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Sample records for clinically relevant subtypes

  1. Histological subtypes of solitary pulmonary nodules of adenocarcinoma and their clinical relevance

    PubMed Central

    Hu, Hui-Di; Wan, Ming-Yue; Xu, Chun-Hua; Zhan, Ping; Zou, Jue; Zhang, Qian-Qian

    2013-01-01

    Objective To explore the histological subtypes of solitary pulmonary nodules (SPNs) of invasive adenocarcinoma and their clinical relevance. Methods A total of 188 patients with pathologically confirmed invasive adenocarcinoma in our hospital from January 2007 to December 2011 were enrolled in this study. In accordance with the new classification of lung adenocarcinoma, all the histological sections were reviewed and classified, and the clinical data were collected and analyzed. Results Of these 188 patients who had been initially diagnosed as SPNs of adenocarcinoma, there were 6 cases of lepidic predominant adenocarcinoma (LPA), 71 cases of acinar predominant adenocarcinoma (APA), 74 cases of papillary predominant adenocarcinoma (PPA), 15 cases of micorpapillary predominant adenocarcinoma (MPA), and 22 cases of solid predominant adenocarcinoma (SPA) with mucin production. The incidence of lymph node metastasis was 80.0% and 81.8% in MPA and SPA, respectively, which was significantly higher than those in LPA, APA, and PPA (all P<0.01). The incidence of LPA was 83.3% (5/6) in women, which was significantly higher than that in men (P=0.037). Conclusions According to the new classification, MPA and SPA have high incidence of lymph node metastasis. LPA is more likely to occur in women. Sub-typing of the lung adenocarcinoma based on the newest international classification criteria is helpful to identify the clinical features of this disease. PMID:24409363

  2. Head and neck cancer subtypes with biological and clinical relevance: Meta-analysis of gene-expression data.

    PubMed

    De Cecco, Loris; Nicolau, Monica; Giannoccaro, Marco; Daidone, Maria Grazia; Bossi, Paolo; Locati, Laura; Licitra, Lisa; Canevari, Silvana

    2015-04-20

    Head and neck squamous cell carcinoma (HNSCC) is a disease with heterogeneous clinical behavior and response to therapies. Despite the introduction of multimodality treatment, 40-50% of patients with advanced disease recur. Therefore, there is an urgent need to improve the classification beyond the current parameters in clinical use to better stratify patients and the therapeutic approaches. Following a meta-analysis approach we built a large training set to whom we applied a Disease-Specific Genomic Analysis (DSGA) to identify the disease component embedded into the tumor data. Eleven independent microarray datasets were used as validation sets. Six different HNSCC subtypes that summarize the aberrant alterations occurring during tumor progression were identified. Based on their main biological characteristics and de-regulated signaling pathways, the subtypes were designed as immunoreactive, inflammatory, human papilloma virus (HPV)-like, classical, hypoxia associated, and mesenchymal. Our findings highlighted a more aggressive behavior for mesenchymal and hypoxia-associated subtypes. The Genomics Drug Sensitivity Project was used to identify potential associations with drug sensitivity and significant differences were observed among the six subtypes. To conclude, we report a robust molecularly defined subtype classification in HNSCC that can improve patient selection and pave the way to the development of appropriate therapeutic strategies. PMID:25821127

  3. Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1

    SciTech Connect

    Verhaak, Roel GW; Hoadley, Katherine A; Purdom, Elizabeth; Wang, Victoria; Qi, Yuan; Wilkerson, Matthew D; Miller, C Ryan; Ding, Li; Golub, Todd; Mesirov, Jill P; Alexe, Gabriele; Lawrence, Michael; O'Kelly, Michael; Tamayo, Pablo; Weir, Barbara A; Gabriel, Stacey; Winckler, Wendy; Gupta, Supriya; Jakkula, Lakshmi; Feiler, Heidi S; Hodgson, J Graeme; James, C David; Sarkaria, Jann N; Brennan, Cameron; Kahn, Ari; Spellman, Paul T; Wilson, Richard K; Speed, Terence P; Gray, Joe W; Meyerson, Matthew; Getz, Gad; Perou, Charles M; Hayes, D Neil; Network, The Cancer Genome Atlas Research

    2009-09-03

    The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.

  4. Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer

    PubMed Central

    Tan, Tuan Zea; Miow, Qing Hao; Huang, Ruby Yun-Ju; Wong, Meng Kang; Ye, Jieru; Lau, Jieying Amelia; Wu, Meng Chu; Bin Abdul Hadi, Luqman Hakim; Soong, Richie; Choolani, Mahesh; Davidson, Ben; Nesland, Jahn M; Wang, Ling-Zhi; Matsumura, Noriomi; Mandai, Masaki; Konishi, Ikuo; Goh, Boon-Cher; Chang, Jeffrey T; Thiery, Jean Paul; Mori, Seiichi

    2013-01-01

    Epithelial ovarian cancer (EOC) is hallmarked by a high degree of heterogeneity. To address this heterogeneity, a classification scheme was developed based on gene expression patterns of 1538 tumours. Five, biologically distinct subgroups — Epi-A, Epi-B, Mes, Stem-A and Stem-B — exhibited significantly distinct clinicopathological characteristics, deregulated pathways and patient prognoses, and were validated using independent datasets. To identify subtype-specific molecular targets, ovarian cancer cell lines representing these molecular subtypes were screened against a genome-wide shRNA library. Focusing on the poor-prognosis Stem-A subtype, we found that two genes involved in tubulin processing, TUBGCP4 and NAT10, were essential for cell growth, an observation supported by a pathway analysis that also predicted involvement of microtubule-related processes. Furthermore, we observed that Stem-A cell lines were indeed more sensitive to inhibitors of tubulin polymerization, vincristine and vinorelbine, than the other subtypes. This subtyping offers new insights into the development of novel diagnostic and personalized treatment for EOC patients. PMID:23666744

  5. High-Resolution Microfluidic Single-Cell Transcriptional Profiling Reveals Clinically Relevant Subtypes among Human Stem Cell Populations Commonly Utilized in Cell-Based Therapies

    PubMed Central

    Rennert, Robert C.; Schäfer, Richard; Bliss, Tonya; Januszyk, Michael; Sorkin, Michael; Achrol, Achal S.; Rodrigues, Melanie; Maan, Zeshaan N.; Kluba, Torsten; Steinberg, Gary K.; Gurtner, Geoffrey C.

    2016-01-01

    Stem cell therapies can promote neural repair and regeneration, yet controversy regarding optimal cell source and mechanism of action has slowed clinical translation, potentially due to undefined cellular heterogeneity. Single-cell resolution is needed to identify clinically relevant subpopulations with the highest therapeutic relevance. We combine single-cell microfluidic analysis with advanced computational modeling to study for the first time two common sources for cell-based therapies, human NSCs and MSCs. This methodology has the potential to logically inform cell source decisions for any clinical application. PMID:27047447

  6. Identification and subtyping of clinically relevant human and ruminant mycoplasmas by use of matrix-assisted laser desorption ionization-time of flight mass spectrometry.

    PubMed

    Pereyre, S; Tardy, F; Renaudin, H; Cauvin, E; Del Prá Netto Machado, L; Tricot, A; Benoit, F; Treilles, M; Bébéar, C

    2013-10-01

    Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) recently emerged as a technology for the identification of bacteria. In this study, we aimed to evaluate its applicability to human and ruminant mycoplasmal identification, which can be demanding and time-consuming when using phenotypic or molecular methods. In addition, MALDI-TOF MS was tested as a subtyping tool for certain species. A total of 29 main spectra (MSP) from 10 human and 13 ruminant mycoplasma (sub)species were included in a mycoplasma MSP database to complete the Bruker MALDI Biotyper database. After broth culture and protein extraction, MALDI-TOF MS was applied for the identification of 119 human and 143 ruminant clinical isolates that were previously identified by antigenic or molecular methods and for subcultures of 73 ruminant clinical specimens that potentially contained several mycoplasma species. MALDI-TOF MS resulted in accurate (sub)species-level identification with a score of ≥1.700 for 96% (251/262) of the isolates. The phylogenetically closest (sub)species were unequivocally distinguished. Although mixtures of the strains were reliably detected up to a certain cellular ratio, only the predominant species was identified from the cultures of polymicrobial clinical specimens. For typing purposes, MALDI-TOF MS proved to cluster Mycoplasma bovis and Mycoplasma agalactiae isolates by their year of isolation and genome profiles, respectively, and Mycoplasma pneumoniae isolates by their adhesin P1 type. In conclusion, MALDI-TOF MS is a rapid, reliable, and cost-effective method for the routine identification of high-density growing mycoplasmal species and shows promising prospects for its capacity for strain typing. PMID:23903545

  7. Development and Validation of a Quantitative PCR Assay Using Multiplexed Hydrolysis Probes for Detection and Quantification of Theileria orientalis Isolates and Differentiation of Clinically Relevant Subtypes

    PubMed Central

    Bogema, D. R.; Deutscher, A. T.; Fell, S.; Collins, D.; Eamens, G. J.

    2015-01-01

    Theileria orientalis is an emerging pathogen of cattle in Asia, Australia, and New Zealand. This organism is a vector-borne hemoprotozoan that causes clinical disease characterized by anemia, abortion, and death, as well as persistent subclinical infections. Molecular methods of diagnosis are preferred due to their sensitivity and utility in differentiating between pathogenic and apathogenic genotypes. Conventional PCR (cPCR) assays for T. orientalis detection and typing are laborious and do not provide an estimate of parasite load. Current real-time PCR assays cannot differentiate between clinically relevant and benign genotypes or are only semiquantitative without a defined clinical threshold. Here, we developed and validated a hydrolysis probe quantitative PCR (qPCR) assay which universally detects and quantifies T. orientalis and identifies the clinically associated Ikeda and Chitose genotypes (UIC assay). Comparison of the UIC assay results with previously validated universal and genotype-specific cPCR results demonstrated that qPCR detects and differentiates T. orientalis with high sensitivity and specificiy. Comparison of quantitative results based on percent parasitemia, determined via blood film analysis and packed cell volume (PCV) revealed significant positive and negative correlations, respectively. One-way analysis of variance (ANOVA) indicated that blood samples from animals with clinical signs of disease contained statistically higher concentrations of T. orientalis DNA than animals with subclinical infections. We propose clinical thresholds to assist in classifying high-, moderate-, and low-level infections and describe how parasite load and the presence of the Ikeda and Chitose genotypes relate to disease. PMID:25588653

  8. An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1

    PubMed Central

    Verhaak, Roel G.W.; Hoadley, Katherine A.; Purdom, Elizabeth; Wang, Victoria; Qi, Yuan; Wilkerson, Matthew D.; Miller, C. Ryan; Ding, Li; Golub, Todd; Mesirov, Jill P.; Alexe, Gabriele; Lawrence, Michael; O’Kelly, Michael; Tamayo, Pablo; Weir, Barbara A.; Gabrie, Stacey; Winckler, Wendy; Gupta, Supriya; Jakkula, Lakshmi; Feiler, Heidi S.; Hodgson, J. Graeme; James, C. David; Sarkaria, Jann N.; Brennan, Cameron; Kahn, Ari; Spellman, Paul T.; Wilson, Richard K.; Speed, Terence P.; Gray, Joe W.; Meyerson, Matthew; Getz, Gad; Perou, Charles M.; Hayes, D. Neil

    2010-01-01

    SUMMARY The Cancer Genome Atlas Network recently catalogued recurrent genomic abnormalities in glioblastoma (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical and Mesenchymal subtypes and integrate multi-dimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define Classical, Mesenchymal, and Proneural, respectively. Gene signatures of normal brain cell types show a strong relation between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype with greatest benefit in Classical and no benefit in Proneural. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies. PMID:20129251

  9. Suicide by cop: clinical risks and subtypes.

    PubMed

    Dewey, Lauren; Allwood, Maureen; Fava, Joanna; Arias, Elizabeth; Pinizzotto, Anthony; Schlesinger, Louis

    2013-01-01

    This study examines whether clinical classification schemes from general suicide research are applicable for cases of suicide by cop (SbC) and whether there are indicators as to why the police might be engaged in the suicide. Using archival law enforcement data, 13 clinical risks were examined among 68 cases of SbC using exploratory factor analysis and k-means cluster analysis. Three subtypes of SbC cases emerged: Mental Illness, Criminality, and Not Otherwise Specified. The subtypes varied significantly on their levels of mental illness, substance use, and criminal activity. Findings suggest that reducing fragmentation between law enforcement and mental health service providers might be a crucial goal for suicide intervention and prevention, at least among cases of SbC. PMID:24224677

  10. Breast cancer intrinsic subtype classification, clinical use and future trends

    PubMed Central

    Dai, Xiaofeng; Li, Ting; Bai, Zhonghu; Yang, Yankun; Liu, Xiuxia; Zhan, Jinling; Shi, Bozhi

    2015-01-01

    Breast cancer is composed of multiple subtypes with distinct morphologies and clinical implications. The advent of microarrays has led to a new paradigm in deciphering breast cancer heterogeneity, based on which the intrinsic subtyping system using prognostic multigene classifiers was developed. Subtypes identified using different gene panels, though overlap to a great extent, do not completely converge, and the avail of new information and perspectives has led to the emergence of novel subtypes, which complicate our understanding towards breast tumor heterogeneity. This review explores and summarizes the existing intrinsic subtypes, patient clinical features and management, commercial signature panels, as well as various information used for tumor classification. Two trends are pointed out in the end on breast cancer subtyping, i.e., either diverging to more refined groups or converging to the major subtypes. This review improves our understandings towards breast cancer intrinsic classification, current status on clinical application, and future trends. PMID:26693050

  11. Cryptosporidium Species and Subtypes and Clinical Manifestations in Children, Peru

    PubMed Central

    Cama, Vitaliano A.; Bern, Caryn; Roberts, Jacqueline; Cabrera, Lilia; Sterling, Charles R.; Ortega, Ynes; Gilman, Robert H.

    2008-01-01

    To determine whether clinical manifestations are associated with genotypes or subtypes of Cryptosporidium spp., we studied a 4-year longitudinal birth cohort of 533 children in Peru. A total of 156 infection episodes were found in 109 children. Data from first infections showed that C. hominis was associated with diarrhea, nausea, vomiting, general malaise, and increased oocyst shedding intensity and duration. In contrast, C. parvum, C. meleagridis, C. canis, and C. felis were associated with diarrhea only. C. hominis subtype families were identified (Ia, Ib, Id, and Ie); all were associated with diarrhea. Ib was also associated with nausea, vomiting, and general malaise. All C. parvum specimens belonged to subtype family IIc. Analysis of risk factors did not show associations with specific Cryptosporidium spp. genotypes or subtypes. These findings strongly suggest that Cryptosporidium spp. and subtypes are linked to different clinical manifestations in children. PMID:18826821

  12. Response to clozapine in a clinically identifiable subtype of schizophrenia

    PubMed Central

    Butcher, Nancy J.; Fung, Wai Lun Alan; Fitzpatrick, Laura; Guna, Alina; Andrade, Danielle M.; Lang, Anthony E.; Chow, Eva W. C.; Bassett, Anne S.

    2015-01-01

    Background Genetic testing in psychiatry promises to improve patient care through advances in personalised medicine. However, there are few clinically relevant examples. Aims To determine whether patients with a well-established genetic subtype of schizophrenia show a different response profile to the antipsychotic clozapine than those with idiopathic schizophrenia. Method We retrospectively studied the long-term safety and efficacy of clozapine in 40 adults with schizophrenia, half with a 22q11.2 deletion (22q11.2DS group) and half matched for age and clinical severity but molecularly confirmed to have no pathogenic copy number variant (idiopathic group). Results Both groups showed similar clinical improvement and significant reductions in hospitalisations, achieved at a lower median dose for those in the 22q11.2DS group. Most common side-effects were similarly prevalent between the two groups, however, half of the 22q11.2DS group experienced at least one rare serious adverse event compared with none of the idiopathic group. Many were successfully retried on clozapine. Conclusions Individuals with 22q11.2DS-schizophrenia respond as well to clozapine treatment as those with other forms of schizophrenia, but may represent a disproportionate number of those with serious adverse events, primarily seizures. Lower doses and prophylactic (for example anticonvulsant) management strategies can help ameliorate side-effect risks. This first systematic evaluation of antipsychotic response in a genetic subtype of schizophrenia provides a proof-of-principle for personalised medicine and supports the utility of clinical genetic testing in schizophrenia. PMID:25745132

  13. The Clinical Utility of Personality Subtypes in Patients with Anorexia Nervosa

    ERIC Educational Resources Information Center

    Wildes, Jennifer E.; Marcus, Marsha D.; Crosby, Ross D.; Ringham, Rebecca M.; Dapelo, Marcela Marin; Gaskill, Jill A.; Forbush, Kelsie T.

    2011-01-01

    Objective: Elucidation of clinically relevant subtypes has been proposed as a means of advancing treatment research, but classifying anorexia nervosa (AN) patients into restricting and binge-eating/purging types has demonstrated limited predictive validity. This study aimed to evaluate whether an approach to classifying eating disorder patients on…

  14. Symptom subtypes of obsessive-compulsive disorder: are they relevant for treatment?

    PubMed

    Starcevic, Vladan; Brakoulias, Vlasios

    2008-08-01

    Several symptom subtypes of obsessive-compulsive disorder (OCD) have been identified on the basis of the predominant obsessions and compulsions. The objectives of the present article were to review the literature on the relationship between OCD symptom subtypes and treatment response and to suggest strategies that might assist with the choice of treatment and improve treatment outcome in patients with various subtypes. An extensive literature search was performed, relevant studies were identified, and their results reported. Overt compulsions were generally associated with a relatively good response to the behaviour therapy technique of exposure and response prevention (ERP) and with poorer response to serotonin re-uptake inhibitors (SRIs). Washing/cleaning and checking compulsions tend to respond well to ERP, whereas the majority of studies show that washing/cleaning compulsions are associated with a poorer response to SRIs. Most studies suggest that patients with the symmetry, ordering and arranging subtype do not fare worse with ERP and SRIs than patients with other symptom subtypes. Some studies suggested that obsessions might respond to SRIs somewhat better than to ERP. In the majority of the studies, hoarding and the subtype characterized by sexual or religious obsessions and absence of overt compulsions ('pure obsessions') have been associated with poor response to ERP and SRIs. It was concluded that treatment strategies cannot be precisely tailored to OCD symptom subtypes. Many other factors influence the outcome of treatment and need to be considered along with the symptom subtypes when making decisions about treatment. While ERP and SRIs remain the mainstay of treatment regardless of the symptom subtype, the addition of cognitive therapy techniques and/or antipsychotic medications may enhance treatment response in the presence of certain features discussed in the article. PMID:18622773

  15. Clinically-inspired automatic classification of ovarian carcinoma subtypes

    PubMed Central

    BenTaieb, Aïcha; Nosrati, Masoud S; Li-Chang, Hector; Huntsman, David; Hamarneh, Ghassan

    2016-01-01

    Context: It has been shown that ovarian carcinoma subtypes are distinct pathologic entities with differing prognostic and therapeutic implications. Histotyping by pathologists has good reproducibility, but occasional cases are challenging and require immunohistochemistry and subspecialty consultation. Motivated by the need for more accurate and reproducible diagnoses and to facilitate pathologists’ workflow, we propose an automatic framework for ovarian carcinoma classification. Materials and Methods: Our method is inspired by pathologists’ workflow. We analyse imaged tissues at two magnification levels and extract clinically-inspired color, texture, and segmentation-based shape descriptors using image-processing methods. We propose a carefully designed machine learning technique composed of four modules: A dissimilarity matrix, dimensionality reduction, feature selection and a support vector machine classifier to separate the five ovarian carcinoma subtypes using the extracted features. Results: This paper presents the details of our implementation and its validation on a clinically derived dataset of eighty high-resolution histopathology images. The proposed system achieved a multiclass classification accuracy of 95.0% when classifying unseen tissues. Assessment of the classifier's confusion (confusion matrix) between the five different ovarian carcinoma subtypes agrees with clinician's confusion and reflects the difficulty in diagnosing endometrioid and serous carcinomas. Conclusions: Our results from this first study highlight the difficulty of ovarian carcinoma diagnosis which originate from the intrinsic class-imbalance observed among subtypes and suggest that the automatic analysis of ovarian carcinoma subtypes could be valuable to clinician's diagnostic procedure by providing a second opinion. PMID:27563487

  16. Lung squamous cell carcinoma mRNA expression subtypes are reproducible, clinically important and correspond to different normal cell types

    PubMed Central

    Wilkerson, Matthew D.; Yin, Xiaoying; Hoadley, Katherine A.; Liu, Yufeng; Hayward, Michele C.; Cabanski, Christopher R.; Muldrew, Kenneth; Miller, C. Ryan; Randell, Scott H.; Socinski, Mark A.; Parsons, Alden M.; Funkhouser, William K.; Lee, Carrie B.; Roberts, Patrick J.; Thorne, Leigh; Bernard, Philip S.; Perou, Charles M.; Hayes, D. Neil

    2010-01-01

    Purpose Lung squamous cell carcinoma (SCC) is clinically and genetically heterogeneous and current diagnostic practices do not adequately substratify this heterogeneity. A robust, biologically-based SCC subclassification may describe this variability and lead to more precise patient prognosis and management. We sought to determine if SCC mRNA expression subtypes exist, are reproducible across multiple patient cohorts, and are clinically relevant. Experimental Design Subtypes were detected by unsupervised consensus clustering in five published discovery cohorts of mRNA microarrays, totaling 382 SCC patients. An independent validation cohort of 56 SCC patients was collected and assayed by microarrays. A nearest-centroid subtype predictor was built using discovery cohorts. Validation cohort subtypes were predicted and evaluated for confirmation. Subtype survival outcome, clinical covariates, and biological processes were compared by statistical and bioinformatic methods. Results Four lung SCC mRNA expression subtypes, named primitive, classical, secretory, and basal, were detected and independently validated (P < 0.001). The primitive subtype had the worst survival outcome (P < 0.05) and is an independent predictor of survival (P < 0.05). Tumor differentiation and patient sex were associated with subtype. The subtypes’ expression profiles contained distinct biological processes (primitive – proliferation, classical – xeniobiotics metabolism, secretory – immune response, basal – cell adhesion) and suggested distinct pharmacologic interventions. Comparison to lung model systems revealed distinct subtype to cell type correspondence. Conclusions Lung SCC consists of four mRNA expression subtypes that have different survival outcomes, patient populations, and biological processes. The subtypes stratify patients for more precise prognosis and targeted research. PMID:20643781

  17. The clinical usefulness of the new LPE specifier for subtyping adolescents with conduct disorder in the DSM 5.

    PubMed

    Jambroes, Tijs; Jansen, Lucres M C; Vermeiren, Robert R J M; Doreleijers, Theo A H; Colins, Olivier F; Popma, Arne

    2016-08-01

    In DSM 5, conduct disorder (CD) has been expanded with a new specifier 'with Limited Prosocial Emotions' (LPE) in addition to the age-of-onset (AoO) subtyping, and is thought to identify a severe antisocial subgroup of CD. However, research in clinical practice has been scarce. Therefore, the current study will examine differences in clinical symptoms between subtypes of CD, based on both subtyping schemes. Subsequently, it will investigate whether the LPE specifier explains unique variance in aggression, added to the AoO subtyping. A sample of 145 adolescents with CD (51 % male, mean age 15.0) from a closed treatment institution participated in this study. CD diagnoses and AoO subtype were assessed using a structured diagnostic interview. The LPE specifier was assessed using the callous-unemotional dimension of the Youth Psychopathy Traits Inventory (YPI). Self-reported proactive and reactive aggression, rule-breaking behavior and internalizing problems within the subtypes were compared. Youth with childhood-onset CD and LPE showed significantly more aggression than adolescent-onset CD without LPE (proactive aggression: F = 3.1, p < 0.05, reactive aggression: F = 3.7, p < 0.05). Hierarchical regression revealed that the LPE specifier uniquely explained 7 % of the variance in reactive aggression, additionally to the AoO subtyping. For proactive aggression, the interaction between AoO and the LPE added 4.5 % to the explained variance. Although the LPE specifier may help to identify a more aggressive subtype of CD in adolescents, the incremental utility seems to be limited. Therefore, clinical relevance of the LPE specifier in high-risk adolescent samples still needs to be investigated thoroughly. PMID:26725044

  18. Psychopathology, trauma and delinquency: subtypes of aggression and their relevance for understanding young offenders

    PubMed Central

    2011-01-01

    Objective To examine the implications of an ontology of aggressive behavior which divides aggression into reactive, affective, defensive, impulsive (RADI) or "emotionally hot"; and planned, instrumental, predatory (PIP) or "emotionally cold." Recent epidemiological, criminological, clinical and neuroscience studies converge to support a connection between emotional and trauma related psychopathology and disturbances in the emotions, self-regulation and aggressive behavior which has important implications for diagnosis and treatment, especially for delinquent populations. Method Selective review of preclinical and clinical studies in normal, clinical and delinquent populations. Results In delinquent populations we observe an increase in psychopathology, and especially trauma related psychopathology which impacts emotions and self-regulation in a manner that hotly emotionally charged acts of aggression become more likely. The identification of these disturbances can be supported by findings in cognitive neuroscience. These hot aggressive acts can be delineated from planned or emotionally cold aggression. Conclusion Our findings support a typology of diagnostic labels for disruptive behaviors, such as conduct disorder and oppositional defiant disorder, as it appears that these acts of hot emotional aggression are a legitimate target for psychopharmacological and other trauma specific interventions. The identification of this subtype of disruptive behavior disorders leads to more specific clinical interventions which in turn promise to improve hitherto unimpressive treatment outcomes of delinquents and patients with disruptive behavior. PMID:21714905

  19. Clinical Relevance of Nontuberculous Mycobacteria, Oman

    PubMed Central

    Al-Mahruqi, Sara H.; Al-Busaidy, Suleiman; Boeree, Martin J.; Al-Zadjali, Samiya; Patel, Arti; Dekhuijzen, P.N. Richard; van Soolingen, Dick

    2009-01-01

    Little is known about the clinical relevance of nontuberculous mycobacteria (NTM) in the Arabian Peninsula. We assessed the prevalence and studied a random sample of isolates at a reference laboratory in Muscat, Oman. NTM cause disease in this region, and their prevalence has increased. PMID:19193276

  20. Clinical Implications of DSM-IV Subtyping of Bipolar Disorders in Referred Children and Adolescents

    ERIC Educational Resources Information Center

    Masi, Gabriele; Perugi, Giulio; Millepiedi, Stefania; Mucci, Maria; Pari, Cinzia; Pfanner, Chiara; Berloffa, Stefano; Toni, Cristina

    2007-01-01

    Objective: According to DSM-IV, bipolar disorders (BDs) include four subtypes, BD I, BD II, cyclothymic disorder, and BD not otherwise specified (NOS). We explore the clinical implications of this subtyping in a naturalistic sample of referred youths with BD I, BD II, and BD-NOS. Method: The sample consisted of 217 patients, 135 males and 82…

  1. Valerian: No Evidence for Clinically Relevant Interactions

    PubMed Central

    Nieber, Karen; Kraft, Karin

    2014-01-01

    In recent popular publications as well as in widely used information websites directed to cancer patients, valerian is claimed to have a potential of adverse interactions with anticancer drugs. This questions its use as a safe replacement for, for example, benzodiazepines. A review on the interaction potential of preparations from valerian root (Valeriana officinalis L. root) was therefore conducted. A data base search and search in a clinical drug interaction data base were conducted. Thereafter, a systematic assessment of publications was performed. Seven in vitro studies on six CYP 450 isoenzymes, on p-glycoprotein, and on two UGT isoenzymes were identified. However, the methodological assessment of these studies did not support their suitability for the prediction of clinically relevant interactions. In addition, clinical studies on various valerian preparations did not reveal any relevant interaction potential concerning CYP 1A2, 2D6, 2E1, and 3A4. Available animal and human pharmacodynamic studies did not verify any interaction potential. The interaction potential of valerian preparations therefore seems to be low and thereby without clinical relevance. We conclude that there is no specific evidence questioning their safety, also in cancer patients. PMID:25093031

  2. Valerian: no evidence for clinically relevant interactions.

    PubMed

    Kelber, Olaf; Nieber, Karen; Kraft, Karin

    2014-01-01

    In recent popular publications as well as in widely used information websites directed to cancer patients, valerian is claimed to have a potential of adverse interactions with anticancer drugs. This questions its use as a safe replacement for, for example, benzodiazepines. A review on the interaction potential of preparations from valerian root (Valeriana officinalis L. root) was therefore conducted. A data base search and search in a clinical drug interaction data base were conducted. Thereafter, a systematic assessment of publications was performed. Seven in vitro studies on six CYP 450 isoenzymes, on p-glycoprotein, and on two UGT isoenzymes were identified. However, the methodological assessment of these studies did not support their suitability for the prediction of clinically relevant interactions. In addition, clinical studies on various valerian preparations did not reveal any relevant interaction potential concerning CYP 1A2, 2D6, 2E1, and 3A4. Available animal and human pharmacodynamic studies did not verify any interaction potential. The interaction potential of valerian preparations therefore seems to be low and thereby without clinical relevance. We conclude that there is no specific evidence questioning their safety, also in cancer patients. PMID:25093031

  3. Millon Clinical Multiaxial Inventory–III Subtypes of Opioid Dependence: Validity and Matching to Behavioral Therapies

    PubMed Central

    Ball, Samuel A.; Nich, Charla; Rounsaville, Bruce J.; Eagan, Dorothy; Carroll, Kathleen M.

    2013-01-01

    The concurrent and predictive validity of 2 different methods of Millon Clinical Multiaxial Inventory–III subtyping (protocol sorting, cluster analysis) was evaluated in 125 recently detoxified opioid-dependent outpatients in a 12-week randomized clinical trial. Participants received naltrexone and relapse prevention group counseling and were assigned to 1 of 3 intervention conditions: (a) no-incentive vouchers, (b) incentive vouchers alone, or (c) incentive vouchers plus relationship counseling. Affective disturbance was the most common Axis I protocol-sorted subtype (66%), antisocial–narcissistic was the most common Axis II subtype (46%), and cluster analysis suggested that a 2-cluster solution (high vs. low psychiatric severity) was optimal. Predictive validity analyses indicated less symptom improvement for the higher problem subtypes, and patient treatment matching analyses indicated that some subtypes had better outcomes in the no-incentive voucher conditions. PMID:15301655

  4. Two Subtypes of Atypical Leiomyoma: Clinical, Histologic, and Molecular Analysis.

    PubMed

    Ubago, Julianne M; Zhang, Qing; Kim, Julie J; Kong, Beihua; Wei, Jian-Jun

    2016-07-01

    Atypical leiomyoma (ALM) is a rare variant of uterine smooth muscle tumors. Several recent studies have suggested that ALM has distinct, but also heterogenous, histologic and molecular features, yet little is known about the biology and histogenesis of ALM. Some have even postulated whether the atypical histologic features represent true atypia or simply degenerative changes. In this study, we analyzed the cytologic features of 60 ALM cases and found that ALM could be further divided into 2 subtypes, type I and type II, based primarily on nuclear features. Type I ALM showed round or oval nuclei, distinct and smooth nuclear membranes, prominent nucleoli with perinucleolar halos, and open coarse chromatin. Type II ALM showed elongated or spindled nuclei, irregular nuclear membranes, pinpoint or no nucleoli, and dark smudgy chromatin. There were also architectural differences between type I and type II ALM. Type I ALM often showed diffuse atypia within the tumor, whereas the atypia in type II ALM was patchy, surrounded by usual-type leiomyoma. The 2 subtypes also differed when we compared the immunohistochemical and molecular patterns. Type II tumors showed significantly higher rates of immunoreactivity for p16, p53, and HMGA2 and showed MED12 mutations more frequently than the type I counterparts. Our findings suggest that the type I and type II subtypes of ALM may arise from 2 different pathways. Type I tumors may be related to fumarate hydratase mutations, whereas type II ALM appear to arise in a existing usual-type leiomyomas. PMID:27015034

  5. Identifying ultrasound and clinical features of breast cancer molecular subtypes by ensemble decision.

    PubMed

    Zhang, Lei; Li, Jing; Xiao, Yun; Cui, Hao; Du, Guoqing; Wang, Ying; Li, Ziyao; Wu, Tong; Li, Xia; Tian, Jiawei

    2015-01-01

    Breast cancer is molecularly heterogeneous and categorized into four molecular subtypes: Luminal-A, Luminal-B, HER2-amplified and Triple-negative. In this study, we aimed to apply an ensemble decision approach to identify the ultrasound and clinical features related to the molecular subtypes. We collected ultrasound and clinical features from 1,000 breast cancer patients and performed immunohistochemistry on these samples. We used the ensemble decision approach to select unique features and to construct decision models. The decision model for Luminal-A subtype was constructed based on the presence of an echogenic halo and post-acoustic shadowing or indifference. The decision model for Luminal-B subtype was constructed based on the absence of an echogenic halo and vascularity. The decision model for HER2-amplified subtype was constructed based on the presence of post-acoustic enhancement, calcification, vascularity and advanced age. The model for Triple-negative subtype followed two rules. One was based on irregular shape, lobulate margin contour, the absence of calcification and hypovascularity, whereas the other was based on oval shape, hypovascularity and micro-lobulate margin contour. The accuracies of the models were 83.8%, 77.4%, 87.9% and 92.7%, respectively. We identified specific features of each molecular subtype and expanded the scope of ultrasound for making diagnoses using these decision models. PMID:26046791

  6. Clinically Relevant Anticancer Polymer Paclitaxel Therapeutics

    PubMed Central

    Yang, Danbo; Yu, Lei; Van, Sang

    2011-01-01

    The concept of utilizing polymers in drug delivery has been extensively explored for improving the therapeutic index of small molecule drugs. In general, polymers can be used as polymer-drug conjugates or polymeric micelles. Each unique application mandates its own chemistry and controlled release of active drugs. Each polymer exhibits its own intrinsic issues providing the advantage of flexibility. However, none have as yet been approved by the U.S. Food and Drug Administration. General aspects of polymer and nano-particle therapeutics have been reviewed. Here we focus this review on specific clinically relevant anticancer polymer paclitaxel therapeutics. We emphasize their chemistry and formulation, in vitro activity on some human cancer cell lines, plasma pharmacokinetics and tumor accumulation, in vivo efficacy, and clinical outcomes. Furthermore, we include a short review of our recent developments of a novel poly(l-γ-glutamylglutamine)-paclitaxel nano-conjugate (PGG-PTX). PGG-PTX has its own unique property of forming nano-particles. It has also been shown to possess a favorable profile of pharmacokinetics and to exhibit efficacious potency. This review might shed light on designing new and better polymer paclitaxel therapeutics for potential anticancer applications in the clinic. PMID:24212604

  7. Millon Clinical Multiaxial Inventory-III Subtypes of Opioid Dependence: Validity and Matching to Behavioral Therapies

    ERIC Educational Resources Information Center

    Ball, Samuel A.; Nich, Charla; Rounsaville, Bruce J.; Eagan, Dorothy; Carroll, Kathleen M.

    2004-01-01

    The concurrent and predictive validity of 2 different methods of Millon Clinical Multiaxial Inventory-III subtyping (protocol sorting, cluster analysis) was evaluated in 125 recently detoxified opioid-dependent outpatients in a 12-week randomized clinical trial. Participants received naltrexone and relapse prevention group counseling and were…

  8. Inhibitory Functioning across ADHD Subtypes: Recent Findings, Clinical Implications and Future Directions

    PubMed Central

    Adams, Zachary W.; Derefinko, Karen J.; Milich, Richard; Fillmore, Mark T.

    2014-01-01

    Although growing consensus supports the role of deficient behavioral inhibition as a central feature of the combined subtype of ADHD (ADHD/C; Barkley, 2007; Nigg, 2001), little research has focused on how this finding generalizes to the primarily inattentive subtype (ADHD/I). This question holds particular relevance in light of recent work suggesting that ADHD/I might be better characterized as a disorder separate from ADHD/C (Diamond, 2005; Milich et al., 2001). The current paper describes major findings in the area of inhibitory performance in ADHD and highlights recent research suggesting important areas of divergence between the subtypes. In particular, preliminary findings point to potential differences between the subtypes with respect to how children process important contextual information from the environment, such as preparatory cues that precede responses and rewarding or punishing feedback following behavior. These suggestive findings are discussed in the context of treatment implications, which could involve differential intervention approaches for each subtype targeted to the specific deficit profiles that characterize each group of children. Future research avenues aimed toward building a sound theoretical model of ADHD/I and a better understanding of its relation to ADHD/C are also presented. Specifically, investigators are encouraged to continue studying the complex interplay between inhibitory and attentional processes, as this area seems particularly promising in its ability to improve our understanding of the potentially distinct pathologies underlying the ADHD subtypes. PMID:19072751

  9. Distribution and Clinical Manifestations of Cryptosporidium Species and Subtypes in HIV/AIDS Patients in Ethiopia

    PubMed Central

    Adamu, Haileeyesus; Petros, Beyene; Zhang, Guoqing; Kassa, Hailu; Amer, Said; Ye, Jianbin; Feng, Yaoyu; Xiao, Lihua

    2014-01-01

    Background Cryptosporidiosis is an important cause for chronic diarrhea and death in HIV/AIDS patients. Among common Cryptosporidium species in humans, C. parvum is responsible for most zoonotic infections in industrialized nations. Nevertheless, the clinical significance of C. parvum and role of zoonotic transmission in cryptosporidiosis epidemiology in developing countries remain unclear. Methodology/Principal Findings In this cross-sectional study, 520 HIV/AIDS patients were examined for Cryptosporidium presence in stool samples using genotyping and subtyping techniques. Altogether, 140 (26.9%) patients were positive for Cryptosporidium spp. by PCR-RFLP analysis of the small subunit rRNA gene, belonging to C. parvum (92 patients), C. hominis (25 patients), C. viatorum (10 patients), C. felis (5 patients), C. meleagridis (3 patients), C. canis (2 patients), C. xiaoi (2 patients), and mixture of C. parvum and C. hominis (1 patient). Sequence analyses of the 60 kDa glycoprotein gene revealed a high genetic diversity within the 82 C. parvum and 19 C. hominis specimens subtyped, including C. parvum zoonotic subtype families IIa (71) and IId (5) and anthroponotic subtype families IIc (2), IIb (1), IIe (1) and If-like (2), and C. hominis subtype families Id (13), Ie (5), and Ib (1). Overall, Cryptosporidium infection was associated with the occurrence of diarrhea and vomiting. Diarrhea was attributable mostly to C. parvum subtype family IIa and C. hominis, whereas vomiting was largely attributable to C. hominis and rare Cryptosporidium species. Calf contact was identified as a significant risk factor for infection with Cryptosporidium spp., especially C. parvum subtype family IIa. Conclusions/Significance Results of the study indicate that C. parvum is a major cause of cryptosporidiosis in HIV-positive patients and zoonotic transmission is important in cryptosporidiosis epidemiology in Ethiopia. In addition, they confirm that different Cryptosporidium species and

  10. Metabolic/Proteomic Signature Defines Two Glioblastoma Subtypes With Different Clinical Outcome

    PubMed Central

    Marziali, G.; Signore, M.; Buccarelli, M.; Grande, S.; Palma, A.; Biffoni, M.; Rosi, A.; D’Alessandris, Q.G.; Martini, M.; Larocca, L. M.; De Maria, R.; Pallini, R.; Ricci-Vitiani, L.

    2016-01-01

    Glioblastoma (GBM) is one of the deadliest human cancers. Because of the extremely unfavorable prognosis of GBM, it is important to develop more effective diagnostic and therapeutic strategies based on biologically and clinically relevant subclassification systems. Analyzing a collection of seventeen patient-derived glioblastoma stem-like cells (GSCs) by gene expression profiling, NMR spectroscopy and signal transduction pathway activation, we identified two GSC clusters, one characterized by a pro-neural-like phenotype and the other showing a mesenchymal-like phenotype. Evaluating the levels of proteins differentially expressed by the two GSC clusters in the TCGA GBM sample collection, we found that SRC activation is associated with a GBM subgroup showing better prognosis whereas activation of RPS6, an effector of mTOR pathway, identifies a subgroup with a worse prognosis. The two clusters are also differentiated by NMR spectroscopy profiles suggesting a potential prognostic stratification based on metabolic evaluation. Our data show that the metabolic/proteomic profile of GSCs is informative of the genomic/proteomic GBM landscape, which differs among tumor subtypes and is associated with clinical outcome. PMID:26857460

  11. [Development of vaccines for HIV-1. Relevance of subtype-specific cellular immunity].

    PubMed

    Rodríguez, Ana María; Turk, Gabriela; Pascutti, María Fernanda; Falivene, Juliana; Gherardi, María Magdalena

    2010-01-01

    It has been almost 30 years since the detection of the first HIV-1 cases and yet an effective and safe vaccine has not been developed. Although, advances in antiretroviral therapy (HAART) have produced a major impact on the pandemic, and even though HIV/aids remains a major concern for developing countries, where access to therapy is limited. The last report from UNAIDS notified 33 million people living with HIV/aids, worldwide, while in Argentina it is estimated that 120,000 persons have been infected. One of the challenges to address and ultimately overcome when developing a vaccine is the high variability of HIV-1. The M group, responsible for the pandemic, is divided into 10 subtypes and several sub-subtypes, in addition to the 48 circulating recombinant forms (CRF) and over one hundred unique recombinant forms (URF). The HIV epidemic in Argentina is as complex as in the rest of the world, characterized by the high prevalence of infections caused by subtype B and BF variants. Despite the wide range of publications focused on the immune response against HIV as well as to vaccine development, how to overcome variability on vaccine antigen selection is still unclear. Studies performed in our laboratory showed the impact of the immunogenicity of BF recombinant variants, both in humans and in animal models. These results are of great concern in vaccine development for our region. PMID:21163746

  12. Complex regional pain syndrome: evidence for warm and cold subtypes in a large prospective clinical sample.

    PubMed

    Bruehl, Stephen; Maihöfner, Christian; Stanton-Hicks, Michael; Perez, Roberto S G M; Vatine, Jean-Jacques; Brunner, Florian; Birklein, Frank; Schlereth, Tanja; Mackey, Sean; Mailis-Gagnon, Angela; Livshitz, Anatoly; Harden, R Norman

    2016-08-01

    Limited research suggests that there may be Warm complex regional pain syndrome (CRPS) and Cold CRPS subtypes, with inflammatory mechanisms contributing most strongly to the former. This study for the first time used an unbiased statistical pattern recognition technique to evaluate whether distinct Warm vs Cold CRPS subtypes can be discerned in the clinical population. An international, multisite study was conducted using standardized procedures to evaluate signs and symptoms in 152 patients with clinical CRPS at baseline, with 3-month follow-up evaluations in 112 of these patients. Two-step cluster analysis using automated cluster selection identified a 2-cluster solution as optimal. Results revealed a Warm CRPS patient cluster characterized by a warm, red, edematous, and sweaty extremity and a Cold CRPS patient cluster characterized by a cold, blue, and less edematous extremity. Median pain duration was significantly (P < 0.001) shorter in the Warm CRPS (4.7 months) than in the Cold CRPS subtype (20 months), with pain intensity comparable. A derived total inflammatory score was significantly (P < 0.001) elevated in the Warm CRPS group (compared with Cold CRPS) at baseline but diminished significantly (P < 0.001) over the follow-up period, whereas this score did not diminish in the Cold CRPS group (time × subtype interaction: P < 0.001). Results support the existence of a Warm CRPS subtype common in patients with acute (<6 months) CRPS and a relatively distinct Cold CRPS subtype most common in chronic CRPS. The pattern of clinical features suggests that inflammatory mechanisms contribute most prominently to the Warm CRPS subtype but that these mechanisms diminish substantially during the first year postinjury. PMID:27023422

  13. Type- and subtype-specific detection of influenza viruses in clinical specimens by rapid culture assay.

    PubMed

    Ziegler, T; Hall, H; Sánchez-Fauquier, A; Gamble, W C; Cox, N J

    1995-02-01

    A rapid culture assay which allows for the simultaneous typing and subtyping of currently circulating influenza A(H1N1), A(H3N2), and B viruses in clinical specimens was developed. Pools of monoclonal antibodies (MAbs) against influenza A and B viruses and MAbs HA1-71 and HA2-76, obtained by immunizing mice with the denatured hemagglutinin subfragments HA1 and HA2 of influenza virus A/Victoria/3/75, were used for immunoperoxidase staining of antigens in infected MDCK cells. MAb HA1-71 reacted exclusively with influenza A viruses of the H3 subtype, while MAb HA2-76 reacted with subtypes H1, H3, H4, H6, H8, H9, H10, H11, and H12, as determined with 78 human, 4 swine, and 10 avian influenza virus reference strains subtyped by the hemagglutination inhibition test. To determine if the technique can be used as a rapid diagnostic test, 263 known influenza virus-positive frozen nasal or throat swabs were inoculated into MDCK cells. After an overnight incubation, the cells were fixed and viral antigens were detected by immunoperoxidase staining. Influenza A viruses of the H1 and H3 subtypes were detected in 31 and 113 specimens, respectively. The subtypes of 10 influenza A virus-positive specimens could not be determined because they contained too little virus. Influenza B viruses were detected in 84 specimens, and 25 specimens were negative. We conclude that this assay is a rapid, convenient, non-labor-intensive, and relatively inexpensive test for detecting, typing, and subtyping influenza viruses in clinical specimens. PMID:7714186

  14. [Clinical relevance of cerebral microbleeds--update].

    PubMed

    Yakushjii, Yusuke; Tanaka, Jun; Hara, Hideo

    2016-04-01

    Cerebral microbleeds (CMBs) on paramagnetic-sensitive magnetic resonance sequences correspond pathologically to clusters of hemosiderin-laden macrophages and have emerged as an important new imaging marker of cerebral small vessel disease (SVD), including intracerebral hemorrhage (ICH). The prevalence of CMBs varies according to the specific disease settings (stroke subtypes and demented disorders) and is highest in ICH patients. The associations of CMBs with aging, hypertension and apolipoprotein E genotype are consistent with the two major underlying pathogenesis of CMBs: hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). The distributional patterns of CMBs might help us understand the predominant SVD pathogenesis of the brain; the strictly lobar type of CMBs often reflects the presence of advanced CAA, while the other types of CMBs, such as "deep or infratentorial CMBs", including the mixed type, are strongly associated with hypertension. PMID:27333747

  15. Towards a brief definition of burnout syndrome by subtypes: Development of the "Burnout Clinical Subtypes Questionnaire" (BCSQ-12)

    PubMed Central

    2011-01-01

    Background Burnout has traditionally been described by means of the dimensions of exhaustion, cynicism and lack of eficacy from the "Maslach Burnout Inventory-General Survey" (MBI-GS). The "Burnout Clinical Subtype Questionnaire" (BCSQ-12), comprising the dimensions of overload, lack of development and neglect, is proposed as a brief means of identifying the different ways this disorder is manifested. The aim of the study is to test the construct and criterial validity of the BCSQ-12. Method A cross-sectional design was used on a multi-occupational sample of randomly selected university employees (n = 826). An exploratory factor analysis (EFA) was performed on half of the sample using the maximum likelihood (ML) method with varimax orthogonal rotation, while confirmatory factor analysis (CFA) was performed on the other half by means of the ML method. ROC curve analysis was preformed in order to assess the discriminatory capacity of BCSQ-12 when compared to MBI-GS. Cut-off points were proposed for the BCSQ-12 that optimized sensitivity and specificity. Multivariate binary logistic regression models were used to estimate effect size as an odds ratio (OR) adjusted for sociodemographic and occupational variables. Contrasts for sex and occupation were made using Mann-Whitney U and Kruskall-Wallis tests on the dimensions of both models. Results EFA offered a solution containing 3 factors with eigenvalues > 1, explaining 73.22% of variance. CFA presented the following indices: χ2 = 112.04 (p < 0.001), χ2/gl = 2.44, GFI = 0.958, AGFI = 0.929, RMSEA = 0.059, SRMR = 0.057, NFI = 0.958, NNFI = 0.963, IFI = 0.975, CFI = 0.974. The area under the ROC curve for 'overload' with respect to the 'exhaustion' was = 0.75 (95% CI = 0.71-0.79); it was = 0.80 (95% CI = 0.76-0.86) for 'lack of development' with respect to 'cynicism' and = 0.74 (95% CI = 0.70-0.78) for 'neglect' with respect to 'inefficacy'. The presence of 'overload' increased the likelihood of suffering from

  16. Idioms of distress among trauma survivors: subtypes and clinical utility.

    PubMed

    Hinton, Devon E; Lewis-Fernández, Roberto

    2010-06-01

    In this introduction to the Special Issue on Trauma and Idioms of Distress, we provide an overview of the concept and typology of "idioms of distress," focusing particularly on their clinical utility. This includes the role of idioms as indicators of trauma exposure, of various types of psychopathology and of levels of distress, risk and functioning. It likewise includes the fact that idioms of distress may profoundly influence the personal meaning of having a trauma-related disorder, may shape the interpersonal course of the disorder and may pattern help-seeking and self-treatment. Finally, it illustrates the fact that idioms may also help clinicians understand sufferers' views of the causes of their distress, constitute key therapeutic targets and help increase therapeutic empathy and treatment adherence. This special issue focuses on the role played by idioms of distress in the local trauma ontology, the associations between the idioms and psychiatric disorders occurring in the context of trauma and the mechanisms by which the idioms profoundly influence the personal and interpersonal course of trauma-related disorders. PMID:20407812

  17. Endothelin receptor subtypes and their functional relevance in human small coronary arteries

    PubMed Central

    Pierre, Lisa N; Davenport, Anthony P

    1998-01-01

    The potent constrictor peptide endothelin (ET) has been implicated in various cardiovascular disorders including myocardial infarction and atherosclerosis. We have investigated the nature of ET receptor subtypes present on human small coronary arteries.Small coronary arteries were mounted in a wire-myograph for in vitro pharmacology. To investigate the ET receptor subtypes present in different segments of the coronary vascular tree, arteries were grouped according to internal diameter. Responses in arteries with small internal diameters (mean 316.7±7.9 μm; Group B) were compared to those in larger arteries (mean 586.2±23.1 μm; Group A).ET-1 consistently and potently contracted arteries from Group A and B, with EC50 values of 1.7 (0.9–3.2) nM (n=15) and 2.3 (1.4–4.2) nM (n=14), respectively. No correlation was observed between ET-1 potency and internal diameter. The response to ET-1 was potently antagonized by the selective ETA receptor antagonist PD156707 in both Group A and Group B, yielding pA2 values of 8.60±0.12 (n=4–6) and 8.38±0.17 (n=4–6), respectively. Slopes from Schild regression were not significantly different from unity.In contrast to ET-1, individual responses to ET-3 were variable. While all arteries from Group A responded to ET-3 (EC50∼69 (23–210) nM) (n=12), no response was obtained in 5 of the 14 tested in Group B. Of those responding, many failed to reach a maximum at concentrations up to 1 μM. ET-1 was more potent than ET-3 in all arteries tested. A biphasic ET-3 response was observed in 8 arteries suggesting that a small ETB population was also present in some patients. The selective ETB receptor agonist sarafotoxin S6c had little or no effect up to 10 nM (n=4–6).Responses to ET-1 and ET-3 were unaffected by removal of the endothelium in arteries from both groups suggesting a lack of functional, relaxant ETB receptors on endothelial cells (n=5).Using autoradiography, specific high density binding of the non

  18. Clinical Relevance of Biomarkers of Oxidative Stress

    PubMed Central

    Frijhoff, Jeroen; Winyard, Paul G.; Zarkovic, Neven; Davies, Sean S.; Stocker, Roland; Cheng, David; Knight, Annie R.; Taylor, Emma Louise; Oettrich, Jeannette; Ruskovska, Tatjana; Gasparovic, Ana Cipak; Cuadrado, Antonio; Weber, Daniela; Poulsen, Henrik Enghusen; Grune, Tilman; Schmidt, Harald H.H.W.

    2015-01-01

    Abstract Significance: Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. Critical Issues: The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use. Future Directions: Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker. Antioxid. Redox Signal. 23, 1144–1170. PMID:26415143

  19. Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics

    PubMed Central

    2010-01-01

    Introduction Breast cancer is a profoundly heterogeneous disease with respect to biologic and clinical behavior. Gene-expression profiling has been used to dissect this complexity and to stratify tumors into intrinsic gene-expression subtypes, associated with distinct biology, patient outcome, and genomic alterations. Additionally, breast tumors occurring in individuals with germline BRCA1 or BRCA2 mutations typically fall into distinct subtypes. Methods We applied global DNA copy number and gene-expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene-expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy-number aberrations and genomic subgroups of breast cancer. Results We identified 31 genomic regions that were highly amplified in > 1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions revealed six genomic subtypes, termed 17q12, basal-complex, luminal-simple, luminal-complex, amplifier, and mixed subtypes. Four of them had striking similarity to intrinsic gene-expression subtypes and showed associations to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having a better prognosis, whereas the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors

  20. [Subtype distribution of Blastocystis isolates and evaluation of clinical symptoms detected in Aydin province, Turkey].

    PubMed

    Ertuğ, Sema; Malatyalı, Erdoğan; Ertabaklar, Hatice; Özlem Çalışkan, Serçin; Bozdoğan, Bülent

    2015-01-01

    The pathogenic potential and genetic diversity of Blastocystis are poorly understood despite being one of the most frequent intestinal parasites in routine fecal examination all around the world as well as Turkey. There are numerous defined subtypes (ST) of Blastocystis which infect animals and nine of them were isolated from human fecal samples. Blastocystis is an anaerobic parasite and generally recognized as nonpathogenic microorganism that colonizes the colon. However recent studies have indicated that the genotypes may be related with the pathogenicity and clinical symptoms of the infection. The aims of this study were to investigate the subtypes of Blastocystis isolates obtained from stool samples submitted to the parasitology laboratory of Adnan Menderes University, Faculty of Medicine, and to evaluate the clinical symptoms of infected cases. A total of 61 cases (40 male, 21 female; age range: 5-69 years, mean age: 35 ± 19.1 years) were included in the study. Stool samples that were positive for Blastocystis cysts in direct microscopic examination, were inoculated in Jones medium and incubated at 37°C for 72 hours for the growth of parasite. Genomic DNAs were isolated from Jones medium directly or frozen samples with a commercial kit (DNAzol, Invitrogen, USA). The subtypes of Blastocystis were detected by polymerase chain reaction (PCR) using ST-specific primers and the symptoms of patients were evaluated retrospectively. Forty-four (72.1%) out of 61 isolates were subtyped by PCR, while 17 (27.9%) could not be typed. The distribution of Blastocystis subtypes were found as follows; ST3 in 17 (38.6%), ST2 in 13 (29.5%), ST1 in 9 (20.5%), ST1 + ST3 in 4 (9.1%), and ST1 + ST2 in one (2.3%) of the samples. The most common symptoms among Blastocystis infected cases were abdominal pain (n= 24, 39.4%), pruritus (n= 22, 36.1%), diarrhea (n= 4, 6.6%) and constipation (n= 2, 3.3%), respectively. This is the first study investigating the genotypes of Blastocystis in

  1. Engineering clinically relevant volumes of vascularized bone

    PubMed Central

    Roux, Brianna M; Cheng, Ming-Huei; Brey, Eric M

    2015-01-01

    Vascularization remains one of the most important challenges that must be overcome for tissue engineering to be consistently implemented for reconstruction of large volume bone defects. An extensive vascular network is needed for transport of nutrients, waste and progenitor cells required for remodelling and repair. A variety of tissue engineering strategies have been investigated in an attempt to vascularize tissues, including those applying cells, soluble factor delivery strategies, novel design and optimization of bio-active materials, vascular assembly pre-implantation and surgical techniques. However, many of these strategies face substantial barriers that must be overcome prior to their ultimate translation into clinical application. In this review recent progress in engineering vascularized bone will be presented with an emphasis on clinical feasibility. PMID:25877690

  2. Toward clinically relevant standardization of image quality.

    PubMed

    Samei, Ehsan; Rowberg, Alan; Avraham, Ellie; Cornelius, Craig

    2004-12-01

    In recent years, notable progress has been made on standardization of medical image presentations in the definition and implementation of the Digital Imaging and Communications in Medicine (DICOM) Grayscale Standard Display Function (GSDF). In parallel, the American Association of Physicists in Medicine (AAPM) Task Group 18 has provided much needed guidelines and tools for visual and quantitative assessment of medical display quality. In spite of these advances, however, there are still notable gaps in the effectiveness of DICOM GSDF to assure consistent and high-quality display of medical images. In additions the degree of correlation between display technical data and diagnostic usability and performance of displays remains unclear. This article proposes three specific steps that DICOM, AAPM, and ACR may collectively take to bridge the gap between technical performance and clinical use: (1) DICOM does not provide means and acceptance criteria to evaluate the conformance of a display device to GSDF or to address other image quality characteristics. DICOM can expand beyond luminance response, extending the measurable, quantifiable elements of TG18 such as reflection and resolution. (2) In a large picture archiving and communication system (PACS) installation, it is critical to continually track the appropriate use and performance of multiple display devices. DICOM may help with this task by adding a Device Service Class to the standard to provide for communication and control of image quality parameters between applications and devices, (3) The question of clinical significance of image quality metrics has rarely been addressed by prior efforts. In cooperation with AAPM, the American College of Radiology (ACR), and the Society for Computer Applications in Radiology (SCAR), DICOM may help to initiate research that will determine the clinical consequence of variations in image quality metrics (eg, GSDF conformance) and to define what constitutes image quality from a

  3. Clinical relevance of animal models of schizophrenia.

    PubMed

    Koch, Michael

    2013-01-01

    Animal models and endophenotypes of mental disorders are regarded as preclinical heuristic approaches aiming at understanding the etiopathogenesis of these diseases, and at developing drug treatment strategies. A frequently used translational model of sensorimotor gating and its deficits in some neuropsychiatric disorders is prepulse inhibition (PPI) of startle. PPI is reduced in schizophrenia patients, but the exact relationship between symptoms and reduced PPI is still unclear. Recent findings suggest that the levels of PPI in humans and animals may be predictive of certain cognitive functions. Hence, this simple measure of reflex suppression may be of use for clinical research. PPI is the reduction of the acoustic startle response that occurs when a weak prestimulus is presented shortly prior to a startling noise pulse. It is considered a measure of sensorimotor gating and is regulated by a cortico-limbic striato-pallidal circuit. However, PPI does not only occur in the domain of startle. PPI of alpha, gamma, and theta oscillations at frontal and central locations has been found, suggesting a relationship between PPI and cognitive processes. In fact, levels of PPI in healthy subjects and in animals predict their performance in cognitive tasks mainly mediated by the frontal cortex. Taken together, PPI might reflect a more general filtering performance leading to gating of intrusive sensory, motor, and cognitive input, thereby improving cognitive function. Hence, PPI might be used in clinical settings to predict the impact of drugs or psychotherapy on cognitive performance in neuropsychiatric patients. PMID:24053035

  4. Biofilms: Survival Mechanisms of Clinically Relevant Microorganisms

    PubMed Central

    Donlan, Rodney M.; Costerton, J. William

    2002-01-01

    Though biofilms were first described by Antonie van Leeuwenhoek, the theory describing the biofilm process was not developed until 1978. We now understand that biofilms are universal, occurring in aquatic and industrial water systems as well as a large number of environments and medical devices relevant for public health. Using tools such as the scanning electron microscope and, more recently, the confocal laser scanning microscope, biofilm researchers now understand that biofilms are not unstructured, homogeneous deposits of cells and accumulated slime, but complex communities of surface-associated cells enclosed in a polymer matrix containing open water channels. Further studies have shown that the biofilm phenotype can be described in terms of the genes expressed by biofilm-associated cells. Microorganisms growing in a biofilm are highly resistant to antimicrobial agents by one or more mechanisms. Biofilm-associated microorganisms have been shown to be associated with several human diseases, such as native valve endocarditis and cystic fibrosis, and to colonize a wide variety of medical devices. Though epidemiologic evidence points to biofilms as a source of several infectious diseases, the exact mechanisms by which biofilm-associated microorganisms elicit disease are poorly understood. Detachment of cells or cell aggregates, production of endotoxin, increased resistance to the host immune system, and provision of a niche for the generation of resistant organisms are all biofilm processes which could initiate the disease process. Effective strategies to prevent or control biofilms on medical devices must take into consideration the unique and tenacious nature of biofilms. Current intervention strategies are designed to prevent initial device colonization, minimize microbial cell attachment to the device, penetrate the biofilm matrix and kill the associated cells, or remove the device from the patient. In the future, treatments may be based on inhibition of genes

  5. Prognosis of 234 rosacea patients according to clinical subtype: The significance of central facial erythema in the prognosis of rosacea.

    PubMed

    Lee, Woo Jin; Lee, Ye Jin; Lee, Mi Hye; Won, Chong Hyun; Chang, Sung Eun; Choi, Jee Ho; Lee, Mi Woo

    2016-05-01

    Rosacea has a wide spectrum of clinical features, which include persistent facial redness, flushing, telangiectasia, inflammatory papules/pustules, hypertrophy and/or ocular features. The prognosis of rosacea according to clinical subtype has not been evaluated. We analyzed the prognosis of rosacea in 234 patients, which included 120 patients with mixed subtype, 75 with the erythematotelangiectatic rosacea subtype and 39 with the papulopustular rosacea (PPR) subtype. The prognosis of rosacea was classified as: (i) no improvement; (ii) partial remission; and (iii) complete remission. The frequencies of complete remission, time to complete remission and 1-year complete remission rate were compared between subtypes. Follow-up periods ranged 2-72 months (median follow-up, 17.5). Aggravation of the disease was found in 50.4% of patients during follow up. Partial or complete remission was noted in 61.5% and 20.9% of patients, respectively. The median time to complete remission was 56.0 months. The prognosis of disease was more favorable for patients with the PPR subtype than for patients with other subtypes with respect to the frequency of complete remission, median time to complete remission and the 2-year complete remission rate. In conclusion, papulopustular rosacea without remarkable centrofacial erythema showed a more favorable prognosis than other subtypes. Erythematotelangiectatic lesions in rosacea patients present a challenge for the treatment of rosacea. PMID:26507367

  6. CSF Proteomics Identifies Specific and Shared Pathways for Multiple Sclerosis Clinical Subtypes

    PubMed Central

    Avsar, Timucin; Durası, İlknur Melis; Uygunoğlu, Uğur; Tütüncü, Melih; Demirci, Nuri Onat; Saip, Sabahattin; Sezerman, O. Uğur; Siva, Aksel; Tahir Turanlı, Eda

    2015-01-01

    Multiple sclerosis (MS) is an immune-mediated, neuro-inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS) with a heterogeneous clinical presentation and course. There is a remarkable phenotypic heterogeneity in MS, and the molecular mechanisms underlying it remain unknown. We aimed to investigate further the etiopathogenesis related molecular pathways in subclinical types of MS using proteomic and bioinformatics approaches in cerebrospinal fluids of patients with clinically isolated syndrome, relapsing remitting MS and progressive MS (n=179). Comparison of disease groups with controls revealed a total of 151 proteins that are differentially expressed in clinically different MS subtypes. KEGG analysis using PANOGA tool revealed the disease related pathways including aldosterone-regulated sodium reabsorption (p=8.02x10-5) which is important in the immune cell migration, renin-angiotensin (p=6.88x10-5) system that induces Th17 dependent immunity, notch signaling (p=1.83x10-10) pathway indicating the activated remyelination and vitamin digestion and absorption pathways (p=1.73x10-5). An emerging theme from our studies is that whilst all MS clinical forms share common biological pathways, there are also clinical subtypes specific and pathophysiology related pathways which may have further therapeutic implications. PMID:25942430

  7. Chronic HCV infection: epidemiological and clinical relevance

    PubMed Central

    2012-01-01

    Hepatitis C virus (HCV), first recognized as a cause of transfusion-associated acute and chronic hepatitis in 1989, plays a major role as a cause of chronic liver injury, with potential for neoplastic degeneration. It is mainly transmitted by the parenteral route. However, although with lower efficiency, it may be also transmitted by sexual intercourses and by the mother-to-child route. Epidemiological evidence shows that a wave of infection occurred in the 1945-65 period (baby boomers) in western countries. After acute infection, as many as 50-85% of the patients fail to clear the virus resulting in chronic liver infection and/or disease. It is estimated that, on a global scale, about 170 million people are chronically infected with HCV, leading to about 350.000 deaths yearly. Among western countries southern Europe, and particularly Italy, is among the most affected areas. The impact on the public health systems is noteworthy, with high number of hospitalizations due to chronic liver disease, cirrhosis or hepatocellular carcinoma. While waiting for a safe and effective vaccine to be made available, new promising direct-acting antiviral (DAA) drugs offer a better therapeutic scenario than in the past even for the poor responder genotypes 1 and 4, provided that effective screening and care is offered. However, the long and aspecific prodromic period before clinical symptoms develop is a major obstacle to early detection and treatment. Effective screening strategies may target at-risk groups or age specific groups, as recently recommended by the CDC. PMID:23173556

  8. Subtyping Stuttering II

    PubMed Central

    Seery, Carol Hubbard; Watkins, Ruth V.; Mangelsdorf, Sarah C.; Shigeto, Aya

    2007-01-01

    This paper is the second in a series of two articles exploring subtypes of stuttering, and it addresses the question of whether and how language ability and temperament variables may be relevant to the study of subtypes within the larger population of children who stutter. Despite observations of varied profiles among young children who stutter, efforts to identify and characterize subtypes of stuttering have had limited influence on theoretical or clinical understanding of the disorder. This manuscript briefly highlights research on language and temperament in young children who stutter, and considers whether the results can provide guidance for efforts to more effectively investigate and elucidate subtypes in childhood stuttering. Issues from the literature that appear relevant to research on stuttering subtypes include: (a) the question of whether stuttering is best characterized as categorical or continuous; (b) interpretation of individual differences in skills and profiles; and (c) the fact that, during the preschool years, the interaction among domains such as language and temperament are changing very rapidly, resulting in large differences in developmental profiles within relatively brief chronological age periods. PMID:17825669

  9. Clinical characteristics and post-surgical outcomes of focal cortical dysplasia subtypes.

    PubMed

    Xue, Hai; Cai, Lixin; Dong, Sheng; Li, Yongjie

    2016-01-01

    We retrospectively studied 105 patients with a focal cortical dysplasia (FCD) diagnosed on pathological examination, and investigated the long term postoperative seizure outcomes, different clinical characteristics of the three FCD subtypes, particularly type I and II, and surgical outcomes for each group. FCD is a common cause of drug-resistant epilepsy, which is divided into three different subtypes according to its involvement at different stages of brain development. Each of these groups may have different characteristics and may even have different surgical outcomes. After treatment, 55% of patients were completely seizure-free, with two significant predictive variables for poorer outcomes: focal MRI findings and electrode implantation. FCD type I had relatively poor surgical outcomes compared to FCD type II and type IIIa. Compared with FCD type I, type II, particularly IIb, had a higher frequency of seizure attacks, predominantly located in the extratemporal lobes, and was more readily detected and diagnosed via focal lesions on MRI and localized electroencephalogram abnormalities. FCD type II patients seem to show better surgical outcomes than FCD type I, but the difference was not significant. Larger cohort studies are needed for further evaluation of the seizure outcomes of different FCD subtypes. PMID:26314661

  10. Clinical Relevance of Prognostic and Predictive Molecular Markers in Gliomas.

    PubMed

    Siegal, Tali

    2016-01-01

    Sorting and grading of glial tumors by the WHO classification provide clinicians with guidance as to the predicted course of the disease and choice of treatment. Nonetheless, histologically identical tumors may have very different outcome and response to treatment. Molecular markers that carry both diagnostic and prognostic information add useful tools to traditional classification by redefining tumor subtypes within each WHO category. Therefore, molecular markers have become an integral part of tumor assessment in modern neuro-oncology and biomarker status now guides clinical decisions in some subtypes of gliomas. The routine assessment of IDH status improves histological diagnostic accuracy by differentiating diffuse glioma from reactive gliosis. It carries a favorable prognostic implication for all glial tumors and it is predictive for chemotherapeutic response in anaplastic oligodendrogliomas with codeletion of 1p/19q chromosomes. Glial tumors that contain chromosomal codeletion of 1p/19q are defined as tumors of oligodendroglial lineage and have favorable prognosis. MGMT promoter methylation is a favorable prognostic marker in astrocytic high-grade gliomas and it is predictive for chemotherapeutic response in anaplastic gliomas with wild-type IDH1/2 and in glioblastoma of the elderly. The clinical implication of other molecular markers of gliomas like mutations of EGFR and ATRX genes and BRAF fusion or point mutation is highlighted. The potential of molecular biomarker-based classification to guide future therapeutic approach is discussed and accentuated. PMID:26508407

  11. Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms

    PubMed Central

    Pietra, D; Rumi, E; Ferretti, V V; Buduo, C A Di; Milanesi, C; Cavalloni, C; Sant'Antonio, E; Abbonante, V; Moccia, F; Casetti, I C; Bellini, M; Renna, M C; Roncoroni, E; Fugazza, E; Astori, C; Boveri, E; Rosti, V; Barosi, G; Balduini, A; Cazzola, M

    2016-01-01

    A quarter of patients with essential thrombocythemia or primary myelofibrosis carry a driver mutation of CALR, the calreticulin gene. A 52-bp deletion (type 1) and a 5-bp insertion (type 2 mutation) are the most frequent variants. These indels might differentially impair the calcium binding activity of mutant calreticulin. We studied the relationship between mutation subtype and biological/clinical features of the disease. Thirty-two different types of CALR variants were identified in 311 patients. Based on their predicted effect on calreticulin C-terminal, mutations were classified as: (i) type 1-like (65%); (ii) type 2-like (32%); and (iii) other types (3%). Corresponding CALR mutants had significantly different estimated isoelectric points. Patients with type 1 mutation, but not those with type 2, showed abnormal cytosolic calcium signals in cultured megakaryocytes. Type 1-like mutations were mainly associated with a myelofibrosis phenotype and a significantly higher risk of myelofibrotic transformation in essential thrombocythemia. Type 2-like CALR mutations were preferentially associated with an essential thrombocythemia phenotype, low risk of thrombosis despite very-high platelet counts and indolent clinical course. Thus, mutation subtype contributes to determining clinical phenotype and outcomes in CALR-mutant myeloproliferative neoplasms. CALR variants that markedly impair the calcium binding activity of mutant calreticulin are mainly associated with a myelofibrosis phenotype. PMID:26449662

  12. Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms.

    PubMed

    Pietra, D; Rumi, E; Ferretti, V V; Di Buduo, C A; Milanesi, C; Cavalloni, C; Sant'Antonio, E; Abbonante, V; Moccia, F; Casetti, I C; Bellini, M; Renna, M C; Roncoroni, E; Fugazza, E; Astori, C; Boveri, E; Rosti, V; Barosi, G; Balduini, A; Cazzola, M

    2016-02-01

    A quarter of patients with essential thrombocythemia or primary myelofibrosis carry a driver mutation of CALR, the calreticulin gene. A 52-bp deletion (type 1) and a 5-bp insertion (type 2 mutation) are the most frequent variants. These indels might differentially impair the calcium binding activity of mutant calreticulin. We studied the relationship between mutation subtype and biological/clinical features of the disease. Thirty-two different types of CALR variants were identified in 311 patients. Based on their predicted effect on calreticulin C-terminal, mutations were classified as: (i) type 1-like (65%); (ii) type 2-like (32%); and (iii) other types (3%). Corresponding CALR mutants had significantly different estimated isoelectric points. Patients with type 1 mutation, but not those with type 2, showed abnormal cytosolic calcium signals in cultured megakaryocytes. Type 1-like mutations were mainly associated with a myelofibrosis phenotype and a significantly higher risk of myelofibrotic transformation in essential thrombocythemia. Type 2-like CALR mutations were preferentially associated with an essential thrombocythemia phenotype, low risk of thrombosis despite very-high platelet counts and indolent clinical course. Thus, mutation subtype contributes to determining clinical phenotype and outcomes in CALR-mutant myeloproliferative neoplasms. CALR variants that markedly impair the calcium binding activity of mutant calreticulin are mainly associated with a myelofibrosis phenotype. PMID:26449662

  13. Subtypes of chronic urticaria in patients attending allergy clinics in Venezuela.

    PubMed

    Sánchez-Borges, M; Caballero-Fonseca, F; Capriles-Hulett, A

    2014-11-01

    Chronic urticaria (CU) is one of the most puzzling clinical entities confronted by the medical profession. It is a common motive for consultation, and in a sizable proportion of patients no identifiable cause is evident. Since there are relatively few publications regarding CU in developing countries, we performed a prospective 3-year study on the demographic and clinical features of patients with CU. Four hundred and twenty-three subjects were studied, 52 children and 371 adults, 295 females (69.7%), with a mean age of 38.4 ± 17.8 years. More often, wheals and angioedema (AE) were present on the head, upper and lower limbs and the trunk. AE was present in 162 patients (38.4%). The most frequent subtypes were chronic spontaneous urticaria, aspirin-exacerbated cutaneous disease, dermographic urticaria, and combinations of various subtypes. A better understanding of the characteristics of patients suffering CU is helpful for clinicians dealing with this ailment, and provides guidance for new investigations on its pathogenesis, which will hopefully result in a better management of this vexing condition. PMID:25398164

  14. A newer and broader definition of burnout: Validation of the "Burnout Clinical Subtype Questionnaire (BCSQ-36)"

    PubMed Central

    2010-01-01

    Background Burnout syndrome has been clinically characterised by a series of three subtypes: frenetic, underchallenged and worn-out, with reference to coping strategies for stress and frustration at work with different degrees of dedication. The aims of the study are to present an operating definition of these subtypes in order to assess their reliability and convergent validity with respect to a standard burnout criterion and to examine differences with regard to sex and the temporary nature of work contracts. Method An exploratory factor analysis was performed by the main component method on a range of items devised by experts. The sample was composed of 409 employees of the University of Zaragoza, Spain. The reliability of the scales was assessed with Cronbach's α, convergent validity in relation to the Maslach Burnout Inventory with Pearson's r, and differences with Student's t-test and the Mann-Whitney U test. Results The factorial validity and reliability of the scales were good. The subtypes presented relations of differing degrees with the criterion dimensions, which were greater when dedication to work was lower. The frenetic profile presented fewer relations with the criterion dimensions while the worn-out profile presented relations of the greatest magnitude. Sex was not influential in establishing differences. However, the temporary nature of work contracts was found to have an effect: temporary employees exhibited higher scores in the frenetic profile (p < 0.001), while permanent employees did so in the underchallenged (p = 0.018) and worn-out (p < 0.001) profiles. Conclusions The classical Maslach description of burnout does not include the frenetic profile; therefore, these patients are not recognised. The developed questionnaire may be a useful tool for the design and appraisal of specific preventive and treatment approaches based on the type of burnout experienced. PMID:20525178

  15. Phosphoinositide system-linked serotonin receptor subtypes and their pharmacological properties and clinical correlates.

    PubMed Central

    Pandey, S C; Davis, J M; Pandey, G N

    1995-01-01

    Serotonergic neurotransmission represents a complex mechanism involving pre- and post-synaptic events and distinct 5-HT receptor subtypes. Serotonin (5-HT) receptors have been classified into several categories, and they are termed as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 type receptors. 5-HT1 receptors have been further subdivided into 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F. 5-HT2 receptors have been divided into 5-HT2A, 5-HT2B and 5-HT2C receptors. All 5-HT2 receptor subtypes are linked to the multifunctional phosphoinositide (PI) signalling system. 5-HT3 receptors are considered ion-gated receptors and are also linked to the PI signalling system by an unknown mechanism. The 5-HT2A receptor subtype is the most widely studied of the 5-HT receptors in psychiatric disorders (for example, suicide, depression and schizophrenia) as well as in relation to the mechanism of action of antidepressant drugs. The roles of 5-HT2C and 5-HT3 receptors in psychiatric disorders are less clear. These 5-HT receptors also play an important role in alcoholism. It has been shown that 5-HT2A, 5-HT2C and 5-HT3 antagonists cause attenuation of alcohol intake in animals and humans. However, the exact mechanisms are unknown. The recent cloning of the cDNAs for 5-HT2A, 5-HT2C and 5-HT3 receptors provides the opportunity to explore the molecular mechanisms responsible for the alterations in these receptors during illness as well as pharmacotherapy. This review article will focus on the current research into the pharmacological properties, molecular biology, and clinical correlates of 5-HT2A, 5-HT2C and 5-HT3 receptors. PMID:7786883

  16. Electrochemical Methods for the Analysis of Clinically Relevant Biomolecules.

    PubMed

    Labib, Mahmoud; Sargent, Edward H; Kelley, Shana O

    2016-08-24

    Rapid progress in identifying biomarkers that are hallmarks of disease has increased demand for high-performance detection technologies. Implementation of electrochemical methods in clinical analysis may provide an effective answer to the growing need for rapid, specific, inexpensive, and fully automated means of biomarker analysis. This Review summarizes advances from the past 5 years in the development of electrochemical sensors for clinically relevant biomolecules, including small molecules, nucleic acids, and proteins. Various sensing strategies are assessed according to their potential for reaching relevant limits of sensitivity, specificity, and degrees of multiplexing. Furthermore, we address the remaining challenges and opportunities to integrate electrochemical sensing platforms into point-of-care solutions. PMID:27428515

  17. Clinical Relevance of Discourse Characteristics after Right Hemisphere Brain Damage

    ERIC Educational Resources Information Center

    Blake, Margaret Lehman

    2006-01-01

    Purpose: Discourse characteristics of adults with right hemisphere brain damage are similar to those reported for healthy older adults, prompting the question of whether changes are due to neurological lesions or normal aging processes. The clinical relevance of potential differences across groups was examined through ratings by speech-language…

  18. Clinically relevant pharmacokinetic herb-drug interactions in antiretroviral therapy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    For healthcare professionals, the volume of literature available on herb-drug interactions often makes it difficult to separate experimental/potential interactions from those deemed clinically relevant. There is a need for concise and conclusive information to guide pharmacotherapy in HIV/AIDS. In t...

  19. Childhood maltreatment and psychopathology: A case for ecophenotypic variants as clinically and neurobiologically distinct subtypes

    PubMed Central

    Teicher, Martin H.; Samson, Jacqueline A.

