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Sample records for clinically relevant subtypes

  1. Sample Level Enrichment Analysis of KEGG Pathways Identifies Clinically Relevant Subtypes of Glioblastoma

    PubMed Central

    Wanggou, Siyi; Feng, Chengyuan; Xie, Yuanyang; Ye, Linrong; Wang, Feiyifan; Li, Xuejun

    2016-01-01

    Background: Glioblastoma is the most lethal primary brain tumor in adults. Aberrant signal transduction pathways, associated with the progression of glioblastoma, have been identified recently and may offer a potential gene therapy strategy. Methods and Findings: We first used the sample level enrichment analysis to transfer gene expression profile of TCGA dataset into pathway enrichment z-score matrix. Then, we classified glioblastoma into five subtypes (Cluster A to Cluster E) by the consensus clustering and silhouette analysis. Principle component analysis showed the five subtype could be separated by first three principle components. Integrative omics data showed that mesenchymal subtype was rich in Cluster A, neural subtype was centered in Cluster D and proneural subtype was gathered in Cluster E, while Cluster E showed a high percentage of G-CIMP subtype. Additionally, according to analyze the overall survival and progression free survival of each subtype by Kaplan-Merie analysis and Cox hazard proportion model, we identified Cluster D and Cluster E received a better prognosis. Conclusions: We report a clinically relevant classification of glioblastoma based on sample level KEGG pathway enrichment profile and this novel classification system provided new insights into the heterogeneity of glioblastoma, and may be used as an important clinical tool to predict the prognosis.

  2. Hepatitis C Genotype 4: Genotypic Diversity, Epidemiological Profile, and Clinical Relevance of Subtypes in Saudi Arabia

    PubMed Central

    Al Ashgar, Hamad I; Khan, Mohammed Q.; Al-Ahdal, Mohammed; Al Thawadi, Sahar; Helmy, Ahmad Salem; Al Qahtani, Ahmed; Sanai, Faisal M.

    2013-01-01

    Background/Aim: Hepatitis C virus genotypes 4 (HCV-4) is the most prevalent genotype in Saudi Arabia, although it's various subtypes, mode and route of transmission remains unknown. The aim of this study was to analyze (i) the variability of the HCV-4 subtypes, the route and source of HCV transmission and (ii) the influence of HCV-4 subtypes on their therapeutic response. Patients and Methods: Sixty-four HCV-4 patients were analyzed retrospectively for the prevalence of various sub-genotypes and the possible mode of transmission, and it was correlated with their treatment response to pegylated interferon (PEG-IFN) α-2a and ribavirin therapy. Results: Positive history of blood or blood products transfusion was noted in 22 patients (34%), hemodialysis in 10 patients (15.6%), surgery in 7 patients (11%), and unknown etiology in 25 patients (39%). Prevalence of HCV-4 subtypes was 4a = 48.4% (31/64), 4d = 39% (25/64), 4n = 6.25% (4/64), and remaining combined (4m, 4l, 4r, 4o) 6.25% (4/64). No significant correlation between subtypes and the source of transmission was recognized (P = 0.62). Sustained virological response in all HCV-4 patients was 64% (41/64), while in each subtypes separately it was 4a 77.4% (24/31), 4d 52% (13/25), and combined (4n, 4m, 4l, 4r, 4o) 62.5% (5/8) (P = 0.046). Conclusion: No obvious cause for the mode of HCV transmission was noted in majority of the patients. No significant correlation was observed between HCV-4 subtypes and the source of HCV infection. 4a and 4d subtypes were the most common in Saudi Arabia, and patients infected with 4a subtype responded significantly better to combination therapy than to 4d subtype. PMID:23319035

  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

    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 Central

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

    2013-01-01

    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

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

    2015-03-01

    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.

  8. 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.

  9. Clinical implications of the intrinsic molecular subtypes of breast cancer.

    PubMed

    Prat, Aleix; Pineda, Estela; Adamo, Barbara; Galván, Patricia; Fernández, Aranzazu; Gaba, Lydia; Díez, Marc; Viladot, Margarita; Arance, Ana; Muñoz, Montserrat

    2015-11-01

    Gene-expression profiling has had a considerable impact on our understanding of breast cancer biology. During the last 15 years, 5 intrinsic molecular subtypes of breast cancer (Luminal A, Luminal B, HER2-enriched, Basal-like and Claudin-low) have been identified and intensively studied. In this review, we will focus on the current and future clinical implications of the intrinsic molecular subtypes beyond the current pathological-based classification endorsed by the 2013 St. Gallen Consensus Recommendations. Within hormone receptor-positive and HER2-negative early breast cancer, the Luminal A and B subtypes predict 10-year outcome regardless of systemic treatment administered as well as residual risk of distant recurrence after 5 years of endocrine therapy. Within clinically HER2-positive disease, the 4 main intrinsic subtypes can be identified and dominate the biological and clinical phenotype. From a clinical perspective, patients with HER2+/HER2-enriched disease seem to benefit the most from neoadjuvant trastuzumab, or dual HER2 blockade with trastuzumab/lapatinib, in combination with chemotherapy, and patients with HER2+/Luminal A disease seem to have a relative better outcome compared to the other subtypes. Finally, within triple-negative breast cancer (TNBC), the Basal-like disease predominates (70-80%) and, from a biological perspective, should be considered a cancer-type by itself. Importantly, the distinction between Basal-like versus non-Basal-like within TNBC might predict survival following (neo)adjvuvant multi-agent chemotherapy, bevacizumab benefit in the neoadjuvant setting (CALGB40603), and docetaxel vs. carboplatin benefit in first-line metastatic disease (TNT study). Overall, this data suggests that intrinsic molecular profiling provides clinically relevant information beyond current pathology-based classifications.

  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. 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

  12. 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…

  13. 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

  14. Cognitive function in schizoaffective disorder and clinical subtypes of schizophrenia.

    PubMed

    Goldstein, Gerald; Shemansky, Wendy Jo; Allen, Daniel N

    2005-03-01

    Cognitive studies of patients with Schizoaffective Disorder typically indicate that the cognitive function of these patients resembles that of patients with Schizophrenic Disorder more than it does patients with nonpsychotic Mood Disorder. In this study patients with Schizoaffective Disorder were compared with patients with Paranoid, Undifferentiated and Residual clinical subtypes on a number of measures of cognitive function. Multivariate analyses of variance indicated that the cognitive function of Schizoaffective and Paranoid patients had more intact cognitive function that did Undifferentiated and Residual patients. Application of cluster analysis indicated that there were relative high percentages of Schizoaffective and Paranoid patients in a "Neuropsychologically Normal" cluster. It was concluded that Schizoaffective Disorder as well as other clinical subtypes of schizophrenia are cognitively heterogeneous, and it was suggested that a subgroup of patients with Schizoaffective Disorder may not differ in cognitive ability from patients with nonpsychotic Mood Disorder.

  15. 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

  16. 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…

  17. 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

  18. 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

  19. 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

  20. [Clinical relevance of cardiopulmonary reflexes in anesthesiology].

    PubMed

    Guerri-Guttenberg, R A; Siaba-Serrate, F; Cacheiro, F J

    2013-10-01

    The baroreflex, chemoreflex, pulmonary reflexes, Bezold-Jarisch and Bainbridge reflexes and their interaction with local mechanisms, are a demonstration of the richness of cardiovascular responses that occur in human beings. As well as these, the anesthesiologist must contend with other variables that interact by attenuating or accentuating cardiopulmonary reflexes such as, anesthetic drugs, surgical manipulation, and patient positioning. In the present article we review these reflexes and their clinical relevance in anesthesiology.

  1. Cryptosporidiosis in Kuwaiti children: association of clinical characteristics with Cryptosporidium species and subtypes.

    PubMed

    Iqbal, Jamshaid; Khalid, Nabila; Hira, Parsotam Ravjee

    2011-05-01

    To determine the association of clinical characteristics with Cryptosporidium types and subtypes, faecal specimens from 2548 children with diarrhoea were screened by microscopy for Cryptosporidium spp., and positive specimens were genotyped and subtyped by PCR-RFLP. A total of 87 of the 2548 children (3.4 %) had cryptosporidial diarrhoea by microscopy and the majority (41.4 %) of the infected children were in the 4-8-year-old age group. Molecular characterization of the 83 children studied further (4 had mixed infections and were not subtyped) showed that Cryptosporidium parvum was the most commonly identified species (73.5 %) and consisted of three subtypes: IIa and IId were the most common (80.3 %), followed by IIc. Twenty-two (26.5 %) of the children had Cryptosporidium hominis and showed three subtypes: Id was the most common (54.5 %), followed by Ia (36.4 %) and Ie. Associated clinical manifestations varied between C. parvum and C. hominis. Diarrhoea associated with subtype Id, the most commonly identified C. hominis subtype, was more severe than that associated with other subtypes. In conclusion, this study confirmed a very different Cryptosporidium genotype and subtype distribution compared with other tropical countries among Kuwaiti children with diarrhoea, with a predominance of C. parvum IIa and IId. In addition, subtype Id of C. hominis was associated with more diverse and severe clinical manifestations in infected children, suggesting that parasite genetics may play an important role in the clinical manifestations of human cryptosporidiosis.

  2. The clinically relevant pharmacogenomic changes in acute myelogenous leukemia.

    PubMed

    Emadi, Ashkan; Karp, Judith E

    2012-08-01

    Acute myelogenous leukemia (AML) is an extremely heterogeneous neoplasm with several clinical, pathological, genetic and molecular subtypes. Combinations of various doses and schedules of cytarabine and different anthracyclines have been the mainstay of treatment for all forms of AMLs in adult patients. Although this combination, with the addition of an occasional third agent, remains effective for treatment of some young-adult patients with de novo AML, the prognosis of AML secondary to myelodysplastic syndromes or myeloproliferative neoplasms, treatment-related AML, relapsed or refractory AML, and AML that occurs in older populations remains grim. Taken into account the heterogeneity of AML, one size does not and should not be tried to fit all. In this article, the authors review currently understood, applicable and relevant findings related to cytarabine and anthracycline drug-metabolizing enzymes and drug transporters in adult patients with AML. To provide a prime-time example of clinical applicability of pharmacogenomics in distinguishing a subset of patients with AML who might be better responders to farnesyltransferase inhibitors, the authors also reviewed findings related to a two-gene transcript signature consisting of high RASGRP1 and low APTX, the ratio of which appears to positively predict clinical response in AML patients treated with farnesyltransferase inhibitors.

  3. Women with epilepsy: clinically relevant issues.

    PubMed

    Bangar, S; Shastri, Abhishek; El-Sayeh, Hany; Cavanna, Andrea E

    2016-01-01

    Women with epilepsy (WWE) face specific challenges throughout their lifespan due to the effects of seizures and antiepileptic drugs on hormonal function, potentially affecting both sexual and reproductive health. This review article addresses the most common issues of practical relevance to clinicians treating WWE: epidemiology and clinical presentations (including catamenial epilepsy), contraception, reproductive and sexual dysfunction, pregnancy, lactation, menopause-related issues (including bone health), and mental health aspects. Awareness of these gender-specific issues and implementation/adaptation of effective interventions for WWE results in significantly improved health-related quality of life in this patient population. PMID:27678205

  4. Clinical Evaluation of 168 Korean Patients with Rosacea: The Sun Exposure Correlates with the Erythematotelangiectatic Subtype

    PubMed Central

    Bae, You In; Yun, Sook-Jung; Lee, Jee-Bum; Kim, Seong-Jin; Won, Young Ho

    2009-01-01

    Background Although rosacea is a chronic cutaneous inflammatory disorder that's commonly seen in adults, the etiology and pathogenesis of the illness remain unclear. A well established diagnostic classification and grading system may play a critical role in performing research and it would serve as a diagnostic reference in the clinical field. Objective We sought to classify the patients with the new standard classification and grading system and we wanted determine the peculiar features and relationships of each subtype. We also analyzed the relationships between the degree of sun exposure and each subtype. Methods We reviewed the medical records and clinical photos of 168 patients who were diagnosed with rosacea from 2002 to 2007 at our hospital. The standard classification and grading system suggested by the National Rosacea Society (NRS) Expert Committee was adopted to evaluate each patient's subtype and the severity. Results The male:female ratio was 1:2.29. The mean age at the time of diagnosis was 47.8 years. The mean duration of disease was 3.5 years. Sun exposure and hot baths/exercise were the two most common precipitating factors, while the majority of patients did not have any specific factor that relieved their symptoms. According to the NRS classification and grading system, the patients were classified into four subtypes. One hundred sixty two (96.4%) patients were diagnosed with the erythematotelangiectatic subtype irrespective of severity. Eighty five (50.6%) patients had the papulopustular subtype and 24 (14.3%) patients had ocular rosacea. Eight (4.8%) patients displayed mild phymatous change. The degree of sun exposure had significant correlation with the development and severity of the erythematotelangiectatic subtype (p<0.05), while it had no correlation with the papulopustular, ocular and phymatous subtypes. Conclusion Although the erythematotelangiectatic subtype was the most common subtype of rosacea, many patients also had other subtypes

  5. Mirror neurons and their clinical relevance.

    PubMed

    Rizzolatti, Giacomo; Fabbri-Destro, Maddalena; Cattaneo, Luigi

    2009-01-01

    One of the most exciting events in neurosciences over the past few years has been the discovery of a mechanism that unifies action perception and action execution. The essence of this 'mirror' mechanism is as follows: whenever individuals observe an action being done by someone else, a set of neurons that code for that action is activated in the observers' motor system. Since the observers are aware of the outcome of their motor acts, they also understand what the other individual is doing without the need for intermediate cognitive mediation. In this Review, after discussing the most pertinent data concerning the mirror mechanism, we examine the clinical relevance of this mechanism. We first discuss the relationship between mirror mechanism impairment and some core symptoms of autism. We then outline the theoretical principles of neurorehabilitation strategies based on the mirror mechanism. We conclude by examining the relationship between the mirror mechanism and some features of the environmental dependency syndromes.

  6. 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…

  7. 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

  8. 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

  9. 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

  10. 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

  11. Clinical relevance of host immunity in breast cancer: from TILs to the clinic.

    PubMed

    Savas, Peter; Salgado, Roberto; Denkert, Carsten; Sotiriou, Christos; Darcy, Phillip K; Smyth, Mark J; Loi, Sherene

    2016-04-01

    The clinical relevance of the host immune system in breast cancer has long been unexplored. Studies developed over the past decade have highlighted the biological heterogeneity of breast cancer, prompting researchers to investigate whether the role of the immune system in this malignancy is similar across different molecular subtypes of the disease. The presence of high levels of lymphocytic infiltration has been consistently associated with a more-favourable prognosis in patients with early stage triple-negative and HER2-positive breast cancer. These infiltrates seem to reflect favourable host antitumour immune responses, suggesting that immune activation is important for improving survival outcomes. In this Review, we discuss the composition of the immune infiltrates observed in breast cancers, as well as data supporting the clinical relevance of host antitumour immunity, as represented by lymphocytic infiltration, and how this biomarker could be used in the clinical setting. We also discuss the rationale for enhancing immunity in breast cancer, including early data on the efficacy of T-cell checkpoint inhibition in this setting.

  12. Characterization of Rheumatoid Arthritis Subtypes Using Symptom Profiles, Clinical Chemistry and Metabolomics Measurements

    PubMed Central

    van der Kooij, Anita J.; Reijmers, Theo H.; Schroën, Yan; Wang, Mei; Xu, Zhiliang; Wang, Xinchang; Kong, Hongwei; Xu, Guowang; Hankemeier, Thomas; Meulman, Jacqueline J.; van der Greef, Jan

    2012-01-01

    Objective The aim is to characterize subgroups or phenotypes of rheumatoid arthritis (RA) patients using a systems biology approach. The discovery of subtypes of rheumatoid arthritis patients is an essential research area for the improvement of response to therapy and the development of personalized medicine strategies. Methods In this study, 39 RA patients are phenotyped using clinical chemistry measurements, urine and plasma metabolomics analysis and symptom profiles. In addition, a Chinese medicine expert classified each RA patient as a Cold or Heat type according to Chinese medicine theory. Multivariate data analysis techniques are employed to detect and validate biochemical and symptom relationships with the classification. Results The questionnaire items ‘Red joints’, ‘Swollen joints’, ‘Warm joints’ suggest differences in the level of inflammation between the groups although c-reactive protein (CRP) and rheumatoid factor (RHF) levels were equal. Multivariate analysis of the urine metabolomics data revealed that the levels of 11 acylcarnitines were lower in the Cold RA than in the Heat RA patients, suggesting differences in muscle breakdown. Additionally, higher dehydroepiandrosterone sulfate (DHEAS) levels in Heat patients compared to Cold patients were found suggesting that the Cold RA group has a more suppressed hypothalamic-pituitary-adrenal (HPA) axis function. Conclusion Significant and relevant biochemical differences are found between Cold and Heat RA patients. Differences in immune function, HPA axis involvement and muscle breakdown point towards opportunities to tailor disease management strategies to each of the subgroups RA patient. PMID:22984493

  13. 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

  14. Neuroendocrine prostate cancer: subtypes, biology, and clinical outcomes.

    PubMed

    Aggarwal, Rahul; Zhang, Tian; Small, Eric J; Armstrong, Andrew J

    2014-05-01

    Neuroendocrine prostate cancer (NEPC) encompasses various clinical contexts, ranging from the de novo presentation of small cell prostatic carcinoma to a treatment-emergent transformed phenotype that arises from typical adenocarcinoma of the prostate. The development of resistance to potent androgen receptor signaling inhibition may be associated with the emergence of aggressive phenotype, advanced castration-resistant NEPC. Clinically, small cell prostate cancer and NEPC are often manifested by the presence of visceral or large soft tissue metastatic disease, a disproportionately low serum prostate-specific antigen level relative to the overall burden of disease, and a limited response to targeting of the androgen signaling axis. These tumors are often characterized by loss of androgen receptor expression, loss of retinoblastoma tumor suppressor copy number or expression, amplification of Aurora kinase A and N-Myc, and activation of the PI3K pathway. However, a consensus phenotype-genotype definition of NEPC has yet to emerge, and molecularly based biomarkers are needed to expand on traditional morphologic and immunohistochemical markers of NEPC to fully define the spectrum of this aggressive, androgen receptor-independent disease. Emerging studies implicate a shared clonal origin with prostatic adenocarcinoma in many cases, with the adaptive emergence of unique cellular programming and gene expression profiles. Ongoing clinical studies are focused on developing novel targeted therapeutic approaches for this high-risk, lethal subset of disease, to improve on the limited durations of response often observed with traditional platinum-based chemotherapy.

  15. Locus Heterogeneity for Waardenburg Syndrome is Predictive of Clinical Subtypes

    PubMed Central

    Farrer, Lindsay A.; Arnos, Kathleen S.; Asher, James H.; Baldwin, Clinton T.; Diehl, Scott R.; Friedman, Thomas B.; Greenberg, Jacquie; Grundfast, Kenneth M.; Hoth, Christopher; Lalwani, Anil K.; Landa, Barbara; Leverton, Kate; Milunsky, Aubrey; Morell, Robert; Nance, Walter E.; Newton, Valerie; Ramesar, Rajkumar; Rao, Valluri S.; Reynolds, Jennifer E.; Agustin, Theresa B. San; Wilcox, Edward R.; Winship, Ingrid; Read, Andrew P.

    1994-01-01

    Waardenburg syndrome (WS) is a dominantly inherited and clinically variable syndrome of deafness, pigmentary changes, and distinctive facial features. Clinically, WS type I (WS1) is differentiated from WS type II (WS2) by the high frequency of dystopia canthorum in the family. In some families, WS is caused by mutations in the PAX3 gene on chromosome 2q. We have typed microsatellite markers within and flanking PAX3 in 41 WS1 kindreds and 26 WS2 kindreds in order to estimate the proportion of families with probable mutations in PAX3 and to study the relationship between phenotypic and genotypic heterogeneity. Evaluation of heterogeneity in location scores obtained by multilocus analysis indicated that WS is linked to PAX3 in 60% of all WS families and in 100% of WS1 families. None of the WS2 families were linked. In those families in which equivocal lod scores (between −2 and +1) were found, PAX3 mutations have been identified in 5 of the 15 WS1 families but in none of the 4 WS2 families. Although preliminary studies do not suggest any association between the phenotype and the molecular pathology in 20 families with known PAX3 mutations and in four patients with chromosomal abnormalities in the vicinity of PAX3, the presence of dystopia in multiple family members is a reliable indicator for identifying families likely to have a defect in PAX3. ImagesFigure 1 PMID:7942851

  16. [The relevance of clinical risk management].

    PubMed

    Gulino, Matteo; Vergallo, Gianluca Montanari; Frati, Paola

    2011-01-01

    Medical activity includes a risk of possible injury or complications for the patients, that should drive the Health Care Institutions to introduce and/ or improve clinical Risk management instruments. Although Italy is still lacking a National project of Clinical Risk Management, a number of efforts have been made by different Italian Regions to introduce instruments of risk management. In addition, most of National Health Care Institutions include actually a Department specifically in charge to manage the clinical risk. Despite the practical difficulties, the results obtained until now suggest that the risk management may represent a useful instrument to contribute to the reduction of errors in clinical conduct. Indeed, the introduction of adequate instruments of prevention and management of clinical risk may help to ameliorate the quality of health care Institution services.

  17. 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

  18. DENDRITIC CELLS: ARE THEY CLINICALLY RELEVANT?

    PubMed Central

    Palucka, Karolina; Ueno, Hideki; Roberts, Lee; Fay, Joseph; Banchereau, Jacques

    2010-01-01

    Cancer vaccines have undergone a renaissance due to recent clinical trials showing promising immunological data and some clinical benefit to patients. Current trials exploiting dendritic cells (DCs) as vaccines have shown durable tumor regressions in a fraction of patients. Clinical efficacy of current vaccines is hampered by myeloid-derived suppressor cells, inflammatory type 2 T cells and regulatory T cells (Tregs), all of which prevent the generation of effector cells. To improve the clinical efficacy of DC vaccines, we need to design novel and improved strategies that can boost adaptive immunity to cancer, help overcome Tregs and allow the breakdown of the immunosuppressive tumor microenvironment. This can be achieved by exploiting the fast increasing knowledge about the DC system, including the existence of distinct DC subsets. Critical to the design of better vaccines is the concept of distinct DC subsets and distinct DC activation pathways, all contributing to the generation of unique adaptive immune responses. Such novel DC vaccines will be used as monotherapy in patients with resected disease and in combination with antibodies and/or drugs targeting suppressor pathways and modulation of the tumor environment in patients with metastatic disease. PMID:20693842

  19. Engineering clinically relevant volumes of vascularized bone.

    PubMed

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

    2015-05-01

    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.

  20. 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

  1. Clinical relevance of fascial tissue and dysfunctions.

    PubMed

    Klingler, W; Velders, M; Hoppe, K; Pedro, M; Schleip, R

    2014-01-01

    Fascia is composed of collagenous connective tissue surrounding and interpenetrating skeletal muscle, joints, organs, nerves, and vascular beds. Fascial tissue forms a whole-body, continuous three-dimensional viscoelastic matrix of structural support. The classical concept of its mere passive role in force transmission has recently been disproven. Fascial tissue contains contractile elements enabling a modulating role in force generation and also mechanosensory fine-tuning. This hypothesis is supported by in vitro studies demonstrating an autonomous contraction of human lumbar fascia and a pharmacological induction of temporary contraction in rat fascial tissue. The ability of spontaneous regulation of fascial stiffness over a time period ranging from minutes to hours contributes more actively to musculoskeletal dynamics. Imbalance of this regulatory mechanism results in increased or decreased myofascial tonus, or diminished neuromuscular coordination, which are key contributors to the pathomechanisms of several musculoskeletal pathologies and pain syndromes. Here, we summarize anatomical and biomechanical properties of fascial tissue with a special focus on fascial dysfunctions and resulting clinical manifestations. Finally, we discuss current and future potential treatment options that can influence clinical manifestations of pain syndromes associated with fascial tissues.

  2. Clinically relevant subgroups in COPD and asthma.

    PubMed

    Turner, Alice M; Tamasi, Lilla; Schleich, Florence; Hoxha, Mehmet; Horvath, Ildiko; Louis, Renaud; Barnes, Neil

    2015-06-01

    As knowledge of airways disease has grown, it has become apparent that neither chronic obstructive pulmonary disease (COPD) nor asthma is a simple, easily defined disease. In the past, treatment options for both diseases were limited; thus, there was less need to define subgroups. As treatment options have grown, so has our need to predict who will respond to new drugs. To date, identifying subgroups has been largely reported by detailed clinical characterisation or differences in pathobiology. These subgroups are commonly called "phenotypes"; however, the problem of defining what constitutes a phenotype, whether this should include comorbid diseases and how to handle changes over time has led to the term being used loosely. In this review, we describe subgroups of COPD and asthma patients whose clinical characteristics we believe have therapeutic or major prognostic implications specific to the lung, and whether these subgroups are constant over time. Finally, we will discuss whether the subgroups we describe are common to both asthma and COPD, and give some examples of how treatment might be tailored in patients where the subgroup is clear, but the label of asthma or COPD is not. PMID:26028640

  3. Validation of a clinical classification for subtypes of acute cerebral infarction.

    PubMed Central

    Anderson, C S; Taylor, B V; Hankey, G J; Stewart-Wynne, E G; Jamrozik, K D

    1994-01-01

    The validity of a clinical classification system was assessed for subtypes of cerebral infarction for use in clinical trials of putative stroke therapies and clinical decision making in a population based stroke register (n = 536) compiled in Perth, Western Australia in 1989-90. The Perth Community Stroke Project (PCSS) used definitions and methodology similar to the Oxfordshire Community Stroke Project (OCSP) where the classification system was developed. In the PCSS, 421 cases of cerebral infarction and primary intracerebral haemorrhage (PICH), confirmed by brain imaging or necropsy, were classified into the subtypes total anterior circulation syndrome (TACS), partial anterior circulation syndrome (PACS), lacunar syndrome (LACS), and posterior circulation syndrome (POCS). In this relatively unselected population, relying exclusively on LACS for a diagnosis of PICH had a very low sensitivity (6%) and positive predictive value (3%). Comparison of the frequencies and outcomes (at one year after the onset of symptoms) for each subgroup of first ever cerebral infarction in the PCSS (n = 248) with the OCSP (n = 543) registers showed uniformity only for LACI. For example, there were 27% of cases of TACI in the PCSS compared with 17% in the OCSP (difference = 10%; 95% confidence interval (95% CI) 4% to 16%) and 15% of cases in the PCSS compared with 24% in the OCSP were POCI (difference = 9%; 95% CI 3% to 15%). Case fatalities and long-term handicap across the subgroups were not significantly different between studies, but the frequencies of recurrent stroke were significantly greater for POCI in the OCSP compared with the PCSS. Although this classification system defines subtypes of stroke with different outcomes, simple clinical measures-level of consciousness, paresis, disability, and incontinence at onset-are more powerful predictors of death or dependency at one year. It is concluded that simple clinical measures that reflect the severity of the neurological deficit

  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. 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

  6. 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

  7. Pan-Cancer Analyses Reveal Long Intergenic Non-Coding RNAs Relevant to Tumor Diagnosis, Subtyping and Prognosis.

    PubMed

    Ching, Travers; Peplowska, Karolina; Huang, Sijia; Zhu, Xun; Shen, Yi; Molnar, Janos; Yu, Herbert; Tiirikainen, Maarit; Fogelgren, Ben; Fan, Rong; Garmire, Lana X

    2016-05-01

    Long intergenic noncoding RNAs (lincRNAs) are a relatively new class of non-coding RNAs that have the potential as cancer biomarkers. To seek a panel of lincRNAs as pan-cancer biomarkers, we have analyzed transcriptomes from over 3300 cancer samples with clinical information. Compared to mRNA, lincRNAs exhibit significantly higher tissue specificities that are then diminished in cancer tissues. Moreover, lincRNA clustering results accurately classify tumor subtypes. Using RNA-Seq data from thousands of paired tumor and adjacent normal samples in The Cancer Genome Atlas (TCGA), we identify six lincRNAs as potential pan-cancer diagnostic biomarkers (PCAN-1 to PCAN-6). These lincRNAs are robustly validated using cancer samples from four independent RNA-Seq data sets, and are verified by qPCR in both primary breast cancers and MCF-7 cell line. Interestingly, the expression levels of these six lincRNAs are also associated with prognosis in various cancers. We further experimentally explored the growth and migration dependence of breast and colon cancer cell lines on two of the identified lncRNAs. In summary, our study highlights the emerging role of lincRNAs as potentially powerful and biologically functional pan-cancer biomarkers and represents a significant leap forward in understanding the biological and clinical functions of lincRNAs in cancers.

  8. The clinical relevance of autoantibodies in scleroderma.

    PubMed

    Ho, Khanh T; Reveille, John D

    2003-01-01

    Scleroderma (systemic sclerosis) is associated with several autoantibodies, each of which is useful in the diagnosis of affected patients and in determining their prognosis. Anti-centromere antibodies (ACA) and anti-Scl-70 antibodies are very useful in distinguishing patients with systemic sclerosis (SSc) from healthy controls, from patients with other connective tissue disease, and from unaffected family members. Whereas ACA often predict a limited skin involvement and the absence of pulmonary involvement, the presence of anti-Scl-70 antibodies increases the risk for diffuse skin involvement and scleroderma lung disease. Anti-fibrillarin autoantibodies (which share significant serologic overlap with anti-U3-ribonucleoprotein antibodies) and anti-RNA-polymerase autoantibodies occur less frequently and are also predictive of diffuse skin involvement and systemic disease. Anti-Th/To and PM-Scl, in contrast, are associated with limited skin disease, but anti-Th/To might be a marker for the development of pulmonary hypertension. Other autoantibodies against extractable nuclear antigens have less specificity for SSc, including anti-Ro, which is a risk factor for sicca symptoms in patients with SSc, and anti-U1-ribonucleoprotein, which in high titer is seen in patients with SSc/systemic lupus erythematosus/polymyositis overlap syndromes. Limited reports of other autoantibodies (anti-Ku, antiphospholipid) have not established them as being clinically useful in following patients with SSc.

  9. Pharmacogenetic analysis of clinically relevant genetic polymorphisms.

    PubMed

    McLeod, Howard L

    2005-11-15

    The ascertainment of the human genome sequence has generated great enthusiasm for the use of gene-based approaches to improve virtually all aspects of medical care. Particular interest has focused on the field of pharmacogenetics--for example, the use of an individual's genetic profile to optimize drug prescription. This approach takes advantage of the presence of single-nucleotide polymorphisms (SNPs) or other genetic variants in every gene in the human genome. There are currently > 9 million SNPs in the human SNP database dbSNP, with an estimated 11 million variants ultimately to be found in the human population. To date, the preponderance of interest in this field has centered on the potential of applying this approach to subacute or chronic illnesses, such as cancer, cardiovascular disease, human immunodeficiency virus infection, or rheumatologic disorders. In contrast, little attention has been devoted to the potential utility of implementing the pharmacogenomic methodology for guiding drug selection for acutely ill patients in the critical care environment. Although such an approach has theoretical appeal as a means of enhancing quality and improving outcomes in this setting, several obstacles currently exist and slow the progress toward clinical application. PMID:16237646

  10. 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

  11. Race and hypertension. What is clinically relevant?

    PubMed

    Rutledge, D R

    1994-06-01

    Hypertension, once considered rare in Africa, occurs frequently in most Black populations outside of the continent as well as within more urban areas of Africa. The frequency of hypertension in Black citizens of the US is among the highest in the world. Pathophysiological mechanisms suggest the frequency of salt-sensitive blood pressure is more common in Black patients. More Black than White patients initially present with volume expansion. However, in Black patients there appears to be no significant relationship between plasma renin activity, plasma volume and blood pressure. The syndrome of insulin resistance has also been reported in African Americans. Future studies should address this issue, both because it relates to identifying individuals at risk for development of high blood pressure and because it has implications for initial selection of antihypertensive therapy. Hypertensive kidney disease is prevalent in Black people. Lowering the blood pressure with diuretic-based therapies has not been shown to delay or prevent the loss of kidney function in patients with this condition, suggesting that this treatment approach may not be optimal. Lifestyle modifications remain the initial therapeutic regimen. Because diuretics and beta-blockers have been shown to reduce cardiovascular morbidity and mortality in controlled clinical trials, they are preferred therapies. The Hypertension Detection and Follow-up Program showed significant reductions in morbidity and mortality in Black patients using primarily diuretic-based therapies. However, controversy persists regarding use of diuretics since some investigators believe that greater reductions in overall cardiovascular risk may be achieved in Black patients using other agents. These agents may eventually be able to exert a beneficial cardiovascular effect in addition to and independent of their blood pressure-lowering effect. Long term data documenting reduced morbidity and mortality rates with other agents are

  12. Allergy to peanut oil--clinically relevant?

    PubMed

    Ring, J; Möhrenschlager, M

    2007-04-01

    The increasing prevalence of food allergies (especially allergy to peanuts) has led to a discussion of how safe topical preparations containing peanut oil are with respect to allergy. The major allergens from peanuts are proteins that have been characterized at a molecular level and cloned. Clinical signs of peanut allergy symptoms can be observed on the skin (urticaria), or in the gastrointestinal and/or respiratory tract culminating in cardiovascular symptoms and anaphylactic reactions. In most cases, symptoms are elicited by oral uptake; rarely, a contact urticaria has been described. In vegetable oils, the contents of protein differ depending on the production process: crude oils contain approximately 100 times more proteins than refined oils. This has clear-cut implications for allergic individuals. Quantitative data are available regarding elicitation of symptoms in allergic individuals with a threshold dose of 0.1-1 mg peanut allergen in oral provocation tests. There are anecdotal reports of adverse reactions after topical use of peanut oils. In one epidemiological trial, an association between topical use of skin care products containing peanut oil and the development of peanut allergy was observed; however, the data reflect a retrospective analysis without specifying skin care products containing peanut oil and also without analysing the quantity of topicals used. In contrast, oral tolerance was prevented and allergic sensitization was enhanced in a mouse model using high concentrations of peanut protein. So far, no reliable data are available regarding doses required to induce sensitization against peanut allergen via the epidermal route. A possible induction of sensitization against peanut proteins through contact with the skin via skin care products and the respective protein concentrations is a matter of speculation. Patients with atopic diseases, namely eczema, need appropriate skin care because of the disturbed skin barrier function. The benefit of

  13. [Relevancy of the clinical subjects in medical training].

    PubMed

    de Juan, J; Mateo Martínez, M; Cuenca, N; Fernández Jover, E; García Barbero, M

    1989-09-01

    A judgment of the relevance of twelve clinical science courses for preparing the students to the practice of medicine and to the development of the scientific mind, was tested by the Pair Comparison and Equal-Appearing Interval methods. The test groups consisted of medical school faculty members, medical students and physicians. Three groups of clinical sciences, according its relevancy for preparing the students for a career as physicians, were identified Internal Medicine, Pediatrics, Surgery and Public Health, comprised the group of maximum relevancy; History of Medicine, Medicolegal and Radiological studies, formed a group of lowest relevancy. The remainder sciences (Ophthalmology, Obstetrics and Gynecology, Otorhinolaryngology, Dermatology and Psychiatry, formed a middle group. Few differences were found when we considered the relevancy to the development of the scientific mind.

  14. 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

  15. 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

  16. Clinical Evidence for Three Distinct Gastric Cancer Subtypes: Time for a New Approach

    PubMed Central

    Bittoni, Alessandro; Scartozzi, Mario; Giampieri, Riccardo; Faloppi, Luca; Bianconi, Maristella; Mandolesi, Alessandra; Prete, Michela Del; Pistelli, Mirco; Cecchini, Luca; Bearzi, Italo; Cascinu, Stefano

    2013-01-01

    Background Recently, a new classification for gastric cancer (GC) has been proposed, based on Lauren's histology and on anatomic tumour location, identifying three subtypes of disease: type 1 (proximal non diffuse GC), type 2 (diffuse GC) and type 3 (distal non diffuse GC). Aim of our analysis was to compare clinical outcome according to different GC subtypes (1,2,3) in metastatic GC patients receiving first-line chemotherapy. Patients and Methods Advanced GC pts treated with a first-line combination chemotherapy were included in our analysis. Pts were divided in three subgroups (type 1, type 2 and type 3) as previously defined. Results A total of 248 advanced GC pts were included: 45.2% belonged to type 2, 43.6% to type 3 and 11.2% to type 1. Patients received a fluoropyrimidine-based chemotherapy doublet or three drugs regimens including a platinum derivate and a fluoropyrimidine with the addition of an anthracycline, a taxane or mytomicin C. RR was higher in type 1 pts (RR = 46.1%) and type 3 (34,3%) compared to type 2 (20,4%), (p = 0.015). Type 2 presented a shorter PFS, median PFS = 4.2 months, compared to type 1, mPFS = 7.2 months, and type 3, mPFS = 5.9 months (p = 0.011) and also a shorter OS (p = 0.022). Conclusions Our analysis suggests that GC subtypes may be important predictors of benefit from chemotherapy in advanced GC patients. Future clinical trials should take in account these differences for a better stratification of patients. PMID:24265697

  17. 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.

  18. 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

  19. 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

  20. 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...

  1. 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

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

    ERIC Educational Resources Information Center

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

    2012-01-01

    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 less than 0.002 adjusted for multiple…

  4. [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

  5. Walnut allergens: molecular characterization, detection and clinical relevance.

    PubMed

    Costa, J; Carrapatoso, I; Oliveira, M B P P; Mafra, I

    2014-03-01

    Food-induced allergies have been regarded as an emergent problem of public health. Classified as important allergenic ingredients, the presence of walnut and other nuts as hidden allergens in processed foods constitutes a risk for sensitized individuals, being a real problem of allergen management. Attending to the increasing importance dedicated to walnut allergy, this review intends to provide the relevant and up-to-date information on main issues such as the prevalence of walnut allergy, the clinical threshold levels, the molecular characterization of walnut allergens and their clinical relevance, as well as the methodologies for walnut allergen detection in foods. As the walnut used in human diet comes from Juglans regia and Juglans nigra, the molecular characterization of the allergens from both species included in the prolamins (Jug r 1, Jug n 1 and Jug r 3), cupins (Jug r 2, Jug n 2 and Jug r 4) and profilins (Jug r 5), together with respective clinical relevance, were compiled in this review. The most recent progresses on walnut allergen detection techniques (protein- and DNA-based) are described and critically compared, including the emergent multitarget approaches.

  6. 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

  7. Differences in the diagnostic accuracy of acute stroke clinical subtypes defined by multimodal magnetic resonance imaging

    PubMed Central

    Allder, S; Moody, A; Martel, A; Morgan, P; Delay, G; Gladman, J; Lennox, G

    2003-01-01

    Background: Despite its importance for acute stroke management, little is known about the underlying pathophysiology when patients with acute stroke are classified using clinical methods. Objective: To examine the relation between the magnetic resonance defined stroke subtype and clinical stroke classifications using diffusion weighted imaging (DWI), perfusion weighted imaging (PWI), and angiographic magnetic resonance techniques. Methods: Consecutive patients with clinical syndromes consistent with acute anterior circulation stroke were assessed clinically within six hours of onset and scanned as soon as possible using multimodal magnetic resonance imaging (MRI). Patients were classified clinically into total or partial anterior circulation syndromes using the Oxford classification, or according the severity of the National Institutes of Health stroke scale (NIHSS) (severe > 15; mild/moderate ≤ 15). At day seven, patients were classified by combining clinical course and MRI data as misdiagnosed, misclassified, suffering transient ischaemic attack, infarct with recanalisation, or infarction with persisting occlusion. Patients with occlusion were further divided on the basis of a large diffusion–perfusion mismatch. Results: 84 patients with clinical anterior circulation syndromes were studied. Using the NIHSS, 42 were mild to moderate (0–15) and 42 were severe (> 15). There were 42 with partial anterior circulation syndromes (PACS) and 42 with total anterior circulation syndromes (TACS). Patients with TACS or severe stroke were more likely to have actually suffered a stroke (Fischer's exact test, p = 0.01), to have a correctly classified stroke (χ2 28.2, p < 0.01), to have persisting occlusion (χ2 30.6, p < 0.01), and to have a large DWI–PWI mismatch (χ2 17.1, p < 0.01). Conclusions: There is more inaccuracy in patients presenting with acute PACS or clinically mild to moderate anterior circulation stroke than in those with TACS or severe acute stroke

  8. 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…

  9. Cerebral infarction in diabetes: Clinical pattern, stroke subtypes, and predictors of in-hospital mortality

    PubMed Central

    Arboix, Adrià; Rivas, Antoni; García-Eroles, Luis; de Marcos, Lourdes; Massons, Joan; Oliveres, Montserrat

    2005-01-01

    Background To compare the characteristics and prognostic features of ischemic stroke in patients with diabetes and without diabetes, and to determine the independent predictors of in-hospital mortality in people with diabetes and ischemic stroke. Methods Diabetes was diagnosed in 393 (21.3%) of 1,840 consecutive patients with cerebral infarction included in a prospective stroke registry over a 12-year period. Demographic characteristics, cardiovascular risk factors, clinical events, stroke subtypes, neuroimaging data, and outcome in ischemic stroke patients with and without diabetes were compared. Predictors of in-hospital mortality in diabetic patients with ischemic stroke were assessed by multivariate analysis. Results People with diabetes compared to people without diabetes presented more frequently atherothrombotic stroke (41.2% vs 27%) and lacunar infarction (35.1% vs 23.9%) (P < 0.01). The in-hospital mortality in ischemic stroke patients with diabetes was 12.5% and 14.6% in those without (P = NS). Ischemic heart disease, hyperlipidemia, subacute onset, 85 years old or more, atherothrombotic and lacunar infarcts, and thalamic topography were independently associated with ischemic stroke in patients with diabetes, whereas predictors of in-hospital mortality included the patient's age, decreased consciousness, chronic nephropathy, congestive heart failure and atrial fibrillation Conclusion Ischemic stroke in people with diabetes showed a different clinical pattern from those without diabetes, with atherothrombotic stroke and lacunar infarcts being more frequent. Clinical factors indicative of the severity of ischemic stroke available at onset have a predominant influence upon in-hospital mortality and may help clinicians to assess prognosis more accurately. PMID:15833108

  10. 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

  11. 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

  12. 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

  13. Clinical and microarray analysis of breast cancers of all subtypes from two prospective preoperative chemotherapy studies

    PubMed Central

    Okuma, H S; Koizumi, F; Hirakawa, A; Nakatochi, M; Komori, O; Hashimoto, J; Kodaira, M; Yunokawa, M; Yamamoto, H; Yonemori, K; Shimizu, C; Fujiwara, Y; Tamura, K

    2016-01-01

    Background: We aimed to analyse clinical and gene expression profiles to predict pathologic complete response and disease-free survival using two consecutive, prospective, preoperative chemotherapy trial cohorts. Methods: Clinicopathological and gene expression data were evaluated in a cohort from two consecutive phase II preoperative studies that included patients with stage IIA–IIIC breast cancer of all subtypes. Analysed specimens were obtained before preoperative chemotherapy, and cDNA microarray analyses were performed using the Affymetrix Gene Chip U133 plus 2.0. Results: Between December 2005 and December 2010, 122 patients were analysed. The pathologic complete response rate was significantly higher in HER2+ and HR−/HER2− cancers. Age, pathologic complete response, HR−/HER2− status, and lymph node positivity (⩾4) were significant poor prognostic factors for disease-free survival. For the cDNA microarray analyses, sufficient tumour samples were available from 78 of the 107 patients (73%). An 8-gene signature predictive of pathologic complete response and a 17-gene signature predictive of prognosis were identified. Patients were categorised into low-risk (n=45) and high-risk groups (n=33) (HR 70.0, P=0.004). Conclusions: This study yielded preliminary data on the expression of specific genes predicting pathologic complete response and disease-free survival in a cohort of chemonaïve breast cancer patients. Further validation may distinguish those who would benefit most from perioperative chemotherapy as well as those needing further intervention. PMID:27415010

  14. 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

  15. Lifestyle interventions for type 2 diabetes. Relevance for clinical practice.

    PubMed Central

    Harris, Stewart B.; Petrella, Robert J.; Leadbetter, Wendy

    2003-01-01

    OBJECTIVE: To review evidence from literature on type 2 diabetes pertinent to physical activity and diet and lifestyle modification, and to determine the relevance of this evidence to clinical practice. QUALITY OF EVIDENCE: Direct (level I) evidence supports interventions for physical activity and diet modification for primary prevention and management of type 2 diabetes. Few studies examine the effectiveness of primary health care providers' making such interventions. MAIN MESSAGE: Family physicians have an important role in identifying people at risk of developing type 2 diabetes and managing those diagnosed with the disease, yet they struggle to deliver practice-based interventions that promote sustainable behaviour change among their patients. CONCLUSION: It is evident that supporting patients to make changes in their physical activity and dietary habits can prevent onset of type 2 diabetes. Translating this finding into effective recommendations for clinical practice requires further effort and evaluation. PMID:14708927

  16. [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

  17. 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

  18. Clinical manifestations of pancreas disease outbreaks in Norwegian marine salmon farming - variations due to salmonid alphavirus subtype.

    PubMed

    Jansen, M D; Jensen, B Bang; Brun, E

    2015-04-01

    Pancreas disease (PD) in Norwegian salmonid aquaculture has traditionally been caused by salmonid alphavirus (SAV) subtype 3. Following the isolation of a novel SAV subtype in 2010, marine SAV2, two separate endemic areas have developed. It has been debated whether disease outbreaks due to marine SAV2 result in milder clinical manifestations compared to outbreaks caused by SAV3. The aim of this study was to descriptively investigate site-level differences in the clinical manifestations of marine SAV2 and SAV3 at Norwegian seawater sites diagnosed with PD in 2012. The findings suggest that Norwegian PD outbreaks caused by marine SAV2 result in lower mortality and milder clinical signs compared to outbreaks caused by SAV3. For sites without reported PD-related mortality, there was no difference in the mortality levels between sites infected by marine SAV2 and SAV3. The results also indicate that there are no differences in grading quality at slaughter between the SAV subtypes.

  19. 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

  20. 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

  1. Relevance of molecular medicine to clinical obstetrics and gynecology.

    PubMed

    Cohen, D P; Layman, L C

    1997-01-01

    Understanding molecular biology can improve the clinical acumen of the practicing obstetrician/gynecologist. An area of basic research now becoming clinically relevant involves the G proteins and G protein-coupled receptors. Clinicians already manipulate G protein-coupled receptors in their daily practice. Examples include the administration of oxytocin (oxytocin receptors), beta-2 tocolytic agents (beta 2-adrenergic receptors), GnRH agonists (GnRH receptors), exogenous gonadotropins (FSH and LH receptors), and bromocriptine (dopamine receptor). Clinically important disorders presenting to the obstetrician/gynecologist include some forms of precocious puberty, delayed puberty, premature ovarian failure, and pituitary adenomas which are due to mutations of G proteins and G protein-coupled receptors. The importance of these proteins is demonstrated by the fact that G protein-related genes comprise about 1 percent of the human genome. Additionally, the knowledge that some G protein gene mutations are present in the germ line, and others are somatic cell in origin (and not heritable), aids in more accurate genetic counseling to patients.

  2. 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

  3. 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

  4. The Current and Potential Clinical Relevance of Heart Failure Biomarkers.

    PubMed

    Gandhi, Parul U; Testani, Jeffrey M; Ahmad, Tariq

    2015-10-01

    Heart failure is a growing epidemic, and our understanding of the intricacies of its pathophysiology continues to evolve. Over the last decade, biomarkers of heart failure have been extensively investigated, particularly for diagnosis and risk stratification. While the natriuretic peptides remain the gold standard heart failure biomarker, they are plagued by their non-specific nature; furthermore, the strategy of natriuretic peptide-guided care remains elusive. Multiple candidate markers indicative of other physiologic aspects of heart failure have been identified and studied, including soluble ST2, galectin-3, and high-sensitivity cardiac troponins. Each of these biomarkers has the potential to provide unique therapeutically relevant information. Ultimately, a multi-marker approach may be applied to improve care of patients with heart failure. Definitive clinical trials and the use of advanced statistical analytic techniques are needed to truly determine the optimal strategy of biomarker-assisted diagnosis, prognostication, and management of patients who suffer from this devastating condition.

  5. Clinical relevance of advanced glycation endproducts for vascular surgery.

    PubMed

    Meerwaldt, R; van der Vaart, M G; van Dam, G M; Tio, R A; Hillebrands, J-L; Smit, A J; Zeebregts, C J

    2008-08-01

    Atherosclerosis is the main contributor to cardiovascular disease and leads to intimal plaque formation, which may progress to plaque rupture with subsequent thromboembolic events and/or occlusion of the arterial lumen. There is increasing evidence that the development or progression of atherosclerosis is associated with advanced glycation endproducts (AGEs). AGEs are a heterogeneous group of compounds formed by the non-enzymatic reaction of reducing sugars with proteins, lipids, and nucleic acids. An increased understanding of the mechanisms of formation and interaction of AGEs has allowed the development of several potential anti-AGE strategies. This review summarizes AGE formation and biochemistry, the pathogeneic role of AGEs in cardiovascular disease, anti-AGE therapies and clinical relevance to vascular surgery. PMID:18356091

  6. [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

  7. Clinical relevance of advanced glycation endproducts for vascular surgery.

    PubMed

    Meerwaldt, R; van der Vaart, M G; van Dam, G M; Tio, R A; Hillebrands, J-L; Smit, A J; Zeebregts, C J

    2008-08-01

    Atherosclerosis is the main contributor to cardiovascular disease and leads to intimal plaque formation, which may progress to plaque rupture with subsequent thromboembolic events and/or occlusion of the arterial lumen. There is increasing evidence that the development or progression of atherosclerosis is associated with advanced glycation endproducts (AGEs). AGEs are a heterogeneous group of compounds formed by the non-enzymatic reaction of reducing sugars with proteins, lipids, and nucleic acids. An increased understanding of the mechanisms of formation and interaction of AGEs has allowed the development of several potential anti-AGE strategies. This review summarizes AGE formation and biochemistry, the pathogeneic role of AGEs in cardiovascular disease, anti-AGE therapies and clinical relevance to vascular surgery.

