevated Electron Paramagnetic Resonance signal of lipoperoxiradical compared to less severe stroke. Cerebrospinal fluid nitrate levels in less severe stroke patients were higher than those for severe stroke and control. Positive correlation was established between the initial interleukin-6 content and ischemic lesion size as well as with National Institute Health Stroke Scale score on the seventh day. Initial interleukin-6 and nitrate levels in cerebrospinal fluid found to be significant for functional outcome of stroke at one month.</p> <p><b>Conclusion</b></p> <p>According to present study the cerebrospinal fluid contents of interleukin-6 and nitrates seem to be the most reliable prognostic factors in acute phase of ischemic stroke.</p

Drug Repurposing: Far Beyond New Targets for Old Drugs

Repurposing drugs requires finding novel therapeutic indications compared to the ones for which they were already approved. This is an increasingly utilized strategy for finding novel medicines, one that capitalizes on previous investments while derisking clinical activities. This approach is of interest primarily because we continue to face significant gaps in the drug–target interactions matrix and to accumulate safety and efficacy data during clinical studies. Collecting and making publicly available as much data as possible on the target profile of drugs offer opportunities for drug repurposing, but may limit the commercial applications by patent applications. Certain clinical applications may be more feasible for repurposing than others because of marked differences in side effect tolerance. Other factors that ought to be considered when assessing drug repurposing opportunities include relevance to the disease in question and the intellectual property landscape. These activities go far beyond the identification of new targets for old drugs

Recombinant Trimeric HA Protein Immunogenicity of H5N1 Avian Influenza Viruses and Their Combined Use with Inactivated or Adenovirus Vaccines

[[abstract]]Background:The highly pathogenic avian influenza (HPAI) H5N1 virus continues to cause disease in poultry and humans. The hemagglutinin (HA) envelope protein is the primary target for subunit vaccine development.Methodology/Principal Findings:We used baculovirus-insect cell expression to obtain trimeric recombinant HA (rHA) proteins from two HPAI H5N1 viruses. We investigated trimeric rHA protein immunogenicity in mice via immunizations, and found that the highest levels of neutralizing antibodies resulted from coupling with a PELC/CpG adjuvant. We also found that the combined use of trimeric rHA proteins with (a) an inactivated H5N1 vaccine virus, or (b) a recombinant adenovirus encoding full-length HA sequences for prime-boost immunization, further improved antibody responses against homologous and heterologous H5N1 virus strains. Data from cross-clade prime-boost immunization regimens indicate that sequential immunization with different clade HA antigens increased antibody responses in terms of total IgG level and neutralizing antibody titers.Conclusion/Significance:Our findings suggest that the use of trimeric rHA in prime-boost vaccine regimens represents an alternative strategy for recombinant H5N1 vaccine development

Trapping virtual pores by crystal retro-engineering

Stable guest-free porous molecular crystals are uncommon. By contrast, organic molecular crystals with guest-occupied cavities are frequently observed, but these cavities tend to be unstable and collapse on removal of the guests—this feature has been referred to as ‘virtual porosity’. Here, we show how we have trapped the virtual porosity in an unstable low-density organic molecular crystal by introducing a second molecule that matches the size and shape of the unstable voids. We call this strategy ‘retro-engineering’ because it parallels organic retrosynthetic analysis, and it allows the metastable two-dimensional hexagonal pore structure in an organic solvate to be trapped in a binary cocrystal. Unlike the crystal with virtual porosity, the cocrystal material remains single crystalline and porous after removal of guests by heating

Evaluation of invasive and non-invasive methods for the diagnosis of Helicobacter pylori infection in symptomatic children and adolescents