    2014-01-01

    Objective Childhood maltreatment increases risk for psychopathology. For some highly prevalent disorders (i.e., major depression, substance abuse, anxiety disorders and posttraumatic stress disorder) there is a substantial subset of individuals with maltreatment histories and a substantial subset without. Do those with maltreatment histories represent a clinically and biologically distinct subtype? Method The authors review literature on maltreatment as a risk factor for these disorders and on the clinical differences between individuals with and without maltreatment who share the same diagnoses. Neurobiological findings in maltreated individuals are reviewed and compared to findings reported for these disorders. Results Maltreated individuals with depressive, anxiety and substance use disorders show an earlier age of onset, greater symptom severity, more comorbidity, increased risk for suicide and poorer treatment response than non-maltreated individuals with the same diagnoses. Imaging findings associated with these disorders, such as reduced hippocampal volume and amygdala hyperreactivity are more consistently observed in maltreated individuals and may represent a maltreatment-related risk factor. Maltreated individuals also differ from others due to epigenetic modifications and genetic polymorphisms that interact with experience to increase risk for psychopathology. Conclusions Phenotypic expression of psychopathology may be strongly influenced by exposure to maltreatment leading to a constellation of ecophenotypes. While these ecophenotypes fit within conventional diagnostic boundaries, they likely represent distinct subtypes. Recognition of this distinction may be essential in determining the biological bases of these disorders. Further, treatment guidelines and algorithms may be enhanced if maltreated and non-maltreated individuals with the same diagnostic labels are differentiated. PMID:23982148

  20. Blastocystis and urticaria: Examination of subtypes and morphotypes in an unusual clinical manifestation.

    PubMed

    Casero, Rodolfo Daniel; Mongi, Florencia; Sánchez, Angie; Ramírez, Juan David

    2015-08-01

    Blastocystis is a human common enteric protist that may colonize a large variety of non-human hosts linked to symptoms and diseases such as abdominal pain, constipation, diarrhea, urticaria, flatulence and irritable bowel syndrome (IBS). Blastocystis exhibits remarkable genetic diversity and multiple subtypes (STs) within the genus with no absolute associations with clinical symptomatology. Here we analyzed fecal samples from Argentinean patients (n=270) belonging to symptomatic (urticaria and non-specific gastrointestinal symptoms, n=39) and asymptomatic control (n=28). Those patients infected with Blastocystis (n=67) were submitted for morphological analysis, DNA extraction, 18S PCR, sequencing and STs identification according to DNA barcoding. Blastocystis vacuolar forms were the predominant morphotype (75%), ameboid-like forms were evidenced in 1.5% of samples. Blastocystis ST3 was detected in 71.6% (n=48), of which 71.4%, (n=35) and 28.6% (n=14) belonged to symptomatic and asymptomatic respectively. Other subtypes identified were ST1 (14.9%), ST6 (7.5%) and ST2 (5.9%). Blastocystis 18S barcoding evidenced in non-urticaria symptomatic patients and asymptomatic control group the presence of allele 134 (ST3) (p<0.0001), while allele 34 (ST3) was detected in 85.7% (18/21) of symptomatic uricaria as compared with control group (1/21) (p<0.0001). The presence of a particular allele (a34) significantly associated with urticaria patients was detected and the clinical implications of these findings are herein discussed. PMID:25976414

  1. Conditions for the relevance of infant research to clinical psychoanalysis.

    PubMed

    Fajardo, B

    1993-10-01

    There is increased pluralism within psychoanalysis today, and the practice of psychoanalysis rests on many different theories and distinctly different epistemologic perspectives about the nature of the truth, the position of the observer-analyst in the process, and the phenomena to be observed. The relevance of developmental observation research to clinical psychoanalysis will vary with the epistemological perspective of the practitioner, and to be relevant the perspective of the researcher must 'match' that of the clinician. Additionally, its relevance is conditioned by what is considered 'empirical' data, i.e. whether the data are defined behaviourally or by empathic judgements of an observer. Three broad categories of psychoanalytic perspectives are discussed: empirical-natural science, hermeneutic-empirical, and hermeneutic-constructivist. A patient in analysis is described, with details of two sessions. Three imaginary consultants, each representing one of the major epistemological clinical perspectives, comment on the material to demonstrate the relationship among technique, epistemology, and the ways infants and developmental observation research may be relevant (or not relevant). PMID:8307704

  2. High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer

    PubMed Central

    van den Broek, Evert; Dijkstra, Maurits J. J.; Krijgsman, Oscar; Sie, Daoud; Haan, Josien C.; Traets, Joleen J. H.; van de Wiel, Mark A.; Nagtegaal, Iris D.; Punt, Cornelis J. A.; Carvalho, Beatriz; Ylstra, Bauke; Abeln, Sanne; Meijer, Gerrit A.; Fijneman, Remond J. A.

    2015-01-01

    Background Cancer is caused by somatic DNA alterations such as gene point mutations, DNA copy number aberrations (CNA) and structural variants (SVs). Genome-wide analyses of SVs in large sample series with well-documented clinical information are still scarce. Consequently, the impact of SVs on carcinogenesis and patient outcome remains poorly understood. This study aimed to perform a systematic analysis of genes that are affected by CNA-associated chromosomal breaks in colorectal cancer (CRC) and to determine the clinical relevance of recurrent breakpoint genes. Methods Primary CRC samples of patients with metastatic disease from CAIRO and CAIRO2 clinical trials were previously characterized by array-comparative genomic hybridization. These data were now used to determine the prevalence of CNA-associated chromosomal breaks within genes across 352 CRC samples. In addition, mutation status of the commonly affected APC, TP53, KRAS, PIK3CA, FBXW7, SMAD4, BRAF and NRAS genes was determined for 204 CRC samples by targeted massive parallel sequencing. Clinical relevance was assessed upon stratification of patients based on gene mutations and gene breakpoints that were observed in >3% of CRC cases. Results In total, 748 genes were identified that were recurrently affected by chromosomal breaks (FDR <0.1). MACROD2 was affected in 41% of CRC samples and another 169 genes showed breakpoints in >3% of cases, indicating that prevalence of gene breakpoints is comparable to the prevalence of well-known gene point mutations. Patient stratification based on gene breakpoints and point mutations revealed one CRC subtype with very poor prognosis. Conclusions We conclude that CNA-associated chromosomal breaks within genes represent a highly prevalent and clinically relevant subset of SVs in CRC. PMID:26375816

  3. Differences in Clinical Manifestations of Acute and Early HIV-1 Infection between HIV-1 Subtypes in African Women

    PubMed Central

    Watkins, Richard R.; Morrison, Charles S.; Kwok, Cynthia; Chipato, Tsungai; Musoke, Robert; Arts, Eric J.; Nankya, Immaculate; Salata, Robert A.

    2015-01-01

    Little is known about the differences in clinical manifestations between women with various HIV-1 subtypes during acute (AI) and early (EI) HIV infection. In a longitudinal cohort study, clinical signs and symptoms among Uganda and Zimbabwe women with AI and EI were compared with HIV-negative controls; symptoms were assessed quarterly for 15 to 24 months. Early HIV infection was defined as the first visit during which a woman tested HIV antibody positive. Women who were HIV negative serologically but DNA polymerase chain reaction positive were considered AI. In all, 26 women were classified AI and 192 EI, with 654 HIV-negative controls. Primary HIV infection (AI and EI) was associated with unexplained fever (P <.01), weight loss (P <.01), fatigue (P <.01), inguinal adenopathy (P <.01), and cervical friability (P =.01). More women with subtype C infection had unexplained fever, fatigue, and abnormal vaginal discharge compared to subtype A or D infection. Inguinal adenopathy occurred less often in women with subtype A infection than those with subtype C or D infection. PMID:24106054

  4. Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes

    PubMed Central

    Matsuo, Hirotaka; Yamamoto, Ken; Nakaoka, Hirofumi; Nakayama, Akiyoshi; Sakiyama, Masayuki; Chiba, Toshinori; Takahashi, Atsushi; Nakamura, Takahiro; Nakashima, Hiroshi; Takada, Yuzo; Danjoh, Inaho; Shimizu, Seiko; Abe, Junko; Kawamura, Yusuke; Terashige, Sho; Ogata, Hiraku; Tatsukawa, Seishiro; Yin, Guang; Okada, Rieko; Morita, Emi; Naito, Mariko; Tokumasu, Atsumi; Onoue, Hiroyuki; Iwaya, Keiichi; Ito, Toshimitsu; Takada, Tappei; Inoue, Katsuhisa; Kato, Yukio; Nakamura, Yukio; Sakurai, Yutaka; Suzuki, Hiroshi; Kanai, Yoshikatsu; Hosoya, Tatsuo; Hamajima, Nobuyuki; Inoue, Ituro; Kubo, Michiaki; Ichida, Kimiyoshi; Ooyama, Hiroshi; Shimizu, Toru; Shinomiya, Nariyoshi

    2016-01-01

    Objective Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only. Methods A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls. Results Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10−8), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10−12; OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10−23; OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10−9; OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case–control ORs for two distinct types of gout (r=0.96 [p=4.8×10−4] for urate clearance and r=0.96 [p=5.0×10−4] for urinary urate excretion). Conclusions Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics. PMID:25646370

  5. Translation of neurological biomarkers to clinically relevant platforms.

    PubMed

    Hayes, Ronald L; Robinson, Gillian; Muller, Uwe; Wang, Kevin K W

    2009-01-01

    Like proteomics more generally, neuroproteomics has recently been linked to the discovery of biochemical markers of central nervous system (CNS) injury and disease. Although neuroproteomics has enjoyed considerable success in discovery of candidate biomarkers, there are a number of challenges facing investigators interested in developing clinically useful platforms to assess biomarkers for damage to the CNS. These challenges include intrinsic physiological complications such as the blood-brain barrier. Effective translation of biomarkers to clinical practice also requires development of entirely novel pathways and product development strategies. Drawing from lessons learned from applications of biomarkers to traumatic brain injury, this study outlines major elements of such a pathway. As with other indications, biomarkers can have three major areas of application: (1) drug development; (2) diagnosis and prognosis; (3) patient management. Translation of CNS biomarkers to practical clinical platforms raises a number of integrated elements. Biomarker discovery and initial selection needs to be integrated at the earliest stages with components that will allow systematic prioritization and triage of biomarker candidates. A number of important criteria need to be considered in selecting clinical biomarker candidates. Development of proof of concept assays and their optimization and validation represent an often overlooked feature of biomarker translational research. Initial assay optimization should confirm that assays can detect biomarkers in relevant clinical samples. Since access to human clinical samples is critical to identification of biomarkers relevant to injury and disease as well as for assay development, design of human clinical validation studies is an important component of translational biomarker research platforms. Although these clinical studies share much in common with clinical trials for assessment of drug therapeutic efficacy, there are a number of

  6. Hypoxia in tumors: pathogenesis-related classification, characterization of hypoxia subtypes, and associated biological and clinical implications.

    PubMed

    Vaupel, Peter; Mayer, Arnulf

    2014-01-01

    Hypoxia is a hallmark of tumors leading to (mal-)adaptive processes, development of aggressive phenotypes and treatment resistance. Based on underlying mechanisms and their duration, two main types of hypoxia have been identified, coexisting with complex spatial and temporal heterogeneities. Chronic hypoxia is mainly caused by diffusion limitations due to enlarged diffusion distances and adverse diffusion geometries (e.g., concurrent vs. countercurrent microvessels, Krogh- vs. Hill-type diffusion geometry) and, to a lesser extent, by hypoxemia (e.g., in anemic patients, HbCO formation in heavy smokers), and a compromised perfusion or flow stop (e.g., due to disturbed Starling forces or intratumor solid stress). Acute hypoxia mainly results from transient disruptions in perfusion (e.g., vascular occlusion by cell aggregates), fluctuating red blood cell fluxes or short-term contractions of the interstitial matrix. In each of these hypoxia subtypes oxygen supply is critically reduced, but perfusion-dependent nutrient supply, waste removal, delivery of anticancer or diagnostic agents, and repair competence can be impaired or may not be affected. This detailed differentiation of tumor hypoxia may impact on our understanding of tumor biology and may aid in the development of novel treatment strategies, tumor detection by imaging and tumor targeting, and is thus of great clinical relevance. PMID:24729210

  7. Subtypes of Post-Traumatic Epilepsy: Clinical, Electrophysiological, and Imaging Features

    PubMed Central

    Gupta, Puneet K.; Sayed, Nasreen; Ding, Kan; Agostini, Mark A.; Van Ness, Paul C.; Yablon, Stuart; Madden, Christopher; Mickey, Bruce; D'Ambrosio, Raimondo

    2014-01-01

    Abstract Post-traumatic epilepsy (PTE) is a consequence of traumatic brain injury (TBI), occurring in 10–25% of patients with moderate to severe injuries. The development of animal models for testing antiepileptogenic therapies and validation of biomarkers to follow epileptogenesis in humans necessitates sophisticated understanding of the subtypes of PTE, which is the objective of this study. In this study, retrospective review was performed of patients with moderate to severe TBI with subsequent development of medically refractory epilepsy referred for video-electroencephalography (EEG) monitoring at a single center over a 10-year period. Information regarding details of injury, neuroimaging studies, seizures, video-EEG, and surgery outcomes were collected and analyzed. There were 123 patients with PTE identified, representing 4.3% of all patients evaluated in the epilepsy monitoring unit. Most of them had localization-related epilepsy, of which 57% had temporal lobe epilepsy (TLE), 35% had frontal lobe epilepsy (FLE), and 3% each had parietal and occipital lobe epilepsy. Of patients with TLE, 44% had mesial temporal sclerosis (MTS), 26% had temporal neocortical lesions, and 30% were nonlesional. There was no difference in age at injury between the different PTE subtypes. Twenty-two patients, 13 of whom had MTS, proceeded to surgical resection. At a mean follow-up of 2.5 years, Engel Class I outcomes were seen in 69% of those with TLE and 33% of those with FLE. Our findings suggest PTE is a heterogeneous condition, and careful evaluation with video-EEG monitoring and high resolution MRI can identify distinct syndromes. These results have implications for the design of clinical trials of antiepileptogenic therapies for PTE. PMID:24693960

  8. Subtypes of post-traumatic epilepsy: clinical, electrophysiological, and imaging features.

    PubMed

    Gupta, Puneet K; Sayed, Nasreen; Ding, Kan; Agostini, Mark A; Van Ness, Paul C; Yablon, Stuart; Madden, Christopher; Mickey, Bruce; D'Ambrosio, Raimondo; Diaz-Arrastia, Ramon

    2014-08-15

    Post-traumatic epilepsy (PTE) is a consequence of traumatic brain injury (TBI), occurring in 10-25% of patients with moderate to severe injuries. The development of animal models for testing antiepileptogenic therapies and validation of biomarkers to follow epileptogenesis in humans necessitates sophisticated understanding of the subtypes of PTE, which is the objective of this study. In this study, retrospective review was performed of patients with moderate to severe TBI with subsequent development of medically refractory epilepsy referred for video-electroencephalography (EEG) monitoring at a single center over a 10-year period. Information regarding details of injury, neuroimaging studies, seizures, video-EEG, and surgery outcomes were collected and analyzed. There were 123 patients with PTE identified, representing 4.3% of all patients evaluated in the epilepsy monitoring unit. Most of them had localization-related epilepsy, of which 57% had temporal lobe epilepsy (TLE), 35% had frontal lobe epilepsy (FLE), and 3% each had parietal and occipital lobe epilepsy. Of patients with TLE, 44% had mesial temporal sclerosis (MTS), 26% had temporal neocortical lesions, and 30% were nonlesional. There was no difference in age at injury between the different PTE subtypes. Twenty-two patients, 13 of whom had MTS, proceeded to surgical resection. At a mean follow-up of 2.5 years, Engel Class I outcomes were seen in 69% of those with TLE and 33% of those with FLE. Our findings suggest PTE is a heterogeneous condition, and careful evaluation with video-EEG monitoring and high resolution MRI can identify distinct syndromes. These results have implications for the design of clinical trials of antiepileptogenic therapies for PTE. PMID:24693960

  9. [Genomic diagnosis of thrombophilia in women: clinical relevance].

    PubMed

    Luxembourg, B; Lindhoff-Last, E

    2007-02-01

    The detection of the DNA-sequence of human coagulation factors and inhibitors has introduced the possibility of differentiated mutation analysis in patients with venous thrombosis. Since venous thromboembolism is a multifactorial disease, women are at an increased risk to develop venous thrombosis due to hormonal contraception, during pregnancy and the puerperium. In addition, pregnancy complications like early or late fetal loss, pregnancy-induced hypertensive disorders and very recently recurrent embryo implantation failure have been suspected to be associated with thrombophilia. Therefore, it is of major importance to define inherited thrombophilic disorders, in which genetic diagnosis is of clinical relevance. While most of the genetic defects described so far represent a risk factor for venous thrombosis, only a minority of these defects actually needs DNA analysis to be detected: mutation analysis is clinically relevant, when factor V Leiden mutation is suspected, because relative risks concerning venous thrombosis as well as pregnancy complications clearly differ between homozygote and heterozygote forms of this frequently observed mutation. Similarly detection of the prothrombin mutation G20210A is of clinical relevance, although data for the very rarely observed homozygote variant are not sufficiently available. In contrast, detection of the homozygote variant of the MTHFR-mutation C677T is not useful, since clinical relevance could not be proven in a majority of studies concerning women specific risk situations. Inherited deficiencies of antithrombin, protein C and protein S are rare with high rates of different mutations. Genetic analysis seems only useful in patients with wide intraindividual variations of coagulation inhibitor activities. Genetic analysis concerning the PAI-1 4G/5G polymorphism or the factor XIII Val34Leu polymorphism can not be recommended in women specific risk situations because of insufficient data. PMID:17279273

  10. Juxtaposed atrial appendages: A curiosity with some clinical relevance

    PubMed Central

    Singhi, Anil Kumar; Pradhan, Priya; Agarwal, Ravi; Sivakumar, Kothandum

    2016-01-01

    If the atrial appendages lie adjacent to each other on same side of the great arteries, instead of encircling their roots, they are referred as juxtaposed. Right juxtaposition of atrial appendages is less common than left juxtaposition. The images demonstrate the classical radiological, echocardiographic, and surgical images of juxtaposed atrial appendages. Their clinical incidence, associations, and relevance during interventional and surgical procedures are discussed. PMID:27212860

  11. Cutaneous and Mucosal Lichen Planus: A Comprehensive Review of Clinical Subtypes, Risk Factors, Diagnosis, and Prognosis

    PubMed Central

    2014-01-01

    Lichen planus (LP) is a chronic inflammatory disorder that most often affects middle-aged adults. LP can involve the skin or mucous membranes including the oral, vulvovaginal, esophageal, laryngeal, and conjunctival mucosa. It has different variants based on the morphology of the lesions and the site of involvement. The literature suggests that certain presentations of the disease such as esophageal or ophthalmological involvement are underdiagnosed. The burden of the disease is higher in some variants including hypertrophic LP and erosive oral LP, which may have a more chronic pattern. LP can significantly affect the quality of life of patients as well. Drugs or contact allergens can cause lichenoid reactions as the main differential diagnosis of LP. LP is a T-cell mediated immunologic disease but the responsible antigen remains unidentified. In this paper, we review the history, epidemiology, and clinical subtypes of LP. We also review the histopathologic aspects of the disease, differential diagnoses, immunopathogenesis, and the clinical and genetic correlations. PMID:24672362

  12. Clinically Relevant Cardiovascular Findings Detected on Staging Computed Tomography in Patients with Several Malignancies.

    PubMed

    Surov, Alexey; Bach, Andreas Gunter; Schramm, Dominik

    2016-08-01

    We evaluated the frequency and subtypes of clinically relevant cardiovascular (CV) findings identified on staging computed tomography (CT) in a large sample. Patients (n = 5026) with different malignant diseases were staged by CT. Clinically relevant CV findings (CRCFs) were included into the study. The CRCFs were defined as cardiac aneurysm, cardiac thrombus, venous thrombosis, arterial thrombosis, arterial dissection, pulmonary thromboembolism, arterial dissection, and dislocation of venous ports/central venous catheters. The CRCFs were identified in 342 patients (6.8% of all patients). Overall, 491 CRCFs were identified in the patients (1.4 per patient). In 203 (59.4%) patients, 1 CRCF; in 129, 2 (37.7%) CRCFs; and in 10 (2.9%) cases, 3 CRCFs were detected. There were incidental venous thrombosis (n = 298, 60.7% of all CRCFs), pulmonary thromboembolism (n = 84, 17.1%), arterial aneurysms (n = 44, 8.9%), arterial thrombosis (n = 43, 8.8%), heart thrombus (n = 15, 3.1%), arterial dissection (n = 3, 0.6%), heart aneurysms (n = 2, 0.4%), and port catheter dislocation (n = 2, 0.4%). The identified CRCF can be associated with potential hazardous complications. The CV system should be carefully evaluated in staging CT investigations. PMID:26399716

  13. Associations of Age, Gender, and Subtypes With ADHD Symptoms and Related Comorbidity in a Danish Sample of Clinically Referred Adults.

    PubMed

    Soendergaard, Helle Moeller; Thomsen, Per Hove; Pedersen, Erik; Pedersen, Pernille; Poulsen, Agnethe Elkjaer; Winther, Lars; Nielsen, Jette Moeskjaer; Henriksen, Anne; Rungoe, Berit; Soegaard, Hans Joergen

    2014-01-10

    Objective: The aim was to examine associations of age and gender with ADHD subtypes and subsequently to examine associations of age, gender, and subtypes with comorbid psychiatric disorders. Method: Odds ratios were calculated and logistic regression performed using information from a clinical sample of 155 ADHD adults referred to a Danish specialized ADHD unit from 2010 to 2011. Results: A majority of men (65%) was found in the sample. Most patients were subtyped ADHD combined (78%), followed by ADHD inattentive (18%), and ADHD hyperactive-impulsive (4%). No significant differences were found in gender and age across subtypes. Current comorbid disorders were found in 57% of the ADHD patients. Significantly more comorbidity was found in the ADHD combined type and in patients ≥25 years. Significantly more men had substance use disorders and significantly more women had personality disorders. Conclusion: When assessing adult ADHD patients' age, gender, subtype, and related comorbid symptom profiles should be taken into account. (J. of Att. Dis. XXXX; XX(X) XX-XX). PMID:24412968

  14. A Systematic Approach for Discovering Novel, Clinically Relevant Bacteria

    PubMed Central

    Simmon, Keith E.; Fisher, Mark A.

    2012-01-01

    Sequencing of the 16S rRNA gene (16S) is a reference method for bacterial identification. Its expanded use has led to increased recognition of novel bacterial species. In most clinical laboratories, novel species are infrequently encountered, and their pathogenic potential is often difficult to assess. We reviewed partial 16S sequences from >26,000 clinical isolates, analyzed during February 2006–June 2010, and identified 673 that have <99% sequence identity with valid reference sequences and are thus possibly novel species. Of these 673 isolates, 111 may represent novel genera (<95% identity). Isolates from 95 novel taxa were recovered from multiple patients, indicating possible clinical relevance. Most repeatedly encountered novel taxa belonged to the genera Nocardia (14 novel taxa, 42 isolates) and Actinomyces (12 novel taxa, 52 isolates). This systematic approach for recognition of novel species with potential diagnostic or therapeutic relevance provides a basis for epidemiologic surveys and improvement of sequence databases and may lead to identification of new clinical entities. PMID:22377371

  15. Inhibitory Functioning across ADHD Subtypes: Recent Findings, Clinical Implications, and Future Directions

    ERIC Educational Resources Information Center

    Adams, Zachary W.; Derefinko, Karen J.; Milich, Richard; Fillmore, Mark T.

    2008-01-01

    Although growing consensus supports the role of deficient behavioral inhibition as a central feature of the combined subtype of ADHD (ADHD/C; Barkley 1997 "Psychol Bull" 121:65-94; Nigg 2001 "Psychol Bull" 127:571-598), little research has focused on how this finding generalizes to the primarily inattentive subtype (ADHD/I). This question holds…

  16. Serum Level of Vascular Endothelial Growth Factor in Patients with Different Clinical SubtypeS of Oral Lichen Planus

    PubMed Central

    Mardani, Maryam; Ghabanchi, Jannan; Fattahi, Mohammad Javad; Tadbir, Azadeh Andisheh

    2012-01-01

    Background: Oral lichen planus is a chronic inflammatory disease with a poorly understood etiology. The role of angiogenesis in the development of different chronic inflammatory diseases is of great concern. Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis. We aimed to evaluate the serum level of VEGF in patients with oral lichen planus compared with normal individuals and consider its clinical significance. Methods: In this case-control study, 36 serum samples from patients diagnosed with oral lichen planus admitted to the Oral Medicine Department of the School of Dentistry at Shiraz University of Medical Sciences (14 men, 22 women, mean [±SD] age: 38.8 [±6.07] years) and 23 serum samples from healthy individuals (9 men, 14 women, mean [±SD] age: 38.7 [±4.9] years) were collected. VEGF concentration was measured using the ELISA method. The Mann-Whitney test was used for statistical analysis. Results: The serum VEGF level was significantly higher in patients with oral lichen planus compared with the healthy controls (112.97 [±63.2] vs. 66.21 [±56.2] ngr/ml, P<0.001). A similar difference was also observed between the two types of oral lichen planus, being more pronounced in the erosive form (P<0.001). Conclusion: Serum VEGF can be used as a useful and suitable marker to scrutinize the disease activity. PMID:23390328

  17. Lagooning of wastewaters favors dissemination of clinically relevant Pseudomonas aeruginosa.

    PubMed

    Petit, Stéphanie M-C; Lavenir, Raphaël; Colinon-Dupuich, Céline; Boukerb, Amine M; Cholley, Pascal; Bertrand, Xavier; Freney, Jean; Doléans-Jordheim, Anne; Nazaret, Sylvie; Laurent, Frédéric; Cournoyer, Benoit

    2013-10-01

    The significance of wastewater treatment lagoons (WWTLs) as point sources of clinically relevant Pseudomonas aeruginosa that can disseminate through rural and peri-urban catchments was investigated. A panel of P. aeruginosa strains collected over three years from WWTLs and community-acquired infections was compared by pulsed field gel electrophoresis (PFGE) DNA fingerprinting and multilocus sequence typing (MLST). Forty-four distantly related PFGE profiles and four clonal complexes were found among the WWTL strains analyzed. Some genotypes were repeatedly detected from different parts of WWTLs, including the influent, suggesting an ability to migrate and persist over time. MLST showed all investigated lineages to match sequence types described in other countries and strains from major clinical clones such as PA14 of ST253 and "C" of ST17 were observed. Some of these genotypes matched isolates from community-acquired infections recorded in the WWTL geographic area. Most WWTL strains harbored the main P. aeruginosa virulence genes; 13% harbored exoU-encoded cytoxins, but on at least six different genomic islands, with some of these showing signs of genomic instability. P. aeruginosa appeared to be highly successful opportunistic colonizers of WWTLs. Lagooning of wastewaters was found to favor dissemination of clinically relevant P. aeruginosa among peri-urban watersheds. PMID:23792168

  18. Real time and label free profiling of clinically relevant exosomes.

    PubMed

    Sina, Abu Ali Ibn; Vaidyanathan, Ramanathan; Dey, Shuvashis; Carrascosa, Laura G; Shiddiky, Muhammad J A; Trau, Matt

    2016-01-01

    Tumor-derived exosomes possess significant clinical relevance due to their unique composition of genetic and protein material that is representative of the parent tumor. Specific isolation as well as identification of proportions of these clinically relevant exosomes (CREs) from biological samples could help to better understand their clinical significance as cancer biomarkers. Herein, we present a simple approach for quantification of the proportion of CREs within the bulk exosome population isolated from patient serum. This proportion of CREs can potentially inform on the disease stage and enable non-invasive monitoring of inter-individual variations in tumor-receptor expression levels. Our approach utilises a Surface Plasmon Resonance (SPR) platform to quantify the proportion of CREs in a two-step strategy that involves (i) initial isolation of bulk exosome population using tetraspanin biomarkers (i.e., CD9, CD63), and (ii) subsequent detection of CREs within the captured bulk exosomes using tumor-specific markers (e.g., human epidermal growth factor receptor 2 (HER2)). We demonstrate the isolation of bulk exosome population and detection of as low as 10% HER2(+) exosomes from samples containing designated proportions of HER2(+) BT474 and HER2(-) MDA-MB-231 cell derived exosomes. We also demonstrate the successful isolation of exosomes from a small cohort of breast cancer patient samples and identified that approximately 14-35% of their bulk population express HER2. PMID:27464736

  19. Clinically Relevant Pharmacokinetic Herb-drug Interactions in Antiretroviral Therapy.

    PubMed

    Fasinu, Pius S; Gurley, Bill J; Walker, Larry A

    2015-01-01

    For healthcare professionals, the volume of literature available on herb-drug interactions often makes it difficult to separate experimental/potential interactions from those deemed clinically relevant. There is a need for concise and conclusive information to guide pharmacotherapy in HIV/AIDS. In this review, the bases for potential interaction of medicinal herbs with specific antiretroviral drugs are presented, and several botanicals are discussed for which clinically relevant interactions in humans are established. Such studies have provided, in most cases, sufficient ground to warrant the avoidance of concurrent administration of antiretroviral (ARVs) drugs with St John's wort (Hypericum perforatum), black pepper (Piper species) and grapefruit juice. Other botanicals that require caution in the use with antiretrovirals include African potato (Hypoxis hemerocallidea), ginkgo (Ginkgo biloba), ginseng (Panax species), garlic (Allium sativum), goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum). The knowledge of clinically significant herb-drug interaction will be important in order to avoid herb-induced risk of sub-therapeutic exposure to ARVs (which can lead to viral resistance) or the precipitation of toxicity (which may lead to poor compliance and/or discontinuation of antiretroviral therapy). PMID:26526838

  20. Real time and label free profiling of clinically relevant exosomes

    PubMed Central

    Sina, Abu Ali Ibn; Vaidyanathan, Ramanathan; Dey, Shuvashis; Carrascosa, Laura G.; Shiddiky, Muhammad J. A.; Trau, Matt

    2016-01-01

    Tumor-derived exosomes possess significant clinical relevance due to their unique composition of genetic and protein material that is representative of the parent tumor. Specific isolation as well as identification of proportions of these clinically relevant exosomes (CREs) from biological samples could help to better understand their clinical significance as cancer biomarkers. Herein, we present a simple approach for quantification of the proportion of CREs within the bulk exosome population isolated from patient serum. This proportion of CREs can potentially inform on the disease stage and enable non-invasive monitoring of inter-individual variations in tumor-receptor expression levels. Our approach utilises a Surface Plasmon Resonance (SPR) platform to quantify the proportion of CREs in a two-step strategy that involves (i) initial isolation of bulk exosome population using tetraspanin biomarkers (i.e., CD9, CD63), and (ii) subsequent detection of CREs within the captured bulk exosomes using tumor-specific markers (e.g., human epidermal growth factor receptor 2 (HER2)). We demonstrate the isolation of bulk exosome population and detection of as low as 10% HER2(+) exosomes from samples containing designated proportions of HER2(+) BT474 and HER2(−) MDA-MB-231 cell derived exosomes. We also demonstrate the successful isolation of exosomes from a small cohort of breast cancer patient samples and identified that approximately 14–35% of their bulk population express HER2. PMID:27464736

  1. Biological and clinical relevance of stem cells in pancreatic adenocarcinoma

    PubMed Central

    Rasheed, Zeshaan A; Matsui, William

    2013-01-01

    Cancer stem cells (CSC) have been identified in a growing number of human malignancies. CSC are functionally defined by their ability to self-renew and recapitulate tumors in the ectopic setting, and a growing number of studies have shown that they display other functional characteristics, such as invasion and drug resistance. These unique functional properties implicate a role for CSC in clinical consequences, such as initial tumor formation, relapse following treatment, metastasis, and resistance, suggesting they are a major factor in directing clinical outcomes. Pancreatic adenocarcinoma is a highly-aggressive disease with a propensity for early metastasis and drug resistance. Tumorigenic pancreatic cancer cells have been identified using the cell surface antigens CD44, CD24, and CD133, as well as the high expression of aldehyde dehydrogenase (ALDH). In vitro and in vivo studies have shown that ALDH- and CD133-expressing pancreatic CSC have a greater propensity for metastasis, and ALDH-expressing CSC have been shown to be resistant to conventional chemotherapy. In clinical samples from patients with resected pancreatic adenocarcinoma, the presence of ALDH-expressing CSC was associated with worse overall survival. The development of CSC-targeting therapies might be important in changing the clinical outcomes of patients with this disease, and others and we have begun to identify novel compounds that block CSC function. This review will discuss the biological and clinical relevance of CSC in pancreatic cancer, and will discuss novel therapeutic strategies to target them. PMID:22320910

  2. Nonmotor Symptoms in Parkinson's Disease in 2012: Relevant Clinical Aspects

    PubMed Central

    Bonnet, Anne Marie; Jutras, Marie France; Czernecki, Virginie; Corvol, Jean Christophe; Vidailhet, Marie

    2012-01-01

    Nonmotor symptoms (NMSs) of Parkinson's disease (PD) are common, but they are often underrecognized in clinical practice, because of the lack of spontaneous complaints by the patients, and partly because of the absence of systematic questioning by the consulting physician. However, valid specific instruments for identification and assessment of these symptoms are available in 2012. The administration of the self-completed screening tool, NMSQuest, associated with questioning during the consultation, improves the diagnosis of NMSs. NMSs play a large role in degradation of quality of life. More relevant NMSs are described in this review, mood disorders, impulse control disorders, cognitive deficits, hallucinations, pain, sleep disorders, and dysautonomia. PMID:22888466

  3. Quantifying Clinical Relevance in the Treatment of Schizophrenia

    PubMed Central

    Correll, Christoph U.; Kishimoto, Taishiro; Nielsen, Jimmi; Kane, John M.

    2012-01-01

    Background To optimize the management of patients with schizophrenia, quantification of treatment effects is crucial. While in research studies, the use of quantitative assessments is ubiquitous; this is not the case in routine clinical practice, creating an important translational practice gap. Objective To examine the relevance, methodology, reporting and application of measurement based approaches in the management of schizophrenia. Methods We summarize methodological aspects in the assessment of therapeutic and adverse antipsychotic effects in schizophrenia, including definitions and methods of measurement based assessments and factors that can interfere with the valid quantification of treatment effects. Finally, we propose pragmatic and clinically meaningful ways to measure and report treatment outcomes. Results While rating scales are ubiquitous in schizophrenia research and provide the evidence base for treatment guidelines, time constraints, lack of familiarity with and/or training in validated assessment tools limits their routine clinical use. Simple, but valid assessment instruments need to be developed and implemented to bridge this research-practice gap. Moreover, results from research trials need to be communicated in clinically meaningful ways. This includes the reporting of effect sizes, numbers-needed-to-treat and -harm, confidence intervals and absolute risk differences. Some important outcomes, such as treatment response, should be reported in escalating intervals using incrementally more stringent psychopathology improvements. Nevertheless, even with quantification, it remains challenging to weigh individual efficacy and adverse effect outcomes against each other and to decide on the targeted/desired improvement or outcome, while also incorporating that in patient-centered and shared decision methods. Conclusions Quantification of treatment effects in schizophrenia is relevant for patient management, research, and the evaluation of health care

  4. Clinical relevance of dissolution testing in quality by design.

    PubMed

    Dickinson, Paul A; Lee, Wang Wang; Stott, Paul W; Townsend, Andy I; Smart, John P; Ghahramani, Parviz; Hammett, Tracey; Billett, Linda; Behn, Sheena; Gibb, Ryan C; Abrahamsson, Bertil

    2008-06-01

    Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes. In vitro dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of in vitro dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables, in vivo relevance of in vitro dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound. PMID:18686045

  5. Laboratory Exercises to Teach Clinically Relevant Chemistry of Antibiotics

    PubMed Central

    Chelette, Candace T.

    2014-01-01

    Objectives. To design, implement, and evaluate student performance on clinically relevant chemical and spectral laboratory exercises on antibiotics. Design. In the first of 2 exercises, second-year pharmacy students enrolled in an integrated laboratory sequence course studied the aqueous stability of ß-lactam antibiotics using a spectral visual approach. In a second exercise, students studied the tendency of tetracycline, rifamycins, and fluoroquinolones to form insoluble chelate complexes (turbidity) with polyvalent metals. Assessment. On a survey to assess achievement of class learning objectives, students agreed the laboratory activities helped them better retain important information concerning antibiotic stability and interactions. A significant improvement was observed in performance on examination questions related to the laboratory topics for 2012 and 2013 students compared to 2011 students who did not complete the laboratory. A 1-year follow-up examination question administered in a separate course showed >75% of the students were able to identify rifamycins-food interactions compared with <25% of students who had not completed the laboratory exercises. Conclusion. The use of spectral visual approaches allowed students to investigate antibiotic stability and interactions, thus reinforcing the clinical relevance of medicinal chemistry. Students’ performance on questions at the 1-year follow-up suggested increased retention of the concepts learned as a result of completing the exercises. PMID:24672070

  6. [Cross reactivity of food allergens and its clinical relevance].

    PubMed

    Moneret-Vautrin, Denise Anne

    2005-10-01

    Cross-reactions between food allergens and other allergens are a major focus of interest. They include cross-allergies between Betulaceae and Compositae pollen, and also between fruits and vegetables (Prunoideae and Apiaceae). Cross-allergies between animal allergens include mites, cockroaches and crustaceans, milk and meat, animal epithelia, meat and egg. Cross-reactivity results from homology between protein sequences, and is highly likely when this homology reaches about 70%. Phylogenetically similar proteins occur in all species and are known as pan allergens. Profilins, Bet v1 homologues, and lipid transfer proteins have varying degrees of clinical relevance. The involvement of cross-reactivity in the persistence of sensitization and in allergic disorders is unclear. The consequences of cross-reactivity during specific immunotherapy with total allergenic extracts are random. Interpretation of biological tests of IgE binding is also biased by cross-reactivity. The use of panels of major recombinant allergens should help to identify specific sensitization profiles as well as clinically relevant sensitization. Cross-reactivity between epitopes of inhalants and of food allergens may perpetuate and intensify allergic disorders. The consequences of cross-reactivity between allergens and autologous proteins are unknown. PMID:16669147

  7. Degree of Glutathione Deficiency and Redox Imbalance Depend on Subtype of Mitochondrial Disease and Clinical Status

    PubMed Central

    Enns, Gregory M.; Moore, Tereza; Le, Anthony; Atkuri, Kondala; Shah, Monisha K.; Cusmano-Ozog, Kristina; Niemi, Anna-Kaisa; Cowan, Tina M.

    2014-01-01

    Mitochondrial disorders are associated with decreased energy production and redox imbalance. Glutathione plays a central role in redox signaling and protecting cells from oxidative damage. In order to understand the consequences of mitochondrial dysfunction on in vivo redox status, and to determine how this varies by mitochondrial disease subtype and clinical severity, we used a sensitive tandem mass spectrometry assay to precisely quantify whole blood reduced (GSH) and oxidized (GSSG) glutathione levels in a large cohort of mitochondrial disorder patients. Glutathione redox potential was calculated using the Nernst equation. Compared to healthy controls (n = 59), mitochondrial disease patients (n = 58) as a group showed significant redox imbalance (redox potential −251 mV±9.7, p<0.0001) with an increased level of oxidation by ∼9 mV compared to controls (−260 mV±6.4). Underlying this abnormality were significantly lower whole blood GSH levels (p = 0.0008) and GSH/GSSG ratio (p = 0.0002), and significantly higher GSSG levels (p<0.0001) in mitochondrial disease patients compared to controls. Redox potential was significantly more oxidized in all mitochondrial disease subgroups including Leigh syndrome (n = 15), electron transport chain abnormalities (n = 10), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (n = 8), mtDNA deletion syndrome (n = 7), mtDNA depletion syndrome (n = 7), and miscellaneous other mitochondrial disorders (n = 11). Patients hospitalized in metabolic crisis (n = 7) showed the greatest degree of redox imbalance at −242 mV±7. Peripheral whole blood GSH and GSSG levels are promising biomarkers of mitochondrial dysfunction, and may give insights into the contribution of oxidative stress to the pathophysiology of the various mitochondrial disorders. In particular, evaluation of redox potential may be useful in monitoring of clinical status or response to redox

  8. Fine Mapping Major Histocompatibility Complex Associations in Psoriasis and Its Clinical Subtypes

    PubMed Central

    Okada, Yukinori; Han, Buhm; Tsoi, Lam C.; Stuart, Philip E.; Ellinghaus, Eva; Tejasvi, Trilokraj; Chandran, Vinod; Pellett, Fawnda; Pollock, Remy; Bowcock, Anne M.; Krueger, Gerald G.; Weichenthal, Michael; Voorhees, John J.; Rahman, Proton; Gregersen, Peter K.; Franke, Andre; Nair, Rajan P.; Abecasis, Gonçalo R.; Gladman, Dafna D.; Elder, James T.; de Bakker, Paul I.W.; Raychaudhuri, Soumya

    2014-01-01

    Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C∗06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10−364). Stepwise analysis revealed multiple HLA-C∗06:02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C∗12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10−8), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (pomnibus = 2.2 × 10−11), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC. PMID:25087609

  9. Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes.

    PubMed

    Okada, Yukinori; Han, Buhm; Tsoi, Lam C; Stuart, Philip E; Ellinghaus, Eva; Tejasvi, Trilokraj; Chandran, Vinod; Pellett, Fawnda; Pollock, Remy; Bowcock, Anne M; Krueger, Gerald G; Weichenthal, Michael; Voorhees, John J; Rahman, Proton; Gregersen, Peter K; Franke, Andre; Nair, Rajan P; Abecasis, Gonçalo R; Gladman, Dafna D; Elder, James T; de Bakker, Paul I W; Raychaudhuri, Soumya

    2014-08-01

    Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C(∗)06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10(-364)). Stepwise analysis revealed multiple HLA-C(∗)06:02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C(∗)12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10(-8)), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (Pomnibus = 2.2 × 10(-11)), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC. PMID:25087609

  10. Clinical Differences between Subtypes of Atrial Fibrillation and Flutter: Cross-Sectional Registry of 407 Patients

    PubMed Central

    Almeida, Eduardo Dytz; Guimarães, Raphael Boesche; Stephan, Laura Siga; Medeiros, Alexandre Kreling; Foltz, Katia; Santanna, Roberto Tofani; Pires, Leonardo Martins; Kruse, Marcelo Lapa; de Lima, Gustavo Glotz; Leiria, Tiago Luiz Luz

    2015-01-01

    Introduction Atrial fibrillation and atrial flutter account for one third of hospitalizations due to arrhythmias, determining great social and economic impacts. In Brazil, data on hospital care of these patients is scarce. Objective To investigate the arrhythmia subtype of atrial fibrillation and flutter patients in the emergency setting and compare the clinical profile, thromboembolic risk and anticoagulants use. Methods Cross-sectional retrospective study, with data collection from medical records of every patient treated for atrial fibrillation and flutter in the emergency department of Instituto de Cardiologia do Rio Grande do Sul during the first trimester of 2012. Results We included 407 patients (356 had atrial fibrillation and 51 had flutter). Patients with paroxysmal atrial fibrillation were in average 5 years younger than those with persistent atrial fibrillation. Compared to paroxysmal atrial fibrillation patients, those with persistent atrial fibrillation and flutter had larger atrial diameter (48.6 ± 7.2 vs. 47.2 ± 6.2 vs. 42.3 ± 6.4; p < 0.01) and lower left ventricular ejection fraction (66.8 ± 11 vs. 53.9 ± 17 vs. 57.4 ± 16; p < 0.01). The prevalence of stroke and heart failure was higher in persistent atrial fibrillation and flutter patients. Those with paroxysmal atrial fibrillation and flutter had higher prevalence of CHADS2 score of zero when compared to those with persistent atrial fibrillation (27.8% vs. 18% vs. 4.9%; p < 0.01). The prevalence of anticoagulation in patients with CHA2DS2-Vasc ≤ 2 was 40%. Conclusions The population in our registry was similar in its comorbidities and demographic profile to those of North American and European registries. Despite the high thromboembolic risk, the use of anticoagulants was low, revealing difficulties for incorporating guideline recommendations. Public health strategies should be adopted in order to improve these rates. PMID:26016782

  11. A magnetic resonance imaging study of adhesio interthalamica in clinical subtypes of schizophrenia

    PubMed Central

    Haghir, Hossein; Mokhber, Naghmeh; Azarpazhooh, Mahmoud-Reza; Haghighi, Mehri Baghban; Radmard, Mahla

    2013-01-01

    Context: Previous studies have suggested subtle anatomical brain differences between patients with schizophrenia and healthy control subjects. However, the results are inconsistent and there is no study investigating the various subtypes of this mental disorder separately. Aim: This study was conducted to compare the rate of absence of adhesio interthalamica (AI), a midline brain structure, between 3 subtypes of schizophrenia (paranoid, undifferentiated, and residual) and healthy control group, using magnetic resonance imaging (MRI). Materials and Methods: A total of 29 schizophrenia patients (21 men, 8 women) of three subtypes (paranoid, undifferentiated, and residual) were compared with 29 age- and gender-matched healthy controls. All subjects underwent 3-D brain MRI of full coronal series, 1.5-mm slices without interslice gaps. If the grey matter band connecting the thalami could not be identified on two or more coronal adjacent slices, the AI was considered as absent. The results were statistically analyzed. Results: The incidence rate of AI absence in patients with heterogenous subtypes of schizophrenia was was similar to control group, even when patients and controls of each gender were compared separately (P>0.05). In residual subtype, patients showed a significant priority in AI absence in comparison with the control group (P=0.041), which was not seen in paranoid and undifferentiated subtypes (P>0.05). Conclusion: Residual subtype of schizophrenia is associated with higher rate of AI absence in this study. Subsequent studies are required to determine if the absence of AI is a cause of residual schizophrenia or an effect. PMID:23825846

  12. Development of Clinically Relevant Implantable Pressure Sensors: Perspectives and Challenges

    PubMed Central

    Clausen, Ingelin; Glott, Thomas

    2014-01-01

    This review describes different aspects to consider when developing implantable pressure sensor systems. Measurement of pressure is in general highly important in clinical practice and medical research. Due to the small size, light weight and low energy consumption Micro Electro Mechanical Systems (MEMS) technology represents new possibilities for monitoring of physiological parameters inside the human body. Development of clinical relevant sensors requires close collaboration between technological experts and medical clinicians. Site of operation, size restrictions, patient safety, and required measurement range and resolution, are only some conditions that must be taken into account. An implantable device has to operate under very hostile conditions. Long-term in vivo pressure measurements are particularly demanding because the pressure sensitive part of the sensor must be in direct or indirect physical contact with the medium for which we want to detect the pressure. New sensor packaging concepts are demanded and must be developed through combined effort between scientists in MEMS technology, material science, and biology. Before launching a new medical device on the market, clinical studies must be performed. Regulatory documents and international standards set the premises for how such studies shall be conducted and reported. PMID:25248071

  13. Cognitive control in alcohol use disorder: deficits and clinical relevance

    PubMed Central

    Wilcox, Claire E.; Dekonenko, Charlene J.; Mayer, Andrew R.; Bogenschutz, Michael P.; Turner, Jessica A.

    2014-01-01

    Cognitive control refers to the internal representation, maintenance, and updating of context information in the service of exerting control over thoughts and behavior. Deficits in cognitive control likely contribute to difficulty in maintaining abstinence in individuals with alcohol use disorders (AUD). In this article, we define three cognitive control processes in detail (response inhibition, distractor interference control, and working memory), review the tasks measuring performance in these areas, and summarize the brain networks involved in carrying out these processes. Next, we review evidence of deficits in these processes in AUD, including both metrics of task performance and functional neuroimaging. Finally, we explore the clinical relevance of these deficits by identifying predictors of clinical outcome and markers that appear to change (improve) with treatment. We observe that individuals with AUD experience deficits in some, but not all, metrics of cognitive control. Deficits in cognitive control may predict clinical outcome in AUD, but more work is necessary to replicate findings. It is likely that performance on tasks requiring cognitive control improves with abstinence, and with some psychosocial and medication treatments. Future work should clarify which aspects of cognitive control are most important to target during treatment of AUD. PMID:24361772

  14. Clinical efficacy of serum lipase subtype analysis for the differential diagnosis of pancreatic and non-pancreatic lipase elevation

    PubMed Central

    Bang, Chang Seok; Kim, Jin Bong; Park, Sang Hyun; Baik, Gwang Ho; Su, Ki Tae; Yoon, Jai Hoon; Kim, Yeon Soo; Kim, Dong Joon

    2016-01-01

    Background/Aims: Non-pancreatic elevations of serum lipase have been reported, and differential diagnosis is necessary for clinical practice. This study aimed to evaluate the clinical efficacy of serum lipase subtype analysis for the differential diagnosis of pancreatic and non-pancreatic lipase elevation. Methods: Patients who were referred for the serum lipase elevation were prospectively enrolled. Clinical findings and serum lipase subtypes were analyzed and compared by dividing the patients into pancreatitis and non-pancreatitis groups. Results: A total of 34 patients (12 pancreatitis vs. 22 non-pancreatitis cases) were enrolled. In univariate analysis, the fraction of pancreatic lipase (FPL) in the total amount of serum lipase subtypes was statistically higher in patients with pancreatitis ([median, 0.004; interquartile range [IQR], 0.003 to 0.011] vs. [median, 0.002; IQR, 0.001 to 0.004], p = 0.04). Based on receiver operating characteristic curve analysis for the prediction of acute pancreatitis, FPL was the most valuable predictor (area under the receiver-operating characteristic curve [AUROC], 0.72; 95% confidence interval [CI], 0.54 to 0.86; sensitivity, 83.3%; specificity, 63.6%; positive predictive value, 55.6%; negative predictive value, 97.5%). In multivariate analysis, a cut-off value higher than 0.0027 for the FPL was associated with acute pancreatitis (odds ratio, 8.3; 95% CI, 1.3 to 51.7; p = 0.02). Conclusions: The results did not support that serum lipase subtype analysis could replace standard lipase measurement for the diagnosis of acute pancreatitis. However, the test demonstrated adequate sensitivity for use in triage or as an add-on test for serum lipase elevation. PMID:27243230

  15. [Endpoints in clinical trials and their relevance for patients].

    PubMed

    Faber, Ulrike

    2010-01-01

    Patient participation, which has been established since 2004, has brought more attention to patients' concerns in healthcare. More and more endpoints in clinical trials are defined with respect to their relevance for patients. But this development has still been found wanting. For important drugs, no evidence-based benefit has been demonstrated in the benefit assessment, which also has become possible since 2004. Furthermore, this assessment has arrived too late for patients who have been medicated for a long time. Healthcare policies, applicants and stakeholders have contributed a lot to the patients' scepticism towards benefit assessments, though, in principle, patients are interested in high evidence levels and reasonable pricing. New drugs are often licensed under less ambitious conditions. Whether this is in the patients' interest needs to be put up for a large-scale, and societal, discussion. PMID:20608257

  16. Molecular Subtypes of Breast Cancer Are Not Associated with the Clinical Under- or Overstaging of Breast Cancer.

    PubMed

    Espinola, Juliana Pinho; Peres, Raquel Mary Rodrigues; Serra, Kátia Piton; Derchain, Sophie Françoise Mauricette; Sarian, Luis Otávio

    2016-05-01

    Purpose to evaluate the agreement between the clinical and pathological stagings of breast cancer based on clinical and molecular features. Methods this was a cross-sectional study, in which clinical, epidemiological and pathological data were collected from 226 patients who underwent surgery at the Prof. Dr. José Aristodemo Pinotti Women's Hospital (CAISM/Unicamp) from January 2008 to September 2010. Patients were staged clinically and pathologically, and were classified as: understaged, when the clinical staging was lower than the pathological staging; correctly staged, when the clinical staging was the same as the pathological one; and overstaged, when the clinical staging was greater than the pathological staging. Results understaged patients were younger (52.2 years; p < 0.01) and more symptomatic at diagnosis (p = 0.04) when compared with correctly or overstaged patients. Clinicopathological surrogate subtype, menopausal status, parity, hormone replace therapy and histology were not associated with differences in staging. Women under 57 years of age were clinically understaged mainly due to underestimation of T (tumor staging) (p < 0.001), as were the premenopausal women (p < 0.01). Patients whose diagnosis was made due to clinical complaints, and not by screening, were clinically understaged due to underestimation of N (lymph nodes staging) (p < 0.001). Conclusion the study shows that the clinicopathological surrogate subtype is not associated with differences in staging, while younger women diagnosed because of clinical complaints tend to have their breast tumors understaged during clinical evaluation. PMID:27187929

  17. Streptococcus pyogenes biofilms—formation, biology, and clinical relevance

    PubMed Central

    Fiedler, Tomas; Köller, Thomas; Kreikemeyer, Bernd

    2015-01-01

    Streptococcus pyogenes (group A streptococci, GAS) is an exclusive human bacterial pathogen. The virulence potential of this species is tremendous. Interactions with humans range from asymptomatic carriage over mild and superficial infections of skin and mucosal membranes up to systemic purulent toxic-invasive disease manifestations. Particularly the latter are a severe threat for predisposed patients and lead to significant death tolls worldwide. This places GAS among the most important Gram-positive bacterial pathogens. Many recent reviews have highlighted the GAS repertoire of virulence factors, regulators and regulatory circuits/networks that enable GAS to colonize the host and to deal with all levels of the host immune defense. This covers in vitro and in vivo studies, including animal infection studies based on mice and more relevant, macaque monkeys. It is now appreciated that GAS, like many other bacterial species, do not necessarily exclusively live in a planktonic lifestyle. GAS is capable of microcolony and biofilm formation on host cells and tissues. We are now beginning to understand that this feature significantly contributes to GAS pathogenesis. In this review we will discuss the current knowledge on GAS biofilm formation, the biofilm-phenotype associated virulence factors, regulatory aspects of biofilm formation, the clinical relevance, and finally contemporary treatment regimens and future treatment options. PMID:25717441

  18. Different aspects of dysexecutive syndrome in patients with moyamoya disease and its clinical subtypes.

    PubMed

    Fang, Lingling; Huang, Jia; Zhang, Qian; Chan, Raymond C K; Wang, Rong; Wan, Weiqing

    2016-08-01

    OBJECTIVE Dysexecutive syndrome is common in patients with moyamoya disease (MMD), a chronic cerebrovascular disease that is characterized by stenosis of the bilateral internal carotid arteries and progressive collateral revascularization, and MMD can be classified as ischemic or hemorrhagic according to the disease presentation and history. In this study, the authors aimed to determine which aspects of executive function are impaired in patients with MMD, in addition to the specific dysexecutive functions present among its clinical subtypes and the mechanisms underlying dysexecutive function in these patients. METHODS The authors administered 5 typical executive function tests (the Stroop test, the Hayling Sentence Completion Test [HSCT], the verbal fluency [VF] test, the N-back test, and the Sustained Attention to Response Task [SART]) to 49 patients with MMD and 47 IQ-, age-, education-, and social status-matched healthy controls. The dysexecutive questionnaire (DEX) was also used to assess participants' subjective feelings about their executive function. A total of 39 of the patients were evaluated by CT perfusion (CTP) before the assessments were performed, and the correlations among the performances of the patients on the above tests with the parameters of cerebral blood volume, cerebral blood flow (CBF), mean transit time (MTT), and time-to-peak (TTP) in the frontal lobes of these patients were also analyzed. RESULTS Many aspects of executive function in the patients with MMD were significantly poorer than those in the healthy controls, and the patients performed particularly poorer on the VF test, HSCT, N-back test, and SART. The patients with hemorrhagic MMD exhibited worse executive inhibition, executive processing, and semantic inhibition compared with those with ischemic MMD, but the latter group presented a worse working memory and poorer sustained attention. There were no significant differences in the DEX scores between the patients with MMD and

  19. Clinically and pharmacologically relevant interactions of antidiabetic drugs.

    PubMed

    May, Marcus; Schindler, Christoph

    2016-04-01

    Patients with type 2 diabetes mellitus often require multifactorial pharmacological treatment due to different comorbidities. An increasing number of concomitantly taken medications elevate the risk of the patient experiencing adverse drug effects or drug interactions. Drug interactions can be divided into pharmacokinetic and pharmacodynamic interactions affecting cytochrome (CYP) enzymes, absorption properties, transporter activities and receptor affinities. Furthermore, nutrition, herbal supplements, patient's age and gender are of clinical importance. Relevant drug interactions are predominantly related to sulfonylureas, thiazolidinediones and glinides. Although metformin has a very low interaction potential, caution is advised when drugs that impair renal function are used concomitantly. With the exception of saxagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitors also show a low interaction potential, but all drugs affecting the drug transporter P-glycoprotein should be used with caution. Incretin mimetics and sodium-glucose cotransporter-2 (SGLT-2) inhibitors comprise a very low interaction potential and are therefore recommended as an ideal combination partner from the clinical-pharmacologic point of view. PMID:27092232

  20. Dissociative absorption: An empirically unique, clinically relevant, dissociative factor.

    PubMed

    Soffer-Dudek, Nirit; Lassri, Dana; Soffer-Dudek, Nir; Shahar, Golan

    2015-11-01

    Research of dissociative absorption has raised two questions: (a) Is absorption a unique dissociative factor within a three-factor structure, or a part of one general dissociative factor? Even when three factors are found, the specificity of the absorption factor is questionable. (b) Is absorption implicated in psychopathology? Although commonly viewed as "non-clinical" dissociation, absorption was recently hypothesized to be specifically associated with obsessive-compulsive symptoms. To address these questions, we conducted exploratory and confirmatory factor analyses on 679 undergraduates. Analyses supported the three-factor model, and a "purified" absorption scale was extracted from the original inclusive absorption factor. The purified scale predicted several psychopathology scales. As hypothesized, absorption was a stronger predictor of obsessive-compulsive symptoms than of general psychopathology. In addition, absorption was the only dissociative scale that longitudinally predicted obsessive-compulsive symptoms. We conclude that absorption is a unique and clinically relevant dissociative tendency that is particularly meaningful to obsessive-compulsive symptoms. PMID:26241024

  1. Clinically relevant interpretation of solid phase assays for HLA antibody

    PubMed Central

    Bettinotti, Maria P.; Zachary, Andrea A.; Leffell, Mary S.

    2016-01-01

    Purpose of review Accurate and timely detection and characterization of human leukocyte antigen (HLA) antibodies are critical for pre-transplant and post-transplant immunological risk assessment. Solid phase immunoassays have provided increased sensitivity and specificity, but test interpretation is not always straightforward. This review will discuss the result interpretation considering technical limitations; assessment of relative antibody strength; and the integration of data for risk stratification from complementary testing and the patient's immunological history. Recent findings Laboratory and clinical studies have provided insight into causes of test failures – false positive reactions because of antibodies to denatured HLA antigens and false negative reactions resulting from test interference and/or loss of native epitopes. Test modifications permit detection of complement-binding antibodies and determination of the IgG subclasses. The high degree of specificity of single antigen solid phase immunoassays has revealed the complexity and clinical relevance of antibodies to HLA-C, HLA-DQ, and HLA-DP antigens. Determination of antibody specificity for HLA epitopes enables identification of incompatible antigens not included in test kits. Summary Detection and characterization of HLA antibodies with solid phase immunoassays has led to increased understanding of the role of those antibodies in graft rejection, improved treatment of antibody-mediated rejection, and increased opportunities for transplantation. However, realization of these benefits requires careful and accurate interpretation of test results. PMID:27200498

  2. Resveratrol and Calcium Signaling: Molecular Mechanisms and Clinical Relevance

    PubMed Central

    McCalley, Audrey E.; Kaja, Simon; Payne, Andrew J.; Koulen, Peter

    2014-01-01

    Resveratrol is a naturally occurring compound contributing to cellular defense mechanisms in plants. Its use as a nutritional component and/or supplement in a number of diseases, disorders, and syndromes such as chronic diseases of the central nervous system, cancer, inflammatory diseases, diabetes, and cardiovascular diseases has prompted great interest in the underlying molecular mechanisms of action. The present review focuses on resveratrol, specifically its isomer trans-resveratrol, and its effects on intracellular calcium signaling mechanisms. As resveratrol's mechanisms of action are likely pleiotropic, its effects and interactions with key signaling proteins controlling cellular calcium homeostasis are reviewed and discussed. The clinical relevance of resveratrol's actions on excitable cells, transformed or cancer cells, immune cells and retinal pigment epithelial cells are contrasted with a review of the molecular mechanisms affecting calcium signaling proteins on the plasma membrane, cytoplasm, endoplasmic reticulum, and mitochondria. The present review emphasizes the correlation between molecular mechanisms of action that have recently been identified for resveratrol and their clinical implications. PMID:24905603

  3. Clinically Relevant Measures of Fit? A Note of Caution

    PubMed Central

    Cook, Nancy R.

    2012-01-01

    Risk reclassification methods have become popular in the medical literature as a means of comparing risk prediction models. In this issue of the Journal, Pencina et al. (Am J Epidemiol. 2012;176(6):492–494) present further results for continuous measures of model discrimination and describe their characteristics in nested models with normally distributed variables. Measures include the change in the area under the receiver operating characteristic curve, the integrated discrimination improvement, and the continuous net reclassification improvement. Although theoretically interesting, these continuous measures may not be the most appropriate to assess clinical utility. The continuous net reclassification improvement, in particular, is a measure of effect rather than model improvement and can sometimes exhibit erratic behavior, as illustrated in 2 examples. Caution is needed before using this as a measure of improvement. Further, the test of the continuous net reclassification improvement and that for the integrated discrimination improvement are similar to the likelihood ratio test in nested models and may be overinterpreted. Reclassification in risk strata, while requiring thresholds, may be more relevant clinically with its ability to examine potential changes in treatment decisions. PMID:22875759

  4. Burnout syndrome among dental students: a short version of the "Burnout Clinical Subtype Questionnaire" adapted for students (BCSQ-12-SS)

    PubMed Central

    2011-01-01

    Background Burnout has been traditionally defined in relation to the dimensions of "exhaustion", "cynicism", and "inefficiency". More recently, the Burnout Clinical Subtype Questionnaire (BCSQ-12) further established three different subtypes of burnout: the "frenetic" subtype (related to "overload"), the "under-challenged" subtype (related to "lack of development"), and the "worn-out" subtype (related to "neglect"). However, to date, these definitions have not been applied to students. The aims of this research were (1) to adapt a Spanish version of the BCSQ-12 for use with students, (2) to test its factorial validity, internal consistency, convergent and discriminant validity, and (3) to assess potential socio-demographic and occupational risk factors associated with the development of the subtypes. Method We used a cross-sectional design on a sample of dental students (n = 314) from Santiago and Huesca universities (Spain). Participants completed the Burnout Clinical Subtype Questionnaire Student Survey (BCSQ-12-SS), the Maslach Burnout Inventory Student Survey (MBI-SS), and a series of socio-demographic and occupational questions formulated for the specific purpose of this study. Data were subjected to exploratory factor analysis (EFA) using the principal component method with varimax orthogonal rotation. To assess the relations with the criterion, we calculated the Pearson correlation coefficient (r), multiple correlation coefficient (Ry.123), and the coefficient of determination (R2y.123). To assess the association between the subtypes and the socio-demographic variables, we examined the adjusted odds ratio (OR) obtained from multivariate logistic regression models. Results Factorial analyses supported the theoretical proposition of the BCSQ-12-SS, with α-values exceeding 0.80 for all dimensions. The "overload-exhaustion" relation was r = 0.59 (p < 0.001), "lack of development"-"cynicism", r = 0.49 (p < 0.001), "neglect"-"inefficiency", r = 0.47 (p < 0

  5. Clinical Relevance of HLA Gene Variants in HBV Infection

    PubMed Central

    Wang, Li; Zou, Zhi-Qiang; Wang, Kai

    2016-01-01

    Host gene variants may influence the natural history of hepatitis B virus (HBV) infection. The human leukocyte antigen (HLA) system, the major histocompatibility complex (MHC) in humans, is one of the most important host factors that are correlated with the clinical course of HBV infection. Genome-wide association studies (GWASs) have shown that single nucleotide polymorphisms (SNPs) near certain HLA gene loci are strongly associated with not only persistent HBV infection but also spontaneous HBV clearance and seroconversion, disease progression, and the development of liver cirrhosis and HBV-related hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB). These variations also influence the efficacy of interferon (IFN) and nucleot(s)ide analogue (NA) treatment and response to HBV vaccines. Meanwhile, discrepant conclusions were reached with different patient cohorts. It is therefore essential to identify the associations of specific HLA allele variants with disease progression and viral clearance in chronic HBV infection among different ethnic populations. A better understanding of HLA polymorphism relevance in HBV infection outcome would enable us to elucidate the roles of HLA SNPs in the pathogenesis and clearance of HBV in different areas and ethnic groups, to improve strategies for the prevention and treatment of chronic HBV infection. PMID:27243039

  6. Clinically Relevant Chromosomally Encoded Multidrug Resistance Efflux Pumps in Bacteria

    PubMed Central

    Piddock, Laura J. V.

    2006-01-01

    Efflux pump genes and proteins are present in both antibiotic-susceptible and antibiotic-resistant bacteria. Pumps may be specific for one substrate or may transport a range of structurally dissimilar compounds (including antibiotics of multiple classes); such pumps can be associated with multiple drug (antibiotic) resistance (MDR). However, the clinical relevance of efflux-mediated resistance is species, drug, and infection dependent. This review focuses on chromosomally encoded pumps in bacteria that cause infections in humans. Recent structural data provide valuable insights into the mechanisms of drug transport. MDR efflux pumps contribute to antibiotic resistance in bacteria in several ways: (i) inherent resistance to an entire class of agents, (ii) inherent resistance to specific agents, and (iii) resistance conferred by overexpression of an efflux pump. Enhanced efflux can be mediated by mutations in (i) the local repressor gene, (ii) a global regulatory gene, (iii) the promoter region of the transporter gene, or (iv) insertion elements upstream of the transporter gene. Some data suggest that resistance nodulation division systems are important in pathogenicity and/or survival in a particular ecological niche. Inhibitors of various efflux pump systems have been described; typically these are plant alkaloids, but as yet no product has been marketed. PMID:16614254

  7. Clinical Relevance of Autoantibodies in Patients with Autoimmune Bullous Dermatosis

    PubMed Central

    Mihályi, Lilla; Kiss, Mária; Dobozy, Attila; Kemény, Lajos; Husz, Sándor

    2012-01-01

    The authors present their experience related to the diagnosis, treatment, and followup of 431 patients with bullous pemphigoid, 14 patients with juvenile bullous pemphigoid, and 273 patients with pemphigus. The detection of autoantibodies plays an outstanding role in the diagnosis and differential diagnosis. Paraneoplastic pemphigoid is suggested to be a distinct entity from the group of bullous pemphigoid in view of the linear C3 deposits along the basement membrane of the perilesional skin and the “ladder” configuration of autoantibodies demonstrated by western blot analysis. It is proposed that IgA pemphigoid should be differentiated from the linear IgA dermatoses. Immunosuppressive therapy is recommended in which the maintenance dose of corticosteroid is administered every second day, thereby reducing the side effects of the corticosteroids. Following the detection of IgA antibodies (IgA pemphigoid, linear IgA bullous dermatosis, and IgA pemphigus), diamino diphenyl sulfone (dapsone) therapy is preferred alone or in combination. The clinical relevance of autoantibodies in patients with autoimmune bullous dermatosis is stressed. PMID:23320017

  8. Epileptic Neuronal Networks: Methods of Identification and Clinical Relevance

    PubMed Central

    Stefan, Hermann; Lopes da Silva, Fernando H.

    2012-01-01

    The main objective of this paper is to examine evidence for the concept that epileptic activity should be envisaged in terms of functional connectivity and dynamics of neuronal networks. Basic concepts regarding structure and dynamics of neuronal networks are briefly described. Particular attention is given to approaches that are derived, or related, to the concept of causality, as formulated by Granger. Linear and non-linear methodologies aiming at characterizing the dynamics of neuronal networks applied to EEG/MEG and combined EEG/fMRI signals in epilepsy are critically reviewed. The relevance of functional dynamical analysis of neuronal networks with respect to clinical queries in focal cortical dysplasias, temporal lobe epilepsies, and “generalized” epilepsies is emphasized. In the light of the concepts of epileptic neuronal networks, and recent experimental findings, the dichotomic classification in focal and generalized epilepsy is re-evaluated. It is proposed that so-called “generalized epilepsies,” such as absence seizures, are actually fast spreading epilepsies, the onset of which can be tracked down to particular neuronal networks using appropriate network analysis. Finally new approaches to delineate epileptogenic networks are discussed. PMID:23532203

  9. Clinically and pharmacologically relevant interactions of antidiabetic drugs

    PubMed Central

    May, Marcus; Schindler, Christoph

    2016-01-01

    Patients with type 2 diabetes mellitus often require multifactorial pharmacological treatment due to different comorbidities. An increasing number of concomitantly taken medications elevate the risk of the patient experiencing adverse drug effects or drug interactions. Drug interactions can be divided into pharmacokinetic and pharmacodynamic interactions affecting cytochrome (CYP) enzymes, absorption properties, transporter activities and receptor affinities. Furthermore, nutrition, herbal supplements, patient’s age and gender are of clinical importance. Relevant drug interactions are predominantly related to sulfonylureas, thiazolidinediones and glinides. Although metformin has a very low interaction potential, caution is advised when drugs that impair renal function are used concomitantly. With the exception of saxagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitors also show a low interaction potential, but all drugs affecting the drug transporter P-glycoprotein should be used with caution. Incretin mimetics and sodium–glucose cotransporter-2 (SGLT-2) inhibitors comprise a very low interaction potential and are therefore recommended as an ideal combination partner from the clinical–pharmacologic point of view. PMID:27092232

  10. Subtyping Clinical Specimens of Influenza A Virus by Use of a Simple Method To Amplify RNA Targets

    PubMed Central

    Wang, Jingjing; Tai, Warren; Angione, Stephanie L.; John, Amrita R.; Opal, Steven M.; Artenstein, Andrew W.

    2013-01-01

    This work presents the clinical application of a robust and unique approach for RNA amplification, called a simple method for amplifying RNA targets (SMART), for the detection and identification of subtypes of H1N1 pandemic, H1N1 seasonal, and H3N2 seasonal influenza virus. While all the existing amplification techniques rely on the diffusion of two molecules to complex RNA structures, the SMART achieves fast and efficient amplification via single-molecule diffusion. The SMART utilizes amplifiable single-stranded DNA (ssDNA) probes, which serve as reporter molecules for capturing specific viral RNA (vRNA) sequences and are subsequently separated on a microfluidic chip under zero-flow conditions. The probe amplification and detection are performed using an isothermal (41°C) amplification scheme via a modified version of nucleic acid sequence-based amplification (NASBA). In our study, 116 consecutive, deidentified, clinical nasopharyngeal swab samples were analyzed independently in a blinded fashion using the SMART, reverse transcription-PCR (RT-PCR), antigen (Ag) testing, and viral culture. The SMART was shown to have a limit of detection (LOD) of approximately 105 vRNA copies/ml, corresponding with a time-to-positivity (TTP) value of 70 min for real-time detection. The SMART correctly detected influenza virus in 98.3% of the samples with a subtyping accuracy of 95.7%. This work demonstrates that the SMART represents a highly accurate diagnostic platform for the detection and subtyping of influenza virus in clinical specimens and offers significant advantages over the current commercially available diagnostic tools. PMID:23903546

  11. Putative cancer-initiating stem cells in cell culture models for molecular subtypes of clinical breast cancer

    PubMed Central

    TELANG, NITIN

    2015-01-01

    Cancer-initiating stem cells (CISC) represent a minor subpopulation of heterogeneous breast cancer. CISC are responsible for the acquired resistance to conventional chemoendocrine therapy and eventual relapse observed in patients with breast cancer. Certain molecular subtypes of clinical breast cancer that exhibit differential expression of genes coding for hormone and growth factor receptors differ in their response to conventional chemoendocrine therapy and targeted therapeutic inhibitors. Thus, the development of reliable cell culture models for CISC may provide a valuable experimental approach for the study of stem cell-targeted therapy for the treatment of breast cancer. The present study utilized optimized cell culture systems as experimental models for different molecular subtypes of clinical breast cancer, including luminal A, human epidermal growth factor receptor (HER)-2-enriched and triple negative breast cancer. Biomarker end points, including control of homeostatic growth, cancer risk and drug resistance, were quantitatively analyzed in the selected models. The results of the analyses indicated that, compared with the non-tumorigenic controls, the cell models representing the aforementioned molecular subtypes of clinical breast cancer exhibited aberrant cell cycle progression, downregulated cellular apoptosis and loss of control of homeostatic growth, as evidenced by hyperproliferation. Additionally, these models displayed persistent cancer risk, as indicated by their high incidence and frequency of anchorage-independent (AI) colony formation in vitro and their tumor development capacity in vivo. Furthermore, in the presence of maximum cytostatic drug concentrations, the drug-resistant phenotypes isolated from the parental drug-sensitive cell lines representing luminal A, HER-2-enriched and triple negative breast cancer exhibited an 11.5, 5.0 and 6.2 fold increase in cell growth, and a 5.6, 5.4 and 4.4 fold increase in the number of AI colonies

  12. Replication Study of the Milwaukee Inventory for Subtypes of Trichotillomania–Adult Version in a Clinically Characterized Sample

    PubMed Central

    Keuthen, Nancy J.; Tung, Esther S.; Woods, Douglas W.; Franklin, Martin E.; Altenburger, Erin M.; Pauls, David L.; Flessner, Christopher A.

    2015-01-01

    In the present study, we evaluated the Milwaukee Inventory for Subtypes of Trichotillomania–Adult Version (MIST-A) in a replication sample of clinically characterized hair pullers using exploratory factor analysis (EFA; N = 193). EFA eigenvalues and visual inspection of our scree plot revealed a two-factor solution. Factor structure coefficients and internal consistencies suggested a 13-item scale with an 8-item “Intention” scale and a 5-item “Emotion” scale. Both scales displayed good construct and discriminant validity. These findings indicate the need for a revised scale that provides a more refined assessment of pulling phenomenology that can facilitate future treatment advances. PMID:25868534

  13. Clinical relevance vs. statistical significance: Using neck outcomes in patients with temporomandibular disorders as an example.

    PubMed

    Armijo-Olivo, Susan; Warren, Sharon; Fuentes, Jorge; Magee, David J

    2011-12-01

    Statistical significance has been used extensively to evaluate the results of research studies. Nevertheless, it offers only limited information to clinicians. The assessment of clinical relevance can facilitate the interpretation of the research results into clinical practice. The objective of this study was to explore different methods to evaluate the clinical relevance of the results using a cross-sectional study as an example comparing different neck outcomes between subjects with temporomandibular disorders and healthy controls. Subjects were compared for head and cervical posture, maximal cervical muscle strength, endurance of the cervical flexor and extensor muscles, and electromyographic activity of the cervical flexor muscles during the CranioCervical Flexion Test (CCFT). The evaluation of clinical relevance of the results was performed based on the effect size (ES), minimal important difference (MID), and clinical judgement. The results of this study show that it is possible to have statistical significance without having clinical relevance, to have both statistical significance and clinical relevance, to have clinical relevance without having statistical significance, or to have neither statistical significance nor clinical relevance. The evaluation of clinical relevance in clinical research is crucial to simplify the transfer of knowledge from research into practice. Clinical researchers should present the clinical relevance of their results. PMID:21658987

  14. Antithymocyte Globulin at Clinically Relevant Concentrations Kills Leukemic Blasts.

    PubMed

    Dabas, Rosy; Lee, Rachelle; Servito, Maria Theresa; Dharmani-Khan, Poonam; Modi, Monica; van Slyke, Tiffany; Luider, Joanne; Durand, Caylib; Larratt, Loree; Brandwein, Joseph; Morris, Don; Daly, Andrew; Khan, Faisal M; Storek, Jan

    2016-05-01

    In contrast to cyclosporine or methotrexate, rabbit antithymocyte globulin (ATG) used for graft-versus-host disease (GVHD) prophylaxis with myeloablative conditioning does not increase the risk of relapse after hematopoietic cell transplantation. The reason for this is unknown. We hypothesized that ATG at concentrations achieved with our standard ATG dose of 4.5 mg/kg exerts antileukemic activity. We measured ATG-induced killing of leukemic blasts via complement-dependent cytotoxicity (CDC) and via complement-independent cytotoxicity (CIC) in marrow or blood from 36 patients with newly diagnosed acute leukemia. The median percentage of blasts killed by CDC was 0.3% at 1 mg/L ATG, 2.8% at 10 mg/L ATG, 12.6% at 25 mg/L ATG, and 42.2% at 50 mg/L ATG. The median percentage of blasts killed by CIC after a 4-hour incubation with ATG was 1.9% at 1 mg/L ATG, 7.15% at 10 mg/L ATG, 12.1% at 25 mg/L ATG, and 13.9% at 50 mg/L ATG. CIC appeared to represent a direct induction of apoptosis by ATG. There was a high variability in the sensitivity of the blasts to ATG; at 50 mg/L, the percentage of blasts killed ranged from 2.6% to 97.2% via CDC and from 1.4% to 69.9% via CIC. In conclusion, ATG at clinically relevant concentrations kills leukemic blasts in vitro. Some acute leukemias are highly sensitive to ATG, whereas others are relatively resistant. This finding could lead to personalized administration of ATG. PMID:26779931

  15. Heterotopic ossification in cervical disc arthroplasty: Is it clinically relevant?

    PubMed Central

    Barbagallo, Giuseppe M.; Corbino, Leonardo A.; Olindo, Giuseppe; Albanese, Vincenzo

    2010-01-01

    Study design: Retrospective cohort study. Objective: To analyze the presence and clinical relevance of heterotopic ossification (HO) at 3 years mean follow-up. Methods: Thirty patients suffering from cervical radiculopathy and/or myelopathy treated with anterior disc replacement (ADR) were studied. HO was classified using the McAfee grading system. Range of motion was measured from flexion and extension x-rays. Short-form 36 and neck disability index (NDI) assessed functional outcome. Results: Forty-five prostheses were implanted in 30 patients with cervical radiculopathy and/or myelopathy, mean age 40.9 years. Nineteen patients received 1 level and 11 patients received multilevel disc replacement. The incidence rate of HO was 42.2% (19 levels). Segmental range of motion was ≥3° in 93.8% of patients with HO. There was no significant difference in functional scores between those who did and those who did not develop HO. Males tended to develop HO more frequently than females, though this was not statistically significant. The indication for surgery (soft disc hernia or spondylosis) was not associated with the formation of HO. Conclusions: Functional improvement is maintained despite the presence of HO following cervical disc arthroplasty. Indications for arthroplasty should not be halted by the risk of HO. Methods evaluation and class of evidence (CoE) Methodological principle: Study design:  Prospective cohort  Retrospective cohort •  Case-control  Case series Methods  Patients at similar point in course of treatment •  Follow-up ≥85%  Similarity of treatment protocols for patient groups •  Patients followed for long enough for outcomes to occur •  Control for extraneous risk factors* Evidence class: III *Authors must provide a description of robust baseline characteristics, and control for those that are potential prognostic factors. The definiton of the different classes of evidence is available on page 83. PMID:23544019

  16. Subtyping Somatic Tinnitus: A Cross-Sectional UK Cohort Study of Demographic, Clinical and Audiological Characteristics

    PubMed Central

    Ward, Jamie; Vella, Claire; Hoare, Derek J.; Hall, Deborah A.

