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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. 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

  20. 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

  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

    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

  8. 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

  9. 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

  10. [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

  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. 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

  18. 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

  19. 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

  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. 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

  9. 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

  10. 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

  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. 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

  13. 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

  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 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

  20. 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

  1. 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

  2. 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

  3. 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

  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 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

  6. 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

  7. 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

  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. 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

  11. 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

  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. 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

  20. 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

  1. 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

  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. [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

  6. [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

  7. 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

  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. 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

  12. 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

  13. 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

  14. [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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  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. 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

  3. 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…

  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. 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

  9. 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

  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. 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

  20. 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

  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. 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

  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. 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

  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. 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

  7. 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

  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. 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

  3. 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

  4. 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

  5. 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

  6. 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.

  7. [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

  8. 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

  9. 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

  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. 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

  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. 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

  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. 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

  18. 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

  19. 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

  20. 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

  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. 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

  4. 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.

  5. 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

  6. 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

  7. 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

  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. 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

  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