  8. 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

  9. 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

  10. 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

  11. 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

  12. Resveratrol and calcium signaling: molecular mechanisms and clinical relevance.

    PubMed

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

    2014-06-05

    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.

  13. 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

  14. 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

  15. 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

  16. Structure-based prediction of subtype-selectivity of Histamine H3 receptor selective antagonists in clinical trials

    PubMed Central

    Kim, Soo-Kyung; Fristrup, Peter; Abrol, Ravinder; Goddard, William A.

    2011-01-01

    Histamine receptors (HRs) are excellent drug targets for the treatment of diseases such as schizophrenia, psychosis, depression, migraine, allergies, asthma ulcers, and hypertension. Among them, the human H3 Histamine receptor (hH3HR) antagonists have been proposed for specific therapeutic applications, including treatment of Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), epilepsy, and obesity.1 However, many of these drug candidates cause undesired side effects through the cross-reactivity with other histamine receptor subtypes. In order to develop improved selectivity and activity for such treatments it would be useful to have the three dimensional structures for all four HRs. We report here the predicted structures of four HR subtypes (H1, H2, H3, and H4) using the GEnSeMBLE (GPCR Ensemble of Structures in Membrane BiLayer Environment) Monte Carlo protocol.2 sampling ~ 35 million combinations of helix packings to predict the 10 most stable packings for each of the four subtypes. Then we used these best 10 protein structures with the DarwinDock Monte Carlo protocol to sample ~ 50,000*20 poses to predict the optimum ligand-protein structures for various agonists and antagonists. We find that E2065.46 contributes most in binding H3 selective agonists (5, 6, 7) in agreement with experimental mutation studies. We also find that conserved E5.46/ S5.43 in both of hH3HR and hH4HR are involved in H3/ H4 subtype selectivity. In addition, we find that M3786.55 in hH3HR provides additional hydrophobic interactions different from hH4HR (the corresponding amino acid of T3236.55 in hH4HR) to provide additional subtype bias. From these studies we developed a pharmacophore model based on our predictions for known hH3HR selective antagonists in clinical study [ABT-239 1, GSK-189,254 2, PF-3654746 3, and BF2.649 (Tiprolisant) 4] that suggests critical selectivity directing elements are: the basic proton interacting with D1143.32, the spacer, the aromatic

  17. MM2 subtype of sporadic Creutzfeldt-Jakob disease may underlie the clinical presentation of progressive supranuclear palsy.

    PubMed

    Petrovic, Igor N; Martin-Bastida, Antonio; Massey, Luke; Ling, Helen; O'Sullivan, Sean S; Williams, David R; Holton, Janice L; Revesz, Tamas; Ironside, James W; Lees, Andrew J; Silveira-Moriyama, Laura

    2013-04-01

    The classical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) is rapid progressive dementia often associated with myoclonus and ataxia followed by death in less than a year from diagnosis. The few patients in the literature who presented with parkinsonism and who were suspected to have progressive supranuclear palsy (PSP) all ran a malignant course and most of them died within 3 years of diagnosis. We screened the Queen Square Brain Bank database and, among 213 patients with a clinical diagnosis of PSP, we found ten patients with 3 years or less disease duration, including one patient with CJD pathology. We report this patient and review other similar cases from the literature. Ten additional cases with similar presentation were identified in the literature. The mean disease duration was 24.2 months. The classical clinical, radiological and laboratory findings for sCJD were absent in the majority of these cases. Clinical presentation of these patients consists of: early falls, prominent dementia, early vertical supranuclear gaze palsy and symmetric akinetic syndrome. In the patients who were subtyped at post-mortem, all four represented the MM2 subtype of sCJD. A rapidly progressive course of PSP with early falls, cognitive impairments and vertical supranuclear gaze palsy should raise suspicion of underlying sCJD pathology regardless of absence of supportive findings on ancillary tests. This case and the literature support the notion that biochemical properties of the prion protein can influence the clinical presentation of sCJD.

  18. Almond allergens: molecular characterization, detection, and clinical relevance.

    PubMed

    Costa, Joana; Mafra, Isabel; Carrapatoso, Isabel; Oliveira, Maria Beatriz P P

    2012-02-15

    Almond ( Prunus dulcis ) has been widely used in all sorts of food products (bakery, pastry, snacks), mostly due to its pleasant flavor and health benefits. However, it is also classified as a potential allergenic seed known to be responsible for triggering several mild to life-threatening immune reactions in sensitized and allergic individuals. Presently, eight groups of allergenic proteins have been identified and characterized in almond, namely, PR-10 (Pru du 1), TLP (Pru du 2), prolamins (Pru du 2S albumin, Pru du 3), profilins (Pru du 4), 60sRP (Pru du 5), and cupin (Pru du 6, Pru du γ-conglutin), although only a few of them have been tested for reactivity with almond-allergic sera. To protect sensitized individuals, labeling regulations have been implemented for foods containing potential allergenic ingredients, impelling the development of adequate analytical methods. This work aims to present an updated and critical overview of the molecular characterization and clinical relevance of almond allergens, as well as review the main methodologies used to detect and quantitate food allergens with special emphasis on almond. PMID:22260748

  19. 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

  20. Biology and Clinical Relevance of Acute Myeloid Leukemia Stem Cells.

    PubMed

    Reinisch, Andreas; Chan, Steven M; Thomas, Daniel; Majeti, Ravindra

    2015-07-01

    Evidence for the cancer stem cell model was first demonstrated in xenotransplanted blood and bone marrow samples from patients with acute myeloid leukemia (AML) almost two decades ago, supporting the concept that a rare clonal and mutated leukemic stem cell (LSC) population is sufficient to drive leukemic growth. The inability to eliminate LSCs with conventional therapies is thought to be the primary cause of disease relapse in AML patients, and as such, novel therapies with the ability to target this population are required to improve patient outcomes. An important step towards this goal is the identification of common immunophenotypic surface markers and biological properties that distinguish LSCs from normal hematopoietic stem and progenitor cells (HSPCs) across AML patients. This work has resulted in the development of a large number of potential LSC-selective therapies that target cell surface molecules, intracellular signaling pathways, and the bone marrow microenvironment. Here, we will review the basic biology, immunophenotypic detection, and clinical relevance of LSCs, as well as emerging biological and small-molecule strategies that either directly target LSCs or indirectly target these cells through modulation of their microenvironment.

  1. Clinical relevance: an issue in biostatistical training of medical students.

    PubMed

    Knapp, R G; Miller, M C

    1987-01-01

    Significant trends in teaching biostatistics to medical students include: recognition of the dependence of advancement in the medical sciences upon the quantitative sciences; integration of biostatistics and other disciplines such as epidemiology and community medicine; increased emphasis on clinical relevance through the introduction of such topics as medical decision-making, evaluation of diagnostic test, genetic counselling and evaluating health-science literature; growing emphasis on analytic skills and computer literacy as precipitated by the presence of computer-based patient and medical information systems, expert systems, imaging and signal analysis systems; the emergence of new applications of statistics in health and medicine; and changes in the learning environment, for example emphasis on small-group discussions and problem-solving sessions. The evolution and future directions of biometrical training in medicine as precipitated by these trends, and the response of course directors at the Medical University of South Carolina to the demand for a 'new' curriculum in biostatistics for medical students are described. PMID:3821598

  2. 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

  3. Almond allergens: molecular characterization, detection, and clinical relevance.

    PubMed

    Costa, Joana; Mafra, Isabel; Carrapatoso, Isabel; Oliveira, Maria Beatriz P P

    2012-02-15

    Almond ( Prunus dulcis ) has been widely used in all sorts of food products (bakery, pastry, snacks), mostly due to its pleasant flavor and health benefits. However, it is also classified as a potential allergenic seed known to be responsible for triggering several mild to life-threatening immune reactions in sensitized and allergic individuals. Presently, eight groups of allergenic proteins have been identified and characterized in almond, namely, PR-10 (Pru du 1), TLP (Pru du 2), prolamins (Pru du 2S albumin, Pru du 3), profilins (Pru du 4), 60sRP (Pru du 5), and cupin (Pru du 6, Pru du γ-conglutin), although only a few of them have been tested for reactivity with almond-allergic sera. To protect sensitized individuals, labeling regulations have been implemented for foods containing potential allergenic ingredients, impelling the development of adequate analytical methods. This work aims to present an updated and critical overview of the molecular characterization and clinical relevance of almond allergens, as well as review the main methodologies used to detect and quantitate food allergens with special emphasis on almond.

  4. Epileptic neuronal networks: methods of identification and clinical relevance.

    PubMed

    Stefan, Hermann; Lopes da Silva, Fernando H

    2013-01-01

    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.

  5. 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

  6. Clinical features of human salmonellosis caused by bovine-associated subtypes in New York.

    PubMed

    Cummings, Kevin J; Warnick, Lorin D; Gröhn, Yrjö T; Hoelzer, Karin; Root, Timothy P; Siler, Julie D; McGuire, Suzanne M; Wright, Emily M; Zansky, Shelley M; Wiedmann, Martin

    2012-09-01

    The objective of this study was to identify patient symptoms and case outcomes that were more likely to occur as a result of Salmonella infections caused by bovine-associated subtypes (isolates that matched contemporary bovine isolates from New York by serovar and pulsed-field gel electrophoresis pattern), as compared to salmonellosis caused by non-bovine-associated subtypes. Data were collected in 34 counties of New York that comprise the Foodborne Diseases Active Surveillance Network (FoodNet) catchment area of the Centers for Disease Control and Prevention Emerging Infections Program. Patients with specimen collection dates between March 1, 2008 and March 1, 2010 were included. Symptoms and outcomes of 40 cases infected with bovine-associated Salmonella subtypes were compared to those of 379 control-cases infected with Salmonella isolates that were not bovine-associated. Cases were significantly more likely to have invasive salmonellosis (odds ratio, 3.8; p-value=0.02), after adjusting for age group, gender, and race. In addition, there was a marginal association between case status and the presence of blood in the stool (p-value=0.1) while ill. These findings might have implications for patient management, as a history of consuming undercooked foods of bovine origin or having direct contact with cattle in the few days prior to illness could be useful for suggesting a more proactive diagnostic approach as well as close monitoring for the need to implement more aggressive therapy.

  7. First clinical isolates of Cronobacter spp. (Enterobacter sakazakii) in Argentina: characterization and subtyping by pulsed-field gel electrophoresis.

    PubMed

    Asato, Valeria C; Vilches, Viviana E; Pineda, María G; Casanueva, Enrique; Cane, Alejandro; Moroni, Mirian P; Brengi, Silvina P; Pichel, Mariana G

    2013-01-01

    Cronobacter species are opportunistic pathogens associated with severe infections in neonates and immunocompromised infants. From January 2009 through September 2010, two cases of neonatal infections associated with Cronobacter malonaticus and one case associated with Cronobacter sakazakii, two of them fatal, were reported in the same hospital. These are the first clinical isolates of Cronobacter spp. in Argentina. The objective of this work was to characterize and subtype clinical isolates of Cronobacter spp. in neonate patients, as well as to establish the genetic relationship between these isolates and the foodborne isolates previously identified in the country. Pulsed-field gel electrophoresis analysis showed a genetic relationship between the C. malonaticus isolates from two patients. Different results were found when the pulsed-field gel electrophoresis patterns of clinical isolates were compared with those deposited in the National Database of Cronobacter spp.

  8. 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

  9. 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

  10. 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

  11. Recent advances and clinical implications of the micropapillary histological subtype in lung adenocarcinomas.

    PubMed

    Lee, Ming-Ching; Buitrago, Daniel H; Kadota, Kyuichi; Jones, David R; Adusumilli, Prasad S

    2014-06-01

    Micropapillary (MIP) histologic subtype included in the classification of lung adenocarcinomas (ADCs) is associated with both size- and stage-independent poor prognoses. MIP pattern in lung ADCs, even at small, early stages, correlates with high lymphovascular invasion, visceral pleural invasion and lymph node metastases. Recently, we reported that patients with a MIP component are at a higher risk of locoregional recurrence after limited resection. Identification of a MIP pattern is only possible with permanent pathologic sections; preoperative imaging, cytology or intraoperative frozen section specimens remain unreliable. The intermixed, heterogenous morphology of lung ADC presents a technical challenge in investigating the molecular biology of cells with MIP morphology. A comprehensive understanding of the biology of MIP morphology is vital for therapeutic interventions.

  12. 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).

  13. 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

  14. [The clinical relevance of opioid-induced hyperalgesia remains unresolved].

    PubMed

    Sørensen, Jakob; Sjøgren, Per

    2011-03-28

    Opioids are widely used as analgesics in chronic pain of malignant as well as non-malignant origin. During opioid treatment, pain is occasionally worsened. This could be due to progression of the disease or tolerance or opioid-induced hyperalgesia (OIH). The present article summarizes the preclinical and clinical data in support of the existence of OIH. Further, possible mechanisms and potential treatments are outlined. We conclude that only a few clinical studies on OIH are available. However, a growing body of experimental data supports the presence of OIH in clinical settings. Diagnostic tools for assessment of OIH have yet to be developed.

  15. Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon?

    PubMed

    Tompkins, D Andrew; Campbell, Claudia M

    2011-04-01

    Opioids have become the unequivocal therapy of choice in treating many varieties of chronic pain. With the increased prescription of opioids, some unintended consequences have occurred. After prolonged opioid exposure, opioid-induced hyperalgesia (OIH), the paradoxical effect that opioid therapy may in fact enhance or aggravate preexisting pain, may occur. Over the past several decades, an increasing number of laboratory and clinical reports have suggested lowered pain thresholds and heightened atypical pain unrelated to the original perceived pain sensations as hallmarks of OIH. However, not all evidence supports the clinical importance of OIH, and some question whether the phenomenon exists at all. Here, we present a nonexhaustive, brief review of the recent literature. OIH will be reviewed in terms of preclinical and clinical evidence for and against its existence; recommendations for clinical evaluation and intervention also will be discussed.

  16. 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

  17. 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

  18. 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

  19. 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

  20. Personality subtypes in adolescents with anorexia nervosa.

    PubMed

    Gazzillo, Francesco; Lingiardi, Vittorio; Peloso, Anna; Giordani, Silvia; Vesco, Serena; Zanna, Valeria; Filippucci, Ludovica; Vicari, Stefano

    2013-08-01

    The aims of this study are to (1) empirically identify the personality subtypes of adolescents with anorexic disorders and (2) investigate the personality disorders, identity disturbances, and affective features associated with the different subtypes. We assessed 102 adolescent patients with Eating Disorders (anorexia nervosa and eating disorder not otherwise specified) using three clinical instruments: the Shedler-Westen Assessment Procedure for Adolescents (SWAP-200-A) (Westen D, Shedler J, Durrett C, Glass S, Martens A. Personality diagnoses in adolescence: DSM-IV Axis II diagnoses and an empirically derived alternative. Am J Psychiatry 2003;160:952-966), the Affective Regulation and Experience Questionnaire (AREQ) (Zittel Conklin C, Bradley R, Westen D. Affect regulation in borderline personality disorder. J Nerv Ment Dis 2006;194:69-77), and the Identity Disorder Questionnaire (IDQ) (Wilkinson-Ryan T, Westen D. Identity disturbance in borderline personality disorder: An empirical investigation. Am J Psychiatry 2000;157:528-541). We performed a Q factor analysis of the SWAP-200-A descriptions of our sample to identify personality subtypes. We correlated these personality styles with AREQ and IDQ factors and explored the personality differences among individuals with the different types of ED. The Q factor analysis identified three personality subtypes: high-functioning/perfectionist, emotionally dysregulated, and overcontrolled/constricted. Each subtype showed specific identity and affective features, comorbidities with different personality disorders, and clinical implications. These results contribute to the understanding of adolescents with ED and seem to be relevant for treatment planning.

  1. 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…

  2. Comprehensive analysis of long non-coding RNAs in human breast cancer clinical subtypes.

    PubMed

    Su, Xiaoping; Malouf, Gabriel G; Chen, Yunxin; Zhang, Jianping; Yao, Hui; Valero, Vicente; Weinstein, John N; Spano, Jean-Philippe; Meric-Bernstam, Funda; Khayat, David; Esteva, Francisco J

    2014-10-30

    Accumulating evidence highlights the potential role of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets in solid tumors. However, the role of lncRNA expression in human breast cancer biology, prognosis and molecular classification remains unknown. Herein, we established the lncRNA profile of 658 infiltrating ductal carcinomas of the breast from The Cancer Genome Atlas project. We found lncRNA expression to correlate with the gene expression and chromatin landscape of human mammary epithelial cells (non-transformed) and the breast cancer cell line MCF-7. Unsupervised consensus clustering of lncRNA revealed four subgroups that displayed different prognoses. Gene set enrichment analysis for cis- and trans-acting lncRNAs showed enrichment for breast cancer signatures driven by master regulators of breast carcinogenesis. Interestingly, the lncRNA HOTAIR was significantly overexpressed in the HER2-enriched subgroup, while the lncRNA HOTAIRM1 was significantly overexpressed in the basal-like subgroup. Estrogen receptor (ESR1) expression was associated with distinct lncRNA networks in lncRNA clusters III and IV. Importantly, almost two thirds of the lncRNAs were marked by enhancer chromatin modifications (i.e., H3K27ac), suggesting that expressed lncRNA in breast cancer drives carcinogenesis through increased activity of neighboring genes. In summary, our study depicts the first lncRNA subtype classification in breast cancer and provides the framework for future studies to assess the interplay between lncRNAs and the breast cancer epigenome.

  3. Efficacy of mirtazapine in clinically relevant subgroups of depressed patients.

    PubMed

    Nutt, D J

    1998-01-01

    Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) with a novel mode of action that differs from other antidepressants that are currently available. Clinical trials have demonstrated it to have good antidepressant efficacy and excellent tolerability. Analysis of the results of placebo-controlled trials in moderately or severely depressed patients have shown mirtazapine to be effective in clinically important subgroups of depressed patients, particularly anxious patients, patients with sleep disturbance, retarded patients, and agitated patients. The efficacy and tolerability of mirtazapine are attributable to its pharmacological profile. It is likely that the overall antidepressant activity arises from its dual action, enhancing both noradrenergic and 5-HT1 receptor-mediated serotonergic neurotransmission, while the anxiolytic and sleep-improving properties of mirtazapine are attributable to the specific blockade of 5-HT2 and 5-HT3 receptors. PMID:9597345

  4. Tolerance in liver transplantation: Biomarkers and clinical relevance

    PubMed Central

    Baroja-Mazo, Alberto; Revilla-Nuin, Beatriz; Parrilla, Pascual; Martínez-Alarcón, Laura; Ramírez, Pablo; Pons, José Antonio

    2016-01-01

    Transplantation is the optimal treatment for end-stage organ failure, and modern immunosuppression has allowed important progress in short-term outcomes. However, immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus, a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor FoxP3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. Likewise, other immune cells, such as dendritic cells, monocyte/macrophages or natural killer cells, have been described as part of the process known as “operational tolerance”. However, translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way, a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multi-center clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio. PMID:27678350

  5. [Antipsychotics and hyperpolactinaemia: pathophysiology, clinical relevance, diagnosis and therapy].

    PubMed

    Riecher-Rössler, Anita; Schmid, Christoph; Bleuer, Stefan; Birkhäuser, Martin

    2009-01-01

    Hyperprolactinaemia is a frequent but often neglected side effect of typical, but also of many atypical antipsychotics such as amisulpiride, risperidone or ziprasidone. Besides galactorrhoea, potential consequences are suppression of the hypothalamic-pituitary-gonadal axis with hypogonadism, sexual dysfunction, infertility and in women also irregularities of the menstrual cycle and amenorrhoea. Potential long term consequences are mainly osteopenia and osteoporosis with an enhanced risk of fractures. Hyperprolactinaemia, if not clearly caused by a prolactin inducing antipsychotic, should always be thoroughly investigated. Ideally, prolactin should be measured before starting a patient on a new antipsychotic. Furthermore, before neuroleptic treatment is begun, and also in regular intervals after that, patients should be asked about potential clinical signs of hyperprolactinaemia. Hyperprolactinaemia which is clearly due to antipsychotics but without clinical symptoms only requires regular controls of bone mineral density. However, if clinical symptoms occur, switching to a prolactin sparing antipsychotic may be necessary. In these cases fertility is often regained and the women concerned have to be informed about the enhanced risk of pregnancy and counselled regarding contraception. If switching is not possible, estradiol has to be substituted in women. Also in men with hypogonadism hormonesubstitution (with testosterone) is usually indicated. Generally hyperprolactinaemia in psychiatric patients should be taken more seriously in the future.

  6. The Clinical Relevance of Beta Blockers in Ovarian Carcinoma

    PubMed Central

    Hefner, J.; Csef, H.

    2016-01-01

    The last ten years have seen hardly any improvement in the prognosis of ovarian carcinoma. There is a great need for new treatment strategies, and a recent retrospective study showing a survival advantage with the use of beta blockers met with a very positive response. This systematic review summarizes the current state of knowledge and research on the topic: A database analysis identified six clinical studies showing inconsistent results with respect to the administration of beta blockers and disease course. The 13 preclinical studies identified showed almost without exception both that catecholamines had detrimental effects on tumour progression, and that these effects could be influenced by pharmacological blockade. Overall the available evidence does not justify the use of beta blockers in clinical practice for ovarian carcinoma at the present time. This article also outlines details of research design required for further studies needed on the subject. Preclinical research findings are however very impressive: They not only form an important basis for the development of future clinical studies but also, through revealing new pathomechanisms, they already make an important contribution towards the development of new treatment strategies for ovarian carcinoma. PMID:27761025

  7. Tolerance in liver transplantation: Biomarkers and clinical relevance.

    PubMed

    Baroja-Mazo, Alberto; Revilla-Nuin, Beatriz; Parrilla, Pascual; Martínez-Alarcón, Laura; Ramírez, Pablo; Pons, José Antonio

    2016-09-14

    Transplantation is the optimal treatment for end-stage organ failure, and modern immunosuppression has allowed important progress in short-term outcomes. However, immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus, a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor FoxP3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. Likewise, other immune cells, such as dendritic cells, monocyte/macrophages or natural killer cells, have been described as part of the process known as "operational tolerance". However, translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way, a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multi-center clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio. PMID:27678350

  8. 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

  9. Tolerance in liver transplantation: Biomarkers and clinical relevance

    PubMed Central

    Baroja-Mazo, Alberto; Revilla-Nuin, Beatriz; Parrilla, Pascual; Martínez-Alarcón, Laura; Ramírez, Pablo; Pons, José Antonio

    2016-01-01

    Transplantation is the optimal treatment for end-stage organ failure, and modern immunosuppression has allowed important progress in short-term outcomes. However, immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus, a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor FoxP3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. Likewise, other immune cells, such as dendritic cells, monocyte/macrophages or natural killer cells, have been described as part of the process known as “operational tolerance”. However, translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way, a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multi-center clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio.

  10. ELISA subtypization of anti-ENA autoantibodies in clinical management of autoimmune diseases in Bosnia and Herzegovina.

    PubMed

    Subasic, Djemo; Karamehic, Jasenko; Gavrankapetanovic, Faris; Hodzic, Harun; Kasumovic, Mersija; Delic-Sarac, Marina; Prljaca-Zecevic, Lamija

    2009-01-01

    The basis of autoimmune diseases such as SLE (Systemic Lupus Eritematodes), Sjogren's syndrome, scleroderma, dermatomyositis and polymiositis is the creation of auto-antibodies to the following specific extractable nuclear antigens (ENA):Jo-1, Ssl-70, SS-A, SS-B, Sm and Sm/RNPs. Some of these antigens are in fact enzymes (Jo-1-histidil-tRNA synthetase, Scl-70-topoisomerase) which are inhibited by specific autoantibodies--this leads to disturbance in the metabolism of DNA and protein biosynthesis. During 2009, we analyzed total of 87 serum samples of patients suspected for autoimmune disorder using ANA-IFA and ELISA-ENA-6 methods. After establishing IFA-ANA positivity (83.9%), all serum specimens; ANA positive and negative, were subtypized by ELISA ENA-6 test. Analysis showed the highest incidence of anti-SS-A (56%), and incidence of anti-SS-B (29.8%), anti-Sm/ RNP (11.5%), anti-Jo-1 (2.3%) and anti-Scl-70 (1,1%) auto-antibodies. Also, 78.5% of IFA-ANA negative serum specimens showed high level of positivity (212.50 and 277.0 IU/ml) to SS-A (78.5%) and SS-B (21.4%) antigenes using ELISA-ENA-6 subtypization. Following these results, we conclude that it is necessary to introduce Western blot confirmation testing. After comparing with other clinical findings, we diagnosed the following autoimmune diseases: SLE, Sjogren's syndrome and dermatomiosytis.

  11. The clinical relevance of sexual dysfunction in systemic sclerosis.

    PubMed

    Bruni, C; Raja, J; Denton, C P; Matucci-Cerinic, M

    2015-12-01

    Systemic sclerosis is a chronic multi-organ autoimmune disease, leading to important clinical and psychological implications. Among organ complications, sexual dysfunction is a major issue for both male and female gender, with high prevalence and great impact on quality of life, although frequently not addressed by both clinicians and patients. While erectile dysfunction is the most common cause of sexual problems in males, genital tract and general physical changes are major contributors to sexual impairment in females. This review presents current state of the art on this topic, discussing published data on presentation, evaluation and therapeutic options.

  12. Thyroid Autoantibodies in Pregnancy: Their Role, Regulation and Clinical Relevance

    PubMed Central

    Balucan, Francis S.; Morshed, Syed A.; Davies, Terry F.

    2013-01-01

    Autoantibodies to thyroglobulin and thyroid peroxidase are common in the euthyroid population and are considered secondary responses and indicative of thyroid inflammation. By contrast, autoantibodies to the TSH receptor are unique to patients with Graves' disease and to some patients with Hashimoto's thyroiditis. Both types of thyroid antibodies are useful clinical markers of autoimmune thyroid disease and are profoundly influenced by the immune suppression of pregnancy and the resulting loss of such suppression in the postpartum period. Here, we review these three types of thyroid antibodies and their antigens and how they relate to pregnancy itself, obstetric and neonatal outcomes, and the postpartum. PMID:23691429

  13. Relevance of guideline-based ICD indications to clinical practice.

    PubMed

    Al-Jefairi, Nora; Burri, Haran

    2014-01-01

    The implantable cardioverter-defibrillator (ICD) has established itself as life-saving therapy in patients at risk for sudden cardiac death. Remarkable technological advances have made ICDs easier and safer to implant, with improved therapeutic and diagnostic functions and reduced morbidity. Guidelines on ICD indications have been proposed by American and European scientific societies since a number of years, based upon trials and expert opinion. In the context of variable economic and political constraints, it is questionable whether these guidelines may be applied to all settings. This review discusses the guideline-based indications, critically examines their applicability to clinical practice, and discusses alternatives to ICD therapy.

  14. [Opioid-induced hyperalgesia. Pathophysiology and clinical relevance].

    PubMed

    Koppert, W

    2004-05-01

    Opioids are the drugs of choice for the treatment of moderate to severe acute and chronic pain. However, clinical evidence suggests that opioids can elicit increased sensitivity to noxious stimuli suggesting that administration of opioids can activate both pain inhibitory and pain facilitatory systems. Acute receptor desensitization via uncoupling of the receptor from G-proteins, up-regulation of the cAMP pathway, activation of the N-methyl-D-aspartate (NMDA) receptor system, as well as descending facilitation, have been proposed as potential mechanisms underlying opioid-induced hyperalgesia. Numerous reports exist demonstrating that opioid-induced hyperalgesia is observed both in animal and human experimental models. Brief exposures to micro-receptor agonists induce long-lasting hyperalgesic effects for days, which might by reflected by clinical observations that large doses of intraoperative micro-receptor agonists increased postoperative pain and morphine consumption. Furthermore, the prolonged use of opioids in patients often requires increasing doses and may be accompanied by the development of abnormal pain. Successful strategies that may decrease or prevent opioid-induced hyperalgesia include the concomitant administration of drugs like NMDA-antagonists, alpha(2)-agonists, or non-steroidal anti-inflammatory drugs (NSAIDs), opioid rotation or combinations of opioids with different receptor selectivity.

  15. 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

  16. 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

  17. 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

  18. Taxonomy, epidemiology, and clinical relevance of the genus Arcobacter.

    PubMed

    Collado, Luis; Figueras, Maria José

    2011-01-01

    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.

  19. 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

  20. [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).

  1. 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

  2. Developments in ghrelin biology and potential clinical relevance.

    PubMed

    Smith, Roy G; Jiang, Hong; Sun, Yuxiang

    2005-11-01

    The spiropiperidine, MK0677, has been exploited to characterize and expression clone the growth hormone secretagogue receptor (GHS-R). Cloning of this receptor led to identification of its natural ligands, ghrelin and adenosine. Targeted disruption of the Ghsr gene demonstrated unambiguously that the GH-releasing and orexigenic properties of ghrelin are dependent on Ghsr expression and that the orexigenic signal is mediated through neuropeptide Y and agouti-related peptide neurons. This review summarizes new developments in our understanding of the physiological roles of ghrelin and its receptor (GHS-R). Recent discoveries of the effects of ghrelin on the thymus and proinflammatory and chemotactic cytokine pathways stimulate renewed interest in potential clinical applications, which include age-associated disorders, such as metabolic disease, sarcopenia, congestive heart failure, atherosclerosis and anorexia. PMID:16213742

  3. [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

  4. The clinical relevance of attentional bias in substance use disorders.

    PubMed

    Field, Matt; Marhe, Reshmi; Franken, Ingmar H A

    2014-06-01

    Individuals with substance use disorders typically show an "attentional bias" for substance-related cues: Those cues are able to grab and hold the attention, in preference to other cues in the environment. We discuss the theoretical context for this work before reviewing the measurement of attentional bias, and its relationship to motivational state and relapse to substance use after a period of abstinence. Finally, we discuss the implications of this research for the treatment of substance use disorders. We conclude that attentional bias is associated with subjective craving, and that moment-by-moment fluctuations in attentional bias may precede relapse to substance use. The evidence regarding the predictive relationship between attentional bias assessed in treatment contexts and subsequent relapse is inconsistent. Furthermore, there is currently insufficient evidence to endorse attentional bias modification as a treatment for substance use disorders. Clinical implications and suggestions for future research are highlighted.

  5. Evidence of clinically relevant efficacy for dietary supplements and nutraceuticals.

    PubMed

    Cicero, Arrigo F G; Borghi, Claudio

    2013-06-01

    Beyond the well-known effects on blood pressure (BP) of the DASH and the Mediterranean diets, a large number of studies have investigated the possible a BP-lowering effect from different dietary supplements and nutraceuticals, mostly antioxidant agents with a high tolerability and safety profile. In particular, a relatively large body of evidence support the use of potassium, L-arginine, vitamin C, cocoa flavonoids, coenzyme Q10, controlled-release melatonin, and aged garlic extract. However there is a need for data about the long-term safety of a large part of these products. Moreover, further clinical research is advisable to identify between the available active nutraceuticals and those with the best cost-effectiveness and risk-benefit ratio for widespread use in a general population with low added cardiovascular risk related to uncomplicated hypertension. PMID:23430658

  6. The development of left ventricular torsion and its clinical relevance.

    PubMed

    Shaw, Steven M; Fox, David J; Williams, Simon G

    2008-11-28

    Left ventricular torsion is a measurement derived from the twisting or wringing motion of the heart around its long axis. The calculation is made by measuring the magnitude of rotation at the apex of the heart, and subtracting the rotation at the base. Although the phenomenon of left ventricular twisting was first described in the 17th Century, it wasn't until the 1960s that the first invasive method of measurement was demonstrated. Silver tantalum clips were sutured into the epicardium during cardiac surgery and viewed using cineradiography. Non-invasive torsion measurement has been subsequently developed, adopting Magnetic Resonance Imaging and 2D echocardiography. Interest in the changes of different components of torsion, during various cardiac disease states has developed with the advent of these non-invasive measurement techniques. This review article summarises the history of the development of torsion analysis and describes the known changes of torsion during different clinical circumstances.

  7. [Bacterial genomics and metagenomics: clinical applications and medical relevance].

    PubMed

    Diene, S M; Bertelli, C; Pillonel, T; Schrenzel, J; Greub, G

    2014-11-12

    New sequencing technologies provide in a short time and at low cost high amount of genomic sequences useful for applications such as: a) development of diagnostic PCRs and/or serological tests; b) detection of virulence factors (virulome) or genes/SNPs associated with resistance to antibiotics (resistome) and c) investigation of transmission and dissemination of bacterial pathogens. Thus, bacterial genomics of medical importance is useful to clinical microbiologists, to infectious diseases specialists as well as to epidemiologists. Determining the microbial composition of a sample by metagenomics is another application of new sequencing technologies, useful to understand the impact of bacteria on various non-infectious diseases such as obesity, asthma, or diabetes. Genomics and metagenomics will likely become a specialized diagnostic analysis.

  8. [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.

  9. [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

  10. 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

  11. HIV-1 subtype distribution trends and evidence of transmission clusters among incident cases in a rural clinical cohort in southwest Uganda, 2004-2010.

    PubMed

    Kapaata, Anne; Lyagoba, Frederick; Ssemwanga, Deogratius; Magambo, Brian; Nanyonjo, Maria; Levin, Jonathan; Mayanja, Billy N; Mugasa, Claire; Parry, Chris M; Kaleebu, Pontiano

    2013-03-01

    The high diversity of HIV-1 has been shown to affect disease progression, transmission, and response to antiretroviral therapy and may influence HIV vaccine design. We describe the distribution trends of HIV-1 subtypes over a 7-year period among incident cases in a rural clinical cohort in Southwest Uganda and identify transmission clusters. Viral RNA was extracted from cryopreserved plasma samples from 94 participants who seroconverted and enrolled between 2004 and 2010. Partial gag (p24) and env (gp41) genes were directly sequenced to identify subtypes and transmission clusters with more than 95% bootstrap values. Direct sequencing of the partial pol gene and use of individual participant sexual life histories were also used to confirm these transmission clusters. The overall gag/env subtype distribution was A 28% (n=26), C 1% (n=1), and D 45% (n=42) and 27% (n=25) were intergene unique recombinant forms. The proportions of subtype A, D, or recombinants showed no significant increasing or decreasing trend over this time period (p=0.51). Phylogenetic analysis of the three genes confirmed 13 transmission clusters of which seven clusters were confirmed sexual partners using individual participants' sexual life histories. Subtype D has remained the predominant subtype in this population. From 2004 to 2010, there was no change in the proportions of these subtypes. Phylogenetic analysis and participants' sexual life histories revealed several transmission clusters. The high proportion of transmission clusters observed suggests continued high-risk sexual behavior and mixing in some individuals and possibly super transmitters in this presumed low-risk cohort, but also indicates that many transmissions occur in early HIV infection. This calls for early and targeted effective prevention and treatment intervention in this population.

  12. Histopathologic and clinical subtypes of autoimmune pancreatitis: the Honolulu consensus document.

    PubMed

    Chari, Suresh T; Kloeppel, Guenter; Zhang, Lizhi; Notohara, Kenji; Lerch, Markus M; Shimosegawa, Tooru

    2010-07-01

    Autoimmune pancreatitis (AIP) has been extensively reported from Japan, Europe, and the United States. Whereas the descriptions of AIP from Japan have predominantly been based on the presence of a distinct clinical phenotype, reports from Europe and the United States describe at least 2 histopathologic patterns in patients' condition currently diagnosed as AIP, viz, lymphoplasmacytic sclerosing pancreatitis (LPSP) and idiopathic duct centric pancreatitis (IDCP) or granulocyte epithelial lesion (GEL)-positive pancreatitis. Although the 2 entities share common histopathologic features (periductal lymphoplasmacytic infiltration and peculiar periductal fibrosis), expert pathologists can accurately distinguish them based on other unique histopathologic features. Clinically, the 2 entities have similar clinical presentation (obstructive jaundice/pancreatic mass and a dramatic response to steroids) but differ significantly in their demography, serological characteristics, other organ involvement, and disease relapse. While LPSP is associated with elevation in titers of nonspecific autoantibodies and serum IgG4 levels, IDCP does not have definitive serological autoimmune markers. All experts agreed that the clinical phenotypes associated with LPSP and IDCP should be nosologically distinguished; however, their terminology was debated. Whereas most experts agreed that the entities should be referred to as type 1 and type 2 AIP, respectively, others had concerns regarding use of the term "autoimmune" to describe IDCP. PMID:20562576

  13. Right Hemisphere Dysfunction in ADHD: Visual Hemispatial Inattention and Clinical Subtype.

    ERIC Educational Resources Information Center

    Sandson, Thomas A.; Bachna, Kristie J.; Morin, Mark D.

    2000-01-01

    Adults (N=58) with attention deficit hyperactivity disorder and 29 age-and education-matched controls were evaluated for right hemisphere dysfunction. Findings support the concept of right hemisphere dysfunction in a subset of patients with ADHD, although this subset did not represent a distinct clinical subgroup in terms of medication response,…

  14. Clinically relevant copy number variations detected in cerebral palsy.

    PubMed

    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

    2015-08-03

    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.

  15. 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

  16. 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.

  17. 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

  18. Gathering and Learning From Relevant Clinical Data: A New Framework

    PubMed Central

    Farias, Michael; Friedman, Kevin G.; Lock, James E.; Rathod, Rahul H.

    2015-01-01

    Given the rising costs of health care in today’s economic environment, the need for effective, value-driven care has never been more pressing. While the U.S. health care system strives continually to improve patient outcomes, it struggles with the inadequacies due to variation in care and the inefficiencies of unnecessary resource utilization. The tools traditionally used to study care, from retrospective studies to randomized controlled trials, may be inadequate to address the complicated, interdependent questions related to defining effective care. To overcome the deficiencies of these traditional tools and better optimize our health care system, a new kind of methodology is required—one that integrates the functionality of previously existing tools in a novel way. Standardized Clinical Assessment and Management Plans (SCAMPs) were designed to accomplish this goal. A SCAMP is a care pathway, designed by clinicians, to guide medical decision making around a particular disorder. SCAMPs are unique in that they invite knowledge-based diversions from their recommendations and are accompanied by data collection and continuous improvement processes. Through these mechanisms, SCAMPs successfully reduce practice variation, optimize resource use, and create an integrated medical learning system which overcomes many of the inadequacies of traditional research tools. As such, the SCAMP paradigm may represent an important breakthrough in the effort to define and implement effective health care. PMID:25295963

  19. 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

  20. [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

  1. Clinically Relevant Genetic Variations in Drug Metabolizing Enzymes

    PubMed Central

    Pinto, Navin; Dolan, M. Eileen

    2011-01-01

    In the field of pharmacogenetics, we currently have a few markers to guide physicians as to the best course of therapy for patients. For the most part, these genetic variants are within a drug metabolizing enzyme that has a large effect on the degree or rate at which a drug is converted to its metabolites. For many drugs, response and toxicity are multi-genic traits and understanding relationships between a patient's genetic variation in drug metabolizing enzymes and the efficacy and/or toxicity of a medication offers the potential to optimize therapies. This review will focus on variants in drug metabolizing enzymes with predictable and relatively large impacts on drug efficacy and/or toxicity; some of these drug/gene variant pairs have impacted drug labels by the United States Food and Drug Administration. The challenges in identifying genetic markers and implementing clinical changes based on known markers will be discussed. In addition, the impact of next generation sequencing in identifying rare variants will be addressed. PMID:21453273

  2. The melanomas: a synthesis of epidemiological, clinical, histopathological, genetic, and biological aspects, supporting distinct subtypes, causal pathways, and cells of origin

    PubMed Central

    Whiteman, David C.; Pavan, William J; Bastian, Boris C.

    2012-01-01

    Summary Converging lines of evidence from varied scientific disciplines suggest that cutaneous melanomas comprise biologically distinct subtypes that arise through multiple causal pathways. Understanding the respective relationships of each subtype with etiologic factors such as UV radiation and constitutional factors is the first necessary step toward developing refined prevention strategies for the specific forms of melanoma. Furthermore, classifying this disease precisely into biologically distinct subtypes is the key to developing mechanism- based treatments, as highlighted by recent discoveries. In this review, we outline the historical developments that underpin our understanding of melanoma heterogeneity, and we do this from the perspectives of clinical presentation, histopathology, epidemiology, molecular genetics, and developmental biology. We integrate the evidence from these separate trajectories to catalog the emerging major categories of melanomas and conclude with important unanswered questions relating to the development of melanoma and its cells of origin. PMID:21707960

  3. Spectrum of clinically relevant Exophiala species in the United States.

    PubMed

    Zeng, J S; Sutton, D A; Fothergill, A W; Rinaldi, M G; Harrak, M J; de Hoog, G S

    2007-11-01

    Numerous members of the genus Exophiala are potential agents of human and animal mycoses. The majority of these infections are cutaneous and superficial, but also fatal systemic infections are known. We re-identified 188 clinical isolates from the United States, which had a preliminary morphological identification of Exophiala species, by sequencing internal transcribed spacer (ITS) region of the rRNA. Molecular identifications of the strains were as follows, in order of frequency: 55 E. dermatitidis (29.3%), 37 E. xenobiotica (19.7%), 35 E. oligosperma (18.6%), 13 E. lecanii-corni (6.9%), 12 E. phaeomuriformis (6.4%), 7 E. jeanselmei (3.7%), 7 E. bergeri (3.7%), 6 E. mesophila (3.2%), 5 E. spinifera (2.7%), 3 Exophiala sp. 1 (1.6%), 3 E. attenuata (1.6%), 3 Phialophora europaea (1.3%), 1 E. heteromorpha (0.5%), and 1 Exophiala sp. 2 (0.5%) strains. Exophiala strains were repeatedly isolated from deep infections (39.9%) involving lung, pleural fluid, sputum, digestive organs (stomach, intestines, bile), heart, brain, spleen, bone marrow, blood, dialysis fluid, lymph node, joint, breast, middle ear, throat, and intraocular tissues. About 38.3% of the Exophiala spp. strains were agents of cutaneous infections including skin, mucous membranes, nail, and corneal epithelium lesions. The other strains caused superficial infections (0.5%, including hair) or subcutaneous infection (12.0%, including paranasal sinusitis, mycetoma, and subcutaneous cyst). The systemic infections were preponderantly caused by E. dermatitidis, E. oligosperma, E. phaeomuriformis, E. xenobiotica, and E. lecanii-corni. Strains of E. bergeri, E. spinifera, E. jeanselmei, E. mesophila, and E. attenuata mainly induced cutaneous and subcutaneous infections. Since relatively few unknown ITS motifs were encountered, we suppose that the list of opportunistic Exophiala species in temperate climates is nearing completion, but a number of species still have to be described. PMID:17596364

  4. Spectrum of Clinically Relevant Exophiala Species in the United States▿

    PubMed Central

    Zeng, J. S.; Sutton, D. A.; Fothergill, A. W.; Rinaldi, M. G.; Harrak, M. J.; de Hoog, G. S.

    2007-01-01

    Numerous members of the genus Exophiala are potential agents of human and animal mycoses. The majority of these infections are cutaneous and superficial, but also fatal systemic infections are known. We re-identified 188 clinical isolates from the United States, which had a preliminary morphological identification of Exophiala species, by sequencing internal transcribed spacer (ITS) region of the rRNA. Molecular identifications of the strains were as follows, in order of frequency: 55 E. dermatitidis (29.3%), 37 E. xenobiotica (19.7%), 35 E. oligosperma (18.6%), 13 E. lecanii-corni (6.9%), 12 E. phaeomuriformis (6.4%), 7 E. jeanselmei (3.7%), 7 E. bergeri (3.7%), 6 E. mesophila (3.2%), 5 E. spinifera (2.7%), 3 Exophiala sp. 1 (1.6%), 3 E. attenuata (1.6%), 3 Phialophora europaea (1.3%), 1 E. heteromorpha (0.5%), and 1 Exophiala sp. 2 (0.5%) strains. Exophiala strains were repeatedly isolated from deep infections (39.9%) involving lung, pleural fluid, sputum, digestive organs (stomach, intestines, bile), heart, brain, spleen, bone marrow, blood, dialysis fluid, lymph node, joint, breast, middle ear, throat, and intraocular tissues. About 38.3% of the Exophiala spp. strains were agents of cutaneous infections including skin, mucous membranes, nail, and corneal epithelium lesions. The other strains caused superficial infections (0.5%, including hair) or subcutaneous infection (12.0%, including paranasal sinusitis, mycetoma, and subcutaneous cyst). The systemic infections were preponderantly caused by E. dermatitidis, E. oligosperma, E. phaeomuriformis, E. xenobiotica, and E. lecanii-corni. Strains of E. bergeri, E. spinifera, E. jeanselmei, E. mesophila, and E. attenuata mainly induced cutaneous and subcutaneous infections. Since relatively few unknown ITS motifs were encountered, we suppose that the list of opportunistic Exophiala species in temperate climates is nearing completion, but a number of species still have to be described. PMID:17596364

  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. 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…

  7. 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

  8. 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.

  9. Histopathologic and clinical subtypes of autoimmune pancreatitis: the honolulu consensus document.

    PubMed

    Chari, Suresh T; Kloeppel, Guenter; Zhang, Lizhi; Notohara, Kenji; Lerch, Markus M; Shimosegawa, Tooru

    2010-01-01

    Autoimmune pancreatitis (AIP) has been extensively reported from Japan, Europe and the USA. While the descriptions of AIP from Japan have predominantly been based on the presence of a distinct clinical phenotype, reports from Europe and the USA describe at least 2 histopathologic patterns in patients diagnosed with AIP, namely lymphoplasmacytic sclerosing pancreatitis (LPSP) and idiopathic duct-centric pancreatitis (IDCP) or granulocytic epithelial lesion- positive pancreatitis. While the 2 entities share common histopathologic features (periductal lymphoplasmacytic infiltration and peculiar periductal fibrosis), expert pathologists can accurately distinguish them on the basis of other unique histopathologic features. Clinically, the 2 entities have a similar presentation (obstructive jaundice/pancreatic mass and a dramatic response to steroids), but they differ significantly in their demography, serology, involvement of other organs and disease relapse rate. While LPSP is associated with elevation of titers of nonspecific autoantibodies and serum IgG4 levels, IDCP does not have definitive serologic autoimmune markers. All experts agreed that the clinical phenotypes associated with LPSP and IDCP should be nosologically distinguished; however, their terminology was controversial. While most experts agreed that the entities should be referred to as type 1 and type 2 AIP, respectively, others had concerns regarding use of the term 'autoimmune' to describe IDCP. and IAP. PMID:21242705

  10. 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

  11. Indication of metronomic chemotherapy for metastatic breast cancer: Clinical outcomes and responsive subtypes

    PubMed Central

    KONTANI, KEIICHI; HASHIMOTO, SHIN-ICHIRO; MURAZAWA, CHISA; NORIMURA, SHOKO; TANAKA, HIROAKI; OHTANI, MASAHIRO; FUJIWARA-HONJO, NAOMI; DATE, MANABU; TERAMOTO, KOJI; HOUCHI, HITOSHI; YOKOMISE, HIROYASU

    2016-01-01

    The survival of patients with metastatic breast cancer (MBC) has not improved, despite recent advances in therapeutic strategies. This is mainly due to the fact that cytotoxic agents cannot be administered over a long period, even if they exhibit favorable activity, due to treatment-related side effects or acquisition of tumor resistance to the administered agents. Thus, the development of therapeutic strategies that may be used over a long time period is required to improve survival. We assessed the availability and clinical outcomes of metronomic chemotherapy, which is defined as continuous or frequent treatment with low doses of cytotoxic drugs. A total of 80 patients with MBC received chemotherapy in the metastatic setting, and the clinicopathological factors and clinical outcomes were retrospectively compared between 52 patients who received metronomic regimens and 28 patients who received other cytotoxic regimens. As regards clinical outcomes, the median time-to-treatment failure (TTF) and overall survival (OS) were significantly longer in the metronomic group compared with those in the non-metronomic group (TTF, 15 vs. 4 months, P=0.0001; and OS, 53 vs. 28 months P=0.0012, respectively). In the metronomic group, none of the 18 patients who responded to the regimen had triple-negative (TN) cancer (17 had luminal-type tumors and 1 had a human epidermal factor receptor 2-type tumor). Furthermore, TTF and OS were significantly longer in patients with non-TN cancer compared with those in patients with TN cancer in the metronomic group (TTF, 16 vs. 7 months, P=0.0014; and OS, 108 vs. 20 months, P=0.000007, respectively). The proportion of patients who experienced treatment-related adverse events was significantly lower in the metronomic group compared with that in the non-metronomic group (36.5 vs. 61.5%, respectively; P=0.038). In conclusion, metronomic chemotherapy is a viable option for luminal-type MBC in terms of effectiveness and minimal toxicity, regardless

  12. Do HIV-1 non-B subtypes differentially impact resistance mutations and clinical disease progression in treated populations? Evidence from a systematic review.