    2015-01-01

    Somatic tinnitus is the ability to modulate the psychoacoustic features of tinnitus by somatic manoeuvres. The condition is still not fully understood and further identification of this subtype is essential, particularly for the purpose of establishing protocols for both its diagnosis and treatment. This study aimed to investigate the characteristics of somatic tinnitus within a large UK cohort using a largely unselected sample. We believe this to be relatively unique in comparison to current literature on the topic. This was investigated by using a total of 608 participant assessments from a set of recognised tinnitus and audiology measures. Results from a set of chi-square tests of association found that amongst the individuals with somatic tinnitus, a higher proportion had pulsatile tinnitus (different from heartbeat), were under the age of 40, reported variation in the loudness of their tinnitus and reported temporomandibular joint (TMJ) disorder. The same pattern of results was confirmed using a multivariate analysis of the data based on logistic regression. These findings have strong implications towards the profiling of somatic tinnitus as a distinct subtype of general tinnitus. PMID:25996779

  17. Pretreatment HIV Drug Resistance and HIV-1 Subtype C Are Independently Associated With Virologic Failure: Results From the Multinational PEARLS (ACTG A5175) Clinical Trial

    PubMed Central

    Kantor, Rami; Smeaton, Laura; Vardhanabhuti, Saran; Hudelson, Sarah E.; Wallis, Carol L.; Tripathy, Srikanth; Morgado, Mariza G.; Saravanan, Shanmugham; Balakrishnan, Pachamuthu; Reitsma, Marissa; Hart, Stephen; Mellors, John W.; Halvas, Elias; Grinsztejn, Beatriz; Hosseinipour, Mina C.; Kumwenda, Johnstone; La Rosa, Alberto; Lalloo, Umesh G.; Lama, Javier R.; Rassool, Mohammed; Santos, Breno R.; Supparatpinyo, Khuanchai; Hakim, James; Flanigan, Timothy; Kumarasamy, Nagalingeswaran; Campbell, Thomas B.; Eshleman, Susan H.

    2015-01-01

    Background. Evaluation of pretreatment HIV genotyping is needed globally to guide treatment programs. We examined the association of pretreatment (baseline) drug resistance and subtype with virologic failure in a multinational, randomized clinical trial that evaluated 3 antiretroviral treatment (ART) regimens and included resource-limited setting sites. Methods. Pol genotyping was performed in a nested case-cohort study including 270 randomly sampled participants (subcohort), and 218 additional participants failing ART (case group). Failure was defined as confirmed viral load (VL) >1000 copies/mL. Cox proportional hazards models estimated resistance–failure association. Results. In the representative subcohort (261/270 participants with genotypes; 44% women; median age, 35 years; median CD4 cell count, 151 cells/µL; median VL, 5.0 log10 copies/mL; 58% non-B subtypes), baseline resistance occurred in 4.2%, evenly distributed among treatment arms and subtypes. In the subcohort and case groups combined (466/488 participants with genotypes), used to examine the association between resistance and treatment failure, baseline resistance occurred in 7.1% (9.4% with failure, 4.3% without). Baseline resistance was significantly associated with shorter time to virologic failure (hazard ratio [HR], 2.03; P = .035), and after adjusting for sex, treatment arm, sex–treatment arm interaction, pretreatment CD4 cell count, baseline VL, and subtype, was still independently associated (HR, 2.1; P = .05). Compared with subtype B, subtype C infection was associated with higher failure risk (HR, 1.57; 95% confidence interval [CI], 1.04–2.35), whereas non-B/C subtype infection was associated with longer time to failure (HR, 0.47; 95% CI, .22–.98). Conclusions. In this global clinical trial, pretreatment resistance and HIV-1 subtype were independently associated with virologic failure. Pretreatment genotyping should be considered whenever feasible. Clinical Trials

  18. Mucosal vaccination with formalin-inactivated avian metapneumovirus Subtype C reduces clinical signs of disease but enhances local pathology of turkeys following challenge

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Studies were performed to determine if mucosal vaccination with inactivated avian metapneumovirus (aMPV) subtype C protected turkey poults from clinical disease and virus replication following mucosal challenge. Although decreases in clinical disease were observed in vaccinated groups, the vaccine...

  19. In pursuit of defining clinical relevance of positive patch tests results.

    PubMed

    Wolf, Ronni; Davidovici, Batya; Stone, Stephen P; Tuzun, Yalcin

    2007-01-01

    According to the current classification of clinical relevance of the positive patch test reactions, the positive results of patients who are allergic to various allergens that are not responsible for the present dermatitis do not fit into the category of "relevant to present dermatitis" but should be defined as "relevant to a preceding bout of dermatitis." This seems to us inappropriate and misleading because reexposure to the sensitizing agent would quickly revert their reaction to "relevant to present dermatitis." We suggest an alternative possibility to the current division of the various types of clinical relevance, namely, "relevance to a present allergy other than the presenting dermatitis." PMID:17870528

  20. Cytotoxic chemotherapy: Still the mainstay of clinical practice for all subtypes metastatic breast cancer.

    PubMed

    Twelves, Chris; Jove, Maria; Gombos, Andrea; Awada, Ahmad

    2016-04-01

    Cytotoxic chemotherapy remains central to the treatment of all subtypes of metastatic breast cancer (MBC). We review evidence-based chemotherapy options for women with MBC after an anthracycline and a taxane including re-challenge with anthracycline or taxane, capecitabine, eribulin and ixabepilone as a single agent or combination with capecitabine (not approved in the EU); and the vinca alkaloid vinflunine as single agent or combined with either capecitabine/gemcitabine (also not approved EU or USA). Etirinotecan pegol, comprising irinotecan bound to polyethylene glycol by a biodegradable linker, is a new cytotoxic agent for patients with MBC that has achieved encouraging response rates in phase II studies; it has been further evaluated in the phase III BEACON trial. New cytotoxics should address novel targets or modes of delivery, achieve meaningful improvements in outcomes and seek to identify predictive biomarker(s). PMID:26857987

  1. Characterization of Mycobacterium Abscessus Subtypes in Shanghai of China: Drug Sensitivity and Bacterial Epidemicity as well as Clinical Manifestations.

    PubMed

    Luo, Liulin; Li, Bing; Chu, Haiqing; Huang, Dongdong; Zhang, Zhemin; Zhang, Jingbo; Gui, Tao; Xu, Liyun; Zhao, Lan; Sun, Xiwen; Xiao, Heping

    2016-01-01

    The aim of the study was to investigate the epidemic characteristics of Mycobacterium abscessus in Shanghai.Fifty-five strains from 55 M. abscessus pulmonary disease patients were isolated. Drug sensitivity was measured by a broth microdilution method. Subtypes of M. abscessus were identified by DNA sequencing. Multilocus sequence typing (MLST), mining spanning tree (MST), and pulsed-field gel electrophoresis (PFGE) were used to analyze sequence types (ST) and clonal complexes (CC). Clinical manifestations were assessed by CT imaging.We identified 42 A isolates, 11 M, and 2 B-subtypes. A and M were highly sensitive to tigecycline and amikacin (97.6-100%). The A-type easily developed drug resistance against clarithromycin. Both types were highly resistance to sulfonamides, moxifloxacin, doxycycline, imipenem, and tobramycin. MLST analysis identified 41 STs including 32 new STs. The MST algorithm distributed 55 isolates into 12 separate CC. The PFGE analysis exhibited 53 distinct restriction patterns and the M-type was closely clustered according to their ST and CC numbers. CT imaging showed that tree-in-bud and patch shadow were commonly observed in M-type, whereas pulmonary cavities were often found in A-type infection patients (P < 0.001).ST1 in A and ST23 in M-type were the main epidemic strains in Shanghai. The M-type appeared to be prone to epidemic nosocomial transmission. PMID:26817866

  2. Characteristics of DSM-IV Attention Deficit Hyperactivity Disorder Combined and Predominantly Inattentive Subtypes in a Turkish Clinical Sample

    PubMed Central

    Oner, Pinar; Cop, Esra; Munir, Kerim M.

    2014-01-01

    Consecutively referred subjects (N = 537) to an outpatient clinic were evaluated to compare the Attention Deficit Hyperactivity Disorder Combined (ADHD-C) and predominantly inattentive (ADHD-PI) subtypes using parent and teacher ratings and neuropsychological variables. Statistical significance was at P < 0.002 adjusted for multiple comparisons. ADHD-PI subjects were older, more likely to be female, higher socioeconomic status, had lower Child Behavior Checklist and Teacher Report Form Aggression, Delinquency and Social Problems scores, and higher Withdrawal and Competence scores, compared to ADHD-C subjects. Comorbid conduct problems were more common among ADHD-C subjects. There were no differences in terms of anxiety/depression, and neuropsychological measures. The study is unique in that it provides data on a broad range of measures from a middle income developing country with important confirmation of similar pattern of differences and similarities between ADHD-C and ADHD-PI subtypes previously reported in North American and Western European samples. PMID:22249362

  3. [Alpha1-adrenoceptor subtypes and alpha1-adrenoceptor antagonists].

    PubMed

    Muramatsu, Ikunobu; Suzuki, Fumiko; Tanaka, Takashi; Yamamoto, Hatsumi; Morishima, Shigeru

    2006-03-01

    Alpha(1)-adrenoceptors are widely distributed in the human body and play important physiologic roles. Three alpha(1)-adrenoceptor subtypes (alpha(1A), alpha(1B) and alpha(1D)) have been cloned and show different pharmacologic profiles. In addition, a putative alpha(1)-adrenoceptor (alpha(1L) subtype) has also been proposed. Recently, three drugs (tamsulosin, naftopidil, and silodosin) have been developed in Japan for the treatment of urinary obstruction in patients with benign prostatic hyperplasia. In this review, we describe recent alpha(1)-adrenoceptor subclassifications and the pharmacologic characteristics (subtype selectivity and clinical relevance) of alpha(1)-adrenoceptor antagonists. PMID:16518082

  4. Prevalence of the different Axis I clinical subtypes in a sample of patients with orofacial pain and temporomandibular disorders in the Andalusian Healthcare Service

    PubMed Central

    Blanco-Aguilera, Antonio; Blanco-Aguilera, Elena; Serrano-del-Rosal, Rafael; Biedma-Velázquez, Lourdes; Rodríguez-Torronteras, Alejandro; Segura-Saint-Gerons, Rafael

    2016-01-01

    Background The main objective of this paper is to analyze the prevalence of each of the different clinical subtypes of temporomandibular disorders (TMD) in a sample of patients with this pathology. In addition, a second objective was to analyze their distribution according to gender. Material and Methods To this end, the results of 1603 patients who went to the Unit of Temporomandibular Disorders in the Córdoba Healthcare District because they suffered from this pathology were analyzed. In order to diagnose them, the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) were applied, analyzing the different Axis I subtypes (myopathy, discopathy and arthropathy) and obtaining the combined Axis I for each patient and the relation of all these variables according to gender. The null-hypothesis test confirmed the lack of connection between the gender variable and the different subtypes in the clinical analysis, and between the former and the combined Axis I of the RDC/TMD. Results The prevalence was high for the muscle disorders subtype in general, showing an 88.7% prevalence, while the presence of discopathies or arthropathies was much lower. Among discopathies, the most frequent ones were disc displacements with reduction, with 39.7% and 42.8% for the left and right temporomandibular joints (TMJ), respectively, while the prevalence of arthropathies was 26.3% for the right TMJ and 32.9% for the left TMJ. The bivariate analysis on the connection with gender reveals a p≥ 0.05 value for the muscle and arthralgia subtypes. Conclusions The patients seen at the TMD Unit where mostly middle-aged women whose main clinical axis subtype was the muscle disorder subtype. For their part, both discopathies and arthropathies, although present, are much less prevalent. Key words:RDCTMD, axis I, orofacial pain, temporomandibular disorders, gender. PMID:26615508

  5. Clinical subtypes of chronic traumatic encephalopathy: literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome

    PubMed Central

    2014-01-01

    The long-term consequences of repetitive head impacts have been described since the early 20th century. Terms such as punch drunk and dementia pugilistica were first used to describe the clinical syndromes experienced by boxers. A more generic designation, chronic traumatic encephalopathy (CTE), has been employed since the mid-1900s and has been used in recent years to describe a neurodegenerative disease found not just in boxers but in American football players, other contact sport athletes, military veterans, and others with histories of repetitive brain trauma, including concussions and subconcussive trauma. This article reviews the literature of the clinical manifestations of CTE from 202 published cases. The clinical features include impairments in mood (for example, depression and hopelessness), behavior (for example, explosivity and violence), cognition (for example, impaired memory, executive functioning, attention, and dementia), and, less commonly, motor functioning (for example, parkinsonism, ataxia, and dysarthria). We present proposed research criteria for traumatic encephalopathy syndrome (TES) which consist of four variants or subtypes (TES behavioral/mood variant, TES cognitive variant, TES mixed variant, and TES dementia) as well as classifications of ‘probable CTE’ and ‘possible CTE’. These proposed criteria are expected to be modified and updated as new research findings become available. They are not meant to be used for a clinical diagnosis. Rather, they should be viewed as research criteria that can be employed in studies of the underlying causes, risk factors, differential diagnosis, prevention, and treatment of CTE and related disorders. PMID:25580160

  6. PCR-single-stranded confirmational polymorphism analysis for non-culture-based subtyping of meningococcal strains in clinical specimens.

    PubMed Central

    Newcombe, J; Dyer, S; Blackman, L; Cartwright, K; Palmer, W H; McFadden, J; Blackwell, L

    1997-01-01

    Subspecific typing of clinical meningococcal strains is important in the investigation of outbreaks and for disease surveillance. Serogrouping, typing, and subtyping of strains currently require isolation of a meningococcus from one or more clinical specimens. However, the increasing widespread practice of preadmission administration of parenteral antibiotics has resulted in a decrease in the frequency of positive cultures obtained from blood and cerebrospinal fluid. Confirmation of meningococcal disease can be obtained by meningococcus-specific PCR from both cerebrospinal fluid (H. Ni et al., Lancet 340:1432-1434, 1992) and peripheral blood (J. Newcombe et al., J. Clin. Microbiol. 34:1637-1640, 1996) specimens. However, current PCR protocols do not yield epidemiologically useful typing information. We report here the use of PCR-single-stranded confirmational polymorphism (PCR-SSCP) analysis to amplify and type meningococcal DNA present in clinical specimens. PCR-SSCP analysis with the VR1 region of the Neisseria meningitidis porA gene as the target produced unique banding patterns for each serosubtype. Direct PCR-SSCP of clinical specimens can therefore provide typing data that can be used to investigate the epidemiology of clusters of cases and outbreaks and for disease surveillance in situations in which culture of patient specimens proves negative. PMID:9196199

  7. Understanding inflammation in juvenile idiopathic arthritis: How immune biomarkers guide clinical strategies in the systemic onset subtype.

    PubMed

    Swart, Joost F; de Roock, Sytze; Prakken, Berent J

    2016-09-01

    The translation of basic insight in immunological mechanisms underlying inflammation into clinical practice of inflammatory diseases is still challenging. Here we describe how-through continuous dialogue between bench and bedside-immunological knowledge translates into tangible clinical use in a complex inflammatory disease, juvenile idiopathic arthritis (JIA). Systemic JIA (sJIA) is an autoinflammatory disease, leading to the very successful use of IL-1 antagonists. Further immunological studies identified new immune markers for diagnosis, prediction of complications, response to and successful withdrawal of therapy. Myeloid related protein (MRP)8, MRP14, S100A12, and Interleukin-18 are already used daily in clinic as markers for active sJIA. For non-sJIA subtypes, HLA-B27, antinuclear-antibodies, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein are still used for classification, prognosis or active disease. MRP8, MRP14, and S100A12 are now under study for clinical practice. We believe that with biomarkers, algorithms can soon be designed for the individual risk of disease, complications, damage, prediction of response to, and successful withdrawal of therapy. In that way, less time will be lost and less pain will be suffered by the patients. In this review, we describe the current status of immunological biomarkers used in diagnosis and treatment of JIA. PMID:27461267

  8. Epidemiological, Clinical and Antiretroviral Susceptibility Characterization of Human Immunodeficiency Virus Subtypes B and Non-B in Pernambuco, Northeast Brazil

    PubMed Central

    Lima, Kledoaldo; de Souza Leal, Élcio; Cavalcanti, Ana Maria Salustiano; Salustiano, Daniela Medeiros; de Medeiros, Luzidalva Barbosa; da Silva, Sirleide Pereira; Lacerda, Heloísa Ramos

    2016-01-01

    Background HIV-1 diversity causes important differences in the virus’ biological properties and their interactions with hosts, such as cell tropism, responses to antiretroviral therapy, drug-resistance, and disease progression. Objectives We evaluated the interrelationship of phylogenetic inference with epidemiological and laboratory data for HIV-1 isolates circulating in Pernambuco, Northeast Region—Brazil. Study design A total of 168 HIV-1 pol sequences were analysed, 64 were obtained from 2002–2003, and 104, from 2007–2009. Socio-demographic, clinical, and behavioural data were obtained from medical records. Laboratory testing enabled the determination of recent HIV-1 infections and co-infections with HBV, HCV, HTLV, or syphilis. Surveillance drug-resistance mutation analysis and antiretroviral susceptibility profiling were performed using HIV Drug-Resistance Database. Results HIV-1 non-B was associated with female, lower education, lower viral loads, and higher T cell counts mean. Frequencies of co-infection HIV-HBV, HIV-HCV, and HIV-syphilis were 27.8% (95% CI: 19.8–37.7), 1.04% (95% CI: 0.05–5.00) and 14.7% (95% CI: 8.6–23.0), respectively. Drug-resistant mutations rate was 2.98% (95% CI: 1.10–6.47). HIV-HBV subtype B co-infection was associated with men who have sex with men (MSM), higher education, higher viral loads and males. HIV-syphilis subtype non-B co-infection was associated with MSM status, lower T cell counts and males. Conclusions Data showed the importance of molecular characterisations of the HIV-1 epidemic and its relation with epidemiological and clinical characteristics of the population, as well as its association with other infectious diseases, so they can effort to improve preventive measures for health services and more information about the progress and effects of the epidemic in Northeastern–Brazil. PMID:27218259

  9. Mortality in mild cognitive impairment varies by subtype, sex and lifestyle factors. The Mayo Clinic Study of Aging

    PubMed Central

    Vassilaki, Maria; Cha, Ruth H.; Aakre, Jeremiah A.; Therneau, Terry M.; Geda, Yonas E.; Mielke, Michelle M.; Knopman, David S.; Petersen, Ronald C.; Roberts, Rosebud O.

    2015-01-01

    Background Etiologic differences in mild cognitive impairment (MCI) subtypes may impact mortality. Objective To assess the rate of death in MCI overall, and by subtype, in the population-based Mayo Clinic Study of Aging. Methods Participants aged 70–89 years at enrollment were clinically evaluated at baseline and 15-month intervals to assess diagnoses of MCI and dementia. Mortality in MCI cases vs. cognitively normal (CN) individuals was estimated using Cox proportional hazards models. Results Over a median follow-up of 5.8 years, 331 of 862 (38.4%) MCI cases and 224 of 1292 (17.3%) cognitively normal participants died. Compared to CN individuals, mortality was elevated in persons with MCI (hazard ratio [HR] = 2.03; 95% CI: 1.61 to 2.55), and was higher for non-amnestic MCI (naMCI; HR = 2.47; 95% CI: 1.80 to 3.39) than for amnestic MCI (aMCI; HR = 1.89; 95% CI: 1.48 to 2.41) after adjusting for confounders. Mortality varied significantly by sex, education, history of heart disease, and engaging in moderate physical exercise (p for interaction <0.05 for all). Mortality rate estimates were highest in MCI cases who were men, did not exercise, had heart disease, and had higher education vs. CN without these factors, and for naMCI cases vs. aMCI cases without these factors. Conclusions These findings suggest stronger impact of etiologic factors on naMCI mortality. Prevention of heart disease, exercise vigilance, may reduce MCI mortality. Delayed MCI diagnosis in persons with higher education impacts mortality, and higher mortality in men may explain similar dementia incidence by sex in our cohort. PMID:25697699

  10. Anomalous course of the extensor pollicis longus: clinical relevance.

    PubMed

    Rubin, Guy; Wolovelsky, Alejandro; Rinott, Micha; Rozen, Nimrod

    2011-11-01

    The extensor pollicis longus (EPL) is a consistent structure with rare anomalies, the most common being a group of different tendon duplications passing through the fourth compartment without symptoms. The second form comprises anomalies in the course of the EPL having significant clinical importance due to the predisposition for creating tenosynovitis of the EPL mimicking other types of tendon tenosynovitis. Clinical symptoms of radial dorsal wrist pain mimicking intersection syndrome or de-Quervain disease with the "absent snuff box" sign should raise suspicions for an anomaly in the course of the EPL. PMID:21407056

  11. CLINICALLY RELEVANT IGE-CROSS-REACTIVITY OF NUT ALLERGENS

    EPA Science Inventory

    All data resulting from this study will be catalogued in SDAP .This work will generate important information relating the structure/ physicochemical properties of cross-reactive IgE epitopes to clinical response, and model factors that underlie allergen recognition by the immu...

  12. A Laboratory Course in Clinical Biochemistry Emphasizing Interest and Relevance

    ERIC Educational Resources Information Center

    Schwartz, Peter L.

    1975-01-01

    Ten laboratory experiments are described which are used in a successful clinical biochemistry laboratory course (e.g. blood alcohol, glucose tolerance, plasma triglycerides, coronary risk index, gastric analysis, vitamin C and E). Most of the experiments are performed on the students themselves using simple equipment with emphasis on useful…

  13. Differences in the Genetic Susceptibility to Age-Related Macular Degeneration Clinical Subtypes

    PubMed Central

    Shen, Ling; Hoffmann, Thomas J.; Melles, Ronald B.; Sakoda, Lori C.; Kvale, Mark N.; Banda, Yambazi; Schaefer, Catherine; Risch, Neil; Jorgenson, Eric

    2015-01-01

    Purpose We compared across age-related macular degeneration (AMD) subtypes the effect of AMD risk variants, their predictive power, and heritability. Methods The prevalence of AMD was estimated among active non-Hispanic white Kaiser Permanente Northern California members who were at least 65 years of age as of June 2013. The genetic analysis included 5,170 overall AMD cases ascertained from electronic health records (EHR), including 1,239 choroidal neovascularization (CNV) cases and 1,060 nonexudative AMD cases without CNV, and 23,130 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Imputation was based on the 1000 Genomes Project reference panel. Results The narrow-sense heritability due to common autosomal single nucleotide polymorphisms (SNPs) was 0.37 for overall AMD, 0.19 for AMD unspecified, 0.20 for nonexudative AMD, and 0.60 for CNV. For the 19 previously reported AMD risk loci, the area under the receiver operating characteristic (ROC) curve was 0.675 for overall AMD, 0.640 for AMD unspecified, 0.678 for nonexudative AMD, and 0.766 for CNV. The individual effects on the risk of AMD for 18 of the 19 SNPs were in a consistent direction with those previously reported, including a protective effect of the APOE ε4 allele. Conversely, the risk of AMD was significantly increased in carriers of the ε2 allele. Conclusions These findings provide an independent confirmation of many of the previously identified AMD risk loci, and support a potentially greater role of genetic factors in the development of CNV. The replication of established associations validates the use of EHR in genetic studies of ophthalmologic traits. PMID:26176866

  14. [Long loop reflexes--a clinically relevant method].

    PubMed

    Claus, D

    1986-02-01

    Late reflex potentials have been know for a long time. On the upper limb it has been proven that these potentials have a transcortical pathway. The electrical stimulation of nerve trunks is easily applicable in clinical practice and produces clear long-loop responses. The typical results can be reproduced for extrapyramidal, cerebellar and pyramidal lesions by this method. The long-loop reflex is sensitive to lesions in the course of the pyramidal tract. PMID:3007315

  15. The Assessment of Schizotypy and Its Clinical Relevance

    PubMed Central

    Mason, Oliver J.

    2015-01-01

    This article reviews several approaches to assessing schizotypal traits using a wide variety of self-report and interview measures. It makes a distinction between clinical approaches largely based on syndrome and symptom definitions, and psychometric approaches to measuring personality traits. The review presents a brief description of the content and psychometric properties of both sets of measures; these cover both the broad rubric of schizotypy often, but not exclusively based on DSM conceptions, as well as measures with a more specific focus. Measurement of schizotypy has taken place within clinical and nonclinical research utilizing a range of designs and methodologies. Several of these are elucidated with respect to the assessment choices open to researchers, and the implications of the measures chosen. These paradigms include the case–control study, “high risk”/“ultra-high risk” groups, a variety of nonclinical groups and other groups of interest, large scale epidemiology and “in vivo” designs. Evidence from a wide variety of designs continues to provide evidence of the validity of both clinical and personality approaches to schizotypal assessment. PMID:25810054

  16. Clinical relevance of molecular diagnosis in pet allergy.

    PubMed

    Uriarte, S A; Sastre, J

    2016-07-01

    We describe the pattern of sensitisation to pet IgE components and its association with clinical symptoms. Hundred and fifty nine consecutive patients with rhinitis/asthma sensitised to dog, cat, and horse were recruited. Specific IgE to whole extracts and to pet recombinant allergens were performed. Only 5% of patients were monosensitised to animal allergens. Specific IgE to Can f 1 was significantly associated with persistent rhinitis, Can f 2 with asthma diagnosis, Can f 3 with moderate/severe rhinitis (M/S-R) and asthma diagnosis (AD), and Can f 5 with persistent and M/S-R. Positive IgE to Fel d 2 was significantly associated with M/S-R and AD, Equ c 1 with M/S-R and Equ c 3 with persistent rhinitis, AD and severe asthma. Sensitisation to ≥2 molecules or to pet albumins was associated with more severe respiratory symptoms. Molecular diagnosis in patients with pet allergy may also help clinicians to predict clinical symptoms and their severity. PMID:27108666

  17. Exercise blood pressure: clinical relevance and correct measurement.

    PubMed

    Sharman, J E; LaGerche, A

    2015-06-01

    Blood pressure (BP) is a mandatory safety measure during graded intensity clinical exercise stress testing. While it is generally accepted that exercise hypotension is a poor prognostic sign linked to severe cardiac dysfunction, recent meta-analysis data also implicate excessive rises in submaximal exercise BP with adverse cardiovascular events and mortality, irrespective of resting BP. Although more data is needed to derive submaximal normative BP thresholds, the association of a hypertensive response to exercise with increased cardiovascular risk may be due to underlying hypertension that has gone unnoticed by conventional resting BP screening methods. Delayed BP decline during recovery is also associated with adverse clinical outcomes. Thus, above and beyond being used as a routine safety measure during stress testing, exercise (and recovery) BP may be useful for identifying high-risk individuals and also as an aid to optimise care through appropriate follow-up after exercise stress testing. Accordingly, careful attention should be paid to correct measurement of exercise stress test BP (before, during and after exercise) using a standardised approach with trained operators and validated BP monitoring equipment (manual or automated). Recommendations for exercise BP measurement based on consolidated international guidelines and expert consensus are presented in this review. PMID:25273859

  18. Update on Eosinophilic Meningoencephalitis and Its Clinical Relevance

    PubMed Central

    Graeff-Teixeira, Carlos; da Silva, Ana Cristina Arámburu; Yoshimura, Kentaro

    2009-01-01

    Summary: Eosinophilic meningoencephalitis is caused by a variety of helminthic infections. These worm-specific infections are named after the causative worm genera, the most common being angiostrongyliasis, gnathostomiasis, toxocariasis, cysticercosis, schistosomiasis, baylisascariasis, and paragonimiasis. Worm parasites enter an organism through ingestion of contaminated water or an intermediate host and can eventually affect the central nervous system (CNS). These infections are potentially serious events leading to sequelae or death, and diagnosis depends on currently limited molecular methods. Identification of parasites in fluids and tissues is rarely possible, while images and clinical examinations do not lead to a definitive diagnosis. Treatment usually requires the concomitant administration of corticoids and anthelminthic drugs, yet new compounds and their extensive and detailed clinical evaluation are much needed. Eosinophilia in fluids may be detected in other infectious and noninfectious conditions, such as neoplastic disease, drug use, and prosthesis reactions. Thus, distinctive identification of eosinophils in fluids is a necessary component in the etiologic diagnosis of CNS infections. PMID:19366917

  19. The incidence and clinical relevance of drug interactions in pediatrics

    PubMed Central

    Qorraj-Bytyqi, Hasime; Hoxha, Rexhep; Krasniqi, Shaip; Bahtiri, Elton; Kransiqi, Valon

    2012-01-01

    Objective: To investigate the prevalence of the major drug interactions in children and verify the rate and profile of drug interactions in hospitalized pediatric patients. Materials and Methods: A retrospective study was designed and data collected from the files of hospitalized children in Pulmonology, Nephrology, and Gastroenterology wards of a Pediatric Clinic, from July 1999 to 2004. Results: From the analyzed material, we detected 34 cases of interactions, of which 1 was pharmacodynamics interaction, 13 were pharmacokinetic interactions, and 20 of unknown mechanisms. According to the rate of significance, 4 cases were categorized in the first significance rate of interaction, 18 cases in the second significance rate, 1 case of the third significance rate, 4 cases of the fourth significance rate, and 7 cases of the fifth significance rate. According to onset of cases, 33 cases were of delayed onset, and according to severity of interactions, in 7 cases we noticed major severity interaction, in 19 cases moderate severity and in 8 cases minor severity. Conclusions: The presence of drug interactions is a permanent risk in the pediatric clinic. Then, we can conclude that continued education, computer system for prescriptions, pharmacotherapy monitoring of patients, and the pharmacist participation in the multidisciplinary team are some manners of improving the treatment to hospitalized patients. PMID:23326100

  20. Clinically Relevant Doses of Enalapril Mitigate Multiple Organ Radiation Injury.

    PubMed

    Cohen, Eric P; Fish, Brian L; Moulder, John E

    2016-03-01

    Angiotensin-converting enzyme inhibitors (ACEi) are effective mitigators of radiation nephropathy. To date, their experimental use has been in fixed-dose regimens. In clinical use, doses of ACEi and other medication may be escalated to achieve greater benefit. We therefore used a rodent model to test the ACEi enalapril as a mitigator of radiation injury in an escalating-dose regimen. Single-fraction partial-body irradiation (PBI) with one hind limb out of the radiation field was used to model accidental or belligerent radiation exposures. PBI doses of 12.5, 12.75 and 13 Gy were used to establish multi-organ injury. One third of the rats underwent PBI alone, and two thirds of the rats had enalapril started five days after PBI at a dose of 30 mg/l in the drinking water. When there was established azotemic renal injury enalapril was escalated to a 60 mg/l dose in half of the animals and then later to a 120 mg/l dose. Irradiated rats on enalapril had significant mitigation of combined pulmonary and renal morbidity and had significantly less azotemia. Dose escalation of enalapril did not significantly improve outcomes compared to fixed-dose enalapril. The current data support use of the ACEi enalapril at a fixed and clinically usable dose to mitigate radiation injury after partial-body radiation exposure. PMID:26934483

  1. Osteoprotegerin and Vascular Calcification: Clinical and Prognostic Relevance.

    PubMed

    Makarović, Sandra; Makarović, Zorin; Steiner, Robert; Mihaljević, Ivan; Milas-Ahić, Jasminka

    2015-06-01

    Osteoprotegerin (OPG) is a key regulator in bone metabolism, that also has effect in vascular system. Studies suggest that osteoprotegerin is a critical arterial calcification inhibitor, and is released by endothelial cells as a protective mechanism for their survival in certain pathological conditions, such as diabetes mellitus, chronic kidney disease, and other metabolic disorders. That has been shown in studies in vitro and in animal models. The discovery that OPG deficient mice (OPG -/- mice) develop severe osteoporosis and arterial calcification, has led to conclusion that osteoprotegerin might be mulecule linking vascular and bone system. Paradoxically however, clinical trials have shown recently that OPG serum levels is increased in coronary artery disease and correlates with its severity, ischemic cardial decompensation, and future cardiovascular events. Therefore it is possible that osteoprotegerin could have a new function as a potential biomarker in early identification and monitoring patients with cardiovascular disease. Amongst that osteoprotegerin is in association with well known atherosclerosis risc factors: undoubtedly it is proven its relationship with age, smoking and diabetes mellitus. There is evidence regarding presence of hyperlipoproteinemia and increased serum levels of osteoprotegerin. Also the researches have been directed in genetic level, linking certain single nucleotid genetic polymorphisms of osteoprotegerin and vascular calcification appearance. This review emphasises multifactorial role of OPG, presenting numerous clinical and experimental studies regarding its role in vascular pathology, suggesting a novel biomarker in cardiovascular diseases, showing latest conclusions about this interesting topic that needs to be further explored. PMID:26753467

  2. Taxonomy, Epidemiology, and Clinical Relevance of the Genus Arcobacter

    PubMed Central

    Collado, Luis; Figueras, Maria José

    2011-01-01

    Summary: The genus Arcobacter, defined almost 20 years ago from members of the genus Campylobacter, has become increasingly important because its members are being considered emergent enteropathogens and/or potential zoonotic agents. Over recent years information that is relevant for microbiologists, especially those working in the medical and veterinary fields and in the food safety sector, has accumulated. Recently, the genus has been enlarged with several new species. The complete genomes of Arcobacter butzleri and Arcobacter nitrofigilis are available, with the former revealing diverse pathways characteristic of free-living microbes and virulence genes homologous to those of Campylobacter. The first multilocus sequence typing analysis showed a great diversity of sequence types, with no association with specific hosts or geographical regions. Advances in detection and identification techniques, mostly based on molecular methods, have been made. These microbes have been associated with water outbreaks and with indicators of fecal pollution, with food products and water as the suspected routes of transmission. This review updates this knowledge and provides the most recent data on the taxonomy, species diversity, methods of detection, and identification of these microbes as well as on their virulence potential and implication in human and animal diseases. PMID:21233511

  3. Intramuscular preparations of antipsychotics: uses and relevance in clinical practice.

    PubMed

    Altamura, A Cario; Sassella, Francesca; Santini, Annalisa; Montresor, Clauno; Fumagalli, Sara; Mundo, Emanuela

    2003-01-01

    Intramuscular formulations of antipsychotics can be sub-divided into two groups on the basis of their pharmacokinetic features: short-acting preparations and long-acting or depot preparations. Short-acting intramuscular formulations are used to manage acute psychotic episodes. On the other hand, long-acting compounds, also called "depot", are administered as antipsychotic maintenance treatment to ensure compliance and to eliminate bioavailability problems related to absorption and first pass metabolism. Adverse effects of antipsychotics have been studied with particular respect to oral versus short- and long-acting intramuscular formulations of the different compounds. For short-term intramuscular preparations the main risk with classical compounds are hypotension and extrapyramidal side effects (EPS). Data on the incidence of EPS with depot formulations are controversial: some studies point out that the incidence of EPS is significantly higher in patients receiving depot preparations, whereas others show no difference between oral and depot antipsychotics. Studies on the strategies for switching patients from oral to depot treatment suggest that this procedure is reasonably well tolerated, so that in clinical practice depot antipsychotic therapy is usually begun while the oral treatment is still being administered, with gradual tapering of the oral dose. Efficacy, pharmacodynamics and clinical pharmacokinetics of haloperidol decanoate, fluphenazine enanthate and decanoate, clopenthixol decanoate, zuclopenthixol decanoate and acutard, flupenthixol decanoate, perphenazine enanthate, pipothiazine palmitate and undecylenate, and fluspirilene are reviewed. In addition, the intramuscular preparations of atypical antipsychotics and clinical uses are reviewed. Olanzapine and ziprasidone are available only as short-acting preparations, while risperidone is to date the only novel antipsychotic available as depot formulation. To date, acutely ill, agitated psychotic patients

  4. Data on alteration of hormone and growth factor receptor profiles over progressive passages of breast cancer cell lines representing different clinical subtypes.

    PubMed

    Nair, Madhumathy G; Desai, Krisha; Prabhu, Jyothi S; Hari, P S; Remacle, Jose; Sridhar, T S

    2016-09-01

    Human breast cancers are a highly heterogeneous group of tumours consisting of several molecular subtypes with a variable profile of hormone, growth factor receptors and cytokeratins [1]. Here, the data shows immunofluorescence profiling of four different cell lines belonging to distinct clinical subtypes of breast cancer. Post revival, the cell lines were passaged in culture and immunophenotyping was done for ER, HER-2, AR and EGFR. Data for the markers from early passage (5th) through passages as late as 25 for the different cell lines is presented. PMID:27508248

  5. Anatomical features and clinical relevance of a persistent trigeminal artery

    PubMed Central

    Alcalá-Cerra, Gabriel; Tubbs, R S; Niño-Hernández, Lucía M

    2012-01-01

    Background: Although persistent trigeminal artery (PTA) is uncommonly identified, knowledge of this structure is essential for clinicians who interpret cranial imaging, perform invasive studies of the cerebral vasculature, and operate this region. Methods: A review of the medical literature using standard search engines was performed to locate articles regarding the PTA, with special attention with anatomical descriptions. Results: Although anatomical reports of PTA anatomy are very scarce, those were analyzed to describe in detail the current knowledge about its anatomical relationships and variants. Additionally, the embryology, classification, clinical implications, and imaging modalities of this vessel are extensively discussed. Conclusions: Through a comprehensive review of isolated reports of the PTA, the clinician can better understand and treat patients with such an anatomical derailment. PMID:23087827

  6. [Clinical relevance of the early detection of arthrosis].

    PubMed

    Willauschus, W; Herrmann, J; Wirtz, P; Weseloh, G

    1995-01-01

    In the years 1989 to 1992 615 local persons underwent yearly examinations for analysis of osteoarthrosis of the hip and knee by means of comprehensive documentation of orthopaedic health history and clinical findings. Of special interest in our investigation were the Altman ACR criteria for osteoarthrosis of the hip and knee over the years. We can show, that finding the diagnosis is as accurate with the ACR criteria as well as the far more extensive Lequesne and Tegner-Lysholm score. Analysis of the investigations over the years revealed clearly different results in the frequency of osteoarthrosis. The reason is the nature of osteoarthrosis changing between silent and active phases especially during time of onset. Our investigations show, that valuable criteria exists for detection of early osteoarthrosis, however apparent are deficits for observing its course. PMID:8571651

  7. [Dualistic classification of epithelial ovarian cancer: Is it clinically relevant?].

    PubMed

    Devouassoux-Shisheboran, Mojgan; Genestie, Catherine; Ray-Coquard, Isabelle

    2016-03-01

    Malignant epithelial tumors (carcinomas) are the most common ovarian cancers and the most lethal gynecological malignancies. Based on their heterogeneous morphology, a dualistic model of carcinogenesis was proposed in 2004. Type I carcinomas, composed of low grade serous, endometrioid, mucinous, clear cell carcinomas and malignant Brenner tumors, were distinct from type II carcinomas (high grade serous, undifferentiated carcinomas and carcinosarcomas). However, clinical studies failed to demonstrate the prognostic value of such a classification. The main reproach to this dualistic model was that it lumped together in type I tumors, heterogeneous lesions such as clear cell and mucinous carcinomas. Recent advances on molecular genetic alterations and precursor lesions favor the classification of ovarian carcinomas as five distinct diseases. The dualistic model of carcinogenesis in type I and II can finally be applied only to serous ovarian carcinomas (low grade and high grade). PMID:26853278

  8. Erythropoiesis in vertebrates: from ontogeny to clinical relevance.

    PubMed

    Nogueira-Pedro, Amanda; dos Santos, Guilherme G; Oliveira, Dalila C; Hastreiter, Araceli A; Fock, Ricardo Ambrosio

    2016-01-01

    Erythropoiesis is a complex process that starts in the course of embryo formation and it is maintained throughout the life of an organism. During the fetal development, erythropoiesis arises from different body sites and erythroblast maturation occurs in the fetal liver. After birth, erythropoiesis and erythroblast maturation take place exclusively in the bone marrow, generating a lifetime reservoir of red blood cells (RBCs), which are responsible for transporting oxygen through the bloodstream to tissues and organs. Several transcription factors and cytokines, such as GATA-1, GATA-2, FOG-1 and erythropoietin (EPO), constitute an elaborated molecular network that regulates erythropoiesis as they are involved in the differentiation and maturation of RBCs. The profound understanding of erythropoiesis is fundamental to avoid, treat or even soften the effects of erythropoietic clinical disorders and may be useful to improve patients' well-being. PMID:26709649

  9. Nutritional and clinical relevance of lutein in human health.

    PubMed

    Granado, F; Olmedilla, B; Blanco, I

    2003-09-01

    Lutein is one of the most widely found carotenoids distributed in fruits and vegetables frequently consumed. Its presence in human tissues is entirely of dietary origin. Distribution of lutein among tissues is similar to other carotenoids but, along with zeaxanthin, they are found selectively at the centre of the retina, being usually referred to as macular pigments. Lutein has no provitamin A activity in man but it displays biological activities that have attracted great attention in relation to human health. Epidemiological studies have shown inconsistent associations between high intake or serum levels of lutein and lower risk for developing cardiovascular disease, several types of cancer, cataracts and age-related maculopathy. Also, lutein supplementation has provided both null and positive results on different biomarkers of oxidative stress although it is effective in increasing macular pigment concentration and in improving visual function in some, but not all, subjects with different eye pathologies. Overall, data suggest that whereas serum levels of lutein have, at present, no predictive, diagnostic or prognostic value in clinical practice, its determination may be very helpful in assessing compliance and efficacy of intervention as well as potential toxicity. In addition, available evidence suggests that a serum lutein concentration between 0.6 and 1.05 micromol/l seems to be a safe, dietary achievable and desirable target potentially associated with beneficial impact on visual function and, possibly, on the development of other chronic diseases. The use of lutein as a biomarker of exposure in clinical practice may provide some rationale for assessing its relationship with human health as well as its potential use within the context of evidence-based medicine. PMID:14513828

  10. [Nitrofurantoin--clinical relevance in uncomplicated urinary tract infections].

    PubMed

    Stock, Ingo

    2014-07-01

    The nitrofuran derivative nitrofurantoin has been used for more than 60 years for the antibacterial therapy of uncomplicated urinary tract infections (UTI). Despite its long application, this antibiotic retained good activity against Escherichia coli and some other pathogens of uncomplicated urinary tract infections such as Staphylococcus saprophyticus and Enterococcus species. Nitrofurantoin therapy has been shown to be accompanied by numerous adverse drug effects. Among these, there are also serious side effects such as pulmonary reactions and polyneuropathy, which mainly occur in long-term use. Recent studies, however, have shown a good efficacy and tolerability of short-term nitrofurantoin therapy comparable to previous established standard therapeutic regimens applying cotrimoxazole or quinolones. Because of these data and the alarming resistance rates of uropathogenic Escherichia coli to cotrimoxazole and quinolones that have been increased markedly in several countries, the clinical significance ofnitrofurantoin has been raised again. In many current treatment guidelines, e. g., the international clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women published by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases, nitrofurantoin has been recommended as one first-line antibiotic of empiric antibacterial treatment of uncomplicated cystitis in otherwise healthy women. In Germany, however, nitrofurantoin should only be applied if more effective and less risky antibiotics cannot be used. Nitrofurantoin is contraindicated in the last three months of pregnancy and in patients suffering from renal impairment of each degree. Despite compatibility concerns, nitrofurantoin has also been recommended for the re-infection prophylaxis of recurrent uncomplicated urinary tract infections in Germany and several other countries. PMID:25065160

  11. Alternaria infections: laboratory diagnosis and relevant clinical features.

    PubMed

    Pastor, F J; Guarro, J

    2008-08-01

    The genus Alternaria contains several species of melanized hyphomycetes that cause opportunistic human infections. The published literature contains 210 reported cases of human alternarioses between 1933 and the present day. The most frequent clinical manifestations are cutaneous and subcutaneous infections (74.3%), followed by oculomycosis (9.5%), invasive and non-invasive rhinosinusitis (8.1%) and onychomycosis (8.1%). Immunosuppression is frequently associated with cutaneous and subcutaneous infections and rhinosinusitis. The most important risk factors for cutaneous and subcutaneous infections are solid organ transplantation and Cushing's syndrome, and those for rhinosinusitis are bone marrow transplants. Having been exposed to soil and garbage is common in all cases of oculomycosis, with corticotherapy being a risk factor in 50% of these cases. Previous contact with soil and/or trauma to the nails is associated with most cases of onychomycosis. In general, alternariosis shows a good response to conventional antifungal drugs. On some occasions, steroid suppression or reduction is sufficient to resolve an infection. Itraconazole is the antifungal drug used most frequently to successfully treat onychomycosis and cutaneous and subcutaneous infections. Posaconazole and voriconazole are promising therapeutic options, with the latter being especially so for oculomycosis. PMID:18727797

  12. MicroRNAs: Clinical Relevance in Colorectal Cancer

    PubMed Central

    Thomas, Joe; Ohtsuka, Masahisa; Pichler, Martin; Ling, Hui

    2015-01-01

    Colorectal cancer is one of the most common cancer diagnoses and causes of mortality worldwide. MicroRNAs are a class of small, non-coding regulatory RNAs that have shown strong associations with colorectal cancer. Through the repression of target messenger RNAs, microRNAs modulate many cellular pathways, such as those involved in cell proliferation, apoptosis, and differentiation. The utilization of microRNAs has shown significant promise in the diagnosis and prognosis of colorectal cancer, owing to their unique expression profile associations with cancer types and malignancies. Moreover, microRNA therapeutics with mimics or antagonists show great promise in preclinical studies, which encourages further development of their clinical use for colorectal cancer patients. The unique ability of microRNAs to affect multiple downstream pathways represents a novel approach for cancer therapy. Although still early in its development, we believe that microRNAs can be used in the near future as biomarkers and therapeutic targets for colorectal cancer. PMID:26602923

  13. Clinically relevant drug-drug interactions between antiretrovirals and antifungals

    PubMed Central

    Vadlapatla, Ramya Krishna; Patel, Mitesh; Paturi, Durga K; Pal, Dhananjay; Mitra, Ashim K

    2015-01-01

    Introduction Complete delineation of the HIV-1 life cycle has resulted in the development of several antiretroviral drugs. Twenty-five therapeutic agents belonging to five different classes are currently available for the treatment of HIV-1 infections. Advent of triple combination antiretroviral therapy has significantly lowered the mortality rate in HIV patients. However, fungal infections still represent major opportunistic diseases in immunocompromised patients worldwide. Areas covered Antiretroviral drugs that target enzymes and/or proteins indispensable for viral replication are discussed in this article. Fungal infections, causative organisms, epidemiology and preferred treatment modalities are also outlined. Finally, observed/predicted drug-drug interactions between antiretrovirals and antifungals are summarized along with clinical recommendations. Expert opinion Concomitant use of amphotericin B and tenofovir must be closely monitored for renal functioning. Due to relatively weak interactive potential with the CYP450 system, fluconazole is the preferred antifungal drug. High itraconazole doses (> 200 mg/day) are not advised in patients receiving booster protease inhibitor (PI) regimen. Posaconazole is contraindicated in combination with either efavirenz or fosamprenavir. Moreover, voriconazole is contraindicated with high-dose ritonavir-boosted PI. Echino-candins may aid in overcoming the limitations of existing antifungal therapy. An increasing number of documented or predicted drug-drug interactions and therapeutic drug monitoring may aid in the management of HIV-associated opportunistic fungal infections. PMID:24521092

  14. What Is the Biological and Clinical Relevance of Fibrin?

    PubMed

    Litvinov, Rustem I; Weisel, John W

    2016-06-01

    As our knowledge of the structure and functions of fibrinogen and fibrin has increased tremendously, several key findings have given some people a superficial impression that the biological and clinical significance of these clotting proteins may be less than earlier thought. Most strikingly, studies of fibrinogen knockout mice demonstrated that many of these mice survive to weaning and beyond, suggesting that fibrin(ogen) may not be entirely necessary. Humans with afibrinogenemia also survive. Furthermore, in recent years, the major emphasis in the treatment of arterial thrombosis has been on inhibition of platelets, rather than fibrin. In contrast to the initially apparent conclusions from these results, it has become increasingly clear that fibrin is essential for hemostasis; is a key factor in thrombosis; and plays an important biological role in infection, inflammation, immunology, and wound healing. In addition, fibrinogen replacement therapy has become a preferred, major treatment for severe bleeding in trauma and surgery. Finally, fibrin is a unique biomaterial and is used as a sealant or glue, a matrix for cells, a scaffold for tissue engineering, and a carrier and/or a vector for targeted drug delivery. PMID:27056152

  15. Clinically relevant copy number variations detected in cerebral palsy

    PubMed Central

    Oskoui, Maryam; Gazzellone, Matthew J.; Thiruvahindrapuram, Bhooma; Zarrei, Mehdi; Andersen, John; Wei, John; Wang, Zhuozhi; Wintle, Richard F.; Marshall, Christian R.; Cohn, Ronald D.; Weksberg, Rosanna; Stavropoulos, Dimitri J.; Fehlings, Darcy; Shevell, Michael I.; Scherer, Stephen W.

    2015-01-01

    Cerebral palsy (CP) represents a group of non-progressive clinically heterogeneous disorders that are characterized by motor impairment and early age of onset, frequently accompanied by co-morbidities. The cause of CP has historically been attributed to environmental stressors resulting in brain damage. While genetic risk factors are also implicated, guidelines for diagnostic assessment of CP do not recommend for routine genetic testing. Given numerous reports of aetiologic copy number variations (CNVs) in other neurodevelopmental disorders, we used microarrays to genotype a population-based prospective cohort of children with CP and their parents. Here we identify de novo CNVs in 8/115 (7.0%) CP patients (∼1% rate in controls). In four children, large chromosomal abnormalities deemed likely pathogenic were found, and they were significantly more likely to have severe neuromotor impairments than those CP subjects without such alterations. Overall, the CNV data would have impacted our diagnosis or classification of CP in 11/115 (9.6%) families. PMID:26236009

  16. Longitudinal Metagenomic Analysis of Hospital Air Identifies Clinically Relevant Microbes

    PubMed Central

    King, Paula; Pham, Long K.; Waltz, Shannon; Sphar, Dan; Yamamoto, Robert T.; Conrad, Douglas; Taplitz, Randy; Torriani, Francesca

    2016-01-01

    We describe the sampling of sixty-three uncultured hospital air samples collected over a six-month period and analysis using shotgun metagenomic sequencing. Our primary goals were to determine the longitudinal metagenomic variability of this environment, identify and characterize genomes of potential pathogens and determine whether they are atypical to the hospital airborne metagenome. Air samples were collected from eight locations which included patient wards, the main lobby and outside. The resulting DNA libraries produced 972 million sequences representing 51 gigabases. Hierarchical clustering of samples by the most abundant 50 microbial orders generated three major nodes which primarily clustered by type of location. Because the indoor locations were longitudinally consistent, episodic relative increases in microbial genomic signatures related to the opportunistic pathogens Aspergillus, Penicillium and Stenotrophomonas were identified as outliers at specific locations. Further analysis of microbial reads specific for Stenotrophomonas maltophilia indicated homology to a sequenced multi-drug resistant clinical strain and we observed broad sequence coverage of resistance genes. We demonstrate that a shotgun metagenomic sequencing approach can be used to characterize the resistance determinants of pathogen genomes that are uncharacteristic for an otherwise consistent hospital air microbial metagenomic profile. PMID:27482891

  17. Clinically relevant drug interactions between anticancer drugs and psychotropic agents.

    PubMed

    Yap, K Y-L; Tay, W L; Chui, W K; Chan, A

    2011-01-01

    Drug interactions are commonly seen in the treatment of cancer patients. Psychotropics are often indicated for these patients since they may also suffer from pre-existing psychological disorders or experience insomnia and anxiety associated with cancer therapy. Thus, the risk of anticancer drug (ACD)-psychotropic drug-drug interactions (DDIs) is high. Drug interactions were compiled from the British National Formulary (53rd edn), Lexi-Comp's Drug Information Handbook (15th edn), Micromedex (v5.1), Hansten & Horn's Drug Interactions (2000) and Drug Interaction Facts (2008 edn). Product information of the individual drugs, as well as documented literature on ACD-psychotropic interactions from PubMed and other databases was also incorporated. This paper identifies clinically important ACD-psychotropic DDIs that are frequently observed. Pharmacokinetic DDIs were observed for tyrosine kinase inhibitors, corticosteroids and antimicrotubule agents due to their inhibitory or inductive effects on cytochrome P450 isoenzymes. Pharmacodynamic DDIs were identified for thalidomide with central nervous system depressants, procarbazine with antidepressants, myelosuppressive ACDs with clozapine and anthracyclines with QT-prolonging psychotropics. Clinicians should be vigilant when psychotropics are prescribed concurrently with ACDs. Close monitoring of plasma drug levels should be carried out to avoid toxicity in the patient, as well as to ensure adequate chemotherapeutic and psychotropic coverage. PMID:20030690

  18. Differential colorectal carcinogenesis: Molecular basis and clinical relevance.

    PubMed

    Morán, Alberto; Ortega, Paloma; de Juan, Carmen; Fernández-Marcelo, Tamara; Frías, Cristina; Sánchez-Pernaute, Andrés; Torres, Antonio José; Díaz-Rubio, Eduardo; Iniesta, Pilar; Benito, Manuel

    2010-03-15

    Colorectal cancer (CCR) is one of the most frequent cancers in developed countries. It poses a major public health problem and there is renewed interest in understanding the basic principles of the molecular biology of colorectal cancer. It has been established that sporadic CCRs can arise from at least two different carcinogenic pathways. The traditional pathway, also called the suppressor or chromosomal instability pathway, follows the Fearon and Vogelstein model and shows mutation in classical oncogenes and tumour suppressor genes, such as K-ras, adenomatous polyposis coli, deleted in colorectal cancer, or p53. Alterations in the Wnt pathway are also very common in this type of tumour. The second main colorectal carcinogenesis pathway is the mutator pathway. This pathway is present in nearly 15% of all cases of sporadic colorectal cancer. It is characterized by the presence of mutations in the microsatellite sequences caused by a defect in the DNA mismatch repair genes, mostly in hMLH1 or hMSH2. These two pathways have clear molecular differences, which will be reviewed in this article, but they also present distinct histopathological features. More strikingly, their clinical behaviours are completely different, having the "mutator" tumours a better outcome than the "suppressor" tumours. PMID:21160823

  19. [Neurodermatitis and food allergy. Clinical relevance of testing procedures].

    PubMed

    Stiening, H; Szczepanski, R; von Mühlendahl, K E; Kalveram, C

    1990-12-01

    In 132 children with neurodermitis, we measured specific IgG and IgE antibodies against components of cow's milk, soy milk, and egg. In addition we performed epidermal tests by rubbing the nutrients onto the intact skin. The results were compared to the effect of complete omission of milk, egg, and soy during four weeks and with the outcome of subsequent reexposition. We used standardized scales to evaluate the neurodermitis and the skin reactions and for the clinical response to the oral challenge. The best prediction for the outcome of the oral challenge was obtained by the epidermal test which had to be done with whole milk, soy milk and egg white; there was no further advantage in testing egg yolk or soy oil. IgE antibodies followed next in their predictive value. No further precision was gained by the combination of epidermal testing with IgE results, by the measurement of IgE antibodies to the constituents of cow's milk, of IgG antibodies, and of the platelet count during oral challenging. Positive reactions to oral administration after four weeks' omission of allergenic food were relatively frequent in the age group below three years, but rare in school children and adolescents. PMID:2087240

  20. Patients with obsessive-compulsive disorder and hoarding symptoms: a distinctive clinical subtype?

    PubMed

    Fontenelle, Leonardo F; Mendlowicz, Mauro V; Soares, Isabela D; Versiani, Márcio

    2004-01-01

    We investigated whether patients with obsessive-compulsive disorder (OCD) and hoarding symptoms can be differentiated from their counterparts with other types of obsessions and compulsions in terms of sociodemographic and clinical features. Ninety-seven patients with OCD were assessed with a sociodemographic and clinical questionnaire, the Structured Clinical Interview for DSM-IV (SCID-I), the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Beck Depression Inventory (BDI), the Hamilton Rating Scale for Depression (HDRS), and the Global Assessment of Functioning (GAF). Fifteen patients who reported hoarding symptoms in the Y-BOCS checklist (15.6% of the total sample) were compared and contrasted with 82 patients without those symptoms using the Mann-Whitney U test for continuous variables and the Pearson's goodness-of-fit chi-square test for categorical ones; Fisher's exact test was employed when indicated. Hoarders were characterized by (1) higher educational levels (chi(2) = 7.49; df = 2; P =.02); (2) earlier age at onset (Z = -2.99; P =.003); (3) higher rates of symmetry obsessions (chi(2) = 7.03; df = 1; P =.01); (4) greater frequency of ordering (chi(2) = 10.08; df = 1; P =.004); (5) rituals repetition (chi(2) = 4.42; df = 1; P =.03); (6) counting compulsions (chi(2) = 5.92; df = 1; P =.02); and (7) significantly higher rates of comorbidity with bipolar II disorder (chi(2) = 10.62; df = 1; P =.02) and (8) with eating disorders (chi(2) = 7.42; df = 1; P =.02). In conclusion, patients with OCD exhibiting hoarding feature a distinctive sociodemographic and clinical profile. It remains to be investigated whether these phenotypical characteristics are underlined by specific neurobiological mechanisms. PMID:15332201

  1. Subtyping adolescents with bulimia nervosa.

    PubMed

    Chen, Eunice Y; Le Grange, Daniel

    2007-12-01

    Cluster analyses of eating disorder patients have yielded a "dietary-depressive" subtype, typified by greater negative affect, and a "dietary" subtype, typified by dietary restraint. This study aimed to replicate these findings in an adolescent sample with bulimia nervosa (BN) from a randomized controlled trial and to examine the validity and reliability of this methodology. In the sample of BN adolescents (N=80), cluster analysis revealed a "dietary-depressive" subtype (37.5%) and a "dietary" subtype (62.5%) using the Beck Depression Inventory, Rosenberg Self-Esteem Scale and Eating Disorder Examination Restraint subscale. The "dietary-depressive" subtype compared to the "dietary" subtype was significantly more likely to: (1) report co-occurring disorders, (2) greater eating and weight concerns, and (3) less vomiting abstinence at post-treatment (all p's<.05). The cluster analysis based on "dietary" and "dietary-depressive" subtypes appeared to have concurrent validity, yielding more distinct groups than subtyping by vomiting frequency. In order to assess the reliability of the subtyping scheme, a larger sample of adolescents with mixed eating and weight disorders in an outpatient eating disorder clinic (N=149) was subtyped, yielding similar subtypes. These results support the validity and reliability of the subtyping strategy in two adolescent samples. PMID:17949682

  2. The Clinical Utility of the Proposed DSM-5 Callous-Unemotional Subtype of Conduct Disorder in Young Girls

    ERIC Educational Resources Information Center

    Pardini, Dustin; Stepp, Stephanie; Hipwell, Alison; Stouthamer-Loeber, Magda; Loeber, Rolf

    2012-01-01

    Objective: A callous-unemotional (CU) subtype of conduct disorder (CD) has been proposed as an addition to the fifth edition of the "Diagnostic and Statistic Manual of Mental Disorders (DSM-5)." This study tested the hypothesis that young girls with the CU subtype of CD would exhibit more severe antisocial behavior and less severe internalizing…

  3. A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

    PubMed Central

    Sadanandam, Anguraj; Wullschleger, Stephan; Lyssiotis, Costas A.; Grötzinger, Carsten; Barbi, Stefano; Bersani, Samantha; Körner, Jan; Wafy, Ismael; Mafficini, Andrea; Lawlor, Rita T.; Simbolo, Michele; Asara, John M.; Bläker, Hendrik; Cantley, Lewis C.; Wiedenmann, Bertram; Scarpa, Aldo; Hanahan, Douglas

    2016-01-01

    Seeking to assess the representative and instructive value of an engineered mouse model of pancreatic neuroendocrine tumors (PanNET) for its cognate human cancer, we profiled and compared mRNA and miRNA transcriptomes of tumors from both. Mouse PanNET tumors could be classified into two distinctive subtypes, well-differentiated islet/insulinoma tumors (IT) and poorly differentiated tumors associated with liver metastases, dubbed metastasis-like primary (MLP). Human PanNETs were independently classified into these same two subtypes, along with a third, specific gene mutation–enriched subtype. The MLP subtypes in human and mouse were similar to liver metastases in terms of miRNA and mRNA transcriptome profiles and signature genes. The human/mouse MLP subtypes also similarly expressed genes known to regulate early pancreas development, whereas the IT subtypes expressed genes characteristic of mature islet cells, suggesting different tumorigenesis pathways. In addition, these subtypes exhibit distinct metabolic profiles marked by differential pyruvate metabolism, substantiating the significance of their separate identities. SIGNIFICANCE This study involves a comprehensive cross-species integrated analysis of multi-omics profiles and histology to stratify PanNETs into subtypes with distinctive characteristics. We provide support for the RIP1-TAG2 mouse model as representative of its cognate human cancer with prospects to better understand PanNET heterogeneity and consider future applications of personalized cancer therapy. PMID:26446169

  4. DNA methylation patterns in luminal breast cancers differ from non-luminal subtypes and can identify relapse risk independent of other clinical variables.

    PubMed

    Kamalakaran, Sitharthan; Varadan, Vinay; Giercksky Russnes, Hege E; Levy, Dan; Kendall, Jude; Janevski, Angel; Riggs, Michael; Banerjee, Nilanjana; Synnestvedt, Marit; Schlichting, Ellen; Kåresen, Rolf; Shama Prasada, K; Rotti, Harish; Rao, Ramachandra; Rao, Laxmi; Eric Tang, Man-Hung; Satyamoorthy, K; Lucito, Robert; Wigler, Michael; Dimitrova, Nevenka; Naume, Bjorn; Borresen-Dale, Anne-Lise; Hicks, James B

    2011-02-01

    The diversity of breast cancers reflects variations in underlying biology and affects the clinical implications for patients. Gene expression studies have identified five major subtypes- Luminal A, Luminal B, basal-like, ErbB2+ and Normal-Like. We set out to determine the role of DNA methylation in subtypes by performing genome-wide scans of CpG methylation in breast cancer samples with known expression-based subtypes. Unsupervised hierarchical clustering using a set of most varying loci clustered the tumors into a Luminal A majority (82%) cluster, Basal-like/ErbB2+ majority (86%) cluster and a non-specific cluster with samples that were also inconclusive in their expression-based subtype correlations. Contributing methylation loci were both gene associated loci (30%) and non-gene associated (70%), suggesting subtype dependant genome-wide alterations in the methylation landscape. The methylation patterns of significant differentially methylated genes in luminal A tumors are similar to those identified in CD24 + luminal epithelial cells and the patterns in basal-like tumors similar to CD44 + breast progenitor cells. CpG islands in the HOXA cluster and other homeobox (IRX2, DLX2, NKX2-2) genes were significantly more methylated in Luminal A tumors. A significant number of genes (2853, p < 0.05) exhibited expression-methylation correlation, implying possible functional effects of methylation on gene expression. Furthermore, analysis of these tumors by using follow-up survival data identified differential methylation of islands proximal to genes involved in Cell Cycle and Proliferation (Ki-67, UBE2C, KIF2C, HDAC4), angiogenesis (VEGF, BTG1, KLF5), cell fate commitment (SPRY1, OLIG2, LHX2 and LHX5) as having prognostic value independent of subtypes and other clinical factors. PMID:21169070

  5. Stone culture retrieved during percutaneous nephrolithotomy: is it clinically relevant?

    PubMed

    Osman, Yasser; Elshal, Ahmed M; Elawdy, Mohamed M; Omar, Helmy; Gaber, Asaad; Elsawy, Essam; El-Nahas, Ahmed R

    2016-08-01

    Stone culture has been frequently investigated following percutaneous nephrolithotomy (PNL) in the last decade. We aimed to crucially define the clinical role of stone culture in modifying the treatment plan in patients with postoperative sepsis. Between June 2012 and April 2013, a total of 79 consecutive PNL procedures were included. Perioperative data were prospectively maintained. Preoperative urine sample, retrieved stone fragments and postoperative nephrostomy tube urine sample were cultured and antibiotic sensitivity tests were performed. The occurrence of at least two of the systemic inflammatory response syndrome (SIRS) events during their inpatient stay was diagnostic of SIRS. The antibiotic regimen utilized and its modifications were reported. The preoperative culture was positive in 26 patients (32.9 %). The culture of stone fragments showed significant bacterial growth in 23 (29.1 %) cases. Significant growth on stone culture was significantly associated with the presence of preoperative urinary catheters and positive preoperative urine culture (P = 0.001, 0.006 respectively). Postoperative culture was positive in only six patients (7.6 %). SIRS was diagnosed in the first postoperative day in 12 patients (15.2 %). Leukocytosis was the only predictor of SIRS. Neither preoperative culture, stone culture nor postoperative culture was predictor of SIRS. Stone culture was positive in four patients with SIRS. Stone culture changed the treatment plan in only one patient. Our data do not support the routine implementation of stone culture in the PNL workup, as it did not indicate a change of antibiotic regimen in most of the cases. PMID:26781741

  6. Clinical relevance of sarcopenia in patients with cirrhosis

    PubMed Central

    Montano-Loza, Aldo J

    2014-01-01

    The most commonly recognized complications in cirrhotic patients include ascites, hepatic encephalopathy, variceal bleeding, susceptibility for infections, kidney dysfunction, and hepatocellular carcinoma; however, severe muscle wasting or sarcopenia are the most common and frequently unseen complications which negatively impact survival, quality of life, and response to stressor, such as infections and surgeries. At present, D’Amico stage classification, Child-Pugh, and MELD scores constitute the best tools to predict mortality in patients with cirrhosis; however, one of their main limitations is the lack of assessing the nutritional and functional status. Currently, numerous methods are available to evaluate the nutrition status of the cirrhotic patient; nevertheless, most of these techniques have limitations primarily because lack of objectivity, reproducibility, and prognosis discrimination. In this regard, an objective and reproducible technique, such as muscle mass quantification with cross-sectional imaging studies (computed tomography scan or magnetic resonance imaging) constitute an attractive index of nutritional status in cirrhosis. Sarcopenia is part of the frailty complex present in cirrhotic patients, resulting from cumulative declines across multiple physiologic systems and characterized by impaired functional capacity, decreased reserve, resistance to stressors, and predisposition to poor outcomes. In this review, we discuss the current accepted and new methods to evaluate prognosis in cirrhosis. Also, we analyze the current knowledge regarding incidence and clinical impact of malnutrition and sarcopenia in patients with cirrhosis and their impact after liver transplantation. Finally, we discuss existing and potential novel therapeutic approaches for malnutrition in cirrhosis, emphasizing the recognition of sarcopenia in an effort to reduced morbidity related and improved survival in cirrhosis. PMID:25009378

  7. Estrogen Receptors Alpha (ERα) and Beta (ERβ): Subtype-Selective Ligands and Clinical Potential

    PubMed Central

    Paterni, Ilaria; Granchi, Carlotta; Katzenellenbogen, John A.; Minutolo, Filippo

    2014-01-01

    Estrogen receptors alpha (ERα) and beta (ERβ) are nuclear transcription factors that are involved in the regulation of many complex physiological processes in humans. Modulation of these receptors by prospective therapeutic agents is currently being considered for prevention and treatment of a wide variety of pathological conditions, such as, cancer, metabolic and cardiovascular diseases, neurodegeneration, inflammation, and osteoporosis. This review provides an overview and update of compounds that have been recently reported as modulators of ERs, with a particular focus on their potential clinical applications. PMID:24971815

  8. Clinical value of molecular subtyping multiple myeloma using gene expression profiling.

    PubMed

    Weinhold, N; Heuck, C J; Rosenthal, A; Thanendrarajan, S; Stein, C K; Van Rhee, F; Zangari, M; Hoering, A; Tian, E; Davies, F E; Barlogie, B; Morgan, G J

    2016-02-01

    Using a data set of 1217 patients with multiple myeloma enrolled in Total Therapies, we have examined the impact of novel therapies on molecular and risk subgroups and the clinical value of molecular classification. Bortezomib significantly improved the progression-free survival (PFS) and overall survival (OS) of the MMSET (MS) subgroup. Thalidomide and bortezomib positively impacted the PFS of low-risk (LoR) cases defined by the GEP70 signature, whereas high-risk (HiR) cases showed no significant changes in outcome. We show that molecular classification is important if response rates are to be used to predict outcomes. The t(11;14)-containing CD-1 and CD-2 subgroups showed clear differences in time to response and cumulative response rates but similar PFS and OS. Furthermore, complete remission was not significantly associated with the outcome of the MAF/MAFB (MF) subgroup or HiR cases. HiR cases were enriched in the MF, MS and proliferation subgroups, but the poor outcome of these groups was not linked to subgroup-specific characteristics such as MAF overexpression per se. It is especially important to define risk status if HiR cases are to be managed appropriately because of their aggressive clinical course, high rates of early relapse and the need to maintain therapeutic pressure on the clone. PMID:26526987

  9. Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme

    PubMed Central

    Liang, Yu; Diehn, Maximilian; Watson, Nathan; Bollen, Andrew W.; Aldape, Ken D.; Nicholas, M. Kelly; Lamborn, Kathleen R.; Berger, Mitchel S.; Botstein, David; Brown, Patrick O.; Israel, Mark A.

    2005-01-01

    Glioblastoma multiforme (GBM) is the most common form of malignant glioma, characterized by genetic instability, intratumoral histopathological variability, and unpredictable clinical behavior. We investigated global gene expression in surgical samples of brain tumors. Gene expression profiling revealed large differences between normal brain samples and tumor tissues and between GBMs and lower-grade oligodendroglial tumors. Extensive differences in gene expression were found among GBMs, particularly in genes involved in angiogenesis, immune cell infiltration, and extracellular matrix remodeling. We found that the gene expression patterns in paired specimens from the same GBM invariably were more closely related to each other than to any other tumor, even when the paired specimens had strikingly divergent histologies. Survival analyses revealed a set of ≈70 genes more highly expressed in rapidly progressing tumors that stratified GBMs into two groups that differed by >4-fold in median duration of survival. We further investigated one gene from the group, FABP7, and confirmed its association with survival in two unrelated cohorts totaling 105 patients. Expression of FABP7 enhanced the motility of glioma-derived cells in vitro. Our analyses thus identify and validate a prognostic marker of both biologic and clinical significance and provide a series of putative markers for additional evaluation. PMID:15827123

  10. Prognostic Factors Toward Clinically Relevant Radiographic Progression in Patients With Rheumatoid Arthritis in Clinical Practice

    PubMed Central

    Koga, Tomohiro; Okada, Akitomo; Fukuda, Takaaki; Hidaka, Toshihiko; Ishii, Tomonori; Ueki, Yukitaka; Kodera, Takao; Nakashima, Munetoshi; Takahashi, Yuichi; Honda, Seiyo; Horai, Yoshiro; Watanabe, Ryu; Okuno, Hiroshi; Aramaki, Toshiyuki; Izumiyama, Tomomasa; Takai, Osamu; Miyashita, Taiichiro; Sato, Shuntaro; Kawashiri, Shin-ya; Iwamoto, Naoki; Ichinose, Kunihiro; Tamai, Mami; Origuchi, Tomoki; Nakamura, Hideki; Aoyagi, Kiyoshi; Eguchi, Katsumi; Kawakami, Atsushi

    2016-01-01

    Abstract To determine prognostic factors of clinically relevant radiographic progression (CRRP) in patients with rheumatoid arthritis (RA) in clinical practice. We performed a multicenter prospective study in Japan of biological disease-modifying antirheumatic drug (bDMARD)-naive RA patients with moderate to high disease activity treated with conventional synthetic DMARDs (csDMARDs) at study entry. We longitudinally observed 408 patients for 1 year and assessed disease activity every 3 months. CRRP was defined as yearly progression of modified total Sharp score (mTSS) > 3.0 U. We also divided the cohort into 2 groups based on disease duration (<3 vs ≥3 years) and performed a subgroup analysis. CRRP was found in 10.3% of the patients. A multiple logistic regression analysis revealed that the independent variables to predict the development of CRRP were: CRP at baseline (0.30 mg/dL increase, 95% confidence interval [CI] 1.01–1.11), time-integrated Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) during the 1 year postbaseline (12.4-unit increase, 95%CI 1.17–2.59), RA typical erosion at baseline (95%CI 1.56–21.1), and the introduction of bDMARDs (95%CI 0.06–0.38). The subgroup analysis revealed that time-integrated DAS28-ESR is not a predictor whereas the introduction of bDMARDs is a significant protective factor for CRRP in RA patients with disease duration <3 years. We identified factors that could be used to predict the development of CRRP in RA patients treated with DMARDs. These variables appear to be different based on the RA patients’ disease durations. PMID:27124044

  11. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes.

    PubMed

    Rumi, Elisa; Pietra, Daniela; Ferretti, Virginia; Klampfl, Thorsten; Harutyunyan, Ashot S; Milosevic, Jelena D; Them, Nicole C C; Berg, Tiina; Elena, Chiara; Casetti, Ilaria C; Milanesi, Chiara; Sant'antonio, Emanuela; Bellini, Marta; Fugazza, Elena; Renna, Maria C; Boveri, Emanuela; Astori, Cesare; Pascutto, Cristiana; Kralovics, Robert; Cazzola, Mario

    2014-03-01

    Patients with essential thrombocythemia may carry JAK2 (V617F), an MPL substitution, or a calreticulin gene (CALR) mutation. We studied biologic and clinical features of essential thrombocythemia according to JAK2 or CALR mutation status and in relation to those of polycythemia vera. The mutant allele burden was lower in JAK2-mutated than in CALR-mutated essential thrombocythemia. Patients with JAK2 (V617F) were older, had a higher hemoglobin level and white blood cell count, and lower platelet count and serum erythropoietin than those with CALR mutation. Hematologic parameters of patients with JAK2-mutated essential thrombocythemia or polycythemia vera were related to the mutant allele burden. While no polycythemic transformation was observed in CALR-mutated patients, the cumulative risk was 29% at 15 years in those with JAK2-mutated essential thrombocythemia. There was no significant difference in myelofibrotic transformation between the 2 subtypes of essential thrombocythemia. Patients with JAK2-mutated essential thrombocythemia and those with polycythemia vera had a similar risk of thrombosis, which was twice that of patients with the CALR mutation. These observations are consistent with the notion that JAK2-mutated essential thrombocythemia and polycythemia vera represent different phenotypes of a single myeloproliferative neoplasm, whereas CALR-mutated essential thrombocythemia is a distinct disease entity. PMID:24366362

  12. Variations in DNA subtype, antifungal susceptibility, and slime production among clinical isolates of Candida parapsilosis.

    PubMed

    Pfaller, M A; Messer, S A; Hollis, R J

    1995-01-01

    Candida parapsilosis is an important nosocomial pathogen that can proliferate in high concentrations of glucose and form biofilms on prosthetic materials. We investigated the genotypic diversity, slime production, and antifungal susceptibility among 60 isolates of C. parapsilosis from 44 patients and 10 patient care providers from five different medical centers. Molecular typing was performed using macrorestriction digest profiles with BssHII followed by pulsed-field gel electrophoresis (REAG) and by electrophoretic karyotyping (EK). Slime production was evaluated by growing the organisms in Sabouraud broth with 8% glucose and examining the walls of the tubes for the presence of an adherent slime layer. Antifungal susceptibility to amphotericin B, 5-fluorocytosine, fluconazole, and itraconazole was determined using National Committee for Clinical Laboratory Standards proposed standard methods. Overall 28 different DNA types were identified by REAG and EK methods. MIC90 values ranged from 0.12 microgram/ml for itraconazole to 1.0 microgram/ml for fluconazole and amphotericin B. Sixty-five percent of the isolates produced slime: 37% were moderately to strongly positive, 28% were weakly positive, and 35% were negative. Overall, 83% of blood and catheter isolates were slime positive versus 53% of isolates from all other sites (P < 0.05). These data underscore the genetic diversity and susceptibility of C. parapsilosis to antifungal agents. Slime production may be important in enabling C. parapsilosis to cause catheter-related bloodstream infections. PMID:7789100

  13. Comparable Antigenicity and Immunogenicity of Oligomeric Forms of a Novel, Acute HIV-1 Subtype C gp145 Envelope for Use in Preclinical and Clinical Vaccine Research

    PubMed Central

    Wieczorek, Lindsay; Krebs, Shelly J.; Kalyanaraman, Vaniambadi; Whitney, Stephen; Tovanabutra, Sodsai; Moscoso, Carlos G.; Sanders-Buell, Eric; Williams, Constance; Slike, Bonnie; Molnar, Sebastian; Dussupt, Vincent; Alam, S. Munir; Chenine, Agnes-Laurence; Tong, Tina; Hill, Edgar L.; Liao, Hua-Xin; Hoelscher, Michael; Maboko, Leonard; Zolla-Pazner, Susan; Haynes, Barton F.; Pensiero, Michael; McCutchan, Francine; Malek-Salehi, Shawyon; Cheng, R. Holland; Robb, Merlin L.; VanCott, Thomas; Michael, Nelson L.; Marovich, Mary A.; Alving, Carl R.; Matyas, Gary R.; Rao, Mangala

    2015-01-01

    ABSTRACT Eliciting broadly reactive functional antibodies remains a challenge in human immunodeficiency virus type 1 (HIV-1) vaccine development that is complicated by variations in envelope (Env) subtype and structure. The majority of new global HIV-1 infections are subtype C, and novel antigenic properties have been described for subtype C Env proteins. Thus, an HIV-1 subtype C Env protein (CO6980v0c22) from an infected person in the acute phase (Fiebig stage I/II) was developed as a research reagent and candidate immunogen. The gp145 envelope is a novel immunogen with a fully intact membrane-proximal external region (MPER), extended by a polylysine tail. Soluble gp145 was enriched for trimers that yielded the expected “fan blade” motifs when visualized by cryoelectron microscopy. CO6980v0c22 gp145 reacts with the 4E10, PG9, PG16, and VRC01 HIV-1 neutralizing monoclonal antibodies (MAbs), as well as the V1/V2-specific PGT121, 697, 2158, and 2297 MAbs. Different gp145 oligomers were tested for immunogenicity in rabbits, and purified dimers, trimers, and larger multimers elicited similar levels of cross-subtype binding and neutralizing antibodies to tier 1 and some tier 2 viruses. Immunized rabbit sera did not neutralize the highly resistant CO6980v0c22 pseudovirus but did inhibit the homologous infectious molecular clone in a peripheral blood mononuclear cell (PBMC) assay. This Env is currently in good manufacturing practice (GMP) production to be made available for use as a clinical research tool and further evaluation as a candidate vaccine. IMPORTANCE At present, the product pipeline for HIV vaccines is insufficient and is limited by inadequate capacity to produce large quantities of vaccine to standards required for human clinical trials. Such products are required to evaluate critical questions of vaccine formulation, route, dosing, and schedule, as well as to establish vaccine efficacy. The gp145 Env protein presented in this study forms physical trimers

  14. Prevalence and clinical outcomes of young breast cancer (YBC) patients according to intrinsic breast cancer subtypes: Single institutional experience in Korea.

