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Sample records for clinically relevant species

  1. Assessment of relevant fungal species in clinical solid wastes.

    PubMed

    Noman, Efaq Ali; Al-Gheethi, A A; Rahman, Nik Norulaini Nik Ab; Nagao, H; Ab Kadir, M O

    2016-10-01

    The study aimed to determine the fungal diversity in clinical waste samples from a healthcare facility in Penang Malaysia. Different fungi species were detected in 83.75 % of the 92 clinical waste samples that were screened from different sections of the healthcare facility. One hundred fifty fungal isolates comprising of 8 genera and 36 species were obtained. They were purified by using single spore isolation technique. Subsequently, the isolates were identified by phenotypic method based on morphological and culture characteristics on different culture media. Among all fungal isolates, Aspergillus spp. in section Nigri 10.2 %, Aspergillus niger 9.5 %, Aspergillus fumigatus 8.8 %, Penicillium. simplicissium 8 %, Aspergillus tubingensis 7.3 %, Aspergillus terreus var. terreus 6.6 %, Penicillium waksmanii 5.9 % and Curvularia lunata 6.5 % were the most frequent. Among five sections of the Wellness Centre, the clinical wastes collected from the diagnostic labs of haematology section had the highest numbers of fungal species (29 species). Glove wastes had the highest numbers of fungal species (19 species) among 17 types of clinical wastes screened. Among all fungal species, Aspergillus spp. exhibited higher growth at 37 °C than at 28 °C, indicating the potential of these opportunistic fungi to cause diseases in human. These results indicated the potential of hospital wastes as reservoirs for fungal species.

  2. Clinical relevance of infections with zoonotic and human oral species of Campylobacter.

    PubMed

    Lee, Soomin; Lee, Jeeyeon; Ha, Jimyeong; Choi, Yukyung; Kim, Sejeong; Lee, Heeyoung; Yoon, Yohan; Choi, Kyoung-Hee

    2016-07-01

    Genus Campylobacter has been recognized as a causative bacterial agent of animal and human diseases. Human Campylobacter infections have caused more concern. Campylobacters can be classified into two groups in terms of their original host: zoonotic and human oral species. The major zoonotic species are Campylobacter jejuni and Campylobacter coli, which mostly reside in the intestines of avian species and are transmitted to humans via consumption of contaminated poultry products, thus causing human gastroenteritis and other diseases as sequelae. The other campylobacters, human oral species, include C. concisus, C. showae, C. gracilis, C. ureolyticus, C. curvus, and C. rectus. These species are isolated from the oral cavity, natural colonization site, but have potential clinical relevance in the periodontal region to varying extent. Two species, C. jejuni and C. coli, are believed to be mainly associated with intestinal diseases, but recent studies suggested that oral Campylobacter species also play a significant role in intestinal diseases. This review offers an outline of the two Campylobacter groups (zoonotic and human oral), their virulence traits, and the associated illnesses including gastroenteritis.

  3. Species Recognition and Clinical Relevance of the Zygomycetous Genus Lichtheimia (syn. Absidia Pro Parte, Mycocladus) ▿

    PubMed Central

    Alastruey-Izquierdo, Ana; Hoffmann, Kerstin; de Hoog, G. Sybren; Rodriguez-Tudela, Juan Luis; Voigt, Kerstin; Bibashi, Evangelia; Walther, Grit

    2010-01-01

    The zygomycete genus Lichtheimia (syn. Absidia pro parte, Mycocladus) consists of saprotrophic fungi inhabiting soil or dead plant material. Lichtheimia corymbifera (syn. Absidia corymbifera, Mycocladus corymbifer) and Lichtheimia ramosa (syn. Absidia ramosa, Mycocladus ramosus) may cause fulminant infections in patients with impaired immunity. The present study investigated the species boundaries in Lichtheimia using genealogical concordance phylogenetic species recognition (by comparison of the genealogies of the internal transcribed spacer [ITS] sequence, the D1/D2 region of the large subunit [LSU], and actin), biological species recognition by mating tests, as well as morphological and physiological characteristics. The three molecular markers used were selected by evaluating the polymorphisms and paralogies of several loci, including those for β-tubulin, translation elongation factor 1α, the two largest subunits of the RNA polymerase II (RPB1 and RPB2), the mitochondrial cytochrome c oxidase subunit I (COI), and the mitochondrial small-subunit (mtSSU) rDNA, among four strains belonging to different putative species. Comparing the genealogies of the ITS, LSU, and actin genes, we recognized seven phylogenetic species. However, mating tests did not show intrinsic reproductive barriers for two pairs of the phylogenetic species. Therefore, we regard five species in Lichtheima to be confirmed: Lichtheimia corymbifera, L. ornata comb. nov., L. ramosa, L. hyalospora, and L. sphaerocystis sp. nov. Only the first three species seem to have clinical relevance. Lichtheimia blakesleeana is reduced to a synonym of Lichtheimia hyalospora. We provide a detailed description of Lichtheimia sphaerocystis sp. nov. and a key for the identification of all accepted species identified in the present study on the basis of their morphological traits and growth at different temperatures. PMID:20357218