    PubMed

    Bhargava, Madhavi; Cajas, Jorge Martinez; Wainberg, Mark A; Klein, Marina B; Pant Pai, Nitika

    2014-01-01

    There are 31 million adults living with HIV-1 non-B subtypes globally, and about 10 million are on antiretroviral therapy (ART). Global evidence to guide clinical practice on ART response in HIV-1 non-B subtypes remains limited. We systematically searched 11 databases for the period 1996 to 2013 for evidence. Outcomes documented included time to development of AIDS and/or death, resistance mutations, opportunistic infections, and changes in CD4 cell counts and viral load. A lack of consistent reporting of all clinical end points precluded a meta-analysis. In sum, genetic diversity that precipitated differences in disease progression in ART-naïve populations was minimized in ART-experienced populations, although variability in resistance mutations persisted across non-B subtypes. To improve the quality of patient care in global settings, recording HIV genotypes at baseline and at virologic failure with targeted non-B subtype-based point-of-care resistance assays and timely phasing out of resistance-inducing ART regimens is recommended.

  13. 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

  14. The Common p.R114W HNF4A Mutation Causes a Distinct Clinical Subtype of Monogenic Diabetes.

    PubMed

    Laver, Thomas W; Colclough, Kevin; Shepherd, Maggie; Patel, Kashyap; Houghton, Jayne A L; Dusatkova, Petra; Pruhova, Stepanka; Morris, Andrew D; Palmer, Colin N; McCarthy, Mark I; Ellard, Sian; Hattersley, Andrew T; Weedon, Michael N

    2016-10-01

    HNF4A mutations cause increased birth weight, transient neonatal hypoglycemia, and maturity onset diabetes of the young (MODY). The most frequently reported HNF4A mutation is p.R114W (previously p.R127W), but functional studies have shown inconsistent results; there is a lack of cosegregation in some pedigrees and an unexpectedly high frequency in public variant databases. We confirm that p.R114W is a pathogenic mutation with an odds ratio of 30.4 (95% CI 9.79-125, P = 2 × 10(-21)) for diabetes in our MODY cohort compared with control subjects. p.R114W heterozygotes did not have the increased birth weight of patients with other HNF4A mutations (3,476 g vs. 4,147 g, P = 0.0004), and fewer patients responded to sulfonylurea treatment (48% vs. 73%, P = 0.038). p.R114W has reduced penetrance; only 54% of heterozygotes developed diabetes by age 30 years compared with 71% for other HNF4A mutations. We redefine p.R114W as a pathogenic mutation that causes a distinct clinical subtype of HNF4A MODY with reduced penetrance, reduced sensitivity to sulfonylurea treatment, and no effect on birth weight. This has implications for diabetes treatment, management of pregnancy, and predictive testing of at-risk relatives. The increasing availability of large-scale sequence data is likely to reveal similar examples of rare, low-penetrance MODY mutations.

  15. The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes

    PubMed Central

    Laver, Thomas W; Colclough, Kevin; Shepherd, Maggie; Patel, Kashyap; Houghton, Jayne AL; Dusatkova, Petra; Pruhova, Stepanka; Morris, Andrew D; Palmer, Colin N; McCarthy, Mark I; Ellard, Sian; Hattersley, Andrew T; Weedon, Michael N

    2016-01-01

    HNF4A mutations cause increased birth weight, transient neonatal hypoglycaemia and maturity onset diabetes of the young (MODY). The most frequently reported HNF4A mutation is p.R114W (previously p.R127W) but functional studies have shown inconsistent results, there is lack of co-segregation in some pedigrees and an unexpectedly high frequency in public variant databases. We confirm that p.R114W is a pathogenic mutation with an odds ratio of 30.4 (95% CI: 9.79 – 125, P=2x10-21) for diabetes in our MODY cohort compared to controls. p.R114W heterozygotes do not have the increased birth weight of patients with other HNF4A mutations (3476g vs. 4147g, P=0.0004) and fewer patients responded to sulfonylurea treatment (48% vs. 73%, P=0.038). p.R114W has reduced penetrance; only 54% of heterozygotes developed diabetes by age 30 compared to 71% for other HNF4A mutations. We re-define p.R114W as a pathogenic mutation causing a distinct clinical subtype of HNF4A MODY with reduced penetrance, reduced sensitivity to sulfonylurea treatment and no effect on birth weight. This has implications for diabetes treatment, management of pregnancy and predictive testing of at-risk relatives. The increasing availability of large-scale sequence data is likely to reveal similar examples of rare, low-penetrance MODY mutations. PMID:27486234

  16. 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

  17. 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

  18. 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

  19. The Common p.R114W HNF4A Mutation Causes a Distinct Clinical Subtype of Monogenic Diabetes.

    PubMed

    Laver, Thomas W; Colclough, Kevin; Shepherd, Maggie; Patel, Kashyap; Houghton, Jayne A L; Dusatkova, Petra; Pruhova, Stepanka; Morris, Andrew D; Palmer, Colin N; McCarthy, Mark I; Ellard, Sian; Hattersley, Andrew T; Weedon, Michael N

    2016-10-01

    HNF4A mutations cause increased birth weight, transient neonatal hypoglycemia, and maturity onset diabetes of the young (MODY). The most frequently reported HNF4A mutation is p.R114W (previously p.R127W), but functional studies have shown inconsistent results; there is a lack of cosegregation in some pedigrees and an unexpectedly high frequency in public variant databases. We confirm that p.R114W is a pathogenic mutation with an odds ratio of 30.4 (95% CI 9.79-125, P = 2 × 10(-21)) for diabetes in our MODY cohort compared with control subjects. p.R114W heterozygotes did not have the increased birth weight of patients with other HNF4A mutations (3,476 g vs. 4,147 g, P = 0.0004), and fewer patients responded to sulfonylurea treatment (48% vs. 73%, P = 0.038). p.R114W has reduced penetrance; only 54% of heterozygotes developed diabetes by age 30 years compared with 71% for other HNF4A mutations. We redefine p.R114W as a pathogenic mutation that causes a distinct clinical subtype of HNF4A MODY with reduced penetrance, reduced sensitivity to sulfonylurea treatment, and no effect on birth weight. This has implications for diabetes treatment, management of pregnancy, and predictive testing of at-risk relatives. The increasing availability of large-scale sequence data is likely to reveal similar examples of rare, low-penetrance MODY mutations. PMID:27486234

  20. 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

  1. 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

  2. How relevant is undergraduate medical law teaching to clinical practice? A graduates' perspective.

    PubMed

    Koehler, Nicole; McMenamin, Christine

    2012-12-01

    The Monash University medical law tutorial program was implemented in 2002. A major aim of this program is to enable medical students to recognise and understand their legal obligations in clinical practice, thereby improving clinical standards and contributing to better patient outcomes. The present study examined whether, from a graduate perspective, the medical law tutorial program provides adequate legal information of relevance for a clinical context. Monash University medical graduates from 2007 to 2009 who were working at a Victorian hospital or who were members of the Royal Australian College of General Practitioners were invited to participate in the study. Fifty-six participants completed the survey. Overall, participants had positive perceptions of the medical law program. The medical law program is an essential component of students' medical education and provides information relevant to future clinical practice.

  3. Clinical analysis of 670 cases in two trials of the European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group subtyped according to the Revised European-American Classification of Lymphoid Neoplasms: a comparison with the Working Formulation.

    PubMed

    Pittaluga, S; Bijnens, L; Teodorovic, I; Hagenbeek, A; Meerwaldt, J H; Somers, R; Thomas, J; Noordijk, E M; De Wolf-Peeters, C

    1996-05-15

    In the Working Formulation (WF), non-Hodgkin's lymphomas (NHL) are grouped according to their clinical behavior. These disorders are listed as entities defined by morphology, phenotype, and cytogenetics in the proposed Revised European-American Classification of Lymphoid Neoplasms (REAL), the clinical relevance of which is still debated. We analyzed 670 NHL cases included in two randomized clinical trials (EORTC 20855 WF-intermediate/high-grade and 20856 WF-low-grade malignancy) with histologic material available for review. Based on hematoxylin-eosin-stained sections, 77% of cases could be subtyped. Immunophenotyping was considered to be mandatory only in diagnosing T-cell lymphoma and anaplastic large-cell lymphoma. Of 522 cases subtyped, 11% were mantle cell lymphoma (MCL), 5% were marginal zone B-cell lymphoma (MZBCL), 46% were follicle center lymphoma, and 32% were diffuse large B-cell lymphoma. Statistical analysis and comparisons between classifications were made only within each trial and treatment group. MCL and MZBCL were characterized by a shorter median survival (3.4 and 4.1 years, respectively) in comparison with low- and intermediate-grade WF groups (> 9.3 and 5.8 years, respectively). In terms of progression-free survival, MCL showed a behavior similar to the low-grade group, with frequent relapses. Follicle center cell lymphomas behaved as low-grade lymphomas as defined by the WF and diffuse large B-cell lymphomas as the WF-intermediate grade group. Because several NHL entities have a clinical behavior of their own, their recognition by the REAL classification offers clinicians additional information that is not obtained when the WF is used. PMID:8639796

  4. Clinical analysis of 670 cases in two trials of the European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group subtyped according to the Revised European-American Classification of Lymphoid Neoplasms: a comparison with the Working Formulation.

    PubMed

    Pittaluga, S; Bijnens, L; Teodorovic, I; Hagenbeek, A; Meerwaldt, J H; Somers, R; Thomas, J; Noordijk, E M; De Wolf-Peeters, C

    1996-05-15

    In the Working Formulation (WF), non-Hodgkin's lymphomas (NHL) are grouped according to their clinical behavior. These disorders are listed as entities defined by morphology, phenotype, and cytogenetics in the proposed Revised European-American Classification of Lymphoid Neoplasms (REAL), the clinical relevance of which is still debated. We analyzed 670 NHL cases included in two randomized clinical trials (EORTC 20855 WF-intermediate/high-grade and 20856 WF-low-grade malignancy) with histologic material available for review. Based on hematoxylin-eosin-stained sections, 77% of cases could be subtyped. Immunophenotyping was considered to be mandatory only in diagnosing T-cell lymphoma and anaplastic large-cell lymphoma. Of 522 cases subtyped, 11% were mantle cell lymphoma (MCL), 5% were marginal zone B-cell lymphoma (MZBCL), 46% were follicle center lymphoma, and 32% were diffuse large B-cell lymphoma. Statistical analysis and comparisons between classifications were made only within each trial and treatment group. MCL and MZBCL were characterized by a shorter median survival (3.4 and 4.1 years, respectively) in comparison with low- and intermediate-grade WF groups (> 9.3 and 5.8 years, respectively). In terms of progression-free survival, MCL showed a behavior similar to the low-grade group, with frequent relapses. Follicle center cell lymphomas behaved as low-grade lymphomas as defined by the WF and diffuse large B-cell lymphomas as the WF-intermediate grade group. Because several NHL entities have a clinical behavior of their own, their recognition by the REAL classification offers clinicians additional information that is not obtained when the WF is used.

  5. 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

    2016-04-04

    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.

  6. 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…

  7. 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…

  8. 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

  9. 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.

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. Clinical relevance of as-needed treatment with nalmefene in alcohol-dependent patients.

    PubMed

    Aubin, Henri-Jean; Reimer, Jens; Nutt, David J; Bladström, Anna; Torup, Lars; François, Clément; Chick, Jonathan

    2015-01-01

    Nalmefene is the first drug approved for reduction of alcohol consumption. The aim of this study was to evaluate the clinical relevance of treatment with nalmefene in alcohol-dependent patients with a high drinking risk level from two randomised placebo-controlled 6-month studies (NCT00811720 and NCT00812461). Response criteria were based on alcohol consumption, Clinical Global Impression, and Short Form Health Survey mental component summary scores at month 6, analysed using logistic regression. The proportion of responders was higher in the nalmefene group than in the placebo group with odds ratios significantly in favour of nalmefene for all responder criteria; numbers-needed-to-treat ranged from 6 to 10. Significant differences from placebo in clinician-rated and patient-reported outcomes, and liver enzymes further supported the clinical relevance of the treatment effect. In conclusion, this study supports the clinical relevance of nalmefene treatment in patients with alcohol dependence. Nalmefene may help to reduce the alcohol-related burden and the large treatment gap, with currently less than 10% of alcohol-dependent patients in Europe receiving treatment.

  16. 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

  17. 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.

  18. 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

  19. 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

  20. Detection of clinically relevant levels of protein analyte under physiologic buffer using planar field effect transistors.

    PubMed

    Gupta, Samit; Elias, Mark; Wen, Xuejin; Shapiro, John; Brillson, Leonard; Lu, Wu; Lee, Stephen Craig

    2008-12-01

    Electrochemical detection of protein binding at physiological salt concentration by planar field effect transistor platforms has yet to be documented convincingly. Here we report detection of streptavidin and clinically relevant levels of biotinylated monokine induced by interferon gamma (MIG) at physiological salt concentrations with AlGaN heterojunction field effect transistors (HFETs). The AlGaN HFETs are functionalized with a silane linker and analyte-specific affinity elements. Polarity of sensor responses is as expected from n-type HFETs to negatively and positively charged analytes. Sensitivity of the HFET sensors increases when salt concentration decreases, and the devices also exhibit dose-dependent responses to analyte. Detection of clinically relevant MIG concentrations at physiological salt levels demonstrates the potential for AlGaN devices to be used in development of in vivo biosensors.

  1. Clinically Relevant Physical Benefits of Exercise Interventions in Breast Cancer Survivors.

    PubMed

    Kirkham, Amy A; Bland, Kelcey A; Sayyari, Sarah; Campbell, Kristin L; Davis, Margot K

    2016-02-01

    Evidence is currently limited for the effect of exercise on breast cancer clinical outcomes. However, several of the reported physical benefits of exercise, including peak oxygen consumption, functional capacity, muscle strength and lean mass, cardiovascular risk factors, and bone health, have established associations with disability, cardiovascular disease risk, morbidity, and mortality. This review will summarize the clinically relevant physical benefits of exercise interventions in breast cancer survivors and discuss recommendations for achieving these benefits. It will also describe potential differences in intervention delivery that may impact outcomes and, lastly, describe current physical activity guidelines for cancer survivors. PMID:26769117

  2. 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

  3. 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

  4. 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.

  5. Clinical evaluation of the efficacy of methylnaltrexone in resolving constipation induced by different opioid subtypes combined with laboratory analysis of immunomodulatory and antiangiogenic effects of methylnaltrexone

    PubMed Central

    2014-01-01

    Background Opioid-induced constipation (OIC) is one of the major symptoms in palliative care with a prevalence of 30-50%. Methylnaltrexone for the treatment of OIC is significantly more effective than placebo, but only in about fifty percent of the patients regardless of dose increase. Dose increases cause increased toxicity without additional efficacy, and are therefore not recommended. While methylnaltrexone is a μ-receptor antagonist, only a few opioids are solely μ-receptor agonists. Therefore, the response to methylnaltrexone may be determined by the receptor-profile of a specific opioid. In addition, methylnaltrexone may also affect the immune system and angiogenesis as was found in pre-clinical studies. Primary aim of this study is to determine differences in the efficacy of methylnaltrexone prescribed to resolve opioid induced constipation between three commonly used opioid subtypes: morphine sulphate, oxycodone and fentanyl. Secondary aim is to explore potential immunomodulatory and antiangiogenic effects of methylnaltrexone. Methods In this multi-center, prospective, parallel group trial we will evaluate the efficacy of methylnaltrexone in resolving OIC occurring as a side effect of the most common opioid subtypes: morphine, oxycodone and fentanyl. In total 195 patients with OIC despite prophylactic laxatives will receive methylnaltrexone every other day up to fourteen days. Patients will report its effect in a laxation diary. Group allocation is based on the opioid type the patient is using. At the start and end of the study period patients complete the Bowel Function Index questionnaire. A subgroup of the patients will donate blood for analysis of immunomodulatory- and anti-angiogenic effects of methylnaltrexone. Discussion In this study we aim to determine the efficacy of methylnaltrexone per opioid subtype to reduce constipation. We expect that the outcome of this study will improve the clinical use of methylnaltraxone. Trial registration This trial

  6. 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

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

    PubMed Central

    Price, Travis K.; Dune, Tanaka; Hilt, Evann E.; Thomas-White, Krystal J.; Kliethermes, Stephanie; Brincat, Cynthia; Brubaker, Linda; Wolfe, Alan J.

    2016-01-01

    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

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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

  13. Detection of clinically relevant exonic copy-number changes by array CGH.

    PubMed

    Boone, Philip M; Bacino, Carlos A; Shaw, Chad A; Eng, Patricia A; Hixson, Patricia M; Pursley, Amber N; Kang, Sung-Hae L; Yang, Yaping; Wiszniewska, Joanna; Nowakowska, Beata A; del Gaudio, Daniela; Xia, Zhilian; Simpson-Patel, Gayle; Immken, LaDonna L; Gibson, James B; Tsai, Anne C-H; Bowers, Jennifer A; Reimschisel, Tyler E; Schaaf, Christian P; Potocki, Lorraine; Scaglia, Fernando; Gambin, Tomasz; Sykulski, Maciej; Bartnik, Magdalena; Derwinska, Katarzyna; Wisniowiecka-Kowalnik, Barbara; Lalani, Seema R; Probst, Frank J; Bi, Weimin; Beaudet, Arthur L; Patel, Ankita; Lupski, James R; Cheung, Sau Wai; Stankiewicz, Pawel

    2010-12-01

    Array comparative genomic hybridization (aCGH) is a powerful tool for the molecular elucidation and diagnosis of disorders resulting from genomic copy-number variation (CNV). However, intragenic deletions or duplications--those including genomic intervals of a size smaller than a gene--have remained beyond the detection limit of most clinical aCGH analyses. Increasing array probe number improves genomic resolution, although higher cost may limit implementation, and enhanced detection of benign CNV can confound clinical interpretation. We designed an array with exonic coverage of selected disease and candidate genes and used it clinically to identify losses or gains throughout the genome involving at least one exon and as small as several hundred base pairs in size. In some patients, the detected copy-number change occurs within a gene known to be causative of the observed clinical phenotype, demonstrating the ability of this array to detect clinically relevant CNVs with subkilobase resolution. In summary, we demonstrate the utility of a custom-designed, exon-targeted oligonucleotide array to detect intragenic copy-number changes in patients with various clinical phenotypes.

  14. Detection of Clinically Relevant Exonic Copy-Number Changes by Array CGH

    PubMed Central

    Boone, Philip M.; Bacino, Carlos A.; Shaw, Chad A.; Eng, Patricia A.; Hixson, Patricia M.; Pursley, Amber N.; Kang, Sung-Hae L.; Yang, Yaping; Wiszniewska, Joanna; Nowakowska, Beata A.; Gaudio, Daniela del; Xia, Zhilian; Simpson-Patel, Gayle; Immken, LaDonna L.; Gibson, James B.; Tsai, Anne C.-H.; Bowers, Jennifer A.; Reimschisel, Tyler E.; Schaaf, Christian P.; Potocki, Lorraine; Scaglia, Fernando; Gambin, Tomasz; Sykulski, Maciej; Bartnik, Magdalena; Derwinska, Katarzyna; Wisniowiecka-Kowalnik, Barbara; Lalani, Seema R.; Probst, Frank J.; Bi, Weimin; Beaudet, Arthur L.; Patel, Ankita; Lupski, James R.; Cheung, Sau Wai; Stankiewicz, Pawel

    2011-01-01

    Array comparative genomic hybridization (aCGH) is a powerful tool for the molecular elucidation and diagnosis of disorders resulting from genomic copy-number variation (CNV). However, intragenic deletions or duplications—those including genomic intervals of a size smaller than a gene—have remained beyond the detection limit of most clinical aCGH analyses. Increasing array probe number improves genomic resolution, although higher cost may limit implementation, and enhanced detection of benign CNV can confound clinical interpretation. We designed an array with exonic coverage of selected disease and candidate genes and used it clinically to identify losses or gains throughout the genome involving at least one exon and as small as several hundred base pairs in size. In some patients, the detected copy-number change occurs within a gene known to be causative of the observed clinical phenotype, demonstrating the ability of this array to detect clinically relevant CNVs with subkilobase resolution. In summary, we demonstrate the utility of a custom-designed, exon-targeted oligonucleotide array to detect intragenic copy-number changes in patients with various clinical phenotypes. PMID:20848651

  15. Clinical and socioeconomic impact of different types and subtypes of seasonal influenza viruses in children during influenza seasons 2007/2008 and 2008/2009

    PubMed Central

    2011-01-01

    Background There are few and debated data regarding possible differences in the clinical presentations of influenza A/H1N1, A/H3N2 and B viruses in children. This study evaluates the clinical presentation and socio-economic impact of laboratory-confirmed influenza A/H1N1, A/H3N2 or B infection in children attending an Emergency Room because of influenza-like illness. Methods Among the 4,726 children involved, 662 had influenza A (143 A/H1N1 and 519 A/H3N2) and 239 influenza B infection detected by means of real-time polymerase chain reaction. Upon enrolment, systematic recordings were made of the patients' demographic characteristics and medical history using standardised written questionnaires. The medical history of the children was re-evaluated 5-7 days after enrolment and until the resolution of their illness by means of interviews and a clinical examination by trained investigators using standardised questionnaires. During this evaluation, information was also obtained regarding illnesses and related morbidity among households. Results Children infected with influenza A/H1N1 were significantly younger (mean age, 2.3 yrs) than children infected with influenza A/H3N2 (mean age, 4.7 yrs; p < 0.05)) or with influenza B (mean age, 5.2 yrs; p < 0.05). Adjusted for age and sex, children with influenza A/H3N2 in comparison with those infected by either A/H1N1 or with B influenza virus were more frequently affected by fever (p < 0.05) and lower respiratory tract involvement (p < 0.05), showed a worse clinical outcome (p < 0.05), required greater drug use (p < 0.05), and suffered a worse socio-economic impact (p < 0.05). Adjusted for age and sex, children with influenza B in comparison with those infected by A/H1N1 influenza virus had significantly higher hospitalization rates (p < 0.05), the households with a disease similar to that of the infected child (p < 0.05) and the need for additional household medical visits (p < 0.05). Conclusions Disease due to influenza A

  16. 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

  17. 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.

  18. 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

  19. 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

  20. 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

  1. 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

  2. Determination of clinically relevant content for a musculoskeletal anatomy curriculum for physical medicine and rehabilitation residents.

    PubMed

    Lisk, Kristina; Flannery, John F; Loh, Eldon Y; Richardson, Denyse; Agur, Anne M R; Woods, Nicole N

    2014-01-01

    To address the need for more clinical anatomy training in residency education, many postgraduate programs have implemented structured anatomy courses into their curriculum. Consensus often does not exist on specific content and level of detail of the content that should be included in such curricula. This article describes the use of the Delphi method to identify clinically relevant content to incorporate in a musculoskeletal anatomy curriculum for Physical Medicine and Rehabilitation (PM&R) residents. A two round modified Delphi involving PM&R experts was used to establish the curricular content. The anatomical structures and clinical conditions presented to the expert group were compiled using multiple sources: clinical musculoskeletal anatomy cases from the PM&R residency program at the University of Toronto; consultation with PM&R experts; and textbooks. In each round, experts rated the importance of each curricular item to PM&R residency education using a five-point Likert scale. Internal consistency (Cronbach's alpha) was used to determine consensus at the end of each round and agreement scores were used as an outcome measure to determine the content to include in the curriculum. The overall internal consistency in both rounds was 0.99. A total of 37 physiatrists from across Canada participated and the overall response rate over two rounds was 97%. The initial curricular list consisted of 361 items. After the second iteration, the list was reduced by 44%. By using a national consensus method we were able to objectively determine the relevant anatomical structures and clinical musculoskeletal conditions important in daily PM&R practice.

  3. 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

  4. 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

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

    PubMed Central

    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

    2014-01-01

    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 8 hour shift. The most sensitive components of the test were the primers and probes targeting the A/H1pdm09 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 sub typing 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

  6. 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

  7. Finding the common core: evidence-based practices, clinically relevant evidence, and core mechanisms of change.

    PubMed

    Sexton, Thomas L; Kelley, Susan Douglas

    2010-03-01

    Improving the quality of children's mental health care can benefit from the adoption of evidence based and evidence informed treatments. However, the promise of moving science into practice is hampered by three core elements that need to be addressed in the current conversation among key stakeholders: (1) expanding our understanding of the clinical relevance of different types of evidence, (2) emphasizing the identification of core mechanisms of change, and (3) re-conceptualizing what evidence-based practice means. This paper focuses on these elements in an attempt to find a common core among stakeholders that may create opportunities for more inclusive conversation to move the field of children's mental health care forward.

  8. The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes.

    PubMed

    Meerwaldt, Robbert; Links, Thera; Zeebregts, Clark; Tio, Rene; Hillebrands, Jan-Luuk; Smit, Andries

    2008-01-01

    Cardiovascular disease is the major cause of morbidity and mortality associated with diabetes. There is increasing evidence that advanced glycation endproducts (AGEs) play a pivotal role in atherosclerosis, in particular in diabetes. AGE accumulation is a measure of cumulative metabolic and oxidative stress, and may so represent the "metabolic memory". Furthermore, increased AGE accumulation is closely related to the development of cardiovascular complications in diabetes. This review article will focus on the clinical relevance of measuring AGE accumulation in diabetic patients by focusing on AGE formation, AGEs as predictors of long-term complications, and interventions against AGEs. PMID:18840258

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

    PubMed

    Jauchem, James R

    2013-09-01

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

  10. Clinically applied medical ethnography: relevance to cultural competence in patient care.

    PubMed

    Engebretson, Joan

    2011-06-01

    Medical anthropology provides an excellent resource for nursing research that is relevant to clinical nursing. By expanding the understanding of ethnographic research beyond ethnicity, nurses can conduct research that explores patient's constructions and explanatory models of health and healing and how they make meaning out of chronic conditions and negotiate daily life. These findings can have applicability to culturally competent care at both the organizational or systems level, as well as in the patient/provider encounter. Individual patient care can be improved by applying ethnographic research findings to build provider expertise and then using a cultural negotiation process for individualized patient care.

  11. The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes

    PubMed Central

    Meerwaldt, Robbert; Links, Thera; Zeebregts, Clark; Tio, Rene; Hillebrands, Jan-Luuk; Smit, Andries

    2008-01-01

    Cardiovascular disease is the major cause of morbidity and mortality associated with diabetes. There is increasing evidence that advanced glycation endproducts (AGEs) play a pivotal role in atherosclerosis, in particular in diabetes. AGE accumulation is a measure of cumulative metabolic and oxidative stress, and may so represent the "metabolic memory". Furthermore, increased AGE accumulation is closely related to the development of cardiovascular complications in diabetes. This review article will focus on the clinical relevance of measuring AGE accumulation in diabetic patients by focusing on AGE formation, AGEs as predictors of long-term complications, and interventions against AGEs. PMID:18840258

  12. The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes.

    PubMed

    Meerwaldt, Robbert; Links, Thera; Zeebregts, Clark; Tio, Rene; Hillebrands, Jan-Luuk; Smit, Andries

    2008-10-07

    Cardiovascular disease is the major cause of morbidity and mortality associated with diabetes. There is increasing evidence that advanced glycation endproducts (AGEs) play a pivotal role in atherosclerosis, in particular in diabetes. AGE accumulation is a measure of cumulative metabolic and oxidative stress, and may so represent the "metabolic memory". Furthermore, increased AGE accumulation is closely related to the development of cardiovascular complications in diabetes. This review article will focus on the clinical relevance of measuring AGE accumulation in diabetic patients by focusing on AGE formation, AGEs as predictors of long-term complications, and interventions against AGEs.

  13. Multi-Phenotypic subtyping of circulating tumor cells using sequential fluorescent quenching and restaining

    PubMed Central

    Adams, Daniel L; Alpaugh, R. Katherine; Tsai, Susan; Tang, Cha-Mei; Stefansson, Steingrimur

    2016-01-01

    In tissue biopsies formalin fixed paraffin embedded cancer blocks are micro-sectioned producing multiple semi-identical specimens which are analyzed and subtyped proteomically, and genomically, with numerous biomarkers. In blood based biopsies (BBBs), blood is purified for circulating tumor cells (CTCs) and clinical utility is typically limited to cell enumeration, as only 2–3 positive fluorescent markers and 1 negative marker can be used. As such, increasing the number of subtyping biomarkers on each individual CTC could dramatically enhance the clinical utility of BBBs, allowing in depth interrogation of clinically relevant CTCs. We describe a simple and inexpensive method for quenching the specific fluors of fluorescently stained CTCs followed by sequential restaining with additional biomarkers. As proof of principle a CTC panel, immunosuppression panel and stem cell panel were used to sequentially subtype individual fluorescently stained patient CTCs, suggesting a simple and universal technique to analyze multiple clinically applicable immunomarkers from BBBs. PMID:27647345

  14. Multi-Phenotypic subtyping of circulating tumor cells using sequential fluorescent quenching and restaining

    NASA Astrophysics Data System (ADS)

    Adams, Daniel L.; Alpaugh, R. Katherine; Tsai, Susan; Tang, Cha-Mei; Stefansson, Steingrimur

    2016-09-01

    In tissue biopsies formalin fixed paraffin embedded cancer blocks are micro-sectioned producing multiple semi-identical specimens which are analyzed and subtyped proteomically, and genomically, with numerous biomarkers. In blood based biopsies (BBBs), blood is purified for circulating tumor cells (CTCs) and clinical utility is typically limited to cell enumeration, as only 2–3 positive fluorescent markers and 1 negative marker can be used. As such, increasing the number of subtyping biomarkers on each individual CTC could dramatically enhance the clinical utility of BBBs, allowing in depth interrogation of clinically relevant CTCs. We describe a simple and inexpensive method for quenching the specific fluors of fluorescently stained CTCs followed by sequential restaining with additional biomarkers. As proof of principle a CTC panel, immunosuppression panel and stem cell panel were used to sequentially subtype individual fluorescently stained patient CTCs, suggesting a simple and universal technique to analyze multiple clinically applicable immunomarkers from BBBs.

  15. Multi-Phenotypic subtyping of circulating tumor cells using sequential fluorescent quenching and restaining.

    PubMed

    Adams, Daniel L; Alpaugh, R Katherine; Tsai, Susan; Tang, Cha-Mei; Stefansson, Steingrimur

    2016-01-01

    In tissue biopsies formalin fixed paraffin embedded cancer blocks are micro-sectioned producing multiple semi-identical specimens which are analyzed and subtyped proteomically, and genomically, with numerous biomarkers. In blood based biopsies (BBBs), blood is purified for circulating tumor cells (CTCs) and clinical utility is typically limited to cell enumeration, as only 2-3 positive fluorescent markers and 1 negative marker can be used. As such, increasing the number of subtyping biomarkers on each individual CTC could dramatically enhance the clinical utility of BBBs, allowing in depth interrogation of clinically relevant CTCs. We describe a simple and inexpensive method for quenching the specific fluors of fluorescently stained CTCs followed by sequential restaining with additional biomarkers. As proof of principle a CTC panel, immunosuppression panel and stem cell panel were used to sequentially subtype individual fluorescently stained patient CTCs, suggesting a simple and universal technique to analyze multiple clinically applicable immunomarkers from BBBs. PMID:27647345

  16. Anti-apoptotic role and clinical relevance of neurotrophins in diffuse large B-cell lymphomas

    PubMed Central

    Dubanet, Lydie; Bentayeb, Hafidha; Petit, Barbara; Olivrie, Agnès; Saada, Sofiane; de la Cruz-Morcillo, Miguel A; Lalloué, Fabrice; Gourin, Marie-Pierre; Bordessoule, Dominique; Faumont, Nathalie; Delage-Corre, Manuela; Fauchais, Anne-Laure; Jauberteau, Marie-Odile; Troutaud, Danielle

    2015-01-01

    Background: Diffuse large B-cell lymphoma (DLBCL) is a fatal malignancy that needs to identify new targets for additional therapeutic options. This study aimed to clarify the clinical and biological significance of endogenous neurotrophin (nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)) in DLBCL biopsy samples and cell lines. Methods: We analysed expression of NGF, BDNF, and their receptors (Trk, p75NTR) in 51 biopsies and cell lines by immunohistochemistry, immunofluorescence, and western blotting. To investigate the biological role of BDNF/TrkB/p75NTR axis, effects of neurotrophin signalling inhibition were determined on tumour cell survival and vascular endothelial growth factor (VEGF) secretion. The pharmacological pan-Trk inhibitor K252a was used for in vitro and in vivo studies. Results: A BDNF/TrkB axis was expressed in all biopsies, which was independent of the germinal centre B-cell (GCB)/non-GCB profile. p75NTR, TrkB, and BDNF tumour scores were significantly correlated and high NGF expression was significantly associated with MUM1/IRF4, and the non-GCB subtype. Diffuse large B-cell lymphoma cell lines co-expressed neurotrophins and their receptors. The full-length TrkB receptor was found in all cell lines, which was also phosphorylated at Tyr-817. p75NTR was associated to Trk and not to its cell death co-receptor sortilin. In vitro, inhibition of neurotrophin signalling induced cell apoptosis. K252a caused cell apoptosis, decreased VEGF secretion, and potentiated rituximab effect, notably in less rituximab-sensitive cells. In vivo, K252a significantly reduced tumour growth and potentiated the effects of rituximab in a GCB-DLBCL xenograft model. Conclusions: This work argues for a pro-survival role of endogenous neurotrophins in DLBCLs and inhibition of Trk signalling might be a potential treatment strategy for rituximab resistant subgroups. PMID:26284337

  17. 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

  18. Developmental regulation of human cortex transcription and its clinical relevance at base resolution

    PubMed Central

    Jaffe, Andrew E.; Shin, Jooheon; Collado-Torres, Leonardo; Leek, Jeffrey T.; Tao, Ran; Li, Chao; Gao, Yuan; Jia, Yankai; Maher, Brady J.; Hyde, Thomas M.

    2014-01-01

    Transcriptome analysis of human brain provides fundamental insight about development and disease, but largely relies on existing annotation. We sequenced transcriptomes of 72 prefrontal cortex samples across six life stages, and identified 50,650 differentially expression regions (DERs) associated with developmental and aging, agnostic of annotation. While many DERs annotated to non-exonic sequence (41.1%), most were similarly regulated in cytosolic mRNA extracted from independent samples. The DERs were developmentally conserved across 16 brain regions and within the developing mouse cortex, and were expressed in diverse cell and tissue types. The DERs were further enriched for active chromatin marks and clinical risk for neurodevelopmental disorders like schizophrenia. Lastly, we demonstrate quantitatively that these DERs associate with a changing neuronal phenotype related to differentiation and maturation. These data highlight conserved molecular signatures of transcriptional dynamics across brain development, some potential clinical relevance and the incomplete annotation of the human brain transcriptome. PMID:25501035

  19. Clinical empathy and narrative competence: the relevance of reading talmudic legends as literary fiction.

    PubMed

    Davidson, John H

    2015-04-01

    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.

  20. 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

  1. Covariate pharmacokinetic model building in oncology and its potential clinical relevance.

    PubMed

    Joerger, Markus

    2012-03-01

    When modeling pharmacokinetic (PK) data, identifying covariates is important in explaining interindividual variability, and thus increasing the predictive value of the model. Nonlinear mixed-effects modeling with stepwise covariate modeling is frequently used to build structural covariate models, and the most commonly used software-NONMEM-provides estimations for the fixed-effect parameters (e.g., drug clearance), interindividual and residual unidentified random effects. The aim of covariate modeling is not only to find covariates that significantly influence the population PK parameters, but also to provide dosing recommendations for a certain drug under different conditions, e.g., organ dysfunction, combination chemotherapy. A true covariate is usually seen as one that carries unique information on a structural model parameter. Covariate models have improved our understanding of the pharmacology of many anticancer drugs, including busulfan or melphalan that are part of high-dose pretransplant treatments, the antifolate methotrexate whose elimination is strongly dependent on GFR and comedication, the taxanes and tyrosine kinase inhibitors, the latter being subject of cytochrome p450 3A4 (CYP3A4) associated metabolism. The purpose of this review article is to provide a tool to help understand population covariate analysis and their potential implications for the clinic. Accordingly, several population covariate models are listed, and their clinical relevance is discussed. The target audience of this article are clinical oncologists with a special interest in clinical and mathematical pharmacology.

  2. Old and new basal insulin formulations: understanding pharmacodynamics is still relevant in clinical practice.

    PubMed

    Rossetti, P; Ampudia-Blasco, F J; Ascaso, J F

    2014-08-01

    Long-acting insulin analogues have been developed to mimic the physiology of basal insulin secretion more closely than human insulin formulations (Neutral Protamine Hagedorn, NPH). However, the clinical evidence in favour of analogues is still controversial. Although their major benefit as compared with NPH is a reduction in the hypoglycaemia risk, some cost/effectiveness analyses have not been favourable to analogues, largely because of their higher price. Nevertheless, these new formulations have conquered the insulin market. Human insulin represents currently no more than 20% of market share. Despite (in fact because of) the widespread use of insulin analogues it remains critical to analyse the pharmacodynamics (PD) of basal insulin formulations appropriately to interpret the results of clinical trials correctly. Importantly, these data may help physicians in tailoring insulin therapy to patients' individual needs and, additionally, when clinical evidence is not available, to optimize insulin treatment. For patients at low risk for/from hypoglycaemia, it might be acceptable and also cost-effective not to use long-acting insulin analogues as basal insulin replacement. Conversely, in patients with a higher degree of insulin deficiency and increased risk for hypoglycaemia, analogues are the best option due to their more physiological profile, as has been shown in PD and clinical studies. From this perspective optimizing basal insulin treatment, especially in type 2 diabetes patients who are less prone to hypoglycaemia, would be suitable making significant resources available for other relevant aspects of diabetes care. PMID:24401118

  3. Colonization, Pathogenicity, Host Susceptibility and Therapeutics for Staphylococcus aureus: What is the Clinical Relevance?1

    PubMed Central

    Tong, Steven Y.C.; Chen, Luke F.; Fowler, Vance G.

    2011-01-01

    Staphylococcus aureus is a human commensal that can also cause a broad spectrum of clinical disease. Factors associated with clinical disease are myriad and dynamic and include pathogen virulence, antimicrobial resistance and host susceptibility. Additionally, infection control measures aimed at the environmental niches of S. aureus and therapeutic advances continue to impact upon the incidence and outcomes of staphylococcal infections. This review article focuses on the clinical relevance of advances in our understanding of staphylococcal colonization, virulence, host susceptibility and therapeutics. Over the past decade key developments have arisen. First, rates of nosocomial methicillin-resistant S. aureus (MRSA) infections have significantly declined in many countries. Second, we have made great strides in our understanding of the molecular pathogenesis of S. aureus in general and community-associated MRSA in particular. Third, host risk factors for invasive staphylococcal infections, such as advancing age, increasing numbers of invasive medical interventions, and a growing proportion of patients with healthcare contact, remain dynamic. Finally, several new antimicrobial agents active against MRSA have become available for clinical use. Humans and S. aureus co-exist and the dynamic interface between host, pathogen and our attempts to influence these interactions will continue to rapidly change. Although progress has been made in the past decade, we are likely to face further surprises such as the recent waves of community-associated MRSA. PMID:22160374

  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. 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.

  6. 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

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

    PubMed

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

    2015-06-01

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

  8. 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

  9. 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

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

    PubMed Central

    Grossmann, Sebastian; Nowak, Piotr; Neogi, Ujjwal

    2015-01-01

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

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

    PubMed

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

    2015-07-01

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

  12. Desktop transcriptome sequencing from archival tissue to identify clinically relevant translocations.

    PubMed

    Sweeney, Robert T; Zhang, Bing; Zhu, Shirley X; Varma, Sushama; Smith, Kevin S; Montgomery, Stephen B; van de Rijn, Matt; Zehnder, Jim; West, Robert B

    2013-06-01

    Somatic mutations, often translocations or single nucleotide variations, are pathognomonic for certain types of cancers and are increasingly of clinical importance for diagnosis and prediction of response to therapy. Conventional clinical assays only evaluate 1 mutation at a time, and targeted tests are often constrained to identify only the most common mutations. Genome-wide or transcriptome-wide high-throughput sequencing (HTS) of clinical samples offers an opportunity to evaluate for all clinically significant mutations with a single test. Recently a "desktop version" of HTS has become available, but most of the experience to date is based on data obtained from high-quality DNA from frozen specimens. In this study, we demonstrate, as a proof of principle, that translocations in sarcomas can be diagnosed from formalin-fixed paraffin-embedded (FFPE) tissue with desktop HTS. Using the first generation MiSeq platform, full transcriptome sequencing was performed on FFPE material from archival blocks of 3 synovial sarcomas, 3 myxoid liposarcomas, 2 Ewing sarcomas, and 1 clear cell sarcoma. Mapping the reads to the "sarcomatome" (all known 83 genes involved in translocations and mutations in sarcoma) and using a novel algorithm for ranking fusion candidates, the pathognomonic fusions and the exact breakpoints were identified in all cases of synovial sarcoma, myxoid liposarcoma, and clear cell sarcoma. The Ewing sarcoma fusion gene was detectable in FFPE material only with a sequencing platform that generates greater sequencing depth. The results show that a single transcriptome HTS assay, from FFPE, has the potential to replace conventional molecular diagnostic techniques for the evaluation of clinically relevant mutations in cancer.

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

    PubMed

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

    2016-04-01

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

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

    PubMed

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

    2015-10-01

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

  15. Identification of relevant single-nucleotide polymorphisms in Pneumocystis jirovecii: relationship with clinical data.

    PubMed

    Esteves, F; Gaspar, J; Marques, T; Leite, R; Antunes, F; Mansinho, K; Matos, O

    2010-07-01

    Pneumocystis jirovecii is a poorly understood pathogen that causes opportunistic pneumonia (Pneumocystis pneumonia (PcP)) in patients with AIDS. The present study was aimed at correlating genetic differences in P. jirovecii isolates and clinical patient data. A description of genetic diversity in P. jirovecii isolates from human immunodeficiency virus-positive patients, based on the identification of multiple single-nucleotide polymorphisms (SNPs) at five distinct loci encoding mitochondrial large-subunit rRNA (mtLSU rRNA), cytochrome b (CYB), superoxide dismutase (SOD), dihydrofolate reductase (DHFR), and dihydropteroate synthase (DHPS), was achieved using PCR with DNA sequencing and restriction fragment length polymorphism analysis. The statistical analysis revealed several interesting correlations among the four most relevant SNPs (mt85, SOD110, SOD215, and DHFR312) and specific clinical parameters: mt85C was associated with undiagnosed or atypical PcP episodes and favourable follow-up; SOD215C was associated with favourable follow-up; and DHFR312T was associated with PcP cases presenting moderate to high parasite burdens. The genotypes mt85C/SOD215C and SOD110T/SOD215C were found to be associated with less virulent P. jirovecii infections, whereas the genotype SOD110T/SOD215T was found to be related to more virulent PcP episodes. The present work demonstrated that potential P. jirovecii haplotypes may be related to the clinical data and outcome of PcP.

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

    PubMed Central

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

    2014-01-01

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

  17. Clinical relevance of studies on the accuracy of visual inspection for detecting caries lesions: a systematic review.

    PubMed

    Gimenez, Thais; Piovesan, Chaiana; Braga, Mariana M; Raggio, Daniela P; Deery, Chris; Ricketts, David N; Ekstrand, Kim R; Mendes, Fausto Medeiros

    2015-01-01

    Although visual inspection is the most commonly used method for caries detection, and consequently the most investigated, studies have not been concerned about the clinical relevance of this procedure. Therefore, we conducted a systematic review in order to perform a critical evaluation considering the clinical relevance and methodological quality of studies on the accuracy of visual inspection for assessing caries lesions. Two independent reviewers searched several databases through July 2013 to identify papers/articles published in English. Other sources were checked to identify unpublished literature. The eligible studies were those which (1) assessed the accuracy of the visual method for detecting caries lesions on occlusal, approximal or smooth surfaces, in primary or permanent teeth, (2) used a reference standard, and (3) reported data about sample size and accuracy of the methods. Aspects related to clinical relevance and the methodological quality of the studies were evaluated. 96 of the 5,578 articles initially identified met the inclusion criteria. In general, most studies failed in considering some clinically relevant aspects: only 1 included study validated activity status of lesions, no study considered its prognosis, 79 studies did not consider a clinically relevant outcome, and only 1 evaluated a patient-centred outcome. Concerning methodological quality, the majority of the studies presented a high risk of bias in sample selection. In conclusion, studies on the accuracy of the visual method for caries detection should consider clinically relevant outcomes besides accuracy; moreover, they should be conducted with higher methodological quality, mainly regarding sample selection.

  18. Clinically Relevant Mutant DNA Gyrase Alters Supercoiling, Changes the Transcriptome, and Confers Multidrug Resistance

    PubMed Central

    Webber, Mark A.; Ricci, Vito; Whitehead, Rebekah; Patel, Meha; Fookes, Maria; Ivens, Alasdair; Piddock, Laura J. V.

    2013-01-01

    ABSTRACT Bacterial DNA is maintained in a supercoiled state controlled by the action of topoisomerases. Alterations in supercoiling affect fundamental cellular processes, including transcription. Here, we show that substitution at position 87 of GyrA of Salmonella influences sensitivity to antibiotics, including nonquinolone drugs, alters global supercoiling, and results in an altered transcriptome with increased expression of stress response pathways. Decreased susceptibility to multiple antibiotics seen with a GyrA Asp87Gly mutant was not a result of increased efflux activity or reduced reactive-oxygen production. These data show that a frequently observed and clinically relevant substitution within GyrA results in altered expression of numerous genes, including those important in bacterial survival of stress, suggesting that GyrA mutants may have a selective advantage under specific conditions. Our findings help contextualize the high rate of quinolone resistance in pathogenic strains of bacteria and may partly explain why such mutant strains are evolutionarily successful. PMID:23882012

  19. [Calcinosis of the carotid siphon--morphology, differential diagnosis and clinical relevance].

    PubMed

    Eppinger, B; Schumacher, M

    1986-11-01

    In order to determine the clinical significance and hemodynamic relevance of carotid siphon calcification 241 patients were investigated by doppler sonography and skull x-ray. Comparing 139 patients with and 60 patients without siphon calcification, we examined the predictive value of carotid calcification regarding obstructive vessel disease as indicated by doppler sonography. Both groups were compared with 42 patients who all had doppler sonographic signs of severe carotid stenosis. No significant difference was found regarding the incidence of stenosis between the groups with and without siphon calcification (13% vs. 15%). Interpreting siphon calcification as a general sign of atherosclerosis seems therefore not justified. An over proportionally high rate (61.9%) of siphon calcification can only be expected by selected patients with severe obstructive vessels disease. Etiological factors are discussed and differential diagnosis of siphon calcification is demonstrated by cases.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2015-10-15

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

  3. Transitional cardiovascular physiology and comprehensive hemodynamic monitoring in the neonate: relevance to research and clinical care.

    PubMed

    Azhibekov, Timur; Noori, Shahab; Soleymani, Sadaf; Seri, Istvan

    2014-02-01

    A thorough understanding of developmental cardiovascular physiology is essential for early recognition of cardiovascular compromise, selective screening of at-risk groups of neonates, and individualized management using pathophysiology-targeted interventions. Although we have gained a better understanding of the physiology and pathophysiology of postnatal cardiovascular transition over the past decade with the use of sophisticated methods to study neonatal hemodynamics, most aspects of neonatal hemodynamics remain incompletely understood. In addition, targeted therapeutic interventions of neonatal hemodynamic compromise have not been shown to improve mortality and clinically relevant outcomes. However, the recent development of comprehensive hemodynamic monitoring systems capable of non-invasive, continuous and simultaneous bedside assessment of cardiac output, organ blood flow, microcirculation, and tissue oxygen delivery has made sophisticated analysis of the obtained physiologic data possible and has created new research opportunities with the potential of direct implications to patient care.

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

    SciTech Connect

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

    2011-02-15

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

  5. Gene expression profiling identifies distinct molecular subgroups of leiomyosarcoma with clinical relevance

    PubMed Central

    Lee, Yin-Fai; Roe, Toby; Mangham, D Chas; Fisher, Cyril; Grimer, Robert J; Judson, Ian

    2016-01-01

    Background: Soft tissue sarcomas are heterogeneous and a major complication in their management is that the existing classification scheme is not definitive and is still evolving. Leiomyosarcomas, a major histologic category of soft tissue sarcomas, are malignant tumours displaying smooth muscle differentiation. Although defined as a single group, they exhibit a wide range of clinical behaviour. We aimed to carry out molecular classification to identify new molecular subgroups with clinical relevance. Methods: We used gene expression profiling on 20 extra-uterine leiomyosarcomas and cross-study analyses for molecular classification of leiomyosarcomas. Clinical significance of the subgroupings was investigated. Results: We have identified two distinct molecular subgroups of leiomyosarcomas. One group was characterised by high expression of 26 genes that included many genes from the sub-classification gene cluster proposed by Nielsen et al. These sub-classification genes include genes that have importance structurally, as well as in cell signalling. Notably, we found a statistically significant association of the subgroupings with tumour grade. Further refinement led to a group of 15 genes that could recapitulate the tumour subgroupings in our data set and in a second independent sarcoma set. Remarkably, cross-study analyses suggested that these molecular subgroups could be found in four independent data sets, providing strong support for their existence. Conclusions: Our study strongly supported the existence of distinct leiomyosarcoma molecular subgroups, which have clinical association with tumour grade. Our findings will aid in advancing the classification of leiomyosarcomas and lead to more individualised and better management of the disease. PMID:27607470

  6. Hypersensitivities for acetaldehyde and other agents among cancer cells null for clinically relevant Fanconi anemia genes.