    PubMed

    Park, Yeon Hee; Lee, Su Jin; Jung, Hyun Ae; Kim, Sung Min; Kim, Moon Jin; Kil, Won Ho; Lee, Jeong Eon; Nam, Seok Jin; Ahn, Jin Seok; Im, Young-Hyuck

    2015-06-01

    The purpose of our study was to investigate and identify comprehensively the clinicopathological features and long-term outcome of young breast cancer (YBC) according to intrinsic subtype. We analyzed clinical and pathological characteristics of 2844 women who were diagnosed with invasive breast cancer from 2000 to 2007 and the treatment outcomes by age at diagnosis. The median age of the patients was 46 years (range, 21-83 years), and we divided them into three age group: ≤35 years (Group 1), 36-50 years (Group 2), and >50 years (Group 3). During a median follow-up of 100 months, the 5-year recurrence-free survival rate (RFSR) and overall survival rate (OSR) were 90.8% and 94.6%, respectively. The 10-year estimated RFSR and OSR were 81.9% and 86.9%, respectively. The prognosis of TN subtype appeared not to be worse than that of other subtypes in Group 1. In Group 1 alone (≤35 years), subtype was not identified as an independent risk factor for distant recurrence-free survival (DRFS) in a Cox-regression multivariate model (hazard ratio, 0.85; 95% CI, 0.68-1.06; p = 0.148). This analysis revealed a very high prevalence of YBC in this cohort. The poor outcomes of YBC patients might result from an increased frequency of triple negative (TN)/HER2 subtypes and the more aggressive clinical behavior of ER-positive tumors compared with older patients. Further research to elucidate the biologic difference of the ER+ tumors of YBC patients is warranted. PMID:25728283

  15. Long noncoding RNA HOTAIR is relevant to cellular proliferation, invasiveness, and clinical relapse in small-cell lung cancer

    PubMed Central

    Ono, Hiroshi; Motoi, Noriko; Nagano, Hiroko; Miyauchi, Eisaku; Ushijima, Masaru; Matsuura, Masaaki; Okumura, Sakae; Nishio, Makoto; Hirose, Tetsuro; Inase, Naohiko; Ishikawa, Yuichi

    2014-01-01

    Small-cell lung cancer (SCLC) is a subtype of lung cancer with poor prognosis. To identify accurate predictive biomarkers and effective therapeutic modalities, we focus on a long noncoding RNA, Hox transcript antisense intergenic RNA (HOTAIR), and investigated its expression, cellular functions, and clinical relevance in SCLC. In this study, HOTAIR expression was assessed in 35 surgical SCLC samples and 10 SCLC cell lines. The efficacy of knockdown of HOTAIR by siRNA transfection was evaluated in SBC-3 cells in vitro, and the gene expression was analyzed using microarray. HOTAIR was expressed highly in pure, rather than combined, SCLC (P = 0.012), that the subgroup with high expression had significantly more pure SCLC (P = 0.04), more lymphatic invasion (P = 0.03) and more relapse (P = 0.04) than the low-expression subgroup. The knockdown of HOTAIR in SBC-3 cells led to decreased proliferation activity and decreased invasiveness in vitro. Gene expression analysis indicated that depletion of HOTAIR resulted in upregulation of cell adhesion-related genes such as ASTN1, PCDHA1, and mucin production-related genes such as MUC5AC, and downregulation of genes involved in neuronal growth and signal transduction including NTM and PTK2B. Our results suggest that HOTAIR has an oncogenic role in SCLC and could be a prognostic biomarker and therapeutic target. PMID:24591352

  16. Early Benefit Assessments in Oncology in Germany: How Can a Clinically Relevant Endpoint Not Be Relevant to Patients?

    PubMed

    Ruof, Jörg; Flückiger, Olivier; Andre, Niko

    2015-09-01

    After 4 years of early benefit assessment (EBA) in Germany, it is becoming evident that the Federal Joint Committee (FJC) frequently considers well-established clinical endpoints as not being relevant to patients. Focusing on assessments of oncology medicines, we analysed the FJC's view on primary endpoints and compared it with the approach used by regulatory authorities. Mortality data were accepted by both stakeholders. Whereas regulatory authorities accepted primary morbidity endpoints such as progression-free survival and response rates, the FJC mostly excluded these from its assessments. Health-related quality of life (HRQoL) data have been poorly reflected in the approval process; for EBAs, those data have rarely impacted on benefit ratings. We argue that agreement between regulatory authorities and the FJC is required regarding primary study endpoints that are relevant to patients, and that clarification of acceptable endpoints by the FJC, especially in the morbidity domain, has to be provided. Moreover, in order to fully acknowledge the benefit of a new medicinal product, mortality, morbidity and HRQoL should be weighted differentially, according to the condition. PMID:26286202

  17. Power and sample size determination when assessing the clinical relevance of trial results by 'responder analyses'.

    PubMed

    Kieser, Meinhard; Röhmel, Joachim; Friede, Tim

    2004-11-15

    A fundamental issue in regulatory decision making is the assessment of the benefit/risk profile of a compound. In order to do this, establishing the existence of a treatment effect by a significance test is not sufficient, but the clinical relevance of a potential benefit must also be taken into account. A number of regulatory guidelines propose that clinical relevance should be assessed by considering the rate of responders, i.e. the proportion of patients who are observed to achieve an apparently meaningful benefit. In this paper, we present methods for planning clinical trials that aim at demonstrating both statistical and clinical significance in superiority trials. Procedures based on analytical calculations are derived for normally distributed data and the case of a single endpoint as well as multiple primary outcomes. A bootstrap procedure is proposed that can be applied to non-normal data. Application is illustrated by a clinical trial in Alzheimer's disease. PMID:15490433

  18. Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors

    PubMed Central

    Daemen, Anneleen; Peterson, David; Sahu, Nisebita; McCord, Ron; Du, Xiangnan; Liu, Bonnie; Kowanetz, Katarzyna; Hong, Rebecca; Moffat, John; Gao, Min; Boudreau, Aaron; Mroue, Rana; Corson, Laura; O’Brien, Thomas; Qing, Jing; Sampath, Deepak; Merchant, Mark; Yauch, Robert; Manning, Gerard; Settleman, Jeffrey; Hatzivassiliou, Georgia; Evangelista, Marie

    2015-01-01

    Although targeting cancer metabolism is a promising therapeutic strategy, clinical success will depend on an accurate diagnostic identification of tumor subtypes with specific metabolic requirements. Through broad metabolite profiling, we successfully identified three highly distinct metabolic subtypes in pancreatic ductal adenocarcinoma (PDAC). One subtype was defined by reduced proliferative capacity, whereas the other two subtypes (glycolytic and lipogenic) showed distinct metabolite levels associated with glycolysis, lipogenesis, and redox pathways, confirmed at the transcriptional level. The glycolytic and lipogenic subtypes showed striking differences in glucose and glutamine utilization, as well as mitochondrial function, and corresponded to differences in cell sensitivity to inhibitors of glycolysis, glutamine metabolism, lipid synthesis, and redox balance. In PDAC clinical samples, the lipogenic subtype associated with the epithelial (classical) subtype, whereas the glycolytic subtype strongly associated with the mesenchymal (QM-PDA) subtype, suggesting functional relevance in disease progression. Pharmacogenomic screening of an additional ∼200 non-PDAC cell lines validated the association between mesenchymal status and metabolic drug response in other tumor indications. Our findings highlight the utility of broad metabolite profiling to predict sensitivity of tumors to a variety of metabolic inhibitors. PMID:26216984

  19. The Clinical Utility of the Proposed DSM-5 Callous-Unemotional Subtype of Conduct Disorder in Young Girls

    PubMed Central

    Pardini, Dustin; Stepp, Stephanie; Hipwell, Alison; Stouthamer-Loeber, Magda; Loeber, Rolf

    2012-01-01

    Objective A callous-unemotional (CU) subtype of conduct disorder (CD) has been proposed as an addition to the fifth edition of the Diagnostic and Statistic Manual of Mental Disorders (DSM-5). This study tested the hypothesis that young girls with the CU subtype of CD will exhibit more severe antisocial behavior and less severe internalizing problems over time relative to girls with CD alone. Secondly, the developmental outcomes of girls with CU traits in the absence of CD was examined because these girls will be overlooked by the proposed CU subtyping scheme. Method Theses issues were examined in a community sample of 1862 girls aged 6-8 at study onset. Outcomes included internalizing and externalizing problems, academic achievement, and global impairment assessed concurrently and at a six year follow-up. Results Girls with the CU subtype of CD had higher levels of externalizing disorder symptoms, bullying, relational aggression, and global impairment than girls with CD alone. Girls with CD alone tended to have more anxiety problems than girls with the CU subtype of CD. Girls with high CU traits without CD exhibited higher ODD and ADHD symptoms and lower academic achievement at the six-year follow-up relative to girls without CU traits and CD. Group differences at the six year follow-up were primarily accounted for by baseline differences on the outcomes. Conclusions The proposed DSM-5 CU subtype of CD identifies young girls who exhibit lower anxiety problems and more severe aggression, CD symptoms, academic problems and global impairment across time than girls with CD alone. PMID:22176940

  20. Review: development of clinically relevant scaffolds for vascularised bone tissue engineering.

    PubMed

    Liu, Yuchun; Lim, Jing; Teoh, Swee-Hin

    2013-01-01

    Clinical translation of scaffold-based bone tissue engineering (BTE) therapy still faces many challenges despite intense investigations and advancement over the years. To address these clinical barriers, it is important to analyse the current technical challenges in constructing a clinically relevant scaffold and subsequent clinical issues relating to bone repair. This review highlights the key challenges hampering widespread clinical translation of scaffold-based vascularised BTE, with a focus on the repair of large non-union defects. The main limitations of current scaffolds include the lack of sufficient vascularisation, insufficient mechanical strength as well as issues relating to the osseointegration of the bioresorbable scaffold and bone infection management. Critical insights on the current trends of scaffold technologies and future directions for advancing next-generation BTE scaffolds into the clinical realm are discussed. Considerations concerning regulatory approval and the route towards commercialisation of the scaffolds for widespread clinical utility will also be introduced. PMID:23142624

  1. Acute Effects of Outdoor Air Pollution on Emergency Department Visits Due to Five Clinical Subtypes of Coronary Heart Diseases in Shanghai, China

    PubMed Central

    Xie, Juan; He, Mingzhen; Zhu, Weiying

    2014-01-01

    Background Air pollution can be a contributing cause to the development and exacerbation of coronary heart disease (CHD), but there is little knowledge about the acute effects of air pollution on different clinical subtypes of CHD. Methods We conducted a time-series study to investigate the association of air pollution (particulate matter with an aerodynamic diameter < 10 µm [PM10], sulfur dioxide [SO2], and nitrogen dioxide [NO2]) on emergency department (ED) visits due to five different subtypes of CHD in Shanghai, China, from 2010 to 2012. We applied an over-dispersed Poisson generalized addictive model to analyze the associations after controlling for the seasonality, day of the week, and weather conditions. Results We identified a total of 47 523 ED visits for CHD. A 10-µg/m3 increase in the present-day concentrations of PM10, SO2, and NO2 was associated with respective increases of 1.10% (95% confidence interval [CI] 0.33%–1.87%), 0.90% (95% CI −0.14%–1.93%), and 1.44% (95% CI 0.63%–2.26%) for total ED visits for CHD. These associations varied greatly by clinical type, with strong effects on sudden cardiac death, moderate effects on acute myocardial infarction and angina, weak effects on ischemic cardiomyopathy, and no effect on occult CHD. The associations were stronger among people aged 65 years or more than in younger individuals and in the cool season versus the warm one. Conclusions Outdoor air pollution may have different effects of air pollution on 5 subtypes of CHD. Our results might be useful for the primary prevention of various subtypes of CHD exacerbated by air pollution. PMID:24998952

  2. Chorea as a clinical feature of the basophilic inclusion body disease subtype of fused-in-sarcoma-associated frontotemporal lobar degeneration.

    PubMed

    Kawakami, Ito; Kobayashi, Zen; Arai, Tetsuaki; Yokota, Osamu; Nonaka, Takashi; Aoki, Naoya; Niizato, Kazuhiro; Oshima, Kenichi; Higashi, Shinji; Katsuse, Omi; Hosokawa, Masato; Hasegawa, Masato; Akiyama, Haruhiko

    2016-01-01

    Choreoathetoid involuntary movements are rarely reported in patients with frontotemporal lobar degeneration (FTLD), suggesting their exclusion as a supportive feature in clinical diagnostic criteria for FTLD. Here, we identified three cases of the behavioral variant of frontotemporal dementia (bvFTD) that display chorea with fused in sarcoma (FUS)-positive inclusions (FTLD-FUS) and the basophilic inclusion body disease (BIBD) subtype. We determined the behavioral and cognitive features in this group that were distinct from other FTLD-FUS cases. We also reviewed the clinical records of 72 FTLD cases, and clarified additional clinical features that are predictive of the BIBD pathology. Symptom onset in the three patients with chorea was at 44.0 years of age (±12.0 years), and occurred in the absence of a family history of dementia. The cases were consistent with a clinical form of FTD known as bvFTD, as well as reduced neurological muscle tone in addition to chorea. The three patients showed no or mild parkinsonism, which by contrast, increased substantially in the other FTLD cases until a later stage of disease. The three patients exhibited severe caudate atrophy, which has previously been reported as a histological feature distinguishing FTLD-FUS from FTLD-tau or FTLD-TAR DNA-binding protein 43. Thus, our findings suggest that the clinical feature of choreoathetosis in bvFTD might be associated with FTLD-FUS, and in particular, with the BIBD subtype. PMID:27044537

  3. Clinically Relevant Changes in Emotional Expression in Children with ADHD Treated with Lisdexamfetamine Dimesylate

    ERIC Educational Resources Information Center

    Katic, Alain; Ginsberg, Lawrence; Jain, Rakesh; Adeyi, Ben; Dirks, Bryan; Babcock, Thomas; Scheckner, Brian; Richards, Cynthia; Lasser, Robert; Turgay, Atilla; Findling, Robert L.

    2012-01-01

    Objective: To describe clinically relevant effects of lisdexamfetamine dimesylate (LDX) on emotional expression (EE) in children with ADHD. Method: Children with ADHD participated in a 7-week, open-label, LDX dose-optimization study. Expression and Emotion Scale for Children (EESC) change scores were analyzed post hoc using two methods to…

  4. Preterm piglets are a clinically relevant model of pediatric GI disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The goal of our research is to establish how nutritional support, enteral versus parenteral, affects gut function and susceptibility to disease in early development. We and others have used the neonatal pig to establish unique models of clinically relevant problems in pediatric gastroenterology, esp...

  5. A Bridge between Two Cultures: Uncovering the Chemistry Concepts Relevant to the Nursing Clinical Practice

    ERIC Educational Resources Information Center

    Brown, Corina E.; Henry, Melissa L. M.; Barbera, Jack; Hyslop, Richard M.

    2012-01-01

    This study focused on the undergraduate course that covers basic topics in general, organic, and biological (GOB) chemistry at a mid-sized state university in the western United States. The central objective of the research was to identify the main topics of GOB chemistry relevant to the clinical practice of nursing. The collection of data was…

  6. HEPA and PARSE: Systematic discovery of clinically relevant tumor-specific antigens.

    PubMed

    Xu, Qing-Wen; Zhang, Yu; Wang, Xiao-Song

    2013-03-01

    The effective discovery of tumor-specific antigens (TSAs) holds the key for the development of new diagnostic assays and immunotherapeutic approaches against cancer. Here, we discuss our recently developed technologies, HEPA and PARSE, which allow for the systematic identification of TSAs, generating a reservoir of immunologically and clinically relevant targets. PMID:23802073

  7. Immunophenotypic and Clinical Differences Between the Nasal and Extranasal Subtypes of Upper Aerodigestive Tract Natural Killer/T-Cell Lymphoma

    SciTech Connect

    Liu, Qing-Feng; Wang, Wei-Hu; Wang, Shu-Lian; Liu, Yue-Ping; Huang, Wen-Ting; Lu, Ning; Zhou, Li-Qiang; Ouyang, Han; Jin, Jing; Li, Ye-Xiong

    2014-03-15

    Purpose: To investigate, in a large cohort of patients, the immunophenotypic and clinical differences of nasal and extranasal extranodal nasal-type natural killer/T-cell lymphoma of the upper aerodigestive tract (UADT-NKTCL) and examine the relevance of the immunophenotype on the clinical behavior, prognosis, and treatment. Methods and Materials: A total of 231 patients with UADT-NKTCL were recruited. One hundred eighty-one patients had primary location in the nasal cavity (nasal UADT-NKTCL), and 50 patients had primary extranasal UADT-NKTCL. Results: Patients with extranasal UADT-NKTCL had more adverse clinical features, including advanced-stage disease, regional lymph node involvement, B symptoms, and poor performance status, than patients with nasal UADT-NKTCL. In addition, CD56 and granzyme B were less frequently expressed in extranasal UADT-NKTCL. The 5-year overall survival rate was 74.1% for the entire group and 76.0% for early-stage disease. The 5-year overall survival rate for extranasal UADT-NKTCL was similar or superior to that of nasal UADT-NKTCL for all disease stages (76.9% vs 73.4%, P=.465), stage I disease (75.9% vs 79.2%, P=.786), and stage II disease (83.3% vs 50.3%, P=.018). CD56 expression and a Ki-67 proliferation rate ≥50% predicted poorer survival for extranasal UADT-NKTCL but not for nasal UADT-NKTCL. Conclusions: Patients with nasal and extranasal UADT-NKTCL have significantly different clinical features, immunophenotypes, and prognosis. Extranasal UADT-NKTCL should be considered as a distinct subgroup apart from the most commonly diagnosed prototype of nasal UADT-NKTCL.

  8. Evaluating immunologic response and clinical deterioration in treatment-naïve patients initiating first-line therapies infected with HIV-1 CRF01_AE and subtype B

    PubMed Central

    Oyomopito, Rebecca A.; Li, Patrick CK.; Sungkanuparph, Somnuek; Phanuphak, Praphan; Tee, Kok Keng; Sirisanthana, Thira; Kantipong, Pacharee; Oka, Shinichi; Lee, Chris KC.; Kamarulzaman, Adeeba; Choi, Jun Yong; Sohn, Annette H.; Law, Matthew; Chen, Yi-Ming A.

    2012-01-01

    Background HIV-1 group M viruses diverge 25%–35% in envelope, important for viral attachment during infection, and 10–15% in the pol region, under selection pressure from common antiretrovirals. In Asia, subtypes B and CRF01_AE are common genotypes. Our objectives were to determine whether clinical, immunologic or virologic treatment responses differed by genotype in treatment-naïve patients initiating first-line therapy. Methods Prospectively collected, longitudinal data from patients in Thailand, Hong Kong, Malaysia, Japan, Taiwan and South Korea were provided for analysis. Covariates included demographics, hepatitis B and C coinfections, baseline CD4 T lymphocyte count and plasma HIV-1 RNA levels. Clinical deterioration (a new diagnosis of CDC category B/AIDS-defining illness or death) was assessed by proportional hazards models. Surrogate endpoints were 12-month change in CD4 cell count and virologic suppression post-therapy, evaluated by linear and logistic regression, respectively. Results Of 1105 patients, 1036 (93.8%) infected with CRF01_AE or subtype B were eligible for inclusion in clinical deterioration analyses and contributed 1546.7 person-years of follow-up (median:413 days, IQR:169–672 days). Patients >40 years demonstrated smaller immunological increases (p=0.002) and higher risk of clinical deterioration (HR=2.17; p=0.008). Patients with baseline CD4 cell counts >200 cells/μL had lower risk of clinical deterioration (HR=0.373; p=0.003). A total of 532 patients (48.1% of eligible) had CD4 counts available at baseline and 12 months post-therapy for inclusion in immunolgic analyses. Patients infected with subtype B had larger increases in CD4 counts at 12 months (p=0.024). A total of 530 patients (48.0% of eligible) were included in virologic analyses with no differences in response found between genotypes. Conclusions Results suggest that patients infected with CRF01_AE have reduced immunologic response to therapy at 12 months, compared to

  9. There’s an App for That? Highlighting the Difficulty in Finding Clinically Relevant Smartphone Applications

    PubMed Central

    Wiechmann, Warren; Kwan, Daniel; Bokarius, Andrew; Toohey, Shannon L.

    2016-01-01

    Introduction The use of personal mobile devices in the medical field has grown quickly, and a large proportion of physicians use their mobile devices as an immediate resource for clinical decision-making, prescription information and other medical information. The iTunes App Store (Apple, Inc.) contains approximately 20,000 apps in its “Medical” category, providing a robust repository of resources for clinicians; however, this represents only 2% of the entire App Store. The App Store does not have strict criteria for identifying content specific to practicing physicians, making the identification of clinically relevant content difficult. The objective of this study is to quantify the characteristics of existing medical applications in the iTunes App Store that could be used by emergency physicians, residents, or medical students. Methods We found applications related to emergency medicine (EM) by searching the iTunes App Store for 21 terms representing core content areas of EM, such as “emergency medicine,” “critical care,” “orthopedics,” and “procedures.” Two physicians independently reviewed descriptions of these applications in the App Store and categorized each as the following: Clinically Relevant, Book/Published Source, Non-English, Study Tools, or Not Relevant. A third physician reviewer resolved disagreements about categorization. Descriptive statistics were calculated. Results We found a total of 7,699 apps from the 21 search terms, of which 17.8% were clinical, 9.6% were based on a book or published source, 1.6% were non-English, 0.7% were clinically relevant patient education resources, and 4.8% were study tools. Most significantly, 64.9% were considered not relevant to medical professionals. Clinically relevant apps make up approximately 6.9% of the App Store’s “Medical” Category and 0.1% of the overall App Store. Conclusion Clinically relevant apps represent only a small percentage (6.9%) of the total App volume within the

  10. Relevance of multicultural training to students' applications to clinical psychology programs.

    PubMed

    Bernal, M E; Sirolli, A A; Weisser, S K; Ruiz, J A; Chamberlain, V J; Knight, G P

    1999-02-01

    Interest in the efficacy of multicultural training for practitioners and scientists working with multicultural populations has led to questions about the characteristics of students who seek this training. Students of ethnic minority background, as compared with White students, may be more likely to seek programs that offer this training, and their ethnic or racial identity may be related to this preference. This study explores the relevance of multicultural training to White and ethnic minority graduate students in accredited clinical psychology programs. Students rated the relevance of multicultural and general training components to their decisions about where to apply to graduate school. The ethnic minority students' mean ratings of the relevance of multicultural components were higher than those of White students, and the degree of ethnic minority students' ethnic identification was positively correlated to these relevance ratings. PMID:15603238

  11. Clinical usefulness and relevance of intermediate endpoints for cytotoxic neoadjuvant therapy.

    PubMed

    Fontanella, Caterina; Loibl, Sibylle; von Minckwitz, Gunter

    2015-11-01

    Intermediate endpoints are surrogate markers of treatment efficacy assessed earlier than the true outcome of interest. Tumor response after systemic neoadjuvant therapy is considered a suitable intermediate endpoint, especially for specific breast cancer subtypes. Response can be evaluated either after only 1 cycle of treatment by clinical evaluation or at the end of the planned neoadjuvant treatment by histomorphologic examination of all surgically removed tissues from the breast and regional nodes. Although several meta-analyses showed a lower risk of death among patients who attain a pathologic complete response (pCR) compared with patients with residual tumor in breast and/or lymph nodes after neoadjuvant therapy, a statistically significant linkage between increased pCR rate by a specific treatment and improvement of survival by the same treatment has not been demonstrated yet. Therefore, formal surrogacy of pCR is not established. Moreover, the better definition of pCR is still an open issue: a large pooled analysis demonstrated that patients who attained ypT0 ypN0 (no invasive or non-invasive residual cancer in breast and nodes) experienced longer DFS (p < 0.001) compared with patients who attained ypTis ypN0 (no invasive residual in breast and nodes irrespective of residual non-invasive disease). Nevertheless, the Food and Drug Administration (FDA) recently allowed using pCR as a surrogate endpoint for accelerated approval process. Several meta-analyses demonstrated the greatest prognostic value of pCR in more aggressive breast cancer subtypes (i.e. triple-negative, HER2-positive, or high grade breast cancer). Usefulness of an earlier intermediate endpoints was prospectively demonstrated in the GeparTrio trial in which patients showing an early response achieved 4-times more frequently a pCR than those without early response. PMID:26279131

  12. Comprehensive Characterization of Reference Standard Lots of HIV-1 Subtype C Gp120 Proteins for Clinical Trials in Southern African Regions.

    PubMed

    Wang, Zihao; Lorin, Clarisse; Koutsoukos, Marguerite; Franco, David; Bayat, Babak; Zhang, Ying; Carfi, Andrea; Barnett, Susan W; Porter, Frederick

    2016-01-01

    Two HIV-1 subtype C gp120 protein candidates were the selected antigens for several experimental vaccine regimens now under evaluation in HVTN 100 Phase I/II clinical trial aiming to support the start of the HVTN 702 Phase IIb/III trial in southern Africa, which is designed to confirm and extend the partial protection seen against HIV-1 infection in the RV144 Thai trial. Here, we report the comprehensive physicochemical characterization of the gp120 reference materials that are representative of the clinical trial materials. Gp120 proteins were stably expressed in Chinese Hamster Ovary (CHO) cells and subsequently purified and formulated. A panel of analytical techniques was used to characterize the physicochemical properties of the two protein molecules. When formulated in the AS01 Adjuvant System, the bivalent subtype C gp120 antigens elicited 1086.C- and TV1.C-specific binding antibody and CD4+ T cell responses in mice. All the characteristics were highly representative of the Clinical Trial Materials (CTM). Data from this report demonstrate the immunogenicity of the gp120 antigens, provide comprehensive characterization of the molecules, set the benchmark for assessment of current and future CTM lots, and lay the physicochemical groundwork for interpretation of future clinical trial data. PMID:27187483

  13. Comprehensive Characterization of Reference Standard Lots of HIV-1 Subtype C Gp120 Proteins for Clinical Trials in Southern African Regions

    PubMed Central

    Wang, Zihao; Lorin, Clarisse; Koutsoukos, Marguerite; Franco, David; Bayat, Babak; Zhang, Ying; Carfi, Andrea; Barnett, Susan W.; Porter, Frederick

    2016-01-01

    Two HIV-1 subtype C gp120 protein candidates were the selected antigens for several experimental vaccine regimens now under evaluation in HVTN 100 Phase I/II clinical trial aiming to support the start of the HVTN 702 Phase IIb/III trial in southern Africa, which is designed to confirm and extend the partial protection seen against HIV-1 infection in the RV144 Thai trial. Here, we report the comprehensive physicochemical characterization of the gp120 reference materials that are representative of the clinical trial materials. Gp120 proteins were stably expressed in Chinese Hamster Ovary (CHO) cells and subsequently purified and formulated. A panel of analytical techniques was used to characterize the physicochemical properties of the two protein molecules. When formulated in the AS01 Adjuvant System, the bivalent subtype C gp120 antigens elicited 1086.C- and TV1.C-specific binding antibody and CD4+ T cell responses in mice. All the characteristics were highly representative of the Clinical Trial Materials (CTM). Data from this report demonstrate the immunogenicity of the gp120 antigens, provide comprehensive characterization of the molecules, set the benchmark for assessment of current and future CTM lots, and lay the physicochemical groundwork for interpretation of future clinical trial data. PMID:27187483

  14. A Software System to Collect Expert Relevance Ratings of Medical Record Items for Specific Clinical Tasks

    PubMed Central

    Krishnaraj, Arun; Alkasab, Tarik K

    2014-01-01

    Development of task-specific electronic medical record (EMR) searches and user interfaces has the potential to improve the efficiency and safety of health care while curbing rising costs. The development of such tools must be data-driven and guided by a strong understanding of practitioner information requirements with respect to specific clinical tasks or scenarios. To acquire this important data, this paper describes a model by which expert practitioners are leveraged to identify which components of the medical record are most relevant to a specific clinical task. We also describe the computer system that was created to efficiently implement this model of data gathering. The system extracts medical record data from the EMR of patients matching a given clinical scenario, de-identifies the data, breaks the data up into separate medical record items (eg, radiology reports, operative notes, laboratory results, etc), presents each individual medical record item to experts under the hypothetical of the given clinical scenario, and records the experts’ ratings regarding the relevance of each medical record item to that specific clinical scenario or task. After an iterative process of data collection, these expert relevance ratings can then be pooled and used to design point-of-care EMR searches and user interfaces tailored to the task-specific needs of practitioners. PMID:25600925

  15. Development and clinical testing of a simple, low-density gel element array for influenza identification, subtyping, and H275Y detection.

    PubMed

    Chandler, Darrell P; Griesemer, Sara B; Knickerbocker, Christopher; Golova, Julia B; Lambarqui, Amine; Perov, Alexander N; Zimmerman, Cynthia; Wiles, Cory; Rudy, George B; St George, Kirsten

    2014-11-01

    The objectives of this study were to develop a user-friendly, gel element microarray test for influenza virus detection, subtyping, and neuraminidase inhibitor resistance detection, assess the performance characteristics of the assay, and perform a clinical evaluation on retrospective nasopharyngeal swab specimens. A streamlined microarray workflow enabled a single user to run up to 24 tests in an 8h shift. The most sensitive components of the test were the primers and probes targeting the A/H1 pdm09 HA gene with an analytical limit of detection (LoD) <100 gene copies (gc) per reaction. LoDs for all targets in nasopharyngeal swab samples were ≤1000 gc, with the exception of one target in the seasonal A/H1N1 subtype. Seasonal H275Y variants were detectable in a mixed population when present at >5% with wild type virus, while the 2009 pandemic H1N1 H275Y variant was detectable at ≤1% in a mixture with pandemic wild type virus. Influenza typing and subtyping results concurred with those obtained with real-time RT-PCR assays on more than 97% of the samples tested. The results demonstrate that a large panel of single-plex, real-time RT-PCR tests can be translated to an easy-to-use, sensitive, and specific microarray test for potential diagnostic use. PMID:25066276

  16. Clinical relevance is associated with allergen-specific wheal size in skin prick testing

    PubMed Central

    Haahtela, T; Burbach, G J; Bachert, C; Bindslev-Jensen, C; Bonini, S; Bousquet, J; Bousquet-Rouanet, L; Bousquet, P J; Bresciani, M; Bruno, A; Canonica, G W; Darsow, U; Demoly, P; Durham, S R; Fokkens, W J; Giavi, S; Gjomarkaj, M; Gramiccioni, C; Kowalski, M L; Losonczy, G; Orosz, M; Papadopoulos, N G; Stingl, G; Todo-Bom, A; von Mutius, E; Köhli, A; Wöhrl, S; Järvenpää, S; Kautiainen, H; Petman, L; Selroos, O; Zuberbier, T; Heinzerling, L M

    2014-01-01

    Background Within a large prospective study, the Global Asthma and Allergy European Network (GA2LEN) has collected skin prick test (SPT) data throughout Europe to make recommendations for SPT in clinical settings. Objective To improve clinical interpretation of SPT results for inhalant allergens by providing quantitative decision points. Methods The GA2LEN SPT study with 3068 valid data sets was used to investigate the relationship between SPT results and patient-reported clinical relevance for each of the 18 inhalant allergens as well as SPT wheal size and physician-diagnosed allergy (rhinitis, asthma, atopic dermatitis, food allergy). The effects of age, gender, and geographical area on SPT results were assessed. For each allergen, the wheal size in mm with an 80% positive predictive value (PPV) for being clinically relevant was calculated. Results Depending on the allergen, from 40% (blatella) to 87–89% (grass, mites) of the positive SPT reactions (wheal size ≥ 3 mm) were associated with patient-reported clinical symptoms when exposed to the respective allergen. The risk of allergic symptoms increased significantly with larger wheal sizes for 17 of the 18 allergens tested. Children with positive SPT reactions had a smaller risk of sensitizations being clinically relevant compared with adults. The 80% PPV varied from 3 to 10 mm depending on the allergen. Conclusion These ‘reading keys’ for 18 inhalant allergens can help interpret SPT results with respect to their clinical significance. A SPT form with the standard allergens including mm decision points for each allergen is offered for clinical use. PMID:24283409

  17. Clinical challenges and the relevance of materials testing for posterior composite restorations.

    PubMed

    Sarrett, David C

    2005-01-01

    Posterior composite restorations have been in use for approximately 30 years. The early experiences with this treatment indicated there were more clinical challenges and higher failure rates than amalgam restorations. Since the early days of posterior composites, many improvements in materials, techniques, and instruments for placing these restorations have occurred. This paper reviews what is known regarding current clinical challenges with posterior composite restorations and reviews the primary method for collecting clinical performance data. This review categorizes the challenges as those related to the restorative materials, those related to the dentist, and those related to the patient. The clinical relevance of laboratory tests is discussed from the perspective of solving the remaining clinical challenges of current materials and of screening new materials. The clinical problems related to early composite materials are no longer serious clinical challenges. Clinical data indicate that secondary caries and restoration fracture are the most common clinical problems and merit further investigation. The effect of the dentist and patient on performance of posterior composite restorations is unclear and more clinical data from hypothesis-driven clinical trials are needed to understand these factors. Improvements in handling properties to ensure void-free placement and complete cure should be investigated to improve clinical outcomes. There is a general lack of data that correlates clinical performance with laboratory materials testing. A proposed list of materials tests that may predict performance in a variety of clinical factors is presented. Polymerization shrinkage and the problems that have been attributed to this property of composite are reviewed. There is a lack of evidence that indicates polymerization shrinkage is the primary cause of secondary caries. It is recommended that composite materials be developed with antibacterial properties as a way of

  18. Music's relevance for children with cancer: music therapists' qualitative clinical data-mining research.

    PubMed

    O'Callaghan, Clare; Dun, Beth; Baron, Annette; Barry, Philippa

    2013-01-01

    Music is central in most children's lives. Understanding its relevance will advance efficacious pediatric supportive cancer care. Qualitative clinical data-mining uncovered four music therapists' perspectives about music and music therapy's relevance for pediatric oncology patients up to 14 years old. Inductive and comparative thematic analysis was performed on focus group transcripts and qualitative interrater reliability integrated. Music can offer children a safe haven for internalizing a healthy self-image alongside patient identity. Music therapy can calm, relieve distress, promote supportive relationships, enable self-care, and inspire playful creativity, associated with "normalcy" and hope. Preferred music and music therapy should be available in pediatric oncology. PMID:23521381

  19. Improving biological relevancy of transcriptional biomarkers experiments by applying the MIQE guidelines to pre-clinical and clinical trials.

    PubMed

    Dooms, M; Chango, A; Barbour, E; Pouillart, P; Abdel Nour, A M

    2013-01-01

    The "Minimum Information for the Publication of qPCR Experiments" (MIQE [3]) guidelines are very much targeted at basic research experiments and have to our knowledge not been applied to qPCR assays carried out in the context of clinical trials. This report details the use of the MIQE qPCR app for iPhone (App Store, Apple) to assess the MIQE compliance of one clinical and five pre-clinical trials. This resulted in the need to include 14 modifications that make the guidelines more relevant for the assessment of this special type of application. We also discuss the need for flexibility, since while some parameters increase experimental quality, they also require more reagents and more time, which is not always feasible in a clinical setting. PMID:22910527

  20. Early responses in randomized clinical trials of triptans in acute migraine treatment. Are they clinically relevant? A comment.

    PubMed

    Tfelt-Hansen, Peer

    2010-07-01

    One can question the clinical relevance of early headache responses after oral and intranasal triptans. Thus, for pain-free the early responses were significant but in absolute values they were only a few percentages: the therapeutic gains (TGs) were 1.8% (95% CI = 0.3-3%) for oral almotriptan 12.5 after 30 minutes and 1.0% (95% CI = 0-2%) after intranasal zolmitriptan 5 mg after 15 minutes. These results are compared with subcutaneous sumatriptan 6 mg which has TGs of 11% (95% CI = 7-15%) to 14% (95% CI = 11-17%) for pain-free after 30 minutes. Subcutaneous sumatriptan has a 2 times higher response rate than intranasal zolmitriptan and is 5 times more effective than oral almotriptan at these early time points. It is concluded that if a very early and clinically relevant effect is desired then the migraine patient should use the subcutaneous administration form of sumatriptan. PMID:19178578

  1. Interference of cationic polymeric nanoparticles with clinical chemistry tests--clinical relevance.

    PubMed

    Shcharbin, Dzmitry; Shcharbina, Natallia; Milowska, Katarzyna; de la Mata, Francisco Javier; Muñoz-Fernandez, Maria Angeles; Mignani, Serge; Gomez-Ramirez, Rafael; Majoral, Jean-Pierre; Bryszewska, Maria

    2014-10-01

    The development of medical nanosystems requires knowledge of their behavior in vivo. Clinical chemistry tests are widely used to estimate the systemic toxicity of nanoparticles. In this paper we have explored the impact of small positively charged nanoparticles-poly(amidoamine), phosphorous and carbosilane dendrimers - on biochemical parameters of standardized serum in vitro. All the dendrimers could shift the main biochemical parameters. Thus, in the case of patients having the normal, but 'boundary', values of biochemical parameters, nanoparticle-induced changes can be wrongly interpreted as evidence of some dysfunctions (hepatic, renal, etc.). Moreover, the effects of nanoparticles of metals, carbon nanotubes, quantum dots, fullerenes, dendrimers having been sized up to 4000 nm and the hundreds of reactive groups, can be significantly higher. Thus, preliminary evaluation of any nanomaterial in vitro is required in clinical chemistry tests before its application in vivo to draw the correct conclusions and benefit animals. PMID:25091374

  2. Yeast identification in routine clinical microbiology laboratory and its clinical relevance.

    PubMed

    Agarwal, S; Manchanda, V; Verma, N; Bhalla, P

    2011-01-01

    Rapid identification of yeast infections is helpful in prompt appropriate antifungal therapy. In the present study, the usefulness of chromogenic medium, slide culture technique and Vitek2 Compact (V2C) has been analysed. A total of 173 clinical isolates of yeast species were included in the study. An algorithm to identify such isolates in routine clinical microbiology laboratory was prepared and followed. Chromogenic medium was able to identify Candida albicans, C. tropicalis, C. krusei, C. parapsilosis and Trichosporon asahii. Chromogenic medium was also helpful in identifying "multi-species" yeast infections. The medium was unable to provide presumptive identification of C. pelliculosa, C. utilis, C. rugosa, C. glabrata and C. hemulonii. Vitek 2 compact (V2C) differentiated all pseudohypae non-producing yeast species. The algorithm followed was helpful in timely presumptive identification and final diagnosis of yeast infections, including multi-species yeast infections. PMID:21654115

  3. Clinically relevant exaggerated pharmacodynamic response to dual antiplatelet therapy detected by Thromboelastogram® Platelet Mapping™

    PubMed Central

    Hiller, Kenneth N.

    2016-01-01

    Dual antiplatelet therapy (DAPT) is the standard of care for primary and secondary prevention strategies in patients with coronary artery disease after stenting. Current guidelines recommend that DAPT be continued for 12 months in patients after receiving drug eluting stents. Approximately 5% of these patients will present within this 12-month period for noncardiac surgery. This case report describes a clinically relevant exaggerated pharmacodynamic response to DAPT detected by preoperative assessment of platelet function. Based on the clinical history and physical exam and subsequent lab results, a general anesthetic was performed rather than a spinal anesthetic and the surgical procedure was changed. An exaggerated pharmacodynamic response to DAPT poses its own set of risks (unexpected uncontrolled bleeding, epidural hematoma following neuraxial block placement) that point-of-care aggregation testing may decrease or mitigate by altering clinical decision making. If the clinical history and physical exam reveal possible platelet dysfunction in patients receiving DAPT, preoperative platelet function testing should be considered. PMID:27006555

  4. Oral Mineralocorticoid-Receptor Antagonists: Real-Life Experience in Clinical Subtypes of Nonresolving Central Serous Chorioretinopathy With Chronic Epitheliopathy

    PubMed Central

    Daruich, Alejandra; Matet, Alexandre; Dirani, Ali; Gallice, Mathilde; Nicholson, Luke; Sivaprasad, Sobha; Behar-Cohen, Francine

    2016-01-01

    Purpose To evaluate the efficacy and safety of oral mineralocorticoid-receptor antagonist (MRa) therapy in three clinical presentations of nonresolving central serous chorioretinopathy (CSCR) with chronic epitheliopathy. Methods Retrospective case series of consecutive patients with nonresolving CSCR treated with oral eplerenone or spironolactone. Treatment criteria were: persistent CSCR with subretinal fluid (SRF) lasting longer than 4 months; recurrent CSCR with SRF lasting longer than 2 months; persistent CSCR (SRF ≥ 4 months) with fundus autofluorescence gravitational tracks. Outcomes at 1, 3, and 6 months were: foveal SRF height, central macular thickness (CMT), subfoveal choroidal thickness (SFCT), best-corrected visual acuity (BCVA), and occurrence of side effects. Results Among 54 eyes from 42 patients (mean age: 53 years), mean foveal SRF, CMT, and SFCT decreased significantly at 1, 3, and 6 months after treatment initiation. Mean BCVA improved significantly at 6 months. In the subgroup analysis, mean foveal SRF, CMT, and SFCT decreased significantly at 3 and 6 months in the persistent and recurrent groups. In persistent cases with tracks, a significant diminution of mean CMT and SFCT was achieved at 6 months. Treatment-related side effects were observed in 6 patients, prompting treatment discontinuation in one case. Conclusion Response to treatment was observed in the three subgroups. In persistent CSCR with tracks the response was delayed compared with persistent and recurrent cases, suggesting that longer treatment durations would be beneficial in patients with gravitational tracks of RPE alteration. Translational Relevance The clinical response to oral MRa is consistent with the involvement of the mineralocorticoid pathway in CSCR pathogenesis. PMID:26966638

  5. Clinically Relevant Transmitted Drug Resistance to First Line Antiretroviral Drugs and Implications for Recommendations

    PubMed Central

    Monge, Susana; Guillot, Vicente; Alvarez, Marta; Chueca, Natalia; Stella, Natalia; Peña, Alejandro; Delgado, Rafael; Córdoba, Juan; Aguilera, Antonio; Vidal, Carmen; García, Federico; CoRIS

    2014-01-01

    Background The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list. Methods We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007–2011. Using the Stanford algorithm “Low-level resistance”, “Intermediate resistance” and “High-level resistance” categories were considered as “Resistant”. Results 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8–7.7)], and 221 harbored TDR using the WHO list [7.9% (6.9–9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8–2.9) vs. 3.6% (2.9–4.3) by the WHO list] and PIs [0.8% (0.4–1.1) vs. 1.7% (1.2–2.2)], while it was higher for NNRTIs [4.6% (3.8–5.3) vs. 3.7% (3.0–4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02). Conclusions Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations. PMID:24637804

  6. Taijin Kyofusho and Social Anxiety and Their Clinical Relevance in Indonesia and Switzerland

    PubMed Central

    Vriends, N.; Pfaltz, M. C.; Novianti, P.; Hadiyono, J.

    2013-01-01

    Background: Taijin Kyofusho Scale (TKS) is an interpersonal fear to offend others and is defined by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) as a culturally bound syndrome that occurs in Japan and Korea. Recently, cases with TKS have also been recognized in other cultures. The present questionnaire study investigated self-report TKS symptoms and social anxiety symptoms, and their clinical relevance in an Indonesian and Swiss sample. It also investigated whether self-construal is associated with TKS and social anxiety, and if self-construal is a mediator of the expected association between cultural background and social anxiety and TKS symptoms. Method: 311 Indonesian and 349 Swiss university students filled out the Liebowitz Social Anxiety Scale, the Taijin Kyofusho Scale, the Self-Construal Scale, self-report social phobia DSM-IV criteria, and rated their wish for professional help to deal with social fears. Results: TKS and social anxiety symptoms were higher in the Indonesian than the Swiss sample. TKS symptoms were associated with clinical relevance in Indonesia, whereas in Switzerland only social anxiety symptoms were associated with clinical relevance. Independent self-construal was negatively associated and interdependent self-construal was positively associated with TKS and social anxiety symptoms. Interdependent self-construal mediated the association between cultural background and these symptoms. Discussion: TKS might be a clinically relevant syndrome in all individuals or cultures with an interdependent self-construal or less independent self-construal. The proposal to include the fear of offending others in the DSM-V criteria of social phobia is supported by the present findings. PMID:23382720

  7. Clinical relevance of cyclic GMP modulators: A translational success story of network pharmacology.

    PubMed

    Oettrich, J M; Dao, V T; Frijhoff, J; Kleikers, Pwm; Casas, A I; Hobbs, A J; Schmidt, H H H W

    2016-04-01

    Therapies that modulate cyclic guanosine-3'-5'-monophosphate (cGMP) have emerged as one of the most successful areas in recent drug discovery and clinical pharmacology. Historically, their focus has been on cardiovascular disease phenotypes; however, cGMP's relevance is likely to go beyond this rather limited organ-based set of indications. Moreover, the multitude of targets and their apparent interchangeability is a proof-of-concept of network pharmacology. PMID:26765222

  8. Bystander signalling: exploring clinical relevance through new approaches and new models.

    PubMed

    Butterworth, K T; McMahon, S J; Hounsell, A R; O'Sullivan, J M; Prise, K M

    2013-10-01

    Classical radiation biology research has centred on nuclear DNA as the main target of radiation-induced damage. Over the past two decades, this has been challenged by a significant amount of scientific evidence clearly showing radiation-induced cell signalling effects to have important roles in mediating overall radiobiological response. These effects, generally termed radiation-induced bystander effects (RIBEs) have challenged the traditional DNA targeted theory in radiation biology and highlighted an important role for cells not directly traversed by radiation. The multiplicity of experimental systems and exposure conditions in which RIBEs have been observed has hindered precise definitions of these effects. However, RIBEs have recently been classified for different relevant human radiation exposure scenarios in an attempt to clarify their role in vivo. Despite significant research efforts in this area, there is little direct evidence for their role in clinically relevant exposure scenarios. In this review, we explore the clinical relevance of RIBEs from classical experimental approaches through to novel models that have been used to further determine their potential implications in the clinic. PMID:23849503

  9. [Serious clinical course of myocarditis with "apical ballooning": first presentation of pathogenicity of HHV6 subtype A in myocarditis].

    PubMed

    Bigalke, B; Klingel, K; May, A E; Beyer, M; Hövelborn, T; Kandolf, R; Gawaz, M

    2005-11-01

    We report of a 67 year-old female who has suffered a flu-like infection three days ago and presented with symptoms of acute coronary syndrome. Coronary heart disease could be excluded. The ventriculography showed a moderate reduced left ventricular function characterized by "apical ballooning". Endomyocardial biopsies and EDTA blood gave a direct proof of human herpes virus 6 subtype A. Histological and immunohistochemical analysis revealed a myocarditis with areas of interstitial macrophages and fibrosis. This case presents for the first time the cross-link of myocarditis with HHV6A infection and the appearance of "apical ballooning". PMID:16170511

  10. Advanced Multi-Axis Spine Testing: Clinical Relevance and Research Recommendations

    PubMed Central

    Holsgrove, Timothy P.; Nayak, Nikhil R.; Welch, William C.

    2015-01-01

    Back pain and spinal degeneration affect a large proportion of the general population. The economic burden of spinal degeneration is significant, and the treatment of spinal degeneration represents a large proportion of healthcare costs. However, spinal surgery does not always provide improved clinical outcomes compared to non-surgical alternatives, and modern interventions, such as total disc replacement, may not offer clinically relevant improvements over more established procedures. Although psychological and socioeconomic factors play an important role in the development and response to back pain, the variation in clinical success is also related to the complexity of the spine, and the multi-faceted manner by which spinal degeneration often occurs. The successful surgical treatment of degenerative spinal conditions requires collaboration between surgeons, engineers, and scientists in order to provide a multi-disciplinary approach to managing the complete condition. In this review, we provide relevant background from both the clinical and the basic research perspectives, which is synthesized into several examples and recommendations for consideration in increasing translational research between communities with the goal of providing improved knowledge and care. Current clinical imaging, and multi-axis testing machines, offer great promise for future research by combining invivo kinematics and loading with in-vitro testing in six degrees of freedom to offer more accurate predictions of the performance of new spinal instrumentation. Upon synthesis of the literature, it is recommended that in-vitro tests strive to recreate as many aspects of the in-vivo environment as possible, and that a physiological preload is a critical factor in assessing spinal biomechanics in the laboratory. A greater link between surgical procedures, and the outcomes in all three anatomical planes should be considered in both the in-vivo and in-vitro settings, to provide data relevant to

  11. Affective dysregulation and reality distortion: a 10-year prospective study of their association and clinical relevance.

    PubMed

    van Rossum, Inge; Dominguez, Maria-de-Gracia; Lieb, Roselind; Wittchen, Hans-Ulrich; van Os, Jim

    2011-05-01

    Evidence from clinical patient populations indicates that affective dysregulation is strongly associated with reality distortion, suggesting that a process of misassignment of emotional salience may underlie this connection. To examine this in more detail without clinical confounds, affective regulation-reality distortion relationships, and their clinical relevance, were examined in a German prospective cohort community study. A cohort of 2524 adolescents and young adults aged 14-24 years at baseline was examined by experienced psychologists. Presence of psychotic experiences and (hypo)manic and depressive symptoms was assessed at 2 time points (3.5 and up to 10 years after baseline) using the Munich-Composite International Diagnostic Interview. Associations were tested between level of affective dysregulation on the one hand and incidence of psychotic experiences, persistence of these experiences, and psychotic Impairment on the other. Most psychotic experiences occurred in a context of affective dysregulation, and bidirectional dose-response was apparent with greater level of both affective dysregulation and psychotic experiences. Persistence of psychotic experiences was progressively more likely with greater level of (hypo)manic symptoms (odds ratio [OR] trend=1.51, P<.001) and depressive symptoms (OR trend=1.15, P=.012). Similarly, psychotic experiences of clinical relevance were progressively more likely to occur with greater level of affective dysregulation (depressive symptoms: OR trend=1.28, P=.002; (hypo)manic symptoms: OR trend=1.37, P=.036). Correlated genetic liabilities underlying affective and nonaffective psychotic syndromes may be expressed as correlated dimensions in the general population. Also, affective dysregulation may contribute causally to the persistence and clinical relevance of reality distortion, possibly by facilitating a mechanism of aberrant salience attribution. PMID:19793794

  12. The Clinical Urine Culture: Enhanced Techniques Improve Detection of Clinically Relevant Microorganisms.

    PubMed

    Price, Travis K; Dune, Tanaka; Hilt, Evann E; Thomas-White, Krystal J; Kliethermes, Stephanie; Brincat, Cynthia; Brubaker, Linda; Wolfe, Alan J; Mueller, Elizabeth R; Schreckenberger, Paul C

    2016-05-01

    Enhanced quantitative urine culture (EQUC) detects live microorganisms in the vast majority of urine specimens reported as "no growth" by the standard urine culture protocol. Here, we evaluated an expanded set of EQUC conditions (expanded-spectrum EQUC) to identify an optimal version that provides a more complete description of uropathogens in women experiencing urinary tract infection (UTI)-like symptoms. One hundred fifty adult urogynecology patient-participants were characterized using a self-completed validated UTI symptom assessment (UTISA) questionnaire and asked "Do you feel you have a UTI?" Women responding negatively were recruited into the no-UTI cohort, while women responding affirmatively were recruited into the UTI cohort; the latter cohort was reassessed with the UTISA questionnaire 3 to 7 days later. Baseline catheterized urine samples were plated using both standard urine culture and expanded-spectrum EQUC protocols: standard urine culture inoculated at 1 μl onto 2 agars incubated aerobically; expanded-spectrum EQUC inoculated at three different volumes of urine onto 7 combinations of agars and environments. Compared to expanded-spectrum EQUC, standard urine culture missed 67% of uropathogens overall and 50% in participants with severe urinary symptoms. Thirty-six percent of participants with missed uropathogens reported no symptom resolution after treatment by standard urine culture results. Optimal detection of uropathogens could be achieved using the following: 100 μl of urine plated onto blood (blood agar plate [BAP]), colistin-nalidixic acid (CNA), and MacConkey agars in 5% CO2 for 48 h. This streamlined EQUC protocol achieved 84% uropathogen detection relative to 33% detection by standard urine culture. The streamlined EQUC protocol improves detection of uropathogens that are likely relevant for symptomatic women, giving clinicians the opportunity to receive additional information not currently reported using standard urine culture

  13. Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors.

    PubMed

    Papale, Alessandro; Morella, Ilaria Maria; Indrigo, Marzia Tina; Eugene Bernardi, Rick; Marrone, Livia; Marchisella, Francesca; Brancale, Andrea; Spanagel, Rainer; Brambilla, Riccardo; Fasano, Stefania

    2016-01-01

    Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction. PMID:27557444

  14. Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors

    PubMed Central

    Papale, Alessandro; Morella, Ilaria Maria; Indrigo, Marzia Tina; Bernardi, Rick Eugene; Marrone, Livia; Marchisella, Francesca; Brancale, Andrea; Spanagel, Rainer; Brambilla, Riccardo; Fasano, Stefania

    2016-01-01

    Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction. DOI: http://dx.doi.org/10.7554/eLife.17111.001 PMID:27557444

  15. HEMATOPOIETIC STEM CELL GENE THERAPY: ASSESSING THE RELEVANCE OF PRE-CLINICAL MODELS

    PubMed Central

    Larochelle, Andre; Dunbar, Cynthia E.

    2013-01-01

    The modern laboratory mouse has become a central tool for biomedical research with a notable influence in the field of hematopoiesis. Application of retroviral-based gene transfer approaches to mouse hematopoietic stem cells (HSCs) has led to a sophisticated understanding of the hematopoietic hierarchy in this model. However, the assumption that gene transfer methodologies developed in the mouse could be similarly applied to human HSCs for the treatment of human diseases left the field of gene therapy in a decade-long quandary. It is not until more relevant humanized xenograft mouse models and phylogenetically related large animal species were used to optimize gene transfer methodologies that unequivocal clinical successes were achieved. However, the subsequent reporting of severe adverse events in these clinical trials casted doubts on the predictive value of conventional pre-clinical testing, and encouraged the development of new assays for assessing the relative genotoxicity of various vector designs. PMID:24014892

  16. Current strategies and findings in clinically relevant post-translational modification-specific proteomics

    PubMed Central

    Pagel, Oliver; Loroch, Stefan; Sickmann, Albert; Zahedi, René P

    2015-01-01

    Mass spectrometry-based proteomics has considerably extended our knowledge about the occurrence and dynamics of protein post-translational modifications (PTMs). So far, quantitative proteomics has been mainly used to study PTM regulation in cell culture models, providing new insights into the role of aberrant PTM patterns in human disease. However, continuous technological and methodical developments have paved the way for an increasing number of PTM-specific proteomic studies using clinical samples, often limited in sample amount. Thus, quantitative proteomics holds a great potential to discover, validate and accurately quantify biomarkers in body fluids and primary tissues. A major effort will be to improve the complete integration of robust but sensitive proteomics technology to clinical environments. Here, we discuss PTMs that are relevant for clinical research, with a focus on phosphorylation, glycosylation and proteolytic cleavage; furthermore, we give an overview on the current developments and novel findings in mass spectrometry-based PTM research. PMID:25955281

  17. Retrieving clinically relevant diabetic retinopathy images using a multi-class multiple-instance framework

    NASA Astrophysics Data System (ADS)

    Chandakkar, Parag S.; Venkatesan, Ragav; Li, Baoxin

    2013-02-01

    Diabetic retinopathy (DR) is a vision-threatening complication from diabetes mellitus, a medical condition that is rising globally. Unfortunately, many patients are unaware of this complication because of absence of symptoms. Regular screening of DR is necessary to detect the condition for timely treatment. Content-based image retrieval, using archived and diagnosed fundus (retinal) camera DR images can improve screening efficiency of DR. This content-based image retrieval study focuses on two DR clinical findings, microaneurysm and neovascularization, which are clinical signs of non-proliferative and proliferative diabetic retinopathy. The authors propose a multi-class multiple-instance image retrieval framework which deploys a modified color correlogram and statistics of steerable Gaussian Filter responses, for retrieving clinically relevant images from a database of DR fundus image database.

  18. Clinical Relevance of Nontuberculous Mycobacteria Isolated from Sputum in a Gold Mining Workforce in South Africa: An Observational, Clinical Study

    PubMed Central

    van Halsema, Clare L.; Chihota, Violet N.; Gey van Pittius, Nicolaas C.; Fielding, Katherine L.; Lewis, James J.; van Helden, Paul D.; Churchyard, Gavin J.; Grant, Alison D.

    2015-01-01

    Background. The clinical relevance of nontuberculous mycobacteria (NTM), detected by liquid more than solid culture in sputum specimens from a South African mining workforce, is uncertain. We aimed to describe the current spectrum and relevance of NTM in this population. Methods. An observational study including individuals with sputum NTM isolates, recruited at workforce tuberculosis screening and routine clinics. Symptom questionnaires were administered at the time of sputum collection and clinical records and chest radiographs reviewed retrospectively. Results. Of 232 individuals included (228 (98%) male, median age 44 years), M. gordonae (60 individuals), M. kansasii (50), and M. avium complex (MAC: 38) were the commonest species. Of 38 MAC isolates, only 2 (5.3%) were from smear-positive sputum specimens and 30/38 grew in liquid but not solid culture. MAC was especially prevalent among symptomatic, HIV-positive individuals. HIV prevalence was high: 57/74 (77%) among those tested. No differences were found in probability of death or medical separation by NTM species. Conclusions. M. gordonae, M. kansasii, and MAC were the commonest NTM among miners with suspected tuberculosis, with most MAC from smear-negative specimens in liquid culture only. HIV testing and identification of key pathogenic NTM in this setting are essential to ensure optimal treatment. PMID:26180817

  19. Clinical relevance of tests on bond strength, microleakage and marginal adaptation.

    PubMed

    Heintze, Siegward D

    2013-01-01

    Dental adhesive systems should provide a variety of capabilities, such as bonding of artificial materials to dentin and enamel, sealing of dentinal tubules, reduction of post-operative sensitivity and marginal sealing to reduce marginal staining and caries. In the laboratory, numerous surrogate parameters that should predict the performance of different materials, material combinations and operative techniques are assessed. These surrogate parameters include bond strength tests of various kinds, evaluation of microleakage with tracer penetration between restorative and tooth, two-dimensional analysis of marginal quality with microscopes and mapping of the micromorphology of the bonding interface. Many of these tests are not systematically validated and show therefore different results between different research institutes. The correlation with clinical phenomena has only partly been established to date. There is some evidence, that macrotensile and microtensile bond strength tests correlate better with clinical retention of cervical restorations than macroshear and microshear bond tests but only if data from different test institutes are pooled. Also there is some evidence that marginal adaptation has a moderate correlation in cervical restorations with clinical retention and in Class II restorations (proximal enamel) with clinical marginal staining. There is moderate evidence that microleakage tests with dye penetration does not correlate with any of the clinical parameters (post-operative hypersensitivity, retention, marginal staining). A rationale which helps the researcher to select and apply clinically relevant test methods in the laboratory is presented in the paper. PMID:22920539

  20. Completeness of Reporting of Patient-Relevant Clinical Trial Outcomes: Comparison of Unpublished Clinical Study Reports with Publicly Available Data

    PubMed Central

    Wieseler, Beate; Wolfram, Natalia; McGauran, Natalie; Kerekes, Michaela F.; Vervölgyi, Volker; Kohlepp, Petra; Kamphuis, Marloes; Grouven, Ulrich

    2013-01-01

    Background Access to unpublished clinical study reports (CSRs) is currently being discussed as a means to allow unbiased evaluation of clinical research. The Institute for Quality and Efficiency in Health Care (IQWiG) routinely requests CSRs from manufacturers for its drug assessments. Our objective was to determine the information gain from CSRs compared to publicly available sources (journal publications and registry reports) for patient-relevant outcomes included in IQWiG health technology assessments (HTAs) of drugs. Methods and Findings We used a sample of 101 trials with full CSRs received for 16 HTAs of drugs completed by IQWiG between 15 January 2006 and 14 February 2011, and analyzed the CSRs and the publicly available sources of these trials. For each document type we assessed the completeness of information on all patient-relevant outcomes included in the HTAs (benefit outcomes, e.g., mortality, symptoms, and health-related quality of life; harm outcomes, e.g., adverse events). We dichotomized the outcomes as “completely reported” or “incompletely reported.” For each document type, we calculated the proportion of outcomes with complete information per outcome category and overall. We analyzed 101 trials with CSRs; 86 had at least one publicly available source, 65 at least one journal publication, and 50 a registry report. The trials included 1,080 patient-relevant outcomes. The CSRs provided complete information on a considerably higher proportion of outcomes (86%) than the combined publicly available sources (39%). With the exception of health-related quality of life (57%), CSRs provided complete information on 78% to 100% of the various benefit outcomes (combined publicly available sources: 20% to 53%). CSRs also provided considerably more information on harms. The differences in completeness of information for patient-relevant outcomes between CSRs and journal publications or registry reports (or a combination of both) were statistically

  1. Animal African Trypanosomiasis: Time to Increase Focus on Clinically Relevant Parasite and Host Species.

    PubMed

    Morrison, Liam J; Vezza, Laura; Rowan, Tim; Hope, Jayne C

    2016-08-01

    Animal African trypanosomiasis (AAT), caused by Trypanosoma congolense and Trypanosoma vivax, remains one of the most important livestock diseases in sub-Saharan Africa, particularly affecting cattle. Despite this, our detailed knowledge largely stems from the human pathogen Trypanosoma brucei and mouse experimental models. In the postgenomic era, the genotypic and phenotypic differences between the AAT-relevant species of parasite or host and their model organism counterparts are increasingly apparent. Here, we outline the timeliness and advantages of increasing the research focus on both the clinically relevant parasite and host species, given that improved tools and resources for both have been developed in recent years. We propose that this shift of emphasis will improve our ability to efficiently develop tools to combat AAT. PMID:27167665

  2. Clinical relevance of model based computer-assisted diagnosis and therapy

    NASA Astrophysics Data System (ADS)

    Schenk, Andrea; Zidowitz, Stephan; Bourquain, Holger; Hindennach, Milo; Hansen, Christian; Hahn, Horst K.; Peitgen, Heinz-Otto

    2008-03-01

    The ability to acquire and store radiological images digitally has made this data available to mathematical and scientific methods. With the step from subjective interpretation to reproducible measurements and knowledge, it is also possible to develop and apply models that give additional information which is not directly visible in the data. In this context, it is important to know the characteristics and limitations of each model. Four characteristics assure the clinical relevance of models for computer-assisted diagnosis and therapy: ability of patient individual adaptation, treatment of errors and uncertainty, dynamic behavior, and in-depth evaluation. We demonstrate the development and clinical application of a model in the context of liver surgery. Here, a model for intrahepatic vascular structures is combined with individual, but in the degree of vascular details limited anatomical information from radiological images. As a result, the model allows for a dedicated risk analysis and preoperative planning of oncologic resections as well as for living donor liver transplantations. The clinical relevance of the method was approved in several evaluation studies of our medical partners and more than 2900 complex surgical cases have been analyzed since 2002.

  3. Isolated fat pad sign in acute elbow injury: is it clinically relevant?

    PubMed

    Jie, Kim E; van Dam, Lisette F; Hammacher, Eric R

    2016-06-01

    An isolated fat pad sign (i.e. joint effusion without a visible fracture), commonly seen in acute elbow injury, is associated with occult fracture and treated as such. However, the clinical relevance of an isolated fat pad is unclear, thereby questioning the need for specialized follow-up. In this study, 111 patients (median age 15 years, interquartile range 9-27 years) with an isolated fat pad sign after acute elbow injury were included. The clinical relevance of an isolated fat pad sign was derived from descriptives on pain, elbow function, treatment change, number of revisits and recovery time after 1 week follow-up and long-term follow-up. Treatment alterations were rarely made and none of the patients needed an operative intervention; also, none of the patients had persistent symptoms. The median recovery time was 3 weeks (interquartile range 2-12 weeks). This study shows that, unless symptoms persist or worsen, regular follow-up at a specialized outpatient clinic is not needed. PMID:26153882

  4. Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms.

    PubMed

    Korpal, Manav; Feala, Jacob; Puyang, Xiaoling; Zou, Jian; Ramos, Alex H; Wu, Jeremy; Baumeister, Timm; Yu, Lihua; Warmuth, Markus; Zhu, Ping

    2015-01-01

    Although targeted therapies are initially effective, resistance inevitably emerges. Several methods, such as genetic analysis of resistant clinical specimens, have been applied to uncover these resistance mechanisms to facilitate follow-up care. Although these approaches have led to clinically relevant discoveries, difficulties in attaining the relevant patient material or in deconvoluting the genomic data collected from these specimens have severely hampered the path towards a cure. To this end, we here describe a tool for expeditious discovery that may guide improvement in first-line therapies and alternative clinical management strategies. By coupling preclinical in vitro or in vivo drug selection with next-generation sequencing, it is possible to identify genomic structural variations and/or gene expression alterations that may serve as functional drivers of resistance. This approach facilitates the spontaneous emergence of alterations, enhancing the probability that these mechanisms may be observed in the patients. In this protocol we provide guidelines to maximize the potential for uncovering single nucleotide variants that drive resistance using adherent lines. PMID:26710000

  5. Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

    PubMed Central

    Korpal, Manav; Feala, Jacob; Puyang, Xiaoling; Zou, Jian; Ramos, Alex H.; Wu, Jeremy; Baumeister, Timm; Yu, Lihua; Warmuth, Markus; Zhu, Ping

    2015-01-01

    Although targeted therapies are initially effective, resistance inevitably emerges. Several methods, such as genetic analysis of resistant clinical specimens, have been applied to uncover these resistance mechanisms to facilitate follow-up care. Although these approaches have led to clinically relevant discoveries, difficulties in attaining the relevant patient material or in deconvoluting the genomic data collected from these specimens have severely hampered the path towards a cure. To this end, we here describe a tool for expeditious discovery that may guide improvement in first-line therapies and alternative clinical management strategies. By coupling preclinical in vitro or in vivo drug selection with next-generation sequencing, it is possible to identify genomic structural variations and/or gene expression alterations that may serve as functional drivers of resistance. This approach facilitates the spontaneous emergence of alterations, enhancing the probability that these mechanisms may be observed in the patients. In this protocol we provide guidelines to maximize the potential for uncovering single nucleotide variants that drive resistance using adherent lines. PMID:26710000

  6. Prioritizing Clinically Relevant Copy Number Variation from Genetic Interactions and Gene Function Data

    PubMed Central

    Foong, Justin; Girdea, Marta; Stavropoulos, James; Brudno, Michael

    2015-01-01

    It is becoming increasingly necessary to develop computerized methods for identifying the few disease-causing variants from hundreds discovered in each individual patient. This problem is especially relevant for Copy Number Variants (CNVs), which can be cheaply interrogated via low-cost hybridization arrays commonly used in clinical practice. We present a method to predict the disease relevance of CNVs that combines functional context and clinical phenotype to discover clinically harmful CNVs (and likely causative genes) in patients with a variety of phenotypes. We compare several feature and gene weighing systems for classifying both genes and CNVs. We combined the best performing methodologies and parameters on over 2,500 Agilent CGH 180k Microarray CNVs derived from 140 patients. Our method achieved an F-score of 91.59%, with 87.08% precision and 97.00% recall. Our methods are freely available at https://github.com/compbio-UofT/cnv-prioritization. Our dataset is included with the supplementary information. PMID:26437450

  7. Impulsivity is relevant for trauma exposure and PTSD symptoms in a non-clinical population.

    PubMed

    Netto, Liana R; Pereira, Juliana L; Nogueira, José F; Cavalcanti-Ribeiro, Patrícia; Santana, Rejane Conceição; Teles, Carlos A; Koenen, Karestan C; Quarantini, Lucas C

    2016-05-30

    Impulsivity is a relevant construct for explaining both normal individual differences in personality and more extreme personality disorder, and is often investigated within clinical populations. This study aims to explore the college students' impulsivity patterns and to investigate the association across levels of impulsivity with trauma exposure and PTSD development in a non-clinical population. A one-phase census survey of seven college institutions assessed 2213 students in three metropolitan regions of Northeastern Brazil. All subjects anonymously completed a self-applied protocol consisting of: a socio-demographic questionnaire, Trauma History Questionnaire (THQ), PTSD Checklist (PCL-C), and Barratt Impulsiveness Scale (BIS-11). The median for frequency of trauma exposure was 4 events for people with low and normal impulsivity, and 6 for highly impulsive ones. Individuals with higher impulsivity presented earlier exposition than non-impulsive ones, and worst outcome: 12.4% with PTSD, against 8.4% and 2.3% (normal and low impulsivity). Of the three factors of impulsivity, the Attentional factor conferred the strongest association with PTSD development. Results suggest that impulsivity is also a relevant trait in a non-clinical population and is associated with trauma exposure and PTSD. Strategies to promote mental health in adolescents may be pertinent, especially with the aim of managing impulsivity. PMID:27016879

  8. MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?

    PubMed

    de la Torre, Rafael; Yubero-Lahoz, Samanta; Pardo-Lozano, Ricardo; Farré, Magí

    2012-01-01

    In vitro human studies show that the metabolism of most amphetamine-like psychostimulants is regulated by the polymorphic cytochrome P450 isozyme CYP2D6. Two compounds, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), were selected as archetypes to discuss the translation and clinical significance of in vitro to in vivo findings. Both compounds were chosen based on their differential interaction with CYP2D6 and their high abuse prevalence in society. Methamphetamine behaves as both a weak substrate and competitive inhibitor of CYP2D6, while MDMA acts as a high affinity substrate and potent mechanism-based inhibitor (MBI) of the enzyme. The MBI behavior of MDMA on CYP2D6 implies that subjects, irrespective of their genotype/phenotype, are phenocopied to the poor metabolizer (PM) phenotype. The fraction of metabolic clearance regulated by CYP2D6 for both drugs is substantially lower than expected from in vitro studies. Other isoenzymes of cytochrome P450 and a relevant contribution of renal excretion play a part in their clearance. These facts tune down the potential contribution of CYP2D6 polymorphism in the clinical outcomes of both substances. Globally, the clinical relevance of CYP2D6 polymorphism is lower than that predicted by in vitro studies. PMID:23162568

  9. [Molecular Prognostic Markers and Their Clinical Relevance in Chronic Lymphocytic Leukemia].

    PubMed

    Navrkalová, V; Kantorová, B; Jarošová, M; Pospíšilová, Š

    2015-01-01

    Chronic lymphocytic leukemia is the most common leukemia in Western countries affecting particularly elderly adults. Despite the constantly improving therapy options, chronic lymphocytic leukemia is still an incurable disease owing to considerable clinical and bio-logical heterogeneity. Pathogenesis of chronic lymphocytic leukemia is not fully understood; however, aberrant antigenic stimulation, apoptosis deregulation and microenvironmental interactions play a crucial role in disease development. The most important molecular prognostic markers with clinical relevance include mutation status of heavychain immunoglobulin genes (IGHV), presence of cytogenetic aberrations and TP53 and ATM gene mutations. Recent implementation of next generation sequencing technologies has enabled more accurate analysis of both wellestablished and novel potential prognostic markers. The most relevant candidates are mutations in SF3B1, NOTCH1 and BIRC3 genes, which are now intensively studied with respect to their clinical importance. The other examined molecular mechanisms of chronic lympho-cytic leukemia pathogenesis include deregulation of B cell receptor signalization and abnormal regulation of gene expression by microRNA. The precise characterization of molecular abnormalities improves the risk stratification of chronic lymphocytic leukemia patients, which could possibly benefit from new treatment approaches. PMID:26489496

  10. Enrichment methods to detect bone marrow micrometastases in breast carcinoma patients: clinical relevance

    PubMed Central

    Choesmel, Valérie; Pierga, Jean-Yves; Nos, Claude; Vincent-Salomon, Anne; Sigal-Zafrani, Brigitte; Thiery, Jean-Paul; Blin, Nathalie

    2004-01-01

    Introduction Improving technologies for the detection and purification of bone marrow (BM) micrometastatic cells in breast cancer patients should lead to earlier prognosis of the risk of relapse and should make it possible to design more appropriate therapies. The technique used has to overcome the challenges resulting from the small number of target cells (one per million hematopoietic cells) and the heterogeneous expression of micrometastatic cell markers. In the present study, we have assessed the clinical relevance of current methods aimed at detecting rare disseminated carcinoma cells. Methods BM aspirates from 32 carcinoma patients were screened for the presence of micrometastatic cells positive for epithelial cell adhesion molecule and positive for cytokeratins, using optimized immunodetection methods. A comparison with data obtained for 46 control BM aspirates and a correlation with the clinical status of patients were performed. Results We developed a sensitive and efficient immunomagnetic protocol for the enrichment of BM micrometastases. This method was used to divide 32 breast carcinoma patients into three categories according to their epithelial cell adhesion molecule status. These categories were highly correlated with the recently revised American Joint Committee on Cancer staging system for breast cancer, demonstrating the clinical relevance of this simple and reliable immunomagnetic technique. We also evaluated immunocytochemical detection of cytokeratin-positive cells and cytomorphological parameters. Immunocytochemistry-based methods for the detection of BM micrometastases did not provide any information about the clinical status of patients, but helped to refine the immunomagnetic data by confirming the presence of micrometastases in some cases. We also tested a new density gradient centrifugation system, able to enrich the tumor fraction of BM specimens by twofold to threefold as compared with standard Ficoll methods. Conclusion These improved

  11. The changes of subtypes in pediatric diabetes and their clinical and laboratory characteristics over the last 20 years

    PubMed Central

    Kwon, Eun Byul; Lee, Hae Sang; Shim, Young Seok; Jeong, Hwal Rim

    2016-01-01

    Purpose We studied the changes in subtypes of diabetes mellitus (DM) in children and evaluated the characteristics of each group over the past 20 years. In addition, we also examined the correlation between the glycated hemoglobin (HbA1c) values at the time of diagnosis and lipid profiles. Methods The patients were divided into 2 groups: there were a total of 190 patients under 20 years of age firstly diagnosed with DM in Ajou University Hospital. The patients in groups I and II were diagnosed from September 1995 to December 2004 and from January 2005 to April 2014, respectively. Results The characteristics were compared between the 2 groups of patients. The result showed an increase in percentage of type 2 diabetes and maturity onset diabetes of the young (MODY) patients between the 2 groups. HbA1c and total cholesterol level had statistical significances to explain increasing the low-density lipoprotein cholesterol level among age, HbA1c, total cholesterol level, and z-scores of weight and body mass index (BMI) in type 2 diabetes. R-square was 0.074. However, z-score of BMI and total cholesterol level, not HbA1c, had statistical significances in type 1 diabetic patients. R-square was 0.323. Conclusion The increase in the proportions of both type 2 diabetes and MODY in the last 10 years needed to be reminded when diagnosing the subtypes of DM, and the dyslipidemia should be attended more as a common problem of pediatric diabetic patients. PMID:27462584

  12. Clinical evaluation of microRNA-145 expression in renal cell carcinoma: a promising molecular marker for discriminating and staging the clear cell histological subtype.

    PubMed

    Papadopoulos, Emmanuel I; Petraki, Constantina; Gregorakis, Alkiviadis; Fragoulis, Emmanuel G; Scorilas, Andreas

    2016-06-01

    The vast majority of malignancies detected in renal parenchyma are diagnosed as renal cell carcinoma (RCC), whose subtype discrimination and determination of prognosis may contribute to the selection of the adequate therapy. Recently, a new class of small non-coding RNAs, known as microRNAs, has proven to be among the most promising biomarkers for providing this information. Herein, we sought to add up to this knowledge by evaluating the expression levels of microRNA-145 (miR-145) in RCC. For that purpose, total RNA from 58 cancerous and 44 adjacent non-cancerous renal tissues was firstly extracted and then polyadenylated and reverse transcribed to cDNA. MiR-145 levels were finally analyzed by developing and applying a highly sensitive real-time PCR protocol, while their clinical significance was determined via comprehensive statistical analysis. Our data showed that miR-145 was significantly downregulated in cancerous samples and could discriminate between clear cell and non-clear cell subtypes. Moreover, miR-145 expression was found to be correlated with primary tumor staging of cancerous samples, something also noticed in the clear cell RCC subset, in which miR-145 levels were negatively correlated with tumor size as well. Overall, these results indicate that miR-145 might constitute a promising molecular marker for RCC classification and staging. PMID:26866880

  13. Current HER2 Testing Recommendations and Clinical Relevance as a Predictor of Response to Targeted Therapy.

    PubMed

    Ballinger, Tarah J; Sanders, Melinda E; Abramson, Vandana G

    2015-06-01

    Clinical decision-making in the treatment of breast cancer depends on an accurate determination and understanding of human epidermal growth factor receptor 2 (HER2) status. The guidelines for HER2 testing were recently updated in late 2013, but limitations continue to exist in the interpretation and clinical application of results when the tumor specimens do not fall neatly into positive or negative categories with immunohistochemistry and fluorescence in situ hybridization testing. The issues, including discordance between pathologists or laboratories, polysomy, and genetic heterogeneity, present challenging situations that are difficult to translate into clinical significance. The present review discussed the changes in the updated American Society of Clinical Oncology/College of American Pathologists guidelines, the clinical relevance of complex issues in HER2 testing, and the implications of the results on the response to HER2-targeted therapies. Great advances have been made in the treatment of HER2-positive breast cancer; however, the challenge remains to determine the best testing analysis that will identify patients who will benefit the most from these therapies. PMID:25516402

  14. Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development.

    PubMed Central

    Gerrits, C. J.; de Jonge, M. J.; Schellens, J. H.; Stoter, G.; Verweij, J.