  4. Silica Desiccant Packets for Storage and Transport of Streptococcus pneumoniae and Other Clinically Relevant Species

    PubMed Central

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

    2013-01-01

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

  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. 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.

  7. Description of Enterobacter ludwigii sp. nov., a novel Enterobacter species of clinical relevance.

    PubMed

    Hoffmann, Harald; Stindl, Sibylle; Stumpf, Anita; Mehlen, Andre; Monget, Daniel; Heesemann, Jürgen; Schleifer, Karl H; Roggenkamp, Andreas

    2005-04-01

    A new species, Enterobacter ludwigii, is presented on the basis of the characteristics of 16 strains, which were isolated from clinical specimens. These bacteria form a distinct genetic cluster in phylogenetic analyses of the population structure of the Enterobacter cloacae complex. As determined by DNA-DNA cross-hybridization experiments in microplates, this genetic cluster can be delineated from the other species of the E. cloacae complex with deltaTm values equal to or above 5 degrees C with Enterobacter hormaechei being the closest relative. The bacteria are gram-negative, fermentative, motile rods with the general characteristics of the genus Enterobacter and the E. cloacae complex in particular. E. ludwigii can be differentiated from the other Enterobacter species by its growth on myo-inositol and 3-0-methyl-D-glucopyranose. The type strain is EN-119 (= DSM 16688T = CIP 108491T).

  8. The 'species complex' issue in clinically relevant fungi: A case study in Scedosporium apiospermum.

    PubMed

    Chen, Min; Zeng, Jingsi; De Hoog, G Sybren; Stielow, Benjamin; Gerrits Van Den Ende, A H G; Liao, Wanqing; Lackner, Michaela

    2016-02-01

    The genus Scedosporium currently comprises six species, Scedosporium apiospermum, Scedosporium boydii, Pseudallescheria angusta, Scedosporium minutisporum, Scedosporium dehoogii, and Scedosporium aurantiacum, most of which can be distinguished with the primary fungal DNA barcode, the ITS1/2 region of the rDNA gene cluster. In the present study, four additional genetic loci were explored from a phylogenetic point of view enabling a barcoding approach based on K2P pairwise distances to resolve the taxa Scedosporium. We included partial γ-actin (ACT), β-tubulin (BT2), elongation factor 1α (TEF1), and the small ribosomal protein 60S L10 (L1) (RP60S). Phylogenetic inference of each marker individually showed that four out of six species within Scedosporium can be distinguished unambiguously, while strains of S. apiospermum, S. boydii, and P. angusta showed occasional recombination, and accordingly, no genealogical concordance between markers was obtainable. We defined S. apiospermum, S. boydii, and P. angusta as the 'S. apiospermum species complex' since observed differences were not consistent between lineages, and no clinical differences are known between entities within the complex. While BT2 revealed the best performance among the genetic loci tested at the lineage level, barcoding of the ITS region is sufficient for distinction of all entities in Scedosporium at the species or 'complex' level.

  9. Microbiological Features and Clinical Relevance of New Species of the Genus Mycobacterium

    PubMed Central

    2014-01-01

    SUMMARY Nontuberculous mycobacteria (NTM) are present in the environment, mainly in water, and are occasionally responsible for opportunistic infections in humans. Despite the fact that NTM are characterized by a moderate pathogenicity, the diseases caused by NTM at various body sites are increasing on a worldwide level. Among over 150 officially recognized NTM species, only two or three dozen are familiar to clinicians, and even to most microbiologists. In this paper, approximately 50 new species described in the last 8 years are reviewed, and their role in human infections is assessed on the basis of reported clinical cases. The small number of reports concerning most of the “new” mycobacterial species is responsible for the widespread conviction that they are very rare. Their role is actually largely underestimated, mainly because they often remain unrecognized and misidentified. Aiming to minimize such bias, emphasis has been placed on more common identification pitfalls. Together with new NTM, new members of the Mycobacterium tuberculosis complex described in the last few years are also an object of the present review. PMID:25278573