    PubMed

    Ghosh, Soma; Sur, Surojit; Yerram, Sashidhar R; Rago, Carlo; Bhunia, Anil K; Hossain, M Zulfiquer; Paun, Bogdan C; Ren, Yunzhao R; Iacobuzio-Donahue, Christine A; Azad, Nilofer A; Kern, Scott E

    2014-01-01

    Large-magnitude numerical distinctions (>10-fold) among drug responses of genetically contrasting cancers were crucial for guiding the development of some targeted therapies. Similar strategies brought epidemiological clues and prevention goals for genetic diseases. Such numerical guides, however, were incomplete or low magnitude for Fanconi anemia pathway (FANC) gene mutations relevant to cancer in FANC-mutation carriers (heterozygotes). We generated a four-gene FANC-null cancer panel, including the engineering of new PALB2/FANCN-null cancer cells by homologous recombination. A characteristic matching of FANCC-null, FANCG-null, BRCA2/FANCD1-null, and PALB2/FANCN-null phenotypes was confirmed by uniform tumor regression on single-dose cross-linker therapy in mice and by shared chemical hypersensitivities to various inter-strand cross-linking agents and γ-radiation in vitro. Some compounds, however, had contrasting magnitudes of sensitivity; a strikingly high (19- to 22-fold) hypersensitivity was seen among PALB2-null and BRCA2-null cells for the ethanol metabolite, acetaldehyde, associated with widespread chromosomal breakage at a concentration not producing breaks in parental cells. Because FANC-defective cancer cells can share or differ in their chemical sensitivities, patterns of selective hypersensitivity hold implications for the evolutionary understanding of this pathway. Clinical decisions for cancer-relevant prevention and management of FANC-mutation carriers could be modified by expanded studies of high-magnitude sensitivities.

  7. Clinically-Relevant Measures Associated with Altered Contact Forces in Patients with Anterior Cruciate Ligament Deficiency

    PubMed Central

    Gardinier, Emily S.; Manal, Kurt; Buchanan, Thomas S.; Snyder-Mackler, Lynn

    2014-01-01

    Background Knee joint contact forces are altered after anterior cruciate ligament injury during walking and may be related to clinically-relevant measures of impairments or self-reported function. The purpose of this study was to investigate the association of several clinically-relevant measures with altered knee contact forces in patients with anterior cruciate ligament injury. Methods Data for this study represent a cross-sectional observational analysis of thirty-seven (23 M, 14 F) patients with complete unilateral anterior cruciate ligament injury. Gait analysis with electromyography was used to obtain estimates of tibiofemoral joint contact force using an electromyography-driven musculoskeletal model. Multivariable linear regression was used to identify measures associated with tibiofemoral joint contact force. Findings Involved knee extensor muscle strength and patient-reported knee function on the Global Rating Scale of Perceived Function were significantly associated with peak tibiofemoral contact force for the involved limb. Patients who were stronger and who perceived higher knee function walked with greater contact forces on their involved knees. After controlling for walking speed, involved extensor strength explained 8.9% of the variance in involved peak tibiofemoral contact force and score on the Global Rating Scale explained an additional 9.4% of the variance. Interpretation Improvements in involved quadriceps strength and overall function as measured by patient self-report may be important for increasing involved limb contact forces, thereby restoring loading symmetry in these patients who demonstrate decreased involved limb loading after injury. These results highlight the potential value of studying the recovery of strength, self-reported function and joint loading symmetry in patients with anterior cruciate ligament injury. PMID:24746854

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

    PubMed Central

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

    2013-01-01

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

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

    SciTech Connect

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

    2009-04-01

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

  10. Chromosomal patterns of gene expression from microarray data: methodology, validation and clinical relevance in gliomas

    PubMed Central

    Turkheimer, Federico E; Roncaroli, Federico; Hennuy, Benoit; Herens, Christian; Nguyen, Minh; Martin, Didier; Evrard, Annick; Bours, Vincent; Boniver, Jacques; Deprez, Manuel

    2006-01-01

    Background Expression microarrays represent a powerful technique for the simultaneous investigation of thousands of genes. The evidence that genes are not randomly distributed in the genome and that their coordinated expression depends on their position on chromosomes has highlighted the need for mathematical approaches to exploit this dependency for the analysis of expression data-sets. Results We have devised a novel mathematical technique (CHROMOWAVE) based on the Haar wavelet transform and applied it to a dataset obtained with the Affymetrix® HG-U133_Plus_2 array in 27 gliomas. CHROMOWAVE generated multi-chromosomal pattern featuring low expression in chromosomes 1p, 4, 9q, 13, 18, and 19q. This pattern was not only statistically robust but also clinically relevant as it was predictive of favourable outcome. This finding was replicated on a data-set independently acquired by another laboratory. FISH analysis indicated that monosomy 1p and 19q was a frequent feature of tumours displaying the CHROMOWAVE pattern but that allelic loss on chromosomes 4, 9q, 13 and 18 was much less common. Conclusion The ability to detect expression changes of spatially related genes and to map their position on chromosomes makes CHROMOWAVE a valuable screening method for the identification and display of regional gene expression changes of clinical relevance. In this study, FISH data showed that monosomy was frequently associated with diffuse low gene expression on chromosome 1p and 19q but not on chromosomes 4, 9q, 13 and 18. Comparative genomic hybridisation, allelic polymorphism analysis and methylation studies are in progress in order to identify the various mechanisms involved in this multi-chromosomal expression pattern. PMID:17140431

  11. Genome-wide DNA methylation analysis of neuroblastic tumors reveals clinically relevant epigenetic events and large-scale epigenomic alterations localized to telomeric regions.

    PubMed

    Buckley, Patrick G; Das, Sudipto; Bryan, Kenneth; Watters, Karen M; Alcock, Leah; Koster, Jan; Versteeg, Rogier; Stallings, Raymond L

    2011-05-15

    The downregulation of specific genes through DNA hypermethylation is a major hallmark of cancer, although the extent and genomic distribution of hypermethylation occurring within cancer genomes is poorly understood. We report on the first genome-wide analysis of DNA methylation alterations in different neuroblastic tumor subtypes and cell lines, revealing higher order organization and clinically relevant alterations of the epigenome. The methylation status of 33,485 discrete loci representing all annotated CpG islands and RefSeq gene promoters was assessed in primary neuroblastic tumors and cell lines. A comparison of genes that were hypermethylated exclusively in the clinically favorable ganglioneuroma/ganglioneuroblastoma tumors revealed that nine genes were associated with poor clinical outcome when overexpressed in the unfavorable neuroblastoma (NB) tumors. Moreover, an integrated DNA methylation and copy number analysis identified 80 genes that were recurrently concomitantly deleted and hypermethylated in NB, with 37 reactivated by 5-aza-deoxycytidine. Lower expression of four of these genes was correlated with poor clinical outcome, further implicating their inactivation in aggressive disease pathogenesis. Analysis of genome-wide hypermethylation patterns revealed 70 recurrent large-scale blocks of contiguously hypermethylated promoters/CpG islands, up to 590 kb in length, with a distribution bias toward telomeric regions. Genome-wide hypermethylation events in neuroblastic tumors are extensive and frequently occur in large-scale blocks with a significant bias toward telomeric regions, indicating that some methylation alterations have occurred in a coordinated manner. Our results indicate that methylation contributes toward the clinicopathological features of neuroblastic tumors, revealing numerous genes associated with poor patient survival in NB.

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2012-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  15. Serology and clinical relevance of Corynebacterium pseudotuberculosis in native Korean goats (Capra hircus coreanae).

    PubMed

    Jung, Byeong Yeal; Lee, Seung-Hun; Kim, Ha-Young; Byun, Jae-Won; Shin, Dong-Ho; Kim, Daekeun; Kwak, Dongmi

    2015-04-01

    This study was conducted to assess the seroprevalence and clinical relevance of Corynebacterium pseudotuberculosis, which is the causative agent of caseous lymphadenitis (CLA), in native Korean goats (Capra hircus coreanae). A total of 466 native Korean goats from 40 herds (11 to 12 samples per herd) were randomly selected throughout the nation and evaluated by direct palpation, bacterial isolation, ELISA, and PCR. In serological examinations, 267 (57.3 %) of the goats tested were positive against C. pseudotuberculosis. When seroprevalence was analyzed according to age, region, and season, statistically significant differences were observed in relation to all three parameters (P < 0.05). For clinical examination, the superficial lymph nodes of all goats were palpated to diagnose CLA. Pus samples taken from superficial abscesses were used for bacterial isolation. Among the 466 goats tested, 34 (7.3 %) were presumptively diagnosed with CLA, and C. pseudotuberculosis was isolated from 24 goats (70.6 % of goats with CLA lesions) whose infections were confirmed by PCR. Considering the high seroprevalence and bacterial isolation rate from most of the superficial CLA lesions, it is suspected that many internal CLA lesions exist in this goat population. These results suggest that C. pseudotuberculosis infection is widespread in native Korean goats, and appropriate control programs need to be established.

  16. Detection of Adriamycin-DNA adducts by accelerator mass spectrometry at clinically relevant Adriamycin concentrations.

    PubMed

    Coldwell, Kate E; Cutts, Suzanne M; Ognibene, Ted J; Henderson, Paul T; Phillips, Don R

    2008-09-01

    Limited sensitivity of existing assays has prevented investigation of whether Adriamycin-DNA adducts are involved in the anti-tumour potential of Adriamycin. Previous detection has achieved a sensitivity of a few Adriamycin-DNA adducts/10(4) bp DNA, but has required the use of supra-clinical drug concentrations. This work sought to measure Adriamycin-DNA adducts at sub-micromolar doses using accelerator mass spectrometry (AMS), a technique with origins in geochemistry for radiocarbon dating. We have used conditions previously validated (by less sensitive decay counting) to extract [(14)C]Adriamycin-DNA adducts from cells and adapted the methodology to AMS detection. Here we show the first direct evidence of Adriamycin-DNA adducts at clinically-relevant Adriamycin concentrations. [(14)C]Adriamycin treatment (25 nM) resulted in 4.4 +/- 1.0 adducts/10(7) bp ( approximately 1300 adducts/cell) in MCF-7 breast cancer cells, representing the best sensitivity and precision reported to date for the covalent binding of Adriamycin to DNA. The exceedingly sensitive nature of AMS has enabled over three orders of magnitude increased sensitivity of Adriamycin-DNA adduct detection and revealed adduct formation within an hour of drug treatment. This method has been shown to be highly reproducible for the measurement of Adriamycin-DNA adducts in tumour cells in culture and can now be applied to the detection of these adducts in human tissues.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-05-01

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

  19. Education in the clinical context: establishing a strategic framework to ensure relevance.

    PubMed

    Henderson, Amanda; Fox, Robyn; Armit, Lyn

    2008-01-01

    Quality contemporary practice relies on nurses to provide health care within an embedded nexus of clinical, professional and organisational learning that leads them through a career trajectory that encourages lifelong development. Within complex health service environments this is fraught with difficulties. Enhancing practice is multifaceted requiring not just education for the acquisition of skills and abilities but time and space for reflection on experience within the clinical context. This ultimately leads to professional knowledge development. Queensland Health has developed a Nursing and Midwifery Staff Development Framework to assist nurses in structuring their experiences in the practice setting to enable their professional goals. Learning is guided within this framework through its collective modus operandi, that is, the development of teams that overlap to identify and progress the educational agenda; resources to develop consistent relevant learning material that incorporates evidence obtained through practices and the literature; and educator and clinician networks across health services throughout the state, and furthermore, links with the tertiary sector to assist in marketing, applicability and synergy with further education.

  20. Relevance of cellular to clinical electrophysiology in interpreting antiarrhythmic drug action.

    PubMed

    Vaughan Williams, E M

    1989-12-01

    The usefulness of cellular electrophysiologic techniques in elucidating the fundamental actions of antiarrhythmic drugs is contrasted with their apparent lack of relevance to the selection of drugs for the treatment of particular arrhythmias. Clinical electrophysiologists employ different techniques, but their results may be explained in terms of cellular drug actions. The varying clinical effects of class IA, IB and IC agents are due to differences in the speed of their attachment to, and detachment from, sodium channels. The role of sympathetic activity in arrhythmogenesis is complex, but again readily explicable in terms of the electrophysiologic cellular actions of stimulation of the individual types of adrenoceptors (alpha 1, alpha 2, beta 1 and beta 2) and the distribution of these receptors, and of the longterm effects of sympathetic deprivation, either by antisympathetic drugs (class II) or by sympathetic denervation. Delayed repolarization (e.g., by class III drugs or prolonged beta blockade) is antiarrhythmic because it is homogeneous, despite the incidental prolongation of QT. If, however, QT is prolonged by heterogeneity of conduction or repolarization, or by partial sympathetic denervation (long QT syndrome or post myocardial infarction), this indicates increased risk of arrhythmia. Finally, the efficacy of calcium antagonists (class IV) in supraventricular arrhythmias is attributable to the cellular electrophysiologic characteristics of sinoatrial and atrioventricular nodal and transitional elements.

  1. Assessment of viability after myocardial infarction. Clinical relevance and methodological problems.

    PubMed

    Fragasso, G; Margonato, A; Chierchia, S L

    1993-01-01

    In patients with myocardial infarction, the distinction between reversible and irreversible ventricular dysfunction has important clinical implications since dysfunctional but viable myocardium will resume contraction following revascularization. Various methods have been developed for the identification of potentially reversible myocardial dysfunction. Thallium reinjection, immediately after stress-redistribution imaging, may provide evidence of myocardial viability by demonstrating thallium uptake in regions with apparently 'irreversible' defects. Hypoperfused, hypocontractile segments may recover function after revascularization, when exhibiting increased 18F-fluoro-deoxy-glucose uptake on positron emission tomography. Improved contractile function by selective beta 1 adrenergic stimulation with low dose dobutamine may also indicate the presence of viable tissue and predict subsequent improvement upon restoration of adequate flow. Finally, exercise-induced ST segment elevation on leads exploring a recent myocardial infarction has also been shown to indicate the presence of viable, potentially salvageable tissue. We discuss here these and several other methods that have been proposed for the detection of residual myocardial viability. Their advantages, limitations, and relevance to clinical problems are also discussed.

  2. Standardizing Analysis of Circulating MicroRNA: Clinical and Biological Relevance

    PubMed Central

    Farina, Nicholas H.; Wood, Marie E.; Perrapato, Scott D.; Francklyn, Christopher S.; Stein, Gary S.; Stein, Janet L.; Lian, Jane B.

    2014-01-01

    Circulating microRNAs (c-miRNAs) provide a new dimension as clinical biomarkers for disease diagnosis, progression, and response to treatment. However, the discovery of individual miRNAs from biofluids that reliably reflect disease states is in its infancy. The highly variable nature of published studies exemplifies a need to standardize the analysis of miRNA in circulation. Here, we show that differential sample handling of serum leads to inconsistent and incomparable results. We present a standardized method of RNA isolation from serum that eliminates multiple freeze/thaw cycles, provides at least 3 normalization mechanisms, and can be utilized in studies that compare both archived and prospectively collected samples. It is anticipated that serum processed as described here can be profiled, either globally or on a gene by gene basis, for c-miRNAs and other non-coding RNA in the circulation to reveal novel, clinically relevant epigenetic signatures for a wide range of diseases. PMID:24357537

  3. Clinical relevance of nalmefene versus placebo in alcohol treatment: Reduction in mortality risk

    PubMed Central

    Roerecke, Michael; Sørensen, Per; Laramée, Philippe; Rahhali, Nora; Rehm, Jürgen

    2015-01-01

    Reduction of long-term mortality risk, an important clinical outcome for people in alcohol dependence treatment, can rarely be established in randomized controlled trials (RCTs). We calculated the reduction in all-cause mortality risk using data from short-term (6 and 12 months) double-blind RCTs comparing as-needed nalmefene treatment to placebo, and mortality risks from meta-analyses on all-cause-mortality risk by reduction of drinking in people with alcohol dependence. A reduction in drinking in the RCTs was defined by shifts in drinking risk levels established by the European Medicines Agency. Results showed that the reduction of drinking in the nalmefene group was associated with a reduction in mortality risk by 8% (95% CI: 2%, 13%) when compared to the placebo group. Sensitivity analyses confirmed a significant effect. Thus comparing the difference between nalmefene and placebo in reduction in drinking levels with results on all-cause mortality risk from meta-analyses indicated a clinically relevant reduction in mortality risk. Given the high mortality risk of people with alcohol dependence, abstinence or a reduction in drinking have been shown to reduce mortality risk and should be considered treatment goals. PMID:26349557

  4. Clinical relevance of nalmefene versus placebo in alcohol treatment: reduction in mortality risk.

    PubMed

    Roerecke, Michael; Sørensen, Per; Laramée, Philippe; Rahhali, Nora; Rehm, Jürgen

    2015-11-01

    Reduction of long-term mortality risk, an important clinical outcome for people in alcohol dependence treatment, can rarely be established in randomized controlled trials (RCTs). We calculated the reduction in all-cause mortality risk using data from short-term (6 and 12 months) double-blind RCTs comparing as-needed nalmefene treatment to placebo, and mortality risks from meta-analyses on all-cause-mortality risk by reduction of drinking in people with alcohol dependence. A reduction in drinking in the RCTs was defined by shifts in drinking risk levels established by the European Medicines Agency. Results showed that the reduction of drinking in the nalmefene group was associated with a reduction in mortality risk by 8% (95% CI: 2%, 13%) when compared to the placebo group. Sensitivity analyses confirmed a significant effect. Thus comparing the difference between nalmefene and placebo in reduction in drinking levels with results on all-cause mortality risk from meta-analyses indicated a clinically relevant reduction in mortality risk. Given the high mortality risk of people with alcohol dependence, abstinence or a reduction in drinking have been shown to reduce mortality risk and should be considered treatment goals.

  5. Using Language Models to Identify Relevant New Information in Inpatient Clinical Notes

    PubMed Central

    Zhang, Rui; Pakhomov, Serguei V.; Lee, Janet T.; Melton, Genevieve B.

    2014-01-01

    Redundant information in clinical notes within electronic health record (EHR) systems is ubiquitous and may negatively impact the use of these notes by clinicians, and, potentially, the efficiency of patient care delivery. Automated methods to identify redundant versus relevant new information may provide a valuable tool for clinicians to better synthesize patient information and navigate to clinically important details. In this study, we investigated the use of language models for identification of new information in inpatient notes, and evaluated our methods using expert-derived reference standards. The best method achieved precision of 0.743, recall of 0.832 and F1-measure of 0.784. The average proportion of redundant information was similar between inpatient and outpatient progress notes (76.6% (SD=17.3%) and 76.7% (SD=14.0%), respectively). Advanced practice providers tended to have higher rates of redundancy in their notes compared to physicians. Future investigation includes the addition of semantic components and visualization of new information. PMID:25954438

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

    PubMed

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

    2016-08-01

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

  7. Two Unique Glioma Subtypes Revealed.

    PubMed

    Poh, Alissa

    2016-04-01

    A comprehensive analysis of 1,122 diffuse glioma samples from The Cancer Genome Atlas has revealed two new subtypes of this common brain cancer, with molecular and clinical features that diverge from the norm. The study findings also support the use of DNA methylation profiles to improve glioma classification and treatment.

  8. New insights of an old defense system: structure, function, and clinical relevance of the complement system.

    PubMed

    Ehrnthaller, Christian; Ignatius, Anita; Gebhard, Florian; Huber-Lang, Markus

    2011-01-01

    The complement system was discovered a century ago as a potent defense cascade of innate immunity. After its first description, continuous experimental and clinical research was performed, and three canonical pathways of activation were established. Upon activation by traumatic or surgical tissue damage, complement reveals beneficial functions of pathogen and danger defense by sensing and clearing injured cells. However, the latest research efforts have provided a more distinct insight into the complement system and its clinical subsequences. Complement has been shown to play a significant role in the pathogenesis of various inflammatory processes such as sepsis, multiorgan dysfunction, ischemia/reperfusion, cardiovascular diseases and many others. The three well-known activation pathways of the complement system have been challenged by newer findings that demonstrate direct production of central complement effectors (for example, C5a) by serine proteases of the coagulation cascade. In particular, thrombin is capable of producing C5a, which not only plays a decisive role on pathogens and infected/damaged tissues, but also acts systemically. In the case of uncontrolled complement activation, "friendly fire" is generated, resulting in the destruction of healthy host tissue. Therefore, the traditional research that focuses on a mainly positive-acting cascade has now shifted to the negative effects and how tissue damage originated by the activation of the complement can be contained. In a translational approach including structure-function relations of this ancient defense system, this review provides new insights of complement-mediated clinical relevant diseases and the development of complement modulation strategies and current research aspects.

  9. Vasopressin in preeclampsia: a novel very early human pregnancy biomarker and clinically relevant mouse model.

    PubMed

    Santillan, Mark K; Santillan, Donna A; Scroggins, Sabrina M; Min, James Y; Sandgren, Jeremy A; Pearson, Nicole A; Leslie, Kimberly K; Hunter, Stephen K; Zamba, Gideon K D; Gibson-Corley, Katherine N; Grobe, Justin L

    2014-10-01

    Preeclampsia, a cardiovascular disorder of late pregnancy, is characterized as a low-renin hypertensive state relative to normotensive pregnancy. Because other nonpregnant low-renin hypertensive disorders often exhibit and are occasionally dependent on elevated arginine vasopressin (AVP) secretion, we hypothesized a possible use for plasma AVP measurements in the prediction of preeclampsia. Copeptin is an inert prosegment of AVP that is secreted in a 1:1 molar ratio and exhibits a substantially longer biological half-life compared with AVP, rendering it a clinically useful biomarker of AVP secretion. Copeptin was measured throughout pregnancy in maternal plasma from preeclamptic and control women. Maternal plasma copeptin was significantly higher throughout preeclamptic pregnancies versus control pregnancies. While controlling for clinically significant confounders (age, body mass index, chronic essential hypertension, twin gestation, diabetes mellitus, and history of preeclampsia) using multivariate regression, the association of higher copeptin concentration and the development of preeclampsia remained significant. Receiver operating characteristic analyses reveal that as early as the sixth week of gestation, elevated maternal plasma copeptin concentration is a highly significant predictor of preeclampsia throughout pregnancy. Finally, chronic infusion of AVP during pregnancy (24 ng per hour) is sufficient to phenocopy preeclampsia in C57BL/6J mice, causing pregnancy-specific hypertension, renal glomerular endotheliosis, proteinuria, and intrauterine growth restriction. These data implicate AVP release as a novel predictive biomarker for preeclampsia very early in pregnancy, identify chronic AVP infusion as a novel and clinically relevant model of preeclampsia in mice, and are consistent with a potential causative role for AVP in preeclampsia in humans.

  10. Is a raised intraepithelial lymphocyte count with normal duodenal villous architecture clinically relevant?

    PubMed Central

    Mahadeva, S; Wyatt, J I; Howdle, P D

    2002-01-01

    Background: A raised intraepithelial lymphocyte (IEL) count with normal villous architecture is a recognised finding in latent coeliac disease. Little information is available in cases without gluten sensitive enteropathy in adults. Aims: To assess the frequency of such a finding in routine practice and to determine whether it is clinically relevant. Methods: Patients with subjectively increased IELs as the only abnormality were identified prospectively from a routine duodenal biopsy series over a 12 month period. The biopsy specimens in these index cases were re-examined together with two controls with normal histology for each case, and three counts of IEL/100 epithelial cells were made in all samples. The index cases were then contacted and interviewed to obtain clinical information, approximately 12 months from the initial biopsy. Further data were obtained from their clinical records. Results: Fourteen of 626 (2.2%) patients who had duodenal biopsies over the 12 month period had a subjective increase in IELs with normal villous architecture. Fifteen patients with newly diagnosed gluten sensitive enteropathy were also identified during the study period. Formal counting of the index cases and controls revealed a significant difference in IELs/100 epithelial cell counts between the two (mean, 38 (SD, 6.2) v 12.4 (4.6); p < 0.0001). Three of the 14 index cases tested had a positive coeliac antibody test compared with 12 of 15 newly diagnosed patients with coeliac disease and 10 of 93 patients with normal histology. The major clinical diagnostic categories in raised IEL cases were those with positive coeliac serology (n = 3), unexplained anaemia (n = 3), and chronic liver disease (n = 3). Six of 10 patients who were interviewed had ongoing gastrointestinal symptoms one year later. Three patients had had follow up duodenal biopsies, at the discretion of their responsible clinicians, with no change in IEL counts despite the commencement of a gluten free diet in two

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

    PubMed

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

    2014-09-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2009-11-01

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

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

    PubMed

    Calder, Philip C

    2015-04-01

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

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

    PubMed Central

    Ivey, Adam; Huntly, Brian J. P.

    2016-01-01

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

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

    PubMed

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

    2009-01-01

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

  16. Headache and psychiatric comorbidity: historical context, clinical implications, and research relevance.

    PubMed

    Lake, Alvin E; Rains, Jeanetta C; Penzien, Donald B; Lipchik, Gay L

    2005-05-01

    The comorbidity of headache and psychiatric disorders is a well-recognized clinical phenomenon warranting further systematic research. Affective disorders occur with at least three-fold greater frequency among migraineurs than among the general population, and the prevalence increases in clinical populations, especially with chronic daily headache. When present, psychiatric comorbidity complicates headache management and portends a poorer prognosis for headache treatment. However, the relationship between headache and psychopathology has historically been misunderstood, and measures of psychopathology have not always met the standard of formal Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria. In some cases, headache has been inappropriately attributed to psychological or psychiatric features, based on anecdotal observations. The challenge for future studies is to employ research methods and designs that accurately identify and classify the subset of headache patients with psychiatric disorders, evaluate their impact on headache symptoms and treatment, and identify optimal behavioral and pharmacologic treatment strategies. This article offers methodological considerations and recommendations for future research including: (i) ascribing dual-International Classification of Headache Disorders, 2nd ed. (ICHD-2) headache and DSM-IV psychiatric diagnoses according to reliable and valid diagnostic criteria, (ii) differentiating subclinical levels of depression and anxiety from major psychiatric disorders, (iii) encouraging validation studies of the recently published ICHD-2 diagnoses for "headache attributed to psychiatric disorder," (iv) expanding epidemiological research to address the range of DSM-IV Axis I and II psychiatric diagnoses among various headache populations, (v) identifying relevant psychiatric and behavioral mediator/moderator variables, and (vi) developing empirically based screening and treatment algorithms.

  17. Clinically-relevant reperfusion in acute ischemic stroke MTT performs better than Tmax and TTP

    PubMed Central

    Kong, Linglong; Zhu, Hongtu; Vo, Katie D.; Powers, William J.; Lin, Weili; Lee, Jin-Moo

    2014-01-01

    Background While several MRI parameters are used to assess tissue perfusion during hyperacute stroke, it is unclear which is optimal for measuring clinically-relevant reperfusion. We directly compared MTT prolongation (MTTp), TTP, and time-to-maximum (Tmax) to determine which best predicted neurological improvement and tissue salvage following early reperfusion. Methods Acute ischemic stroke patients underwent three MRI's: <4.5hr (tp1), at 6hr (tp2), and at 1 month after onset. Perfusion deficits at tp1 and tp2 were defined by MTTp, TTP, or Tmax beyond four commonly-used thresholds. Percent reperfusion (%Reperf) was calculated for each parameter and threshold. Regression analysis was used to fit %Reperf for each parameter and threshold as a predictor of neurological improvement [defined as admission National Institutes of Health Stroke Scale (NIHSS) – 1 month NIHSS (ΔNIHSS)] after adjusting for baseline clinical variables. Volume of reperfusion, for each parameter and threshold, was correlated with tissue salvage, defined as tp1 perfusion deficit volume – final infarct volume. Results 50 patients were scanned at 2.7 hours and 6.2 hours after stroke onset. %Reperf predicted ΔNIHSS for all MTTp thresholds, for Tmax > 6s and > 8s, but for no TTP thresholds. Tissue salvage significantly correlated with reperfusion for all MTTp thresholds and with Tmax > 6s, while there was no correlation with any TTP threshold. Among all parameters, reperfusion defined by MTTp was most strongly associated with ΔNIHSS (MTTp>3s, p=0.0002) and tissue salvage (MTTp> 3s and 4s, P<0.0001). Conclusion MTT-defined reperfusion was the best predictor of neurological improvement and tissue salvage in hyperacute ischemic stroke. PMID:24500786

  18. Personality profiles in Eating Disorders: further evidence of the clinical utility of examining subtypes based on temperament.

    PubMed

    Turner, Brianna J; Claes, Laurence; Wilderjans, Tom F; Pauwels, Els; Dierckx, Eva; Chapman, Alexander L; Schoevaerts, Katrien

    2014-09-30

    Despite recent modifications to the DSM-V diagnostic criteria for Eating Disorders (ED; American Psychiatric Association, 2013), sources of variability in the clinical presentation of ED patients remain poorly understood. Consistent with previous research that has used underlying personality dimensions to identify distinct subgroups of ED patients, the present study examined (1) whether we could identify clinically meaningful subgroups of patients based on temperamental factors including Behavioral Inhibition (BIS), Behavioral Activation (BAS) and Effortful Control (EC), and (2) whether the identified subgroups would also differ with respect to ED, Axis-I and Axis-II psychopathology. One hundred and forty five ED inpatients participated in this study. Results of a k-means analysis identified three distinct groups of patients: an Overcontrolled/Inhibited group (n=53), an Undercontrolled/Dysregulated group (n=58) and a Resilient group (n=34). Further, group comparisons revealed that patients in the Undercontrolled/Dysregulated group demonstrated more severe symptoms of bulimia, hostility and Cluster B Personality Disorders compared to the other groups, while patients in the Resilient group demonstrated the least severe psychopathology. These findings have important implications for understanding how individual differences in personality may impact patterns of ED symptoms and co-occurring psychopathology in patients with ED.

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

    PubMed

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

    2012-01-01

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

  20. Congenital myopathies--clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom.

    PubMed

    Maggi, L; Scoto, M; Cirak, S; Robb, S A; Klein, A; Lillis, S; Cullup, T; Feng, L; Manzur, A Y; Sewry, C A; Abbs, S; Jungbluth, H; Muntoni, F

    2013-03-01

    The congenital myopathies are a group of inherited neuromuscular disorders mainly defined on the basis of characteristic histopathological features. We analysed 66 patients assessed at a single centre over a 5 year period. Of the 54 patients where muscle biopsy was available, 29 (54%) had a core myopathy (central core disease, multi-minicore disease), 9 (17%) had nemaline myopathy, 7 (13%) had myotubular/centronuclear myopathy, 2 (4%) had congenital fibre type disproportion, 6 (11%) had isolated type 1 predominance and 1 (2%) had a mixed core-rod myopathy. Of the 44 patients with a genetic diagnosis, RYR1 was mutated in 26 (59%), ACTA1 in 7 (16%), SEPN1 in 7 (16%), MTM1 in 2 (5%), NEB in 1 (2%) and TPM3 in 1 (2%). Clinically, 77% of patients older than 18 months could walk independently. 35% of all patients required ventilatory support and/or enteral feeding. Clinical course was stable or improved in 57/66 (86%) patients, whilst 4 (6%) got worse and 5 (8%) died. These findings indicate that core myopathies are the most common form of congenital myopathies and that more than half can be attributed to RYR1 mutations. The underlying genetic defect remains to be identified in 1/3 of congenital myopathies cases. PMID:23394784

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

    PubMed

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

    2012-01-01

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

  2. Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy.

    PubMed

    Ling, Karen K Y; Gibbs, Rebecca M; Feng, Zhihua; Ko, Chien-Ping

    2012-01-01

    Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation (<50% fully innervated endplates) occurs selectively in many vulnerable axial muscles and several appendicular muscles at the disease end stage. Since these vulnerable muscles were located throughout the body and were comprised of varying muscle fiber types, it is unlikely that muscle location or fiber type determines susceptibility to denervation. Furthermore, we found a similar extent of neurofilament accumulation at NMJs in both vulnerable and resistant muscles before the onset of denervation, suggesting that neurofilament accumulation does not predict subsequent NMJ denervation. Since vulnerable muscles were initially innervated, but later denervated, loss of innervation in SMA may be attributed to defects in synapse maintenance. Finally, we found that denervation was amendable by trichostatin A (TSA) treatment, which increased innervation in clinically relevant muscles in TSA-treated SMNΔ7 mice. Our findings suggest that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy.

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

    PubMed

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

    2016-07-01

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

  4. A Model of Auditory-Cognitive Processing and Relevance to Clinical Applicability.

    PubMed

    Edwards, Brent

    2016-01-01

    Hearing loss and cognitive function interact in both a bottom-up and top-down relationship. Listening effort is tied to these interactions, and models have been developed to explain their relationship. The Ease of Language Understanding model in particular has gained considerable attention in its explanation of the effect of signal distortion on speech understanding. Signal distortion can also affect auditory scene analysis ability, however, resulting in a distorted auditory scene that can affect cognitive function, listening effort, and the allocation of cognitive resources. These effects are explained through an addition to the Ease of Language Understanding model. This model can be generalized to apply to all sounds, not only speech, representing the increased effort required for auditory environmental awareness and other nonspeech auditory tasks. While the authors have measures of speech understanding and cognitive load to quantify these interactions, they are lacking measures of the effect of hearing aid technology on auditory scene analysis ability and how effort and attention varies with the quality of an auditory scene. Additionally, the clinical relevance of hearing aid technology on cognitive function and the application of cognitive measures in hearing aid fittings will be limited until effectiveness is demonstrated in real-world situations. PMID:27355775

  5. Clinical relevancy and risks of potential drug–drug interactions in intensive therapy

    PubMed Central

    Rodrigues, Aline Teotonio; Stahlschmidt, Rebeca; Granja, Silvia; Falcão, Antonio Luis Eiras; Moriel, Patricia; Mazzola, Priscila Gava

    2014-01-01

    Purpose Evaluate the potential Drug–Drug Interactions (pDDI) found in prescription orders of adult Intensive Care Unit (ICU) of a Brazilian public health system hospital; quantify and qualify the pDDI regarding their severity and risks to the critical patient, using the database from Micromedex®. Methods Prospective study (January–December of 2011) collecting and evaluating 369 prescription orders (convenient sampling), one per patient. Results During the study 1844 pDDIs were identified and distributed in 405 pairs (medication A × medication B combination). There was an average of 5.00 ± 5.06 pDDIs per prescription order, the most prevalent being moderate and important interactions, present in 74% and 67% of prescription orders, respectively. In total, there were 9 contraindicated, 129 important and 204 moderate pDDIs. Among them 52 had as management recommendation to “avoid concomitant use” or “suspension of medication”, while 306 had as recommendation “continuous and adequate monitoring”. Conclusion The high number of pDDIs found in the study combined with the evaluation of the clinical relevancy of the most frequent pDDIs in the ICU shows that moderate and important interactions are highly incident. As the majority of them demand monitoring and adequate management, being aware of these interactions is major information for the safe and individualized risk management. PMID:27134536

  6. HIV1-viral protein R (Vpr) mutations: associated phenotypes and relevance for clinical pathologies.

    PubMed

    Soares, Rui; Rocha, Graça; Meliço-Silvestre, António; Gonçalves, Teresa

    2016-09-01

    Over the last 30 years, research into HIV has advanced the knowledge of virus genetics and the development of efficient therapeutic strategies. HIV-1 viral protein R (Vpr) is a specialized and multifunctional protein that plays important roles at multiple stages of the HIV-1 viral life cycle. This protein interacts with a number of cellular and viral proteins and with multiple activities including nuclear transport of the pre-integration complex (PIC) to the nucleus, transcriptional activation, cell cycle arrest at G2/M transition phase and induction of cell death via apoptosis. Specifically, Vpr has been shown to control many host cell functions through a variety of biological processes and by interaction with several cellular pathways. The different functions of Vpr may enhance viral replication and impair the immune system in HIV-1 infected patients. Importantly, functional defects induced by mutations in the Vpr protein correlate with slow disease progression of HIV-infected patients. Vpr is also associated with other concomitant pathologies developed by these patients, which may lead it to be considered as a potential novel therapeutic target. This review will focus on HIV-1 Vpr, mainly on the importance of its structural mutations on the progression of HIV infection, associated phenotypes and relevance for clinical pathologies. Copyright © 2016 John Wiley & Sons, Ltd.

  7. Developments in FINDbase worldwide database for clinically relevant genomic variation allele frequencies.

    PubMed

    Papadopoulos, Petros; Viennas, Emmanouil; Gkantouna, Vassiliki; Pavlidis, Cristiana; Bartsakoulia, Marina; Ioannou, Zafeiria-Marina; Ratbi, Ilham; Sefiani, Abdelaziz; Tsaknakis, John; Poulas, Konstantinos; Tzimas, Giannis; Patrinos, George P

    2014-01-01

    FINDbase (http://www.findbase.org) aims to document frequencies of clinically relevant genomic variations, namely causative mutations and pharmacogenomic markers, worldwide. Each database record includes the population, ethnic group or geographical region, the disorder name and the related gene, accompanied by links to any related databases and the genetic variation together with its frequency in that population. Here, we report, in addition to the regular data content updates, significant developments in FINDbase, related to data visualization and querying, data submission, interrelation with other resources and a new module for genetic disease summaries. In particular, (i) we have developed new data visualization tools that facilitate data querying and comparison among different populations, (ii) we have generated a new FINDbase module, built around Microsoft's PivotViewer (http://www.getpivot.com) software, based on Microsoft Silverlight technology (http://www.silverlight.net), that includes 259 genetic disease summaries from five populations, systematically collected from the literature representing the documented genetic makeup of these populations and (iii) the implementation of a generic data submission tool for every module currently available in FINDbase.

  8. Characterization and identification of clinically relevant microorganisms using rapid evaporative ionization mass spectrometry.

    PubMed

    Strittmatter, Nicole; Rebec, Monica; Jones, Emrys A; Golf, Ottmar; Abdolrasouli, Alireza; Balog, Julia; Behrends, Volker; Veselkov, Kirill A; Takats, Zoltan

    2014-07-01

    Rapid evaporative ionization mass spectrometry (REIMS) was investigated for its suitability as a general identification system for bacteria and fungi. Strains of 28 clinically relevant bacterial species were analyzed in negative ion mode, and corresponding data was subjected to unsupervised and supervised multivariate statistical analyses. The created supervised model yielded correct cross-validation results of 95.9%, 97.8%, and 100% on species, genus, and Gram-stain level, respectively. These results were not affected by the resolution of the mass spectral data. Blind identification tests were performed for strains cultured on different culture media and analyzed using different instrumental platforms which led to 97.8-100% correct identification. Seven different Escherichia coli strains were subjected to different culture conditions and were distinguishable with 88% accuracy. In addition, the technique proved suitable to distinguish five pathogenic Candida species with 98.8% accuracy without any further modification to the experimental workflow. These results prove that REIMS is sufficiently specific to serve as a culture condition-independent tool for the identification and characterization of microorganisms.

  9. Adaptive control of drug dosage regimens: basic foundations, relevant issues, and clinical examples.

    PubMed

    Jelliffe, R W; Maire, P; Sattler, F; Gomis, P; Tahani, B

    1994-06-01

    In this paper we examine several of the fundamental foundations and relevant clinical issues in adaptive control of drug dosage regimens for patients. Truly individualized therapy with drugs having narrow margins of safety first requires a practical pharmacokinetic/dynamic model of the behavior of a drug. Past experience with a drug is stored in the form of a population model. Next, using the information in such a model and its relationship to the incidence of adverse reactions, a specific, explicit therapeutic goal must be selected by the responsible clinician, based on the patient's need for the drug and the risk of adverse reactions felt to be justified by each patient's need, small, moderate, or great. Individualized drug therapy thus begins with the selection of individualized therapeutic goals (low, moderate, or high) for each patient. Using subsequent feedback from the patient's serum drug levels, and using Bayesian fitting, the model is then linked to each patient as a patient-specific model. Control of the model by the dosage regimen increasingly controls the patient, to better obtain the desired explicit therapeutic goals. This process is essentially similar to that of a flight control or missile guidance system.

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

    PubMed Central

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

    2016-01-01

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

  11. HIV1-viral protein R (Vpr) mutations: associated phenotypes and relevance for clinical pathologies.

    PubMed

    Soares, Rui; Rocha, Graça; Meliço-Silvestre, António; Gonçalves, Teresa

    2016-09-01

    Over the last 30 years, research into HIV has advanced the knowledge of virus genetics and the development of efficient therapeutic strategies. HIV-1 viral protein R (Vpr) is a specialized and multifunctional protein that plays important roles at multiple stages of the HIV-1 viral life cycle. This protein interacts with a number of cellular and viral proteins and with multiple activities including nuclear transport of the pre-integration complex (PIC) to the nucleus, transcriptional activation, cell cycle arrest at G2/M transition phase and induction of cell death via apoptosis. Specifically, Vpr has been shown to control many host cell functions through a variety of biological processes and by interaction with several cellular pathways. The different functions of Vpr may enhance viral replication and impair the immune system in HIV-1 infected patients. Importantly, functional defects induced by mutations in the Vpr protein correlate with slow disease progression of HIV-infected patients. Vpr is also associated with other concomitant pathologies developed by these patients, which may lead it to be considered as a potential novel therapeutic target. This review will focus on HIV-1 Vpr, mainly on the importance of its structural mutations on the progression of HIV infection, associated phenotypes and relevance for clinical pathologies. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27264019

  12. Clinical Relevance of Liver Kinase B1(LKB1) Protein and Gene Expression in Breast Cancer

    PubMed Central

    Chen, I-Chun; Chang, Yuan-Ching; Lu, Yen-Shen; Chung, Kuei-Pin; Huang, Chiun-Sheng; Lu, Tzu-Pin; Kuo, Wen-Hung; Wang, Ming-Yang; Kuo, Kuan-Ting; Wu, Pei-Fang; Hsueh, Tsu-Hsin; Shen, Chen-Yang; Lin, Ching-Hung; Cheng, Ann-Lii

    2016-01-01

    Liver kinase B1 (LKB1) is a tumor suppressor, and its loss might lead to activation of the mammalian target of rapamycin (mTOR) and tumorigenesis. This study aimed to determine the clinical relevance of LKB1 gene and protein expression in breast cancer patients. LKB1 protein expression was evaluated using immunohistochemistry in tumors from early breast cancer patients in two Taiwanese medical centers. Data on LKB1 gene expression were obtained from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data set. The correlations between LKB1 expression, clinicopathologic factors, and patient outcome were analyzed. LKB1 expression was significantly associated with estrogen receptor (ER) expression in 2 of the 4 cohorts, but not with other clinicopathologic factors. LKB1 expression was not a predictor for relapse-free survival, overall survival (OS), or breast cancer-specific survival. In a subgroup analysis of the two Taiwanese cohorts, high LKB1 protein expression was predictive of high OS in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients (P = 0.013). Our study results indicate that LKB1 expression is not prognostic in the whole population of breast cancer patients, but it is a potential predictor of OS in the subset of HER2-positive patients PMID:26877155

  13. Analysis of clinically relevant mechanical and thermal characteristics of titanium foam spinal implants during drilling.

    PubMed

    Ito, Kiyoshi; Horiuchi, Tetsuyoshi; Murata, Takahiro; Hongo, Kazuhiro

    2015-09-01

    Although high biocompatibility promotes the use of titanium (Ti) alloy in spinal implants, this material shows high stiffness, which is an issue for removal by drilling. The recently developed, porous Ti foam implants, which have shown enhanced osteoformation, may overcome this flaw. Thus, this study aimed to compare the mechanical and thermal characteristics of Ti-foam (80 % porosity) and conventional Ti alloy (0 % porosity) implants drilled in clinically relevant conditions. Mechanical properties were analyzed by measuring axial and torque forces using a pressure sensor with a drill of 2.5-mm diameter at a rotation frequency of 20 Hz. Thermography was used to evaluate the heat generated by a diamond burr attached to a high-speed (80,000 rpm) drill. The torque and axial strengths of Ti foam (13.63 ± 1.43 and 82.60 ± 7.78 N, respectively) were significantly lower (P = 0.001) than those of Ti alloy (73.58 ± 13.60 and 850.72 ± 146.99 N, respectively). Furthermore, irrigation reduced the area of local heating for Ti foam to 56-82 % of that for Ti alloy, indicating lower thermal conductivity. These data suggest that the use of Ti foam implants may be advantageous in cases with a probability of implant drilling in the future.

  14. Protein abundance of clinically relevant multidrug transporters along the entire length of the human intestine.

    PubMed

    Drozdzik, Marek; Gröer, Christian; Penski, Jette; Lapczuk, Joanna; Ostrowski, Marek; Lai, Yurong; Prasad, Bhagwat; Unadkat, Jashvant D; Siegmund, Werner; Oswald, Stefan

    2014-10-01

    Intestinal transporters are crucial determinants in the oral absorption of many drugs. We therefore studied the mRNA expression (N = 33) and absolute protein content (N = 10) of clinically relevant transporters in healthy epithelium of the duodenum, the proximal and distal jejunum and ileum, and the ascending, transversal, descending, and sigmoidal colon of six organ donors (24-54 years). In the small intestine, the abundance of nearly all studied proteins ranged between 0.2 and 1.6 pmol/mg with the exception of those of OCT3 (<0.1 pmol/mg) and PEPT1 (2.6-4.9 pmol/mg) that accounted for ∼50% of all measured transporters. OATP1A2 was not detected in any intestinal segment. ABCB1, ABCG2, PEPT1, and ASBT were significantly more abundant in jejunum and ileum than in colon. In contrast to this, the level of expression of ABCC2, ABCC3, and OCT3 was found to be highest in colon. Site-dependent differences in the levels of gene and protein expression were observed for ABCB1 and ASBT. Significant correlations between mRNA and protein levels have been found for ABCG2, ASBT, OCT3, and PEPT1 in the small intestine. Our data provide further physiological pieces of the puzzle required to predict intestinal drug absorption in humans.

  15. Comparative Transcriptional Analysis of Clinically Relevant Heat Stress Response in Clostridium difficile Strain 630

    PubMed Central

    Ternan, Nigel G.; Jain, Shailesh; Srivastava, Malay; McMullan, Geoff

    2012-01-01

    Clostridium difficile is considered to be one of the most important causes of health care-associated infections worldwide. In order to understand more fully the adaptive response of the organism to stressful conditions, we examined transcriptional changes resulting from a clinically relevant heat stress (41°C versus 37°C) in C. difficile strain 630 and identified 341 differentially expressed genes encompassing multiple cellular functional categories. While the transcriptome was relatively resilient to the applied heat stress, we noted upregulation of classical heat shock genes including the groEL and dnaK operons in addition to other stress-responsive genes. Interestingly, the flagellin gene (fliC) was downregulated, yet genes encoding the cell-wall associated flagellar components were upregulated suggesting that while motility may be reduced, adherence – to mucus or epithelial cells – could be enhanced during infection. We also observed that a number of phage associated genes were downregulated, as were genes associated with the conjugative transposon Tn5397 including a group II intron, thus highlighting a potential decrease in retromobility during heat stress. These data suggest that maintenance of lysogeny and genome wide stabilisation of mobile elements could be a global response to heat stress in this pathogen. PMID:22860125

  16. Anatomical Description and Clinical Relevance of a Rare Variation in the Mesenteric Arterial Arcade Pattern

    PubMed Central

    Hansdak, Ranjeeta; Thakur, Avinash; Mehta, Vandana; Rath, Gayatri

    2015-01-01

    Solitary vascular variations of the mesenteric arteries are extremely rare and have been seldom reported in the past. The aim of this study is to emphasize the anatomical and clinical relevance of one such rare variation of inferior mesenteric artery (IMA). The current case anomaly was incidentally observed while guiding the undergraduate medical students in the dissection of the mesenteric region of the abdomen in an Indian cadaver. An Accessory left colic artery was seen to be branching off from the Inferior Mesenteric artery and further dividing into two transverse branches which took part in the formation of arterial arc for the perfusion of the transverse and the descending colon. Awareness of such aberrant branches of Inferior Mesenteric artery helps in optimal selection of the mode of treatment or operative planning. Additionally, this knowledge minimizes possible iatrogenic injuries resulting from surgeries. Moreover, surgical anatomy of anomalous branches of Inferior Mesenteric artery is extremely essential for planning and successfully executing reconstructive procedures using these branches as pedicles for the transposed part of the colon. PMID:26435936

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

    PubMed Central

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

    2015-01-01

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

  18. Differences in resistance mutations among HIV-1 non-subtype B infections: a systematic review of evidence (1996–2008)

    PubMed Central

    2009-01-01

    Ninety percent of HIV-1-infected people worldwide harbour non-subtype B variants of HIV-1. Yet knowledge of resistance mutations in non-B HIV-1 and their clinical relevance is limited. Although a few reviews, editorials and perspectives have been published alluding to this lack of data among non-B subtypes, no systematic review has been performed to date. With this in mind, we conducted a systematic review (1996–2008) of all published studies performed on the basis of non-subtype B HIV-1 infections treated with antiretroviral drugs that reported genotype resistance tests. Using an established search string, 50 studies were deemed relevant for this review. These studies reported genotyping data from non-B HIV-1 infections that had been treated with either reverse transcriptase inhibitors or protease inhibitors. While most major resistance mutations in subtype B were also found in non-B subtypes, a few novel mutations in non-B subtypes were recognized. The main differences are reflected in the discoveries that: (i) the non-nucleoside reverse transcriptase inhibitor resistance mutation, V106M, has been seen in subtype C and CRF01_AE, but not in subtype B, (ii) the protease inhibitor mutations L89I/V have been reported in C, F and G subtypes, but not in B, (iii) a nelfinavir selected non-D30N containing pathway predominated in CRF01_AE and CRF02_AG, while the emergence of D30N is favoured in subtypes B and D, (iv) studies on thymidine analog-treated subtype C infections from South Africa, Botswana and Malawi have reported a higher frequency of the K65R resistance mutation than that typically seen with subtype B. Additionally, some substitutions that seem to impact non-B viruses differentially are: reverse transcriptase mutations G196E, A98G/S, and V75M; and protease mutations M89I/V and I93L. Polymorphisms that were common in non-B subtypes and that may contribute to resistance tended to persist or become more frequent after drug exposure. Some, but not all, are

  19. The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers | Office of Cancer Genomics

    Cancer.gov

    Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We characterized the global A-to-I RNA editing profiles of 6,236 patient samples of 17 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions.