    1997-01-01

    Topoisomerase I inhibitors constitute a new class of anti-cancer agents. Recently, topotecan and irinotecan were registered for clinical use in ovarian cancer and colorectal cancer respectively. Cytotoxicity of topoisomerase I inhibitors is S-phase specific, and in vitro and in vivo studies have suggested that, for efficacy, prolonged exposure might be more important than short-term exposure to high concentration. Clinical development of those topoisomerase I inhibitors that have reached this stage is also focused on schedules aiming to achieve prolonged exposure. In this review, we summarize all published preclinical studies on this topic for topoisomerase I inhibitors in clinical development, namely 20-S-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin, topotecan, irinotecan and GI147211. In addition, preliminary data on clinical studies concerning this topic are also reviewed. The data suggest that prolonged exposure may indeed be relevant for anti-tumour activity. However, the optimal schedule is yet to be determined. Finally, clinical data are yet too immature to draw definitive conclusions. PMID:9328159

  15. The clinical relevance of the effect of ospemifene on symptoms of vulvar and vaginal atrophy

    PubMed Central

    Panay, N.; Bruyniks, N.; Castelo-Branco, C.; De Villiers, T. J.; Simon, J. A.

    2015-01-01

    Objectives To explore clinically relevant differences in severity of vulvar and vaginal atrophy (VVA) in postmenopausal women treated with ospemifene compared with placebo. Methods Analysis of two multicenter, randomized, double-blind, 12-week phase-III studies in postmenopausal women (40–80 years, with VVA, treated with ospemifene 60 mg/day or placebo (Study 310 and Study 821)). Severity of vaginal dryness and dyspareunia were evaluated using a four-point scoring system and clinically relevant differences between ospemifene and placebo were analyzed and are presented as improvement (reduction in ≥ 1 unit on four-point scoring system), substantial improvement (reduction in 2–3 units on four-point scoring system) and relief (severity score of mild/none after 12 weeks). Results In Study 310, significantly more women with a most bothersome symptom of dyspareunia had improvement (68.3% vs. 54.1%; p = 0.0255) or relief (57.5% vs. 41.8%; p = 0.0205) in the severity of dyspareunia from baseline to week 12 with ospemifene compared with placebo. For those with a most bothersome symptom of vaginal dryness, significantly more experienced improvement (74.6% vs. 57.7%; p = 0.0101), substantial improvement (42.4% vs. 26.9%; p = 0.0172) and relief (66.1% vs. 49.0%; p = 0.0140) of vaginal dryness from baseline to week 12 with ospemifene compared with placebo. Proportions of women with improvement/substantial improvement/relief of symptoms of vaginal dryness or dyspareunia were similar in Study 821. Clinically relevant differences were noticeable by week 4. Conclusions Treatment with ospemifene was consistently associated with greater improvement, substantial improvement or relief in the severity of the most bothersome symptoms of vaginal dryness or dyspareunia compared with placebo. PMID:25335119

  16. Clinically relevant doses of chemotherapy agents reversibly block formation of glioblastoma neurospheres

    PubMed Central

    Mihaliak, Alicia M.; Gilbert, Candace A.; Li, Li; Daou, Marie-Claire; Moser, Richard P.; Reeves, Andrew; Cochran, Brent H.; Ross, Alonzo H.

    2010-01-01

    Glioblastoma patients have a poor prognosis, even after surgery, radiotherapy, and chemotherapy with temozolomide or 1,3-bis(2-chloroethy)-1-nitrosourea. We developed an in vitro recovery model using neurosphere cultures to analyze the efficacy of chemotherapy treatments, and tested whether glioblastoma neurosphere initiating cells are resistant. Concentrations of chemotherapy drugs that inhibit neurosphere formation are similar to clinically relevant doses. Some lines underwent a transient cell cycle arrest and a robust recovery of neurosphere formation. These results indicate that glioblastoma neurospheres can regrow after treatment with chemotherapy drugs. This neurosphere recovery assay will facilitate studies of chemo-resistant subpopulations and methods to enhance glioblastoma therapy. PMID:20435409

  17. Stability of Novel Siderophore Cephalosporin S-649266 against Clinically Relevant Carbapenemases.

    PubMed

    Ito-Horiyama, Tsukasa; Ishii, Yoshikazu; Ito, Akinobu; Sato, Takafumi; Nakamura, Rio; Fukuhara, Norio; Tsuji, Masakatsu; Yamano, Yoshinori; Yamaguchi, Keizo; Tateda, Kazuhiro

    2016-07-01

    To better understand the antibacterial activity of S-649266 against carbapenemase producers, its stability against clinically relevant carbapenemases was investigated. The catalytic efficiencies (kcat/Km) of IMP-1, VIM-2, and L1 for S-649266 were 0.0048, 0.0050, and 0.024 μM(-1) s(-1), respectively, which were more than 260-fold lower than that for meropenem. Only slight hydrolysis of S-649266 against KPC-3 was observed. NDM-1 hydrolyzed meropenem 3-fold faster than S-649266 at 200 μM. PMID:27139465

  18. In Vitro Combination of Voriconazole and Miltefosine against Clinically Relevant Molds

    PubMed Central

    Imbert, S.; Palous, M.; Meyer, I.; Dannaoui, E.; Mazier, D.; Datry, A.

    2014-01-01

    Invasive infections caused by filamentous fungi are a major threat for immunocompromised patients. Innate/acquired resistance to antifungal drugs might necessitate combination therapies. We assessed the potential combination of voriconazole with miltefosine, an original drug with antifungal activity against 33 clinically relevant mold isolates, including both azole-susceptible and -resistant Aspergillus. Using complete inhibition as an endpoint, interactions were indifferent for 32/33 isolates. An alternative 50% inhibition endpoint showed synergistic interactions for 14/33 isolates. Antagonism was absent. PMID:25199776

  19. Clinical Empathy and Narrative Competence: The Relevance of Reading Talmudic Legends as Literary Fiction

    PubMed Central

    Davidson, John H.

    2015-01-01

    The “curative potential” in almost any clinical setting depends on a caregiver establishing and maintaining an empathic connection with patients so as to achieve “narrative competence” in discerning and acting in accord with their preferences and best interests. The “narrative medicine” model of shared “close reading of literature and reflective writing” among clinicians as a means of fostering a capacity for clinical empathy has gained validation with recent empirical studies demonstrating the enhancement of theory of mind (ToM), broadly conceived as empathy, in readers of literary fiction. Talmudic legends, like that of Rabbi Judah’s death, are under-appreciated, relevant sources of literary fiction for these efforts. The limitations of narrative medicine are readily counterbalanced by simultaneously practiced attention to traditional bioethical principles, including—especially—beneficence, non-maleficence, and autonomy. PMID:25973266

  20. Diagnosing pubovisceral avulsions: a systematic review of the clinical relevance of a prevalent anatomical defect.

    PubMed

    Lammers, Karin; Fütterer, Jurgen J; Prokop, Mathias; Vierhout, Mark E; Kluivers, Kirsten B

    2012-12-01

    The aims of this systematic literature review were to assess whether the detection of pubovisceral avulsions using magnetic resonance (MR) imaging or perineal ultrasonography was clinically relevant in women with pelvic floor dysfunction and to evaluate the relation with anatomy, symptoms, and recurrence after surgery. We performed a systematic literature review using three bibliographical databases (PubMed, Embase, and CINAHL) as data sources. Clinical studies were included in which pubovisceral avulsions were studied in relation to pelvic organ prolapse (POP) stage, pelvic floor symptoms, and/or recurrence of POP after surgery. Ultimately, 21 studies met the inclusion criteria. POP stage and recurrence of POP after surgery were strongly associated with pubovisceral avulsions. Contradictory results were found regarding the relation between pubovisceral avulsions and urinary symptoms and symptoms of anorectal dysfunction. Pubovisceral avulsions, as diagnosed by MR imaging or perineal ultrasonography, are associated with higher stages of POP and recurrence of POP after surgery. PMID:22581241

  1. A high-throughput panel for identifying clinically relevant mutation profiles in melanoma.

    PubMed

    Dutton-Regester, Ken; Irwin, Darryl; Hunt, Priscilla; Aoude, Lauren G; Tembe, Varsha; Pupo, Gulietta M; Lanagan, Cathy; Carter, Candace D; O'Connor, Linda; O'Rourke, Michael; Scolyer, Richard A; Mann, Graham J; Schmidt, Christopher W; Herington, Adrian; Hayward, Nicholas K

    2012-04-01

    Success with molecular-based targeted drugs in the treatment of cancer has ignited extensive research efforts within the field of personalized therapeutics. However, successful application of such therapies is dependent on the presence or absence of mutations within the patient's tumor that can confer clinical efficacy or drug resistance. Building on these findings, we developed a high-throughput mutation panel for the identification of frequently occurring and clinically relevant mutations in melanoma. An extensive literature search and interrogation of the Catalogue of Somatic Mutations in Cancer database identified more than 1,000 melanoma mutations. Applying a filtering strategy to focus on mutations amenable to the development of targeted drugs, we initially screened 120 known mutations in 271 samples using the Sequenom MassARRAY system. A total of 252 mutations were detected in 17 genes, the highest frequency occurred in BRAF (n = 154, 57%), NRAS (n = 55, 20%), CDK4 (n = 8, 3%), PTK2B (n = 7, 2.5%), and ERBB4 (n = 5, 2%). Based on this initial discovery screen, a total of 46 assays interrogating 39 mutations in 20 genes were designed to develop a melanoma-specific panel. These assays were distributed in multiplexes over 8 wells using strict assay design parameters optimized for sensitive mutation detection. The final melanoma-specific mutation panel is a cost effective, sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular-based therapeutics for the treatment of melanoma. When used in a clinical research setting, the panel may rapidly and accurately identify potentially effective treatment strategies using novel or existing molecularly targeted drugs. PMID:22383533

  2. Does psychomotor retardation define a clinically relevant phenotype of unipolar depression?

    PubMed Central

    Calugi, S; Cassano, GB; Litta, A; Rucci, P; Benvenuti, A; Miniati, M; Lattanzi, L; Mantua; Lombardi; Fagiolini, A; Frank, E

    2012-01-01

    Background The recognition and assessment of psychomotor retardation may have implications for better definition of the clinical phenotypes of depression. The aim of this study was to assess the clinical correlates of psychomotor retardation endorsed at any time during the patients lifetime (LPR). Methods The study sample included 291 patients with non-psychotic Major Depressive Disorder (MDD) participating in the clinical trial, “Depression: The Search for Treatment-relevant Phenotypes.” Psychomotor Retardation was measured using a factor derived from the Mood Spectrum Self-Report (MOODS-SR) assessment. Using a pre-defined cut-off score on the lifetime psychomotor retardation (LPR) factor of the MOODS-SR, participants were classified into high and low scorers. Logistic regression analysis was used to evaluate the relationship between LPR and subthreshold bipolarity. Results Compared to low scorers, participants with high scores on LPR factor had greater severity of depression and more bipolarity indicators. Conclusions The MOODS-SR appears to be helpful to identify clinical phenotypes of unipolar depression and to highlight the usefulness of a lifetime approach to the assessment of psychopathology in the characterisation of patients with unipolar depression. PMID:20833434

  3. Clinically relevant concentrations of di (2-ethylhexyl) phthalate (DEHP) uncouple cardiac syncytium

    SciTech Connect

    Gillum, Nikki; Karabekian, Zaruhi; Swift, Luther M.; Brown, Ronald P.; Kay, Matthew W.; Sarvazyan, Narine

    2009-04-01

    Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer found in a variety of polyvinyl chloride (PVC) medical products. The results of studies in experimental animals suggest that DEHP leached from flexible PVC tubing may cause health problems in some patient populations. While the cancerogenic and reproductive effects of DEHP are well recognized, little is known about the potential adverse impact of phthalates on the heart. This study examined the effects of clinically relevant concentrations of DEHP on neonatal rat cardiomyocytes. It was found that application of DEHP to a confluent, synchronously beating cardiac cell network, leads to a marked, concentration-dependent decrease in conduction velocity and asynchronous cell beating. The mechanism behind these changes was a loss of gap junctional connexin-43, documented using Western blot analysis, dye-transfer assay and immunofluorescence. In addition to its effect on electrical coupling, DEHP treatment also affected the mechanical movement of myocyte layers. The latter was linked to the decreased stiffness of the underlying fibroblasts, as the amount of triton-insoluble vimentin was significantly decreased in DEHP-treated samples. The data indicate that DEHP, in clinically relevant concentrations, can impair the electrical and mechanical behavior of a cardiac cell network. Applicability of these findings to human patients remains to be established.

  4. Impact analysis studies of clinical prediction rules relevant to primary care: a systematic review

    PubMed Central

    Wallace, Emma; Uijen, Maike J M; Clyne, Barbara; Zarabzadeh, Atieh; Keogh, Claire; Galvin, Rose; Smith, Susan M; Fahey, Tom

    2016-01-01

    Objectives Following appropriate validation, clinical prediction rules (CPRs) should undergo impact analysis to evaluate their effect on patient care. The aim of this systematic review is to narratively review and critically appraise CPR impact analysis studies relevant to primary care. Setting Primary care. Participants Adults and children. Intervention Studies that implemented the CPR compared to usual care were included. Study design Randomised controlled trial (RCT), controlled before–after, and interrupted time series. Primary outcome Physician behaviour and/or patient outcomes. Results A total of 18 studies, incorporating 14 unique CPRs, were included. The main study design was RCT (n=13). Overall, 10 studies reported an improvement in primary outcome with CPR implementation. Of 6 musculoskeletal studies, 5 were effective in altering targeted physician behaviour in ordering imaging for patients presenting with ankle, knee and neck musculoskeletal injuries. Of 6 cardiovascular studies, 4 implemented cardiovascular risk scores, and 3 reported no impact on physician behaviour outcomes, such as prescribing and referral, or patient outcomes, such as reduction in serum lipid levels. 2 studies examined CPRs in decision-making for patients presenting with chest pain and reduced inappropriate admissions. Of 5 respiratory studies, 2 were effective in reducing antibiotic prescribing for sore throat following CPR implementation. Overall, study methodological quality was often unclear due to incomplete reporting. Conclusions Despite increasing interest in developing and validating CPRs relevant to primary care, relatively few have gone through impact analysis. To date, research has focused on a small number of CPRs across few clinical domains only. PMID:27008685

  5. Antibiofilm Activity of the Brown Alga Halidrys siliquosa against Clinically Relevant Human Pathogens

    PubMed Central

    Busetti, Alessandro; Thompson, Thomas P.; Tegazzini, Diana; Megaw, Julianne; Maggs, Christine A.; Gilmore, Brendan F.

    2015-01-01

    The marine brown alga Halidrys siliquosa is known to produce compounds with antifouling activity against several marine bacteria. The aim of this study was to evaluate the antimicrobial and antibiofilm activity of organic extracts obtained from the marine brown alga H. siliquosa against a focused panel of clinically relevant human pathogens commonly associated with biofilm-related infections. The partially fractionated methanolic extract obtained from H. siliquosa collected along the shores of Co. Donegal; Ireland; displayed antimicrobial activity against bacteria of the genus Staphylococcus; Streptococcus; Enterococcus; Pseudomonas; Stenotrophomonas; and Chromobacterium with MIC and MBC values ranging from 0.0391 to 5 mg/mL. Biofilms of S. aureus MRSA were found to be susceptible to the algal methanolic extract with MBEC values ranging from 1.25 mg/mL to 5 mg/mL respectively. Confocal laser scanning microscopy using LIVE/DEAD staining confirmed the antimicrobial nature of the antibiofilm activity observed using the MBEC assay. A bioassay-guided fractionation method was developed yielding 10 active fractions from which to perform purification and structural elucidation of clinically-relevant antibiofilm compounds. PMID:26058011

  6. Efficacious and Clinically Relevant Conditioned Medium of Human Adipose-derived Stem Cells for Therapeutic Angiogenesis

    PubMed Central

    Bhang, Suk Ho; Lee, Seahyoung; Shin, Jung-Youn; Lee, Tae-Jin; Jang, Hyeon-Ki; Kim, Byung-Soo

    2014-01-01

    Using stem cell–conditioned medium (CM) might be a viable alternative to stem cell transplantation, which is often hampered by low grafting efficiency and potential tumorigenesis, but the concentrations of angiogenic growth factors in CM are too low for therapeutic use and some components of the medium are not for human use. We used three-dimensional (3D) spheroid culture of human adipose-derived stem cells (ADSCs) with clinically relevant medium composed of amino acids, vitamins, glucose, and human serum to produce clinically relevant CM containing angiogenic and/or antiapoptotic factors such as vascular endothelial cell growth factor, fibroblast growth factor 2, hepatocyte growth factor, and chemokine (C-X-C motif) ligand 12. The concentrations of these factors were 23- to 27-fold higher than that in CM produced by conventional monolayer culture. Compared with injection of either monolayer culture CM or human ADSC, injection of spheroid culture CM to an ischemic region in mice significantly enhanced endothelial cell growth, CD34+/PTPRC− (endothelial progenitor) cell mobilization from bone marrow, and bone marrow cell homing to the ischemic region, resulting in improved blood vessel density, limb salvage, and blood perfusion in a mouse hindlimb ischemia model. The stem cell CM developed in this study will likely be an effective alternative to conventional stem cell transplantation therapy. PMID:24413377

  7. Antibiofilm Activity of the Brown Alga Halidrys siliquosa against Clinically Relevant Human Pathogens.

    PubMed

    Busetti, Alessandro; Thompson, Thomas P; Tegazzini, Diana; Megaw, Julianne; Maggs, Christine A; Gilmore, Brendan F

    2015-06-01

    The marine brown alga Halidrys siliquosa is known to produce compounds with antifouling activity against several marine bacteria. The aim of this study was to evaluate the antimicrobial and antibiofilm activity of organic extracts obtained from the marine brown alga H. siliquosa against a focused panel of clinically relevant human pathogens commonly associated with biofilm-related infections. The partially fractionated methanolic extract obtained from H. siliquosa collected along the shores of Co. Donegal; Ireland; displayed antimicrobial activity against bacteria of the genus Staphylococcus; Streptococcus; Enterococcus; Pseudomonas; Stenotrophomonas; and Chromobacterium with MIC and MBC values ranging from 0.0391 to 5 mg/mL. Biofilms of S. aureus MRSA were found to be susceptible to the algal methanolic extract with MBEC values ranging from 1.25 mg/mL to 5 mg/mL respectively. Confocal laser scanning microscopy using LIVE/DEAD staining confirmed the antimicrobial nature of the antibiofilm activity observed using the MBEC assay. A bioassay-guided fractionation method was developed yielding 10 active fractions from which to perform purification and structural elucidation of clinically-relevant antibiofilm compounds. PMID:26058011

  8. Isoflurane and desflurane at clinically relevant concentrations induce amyloid {beta}-peptide oligomerization: An NMR study

    SciTech Connect

    Mandal, Pravat K Fodale, Vincenzo

    2009-02-13

    Current understanding on Alzheimer's disease (AD) reveals that soluble amyloid {beta}-peptide (A{beta}) oligomeric formation plays an important role in AD pathophysiology. A potential role for several inhaled anesthetics in promoting A{beta} oligomer formation has been suggested. Using a nuclear magnetic resonance (NMR) study, we previously demonstrated that at a high concentration (higher than clinically relevant concentrations), the inhaled anesthetics halothane and isoflurane, interact with specific amino acid residues (G29, A30, and I31) and induce A{beta} oligomerization. The present study confirms this is true at a clinically relevant concentration. Isoflurane and desflurane induce A{beta} oligomerization by inducing chemical shift changes of the critical amino acid residues (G29, A30, and I31), reinforcing the evidence that perturbation of these three crucial residues indeed plays an important role in oligomerization. These findings support the emerging hypothesis that several commonly used inhaled anesthetics could be involved in neurodegeneration, as well as risk factor for accelerating the onset of AD.

  9. Testing small molecule analogues of the Acanthocheilonema viteae immunomodulator ES-62 against clinically relevant allergens.

    PubMed

    Janicova, L; Rzepecka, J; Rodgers, D T; Doonan, J; Bell, K S; Lumb, F E; Suckling, C J; Harnett, M M; Harnett, W

    2016-06-01

    ES-62 is a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae that protects against ovalbumin (OVA)-induced airway hyper-responsiveness in mice by virtue of covalently attached anti-inflammatory phosphorylcholine (PC) residues. We have recently generated a library of small molecule analogues (SMAs) of ES-62 based around its active PC moiety as a starting point in novel drug development for asthma and identified two compounds - termed 11a and 12b - that mirror ES-62's protective effects. In this study, we have moved away from OVA, a model allergen, to test the SMAs against two clinically relevant allergens - house dust mite (HDM) and cockroach allergen (CR) extract. We show that both SMAs offer some protection against development of lung allergic responses to CR, in particular reducing eosinophil infiltration, whereas only SMA 12b is effective in protecting against eosinophil-dependent HDM-induced allergy. These data therefore suggest that helminth molecule-induced protection against model allergens may not necessarily translate to clinically relevant allergens. Nevertheless, in this study, we have managed to demonstrate that it is possible to produce synthetic drug-like molecules based on a parasitic worm product that show therapeutic potential with respect to asthma resulting from known triggers in humans. PMID:27059010

  10. Structural brain MRI studies in eye diseases: are they clinically relevant? A review of current findings.

    PubMed

    Prins, Doety; Hanekamp, Sandra; Cornelissen, Frans W

    2016-03-01

    Many eye diseases reduce visual acuity or are associated with visual field defects. Because of the well-defined retinotopic organization of the connections of the visual pathways, this may affect specific parts of the visual pathways and cortex, as a result of either deprivation or transsynaptic degeneration. For this reason, over the past several years, numerous structural magnetic resonance imaging (MRI) studies have examined the association of eye diseases with pathway and brain changes. Here, we review structural MRI studies performed in human patients with the eye diseases albinism, amblyopia, hereditary retinal dystrophies, age-related macular degeneration (AMD) and glaucoma. We focus on two main questions. First, what have these studies revealed? Second, what is the potential clinical relevance of their findings? We find that all the aforementioned eye diseases are indeed associated with structural changes in the visual pathways and brain. As such changes have been described in very different eye diseases, in our view the most parsimonious explanation is that these are caused by the loss of visual input and the subsequent deprivation of the visual pathways and brain regions, rather than by transsynaptic degeneration. Moreover, and of clinical relevance, for some of the diseases - in particular glaucoma and AMD - present results are compatible with the view that the eye disease is part of a more general neurological or neurodegenerative disorder that also affects the brain. Finally, establishing structural changes of the visual pathways has been relevant in the context of new therapeutic strategies to restore retinal function: it implies that restoring retinal function may not suffice to also effectively restore vision. Future structural MRI studies can contribute to (i) further establish relationships between ocular and neurological neurodegenerative disorders, (ii) investigate whether brain degeneration in eye diseases is reversible, (iii) evaluate the use

  11. Subtype-independent near full-length HIV-1 genome sequencing and assembly to be used in large molecular epidemiological studies and clinical management

    PubMed Central

    Grossmann, Sebastian; Nowak, Piotr; Neogi, Ujjwal

    2015-01-01

    Introduction HIV-1 near full-length genome (HIV-NFLG) sequencing from plasma is an attractive multidimensional tool to apply in large-scale population-based molecular epidemiological studies. It also enables genotypic resistance testing (GRT) for all drug target sites allowing effective intervention strategies for control and prevention in high-risk population groups. Thus, the main objective of this study was to develop a simplified subtype-independent, cost- and labour-efficient HIV-NFLG protocol that can be used in clinical management as well as in molecular epidemiological studies. Methods Plasma samples (n=30) were obtained from HIV-1B (n=10), HIV-1C (n=10), CRF01_AE (n=5) and CRF01_AG (n=5) infected individuals with minimum viral load >1120 copies/ml. The amplification was performed with two large amplicons of 5.5 kb and 3.7 kb, sequenced with 17 primers to obtain HIV-NFLG. GRT was validated against ViroSeq™ HIV-1 Genotyping System. Results After excluding four plasma samples with low-quality RNA, a total of 26 samples were attempted. Among them, NFLG was obtained from 24 (92%) samples with the lowest viral load being 3000 copies/ml. High (>99%) concordance was observed between HIV-NFLG and ViroSeq™ when determining the drug resistance mutations (DRMs). The N384I connection mutation was additionally detected by NFLG in two samples. Conclusions Our high efficiency subtype-independent HIV-NFLG is a simple and promising approach to be used in large-scale molecular epidemiological studies. It will facilitate the understanding of the HIV-1 pandemic population dynamics and outline effective intervention strategies. Furthermore, it can potentially be applicable in clinical management of drug resistance by evaluating DRMs against all available antiretrovirals in a single assay. PMID:26115688

  12. RhoA as a Mediator of Clinically Relevant Androgen Action in Prostate Cancer Cells

    PubMed Central

    Schmidt, Lucy J.; Duncan, Kelly; Yadav, Neelu; Regan, Kevin M.; Verone, Alissa R.; Lohse, Christine M.; Pop, Elena A.; Attwood, Kristopher; Wilding, Gregory; Mohler, James L.; Sebo, Thomas J.; Tindall, Donald J.

    2012-01-01

    Recently, we have identified serum response factor (SRF) as a mediator of clinically relevant androgen receptor (AR) action in prostate cancer (PCa). Genes that rely on SRF for androgen responsiveness represent a small fraction of androgen-regulated genes, but distinguish benign from malignant prostate, correlate with aggressive disease, and are associated with biochemical recurrence. Thus, understanding the mechanism(s) by which SRF conveys androgen regulation to its target genes may provide novel opportunities to target clinically relevant androgen signaling. Here, we show that the small GTPase ras homolog family member A (RhoA) mediates androgen-responsiveness of more than half of SRF target genes. Interference with expression of RhoA, activity of the RhoA effector Rho-associated coiled-coil containing protein kinase 1 (ROCK), and actin polymerization necessary for nuclear translocation of the SRF cofactor megakaryocytic acute leukemia (MAL) prevented full androgen regulation of SRF target genes. Androgen treatment induced RhoA activation, increased the nuclear content of MAL, and led to MAL recruitment to the promoter of the SRF target gene FHL2. In clinical specimens RhoA expression was higher in PCa cells than benign prostate cells, and elevated RhoA expression levels were associated with aggressive disease features and decreased disease-free survival after radical prostatectomy. Overexpression of RhoA markedly increased the androgen-responsiveness of select SRF target genes, in a manner that depends on its GTPase activity. The use of isogenic cell lines and a xenograft model that mimics the transition from androgen-stimulated to castration-recurrent PCa indicated that RhoA levels are not altered during disease progression, suggesting that RhoA expression levels in the primary tumor determine disease aggressiveness. Androgen-responsiveness of SRF target genes in castration-recurrent PCa cells continued to rely on AR, RhoA, SRF, and MAL and the presence of

  13. Orthoptic Sequelae Following Conservative Management of Pure Blowout Orbital Fractures: Anecdotal or Clinically Relevant?

    PubMed

    Steinegger, Ken; De Haller, Raoul; Courvoisier, Delphine; Scolozzi, Paolo

    2015-07-01

    The aim of this study was to prospectively assess the prevalence of orthoptic anomalies following conservative management of pure blowout orbital fractures and to evaluate their clinical relevance. Clinical and radiologic data of patients with unilateral conservatively managed pure blowout orbital fractures with a minimum follow-up of 6 months were reviewed. Eligible patients were contacted and invited to undergo an extended ophthalmologic examination as follows: distance and near visual acuities, Hertel exophthalmometry, corneal light reflex (Hirschberg test), ductions and versions in the 6 cardinal fields of gaze, eye deviation with prisms and alternate cover test in all of the 9-gaze directions with Maddox rod, degrees of incyclo/excyclotorsion with right and left eye fixation, horizontal and vertical deviation with Hess-Weiss coordimetry, degree of horizontal/vertical and incyclo/excyclotorsion deviation with Harms wall deviometry, and vertical deviation with Bielschowsky head-tilt test. Of the 69 patients contacted, 49 declined to participate given that they were asymptomatic. Twenty patients agreed to undergo the examination. One patient complained of minimal double vision limited to the extreme downgaze. Four patients had asymptomatic ocular motility disturbances limited to the extreme gaze. Seven patients had asymptomatic horizontal heterophoria. These disturbances did not interfere with daily or professional activities in any of the patients. The current study demonstrated that conservative management of pure orbital blowout fractures can result in orthoptic anomalies. These sequelae were restricted to a very limited portion of the binocular field of the vision and were not found to be clinically relevant. PMID:26102539

  14. Clinical Relevance of Vilazodone Treatment in Patients With Major Depressive Disorder: Categorical Improvement in Symptoms

    PubMed Central

    Culpepper, Larry; Mathews, Maju; Ghori, Razi; Edwards, John

    2014-01-01

    Objective: To assess clinically relevant symptom improvement in patients with major depressive disorder (MDD) receiving vilazodone by using the Montgomery-Asberg Depression Rating Scale (MADRS), a clinician-rated scale used to measure MDD symptom severity and improvement. Method: Pooled data from 2 positive, phase 3, 8-week, double-blind, randomized, placebo-controlled trials in patients with MDD were analyzed. Patients received vilazodone 40 mg/d or placebo; post hoc analyses were conducted on study completers. Depression symptom improvement was evaluated by analyzing the proportions of patients who shifted from the baseline MADRS single-item symptom severity category of ≥ 2 (mild to severe symptoms) to an end-of-study category < 2 (minimal to no symptoms) or from ≥ 4 (moderate to severe symptoms) to ≤ 2 (mild to no symptoms). The proportion of patients who shifted from anxious depression to no anxious depression was also analyzed. Results: The percentage of patients who completed these studies with severity category shift from baseline ≥ 2 to end of study < 2 was significantly higher for vilazodone versus placebo on all MADRS items (odds ratio [OR] range, 1.4–1.7, P < .05) except reduced appetite (OR = 1.3, P = .232). A significantly greater proportion of vilazodone-treated versus placebo-treated patients shifted from baseline ≥ 4 to end of study ≤ 2 on MADRS items of apparent sadness, reported sadness, inner tension, reduced sleep, and lassitude (OR range, 1.5–2.0, P < .05). Additionally, a significantly greater proportion of vilazodone-treated versus placebo-treated patients shifted from anxious depression at baseline to no anxious depression at end of study (OR = 1.5, P = .031). Conclusions: These results suggest that vilazodone treatment is associated with clinically relevant changes in depression symptoms in patients with MDD. Trial Registration: ClinicalTrials.gov identifiers: NCT00285376 and NCT00683592 PMID:24940525

  15. Clinical relevance and contemporary methods for counting blood cells in body fluids suspected of inflammatory disease.

    PubMed

    Fleming, Chérina; Russcher, Henk; Lindemans, Jan; de Jonge, Robert

    2015-10-01

    In many inflammatory diseases, the cellular components in body fluids [cerebrospinal fluid (CSF), serous fluids] are increased, rendering essential diagnostic information. The diagnostic value of the total white blood cell count (WBC) and differential count has been evaluated extensively over the years, and a remarkable amount of knowledge has been gained; yet, there is a great deal of clinical uncertainty whether the diagnosis should be based solely on these variables. In some diseases, such as peritonitis, the total WBC and differential count has high sensitivity; whereas, in differentiating pleural effusions, it lacks the sensitivity required to be clinically useful. Nevertheless, many guidelines consider these tests as cornerstone parameters, and in combination with clinical variables, they can successfully guide clinical decision making in initiating or postponing a treatment course for infection and/or inflammatory diseases while awaiting culture results. Although other methods are available for detecting and differentiating WBCs in body fluids, manual microscopy is still considered the gold standard despite its many limitations. During the last decade, automated analyzers have become a popular method for first line screening. Continued progress in their design has led to major improvements including their speed, improved accuracy and lower variability compared with microscopy. Disadvantages of this method include high imprecision in low ranges (depending on the method) and interfering factors. In a time where automation is at the front line in clinical laboratories, it is essential the results obtained are precise, accurate and reproducible. This review provides an overview of the relevance for cell counting in a variety of diagnostic body fluids, and highlights the current technologies used. PMID:25879321

  16. Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations.

    PubMed

    Feng, Meizhen; Sachs, Nancy A; Xu, Min; Grobler, Jay; Blair, Wade; Hazuda, Daria J; Miller, Michael D; Lai, Ming-Tain

    2016-04-01

    Doravirine (DOR), which is currently in a phase 3 clinical trial, is a novel human immunodeficiency type 1 virus (HIV-1) nonnucleoside reverse transcriptase inhibitor (NNRTI). DOR exhibits potent antiviral activity against wild-type virus and K103N, Y181C, and K103N/Y181C mutant viruses, with 50% inhibitory concentrations (IC50s) of 12, 21, 31, and 33 nM, respectively, when measured in 100% normal human serum (NHS). To assess the potential for DOR to suppress NNRTI-associated and rilpivirine (RPV)-specific mutants at concentrations achieved in the clinic setting, inhibitory quotients (IQs) were calculated by determining the ratio of the clinical trough concentration over the antiviral IC50for each virus with DOR and RPV and efavirenz (EFV). DOR displayed IQs of 39, 27, and 25 against the K103N, Y181C, and K103N/Y181C mutants, respectively. In contrast, RPV exhibited IQs of 4.6, 1.4, and 0.8, and EFV showed IQs of 2.5, 60, and 1.9 against these viruses, respectively. DOR also displayed higher IQs than those of RPV and EFV against other prevalent NNRTI-associated mutants, with the exception of Y188L. Both DOR and EFV exhibited higher IQs than RPV when analyzed with RPV-associated mutants. Resistance selections were conducted with K103N, Y181C, G190A, and K103N/Y181C mutants at clinically relevant concentrations of DOR, RPV, and EFV. No viral breakthrough was observed with DOR, whereas breakthrough viruses were readily detected with RPV and EFV against Y181C and K103N viruses, respectively. These data suggest that DOR should impose a higher barrier to the development of resistance than RPV and EFV at the concentrations achieved in the clinic setting. PMID:26833152

  17. Unsupervised Placental Gene Expression Profiling Identifies Clinically Relevant Subclasses of Human Preeclampsia.

    PubMed

    Leavey, Katherine; Benton, Samantha J; Grynspan, David; Kingdom, John C; Bainbridge, Shannon A; Cox, Brian J

    2016-07-01

    Preeclampsia (PE) is a complex, hypertensive disorder of pregnancy, demonstrating considerable variability in maternal symptoms and fetal outcomes. Unfortunately, prior research has not accounted for this variability, resulting in a lack of robust biomarkers and effective treatments for PE. Here, we created a large (N=330) clinically relevant human placental microarray data set, consisting of 7 previously published studies and 157 highly annotated new samples from a single BioBank. Applying unsupervised clustering to this combined data set identified 3 clinically significant probable etiologies of PE: "maternal", with healthy placentas and term deliveries; "canonical", exhibiting expected clinical, ontological, and histopathologic features of PE; and "immunologic" with severe fetal growth restriction and evidence of maternal antifetal rejection. Moreover, these groups could be distinguished using a small quantitative polymerase chain reaction panel and demonstrated varying influence of maternal factors on PE development. An additional subclass of PE placentas was also revealed to form because of chromosomal abnormalities in these samples, supported by array-based comparative genomic hybridization analysis. Overall, our findings represent a new paradigm in our understanding of the origins and maternal-placental contributions to the pathology of PE. The study of PE represents a unique opportunity to access human tissue associated with a complex hypertensive disorder, and our novel approach could be applied to other hypertensive and heterogeneous human diseases. PMID:27160201

  18. Cell-surface central nervous system autoantibodies: Clinical relevance and emerging paradigms

    PubMed Central

    Irani, Sarosh R; Gelfand, Jeffrey M; Al-Diwani, Adam; Vincent, Angela

    2014-01-01

    The recent discovery of several potentially pathogenic autoantibodies has helped identify patients with clinically distinctive central nervous system diseases that appear to benefit from immunotherapy. The associated autoantibodies are directed against the extracellular domains of cell-surface–expressed neuronal or glial proteins such as LGI1, N-methyl-D-aspartate receptor, and aquaporin-4. The original descriptions of the associated clinical syndromes were phenotypically well circumscribed. However, as availability of antibody testing has increased, the range of associated patient phenotypes and demographics has expanded. This in turn has led to the recognition of more immunotherapy-responsive syndromes in patients presenting with cognitive and behavioral problems, seizures, movement disorders, psychiatric features, and demyelinating disease. Although antibody detection remains diagnostically important, clinical recognition of these distinctive syndromes should ensure early and appropriate immunotherapy administration. We review the emerging paradigm of cell-surface–directed antibody–mediated neurological diseases, describe how the associated disease spectrums have broadened since the original descriptions, discuss some of the methodological issues regarding techniques for antibody detection and emphasize considerations surrounding immunotherapy administration. As these disorders continue to reach mainstream neurology and even psychiatry, more cell-surface–directed antibodies will be discovered, and their possible relevance to other more common disease presentations should become more clearly defined. PMID:24930434

  19. The Clinical Relevance of Force Platform Measures in Multiple Sclerosis: A Review

    PubMed Central

    Prosperini, Luca; Pozzilli, Carlo

    2013-01-01

    Balance impairment and falls are frequent in patients with multiple sclerosis (PwMS), and they may occur even at the earliest stage of the disease and in minimally impaired patients. The introduction of computer-based force platform measures (i.e., static and dynamic posturography) has provided an objective and sensitive tool to document both deficits and improvements in balance. By using more challenging test conditions, force platform measures can also reveal subtle balance disorders undetectable by common clinical scales. Furthermore, posturographic techniques may also allow to reliably identify PwMS who are at risk of accidental falls. Although force platform measures offer several theoretical advantages, only few studies extensively investigated their role in better managing PwMS. Standardised procedures, as well as clinical relevance of changes detected by static or dynamic posturography, are still lacking. In this review, we summarized studies which investigated balance deficit by means of force platform measures, focusing on their ability in detecting patients at high risk of falls and in estimating rehabilitation-induced changes, highlighting the pros and the cons with respect to clinical scales. PMID:23766910

  20. Clinically Relevant Injury Patterns After an Anterior Cruciate Ligament Injury Provide Insight Into Injury Mechanisms

    PubMed Central

    Levine, Jason W.; Kiapour, Ata M.; Quatman, Carmen E.; Wordeman, Samuel C.; Goel, Vijay K.; Hewett, Timothy E.; Demetropoulos, Constantine K.

    2014-01-01

    Background The functional disability and high costs of treating anterior cruciate ligament (ACL) injuries have generated a great deal of interest in understanding the mechanism of noncontact ACL injuries. Secondary bone bruises have been reported in over 80% of partial and complete ACL ruptures. Purpose The objectives of this study were (1) to quantify ACL strain under a range of physiologically relevant loading conditions and (2) to evaluate soft tissue and bony injury patterns associated with applied loading conditions thought to be responsible for many noncontact ACL injuries. Study Design Controlled laboratory study. Methods Seventeen cadaveric legs (age, 45 ± 7 years; 9 female and 8 male) were tested utilizing a custom-designed drop stand to simulate landing. Specimens were randomly assigned between 2 loading groups that evaluated ACL strain under either knee abduction or internal tibial rotation moments. In each group, combinations of anterior tibial shear force, and knee abduction and internal tibial rotation moments under axial impact loading were applied sequentially until failure. Specimens were tested at 25° of flexion under simulated 1200-N quadriceps and 800-N hamstring loads. A differential variable reluctance transducer was used to calculate ACL strain across the anteromedial bundle. A general linear model was used to compare peak ACL strain at failure. Correlations between simulated knee injury patterns and loading conditions were evaluated by the χ2 test for independence. Results Anterior cruciate ligament failure was generated in 15 of 17 specimens (88%). A clinically relevant distribution of failure patterns was observed including medial collateral ligament tears and damage to the menisci, cartilage, and subchondral bone. Only abduction significantly contributed to calculated peak ACL strain at failure (P = .002). While ACL disruption patterns were independent of the loading mechanism, tibial plateau injury patterns (locations) were

  1. In Vivo Photoacoustic and Fluorescence Cystography Using Clinically Relevant Dual Modal Indocyanine Green

    PubMed Central

    Park, Sungjo; Kim, Jeesu; Jeon, Mansik; Song, Jaewon; Kim, Chulhong

    2014-01-01

    Conventional X-ray-based cystography uses radio-opaque materials, but this method uses harmful ionizing radiation and is not sensitive. In this study, we demonstrate nonionizing and noninvasive photoacoustic (PA) and fluorescence (FL) cystography using clinically relevant indocyanine green (ICG) in vivo. After transurethral injection of ICG into rats through a catheter, their bladders were photoacoustically and fluorescently visualized. A deeply positioned bladder below the skin surface (i.e., ∼1.5–5 mm) was clearly visible in the PA and FL image using a laser pulse energy of less than 2 mJ/cm2 (1/15 of the safety limit). Then, the in vivo imaging results were validated through in situ studies. Our results suggest that dual modal cystography can provide a nonionizing and noninvasive imaging tool for bladder mapping. PMID:25337743

  2. Blood lactate concentration after exposure to conducted energy weapons (including TASER® devices): is it clinically relevant?

    PubMed

    Jauchem, James R

    2013-09-01

    In previous studies, blood lactate concentration (BLac) consistently increased in anesthetized animals and in human subjects after exposures to TASER(®) conducted energy weapons (CEWs). Some have suggested the increased BLac would have detrimental consequences. In the current review, the following are evaluated: (a) the nature of muscle contractions due to CEWs, (b) general aspects of increased BLac, (c) previous studies of conventional neuromuscular electrical stimulation and CEW exposures, and (d) BLac in disease states. On the basis of these analyses, one can conclude that BLac, per se (independent of acidemia), would not be clinically relevant immediately after short-duration CEW applications, due to the short time course of any increase. PMID:23605975

  3. Expanding the scope and relevance of health interventions: Moving beyond clinical trials and behavior change models

    PubMed Central

    Rigg, Khary K.; Cook, Hilary H.; Murphy, John W.

    2014-01-01

    An overemphasis on clinical trials and behavior change models has narrowed the knowledge base that can be used to design interventions. The overarching point is that the process of overanalyzing variables is impeding the process of gaining insight into the everyday experiences that shape how people define health and seek treatment. This claim is especially important to health decision-making and behavior change because subtle interpretations often influence the decisions that people make. This manuscript provides a critique of traditional approaches to developing health interventions, and theoretically justifies what and why changes are warranted. The limited scope of these models is also discussed, and an argument is made to adopt a strategy that includes the perceptions of people as necessary for understanding health and health-related decision-making. Three practical strategies are suggested to be used with the more standard approaches to assessing the effectiveness and relevance of health interventions. PMID:25053530

  4. B in TB: B Cells as Mediators of Clinically Relevant Immune Responses in Tuberculosis

    PubMed Central

    Rao, Martin; Valentini, Davide; Poiret, Thomas; Dodoo, Ernest; Parida, Shreemanta; Zumla, Alimuddin; Brighenti, Susanna; Maeurer, Markus

    2015-01-01

    The protective role of B cells and humoral immune responses in tuberculosis infection has been regarded as inferior to cellular immunity directed to the intracellular pathogen Mycobacterium tuberculosis. However, B-cell–mediated immune responses in tuberculosis have recently been revisited in the context of B-cell physiology and antigen presentation. We discuss in this review the diverse functions of B cells in tuberculosis, with a focus on their biological and clinical relevance to progression of active disease. We also present the peptide microarray platform as a promising strategy to discover unknown antigenic targets of M. tuberculosis that could contribute to the better understanding of epitope focus of the humoral immune system against M. tuberculosis. PMID:26409285

  5. Environmental microbiota represents a natural reservoir for dissemination of clinically relevant metallo-beta-lactamases.

    PubMed

    Scotta, Claudia; Juan, Carlos; Cabot, Gabriel; Oliver, Antonio; Lalucat, Jorge; Bennasar, Antonio; Albertí, Sebastián

    2011-11-01

    A total of 10 metallo-β-lactamase-producing isolates of six different species, including Brevundimonas diminuta (n = 3), Rhizobium radiobacter (n = 2), Pseudomonas monteilii (n = 1), Pseudomonas aeruginosa (n = 2), Ochrobactrum anthropi (n = 1), and Enterobacter ludwigii (n = 1), were detected in the sewage water of a hospital. The presence of bla(VIM-13) associated with a Tn1721-class 1 integron structure was detected in all but one of the isolates (E. ludwigii, which produced VIM-2), and in two of them (R. radiobacter), this structure was located on a plasmid, suggesting that environmental bacteria represent a reservoir for the dissemination of clinically relevant metallo-β-lactamase genes. PMID:21859934

  6. Per-beam, planar IMRT QA passing rates do not predict clinically relevant patient dose errors

    SciTech Connect

    Nelms, Benjamin E.; Zhen Heming; Tome, Wolfgang A.

    2011-02-15

    Purpose: The purpose of this work is to determine the statistical correlation between per-beam, planar IMRT QA passing rates and several clinically relevant, anatomy-based dose errors for per-patient IMRT QA. The intent is to assess the predictive power of a common conventional IMRT QA performance metric, the Gamma passing rate per beam. Methods: Ninety-six unique data sets were created by inducing four types of dose errors in 24 clinical head and neck IMRT plans, each planned with 6 MV Varian 120-leaf MLC linear accelerators using a commercial treatment planning system and step-and-shoot delivery. The error-free beams/plans were used as ''simulated measurements'' (for generating the IMRT QA dose planes and the anatomy dose metrics) to compare to the corresponding data calculated by the error-induced plans. The degree of the induced errors was tuned to mimic IMRT QA passing rates that are commonly achieved using conventional methods. Results: Analysis of clinical metrics (parotid mean doses, spinal cord max and D1cc, CTV D95, and larynx mean) vs IMRT QA Gamma analysis (3%/3 mm, 2/2, 1/1) showed that in all cases, there were only weak to moderate correlations (range of Pearson's r-values: -0.295 to 0.653). Moreover, the moderate correlations actually had positive Pearson's r-values (i.e., clinically relevant metric differences increased with increasing IMRT QA passing rate), indicating that some of the largest anatomy-based dose differences occurred in the cases of high IMRT QA passing rates, which may be called ''false negatives.'' The results also show numerous instances of false positives or cases where low IMRT QA passing rates do not imply large errors in anatomy dose metrics. In none of the cases was there correlation consistent with high predictive power of planar IMRT passing rates, i.e., in none of the cases did high IMRT QA Gamma passing rates predict low errors in anatomy dose metrics or vice versa. Conclusions: There is a lack of correlation between

  7. Clinically Relevant Progestins Regulate Neurogenic and Neuroprotective Responses in Vitro and in Vivo

    PubMed Central

    Liu, Lifei; Zhao, Liqin; She, Hongyun; Chen, Shuhua; Wang, Jun Ming; Wong, Charisse; McClure, Kelsey; Sitruk-Ware, Regine; Brinton, Roberta Diaz

    2010-01-01

    Previously, we demonstrated that progesterone (P4) promoted adult rat neural progenitor cell (rNPC) proliferation with concomitant regulation of cell-cycle gene expression via the P4 receptor membrane component/ERK pathway. Here, we report the efficacy of seven clinically relevant progestins alone or in combination with 17β-estradiol (E2) on adult rNPC proliferation and hippocampal cell viability in vitro and in vivo. In vitro analyses indicated that P4, norgestimate, Nestorone, norethynodrel, norethindrone, and levonorgestrel (LNG) significantly increased in rNPC proliferation, whereas norethindrone acetate was without effect, and medroxyprogesterone acetate (MPA) inhibited rNPC proliferation. Proliferative progestins in vitro were also neuroprotective. Acute in vivo exposure to P4 and Nestorone significantly increased proliferating cell nuclear antigen and cell division cycle 2 expression and total number of hippocampal 5-bromo-2-deoxyuridine (BrdU)-positive cells, whereas LNG and MPA were without effect. Mechanistically, neurogenic progestins required activation of MAPK to promote proliferation. P4, Nestorone, and LNG significantly increased ATP synthase subunit α (complex V, subunit α) expression, whereas MPA was without effect. In combination with E2, P4, Nestorone, LNG, and MPA significantly increased BrdU incorporation. However, BrdU incorporation induced by E2 plus LNG or MPA was paralleled by a significant increase in apoptosis. A rise in Bax/Bcl-2 ratio paralleled apoptosis induced by LNG and MPA. With the exception of P4, clinical progestins antagonized E2-induced rise in complex V, subunit α. These preclinical translational findings indicate that the neurogenic response to clinical progestins varies dramatically. Progestin impact on the regenerative capacity of the brain has clinical implications for contraceptive and hormone therapy formulations prescribed for pre- and postmenopausal women. PMID:20943809

  8. Expression, regulation and clinical relevance of the ATPase inhibitory factor 1 in human cancers

    PubMed Central

    Sánchez-Aragó, M; Formentini, L; Martínez-Reyes, I; García-Bermudez, J; Santacatterina, F; Sánchez-Cenizo, L; Willers, I M; Aldea, M; Nájera, L; Juarránz, Á; López, E C; Clofent, J; Navarro, C; Espinosa, E; Cuezva, J M

    2013-01-01

    Recent findings in colon cancer cells indicate that inhibition of the mitochondrial H+-adenosine triphosphate (ATP) synthase by the ATPase inhibitory factor 1 (IF1) promotes aerobic glycolysis and a reactive oxygen species (ROS)-mediated signal that enhances proliferation and cell survival. Herein, we have studied the expression, biological relevance, mechanism of regulation and potential clinical impact of IF1 in some prevalent human carcinomas. We show that IF1 is highly overexpressed in most (>90%) of the colon (n=64), lung (n=30), breast (n=129) and ovarian (n=10) carcinomas studied as assessed by different approaches in independent cohorts of cancer patients. The expression of IF1 in the corresponding normal tissues is negligible. By contrast, the endometrium, stomach and kidney show high expression of IF1 in the normal tissue revealing subtle differences by carcinogenesis. The overexpression of IF1 also promotes the activation of aerobic glycolysis and a concurrent ROS signal in mitochondria of the lung, breast and ovarian cancer cells mimicking the activity of oligomycin. IF1-mediated ROS signaling activates cell-type specific adaptive responses aimed at preventing death in these cell lines. Remarkably, regulation of IF1 expression in the colon, lung, breast and ovarian carcinomas is exerted at post-transcriptional levels. We demonstrate that IF1 is a short-lived protein (t1/2 ∼100 min) strongly implicating translation and/or protein stabilization as main drivers of metabolic reprogramming and cell survival in these human cancers. Analysis of tumor expression of IF1 in cohorts of breast and colon cancer patients revealed its relevance as a predictive marker for clinical outcome, emphasizing the high potential of IF1 as therapeutic target. PMID:23608753

  9. Direct toxic effects of aqueous extract of cigarette smoke on cardiac myocytes at clinically relevant concentrations

    SciTech Connect

    Yamada, Shigeyuki; Zhang Xiuquan; Kadono, Toshie; Matsuoka, Nobuhiro; Rollins, Douglas; Badger, Troy; Rodesch, Christopher K.; Barry, William H.

    2009-04-01

    Aims: Our goal was to determine if clinically relevant concentrations of aqueous extract of cigarette smoke (CSE) have direct deleterious effects on ventricular myocytes during simulated ischemia, and to investigate the mechanisms involved. Methods: CSE was prepared with a smoking chamber. Ischemia was simulated by metabolic inhibition (MI) with cyanide (CN) and 0 glucose. Adult rabbit and mouse ventricular myocyte [Ca{sup 2+}]{sub i} was measured by flow cytometry using fluo-3. Mitochondrial [Ca{sup 2+}] was measured with confocal microscopy, and Rhod-2 fluorescence. The mitochondrial permeability transition (MPT) was detected by TMRM fluorescence and myocyte contracture. Myocyte oxidative stress was quantified by dichlorofluorescein (DCF) fluorescence with confocal microscopy. Results: CSE 0.1% increased myocyte contracture caused by MI. The nicotine concentration (HPLC) in 0.1% CSE was 15 ng/ml, similar to that in humans after smoking cigarettes. CSE 0.1% increased mitochondrial Ca{sup 2+} uptake, and increased the susceptibility of mitochondria to the MPT. CSE 0.1% increased DCF fluorescence in isolated myocytes, and increased [Ca{sup 2+}]{sub i} in paced myocytes exposed to 2.0 mM CN, 0 glucose (P-MI). These effects were inhibited by the superoxide scavenger Tiron. The effect of CSE on [Ca{sup 2+}]{sub i} during P-MI was also prevented by ranolazine. Conclusions: CSE in clinically relevant concentrations increases myocyte [Ca{sup 2+}]{sub i} during simulated ischemia, and increases myocyte susceptibility to the MPT. These effects appear to be mediated at least in part by oxidative radicals in CSE, and likely contribute to the effects of cigarette smoke to increase myocardial infarct size, and to decrease angina threshold.

  10. Two Different Serum MiRNA Signatures Correlate with the Clinical Outcome and Histological Subtype in Pleural Malignant Mesothelioma Patients

    PubMed Central

    Lombardi, Angela; Di Domenico, Marina; Fiorelli, Alfonso; Feola, Antonia; Perna, Alessandra F.; Santini, Mario; Caraglia, Michele; Ingrosso, Diego

    2015-01-01

    Pleural malignant mesothelioma (MPM) is a detrimental neoplasm affecting pleural sheets and determining a high rate of mortality. In this study, we have enrolled 14 consecutive patients (13 males and 1 female) with MPM (mean age: 70.3 ± 4.6 years). We have collected serum for the determination of a miRNA profiling using a low-density microarray real time PCR system in the serum of patients and comparing it with that one of 10 control counterparts affected by not-cancer-related pleural effusions. In the patients 5 miRNAs were up-regulated (miR101, miR25, miR26b, miR335 and miR433), 2 miRNA were downregulated (miR191, miR223) and two miRNAs were expressed exclusively in patients (miR29a and miR516). Based upon the changes in the expression of the above mentioned miRNAs we detected two distinctive miRNA signatures predicting histotype and survival in these patients: I) patients with more than 3/9 upregulated miRNAs or 3/9 upregulated miRNAs and miR516 not recordable or unchanged (signature A); II) patients with at least 3/9 downregulated or unchanged miRNAs and/or miR29a downregulated (signature B). Based upon these criteria, 5 patients were stratified in signature A and the remaining 9 in signature B. Patients with signature A had a significant shorter median survival than those with signature B (7 months vs. 17 months, 95% CI: 0.098–1.72, p = 0.0021), had a sarcomatoid or mixed histological MPM subtype and were diagnosed in stage II (3/5) and stage III (2/5). In conclusion, we suggest that miRNA signature A is predictive of sarcomatoid histotype and of worse prognosis in MPM. PMID:26262875

  11. Distinctive Patterns of Initially Presenting Metastases and Clinical Outcomes According to the Histological Subtypes in Stage IV Non-Small Cell Lung Cancer

    PubMed Central

    Lee, Dong Soo; Kim, Yeon S.; Kay, Chul S.; Kim, Sung H.; Yeo, Chang D.; Kim, Jin W.; Kim, Seung Joon; Kim, Young K.; Ko, Yoon H.; Kang, Jin H.; Lee, Kyo Y.

    2016-01-01

    Abstract This study was designed to compare the primary patterns of metastases and clinical outcomes between adenocarcinoma (Adenoca) and squamous cell carcinoma (SQ) in initially diagnosed stage IV non-small cell lung cancer (NSCLC). Between June 2007 and June 2013, a total of 427 eligible patients were analyzed. These patients were histologically confirmed as Adenoca or SQ and underwent systemic imaging studies, including 18F-fluorodeoxyglucose positron emission tomography/computed tomography and brain imaging. Synchronous metastatic sites were categorized into 7 areas, and whole-body metastatic scores were calculated from 1 to 7 by summation of each involved region. We compared the patient, tumor, and metastatic characteristics according to the histological subtypes, and examined clinical outcomes. The enrolled study cohort comprised 81% (n = 346) Adenoca patients and 19% (n = 81) SQ patients. The median age of the study population was 65 years (range, 30–94 years), and 263 (61.6%) patients were male. The most common metastatic sites were thoracic lymph nodes (LNs) (84.3%), followed by lung to lung/lymphangitic spread (59%) and bone (54.8%). The distribution of patient characteristics revealed that age ≥65 years (69.1% vs 50.6%; P = 0.003) and male sex (84% vs 56.4%; P < 0.001) were more frequently found in SQ patients. Regarding metastatic features, bone metastasis (60.4% vs 30.9%; P < 0.001), lung to lung/lymphangitic metastasis (63% vs 42%; P = 0.001), and brain metastasis (35% vs 16%; P = 0.001) were significantly and more frequently found in Adenoca patients. Patients with high metastatic scores (score 3–6) were more frequently found to have Adenoca (91.6% vs 73.4%; P < 0.001). In multivariate prognostic evaluation, sex (P = 0.001), age (P < 0.001), histology (P < 0.001), LN status (P = 0.032), pleural/pericardial metastasis (P = 0.003), abdomen/pelvis metastasis (P < 0.001), axilla

  12. The Clinically-tested S1P Receptor Agonists, FTY720 and BAF312, Demonstrate Subtype-Specific Bradycardia (S1P1) and Hypertension (S1P3) in Rat

    PubMed Central

    Fryer, Ryan M.; Muthukumarana, Akalushi; Harrison, Paul C.; Nodop Mazurek, Suzanne; Chen, Rong Rhonda; Harrington, Kyle E.; Dinallo, Roger M.; Horan, Joshua C.; Patnaude, Lori; Modis, Louise K.; Reinhart, Glenn A.

    2012-01-01

    Sphingosine-1-phospate (S1P) and S1P receptor agonists elicit mechanism-based effects on cardiovascular function in vivo. Indeed, FTY720 (non-selective S1PX receptor agonist) produces modest hypertension in patients (2–3 mmHg in 1-yr trial) as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, likely dependent upon the cardiovascular response in question (e.g. bradycardia, hypertension), and perhaps even species-dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, we characterized the S1P receptor subtype specificity for each compound in vitro and, in vivo, the cardiovascular effects of FTY720 and the more selective S1P1,5 agonist, BAF312, were tested during acute i.v. infusion in anesthetized rats and after oral administration for 10 days in telemetry-instrumented conscious rats. Acute i.v. infusion of FTY720 (0.1, 0.3, 1.0 mg/kg/20 min) or BAF312 (0.5, 1.5, 5.0 mg/kg/20 min) elicited acute bradycardia in anesthetized rats demonstrating an S1P1 mediated mechanism-of-action. However, while FTY720 (0.5, 1.5, 5.0 mg/kg/d) elicited dose-dependent hypertension after multiple days of oral administration in rat at clinically relevant plasma concentrations (24-hr mean blood pressure = 8.4, 12.8, 16.2 mmHg above baseline vs. 3 mmHg in vehicle controls), BAF312 (0.3, 3.0, 30.0 mg/kg/d) had no significant effect on blood pressure at any dose tested suggesting that hypertension produced by FTY720 is mediated S1P3 receptors. In summary, in vitro selectivity results in combination with studies performed in anesthetized and conscious rats administered two clinically tested S1P agonists, FTY720 or BAF312, suggest that S1P1 receptors mediate bradycardia while hypertension is mediated by S1P3 receptor activation. PMID:23285242

  13. The clinically-tested S1P receptor agonists, FTY720 and BAF312, demonstrate subtype-specific bradycardia (S1P₁) and hypertension (S1P₃) in rat.

    PubMed

    Fryer, Ryan M; Muthukumarana, Akalushi; Harrison, Paul C; Nodop Mazurek, Suzanne; Chen, Rong Rhonda; Harrington, Kyle E; Dinallo, Roger M; Horan, Joshua C; Patnaude, Lori; Modis, Louise K; Reinhart, Glenn A

    2012-01-01

    Sphingosine-1-phospate (S1P) and S1P receptor agonists elicit mechanism-based effects on cardiovascular function in vivo. Indeed, FTY720 (non-selective S1P(X) receptor agonist) produces modest hypertension in patients (2-3 mmHg in 1-yr trial) as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, likely dependent upon the cardiovascular response in question (e.g. bradycardia, hypertension), and perhaps even species-dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, we characterized the S1P receptor subtype specificity for each compound in vitro and, in vivo, the cardiovascular effects of FTY720 and the more selective S1P₁,₅ agonist, BAF312, were tested during acute i.v. infusion in anesthetized rats and after oral administration for 10 days in telemetry-instrumented conscious rats. Acute i.v. infusion of FTY720 (0.1, 0.3, 1.0 mg/kg/20 min) or BAF312 (0.5, 1.5, 5.0 mg/kg/20 min) elicited acute bradycardia in anesthetized rats demonstrating an S1P₁ mediated mechanism-of-action. However, while FTY720 (0.5, 1.5, 5.0 mg/kg/d) elicited dose-dependent hypertension after multiple days of oral administration in rat at clinically relevant plasma concentrations (24-hr mean blood pressure = 8.4, 12.8, 16.2 mmHg above baseline vs. 3 mmHg in vehicle controls), BAF312 (0.3, 3.0, 30.0 mg/kg/d) had no significant effect on blood pressure at any dose tested suggesting that hypertension produced by FTY720 is mediated S1P₃ receptors. In summary, in vitro selectivity results in combination with studies performed in anesthetized and conscious rats administered two clinically tested S1P agonists, FTY720 or BAF312, suggest that S1P₁ receptors mediate bradycardia while hypertension is mediated by S1P₃ receptor activation. PMID:23285242

  14. Clinical and Neurobiological Relevance of Current Animal Models of Autism Spectrum Disorders.

    PubMed

    Kim, Ki Chan; Gonzales, Edson Luck; Lázaro, María T; Choi, Chang Soon; Bahn, Geon Ho; Yoo, Hee Jeong; Shin, Chan Young

    2016-05-01

    Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments, as well as repetitive and restrictive behaviors. The phenotypic heterogeneity of ASD has made it overwhelmingly difficult to determine the exact etiology and pathophysiology underlying the core symptoms, which are often accompanied by comorbidities such as hyperactivity, seizures, and sensorimotor abnormalities. To our benefit, the advent of animal models has allowed us to assess and test diverse risk factors of ASD, both genetic and environmental, and measure their contribution to the manifestation of autistic symptoms. At a broader scale, rodent models have helped consolidate molecular pathways and unify the neurophysiological mechanisms underlying each one of the various etiologies. This approach will potentially enable the stratification of ASD into clinical, molecular, and neurophenotypic subgroups, further proving their translational utility. It is henceforth paramount to establish a common ground of mechanistic theories from complementing results in preclinical research. In this review, we cluster the ASD animal models into lesion and genetic models and further classify them based on the corresponding environmental, epigenetic and genetic factors. Finally, we summarize the symptoms and neuropathological highlights for each model and make critical comparisons that elucidate their clinical and neurobiological relevance. PMID:27133257

  15. The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant

    PubMed Central

    Reynders, Kobe; Illidge, Tim; Siva, Shankar; Chang, Joe Y.; De Ruysscher, Dirk

    2016-01-01

    Background Recently, immunologic responses to localized irradiation are proposed as mediator of systemic effects after localized radiotherapy (called the abscopal effect). Here, we give an overview of both preclinical and clinical data about the abscopal effect in particular and link them with the immunogenic properties of radiotherapy. Methods We searched Medline and Embase with the search term “abscopal” from 1960 until July, 2014. Only papers that cover radiotherapy in an oncological setting were selected and only if no concurrent cytotoxic treatment was given. Targeted immune therapy was allowed. Results Twenty-three case reports, one retrospective study and 13 preclinical papers were selected. Eleven preclinical papers used a combination of immune modification and radiotherapy to achieve abscopal effects. Patient age range (28 to 83 years) and radiation dose (median total dose 32 Gy) varied. Fractionation size ranged from 1,2 Gy to 26 Gy. Time to documented abscopal response ranged between less than one and 24 months, with a median reported time of 5 months. Once an abscopal response was achieved, a median time of 13 months went by before disease progression occurred or the reported follow-up ended (range 3–39 months). Conclusion Preclinical data points heavily towards a strong synergy between radiotherapy and immune treatments. Recent case reports already illustrate that such a systemic effect of radiotherapy is possible when enhanced by targeted immune treatments. However, several issues concerning dosage, timing, patient selection and toxicity need to be resolved before the abscopal effect can become clinically relevant. PMID:25872878

  16. Enhancement in dentin collagen’s biological stability after proanthocyanidins treatment in clinically relevant time periods

    PubMed Central

    Liu, Yi; Chen, Mingsheng; Yao, Xiaomei; Xu, Changqi; Zhang, Ying; Wang, Yong

    2013-01-01

    Objective To investigate whether proanthocyanidins (PA) is capable of improving dentin collagen’s biological stability through cross-linking within time periods that are clinically relevant. Materials and methods Demineralized dentin collagen slabs were treated with 3.75 wt% PA solution for 10 s, 1 min, 30 min, 60 min, 120 min, 360 min, and 720 min, respectively. The resultant cross-linked collagen samples were subject to digestion with 0.1% collagenase at 37 °C for 2 h, 6 h, 12 h, 24 h, 36 h, and 48 h. The percentage of weight loss after digestion was calculated to evaluate PA-treated collagen’s resistance toward enzymatic degradation. Fourier-Transformed Infrared (FTIR) spectroscopy was used to probe evidences of PA-collagen interactions after various periods of PA treatment. Results The collagenase digestion assay suggests that PA treatment as short as 10 s can enhance collagen’s resistance toward enzymatic challenge. The FTIR spectroscopy further verifies that PA is indeed incorporated into collagen regardless of treatment time, possibly via a mechanism involving the chemical interactions between PA and collagen. Significance This study confirmed that PA can effectively cross-link collagen and improve its biological stability in time periods as short as 10 s. The use of PA as a priming agent is therefore clinically feasible and is a promising approach to improving the durability of current dentin bonding systems. PMID:23434233

  17. Clinical and Neurobiological Relevance of Current Animal Models of Autism Spectrum Disorders

    PubMed Central

    Kim, Ki Chan; Gonzales, Edson Luck; Lázaro, María T.; Choi, Chang Soon; Bahn, Geon Ho; Yoo, Hee Jeong; Shin, Chan Young

    2016-01-01

    Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments, as well as repetitive and restrictive behaviors. The phenotypic heterogeneity of ASD has made it overwhelmingly difficult to determine the exact etiology and pathophysiology underlying the core symptoms, which are often accompanied by comorbidities such as hyperactivity, seizures, and sensorimotor abnormalities. To our benefit, the advent of animal models has allowed us to assess and test diverse risk factors of ASD, both genetic and environmental, and measure their contribution to the manifestation of autistic symptoms. At a broader scale, rodent models have helped consolidate molecular pathways and unify the neurophysiological mechanisms underlying each one of the various etiologies. This approach will potentially enable the stratification of ASD into clinical, molecular, and neurophenotypic subgroups, further proving their translational utility. It is henceforth paramount to establish a common ground of mechanistic theories from complementing results in preclinical research. In this review, we cluster the ASD animal models into lesion and genetic models and further classify them based on the corresponding environmental, epigenetic and genetic factors. Finally, we summarize the symptoms and neuropathological highlights for each model and make critical comparisons that elucidate their clinical and neurobiological relevance. PMID:27133257

  18. Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use.

    PubMed

    Taylor, Charles P; Traynelis, Stephen F; Siffert, Joao; Pope, Laura E; Matsumoto, Rae R

    2016-08-01

    Dextromethorphan (DM) has been used for more than 50years as an over-the-counter antitussive. Studies have revealed a complex pharmacology of DM with mechanisms beyond blockade of N-methyl-d-aspartate (NMDA) receptors and inhibition of glutamate excitotoxicity, likely contributing to its pharmacological activity and clinical potential. DM is rapidly metabolized to dextrorphan, which has hampered the exploration of DM therapy separate from its metabolites. Coadministration of DM with a low dose of quinidine inhibits DM metabolism, yields greater bioavailability and enables more specific testing of the therapeutic properties of DM apart from its metabolites. The development of the drug combination DM hydrobromide and quinidine sulfate (DM/Q), with subsequent approval by the US Food and Drug Administration for pseudobulbar affect, led to renewed interest in understanding DM pharmacology. This review summarizes the interactions of DM with brain receptors and transporters and also considers its metabolic and pharmacokinetic properties. To assess the potential clinical relevance of these interactions, we provide an analysis comparing DM activity from in vitro functional assays with the estimated free drug DM concentrations in the brain following oral DM/Q administration. The findings suggest that DM/Q likely inhibits serotonin and norepinephrine reuptake and also blocks NMDA receptors with rapid kinetics. Use of DM/Q may also antagonize nicotinic acetylcholine receptors, particularly those composed of α3β4 subunits, and cause agonist activity at sigma-1 receptors. PMID:27139517

  19. Warfarin accelerates ectopic mineralization in Abcc6(-/-) mice: clinical relevance to pseudoxanthoma elasticum.

    PubMed

    Li, Qiaoli; Guo, Haitao; Chou, David W; Harrington, Dominic J; Schurgers, Leon J; Terry, Sharon F; Uitto, Jouni

    2013-04-01

    Pseudoxanthoma elasticum (PXE) is a multisystem ectopic mineralization disorder caused by mutations in the ABCC6 gene. Warfarin, a commonly used anticoagulant, is associated with increased mineralization of the arterial blood vessels and cardiac valves. We hypothesized that warfarin may accelerate ectopic tissue mineralization in PXE, with clinical consequences. To test this hypothesis, we developed a model in which Abcc6(-/-) mice, which recapitulate features of PXE, were fed a diet supplemented with warfarin and vitamin K1. Warfarin action was confirmed by significantly increased serum levels of oxidized vitamin K. For mice placed on a warfarin-containing diet, quantitative chemical and morphometric analyses revealed massive accumulation of mineral deposits in a number of tissues. Mice fed a warfarin-containing diet were also shown to have abundant uncarboxylated form of matrix Gla protein, which allowed progressive tissue mineralization to ensue. To explore the clinical relevance of these findings, 1747 patients with PXE from the approximately 4000 patients in the PXE International database were surveyed about the use of warfarin. Of the 539 respondents, 2.6% reported past or present use of warfarin. Based on the prevalence of PXE (approximately 1:50,000), thousands of patients with PXE worldwide may be at risk for worsening of PXE as a result of warfarin therapy. PMID:23415960

  20. Clinical Relevance of CYP2D6 Genetics for Tamoxifen Response in Breast Cancer

    PubMed Central

    Brauch, Hiltrud; Schroth, Werner; Eichelbaum, Michel; Schwab, Matthias; Harbeck, Nadia

    2008-01-01

    Summary Tamoxifen is a standard endocrine therapy for the prevention and treatment of steroid hormone receptor-positive breast cancer. Tamoxifen requires enzymatic activation by CYP 450 enzymes for the formation of clinically relevant metabolites, 4-OH-tamoxifen and endoxifen, which both have a greater affinity to the estrogen receptor and ability to inhibit cell proliferation when compared to the parent drug. CYP2D6 is the key enzyme in this biotransformation, and recent mechanistic, pharmacologic, and clinical pharmacogenetic evidence suggests that genetic variants and drug interaction by CYP2D6 inhibitors influence plasma concentrations of active tamoxifen metabolites and outcome of patients treated with adjuvant tamoxifen. Particularly, non-functional (poor metabolizer) and severely impaired (intermediate metabolizer) CYP2D6 variants are associated with higher recurrence rates. Accordingly, CYP2D6 genotyping prior to treatment for prediction of metabolizer status and outcome may open new avenues for the individualization of endocrine treatment choice and benefit. Moreover, strong CYP2D6 inhibitors such as the selective serotonin reuptake inhibitor paroxetine should be avoided as co-medication. PMID:20824020

  1. The Taccalonolides: Microtubule Stabilizers that Circumvent Clinically Relevant Taxane Resistance Mechanisms

    PubMed Central

    Risinger, April L.; Jackson, Evelyn M.; Polin, Lisa A.; Helms, Gregory L.; LeBoeuf, Desiree A.; Joe, Patrick A.; Hopper-Borge, Elizabeth; Ludueña, Richard F.; Kruh, Gary D.; Mooberry, Susan L.

    2009-01-01

    The taccalonolides are a class of structurally and mechanistically distinct microtubule-stabilizing agents isolated from Tacca chantrieri. A crucial feature of the taxane family of microtubule stabilizers is their susceptibility to cellular resistance mechanisms including overexpression of P-glycoprotein, MRP7 and the βIII isotype of tubulin. The ability of four taccalonolides, A, E, B and N, to circumvent these multidrug resistance mechanisms was studied. Taccalonolides A, E, B and N were effective in vitro against cell lines that overexpress P-glycoprotein and MRP7. In addition, taccalonolides A and E were highly active in vivo against a doxorubicin- and paclitaxel- resistant Pgp-expressing tumor, Mam17/ADR. An isogenic HeLa-derived cell line that expresses the βIII isotype of tubulin was generated to evaluate the effect of βIII-tubulin on drug sensitivity. When compared with parental HeLa cells, the βIII-tubulin overexpressing cell line was less sensitive to paclitaxel, docetaxel, epothilone B and vinblastine. In striking contrast, the βIII-tubulin overexpressing cell line showed greater sensitivity to all four taccalonolides. These data cumulatively suggest that the taccalonolides have advantages over the taxanes in their ability to circumvent multiple drug resistance mechanisms. The ability of the taccalonolides to overcome clinically relevant mechanisms of drug resistance in vitro and in vivo confirms that the taccalonolides represent a valuable addition to the family of microtubule-stabilizing compounds with clinical potential. PMID:18974132

  2. Does the choice of display system influence perception and visibility of clinically relevant features in digital pathology images?

    NASA Astrophysics Data System (ADS)

    Kimpe, Tom; Rostang, Johan; Avanaki, Ali; Espig, Kathryn; Xthona, Albert; Cocuranu, Ioan; Parwani, Anil V.; Pantanowitz, Liron

    2014-03-01

    Digital pathology systems typically consist of a slide scanner, processing software, visualization software, and finally a workstation with display for visualization of the digital slide images. This paper studies whether digital pathology images can look different when presenting them on different display systems, and whether these visual differences can result in different perceived contrast of clinically relevant features. By analyzing a set of four digital pathology images of different subspecialties on three different display systems, it was concluded that pathology images look different when visualized on different display systems. The importance of these visual differences is elucidated when they are located in areas of the digital slide that contain clinically relevant features. Based on a calculation of dE2000 differences between background and clinically relevant features, it was clear that perceived contrast of clinically relevant features is influenced by the choice of display system. Furthermore, it seems that the specific calibration target chosen for the display system has an important effect on the perceived contrast of clinically relevant features. Preliminary results suggest that calibrating to DICOM GSDF calibration performed slightly worse than sRGB, while a new experimental calibration target CSDF performed better than both DICOM GSDF and sRGB. This result is promising as it suggests that further research work could lead to better definition of an optimized calibration target for digital pathology images resulting in a positive effect on clinical performance.

  3. Clinical relevance of molecular aberrations in paediatric acute myeloid leukaemia at first relapse.

    PubMed

    Bachas, Costa; Schuurhuis, Gerrit Jan; Reinhardt, Dirk; Creutzig, Ursula; Kwidama, Zinia J; Zwaan, C Michel; van den Heuvel-Eibrink, Marry M; De Bont, Evelina S J M; Elitzur, Sarah; Rizzari, Carmelo; de Haas, Valérie; Zimmermann, Martin; Cloos, Jacqueline; Kaspers, Gertjan J L

    2014-09-01

    Outcome for relapsed paediatric acute myeloid leukaemia (AML) remains poor. Strong prognostic factors at first relapse are lacking, which hampers optimization of therapy. We assessed the frequency of molecular aberrations (FLT3, NRAS, KRAS, KIT, WT1 and NPM1 genes) at first relapse in a large set (n = 198) of relapsed non-French-American-British M3, non-Down syndrome AML patients that received similar relapse treatment. We correlated molecular aberrations with clinical and biological factors and studied their prognostic relevance. Hotspot mutations in the analysed genes were detected in 92 out of 198 patients (46·5%). In 72 of these 92 patients (78%), molecular aberrations were mutually exclusive for the currently analysed genes. FLT3-internal tandem repeat (ITD) (18% of total group) mutations were most frequent, followed by NRAS (10·2%), KRAS (8%), WT1 (8%), KIT (8%), NPM1 (5%) and FLT3-tyrosine kinase domain (3%) mutations. Presence of a WT1 aberration was an independent risk factor for second relapse (Hazard Ratio [HR] = 2·74, P = 0·013). In patients who achieved second complete remission (70·2%), WT1 and FLT3-ITD aberrations were independent risk factors for poor overall survival (HR = 2·32, P = 0·038 and HR = 1·89, P = 0·045 respectively). These data show that molecular aberrations at first relapse are of prognostic relevance and potentially useful for risk group stratification of paediatric relapsed AML and for identification of patients eligible for personalized treatment. PMID:24962064

  4. [Subtypes of cocaine addicts with and without associated problematic alcohol use: towards a neuropsychology of personality applied to clinical practice].

    PubMed

    Pedrero Pérez, Eduardo J; Ruiz Sánchez de León, José M

    2012-01-01

    It is important to know which personality factors are associated with addiction so to distinguish addicts that require specialized treatment from those who do not, and to identify those addicts who achieve abstinence from those who continue their substance use despite the negative consequences. Cloninger's model includes biological and psychosocial variables that can be characterized in neuropsychological terms. Two samples were analyzed: individuals who had begun cocaine addiction treatment (n=183) and a non-clinical population sample (n = 183), matched for sex, age and educational level. Alcohol abuse/dependence was monitored as an independent variable. Significant differences and large effect size were found between addicts and non-clinical population in Novelty Seeking and Self-Directedness, and to a lesser extent, in Harm Avoidance. These differences increase when problematic use of alcohol is added. According to the profile of traits, clusters of addicts were established and differences were obtained in variables such as functional/dysfunctional impulsivity, dysexecutive symptoms and perceived stress. Six clusters were identified, some of minor severity, the most severely problematic clusters being characterized by higher levels of dysfunctional impulsivity, more dysexecutive symptoms and higher levels of perceived stress. Self-Directedness seems to reflect the deficit of prefrontal systems in the regulation of behavior, as well as in emotion and impulse control. It is proposed that evaluation of the personality is more useful than the mere assessment of symptoms for classifying addicts, determining their needs and designing a therapeutic itinerary. PMID:23241716

  5. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance.