CONTEXT: Multiple diagnostic methods are available for the detection of Helicobacter pylori infection, but at present no single one can be used as the gold standard. OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy of 3 invasive and 2 non-invasive methods for detection of Helicobacter pylori infection in symptomatic children and adolescents. DESIGN: Prospective cohort study SETTING: Peptic Disease outpatients service, Discipline of Pediatric Gastroenterology, Universidade Federal de São Paulo (UNIFESP) / Escola Paulista de Medicina. PATIENTS: Forty-seven patients who underwent endoscopy because of dyspeptic symptoms. DIAGNOSTIC METHODS: Endoscopy with gastric biopsies for 3 invasive (rapid urease test, histology and culture) and 2 non-invasive methods (a commercial ELISA serology and 13carbon urea breath test - isotope ratio mass spectrometry) for detection of Helicobacter pylori infection. MAIN MEASUREMENTS: Sensitivity, specificity, positive and negative predictive values of each method and agreement and disagreement rates between the methods. RESULTS: Forty-seven patients [mean age, 11y9mo (SD 2y10mo), 27 female and 20 male]; 62% of them were Helicobacter pylori-positive. All methods agreed in 61%, and were negative in 21% and positive in 40%. The greatest concordance between 2 methods occurred between the invasive methods: histology and rapid urease test (89.6%) and histology and culture (87.5%). The greatest sensitivity, considering Helicobacter pylori-positive cases, for any combination of 3 or more tests, was achieved by the rapid urease test (S=100%), followed by histology, serology and 13carbon-urea breath test (S=93.1%) and lastly by culture (S=79.3%). The highest specificity was obtained by histology (100%) and culture (100%), followed by the rapid urease test (84.2%), serology (78.9%) and 13carbon-urea breath test (78.9%). CONCLUSIONS: Our results suggest that among invasive methods, an association between the rapid urease test and histology constituted the best choice for the detection of Helicobacter pylori infection. If results of histology and the rapid urease test are different, serology may be recommended.CONTEXTO: Vários métodos diagnósticos estão disponíveis para a detecção da infecção por Helicobacter pylori (Hp), porém, até o presente momento, não há um teste que possa ser utilizado isoladamente como padrão-ouro. OBJETIVO: Avaliar a acurácia de três métodos invasivos e dois não-invasivos na detecção da infecção por Hp em crianças e adolescentes sintomáticos. TIPO DE ESTUDO: Estudo coorte prospectivo. LOCAL: Ambulatório de Doença Péptica, Disciplina de Gastroenterologia Pediátrica, Universidade Federal de São Paulo (UNIFESP) / Escola Paulista de Medicina. PACIENTES: 47 pacientes sintomáticos que realizaram exame endoscópico devido a sintomas dispépticos. MÉTODOS DIAGNÓSTICOS: Exame endoscópico com biopsias gástricas para três métodos invasivos (teste rápido da urease, histologia e cultura) e dois métodos não-invasivos (teste sorológico ELISA industrializado e teste respiratório com uréia marcada com Carbono13). VARIÁVEIS ESTUDADAS: Sensibilidade, especificidade, valor preditivo positivo e negativo de cada método e taxas de concordância e discordância entre os métodos. RESULTADOS: 47 pacientes [idade média de 11a9m (DP 2a10m), 27 do sexo feminino e 20 do masculino], 62% deles com infecção por Hp. Todos os 5 métodos concordaram em 61%, sendo negativo em 21% e positivo em 40%. As maiores concordâncias entre dois métodos ocorreram entre os métodos invasivos: histologia e teste rápido da urease (89,6%) e entre a histologia e cultura (87,5%). A maior sensibilidade, considerando como Hp positivo, qualquer combinação de 3 ou mais testes, foi encontrada no teste rápido da urease (S=100%), seguido pela histologia, sorologia e o teste respiratório com uréia marcada com Carbono13 (S=93,1%) e por fim a cultura (S=79,3%). A maior especificidade foi obtida pela histologia e cultura (100%), seguidos pelo teste rápido da urease (84,2%), sorologia (78,9%) e teste respiratório com uréia marcada com Carbono13 (78,9%). CONCLUSÕES: Nossos resultados sugerem que, entre os métodos invasivos, a associação do teste rápido da urease e histologia constituem a melhor escolha para a detecção da infecção por Hp. Se os resultados da histologia e do teste rápido da urease forem discordantes é recomendada a sorologia.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Pediatric DepartmentUNIFESP, EPM, Pediatric DepartmentSciEL

"I am nothing": experiences of loss among women suffering from severe birth injuries in Tanzania

\ud Despite the increased attention on maternal mortality during recent decades, which has resulted in maternal health being defined as a Millennium Development Goal (MDG), the disability and suffering from obstetric fistula remains a neglected issue in global health. Continuous leaking of urine and the physical, emotional and social suffering associated with it, has a profound impact on women's quality of life. This study seeks to explore the physical, cultural and psychological dimensions of living with obstetric fistula, and demonstrate how these experiences shape the identities of women affected by the condition. A cross-sectional study with qualitative and quantitative components was used to explore the experiences of Tanzanian women living with obstetric fistula and those of their husbands. The study was conducted at the Comprehensive Community Based Rehabilitation Tanzania hospital in Dar es Salaam, Bugando Medical Centre in Mwanza, and Mpwapwa district, in Dodoma region. Conveniently selected samples of 16 women were interviewed, and 151 additional women responded to a questionnaire. In addition, 12 women affected by obstetric fistula and six husbands of these affected women participated in a focus group discussions. Data were analysed using content data analysis framework and statistical package for the social sciences (SPSS) version 15 for Microsoft windows. The study revealed a deep sense of loss. Loss of body control, loss of the social roles as women and wives, loss of integration in social life, and loss of dignity and self-worth were located at the core of these experiences. The women living with obstetric fistula experience a deep sense of loss that had negative impact on their identity and quality of life. Acknowledging affected women's real-life experiences is important in order to understand the occurrence and management of obstetric fistula, as well as prospects after treatment. This knowledge will help to improve women's sense of self-worth and maintain their identity as women, wives, friends and community members. Educational programmes to empower women socially and economically and counselling of families of women living with obstetric fistula may help these women receive medical and social support that is necessary.\u