  20. Innovative perspectives of immunotherapy in head and neck cancer. From relevant scientific rationale to effective clinical practice.

    PubMed

    Lalami, Y; Awada, A

    2016-02-01

    It is now well established that head and neck cancer carcinogenesis is characterized by genetic instability and several immune defects, leading to unique host-tumor interactions. In such condition, recent improved comprehension and relevant findings could lead to identification of innovative molecular therapeutic targets, achieving considerable clinical and translational research. This review aims to summarize and to highlight most recent and relevant scientific rationale in this era of immunotherapy revival, and to correlate it to the near future clinical practice for the management of this challenging disease.

  1. Clinical Utility of Subtyping Binge Eating Disorder by History of Anorexia or Bulimia Nervosa in a Treatment Sample

    PubMed Central

    Utzinger, Linsey M.; Mitchell, James E.; Cao, Li; Crosby, Ross D.; Crow, Scott J.; Wonderlich, Stephen A.; Peterson, Carol B.

    2016-01-01

    Objective This study examined whether having a history of anorexia nervosa (AN) or bulimia nervosa (BN) is associated with response to treatment in adults with binge eating disorder (BED). Method Data from 189 adults diagnosed with BED who were randomly assigned to one of three group cognitive-behavioral (CBT) treatments were analyzed to compare those with and without a history of AN/BN. Results A total of 16% of the sample had a history of AN/BN. The BED subgroup with a history of AN/BN presented with higher rates of mood disorders and greater eating-related symptom severity at baseline. Participants with a history of AN/BN also had higher global eating disorder (ED) symptoms at end of treatment (EOT), and more frequent objective binge-eating episodes at EOT and 12-month follow-up. Discussion These findings suggest that in adults with BED, a history of AN/BN is predictive of greater eating-related symptom severity following group-based CBT and poorer short- and long-term binge-eating outcomes. These findings suggest that considering ED history in the treatment of adults with BED may be clinically useful. PMID:25959549

  2. Refining developmental coordination disorder subtyping with multivariate statistical methods

    PubMed Central

    2012-01-01

    Background With a large number of potentially relevant clinical indicators penalization and ensemble learning methods are thought to provide better predictive performance than usual linear predictors. However, little is known about how they perform in clinical studies where few cases are available. We used Random Forests and Partial Least Squares Discriminant Analysis to select the most salient impairments in Developmental Coordination Disorder (DCD) and assess patients similarity. Methods We considered a wide-range testing battery for various neuropsychological and visuo-motor impairments which aimed at characterizing subtypes of DCD in a sample of 63 children. Classifiers were optimized on a training sample, and they were used subsequently to rank the 49 items according to a permuted measure of variable importance. In addition, subtyping consistency was assessed with cluster analysis on the training sample. Clustering fitness and predictive accuracy were evaluated on the validation sample. Results Both classifiers yielded a relevant subset of items impairments that altogether accounted for a sharp discrimination between three DCD subtypes: ideomotor, visual-spatial and constructional, and mixt dyspraxia. The main impairments that were found to characterize the three subtypes were: digital perception, imitations of gestures, digital praxia, lego blocks, visual spatial structuration, visual motor integration, coordination between upper and lower limbs. Classification accuracy was above 90% for all classifiers, and clustering fitness was found to be satisfactory. Conclusions Random Forests and Partial Least Squares Discriminant Analysis are useful tools to extract salient features from a large pool of correlated binary predictors, but also provide a way to assess individuals proximities in a reduced factor space. Less than 15 neuro-visual, neuro-psychomotor and neuro-psychological tests might be required to provide a sensitive and specific diagnostic of DCD on this

  3. The clinical value of human leukocyte antigen HLA-DRB1 subtypes associated to Graves' disease in Romanian population.

    PubMed

    Martin, Sorina; Dutescu, Monica Irina; Sirbu, Anca; Barbu, Carmen; Albu, Alice; Florea, Suzana; Fica, Simona

    2014-01-01

    The aim of this study was to identify the primary susceptibility HLA-DRB1 alleles associated with GD in Romanian population and to seek whether specific HLA-DRB1 haplotypes are associated with differences in the clinical presentation of GD at diagnosis. Molecular typing of HLA-DRB1 alleles was performed in 77 Romanian Caucasian GD patients and 445 racially matched controls. In GD patients, age, presence of eye disease, goiter grade, autoantibody status and titer, TSH, FT4, FT3, TT3 levels were recorded at diagnosis. The allelic frequencies of HLA-DRB1*03 (41.55% vs. 17.75%, p < 0.0001, χ(2) = 20.81) and DRB1*11 (42.85% vs. 30.56%, p = 0.045, χ(2) = 3.98)were higher, whereas those of HLA-DRB1*01(3.89% vs. 16.40%, p = 0.007, χ(2) = 7.281) and DRB1*15 (10.38% vs. 21.34%, p = 0.038, χ(2) = 4.309)were lower in GD patients than in controls. FT4/TT3 ratio (p = 0.015) and anti-thyroglobulin antibodies (p = 0.024) were higher in *03/11 patients compared to *X/X, *11/Z, *03/Y patients (where X is any other allele than *03 and *11, Y is any other allele than *11, Z is any other allele than *03). In conclusion, HLA-DRB1*03 and DRB1*11 may be the primary susceptibility HLA-DRB1 alleles associated with GD in Romanian population, whereas HLA-DRB1*01 and DRB1*15 seem to be protective. At diagnosis, HLA-DRB1*03/11 GD patients had higher FT4/TT3 ratio and anti-thyroglobulin antibody levels.

  4. Ciclopirox: recent nonclinical and clinical data relevant to its use as a topical antimycotic agent.

    PubMed

    Subissi, Alessandro; Monti, Daniela; Togni, Giuseppe; Mailland, Federico

    2010-11-12

    Ciclopirox is a topical antimycotic agent belonging to the chemical class of hydroxypyridones and not related to azoles or any other class of antifungal agents. Its antimicrobial profile includes nearly all of the clinically relevant dermatophytes, yeasts and moulds, and is therefore broader than that of most other antimycotics. It is also active against certain frequently azole-resistant Candida species and against some bacteria. The mechanism of action of ciclopirox is different from that of other topical antifungal drugs, which generally act through ergosterol inhibition. The high affinity of ciclopirox for trivalent metal cations, resulting in inhibition of the metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell, appears to be the major determinant of its antimicrobial activity. This unique and multilevel mechanism of action provides a very low potential for the development of resistance in pathogenic fungi, with cases of resistance rarely reported. Ciclopirox also displays mild anti-inflammatory effects in biochemical and pharmacological models; effects also shown in small clinical studies. Scavenging of reactive oxygen species released from inflammatory cells is a likely contributor to these anti-inflammatory effects. Ciclopirox, and its olamine salt, is available in multiple topical formulations, suitable for administration onto the skin and nails and into the vagina. The pharmaceutical forms most widely investigated are 1% ciclopirox olamine cream and 8% ciclopirox acid nail lacquer, but lotion, spray, shampoo, pessary, solution, gel and douche formulations have also been used. Ciclopirox penetrates into the deep layers of the skin, mucosal membranes and nail keratin, reaching concentrations exceeding the minimal fungicidal concentrations for most medically important fungi. A large number of clinical trials were and are still being performed with ciclopirox, starting in the early 1980s. Ciclopirox was first

  5. Clinical relevance of circulating cell-free microRNAs in ovarian cancer.

    PubMed

    Nakamura, Koji; Sawada, Kenjiro; Yoshimura, Akihiko; Kinose, Yasuto; Nakatsuka, Erika; Kimura, Tadashi

    2016-01-01

    Ovarian cancer is the leading cause of death among gynecologic malignancies. Since ovarian cancer develops asymptomatically, it is often diagnosed at an advanced and incurable stage. Despite many years of research, there is still a lack of reliable diagnostic markers and methods for early detection and screening. Recently, it was discovered that cell-free microRNAs (miRNAs) circulate in the body fluids of healthy and diseased patients, suggesting that they may serve as a novel diagnostic marker. This review summarizes the current knowledge regarding the potential clinical relevance of circulating cell-free miRNA for ovarian cancer diagnosis, prognosis, and therapeutics. Despite the high levels of ribonucleases in many types of body fluids, most of the circulating miRNAs are packaged in microvesicles, exosomes, or apoptotic bodies, are binding to RNA-binding protein such as argonaute 2 or lipoprotein complexes, and are thus highly stable. Cell-free miRNA signatures are known to be parallel to those from the originating tumor cells, indicating that circulating miRNA profiles accurately reflect the tumor profiles. Since it is well established that the dysregulation of miRNAs is involved in the tumorigenesis of ovarian cancer, cell-free miRNAs circulating in body fluids such as serum, plasma, whole blood, and urine may reflect not only the existence of ovarian cancer but also tumor histology, stage, and prognoses of the patients. Several groups have successfully demonstrated that serum or plasma miRNAs are able to discriminate patients with ovarian cancer patients from healthy controls, suggesting that the addition of these miRNAs to current testing regimens may improve diagnosis accuracies for ovarian cancer. Furthermore, recent studies have revealed that changes in levels of cell-free circulating miRNAs are associated with the condition of cancer patients. Discrepancies between the results across studies due to the lack of an established endogenous miRNA control to

  6. The clinical relevance of axillary reverse mapping (ARM): study protocol for a randomized controlled trial

    PubMed Central

    2013-01-01

    Background Axillary lymph node dissection (ALND) in patients with breast cancer has the potential to induce side-effects, including upper-limb lymphedema. Axillary reverse mapping (ARM) is a technique that enables discrimination of the lymphatic drainage of the breast from that of the upper limb in the axillary lymph node (LN) basin. If lymphedema is caused by removing these lymphatics and nodes in the upper limb, the possibility of identifying these lymphatics would enable surgeons to preserve them. The aim of this study is to determine the clinical relevance of selective axillary LN and lymphatic preservation by means of ARM. To minimize the risk of overlooking tumor-positive ARM nodes and the associated risk of undertreatment, we will only include patients with a tumor-positive sentinel lymph node (SLN). Patients who are candidates for ALND because of a proven positive axillary LN at clinical examination can be included in a registration study. Methods/design The study will enroll 280 patients diagnosed with SLN biopsy-proven metastasis of invasive breast cancer with an indication for a completion ALND. Patients will be randomized to undergo standard ALND or an ALND in which the ARM nodes and their corresponding lymphatics will be left in situ. Primary outcome is the presence of axillary surgery-related lymphedema at 6, 12, and 24 months post-operatively, measured by the water-displacement method. Secondary outcome measures include pain, paresthesia, numbness, and loss of shoulder mobility, quality of life, and axillary recurrence risk. Discussion The benefit of ALND in patients with a positive SLN is a subject of debate. For many patients, an ALND will remain the treatment of choice. This multicenter randomized trial will provide evidence of whether or not axillary LN preservation by means of ARM decreases the side-effects of an ALND. Enrolment of patients will start in April 2013 in five breast-cancer centers in the Netherlands, and is expected to conclude by

  7. Cortical atrophy patterns in multiple sclerosis are non-random and clinically relevant.

    PubMed

    Steenwijk, Martijn D; Geurts, Jeroen J G; Daams, Marita; Tijms, Betty M; Wink, Alle Meije; Balk, Lisanne J; Tewarie, Prejaas K; Uitdehaag, Bernard M J; Barkhof, Frederik; Vrenken, Hugo; Pouwels, Petra J W

    2016-01-01

    of two cortical thickness patterns (bilateral sensorimotor cortex and bilateral insula), and global cortical thickness. The final model predicting average cognition (adjusted R(2) = 0.469; P < 0.001) consisted of age, the loadings of two cortical thickness patterns (bilateral posterior cingulate cortex and bilateral temporal pole), overall white matter lesion load and normal-appearing white matter integrity. Although white matter pathology measures were part of the final clinical regression models, they explained limited incremental variance (to a maximum of 4%). Several cortical atrophy patterns relevant for multiple sclerosis were found. This suggests that cortical atrophy in multiple sclerosis occurs largely in a non-random manner and develops (at least partly) according to distinct anatomical patterns. In addition, these cortical atrophy patterns showed stronger associations with clinical (especially cognitive) dysfunction than global cortical atrophy.

  8. NT-ProBNP Levels in Saliva and Its Clinical Relevance to Heart Failure

    PubMed Central

    Foo, Jared Yong Yang; Wan, Yunxia; Kostner, Karam; Arivalagan, Alicia; Atherton, John; Cooper-White, Justin; Dimeski, Goce; Punyadeera, Chamindie

    2012-01-01

    Background Current blood based diagnostic assays to detect heart failure (HF) have large intra-individual and inter-individual variations which have made it difficult to determine whether the changes in the analyte levels reflect an actual change in disease activity. Human saliva mirrors the body’s health and well being and ∼20% of proteins that are present in blood are also found in saliva. Saliva has numerous advantages over blood as a diagnostic fluid which allows for a non-invasive, simple, and safe sample collection. The aim of our study was to develop an immunoassay to detect NT-proBNP in saliva and to determine if there is a correlation with blood levels. Methods Saliva samples were collected from healthy volunteers (n = 40) who had no underlying heart conditions and HF patients (n = 45) at rest. Samples were stored at −80°C until analysis. A customised homogeneous sandwich AlphaLISA(R) immunoassay was used to quantify NT-proBNP levels in saliva. Results Our NT-proBNP immunoassay was validated against a commercial Roche assay on plasma samples collected from HF patients (n = 37) and the correlation was r2 = 0.78 (p<0.01, y = 1.705× +1910.8). The median salivary NT-proBNP levels in the healthy and HF participants were <16 pg/mL and 76.8 pg/mL, respectively. The salivary NT-proBNP immunoassay showed a clinical sensitivity of 82.2% and specificity of 100%, positive predictive value of 100% and negative predictive value of 83.3%, with an overall diagnostic accuracy of 90.6%. Conclusion We have firstly demonstrated that NT-proBNP can be detected in saliva and that the levels were higher in heart failure patients compared with healthy control subjects. Further studies will be needed to demonstrate the clinical relevance of salivary NT-proBNP in unselected, previously undiagnosed populations. PMID:23119023

  9. Effect of ethanol at clinically relevant concentrations on atrial inward rectifier potassium current sensitive to acetylcholine.

    PubMed

    Bébarová, Markéta; Matejovič, Peter; Pásek, Michal; Hořáková, Zuzana; Hošek, Jan; Šimurdová, Milena; Šimurda, Jiří

    2016-10-01

    Alcohol intoxication tends to induce arrhythmias, most often the atrial fibrillation. To elucidate arrhythmogenic mechanisms related to alcohol consumption, the effect of ethanol on main components of the ionic membrane current is investigated step by step. Considering limited knowledge, we aimed to examine the effect of clinically relevant concentrations of ethanol (0.8-80 mM) on acetylcholine-sensitive inward rectifier potassium current I K(Ach). Experiments were performed by the whole-cell patch clamp technique at 23 ± 1 °C on isolated rat and guinea-pig atrial myocytes, and on expressed human Kir3.1/3.4 channels. Ethanol induced changes of I K(Ach) in the whole range of concentrations applied; the effect was not voltage dependent. The constitutively active component of I K(Ach) was significantly increased by ethanol with the maximum effect (an increase by ∼100 %) between 8 and 20 mM. The changes were comparable in rat and guinea-pig atrial myocytes and also in expressed human Kir3.1/3.4 channels (i.e., structural correlate of I K(Ach)). In the case of the acetylcholine-induced component of I K(Ach), a dual ethanol effect was apparent with a striking heterogeneity of changes in individual cells. The effect correlated with the current magnitude in control: the current was increased by eth-anol in the cells showing small current in control and vice versa. The average effect peaked at 20 mM ethanol (an increase of the current by ∼20 %). Observed changes of action potential duration agreed well with the voltage clamp data. Ethanol significantly affected both components of I K(Ach) even in concentrations corresponding to light alcohol consumption.

  10. Molecular Mechanisms of Glutamine Synthetase Mutations that Lead to Clinically Relevant Pathologies

    PubMed Central

    Frieg, Benedikt; Görg, Boris; Homeyer, Nadine; Keitel, Verena; Häussinger, Dieter; Gohlke, Holger

    2016-01-01

    Glutamine synthetase (GS) catalyzes ATP-dependent ligation of ammonia and glutamate to glutamine. Two mutations of human GS (R324C and R341C) were connected to congenital glutamine deficiency with severe brain malformations resulting in neonatal death. Another GS mutation (R324S) was identified in a neurologically compromised patient. However, the molecular mechanisms underlying the impairment of GS activity by these mutations have remained elusive. Molecular dynamics simulations, free energy calculations, and rigidity analyses suggest that all three mutations influence the first step of GS catalytic cycle. The R324S and R324C mutations deteriorate GS catalytic activity due to loss of direct interactions with ATP. As to R324S, indirect, water-mediated interactions reduce this effect, which may explain the suggested higher GS residual activity. The R341C mutation weakens ATP binding by destabilizing the interacting residue R340 in the apo state of GS. Additionally, the mutation is predicted to result in a significant destabilization of helix H8, which should negatively affect glutamate binding. This prediction was tested in HEK293 cells overexpressing GS by dot-blot analysis: Structural stability of H8 was impaired through mutation of amino acids interacting with R341, as indicated by a loss of masking of an epitope in the glutamate binding pocket for a monoclonal anti-GS antibody by L-methionine-S-sulfoximine; in contrast, cells transfected with wild type GS showed the masking. Our analyses reveal complex molecular effects underlying impaired GS catalytic activity in three clinically relevant mutants. Our findings could stimulate the development of ATP binding-enhancing molecules by which the R324S mutant can be repaired extrinsically. PMID:26836257

  11. Molecular Mechanisms of Glutamine Synthetase Mutations that Lead to Clinically Relevant Pathologies.

    PubMed

    Frieg, Benedikt; Görg, Boris; Homeyer, Nadine; Keitel, Verena; Häussinger, Dieter; Gohlke, Holger

    2016-02-01

    Glutamine synthetase (GS) catalyzes ATP-dependent ligation of ammonia and glutamate to glutamine. Two mutations of human GS (R324C and R341C) were connected to congenital glutamine deficiency with severe brain malformations resulting in neonatal death. Another GS mutation (R324S) was identified in a neurologically compromised patient. However, the molecular mechanisms underlying the impairment of GS activity by these mutations have remained elusive. Molecular dynamics simulations, free energy calculations, and rigidity analyses suggest that all three mutations influence the first step of GS catalytic cycle. The R324S and R324C mutations deteriorate GS catalytic activity due to loss of direct interactions with ATP. As to R324S, indirect, water-mediated interactions reduce this effect, which may explain the suggested higher GS residual activity. The R341C mutation weakens ATP binding by destabilizing the interacting residue R340 in the apo state of GS. Additionally, the mutation is predicted to result in a significant destabilization of helix H8, which should negatively affect glutamate binding. This prediction was tested in HEK293 cells overexpressing GS by dot-blot analysis: Structural stability of H8 was impaired through mutation of amino acids interacting with R341, as indicated by a loss of masking of an epitope in the glutamate binding pocket for a monoclonal anti-GS antibody by L-methionine-S-sulfoximine; in contrast, cells transfected with wild type GS showed the masking. Our analyses reveal complex molecular effects underlying impaired GS catalytic activity in three clinically relevant mutants. Our findings could stimulate the development of ATP binding-enhancing molecules by which the R324S mutant can be repaired extrinsically.

  12. Pharmacological characterization of lysophosphatidic acid-induced pain with clinically relevant neuropathic pain drugs.

    PubMed

    Ogawa, K; Takasu, K; Shinohara, S; Yoneda, Y; Kato, A

    2012-08-01

    Lysophosphatidic acid (LPA), an initiator of neuropathic pain, causes allodynia. However, few studies have evaluated the pharmacological profile of LPA-induced pain. In this study, a LPA-induced pain model was developed and pharmacologically characterized with clinically relevant drugs used for neuropathic pain, including antiepileptics, non-steroidal anti-inflammatory agents, analgesics, local anaesthetics/antiarrhythmics and antidepressants. Gabapentin (1-30 mg/kg, p.o.) significantly reversed LPA-induced allodynia, but neither indomethacin (30 mg/kg, p.o.) nor morphine (0.3-3 mg/kg, s.c.) did, which indicates that LPA-induced pain consists mostly of neuropathic rather than inflammatory pain. Both pregabalin (0.3-10 mg/kg, p.o.) and ω-CgTX MVIIA (0.01-0.03 μg/mouse, i.t.) completely reversed LPA-induced allodynia in a dose-dependent manner. Lidocaine (1-30 mg/kg, s.c.), mexiletine (1-30 mg/kg, p.o.) and carbamazepine (10-100 mg/kg, p.o.) significantly ameliorated LPA-induced allodynia dose dependently. Milnacipran (30 mg/kg, i.p.) produced no significant analgesic effect in LPA-induced allodynia. In LPA-injected mice, expression of the α2δ1 subunit of the voltage-gated calcium channel (VGCC) was increased in the dorsal root ganglion (DRG) and spinal dorsal horn. Furthermore, the VGCC current was potentiated in both the DRG from LPA-injected mice and LPA (1 μM)-treated DRG from saline-injected mice, and the potentiated VGCC current was amended by treatment with gabapentin (100 μM). The LPA-induced pain model described here mimics aspects of the neuropathic pain state, including the sensitization of VGCC, and may be useful for the early assessment of drug candidates to treat neuropathic pain. PMID:22337641

  13. [Clinical relevance of N-acetyltransferase type 2 (NAT2) genetic polymorphism].

    PubMed

    Furet, Y; Bechtel, Y; Le Guellec, C; Bechtel, P R; Autret-Leca, E; Paintaud, G

    2002-01-01

    Polymorphic N-acetyltransferase (NAT2) is involved in the metabolism of several compounds relevant in pharmacology or toxicology, with diverse clinical consequences. Inter-ethnic variations in distribution of the acetylation phenotype are significant. The caffeine test is most often used to assess the acetylation phenotype and to identify rapid and slow acetylators. The NAT2 phenotype could account for the increased risk of certain side effects in slow acetylators treated with isoniazid (particularly peripheral neuropathies and lupus erythematosus), although therapeutic efficacy seems to be independent of the acetylation status. Hypersensibility reactions with sulfonamides (including Lyell and Stevens-Johnson syndromes) are more frequent in slow acetylators, who also show poor tolerance to sulfasalazine and dapsone. In contrast, myelotoxicity induced by amonafide is more frequent in rapid acetylators, probably because of increased production of a toxic metabolite of the drug. In carcinogenesis, NAT2 may play a protective role against bladder cancer, although studies have shown contradictory results. Slow acetylators may have a risk of developing primitive liver cancer. For lung cancer, data are not conclusive, but slow acetylation status may predispose to mesothelioma in subjects exposed to asbestos. No relation has been found between acetylation phenotype and breast cancer. Contradictory results were reported on its role in colorectal cancer. Non-smoking type 1 diabetics may be at increased risk of nephropathy if they are rapid acetylators. Parkinson's disease may be more frequent among slow acetylators, but again, data have shown contradictory results. Finally, a poor acetylator phenotype may predispose to atopic diseases. PMID:12611196

  14. Automated detection of retinal landmarks for the identification of clinically relevant regions in fundus photography

    NASA Astrophysics Data System (ADS)

    Ometto, Giovanni; Calivá, Francesco; Al-Diri, Bashir; Bek, Toke; Hunter, Andrew

    2016-03-01

    Automatic, quick and reliable identification of retinal landmarks from fundus photography is key for measurements used in research, diagnosis, screening and treating of common diseases affecting the eyes. This study presents a fast method for the detection of the centre of mass of the vascular arcades, optic nerve head (ONH) and fovea, used in the definition of five clinically relevant areas in use for screening programmes for diabetic retinopathy (DR). Thirty-eight fundus photographs showing 7203 DR lesions were analysed to find the landmarks manually by two retina-experts and automatically by the proposed method. The automatic identification of the ONH and fovea were performed using template matching based on normalised cross correlation. The centre of mass of the arcades was obtained by fitting an ellipse on sample coordinates of the main vessels. The coordinates were obtained by processing the image with hessian filtering followed by shape analyses and finally sampling the results. The regions obtained manually and automatically were used to count the retinal lesions falling within, and to evaluate the method. 92.7% of the lesions were falling within the same regions based on the landmarks selected by the two experts. 91.7% and 89.0% were counted in the same areas identified by the method and the first and second expert respectively. The inter-repeatability of the proposed method and the experts is comparable, while the 100% intra-repeatability makes the algorithm a valuable tool in tasks like analyses in real-time, of large datasets and of intra-patient variability.

  15. Clonal spread and interspecies transmission of clinically relevant ESBL-producing Escherichia coli of ST410--another successful pandemic clone?

    PubMed

    Schaufler, Katharina; Semmler, Torsten; Wieler, Lothar H; Wöhrmann, Michael; Baddam, Ramani; Ahmed, Niyaz; Müller, Kerstin; Kola, Axel; Fruth, Angelika; Ewers, Christa; Guenther, Sebastian

    2016-01-01

    Clinically relevant extended-spectrum beta-lactamase (ESBL)-producing multi-resistant Escherichia coli have been on the rise for years. Initially restricted to mostly a clinical context, recent findings prove their prevalence in extraclinical settings independent of the original occurrence of antimicrobial resistance in the environment. To get further insights into the complex ecology of potentially clinically relevant ESBL-producing E. coli, 24 isolates from wild birds in Berlin, Germany, and 40 ESBL-producing human clinical E. coli isolates were comparatively analyzed. Isolates of ST410 occurred in both sample groups (six). In addition, three ESBL-producing E. coli isolates of ST410 from environmental dog feces and one clinical dog isolate were included. All 10 isolates were clonally analyzed showing almost identical macrorestriction patterns. They were chosen for whole-genome sequencing revealing that the whole-genome content of these 10 E. coli isolates showed a very high genetic similarity, differing by low numbers of single nucleotide polymorphisms only. This study gives initial evidence for a recent interspecies transmission of a new successful clone of ST410 E. coli between wildlife, humans, companion animals and the environment. The results underline the zoonotic potential of clinically relevant multi-resistant bacteria found in the environment as well as the mandatory nature of the 'One Health' approach.

  16. Clonal spread and interspecies transmission of clinically relevant ESBL-producing Escherichia coli of ST410--another successful pandemic clone?

    PubMed

    Schaufler, Katharina; Semmler, Torsten; Wieler, Lothar H; Wöhrmann, Michael; Baddam, Ramani; Ahmed, Niyaz; Müller, Kerstin; Kola, Axel; Fruth, Angelika; Ewers, Christa; Guenther, Sebastian

    2016-01-01

    Clinically relevant extended-spectrum beta-lactamase (ESBL)-producing multi-resistant Escherichia coli have been on the rise for years. Initially restricted to mostly a clinical context, recent findings prove their prevalence in extraclinical settings independent of the original occurrence of antimicrobial resistance in the environment. To get further insights into the complex ecology of potentially clinically relevant ESBL-producing E. coli, 24 isolates from wild birds in Berlin, Germany, and 40 ESBL-producing human clinical E. coli isolates were comparatively analyzed. Isolates of ST410 occurred in both sample groups (six). In addition, three ESBL-producing E. coli isolates of ST410 from environmental dog feces and one clinical dog isolate were included. All 10 isolates were clonally analyzed showing almost identical macrorestriction patterns. They were chosen for whole-genome sequencing revealing that the whole-genome content of these 10 E. coli isolates showed a very high genetic similarity, differing by low numbers of single nucleotide polymorphisms only. This study gives initial evidence for a recent interspecies transmission of a new successful clone of ST410 E. coli between wildlife, humans, companion animals and the environment. The results underline the zoonotic potential of clinically relevant multi-resistant bacteria found in the environment as well as the mandatory nature of the 'One Health' approach. PMID:26656065

  17. Is the Inattentive Subtype of ADHD Different from the Combined/Hyperactive Subtype?

    ERIC Educational Resources Information Center

    Grizenko, Natalie; Paci, Michael; Joober, Ridha

    2010-01-01

    Objective: To compare the ADHD combined/hyperactive subtype (ADHD/CH) to the ADHD inattentive subtype (ADHD/I) on the level of comorbidity, treatment response, and possible etiological factors. Method: A total of 371 clinically referred children diagnosed with ADHD aged between 6 and 12 years are recruited for a double-blind, placebo-controlled…

  18. Time-driven activity-based costing in an outpatient clinic environment: development, relevance and managerial impact.

    PubMed

    Demeere, Nathalie; Stouthuysen, Kristof; Roodhooft, Filip

    2009-10-01

    Healthcare managers are continuously urged to provide better patient services at a lower cost. To cope with these cost pressures, healthcare management needs to improve its understanding of the relevant cost drivers. Through a case study, we show how to perform a time-driven activity-based costing of five outpatient clinic's departments and provide evidence of the benefits of such an analysis.

  19. Serum proteomic profiles of depressive subtypes.

    PubMed

    Lamers, F; Bot, M; Jansen, R; Chan, M K; Cooper, J D; Bahn, S; Penninx, B W J H

    2016-01-01

    Depression is a highly heterogeneous disorder. Accumulating evidence suggests biological and genetic differences between subtypes of depression that are homogeneous in symptom presentation. We aimed to evaluate differences in serum protein profiles between persons with atypical and melancholic depressive subtypes, and compare these profiles with serum protein levels of healthy controls. We used the baseline data from the Netherlands Study of Depression and Anxiety on 414 controls, 231 persons with a melancholic depressive subtype and 128 persons with an atypical depressive subtype for whom the proteomic data were available. Depressive subtypes were previously established using a data-driven analysis, and 171 serum proteins were measured on a multi-analyte profiling platform. Linear regression models were adjusted for several covariates and corrected for multiple testing using false discovery rate q-values. We observed differences in analytes between the atypical and melancholic subtypes (9 analytes, q<0.05) and between atypical depression and controls (23 analytes, q<0.05). Eight of the nine markers differing between the atypical and melancholic subtype overlapped with markers from the comparison between atypical subtype and controls (mesothelin, leptin, IGFBP1, IGFBP2, FABPa, insulin, C3 and B2M), and were mainly involved in cellular communication and signal transduction, and immune response. No markers differed significantly between the melancholic subtype and controls. To conclude, although some uncertainties exist in our results as a result of missing data imputation and lack of proteomic replication samples, many of the identified analytes are inflammatory or metabolic markers, which supports the notion of atypical depression as a syndrome characterized by metabolic disturbances and inflammation, and underline the importance and relevance of subtypes of depression in biological and genetic research, and potentially in the treatment of depression. PMID:27404283

  20. A systematic review on the effect of sweeteners on glycemic response and clinically relevant outcomes

    PubMed Central

    2011-01-01

    Background The major metabolic complications of obesity and type 2 diabetes may be prevented and managed with dietary modification. The use of sweeteners that provide little or no calories may help to achieve this objective. Methods We did a systematic review and network meta-analysis of the comparative effectiveness of sweetener additives using Bayesian techniques. MEDLINE, EMBASE, CENTRAL and CAB Global were searched to January 2011. Randomized trials comparing sweeteners in obese, diabetic, and healthy populations were selected. Outcomes of interest included weight change, energy intake, lipids, glycated hemoglobin, markers of insulin resistance and glycemic response. Evidence-based items potentially indicating risk of bias were assessed. Results Of 3,666 citations, we identified 53 eligible randomized controlled trials with 1,126 participants. In diabetic participants, fructose reduced 2-hour blood glucose concentrations by 4.81 mmol/L (95% CI 3.29, 6.34) compared to glucose. Two-hour blood glucose concentration data comparing hypocaloric sweeteners to sucrose or high fructose corn syrup were inconclusive. Based on two ≤10-week trials, we found that non-caloric sweeteners reduced energy intake compared to the sucrose groups by approximately 250-500 kcal/day (95% CI 153, 806). One trial found that participants in the non-caloric sweetener group had a decrease in body mass index compared to an increase in body mass index in the sucrose group (-0.40 vs 0.50 kg/m2, and -1.00 vs 1.60 kg/m2, respectively). No randomized controlled trials showed that high fructose corn syrup or fructose increased levels of cholesterol relative to other sweeteners. Conclusions Considering the public health importance of obesity and its consequences; the clearly relevant role of diet in the pathogenesis and maintenance of obesity; and the billions of dollars spent on non-caloric sweeteners, little high-quality clinical research has been done. Studies are needed to determine the role

  1. Rapid, accurate, and comparative differentiation of clinically and industrially relevant microorganisms via multiple vibrational spectroscopic fingerprinting.

    PubMed

    Muhamadali, Howbeer; Subaihi, Abdu; Mohammadtaheri, Mahsa; Xu, Yun; Ellis, David I; Ramanathan, Rajesh; Bansal, Vipul; Goodacre, Royston

    2016-08-15

    Despite the fact that various microorganisms (e.g., bacteria, fungi, viruses, etc.) have been linked with infectious diseases, their crucial role towards sustaining life on Earth is undeniable. The huge biodiversity, combined with the wide range of biochemical capabilities of these organisms, have always been the driving force behind their large number of current, and, as of yet, undiscovered future applications. The presence of such diversity could be said to expedite the need for the development of rapid, accurate and sensitive techniques which allow for the detection, differentiation, identification and classification of such organisms. In this study, we employed Fourier transform infrared (FT-IR), Raman, and surface enhanced Raman scattering (SERS) spectroscopies, as molecular whole-organism fingerprinting techniques, combined with multivariate statistical analysis approaches for the classification of a range of industrial, environmental or clinically relevant bacteria (P. aeruginosa, P. putida, E. coli, E. faecium, S. lividans, B. subtilis, B. cereus) and yeast (S. cerevisiae). Principal components-discriminant function analysis (PC-DFA) scores plots of the spectral data collected from all three techniques allowed for the clear differentiation of all the samples down to sub-species level. The partial least squares-discriminant analysis (PLS-DA) models generated using the SERS spectral data displayed lower accuracy (74.9%) when compared to those obtained from conventional Raman (97.8%) and FT-IR (96.2%) analyses. In addition, whilst background fluorescence was detected in Raman spectra for S. cerevisiae, this fluorescence was quenched when applying SERS to the same species, and conversely SERS appeared to introduce strong fluorescence when analysing P. putida. It is also worth noting that FT-IR analysis provided spectral data of high quality and reproducibility for the whole sample set, suggesting its applicability to a wider range of samples, and perhaps the

  2. Chronic Obstructive Pulmonary Disease Subtypes. Transitions over Time

    PubMed Central

    Esteban, Cristóbal; Arostegui, Inmaculada; Aburto, Myriam; Moraza, Javier; Quintana, José M.; García-Loizaga, Amaia; Basualdo, Luis V.; Aramburu, Amaia; Aizpiri, Susana; Uranga, Ane; Capelastegui, Alberto

    2016-01-01

    Background Although subtypes of chronic obstructive pulmonary disease are recognized, it is unknown what happens to these subtypes over time. Our objectives were to assess the stability of cluster-based subtypes in patients with stable disease and explore changes in clusters over 1 year. Methods Multiple correspondence and cluster analysis were used to evaluate data collected from 543 stable patients included consecutively from 5 respiratory outpatient clinics. Results Four subtypes were identified. Three of them, A, B, and C, had marked respiratory profiles with a continuum in severity of several variables, while the fourth, subtype D, had a more systemic profile with intermediate respiratory disease severity. Subtype A was associated with less dyspnea, better health-related quality of life and lower Charlson comorbidity scores, and subtype C with the most severe dyspnea, and poorer pulmonary function and quality of life, while subtype B was between subtypes A and C. Subtype D had higher rates of hospitalization the previous year, and comorbidities. After 1 year, all clusters remained stable. Generally, patients continued in the same subtype but 28% migrated to another cluster. Together with movement across clusters, patients showed changes in certain characteristics (especially exercise capacity, some variables of pulmonary function and physical activity) and changes in outcomes (quality of life, hospitalization and mortality) depending on the new cluster they belonged to. Conclusions Chronic obstructive pulmonary disease clusters remained stable over 1 year. Most patients stayed in their initial subtype cluster, but some moved to another subtype and accordingly had different outcomes. PMID:27611911

  3. eMBI: Boosting Gene Expression-based Clustering for Cancer Subtypes.

    PubMed

    Chang, Zheng; Wang, Zhenjia; Ashby, Cody; Zhou, Chuan; Li, Guojun; Zhang, Shuzhong; Huang, Xiuzhen

    2014-01-01

    Identifying clinically relevant subtypes of a cancer using gene expression data is a challenging and important problem in medicine, and is a necessary premise to provide specific and efficient treatments for patients of different subtypes. Matrix factorization provides a solution by finding checker-board patterns in the matrices of gene expression data. In the context of gene expression profiles of cancer patients, these checkerboard patterns correspond to genes that are up- or down-regulated in patients with particular cancer subtypes. Recently, a new matrix factorization framework for biclustering called Maximum Block Improvement (MBI) is proposed; however, it still suffers several problems when applied to cancer gene expression data analysis. In this study, we developed many effective strategies to improve MBI and designed a new program called enhanced MBI (eMBI), which is more effective and efficient to identify cancer subtypes. Our tests on several gene expression profiling datasets of cancer patients consistently indicate that eMBI achieves significant improvements in comparison with MBI, in terms of cancer subtype prediction accuracy, robustness, and running time. In addition, the performance of eMBI is much better than another widely used matrix factorization method called nonnegative matrix factorization (NMF) and the method of hierarchical clustering, which is often the first choice of clinical analysts in practice. PMID:25374455

  4. Copper and Anesthesia: Clinical Relevance and Management of Copper Related Disorders

    PubMed Central

    Langley, Adrian; Dameron, Charles T.

    2013-01-01

    Recent research has implicated abnormal copper homeostasis in the underlying pathophysiology of several clinically important disorders, some of which may be encountered by the anesthetist in daily clinical practice. The purpose of this narrative review is to summarize the physiology and pharmacology of copper, the clinical implications of abnormal copper metabolism, and the subsequent influence of altered copper homeostasis on anesthetic management. PMID:23762044

  5. Integrated Classification of Prostate Cancer Reveals a Novel Luminal Subtype with Poor Outcome.

    PubMed

    You, Sungyong; Knudsen, Beatrice S; Erho, Nicholas; Alshalalfa, Mohammed; Takhar, Mandeep; Al-Deen Ashab, Hussam; Davicioni, Elai; Karnes, R Jeffrey; Klein, Eric A; Den, Robert B; Ross, Ashley E; Schaeffer, Edward M; Garraway, Isla P; Kim, Jayoung; Freeman, Michael R

    2016-09-01

    Prostate cancer is a biologically heterogeneous disease with variable molecular alterations underlying cancer initiation and progression. Despite recent advances in understanding prostate cancer heterogeneity, better methods for classification of prostate cancer are still needed to improve prognostic accuracy and therapeutic outcomes. In this study, we computationally assembled a large virtual cohort (n = 1,321) of human prostate cancer transcriptome profiles from 38 distinct cohorts and, using pathway activation signatures of known relevance to prostate cancer, developed a novel classification system consisting of three distinct subtypes (named PCS1-3). We validated this subtyping scheme in 10 independent patient cohorts and 19 laboratory models of prostate cancer, including cell lines and genetically engineered mouse models. Analysis of subtype-specific gene expression patterns in independent datasets derived from luminal and basal cell models provides evidence that PCS1 and PCS2 tumors reflect luminal subtypes, while PCS3 represents a basal subtype. We show that PCS1 tumors progress more rapidly to metastatic disease in comparison with PCS2 or PCS3, including PSC1 tumors of low Gleason grade. To apply this finding clinically, we developed a 37-gene panel that accurately assigns individual tumors to one of the three PCS subtypes. This panel was also applied to circulating tumor cells (CTC) and provided evidence that PCS1 CTCs may reflect enzalutamide resistance. In summary, PCS subtyping may improve accuracy in predicting the likelihood of clinical progression and permit treatment stratification at early and late disease stages. Cancer Res; 76(17); 4948-58. ©2016 AACR.

  6. Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues.

    PubMed

    Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

    2015-12-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.

  7. Within-Farm Changes in Dairy Farm-Associated Salmonella Subtypes and Comparison to Human Clinical Isolates in Michigan, 2000-2001 and 2009.

    PubMed

    Habing, Greg G; Manning, Shannon; Bolin, Carole; Cui, Yuehua; Rudrik, James; Dietrich, Stephen; Kaneene, John B

    2015-09-01

    Temporal changes in the distribution of Salmonella subtypes in livestock populations may have important impacts on human health. The first objective of this research was to determine the within-farm changes in the population of subtypes of Salmonella on Michigan dairy farms that were sampled longitudinally in 2000-2001 and again in 2009. The second objective was to determine the yearly frequency (2001 through 2012) of reported human illnesses in Michigan associated with the same subtypes. Comparable sampling techniques were used to collect fecal and environmental samples from the same 18 Michigan dairy farms in 2000-2001 and 2009. Serotypes, multilocus sequence types (STs), and pulsed-field gel electrophoresis (PFGE) banding patterns were identified for isolates from 6 farms where >1 Salmonella isolate was recovered in both 2000-2001 and 2009. The distribution of STs was significantly different between time frames (P < 0.05); only two of 31 PFGE patterns were identified in both time frames, and each was recovered from the same farm in each time frame. Previously reported within-farm decreases in the frequency of multidrug-resistant (MDR) Salmonella were due to recovery of MDR subtypes of S. enterica serotypes Senftenberg and Typhimurium in 2000-2001 and genetically distinct, pansusceptible subtypes of the same serotypes in 2009. The annual frequency of human illnesses between 2001 and 2012 with a PFGE pattern matching a bovine strain decreased for patterns recovered from dairy farms in 2000-2001 and increased for patterns recovered in 2009. These data suggest important changes in the population of Salmonella on dairy farms and in the frequency of human illnesses associated with cattle-derived subtypes. PMID:26070676

  8. Within-Farm Changes in Dairy Farm-Associated Salmonella Subtypes and Comparison to Human Clinical Isolates in Michigan, 2000-2001 and 2009.

    PubMed

    Habing, Greg G; Manning, Shannon; Bolin, Carole; Cui, Yuehua; Rudrik, James; Dietrich, Stephen; Kaneene, John B

    2015-09-01

    Temporal changes in the distribution of Salmonella subtypes in livestock populations may have important impacts on human health. The first objective of this research was to determine the within-farm changes in the population of subtypes of Salmonella on Michigan dairy farms that were sampled longitudinally in 2000-2001 and again in 2009. The second objective was to determine the yearly frequency (2001 through 2012) of reported human illnesses in Michigan associated with the same subtypes. Comparable sampling techniques were used to collect fecal and environmental samples from the same 18 Michigan dairy farms in 2000-2001 and 2009. Serotypes, multilocus sequence types (STs), and pulsed-field gel electrophoresis (PFGE) banding patterns were identified for isolates from 6 farms where >1 Salmonella isolate was recovered in both 2000-2001 and 2009. The distribution of STs was significantly different between time frames (P < 0.05); only two of 31 PFGE patterns were identified in both time frames, and each was recovered from the same farm in each time frame. Previously reported within-farm decreases in the frequency of multidrug-resistant (MDR) Salmonella were due to recovery of MDR subtypes of S. enterica serotypes Senftenberg and Typhimurium in 2000-2001 and genetically distinct, pansusceptible subtypes of the same serotypes in 2009. The annual frequency of human illnesses between 2001 and 2012 with a PFGE pattern matching a bovine strain decreased for patterns recovered from dairy farms in 2000-2001 and increased for patterns recovered in 2009. These data suggest important changes in the population of Salmonella on dairy farms and in the frequency of human illnesses associated with cattle-derived subtypes.

  9. High-Fidelity Patient Simulators to Expose Undergraduate Students to the Clinical Relevance of Physiology Concepts

    ERIC Educational Resources Information Center

    Harris, David M.; Bellew, Christine; Cheng, Zixi J.; Cendán, Juan C.; Kibble, Jonathan D.

    2014-01-01

    The use of high-fidelity patient simulators (HFPSs) has expanded throughout medical, nursing, and allied health professions education in the last decades. These manikins can be programmed to represent pathological states and are used to teach clinical skills as well as clinical reasoning. First, the students are typically oriented either to the…

  10. How to Respond to a Paranoid Thought: A Comparison of Patients With Clinically Relevant Delusions and Healthy Controls in Chile.

    PubMed

    Wüsten, Caroline; Lincoln, Tania M

    2015-09-01

    Although paranoid thoughts occur frequently in the population, most people do not develop clinically relevant delusions. The main purpose of the study was to explore whether participants without a mental disorder will respond in a more functional way to paranoid thoughts and be more flexible in their cognitive processes than patients with clinically relevant delusions. The Responses to Paranoid Thoughts Scale was translated into Spanish and was completed by patients (n = 36) and healthy controls (n = 39) in Chile (South America). The Beck Cognitive Insight Scale was used to assess cognitive insight. The patients responded in a more depressive, physical, and concealing way to paranoid thoughts than the healthy controls. Moreover, they showed significantly less cognitive insight and self-reflectiveness. Higher cognitive insight and self-reflectiveness were associated with more normalizing and communicative responses to paranoid thoughts.

  11. Time-driven activity-based costing in an outpatient clinic environment: development, relevance and managerial impact.

    PubMed

    Demeere, Nathalie; Stouthuysen, Kristof; Roodhooft, Filip

    2009-10-01

    Healthcare managers are continuously urged to provide better patient services at a lower cost. To cope with these cost pressures, healthcare management needs to improve its understanding of the relevant cost drivers. Through a case study, we show how to perform a time-driven activity-based costing of five outpatient clinic's departments and provide evidence of the benefits of such an analysis. PMID:19505741

  12. Assessing Interpersonal Subtypes in Depression.

    PubMed

    Simon, Sarah; Cain, Nicole M; Wallner Samstag, Lisa; Meehan, Kevin B; Muran, J Christopher

    2015-01-01

    The context-free diagnoses outlined by the Diagnostic and Statistical Manual of Mental Disorders might not provide enough information to represent the heterogeneity observed in depressed patients. Interpersonal factors have been linked to depression in a mutually influencing pathoplastic relationship where certain problems, like submissiveness, are related to symptom chronicity. This study evaluated interpersonal pathoplasticity in a range of depressive presentations. We examined archival data collected from 407 participants who met criteria for major depressive disorder (MDD), dysthymic disorder (DD), or subthreshold depression (sD). Latent profile analysis (LPA) identified 5 interpersonal subtypes (vindictive, intrusive, socially avoidant, exploitable, and cold). Apart from gender, the subtypes did not differ significantly on demographic characteristics, psychiatric comorbidity, or self-report depression severity. Socially avoidant participants were more likely to meet criteria for a clinical depression diagnosis (MDD or DD), whereas vindictive participants were more likely to have sD. Our results indicate that interpersonal problems could account for heterogeneity observed in depression.

  13. Effects of clinically relevant doses of methyphenidate on spatial memory, behavioral sensitization and open field habituation: a time related study.

    PubMed

    Haleem, Darakhshan Jabeen; Inam, Qurrat-ul-Aen; Haleem, Muhammad Abdul

    2015-03-15

    The psychostimulant methylphenidate (MPD) is a first-line drug for the treatment of attention deficit hyperactivity disorder (ADHD). Despite acceptable therapeutic efficacy, there is limited data regarding the long-term consequences of MPD exposure over extended periods. The present study concerns effects of clinically relevant doses of MPD, administered orally to rats for an extended period, on spatial memory, behavioral sensitization and habituation to an open field. Water maze test was used to monitor memory acquisition (2 h after training), retention (day next to training), extinction (1 week after training) and reconsolidation (weekly for 4 weeks). Administration of MPD at doses of 0.25-1.0 mg/kg improved memory acquisition, retention, reconsolidation and impaired memory extinction. Treatment with 0.25 and 0.5 mg/kg MPD for 6 weeks produced a sustained increase in motor activity but higher dose (1.0 mg/kg) elicited behavioral sensitization. High as well as low doses MPD impaired open field habituation. We conclude that clinically relevant doses of MPD enhance memory even if used for extended period. It is suggested that higher (1.0 mg/kg) clinically relevant doses of MPD, if used for extended period, may exacerbate hyperactivity and impulsivity associated with the disease.