    PubMed

    Calder, Philip C

    2015-04-01

    Inflammation is a condition which contributes to a range of human diseases. It involves a multitude of cell types, chemical mediators, and interactions. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 (n-3) fatty acids found in oily fish and fish oil supplements. These fatty acids are able to partly inhibit a number of aspects of inflammation including leukocyte chemotaxis, adhesion molecule expression and leukocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid, production of inflammatory cytokines, and T-helper 1 lymphocyte reactivity. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of marine n-3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes, activation of the anti-inflammatory transcription factor peroxisome proliferator activated receptor γ and binding to the G protein coupled receptor GPR120. These mechanisms are interlinked, although the full extent of this is not yet elucidated. Animal experiments demonstrate benefit from marine n-3 fatty acids in models of rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and asthma. Clinical trials of fish oil in RA demonstrate benefit, but clinical trials of fish oil in IBD and asthma are inconsistent with no overall clear evidence of efficacy. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance". PMID:25149823

  6. Analysis of Clinically Relevant Factors for Pulmonary Hypertension in Maintenance Hemodialysis Patients.

    PubMed

    Shen, Shen; Sun, Qianmei

    2015-01-01

    BACKGROUND Pulmonary hypertension (PH) is common in patients with maintenance hemodialysis (MHD) and is associated with high mortality. This study analyzed clinically relevant factors for pulmonary hypertension in MHD patients and the effect of serum pentraxin3 (PTX3) in the pathogenesis of PH to provide the basis for early diagnosis and treatment of MHD patients with PH. MATERIAL AND METHODS This study included 60 MHD patients (group A) and 30 healthy controls (group B). Group A was further divided into PH and non-PH groups. Clinical characteristics, auxiliary examination results and serum PTX3 level of the PH and non-PH groups were compared. Binary logistic regression was used to assess the risk factors for PH in MHD patients. ROC curve was applied to evaluate the diagnostic value of PTX3 in PH. RESULTS The incidence rate of PH in MHD patients was 50%, and most presented as mild to moderate. Compared with the non-PH group, patients in PH group presented significantly longer atrial diameter, right ventricular diameter and main pulmonary artery diameter (P<0.05), as well as higher PTX3 and NT-proBNP level. Atrial diameter and PTX3 level were the risk factors for PH in MHD patients. AUC of PTX3 was 0.721 (95%CI: 0.590-0.851, P=0.003). CONCLUSIONS The prevalence of PH was higher in MHD patients and mostly presented as mild to moderate. Such patients often developed heart structural changes and cardiac ultrasound was highly recommended. Serum PTX3 level was significantly elevated and could be used as a marker of PH in MHD patients. PMID:26706606

  7. [Clinical relevance of antidepressant-induced activation syndrome: from a perspective of bipolar spectrum disorder].

    PubMed

    Tanaka, Teruaki; Inoue, Takeshi; Suzuki, Katsuji; Kitaichi, Yuji; Masui, Takuya; Denda, Kenzo; Koyama, Tsukasa

    2007-01-01

    Recent concerns have been raised regarding whether antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) might increase suicidal tendencies and intense debate-rages over the pros and cons of their use. Although systematic reviews and population-based studies have been conducted, a consensus on this association remains to be established. Subsequently, the concept of so-called 'activation syndrome' associated with antidepressants has been accepted without its adequate verification. In the present report, we present our experience of seven cases considered of having 'activation syndrome' brought on by antidepressants, and examine its clinical relevance to bipolar spectrum disorder (Ghaemi, et al., 2001) both symptomatologically and diagnostically. Five patients, diagnosed as having major depressive disorder according to the diagnostic manual (DSM-IV), met the criteria of bipolar spectrum disorder and suffered from activation syndrome following the administration of SSRIs, mainly paroxetine. Similarly, hypomania developed in all five cases with depression; the diagnostic criteria of a hypomanic episode were not met. In the remaining two patients, who were both diagnosed with bipolar disorder, one showed irritability and insomnia through imipramine use, and the another developed a hypomanic and/or a mixed state after the co-administration of fluvoxamine and trazodone. From the results of our examination, 'bipolarity', which is the pivotal factor of bipolar spectrum, might exist behind the phenomenon recognized as activation syndrome, and be revealed by antidepressant treatment, just like manic switching. Moreover, the various problems encountered in the current practice of treating mood disorders, including unipolar-bipolar dichotomy, manic switching by antidepressants, and narrow criteria for a mixed episode, were pointed out a new through this concept of activation syndrome. Actually, the understanding of activation syndrome clinically leads to

  8. Modeling clinically relevant blast parameters based on scaling principles produces functional & histological deficits in rats.

    PubMed

    Turner, Ryan C; Naser, Zachary J; Logsdon, Aric F; DiPasquale, Kenneth H; Jackson, Garrett J; Robson, Matthew J; Gettens, Robert T T; Matsumoto, Rae R; Huber, Jason D; Rosen, Charles L

    2013-10-01

    Blast-induced traumatic brain injury represents a leading cause of injury in modern warfare with injury pathogenesis poorly understood. Preclinical models of blast injury remain poorly standardized across laboratories and the clinical relevance unclear based upon pulmonary injury scaling laws. Models capable of high peak overpressures and of short duration may better replicate clinical exposure when scaling principles are considered. In this work we demonstrate a tabletop shock tube model capable of high peak overpressures and of short duration. By varying the thickness of the polyester membrane, peak overpressure can be controlled. We used membranes with a thickness of 0.003, 0.005, 0.007, and 0.010 in to generate peak reflected overpressures of 31.47, 50.72, 72.05, and 90.10 PSI, respectively. Blast exposure was shown to decrease total activity and produce neural degeneration as indicated by fluoro-jade B staining. Similarly, blast exposure resulted in increased glial activation as indicated by an increase in the number of glial fibrillary acidic protein expressing astrocytes compared to control within the corpus callosum, the region of greatest apparent injury following blast exposure. Similar findings were observed with regard to activated microglia, some of which displayed phagocytic-like morphology within the corpus callosum following blast exposure, particularly with higher peak overpressures. Furthermore, hematoxylin and eosin staining showed the presence of red blood cells within the parenchyma and red, swollen neurons following blast injury. Exposure to blast with 90.10 PSI peak reflected overpressure resulted in immediate mortality associated with extensive intracranial bleeding. This work demonstrates one of the first examples of blast-induced brain injury in the rodent when exposed to a blast wave scaled from human exposure based on scaling principles derived from pulmonary injury lethality curves. PMID:23876514

  9. Evaluation and clinically relevant applications of a fluorescent imaging analog to fluorodeoxyglucose positron emission tomography

    NASA Astrophysics Data System (ADS)

    Sheth, Rahul A.; Josephson, Lee; Mahmood, Umar

    2009-11-01

    A fluorescent analog to 2-deoxy-2 [18F] fluoro-D-glucose position emission tomography (FDG-PET) would allow for the introduction of metabolic imaging into intraoperative and minimally invasive settings. We present through in vitro and in vivo experimentation an evaluation of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG), a fluorescently labeled glucose molecule, as a molecular beacon of glucose utilization. The competitive inhibition of 2-NBDG uptake by excess free glucose is directly compared against FDG uptake inhibition in cultured cells. 2-NBDG uptake in the brain of a mouse experiencing a generalized seizure is measured, as well as in subcutaneously implanted tumors in mice during fed and fasting states. Localization of 2-NBDG into malignant tissues is studied by laser scanning microscopy. The clinical relevance of 2-NBDG imaging is examined by performing fluorescence colonoscopy, and by correlating preoperative FDG-PET with intraoperative fluorescence imaging. 2-NBDG exhibits a similar uptake inhibition to FDG by excess glucose in the growth media. Uptake is significantly increased in the brain of an animal experiencing seizures versus control, and in subcutaneous tumors after the animals are kept nil per os (NPO) for 24 h versus ad libidum feeding. The clinical utility of 2-NBDG is confirmed by the demonstration of very high target-to-background ratios in minimally invasive and intraoperative imaging of malignant lesions. We present an optical analog of FDG-PET to extend the applicability of metabolic imaging to minimally invasive and intraoperative settings.

  10. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance

    PubMed Central

    Ivey, Adam; Huntly, Brian J. P.

    2016-01-01

    Recent major advances in understanding the molecular basis of acute myeloid leukemia (AML) provide a double-edged sword. Although defining the topology and key features of the molecular landscape are fundamental to development of novel treatment approaches and provide opportunities for greater individualization of therapy, confirmation of the genetic complexity presents a huge challenge to successful translation into routine clinical practice. It is now clear that many genes are recurrently mutated in AML; moreover, individual leukemias harbor multiple mutations and are potentially composed of subclones with differing mutational composition, rendering each patient’s AML genetically unique. In order to make sense of the overwhelming mutational data and capitalize on this clinically, it is important to identify (1) critical AML-defining molecular abnormalities that distinguish biological disease entities; (2) mutations, typically arising in subclones, that may influence prognosis but are unlikely to be ideal therapeutic targets; (3) mutations associated with preleukemic clones; and (4) mutations that have been robustly shown to confer independent prognostic information or are therapeutically relevant. The reward of identifying AML-defining molecular lesions present in all leukemic populations (including subclones) has been exemplified by acute promyelocytic leukemia, where successful targeting of the underlying PML-RARα oncoprotein has eliminated the need for chemotherapy for disease cure. Despite the molecular heterogeneity and recognizing that treatment options for other forms of AML are limited, this review will consider the scope for using novel molecular information to improve diagnosis, identify subsets of patients eligible for targeted therapies, refine outcome prediction, and track treatment response. PMID:26660431

  11. Effects of progestins of human proliferative endometrium: an in vitro model of potential clinical relevance.

    PubMed

    Illouz, Séverine; Dales, Jean-Philippe; Sferlazzo, Karine; Garcia, Stéphane; Carpentier-Meunier, Séverine; Boubli, Léon; Lavaut, Marie-Noelle; Charpin, Colette

    2003-10-01

    Endometrium biopsy is a useful indicator of endometrium proliferation and is clinically relevant to diagnose cell proliferation and to evaluate response to progestin treatment and to monitor hormone replacement therapy. The aim of our study was to investigate the in vitro effects of progesterone and synthetic progestins on endometrium explants with a particular focus on estradiol receptor (ER) and progesterone receptor (PR) expression which reflects through cell secretion the hormone treatment efficiency. Most widely used progestagens belonging to three distinctive groups were investigated, i.e, medroxyprogesterone acetate (MPA), norethindrone acetate (NOR) and nomegestrol acetate (TX) which are respectively pregnane, 19-nortestosterone and norpregnane derivatives. We used organ culture from human proliferative endometrium, in which tissue integrity, particularly gland/stroma relationships are preserved. Progestins induce epithelial cell secretion and most effects were observed at the highest concentration tested (10(-7) M) and by TX and MPA on homogeneous and on heterogeneous (including also secretory glands) proliferative endometrium respectively. In these conditions, ER as well as PR expression were decreased on both glandular and stromal cells. In contrast, progesterone at 10(-7) M significantly decreased only PR, in glands and in stroma of homogeneous proliferative endometrium, and just in stroma of heterogeneous endometrium. NOR exhibited less effects. At lower concentrations (10(-8) M, 10(-9) M), significantly less effects were observed by synthetic progestins on proliferative endometrium. The experiments show that the different types of progestins do not exhibit in vitro similar effects. Since progestins variably act on proliferative endometrium, the exposure of endometrium explants to progestins may be a useful tool to predict clinical response to hormone therapy (individual "hormonogram") and to monitor endometrium proliferation. PMID:12964029

  12. Analysis of Clinically Relevant Factors for Pulmonary Hypertension in Maintenance Hemodialysis Patients

    PubMed Central

    Shen, Shen; Sun, Qianmei

    2015-01-01

    Background Pulmonary hypertension (PH) is common in patients with maintenance hemodialysis (MHD) and is associated with high mortality. This study analyzed clinically relevant factors for pulmonary hypertension in MHD patients and the effect of serum pentraxin3 (PTX3) in the pathogenesis of PH to provide the basis for early diagnosis and treatment of MHD patients with PH. Material/Methods This study included 60 MHD patients (group A) and 30 healthy controls (group B). Group A was further divided into PH and non-PH groups. Clinical characteristics, auxiliary examination results and serum PTX3 level of the PH and non-PH groups were compared. Binary logistic regression was used to assess the risk factors for PH in MHD patients. ROC curve was applied to evaluate the diagnostic value of PTX3 in PH. Results The incidence rate of PH in MHD patients was 50%, and most presented as mild to moderate. Compared with the non-PH group, patients in PH group presented significantly longer atrial diameter, right ventricular diameter and main pulmonary artery diameter (P<0.05), as well as higher PTX3 and NT-proBNP level. Atrial diameter and PTX3 level were the risk factors for PH in MHD patients. AUC of PTX3 was 0.721 (95%CI: 0.590–0.851, P=0.003). Conclusions The prevalence of PH was higher in MHD patients and mostly presented as mild to moderate. Such patients often developed heart structural changes and cardiac ultrasound was highly recommended. Serum PTX3 level was significantly elevated and could be used as a marker of PH in MHD patients. PMID:26706606

  13. Circulating Tumor Cells: Clinically Relevant Molecular Access Based on a Novel CTC Flow Cell

    PubMed Central

    Winer-Jones, Jessamine P.; Vahidi, Behrad; Arquilevich, Norma; Fang, Cong; Ferguson, Samuel; Harkins, Darren; Hill, Cory; Klem, Erich; Pagano, Paul C.; Peasley, Chrissy; Romero, Juan; Shartle, Robert; Vasko, Robert C.; Strauss, William M.; Dempsey, Paul W.

    2014-01-01

    clinically relevant genetic profiling of CTCs. PMID:24489774

  14. HLA Class I and II Blocks Are Associated to Susceptibility, Clinical Subtypes and Autoantibodies in Mexican Systemic Sclerosis (SSc) Patients

    PubMed Central

    Rodriguez-Reyna, Tatiana S.; Mercado-Velázquez, Pamela; Yu, Neng; Alosco, Sharon; Ohashi, Marina; Lebedeva, Tatiana; Cruz-Lagunas, Alfredo; Núñez-Álvarez, Carlos; Vargas-Alarcón, Gilberto; Granados, Julio; Zúñiga, Joaquin; Yunis, Edmond

    2015-01-01

    Introduction Human leukocyte antigen (HLA) polymorphism studies in Systemic Sclerosis (SSc) have yielded variable results. These studies need to consider the genetic admixture of the studied population. Here we used our previously reported definition of genetic admixture of Mexicans using HLA class I and II DNA blocks to map genetic susceptibility to develop SSc and its complications. Methods We included 159 patients from a cohort of Mexican Mestizo SSc patients. We performed clinical evaluation, obtained SSc-associated antibodies, and determined HLA class I and class II alleles using sequence-based, high-resolution techniques to evaluate the contribution of these genes to SSc susceptibility, their correlation with the clinical and autoantibody profile and the prevalence of Amerindian, Caucasian and African alleles, blocks and haplotypes in this population. Results Our study revealed that class I block HLA-C*12:03-B*18:01 was important to map susceptibility to diffuse cutaneous (dc) SSc, HLA-C*07:01-B*08:01 block to map the susceptibility role of HLA-B*08:01 to develop SSc, and the C*07:02-B*39:05 and C*07:02-B*39:06 blocks to map the protective role of C*07:02 in SSc. We also confirmed previous associations of HLA-DRB1*11:04 and –DRB1*01 to susceptibility to develop SSc. Importantly, we mapped the protective role of DQB1*03:01 using three Amerindian blocks. We also found a significant association for the presence of anti-Topoisomerase I antibody with HLA-DQB1*04:02, present in an Amerindian block (DRB1*08:02-DQB1*04:02), and we found several alleles associated to internal organ damage. The admixture estimations revealed a lower proportion of the Amerindian genetic component among SSc patients. Conclusion This is the first report of the diversity of HLA class I and II alleles and haplotypes Mexican patients with SSc. Our findings suggest that HLA class I and class II genes contribute to the protection and susceptibility to develop SSc and its different clinical

  15. Locating Relevant Patient Information in Electronic Health Record Data Using Representations of Clinical Concepts and Database Structures

    PubMed Central

    Pan, Xuequn; Cimino, James J.

    2014-01-01

    Clinicians and clinical researchers often seek information in electronic health records (EHRs) that are relevant to some concept of interest, such as a disease or finding. The heterogeneous nature of EHRs can complicate retrieval, risking incomplete results. We frame this problem as the presence of two gaps: 1) a gap between clinical concepts and their representations in EHR data and 2) a gap between data representations and their locations within EHR data structures. We bridge these gaps with a knowledge structure that comprises relationships among clinical concepts (including concepts of interest and concepts that may be instantiated in EHR data) and relationships between clinical concepts and the database structures. We make use of available knowledge resources to develop a reproducible, scalable process for creating a knowledge base that can support automated query expansion from a clinical concept to all relevant EHR data. PMID:25954405

  16. Development of a new microtiter plate format for clinically relevant assays.

    PubMed

    Piletska, Elena V; Piletsky, Stanislav S; Whitcombe, Michael J; Chianella, Iva; Piletsky, Sergey A

    2012-02-21

    A new format for the microtiter plate-based assays was proposed. The novelty involves the use of disk-shaped inserts for immobilization of biological and chemical reagents. The internal opening of the disks allows measurements of the reactions by standard microtiter plate readers without any additional steps involving liquid handling. Ideally the plate end-users just have to add the sample and take the measurement without any need of multiple reagent additions or transfer of the liquid to a different plate. The novel assay format also allows handling of reagents which are not soluble in an aqueous environment. As a proof of concept we describe here several model reactions which are compatible with microtiter plate format, such as monitoring enzymatic reactions catalyzed by glucose oxidase (GOx) and urease, measurements of proteins by BCA assay, analysis of pH, and concentration of antioxidants. The "mix and match" approach in the disk-shape format allows multiplexing and could be particularly useful for high throughput screening. One of the potential application areas for this novel assay format could be in a multianalyte system for measurement of clinically relevant analytes in primary care. PMID:22264028

  17. Clinical Relevance and Mechanisms of Antagonism Between the BMP and Activin/TGF-β Signaling Pathways.

    PubMed

    Hudnall, Aaron M; Arthur, Jon W; Lowery, Jonathan W

    2016-07-01

    The transforming growth factor β (TGF-β) superfamily is a large group of signaling molecules that participate in embryogenesis, organogenesis, and tissue homeostasis. These molecules are present in all animal genomes. Dysfunction in the regulation or activity of this superfamily's components underlies numerous human diseases and developmental defects. There are 2 distinct arms downstream of the TGF-β superfamily ligands-the bone morphogenetic protein (BMP) and activin/TGF-β signaling pathways-and these 2 responses can oppose one another's effects, most notably in disease states. However, studies have commonly focused on a single arm of the TGF-β superfamily, and the antagonism between these pathways is unknown in most physiologic and pathologic contexts. In this review, the authors summarize the clinically relevant scenarios in which the BMP and activin/TGF-β pathways reportedly oppose one another and identify several molecular mechanisms proposed to mediate this interaction. Particular attention is paid to experimental findings that may be informative to human pathology to highlight potential therapeutic approaches for future investigation. PMID:27367950

  18. Presence and Persistence of Viable, Clinically Relevant Legionella pneumophila Bacteria in Garden Soil in the Netherlands

    PubMed Central

    van Heijnsbergen, E.; van Deursen, A.; Bouwknegt, M.; Bruin, J. P.; Schalk, J. A. C.

    2016-01-01

    ABSTRACT Garden soils were investigated as reservoirs and potential sources of pathogenic Legionella bacteria. Legionella bacteria were detected in 22 of 177 garden soil samples (12%) by amoebal coculture. Of these 22 Legionella-positive soil samples, seven contained Legionella pneumophila. Several other species were found, including the pathogenic Legionella longbeachae (4 gardens) and Legionella sainthelensi (9 gardens). The L. pneumophila isolates comprised 15 different sequence types (STs), and eight of these STs were previously isolated from patients according to the European Working Group for Legionella Infections (EWGLI) database. Six gardens that were found to be positive for L. pneumophila were resampled after several months, and in three gardens, L. pneumophila was again isolated. One of these gardens was resampled four times throughout the year and was found to be positive for L. pneumophila on all occasions. IMPORTANCE Tracking the source of infection for sporadic cases of Legionnaires' disease (LD) has proven to be hard. L. pneumophila ST47, the sequence type that is most frequently isolated from LD patients in the Netherlands, is rarely found in potential environmental sources. As L. pneumophila ST47 was previously isolated from a garden soil sample during an outbreak investigation, garden soils were investigated as reservoirs and potential sources of pathogenic Legionella bacteria. The detection of viable, clinically relevant Legionella strains indicates that garden soil is a potential source of Legionella bacteria, and future research should assess the public health implication of the presence of L. pneumophila in garden soil. PMID:27316958

  19. Silica desiccant packets for storage and transport of Streptococcus pneumoniae and other clinically relevant species.

    PubMed

    Pell, Casey L; Williams, Melanie J; Dunne, Eileen M; Porter, Barbara D; Satzke, Catherine

    2013-01-01

    Bacterial isolates are often transported between laboratories for research and diagnostic purposes. Silica desiccant packets (SDPs), which are inexpensive and do not require freezing, were evaluated for storage and recovery of bacterial isolates. Conditions such as inoculum size, swab type and temperature of storage were investigated using ten Streptococcus pneumoniae isolates. The optimized protocol was then tested using 49 additional S. pneumoniae isolates representing 40 serogroups. Overall, S. pneumoniae growth was considered satisfactory (>100 colony forming units) for 98/109 (89.9%) and 20/20 (100%) swabs after 14 days at room temperature or 28 days at 4° C, respectively. Storage in SDPs did not impact on the ability of S. pneumoniae isolates to be subsequently serotyped. When the survival of nine other clinically relevant bacterial species was tested, seven were viable after 28 days at room temperature, the exceptions being Neisseria gonorrhoeae and Haemophilus influenzae. SDPs are suitable for transport and short-term storage of bacterial species including S. pneumoniae. PMID:23940811

  20. Update on the Human Broad Tapeworm (Genus Diphyllobothrium), Including Clinical Relevance

    PubMed Central

    Scholz, Tomáš; Garcia, Hector H.; Kuchta, Roman; Wicht, Barbara

    2009-01-01

    Summary: Tapeworms (Cestoda) continue to be an important cause of morbidity in humans worldwide. Diphyllobothriosis, a human disease caused by tapeworms of the genus Diphyllobothrium, is the most important fish-borne zoonosis caused by a cestode parasite. Up to 20 million humans are estimated to be infected worldwide. Besides humans, definitive hosts of Diphyllobothrium include piscivorous birds and mammals, which represent a significant zoonotic reservoir. The second intermediate hosts include both freshwater and marine fish, especially anadromous species such as salmonids. The zoonosis occurs most commonly in countries where the consumption of raw or marinated fish is a frequent practice. Due to the increasing popularity of dishes utilizing uncooked fish, numerous cases of human infections have appeared recently, even in the most developed countries. As many as 14 valid species of Diphyllobothrium can cause human diphyllobothriosis, with D. latum and D. nihonkaiense being the most important pathogens. In this paper, all taxa from humans reported are reviewed, with brief information on their life history and their current distribution. Data on diagnostics, epidemiology, clinical relevance, and control of the disease are also summarized. The importance of reliable identification of human-infecting species with molecular tools (sequences of mitochondrial genes) as well as the necessity of epidemiological studies aimed at determining the sources of infections are pointed out. PMID:19136438

  1. Evolving Anisotropy and Degree of Elastolytic Insult in Abdominal Aortic Aneurysms: Potential Clinical Relevance?

    PubMed Central

    Wilson, John S.; Humphrey, J.D.

    2014-01-01

    Accurately estimating patient-specific rupture risk remains a primary challenge in timing interventions for abdominal aortic aneurysms (AAAs). By re-analyzing published biaxial mechanical testing data from surgically repaired human AAAs, material anisotropy emerged as a potentially important determinant of patient-specific lesion progression. That is, based on a new classification scheme, we discovered that anisotropic aneurysmal specimens correlated with increased patient age at surgery when compared with more isotropic specimens (79.7 vs. 70.9 years, p<0.002), despite no significant difference in maximum diameter. Furthermore, using an idealized axisymmetric, finite-element growth and remodeling model of AAA progression, we found that both the initial axial extent of elastin loss and ongoing damage to elastin in the shoulder region of the AAA directly affected the degree of anisotropy as the lesion evolved, with more extensive insults increasing the anisotropy. This effect appeared to be mediated by alterations in axial loading and subsequent differences in orientation of deposited collagen fibers. While the observed increased age before surgical intervention may suggest a potential benefit of anisotropic remodeling, future biaxial tests coupled with pre-surgical data on expansion rates and detailed theoretical analyses of the biostability of a lesion as a function of anisotropy will be required to verify its clinical relevance to patient-specific rupture risk. PMID:25086482

  2. Anatomical Description and Clinical Relevance of a Rare Variation in the Mesenteric Arterial Arcade Pattern

    PubMed Central

    Hansdak, Ranjeeta; Thakur, Avinash; Mehta, Vandana; Rath, Gayatri

    2015-01-01

    Solitary vascular variations of the mesenteric arteries are extremely rare and have been seldom reported in the past. The aim of this study is to emphasize the anatomical and clinical relevance of one such rare variation of inferior mesenteric artery (IMA). The current case anomaly was incidentally observed while guiding the undergraduate medical students in the dissection of the mesenteric region of the abdomen in an Indian cadaver. An Accessory left colic artery was seen to be branching off from the Inferior Mesenteric artery and further dividing into two transverse branches which took part in the formation of arterial arc for the perfusion of the transverse and the descending colon. Awareness of such aberrant branches of Inferior Mesenteric artery helps in optimal selection of the mode of treatment or operative planning. Additionally, this knowledge minimizes possible iatrogenic injuries resulting from surgeries. Moreover, surgical anatomy of anomalous branches of Inferior Mesenteric artery is extremely essential for planning and successfully executing reconstructive procedures using these branches as pedicles for the transposed part of the colon. PMID:26435936

  3. A linear-actuated torsional device to replicate clinically relevant spiral fractures in long bones.

    PubMed

    Edwards, W Brent; Troy, Karen L

    2012-09-01

    To better understand the mechanisms underlying spiral fracture we would like to carry out biomechanical tests of long bones loaded in torsion to failure. A device was fabricated to perform torsional tests of long bones using a single-axis linear actuator. The principal operation of the device was to transform the vertical displacement of a material testing machine's linear actuator into rotational movement using a spur gear and rack system. Accuracy and precision of the device were quantified using cast-acrylic rods with known torque-rotation behavior. Cadaveric experimentation was used to replicate a clinically relevant spiral fracture in eleven human proximal tibiae; strain-gage data were recorded for a single specimen. The device had an experimental error of less than 0.2 Nm and was repeatable to within 0.3%. Strain gage data were in line with those expected from pure torsion and the cadaveric tibiae illustrated spiral fractures at ultimate torque and rotation values of 130.6 +/- 53.2 Nm and 8.3 +/- 1.5 degrees, respectively. Ultimate torque was highly correlated with DXA assessed bone mineral density (r = 0.87; p < 0.00 1). The device presented is applicable to any torsional testing of long bone when only a single-axis linear actuator is available. PMID:23025174

  4. Clinical relevance of symptomatic superficial-vein thrombosis extension: lessons from the CALISTO study.

    PubMed

    Leizorovicz, Alain; Becker, François; Buchmüller, Andrea; Quéré, Isabelle; Prandoni, Paolo; Decousus, Hervé

    2013-09-01

    The clinical relevance of symptomatic extension of spontaneous, acute, symptomatic, lower-limb superficial-vein thrombosis (SVT) is debated. We performed a post hoc analysis of a double-blind trial comparing fondaparinux with placebo. The main study outcome was SVT extension by day 77, whether to ≤ 3 cm or > 3 cm from the sapheno-femoral junction (SFJ). All events were objectively confirmed and validated by an adjudication committee. With placebo (n = 1500), symptomatic SVT extension to ≤ 3 cm or > 3 cm from the SFJ occurred in 54 (3.6%) and 56 (3.7%) patients, respectively, inducing comparable medical resource consumption (eg, anticoagulant drugs and SFJ ligation); subsequent deep-vein thrombosis or pulmonary embolism occurred in 9.3% (5/54) and 8.9% (5/56) of patients, respectively. Fondaparinux was associated with lower incidences of SVT extension to ≤ 3 cm (0.3%; 5/1502; P < .001) and > 3 cm (0.8%; 12/1502; P < .001) from the SFJ and reduced related use of medical resources; no subsequent deep-vein thrombosis or pulmonary embolism was observed in fondaparinux patients. Thus, symptomatic extensions are common SVT complications and, whether or not reaching the SFJ, are associated with a significant risk of venous thromboembolic complications and medical resource consumption, all reduced by fondaparinux. PMID:23821661

  5. HIV1-viral protein R (Vpr) mutations: associated phenotypes and relevance for clinical pathologies.

    PubMed

    Soares, Rui; Rocha, Graça; Meliço-Silvestre, António; Gonçalves, Teresa

    2016-09-01

    Over the last 30 years, research into HIV has advanced the knowledge of virus genetics and the development of efficient therapeutic strategies. HIV-1 viral protein R (Vpr) is a specialized and multifunctional protein that plays important roles at multiple stages of the HIV-1 viral life cycle. This protein interacts with a number of cellular and viral proteins and with multiple activities including nuclear transport of the pre-integration complex (PIC) to the nucleus, transcriptional activation, cell cycle arrest at G2/M transition phase and induction of cell death via apoptosis. Specifically, Vpr has been shown to control many host cell functions through a variety of biological processes and by interaction with several cellular pathways. The different functions of Vpr may enhance viral replication and impair the immune system in HIV-1 infected patients. Importantly, functional defects induced by mutations in the Vpr protein correlate with slow disease progression of HIV-infected patients. Vpr is also associated with other concomitant pathologies developed by these patients, which may lead it to be considered as a potential novel therapeutic target. This review will focus on HIV-1 Vpr, mainly on the importance of its structural mutations on the progression of HIV infection, associated phenotypes and relevance for clinical pathologies. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27264019

  6. A Model of Auditory-Cognitive Processing and Relevance to Clinical Applicability.

    PubMed

    Edwards, Brent

    2016-01-01

    Hearing loss and cognitive function interact in both a bottom-up and top-down relationship. Listening effort is tied to these interactions, and models have been developed to explain their relationship. The Ease of Language Understanding model in particular has gained considerable attention in its explanation of the effect of signal distortion on speech understanding. Signal distortion can also affect auditory scene analysis ability, however, resulting in a distorted auditory scene that can affect cognitive function, listening effort, and the allocation of cognitive resources. These effects are explained through an addition to the Ease of Language Understanding model. This model can be generalized to apply to all sounds, not only speech, representing the increased effort required for auditory environmental awareness and other nonspeech auditory tasks. While the authors have measures of speech understanding and cognitive load to quantify these interactions, they are lacking measures of the effect of hearing aid technology on auditory scene analysis ability and how effort and attention varies with the quality of an auditory scene. Additionally, the clinical relevance of hearing aid technology on cognitive function and the application of cognitive measures in hearing aid fittings will be limited until effectiveness is demonstrated in real-world situations. PMID:27355775

  7. Clinical relevance of infections with zoonotic and human oral species of Campylobacter.

    PubMed

    Lee, Soomin; Lee, Jeeyeon; Ha, Jimyeong; Choi, Yukyung; Kim, Sejeong; Lee, Heeyoung; Yoon, Yohan; Choi, Kyoung-Hee

    2016-07-01

    Genus Campylobacter has been recognized as a causative bacterial agent of animal and human diseases. Human Campylobacter infections have caused more concern. Campylobacters can be classified into two groups in terms of their original host: zoonotic and human oral species. The major zoonotic species are Campylobacter jejuni and Campylobacter coli, which mostly reside in the intestines of avian species and are transmitted to humans via consumption of contaminated poultry products, thus causing human gastroenteritis and other diseases as sequelae. The other campylobacters, human oral species, include C. concisus, C. showae, C. gracilis, C. ureolyticus, C. curvus, and C. rectus. These species are isolated from the oral cavity, natural colonization site, but have potential clinical relevance in the periodontal region to varying extent. Two species, C. jejuni and C. coli, are believed to be mainly associated with intestinal diseases, but recent studies suggested that oral Campylobacter species also play a significant role in intestinal diseases. This review offers an outline of the two Campylobacter groups (zoonotic and human oral), their virulence traits, and the associated illnesses including gastroenteritis. PMID:27350611

  8. Clinically-relevant chemotherapy interactions with complementary and alternative medicines in patients with cancer.

    PubMed

    Yap, Kevin Yi-Lwern; See, Cheng Shang; Chan, Alexandre

    2010-01-01

    Complementary and alternative medicines (CAMs), in particular herbal medicines, are commonly used by cancer patients in conjunction with chemotherapy treatment for their anticancer properties and supportive care. However, the effects of many of these herbs are not well-documented due to limited studies done on them. Severe herb-drug interactions (HDIs) have been recorded in some cases, and failure to recognize these harmful HDIs can lead to dire consequences in cancer patients. This study discusses clinically-relevant interactions between anticancer drugs (ACDs) and herbs classified into 7 categories: cancer treatment and prevention, immune-system-related, alopecia, nausea and vomiting, peripheral neuropathy and pain, inflammation, and fatigue. Some promising patents which contain these herbs and thus may manifest these interactions are also presented in this article. Pharmacokinetic interactions involved mainly induction or inhibition of the cytochrome P450 isozymes and p-glycoprotein, while pharmacodynamic interactions were related to increased risks of central nervous system-related effects, hepatotoxicity and bleeding, among others. Clinicians should be vigilant when treating cancer patients who take CAMs with concurrent chemotherapy since they face a high risk of HDIs. These HDIs can be minimized or avoided by selecting herb-drug pairs which are less likely to interact. Furthermore, close monitoring of pharmacological effects and plasma drug levels should be carried out to avoid toxicity and ensure adequate chemotherapeutic coverage in patients with cancer. PMID:20653549

  9. A clinically relevant model of perinatal global ischemic brain damage in rats.

    PubMed

    Yang, Ting; Zhuang, Lei; Terrando, Niccolò; Wu, Xinmin; Jonhson, Mark R; Maze, Mervyn; Ma, Daqing

    2011-04-01

    We have designed a clinically relevant model of perinatal asphyxia providing intrapartum hypoxia in rats. On gestation day 22 SD rats were anesthetized and the uterine horns were exteriorized and placed in a water bath at 37°C for up to 20min. After this, pups were delivered from the uterus and manually stimulated to initiate breathing in an incubator at 37°C for 1 h in air. Brains were harvested and stained with cresyl violet, caspase-3, and TUNEL to detect morphological and apoptotic changes on postnatal days (PND) 1, 3, and 7. Separate cohorts were maintained until PND 50 and tested for learning and memory using Morris water maze (WM). Survival rate was decreased with longer hypoxic time, and 100% mortality was noted when hypoxia time was beyond 18min. Apoptosis was increased with the duration of hypoxia with neuronal loss and cell shrinkage in the CA1 of hippocampus. The time taken for the juveniles to locate the hidden platform during WM was increased in animals subjected to hypoxia. These data demonstrate that perinatal ischemic injury leads to neuronal death in the hippocampus and long-lasting cognitive dysfunction. This model mimics hypoxic ischemic encephalopathy in humans and may be appropriate for investigating therapeutic interventions. PMID:21281606

  10. Parkinson's Disease with Fatigue: Clinical Characteristics and Potential Mechanisms Relevant to α-Synuclein Oligomer

    PubMed Central

    Zuo, Li-Jun; Yu, Shu-Yang; Wang, Fang; Hu, Yang; Piao, Ying-Shan; Du, Yang; Lian, Teng-Hong; Wang, Rui-Dan; Yu, Qiu-Jin; Wang, Ya-Jie; Wang, Xiao-Min; Chan, Piu; Chen, Sheng-Di; Wang, Yongjun

    2016-01-01

    Background and Purpose The aim of this study was to identify the clinical characteristics and potential mechanisms relevant to pathological proteins in Parkinson's disease (PD) patients who experience fatigue. Methods PD patients (n=102) were evaluated using a fatigue severity scale and scales for motor and nonmotor symptoms. The levels of three pathological proteins—α-synuclein oligomer, β-amyloid (Aβ)1-42, and tau—were measured in 102 cerebrospinal fluid (CSF) samples from these PD patients. Linear regression analyses were performed between fatigue score and the CSF levels of the above-listed pathological proteins in PD patients. Results The frequency of fatigue in the PD patients was 62.75%. The fatigue group had worse motor symptoms and anxiety, depression, and autonomic dysfunction. The CSF level of α-synuclein oligomer was higher and that of Aβ1-42 was lower in the fatigue group than in the non-fatigue group. In multiple linear regression analyses, fatigue severity was significantly and positively correlated with the α-synuclein oligomer level in the CSF of PD patients, after adjusting for confounders. Conclusions PD patients experience a high frequency of fatigue. PD patients with fatigue have worse motor and part nonmotor symptoms. Fatigue in PD patients is associated with an increased α-synuclein oligomer level in the CSF. PMID:26869370

  11. Renal Transporter-Mediated Drug-Drug Interactions: Are They Clinically Relevant?

    PubMed

    Lepist, Eve-Irene; Ray, Adrian S

    2016-07-01

    The kidney, through the distinct processes of passive glomerular filtration and active tubular secretion, plays an important role in the elimination of numerous endobiotics (eg, hormones, metabolites), toxins, nutrients, and drugs. Renal transport pathways mediating active tubular secretion and reabsorption in the proximal tubule are complex, involving apical and basolateral transporters acting in concert. Detailed studies of the molecular mechanisms of net active tubular secretion have established the involvement of multiple transporters with overlapping substrate specificity mediating competing secretion and reabsorption pathways. Although drug interactions arising from inhibition of renal transporters are rare relative to other mechanisms, they can involve commonly administered drugs (eg, cimetidine, metformin), may be underappreciated due to muted effects on plasma pharmacokinetics relative to tissue levels, can affect narrow-therapeutic-index medications (eg, antiarrhythmic, oncology medications), and may disproportionately affect sensitive populations where polypharmacy is common (eg, the elderly, diabetics). In particular, there is the potential for larger-magnitude interactions in subjects with reduced glomerular filtration rates due to the increased relative contribution of tubular secretion. The assessment of additional endpoints in drug-drug interaction studies including pharmacodynamics, positron emission tomography imaging, and metabolomics promises to expand our understanding of the clinical relevance of renal drug interactions. PMID:27385181

  12. Analysis of clinically relevant mechanical and thermal characteristics of titanium foam spinal implants during drilling.

    PubMed

    Ito, Kiyoshi; Horiuchi, Tetsuyoshi; Murata, Takahiro; Hongo, Kazuhiro

    2015-09-01

    Although high biocompatibility promotes the use of titanium (Ti) alloy in spinal implants, this material shows high stiffness, which is an issue for removal by drilling. The recently developed, porous Ti foam implants, which have shown enhanced osteoformation, may overcome this flaw. Thus, this study aimed to compare the mechanical and thermal characteristics of Ti-foam (80 % porosity) and conventional Ti alloy (0 % porosity) implants drilled in clinically relevant conditions. Mechanical properties were analyzed by measuring axial and torque forces using a pressure sensor with a drill of 2.5-mm diameter at a rotation frequency of 20 Hz. Thermography was used to evaluate the heat generated by a diamond burr attached to a high-speed (80,000 rpm) drill. The torque and axial strengths of Ti foam (13.63 ± 1.43 and 82.60 ± 7.78 N, respectively) were significantly lower (P = 0.001) than those of Ti alloy (73.58 ± 13.60 and 850.72 ± 146.99 N, respectively). Furthermore, irrigation reduced the area of local heating for Ti foam to 56-82 % of that for Ti alloy, indicating lower thermal conductivity. These data suggest that the use of Ti foam implants may be advantageous in cases with a probability of implant drilling in the future. PMID:26395362

  13. Using 7 cm immobilized pH gradient strips to determine levels of clinically relevant proteins in wheat grain extracts

    PubMed Central

    Fekecsová, Sona; Danchenko, Maksym; Uvackova, Lubica; Skultety, Ludovit; Hajduch, Martin

    2015-01-01

    The aim of the work was to test a relatively simple proteomics approach based on phenol extraction and two-dimensional gel electrophoresis (2-DE) with 7 cm immobilized pH gradient strips for the determination of clinically relevant proteins in wheat grain. Using this approach, 157 2-DE spots were quantified in biological triplicate, out of which 55 were identified by matrix-assisted laser desorption/ionization – time of flight tandem mass spectrometry. Clinically relevant proteins associated with celiac disease, wheat dependent exercise induced anaphylaxis, baker’s asthma, and food allergy, were detected in 24 2-DE spots. However, alcohol-soluble gliadins were not detected with this approach. The comparison with a recent quantitative study suggested that gel-based and gel-free proteomics approaches are complementary for the detection and quantification of clinically relevant proteins in wheat grain. PMID:26124766

  14. Clinical Utility of Subtyping Binge Eating Disorder by History of Anorexia or Bulimia Nervosa in a Treatment Sample

    PubMed Central

    Utzinger, Linsey M.; Mitchell, James E.; Cao, Li; Crosby, Ross D.; Crow, Scott J.; Wonderlich, Stephen A.; Peterson, Carol B.

    2016-01-01

    Objective This study examined whether having a history of anorexia nervosa (AN) or bulimia nervosa (BN) is associated with response to treatment in adults with binge eating disorder (BED). Method Data from 189 adults diagnosed with BED who were randomly assigned to one of three group cognitive-behavioral (CBT) treatments were analyzed to compare those with and without a history of AN/BN. Results A total of 16% of the sample had a history of AN/BN. The BED subgroup with a history of AN/BN presented with higher rates of mood disorders and greater eating-related symptom severity at baseline. Participants with a history of AN/BN also had higher global eating disorder (ED) symptoms at end of treatment (EOT), and more frequent objective binge-eating episodes at EOT and 12-month follow-up. Discussion These findings suggest that in adults with BED, a history of AN/BN is predictive of greater eating-related symptom severity following group-based CBT and poorer short- and long-term binge-eating outcomes. These findings suggest that considering ED history in the treatment of adults with BED may be clinically useful. PMID:25959549

  15. Alteration of prolyl oligopeptidase and activated α-2-macroglobulin in multiple sclerosis subtypes and in the clinically isolated syndrome.

    PubMed

    Tenorio-Laranga, Jofre; Peltonen, Iida; Keskitalo, Salla; Duran-Torres, Gilberto; Natarajan, Renuka; Männistö, Pekka T; Nurmi, Antti; Vartiainen, Nina; Airas, Laura; Elovaara, Irina; García-Horsman, J Arturo

    2013-06-15

    Prolyl oligopeptidase (PREP) has been considered as a drug target for the treatment of neurodegenerative diseases. In plasma, PREP has been found altered in several disorders of the central nervous system including multiple sclerosis (MS). Oxidative stress and the levels of an endogenous plasma PREP inhibitor have been proposed to decrease PREP activity in MS. In this work, we measured the circulating levels of PREP in patients suffering of relapsing remitting (RR), secondary progressive (SP), primary progressive (PP) MS, and in subjects with clinically isolated syndrome (CIS). We found a significantly lower PREP activity in plasma of RRMS as well as in PPMS patients and a trend to reduced activity in subjects diagnosed with CIS, compared to controls. No signs of oxidative inactivation of PREP, and no correlation with the endogenous PREP inhibitor, identified as activated α-2-macroglobulin (α2M*), were observed in any of the patients studied. However, a significant decrease of α2M* was recorded in MS. In cell cultures, we found that PREP specifically stimulates immune active cells possibly by modifying the levels of fibrinogen β, thymosin β4, and collagen. Our results open new lines of research on the role of PREP and α2M* in MS, aiming to relate them to the diagnosis and prognosis of this devastating disease. PMID:23643808

  16. The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers | Office of Cancer Genomics

    Cancer.gov

    Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We characterized the global A-to-I RNA editing profiles of 6,236 patient samples of 17 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions.

  17. Subtypes of medulloblastoma have distinct developmental origins

    PubMed Central

    Gibson, Paul; Tong, Yiai; Robinson, Giles; Thompson, Margaret C.; Currle, D. Spencer; Eden, Christopher; Kranenburg, Tanya A.; Hogg, Twala; Poppleton, Helen; Martin, Julie; Finkelstein, David; Pounds, Stanley; Weiss, Aaron; Patay, Zoltan; Scoggins, Matthew; Ogg, Robert; Pei, Yanxin; Yang, Zeng-Jie; Brun, Sonja; Lee, Youngsoo; Zindy, Frederique; Lindsey, Janet C.; Taketo, Makoto M.; Boop, Frederick A.; Sanford, Robert A.; Gajjar, Amar; Clifford, Steven C.; Roussel, Martine F.; McKinnon, Peter J.; Gutmann, David H.; Ellison, David W.; Wechsler-Reya, Robert; Gilbertson, Richard J.

    2010-01-01

    Medulloblastoma encompasses a collection of clinically and molecularly diverse tumor subtypes that together comprise the most common malignant childhood brain tumor1–4. These tumors are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) following aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH-subtype)3–8. The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here, we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT-subtype)1,3,4, arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumors infiltrate the dorsal brainstem, while SHH-subtype tumors are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem that included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice and in 15% of cases in which Tp53 was concurrently deleted, progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this

  18. The clinical relevance of axillary reverse mapping (ARM): study protocol for a randomized controlled trial

    PubMed Central

    2013-01-01

    Background Axillary lymph node dissection (ALND) in patients with breast cancer has the potential to induce side-effects, including upper-limb lymphedema. Axillary reverse mapping (ARM) is a technique that enables discrimination of the lymphatic drainage of the breast from that of the upper limb in the axillary lymph node (LN) basin. If lymphedema is caused by removing these lymphatics and nodes in the upper limb, the possibility of identifying these lymphatics would enable surgeons to preserve them. The aim of this study is to determine the clinical relevance of selective axillary LN and lymphatic preservation by means of ARM. To minimize the risk of overlooking tumor-positive ARM nodes and the associated risk of undertreatment, we will only include patients with a tumor-positive sentinel lymph node (SLN). Patients who are candidates for ALND because of a proven positive axillary LN at clinical examination can be included in a registration study. Methods/design The study will enroll 280 patients diagnosed with SLN biopsy-proven metastasis of invasive breast cancer with an indication for a completion ALND. Patients will be randomized to undergo standard ALND or an ALND in which the ARM nodes and their corresponding lymphatics will be left in situ. Primary outcome is the presence of axillary surgery-related lymphedema at 6, 12, and 24 months post-operatively, measured by the water-displacement method. Secondary outcome measures include pain, paresthesia, numbness, and loss of shoulder mobility, quality of life, and axillary recurrence risk. Discussion The benefit of ALND in patients with a positive SLN is a subject of debate. For many patients, an ALND will remain the treatment of choice. This multicenter randomized trial will provide evidence of whether or not axillary LN preservation by means of ARM decreases the side-effects of an ALND. Enrolment of patients will start in April 2013 in five breast-cancer centers in the Netherlands, and is expected to conclude by

  19. Clinical relevance of circulating cell-free microRNAs in ovarian cancer.

    PubMed

    Nakamura, Koji; Sawada, Kenjiro; Yoshimura, Akihiko; Kinose, Yasuto; Nakatsuka, Erika; Kimura, Tadashi

    2016-01-01

    Ovarian cancer is the leading cause of death among gynecologic malignancies. Since ovarian cancer develops asymptomatically, it is often diagnosed at an advanced and incurable stage. Despite many years of research, there is still a lack of reliable diagnostic markers and methods for early detection and screening. Recently, it was discovered that cell-free microRNAs (miRNAs) circulate in the body fluids of healthy and diseased patients, suggesting that they may serve as a novel diagnostic marker. This review summarizes the current knowledge regarding the potential clinical relevance of circulating cell-free miRNA for ovarian cancer diagnosis, prognosis, and therapeutics. Despite the high levels of ribonucleases in many types of body fluids, most of the circulating miRNAs are packaged in microvesicles, exosomes, or apoptotic bodies, are binding to RNA-binding protein such as argonaute 2 or lipoprotein complexes, and are thus highly stable. Cell-free miRNA signatures are known to be parallel to those from the originating tumor cells, indicating that circulating miRNA profiles accurately reflect the tumor profiles. Since it is well established that the dysregulation of miRNAs is involved in the tumorigenesis of ovarian cancer, cell-free miRNAs circulating in body fluids such as serum, plasma, whole blood, and urine may reflect not only the existence of ovarian cancer but also tumor histology, stage, and prognoses of the patients. Several groups have successfully demonstrated that serum or plasma miRNAs are able to discriminate patients with ovarian cancer patients from healthy controls, suggesting that the addition of these miRNAs to current testing regimens may improve diagnosis accuracies for ovarian cancer. Furthermore, recent studies have revealed that changes in levels of cell-free circulating miRNAs are associated with the condition of cancer patients. Discrepancies between the results across studies due to the lack of an established endogenous miRNA control to

  20. Pharmacokinetics of (synthetic) cannabinoids in pigs and their relevance for clinical and forensic toxicology.

    PubMed

    Schaefer, Nadine; Wojtyniak, Jan-Georg; Kettner, Mattias; Schlote, Julia; Laschke, Matthias W; Ewald, Andreas H; Lehr, Thorsten; Menger, Michael D; Maurer, Hans H; Schmidt, Peter H

    2016-06-24

    Synthetic cannabinoids (SCs) are gaining increasing importance in clinical and forensic toxicology. They are consumed without any preclinical safety studies. Thus, controlled human pharmacokinetic (PK) studies are not allowed, although being relevant for interpretation of analytical results in cases of misuse or poisoning. As alternative, in a controlled animal experiment, six pigs per drug received a single intravenous dose of 200μg/kg BW each of Δ(9)-tetrahydrocannabinol (THC), 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210), or 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4). In addition, six pigs received a combination of the three drugs with the identical dose each. The drugs were determined in serum using LC-MS/MS. A population (pop) PK analysis revealed that a three-compartment model described best the PK data of all three cannabinoids. Central volumes of distribution were estimated at 0.29L/kg, 0.20L/kg, and 0.67L/kg for THC, JWH-210, and RCS-4, respectively. Clearances were 0.042L/min/kg, 0.048L/min/kg, and 0.093L/min/kg for THC, JWH-210, and RCS-4, respectively. The popPK THC pig model was upscaled to humans using allometric techniques. Comparison with published human data revealed that the concentration-time profiles could successfully be predicted. These findings indicate that pigs in conjunction with PK modeling technique may serve as a tool for prediction of human PK of SCs. PMID:27113702

  1. Molecular Mechanisms of Glutamine Synthetase Mutations that Lead to Clinically Relevant Pathologies.

    PubMed

    Frieg, Benedikt; Görg, Boris; Homeyer, Nadine; Keitel, Verena; Häussinger, Dieter; Gohlke, Holger

    2016-02-01

    Glutamine synthetase (GS) catalyzes ATP-dependent ligation of ammonia and glutamate to glutamine. Two mutations of human GS (R324C and R341C) were connected to congenital glutamine deficiency with severe brain malformations resulting in neonatal death. Another GS mutation (R324S) was identified in a neurologically compromised patient. However, the molecular mechanisms underlying the impairment of GS activity by these mutations have remained elusive. Molecular dynamics simulations, free energy calculations, and rigidity analyses suggest that all three mutations influence the first step of GS catalytic cycle. The R324S and R324C mutations deteriorate GS catalytic activity due to loss of direct interactions with ATP. As to R324S, indirect, water-mediated interactions reduce this effect, which may explain the suggested higher GS residual activity. The R341C mutation weakens ATP binding by destabilizing the interacting residue R340 in the apo state of GS. Additionally, the mutation is predicted to result in a significant destabilization of helix H8, which should negatively affect glutamate binding. This prediction was tested in HEK293 cells overexpressing GS by dot-blot analysis: Structural stability of H8 was impaired through mutation of amino acids interacting with R341, as indicated by a loss of masking of an epitope in the glutamate binding pocket for a monoclonal anti-GS antibody by L-methionine-S-sulfoximine; in contrast, cells transfected with wild type GS showed the masking. Our analyses reveal complex molecular effects underlying impaired GS catalytic activity in three clinically relevant mutants. Our findings could stimulate the development of ATP binding-enhancing molecules by which the R324S mutant can be repaired extrinsically. PMID:26836257

  2. Molecular Mechanisms of Glutamine Synthetase Mutations that Lead to Clinically Relevant Pathologies

    PubMed Central

    Frieg, Benedikt; Görg, Boris; Homeyer, Nadine; Keitel, Verena; Häussinger, Dieter; Gohlke, Holger

    2016-01-01

    Glutamine synthetase (GS) catalyzes ATP-dependent ligation of ammonia and glutamate to glutamine. Two mutations of human GS (R324C and R341C) were connected to congenital glutamine deficiency with severe brain malformations resulting in neonatal death. Another GS mutation (R324S) was identified in a neurologically compromised patient. However, the molecular mechanisms underlying the impairment of GS activity by these mutations have remained elusive. Molecular dynamics simulations, free energy calculations, and rigidity analyses suggest that all three mutations influence the first step of GS catalytic cycle. The R324S and R324C mutations deteriorate GS catalytic activity due to loss of direct interactions with ATP. As to R324S, indirect, water-mediated interactions reduce this effect, which may explain the suggested higher GS residual activity. The R341C mutation weakens ATP binding by destabilizing the interacting residue R340 in the apo state of GS. Additionally, the mutation is predicted to result in a significant destabilization of helix H8, which should negatively affect glutamate binding. This prediction was tested in HEK293 cells overexpressing GS by dot-blot analysis: Structural stability of H8 was impaired through mutation of amino acids interacting with R341, as indicated by a loss of masking of an epitope in the glutamate binding pocket for a monoclonal anti-GS antibody by L-methionine-S-sulfoximine; in contrast, cells transfected with wild type GS showed the masking. Our analyses reveal complex molecular effects underlying impaired GS catalytic activity in three clinically relevant mutants. Our findings could stimulate the development of ATP binding-enhancing molecules by which the R324S mutant can be repaired extrinsically. PMID:26836257

  3. Clinical Relevance of Disturbances of Sleep and Vigilance in Major Depressive Disorder: A Review

    PubMed Central

    Murck, Harald; Post, Anke

    2010-01-01

    Objective: The primary objective of this article is to provide a concise review of the clinical relevance of sleep and vigilance in major depressive disorder. Data Sources: PubMed was reviewed (1990–2009) and English-language articles were identified using the key words sleep and depression and sleep and antidepressants. Secondary searches included articles cited in sources identified by the primary search. Study Selection: The narrative review provides brief descriptions of the normal physiology of sleep and changes associated with depression, as well as the impact of various treatments on these processes. Data Synthesis: Although it has long been known that sleep disturbances are an important characteristic of depression, relatively few studies have been conducted with the newer-generation antidepressants. Neither of the most widely used classes of antidepressants, the selective serotonin reuptake inhibitors and the serotonin-norepinephrine reuptake inhibitors, have particularly beneficial effects on sleep and, among the medications that reliably improve sleep efficiency, including mirtazapine and the tricyclic antidepressants, problems with daytime sedation can offset therapeutic benefit. Despite relatively widespread use, trazodone has not been demonstrated to be an effective and safe hypnotic in patients taking other antidepressants. For many patients, ongoing concomitant treatment with benzodiazepines and related drugs is the preferred option, again without convincing empirical support of longer-term efficacy. Among newer and investigational antidepressants, agomelatine shows promise with respect to both overall safety and effects on insomnia, although possible negative effects on liver function warrant further study. Conclusions: Sleep disturbances are a significant aspect of depressive syndromes, and relief of insomnia remains an important unmet need in antidepressant therapeutics. Development of a well-tolerated antidepressant medication that rapidly

  4. What's New in the Medicine Cabinet?: A Panoramic Review of Clinically Relevant Information for the Busy Dermatologist.

    PubMed

    Del Rosso, James Q; Zeichner, Joshua

    2014-01-01

    This article is the first in a periodic series of therapeutic topics with short reviews gleaned from major dermatology meetings, especially Scientific Poster Sessions, and is designed to provide information that may assist the readers in adapting information from the literature to their clinical practice. The topics covered in this issue are discussions of the clinical relevance of newer information about acne pathophysiology, acne in adult women, and topical corticosteroid spray formulations for chronic plaque psoriasis. PMID:24563693

  5. Clonal spread and interspecies transmission of clinically relevant ESBL-producing Escherichia coli of ST410--another successful pandemic clone?

    PubMed

    Schaufler, Katharina; Semmler, Torsten; Wieler, Lothar H; Wöhrmann, Michael; Baddam, Ramani; Ahmed, Niyaz; Müller, Kerstin; Kola, Axel; Fruth, Angelika; Ewers, Christa; Guenther, Sebastian

    2016-01-01

    Clinically relevant extended-spectrum beta-lactamase (ESBL)-producing multi-resistant Escherichia coli have been on the rise for years. Initially restricted to mostly a clinical context, recent findings prove their prevalence in extraclinical settings independent of the original occurrence of antimicrobial resistance in the environment. To get further insights into the complex ecology of potentially clinically relevant ESBL-producing E. coli, 24 isolates from wild birds in Berlin, Germany, and 40 ESBL-producing human clinical E. coli isolates were comparatively analyzed. Isolates of ST410 occurred in both sample groups (six). In addition, three ESBL-producing E. coli isolates of ST410 from environmental dog feces and one clinical dog isolate were included. All 10 isolates were clonally analyzed showing almost identical macrorestriction patterns. They were chosen for whole-genome sequencing revealing that the whole-genome content of these 10 E. coli isolates showed a very high genetic similarity, differing by low numbers of single nucleotide polymorphisms only. This study gives initial evidence for a recent interspecies transmission of a new successful clone of ST410 E. coli between wildlife, humans, companion animals and the environment. The results underline the zoonotic potential of clinically relevant multi-resistant bacteria found in the environment as well as the mandatory nature of the 'One Health' approach. PMID:26656065

  6. Switching from posaconazole suspension to tablets increases serum drug levels in leukemia patients without clinically relevant hepatotoxicity.

    PubMed

    Jung, Dong Sik; Tverdek, Frank P; Kontoyiannis, Dimitrios P

    2014-11-01

    We evaluated posaconazole serum concentrations and hepatotoxicity in 12 leukemia patients who transitioned from posaconazole suspension to tablets. Patients who switched to tablets had significantly increased posaconazole concentrations (median: suspension, 748 ng/ml; tablet, 1,910 ng/ml; P < 0.01) without clinically relevant hepatotoxicity. PMID:25199774

  7. Clinically relevant depression in old age: An international study with populations from Canada, Latin America and Eastern Europe.

    PubMed

    Ylli, Alban; Miszkurka, Malgorzata; Phillips, Susan P; Guralnik, Jack; Deshpande, Nandini; Zunzunegui, Maria Victoria

    2016-07-30

    Our aim is to assess cross-national variations in prevalence of clinically relevant depression and to examine the relationships of social and health factors with depression in five diverse populations of older adults, from Canada, Brazil, Colombia and Albania. We used the data from the International Mobility in Aging Study. Clinically relevant depression was defined as a score of ≥16 on the Center for Epidemiologic Study Depression Scale (CES-D). Poisson regressions with robust covariance correction were used to estimate prevalence ratios associated with potential risk factors. Prevalence of clinically relevant depression across research sites varied widely, being consistently higher in women than in men. It was lowest in men from Brazil (6.3%) and highest in women from Albania (46.6%). Low education and insufficient income, living alone, multiple chronic conditions, and poor physical performance were all significantly associated with depression prevalence. Poor physical performance was more strongly associated with depression in men than in women. Similar factors are associated with clinically relevant depression among men and women and across research sites. The large variation in depression prevalence population rates is unexplained by the classical individual factors considered in the study suggesting the impact of country characteristics on depression among older populations. PMID:27183110

  8. Is the Inattentive Subtype of ADHD Different from the Combined/Hyperactive Subtype?

    ERIC Educational Resources Information Center

    Grizenko, Natalie; Paci, Michael; Joober, Ridha

    2010-01-01

    Objective: To compare the ADHD combined/hyperactive subtype (ADHD/CH) to the ADHD inattentive subtype (ADHD/I) on the level of comorbidity, treatment response, and possible etiological factors. Method: A total of 371 clinically referred children diagnosed with ADHD aged between 6 and 12 years are recruited for a double-blind, placebo-controlled…

  9. Identification, classification, and clinical relevance of catalase-negative, gram-positive cocci, excluding the streptococci and enterococci.

    PubMed Central

    Facklam, R; Elliott, J A

    1995-01-01

    Several new genera and species of gram-positive, catalase-negative cocci that can cause infections in humans have been described. Although these bacteria were isolated in the clinical laboratory, they were considered nonpathogenic culture contaminants and were not thought to be the cause of any diseases. Isolation of pure cultures of these bacteria from normally sterile sites has led to the conclusion that these bacteria can be an infrequent cause of infection. This review describes the new bacteria and the procedures useful for clinical laboratories to aid in their identification. The clinical relevance and our experience with the various genera and species are reviewed and discussed. PMID:8665466

  10. Lithogenic activity and clinical relevance of lipids extracted from urines and stones of nephrolithiasis patients.

    PubMed

    Boonla, Chanchai; Youngjermchan, Phantip; Pumpaisanchai, Somkiat; Tungsanga, Kriang; Tosukhowong, Piyaratana

    2011-02-01

    We investigated contents and classes of urinary and stone matrix lipids, and evaluated their clinical relevance in nephrolithiasis patients. Lithogenic role of major lipid classes was explored. Urine (24 h) and stone samples were collected from 47 patients with nephrolithiasis. Control urines were obtained from 29 healthy subjects. Urinary 8-hydroxy-deoxyguanosine (8-OHdG), malondialdehyde (MDA), N-acetyl-β-glucosaminidase (NAG) activity and total proteins were measured. Total lipids were extracted from centrifuged urines (10,000 rpm, 30 min) and stones by chloroform/methanol method. Major classes of lipids were identified using multi-one-dimensional thin-layer chromatography (MOD-TLC). Influence of each lipid class purified from stone matrices on stone formation was evaluated using crystallization and crystal aggregation assays. Urinary NAG activity and 8-OHdG were significantly elevated in nephrolithiasis patients. Total lipids in centrifuged urines of the patients were not significantly different from that of controls. In nephrolithiasis, urinary excretion of total lipids was linearly correlated to urinary MDA, 8-OHdG, NAG activity and total proteins. Lipid contents in stone matrices varied among stone types. Uric acid stone contained lower amount of total lipids than calcium oxalate and magnesium ammonium phosphate stones. MOD-TLC lipid chromatograms of healthy urines, nephrolithiasis urines and stone matrices were obviously different. Triacylglyceride was abundant in urines, but scarcely found in stone matrices. Stone matrices were rich in glycolipids and high-polar lipids (phospholipids/gangliosides). Partially purified glycolipids significantly induced crystal aggregation while cholesterol was a significant inducer of both crystal formation and agglomeration. In conclusion, total lipids in centrifuged urines did not differ between nephrolithiasis and healthy subjects. Our finding suggests that the significant sources of lipids in patients' urine may be

  11. A systematic review on the effect of sweeteners on glycemic response and clinically relevant outcomes

    PubMed Central

    2011-01-01

    Background The major metabolic complications of obesity and type 2 diabetes may be prevented and managed with dietary modification. The use of sweeteners that provide little or no calories may help to achieve this objective. Methods We did a systematic review and network meta-analysis of the comparative effectiveness of sweetener additives using Bayesian techniques. MEDLINE, EMBASE, CENTRAL and CAB Global were searched to January 2011. Randomized trials comparing sweeteners in obese, diabetic, and healthy populations were selected. Outcomes of interest included weight change, energy intake, lipids, glycated hemoglobin, markers of insulin resistance and glycemic response. Evidence-based items potentially indicating risk of bias were assessed. Results Of 3,666 citations, we identified 53 eligible randomized controlled trials with 1,126 participants. In diabetic participants, fructose reduced 2-hour blood glucose concentrations by 4.81 mmol/L (95% CI 3.29, 6.34) compared to glucose. Two-hour blood glucose concentration data comparing hypocaloric sweeteners to sucrose or high fructose corn syrup were inconclusive. Based on two ≤10-week trials, we found that non-caloric sweeteners reduced energy intake compared to the sucrose groups by approximately 250-500 kcal/day (95% CI 153, 806). One trial found that participants in the non-caloric sweetener group had a decrease in body mass index compared to an increase in body mass index in the sucrose group (-0.40 vs 0.50 kg/m2, and -1.00 vs 1.60 kg/m2, respectively). No randomized controlled trials showed that high fructose corn syrup or fructose increased levels of cholesterol relative to other sweeteners. Conclusions Considering the public health importance of obesity and its consequences; the clearly relevant role of diet in the pathogenesis and maintenance of obesity; and the billions of dollars spent on non-caloric sweeteners, little high-quality clinical research has been done. Studies are needed to determine the role

  12. Rapid, accurate, and comparative differentiation of clinically and industrially relevant microorganisms via multiple vibrational spectroscopic fingerprinting.

    PubMed

    Muhamadali, Howbeer; Subaihi, Abdu; Mohammadtaheri, Mahsa; Xu, Yun; Ellis, David I; Ramanathan, Rajesh; Bansal, Vipul; Goodacre, Royston

    2016-08-15

    Despite the fact that various microorganisms (e.g., bacteria, fungi, viruses, etc.) have been linked with infectious diseases, their crucial role towards sustaining life on Earth is undeniable. The huge biodiversity, combined with the wide range of biochemical capabilities of these organisms, have always been the driving force behind their large number of current, and, as of yet, undiscovered future applications. The presence of such diversity could be said to expedite the need for the development of rapid, accurate and sensitive techniques which allow for the detection, differentiation, identification and classification of such organisms. In this study, we employed Fourier transform infrared (FT-IR), Raman, and surface enhanced Raman scattering (SERS) spectroscopies, as molecular whole-organism fingerprinting techniques, combined with multivariate statistical analysis approaches for the classification of a range of industrial, environmental or clinically relevant bacteria (P. aeruginosa, P. putida, E. coli, E. faecium, S. lividans, B. subtilis, B. cereus) and yeast (S. cerevisiae). Principal components-discriminant function analysis (PC-DFA) scores plots of the spectral data collected from all three techniques allowed for the clear differentiation of all the samples down to sub-species level. The partial least squares-discriminant analysis (PLS-DA) models generated using the SERS spectral data displayed lower accuracy (74.9%) when compared to those obtained from conventional Raman (97.8%) and FT-IR (96.2%) analyses. In addition, whilst background fluorescence was detected in Raman spectra for S. cerevisiae, this fluorescence was quenched when applying SERS to the same species, and conversely SERS appeared to introduce strong fluorescence when analysing P. putida. It is also worth noting that FT-IR analysis provided spectral data of high quality and reproducibility for the whole sample set, suggesting its applicability to a wider range of samples, and perhaps the

  13. Designing Ontology-based Patterns for the Representation of the Time-Relevant Eligibility Criteria of Clinical Protocols.

    PubMed

    Crowe, Christopher L; Tao, Cui

    2015-01-01

    The amount of time and money required to screen patients for clinical trial and guideline eligibility presents the need for an automated screening process to streamline clinical trial enrollment and guideline implementation. This paper introduces an ontology-based approach for defining a set of patterns that can be used to represent various types of time-relevant eligibility criteria that may appear in clinical protocols. With a focus only on temporal requirements, we examined the criteria of 600 protocols and extracted a set of 37 representative time-relevant eligibility criteria. 16 patterns were designed to represent these criteria. Using a test set of an additional 100 protocols, it was found that these 16 patterns could sufficiently represent 98.5% of the time-relevant criteria. After the time-relevant criteria are modeled by these patterns, it will allow the potential to (1) use natural language processing algorithms to automatically extract temporal constraints from criteria; and (2) develop computer rules and queries to automate the processing of the criteria. PMID:26306263

  14. Designing Ontology-based Patterns for the Representation of the Time-Relevant Eligibility Criteria of Clinical Protocols

    PubMed Central

    Crowe, Christopher L.; Tao, Cui

    2015-01-01

    The amount of time and money required to screen patients for clinical trial and guideline eligibility presents the need for an automated screening process to streamline clinical trial enrollment and guideline implementation. This paper introduces an ontology-based approach for defining a set of patterns that can be used to represent various types of time-relevant eligibility criteria that may appear in clinical protocols. With a focus only on temporal requirements, we examined the criteria of 600 protocols and extracted a set of 37 representative time-relevant eligibility criteria. 16 patterns were designed to represent these criteria. Using a test set of an additional 100 protocols, it was found that these 16 patterns could sufficiently represent 98.5% of the time-relevant criteria. After the time-relevant criteria are modeled by these patterns, it will allow the potential to (1) use natural language processing algorithms to automatically extract temporal constraints from criteria; and (2) develop computer rules and queries to automate the processing of the criteria. PMID:26306263

  15. eMBI: Boosting Gene Expression-based Clustering for Cancer Subtypes.

    PubMed

    Chang, Zheng; Wang, Zhenjia; Ashby, Cody; Zhou, Chuan; Li, Guojun; Zhang, Shuzhong; Huang, Xiuzhen

    2014-01-01

    Identifying clinically relevant subtypes of a cancer using gene expression data is a challenging and important problem in medicine, and is a necessary premise to provide specific and efficient treatments for patients of different subtypes. Matrix factorization provides a solution by finding checker-board patterns in the matrices of gene expression data. In the context of gene expression profiles of cancer patients, these checkerboard patterns correspond to genes that are up- or down-regulated in patients with particular cancer subtypes. Recently, a new matrix factorization framework for biclustering called Maximum Block Improvement (MBI) is proposed; however, it still suffers several problems when applied to cancer gene expression data analysis. In this study, we developed many effective strategies to improve MBI and designed a new program called enhanced MBI (eMBI), which is more effective and efficient to identify cancer subtypes. Our tests on several gene expression profiling datasets of cancer patients consistently indicate that eMBI achieves significant improvements in comparison with MBI, in terms of cancer subtype prediction accuracy, robustness, and running time. In addition, the performance of eMBI is much better than another widely used matrix factorization method called nonnegative matrix factorization (NMF) and the method of hierarchical clustering, which is often the first choice of clinical analysts in practice. PMID:25374455

  16. Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post- chemotherapy tissues

    PubMed Central

    Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

    2015-01-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens. PMID:26515599

  17. Usefulness of an Implantable Loop Recorder to Detect Clinically Relevant Arrhythmias in Patients With Advanced Fabry Cardiomyopathy.

    PubMed

    Weidemann, Frank; Maier, Sebastian K G; Störk, Stefan; Brunner, Thomas; Liu, Dan; Hu, Kai; Seydelmann, Nora; Schneider, Andreas; Becher, Jan; Canan-Kühl, Sima; Blaschke, Daniela; Bijnens, Bart; Ertl, Georg; Wanner, Christoph; Nordbeck, Peter

    2016-07-15

    Patients with genetic cardiomyopathy that involves myocardial hypertrophy often develop clinically relevant arrhythmias that increase the risk of sudden death. Consequently, guidelines for medical device therapy were established for hypertrophic cardiomyopathy, but not for conditions with only anecdotal evidence of arrhythmias, like Fabry cardiomyopathy. Patients with Fabry cardiomyopathy progressively develop myocardial fibrosis, and sudden cardiac death occurs regularly. Because 24-hour Holter electrocardiograms (ECGs) might not detect clinically important arrhythmias, we tested an implanted loop recorder for continuous heart rhythm surveillance and determined its impact on therapy. This prospective study included 16 patients (12 men) with advanced Fabry cardiomyopathy, relevant hypertrophy, and replacement fibrosis in "loco typico." No patients previously exhibited clinically relevant arrhythmias on Holter ECGs. Patients received an implantable loop recorder and were prospectively followed with telemedicine for a median of 1.2 years (range 0.3 to 2.0 years). The primary end point was a clinically meaningful event, which required a therapy change, captured with the loop recorder. Patients submitted data regularly (14 ± 11 times per month). During follow-up, 21 events were detected (including 4 asystole, i.e., ECG pauses ≥3 seconds) and 7 bradycardia events; 5 episodes of intermittent atrial fibrillation (>3 minutes) and 5 episodes of ventricular tachycardia (3 sustained and 2 nonsustained). Subsequently, as defined in the primary end point, 15 events leaded to a change of therapy. These patients required therapy with a pacemaker or cardioverter-defibrillator implantation and/or anticoagulation therapy for atrial fibrillation. In conclusion, clinically relevant arrhythmias that require further device and/or medical therapy are often missed with Holter ECGs in patients with advanced stage Fabry cardiomyopathy, but they can be detected by telemonitoring with

  18. Staying Tuned to Research in Implicit Cognition: Relevance for Clinical Practice with Anxiety Disorders

    ERIC Educational Resources Information Center

    Teachman, Bethany A.; Woody, Sheila R.

    2004-01-01

    There is a rich theoretical literature on the automatic nature of fear and anxiety and the role of maladaptive fear schemata. Information processing biases, both implicit and explicit, have been demonstrated among clinically anxious persons, but the clinical applications of this work have not been well developed. This article highlights empirical…

  19. High-Fidelity Patient Simulators to Expose Undergraduate Students to the Clinical Relevance of Physiology Concepts

    ERIC Educational Resources Information Center

    Harris, David M.; Bellew, Christine; Cheng, Zixi J.; Cendán, Juan C.; Kibble, Jonathan D.

    2014-01-01

    The use of high-fidelity patient simulators (HFPSs) has expanded throughout medical, nursing, and allied health professions education in the last decades. These manikins can be programmed to represent pathological states and are used to teach clinical skills as well as clinical reasoning. First, the students are typically oriented either to the…

  20. Perspectives on Creating Clinically Relevant Blast Models for Mild Traumatic Brain Injury and Post Traumatic Stress Disorder Symptoms

    PubMed Central

    Brenner, Lisa A.; Bahraini, Nazanin; Hernández, Theresa D.

    2012-01-01

    Military personnel are returning from Iraq and Afghanistan and reporting non-specific physical (somatic), behavioral, psychological, and cognitive symptoms. Many of these symptoms are frequently associated with mild traumatic brain injury (mTBI) and/or post traumatic stress disorder (PTSD). Despite significant attention and advances in assessment and intervention for these two conditions, challenges persist. To address this, clinically relevant blast models are essential in the full characterization of this type of injury, as well as in the testing and identification of potential treatment strategies. In this publication, existing diagnostic challenges and current treatment practices for mTBI and/or PTSD will be summarized, along with suggestions regarding how what has been learned from existing models of PTSD and traditional mechanism (e.g., non-blast) traumatic brain injury can be used to facilitate the development of clinically relevant blast models. PMID:22408635

  1. Clinically relevant interaction between warfarin and scuppernongs, a quercetin containing muscadine grape: continued questions surrounding flavonoid-induced warfarin interactions

    PubMed Central

    Woodward, Christopher J; Deyo, Zachariah M; Donahue, Katrina E; Deal, Allison M; Hawes, Emily M

    2014-01-01

    We present a case of clinically relevant and probable interaction between warfarin and scuppernongs in a 73-year-old woman where ingestion of scuppernongs, a variety of quercetin-containing muscadine grapes, over a period of 2 months was associated with elevations in the International Normalised Ratio to supratherapeutic levels. While muscadine grapes and specifically scuppernongs are found primarily in Southeastern USA, the flavonoid in questionand quercetin is found worldwide as a dietary supplement. PMID:24966255

  2. Time-driven activity-based costing in an outpatient clinic environment: development, relevance and managerial impact.

    PubMed

    Demeere, Nathalie; Stouthuysen, Kristof; Roodhooft, Filip

    2009-10-01

    Healthcare managers are continuously urged to provide better patient services at a lower cost. To cope with these cost pressures, healthcare management needs to improve its understanding of the relevant cost drivers. Through a case study, we show how to perform a time-driven activity-based costing of five outpatient clinic's departments and provide evidence of the benefits of such an analysis. PMID:19505741

  3. Subtypes of Alcohol Dependence in a Nationally Representative Sample

    PubMed Central

    Moss, Howard B.; Chen, Chiung M.; Yi, Hsiao-ye

    2007-01-01

    Objective The authors sought to empirically derive Alcohol Dependence (AD) subtypes based on clinical characteristics using data from a nationally representative epidemiological survey. Method A sample of 1,484 respondents to the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) with past-year AD was subjected to latent class analysis in order to identify homogeneous subtypes. Results The best fitting model was a five-cluster solution. The largest cluster (Cluster 1: ~31%) was comprised of young adults, who rarely sought help for drinking, had moderately high levels of periodic heavy drinking, relatively low rates of comorbidity, and the lowest rate of multigenerational AD (~ 22%). In contrast, Clusters 4 and 5 (~21% and 9%, respectively) had substantial rates of multigenerational AD (53% and 77%, respectively), had the most severe AD criteria profile, were associated with both comorbid psychiatric and other drug use disorders, lower levels of psychosocial functioning, and had engaged in significant help-seeking. Clusters 2 and 3 (~19% each) had the latest onset, the lowest rates of periodic heavy drinking, medium/low levels of comorbidity, moderate levels of help-seeking, and higher psychosocial functioning. Conclusion Five distinct subtypes of AD were derived, distinguishable on the basis of family history, age of AD onset, endorsement of DSM-IV AUD criteria, and the presence of comorbid psychiatric and substance use disorders. These clinically relevant subtypes, derived from the general population, may enhance our understanding of the etiology, treatment, natural history, and prevention of AD and inform the DSM-V research agenda. PMID:17597309

  4. [Molecular Subtypes of Gastric Cancer].

    PubMed

    Hatogai, Ken; Doi, Toshihiko

    2016-03-01

    Gastric cancer has been classified based on the pathological characteristics including microscopic configuration and growth pattern. Although these classifications have been used in studies investigating prognosis and recurrence pattern, they are not considered for decisions regarding the therapeutic strategy. In the ToGA study, trastuzumab, an anti-HER2 monoclonal antibody, demonstrated clinical efficacy for gastric cancer with HER2 overexpression or HER2 gene amplification. Based on these findings of the ToGA study, the definition of HER2-positive gastric cancer was established. Thereafter, several molecular targeted agents, including agents targeting other receptor tyrosine kinases, have been investigated in gastric cancer. However, to date no biomarker, except HER2, has been established. Based on the recent technological development in the field of gene analysis, a comprehensive molecular evaluation of gastric cancer was performed as part of The Cancer Genome Atlas (TCGA) project, and a new molecular classification was proposed that divided gastric cancer into the following 4 subtypes: tumors positive for Epstein-Barr virus, microsatellite instability tumors, genomically stable tumors, and tumors with chromosomal instability. Each subtype has specific molecular alterations including gene mutation and amplification, DNA methylation, and protein overexpression. Additionally, some subtypes were suggested to be correlated with the clinicopathological characteristics or as targets of some molecular targeted agents that are currently under development. The new molecular classification is expected to be a roadmap for patient stratification and clinical trials on molecular targeted therapies in gastric cancer. PMID:27067842

  5. Clinical relevance of autophagic therapy in cancer: Investigating the current trends, challenges, and future prospects.