c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression

Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to SMURF2 targeting the TGFβ receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFβ signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFβ receptor stabilisation. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. In vivo we show that TGFβ receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFβ and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers

A high-order FEM formulation for free and forced vibration analysis of a nonlocal nonlinear graded Timoshenko nanobeam based on the weak form quadrature element method

The purpose of this paper is to provide a high-order finite element method (FEM) formulation of nonlocal nonlinear nonlocal graded Timoshenko based on the weak form quadrature element method (WQEM). This formulation offers the advantages and flexibility of the FEM without its limiting low-order accuracy. The nanobeam theory accounts for the von Kármán geometric nonlinearity in addition to Eringen’s nonlocal constitutive models. For the sake of generality, a nonlinear foundation is included in the formulation. The proposed formulation generates high-order derivative terms that cannot be accounted for using regular first- or second-order interpolation functions. Hamilton’s principle is used to derive the variational statement which is discretized using WQEM. The results of a WQEM free vibration study are assessed using data obtained from a similar problem solved by the differential quadrature method (DQM). The study shows that WQEM can offer the same accuracy as DQM with a reduced computational cost. Currently the literature describes a small number of high-order numerical forced vibration problems, the majority of which are limited to DQM. To obtain forced vibration solutions using WQEM, the authors propose two different methods to obtain frequency response curves. The obtained results indicate that the frequency response curves generated by either method closely match their DQM counterparts obtained from the literature, and this is despite the low mesh density used for the WQEM systems

Gene discovery in EST sequences from the wheat leaf rust fungus Puccinia triticina sexual spores, asexual spores and haustoria, compared to other rust and corn smut fungi

© 2011 Xu et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.DOI: 10.1186/1471-2164-12-161Background.Rust fungi are biotrophic basidiomycete plant pathogens that cause major diseases on plants and trees world-wide, affecting agriculture and forestry. Their biotrophic nature precludes many established molecular genetic manipulations and lines of research. The generation of genomic resources for these microbes is leading to novel insights into biology such as interactions with the hosts and guiding directions for breakthrough research in plant pathology. Results. To support gene discovery and gene model verification in the genome of the wheat leaf rust fungus, Puccinia triticina (Pt), we have generated Expressed Sequence Tags (ESTs) by sampling several life cycle stages. We focused on several spore stages and isolated haustorial structures from infected wheat, generating 17,684 ESTs. We produced sequences from both the sexual (pycniospores, aeciospores and teliospores) and asexual (germinated urediniospores) stages of the life cycle. From pycniospores and aeciospores, produced by infecting the alternate host, meadow rue (Thalictrum speciosissimum), 4,869 and 1,292 reads were generated, respectively. We generated 3,703 ESTs from teliospores produced on the senescent primary wheat host. Finally, we generated 6,817 reads from haustoria isolated from infected wheat as well as 1,003 sequences from germinated urediniospores. Along with 25,558 previously generated ESTs, we compiled a database of 13,328 non-redundant sequences (4,506 singlets and 8,822 contigs). Fungal genes were predicted using the EST version of the self-training GeneMarkS algorithm. To refine the EST database, we compared EST sequences by BLASTN to a set of 454 pyrosequencing-generated contigs and Sanger BAC-end sequences derived both from the Pt genome, and to ESTs and genome reads from wheat. A collection of 6,308 fungal genes was identified and compared to sequences of the cereal rusts, Puccinia graminis f. sp. tritici (Pgt) and stripe rust, P. striiformis f. sp. tritici (Pst), and poplar leaf rust Melampsora species, and the corn smut fungus, Ustilago maydis (Um). While extensive homologies were found, many genes appeared novel and species-specific; over 40% of genes did not match any known sequence in existing databases. Focusing on spore stages, direct comparison to Um identified potential functional homologs, possibly allowing heterologous functional analysis in that model fungus. Many potentially secreted protein genes were identified by similarity searches against genes and proteins of Pgt and Melampsora spp., revealing apparent orthologs. Conclusions. The current set of Pt unigenes contributes to gene discovery in this major cereal pathogen and will be invaluable for gene model verification in the genome sequence