  14. Opioid-induced hyperalgesia: is it clinically relevant for the treatment of pain patients?

    PubMed

    Raffa, Robert B; Pergolizzi, Joseph V

    2013-09-01

    There is a curious and paradoxic phenomenon, reliably demonstrated in animal models, that consists of an increased sensitivity to pain that is apparently induced by the very opioid drugs used to ameliorate the pain. This phenomenon is termed "opioid-induced hyperalgesia." Whether opioid-induced hyperalgesia occurs in humans, and, if so, to what extent and consequence, is far less established. This is a critical question for attempting to treat pain. If opioid-induced hyperalgesia develops in a patient, it would masquerade as tolerance (because the clinical effectiveness of the opioid would be diminished), yet the appropriate clinical adjustment would be precisely the opposite to that of tolerance. It would be to decrease, rather than increase, the dose of opioid. We review the evidence, particularly the clinical evidence, about opioid-induced hyperalgesia and the postulated mechanisms. We conclude that given the clinical ramifications, opioid-induced hyperalgesia is one of the most understudied important aspects of opioid research.

  15. Clinical relevance of autophagic therapy in cancer: Investigating the current trends, challenges, and future prospects.

    PubMed

    Mukhopadhyay, Subhadip; Sinha, Niharika; Das, Durgesh Nandini; Panda, Prashanta Kumar; Naik, Prajna Paramita; Bhutia, Sujit Kumar

    2016-08-01

    Oncophagy (cancer-related autophagy) has a complex dual character at different stages of tumor progression. It remains an important clinical problem to unravel the reasons that propel the shift in the role of oncophagy from tumor inhibition to a protective mechanism that shields full-blown malignancy. Most treatment strategies emphasize curbing protective oncophagy while triggering the oncophagy that is lethal to tumor cells. In this review, we focus on the trends in current therapeutics as well as various challenges in clinical trials to address the oncophagic dilemma and evaluate the potential of these developing therapies. A detailed analysis of the clinical and pre-clinical scenario of the anticancer medicines highlights the various inducers and inhibitors of autophagy. The ways in which tumor stage, the microenvironment and combination drug treatment continue to play an important tactical role are discussed. Moreover, autophagy targets also play a crucial role in developing the best possible solution to this oncophagy paradox. In this review, we provide a comprehensive update on the current clinical impact of autophagy-based cancer therapeutic drugs and try to lessen the gap between translational medicine and clinical science.

  16. Clinical proteomic biomarkers: relevant issues on study design & technical considerations in biomarker development

    PubMed Central

    2014-01-01

    Biomarker research is continuously expanding in the field of clinical proteomics. A combination of different proteomic–based methodologies can be applied depending on the specific clinical context of use. Moreover, current advancements in proteomic analytical platforms are leading to an expansion of biomarker candidates that can be identified. Specifically, mass spectrometric techniques could provide highly valuable tools for biomarker research. Ideally, these advances could provide with biomarkers that are clinically applicable for disease diagnosis and/ or prognosis. Unfortunately, in general the biomarker candidates fail to be implemented in clinical decision making. To improve on this current situation, a well-defined study design has to be established driven by a clear clinical need, while several checkpoints between the different phases of discovery, verification and validation have to be passed in order to increase the probability of establishing valid biomarkers. In this review, we summarize the technical proteomic platforms that are available along the different stages in the biomarker discovery pipeline, exemplified by clinical applications in the field of bladder cancer biomarker research. PMID:24679154

  17. Clinical Performance of a New Soluble CD14-Subtype Immunochromatographic Test for Whole Blood Compared with Chemiluminescent Enzyme Immunoassay: Use of Quantitative Soluble CD14-Subtype Immunochromatographic Tests for the Diagnosis of Sepsis

    PubMed Central

    Sato, Masayuki; Takahashi, Gaku; Shibata, Shigehiro; Onodera, Makoto; Suzuki, Yasushi; Inoue, Yoshihiro; Endo, Shigeatsu

    2015-01-01

    We previously reported that a soluble CD14-subtype (sCD14-ST) immunochromatographic test (ICT) for plasma is more convenient than chemiluminescent enzyme immunoassay (CLEIA), but plasma separation makes bedside measurements difficult. We developed a new sCD14-ST ICT for whole blood and investigated whether quantitative determinations of sCD14-ST by ICT were useful for diagnosing sepsis and severe sepsis/septic shock. We studied 20 patients who fulfilled two or more systemic inflammatory response syndrome (SIRS) criteria and 32 patients who had been diagnosed with sepsis or severe sepsis/septic shock. Whole blood was collected on day 0 (on admission) and day 7, and the sCD14-ST concentration was quantitatively measured by CLEIA and ICT for whole blood. The patients’ Acute Physiology and Chronic Health Evaluation (APACHE) II, Sequential Organ Failure Assessment (SOFA), and Mortality in Emergency Department Sepsis (MEDS) scores were also calculated. The cut-off values obtained by the quantitative measurements made by ICT were 464.5 pg/mL for sepsis and 762.7 pg/mL for severe sepsis/septic shock (P < 0.0001). A Bland–Altman plot showed that no fixed bias or proportional bias was detected between CLEIA and quantitative ICT for whole blood. sCD14-ST concentrations were significantly correlated with APACHE II, SOFA, and MEDS scores (P < 0.0001). These results suggest that the new sCD14-ST ICT for whole blood may be a useful tool for the convenient, rapid bedside diagnosis and treatment of sepsis. PMID:26623644

  18. Study of photoacoustic measurement of bone health based on clinically relevant models

    NASA Astrophysics Data System (ADS)

    Feng, Ting; Kozloff, Ken; Cao, Meng; Cheng, Qian; Yuan, Jie; Wang, Xueding

    2016-02-01

    Photoacoustic (PA) technique involving both ultrasound and light has been explored for potential application in the assessment of bone health. The optical and ultrasound penetration in bone have been studied. The feasibility of conducting 3D PA imaging of bone, and performing quantitative evaluation of bone microstructures by using photoacoustic spectrum analysis (PASA) has also been investigated. The findings from the experiments demonstrate that PA measurement could offer information of bone mineral density and bone microstructure, both relevant to bone health.

  19. Subtyping Stuttering II: Contributions from Language and Temperament

    ERIC Educational Resources Information Center

    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,…

  20. Development and application of two independent real-time PCR assays to detect clinically relevant Mucorales species.

    PubMed

    Springer, Jan; Goldenberger, Daniel; Schmidt, Friderike; Weisser, Maja; Wehrle-Wieland, Elisabeth; Einsele, Hermann; Frei, Reno; Löffler, Jürgen

    2016-03-01

    PCR-based detection of Mucorales species could improve diagnosis of suspected invasive fungal infection, leading to a better patient outcome. This study describes two independent probe-based real-time PCR tests for detection of clinically relevant Mucorales, targeting specific fragments of the 18S and the 28S rRNA genes. Both assays have a short turnaround time, allow fast, specific and very sensitive detection of clinically relevant Mucorales and have the potential to be used as quantitative tests. They were validated on various clinical samples (fresh and formalin-fixed paraffin-embedded specimens, mainly biopsies, n = 17). The assays should be used as add-on tools to complement standard techniques; a combined approach of both real-time PCR assays has 100 % sensitivity. Genus identification by subsequent sequencing is possible for amplicons of the 18S PCR assay. In conclusion, combination of the two independent Mucorales assays described in this study, 18S and 28S, detected all clinical samples associated with proven Mucorales infection (n = 10). Reliable and specific identification of Mucorales is a prerequisite for successful antifungal therapy as these fungi show intrinsic resistance to voriconazole and caspofungin.

  1. Molecular subtypes and imaging phenotypes of breast cancer

    PubMed Central

    2016-01-01

    During the last 15 years, traditional breast cancer classifications based on histopathology have been reorganized into the luminal A, luminal B, human epidermal growth factor receptor 2 (HER2), and basal-like subtypes based on gene expression profiling. Each molecular subtype has shown varying risk for progression, response to treatment, and survival outcomes. Research linking the imaging phenotype with the molecular subtype has revealed that non-calcified, relatively circumscribed masses with posterior acoustic enhancement are common in the basal-like subtype, spiculated masses with a poorly circumscribed margin and posterior acoustic shadowing in the luminal subtype, and pleomorphic calcifications in the HER2-enriched subtype. Understanding the clinical implications of the molecular subtypes and imaging phenotypes could help radiologists guide precision medicine, tailoring medical treatment to patients and their tumor characteristics. PMID:27599892

  2. Miniature Swine as a Clinically Relevant Model of Graft-Versus-Host Disease

    PubMed Central

    Duran-Struuck, Raimon; Huang, Christene A; Orf, Katherine; Bronson, Roderick T; Sachs, David H; Spitzer, Thomas R

    2015-01-01

    Miniature swine provide a preclinical model of hematopoietic cell transplantation (HCT) for studies of graft-versus-host disease. HCT between MHC-matched or ‑mismatched pigs can be performed to mimic clinical scenarios with outcomes that closely resemble those observed in human HCT recipients. With myeloablative conditioning, HCT across MHC barriers is typically fatal, with pigs developing severe (grade III or IV) GVHD involving the gastrointestinal tract, liver, and skin. Unlike rodent models, miniature swine provide an opportunity to perform extended longitudinal studies on individual animals, because multiple tissue biopsies can be harvested without the need for euthanasia. In addition, we have developed a swine GVHD scoring system that parallels that used in the human clinical setting. Given the similarities of GVHD in pigs and humans, we hope that the use of this scoring system facilitates clinical and scientific discourse between the laboratory and the clinic. We anticipate that results of swine studies will support the development of new strategies to improve the identification and treatment of GVHD in clinical HCT scenarios. PMID:26473348

  3. Miniature Swine as a Clinically Relevant Model of Graft-Versus-Host Disease.

    PubMed

    Duran-Struuck, Raimon; Huang, Christene A; Orf, Katherine; Bronson, Roderick T; Sachs, David H; Spitzer, Thomas R

    2015-10-01

    Miniature swine provide a preclinical model of hematopoietic cell transplantation (HCT) for studies of graft-versus-host disease. HCT between MHC-matched or -mismatched pigs can be performed to mimic clinical scenarios with outcomes that closely resemble those observed in human HCT recipients. With myeloablative conditioning, HCT across MHC barriers is typically fatal, with pigs developing severe (grade III or IV) GVHD involving the gastrointestinal tract, liver, and skin. Unlike rodent models, miniature swine provide an opportunity to perform extended longitudinal studies on individual animals, because multiple tissue biopsies can be harvested without the need for euthanasia. In addition, we have developed a swine GVHD scoring system that parallels that used in the human clinical setting. Given the similarities of GVHD in pigs and humans, we hope that the use of this scoring system facilitates clinical and scientific discourse between the laboratory and the clinic. We anticipate that results of swine studies will support the development of new strategies to improve the identification and treatment of GVHD in clinical HCT scenarios. PMID:26473348

  4. Subtype stability in schizophrenia.

    PubMed

    Kendler, K S; Gruenberg, A M; Tsuang, M T

    1985-07-01

    The authors examine the long-term stability of the subtypes of schizophrenia defined by four diagnostic systems. When all patients were considered, agreement between subtype assigned at index and follow-up was modest. This agreement increased considerably when only patients diagnosed as paranoid, hebephrenic, or catatonic at both index and follow-up were considered. As for individual subtypes, stability was highest for paranoid schizophrenia, intermediate for hebephrenia, and virtually absent for undifferentiated schizophrenia. The stability of paranoid schizophrenia was greatest when onset occurred after age 30. As length of follow-up increased, a larger proportion of patients were diagnosed as undifferentiated or residual.

  5. The relevance of clinical balance assessment tools to differentiate balance deficits

    PubMed Central

    Mancini, Martina; Horak, Fay B

    2011-01-01

    Control of balance is complex and involves maintaining postures, facilitating movement, and recovering equilibrium. Balance control consists of controlling the body center of mass over its limits of stability. Clinical balance assessment can help assess fall risk and/or determine the underlying reasons for balance disorders. Most functional balance assessment scales assess fall risk and the need for balance rehabilitation but do not differentiate types of balance deficits. A system approach to clinical balance assessment can differentiate different kinds of balance disorders and a physiological approach can determine underlying sensorimotor mechanisms contributing to balance disorders. Objective measures of balance using computerized systems and wearable inertial sensors can bring more sensitive, specific and responsive balance testing to clinical practice. PMID:20485226

  6. A new cognitive evaluation battery for Down syndrome and its relevance for clinical trials

    PubMed Central

    de Sola, Susana; de la Torre, Rafael; Sánchez-Benavides, Gonzalo; Benejam, Bessy; Cuenca-Royo, Aida; del Hoyo, Laura; Rodríguez, Joan; Catuara-Solarz, Silvina; Sanchez-Gutierrez, Judit; Dueñas-Espin, Ivan; Hernandez, Gimena; Peña-Casanova, Jordi; Langohr, Klaus; Videla, Sebastia; Blehaut, Henry; Farre, Magi; Dierssen, Mara; Cuenca-Royo, Aida

    2015-01-01

    The recent prospect of pharmaceutical interventions for cognitive impairment of Down syndrome (DS) has boosted a number of clinical trials in this population. However, running the trials has raised some methodological challenges and questioned the prevailing methodology used to evaluate cognitive functioning of DS individuals. This is usually achieved by comparing DS individuals to matched healthy controls of the same mental age. We propose a new tool, the TESDAD Battery that uses comparison with age-matched typically developed adults. This is an advantageous method for probing the clinical efficacy of DS therapies, allowing the interpretation and prediction of functional outcomes in clinical trials. In our DS population the TESDAD battery permitted a quantitative assessment of cognitive defects, which indicated language dysfunction and deficits in executive function, as the most important contributors to other cognitive and adaptive behavior outcomes as predictors of functional change in DS. Concretely, auditory comprehension and functional academics showed the highest potential as end-point measures of therapeutic intervention for clinical trials: the former as a cognitive key target for therapeutic intervention, and the latter as a primary functional outcome measure of clinical efficacy. Our results also emphasize the need to explore the modulating effects of IQ, gender and age on cognitive enhancing treatments. Noticeably, women performed significantly better than men of the same age and IQ in most cognitive tests, with the most consistent differences occurring in memory and executive functioning and negative trends rarely emerged on quality of life linked to the effect of age after adjusting for IQ and gender. In sum, the TESDAD battery is a useful neurocognitive tool for probing the clinical efficacy of experimental therapies in interventional studies in the DS population suggesting that age-matched controls are advantageous for determining normalization of

  7. A new cognitive evaluation battery for Down syndrome and its relevance for clinical trials.

    PubMed

    de Sola, Susana; de la Torre, Rafael; Sánchez-Benavides, Gonzalo; Benejam, Bessy; Cuenca-Royo, Aida; Del Hoyo, Laura; Rodríguez, Joan; Catuara-Solarz, Silvina; Sanchez-Gutierrez, Judit; Dueñas-Espin, Ivan; Hernandez, Gimena; Peña-Casanova, Jordi; Langohr, Klaus; Videla, Sebastia; Blehaut, Henry; Farre, Magi; Dierssen, Mara

    2015-01-01

    The recent prospect of pharmaceutical interventions for cognitive impairment of Down syndrome (DS) has boosted a number of clinical trials in this population. However, running the trials has raised some methodological challenges and questioned the prevailing methodology used to evaluate cognitive functioning of DS individuals. This is usually achieved by comparing DS individuals to matched healthy controls of the same mental age. We propose a new tool, the TESDAD Battery that uses comparison with age-matched typically developed adults. This is an advantageous method for probing the clinical efficacy of DS therapies, allowing the interpretation and prediction of functional outcomes in clinical trials. In our DS population the TESDAD battery permitted a quantitative assessment of cognitive defects, which indicated language dysfunction and deficits in executive function, as the most important contributors to other cognitive and adaptive behavior outcomes as predictors of functional change in DS. Concretely, auditory comprehension and functional academics showed the highest potential as end-point measures of therapeutic intervention for clinical trials: the former as a cognitive key target for therapeutic intervention, and the latter as a primary functional outcome measure of clinical efficacy. Our results also emphasize the need to explore the modulating effects of IQ, gender and age on cognitive enhancing treatments. Noticeably, women performed significantly better than men of the same age and IQ in most cognitive tests, with the most consistent differences occurring in memory and executive functioning and negative trends rarely emerged on quality of life linked to the effect of age after adjusting for IQ and gender. In sum, the TESDAD battery is a useful neurocognitive tool for probing the clinical efficacy of experimental therapies in interventional studies in the DS population suggesting that age-matched controls are advantageous for determining normalization of

  8. A new cognitive evaluation battery for Down syndrome and its relevance for clinical trials.

    PubMed

    de Sola, Susana; de la Torre, Rafael; Sánchez-Benavides, Gonzalo; Benejam, Bessy; Cuenca-Royo, Aida; Del Hoyo, Laura; Rodríguez, Joan; Catuara-Solarz, Silvina; Sanchez-Gutierrez, Judit; Dueñas-Espin, Ivan; Hernandez, Gimena; Peña-Casanova, Jordi; Langohr, Klaus; Videla, Sebastia; Blehaut, Henry; Farre, Magi; Dierssen, Mara

    2015-01-01

    The recent prospect of pharmaceutical interventions for cognitive impairment of Down syndrome (DS) has boosted a number of clinical trials in this population. However, running the trials has raised some methodological challenges and questioned the prevailing methodology used to evaluate cognitive functioning of DS individuals. This is usually achieved by comparing DS individuals to matched healthy controls of the same mental age. We propose a new tool, the TESDAD Battery that uses comparison with age-matched typically developed adults. This is an advantageous method for probing the clinical efficacy of DS therapies, allowing the interpretation and prediction of functional outcomes in clinical trials. In our DS population the TESDAD battery permitted a quantitative assessment of cognitive defects, which indicated language dysfunction and deficits in executive function, as the most important contributors to other cognitive and adaptive behavior outcomes as predictors of functional change in DS. Concretely, auditory comprehension and functional academics showed the highest potential as end-point measures of therapeutic intervention for clinical trials: the former as a cognitive key target for therapeutic intervention, and the latter as a primary functional outcome measure of clinical efficacy. Our results also emphasize the need to explore the modulating effects of IQ, gender and age on cognitive enhancing treatments. Noticeably, women performed significantly better than men of the same age and IQ in most cognitive tests, with the most consistent differences occurring in memory and executive functioning and negative trends rarely emerged on quality of life linked to the effect of age after adjusting for IQ and gender. In sum, the TESDAD battery is a useful neurocognitive tool for probing the clinical efficacy of experimental therapies in interventional studies in the DS population suggesting that age-matched controls are advantageous for determining normalization of

  9. Clinical relevance of β₂-glycoprotein-I plasma levels in antiphospholipid syndrome (APS).

    PubMed

    Banzato, Alessandra; Pengo, Vittorio

    2014-06-01

    Antiphospholipid syndrome (APS) is characterized by the presence of antiphospholipid (aPL) antibodies associated with thrombosis or pregnancy morbidity. The antibodies mainly involved in this disorder are directed against β2-glycoprotein I (β2-GPI). β2-GPI plasma level is usually not reported in studies on APS, because it is not regarded as relevant to the diagnosis and prognosis of APS. Nevertheless its measurement may be important for understanding the pathophysiology of the syndrome. This review summarizes available data from the literature on plasma concentrations of β2-GPI in patients with different antibody profiles.

  10. Comparative pathogenesis of a subtype A with a subtype B avian pneumovirus in turkeys.

    PubMed

    Van de Zande, S; Nauwynck, H; De Jonghe, S; Pensaert, M

    1999-06-01

    This paper describes a study in which the pathogenesis of avian pneumovirus strains, isolated in Belgium, and belonging to the two subtypes A and B, were compared in 2-week-old turkeys. After oculonasal inoculation, animals were either observed for clinical signs or killed for pathological and virological examination. Virus titration and immunofluorescence were performed on the conjunctivae, turbinates, sinuses, upper and lower part of the trachea, lungs and air sacs. No differences were seen between the two subtypes concerning respiratory signs, or macroscopic and microscopic lesions in the respiratory tract. Slight variations were found in site and extent of virus replication. First, only subtype A was able to invade the lower parts of the respiratory tract (bronchi), whereas viral antigens were not detected in the lungs with subtype B. Secondly, the subtype A strain infected two times more epithelial cells at all levels of the upper respiratory tract compared to subtype B. Thirdly, the amount of virus produced at different sites along the respiratory tract was lower in subtype B-inoculated turkeys than in subtype A-inoculated ones.

  11. Determination of Clinically Relevant Content for a Musculoskeletal Anatomy Curriculum for Physical Medicine and Rehabilitation Residents

    ERIC Educational Resources Information Center

    Lisk, Kristina; Flannery, John F.; Loh, Eldon Y.; Richardson, Denyse; Agur, Anne M. R.; Woods, Nicole N.

    2014-01-01

    To address the need for more clinical anatomy training in residency education, many postgraduate programs have implemented structured anatomy courses into their curriculum. Consensus often does not exist on specific content and level of detail of the content that should be included in such curricula. This article describes the use of the Delphi…

  12. [Chronic cervical vagal stimulation. Mechanisms of action and clinical relevance for heart failure].

    PubMed

    Kuschyk, J; Doesch, C; Akin, I; Borggrefe, M; Roeger, S

    2015-11-01

    Increased sympathetic nerve activity and reduced vagal activity are associated with increased mortality in patients after myocardial infarction and patients with chronic heart failure; furthermore, vagal withdrawal has been documented to precede acute decompensation. Experimental studies have indicated that increased parasympathetic activity by means of vagal stimulation may reduce mortality in animal models of postinfarction sudden cardiac death and of chronic heart failure. First clinical results have demonstrated that chronic vagus nerve stimulation in heart failure patients with severe systolic dysfunction appears to be safe and tolerable and may improve the quality of life and left ventricular (LV) function. Vagus nerve stimulation gives rise to these potential clinical benefits by multiple mechanisms of action, including reduced heart rate, restoration of heart rate variability and baroreflex sensitivity, suppression of proinflammatory cytokines and antiarrhythmic effects. First clinical results suggest that vagal nerve stimulation is safe and tolerable and could lead to a marked clinical improvement but discrepancies in the findings due to different study designs warrant further discussion. PMID:26555481

  13. Bridging the Divide: Sustainability and Relevance of a Distance Learning Module for Clinical Officers in Tanzania

    ERIC Educational Resources Information Center

    Brigley, Stephen; Hosein, I.; Myemba, I. R.

    2009-01-01

    This paper reports on work by a team from Wales, supported by UNESCO Cymru-Wales, to develop a distance learning module for Tanzanian clinical officers (COs) on the syndromic management and counselling of sexually transmissible infection (STI) and HIV patients. Preparation included documentary analysis and a questionnaire survey to ascertain COs'…

  14. Cato Guldberg and Peter Waage, the history of the Law of Mass Action, and its relevance to clinical pharmacology.

    PubMed

    Ferner, Robin E; Aronson, Jeffrey K

    2016-01-01

    We have traced the historical link between the Law of Mass Action and clinical pharmacology. The Law evolved from the work of the French chemist Claude Louis Berthollet, was first formulated by Cato Guldberg and Peter Waage in 1864 and later clarified by the Dutch chemist Jacobus van 't Hoff in 1877. It has profoundly influenced our qualitative and quantitative understanding of a number of physiological and pharmacological phenomena. According to the Law of Mass Action, the velocity of a chemical reaction depends on the concentrations of the reactants. At equilibrium the concentrations of the chemicals involved bear a constant relation to each other, described by the equilibrium constant, K. The Law of Mass Action is relevant to various physiological and pharmacological concepts, including concentration-effect curves, dose-response curves, and ligand-receptor binding curves, all of which are important in describing the pharmacological actions of medications, the Langmuir adsorption isotherm, which describes the binding of medications to proteins, activation curves for transmembrane ion transport, enzyme inhibition and the Henderson-Hasselbalch equation, which describes the relation between pH, as a measure of acidity and the concentrations of the contributory acids and bases. Guldberg and Waage recognized the importance of dynamic equilibrium, while others failed to do so. Their ideas, over 150 years old, are embedded in and still relevant to clinical pharmacology. Here we explain the ideas and in a subsequent paper show how they are relevant to understanding adverse drug reactions.

  15. The Facts About Sexual (Dys)function in Schizophrenia: An Overview of Clinically Relevant Findings

    PubMed Central

    de Boer, Marrit K.; Castelein, Stynke; Wiersma, Durk; Schoevers, Robert A.; Knegtering, Henderikus

    2015-01-01

    A limited number of studies have evaluated sexual functioning in patients with schizophrenia. Most patients show an interest in sex that differs little from the general population. By contrast, psychiatric symptoms, institutionalization, and psychotropic medication contribute to frequently occurring impairments in sexual functioning. Women with schizophrenia have a better social outcome, longer lasting (sexual) relationships, and more offspring than men with schizophrenia. Still, in both sexes social and interpersonal impairments limit the development of stable sexual relationships. Although patients consider sexual problems to be highly relevant, patients and clinicians not easily discuss these spontaneously, leading to an underestimation of their prevalence and contributing to decreased adherence to treatment. Studies using structured interviews or questionnaires result in many more patients reporting sexual dysfunctions. Although sexual functioning can be impaired by different factors, the use of antipsychotic medication seems to be an important factor. A comparison of different antipsychotics showed high frequencies of sexual dysfunction for risperidone and classical antipsychotics, and lower frequencies for clozapine, olanzapine, quetiapine, and aripiprazole. Postsynaptic dopamine antagonism, prolactin elevation, and α1-receptor blockade may be the most relevant factors in the pathogenesis of antipsychotic-induced sexual dysfunction. Psychosocial strategies to treat antipsychotic-induced sexual dysfunction include psychoeducation and relationship counseling. Pharmacological strategies include lowering the dose or switching to a prolactin sparing antipsychotic. Also, the addition of a dopamine agonist, aripiprazole, or a phosphodiesterase-5 inhibitor has shown some promising results, but evidence is currently scarce. PMID:25721311

  16. Sex offending and sexual appetite: the clinical and theoretical relevance of hypersexual desire.

    PubMed

    Kafka, Martin P

    2003-08-01

    Disinhibited sexual desire, clinically manifested as hypersexual desire disorders, can be operationally defined by considering three behavioral domains associated with sexual motivation or appetitive behavior: (a) sexual preoccupation (time/day consumed by fantasies, urges, and activities), (b) the repetitive frequency of enacted sexual behavior (total sexual outlet/week), and (c) adverse consequences associated with repetitive sexual behavior: Data are presented suggesting that clinical samples of males with paraphilias, paraphilia-related disorders, and sexual coercion may be associated with disinhibited sexual appetite. These conditions need to be addressed by an integrated combination of psychotherapeutic and psychopharmacologic interventions that specifically target disinhibited sexual appetitive behaviors, their antecedents, and consequences. Although combination therapies (empirically based specific psychotherapies in conjunction with psychopharmacological treatments) have demonstrated superior efficacy in many Axis I psychiatric disorders, such combination therapies to reduce paraphilias, paraphilia-related disorders, and adult sexual coercion are currently underutilized in both North and South America and Europe.

  17. [Basic symptoms in schizophrenia, their clinical study and relevance in research].

    PubMed

    Miret, Salvador; Fatjó-Vilas, Mar; Peralta, Víctor; Fañanás, Lourdes

    2016-01-01

    Basic symptoms consist of subtle sub-clinical disturbances subjectively experienced by schizophrenia patients. These are mainly related to drive, affect, thinking and language, perception, memory, motor action, central vegetative functions, control of cognitive processes, and stress tolerance. Initially described by Huber, from a phenomenological approach, basic symptoms are part of the earliest features of schizophrenia, and they can evolve along the course of the disorder. Their assessment during the prodromal phase of the disease (together with ultra-high risk criteria) is one of the 2 main approaches that allow the definition of states of clinical risk for the development of psychosis. The present review provides an updated view of the concept of basic symptoms, highlighting its potential value in establishing neurobiological correlates of interest in aetiopathogenic research.

  18. The Clinical Relevance of Long Non-Coding RNAs in Cancer

    PubMed Central

    Silva, Andreia; Bullock, Marc; Calin, George

    2015-01-01

    Non-coding RNAs have long been associated with cancer development and progression, and since their earliest discovery, their clinical potential in identifying and characterizing the disease has been pursued. Long non-coding (lncRNAs), a diverse class of RNA transcripts >200 nucleotides in length with limited protein coding potential, has been only modestly studied relative to other categories of non-coding RNAs. However, recent data suggests they too may be important players in cancer. In this article, we consider the value of lncRNAs in the clinical setting, and in particular their potential roles as diagnostic and prognostic markers in cancer. Furthermore, we summarize the most significant studies linking lncRNA expression in human biological samples to cancer outcomes. The diagnostic sensitivity, specificity and validity of these non-coding RNA transcripts is compared in the various biological compartments in which they have been detected including tumor tissue, whole body fluids and exosomes. PMID:26516918

  19. The Clinical Relevance of Long Non-Coding RNAs in Cancer.

    PubMed

    Silva, Andreia; Bullock, Marc; Calin, George

    2015-10-27

    Non-coding RNAs have long been associated with cancer development and progression, and since their earliest discovery, their clinical potential in identifying and characterizing the disease has been pursued. Long non-coding (lncRNAs), a diverse class of RNA transcripts >200 nucleotides in length with limited protein coding potential, has been only modestly studied relative to other categories of non-coding RNAs. However, recent data suggests they too may be important players in cancer. In this article, we consider the value of lncRNAs in the clinical setting, and in particular their potential roles as diagnostic and prognostic markers in cancer. Furthermore, we summarize the most significant studies linking lncRNA expression in human biological samples to cancer outcomes. The diagnostic sensitivity, specificity and validity of these non-coding RNA transcripts is compared in the various biological compartments in which they have been detected including tumor tissue, whole body fluids and exosomes.

  20. Circulating tumour cells as tumour biomarkers in melanoma: detection methods and clinical relevance.

    PubMed

    Khoja, L; Lorigan, P; Dive, C; Keilholz, U; Fusi, A

    2015-01-01

    Circulating tumour cells (CTCs) are cells of solid tumour origin detectable in the peripheral blood. Their occurrence is considered a prerequisite step for establishing distant metastases. Metastatic melanoma was the first malignancy in which CTCs were detected and numerous studies have been published on CTC detection in melanoma at various stages of disease. In spite of this, there is no general consensus as to the clinical utility of CTCs in melanoma, largely due to conflicting results from heterogeneous studies and discrepancies in methods of detection between studies. In this review, we examine the possible clinical significance of CTCs in cutaneous, mucosal and ocular melanoma, focusing on detection methods and prognostic value of CTC detection.

  1. Phylogeny of the clinically relevant species of the emerging fungus Trichoderma and their antifungal susceptibilities.

    PubMed

    Sandoval-Denis, Marcelo; Sutton, Deanna A; Cano-Lira, José F; Gené, Josepa; Fothergill, Annette W; Wiederhold, Nathan P; Guarro, Josep

    2014-06-01

    A set of 73 isolates of the emerging fungus Trichoderma isolated from human and animal clinical specimens were characterized morphologically and molecularly using a multilocus sequence analysis that included the internal transcribed spacer (ITS) regions of the nuclear ribosomal DNA and fragments of the translation elongation factor 1 alpha (Tef1), endochitinase CHI18-5 (Chi18-5), and actin 1 (Act1) genes. The most frequent species was Trichoderma longibrachiatum (26%), followed by Trichoderma citrinoviride (18%), the Hypocrea lixii/Trichoderma harzianum species complex (15%), the newly described species Trichoderma bissettii (12%), and Trichoderma orientale (11%). The most common anatomical sites of isolation in human clinical specimens were the respiratory tract (40%), followed by deep tissue (30%) and superficial tissues (26%), while all the animal-associated isolates were obtained from superficial tissue samples. Susceptibilities of the isolates to eight antifungal drugs in vitro showed mostly high MICs, except for voriconazole and the echinocandins.

  2. [Basic symptoms in schizophrenia, their clinical study and relevance in research].

    PubMed

    Miret, Salvador; Fatjó-Vilas, Mar; Peralta, Víctor; Fañanás, Lourdes

    2016-01-01

    Basic symptoms consist of subtle sub-clinical disturbances subjectively experienced by schizophrenia patients. These are mainly related to drive, affect, thinking and language, perception, memory, motor action, central vegetative functions, control of cognitive processes, and stress tolerance. Initially described by Huber, from a phenomenological approach, basic symptoms are part of the earliest features of schizophrenia, and they can evolve along the course of the disorder. Their assessment during the prodromal phase of the disease (together with ultra-high risk criteria) is one of the 2 main approaches that allow the definition of states of clinical risk for the development of psychosis. The present review provides an updated view of the concept of basic symptoms, highlighting its potential value in establishing neurobiological correlates of interest in aetiopathogenic research. PMID:26774677

  3. The default network and self-generated thought: component processes, dynamic control, and clinical relevance

    PubMed Central

    Andrews-Hanna, Jessica R.; Smallwood, Jonathan; Spreng, R. Nathan

    2014-01-01

    Though only a decade has elapsed since the default network was first emphasized as being a large-scale brain system, recent years have brought great insight into the network’s adaptive functions. A growing theme highlights the default network as playing a key role in internally-directed—or self-generated—thought. Here, we synthesize recent findings from cognitive science, neuroscience, and clinical psychology to focus attention on two emerging topics as current and future directions surrounding the default network. First, we present evidence that self-generated thought is a multi-faceted construct whose component processes are supported by different subsystems within the network. Second, we highlight the dynamic nature of the default network, emphasizing its interaction with executive control systems when regulating aspects of internal thought. We conclude by discussing clinical implications of disruptions to the integrity of the network, and consider disorders when thought content becomes polarized or network interactions become disrupted or imbalanced. PMID:24502540

  4. Circulating tumour cells as tumour biomarkers in melanoma: detection methods and clinical relevance.

    PubMed

    Khoja, L; Lorigan, P; Dive, C; Keilholz, U; Fusi, A

    2015-01-01

    Circulating tumour cells (CTCs) are cells of solid tumour origin detectable in the peripheral blood. Their occurrence is considered a prerequisite step for establishing distant metastases. Metastatic melanoma was the first malignancy in which CTCs were detected and numerous studies have been published on CTC detection in melanoma at various stages of disease. In spite of this, there is no general consensus as to the clinical utility of CTCs in melanoma, largely due to conflicting results from heterogeneous studies and discrepancies in methods of detection between studies. In this review, we examine the possible clinical significance of CTCs in cutaneous, mucosal and ocular melanoma, focusing on detection methods and prognostic value of CTC detection. PMID:24907634

  5. Phylogeny of the Clinically Relevant Species of the Emerging Fungus Trichoderma and Their Antifungal Susceptibilities

    PubMed Central

    Sandoval-Denis, Marcelo; Sutton, Deanna A.; Cano-Lira, José F.; Fothergill, Annette W.; Wiederhold, Nathan P.; Guarro, Josep

    2014-01-01

    A set of 73 isolates of the emerging fungus Trichoderma isolated from human and animal clinical specimens were characterized morphologically and molecularly using a multilocus sequence analysis that included the internal transcribed spacer (ITS) regions of the nuclear ribosomal DNA and fragments of the translation elongation factor 1 alpha (Tef1), endochitinase CHI18-5 (Chi18-5), and actin 1 (Act1) genes. The most frequent species was Trichoderma longibrachiatum (26%), followed by Trichoderma citrinoviride (18%), the Hypocrea lixii/Trichoderma harzianum species complex (15%), the newly described species Trichoderma bissettii (12%), and Trichoderma orientale (11%). The most common anatomical sites of isolation in human clinical specimens were the respiratory tract (40%), followed by deep tissue (30%) and superficial tissues (26%), while all the animal-associated isolates were obtained from superficial tissue samples. Susceptibilities of the isolates to eight antifungal drugs in vitro showed mostly high MICs, except for voriconazole and the echinocandins. PMID:24719448

  6. New insights into insulin: The anti-inflammatory effect and its clinical relevance.

    PubMed

    Sun, Qiang; Li, Jia; Gao, Feng

    2014-04-15

    Hyperglycemia, a commonly exhibited metabolic disorder in critically ill patients, activates the body's inflammatory defense mechanism, causing the waterfall release of numerous inflammatory mediators and cytokines, and eventually leads to organ damage. As the only glucose-lowering hormone in the body, insulin not only alleviates the detrimental effects of hyperglycemia through its metabolic regulation, but also directly modulates inflammatory mediators and acts upon immune cells to enhance immunocompetence. In this sense, hyperglycemia is pro-inflammatory whereas insulin is anti-inflammatory. Therefore, during the past 50 years, insulin has not only been used in the treatment of diabetes, but has also been put into practical use in dealing with cardiovascular diseases and critical illnesses. This review summarizes the recent advances regarding the anti-inflammatory effects of insulin in both basic research and clinical trials, with the hope of aiding in the design of further experimental research and promoting effective insulin administration in clinical practice. PMID:24765237

  7. Stem cell transplantation therapy: controversy over ethical issues and clinical relevance.

    PubMed

    Romano, Gaetano

    2004-12-01

    The possibility of regenerating tissues would provide an effective therapeutic tool for the treatment of many pathological conditions, including neurological diseases, spinal cord injuries, cardiopathies, diabetes, hematological illnesses and genetic disorders. While stem cells may have the potential of regenerating a variety of tissues, as indicated by a number of groundbreaking but preliminary reports, ethical issues and safety considerations seem to preclude the use of human embryonic stem cells in the clinical setting. Adult stem cells might circumvent the issues posed by embryonic stem cells, although the potential plasticity of adult stem cells is under scrutiny because of many conflicting and contradictory reports in the field of stem cell research. Indeed, many aspects of the biology of stem cells are still not known. In this respect, stem cell biologists have to address several pressing issues. A better understanding of stem cell biology would almost certainly allow for the establishment of efficient and reliable cell transplantation experimental programs in the clinic.

  8. Clinically relevant variants identified in thoracic aortic aneurysm patients by research exome sequencing.

    PubMed

    Schubert, Jeffrey A; Landis, Benjamin J; Shikany, Amy R; Hinton, Robert B; Ware, Stephanie M

    2016-05-01

    Thoracic aortic aneurysm (TAA) is a genetically heterogeneous disease involving subclinical and progressive dilation of the thoracic aorta, which can lead to life-threatening complications such as dissection or rupture. Genetic testing is important for risk stratification and identification of at risk family members, and clinically available genetic testing panels have been expanding rapidly. However, when past testing results are normal, there is little evidence to guide decision-making about the indications and timing to pursue additional clinical genetic testing. Results from research based genetic testing can help inform this process. Here we present 10 TAA patients who have a family history of disease and who enrolled in research-based exome testing. Nine of these ten patients had previous clinical genetic testing that did not identify the cause of disease. We sought to determine the number of rare variants in 23 known TAA associated genes identified by research-based exome testing. In total, we found 10 rare variants in six patients. Likely pathogenic variants included a TGFB2 variant in one patient and a SMAD3 variant in another. These variants have been reported previously in individuals with similar phenotypes. Variants of uncertain significance of particular interest included novel variants in MYLK and MFAP5, which were identified in a third patient. In total, clinically reportable rare variants were found in 6/10 (60%) patients, with at least 2/10 (20%) patients having likely pathogenic variants identified. These data indicate that consideration of re-testing is important in TAA patients with previous negative or inconclusive results. PMID:26854089

  9. Trabecular bone score (TBS): available knowledge, clinical relevance, and future prospects.

    PubMed

    Bousson, V; Bergot, C; Sutter, B; Levitz, P; Cortet, B

    2012-05-01

    The diagnosis of osteoporosis rests on areal bone mineral density (BMD) measurement using DXA. Cancellous bone microarchitecture is a key determinant of bone strength but cannot be measured using DXA. To meet the need for a clinical tool capable of assessing bone microarchitecture, the TBS was developed. The TBS is a texture parameter that evaluates pixel gray-level variations in DXA images of the lumbar spine. The TBS variations may reflect bone microarchitecture. We explain the general principles used to compute the TBS, and we report the correlations between TBS and microarchitectural parameters. Several limitations of the TBS as it is used now are pointed out. We discuss data from currently available clinical studies on the ability of the TBS to identify patients with fractures and to evaluate the fracture risk. We conclude that this new index emphasizes the failure of the BMD T-score to fully capture the fragility fracture risk. However, although microarchitecture may influence the TBS, today, to the best of our understanding, there is no sufficient evidence that a TBS measurement provides reliable information on the status of the bone microarchitecture for a given patient. The TBS depends on gray-level variations and in a projectional image obtained in vivo, these variations can have many causes. Nevertheless, as clinical studies suggest that the TBS predicts the risk of fracture even after adjustment for BMD, we are encouraged to learn more about this score. Additional studies will have to be performed to assess the advantages and limitations of the TBS, in order to ensure that it is used appropriately in clinical practice.

  10. A gene signature based method for identifying subtypes and subtype-specific drivers in cancer with an application to medulloblastoma

    PubMed Central

    2013-01-01

    Background Subtypes are widely found in cancer. They are characterized with different behaviors in clinical and molecular profiles, such as survival rates, gene signature and copy number aberrations (CNAs). While cancer is generally believed to have been caused by genetic aberrations, the number of such events is tremendous in the cancer tissue and only a small subset of them may be tumorigenic. On the other hand, gene expression signature of a subtype represents residuals of the subtype-specific cancer mechanisms. Using high-throughput data to link these factors to define subtype boundaries and identify subtype-specific drivers, is a promising yet largely unexplored topic. Results We report a systematic method to automate the identification of cancer subtypes and candidate drivers. Specifically, we propose an iterative algorithm that alternates between gene expression clustering and gene signature selection. We applied the method to datasets of the pediatric cerebellar tumor medulloblastoma (MB). The subtyping algorithm consistently converges on multiple datasets of medulloblastoma, and the converged signatures and copy number landscapes are also found to be highly reproducible across the datasets. Based on the identified subtypes, we developed a PCA-based approach for subtype-specific identification of cancer drivers. The top-ranked driver candidates are found to be enriched with known pathways in certain subtypes of MB. This might reveal new understandings for these subtypes. This article is an extended abstract of our ICCABS '12 paper (Chen et al. 2012), with revised methods in iterative subtyping, the use of canonical correlation analysis for driver-identification, and an extra dataset (Northcott90 dataset) for cross-validations. Discussions of the algorithm performance and of the slightly different gene lists identified are also added. Conclusions Our study indicates that subtype-signature defines the subtype boundaries, characterizes the subtype

  11. Imaging in inflammatory bowel disease mucosal healing in ulcerative colitis: relevance for clinical outcomes.

    PubMed

    Schirbel, Anja; Sturm, Andreas

    2012-09-01

    There is growing evidence of the importance of mucosal healing (MH) in ulcerative colitis, but whether or not it should be a future primary treatment goal is still under intense discussion. Within the last decade many clinical trials have focused not only on response and remission rates but also on achievement of MH, while in clinical practice we still make treatment decisions on the basis of clinical symptoms. There is so far no internationally accepted definition of MH and the tools for assessment of MH vary from biomarkers to endoscopy with histological evaluation on the basis of several different scores and indices. This review will focus on present data dealing with methods to assess MH and the importance of MH for the future course of disease, the need for colectomy or risk of developing colorectal cancer and the patient's quality of life. Many questions remain: How and when do we best assess MH? How rapidly do we need to achieve MH? What is the optimal time point to discontinue treatment after achieving MH? Well defined prospective studies are needed to address these important questions. PMID:22664079

  12. A targeted next-generation sequencing method for identifying clinically relevant mutation profiles in lung adenocarcinoma

    PubMed Central

    Shao, Di; Lin, Yongping; Liu, Jilong; Wan, Liang; Liu, Zu; Cheng, Shaomin; Fei, Lingna; Deng, Rongqing; Wang, Jian; Chen, Xi; Liu, Liping; Gu, Xia; Liang, Wenhua; He, Ping; Wang, Jun; Ye, Mingzhi; He, Jianxing

    2016-01-01

    Molecular profiling of lung cancer has become essential for prediction of an individual’s response to targeted therapies. Next-generation sequencing (NGS) is a promising technique for routine diagnostics, but has not been sufficiently evaluated in terms of feasibility, reliability, cost and capacity with routine diagnostic formalin-fixed, paraffin-embedded (FFPE) materials. Here, we report the validation and application of a test based on Ion Proton technology for the rapid characterisation of single nucleotide variations (SNVs), short insertions and deletions (InDels), copy number variations (CNVs), and gene rearrangements in 145 genes with FFPE clinical specimens. The validation study, using 61 previously profiled clinical tumour samples, showed a concordance rate of 100% between results obtained by NGS and conventional test platforms. Analysis of tumour cell lines indicated reliable mutation detection in samples with 5% tumour content. Furthermore, application of the panel to 58 clinical cases, identified at least one actionable mutation in 43 cases, 1.4 times the number of actionable alterations detected by current diagnostic tests. We demonstrated that targeted NGS is a cost-effective and rapid platform to detect multiple mutations simultaneously in various genes with high reproducibility and sensitivity. PMID:26936516

  13. Free radicals and other reactive oxygen metabolites: clinical relevance and the therapeutic efficacy of antioxidant therapy.

    PubMed

    Bulkley, G B

    1993-05-01

    As in any new field, justifiable enthusiasm for the potential for antioxidant therapy has led to hyperbole, hastily designed, poorly conceived clinical trials, and premature reporting of uncontrolled, anecdotal indicators of efficacy that have not held up when subjected to close scrutiny or more careful, controlled trial design. This tendency has been augmented by strong pressure for early positive results from a few, but not most, members of the pharmaceutical industry and by a few clinicians in highly competitive fields who were anxious not to be left behind. The sobering reality of negative or, even worse, indeterminate clinical trials has culled the field and educated those that remain. As a result, we are beginning to see the publication of quite promising results from large, well-controlled, carefully designed clinical studies, many, but not all, of which are quite promising. This has been associated with a much better understanding of the basic mechanism of free radical-mediated human disease, without which further substantial progress would be quite limited. Because the manipulation of oxidant-mediated tissue injury represents treating disease at its most basic level, the therapeutic potential of this approach remains not only promising but exciting. PMID:8488463

  14. Pharmacogenetics and pharmacogenomics: recent developments, their clinical relevance and some ethical, social, and legal implications.

    PubMed

    Norbert, Paul W; Roses, Allen D

    2003-03-01

    In recent debates on novel procedures of molecular medicine pharmacogenomics is attracting more and more attention as a genotype-based approach for improving safety and efficacy of the use of therapeutic substances. Promoted by basic knowledge generated in the field of medical genomics, facilitated by novel technological tools for mapping genetic variation in individuals, and supported by results of initial clinical studies linking specific genotypes to metabolic characteristics of individuals important for assessing drug response, procedures of pharmacogenetics and pharmacogenomics now are starting to impact significantly on clinical research and development and medical practice. In this situation assessing the goals, risk, and benefits of pharmacogenetics and pharmacogenomics is essential for the medically successful, ethically justifiable, and socially acceptable implementation of genotype-based diagnosis and pharmacotherapy. We discuss the current state of the art in pharmacogenetics and pharmacogenomics and introduce a model for evidence based assessment of its goals, risk, and benefits. We differentiate here between pragmatic and normative issues in the development of pharmacogenomics in order to contrast prevailing, insufficiently interest-based modes of public technology assessment with the evidence-based mode that can be established as part of clinical study design. Finally, we provide a framework for the analysis of social accountability that can be used for technology development and technology assessment with regard to pharmacogenomics in particular and molecular medicine in general.

  15. Clinical relevance of IL-6 gene polymorphism in severely injured patients

    PubMed Central

    Jeremić, Vasilije; Alempijević, Tamara; Mijatović, Srđan; Šijački, Ana; Dragašević, Sanja; Pavlović, Sonja; Miličić, Biljana; Krstić, Slobodan

    2014-01-01

    In polytrauma, injuries that may be surgically treated under regular circumstances due to a systemic inflammatory response become life-threatening. The inflammatory response involves a complex pattern of humoral and cellular responses and the expression of related factors is thought to be governed by genetic variations. This aim of this paper is to examine the influence of interleukin (IL) 6 single nucleotide polymorphism (SNP) -174C/G and -596G/A on the treatment outcome in severely injured patients. Forty-seven severely injured patients were included in this study. Patients were assigned an Injury Severity Score. Blood samples were drawn within 24 h after admission (designated day 1) and on subsequent days (24, 48, 72 hours and 7days) of hospitalization. The IL-6 levels were determined through ELISA technique. Polymorphisms were analyzed by a method of Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR). Among subjects with different outcomes, no statistically relevant difference was found with regards to the gene IL-6 SNP-174G/C polymorphism. More than a half of subjects who died had the SNP-174G/C polymorphism, while this polymorphism was represented in a slightly lower number in survivors. The incidence of subjects without polymorphism and those with heterozygous and homozygous gene IL-6 SNP-596G/A polymorphism did not present statistically significant variations between survivors and those who died. The levels of IL-6 over the observation period did not present any statistically relevant difference among subjects without the IL-6 SNP-174 or IL-6 SNP -596 gene polymorphism and those who had either a heterozygous or a homozygous polymorphism. PMID:24856384

  16. Presence of avian pneumovirus subtypes A and B in Japan.

    PubMed

    Mase, Masaji; Yamaguchi, Shigeo; Tsukamoto, Kenji; Imada, Tadao; Imai, Kunitoshi; Nakamura, Kikuyasu

    2003-01-01

    Four avian pneumovirus (APV) isolates from chickens clinically diagnosed with swollen head syndrome were genetically characterized as to the subtypes of the virus in Japan. The results of reverse transcriptase-polymerase chain reactions based on subtype-specific primers and direct sequence analysis of G genes indicated subtypes A and B but not C or D of APV were present in Japan. Several routes or sources are conceivable for APV to invade into Japan.