    PubMed

    Mukhopadhyay, Subhadip; Sinha, Niharika; Das, Durgesh Nandini; Panda, Prashanta Kumar; Naik, Prajna Paramita; Bhutia, Sujit Kumar

    2016-08-01

    Oncophagy (cancer-related autophagy) has a complex dual character at different stages of tumor progression. It remains an important clinical problem to unravel the reasons that propel the shift in the role of oncophagy from tumor inhibition to a protective mechanism that shields full-blown malignancy. Most treatment strategies emphasize curbing protective oncophagy while triggering the oncophagy that is lethal to tumor cells. In this review, we focus on the trends in current therapeutics as well as various challenges in clinical trials to address the oncophagic dilemma and evaluate the potential of these developing therapies. A detailed analysis of the clinical and pre-clinical scenario of the anticancer medicines highlights the various inducers and inhibitors of autophagy. The ways in which tumor stage, the microenvironment and combination drug treatment continue to play an important tactical role are discussed. Moreover, autophagy targets also play a crucial role in developing the best possible solution to this oncophagy paradox. In this review, we provide a comprehensive update on the current clinical impact of autophagy-based cancer therapeutic drugs and try to lessen the gap between translational medicine and clinical science. PMID:26743568

  6. Clinical proteomic biomarkers: relevant issues on study design & technical considerations in biomarker development

    PubMed Central

    2014-01-01

    Biomarker research is continuously expanding in the field of clinical proteomics. A combination of different proteomic–based methodologies can be applied depending on the specific clinical context of use. Moreover, current advancements in proteomic analytical platforms are leading to an expansion of biomarker candidates that can be identified. Specifically, mass spectrometric techniques could provide highly valuable tools for biomarker research. Ideally, these advances could provide with biomarkers that are clinically applicable for disease diagnosis and/ or prognosis. Unfortunately, in general the biomarker candidates fail to be implemented in clinical decision making. To improve on this current situation, a well-defined study design has to be established driven by a clear clinical need, while several checkpoints between the different phases of discovery, verification and validation have to be passed in order to increase the probability of establishing valid biomarkers. In this review, we summarize the technical proteomic platforms that are available along the different stages in the biomarker discovery pipeline, exemplified by clinical applications in the field of bladder cancer biomarker research. PMID:24679154

  7. Clinical Performance of a New Soluble CD14-Subtype Immunochromatographic Test for Whole Blood Compared with Chemiluminescent Enzyme Immunoassay: Use of Quantitative Soluble CD14-Subtype Immunochromatographic Tests for the Diagnosis of Sepsis

    PubMed Central

    Sato, Masayuki; Takahashi, Gaku; Shibata, Shigehiro; Onodera, Makoto; Suzuki, Yasushi; Inoue, Yoshihiro; Endo, Shigeatsu

    2015-01-01

    We previously reported that a soluble CD14-subtype (sCD14-ST) immunochromatographic test (ICT) for plasma is more convenient than chemiluminescent enzyme immunoassay (CLEIA), but plasma separation makes bedside measurements difficult. We developed a new sCD14-ST ICT for whole blood and investigated whether quantitative determinations of sCD14-ST by ICT were useful for diagnosing sepsis and severe sepsis/septic shock. We studied 20 patients who fulfilled two or more systemic inflammatory response syndrome (SIRS) criteria and 32 patients who had been diagnosed with sepsis or severe sepsis/septic shock. Whole blood was collected on day 0 (on admission) and day 7, and the sCD14-ST concentration was quantitatively measured by CLEIA and ICT for whole blood. The patients’ Acute Physiology and Chronic Health Evaluation (APACHE) II, Sequential Organ Failure Assessment (SOFA), and Mortality in Emergency Department Sepsis (MEDS) scores were also calculated. The cut-off values obtained by the quantitative measurements made by ICT were 464.5 pg/mL for sepsis and 762.7 pg/mL for severe sepsis/septic shock (P < 0.0001). A Bland–Altman plot showed that no fixed bias or proportional bias was detected between CLEIA and quantitative ICT for whole blood. sCD14-ST concentrations were significantly correlated with APACHE II, SOFA, and MEDS scores (P < 0.0001). These results suggest that the new sCD14-ST ICT for whole blood may be a useful tool for the convenient, rapid bedside diagnosis and treatment of sepsis. PMID:26623644

  8. Miniature Swine as a Clinically Relevant Model of Graft-Versus-Host Disease

    PubMed Central

    Duran-Struuck, Raimon; Huang, Christene A; Orf, Katherine; Bronson, Roderick T; Sachs, David H; Spitzer, Thomas R

    2015-01-01

    Miniature swine provide a preclinical model of hematopoietic cell transplantation (HCT) for studies of graft-versus-host disease. HCT between MHC-matched or ‑mismatched pigs can be performed to mimic clinical scenarios with outcomes that closely resemble those observed in human HCT recipients. With myeloablative conditioning, HCT across MHC barriers is typically fatal, with pigs developing severe (grade III or IV) GVHD involving the gastrointestinal tract, liver, and skin. Unlike rodent models, miniature swine provide an opportunity to perform extended longitudinal studies on individual animals, because multiple tissue biopsies can be harvested without the need for euthanasia. In addition, we have developed a swine GVHD scoring system that parallels that used in the human clinical setting. Given the similarities of GVHD in pigs and humans, we hope that the use of this scoring system facilitates clinical and scientific discourse between the laboratory and the clinic. We anticipate that results of swine studies will support the development of new strategies to improve the identification and treatment of GVHD in clinical HCT scenarios. PMID:26473348

  9. Improving quality and safety of hospital care: a reappraisal and an agenda for clinically relevant reform.

    PubMed

    Scott, I A; Poole, P J; Jayathissa, S

    2008-01-01

    Improving quality and safety of hospital care is now firmly on the health-care agenda. Various agencies within different levels of government are pursuing initiatives targeting hospitals and health professionals that aim to identify, quantify and lessen medical error and suboptimal care. Although not denying the value of such 'top-down' initiatives, more attention may be needed towards 'bottom-up' reform led by practising physicians. This article discusses factors integral to delivery of safe, high-quality care grouped under six themes: clinical workforce, teamwork, patient participation in care decisions, indications for health-care interventions, clinical governance and information systems. Following this discussion, a 20-point action plan is proposed as an agenda for future reform capable of being led by physicians, together with some cautionary notes about relying too heavily on information technology, use of non-clinical quality personnel and quantitative evaluative approaches as primary strategies in improving quality. PMID:18190414

  10. The relevance of clinical balance assessment tools to differentiate balance deficits

    PubMed Central

    Mancini, Martina; Horak, Fay B

    2011-01-01

    Control of balance is complex and involves maintaining postures, facilitating movement, and recovering equilibrium. Balance control consists of controlling the body center of mass over its limits of stability. Clinical balance assessment can help assess fall risk and/or determine the underlying reasons for balance disorders. Most functional balance assessment scales assess fall risk and the need for balance rehabilitation but do not differentiate types of balance deficits. A system approach to clinical balance assessment can differentiate different kinds of balance disorders and a physiological approach can determine underlying sensorimotor mechanisms contributing to balance disorders. Objective measures of balance using computerized systems and wearable inertial sensors can bring more sensitive, specific and responsive balance testing to clinical practice. PMID:20485226

  11. A new cognitive evaluation battery for Down syndrome and its relevance for clinical trials

    PubMed Central

    de Sola, Susana; de la Torre, Rafael; Sánchez-Benavides, Gonzalo; Benejam, Bessy; Cuenca-Royo, Aida; del Hoyo, Laura; Rodríguez, Joan; Catuara-Solarz, Silvina; Sanchez-Gutierrez, Judit; Dueñas-Espin, Ivan; Hernandez, Gimena; Peña-Casanova, Jordi; Langohr, Klaus; Videla, Sebastia; Blehaut, Henry; Farre, Magi; Dierssen, Mara; Cuenca-Royo, Aida

    2015-01-01

    The recent prospect of pharmaceutical interventions for cognitive impairment of Down syndrome (DS) has boosted a number of clinical trials in this population. However, running the trials has raised some methodological challenges and questioned the prevailing methodology used to evaluate cognitive functioning of DS individuals. This is usually achieved by comparing DS individuals to matched healthy controls of the same mental age. We propose a new tool, the TESDAD Battery that uses comparison with age-matched typically developed adults. This is an advantageous method for probing the clinical efficacy of DS therapies, allowing the interpretation and prediction of functional outcomes in clinical trials. In our DS population the TESDAD battery permitted a quantitative assessment of cognitive defects, which indicated language dysfunction and deficits in executive function, as the most important contributors to other cognitive and adaptive behavior outcomes as predictors of functional change in DS. Concretely, auditory comprehension and functional academics showed the highest potential as end-point measures of therapeutic intervention for clinical trials: the former as a cognitive key target for therapeutic intervention, and the latter as a primary functional outcome measure of clinical efficacy. Our results also emphasize the need to explore the modulating effects of IQ, gender and age on cognitive enhancing treatments. Noticeably, women performed significantly better than men of the same age and IQ in most cognitive tests, with the most consistent differences occurring in memory and executive functioning and negative trends rarely emerged on quality of life linked to the effect of age after adjusting for IQ and gender. In sum, the TESDAD battery is a useful neurocognitive tool for probing the clinical efficacy of experimental therapies in interventional studies in the DS population suggesting that age-matched controls are advantageous for determining normalization of

  12. A new cognitive evaluation battery for Down syndrome and its relevance for clinical trials.

    PubMed

    de Sola, Susana; de la Torre, Rafael; Sánchez-Benavides, Gonzalo; Benejam, Bessy; Cuenca-Royo, Aida; Del Hoyo, Laura; Rodríguez, Joan; Catuara-Solarz, Silvina; Sanchez-Gutierrez, Judit; Dueñas-Espin, Ivan; Hernandez, Gimena; Peña-Casanova, Jordi; Langohr, Klaus; Videla, Sebastia; Blehaut, Henry; Farre, Magi; Dierssen, Mara

    2015-01-01

    The recent prospect of pharmaceutical interventions for cognitive impairment of Down syndrome (DS) has boosted a number of clinical trials in this population. However, running the trials has raised some methodological challenges and questioned the prevailing methodology used to evaluate cognitive functioning of DS individuals. This is usually achieved by comparing DS individuals to matched healthy controls of the same mental age. We propose a new tool, the TESDAD Battery that uses comparison with age-matched typically developed adults. This is an advantageous method for probing the clinical efficacy of DS therapies, allowing the interpretation and prediction of functional outcomes in clinical trials. In our DS population the TESDAD battery permitted a quantitative assessment of cognitive defects, which indicated language dysfunction and deficits in executive function, as the most important contributors to other cognitive and adaptive behavior outcomes as predictors of functional change in DS. Concretely, auditory comprehension and functional academics showed the highest potential as end-point measures of therapeutic intervention for clinical trials: the former as a cognitive key target for therapeutic intervention, and the latter as a primary functional outcome measure of clinical efficacy. Our results also emphasize the need to explore the modulating effects of IQ, gender and age on cognitive enhancing treatments. Noticeably, women performed significantly better than men of the same age and IQ in most cognitive tests, with the most consistent differences occurring in memory and executive functioning and negative trends rarely emerged on quality of life linked to the effect of age after adjusting for IQ and gender. In sum, the TESDAD battery is a useful neurocognitive tool for probing the clinical efficacy of experimental therapies in interventional studies in the DS population suggesting that age-matched controls are advantageous for determining normalization of

  13. Prospective study of catalase-positive coryneform organisms in clinical specimens: identification, clinical relevance, and antibiotic susceptibility.

    PubMed

    Lagrou, K; Verhaegen, J; Janssens, M; Wauters, G; Verbist, L

    1998-01-01

    During a 6-month period, all clinical isolates of catalase-positive coryneform organisms, which were isolated during the routine processing of clinical specimens, were characterized in the laboratory of the 1800-bed University Hospital of Leuven. The distribution of the species in the corynebacteria was: Corynebacterium amycolatum 70 (53%), Corynebacterium jeikeium 16 (12%), Corynebacterium striatum 11 (8%), Corynebacterium afermentans 10 (7%), Corynebacterium minutissimum 9 (6%), CDC coryneform group G 4 (3%), Corynebacterium urealyticum 4 (3%), Corynebacterium glucuronolyticum 1 (0.7%), and Corynebacterium xerosis 1 (0.7%). Of the 150 isolates, 37 (25%) were considered to be infection related and the remaining 113 (75%) were of questionable clinical significance. Susceptibility of the corynebacteria to 12 antibiotics active against Gram-positive organisms was evaluated. C. amycolatum, C. jeikeium, and C. urealyticum were multiresistant, but all isolates were susceptible to teicoplanin and vancomycin. Most of the C. amycolatum strains, and all strains of C. jeikeium and C. striatum, were susceptible to the vibrocidal compound O/129. PMID:9488824

  14. [News with clinical relevance from major scientific meetings 2015--Update Urooncology].

    PubMed

    Skrobek, L; Boegemann, M; Hegele, A

    2016-02-01

    What new developments in urooncology were discussed at the 2015 annual meetings of ASCO, EAU, DGU and ESMO? This review summarises news relevant to the daily diagnosis and treatment of prostate, bladder and kidney cancer. While study results seem to change paradigms in the treatment of prostate cancer, particularly in metastatic but still hormone-sensitive stages, immunotherapeutic strategies for the treatment of kidney and urothelial cancer are very promising and might expand the systemic therapeutic options in the years to come. PMID:26916044

  15. [Is "quality of life" a relevant goal in clinical studies of rehabilitation?].

    PubMed

    Ravnborg, Mads; Storr, Lars

    2008-03-01

    By consensus and in accordance with the WHO, the relevant outcomes of rehabilitation are "function" and "social participation". Nevertheless, most physicians will agree that improved Quality of Life (QoL) is the ultimate goal of medicine. Although many well-validated health-related QoL instruments are available, these are generally flawed due to considerable redundancy and lack of consistent responsiveness. Further efforts are required in order to engineer instruments that are in accordance with the WHO-ICF concept, which will make studies of the interaction between "symptoms", "activity", "social participation" and QoL meaningful. PMID:18364174

  16. Microstructural Changes within the Basal Ganglia Differ between Parkinson Disease Subtypes

    PubMed Central

    Nagae, Lidia M.; Honce, Justin M.; Tanabe, Jody; Shelton, Erika; Sillau, Stefan H.; Berman, Brian D.

    2016-01-01

    Diffusion tensor imaging (DTI) of the substantia nigra has shown promise in detecting and quantifying neurodegeneration in Parkinson disease (PD). It remains unknown, however, whether differences in microstructural changes within the basal ganglia underlie PD motor subtypes. We investigated microstructural changes within the basal ganglia of mild to moderately affected PD patients using DTI and sought to determine if microstructural changes differ between the tremor dominant (TD) and postural instability/gait difficulty (PIGD) subtypes. Fractional anisotropy, mean diffusivity, radial, and axial diffusivity were obtained from bilateral caudate, putamen, globus pallidus, and substantia nigra of 21 PD patients (12 TD and 9 PIGD) and 20 age-matched healthy controls. T-tests and ANOVA methods were used to compare PD patients, subtypes, and controls, and Spearman correlations tested for relationships between DTI and clinical measures. We found our cohort of PD patients had reduced fractional anisotropy within the substantia nigra and increased mean and radial diffusivity within the substantia nigra and globus pallidus compared to controls, and that changes within those structures were largely driven by the PIGD subtype. Across all PD patients fractional anisotropy within the substantia nigra correlated with disease stage, while in PIGD patients increased diffusivity within the globus pallidus correlated with disease stage and motor severity. We conclude that PIGD patients have more severely affected microstructural changes within the substantia nigra compared to TD, and that microstructural changes within the globus pallidus may be particularly relevant for the manifestation of the PIGD subtype. PMID:26941615

  17. Determination of Clinically Relevant Content for a Musculoskeletal Anatomy Curriculum for Physical Medicine and Rehabilitation Residents

    ERIC Educational Resources Information Center

    Lisk, Kristina; Flannery, John F.; Loh, Eldon Y.; Richardson, Denyse; Agur, Anne M. R.; Woods, Nicole N.

    2014-01-01

    To address the need for more clinical anatomy training in residency education, many postgraduate programs have implemented structured anatomy courses into their curriculum. Consensus often does not exist on specific content and level of detail of the content that should be included in such curricula. This article describes the use of the Delphi…

  18. [Chronic cervical vagal stimulation. Mechanisms of action and clinical relevance for heart failure].

    PubMed

    Kuschyk, J; Doesch, C; Akin, I; Borggrefe, M; Roeger, S

    2015-11-01

    Increased sympathetic nerve activity and reduced vagal activity are associated with increased mortality in patients after myocardial infarction and patients with chronic heart failure; furthermore, vagal withdrawal has been documented to precede acute decompensation. Experimental studies have indicated that increased parasympathetic activity by means of vagal stimulation may reduce mortality in animal models of postinfarction sudden cardiac death and of chronic heart failure. First clinical results have demonstrated that chronic vagus nerve stimulation in heart failure patients with severe systolic dysfunction appears to be safe and tolerable and may improve the quality of life and left ventricular (LV) function. Vagus nerve stimulation gives rise to these potential clinical benefits by multiple mechanisms of action, including reduced heart rate, restoration of heart rate variability and baroreflex sensitivity, suppression of proinflammatory cytokines and antiarrhythmic effects. First clinical results suggest that vagal nerve stimulation is safe and tolerable and could lead to a marked clinical improvement but discrepancies in the findings due to different study designs warrant further discussion. PMID:26555481

  19. Bridging the Divide: Sustainability and Relevance of a Distance Learning Module for Clinical Officers in Tanzania

    ERIC Educational Resources Information Center

    Brigley, Stephen; Hosein, I.; Myemba, I. R.

    2009-01-01

    This paper reports on work by a team from Wales, supported by UNESCO Cymru-Wales, to develop a distance learning module for Tanzanian clinical officers (COs) on the syndromic management and counselling of sexually transmissible infection (STI) and HIV patients. Preparation included documentary analysis and a questionnaire survey to ascertain COs'…

  20. ClinVar: public archive of interpretations of clinically relevant variants.

    PubMed

    Landrum, Melissa J; Lee, Jennifer M; Benson, Mark; Brown, Garth; Chao, Chen; Chitipiralla, Shanmuga; Gu, Baoshan; Hart, Jennifer; Hoffman, Douglas; Hoover, Jeffrey; Jang, Wonhee; Katz, Kenneth; Ovetsky, Michael; Riley, George; Sethi, Amanjeev; Tully, Ray; Villamarin-Salomon, Ricardo; Rubinstein, Wendy; Maglott, Donna R

    2016-01-01

    ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) at the National Center for Biotechnology Information (NCBI) is a freely available archive for interpretations of clinical significance of variants for reported conditions. The database includes germline and somatic variants of any size, type or genomic location. Interpretations are submitted by clinical testing laboratories, research laboratories, locus-specific databases, OMIM®, GeneReviews™, UniProt, expert panels and practice guidelines. In NCBI's Variation submission portal, submitters upload batch submissions or use the Submission Wizard for single submissions. Each submitted interpretation is assigned an accession number prefixed with SCV. ClinVar staff review validation reports with data types such as HGVS (Human Genome Variation Society) expressions; however, clinical significance is reported directly from submitters. Interpretations are aggregated by variant-condition combination and assigned an accession number prefixed with RCV. Clinical significance is calculated for the aggregate record, indicating consensus or conflict in the submitted interpretations. ClinVar uses data standards, such as HGVS nomenclature for variants and MedGen identifiers for conditions. The data are available on the web as variant-specific views; the entire data set can be downloaded via ftp. Programmatic access for ClinVar records is available through NCBI's E-utilities. Future development includes providing a variant-centric XML archive and a web page for details of SCV submissions. PMID:26582918

  1. ClinVar: public archive of interpretations of clinically relevant variants

    PubMed Central

    Landrum, Melissa J.; Lee, Jennifer M.; Benson, Mark; Brown, Garth; Chao, Chen; Chitipiralla, Shanmuga; Gu, Baoshan; Hart, Jennifer; Hoffman, Douglas; Hoover, Jeffrey; Jang, Wonhee; Katz, Kenneth; Ovetsky, Michael; Riley, George; Sethi, Amanjeev; Tully, Ray; Villamarin-Salomon, Ricardo; Rubinstein, Wendy; Maglott, Donna R.

    2016-01-01

    ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) at the National Center for Biotechnology Information (NCBI) is a freely available archive for interpretations of clinical significance of variants for reported conditions. The database includes germline and somatic variants of any size, type or genomic location. Interpretations are submitted by clinical testing laboratories, research laboratories, locus-specific databases, OMIM®, GeneReviews™, UniProt, expert panels and practice guidelines. In NCBI's Variation submission portal, submitters upload batch submissions or use the Submission Wizard for single submissions. Each submitted interpretation is assigned an accession number prefixed with SCV. ClinVar staff review validation reports with data types such as HGVS (Human Genome Variation Society) expressions; however, clinical significance is reported directly from submitters. Interpretations are aggregated by variant-condition combination and assigned an accession number prefixed with RCV. Clinical significance is calculated for the aggregate record, indicating consensus or conflict in the submitted interpretations. ClinVar uses data standards, such as HGVS nomenclature for variants and MedGen identifiers for conditions. The data are available on the web as variant-specific views; the entire data set can be downloaded via ftp. Programmatic access for ClinVar records is available through NCBI's E-utilities. Future development includes providing a variant-centric XML archive and a web page for details of SCV submissions. PMID:26582918

  2. The relevance of clinical and radiographic features of jaw lesions: A prospective study.

    PubMed

    Araujo, Juliane Piragine; Lemos, Celso Augusto; Miniello, Thais Gimenez; Alves, Fabio Abreu

    2016-01-01

    The study was carried out in a Brazilian population and the aim was to describe the prevalence and the clinic-radiographical features of jaw lesions. In addition, a comparison between the main diagnosis hypothesis and final diagnosis was accessed. A prospective study which evaluated all patients with jaw lesions diagnosed in an Oral Diagnosis Center, between August 2013 and October 2014. A total of 450 patients were observed for the first time, and 130 had some type of jaw lesion. The mean age of the patients was 35.2 years ± 17.86. Among these, 71 were women (54.62%) and 87 were Caucasian (66.92%). The mandible was affected more frequently (71.43%) than the maxilla (28.57%). Swelling and pain were the most frequent clinical signs and symptoms and were observed in 60 (42.85%) and 38 (27.14%) cases, respectively. The panoramic x-ray was the main radiographic exam utilized (88.57%). Radiolucent lesions accounted for 89 cases (63.57%) and the unilocular form was present in 114 cases (81.43%). A total of 93 cases had histopathological analyses and the periapical cyst was the most frequent lesion. In the other 47 lesions, the diagnosis was conducted by clinical and radiographic management. Bone lesions were frequent, being noted on first visit in approximately 30% of patients; in 1/3 of the cases, the diagnoses were completed with a combination of clinical and radiographic exams. PMID:27556683

  3. Aspergillus alabamensis, a New Clinically Relevant Species in the Section Terrei

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Analyzing a large number of clinical and environmental A. terreus isolates representing diverse geographic locations, we propose for the first time a multi locus sequence approach for analyzing species diversity within Section Terrei. Results of the present study employing sequences generated from ...

  4. Cato Guldberg and Peter Waage, the history of the Law of Mass Action, and its relevance to clinical pharmacology.

    PubMed

    Ferner, Robin E; Aronson, Jeffrey K

    2016-01-01

    We have traced the historical link between the Law of Mass Action and clinical pharmacology. The Law evolved from the work of the French chemist Claude Louis Berthollet, was first formulated by Cato Guldberg and Peter Waage in 1864 and later clarified by the Dutch chemist Jacobus van 't Hoff in 1877. It has profoundly influenced our qualitative and quantitative understanding of a number of physiological and pharmacological phenomena. According to the Law of Mass Action, the velocity of a chemical reaction depends on the concentrations of the reactants. At equilibrium the concentrations of the chemicals involved bear a constant relation to each other, described by the equilibrium constant, K. The Law of Mass Action is relevant to various physiological and pharmacological concepts, including concentration-effect curves, dose-response curves, and ligand-receptor binding curves, all of which are important in describing the pharmacological actions of medications, the Langmuir adsorption isotherm, which describes the binding of medications to proteins, activation curves for transmembrane ion transport, enzyme inhibition and the Henderson-Hasselbalch equation, which describes the relation between pH, as a measure of acidity and the concentrations of the contributory acids and bases. Guldberg and Waage recognized the importance of dynamic equilibrium, while others failed to do so. Their ideas, over 150 years old, are embedded in and still relevant to clinical pharmacology. Here we explain the ideas and in a subsequent paper show how they are relevant to understanding adverse drug reactions. PMID:26174880

  5. Subtyping of Breast Cancer by Immunohistochemistry to Investigate a Relationship between Subtype and Short and Long Term Survival: A Collaborative Analysis of Data for 10,159 Cases from 12 Studies

    PubMed Central

    Schmidt, Marjanka K.; Broeks, Annegien; van Leeuwen, Flora E.; Wesseling, Jelle; Cheang, Maggie C.; Gelmon, Karen; Nielsen, Torsten O.; Blomqvist, Carl; Heikkilä, Päivi; Heikkinen, Tuomas; Nevanlinna, Heli; Akslen, Lars A.; Bégin, Louis R.; Foulkes, William D.; Couch, Fergus J.; Wang, Xianshu; Cafourek, Vicky; Olson, Janet E.; Baglietto, Laura; Giles, Graham G.; Severi, Gianluca; McLean, Catriona A.; Southey, Melissa C.; Rakha, Emad; Green, Andrew R.; Ellis, Ian O.; Sherman, Mark E.; Lissowska, Jolanta; Anderson, William F.; Cox, Angela; Cross, Simon S.; Reed, Malcolm W. R.; Provenzano, Elena; Dawson, Sarah-Jane; Dunning, Alison M.; Humphreys, Manjeet; Easton, Douglas F.; García-Closas, Montserrat; Caldas, Carlos; Pharoah, Paul D.; Huntsman, David

    2010-01-01

    setting could have the potential to improve the targeting of adjuvant chemotherapy to those most likely to benefit. The different patterns of mortality over time also suggest important biological differences between the subtypes that may result in differences in response to specific therapies, and that stratification of breast cancers by clinically relevant subtypes in clinical trials is urgently required. Please see later in the article for the Editors' Summary PMID:20520800

  6. The Facts About Sexual (Dys)function in Schizophrenia: An Overview of Clinically Relevant Findings

    PubMed Central

    de Boer, Marrit K.; Castelein, Stynke; Wiersma, Durk; Schoevers, Robert A.; Knegtering, Henderikus

    2015-01-01

    A limited number of studies have evaluated sexual functioning in patients with schizophrenia. Most patients show an interest in sex that differs little from the general population. By contrast, psychiatric symptoms, institutionalization, and psychotropic medication contribute to frequently occurring impairments in sexual functioning. Women with schizophrenia have a better social outcome, longer lasting (sexual) relationships, and more offspring than men with schizophrenia. Still, in both sexes social and interpersonal impairments limit the development of stable sexual relationships. Although patients consider sexual problems to be highly relevant, patients and clinicians not easily discuss these spontaneously, leading to an underestimation of their prevalence and contributing to decreased adherence to treatment. Studies using structured interviews or questionnaires result in many more patients reporting sexual dysfunctions. Although sexual functioning can be impaired by different factors, the use of antipsychotic medication seems to be an important factor. A comparison of different antipsychotics showed high frequencies of sexual dysfunction for risperidone and classical antipsychotics, and lower frequencies for clozapine, olanzapine, quetiapine, and aripiprazole. Postsynaptic dopamine antagonism, prolactin elevation, and α1-receptor blockade may be the most relevant factors in the pathogenesis of antipsychotic-induced sexual dysfunction. Psychosocial strategies to treat antipsychotic-induced sexual dysfunction include psychoeducation and relationship counseling. Pharmacological strategies include lowering the dose or switching to a prolactin sparing antipsychotic. Also, the addition of a dopamine agonist, aripiprazole, or a phosphodiesterase-5 inhibitor has shown some promising results, but evidence is currently scarce. PMID:25721311

  7. [Basic symptoms in schizophrenia, their clinical study and relevance in research].

    PubMed

    Miret, Salvador; Fatjó-Vilas, Mar; Peralta, Víctor; Fañanás, Lourdes

    2016-01-01

    Basic symptoms consist of subtle sub-clinical disturbances subjectively experienced by schizophrenia patients. These are mainly related to drive, affect, thinking and language, perception, memory, motor action, central vegetative functions, control of cognitive processes, and stress tolerance. Initially described by Huber, from a phenomenological approach, basic symptoms are part of the earliest features of schizophrenia, and they can evolve along the course of the disorder. Their assessment during the prodromal phase of the disease (together with ultra-high risk criteria) is one of the 2 main approaches that allow the definition of states of clinical risk for the development of psychosis. The present review provides an updated view of the concept of basic symptoms, highlighting its potential value in establishing neurobiological correlates of interest in aetiopathogenic research. PMID:26774677

  8. Phylogeny of the Clinically Relevant Species of the Emerging Fungus Trichoderma and Their Antifungal Susceptibilities

    PubMed Central

    Sandoval-Denis, Marcelo; Sutton, Deanna A.; Cano-Lira, José F.; Fothergill, Annette W.; Wiederhold, Nathan P.; Guarro, Josep

    2014-01-01

    A set of 73 isolates of the emerging fungus Trichoderma isolated from human and animal clinical specimens were characterized morphologically and molecularly using a multilocus sequence analysis that included the internal transcribed spacer (ITS) regions of the nuclear ribosomal DNA and fragments of the translation elongation factor 1 alpha (Tef1), endochitinase CHI18-5 (Chi18-5), and actin 1 (Act1) genes. The most frequent species was Trichoderma longibrachiatum (26%), followed by Trichoderma citrinoviride (18%), the Hypocrea lixii/Trichoderma harzianum species complex (15%), the newly described species Trichoderma bissettii (12%), and Trichoderma orientale (11%). The most common anatomical sites of isolation in human clinical specimens were the respiratory tract (40%), followed by deep tissue (30%) and superficial tissues (26%), while all the animal-associated isolates were obtained from superficial tissue samples. Susceptibilities of the isolates to eight antifungal drugs in vitro showed mostly high MICs, except for voriconazole and the echinocandins. PMID:24719448

  9. Under the axis II radar: clinically relevant personality constellations that escape DSM-IV diagnosis.

    PubMed

    Blagov, Pavel S; Bradley, Rebekah; Westen, Drew

    2007-06-01

    Research suggests that personality pathology lies on a continuum from relatively severe to less severe and that subthreshold variants may not be adequately captured by axis II of DSM-IV. In this study, we used a measure of personality and psychopathology designed for experienced clinical observers (the SWAP-200) to derive subthreshold personality constellations in a sample of 159 psychotherapy patients who were high functioning but nevertheless suffered from maladaptive personality patterns. Using Q-factor analysis (an empirical clustering procedure), we identified 4 diagnostic groupings or SPC, which resembled the clinical concept of "neurotic styles": depressive, hostile-competitive, obsessive, and hysterical. The results of this study should stimulate further research on subthreshold personality configurations. PMID:17568295

  10. The default network and self-generated thought: component processes, dynamic control, and clinical relevance

    PubMed Central

    Andrews-Hanna, Jessica R.; Smallwood, Jonathan; Spreng, R. Nathan

    2014-01-01

    Though only a decade has elapsed since the default network was first emphasized as being a large-scale brain system, recent years have brought great insight into the network’s adaptive functions. A growing theme highlights the default network as playing a key role in internally-directed—or self-generated—thought. Here, we synthesize recent findings from cognitive science, neuroscience, and clinical psychology to focus attention on two emerging topics as current and future directions surrounding the default network. First, we present evidence that self-generated thought is a multi-faceted construct whose component processes are supported by different subsystems within the network. Second, we highlight the dynamic nature of the default network, emphasizing its interaction with executive control systems when regulating aspects of internal thought. We conclude by discussing clinical implications of disruptions to the integrity of the network, and consider disorders when thought content becomes polarized or network interactions become disrupted or imbalanced. PMID:24502540

  11. Clinical relevance of ventilation-perfusion inequality determined by inert gas elimination.

    PubMed

    Rodriguez-Roisin, R; Wagner, P D

    1990-04-01

    The first part of this review deals with the basic mechanisms and factors determining hypoxaemia and hypercapnia and the different approaches used in clinical practice and in clinical research to assess the presence of ventilation-perfusion mismatching, shunt and diffusion limitation for oxygen, and more specifically the multiple inert gas elimination technique (MIGET), in pulmonary medicine. The second part reviews three different respiratory disorders where the complex interplay between intrapulmonary and extrapulmonary factors regulating oxygen are essentially interpreted through the results afforded by the MIGET over the last decade. The gas exchange response to bronchodilators in bronchial asthma, an airway disease, and then the major determinants governing abnormal gas exchange in acute pulmonary embolism, a pulmonary vascular disorder, and during haemodialysis, a respiratory entity of extrapulmonary origin, are successively explored in the light of the inert gas method. PMID:2163880

  12. The Clinical Relevance of Long Non-Coding RNAs in Cancer

    PubMed Central

    Silva, Andreia; Bullock, Marc; Calin, George

    2015-01-01

    Non-coding RNAs have long been associated with cancer development and progression, and since their earliest discovery, their clinical potential in identifying and characterizing the disease has been pursued. Long non-coding (lncRNAs), a diverse class of RNA transcripts >200 nucleotides in length with limited protein coding potential, has been only modestly studied relative to other categories of non-coding RNAs. However, recent data suggests they too may be important players in cancer. In this article, we consider the value of lncRNAs in the clinical setting, and in particular their potential roles as diagnostic and prognostic markers in cancer. Furthermore, we summarize the most significant studies linking lncRNA expression in human biological samples to cancer outcomes. The diagnostic sensitivity, specificity and validity of these non-coding RNA transcripts is compared in the various biological compartments in which they have been detected including tumor tissue, whole body fluids and exosomes. PMID:26516918

  13. Minimal residual disease: optimal methods, timing, and clinical relevance for an individual patient.

    PubMed

    Schrappe, Martin

    2012-01-01

    After approximately 20 years of development and after several prospective clinical trials, the detection of minimal residual disease (MRD) has emerged as part of state-of-the-art diagnostics to guide the majority of contemporary treatment programs both in pediatric and adult acute lymphoblastic leukemia (ALL). For ALL, several methods of MRD analysis are available, but 2 are widely applicable. One is based on the detection of aberrant expression of leukemia specific antigens by flow cytometry and the other one uses the specific rearrangements of the TCR or Ig genes, which can be detected by quantitative PCR in the DNA of leukemic cells. In some cases with known fusion genes such as BCR/ABL, RT-PCR can be used as a third method of identifying leukemic cells by analyzing RNA in patient samples. Clinical application of such sophisticated tools in the stratification and treatment of ALL requires reliable, reproducible, and quality-assured methods to ensure patient safety. PMID:23233572

  14. Ultrasound in sports medicine: relevance of emerging techniques to clinical care of athletes.

    PubMed

    Yim, Eugene Sun; Corrado, Gianmichael

    2012-08-01

    The applications of ultrasound in managing the clinical care of athletes have been expanding over the past decade. This review provides an analysis of the research that has been published regarding the use of ultrasound in athletes and focuses on how these emerging techniques can impact the clinical management of athletes by sports medicine physicians. Electronic database literature searches were performed using the subject terms 'ultrasound' and 'athletes' from the years 2003 to 2012. The following databases were searched: PubMed, Web of Science, Cochrane Library, CINAHL, and SPORTDiscus™. The search produced 617 articles in total, with a predominance of articles focused on cardiac and musculoskeletal ultrasound. 266 of the studies involved application of ultrasound in evaluating the cardiovascular properties of athletes, and 151 studies involved musculoskeletal ultrasound. Other applications of ultrasound included abdominal, vascular, bone density and volume status. New techniques in echocardiography have made significant contributions to the understanding of the physiological changes that occur in the athlete's heart in response to the haemodynamic stress associated with different types of activity. The likely application of these techniques will be in managing athletes with hypertrophic cardiomyopathy, and the techniques are near ready for application into clinical practice. These techniques are highly specialized, however, and will require referral to dedicated laboratories to influence the clinical management of athletes. Investigation of aortic root pathology and pulmonary vascular haemodynamics are also emerging, but will require additional studies with larger numbers and outcomes analysis to validate their clinical utility. Some of these techniques are relatively simple, and thus hold the potential to enter clinical management in a point-of-care fashion. Musculoskeletal ultrasound has demonstrated a number of diagnostic and therapeutic techniques

  15. New insights into insulin: The anti-inflammatory effect and its clinical relevance.

    PubMed

    Sun, Qiang; Li, Jia; Gao, Feng

    2014-04-15

    Hyperglycemia, a commonly exhibited metabolic disorder in critically ill patients, activates the body's inflammatory defense mechanism, causing the waterfall release of numerous inflammatory mediators and cytokines, and eventually leads to organ damage. As the only glucose-lowering hormone in the body, insulin not only alleviates the detrimental effects of hyperglycemia through its metabolic regulation, but also directly modulates inflammatory mediators and acts upon immune cells to enhance immunocompetence. In this sense, hyperglycemia is pro-inflammatory whereas insulin is anti-inflammatory. Therefore, during the past 50 years, insulin has not only been used in the treatment of diabetes, but has also been put into practical use in dealing with cardiovascular diseases and critical illnesses. This review summarizes the recent advances regarding the anti-inflammatory effects of insulin in both basic research and clinical trials, with the hope of aiding in the design of further experimental research and promoting effective insulin administration in clinical practice. PMID:24765237

  16. Revisiting the Derivation of Batterer Subtypes: Towards Profiling the Abuser.

    PubMed

    Brasfield, Rebecca

    2015-12-01

    Research directed toward profiling an abuser to develop effective treatment modalities should consider the framework for how batterer subtypes were developed. This article evaluates a seminal work in batterer typology for a review of its method and findings. Findings indicate that the formation of batterer subtypes rely on unstable theory and methods: (a) Variables were not held constant, (b) Theoretical constructs lack clarity, (c) There were unclear boundaries for subtypes. A re-evaluation of this particular line of typology research should address the utility and relevance of these batterer subtypes in an effort to address methodological implications that may help profile and treat abusers. PMID:25516132

  17. Clinically relevant variants identified in thoracic aortic aneurysm patients by research exome sequencing.

    PubMed

    Schubert, Jeffrey A; Landis, Benjamin J; Shikany, Amy R; Hinton, Robert B; Ware, Stephanie M

    2016-05-01

    Thoracic aortic aneurysm (TAA) is a genetically heterogeneous disease involving subclinical and progressive dilation of the thoracic aorta, which can lead to life-threatening complications such as dissection or rupture. Genetic testing is important for risk stratification and identification of at risk family members, and clinically available genetic testing panels have been expanding rapidly. However, when past testing results are normal, there is little evidence to guide decision-making about the indications and timing to pursue additional clinical genetic testing. Results from research based genetic testing can help inform this process. Here we present 10 TAA patients who have a family history of disease and who enrolled in research-based exome testing. Nine of these ten patients had previous clinical genetic testing that did not identify the cause of disease. We sought to determine the number of rare variants in 23 known TAA associated genes identified by research-based exome testing. In total, we found 10 rare variants in six patients. Likely pathogenic variants included a TGFB2 variant in one patient and a SMAD3 variant in another. These variants have been reported previously in individuals with similar phenotypes. Variants of uncertain significance of particular interest included novel variants in MYLK and MFAP5, which were identified in a third patient. In total, clinically reportable rare variants were found in 6/10 (60%) patients, with at least 2/10 (20%) patients having likely pathogenic variants identified. These data indicate that consideration of re-testing is important in TAA patients with previous negative or inconclusive results. PMID:26854089

  18. A targeted next-generation sequencing method for identifying clinically relevant mutation profiles in lung adenocarcinoma

    PubMed Central

    Shao, Di; Lin, Yongping; Liu, Jilong; Wan, Liang; Liu, Zu; Cheng, Shaomin; Fei, Lingna; Deng, Rongqing; Wang, Jian; Chen, Xi; Liu, Liping; Gu, Xia; Liang, Wenhua; He, Ping; Wang, Jun; Ye, Mingzhi; He, Jianxing

    2016-01-01

    Molecular profiling of lung cancer has become essential for prediction of an individual’s response to targeted therapies. Next-generation sequencing (NGS) is a promising technique for routine diagnostics, but has not been sufficiently evaluated in terms of feasibility, reliability, cost and capacity with routine diagnostic formalin-fixed, paraffin-embedded (FFPE) materials. Here, we report the validation and application of a test based on Ion Proton technology for the rapid characterisation of single nucleotide variations (SNVs), short insertions and deletions (InDels), copy number variations (CNVs), and gene rearrangements in 145 genes with FFPE clinical specimens. The validation study, using 61 previously profiled clinical tumour samples, showed a concordance rate of 100% between results obtained by NGS and conventional test platforms. Analysis of tumour cell lines indicated reliable mutation detection in samples with 5% tumour content. Furthermore, application of the panel to 58 clinical cases, identified at least one actionable mutation in 43 cases, 1.4 times the number of actionable alterations detected by current diagnostic tests. We demonstrated that targeted NGS is a cost-effective and rapid platform to detect multiple mutations simultaneously in various genes with high reproducibility and sensitivity. PMID:26936516

  19. Clinical relevance of IL-6 gene polymorphism in severely injured patients.

    PubMed

    Jeremić, Vasilije; Alempijević, Tamara; Mijatović, Srđan; Sijački, Ana; Dragašević, Sanja; Pavlović, Sonja; Miličić, Biljana; Krstić, Slobodan

    2014-05-01

    In polytrauma, injuries that may be surgically treated under regular circumstances due to a systemic inflammatory response become life-threatening. The inflammatory response involves a complex pattern of humoral and cellular responses and the expression of related factors is thought to be governed by genetic variations. This aim of this paper is to examine the influence of interleukin (IL) 6 single nucleotide polymorphism (SNP) -174C/G and -596G/A on the treatment outcome in severely injured patients. Forty-seven severely injured patients were included in this study. Patients were assigned an Injury Severity Score. Blood samples were drawn within 24 h after admission (designated day 1) and on subsequent days (24, 48, 72 hours and 7 days) of hospitalization. The IL-6 levels were determined through ELISA technique. Polymorphisms were analyzed by a method of Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR). Among subjects with different outcomes, no statistically relevant difference was found with regards to the gene IL-6 SNP-174G/C polymorphism. More than a half of subjects who died had the SNP-174G/C polymorphism, while this polymorphism was represented in a slightly lower number in survivors. The incidence of subjects without polymorphism and those with heterozygous and homozygous gene IL-6 SNP-596G/A polymorphism did not present statistically significant variations between survivors and those who died. The levels of IL-6 over the observation period did not present any statistically relevant difference among subjects without the IL-6 SNP-174 or IL- 6 SNP -596 gene polymorphism and those who had either a heterozygous or a homozygous polymorphism. PMID:24856384

  20. Prevention of ventilator-associated pneumonia in the intensive care unit: A review of the clinically relevant recent advancements

    PubMed Central

    Keyt, Holly; Faverio, Paola; Restrepo, Marcos I.

    2014-01-01

    Ventilator-associated pneumonia (VAP) is one of the most commonly encountered hospital-acquired infections in intensive care units and is associated with significant morbidity and high costs of care. The pathophysiology, epidemiology, treatment and prevention of VAP have been extensively studied for decades, but a clear prevention strategy has not yet emerged. In this article we will review recent literature pertaining to evidence-based VAP-prevention strategies that have resulted in clinically relevant outcomes. A multidisciplinary strategy for prevention of VAP is recommended. Those interventions that have been shown to have a clinical impact include the following: (i) Non-invasive positive pressure ventilation for able patients, especially in immunocompromised patients, with acute exacerbation of chronic obstructive pulmonary disease or pulmonary oedema, (ii) Sedation and weaning protocols for those patients who do require mechanical ventilation, (iii) Mechanical ventilation protocols including head of bed elevation above 30 degrees and oral care, and (iv) Removal of subglottic secretions. Other interventions, such as selective digestive tract decontamination, selective oropharyngeal decontamination and antimicrobial-coated endotracheal tubes, have been tested in different studies. However, the evidence for the efficacy of these measures to reduce VAP rates is not strong enough to recommend their use in clinical practice. In numerous studies, the implementation of VAP prevention bundles to clinical practice was associated with a significant reduction in VAP rates. Future research that considers clinical outcomes as primary endpoints will hopefully result in more detailed prevention strategies. PMID:25109715

  1. MicroRNA profiles classify papillary renal cell carcinoma subtypes

    PubMed Central

    Wach, S; Nolte, E; Theil, A; Stöhr, C; T Rau, T; Hartmann, A; Ekici, A; Keck, B; Taubert, H; Wullich, B

    2013-01-01

    Background: Besides the conventional clear-cell renal cell carcinoma (ccRCC), papillary RCC (pRCC) is the second most common renal malignancy. Papillary RCCs can further be subdivided into two distinct subtypes. Although a clinical relevance of pRCC subtyping has been shown, little is known about the molecular characteristics of both pRCC subtypes. Methods: We performed microarray-based microRNA (miRNA) expression profiling of primary ccRCC and pRCC cases. A subset of miRNAs was identified and used to establish a classification model for ccRCC, pRCC types 1 and 2 and normal tissue. Furthermore, we performed gene set enrichment analysis with the predicted miRNA target genes. Results: Only five miRNAs (miR-145, -200c, -210, -502-3p and let-7c) were sufficient to identify the samples with high accuracy. In a collection of 111 tissue samples, 73.9% were classified correctly. An enrichment of miRNA target genes in the family of multidrug-resistance proteins was noted in all tumours. Several components of the Jak-STAT signalling pathway might be targets for miRNAs that define pRCC tumour subtypes. Conclusion: MicroRNAs are able to accurately classify RCC samples. Deregulated miRNAs might contribute to the high chemotherapy resistance of RCC. Furthermore, our results indicate that pRCC type 2 tumours could be dependent on oncogenic MYC signalling. PMID:23799849

  2. Relevance of nucleic acid amplification techniques for diagnosis of respiratory tract infections in the clinical laboratory.

    PubMed Central

    Ieven, M; Goossens, H

    1997-01-01

    Clinical laboratories are increasingly receiving requests to perform nucleic acid amplification tests for the detection of a wide variety of infectious agents. In this paper, the efficiency of nucleic acid amplification techniques for the diagnosis of respiratory tract infections is reviewed. In general, these techniques should be applied only for the detection of microorganisms for which available diagnostic techniques are markedly insensitive or nonexistent or when turnaround times for existing tests (e.g., viral culture) are much longer than those expected with amplification. This is the case for rhinoviruses, coronaviruses, and hantaviruses causing a pulmonary syndrome, Bordetella pertussis, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Coxiella burnetii. For Legionella spp. and fungi, contamination originating from the environment is a limiting factor in interpretation of results, as is the difficulty in differentiating colonization and infection. Detection of these agents in urine or blood by amplification techniques remains to be evaluated. In the clinical setting, there is no need for molecular diagnostic tests for the diagnosis of Pneumocystis carinii. At present, amplification methods for Mycobacterium tuberculosis cannot replace the classical diagnostic techniques, due to their lack of sensitivity and the absence of specific internal controls for the detection of inhibitors of the reaction. Also, the results of interlaboratory comparisons are unsatisfactory. Furthermore, isolates are needed for susceptibility studies. Additional work remains to be done on sample preparation methods, comparison between different amplification methods, and analysis of results. The techniques can be useful for the rapid identification of M. tuberculosis in particular circumstances, as well as the rapid detection of most rifampin-resistant isolates. The introduction of diagnostic amplification techniques into a clinical laboratory implies a level of proficiency for

  3. Relevance and clinical significance of serum resistin level in obese T2DM rhesus monkey models.

    PubMed

    Qi, S-D; He, Z-L; Chen, Y; Ma, J; Yu, W-H; Li, Y-Y; Yang, F-M; Wang, J-B; Chen, L-X; Zhao, Y; Lu, S-Y

    2015-09-01

    Resistin is a type of hormone-like adipocytokines, which is secreted specifically by adipocytes. It may be a key factor in the development of type 2 diabetes mellitus (T2DM) from obesity- associated insulin resistance due to results that show that it has a close relationship with insulin resistance in rodents. We utilized the rhesus monkeys as study objects to preliminarily test the association with glucose metabolism and to conduct a correlation analysis for clinical parameters and serum resistin levels in obese rhesus monkey models of T2DM. The results suggested that resistin was significantly increased in T2DM monkeys (P <0.01), and that resistin had a positive correlation respectively with total cholesterol (TC), low-density lipoprotein (LDL-C), fasting plasma glucose (FPG), fasting insulin (FPI) and glycated hemoglobin (HbA1c), Insulin resistance index (HOA-IR), but a negative correlation with islet β-cell function (HOMA-β). In the course of glucose metabolism, reverse release change of resistin and insulin in T2DM monkeys occurred, but the phenomenon that was not observed in the control group, these findings indicated that resistin negatively regulated and interfered with carbohydrate metabolism in T2DM monkey models. The character of the releasing change of resistin might be a unique process in T2DM. Therefore, all of the results could provide references for clinical diagnostic criteria for human cases of T2DM, and could have clinical significance for obese T2DM diagnosis and degree of insulin resistance. PMID:26069076

  4. Clinical Relevance of Telomere Status and Telomerase Activity in Colorectal Cancer

    PubMed Central

    Fernández-Marcelo, Tamara; Sánchez-Pernaute, Andrés; Pascua, Irene; De Juan, Carmen; Head, Jacqueline; Torres-García, Antonio-José; Iniesta, Pilar

    2016-01-01

    The role of telomeres and telomerase in colorectal cancer (CRC) is well established as the major driving force in generating chromosomal instability. However, their potential as prognostic markers remains unclear. We investigated the outcome implications of telomeres and telomerase in this tumour type. We considered telomere length (TL), ratio of telomere length in cancer to non-cancer tissue (T/N ratio), telomerase activity and TERT levels; their relation with clinical variables and their role as prognostic markers. We analyzed 132 CRCs and paired non-cancer tissues. Kaplan-Meier curves for disease-free survival were calculated for TL, T/N ratio, telomerase activity and TERT levels. Overall, tumours had shorter telomeres than non-tumour tissues (P < 0.001) and more than 80% of CRCs displayed telomerase activity. Telomere lengths of non-tumour tissues and CRCs were positively correlated (P < 0.001). Considering telomere status and clinical variables, the lowest degree of telomere shortening was shown by tumours located in the rectum (P = 0.021). Regarding prognosis studies, patients with tumours showing a mean TL < 6.35 Kb experienced a significantly better clinical evolution (P < 0.001) and none of them with the highest degree of tumour telomere shortening relapsed during the follow-up period (P = 0.043). The mean TL in CRCs emerged as an independent prognostic factor in the Cox analysis (P = 0.017). Telomerase-positive activity was identified as a marker that confers a trend toward a poor prognosis. In CRC, our results support the use of telomere status as an independent prognostic factor. Telomere status may contribute to explaining the different molecular identities of this tumour type. PMID:26913901

  5. Psycho- and immunopharmacological factors relevant to selection of volunteers in clinical studies.

    PubMed

    Meyer, F P

    2001-07-01

    There are many well-known factors and variables which play a role in the evaluation of pharmacokinetic and pharmacodynamic results gained from healthy volunteers. The genetic constitution is influenced by age, sex, circadian and seasonal variations, dietary factors, immunological function, alcohol intake, smoking, etc. Vesell repeatedly pointed out these facts some time ago [Vesell 1982, Vesell and Passananti 1977]. Since Janke [1964], we have suspected that personality traits can also influence the drug response. The following overview is dedicated to this field designated as differential psychopharmacology which, from the point of view ofthe author, has been given too little attention by pharmacologists and clinical pharmacologists. It has been demonstrated that the effect of psychotropic drugs, including placebo, can be differentially influenced by personality traits, e.g. introversion/extroversion, high level neuroticism/low level neuroticism and success motivation/failure motivation. For example, relatively high doses of diazepam (0.3 mg/kg), when compared to placebo, only impaired the psychophysical performance of extroverted volunteers whereas introverted volunteers remained unaffected. Pharmacokinetic parameters, e.g. absorption, biotransformation, can also be affected by the level of neuroticism or by anxiety, as demonstrated for diazepam, caffeine, paracetamol and theophylline. The absorption kinetics of diazepam and caffeine clearly differ between volunteers with high neuroticism scores and those with low neuroticism scores. Emotionally unstable volunteers absorbed the substances more quickly and more completely than emotionally stable volunteers. There were surprising differences in various immunological indices between dominant and submissive subjects. In dominant volunteers the immune system was more activated than in submissive volunteers. In the future, it will become increasingly necessary to obtain results for such target groups and to avoid

  6. Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value

    PubMed Central

    Marisa, Laetitia; de Reyniès, Aurélien; Duval, Alex; Selves, Janick; Gaub, Marie Pierre; Vescovo, Laure; Etienne-Grimaldi, Marie-Christine; Schiappa, Renaud; Guenot, Dominique; Ayadi, Mira; Kirzin, Sylvain; Chazal, Maurice; Fléjou, Jean-François; Benchimol, Daniel; Berger, Anne; Lagarde, Arnaud; Pencreach, Erwan; Piard, Françoise; Elias, Dominique; Parc, Yann; Olschwang, Sylviane; Milano, Gérard; Laurent-Puig, Pierre; Boige, Valérie

    2013-01-01

    Background Colon cancer (CC) pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical practice, perhaps because CC is a heterogeneous disease. The aim of this study was to establish a comprehensive molecular classification of CC based on mRNA expression profile analyses. Methods and Findings Fresh-frozen primary tumor samples from a large multicenter cohort of 750 patients with stage I to IV CC who underwent surgery between 1987 and 2007 in seven centers were characterized for common DNA alterations, including BRAF, KRAS, and TP53 mutations, CpG island methylator phenotype, mismatch repair status, and chromosomal instability status, and were screened with whole genome and transcriptome arrays. 566 samples fulfilled RNA quality requirements. Unsupervised consensus hierarchical clustering applied to gene expression data from a discovery subset of 443 CC samples identified six molecular subtypes. These subtypes were associated with distinct clinicopathological characteristics, molecular alterations, specific enrichments of supervised gene expression signatures (stem cell phenotype–like, normal-like, serrated CC phenotype–like), and deregulated signaling pathways. Based on their main biological characteristics, we distinguished a deficient mismatch repair subtype, a KRAS mutant subtype, a cancer stem cell subtype, and three chromosomal instability subtypes, including one associated with down-regulated immune pathways, one with up-regulation of the Wnt pathway, and one displaying a normal-like gene expression profile. The classification was validated in the remaining 123 samples plus an independent set of 1,058 CC samples, including eight public datasets. Furthermore, prognosis was analyzed in the subset of stage II–III CC samples. The subtypes C4 and C6, but not the subtypes C1, C2, C3, and C5, were independently associated with shorter relapse-free survival

  7. Protein engineering strategies with potential applications for altering clinically relevant cellular pathways at the protein level.

    PubMed

    Regan, Lynne; Hinrichsen, Michael R; Oi, Curran

    2016-05-01

    All diseases can be fundamentally viewed as the result of malfunctioning cellular pathways. Protein engineering offers the potential to develop new tools that will allow these dysfunctional pathways to be better understood, in addition to potentially providing new routes to restore proper function. Here we discuss different approaches that can be used to change the intracellular activity of a protein by intervening at the protein level: targeted protein sequestration, protein recruitment, protein degradation, and selective inhibition of binding interfaces. The potential of each of these tools to be developed into effective therapeutic treatments will also be discussed, along with any major barriers that currently block their translation into the clinic. PMID:27031866

  8. Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance.

    PubMed

    Cattaneo, Marco; Schulz, Rainer; Nylander, Sven

    2014-06-17

    This review constitutes a critical evaluation of recent publications that have described an additional mode of action of the P2Y12 receptor antagonist ticagrelor. The effect is mediated by inhibition of the adenosine transporter ENT1 (type 1 equilibrative nucleoside transporter), which provides protection for adenosine from intracellular metabolism, thus increasing its concentration and biological activity, particularly at sites of ischemia and tissue injury where it is formed. Understanding the mode of action of ticagrelor is of particular interest given that its clinical profile, both in terms of efficacy and adverse events, differs from that of thienopyridine P2Y12 antagonists. PMID:24768873

  9. DGIdb 2.0: mining clinically relevant drug-gene interactions.

    PubMed

    Wagner, Alex H; Coffman, Adam C; Ainscough, Benjamin J; Spies, Nicholas C; Skidmore, Zachary L; Campbell, Katie M; Krysiak, Kilannin; Pan, Deng; McMichael, Joshua F; Eldred, James M; Walker, Jason R; Wilson, Richard K; Mardis, Elaine R; Griffith, Malachi; Griffith, Obi L

    2016-01-01

    The Drug-Gene Interaction Database (DGIdb, www.dgidb.org) is a web resource that consolidates disparate data sources describing drug-gene interactions and gene druggability. It provides an intuitive graphical user interface and a documented application programming interface (API) for querying these data. DGIdb was assembled through an extensive manual curation effort, reflecting the combined information of twenty-seven sources. For DGIdb 2.0, substantial updates have been made to increase content and improve its usefulness as a resource for mining clinically actionable drug targets. Specifically, nine new sources of drug-gene interactions have been added, including seven resources specifically focused on interactions linked to clinical trials. These additions have more than doubled the overall count of drug-gene interactions. The total number of druggable gene claims has also increased by 30%. Importantly, a majority of the unrestricted, publicly-accessible sources used in DGIdb are now automatically updated on a weekly basis, providing the most current information for these sources. Finally, a new web view and API have been developed to allow searching for interactions by drug identifiers to complement existing gene-based search functionality. With these updates, DGIdb represents a comprehensive and user friendly tool for mining the druggable genome for precision medicine hypothesis generation. PMID:26531824

  10. DGIdb 2.0: mining clinically relevant drug–gene interactions

    PubMed Central

    Wagner, Alex H.; Coffman, Adam C.; Ainscough, Benjamin J.; Spies, Nicholas C.; Skidmore, Zachary L.; Campbell, Katie M.; Krysiak, Kilannin; Pan, Deng; McMichael, Joshua F.; Eldred, James M.; Walker, Jason R.; Wilson, Richard K.; Mardis, Elaine R.; Griffith, Malachi; Griffith, Obi L.

    2016-01-01

    The Drug–Gene Interaction Database (DGIdb, www.dgidb.org) is a web resource that consolidates disparate data sources describing drug–gene interactions and gene druggability. It provides an intuitive graphical user interface and a documented application programming interface (API) for querying these data. DGIdb was assembled through an extensive manual curation effort, reflecting the combined information of twenty-seven sources. For DGIdb 2.0, substantial updates have been made to increase content and improve its usefulness as a resource for mining clinically actionable drug targets. Specifically, nine new sources of drug–gene interactions have been added, including seven resources specifically focused on interactions linked to clinical trials. These additions have more than doubled the overall count of drug–gene interactions. The total number of druggable gene claims has also increased by 30%. Importantly, a majority of the unrestricted, publicly-accessible sources used in DGIdb are now automatically updated on a weekly basis, providing the most current information for these sources. Finally, a new web view and API have been developed to allow searching for interactions by drug identifiers to complement existing gene-based search functionality. With these updates, DGIdb represents a comprehensive and user friendly tool for mining the druggable genome for precision medicine hypothesis generation. PMID:26531824

  11. Genotypes and viral variants in chronic hepatitis B: A review of epidemiology and clinical relevance

    PubMed Central

    Croagh, Catherine MN; Desmond, Paul V; Bell, Sally J

    2015-01-01

    The Hepatitis B Virus (HBV) has a worldwide distribution and is endemic in many populations. It is constantly evolving and 10 genotypic strains have been identified with varying prevalences in different geographic regions. Numerous stable mutations in the core gene and in the surface gene of the HBV have also been identified in untreated HBV populations. The genotypes and viral variants have been associated with certain clinical features of HBV related liver disease and Hepatocellular carcinoma. For example Genotype C is associated with later hepatitis B e antigen (HBeAg) seroconversion, and more advanced liver disease. Genotype A is associated with a greater risk of progression to chronicity in adult acquired HBV infections. Genotype D is particularly associated with the precore mutation and HBeAg negative chronic hepatitis B (CHB). The genotypes prevalent in parts of West Africa, Central and South America, E, F and H respectively, are less well studied. Viral variants especially the Basal Core Promotor mutation is associated with increased risk of fibrosis and cancer of the liver. Although not currently part of routine clinical care, evaluation of genotype and viral variants may provide useful adjunctive information in predicting risk about liver related morbidity in patients with CHB. PMID:25848459

  12. Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction.

    PubMed

    Kiyatkin, Eugene A; Ren, Suelynn; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

    2016-01-01

    MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results. PMID:26105141

  13. Clinical relevance of copy number profiling in oral and oropharyngeal squamous cell carcinoma.

    PubMed

    van Kempen, Pauline M W; Noorlag, Rob; Braunius, Weibel W; Moelans, Cathy B; Rifi, Widad; Savola, Suvi; Koole, Ronald; Grolman, Wilko; van Es, Robert J J; Willems, Stefan M

    2015-10-01

    Current conventional treatment modalities in head and neck squamous cell carcinoma (HNSCC) are nonselective and have shown to cause serious side effects. Unraveling the molecular profiles of head and neck cancer may enable promising clinical applications that pave the road for personalized cancer treatment. We examined copy number status in 36 common oncogenes and tumor suppressor genes in a cohort of 191 oropharyngeal squamous cell carcinomas (OPSCC) and 164 oral cavity squamous cell carcinomas (OSCC) using multiplex ligation probe amplification. Copy number status was correlated with human papillomavirus (HPV) status in OPSCC, with occult lymph node status in OSCC and with patient survival. The 11q13 region showed gain or amplifications in 59% of HPV-negative OPSCC, whereas this amplification was almost absent in HPV-positive OPSCC. Additionally, in clinically lymph node-negative OSCC (Stage I-II), gain of the 11q13 region was significantly correlated with occult lymph node metastases with a negative predictive value of 81%. Multivariate survival analysis revealed a significantly decreased disease-free survival in both HPV-negative and HPV-positive OPSCC with a gain of Wnt-induced secreted protein-1. Gain of CCND1 showed to be an independent predictor for worse survival in OSCC. These results show that copy number aberrations, mainly of the 11q13 region, may be important predictors and prognosticators which allow for stratifying patients for personalized treatment of HNSCC. PMID:26194878

  14. Thirty years of human pineal research: do we know its clinical relevance?

    PubMed

    García-Patterson, A; Puig-Domingo, M; Webb, S M

    1996-01-01

    A role for melatonin in humans is becoming evident in an increasing number of clinical situations. Marked variations in the magnitude of the nocturnal melatonin peak are observed throughout the human lifespan. The highest levels occur in children and then fall during puberty and further during adulthood. A negative correlation between circulating melatonin and sex steroids has been observed in a number of instances, and appears to be independent of concomitant gonadotrophins. No clear melatonin pattern has been observed in pituitary tumors, but in large lesions that involve the hypothalamus, a reduced nocturnal rise has been reported. Reported effects of exogenously administered melatonin are variable, probably reflecting differences in dose and timing; a slight stimulation of prolactin, as well as a partial inhibition of gonadotrophins, has been reported, which explains its utility as an oral contraceptive, associated with a progestogen. A potential clinical use of melatonin as an oncostatic drug still awaits confirmation, although experimental data firmly support this possibility. The indole has also been used to hasten entrainment of subjects travelling across various time zones, and has been found to be specially useful in eastward travel. Finally, changes in the normal melatonin circadian pattern have been reported in psychiatric diseases and in sudden infant death syndrome. PMID:8648556

  15. Application of ferrokinetic investigation for differential diagnosis in bone marrow hypoplasia and their clinical relevance.

    PubMed

    Gupta, M; Roth, P; Werner, E; Kaltwasser, J P

    1979-02-01

    In this study, erythropoietic activity of bone marrow has been evaluated by ferrokinetics. For that purpose, the data of radioiron disappearance from plasma and its ultimate incorporation in red blood cells after the injection of about 10 muCi of 59Fe tagged autologous plasma, were analysed and fitted to the sum of three exponentials, using a non-linear least square SAAM-25 program on UNIVAC-1108 computer. A function representing time-activity relationship, was constructed. The functional physiological model of iron metabolism, proposed by Cavill and Ricketts, was used to calculate various ferrokinetic parameters in terms of coefficients and exponents of the time-activity function. After identifying the parameters that could be used as indices of erythropoietic activity of bone marrow, the study was repeated in six patients after they had undergone myelostimulative therapy. A distinct correlation was found between ferrokinetic observations and clinical and biochemical findings. It has been demonstrated that in histologically diagnosed cases with bone marrow hypoplasia, a further differentiation between pure aplasia and those with hypoplasia together with ineffective erythropoiesis was possible. This discrimination which is clinically very important, is only possible by means of kinetic investigations. PMID:499222

  16. Sex- and Subtype-Related Differences in the Comorbidity of Adult ADHDs.

    PubMed

    Groß-Lesch, Silke; Dempfle, Astrid; Reichert, Susanne; Jans, Thomas; Geissler, Julia; Kittel-Schneider, Sarah; Nguyen, Thuy Trang; Reif, Andreas; Lesch, Klaus-Peter; Jacob, Christian Peter

    2013-11-01

    Objective: Comorbidity in adult ADHD (aADHD) has been investigated in a large number of studies using varying research approaches with divergent results. In contrast, there is limited information about sex- or subtype-related differences from studies with small sample size. Method: A large sample of 910 individuals (458 males, 452 females) affected with aADHD was recruited at a tertiary referral center. All probands underwent a four-step procedure for diagnosing aADHD, including the Structured Clinical Interview of Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) Axis I disorders to assess comorbidity. This study will provide additional information regarding the co-morbidity of Axis I disorders in the currently largest clinical referral sample. However, the main objective of this study is to gain information about sex- or subtype-related differences. Results: Affected females show higher rates of mood (61% vs. 49%), anxiety (32% vs. 22%), and eating disorders (16% vs. 1%) than affected males, while substance use disorders were more frequent in affected males (45% vs. 29%), which mirrors sex differences in prevalence in the general population. There were hardly any relevant differences in comorbidities between subtypes, with the exception of the inattentive subtype having an especially low prevalence of panic disorder. Comorbidity in general and substance use disorders in particular, but not sex or subtype, were highly predictive of lower psychosocial status. Conclusion: Sex-related differences in the comorbidity of aADHD are more pronounced than subtype-related differences. (J. of Att. Dis. XXXX; XX(X) XX-XX). PMID:24196345

  17. Decreased interhemispheric functional connectivity in subtypes of Parkinson's disease.

    PubMed

    Hu, Xiaofei; Zhang, Jiuquan; Jiang, Xiaomei; Zhou, Chaoyang; Wei, Luqing; Yin, Xuntao; Wu, Ya; Li, Jing; Zhang, Yanling; Wang, Jian

    2015-03-01

    Parkinson's disease (PD) can be classified into tremor-dominant (TD) subtype and akinetic-rigid (AR) subtype, which exhibit different clinical courses and prognoses. However, the neural mechanisms underlying different subtypes of PD are not well understood. Using voxel-mirrored homotopic connectivity (VMHC), we examined the homotopic resting-state functional connectivity patterns in akinetic-rigid PD (AR-PD) and tremor-dominant PD (TD-PD) to study the neural basis for these disparate manifestations of PD. Twenty-one TD-PD patients, 29 AR-PD patients and 26 normal control subjects participated in this study. Resting-state fMRI data were analyzed using VMHC. Correlations between VMHC values and each clinical characteristic were also calculated. Compared with normal control subjects and subjects with AR-PD, subjects with TD-PD exhibited significantly lower VMHC values in the posterior lobe of the cerebellum. Moreover, tremor scores and VMHC values for the cerebellum were found to be significantly negatively correlated in TD-PD patients. By contrast, subjects with AR-PD exhibited lower VMHC values in the precentral gyrus compared with normal control subjects. These findings suggest that functional coordination between homotopic brain regions is impaired in AR-PD and TD-PD patients. This study provides evidence of both cerebellum-related connectivity deficits in TD-PD. The finding that VMHC values and tremor scores were significantly correlated suggests that VMHC measurements may be of potential clinical relevance in TD-PD. PMID:25577177

  18. Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors.

    PubMed

    Chowanadisai, Winyoo; Messerli, Shanta M; Miller, Daniel H; Medina, Jamie E; Hamilton, Joshua W; Messerli, Mark A; Brodsky, Alexander S

    2016-01-01

    The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05) (S2 Table). Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17-gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition. PMID:26986722

  19. Squalene epoxidase is a bona fide oncogene by amplification with clinical relevance in breast cancer

    PubMed Central

    Brown, David N.; Caffa, Irene; Cirmena, Gabriella; Piras, Daniela; Garuti, Anna; Gallo, Maurizio; Alberti, Saverio; Nencioni, Alessio; Ballestrero, Alberto; Zoppoli, Gabriele

    2016-01-01

    SQLE encodes squalene epoxidase, a key enzyme in cholesterol synthesis. SQLE has sporadically been reported among copy-number driven transcripts in multi-omics cancer projects. Yet, its functional relevance has never been subjected to systematic analyses. Here, we assessed the correlation of SQLE copy number (CN) and gene expression (GE) across multiple cancer types, focusing on the clinico-pathological associations in breast cancer (BC). We then investigated whether any biological effect of SQLE inhibition could be observed in BC cell line models. Breast, ovarian, and colorectal cancers showed the highest CN driven GE among 8,783 cases from 22 cancer types, with BC presenting the strongest one. SQLE overexpression was more prevalent in aggressive BC, and was an independent prognostic factor of unfavorable outcome. Through SQLE pharmacological inhibition and silencing in a panel of BC cell lines portraying the diversity of SQLE CN and GE, we demonstrated that SQLE inhibition resulted in a copy-dosage correlated decrease in cell viability, and in a noticeable increase in replication time, only in lines with detectable SQLE transcript. Altogether, our results pinpoint SQLE as a bona fide metabolic oncogene by amplification, and as a therapeutic target in BC. These findings could have implications in other cancer types. PMID:26777065

  20. Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors

    PubMed Central

    Miller, Daniel H.; Medina, Jamie E.; Hamilton, Joshua W.; Messerli, Mark A.; Brodsky, Alexander S.

    2016-01-01

    The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05) (S2 Table). Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17-gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition. PMID:26986722

  1. Morphogenetic fields within the human dentition: a new, clinically relevant synthesis of an old concept.

    PubMed

    Townsend, Grant; Harris, Edward F; Lesot, Herve; Clauss, Francois; Brook, Alan

    2009-12-01

    This paper reviews the concept of morphogenetic fields within the dentition that was first proposed by Butler (Butler PM. Studies of the mammalian dentition. Differentiation of the post-canine dentition. Proc Zool Soc Lond B 1939;109:1-36), then adapted for the human dentition by Dahlberg (Dahlberg AA. The changing dentition of man. J Am Dent Assoc 1945;32:676-90; Dahlberg AA. The dentition of the American Indian. In: Laughlin WS, editor. The Physical Anthropology of the American Indian. New York: Viking Fund Inc.; 1951. p. 138-76). The clone theory of dental development, proposed by Osborn (Osborn JW. Morphogenetic gradients: fields versus clones. In: Butler PM, Joysey KA, editors Development, function and evolution of teeth. London: Academic Press, 1978. p. 171-201), is then considered before these two important concepts are interpreted in the light of recent findings from molecular, cellular, genetic and theoretical and anthropological investigation. Sharpe (Sharpe PT. Homeobox genes and orofacial development. Connect Tissue Res 1995;32:17-25) put forward the concept of an odontogenic homeobox code to explain how different tooth classes are initiated in different parts of the oral cavity in response to molecular cues and the expression of specific groups of homeobox genes. Recently, Mitsiadis and Smith (Mitsiadis TA, Smith MM. How do genes make teeth to order through development? J Exp Zool (Mol Dev Evol) 2006; 306B:177-82.) proposed that the field, clone and homeobox code models could all be incorporated into a single model to explain dental patterning. We agree that these three models should be viewed as complementary rather than contradictory and propose that this unifying view can be extended into the clinical setting using findings on dental patterning in individuals with missing and extra teeth. The proposals are compatible with the unifying aetiological model developed by Brook (Brook AH. A unifying aetiological explanation for anomalies of tooth number

  2. Multicentre study highlighting clinical relevance of new high-throughput methodologies in molecular epidemiology of Pneumocystis jirovecii pneumonia.

    PubMed

    Esteves, F; de Sousa, B; Calderón, E J; Huang, L; Badura, R; Maltez, F; Bassat, Q; de Armas, Y; Antunes, F; Matos, O

    2016-06-01

    Pneumocystis jirovecii causes severe interstitial pneumonia (PcP) in immunosuppressed patients. This multicentre study assessed the distribution frequencies of epidemiologically relevant genetic markers of P. jirovecii in different geographic populations from Portugal, the USA, Spain, Cuba and Mozambique, and the relationship between the molecular data and the geographical and clinical information, based on a multifactorial approach. The high-throughput typing strategy for P. jirovecii characterization consisted of DNA pooling using quantitative real-time PCR followed by multiplex-PCR/single base extension. The frequencies of relevant P. jirovecii single nucleotide polymorphisms (mt85, SOD110, SOD215, DHFR312, DHPS165 and DHPS171) encoded at four loci were estimated in ten DNA pooled samples representing a total of 182 individual samples. Putative multilocus genotypes of P. jirovecii were shown to be clustered due to geographic differences but were also dependent on clinical characteristics of the populations studied. The haplotype DHFR312T/SOD110C/SOD215T was associated with severe AIDS-related PcP and high P. jirovecii burdens. The frequencies of this genetic variant of P. jirovecii were significantly higher in patients with AIDS-related PcP from Portugal and the USA than in the colonized patients from Portugal, and Spain, and children infected with P. jirovecii from Cuba or Mozambique, highlighting the importance of this haplotype, apparently associated with the severity of the disease and specific clinical groups. Patients from the USA and Mozambique showed higher rates of DHPS mutants, which may suggest the circulation of P. jirovecii organisms potentially related with trimethoprim-sulfamethoxazole resistance in those geographical regions. This report assessed the worldwide distribution of P. jirovecii haplotypes and their epidemiological impact in distinct geographic and clinical populations. PMID:27021425

  3. [Triple therapy in cirrhotic patients and those with advanced fibrosis: relevant aspects in clinical practice].

    PubMed

    Albillos, Agustín; Luis Calleja, José; Molina, Esther; Planas, Ramon; Romero-Gómez, Manuel; Turnes, Juan; Hernández-Guerra, Manuel

    2014-07-01

    The first-line option in the treatment of patients with advanced fibrosis and cirrhosis due to genotype 1 hepatitis C virus is currently triple therapy with boceprevir/telaprevir and pegylated interferon-ribavirin. However, certain limitations could constitute a barrier to starting treatment or achieving sustained viral response in these patients. These limitations include the patient's or physician's perception of treatment effectiveness in routine clinical practice-which can weight against the decision to start treatment-, the advanced stage of the disease with portal hypertension and comorbidity, treatment interruption due to poor adherence, and adverse effects, mainly anemia. In addition, it is now possible to identify patients who could benefit from a shorter therapeutic regimen with a similar cure rate. This review discusses these issues and their possible effect on the use of triple therapy. PMID:25907434

  4. Serotonergic Systems in the Pathophysiology of Ethanol Dependence: Relevance to Clinical Alcoholism.

    PubMed

    Marcinkiewcz, Catherine A

    2015-07-15

    Alcoholism is a progressive brain disorder that is marked by increased sensitivity to the positive and negative reinforcing properties of ethanol, compulsive and habitual use despite negative consequences, and chronic relapse to alcohol drinking despite repeated attempts to reduce intake or abstain from alcohol. Emerging evidence from preclinical and clinical studies implicates serotonin (5-hydroxytryptamine; 5-HT) systems in the pathophysiology of alcohol dependence, suggesting that drugs targeting 5-HT systems may have utility in the treatment of alcohol use disorders. In this Review, we discuss the role of 5-HT systems in alcohol dependence with a focus on 5-HT interactions with neural circuits that govern all three stages of the addiction cycle. We attempt to clarify how 5-HT influences circuit function at these different stages with the goal of identifying neural targets for pharmacological treatment of this debilitating disorder. PMID:25654315

  5. Mechanistic basis and clinical relevance of the role of transforming growth factor-β in cancer

    PubMed Central

    Lin, Run-Long; Zhao, Lu-Jun

    2015-01-01

    Transforming growth factor-β (TGF-β) is a key factor in cancer development and progression. TGF-β can suppress tumorigenesis by inhibiting cell cycle progression and stimulating apoptosis in early stages of cancer progression. However, TGF-β can modulate cancer-related processes, such as cell invasion, distant metastasis, and microenvironment modification that may be used by cancer cells to their advantage in late stages. Corresponding mechanisms include angiogenesis promotion, anti-tumor immunity suppression, and epithelial-to-mesenchymal transition (EMT) induction. The correlation between TGF-β expression and cancer prognosis has also been extensively investigated. Results suggest that TGF-β pathway can be targeted to treat cancer; as such, the feasibility of this treatment is investigated in clinical trials. PMID:26779375

  6. The type I interferons: Basic concepts and clinical relevance in immune-mediated inflammatory diseases.

    PubMed

    López de Padilla, Consuelo M; Niewold, Timothy B

    2016-01-15

    There is increasing scientific and clinical interest in elucidating the biology of type I Interferons, which began approximately 60 years ago with the concept of "viral interference", a property that reduces the ability of a virus to infect cells. Although our understanding of the multiple cellular and molecular functions of interferons has advanced significantly, much remains to be learned and type I Interferons remain an active and fascinating area of inquiry. In this review, we cover some general aspects of type I interferon genes, with emphasis on interferon-alpha, and various aspects of molecular mechanisms triggered by type I interferons and toll-like receptor signaling by the Janus activated kinase/signal transducer activation of transcription (JAK-STAT) pathway and interferon regulatory factor pathway. We will also describe the role of type I interferons in autoimmune and inflammatory diseases, and its potential use as therapeutic agent. PMID:26410416

  7. Functional connectivity in disorders of consciousness: methodological aspects and clinical relevance.

    PubMed

    Marino, Silvia; Bonanno, Lilla; Giorgio, Antonio

    2016-06-01

    This is a Quick Guide about the role of the functional connectivity in the Disorders of Consciousness (DOC). Recent studies on resting state (RS) in DOC, by using functional magnetic resonance imaging (fMRI), showed that functional connectivity is severely impaired above all in the default mode network (DMN). In the vegetative and minimally conscious state, DMN integrity seems to correlate with the level of remaining consciousness, offering the possibility of using this information for diagnostic and prognostic purposes. Although the two principal approaches used in the RS analysis showed several methodological difficulties, especially in DOC patients, functional brain imaging is currently being validated as a valuable addition to the standardized clinical assessments that are already in use. PMID:26089123

  8. Novel Paths to Relevance: How Clinical Ethics Committees Promote Ethical Reflection.

    PubMed

    Magelssen, Morten; Pedersen, Reidar; Førde, Reidun

    2016-09-01

    How may clinical ethics committees (CECs) inspire ethical reflection among healthcare professionals? How may they deal with organizational ethics issues? In recent years, Norwegian CECs have attempted different activites that stretch or go beyond the standard trio of education, consultation, and policy work. We studied the novel activities of Norwegian CECs by examining annual reports and interviewing CEC members. Through qualitative analysis we identified nine categories of novel CEC activities, which we describe by way of examples. In light of the findings, we argue that some novel working methods may be well suited to promote ethical reflection among clinicians, and that the CEC may be a suitable venue for discussing issues of organizational ethics. PMID:26248504

  9. Challenging present concepts in compression therapy: static stiffness index is not consistent and not clinically relevant.