  17. Biologically effective dose distribution based on the linear quadratic model and its clinical relevance

    SciTech Connect

    Lee, S.P.; Smathers, J.B.; Withers, H.R.

    1995-09-30

    Radiotherapy plans based on physical dose distributions do not necessarily entirely reflect the biological effects under various fractionation schemes. Over the past decade, the linear-quadratic (LQ) model has emerged as a convenient tool to quantify biological effects for radiotherapy. In this work, we set out to construct a mechanism to display biologically oriented dose distribution based on the LQ model. A computer program that converts a physical dose distribution calculated by a commercially available treatment planning system to a biologically effective dose (BED) distribution has been developed and verified against theoretical calculations. This software accepts a user`s input of biological parameters for each structure of interest (linear and quadratic dose-response and repopulation kinetic parameters), as well as treatment scheme factors (number of fractions, fractional dose, and treatment time). It then presents a two-dimensional BED display in conjunction with anatomical structures. Furthermore, to facilitate clinicians` intuitive comparison with conventional fractionation regimen, a conversion of BED to normalized isoeffective dose (NID) is also allowed. We have demonstrated the feasibility of constructing a biologically oriented dose distribution for clinical practice of radiotherapy. The discordance between physical dose distributions and the biological counterparts based on the given treatment schemes was quantified. The computerized display of BED at nonprescription points greatly enhanced the versatility of this tool. Although the routine use of this implementation in clinical radiotherapy should be cautiously done, depending largely on the accuracy of the published biological parameters, it may, nevertheless, help the clinicians derive an optimal treatment plan with a particular fractionation scheme or use it as a quantitative tool for outcome analysis in clinical research. 45 refs., 3 figs., 5 tabs.

  18. Clinical Relevance of Telomere Status and Telomerase Activity in Colorectal Cancer.

    PubMed

    Fernández-Marcelo, Tamara; Sánchez-Pernaute, Andrés; Pascua, Irene; De Juan, Carmen; Head, Jacqueline; Torres-García, Antonio-José; Iniesta, Pilar

    2016-01-01

    The role of telomeres and telomerase in colorectal cancer (CRC) is well established as the major driving force in generating chromosomal instability. However, their potential as prognostic markers remains unclear. We investigated the outcome implications of telomeres and telomerase in this tumour type. We considered telomere length (TL), ratio of telomere length in cancer to non-cancer tissue (T/N ratio), telomerase activity and TERT levels; their relation with clinical variables and their role as prognostic markers. We analyzed 132 CRCs and paired non-cancer tissues. Kaplan-Meier curves for disease-free survival were calculated for TL, T/N ratio, telomerase activity and TERT levels. Overall, tumours had shorter telomeres than non-tumour tissues (P < 0.001) and more than 80% of CRCs displayed telomerase activity. Telomere lengths of non-tumour tissues and CRCs were positively correlated (P < 0.001). Considering telomere status and clinical variables, the lowest degree of telomere shortening was shown by tumours located in the rectum (P = 0.021). Regarding prognosis studies, patients with tumours showing a mean TL < 6.35 Kb experienced a significantly better clinical evolution (P < 0.001) and none of them with the highest degree of tumour telomere shortening relapsed during the follow-up period (P = 0.043). The mean TL in CRCs emerged as an independent prognostic factor in the Cox analysis (P = 0.017). Telomerase-positive activity was identified as a marker that confers a trend toward a poor prognosis. In CRC, our results support the use of telomere status as an independent prognostic factor. Telomere status may contribute to explaining the different molecular identities of this tumour type.

  19. A Core-tailored Platform for Pinpointing Clinically Relevant Variants in Human Genomes and Exomes

    PubMed Central

    Richards, D.; Flannery, R.; Kramer, A.; Kutchma, A.; Lerman, J.; Leschly, J.; Majumdar, S.; Marshall, N.; Molloy, M.; Muthiah, A.; Ning, A.; O'Connor, R.; Patel, K.; Rajaraman, V.; Rebres, R.; Sarver, A.; Su, H.; Zhou, W.; Zhu, X.; Bassett, D.; Pearson, Nathan

    2013-01-01

    Genomic studies of human disease and drug response aim to find one or a few causal variants among millions of possible candidates. A streamlined platform for quickly and reliably assessing each variant called in such studies can save months of tedious effort, speeding discoveries for core labs' clinical and research clients, and freeing core staff to solve other data analysis challenges posed by broader clientele. Made to help cores and their clients quickly interpret human genomes, the Ingenuity® Variant Analysis™ platform (www.ingenuity.com/variants) lets users upload, annotate, and thoroughly compare whole or partial human genomes, to smartly shortlist candidate variants, genes, and pathways that may best explain user-specified phenotype(s). Leveraging Ingenuity's deep, structured knowledge base of published findings and robust predictive insight, Variant Analysis runs sophisticated tests of family- and population-scale genetic association, tailored to the user's study design and phenotype, via a simple, fluid interface that also lets one easily review, revise, and share findings. To meet the distinctive challenges of clinical genome interpretation, we have comprehensively curated published clinical assessments and population incidence of individual human sequence variants, supplementing gene- and pathway-level functional knowledge. To help researchers identify new causal candidates, we have built and validated Variant Analysis to run gene- and pathway-level burden tests ∼100x faster than conventional methods. And, by letting users easily and securely share genome data and findings with collaborators, the platform mediates efficient collaborative discovery among researchers studying similar or (as mutual controls) distinct rare diseases. Combining sophisticated functional analytics; statistically robust genetic analysis at the variant, gene, and pathway levels in an intuitive interface, the Variant Analysis platform is built to meet the varied genome

  20. The relevance of cellular to clinical electrophysiology in classifying antiarrhythmic actions.

    PubMed

    Vaughan Williams, E M

    1992-01-01

    The division of class I antiarrhythmic agents (sodium-channel blockers) into Ia, Ib, and Ic subgroups was based on clinical observations. Lidocaine, mexiletine, and tocainide (Ib) did not alter the QRS or H-V interval in sinus rhythm, but prolonged effective refractory period (ERP) in spite of some shortening of the J-T interval. Encainide, flecainide, and lorcainide (Ic) widened the QRS and prolonged H-V in sinus rhythm and at low concentration, but had little effect on the ERP or J-T. These clinical findings could be explained by fast onset/offset kinetics of Ib drugs, that when used in high concentrations, blocked most sodium channels during the action potential plateau; therefore, at the beginning of diastole, insufficient drug-free channels were available to support conduction, and the ERP was prolonged. Rapid dissociation of the drugs after repolarization insured that by the end of diastole most channels were again drug free, so that the QRS and H-V were normal. The Ic compounds were more potent, but of slow onset, so that a steady-state block of Na channels was not achieved until after many beats. Offset was also slow, so that a proportion of channels was persistently unavailable, Na current was reduced, and conduction slowed, causing widening of the QRS and lengthening of H-V. Because the remaining drug-free channels were normal, they recovered rapidly from inactivation, and the ERP was not prolonged. By clinical criteria, moricizine also must be classed as Ic, and its offset/onset kinetics are much slower than those of Ib drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Clinical relevance of electrophysiological tests in the assessment of patients with Huntington's disease.

    PubMed

    Lefaucheur, Jean-Pascal; Bachoud-Levi, Anne-Catherine; Bourdet, Catherine; Grandmougin, Thierry; Hantraye, Philippe; Cesaro, Pierre; Degos, Jean-Denis; Peschanski, Marc; Lisovoski, Fabrice

    2002-11-01

    Assessment programs recently designed to follow-up patients with Huntington's disease (HD) in therapeutic trials have not included electrophysiological testing in the list of mandatory examinations. This omission is likely due to the current lack of data establishing a clear correlation between the electrophysiological results and those of clinical assessment. We address this issue in a cohort of 36 patients at relatively early stages of the disease (I and II). Electrophysiological studies comprised the recording of palmar sympathetic skin responses (SSRs), blink reflexes (BRs), thenar long latency reflexes (LLRs), cortical somatosensory evoked potentials (SEPs), and electromyographic silent periods evoked by transcranial magnetic stimulation (SPs). Results were analyzed with reference to disease duration and staging and to specific cognitive, psychiatric, and motor alteration. SEPs were the most and very sensitive markers, because they were abnormal in 94% of patients. Except for LLRs, alteration of electrophysiological results increased in parallel to the evolution of the disease. Except for LLRs and SSR latency, electrophysiological results correlated with those of specific clinical examinations. In particular, an increased BR latency or a reduced amplitude of the N20 component of SEPs correlated with the extent of bradykinesia, whereas a reduced amplitude of SSRs or of the N30 component of SEPs correlated with hyperkinesia. Overall, electrophysiological tests, in particular SEPs and BRs, appeared sensitive and interesting in the follow-up of HD patients and correlated with various clinical parameters, suggesting that these easy to perform and noninvasive repeatable examinations could be added fruitfully to the assessment programs for HD. PMID:12465071

  2. Relevance of nucleic acid amplification techniques for diagnosis of respiratory tract infections in the clinical laboratory.

    PubMed Central

    Ieven, M; Goossens, H

    1997-01-01

    Clinical laboratories are increasingly receiving requests to perform nucleic acid amplification tests for the detection of a wide variety of infectious agents. In this paper, the efficiency of nucleic acid amplification techniques for the diagnosis of respiratory tract infections is reviewed. In general, these techniques should be applied only for the detection of microorganisms for which available diagnostic techniques are markedly insensitive or nonexistent or when turnaround times for existing tests (e.g., viral culture) are much longer than those expected with amplification. This is the case for rhinoviruses, coronaviruses, and hantaviruses causing a pulmonary syndrome, Bordetella pertussis, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Coxiella burnetii. For Legionella spp. and fungi, contamination originating from the environment is a limiting factor in interpretation of results, as is the difficulty in differentiating colonization and infection. Detection of these agents in urine or blood by amplification techniques remains to be evaluated. In the clinical setting, there is no need for molecular diagnostic tests for the diagnosis of Pneumocystis carinii. At present, amplification methods for Mycobacterium tuberculosis cannot replace the classical diagnostic techniques, due to their lack of sensitivity and the absence of specific internal controls for the detection of inhibitors of the reaction. Also, the results of interlaboratory comparisons are unsatisfactory. Furthermore, isolates are needed for susceptibility studies. Additional work remains to be done on sample preparation methods, comparison between different amplification methods, and analysis of results. The techniques can be useful for the rapid identification of M. tuberculosis in particular circumstances, as well as the rapid detection of most rifampin-resistant isolates. The introduction of diagnostic amplification techniques into a clinical laboratory implies a level of proficiency for

  3. Perceptual accuracy of upper airway compromise in children: Clinical relevance and future directions for research

    PubMed Central

    Esteban, Cynthia; Kopel, Sheryl J.; Jandasek, Barbara; Dansereau, Katie; Fritz, Gregory K.; Klein, Robert B.

    2013-01-01

    Approximately 80% of children with asthma have coexisting allergic rhinitis. The accurate recognition and assessment of asthma and rhinitis symptoms is an integral component of guideline-based treatment for both conditions. This article describes the development and preliminary evaluation of a novel paradigm for testing the accuracy of children's assessment of their upper airway (rhinitis) symptoms. This work is guided by our previous research showing the clinical efficacy of tools to evaluate children's perceptual accuracy of asthma symptoms and linking accurate asthma symptom perception to decreased asthma morbidity (Fritz G, et al., Ethnic differences in perception of lung function: A factor in pediatric asthma disparities? Am J Respir Crit Care Med 182:12–18, 2010; Klein RB, et al., The Asthma Risk Grid: Clinical interpretation of symptom perception, Allergy Asthma Proc 251–256, 2004). The pilot study tests a paradigm that allows for the examination of the correspondence of children's assessment of their upper airway functioning with actual values of upper airway flow through the use of a portable, handheld nasal peak flowmeter. Nine children with persistent asthma were evaluated over a 4-week period. The article describes the rhinitis perceptual accuracy paradigm and reviews the results of a pilot study, showing a large proportion of inaccurate rhinitis symptoms “guesses” by the sample of children with persistent asthma. Patterns of inaccuracy, rhinitis control, and asthma morbidity are also described. Directions for future work are reviewed. The development of clinical tools to evaluate children's accuracy of rhinitis symptoms are needed, given the central role of the self-assessment of symptoms in guideline-based care. Accurate perception of the severity of rhinitis symptoms may enhance rhinitis control, lessen the burden of asthma, and prevent unnecessary emergency use among this high-risk group of children. PMID:24124637

  4. DGIdb 2.0: mining clinically relevant drug-gene interactions.

    PubMed

    Wagner, Alex H; Coffman, Adam C; Ainscough, Benjamin J; Spies, Nicholas C; Skidmore, Zachary L; Campbell, Katie M; Krysiak, Kilannin; Pan, Deng; McMichael, Joshua F; Eldred, James M; Walker, Jason R; Wilson, Richard K; Mardis, Elaine R; Griffith, Malachi; Griffith, Obi L

    2016-01-01

    The Drug-Gene Interaction Database (DGIdb, www.dgidb.org) is a web resource that consolidates disparate data sources describing drug-gene interactions and gene druggability. It provides an intuitive graphical user interface and a documented application programming interface (API) for querying these data. DGIdb was assembled through an extensive manual curation effort, reflecting the combined information of twenty-seven sources. For DGIdb 2.0, substantial updates have been made to increase content and improve its usefulness as a resource for mining clinically actionable drug targets. Specifically, nine new sources of drug-gene interactions have been added, including seven resources specifically focused on interactions linked to clinical trials. These additions have more than doubled the overall count of drug-gene interactions. The total number of druggable gene claims has also increased by 30%. Importantly, a majority of the unrestricted, publicly-accessible sources used in DGIdb are now automatically updated on a weekly basis, providing the most current information for these sources. Finally, a new web view and API have been developed to allow searching for interactions by drug identifiers to complement existing gene-based search functionality. With these updates, DGIdb represents a comprehensive and user friendly tool for mining the druggable genome for precision medicine hypothesis generation.

  5. Efficacy of clinically relevant temozolomide dosing schemes in glioblastoma cancer stem cell lines.

    PubMed

    Beier, Dagmar; Schriefer, Beate; Brawanski, Konstantin; Hau, Peter; Weis, Joachim; Schulz, Jörg B; Beier, Christoph P

    2012-08-01

    The effectiveness of temozolomide (TMZ) dosing schemes and the "rechallenge" of recurrent glioblastoma (GBM) with TMZ are controversial. We therefore compared the efficacy of different TMZ dosing schemes against GBM cancer stem cell (CSC) lines in vitro. In O(6)-methyl-guanidine-methyl-transferase (MGMT)-negative CSC lines, all schedules (1 day on/27 days off, 5 days on/23 days off, 7 days on/7 days off, 21 days on/7 days off, continuous low-dose TMZ) depleted clonogenic cells. In TMZ-resistant CSC lines, the 7 days on/7 days off scheme showed higher toxicity as compared with the other schemes. However, clinically feasible concentrations remained ineffective in highly resistant CSC lines. In addition, none of the schedules induced long-term depletion of clonogenic cells even at the highest concentrations (up to 250 μM). After sublethal TMZ treatment for 5 days, TMZ rechallenge of recovering CSC lines remained effective. Our data advocate CSC lines as in vitro model to address clinical questions. Using this model, our data suggest the effectiveness of TMZ in MGMT-negative CSC lines and support the concept of TMZ rechallenge. The 7 days on/7 days off scheme consistently showed the best activity of all schedules in TMZ-resistant CSC lines.

  6. Thirty years of human pineal research: do we know its clinical relevance?

    PubMed

    García-Patterson, A; Puig-Domingo, M; Webb, S M

    1996-01-01

    A role for melatonin in humans is becoming evident in an increasing number of clinical situations. Marked variations in the magnitude of the nocturnal melatonin peak are observed throughout the human lifespan. The highest levels occur in children and then fall during puberty and further during adulthood. A negative correlation between circulating melatonin and sex steroids has been observed in a number of instances, and appears to be independent of concomitant gonadotrophins. No clear melatonin pattern has been observed in pituitary tumors, but in large lesions that involve the hypothalamus, a reduced nocturnal rise has been reported. Reported effects of exogenously administered melatonin are variable, probably reflecting differences in dose and timing; a slight stimulation of prolactin, as well as a partial inhibition of gonadotrophins, has been reported, which explains its utility as an oral contraceptive, associated with a progestogen. A potential clinical use of melatonin as an oncostatic drug still awaits confirmation, although experimental data firmly support this possibility. The indole has also been used to hasten entrainment of subjects travelling across various time zones, and has been found to be specially useful in eastward travel. Finally, changes in the normal melatonin circadian pattern have been reported in psychiatric diseases and in sudden infant death syndrome. PMID:8648556

  7. Clinical relevance of copy number profiling in oral and oropharyngeal squamous cell carcinoma.

    PubMed

    van Kempen, Pauline M W; Noorlag, Rob; Braunius, Weibel W; Moelans, Cathy B; Rifi, Widad; Savola, Suvi; Koole, Ronald; Grolman, Wilko; van Es, Robert J J; Willems, Stefan M

    2015-10-01

    Current conventional treatment modalities in head and neck squamous cell carcinoma (HNSCC) are nonselective and have shown to cause serious side effects. Unraveling the molecular profiles of head and neck cancer may enable promising clinical applications that pave the road for personalized cancer treatment. We examined copy number status in 36 common oncogenes and tumor suppressor genes in a cohort of 191 oropharyngeal squamous cell carcinomas (OPSCC) and 164 oral cavity squamous cell carcinomas (OSCC) using multiplex ligation probe amplification. Copy number status was correlated with human papillomavirus (HPV) status in OPSCC, with occult lymph node status in OSCC and with patient survival. The 11q13 region showed gain or amplifications in 59% of HPV-negative OPSCC, whereas this amplification was almost absent in HPV-positive OPSCC. Additionally, in clinically lymph node-negative OSCC (Stage I-II), gain of the 11q13 region was significantly correlated with occult lymph node metastases with a negative predictive value of 81%. Multivariate survival analysis revealed a significantly decreased disease-free survival in both HPV-negative and HPV-positive OPSCC with a gain of Wnt-induced secreted protein-1. Gain of CCND1 showed to be an independent predictor for worse survival in OSCC. These results show that copy number aberrations, mainly of the 11q13 region, may be important predictors and prognosticators which allow for stratifying patients for personalized treatment of HNSCC. PMID:26194878

  8. Maintaining the clinical relevance of animal models in translational studies of post-traumatic stress disorder.

    PubMed

    Cohen, Hagit; Matar, Michael A; Zohar, Joseph

    2014-01-01

    The diagnosis of Post-Traumatic Stress Disorder (PTSD) is conditional on directly experiencing or witnessing a significantly threatening event and the presence of a certain minimal number of symptoms from each of four symptom clusters (re-experiencing, avoidance, negative cognition and mood, and hyperarousal) at least one month after the event (DSM 5) (American Psychiatric Association 2013). Only a proportion of the population exposed develops symptoms fulfilling the criteria. The individual heterogeneity in responses of stress-exposed animals suggested that adapting clearly defined and reliably reproducible "diagnostic", i.e. behavioral, criteria for animal responses would augment the clinical validity of the analysis of study data. We designed cut-off (inclusion/exclusion) behavioral criteria (CBC) which classify study subjects as being severely, minimally or partially affected by the stress paradigm, to be applied retrospectively in the analysis of behavioral data. Behavioral response classification enables the researcher to correlate (retrospectively) specific anatomic, bio-molecular and physiological parameters with the degree and pattern of the individual behavioral response, and also introduces "prevalence rates" as a valid study-parameter. The cumulative results of our studies indicate that, by classifying the data from individual subjects according to their response patterns, the animal study can more readily be translated into clinical "follow-up" studies and back again. This article will discuss the concept of the model and its background, and present a selection of studies employing and examining the model, alongside the underlying translational rationale of each.

  9. Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction.

    PubMed

    Kiyatkin, Eugene A; Ren, Suelynn; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

    2016-01-01

    MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results.

  10. Teaching clinically relevant dental anatomy in the dental curriculum: description and assessment of an innovative module.

    PubMed

    Obrez, Ales; Briggs, Charlotte; Buckman, James; Goldstein, Loren; Lamb, Courtney; Knight, William G

    2011-06-01

    The primary objective of the preclinical dental anatomy course in the predoctoral dental curriculum is to introduce students to cognitive and psychomotor skills related to the morphology and spatial and functional relationships of human dentition. Traditionally, didactic content for the subject is found in textbooks and course manuals and summarized by the faculty in lectures to the entire class. Psychomotor skills associated with recognition and reproduction of tooth morphology are traditionally learned by examining preserved tooth specimens and their cross-sections, combined with producing two-dimensional line drawings and carving teeth from wax blocks. These activities have little direct clinical application. In most cases, students are passive in the learning process, and assessment of student performance is unilateral and subjective. A recently revised dental anatomy module at the University of Illinois at Chicago College of Dentistry integrates independent class preparation with active small-group discussion and patient scenario-based wax-up exercises to replace missing tooth structure on manikin teeth. The goal of the revision is to shift emphasis away from decontextualized technical learning toward more active and clinically applicable learning that improves conceptual understanding while contributing to early acquisition of psychomotor skills. This article describes the rationale, components, and advantages of the revised module and presents a pre-post comparison of student learning outcomes for three class cohorts (N=203).

  11. Physiologic and clinical relevance of the insulin-like growth factor binding proteins.

    PubMed

    Cohen, P; Rosenfeld, R G

    1994-08-01

    The insulin-like growht factors (IGFs) are potent mitogenic agents that have been recognized for three decades. Recently, however, the complex milieu in which they operate has begun to be unraveled. Endocrine and autocrine patterns of IGF secretion have been identified and specific receptors that bind IGFs and mediate their biologic actions have been characterized. A family of six peptides, which bind IGFs with high affinity, the IGF binding proteins (IGFBPs), have been recognized as a new class of growth modulators. The IGFBPs can inhibit IGF actions, enhance IGF actions, or function as independent cell regulatory factors, possibly by interacting with their own receptors on the cell membrane. The IGFBPs, in turn, are regulated by a group of proteolytic enzymes, which are capable of cleaving IGFBPs into smaller fragments with lower affinity for the IGFs, thus enhancing IGF action. The size IGFBPs, although similar, have unique biologic properties, and appear to have specific patterns of expression and function. Radioimmunoassays for IGFBP-1, -2, and -3 are currently commercially available and information is accumulating on their diagnostic usefulness. This includes several clinical situations, such as growth disorders, where serum IGFBP-3 is a highly specific screening tool for growth hormone deficiency, various malignancies in which serum IGFBP-2 levels are elevated, and disorders of carbohydrate metabolism that display an inverse relationship between serum IGFBP-1 and insulin secretion. Current clinical practice may include the judicious use of these tests for the diagnosis and for monitoring the therapeutic response, of such disorders. PMID:7951670

  12. DGIdb 2.0: mining clinically relevant drug–gene interactions

    PubMed Central

    Wagner, Alex H.; Coffman, Adam C.; Ainscough, Benjamin J.; Spies, Nicholas C.; Skidmore, Zachary L.; Campbell, Katie M.; Krysiak, Kilannin; Pan, Deng; McMichael, Joshua F.; Eldred, James M.; Walker, Jason R.; Wilson, Richard K.; Mardis, Elaine R.; Griffith, Malachi; Griffith, Obi L.

    2016-01-01

    The Drug–Gene Interaction Database (DGIdb, www.dgidb.org) is a web resource that consolidates disparate data sources describing drug–gene interactions and gene druggability. It provides an intuitive graphical user interface and a documented application programming interface (API) for querying these data. DGIdb was assembled through an extensive manual curation effort, reflecting the combined information of twenty-seven sources. For DGIdb 2.0, substantial updates have been made to increase content and improve its usefulness as a resource for mining clinically actionable drug targets. Specifically, nine new sources of drug–gene interactions have been added, including seven resources specifically focused on interactions linked to clinical trials. These additions have more than doubled the overall count of drug–gene interactions. The total number of druggable gene claims has also increased by 30%. Importantly, a majority of the unrestricted, publicly-accessible sources used in DGIdb are now automatically updated on a weekly basis, providing the most current information for these sources. Finally, a new web view and API have been developed to allow searching for interactions by drug identifiers to complement existing gene-based search functionality. With these updates, DGIdb represents a comprehensive and user friendly tool for mining the druggable genome for precision medicine hypothesis generation. PMID:26531824

  13. Heterochromatin protein 1α: a hallmark of cell proliferation relevant to clinical oncology

    PubMed Central

    De Koning, Leanne; Savignoni, Alexia; Boumendil, Charlène; Rehman, Haniya; Asselain, Bernard; Sastre-Garau, Xavier; Almouzni, Geneviève

    2009-01-01

    Mammalian cells contain three closely related heterochromatin protein 1 (HP1) isoforms, HP1α, β and γ, which, by analogy to their unique counterpart in Schizosaccharomyces pombe, have been implicated in gene silencing, genome stability and chromosome segregation. However, the individual importance of each isoform during normal cell cycle and disease has remained an unresolved issue. Here, we reveal that HP1α shows a proliferation-dependent regulation, which neither HP1β nor γ display. During transient cell cycle exit, the HP1α mRNA and protein levels diminish. Transient depletion of HP1α, but not HP1β or γ, in tumoural and primary human cells leads to defects in chromosome segregation. Notably, analysis of an annotated collection of samples derived from carcinomas reveals an overexpression of HP1α mRNA and protein, which correlates with clinical data and disease outcome. Our results unveil a specific expression pattern for the HP1α isoform, suggesting a unique function related to cell division and tumour growth. The overexpression of HP1α constitutes a new example of a potential epigenetic contribution to tumourigenesis that is of clinical interest for cancer prognosis. PMID:20049717

  14. Nonphosphate-binding effects of sevelamer--are they of clinical relevance?

    PubMed

    Marangon, Nicola; Lindholm, Bengt; Stenvinkel, Peter

    2008-01-01

    Sevelamer is an ion-exchanging resin that binds phosphate in the gut. Because it does so without increasing the calcium load, treatment with sevelamer may lead to less vascular calcification and better survival in chronic kidney disease patients. However, the results of available clinical studies have not been consistent; recent observations challenge the hypothesis that the extra calcium load inherent in calcium-based phosphate binder therapy increases cardiovascular mortality by accelerating vascular calcification. This reemphasizes the fact that we still lack detailed understanding on the complex relationships between vascular calcification, bone metabolism, vascular disease and outcome in the context of uremia. Thus, the role of phosphate binders may be more complex than initially anticipated and not limited to the extra calcium load. Even if detailed mechanisms of action for sevelamer are not yet clearly established (except for its lipid-lowering action), sevelamer may have a number of additional nonphosphate-lowering actions (including lipid lowering as well as improvement in endothelial function, modulation of inflammation and oxidative stress and binding of uremic toxin absorption). Whether these potentially very interesting pleiotropic effects of sevelamer may be translated into significant clinical benefits remains to be established.

  15. Genotypes and viral variants in chronic hepatitis B: A review of epidemiology and clinical relevance

    PubMed Central

    Croagh, Catherine MN; Desmond, Paul V; Bell, Sally J

    2015-01-01

    The Hepatitis B Virus (HBV) has a worldwide distribution and is endemic in many populations. It is constantly evolving and 10 genotypic strains have been identified with varying prevalences in different geographic regions. Numerous stable mutations in the core gene and in the surface gene of the HBV have also been identified in untreated HBV populations. The genotypes and viral variants have been associated with certain clinical features of HBV related liver disease and Hepatocellular carcinoma. For example Genotype C is associated with later hepatitis B e antigen (HBeAg) seroconversion, and more advanced liver disease. Genotype A is associated with a greater risk of progression to chronicity in adult acquired HBV infections. Genotype D is particularly associated with the precore mutation and HBeAg negative chronic hepatitis B (CHB). The genotypes prevalent in parts of West Africa, Central and South America, E, F and H respectively, are less well studied. Viral variants especially the Basal Core Promotor mutation is associated with increased risk of fibrosis and cancer of the liver. Although not currently part of routine clinical care, evaluation of genotype and viral variants may provide useful adjunctive information in predicting risk about liver related morbidity in patients with CHB. PMID:25848459

  16. Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction.

    PubMed

    Kiyatkin, Eugene A; Ren, Suelynn; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

    2016-01-01

    MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results. PMID:26105141

  17. Tests for bactericidal effects of antimicrobial agents: technical performance and clinical relevance.

    PubMed Central

    Peterson, L R; Shanholtzer, C J

    1992-01-01

    Bactericidal testing has been used for several decades as a guide for antimicrobial therapy of serious infections. Such testing is most frequently performed when bactericidal antimicrobial agent therapy is considered necessary (such as when treating infectious endocarditis or infection in an immunocompromised host). It has also been used to ensure that the infecting organism is killed by (not tolerant to) usually bactericidal compounds. However, few data are available to support the role of such tests in direct patient care. Several important variables affect the reproducibility of the test results; however, proposed reference methods are now available for performing the MBC test. With minor modifications, these can provide a standardized approach for laboratories that need to perform them. Currently, little evidence is available to support the routine use of such testing for the care of individual patients. However, testing of new (investigational) antimicrobial agents can be beneficial in determining their potential to provide bactericidal antimicrobial activity during clinical use. New methods to assess bactericidal activity are being developed, but as yet none have been rigorously tested in patient care settings; further, for most of these methods, little information is available as to which technical parameters affect their results. In clinical laboratories, all bactericidal tests must be performed with rigorously standardized techniques and adequate controls, bearing in mind the limitations of the currently available test procedures. PMID:1423219

  18. ADDITIONAL DEMOGRAPHIC AND CLINICAL EVIDENCES ON THE RELEVANCE OF THE SYSTEMIC THERAPY IN ALCOHOL DEPENDENCE.

    PubMed

    Alexinschi, Ovidiu; Chirita, Roxana; Manuela, Padurariu; Ciobica, Alin; Dobrin, Romeo; Petrariu, F D; Timofte, Daniel; Chirita, Vasile

    2015-01-01

    The modern treatment for alcohol dependence is still problematic, in many cases with the costs exceeding benefits. In these conditions a new management approach was developed lately, known as the systemic therapy. In this way, the crystallization and practical transposition of this new treatment approach is represented by the Clubs of Alcoholics in Treatment. These clubs are in fact a form of psycho-social intervention consisting of multi-family communities in order to maintain long-term abstinence from alcohol and to change their lifestyle and behavior. Thus, in the present paper we were interested in understanding the demographics of this systemic theory and how these aspects are influencing the final results of the therapy, as well as studying/confirming how relevant is this systemic approach on the management of alcohol dependence. Our results presented in this report bring additional evidences for the superiority of the systemic, multi-family approach of alcohol-related problems, as complemented to the standard medicinal therapy. Moreover, the data collected from patients in this study might suggest that patients with a higher educational level and therefore better capacity of understanding the information, with family support, and also with a better occupational insertion, have accepted to follow The Clubs of Alcoholics in Treatment program, with a subsequently better evolution. PMID:26793858

  19. Squalene epoxidase is a bona fide oncogene by amplification with clinical relevance in breast cancer

    PubMed Central

    Brown, David N.; Caffa, Irene; Cirmena, Gabriella; Piras, Daniela; Garuti, Anna; Gallo, Maurizio; Alberti, Saverio; Nencioni, Alessio; Ballestrero, Alberto; Zoppoli, Gabriele

    2016-01-01

    SQLE encodes squalene epoxidase, a key enzyme in cholesterol synthesis. SQLE has sporadically been reported among copy-number driven transcripts in multi-omics cancer projects. Yet, its functional relevance has never been subjected to systematic analyses. Here, we assessed the correlation of SQLE copy number (CN) and gene expression (GE) across multiple cancer types, focusing on the clinico-pathological associations in breast cancer (BC). We then investigated whether any biological effect of SQLE inhibition could be observed in BC cell line models. Breast, ovarian, and colorectal cancers showed the highest CN driven GE among 8,783 cases from 22 cancer types, with BC presenting the strongest one. SQLE overexpression was more prevalent in aggressive BC, and was an independent prognostic factor of unfavorable outcome. Through SQLE pharmacological inhibition and silencing in a panel of BC cell lines portraying the diversity of SQLE CN and GE, we demonstrated that SQLE inhibition resulted in a copy-dosage correlated decrease in cell viability, and in a noticeable increase in replication time, only in lines with detectable SQLE transcript. Altogether, our results pinpoint SQLE as a bona fide metabolic oncogene by amplification, and as a therapeutic target in BC. These findings could have implications in other cancer types. PMID:26777065

  20. The anatomy of the sacrococcygeal cornual region and its clinical relevance.

    PubMed

    Woon, Jason T K; Stringer, Mark D

    2014-09-01

    There has been no systematic study of the anatomy of the region between the sacral and coccygeal cornua. Reference texts describe an intercornual ligament connecting these structures. The aim of this study was to investigate the anatomy of this region, which may be relevant to unexplained cases of coccygeal pain (coccydynia) and local nerve blocks. The bony anatomy of the sacrococcygeal (SC) cornual region was analyzed in 33 CT scans obtained from supine adults of mostly European origin with no known SC pathology, 7 μCT scans of cadaver SC specimens, and 105 Asian Indian adult skeletons. A further five cadaver SC specimens were examined histologically. SC cornual fusion was seen in 45% of CT/μCT scans (mean age 67 years, 20 males) and in 20% of adult skeletons (78 males); there was no association with age or sex. In the absence of SC fusion, the mean intersacrococcygeal cornual gap was 7.1 ± 2.4 mm; this was bridged by an intercornual ligament composed of parallel vertical collagen fibers reinforced by elastin fibers on its anterior surface. Small nerve branches were observed adjacent to the ventral aspect of the intercornual ligament and, in one case, traversing the ligament. Ipsilateral sacral and coccygeal cornua are therefore normally bridged by an intercornual ligament that is probably innervated. The cornua are fused on one or both sides in 20-45% of adults. These findings may have implications for some cases of coccydynia and for anesthetists performing local nerve blocks.

  1. Targeting and intracellular trafficking of clinically relevant hTHTR1 mutations in human cell lines.

    PubMed

    Subramanian, Veedamali S; Marchant, Jonathan S; Said, Hamid M

    2007-07-01

    The micronutrient thiamine is required for normal growth and development of human tissues, and is accumulated into cells through the activity of plasma membrane thiamine transporters, e.g. hTHTR1 (human thiamine transporter 1). Recent genetic evidence has linked mutations in hTHTR1 with the manifestation of TRMA (thiamine-responsive megaloblastic anaemia), a condition also associated with diabetes mellitus, sensorineural deafness and retinal disorders. To examine how mutations in hTHTR1 impair thiamine accumulation, we have investigated the targeting and functional properties of several different hTHTR1 mutants in human cell lines derived from epithelia relevant to thiamine absorption or tissues implicated in TRMA pathology. These constructs encompassed two newly identified point mutations (P51L and T158R) and two truncations of hTHTR1 identical with those found in TRMA kindreds (W358X and Delta383fs). Our results reveal a spectrum of mutant phenotypes, underlining that TRMA can result from decreased thiamine transport activity underpinned by changes in hTHTR1 expression levels, cellular targeting and/or protein transport activity.

  2. Valuing health for clinical and economic decisions: directions relevant for rheumatologists.

    PubMed

    Harrison, Mark J; Bansback, Nick J; Marra, Carlo A; Drummond, Michael; Tugwell, Peter S; Boonen, Annelies

    2011-08-01

    The quality-adjusted life-year (QALY) is a construct that integrates the value or preference for a health state over the period of time in that health state. The main use of QALY is in cost-utility analysis, to help make resource allocation decisions when faced with choices. Although the concept of the QALY is appealing, there is ongoing debate regarding their usefulness and approaches to deriving QALY. In 2008, OMERACT engaged in an effort to agree on QALY approaches that can be used in rheumatology. Based on a Web questionnaire and a subsequent meeting, rheumatologists questioned whether it was relevant for OMERACT (1) to investigate use of a QALY that represents the patients' perspective, (2) to explore the validity of the visual analog scale (VAS) to value health, and (3) to understand the validity of mapping health-specific instruments on existing preference instruments. This article discusses the pros and cons of these points in light of current insight from the point of view of health economics and decision-making theory. It also considers the further research agenda toward a QALY approach in rheumatology. PMID:21807800

  3. Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors

    PubMed Central

    Miller, Daniel H.; Medina, Jamie E.; Hamilton, Joshua W.; Messerli, Mark A.; Brodsky, Alexander S.

    2016-01-01

    The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05) (S2 Table). Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17-gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition. PMID:26986722

  4. Preclinical Models Provide Scientific Justification and Translational Relevance for Moving Novel Therapeutics into Clinical Trials for Pediatric Cancer.

    PubMed

    Langenau, David M; Sweet-Cordero, Alejandro; Wechsler-Reya, Robert J; Dyer, Michael A

    2015-12-15

    Despite improvements in survival rates for children with cancer since the 1960s, progress for many pediatric malignancies has slowed over the past two decades. With the recent advances in our understanding of the genomic landscape of pediatric cancer, there is now enthusiasm for individualized cancer therapy based on genomic profiling of patients' tumors. However, several obstacles to effective personalized cancer therapy remain. For example, relatively little data from prospective clinical trials demonstrate the selective efficacy of molecular-targeted therapeutics based on somatic mutations in the patient's tumor. In this commentary, we discuss recent advances in preclinical testing for pediatric cancer and provide recommendations for providing scientific justification and translational relevance for novel therapeutic combinations for childhood cancer. Establishing rigorous criteria for defining and validating druggable mutations will be essential for the success of ongoing and future clinical genomic trials for pediatric malignancies.

  5. Detection of glycopeptide resistance genotypes and identification to the species level of clinically relevant enterococci by PCR.

    PubMed Central

    Dutka-Malen, S; Evers, S; Courvalin, P

    1995-01-01

    A PCR assay that allows simultaneous detection of glycopeptide resistance genotypes and identification to the species level of clinically relevant enterococci (Enterococcus faecium, E. faecalis, E. gallinarum, and E. casseliflavus) was developed. This assay was based on specific amplification of internal fragments of genes encoding D-alanine:D-alanine ligases and related glycopeptide resistance proteins. The specificity of the assay was tested on 5 well-characterized glycopeptide-resistant strains and on 15 susceptible enterococcal type strains. Clinical isolates of enterococci that could not be identified to the species level by conventional methods were identified by the PCR test. This assay offers a specific and rapid alternative to antibiotic susceptibility tests, in particular for detection of low-level vancomycin resistance. PMID:7699051

  6. Morphogenetic fields within the human dentition: a new, clinically relevant synthesis of an old concept.

    PubMed

    Townsend, Grant; Harris, Edward F; Lesot, Herve; Clauss, Francois; Brook, Alan

    2009-12-01

    This paper reviews the concept of morphogenetic fields within the dentition that was first proposed by Butler (Butler PM. Studies of the mammalian dentition. Differentiation of the post-canine dentition. Proc Zool Soc Lond B 1939;109:1-36), then adapted for the human dentition by Dahlberg (Dahlberg AA. The changing dentition of man. J Am Dent Assoc 1945;32:676-90; Dahlberg AA. The dentition of the American Indian. In: Laughlin WS, editor. The Physical Anthropology of the American Indian. New York: Viking Fund Inc.; 1951. p. 138-76). The clone theory of dental development, proposed by Osborn (Osborn JW. Morphogenetic gradients: fields versus clones. In: Butler PM, Joysey KA, editors Development, function and evolution of teeth. London: Academic Press, 1978. p. 171-201), is then considered before these two important concepts are interpreted in the light of recent findings from molecular, cellular, genetic and theoretical and anthropological investigation. Sharpe (Sharpe PT. Homeobox genes and orofacial development. Connect Tissue Res 1995;32:17-25) put forward the concept of an odontogenic homeobox code to explain how different tooth classes are initiated in different parts of the oral cavity in response to molecular cues and the expression of specific groups of homeobox genes. Recently, Mitsiadis and Smith (Mitsiadis TA, Smith MM. How do genes make teeth to order through development? J Exp Zool (Mol Dev Evol) 2006; 306B:177-82.) proposed that the field, clone and homeobox code models could all be incorporated into a single model to explain dental patterning. We agree that these three models should be viewed as complementary rather than contradictory and propose that this unifying view can be extended into the clinical setting using findings on dental patterning in individuals with missing and extra teeth. The proposals are compatible with the unifying aetiological model developed by Brook (Brook AH. A unifying aetiological explanation for anomalies of tooth number

  7. Morphogenetic fields within the human dentition: a new, clinically relevant synthesis of an old concept.

    PubMed

    Townsend, Grant; Harris, Edward F; Lesot, Herve; Clauss, Francois; Brook, Alan

    2009-12-01

    This paper reviews the concept of morphogenetic fields within the dentition that was first proposed by Butler (Butler PM. Studies of the mammalian dentition. Differentiation of the post-canine dentition. Proc Zool Soc Lond B 1939;109:1-36), then adapted for the human dentition by Dahlberg (Dahlberg AA. The changing dentition of man. J Am Dent Assoc 1945;32:676-90; Dahlberg AA. The dentition of the American Indian. In: Laughlin WS, editor. The Physical Anthropology of the American Indian. New York: Viking Fund Inc.; 1951. p. 138-76). The clone theory of dental development, proposed by Osborn (Osborn JW. Morphogenetic gradients: fields versus clones. In: Butler PM, Joysey KA, editors Development, function and evolution of teeth. London: Academic Press, 1978. p. 171-201), is then considered before these two important concepts are interpreted in the light of recent findings from molecular, cellular, genetic and theoretical and anthropological investigation. Sharpe (Sharpe PT. Homeobox genes and orofacial development. Connect Tissue Res 1995;32:17-25) put forward the concept of an odontogenic homeobox code to explain how different tooth classes are initiated in different parts of the oral cavity in response to molecular cues and the expression of specific groups of homeobox genes. Recently, Mitsiadis and Smith (Mitsiadis TA, Smith MM. How do genes make teeth to order through development? J Exp Zool (Mol Dev Evol) 2006; 306B:177-82.) proposed that the field, clone and homeobox code models could all be incorporated into a single model to explain dental patterning. We agree that these three models should be viewed as complementary rather than contradictory and propose that this unifying view can be extended into the clinical setting using findings on dental patterning in individuals with missing and extra teeth. The proposals are compatible with the unifying aetiological model developed by Brook (Brook AH. A unifying aetiological explanation for anomalies of tooth number

  8. Fractal measures of video-recorded trajectories can classify motor subtypes in Parkinson's Disease

    NASA Astrophysics Data System (ADS)

    Figueiredo, Thiago C.; Vivas, Jamile; Peña, Norberto; Miranda, José G. V.

    2016-11-01

    Parkinson's Disease is one of the most prevalent neurodegenerative diseases in the world and affects millions of individuals worldwide. The clinical criteria for classification of motor subtypes in Parkinson's Disease are subjective and may be misleading when symptoms are not clearly identifiable. A video recording protocol was used to measure hand tremor of 14 individuals with Parkinson's Disease and 7 healthy subjects. A method for motor subtype classification was proposed based on the spectral distribution of the movement and compared with the existing clinical criteria. Box-counting dimension and Hurst Exponent calculated from the trajectories were used as the relevant measures for the statistical tests. The classification based on the power-spectrum is shown to be well suited to separate patients with and without tremor from healthy subjects and could provide clinicians with a tool to aid in the diagnosis of patients in an early stage of the disease.

  9. Multicentre study highlighting clinical relevance of new high-throughput methodologies in molecular epidemiology of Pneumocystis jirovecii pneumonia.

    PubMed

    Esteves, F; de Sousa, B; Calderón, E J; Huang, L; Badura, R; Maltez, F; Bassat, Q; de Armas, Y; Antunes, F; Matos, O

    2016-06-01

    Pneumocystis jirovecii causes severe interstitial pneumonia (PcP) in immunosuppressed patients. This multicentre study assessed the distribution frequencies of epidemiologically relevant genetic markers of P. jirovecii in different geographic populations from Portugal, the USA, Spain, Cuba and Mozambique, and the relationship between the molecular data and the geographical and clinical information, based on a multifactorial approach. The high-throughput typing strategy for P. jirovecii characterization consisted of DNA pooling using quantitative real-time PCR followed by multiplex-PCR/single base extension. The frequencies of relevant P. jirovecii single nucleotide polymorphisms (mt85, SOD110, SOD215, DHFR312, DHPS165 and DHPS171) encoded at four loci were estimated in ten DNA pooled samples representing a total of 182 individual samples. Putative multilocus genotypes of P. jirovecii were shown to be clustered due to geographic differences but were also dependent on clinical characteristics of the populations studied. The haplotype DHFR312T/SOD110C/SOD215T was associated with severe AIDS-related PcP and high P. jirovecii burdens. The frequencies of this genetic variant of P. jirovecii were significantly higher in patients with AIDS-related PcP from Portugal and the USA than in the colonized patients from Portugal, and Spain, and children infected with P. jirovecii from Cuba or Mozambique, highlighting the importance of this haplotype, apparently associated with the severity of the disease and specific clinical groups. Patients from the USA and Mozambique showed higher rates of DHPS mutants, which may suggest the circulation of P. jirovecii organisms potentially related with trimethoprim-sulfamethoxazole resistance in those geographical regions. This report assessed the worldwide distribution of P. jirovecii haplotypes and their epidemiological impact in distinct geographic and clinical populations.

  10. Correction of Hyperbilirubinemia in Gunn Rats Using Clinically Relevant Low Doses of Helper-Dependent Adenoviral Vectors

    PubMed Central

    Dimmock, David; Brunetti-Pierri, Nicola; Palmer, Donna J.; Beaudet, Arthur L.

    2011-01-01

    Abstract Crigler–Najjar syndrome type I is a severe inborn error of bilirubin metabolism caused by a complete deficiency of uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) and results in life-threatening unconjugated hyperbilirubinemia. Lifelong correction of hyperbilirubinemia by liver-directed gene therapy using a helper-dependent adenoviral (HDAd) vector has been previously reported in the Gunn rat, a model of Crigler–Najjar syndrome, but was only achieved using high doses (≥3 × 1012 viral particles [vp]/kg), which are likely to elicit a severe toxic response in humans. Therefore, in this study, we investigate strategies to achieve correction of hyperbilirubinemia in the Gunn rat using clinically relevant low HDAd doses. We have found that correction of hyperbilirubinemia in the Gunn rat can be achieved with a low dose of 5 × 1011 vp/kg by using an HDAd vector bearing a more potent UGT1A1 expression cassette. Furthermore, by using hydrodynamic injection of the improved HDAd vector, correction of hyperbilirubinemia in the Gunn rat can be achieved using an even lower dose of 5 × 1010 vp/kg. Although hydrodynamic injection as performed in rats is not acceptable in humans, clinically attractive, minimally invasive methods have been successfully developed to mimic hydrodynamic injection of HDAd vector in non-human primates. Therefore, using an improved expression cassette combined with a more efficient method of vector delivery permits correction of hyperbilirubinemia in the Gunn rat using clinically relevant low HDAd doses and may thus pave the way to clinical application of HDAd vectors for Crigler–Najjar syndrome gene therapy. PMID:20973621

  11. Multicentre study highlighting clinical relevance of new high-throughput methodologies in molecular epidemiology of Pneumocystis jirovecii pneumonia.

    PubMed

    Esteves, F; de Sousa, B; Calderón, E J; Huang, L; Badura, R; Maltez, F; Bassat, Q; de Armas, Y; Antunes, F; Matos, O

    2016-06-01

    Pneumocystis jirovecii causes severe interstitial pneumonia (PcP) in immunosuppressed patients. This multicentre study assessed the distribution frequencies of epidemiologically relevant genetic markers of P. jirovecii in different geographic populations from Portugal, the USA, Spain, Cuba and Mozambique, and the relationship between the molecular data and the geographical and clinical information, based on a multifactorial approach. The high-throughput typing strategy for P. jirovecii characterization consisted of DNA pooling using quantitative real-time PCR followed by multiplex-PCR/single base extension. The frequencies of relevant P. jirovecii single nucleotide polymorphisms (mt85, SOD110, SOD215, DHFR312, DHPS165 and DHPS171) encoded at four loci were estimated in ten DNA pooled samples representing a total of 182 individual samples. Putative multilocus genotypes of P. jirovecii were shown to be clustered due to geographic differences but were also dependent on clinical characteristics of the populations studied. The haplotype DHFR312T/SOD110C/SOD215T was associated with severe AIDS-related PcP and high P. jirovecii burdens. The frequencies of this genetic variant of P. jirovecii were significantly higher in patients with AIDS-related PcP from Portugal and the USA than in the colonized patients from Portugal, and Spain, and children infected with P. jirovecii from Cuba or Mozambique, highlighting the importance of this haplotype, apparently associated with the severity of the disease and specific clinical groups. Patients from the USA and Mozambique showed higher rates of DHPS mutants, which may suggest the circulation of P. jirovecii organisms potentially related with trimethoprim-sulfamethoxazole resistance in those geographical regions. This report assessed the worldwide distribution of P. jirovecii haplotypes and their epidemiological impact in distinct geographic and clinical populations. PMID:27021425

  12. Clinical relevance of circulating antibodies and B lymphocyte markers in allograft rejection.

    PubMed

    Vallin, Patrice; Désy, Olivier; Béland, Stéphanie; Wagner, Eric; De Serres, Sacha A

    2016-03-01

    The main challenge in solid organ transplantation remains to tackle antibody-mediated rejection. Our understanding of the antibody-mediated response and the capacity to detect it has improved in the last decade. However, the sensitivity and specificity of the current clinical tools to monitor B cell activation are perfectible. New strategies, including the refinement in the characterization of HLA and non-HLA antibodies, as well as a better understanding of the circulating B cell phenotype will hopefully help to non-invasively identify patients at risk or undergoing antibody-mediated allograft damage. The current review discusses the current knowledge of the B cell biomarkers in solid organ transplantation, with a focus on circulating antibodies and peripheral B cells. PMID:26721422

  13. [Triple therapy in cirrhotic patients and those with advanced fibrosis: relevant aspects in clinical practice].

    PubMed

    Albillos, Agustín; Luis Calleja, José; Molina, Esther; Planas, Ramon; Romero-Gómez, Manuel; Turnes, Juan; Hernández-Guerra, Manuel

    2014-07-01

    The first-line option in the treatment of patients with advanced fibrosis and cirrhosis due to genotype 1 hepatitis C virus is currently triple therapy with boceprevir/telaprevir and pegylated interferon-ribavirin. However, certain limitations could constitute a barrier to starting treatment or achieving sustained viral response in these patients. These limitations include the patient's or physician's perception of treatment effectiveness in routine clinical practice-which can weight against the decision to start treatment-, the advanced stage of the disease with portal hypertension and comorbidity, treatment interruption due to poor adherence, and adverse effects, mainly anemia. In addition, it is now possible to identify patients who could benefit from a shorter therapeutic regimen with a similar cure rate. This review discusses these issues and their possible effect on the use of triple therapy. PMID:25907434

  14. Molecular Identification and Susceptibility of Clinically Relevant Scedosporium spp. in China

    PubMed Central

    Wang, Hong; Wan, Zhe; Li, Ruoyu; Lu, Qiaoyun; Yu, Jin

    2015-01-01

    As various new sibling species within the Scedosporium spp. have been described recently, this study was conducted to investigate distribution and antifungal susceptibility profiles of the different species of Scedosporium spp. in China. Twenty-one clinical strains of Scedosporium from China and two strains from Japan were reidentified by MLSA. The analysis included BT2, CAL, RPB, SOD, and ACT and the combination of the five loci. Pseudallescheria boydii complex (17 strains) and S. apiospermum (6 strains) were identified. P. boydii complex included four closely related subgroups: P. boydii (9 strains), P. ellipsoidea (6 strains), P. fusoidea (1 strain), and P. angusta (1 strain). There were no significant differences in MICs for neither VOR, POS, nor AMB over all the five species in study. For itraconazole, intraspecific diversity was evident. PMID:26550562

  15. The type I interferons: Basic concepts and clinical relevance in immune-mediated inflammatory diseases.

    PubMed

    López de Padilla, Consuelo M; Niewold, Timothy B

    2016-01-15

    There is increasing scientific and clinical interest in elucidating the biology of type I Interferons, which began approximately 60 years ago with the concept of "viral interference", a property that reduces the ability of a virus to infect cells. Although our understanding of the multiple cellular and molecular functions of interferons has advanced significantly, much remains to be learned and type I Interferons remain an active and fascinating area of inquiry. In this review, we cover some general aspects of type I interferon genes, with emphasis on interferon-alpha, and various aspects of molecular mechanisms triggered by type I interferons and toll-like receptor signaling by the Janus activated kinase/signal transducer activation of transcription (JAK-STAT) pathway and interferon regulatory factor pathway. We will also describe the role of type I interferons in autoimmune and inflammatory diseases, and its potential use as therapeutic agent.

  16. Molecular identification and susceptibility of clinically relevant Scedosporium spp. in China.

    PubMed

    Wang, Hong; Wan, Zhe; Li, Ruoyu; Lu, Qiaoyun; Yu, Jin

    2015-01-01

    As various new sibling species within the Scedosporium spp. have been described recently, this study was conducted to investigate distribution and antifungal susceptibility profiles of the different species of Scedosporium spp. in China. Twenty-one clinical strains of Scedosporium from China and two strains from Japan were reidentified by MLSA. The analysis included BT2, CAL, RPB, SOD, and ACT and the combination of the five loci. Pseudallescheria boydii complex (17 strains) and S. apiospermum (6 strains) were identified. P. boydii complex included four closely related subgroups: P. boydii (9 strains), P. ellipsoidea (6 strains), P. fusoidea (1 strain), and P. angusta (1 strain). There were no significant differences in MICs for neither VOR, POS, nor AMB over all the five species in study. For itraconazole, intraspecific diversity was evident. PMID:26550562

  17. Challenging present concepts in compression therapy: static stiffness index is not consistent and not clinically relevant.

    PubMed

    Kravitz, S; Hegarty-Craver, M; Reid, L

    2016-02-01

    Once a circumferential force is delivered to a limb by a compression device, assuming the tension within the device remains constant, any change in the total force is dependent upon a change in circumference of the limb, with the rate of change (excluding fabric creep) being dependent on the stress strain curve of the device. This article addresses the pre-conceived and well-accepted principle that interface compression delivered by a compression device substantially increases with the position of the limb, based on the positions of sitting (non-weight bearing) to standing and/or during muscle activity (ankle dorsiflexion). Using engineering parameters and clinical measurements, the authors demonstrate that changes in interface pressure are minimal if any, and that the current concept should be modified accordingly. Declaration of interest: This study was sponsored by Carolon. L. Reid, and S. Kravitz are employees of Carolon. M. Hegarty-Craver has received monetary compensation as a researcher for Carolon.

  18. A clinical report of Type III dens invaginatus: relevant aspects of a combined therapeutic approach.

    PubMed

    Silva E Souza, Patricia de Almeida Rodrigues; de Almeida, Bruno Vila Nova; Tartari, Talita; Alves, Ana Claudia Braga Amoras; Tuji, Farbicio Mesquita; Silva E Souza, Mario Honorato

    2013-01-01

    Dens invaginatus is a developmental abnormality that alters dental morphology; as a result, treating this condition is a challenge for endodontic practices. This article describes how a combination of nonsurgical and surgical therapies was utilized to treat a maxillary central incisor with Type III dens invaginatus and vital pulp. The treatment plan included using computed tomography (CT) for a detailed analysis of the dental anatomy and periapical area, endodontic and surgical procedures, and a 4-year follow-up period that included periodic clinical and radiographic examinations. The follow-up examinations revealed a regression of the apical lesion and no other signs or symptoms. Based on the present case report, the authors concluded that this combination of surgical and nonsurgical approaches was effective and that CT is a valuable auxiliary tool for the study of dental anatomy.

  19. Challenging present concepts in compression therapy: static stiffness index is not consistent and not clinically relevant.

    PubMed

    Kravitz, S; Hegarty-Craver, M; Reid, L

    2016-02-01

    Once a circumferential force is delivered to a limb by a compression device, assuming the tension within the device remains constant, any change in the total force is dependent upon a change in circumference of the limb, with the rate of change (excluding fabric creep) being dependent on the stress strain curve of the device. This article addresses the pre-conceived and well-accepted principle that interface compression delivered by a compression device substantially increases with the position of the limb, based on the positions of sitting (non-weight bearing) to standing and/or during muscle activity (ankle dorsiflexion). Using engineering parameters and clinical measurements, the authors demonstrate that changes in interface pressure are minimal if any, and that the current concept should be modified accordingly. Declaration of interest: This study was sponsored by Carolon. L. Reid, and S. Kravitz are employees of Carolon. M. Hegarty-Craver has received monetary compensation as a researcher for Carolon. PMID:26878373

  20. Novel Paths to Relevance: How Clinical Ethics Committees Promote Ethical Reflection.

    PubMed

    Magelssen, Morten; Pedersen, Reidar; Førde, Reidun

    2016-09-01

    How may clinical ethics committees (CECs) inspire ethical reflection among healthcare professionals? How may they deal with organizational ethics issues? In recent years, Norwegian CECs have attempted different activites that stretch or go beyond the standard trio of education, consultation, and policy work. We studied the novel activities of Norwegian CECs by examining annual reports and interviewing CEC members. Through qualitative analysis we identified nine categories of novel CEC activities, which we describe by way of examples. In light of the findings, we argue that some novel working methods may be well suited to promote ethical reflection among clinicians, and that the CEC may be a suitable venue for discussing issues of organizational ethics.

  1. A clinical report of Type III dens invaginatus: relevant aspects of a combined therapeutic approach.

    PubMed

    Silva E Souza, Patricia de Almeida Rodrigues; de Almeida, Bruno Vila Nova; Tartari, Talita; Alves, Ana Claudia Braga Amoras; Tuji, Farbicio Mesquita; Silva E Souza, Mario Honorato

    2013-01-01

    Dens invaginatus is a developmental abnormality that alters dental morphology; as a result, treating this condition is a challenge for endodontic practices. This article describes how a combination of nonsurgical and surgical therapies was utilized to treat a maxillary central incisor with Type III dens invaginatus and vital pulp. The treatment plan included using computed tomography (CT) for a detailed analysis of the dental anatomy and periapical area, endodontic and surgical procedures, and a 4-year follow-up period that included periodic clinical and radiographic examinations. The follow-up examinations revealed a regression of the apical lesion and no other signs or symptoms. Based on the present case report, the authors concluded that this combination of surgical and nonsurgical approaches was effective and that CT is a valuable auxiliary tool for the study of dental anatomy. PMID:23302365

  2. Gain-of-Function Research and the Relevance to Clinical Practice.

    PubMed

    Kilianski, Andy; Nuzzo, Jennifer B; Modjarrad, Kayvon

    2016-05-01

    The ongoing moratorium on gain-of-function (GOF) research with highly pathogenic avian influenza virus, severe acute respiratory syndrome coronavirus, and Middle East respiratory syndrome coronavirus has drawn attention to the current debate on these research practices and the potential benefits and risks they present. While much of the discussion has been steered by members of the microbiology and policy communities, additional input from medical practitioners will be highly valuable toward developing a broadly inclusive policy that considers the relative value and harm of GOF research. This review attempts to serve as a primer on the topic for the clinical community by providing a historical context for GOF research, summarizing concerns about its risks, and surveying the medical products that it has yielded. PMID:26416657

  3. Gain-of-Function Research and the Relevance to Clinical Practice.

    PubMed

    Kilianski, Andy; Nuzzo, Jennifer B; Modjarrad, Kayvon

    2016-05-01

    The ongoing moratorium on gain-of-function (GOF) research with highly pathogenic avian influenza virus, severe acute respiratory syndrome coronavirus, and Middle East respiratory syndrome coronavirus has drawn attention to the current debate on these research practices and the potential benefits and risks they present. While much of the discussion has been steered by members of the microbiology and policy communities, additional input from medical practitioners will be highly valuable toward developing a broadly inclusive policy that considers the relative value and harm of GOF research. This review attempts to serve as a primer on the topic for the clinical community by providing a historical context for GOF research, summarizing concerns about its risks, and surveying the medical products that it has yielded.

  4. Clinical food hypersensitivity: the relevance of duodenal immunoglobulin E-positive cells.

    PubMed

    Caffarelli, C; Romanini, E; Caruana, P; Street, M E; de' Angelis, G

    1998-10-01

    Owing to poor reliability of laboratory tests, diagnosis of food allergy is based on clinical response to double-blind placebo-controlled food challenge. The aim of the present study was to assess the value of duodenal IgE-positive cells in the diagnosis of food allergy. Thirty-one children with a history of possible food allergy underwent duodenal biopsies, skin prick tests, and measurement of serum IgE antibodies, and were put on an elimination diet followed by food challenge. Open food challenges were performed in patients under 12 mo of age, and double-blind placebo-controlled challenges were for suspected foods. On the basis of clinical food hypersensitivity, patients were divided into two groups. Group 1 consisted of 13 children with food allergy. Thirteen of 20 positive provocations elicited reactions within 12 h from the end of the challenge, seven later. Group 2 was the control group and included 18 patients with negative food challenges. The number of IgE-positive cells in biopsy specimens was significantly more elevated in group 1 with respect to group 2 (153.24 +/- 83.13 versus 18.4 +/- 18.9; p < 0.01). Total serum IgE levels were elevated compared with that of the control group (p < 0.01) and correlated with the number of IgE-positive cells (p < 0.001, r = 0.62). Enhanced IgE-containing cells were found in all delayed reactors, but about one-third had negative skin prick tests or specific serum IgE antibodies to the offending foods. Our results showed that systemic reactions to foods are associated with an IgE-mediated response in the duodenal mucosa. Larger studies would be required to assess the predictive value of an increased number of IgE-positive cells in the diagnosis of allergy to food, especially in children with delayed reactions.

  5. Clinical relevance of voltage-gated potassium channel–complex antibodies in children

    PubMed Central

    Hacohen, Yael; Singh, Rahul; Rossi, Meghan; Lang, Bethan; Hemingway, Cheryl; Lim, Ming

    2015-01-01

    Objective: To assess the clinical and immunologic findings in children with voltage-gated potassium channel (VGKC)-complex antibodies (Abs). Methods: Thirty-nine of 363 sera, referred from 2 pediatric centers from 2007 to 2013, had been reported positive (>100 pM) for VGKC-complex Abs. Medical records were reviewed retrospectively and the patients' condition was independently classified as inflammatory (n = 159) or noninflammatory (n = 204). Positive sera (>100 pM) were tested/retested for the VGKC-complex Ab–positive complex proteins LGI1 and CASPR2, screened for binding to live hippocampal neurons, and 12 high-titer sera (>400 pM) tested by radioimmunoassay for binding to VGKC Kv1 subunits with or without intracellular postsynaptic density proteins. Results: VGKC-complex Abs were found in 39 children, including 20% of encephalopathies and 7.6% of other conditions (p = 0.001). Thirty children had inflammatory conditions and 9 had noninflammatory etiologies but titers >400 pM (n = 12) were found only in inflammatory diseases (p < 0.0001). Four sera, including from 2 children with coexisting NMDA receptor Abs and one with Guillain-Barré syndrome and Abs to both LGI1 and CASPR2, bound to hippocampal neurons. None of the sera bound detectably to VGKC Kv1 subunits on live HEK cells, but 4 of 12 >400 pM sera immunoprecipitated VGKC Kv1 subunits, with or without postsynaptic densities, extracted from transfected cells. Conclusion: Positive VGKC-complex Abs cannot be taken to indicate a specific clinical syndrome in children, but appear to be a nonspecific biomarker of inflammatory neurologic diseases, particularly of encephalopathy. Some of the Abs may bind to intracellular epitopes on the VGKC subunits, or to the intracellular interacting proteins, but in many the targets remain undefined. PMID:26296514

  6. Relationship of Premenstrual Syndrome and Premenstrual Dysphoric Disorder with Major Depression: Relevance to Clinical Practice

    PubMed Central

    Padhy, Susanta Kumar; Sarkar, Sidharth; Beherre, Prakash B.; Rathi, Rajesh; Panigrahi, Mahima; Patil, Pradeep Sriram

    2015-01-01

    Background: Premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD) and depressive disorder are fairly common; symptoms do overlap, often under-identified and under-emphasized, particularly in rural India. Objective: The objective was to assess the occurrence of PMS and PMDD in a sample of students and staff of a nursing college and to find their correlation with depression. Materials and Methods: A prospective cohort study; Tertiary Care Hospital in Rural India (Wardha, Maharashtra); 118 female nursing students or staff aged between 18 and 40 years, who were likely to stay within the institution for the study period. The participants were rated on Penn daily symptom report prospectively for a period of 3-month. Those who scored positive were applied diagnostic and statistical manual of mental disorders, 4th edition, text revision (DSM-IV TR) criteria for PMDD; and were applied primary care evaluation of mental disorders depression screening followed by DSM-IV TR criteria for depression. Severity of depression was measured using Hamilton Depression Rating Scale. Results: Main outcome measures were frequency and severity of depression in individuals with PMS and PMDD and their clinical and sociodemographic correlation. The age range of the sample was 18-37 years. Some PMS symptoms were observed in 67%; diagnosis of PMDD in 10%; depressive symptoms in 28% of the sample. 46.4% of those with depressive symptoms had major depression. The diagnosis of major depression was significantly associated with the severity of PMS symptoms as well as the presence of PMDD. Conclusion: Premenstrual syndrome is present in a substantial proportion of young females. Concurrent depression is increased by the severity of PMS symptoms and the presence of PMDD. Gynecologist needs to screen such subjects for depression and refer to mental-health professional early, in routine clinical practice. PMID:25969600

  7. Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing

    PubMed Central

    Jiang, Yong-hui; Yuen, Ryan K.C.; Jin, Xin; Wang, Mingbang; Chen, Nong; Wu, Xueli; Ju, Jia; Mei, Junpu; Shi, Yujian; He, Mingze; Wang, Guangbiao; Liang, Jieqin; Wang, Zhe; Cao, Dandan; Carter, Melissa T.; Chrysler, Christina; Drmic, Irene E.; Howe, Jennifer L.; Lau, Lynette; Marshall, Christian R.; Merico, Daniele; Nalpathamkalam, Thomas; Thiruvahindrapuram, Bhooma; Thompson, Ann; Uddin, Mohammed; Walker, Susan; Luo, Jun; Anagnostou, Evdokia; Zwaigenbaum, Lonnie; Ring, Robert H.; Wang, Jian; Lajonchere, Clara; Wang, Jun; Shih, Andy; Szatmari, Peter; Yang, Huanming; Dawson, Geraldine; Li, Yingrui; Scherer, Stephen W.

    2013-01-01

    Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms. PMID:23849776

  8. Clinical relevance of CHEK2 and NBN mutations in the macedonian population

    PubMed Central

    Kostovska, I Maleva; Jakimovska, M; Kubelka-Sabit, K; Karadjozov, M; Arsovski, A; Stojanovska, L; Plaseska-Karanfilska, D

    2015-01-01

    Clinical importance of the most common CHEK2 (IVS2+1 G>A, 1100delC, I157T and del5395) and NBN (R215W and 657del5) gene mutations for breast cancer development in Macedonian breast cancer patients is unknown. We performed a case-control study including 300 Macedonian breast cancer patients and 283 Macedonian healthy controls. Genotyping was done using a fast and highly accurate single-nucleotide primer extension method for the detection of five mutations in a single reaction. The detection of the del5395 was performed using an allele-specific duplex polymerase chain reaction (PCR) assay. We have found that mutations were more frequent in breast cancer patients (n = 13, 4.3%) than in controls (n = 5, 1.8%), although without statistical significance. Twelve patients were heterozygous for one of the analyzed mutations, while one patient had two mutations (NBN R215W and CHEK2 I157T). The most frequent variant was I157T, found in 10 patients and four controls (p = 0.176) and was found to be associated with familial breast cancer (p = 0.041). CHEK2 1100delC and NBN 657del5 were each found in one patient and not in the control group. CHEK2 IVS2+1G>A and del5395 were not found in our cohort. Frequencies of the studied mutations are low and they are not likely to represent alleles of clinical importance in the Macedonian population. PMID:26929905

  9. Clinical Relevance of Trace Bands on Serum Electrophoresis in Patients Without a History of Gammopathy

    PubMed Central

    Gwathmey, TanYa M.; Willis, Monte S.; Tatreau, Jason; Wang, Shaobin; McCudden, Christopher R.

    2015-01-01

    Serum protein electrophoresis (SPE) and immunofixation is commonly used to screen for plasma cell dyscrasias. Interpretation of these tests is qualitative by nature and can yield trace, faint, or scarcely visible immunoglobulin bands (TFS), which can be difficult to classify. Whether these bands should be reported at all is challenging given their unknown clinical significance. In the present study, we retrospectively analyzed 14,036 physician-ordered protein SPE and immunofixation electrophoresis (IFE) tests on serum and urine specimens (from 4,091 patients) during the period of 2000-2010. We found that 17% of all IFE results evaluated for the presence of monoclonal gammopathies (2,389 out of 14,036) contained TFS bands, representing 4.2% (173 out of 4091) of all patients evaluated. Sixty of these patients (42%) had no previous history of gammopathy, and were clinically evaluated over a mean period of up to five years from the original diagnosis of plasma cell pathology. None of these patients had progressed to multiple myeloma, lymphoplasmacytic lymphoma, plasmacytoma, or leukemia. The remaining 82 patients (58%) had a previous history of gammopathy, but had not progressed to any symptomatic plasma cell dyscrasia. Evaluation of these patients was followed for a median period of 4.3 years, with a mean of 21.5 IFE tests per individual. These data suggest that for patients without a previous history of gammopathy, the presence of TFS bands on serum protein electrophoresis does not warrant frequent follow up investigation as commonly practiced. Routine follow up of patients with a prior history of gammopathy, conversely, are warranted and may contribute to overall survival with multiple treatment options now available. For those interpreting IFE results, it may be worth considering these data when composing comments regarding suggested repeat testing frequency by SPE/IFE or alternate test methods.

  10. Assessment of elasticity of colorectal cancer tissue, clinical utility, pathological and phenotypical relevance

    PubMed Central

    Kawano, Shingo; Kojima, Motohiro; Higuchi, Yoichi; Sugimoto, Motokazu; Ikeda, Koji; Sakuyama, Naoki; Takahashi, Shinichiro; Hayashi, Ryuichi; Ochiai, Atsushi; Saito, Norio

    2015-01-01

    Generally, cancer tissue is palpated as a hard mass. However, the elastic nature of cancer tissue is not well understood. The aim of the present study was to evaluate the clinical utility of measuring the elastic modulus (EM) in colorectal cancer tissue. Using a tactile sensor, we measured the EM of 106 surgically resected colorectal cancer tissues. Data on the EM were compared with clinicopathological findings, including stromal features represented by Azan staining and the α-SMA positive area ratio of the tumor area. Finally, a cDNA microarray profile of the tumors with high EM were compared with the findings of tumors with low EM. A higher EM in tumors was associated with pathological T, N, and M-stage tumors (P < 0.001, P = 0.001 and P = 0.011, respectively). Patients with high EM tumors had shorter disease-free survival than had patients with low EM. The EM showed strongly positive correlation with the Azan staining positive area ratio (r = 0.908) and the α-SMA positive area ratio (r = 0.921). Finally, the cDNA microarray data of the tumors with high EM revealed a distinct gene expression profile compared with data from those tumors with low EM. The assessment of the elasticity of colorectal cancer tissue may allow a more accurate clinical stage and prognosis estimation. The distinct phenotypical features of the high EM tumors and their strong association with stromal features suggest the existence of a biological mechanism involved in this phenomenon that may contribute to future therapy. PMID:26083008

  11. Clinical Relevance of the Tumor Location-Modified Lauren Classification System of Gastric Cancer

    PubMed Central

    Choi, Jang Kyu; Park, Young Suk; Jung, Do Hyun; Son, Sang Yong; Ahn, Sang Hoon; Kim, Hyung Ho

    2015-01-01

    Purpose The Lauren classification system is a very commonly used pathological classification system of gastric adenocarcinoma. A recent study proposed that the Lauren classification should be modified to include the anatomical location of the tumor. The resulting three types were found to differ significantly in terms of genomic expression profiles. This retrospective cohort study aimed to evaluate the clinical significance of the modified Lauren classification (MLC). Materials and Methods A total of 677 consecutive patients who underwent curative gastrectomy from January 2005 to December 2007 for histologically confirmed gastric cancer were included. The patients were divided according to the MLC into proximal non-diffuse (PND), diffuse (D), and distal non-diffuse (DND) type. The groups were compared in terms of clinical features and overall survival. Multivariate analysis served to assess the association between MLC and prognosis. Results Of the 677 patients, 48, 358, and 271 had PND, D, and DND, respectively. Their 5-year overall survival rates were 77.1%, 77.7%, and 90.4%. Compared to D and PND, DND was associated with significantly better overall survival (both P<0.01). Multivariate analysis showed that age, differentiation, lympho-vascular invasion, T and N stage, but not MLC, were independent prognostic factors for overall survival. Multivariate analysis of early gastric cancer patients showed that MLC was an independent prognostic factor for overall survival (odds ratio, 5.946; 95% confidence intervals, 1.524~23.197; P=0.010). Conclusions MLC is prognostic for survival in patients with gastric adenocarcinoma, in early gastric cancer. DND was associated with an improved prognosis compared to PND or D. PMID:26468416

  12. Epigenetic regulation of EFEMP1 in prostate cancer: biological relevance and clinical potential

    PubMed Central

    Almeida, Mafalda; Costa, Vera L; Costa, Natália R; Ramalho-Carvalho, João; Baptista, Tiago; Ribeiro, Franclim R; Paulo, Paula; Teixeira, Manuel R; Oliveira, Jorge; Lothe, Ragnhild A; Lind, Guro E; Henrique, Rui; Jerónimo, Carmen

    2014-01-01

    Epigenetic alterations are common in prostate cancer (PCa) and seem to contribute decisively to its initiation and progression. Moreover, aberrant promoter methylation is a promising biomarker for non-invasive screening. Herein, we sought to characterize EFEMP1 as biomarker for PCa, unveiling its biological relevance in prostate carcinogenesis. Microarray analyses of treated PCa cell lines and primary tissues enabled the selection of differentially methylated genes, among which EFEMP1 was further validated by MSP and bisulfite sequencing. Assessment of biomarker performance was accomplished by qMSP. Expression analysis of EFEMP1 and characterization of histone marks were performed in tissue samples and cancer cell lines to determine the impact of epigenetic mechanisms on EFEMP1 transcriptional regulation. Phenotypic assays, using transfected cell lines, permitted the evaluation of EFEMP1’s role in PCa development. EFEMP1 methylation assay discriminated PCa from normal prostate tissue (NPT; P < 0.001, Kruskall–Wallis test) and renal and bladder cancers (96% sensitivity and 98% specificity). EFEMP1 transcription levels inversely correlated with promoter methylation and histone deacetylation, suggesting that both epigenetic mechanisms are involved in gene regulation. Phenotypic assays showed that EFEMP1 de novo expression reduces malignant phenotype of PCa cells. EFEMP1 promoter methylation is prevalent in PCa and accurately discriminates PCa from non-cancerous prostate tissues and other urological neoplasms. This epigenetic alteration occurs early in prostate carcinogenesis and, in association with histone deacetylation, progressively leads to gene down-regulation, fostering cell proliferation, invasion and evasion of apoptosis. PMID:25211630

  13. Diagnostic and clinical relevance of the autophago-lysosomal network in human gliomas

    PubMed Central

    Jennewein, Lukas; Ronellenfitsch, Michael W.; Antonietti, Patrick; Ilina, Elena I.; Jung, Jennifer; Stadel, Daniela; Flohr, Lisa-Marie; Zinke, Jenny; von Renesse, Janusz; Drott, Ulrich; Baumgarten, Peter; Braczynski, Anne K.; Penski, Cornelia; Burger, Michael C.; Theurillat, Jean-Philippe; Steinbach, Joachim P.; Plate, Karl-Heinz; Dikic, Ivan; Fulda, Simone; Brandts, Christian; Kögel, Donat; Behrends, Christian; Harter, Patrick N.; Mittelbronn, Michel

    2016-01-01

    Recently, the conserved intracellular digestion mechanism ‘autophagy’ has been considered to be involved in early tumorigenesis and its blockade proposed as an alternative treatment approach. However, there is an ongoing debate about whether blocking autophagy has positive or negative effects in tumor cells. Since there is only poor data about the clinico-pathological relevance of autophagy in gliomas in vivo, we first established a cell culture based platform for the in vivo detection of the autophago-lysosomal components. We then investigated key autophagosomal (LC3B, p62, BAG3, Beclin1) and lysosomal (CTSB, LAMP2) molecules in 350 gliomas using immunohistochemistry, immunofluorescence, immunoblotting and qPCR. Autophagy was induced pharmacologically or by altering oxygen and nutrient levels. Our results show that autophagy is enhanced in astrocytomas as compared to normal CNS tissue, but largely independent from the WHO grade and patient survival. A strong upregulation of LC3B, p62, LAMP2 and CTSB was detected in perinecrotic areas in glioblastomas suggesting micro-environmental changes as a driver of autophagy induction in gliomas. Furthermore, glucose restriction induced autophagy in a concentration-dependent manner while hypoxia or amino acid starvation had considerably lesser effects. Apoptosis and autophagy were separately induced in glioma cells both in vitro and in vivo. In conclusion, our findings indicate that autophagy in gliomas is rather driven by micro-environmental changes than by primary glioma-intrinsic features thus challenging the concept of exploitation of the autophago-lysosomal network (ALN) as a treatment approach in gliomas. PMID:26956048

  14. Integrative topological analysis of mass spectrometry data reveals molecular features with clinical relevance in esophageal squamous cell carcinoma.

    PubMed

    Gao, She-Gan; Liu, Rui-Min; Zhao, Yun-Gang; Wang, Pei; Ward, Douglas G; Wang, Guang-Chao; Guo, Xiang-Qian; Gu, Juan; Niu, Wan-Bin; Zhang, Tian; Martin, Ashley; Guo, Zhi-Peng; Feng, Xiao-Shan; Qi, Yi-Jun; Ma, Yuan-Fang

    2016-02-22

    Combining MS-based proteomic data with network and topological features of such network would identify more clinically relevant molecules and meaningfully expand the repertoire of proteins derived from MS analysis. The integrative topological indexes representing 95.96% information of seven individual topological measures of node proteins were calculated within a protein-protein interaction (PPI) network, built using 244 differentially expressed proteins (DEPs) identified by iTRAQ 2D-LC-MS/MS. Compared with DEPs, differentially expressed genes (DEGs) and comprehensive features (CFs), structurally dominant nodes (SDNs) based on integrative topological index distribution produced comparable classification performance in three different clinical settings using five independent gene expression data sets. The signature molecules of SDN-based classifier for distinction of early from late clinical TNM stages were enriched in biological traits of protein synthesis, intracellular localization and ribosome biogenesis, which suggests that ribosome biogenesis represents a promising therapeutic target for treating ESCC. In addition, ITGB1 expression selected exclusively by integrative topological measures correlated with clinical stages and prognosis, which was further validated with two independent cohorts of ESCC samples. Thus the integrative topological analysis of PPI networks proposed in this study provides an alternative approach to identify potential biomarkers and therapeutic targets from MS/MS data with functional insights in ESCC.

  15. Integrative topological analysis of mass spectrometry data reveals molecular features with clinical relevance in esophageal squamous cell carcinoma

    PubMed Central

    Gao, She-Gan; Liu, Rui-Min; Zhao, Yun-Gang; Wang, Pei; Ward, Douglas G.; Wang, Guang-Chao; Guo, Xiang-Qian; Gu, Juan; Niu, Wan-Bin; Zhang, Tian; Martin, Ashley; Guo, Zhi-Peng; Feng, Xiao-Shan; Qi, Yi-Jun; Ma, Yuan-Fang

    2016-01-01

    Combining MS-based proteomic data with network and topological features of such network would identify more clinically relevant molecules and meaningfully expand the repertoire of proteins derived from MS analysis. The integrative topological indexes representing 95.96% information of seven individual topological measures of node proteins were calculated within a protein-protein interaction (PPI) network, built using 244 differentially expressed proteins (DEPs) identified by iTRAQ 2D-LC-MS/MS. Compared with DEPs, differentially expressed genes (DEGs) and comprehensive features (CFs), structurally dominant nodes (SDNs) based on integrative topological index distribution produced comparable classification performance in three different clinical settings using five independent gene expression data sets. The signature molecules of SDN-based classifier for distinction of early from late clinical TNM stages were enriched in biological traits of protein synthesis, intracellular localization and ribosome biogenesis, which suggests that ribosome biogenesis represents a promising therapeutic target for treating ESCC. In addition, ITGB1 expression selected exclusively by integrative topological measures correlated with clinical stages and prognosis, which was further validated with two independent cohorts of ESCC samples. Thus the integrative topological analysis of PPI networks proposed in this study provides an alternative approach to identify potential biomarkers and therapeutic targets from MS/MS data with functional insights in ESCC. PMID:26898710

  16. Understanding the Supersensitive Anti-Drug Antibody Assay: Unexpected High Anti-Drug Antibody Incidence and Its Clinical Relevance

    PubMed Central

    2016-01-01

    Numbers of biotherapeutic products in development have increased over past decade. Despite providing significant benefits to patients with unmet needs, almost all protein-based biotherapeutics could induce unwanted immunogenicity, which result in a loss of efficacy and/or increase the risk of adverse reactions, such as infusion reactions, anaphylaxis, and even life-threatening response to endogenous proteins. Recognizing these possibilities, regulatory agencies request that immunogenicity be assessed as part of the approval process for biotherapeutics. Great efforts have been made to reduce drug immunogenicity through protein engineering. Accordingly the immunogenicity incidence has been reduced from around 80% in murine derived products to 0–10% in fully human products. However, recent improvements in immunogenicity assays have led to unexpectedly high immunogenicity rates, even in fully human products, leading to new challenges in assessing immunogenicity and its clinical relevance. These new immunogenicity assays are becoming supersensitive and able to detect more of anti-drug antibodies (ADA) than with earlier assays. This paper intends to review and discuss our understanding of the supersensitive ADA assay and the unexpected high ADA incidence and its potential clinical relevance. PMID:27340678

  17. The effects of clinically relevant doses of amphetamine and methylphenidate on signal detection and DRL in rats.

    PubMed

    Andrzejewski, Matthew E; Spencer, Robert C; Harris, Rachel L; Feit, Elizabeth C; McKee, Brenda L; Berridge, Craig W

    2014-04-01

    Low dose amphetamine (AMPH) and methylphenidate (MPH, Ritalin(®)) are the most widely prescribed and most effective pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD). Certain low, clinically relevant doses of MPH improve sustained attention and working memory in normal rats, in contrast to higher doses that impair cognitive ability and induce locomotor activity. However, the effects of AMPH of MPH on sustained attention and behavioral inhibition remain poorly characterized. The present experiments examined the actions of AMPH (0.1 and 0.25 mg/kg) and MPH (0.5 and 1.0 mg/kg) in a rat model of 1) sustained attention, where signal and blank trials were interspersed randomly and occurred at unpredictable times, and 2) behavioral inhibition, using a differential reinforcement of low rate (DRL) schedule. In a signal detection paradigm, both 0.5 mg/kg and 1.0 mg/kg MPH and 0.25 mg/kg AMPH improve sustained attention, however neither AMPH nor MPH improve behavioral inhibition on DRL. Taken together with other recent studies, it appears that clinically-relevant doses of AMPH and MPH may preferentially improve attention-related behavior while having little effect on behavioral inhibition. These observations provide additional insight into the basic behavioral actions of low-dose psychostimulants and further suggest that the use of sustained attention tasks may be important in the development of novel pharmacological treatments for ADHD.

  18. Clinical relevance of aberrant polypoid nodule scar after endoscopic submucosal dissection

    PubMed Central

    Arantes, Vitor; Uedo, Noriya; Pedrosa, Moises Salgado; Tomita, Yasuhiko

    2016-01-01

    AIM To describe a series of patients with aberrant polypoid nodule scar developed after gastric endoscopic submucosal dissection (ESD), and to discuss its pathogenesis and clinical management. METHODS We reviewed retrospectively the endoscopic database of two academic institutions located in Brazil and Japan and searched for all patients that underwent ESD to manage gastric neoplasms from 2003 to 2015. The criteria for admission in the study were: (1) successful en bloc ESD procedure with R0 and curative resection confirmed histologically; (2) postoperative endoscopic examination with identification of a polypoid nodule scar (PNS) at ESD scar; (3) biopsies of the PNS with hyperplastic or regenerative tissue, reviewed by two independent experienced gastrointestinal pathologists, one from each Institution. Data were examined for patient demographics, Helicobacter pylori status, precise neoplastic lesion location in the stomach, tumor size, histopathological assessment of the ESD specimen, and postoperative information including medical management, endoscopic and histological findings, and clinical outcome. RESULTS A total of 14 patients (10 men/4 women) fulfilled the inclusion criteria and were enrolled in this study. One center contributed with 8 cases out of 60 patients (13.3%) from 2008 to 2015. The second center contributed with 6 cases (1.7%) out of 343 patients from 2003 to 2015. Postoperative endoscopic follow-up revealed similar findings in all patients: A protruded polypoid appearing nodule situated in the center of the ESD scar surrounded by convergence of folds. Biopsies samples were taken from PNS, and histological assessment revealed in all cases regenerative and hyperplastic tissue, without recurrent tumor or dysplasia. Primary neoplastic lesions were located in the antrum in 13 patients and in the angle in one patient. PNS did not develop in any patient after ESD undertaken for tumors located in the corpus, fundus or cardia. All patients have been

  19. Clinical relevance of aberrant polypoid nodule scar after endoscopic submucosal dissection

    PubMed Central

    Arantes, Vitor; Uedo, Noriya; Pedrosa, Moises Salgado; Tomita, Yasuhiko

    2016-01-01

    AIM To describe a series of patients with aberrant polypoid nodule scar developed after gastric endoscopic submucosal dissection (ESD), and to discuss its pathogenesis and clinical management. METHODS We reviewed retrospectively the endoscopic database of two academic institutions located in Brazil and Japan and searched for all patients that underwent ESD to manage gastric neoplasms from 2003 to 2015. The criteria for admission in the study were: (1) successful en bloc ESD procedure with R0 and curative resection confirmed histologically; (2) postoperative endoscopic examination with identification of a polypoid nodule scar (PNS) at ESD scar; (3) biopsies of the PNS with hyperplastic or regenerative tissue, reviewed by two independent experienced gastrointestinal pathologists, one from each Institution. Data were examined for patient demographics, Helicobacter pylori status, precise neoplastic lesion location in the stomach, tumor size, histopathological assessment of the ESD specimen, and postoperative information including medical management, endoscopic and histological findings, and clinical outcome. RESULTS A total of 14 patients (10 men/4 women) fulfilled the inclusion criteria and were enrolled in this study. One center contributed with 8 cases out of 60 patients (13.3%) from 2008 to 2015. The second center contributed with 6 cases (1.7%) out of 343 patients from 2003 to 2015. Postoperative endoscopic follow-up revealed similar findings in all patients: A protruded polypoid appearing nodule situated in the center of the ESD scar surrounded by convergence of folds. Biopsies samples were taken from PNS, and histological assessment revealed in all cases regenerative and hyperplastic tissue, without recurrent tumor or dysplasia. Primary neoplastic lesions were located in the antrum in 13 patients and in the angle in one patient. PNS did not develop in any patient after ESD undertaken for tumors located in the corpus, fundus or cardia. All patients have been

  20. Are licensed canine parvovirus (CPV2 and CPV2b) vaccines able to elicit protection against CPV2c subtype in puppies?: A systematic review of controlled clinical trials.

    PubMed

    Hernández-Blanco, Beatriz; Catala-López, Ferrán

    2015-10-22

    Severe gastroenteritis caused by canine parvovirus type 2 (CPV2) is a serious life-threatening disease in puppies less than 4-months of age. The emergence of new variants has provoked some concern about the cross-protection elicited by licensed canine parvovirus modified-live type 2 (CPV2) and type 2b (CPV2b) vaccines against the most recent subtype CPV2c. A systematic review was carried out to assess the efficacy of commercial vaccines. We conducted a literature search of Pub Med/MEDLINE from January 1990 to May 2014. This was supplemented by hand-searching of related citations and searches in Google/Google Scholar. Controlled clinical trials in which vaccinated puppies were challenged with CPV2c virus were evaluated. Reporting of outcome measures and results for vaccine efficacy were critically appraised through a variety of clinical signs, serological tests, virus shedding and the ability to overcome maternally derived antibodies (MDA) titres. Six controlled clinical trials were included in the review. In most cases, the results of the selected studies reported benefits in terms of clinical signs, serological tests and virus shedding. However, MDA interference was not considered or evaluated in 5 of the selected trials. No accurate definitions of baseline healthy status and/or clinical outcomes were provided. Methods of randomization, allocation concealment and blinding were usually poorly reported. As a result of the limited number of included studies matching the inclusion criteria, the small sample sizes, short follow-up and the methodological limitations observed, it was not possible to reach a final conclusion regarding the cross-protection of licensed CPV2 and CPV2b vaccines against the subtype 2c in puppies. Further and specifically designed trials are required in order to elucidate whether cross-protection is acquired from licensed CPV vaccines.

  1. The Power of Phase I Studies to Detect Clinical Relevant QTc Prolongation: A Resampling Simulation Study

    PubMed Central

    Ferber, Georg; Lorch, Ulrike; Täubel, Jörg

    2015-01-01

    Concentration-effect (CE) models applied to early clinical QT data from healthy subjects are described in the latest E14 Q&A document as promising analysis to characterise QTc prolongation. The challenges faced if one attempts to replace a TQT study by thorough ECG assessments in Phase I based on CE models are the assurance to obtain sufficient power and the establishment of a substitute for the positive control to show assay sensitivity providing protection against false negatives. To demonstrate that CE models in small studies can reliably predict the absence of an effect on QTc, we investigated the role of some key design features in the power of the analysis. Specifically, the form of the CE model, inclusion of subjects on placebo, and sparse sampling on the performance and power of this analysis were investigated. In this study, the simulations conducted by subsampling subjects from 3 different TQT studies showed that CE model with a treatment effect can be used to exclude small QTc effects. The number of placebo subjects was also shown to increase the power to detect an inactive drug preventing false positives while an effect can be underestimated if time points around tmax are missed. PMID:26509147

  2. The evolution and clinical relevance of prognostic classification systems in myelofibrosis.

    PubMed

    Bose, Prithviraj; Verstovsek, Srdan

    2016-03-01

    Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by often debilitating constitutional symptoms and splenomegaly, bone marrow fibrosis and resultant cytopenias, extramedullary hematopoiesis, risk of leukemic transformation, and shortened survival. Post-polycythemia vera and post-essential thrombocythemia myelofibrosis represent similar entities, although some differences are being recognized. Attempts to classify patients with myelofibrosis into prognostic categories have been made since the late 1980s, and these scoring systems continue to evolve as new information becomes available. Over the last decade, the molecular pathogenesis of MPNs has been elucidated considerably, and the Janus kinase (JAK) 1/2 inhibitor ruxolitinib is the first drug specifically approved by the US Food and Drug Administration to treat patients with intermediate-risk and high-risk myelofibrosis. This article reviews the evolution of prognostic criteria in myelofibrosis, emphasizing the major systems widely in use today, as well as recently described, novel systems that incorporate emerging data regarding somatic mutations. Risk factors for thrombosis and conversion to MPN blast phase also are discussed. Finally, the practical usefulness of the current prognostic classification systems in terms of clinical decision making is discussed, particularly within the context of some of their inherent weaknesses. Cancer 2016;122:681-692. © 2015 American Cancer Society. PMID:26717494

  3. Molecular Probes for Diagnosis of Clinically Relevant Bacterial Infections in Blood Cultures▿

    PubMed Central

    Hansen, Wendy L. J.; Beuving, Judith; Bruggeman, Cathrien A.; Wolffs, Petra F. G.

    2010-01-01

    Broad-range real-time PCR and sequencing of the 16S rRNA gene region is a widely known method for the detection and identification of bacteria in clinical samples. However, because of the need for sequencing, such identification of bacteria is time-consuming. The aim of our study was to develop a more rapid 16S real-time PCR-based identification assay using species- or genus-specific probes. The Gram-negative bacteria were divided into Pseudomonas species, Pseudomonas aeruginosa, Escherichia coli, and other Gram-negative species. Within the Gram-positive species, probes were designed for Staphylococcus species, Staphylococcus aureus, Enterococcus species, Streptococcus species, and Streptococcus pneumoniae. The assay also included a universal probe within the 16S rRNA gene region for the detection of all bacterial DNA. The assay was evaluated with a collection of 248 blood cultures. In this study, the universal probe and the probes targeting Pseudomonas spp., P. aeruginosa, E. coli, Streptococcus spp., S. pneumoniae, Enterococcus spp., and Staphylococcus spp. all had a sensitivity and specificity of 100%. The probe specific for S. aureus showed eight discrepancies, resulting in a sensitivity of 100% and a specificity of 93%. These data showed high agreement between conventional testing and our novel real-time PCR assay. Furthermore, this assay significantly reduced the time needed for identification. In conclusion, using pathogen-specific probes offers a faster alternative for pathogen detection and could improve the diagnosis of bloodstream infections. PMID:20962139

  4. Soluble Epidermal Growth Factor Receptors (sEGFRs) in Cancer: Biological Aspects and Clinical Relevance

    PubMed Central

    Maramotti, Sally; Paci, Massimiliano; Manzotti, Gloria; Rapicetta, Cristian; Gugnoni, Mila; Galeone, Carla; Cesario, Alfredo; Lococo, Filippo

    2016-01-01

    The identification of molecules that can reliably detect the presence of a tumor or predict its behavior is one of the biggest challenges of research in cancer biology. Biological fluids are intriguing mediums, containing many molecules that express the individual health status and, accordingly, may be useful in establishing the potential risk of cancer, defining differential diagnosis and prognosis, predicting the response to treatment, and monitoring the disease progression. The existence of circulating soluble growth factor receptors (sGFRs) deriving from their membrane counterparts has stimulated the interest of researchers to investigate the use of such molecules as potential cancer biomarkers. But what are the origins of circulating sGFRs? Are they naturally occurring molecules or tumor-derived products? Among these, the epidermal growth factor receptor (EGFR) is a cell-surface molecule significantly involved in cancer development and progression; it can be processed into biological active soluble isoforms (sEGFR). We have carried out an extensive review of the currently available literature on the sEGFRs and their mechanisms of regulation and biological function, with the intent to clarify the role of these molecules in cancer (and other pathological conditions) and, on the basis of the retrieved evidences, speculate about their potential use in the clinical setting. PMID:27104520

  5. Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants.

    PubMed

    Kobayashi, Masanori; Nakahara, Koichiro; Seki, Takahiro; Miki, Shigeru; Kawauchi, Shinobu; Suyama, Akemi; Wakasa-Morimoto, Chiaki; Kodama, Makoto; Endoh, Takeshi; Oosugi, Eiichi; Matsushita, Yoshihiro; Murai, Hitoshi; Fujishita, Toshio; Yoshinaga, Tomokazu; Garvey, Edward; Foster, Scott; Underwood, Mark; Johns, Brian; Sato, Akihiko; Fujiwara, Tamio

    2008-11-01

    Resistance passage studies were conducted with five INIs (integrase inhibitors) that have been tested in clinical trials to date: a new naphthyridinone-type INI S/GSK-364735, raltegravir, elvitegravir, L-870,810 and S-1360. In establishing the passage system and starting from concentrations several fold above the EC(50) value, resistance mutations against S-1360 and related diketoacid-type compounds could be isolated from infected MT-2 cell cultures from day 14 to 28. Q148R and F121Y were the two main pathways of resistance to S/GSK-364735. Q148R/K and N155H, which were found in patients failing raltegravir treatment in Phase IIb studies, were observed during passage with raltegravir with this method. The fold resistance of 40 mutant molecular clones versus wild type virus was compared with these five INIs. The overall resistance pattern of S/GSK-364735 was similar to that of raltegravir and other INIs. However, different fold resistances of particular mutations were noted among different INIs, reflecting a potential to develop INIs with distinctly different resistant profiles.

  6. Structure-activity relationship studies on clinically relevant HIV-1 NNRTIs.

    PubMed

    Rawal, R K; Murugesan, V; Katti, S B

    2012-01-01

    In addition to the nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs) and integrase inhibitors (INIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) have contributed significantly in the treatment of HIV-1 infections. More than 60 structurally different classes of compounds have been identified as NNRTIs, which are specifically inhibiting HIV-1 reverse transcriptase (RT). Five NNRTIs (nevirapine, delavirdine, efavirenz, etravirine and rilpivirine) have been approved by US Food and Drug Administration (FDA) for clinical use. The NNRTIs bind with a specific 'pocket' site of HIV-1 RT (allosteric site) that is closely associated with the NRTI binding site. Due to mutations of the amino acid residues surrounding the NNRTI-binding site, NNRTIs are notorious for rapidly eliciting resistance. Though, the emergence of resistant HIV strains can be circumvented if the NNRTIs are used either alone or in combination with NRTIs (AZT, 3TC, ddI, ddC, TVD or d4T) and PIs (Indinavir, nelfinavir, saquinavir, ritonavir and lopinavir etc.) as shown by both a decrease in plasma HIV-1 RNA levels and increased CD4 T-cells. Here we are going to discuss recent advances in structure activity relationship studies on nevirapine, delavirdine, efavirenz, etravirine, rilpivirine and 4-thiazolidinones (priv