    PubMed

    Kravitz, S; Hegarty-Craver, M; Reid, L

    2016-02-01

    Once a circumferential force is delivered to a limb by a compression device, assuming the tension within the device remains constant, any change in the total force is dependent upon a change in circumference of the limb, with the rate of change (excluding fabric creep) being dependent on the stress strain curve of the device. This article addresses the pre-conceived and well-accepted principle that interface compression delivered by a compression device substantially increases with the position of the limb, based on the positions of sitting (non-weight bearing) to standing and/or during muscle activity (ankle dorsiflexion). Using engineering parameters and clinical measurements, the authors demonstrate that changes in interface pressure are minimal if any, and that the current concept should be modified accordingly. Declaration of interest: This study was sponsored by Carolon. L. Reid, and S. Kravitz are employees of Carolon. M. Hegarty-Craver has received monetary compensation as a researcher for Carolon. PMID:26878373

  10. Gain-of-Function Research and the Relevance to Clinical Practice.

    PubMed

    Kilianski, Andy; Nuzzo, Jennifer B; Modjarrad, Kayvon

    2016-05-01

    The ongoing moratorium on gain-of-function (GOF) research with highly pathogenic avian influenza virus, severe acute respiratory syndrome coronavirus, and Middle East respiratory syndrome coronavirus has drawn attention to the current debate on these research practices and the potential benefits and risks they present. While much of the discussion has been steered by members of the microbiology and policy communities, additional input from medical practitioners will be highly valuable toward developing a broadly inclusive policy that considers the relative value and harm of GOF research. This review attempts to serve as a primer on the topic for the clinical community by providing a historical context for GOF research, summarizing concerns about its risks, and surveying the medical products that it has yielded. PMID:26416657

  11. Molecular identification and susceptibility of clinically relevant Scedosporium spp. in China.

    PubMed

    Wang, Hong; Wan, Zhe; Li, Ruoyu; Lu, Qiaoyun; Yu, Jin

    2015-01-01

    As various new sibling species within the Scedosporium spp. have been described recently, this study was conducted to investigate distribution and antifungal susceptibility profiles of the different species of Scedosporium spp. in China. Twenty-one clinical strains of Scedosporium from China and two strains from Japan were reidentified by MLSA. The analysis included BT2, CAL, RPB, SOD, and ACT and the combination of the five loci. Pseudallescheria boydii complex (17 strains) and S. apiospermum (6 strains) were identified. P. boydii complex included four closely related subgroups: P. boydii (9 strains), P. ellipsoidea (6 strains), P. fusoidea (1 strain), and P. angusta (1 strain). There were no significant differences in MICs for neither VOR, POS, nor AMB over all the five species in study. For itraconazole, intraspecific diversity was evident. PMID:26550562

  12. Sperm DNA damage and its clinical relevance in assessing reproductive outcome.

    PubMed

    Sharma, R K; Said, T; Agarwal, A

    2004-06-01

    The routine examination of semen, which assesses sperm concentration, percentage motility and morphology, does not identify subtle defects in sperm chromatin architecture. The focus on the genomic integrity of the male gamete has intensified recently due to the growing concern that genetic diseases may be transmitted via assisted reproductive techniques (ART). Accordingly, the intent of this review is to describe the details of the information pertaining to mitochondrial/nuclear sperm DNA damage with an emphasis on its clinical significance and its relationship with male infertility. Assessment of sperm DNA damage appears to be a potential tool for evaluating semen samples prior to their use in ART. Testing DNA integrity may help select spermatozoa with intact DNA or with the least amount of DNA damage for use in assisted conception. In turn, this may alleviate the financial, social and emotional problems associated with failed ART attempts. PMID:15154089

  13. Molecular Identification and Susceptibility of Clinically Relevant Scedosporium spp. in China

    PubMed Central

    Wang, Hong; Wan, Zhe; Li, Ruoyu; Lu, Qiaoyun; Yu, Jin

    2015-01-01

    As various new sibling species within the Scedosporium spp. have been described recently, this study was conducted to investigate distribution and antifungal susceptibility profiles of the different species of Scedosporium spp. in China. Twenty-one clinical strains of Scedosporium from China and two strains from Japan were reidentified by MLSA. The analysis included BT2, CAL, RPB, SOD, and ACT and the combination of the five loci. Pseudallescheria boydii complex (17 strains) and S. apiospermum (6 strains) were identified. P. boydii complex included four closely related subgroups: P. boydii (9 strains), P. ellipsoidea (6 strains), P. fusoidea (1 strain), and P. angusta (1 strain). There were no significant differences in MICs for neither VOR, POS, nor AMB over all the five species in study. For itraconazole, intraspecific diversity was evident. PMID:26550562

  14. Clinical relevance of circulating antibodies and B lymphocyte markers in allograft rejection.

    PubMed

    Vallin, Patrice; Désy, Olivier; Béland, Stéphanie; Wagner, Eric; De Serres, Sacha A

    2016-03-01

    The main challenge in solid organ transplantation remains to tackle antibody-mediated rejection. Our understanding of the antibody-mediated response and the capacity to detect it has improved in the last decade. However, the sensitivity and specificity of the current clinical tools to monitor B cell activation are perfectible. New strategies, including the refinement in the characterization of HLA and non-HLA antibodies, as well as a better understanding of the circulating B cell phenotype will hopefully help to non-invasively identify patients at risk or undergoing antibody-mediated allograft damage. The current review discusses the current knowledge of the B cell biomarkers in solid organ transplantation, with a focus on circulating antibodies and peripheral B cells. PMID:26721422

  15. Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing

    PubMed Central

    Jiang, Yong-hui; Yuen, Ryan K.C.; Jin, Xin; Wang, Mingbang; Chen, Nong; Wu, Xueli; Ju, Jia; Mei, Junpu; Shi, Yujian; He, Mingze; Wang, Guangbiao; Liang, Jieqin; Wang, Zhe; Cao, Dandan; Carter, Melissa T.; Chrysler, Christina; Drmic, Irene E.; Howe, Jennifer L.; Lau, Lynette; Marshall, Christian R.; Merico, Daniele; Nalpathamkalam, Thomas; Thiruvahindrapuram, Bhooma; Thompson, Ann; Uddin, Mohammed; Walker, Susan; Luo, Jun; Anagnostou, Evdokia; Zwaigenbaum, Lonnie; Ring, Robert H.; Wang, Jian; Lajonchere, Clara; Wang, Jun; Shih, Andy; Szatmari, Peter; Yang, Huanming; Dawson, Geraldine; Li, Yingrui; Scherer, Stephen W.

    2013-01-01

    Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms. PMID:23849776

  16. Relationship of Premenstrual Syndrome and Premenstrual Dysphoric Disorder with Major Depression: Relevance to Clinical Practice

    PubMed Central

    Padhy, Susanta Kumar; Sarkar, Sidharth; Beherre, Prakash B.; Rathi, Rajesh; Panigrahi, Mahima; Patil, Pradeep Sriram

    2015-01-01

    Background: Premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD) and depressive disorder are fairly common; symptoms do overlap, often under-identified and under-emphasized, particularly in rural India. Objective: The objective was to assess the occurrence of PMS and PMDD in a sample of students and staff of a nursing college and to find their correlation with depression. Materials and Methods: A prospective cohort study; Tertiary Care Hospital in Rural India (Wardha, Maharashtra); 118 female nursing students or staff aged between 18 and 40 years, who were likely to stay within the institution for the study period. The participants were rated on Penn daily symptom report prospectively for a period of 3-month. Those who scored positive were applied diagnostic and statistical manual of mental disorders, 4th edition, text revision (DSM-IV TR) criteria for PMDD; and were applied primary care evaluation of mental disorders depression screening followed by DSM-IV TR criteria for depression. Severity of depression was measured using Hamilton Depression Rating Scale. Results: Main outcome measures were frequency and severity of depression in individuals with PMS and PMDD and their clinical and sociodemographic correlation. The age range of the sample was 18-37 years. Some PMS symptoms were observed in 67%; diagnosis of PMDD in 10%; depressive symptoms in 28% of the sample. 46.4% of those with depressive symptoms had major depression. The diagnosis of major depression was significantly associated with the severity of PMS symptoms as well as the presence of PMDD. Conclusion: Premenstrual syndrome is present in a substantial proportion of young females. Concurrent depression is increased by the severity of PMS symptoms and the presence of PMDD. Gynecologist needs to screen such subjects for depression and refer to mental-health professional early, in routine clinical practice. PMID:25969600

  17. Clinical relevance of CHEK2 and NBN mutations in the macedonian population

    PubMed Central

    Kostovska, I Maleva; Jakimovska, M; Kubelka-Sabit, K; Karadjozov, M; Arsovski, A; Stojanovska, L; Plaseska-Karanfilska, D

    2015-01-01

    Clinical importance of the most common CHEK2 (IVS2+1 G>A, 1100delC, I157T and del5395) and NBN (R215W and 657del5) gene mutations for breast cancer development in Macedonian breast cancer patients is unknown. We performed a case-control study including 300 Macedonian breast cancer patients and 283 Macedonian healthy controls. Genotyping was done using a fast and highly accurate single-nucleotide primer extension method for the detection of five mutations in a single reaction. The detection of the del5395 was performed using an allele-specific duplex polymerase chain reaction (PCR) assay. We have found that mutations were more frequent in breast cancer patients (n = 13, 4.3%) than in controls (n = 5, 1.8%), although without statistical significance. Twelve patients were heterozygous for one of the analyzed mutations, while one patient had two mutations (NBN R215W and CHEK2 I157T). The most frequent variant was I157T, found in 10 patients and four controls (p = 0.176) and was found to be associated with familial breast cancer (p = 0.041). CHEK2 1100delC and NBN 657del5 were each found in one patient and not in the control group. CHEK2 IVS2+1G>A and del5395 were not found in our cohort. Frequencies of the studied mutations are low and they are not likely to represent alleles of clinical importance in the Macedonian population. PMID:26929905

  18. Clinical relevance of CHEK2 and NBN mutations in the macedonian population.

    PubMed

    Kostovska, I Maleva; Jakimovska, M; Kubelka-Sabit, K; Karadjozov, M; Arsovski, A; Stojanovska, L; Plaseska-Karanfilska, D

    2015-06-01

    Clinical importance of the most common CHEK2 (IVS2+1 G>A, 1100delC, I157T and del5395) and NBN (R215W and 657del5) gene mutations for breast cancer development in Macedonian breast cancer patients is unknown. We performed a case-control study including 300 Macedonian breast cancer patients and 283 Macedonian healthy controls. Genotyping was done using a fast and highly accurate single-nucleotide primer extension method for the detection of five mutations in a single reaction. The detection of the del5395 was performed using an allele-specific duplex polymerase chain reaction (PCR) assay. We have found that mutations were more frequent in breast cancer patients (n = 13, 4.3%) than in controls (n = 5, 1.8%), although without statistical significance. Twelve patients were heterozygous for one of the analyzed mutations, while one patient had two mutations (NBN R215W and CHEK2 I157T). The most frequent variant was I157T, found in 10 patients and four controls (p = 0.176) and was found to be associated with familial breast cancer (p = 0.041). CHEK2 1100delC and NBN 657del5 were each found in one patient and not in the control group. CHEK2 IVS2+1G>A and del5395 were not found in our cohort. Frequencies of the studied mutations are low and they are not likely to represent alleles of clinical importance in the Macedonian population. PMID:26929905

  19. Clinical relevance of Küttner tumour and IgG4-related dacryoadenitis and sialoadenitis

    PubMed Central

    Furukawa, S; Moriyama, M; Kawano, S; Tanaka, A; Maehara, T; Hayashida, J-N; Goto, Y; Kiyoshima, T; Shiratsuchi, H; Ohyama, Y; Ohta, M; Imabayashi, Y; Nakamura, S

    2015-01-01

    Objectives Küttner tumour (KT), so-called chronic sclerosing sialoadenitis, is characterised by concomitant swelling of the submandibular glands secondary to strong lymphocytic infiltration and fibrosis independent of sialolith formation. However, recent studies have indicated that some patients with KT develop high serum levels of IgG4 and infiltration of IgG4-positive plasma cells, namely IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz's disease. The aim of this study was to clarify the clinical and pathological associations between KT and IgG4-DS. Materials and Methods Fifty-four patients pathologically diagnosed with KT or chronic sialoadenitis were divided into two groups according to the presence or absence of sialolith (KT-S (+) or KT-S (−), respectively). Results There were no significant differences in the clinical findings, including the mean age, sex and disease duration, between the two groups. All patients in the KT-S (+) group showed unilateral swelling without infiltration of IgG4-positive plasma cells or a history of other IgG4-related diseases (IgG4-RD), while those in the KT-S (−) group showed bilateral swelling (37.5%), strong infiltration of IgG4-positive plasma cells (87.5%) and a history of other IgG4-RD (12.5%). Conclusions These results suggest an association between the pathogeneses of KT-S (−) and IgG4-DS, but not KT-S (+). PMID:24844187

  20. Assessment of elasticity of colorectal cancer tissue, clinical utility, pathological and phenotypical relevance

    PubMed Central

    Kawano, Shingo; Kojima, Motohiro; Higuchi, Yoichi; Sugimoto, Motokazu; Ikeda, Koji; Sakuyama, Naoki; Takahashi, Shinichiro; Hayashi, Ryuichi; Ochiai, Atsushi; Saito, Norio

    2015-01-01

    Generally, cancer tissue is palpated as a hard mass. However, the elastic nature of cancer tissue is not well understood. The aim of the present study was to evaluate the clinical utility of measuring the elastic modulus (EM) in colorectal cancer tissue. Using a tactile sensor, we measured the EM of 106 surgically resected colorectal cancer tissues. Data on the EM were compared with clinicopathological findings, including stromal features represented by Azan staining and the α-SMA positive area ratio of the tumor area. Finally, a cDNA microarray profile of the tumors with high EM were compared with the findings of tumors with low EM. A higher EM in tumors was associated with pathological T, N, and M-stage tumors (P < 0.001, P = 0.001 and P = 0.011, respectively). Patients with high EM tumors had shorter disease-free survival than had patients with low EM. The EM showed strongly positive correlation with the Azan staining positive area ratio (r = 0.908) and the α-SMA positive area ratio (r = 0.921). Finally, the cDNA microarray data of the tumors with high EM revealed a distinct gene expression profile compared with data from those tumors with low EM. The assessment of the elasticity of colorectal cancer tissue may allow a more accurate clinical stage and prognosis estimation. The distinct phenotypical features of the high EM tumors and their strong association with stromal features suggest the existence of a biological mechanism involved in this phenomenon that may contribute to future therapy. PMID:26083008

  1. Epigenetic regulation of EFEMP1 in prostate cancer: biological relevance and clinical potential

    PubMed Central

    Almeida, Mafalda; Costa, Vera L; Costa, Natália R; Ramalho-Carvalho, João; Baptista, Tiago; Ribeiro, Franclim R; Paulo, Paula; Teixeira, Manuel R; Oliveira, Jorge; Lothe, Ragnhild A; Lind, Guro E; Henrique, Rui; Jerónimo, Carmen

    2014-01-01

    Epigenetic alterations are common in prostate cancer (PCa) and seem to contribute decisively to its initiation and progression. Moreover, aberrant promoter methylation is a promising biomarker for non-invasive screening. Herein, we sought to characterize EFEMP1 as biomarker for PCa, unveiling its biological relevance in prostate carcinogenesis. Microarray analyses of treated PCa cell lines and primary tissues enabled the selection of differentially methylated genes, among which EFEMP1 was further validated by MSP and bisulfite sequencing. Assessment of biomarker performance was accomplished by qMSP. Expression analysis of EFEMP1 and characterization of histone marks were performed in tissue samples and cancer cell lines to determine the impact of epigenetic mechanisms on EFEMP1 transcriptional regulation. Phenotypic assays, using transfected cell lines, permitted the evaluation of EFEMP1’s role in PCa development. EFEMP1 methylation assay discriminated PCa from normal prostate tissue (NPT; P < 0.001, Kruskall–Wallis test) and renal and bladder cancers (96% sensitivity and 98% specificity). EFEMP1 transcription levels inversely correlated with promoter methylation and histone deacetylation, suggesting that both epigenetic mechanisms are involved in gene regulation. Phenotypic assays showed that EFEMP1 de novo expression reduces malignant phenotype of PCa cells. EFEMP1 promoter methylation is prevalent in PCa and accurately discriminates PCa from non-cancerous prostate tissues and other urological neoplasms. This epigenetic alteration occurs early in prostate carcinogenesis and, in association with histone deacetylation, progressively leads to gene down-regulation, fostering cell proliferation, invasion and evasion of apoptosis. PMID:25211630

  2. Diagnostic and clinical relevance of the autophago-lysosomal network in human gliomas

    PubMed Central

    Jennewein, Lukas; Ronellenfitsch, Michael W.; Antonietti, Patrick; Ilina, Elena I.; Jung, Jennifer; Stadel, Daniela; Flohr, Lisa-Marie; Zinke, Jenny; von Renesse, Janusz; Drott, Ulrich; Baumgarten, Peter; Braczynski, Anne K.; Penski, Cornelia; Burger, Michael C.; Theurillat, Jean-Philippe; Steinbach, Joachim P.; Plate, Karl-Heinz; Dikic, Ivan; Fulda, Simone; Brandts, Christian; Kögel, Donat; Behrends, Christian; Harter, Patrick N.; Mittelbronn, Michel

    2016-01-01

    Recently, the conserved intracellular digestion mechanism ‘autophagy’ has been considered to be involved in early tumorigenesis and its blockade proposed as an alternative treatment approach. However, there is an ongoing debate about whether blocking autophagy has positive or negative effects in tumor cells. Since there is only poor data about the clinico-pathological relevance of autophagy in gliomas in vivo, we first established a cell culture based platform for the in vivo detection of the autophago-lysosomal components. We then investigated key autophagosomal (LC3B, p62, BAG3, Beclin1) and lysosomal (CTSB, LAMP2) molecules in 350 gliomas using immunohistochemistry, immunofluorescence, immunoblotting and qPCR. Autophagy was induced pharmacologically or by altering oxygen and nutrient levels. Our results show that autophagy is enhanced in astrocytomas as compared to normal CNS tissue, but largely independent from the WHO grade and patient survival. A strong upregulation of LC3B, p62, LAMP2 and CTSB was detected in perinecrotic areas in glioblastomas suggesting micro-environmental changes as a driver of autophagy induction in gliomas. Furthermore, glucose restriction induced autophagy in a concentration-dependent manner while hypoxia or amino acid starvation had considerably lesser effects. Apoptosis and autophagy were separately induced in glioma cells both in vitro and in vivo. In conclusion, our findings indicate that autophagy in gliomas is rather driven by micro-environmental changes than by primary glioma-intrinsic features thus challenging the concept of exploitation of the autophago-lysosomal network (ALN) as a treatment approach in gliomas. PMID:26956048

  3. Enchondromatosis: insights on the different subtypes

    PubMed Central

    Pansuriya, Twinkal C; Kroon, Herman M; Bovée, Judith VMG

    2010-01-01

    Enchondromatosis is a rare, heterogeneous skeletal disorder in which patients have multiple enchondromas. Enchondromas are benign hyaline cartilage forming tumors in the medulla of metaphyseal bone. The disorder manifests itself early in childhood without any significant gender bias. Enchondromatosis encompasses several different subtypes of which Ollier disease and Maffucci syndrome are most common, while the other subtypes (metachondromatosis, genochondromatosis, spondyloenchondrodysplasia, dysspondyloenchondromatosis and cheirospondyloenchondromatosis) are extremely rare. Most subtypes are non-hereditary, while some are autosomal dominant or recessive. The gene(s) causing the different enchondromatosis syndromes are largely unknown. They should be distinguished and adequately diagnosed, not only to guide therapeutic decisions and genetic counseling, but also with respect to research into their etiology. For a longtime enchondromas have been considered a developmental disorder caused by the failure of normal endochondral bone formation. With the identification of genetic abnormalities in enchondromas however, they were being thought of as neoplasms. Active hedgehog signaling is reported to be important for enchondroma development and PTH1R mutations have been identified in ∼10% of Ollier patients. One can therefore speculate that the gene(s) causing the different enchondromatosis subtypes are involved in hedgehog/PTH1R growth plate signaling. Adequate distinction within future studies will shed light on whether these subtypes are different ends of a spectrum caused by a single gene, or that they represent truely different diseases. We therefore review the available clinical information for all enchondromatosis subtypes and discuss the little molecular data available hinting towards their cause. PMID:20661403

  4. Are licensed canine parvovirus (CPV2 and CPV2b) vaccines able to elicit protection against CPV2c subtype in puppies?: A systematic review of controlled clinical trials.

    PubMed

    Hernández-Blanco, Beatriz; Catala-López, Ferrán

    2015-10-22

    Severe gastroenteritis caused by canine parvovirus type 2 (CPV2) is a serious life-threatening disease in puppies less than 4-months of age. The emergence of new variants has provoked some concern about the cross-protection elicited by licensed canine parvovirus modified-live type 2 (CPV2) and type 2b (CPV2b) vaccines against the most recent subtype CPV2c. A systematic review was carried out to assess the efficacy of commercial vaccines. We conducted a literature search of Pub Med/MEDLINE from January 1990 to May 2014. This was supplemented by hand-searching of related citations and searches in Google/Google Scholar. Controlled clinical trials in which vaccinated puppies were challenged with CPV2c virus were evaluated. Reporting of outcome measures and results for vaccine efficacy were critically appraised through a variety of clinical signs, serological tests, virus shedding and the ability to overcome maternally derived antibodies (MDA) titres. Six controlled clinical trials were included in the review. In most cases, the results of the selected studies reported benefits in terms of clinical signs, serological tests and virus shedding. However, MDA interference was not considered or evaluated in 5 of the selected trials. No accurate definitions of baseline healthy status and/or clinical outcomes were provided. Methods of randomization, allocation concealment and blinding were usually poorly reported. As a result of the limited number of included studies matching the inclusion criteria, the small sample sizes, short follow-up and the methodological limitations observed, it was not possible to reach a final conclusion regarding the cross-protection of licensed CPV2 and CPV2b vaccines against the subtype 2c in puppies. Further and specifically designed trials are required in order to elucidate whether cross-protection is acquired from licensed CPV vaccines. PMID:26249827

  5. Integrative topological analysis of mass spectrometry data reveals molecular features with clinical relevance in esophageal squamous cell carcinoma.

    PubMed

    Gao, She-Gan; Liu, Rui-Min; Zhao, Yun-Gang; Wang, Pei; Ward, Douglas G; Wang, Guang-Chao; Guo, Xiang-Qian; Gu, Juan; Niu, Wan-Bin; Zhang, Tian; Martin, Ashley; Guo, Zhi-Peng; Feng, Xiao-Shan; Qi, Yi-Jun; Ma, Yuan-Fang

    2016-01-01

    Combining MS-based proteomic data with network and topological features of such network would identify more clinically relevant molecules and meaningfully expand the repertoire of proteins derived from MS analysis. The integrative topological indexes representing 95.96% information of seven individual topological measures of node proteins were calculated within a protein-protein interaction (PPI) network, built using 244 differentially expressed proteins (DEPs) identified by iTRAQ 2D-LC-MS/MS. Compared with DEPs, differentially expressed genes (DEGs) and comprehensive features (CFs), structurally dominant nodes (SDNs) based on integrative topological index distribution produced comparable classification performance in three different clinical settings using five independent gene expression data sets. The signature molecules of SDN-based classifier for distinction of early from late clinical TNM stages were enriched in biological traits of protein synthesis, intracellular localization and ribosome biogenesis, which suggests that ribosome biogenesis represents a promising therapeutic target for treating ESCC. In addition, ITGB1 expression selected exclusively by integrative topological measures correlated with clinical stages and prognosis, which was further validated with two independent cohorts of ESCC samples. Thus the integrative topological analysis of PPI networks proposed in this study provides an alternative approach to identify potential biomarkers and therapeutic targets from MS/MS data with functional insights in ESCC. PMID:26898710

  6. Integrative topological analysis of mass spectrometry data reveals molecular features with clinical relevance in esophageal squamous cell carcinoma

    PubMed Central

    Gao, She-Gan; Liu, Rui-Min; Zhao, Yun-Gang; Wang, Pei; Ward, Douglas G.; Wang, Guang-Chao; Guo, Xiang-Qian; Gu, Juan; Niu, Wan-Bin; Zhang, Tian; Martin, Ashley; Guo, Zhi-Peng; Feng, Xiao-Shan; Qi, Yi-Jun; Ma, Yuan-Fang

    2016-01-01

    Combining MS-based proteomic data with network and topological features of such network would identify more clinically relevant molecules and meaningfully expand the repertoire of proteins derived from MS analysis. The integrative topological indexes representing 95.96% information of seven individual topological measures of node proteins were calculated within a protein-protein interaction (PPI) network, built using 244 differentially expressed proteins (DEPs) identified by iTRAQ 2D-LC-MS/MS. Compared with DEPs, differentially expressed genes (DEGs) and comprehensive features (CFs), structurally dominant nodes (SDNs) based on integrative topological index distribution produced comparable classification performance in three different clinical settings using five independent gene expression data sets. The signature molecules of SDN-based classifier for distinction of early from late clinical TNM stages were enriched in biological traits of protein synthesis, intracellular localization and ribosome biogenesis, which suggests that ribosome biogenesis represents a promising therapeutic target for treating ESCC. In addition, ITGB1 expression selected exclusively by integrative topological measures correlated with clinical stages and prognosis, which was further validated with two independent cohorts of ESCC samples. Thus the integrative topological analysis of PPI networks proposed in this study provides an alternative approach to identify potential biomarkers and therapeutic targets from MS/MS data with functional insights in ESCC. PMID:26898710

  7. Understanding the Supersensitive Anti-Drug Antibody Assay: Unexpected High Anti-Drug Antibody Incidence and Its Clinical Relevance

    PubMed Central

    2016-01-01

    Numbers of biotherapeutic products in development have increased over past decade. Despite providing significant benefits to patients with unmet needs, almost all protein-based biotherapeutics could induce unwanted immunogenicity, which result in a loss of efficacy and/or increase the risk of adverse reactions, such as infusion reactions, anaphylaxis, and even life-threatening response to endogenous proteins. Recognizing these possibilities, regulatory agencies request that immunogenicity be assessed as part of the approval process for biotherapeutics. Great efforts have been made to reduce drug immunogenicity through protein engineering. Accordingly the immunogenicity incidence has been reduced from around 80% in murine derived products to 0–10% in fully human products. However, recent improvements in immunogenicity assays have led to unexpectedly high immunogenicity rates, even in fully human products, leading to new challenges in assessing immunogenicity and its clinical relevance. These new immunogenicity assays are becoming supersensitive and able to detect more of anti-drug antibodies (ADA) than with earlier assays. This paper intends to review and discuss our understanding of the supersensitive ADA assay and the unexpected high ADA incidence and its potential clinical relevance. PMID:27340678

  8. The evolution and clinical relevance of prognostic classification systems in myelofibrosis.

    PubMed

    Bose, Prithviraj; Verstovsek, Srdan

    2016-03-01

    Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by often debilitating constitutional symptoms and splenomegaly, bone marrow fibrosis and resultant cytopenias, extramedullary hematopoiesis, risk of leukemic transformation, and shortened survival. Post-polycythemia vera and post-essential thrombocythemia myelofibrosis represent similar entities, although some differences are being recognized. Attempts to classify patients with myelofibrosis into prognostic categories have been made since the late 1980s, and these scoring systems continue to evolve as new information becomes available. Over the last decade, the molecular pathogenesis of MPNs has been elucidated considerably, and the Janus kinase (JAK) 1/2 inhibitor ruxolitinib is the first drug specifically approved by the US Food and Drug Administration to treat patients with intermediate-risk and high-risk myelofibrosis. This article reviews the evolution of prognostic criteria in myelofibrosis, emphasizing the major systems widely in use today, as well as recently described, novel systems that incorporate emerging data regarding somatic mutations. Risk factors for thrombosis and conversion to MPN blast phase also are discussed. Finally, the practical usefulness of the current prognostic classification systems in terms of clinical decision making is discussed, particularly within the context of some of their inherent weaknesses. Cancer 2016;122:681-692. © 2015 American Cancer Society. PMID:26717494

  9. Clinicians' emotional responses and Psychodynamic Diagnostic Manual adult personality disorders: A clinically relevant empirical investigation.

    PubMed

    Gazzillo, Francesco; Lingiardi, Vittorio; Del Corno, Franco; Genova, Federica; Bornstein, Robert F; Gordon, Robert M; McWilliams, Nancy

    2015-06-01

    The aim of this study is to explore the relationship between level of personality organization and type of personality disorder as assessed with the categories in the Psychodynamic Diagnostic Manual (PDM; PDM Task Force, 2006) and the emotional responses of treating clinicians. We asked 148 Italian clinicians to assess 1 of their adult patients in treatment for personality disorders with the Psychodiagnostic Chart (PDC; Gordon & Bornstein, 2012) and the Personality Diagnostic Prototype (PDP; Gazzillo, Lingiardi, & Del Corno, 2012) and to complete the Therapist Response Questionnaire (TRQ; Betan, Heim, Zittel-Conklin, & Westen, 2005). The patients' level of overall personality pathology was positively associated with helpless and overwhelmed responses in clinicians and negatively associated with positive emotional responses. A parental and disengaged response was associated with the depressive, anxious, and dependent personality disorders; an exclusively parental response with the phobic personality disorder; and a parental and criticized response with narcissistic disorder. Dissociative disorder evoked a helpless and parental response in the treating clinicians whereas somatizing disorder elicited a disengaged reaction. An overwhelmed and disengaged response was associated with sadistic and masochistic personality disorders, with the latter also associated with a parental and hostile/criticized reaction; an exclusively overwhelmed response with psychopathic patients; and a helpless response with paranoid patients. Finally, patients with histrionic personality disorder evoked an overwhelmed and sexualized response in their clinicians whereas there was no specific emotional reaction associated with the schizoid and the obsessive-compulsive disorders. Clinical implications of these findings were discussed. PMID:25868053

  10. Clinical relevance of multiple antibody specificity testing in anti-phospholipid syndrome and recurrent pregnancy loss

    PubMed Central

    Tebo, A E; Jaskowski, T D; Hill, H R; Branch, D W

    2008-01-01

    We wanted to evaluate whether testing for anti-phosholipid antibodies other than anti-cardiolipin (aCL) and anti-beta-2 glycoprotein I (aβ2GPI) immunoglobulin (Ig)G and IgM identifies patients with recurrent pregnancy loss (RPL) who may be positive for anti-phospholipid syndrome (APS). In a cross-sectional study comprising 62 patients with APS, 66 women with RPL, 50 healthy blood donors and 24 women with a history of successful pregnancies, we tested IgM and IgG antibodies to phosphatidic acid, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl glycerol, phosphatidyl inositol and phosphatidyl serine with and without beta-2 glycoprotein I (β2GPI) from a single manufacturer as well as aCL and aβ2GPI antibodies. Diagnostic accuracies of individual and combined anti-phospholipid (aPL) assays were assessed by computing sensitivities, specificities, positive predictive values and negative predictive values together with their 95% confidence intervals. There was a general trend for increased sensitivities in the presence of β2GPI co-factor with significant effect for certain specificities. The overall combined sensitivity of the non-recommended aPL assays was not significantly higher than that of the aCL and aB2GPI tests. Multiple aPL specificities in RPL group is not significantly different from controls and therefore of no clinical significance. PMID:18826497

  11. Clinical relevance of multiple antibody specificity testing in anti-phospholipid syndrome and recurrent pregnancy loss.

    PubMed

    Tebo, A E; Jaskowski, T D; Hill, H R; Branch, D W

    2008-12-01

    We wanted to evaluate whether testing for anti-phosholipid antibodies other than anti-cardiolipin (aCL) and anti-beta-2 glycoprotein I (abeta2GPI) immunoglobulin (Ig)G and IgM identifies patients with recurrent pregnancy loss (RPL) who may be positive for anti-phospholipid syndrome (APS). In a cross-sectional study comprising 62 patients with APS, 66 women with RPL, 50 healthy blood donors and 24 women with a history of successful pregnancies, we tested IgM and IgG antibodies to phosphatidic acid, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl glycerol, phosphatidyl inositol and phosphatidyl serine with and without beta-2 glycoprotein I (beta2GPI) from a single manufacturer as well as aCL and abeta2GPI antibodies. Diagnostic accuracies of individual and combined anti-phospholipid (aPL) assays were assessed by computing sensitivities, specificities, positive predictive values and negative predictive values together with their 95% confidence intervals. There was a general trend for increased sensitivities in the presence of beta2GPI co-factor with significant effect for certain specificities. The overall combined sensitivity of the non-recommended aPL assays was not significantly higher than that of the aCL and aB2GPI tests. Multiple aPL specificities in RPL group is not significantly different from controls and therefore of no clinical significance. PMID:18826497

  12. The Link between the Appendix and Ulcerative Colitis: Clinical Relevance and Potential Immunological Mechanisms.

    PubMed

    Sahami, S; Kooij, I A; Meijer, S L; Van den Brink, G R; Buskens, C J; Te Velde, A A

    2016-02-01

    The human appendix has long been considered as a vestigial organ, an organ that has lost its function during evolution. In recent years, however, reports have emerged that link the appendix to numerous immunological functions in humans. Evidence has been presented for an important role of the appendix in maintaining intestinal health. This theory suggests that the appendix may be a reservoir or 'safe house' from which the commensal gut flora can rapidly be reestablished if it is eradicated from the colon. However, the appendix may also have a role in the development of inflammatory bowel disease (IBD). Several large epidemiological cohort studies have demonstrated the preventive effect of appendectomy on the development of ulcerative colitis, a finding that has been confirmed in murine colitis models. In addition, current studies are examining the possible therapeutic effect of an appendectomy to modulate disease course in patients with ulcerative colitis. This literature review assesses the current knowledge about the clinical and immunological aspects of the vermiform appendix in IBD and suggests that the idea of the appendix as a vestigial remnant should be discarded. PMID:26416189

  13. Molecular Probes for Diagnosis of Clinically Relevant Bacterial Infections in Blood Cultures▿

    PubMed Central

    Hansen, Wendy L. J.; Beuving, Judith; Bruggeman, Cathrien A.; Wolffs, Petra F. G.

    2010-01-01

    Broad-range real-time PCR and sequencing of the 16S rRNA gene region is a widely known method for the detection and identification of bacteria in clinical samples. However, because of the need for sequencing, such identification of bacteria is time-consuming. The aim of our study was to develop a more rapid 16S real-time PCR-based identification assay using species- or genus-specific probes. The Gram-negative bacteria were divided into Pseudomonas species, Pseudomonas aeruginosa, Escherichia coli, and other Gram-negative species. Within the Gram-positive species, probes were designed for Staphylococcus species, Staphylococcus aureus, Enterococcus species, Streptococcus species, and Streptococcus pneumoniae. The assay also included a universal probe within the 16S rRNA gene region for the detection of all bacterial DNA. The assay was evaluated with a collection of 248 blood cultures. In this study, the universal probe and the probes targeting Pseudomonas spp., P. aeruginosa, E. coli, Streptococcus spp., S. pneumoniae, Enterococcus spp., and Staphylococcus spp. all had a sensitivity and specificity of 100%. The probe specific for S. aureus showed eight discrepancies, resulting in a sensitivity of 100% and a specificity of 93%. These data showed high agreement between conventional testing and our novel real-time PCR assay. Furthermore, this assay significantly reduced the time needed for identification. In conclusion, using pathogen-specific probes offers a faster alternative for pathogen detection and could improve the diagnosis of bloodstream infections. PMID:20962139

  14. Resistance to Antibiotics of Clinical Relevance in the Fecal Microbiota of Mexican Wildlife

    PubMed Central

    Cristóbal-Azkarate, Jurgi; Dunn, Jacob C.; Day, Jennifer M. W.; Amábile-Cuevas, Carlos F.

    2014-01-01

    There are a growing number of reports of antibiotic resistance (ATBR) in bacteria living in wildlife. This is a cause for concern as ATBR in wildlife represents a potential public health threat. However, little is known about the factors that might determine the presence, abundance and dispersion of ATBR bacteria in wildlife. Here, we used culture and molecular methods to assess ATBR in bacteria in fecal samples from howler monkeys (Alouatta palliata), spider monkeys (Ateles geoffroyi), tapirs (Tapirus bairdii) and felids (jaguars, Panthera onca; pumas, Puma concolor; jaguarundis, Puma yagouaroundi; and ocelots, Leopardus pardalis) living freely in two regions of the Mexican state of Veracruz under different degrees of human influence. Overall, our study shows that ATBR is commonplace in bacteria isolated from wildlife in southeast Mexico. Most of the resistances were towards old and naturally occurring antibiotics, but we also observed resistances of potential clinical significance. We found that proximity to humans positively affected the presence of ATBR and that ATBR was higher in terrestrial than arboreal species. We also found evidence suggesting different terrestrial and aerial routes for the transmission of ATBR between humans and wildlife. The prevalence and potential ATBR transfer mechanisms between humans and wildlife observed in this study highlight the need for further studies to identify the factors that might determine ATBR presence, abundance and distribution. PMID:25233089

  15. Structure-activity relationship studies on clinically relevant HIV-1 NNRTIs.

    PubMed

    Rawal, R K; Murugesan, V; Katti, S B

    2012-01-01

    In addition to the nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs) and integrase inhibitors (INIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) have contributed significantly in the treatment of HIV-1 infections. More than 60 structurally different classes of compounds have been identified as NNRTIs, which are specifically inhibiting HIV-1 reverse transcriptase (RT). Five NNRTIs (nevirapine, delavirdine, efavirenz, etravirine and rilpivirine) have been approved by US Food and Drug Administration (FDA) for clinical use. The NNRTIs bind with a specific 'pocket' site of HIV-1 RT (allosteric site) that is closely associated with the NRTI binding site. Due to mutations of the amino acid residues surrounding the NNRTI-binding site, NNRTIs are notorious for rapidly eliciting resistance. Though, the emergence of resistant HIV strains can be circumvented if the NNRTIs are used either alone or in combination with NRTIs (AZT, 3TC, ddI, ddC, TVD or d4T) and PIs (Indinavir, nelfinavir, saquinavir, ritonavir and lopinavir etc.) as shown by both a decrease in plasma HIV-1 RNA levels and increased CD4 T-cells. Here we are going to discuss recent advances in structure activity relationship studies on nevirapine, delavirdine, efavirenz, etravirine, rilpivirine and 4-thiazolidinones (privileged scaffold) HIV-1 NNRTIs. PMID:22998569

  16. Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants.

    PubMed

    Kobayashi, Masanori; Nakahara, Koichiro; Seki, Takahiro; Miki, Shigeru; Kawauchi, Shinobu; Suyama, Akemi; Wakasa-Morimoto, Chiaki; Kodama, Makoto; Endoh, Takeshi; Oosugi, Eiichi; Matsushita, Yoshihiro; Murai, Hitoshi; Fujishita, Toshio; Yoshinaga, Tomokazu; Garvey, Edward; Foster, Scott; Underwood, Mark; Johns, Brian; Sato, Akihiko; Fujiwara, Tamio

    2008-11-01

    Resistance passage studies were conducted with five INIs (integrase inhibitors) that have been tested in clinical trials to date: a new naphthyridinone-type INI S/GSK-364735, raltegravir, elvitegravir, L-870,810 and S-1360. In establishing the passage system and starting from concentrations several fold above the EC(50) value, resistance mutations against S-1360 and related diketoacid-type compounds could be isolated from infected MT-2 cell cultures from day 14 to 28. Q148R and F121Y were the two main pathways of resistance to S/GSK-364735. Q148R/K and N155H, which were found in patients failing raltegravir treatment in Phase IIb studies, were observed during passage with raltegravir with this method. The fold resistance of 40 mutant molecular clones versus wild type virus was compared with these five INIs. The overall resistance pattern of S/GSK-364735 was similar to that of raltegravir and other INIs. However, different fold resistances of particular mutations were noted among different INIs, reflecting a potential to develop INIs with distinctly different resistant profiles. PMID:18625269

  17. The Power of Phase I Studies to Detect Clinical Relevant QTc Prolongation: A Resampling Simulation Study

    PubMed Central

    Ferber, Georg; Lorch, Ulrike; Täubel, Jörg

    2015-01-01

    Concentration-effect (CE) models applied to early clinical QT data from healthy subjects are described in the latest E14 Q&A document as promising analysis to characterise QTc prolongation. The challenges faced if one attempts to replace a TQT study by thorough ECG assessments in Phase I based on CE models are the assurance to obtain sufficient power and the establishment of a substitute for the positive control to show assay sensitivity providing protection against false negatives. To demonstrate that CE models in small studies can reliably predict the absence of an effect on QTc, we investigated the role of some key design features in the power of the analysis. Specifically, the form of the CE model, inclusion of subjects on placebo, and sparse sampling on the performance and power of this analysis were investigated. In this study, the simulations conducted by subsampling subjects from 3 different TQT studies showed that CE model with a treatment effect can be used to exclude small QTc effects. The number of placebo subjects was also shown to increase the power to detect an inactive drug preventing false positives while an effect can be underestimated if time points around tmax are missed. PMID:26509147

  18. Soluble Epidermal Growth Factor Receptors (sEGFRs) in Cancer: Biological Aspects and Clinical Relevance

    PubMed Central

    Maramotti, Sally; Paci, Massimiliano; Manzotti, Gloria; Rapicetta, Cristian; Gugnoni, Mila; Galeone, Carla; Cesario, Alfredo; Lococo, Filippo

    2016-01-01

    The identification of molecules that can reliably detect the presence of a tumor or predict its behavior is one of the biggest challenges of research in cancer biology. Biological fluids are intriguing mediums, containing many molecules that express the individual health status and, accordingly, may be useful in establishing the potential risk of cancer, defining differential diagnosis and prognosis, predicting the response to treatment, and monitoring the disease progression. The existence of circulating soluble growth factor receptors (sGFRs) deriving from their membrane counterparts has stimulated the interest of researchers to investigate the use of such molecules as potential cancer biomarkers. But what are the origins of circulating sGFRs? Are they naturally occurring molecules or tumor-derived products? Among these, the epidermal growth factor receptor (EGFR) is a cell-surface molecule significantly involved in cancer development and progression; it can be processed into biological active soluble isoforms (sEGFR). We have carried out an extensive review of the currently available literature on the sEGFRs and their mechanisms of regulation and biological function, with the intent to clarify the role of these molecules in cancer (and other pathological conditions) and, on the basis of the retrieved evidences, speculate about their potential use in the clinical setting. PMID:27104520

  19. Resistance to antibiotics of clinical relevance in the fecal microbiota of Mexican wildlife.

    PubMed

    Cristóbal-Azkarate, Jurgi; Dunn, Jacob C; Day, Jennifer M W; Amábile-Cuevas, Carlos F

    2014-01-01

    There are a growing number of reports of antibiotic resistance (ATBR) in bacteria living in wildlife. This is a cause for concern as ATBR in wildlife represents a potential public health threat. However, little is known about the factors that might determine the presence, abundance and dispersion of ATBR bacteria in wildlife. Here, we used culture and molecular methods to assess ATBR in bacteria in fecal samples from howler monkeys (Alouatta palliata), spider monkeys (Ateles geoffroyi), tapirs (Tapirus bairdii) and felids (jaguars, Panthera onca; pumas, Puma concolor; jaguarundis, Puma yagouaroundi; and ocelots, Leopardus pardalis) living freely in two regions of the Mexican state of Veracruz under different degrees of human influence. Overall, our study shows that ATBR is commonplace in bacteria isolated from wildlife in southeast Mexico. Most of the resistances were towards old and naturally occurring antibiotics, but we also observed resistances of potential clinical significance. We found that proximity to humans positively affected the presence of ATBR and that ATBR was higher in terrestrial than arboreal species. We also found evidence suggesting different terrestrial and aerial routes for the transmission of ATBR between humans and wildlife. The prevalence and potential ATBR transfer mechanisms between humans and wildlife observed in this study highlight the need for further studies to identify the factors that might determine ATBR presence, abundance and distribution. PMID:25233089

  20. Reciprocal regulation of the nitric oxide and cyclooxygenase pathway in pathophysiology: relevance and clinical implications

    PubMed Central

    Kim, Sangwon F.; Mollace, Vincenzo

    2013-01-01

    The nitric oxide (NO) and cyclooxygenase (COX) pathways share a number of similarities. Nitric oxide is the mediator generated from the NO synthase (NOS) pathway, and COX converts arachidonic acid to prostaglandins, prostacyclin, and thromboxane A2. Two major forms of NOS and COX have been identified to date. The constitutive isoforms critically regulate several physiological states. The inducible isoforms are overexpressed during inflammation in a variety of cells, producing large amounts of NO and prostaglandins, which may underlie pathological processes. The cross-talk between the COX and NOS pathways was initially reported by Salvemini and colleagues in 1993, when they demonstrated in a series of in vitro and in vivo studies that NO activates the COX enzymes to produce increased amounts of prostaglandins. Those studies led to the concept that COX enzymes represent important endogenous “receptor” targets for amplifying or modulating the multifaceted roles of NO in physiology and pathology. Since then, numerous studies have furthered our mechanistic understanding of these interactions in pathophysiological settings and delineated potential clinical outcomes. In addition, emerging evidence suggests that the canonical nitroxidative species (NO, superoxide, and/or peroxynitrite) modulate biosynthesis of prostaglandins through non-COX-related pathways. This article provides a comprehensive state-of-the art overview in this area. PMID:23389111

  1. Endoscopic Pancreas Fluid Collection: Methods and Relevance for Clinical Care and Translational Science.

    PubMed

    Hart, Phil A; Topazian, Mark; Raimondo, Massimo; Cruz-Monserrate, Zobeida; Fisher, William E; Lesinski, Gregory B; Steen, Hanno; Conwell, Darwin L

    2016-09-01

    Pancreatic secretions have an important role in the regulation of a normal nutritional state but can be altered owing to a variety of pathophysiological mechanisms in the context of exocrine pancreatic disease. The development of an endoscopic technique for collection of pancreatic fluid, termed endoscopic pancreatic function testing, has led to improved understanding of these alterations and is particularly helpful to characterize chronic pancreatitis. In addition, investigators have found endoscopically collected pancreatic fluid to be a valuable biofluid for the purposes of translational science. Techniques such as proteomic, cytokine, genetic mutation, DNA methylation, and microRNA analyses, among others, can be utilized to gain a better understanding of the molecular characteristics of chronic pancreatitis and other pancreatic diseases. Endoscopic collection of pancreatic fluid is safe and relatively straightforward, permitting opportunities for longitudinal analysis of these translational markers throughout the course of disease. This manuscript summarizes our current knowledge of pancreatic fluid, with an emphasis on proper techniques for sample collection and handling, its clinical utility, and preliminary observations in translational science. PMID:27481304

  2. The 'species complex' issue in clinically relevant fungi: A case study in Scedosporium apiospermum.

    PubMed

    Chen, Min; Zeng, Jingsi; De Hoog, G Sybren; Stielow, Benjamin; Gerrits Van Den Ende, A H G; Liao, Wanqing; Lackner, Michaela

    2016-02-01

    The genus Scedosporium currently comprises six species, Scedosporium apiospermum, Scedosporium boydii, Pseudallescheria angusta, Scedosporium minutisporum, Scedosporium dehoogii, and Scedosporium aurantiacum, most of which can be distinguished with the primary fungal DNA barcode, the ITS1/2 region of the rDNA gene cluster. In the present study, four additional genetic loci were explored from a phylogenetic point of view enabling a barcoding approach based on K2P pairwise distances to resolve the taxa Scedosporium. We included partial γ-actin (ACT), β-tubulin (BT2), elongation factor 1α (TEF1), and the small ribosomal protein 60S L10 (L1) (RP60S). Phylogenetic inference of each marker individually showed that four out of six species within Scedosporium can be distinguished unambiguously, while strains of S. apiospermum, S. boydii, and P. angusta showed occasional recombination, and accordingly, no genealogical concordance between markers was obtainable. We defined S. apiospermum, S. boydii, and P. angusta as the 'S. apiospermum species complex' since observed differences were not consistent between lineages, and no clinical differences are known between entities within the complex. While BT2 revealed the best performance among the genetic loci tested at the lineage level, barcoding of the ITS region is sufficient for distinction of all entities in Scedosporium at the species or 'complex' level. PMID:26781369

  3. Phosphoprotein Stability in Clinical Tissue and Its Relevance for Reverse Phase Protein Microarray Technology

    PubMed Central

    Espina, Virginia; Mueller, Claudius; Liotta, Lance A.

    2013-01-01

    Phosphorylated proteins reflect the activity of specific cell signaling nodes in biological kinase protein networks. Cell signaling pathways can be either activated or deactivated depending on the phosphorylation state of the constituent proteins. The state of these kinase pathways reflects the in vivo activity of the cells and tissue at any given point in time. As such, cell signaling pathway information can be extrapolated to infer which phosphorylated proteins/pathways are driving an individual tumor’s growth. Reverse Phase Protein Microarrays (RPMA) are a sensitive and precise platform that can be applied to the quantitative measurement of hundreds of phosphorylated signal proteins from a small sample of tissue. Pre-analytical variability originating from tissue procurement and preservation may cause significant variability and bias in downstream molecular analysis. Depending on the ex vivo delay time in tissue processing, and the manner of tissue handling, protein biomarkers such as signal pathway phosphoproteins will be elevated or suppressed in a manner that does not represent the biomarker levels at the time of excision. Consequently, assessment of the state of these kinase networks requires stabilization, or preservation, of the phosphoproteins immediately post tissue procurement. We have employed reverse phase protein microarray analysis of phosphoproteins to study the factors influencing stability of phosphoproteins in tissue following procurement. Based on this analysis we have established tissue procurement guidelines for clinical research with an emphasis on quantifying phosphoproteins by RPMA. PMID:21901591

  4. Soluble Epidermal Growth Factor Receptors (sEGFRs) in Cancer: Biological Aspects and Clinical Relevance.

    PubMed

    Maramotti, Sally; Paci, Massimiliano; Manzotti, Gloria; Rapicetta, Cristian; Gugnoni, Mila; Galeone, Carla; Cesario, Alfredo; Lococo, Filippo

    2016-01-01

    The identification of molecules that can reliably detect the presence of a tumor or predict its behavior is one of the biggest challenges of research in cancer biology. Biological fluids are intriguing mediums, containing many molecules that express the individual health status and, accordingly, may be useful in establishing the potential risk of cancer, defining differential diagnosis and prognosis, predicting the response to treatment, and monitoring the disease progression. The existence of circulating soluble growth factor receptors (sGFRs) deriving from their membrane counterparts has stimulated the interest of researchers to investigate the use of such molecules as potential cancer biomarkers. But what are the origins of circulating sGFRs? Are they naturally occurring molecules or tumor-derived products? Among these, the epidermal growth factor receptor (EGFR) is a cell-surface molecule significantly involved in cancer development and progression; it can be processed into biological active soluble isoforms (sEGFR). We have carried out an extensive review of the currently available literature on the sEGFRs and their mechanisms of regulation and biological function, with the intent to clarify the role of these molecules in cancer (and other pathological conditions) and, on the basis of the retrieved evidences, speculate about their potential use in the clinical setting. PMID:27104520

  5. Is (18)F-FDG PET really a promising marker for clinically relevant atherosclerosis?

    PubMed

    Brammen, Lindsay; Palumbo, Barbara; Lupattelli, Graziana; Sinzinger, Helmut

    2014-01-01

    Bural et al (2013), retrospectively investigated 143 subjects who received whole body fluorine-18-fluorodeoxyglucose- positron emission tomography ((18)F-FDG-PET) imaging for the assessment of non-cardiovascular diseases. They reported an increase of (18)F-FDG-positive lesions in various aortic segments, which increased with age, and were more pronounced in subjects being aged below 50 years as compared to those above 50. Bural et al also found the highest segmental (18)F-FDG-uptake in the descending thoracic aorta, but not in the abdominal aorta, where the majority of the most severe atherosclerotic lesions essentially appear. In addition, they did not appreciate any significant gender difference. Despite the severe limitation that no correlation to vascular disease, risk factors, or any clinical parameter was available, this report again raises the question as to what positive (18)F-FDG imaging really reflects and whether it will ever reach the great expectations. Conventional radiotracers revealed an excellent experimental correlation, as well as morphology. Uptake ratios of symptomatic lesion vs. contralateral unaffected side were comparable between (111)In-platelets, (123)I-LDL and (18)FFDG. There was also a mass strategic correlation, but no individual prediction of events at all. Due to better statistics, image quality and solution PET imaging of atherosclerosis holds great promise. However, correlations between various tracers and vascular wall characteristics (and staining methodologies) in 1% cholesterol fed rabbits reveal that (18)F-FDG is not always the best tracer. Vascular foam cell content is reflected by (111)In-HIG > (125)I-oxLp(a) > (18)F-FDG > (125)I-LDL (Brammen L, Palumbo B, Lupattelli G et al. Unpublished data). A close correlation to Framingham risk score is for example not helpful, as this score has a low predictive value of only 0.6. The available clinical correlations between (18)F-FDG-uptake and arterial wall characteristics are poor. For

  6. Microbiological Features and Clinical Relevance of New Species of the Genus Mycobacterium

    PubMed Central

    2014-01-01

    SUMMARY Nontuberculous mycobacteria (NTM) are present in the environment, mainly in water, and are occasionally responsible for opportunistic infections in humans. Despite the fact that NTM are characterized by a moderate pathogenicity, the diseases caused by NTM at various body sites are increasing on a worldwide level. Among over 150 officially recognized NTM species, only two or three dozen are familiar to clinicians, and even to most microbiologists. In this paper, approximately 50 new species described in the last 8 years are reviewed, and their role in human infections is assessed on the basis of reported clinical cases. The small number of reports concerning most of the “new” mycobacterial species is responsible for the widespread conviction that they are very rare. Their role is actually largely underestimated, mainly because they often remain unrecognized and misidentified. Aiming to minimize such bias, emphasis has been placed on more common identification pitfalls. Together with new NTM, new members of the Mycobacterium tuberculosis complex described in the last few years are also an object of the present review. PMID:25278573

  7. Characterising the myocardial interstitial space: the clinical relevance of non-invasive imaging.

    PubMed

    White, Steven K; Sado, Daniel M; Flett, Andrew S; Moon, James C

    2012-05-01

    The myocardial interstitial or extracellular space exists as a complex and dynamic environment, vital for normal cardiac structure and function. The physiological pathways for normal control of collagen turnover, and the pathological development of fibrosis are beginning to be understood, as are their relationships to cardiac remodelling and adverse outcomes. Emerging non-invasive imaging techniques (echocardiography, cardiovascular magnetic resonance, positron emission tomography) may allow a clearer understanding and measurement of these processes in vivo. Preliminary results are exciting, spanning valvular and congenital heart disease, cardiomyopathy and rarer diseases such as amyloid. In this review, such developments and research directions are explored, including the rapid developments in cardiovascular magnetic resonance T1 mapping and its use with contrast to derive extracellular volume. The authors present a state-of-the-art assessment of the strengths and weaknesses of each modality, and distil a framework to equip the reader with an understanding of the technical issues useful for the interpretation of emerging clinical studies. PMID:22422587

  8. Clinical Relevance of Single-Voxel 1H MRS Metabolites in Discriminating Suprasellar Tumors

    PubMed Central

    Virani, Rahul A

    2016-01-01

    Introdution Spatially resolved metabolic data obtained from Proton Magnetic Resonance Spectroscopy (1H MRS) provides information which increases the diagnostic accuracy of imaging sequences in predicting the histology of suprasellar tumors. Aim To evaluate the role of 1H MRS in the diagnosis of various suprasellar tumors. Materials and Methods Sixty cases of various suprasellar, hypothalamic and third ventricular neoplasms were investigated with long-echo single voxel 1H -MRS using 1.5 Tesla clinical imager. Single-voxel spectroscopic examinations were guided by T1-weighted or T2-weighted images. Statistical analysis was carried out using IBM SPSS software version 19. Results We observed that whenever brain tissue was damaged or replaced by any process, NAA was markedly reduced. Extra-axial lesions which do not infiltrate brain or contain neuroglial tissue, didn’t demonstrate any NAA resonances. Cr was used as an internal standard for semi-quantitative evaluation of metabolic changes of other brain metabolites. Increased Cho was seen in processes with elevated cell-membrane turnover. Conclusion Spectra obtained from different tumors exhibit reproducible differences while histologically similar tumors yield characteristic spectra with only minor differences. Pituitary tumors were typically characterized by significant reduction of NAA, Cr peak and moderate elevation of Cho peak. Gliomas were typically characterized by decrease of NAA and Cr peaks and increase of Cho peak. Craniopharyngiomas were typically characterized by significant decrease of all metabolites.

  9. Breadth of neutralization and synergy of clinically relevant human monoclonal antibodies against HCV genotypes 1a, 1b, 2a, 2b, 2c, and 3a

    PubMed Central

    Carlsen, Thomas H.R.; Pedersen, Jannie; Prentoe, Jannick C.; Giang, Erick; Keck, Zhen-Yong; Mikkelsen, Lotte S.; Law, Mansun; Foung, Steven K. H.; Bukh, Jens

    2015-01-01

    Human monoclonal antibodies (HMAbs) with neutralizing capabilities constitute potential immune-based treatments or prophylaxis against hepatitis C virus (HCV). However, lack of cell culture-derived HCV (HCVcc) harboring authentic envelope proteins (E1/E2) has hindered neutralization investigations across genotypes, subtypes, and isolates. We investigated the breadth of neutralization of 10 HMAbs with therapeutic potential against a panel of 16 JFH1-based HCVcc expressing patient-derived Core-NS2 from genotypes 1a (strains H77, TN, and DH6), 1b (J4, DH1, and DH5), 2a (J6, JFH1, and T9), 2b (J8, DH8, and DH10), 2c (S83), and 3a (S52, DBN, and DH11). Virus stocks used for in vitro neutralization analysis contained authentic E1/E2, with the exception of full-length JFH1 that acquired the N417S substitution in E2. The 50% inhibition concentration (IC50) for each HMAb against the HCVcc panel was determined by dose-response neutralization assays in Huh7.5 cells with antibody concentrations ranging from 0.0012 to 100 μg/ml. Interestingly, IC50-values against the different HCVcc’s exhibited large variations among the HMAbs, and only three HMAbs (HC-1AM, HC84.24, and AR4A) neutralized all 16 HCVcc recombinants. Furthermore, the IC50-values for a given HMAb varied greatly with the HCVcc strain, which supports the use of a diverse virus panel. In cooperation analyses, HMAbs HC84.24, AR3A, and, especially HC84.26, demonstrated synergistic effects towards the majority of the HCVcc’s when combined individually with AR4A. Conclusion: Through a neutralization analysis of 10 clinically relevant HMAbs against 16 JFH1-based Core-NS2 recombinants from genotypes 1a, 1b, 2a, 2b, 2c, and 3a, we identified at least 3 HMAbs with potent and broad neutralization potential. The neutralization synergism obtained when pooling the most potent HMAbs could have significant implications for developing novel strategies to treat and control HCV. PMID:25043937

  10. Rectal microbicides: clinically relevant approach to the design of rectal specific placebo formulations

    PubMed Central

    2011-01-01

    Background The objective of this study is to identify the critical formulation parameters controlling distribution and function for the rectal administration of microbicides in humans. Four placebo formulations were designed with a wide range of hydrophilic characteristics (aqueous to lipid) and rheological properties (Newtonian, shear thinning, thermal sensitive and thixotropic). Aqueous formulations using typical polymers to control viscosity were iso-osmotic and buffered to pH 7. Lipid formulations were developed from lipid solvent/lipid gelling agent binary mixtures. Testing included pharmaceutical function and stability as well as in vitro and in vivo toxicity. Results The aqueous fluid placebo, based on poloxamer, was fluid at room temperature, thickened and became shear thinning at 37°C. The aqueous gel placebo used carbopol as the gelling agent, was shear thinning at room temperature and showed a typical decrease in viscosity with an increase in temperature. The lipid fluid placebo, myristyl myristate in isopropyl myristate, was relatively thin and temperature independent. The lipid gel placebo, glyceryl stearate and PEG-75 stearate in caprylic/capric triglycerides, was also shear thinning at both room temperature and 37°C but with significant time dependency or thixotropy. All formulations showed no rectal irritation in rabbits and were non-toxic using an ex vivo rectal explant model. Conclusions Four placebo formulations ranging from fluid to gel in aqueous and lipid formats with a range of rheological properties were developed, tested, scaled-up, manufactured under cGMP conditions and enrolled in a formal stability program. Clinical testing of these formulations as placebos will serve as the basis for further microbicide formulation development with drug-containing products. PMID:21385339

  11. Tendon and Ligament Regeneration and Repair: Clinical Relevance and Developmental Paradigm

    PubMed Central

    Tuan, Rocky S.

    2014-01-01

    Tendon and ligament (T/L) are dense connective tissues connecting bone to muscle and bone to bone, respectively. Similar to other musculoskeletal tissues, T/L arise from the somitic mesoderm, but they are derived from a recently discovered somitic compartment, the syndetome. The adjacent sclerotome and myotome provide inductive signals to the interposing syndetome, thereby upregulating the expression of the transcription factor Scleraxis, which in turn leads to further tenogenic and ligamentogenic differentiation. These advances in the understanding of T/L development have been sought to provide a knowledge base for improving the healing of T/L injuries, a common clinical challenge due to the intrinsically poor natural healing response. Specifically, the three most common tendon injuries involve tearing of the rotator cuff of the shoulder, the flexor tendon of the hand, and the Achilles tendon. At present, injuries to these tissues are treated by surgical repair and/or conservative approaches, including biophysical modalities such as physical rehabilitation and cryotherapy. Unfortunately, the healing tissue forms fibrovascular scar and possesses inferior mechanical and biochemical properties as compared to native T/L. Therefore, tissue engineers have sought to improve upon the natural healing response by augmenting the injured tissue with cells, scaffolds, bioactive agents, and mechanical stimulation. These strategies show promise, both in vitro and in vivo, for improving T/L healing. However, several challenges remain in restoring full T/L function following injury, including uncertainties over the optimal combination of these biological agents as well how to best deliver tissue engineered elements to the injury site. A greater understanding of the molecular mechanisms involved in T/L development and natural healing, coupled with the capability of producing complex biomaterials to deliver multiple growth factors with high spatiotemporal resolution and specificity

  12. Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product-Drug Interaction.

    PubMed

    Gufford, Brandon T; Chen, Gang; Vergara, Ana G; Lazarus, Philip; Oberlies, Nicholas H; Paine, Mary F

    2015-09-01

    Women at high risk of developing breast cancer are prescribed selective estrogen response modulators, including raloxifene, as chemoprevention. Patients often seek complementary and alternative treatment modalities, including herbal products, to supplement prescribed medications. Milk thistle preparations, including silibinin and silymarin, are top-selling herbal products that may be consumed by women taking raloxifene, which undergoes extensive first-pass glucuronidation in the intestine. Key constituents in milk thistle, flavonolignans, were previously shown to be potent inhibitors of intestinal UDP-glucuronosyl transferases (UGTs), with IC50s ≤ 10 μM. Taken together, milk thistle preparations may perpetrate unwanted interactions with raloxifene. The objective of this work was to evaluate the inhibitory effects of individual milk thistle constituents on the intestinal glucuronidation of raloxifene using human intestinal microsomes and human embryonic kidney cell lysates overexpressing UGT1A1, UGT1A8, and UGT1A10, isoforms highly expressed in the intestine that are critical to raloxifene clearance. The flavonolignans silybin A and silybin B were potent inhibitors of both raloxifene 4'- and 6-glucuronidation in all enzyme systems. The Kis (human intestinal microsomes, 27-66 µM; UGT1A1, 3.2-8.3 µM; UGT1A8, 19-73 µM; and UGT1A10, 65-120 µM) encompassed reported intestinal tissue concentrations (20-310 µM), prompting prediction of clinical interaction risk using a mechanistic static model. Silibinin and silymarin were predicted to increase raloxifene systemic exposure by 4- to 5-fold, indicating high interaction risk that merits further evaluation. This systematic investigation of the potential interaction between a widely used herbal product and chemopreventive agent underscores the importance of understanding natural product-drug interactions in the context of cancer prevention. PMID:26070840

  13. Quantification of ligand bias for clinically relevant β2-adrenergic receptor ligands: implications for drug taxonomy.

    PubMed

    van der Westhuizen, Emma T; Breton, Billy; Christopoulos, Arthur; Bouvier, Michel

    2014-03-01

    The concepts of functional selectivity and ligand bias are becoming increasingly appreciated in modern drug discovery programs, necessitating more informed approaches to compound classification and, ultimately, therapeutic candidate selection. Using the β2-adrenergic receptor as a model, we present a proof of concept study that assessed the bias of 19 β-adrenergic ligands, including many clinically used compounds, across four pathways [cAMP production, extracellular signal-regulated kinase 1/2 (ERK1/2) activation, calcium mobilization, and receptor endocytosis] in the same cell background (human embryonic kidney 293S cells). Efficacy-based clustering placed the ligands into five distinct groups with respect to signaling signatures. In some cases, apparent functional selectivity originated from off-target effects on other endogenously expressed adrenergic receptors, highlighting the importance of thoroughly assessing selectivity of the responses before concluding receptor-specific ligand-biased signaling. Eliminating the nonselective compounds did not change the clustering of the 10 remaining compounds. Some ligands exhibited large differences in potency for the different pathways, suggesting that the nature of the receptor-effector complexes influences the relative affinity of the compounds for specific receptor conformations. Calculation of relative effectiveness (within pathway) and bias factors (between pathways) for each of the compounds, using an operational model of agonism, revealed a global signaling signature for all of the compounds relative to isoproterenol. Most compounds were biased toward ERK1/2 activation over the other pathways, consistent with the notion that many proximal effectors converge on this pathway. Overall, we demonstrate a higher level of ligand texture than previously anticipated, opening perspectives for the establishment of pluridimensional correlations between signaling profiles, drug classification, therapeutic efficacy, and

  14. Differential Effectiveness of Clinically-Relevant Analgesics in a Rat Model of Chemotherapy-Induced Mucositis

    PubMed Central

    Whittaker, Alexandra L.; Lymn, Kerry A.; Wallace, Georgia L.; Howarth, Gordon S.

    2016-01-01

    Chemotherapy-induced intestinal mucositis is characterized by pain and a pro-inflammatory tissue response. Rat models are frequently used in mucositis disease investigations yet little is known about the presence of pain in these animals, the ability of analgesics to ameliorate the condition, or the effect that analgesic administration may have on study outcomes. This study investigated different classes of analgesics with the aim of determining their analgesic effects and impact on research outcomes of interest in a rat model of mucositis. Female DA rats were allocated to 8 groups to include saline and chemotherapy controls (n = 8). Analgesics included opioid derivatives (buprenorphine; 0.05mg/kg and tramadol 12.5mg/kg) and NSAID (carprofen; 15mg/kg) in combination with either saline or 5-Fluorouracil (5-FU; 150mg/kg). Research outcome measures included daily clinical parameters, pain score and gut histology. Myeloperoxidase assay was performed to determine gut inflammation. At the dosages employed, all agents had an analgesic effect based on behavioural pain scores. Jejunal myeloperoxidase activity was significantly reduced by buprenorphine and tramadol in comparison to 5-FU control animals (53%, p = 0.0004 and 58%, p = 0.0001). Carprofen had no ameliorating effect on myeloperoxidase levels. None of the agents reduced the histological damage caused by 5-FU administration although tramadol tended to increase villus length even when administered to healthy animals. These data provide evidence that carprofen offers potential as an analgesic in this animal model due to its pain-relieving efficacy and minimal effect on measured parameters. This study also supports further investigation into the mechanism and utility of opioid agents in the treatment of chemotherapy-induced mucositis. PMID:27463799

  15. Laser tumor thermotherapy: Is there a clinically relevant effect on the immune system?

    NASA Astrophysics Data System (ADS)

    Tranberg, Karl-G.

    2006-02-01

    Laser thermotherapy is interesting from an immunological point of view since it can reduce tumor volume without causing immunosuppression at the same time as it may induce and/or enhance tumor immunity. In a rat liver tumor model, we have demonstrated that laser thermotherapy 1) is superior to surgical resection, 2) gives a strong rejection immunity associated with an immune cellular response of tumor-infiltrating macrophages and CD8 lymphocytes, 3) results in pronounced suppression of the growth of a simultaneous untreated tumor (distant bystander effect), 4) produces an increased anti-tumor lymphocyte proliferative response in tumor-draining and systemic lymph nodes and spleen, and 5) results in increased HSP70 immunoreactivity in tumors and tumor-infiltrating macrophages. Thus, the evidence for a laser-induced immunologic effect in tumor-bearing rats is strong. Some observations suggest that laser thermotherapy may be used for inducing favorable immunologic effects also in patients. Thus, we have shown a laser-induced bystander effect in a patient with malignant melanoma. In patients with breast cancer we have shown that laser thermotherapy induces intratumoral infiltration of immunocompetent cells like CD68 macrophages and CD8 lymphocytes. Laser thermotherapy is likely to be beneficial mainly when tumor burden is small, that is, when treatment is performed with curative intent, either with laser alone or together with surgical resection. For optimal effect, it appears likely that thermotherapy should be combined with other therapies. Most likely, a clinically meaningful effect can only be proven in prospective randomized studies comparing thermotherapy with other methods, particularly surgical resection.

  16. D category IV: a group of clinically relevant and phylogenetically diverse partial D

    PubMed Central

    von Zabern, Inge; Wagner, Franz F.; Moulds, Joann M.; Moulds, John J.; Flegel, Willy A.

    2013-01-01

    Background The D typing strategies in several European countries protect carriers of D category VI (DVI) from anti-D immunization but not carriers of other partial D. Besides DVI, one of the clinically most important partial D is D category IV (DIV). A detailed description and direct comparison of the different DIV types was missing. Study design and methods RHD nucleotide sequences were determined from genomic DNA. D epitope patterns were established with commercial monoclonal anti-D panels. Results DIV comprises several variants of the D antigen with distinct serology, molecular structures, evolutionary origins and ethnic prevalences. The DIV phenotype is determined by 350H shared by all, but not limited to, DIV variants which are further divided into DIVa and DIVb. The DIVa phenotype is expressed by DIV type 1.0 harboring 350H and the dispersed amino acids 62F, 137V and 152T. The DIVb phenotype is expressed by DIV type 3 to type 5 representing RHD-CE-D hybrids. 4 of the 6 postulated DIV variants were encountered among 23 DIV samples analyzed. Of 12 DIV carriers with anti-D, 10 were female and 7 likely immunized by pregnancy. 2 DIV related alleles are newly described: DWN which differs from DIV type 4 by 350D and epitope pattern. DNT carries 152T, known to cause a large D antigen density. Conclusion DIV alleles arose from at least 2 independent evolutionary events. DIV type 1.0 with DIVa phenotype belongs to the oldest extant human RHD alleles. DIV type 2 to type 5 with DIVb phenotype arose from more recent gene conversions. Anti-D immunization, especially dreaded in pregnancies, will be avoided not only in carriers of DVI but also in carriers of other D variants like DIV, if our proposed D typing strategy is adopted. PMID:23461862

  17. Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer

    PubMed Central

    Shamanna, Raghavendra A.; Lu, Huiming; Croteau, Deborah L.; Arora, Arvind; Agarwal, Devika; Ball, Graham; Aleskandarany, Mohammed A.; Ellis, Ian O.; Pommier, Yves; Madhusudan, Srinivasan; Bohr, Vilhelm A.

    2016-01-01

    Werner syndrome protein (WRN) is a RecQ helicase that participates in DNA repair, genome stability and cellular senescence. The five human RecQ helicases, RECQL1, Bloom, WRN, RECQL4 and RECQL5 play critical roles in DNA repair and cell survival after treatment with the anticancer drug camptothecin (CPT). CPT derivatives are widely used in cancer chemotherapy to inhibit topoisomerase I and generate DNA double-strand breaks during replication. Here we studied the effects of CPT on the stability and expression dynamics of human RecQ helicases. In the cells treated with CPT, we observed distinct effects on WRN compared to other human RecQ helicases. CPT altered the cellular localization of WRN and induced its degradation by a ubiquitin-mediated proteasome pathway. WRN knockdown cells as well as CPT treated cells became senescent and stained positive for senescence-associated β-galactosidase at a higher frequency compared to control cells. However, the senescent phenotype was attenuated by ectopic expression of WRN suggesting functional implication of WRN degradation in CPT treated cells. Approximately 5-23% of breast cancer tumors are known to respond to CPT-based chemotherapy. Interestingly, we found that the extent of CPT-induced WRN degradation correlates with increasing sensitivity of breast cancer cells to CPT. The abundance of WRN decreased in CPT-treated sensitive cells; however, WRN remained relatively stable in CPT-resistant breast cancer cells. In a large clinical cohort of breast cancer patients, we find that WRN and topoisomerase I expression correlate with an aggressive tumor phenotype and poor prognosis. Our novel observations suggest that WRN abundance along with CPT-induced degradation could be a promising strategy for personalizing CPT-based cancer chemotherapeutic regimens. PMID:26959889

  18. Anti-platelet therapy and aspirin resistance - clinically and chemically relevant?

    PubMed

    Rafferty, M; Walters, M R; Dawson, J

    2010-01-01

    Platelets play a central role in the pathogenesis of the atherothrombosis which ultimately causes myocardial infarction, stroke and peripheral vascular disease. Commonly used oral anti-platelet drugs include aspirin (an irreversible inhibitor of cyclo-oxygenase), clopidogrel (an ADP receptor antagonist), other thienopyridines such as ticlopidine and prasgruel, and dipyridamole (an inhibitor of adenosine reuptake and platelet phosphodiesterase). Newer agents are in development and one, ticagrelor, a reversible ADP receptor antagonist has shown promise. Despite their proven benefit, recurrent vascular events still occur in those taking anti-platelet drugs. This has led to the concept of anti-platelet resistance, most commonly aspirin resistance as this drug is the cornerstone of most regimens. The causes of aspirin resistance are numerous but potential mechanisms include lack of patient adherence, non COX-1 mediated thromboxane A2 synthesis, increased activity of alternate platelet activation pathways, interference of aspirin action by other drugs and probably pharmacogenetic factors. Measurement of platelet response to aspirin is made possible using a number of in-vitro laboratory assays of platelet function which include measurement of thromboxane A2 metabolites as well as newer point-of-care assays of platelet aggregation. The phenomenon of aspirin resistance is important as it raises the possibility of developing strategies to identify those who respond best to a particular anti-platelet regimen, or to development of newer anti-platelet therapies to which more patients respond. This review discusses important aspects of aspirin resistance both in terms of clinical medicine, alternative anti-platelet strategies, and the potential to overcome its various causes. PMID:21062249

  19. Characterization of Biofilm Formation by Clinically Relevant Serotypes of Group A Streptococci†

    PubMed Central

    Lembke, Cordula; Podbielski, Andreas; Hidalgo-Grass, Carlos; Jonas, Ludwig; Hanski, Emanuel; Kreikemeyer, Bernd

    2006-01-01

    Streptococcus pyogenes (group A streptococcus [GAS]) is a frequent cause of purulent infections in humans. As potentially important aspects of its pathogenicity, GAS was recently shown to aggregate, form intratissue microcolonies, and potentially participate in multispecies biofilms. In this study, we show that GAS in fact forms monospecies biofilms in vitro, and we analyze the basic parameters of S. pyogenes in vitro biofilm formation, using Streptococcus epidermidis as a biofilm-positive control. Of nine clinically important serotype strains, M2, M6, M14, and M18 were found to significantly adhere to coated and uncoated polystyrene surfaces. Fibronectin and collagen types I and IV best supported primary adherence of serotype M2 and M18 strains, respectively, whereas serotype M6 and M14 strains strongly bound to uncoated polystyrene surfaces. Absorption measurements of safranin staining, as well as electron scanning and confocal laser scanning microscopy, documented that primary adherence led to subsequent formation of three-dimensional biofilm structures consisting of up to 46 bacterial layers. Of note, GAS isolates belonging to the same serotype were found to be very heterogeneous in their biofilm-forming behavior. Biofilm formation was equally efficient under static and continuous flow conditions and consisted of the classical three steps, including partial disintegration after long-term incubation. Activity of the SilC signaling peptide as a component of a putative quorum-sensing system was found to influence the biofilm structure and density of serotype M14 and M18 strains. Based on the presented methods and results, standardized analyses of GAS biofilms and their impact on GAS pathogenicity are now feasible. PMID:16597993

  20. Altered zinc sensitivity of NMDA receptors harboring clinically-relevant mutations.

    PubMed

    Serraz, Benjamin; Grand, Teddy; Paoletti, Pierre

    2016-10-01

    Recent human genetic studies have identified a surprisingly high number of alterations in genes encoding NMDA receptor (NMDAR) subunits in several common brain diseases. Among NMDAR subunits, the widely-expressed GluN2A subunit appears particularly affected, with tens of de novo or inherited mutations associated with neurodevelopmental conditions including childhood epilepsies and cognitive deficits. Despite the increasing identification of NMDAR mutations of clinical interest, there is still little information about the effects of the mutations on receptor and network function. Here we analyze the impact on receptor expression and function of nine GluN2A missense (i.e. single-point) mutations targeting the N-terminal domain, a large regulatory region involved in subunit assembly and allosteric signaling. While several mutations produced no or little apparent effect on receptor expression, gating and pharmacology, two showed a drastic expression phenotype and two resulted in marked alterations in the sensitivity to zinc, a potent allosteric inhibitor of GluN1/GluN2A receptors and modulator of excitatory synaptic transmission. Surprisingly, both increase (GluN2A-R370W) and decrease (GluN2A-P79R) of zinc sensitivity were observed on receptors containing either one or two copies of the mutated subunits. Overexpression of the mutant subunits in cultured rat neurons confirmed the results from heterologous expression. These results, together with previously published data, indicate that disease-causing mutations in NMDARs produce a wide spectrum of receptor alterations, at least in vitro. They also point to a critical role of the zinc-NMDAR interaction in neuronal function and human health. PMID:27288002

  1. Assessment of the translational value of mouse lupus models using clinically relevant biomarkers.

    PubMed

    Bender, Andrew T; Wu, Yin; Cao, Qiongfang; Ding, Yueyun; Oestreicher, Judith; Genest, Melinda; Akare, Sandeep; Ishizaka, Sally T; Mackey, Matthew F

    2014-06-01

    Lupus is an autoimmune disease with a poorly