  10. Phylogeny and evolution of the aspartyl protease family from clinically relevant Candida species.

    PubMed

    Parra-Ortega, B; Cruz-Torres, H; Villa-Tanaca, L; Hernández-Rodríguez, C

    2009-05-01

    Aspartyl proteases are a class of enzymes that include the yeast aspartyl proteases and secreted aspartyl protease (Sap) superfamilies. Several Sap superfamily members have been demonstrated or suggested as virulence factors in opportunistic pathogens of the genus Candida. Candida albicans, Candida tropicalis, Candida dubliniensis and Candida parapsilosis harbour 10, four, eight and three SAP genes, respectively. In this work, genome mining and phylogenetic analyses revealed the presence of new members of the Sap superfamily in C. tropicalis (8), Candida guilliermondii (8), C. parapsilosis(11) and Candida lusitaniae (3). A total of 12 Sap families, containing proteins with at least 50% similarity, were discovered in opportunistic, pathogenic Candida spp. In several Sap families, at least two subfamilies or orthologous groups were identified, each defined by > 90% sequence similitude, functional similarity and synteny among its members. No new members of previously described Sap families were found in a Candida spp. clinical strain collection; however, the universality of SAPT gene distribution among C. tropicalis strains was demonstrated. In addition, several features of opportunistic pathogenic Candida species, such as gene duplications and inversions, similitude, synteny, putative transcription factor binding sites and genome traits of SAP gene superfamily were described in a molecular evolutionary context.

  11. Rapid identification of biothreat and other clinically relevant bacterial species by use of universal PCR coupled with high-resolution melting analysis.

    PubMed

    Yang, Samuel; Ramachandran, Padmini; Rothman, Richard; Hsieh, Yu-Hsiang; Hardick, Andrew; Won, Helen; Kecojevic, Aleksandar; Jackman, Joany; Gaydos, Charlotte

    2009-07-01

    A rapid assay for eubacterial species identification is described using high-resolution melt analysis to characterize PCR products. Unique melt profiles generated from multiple hypervariable regions of the 16S rRNA gene for 100 clinically relevant bacterial pathogens, including category A and B biothreat agents and their surrogates, allowed highly specific species identification.

  12. Point-of-care salivary microbial tests for detection of cariogenic species--clinical relevance thereof--review.

    PubMed

    Lenčová, E; Broukal, Z; Spížek, J

    2010-11-01

    Dental caries is a highly prevalent multifactorial disease that can result in serious health impairment. It was shown that oral bacteria play a significant role in caries development. Point-of-care (POC) salivary microbial tests for detection of cariogenic species have been investigated as a potential tool for caries risk assessment. This review aims to evaluate clinical relevance of these tests in the light of recent scientific evidence. Methodology involved PubMed search using key words salivary microbial tests, cariogenic bacteria and caries risk prediction. Articles obtained by the search were cross-referenced to obtain further sources. Specificity and negative-predictive value of these tests are higher than their sensitivity and positive value. Predictive power of the POC salivary microbial tests as a single predictor is generally weak, although it increases when included in multifactorial models for caries prediction. Literature findings support the use of these tests for screening of at-risk individuals in a population of young preschool children without visible caries and for motivation of subjects on individual level. POC salivary microbial tests are simple and inexpensive and, therefore, may be advantageous from public health perspective.

  13. Enterobacter and Klebsiella species isolated from fresh vegetables marketed in Valencia (Spain) and their clinically relevant resistances to chemotherapeutic agents.

    PubMed

    Falomir, María Pilar; Rico, Hortensia; Gozalbo, Daniel

    2013-12-01

    Occurrence of antibiotic-resistant pathogenic or commensal enterobacteria in marketed agricultural foodstuffs may contribute to their incorporation into the food chain and constitutes an additional food safety concern. In this work, we have determined the clinically relevant resistances to 11 common chemotherapeutic agents in Enterobacter and Klebsiella isolates from fresh vegetables from various sources (supermarkets and greengrocers' shops in Valencia, Spain). A total of 96 isolates were obtained from 160 vegetables analyzed (50% positive samples): 68 Enterobacter isolates (59 E. cloacae, two E. aerogenes, two E. cancerogenus, one E. gergoviae, and four E. sakazakii, currently Cronobacter spp.), and 28 Klebsiella isolates (19 K. oxytoca and 9 K. pneumoniae). Only seven isolates were susceptible to all agents tested, and no resistances to ceftazidime, ciprofloxacin, gentamicin, and chloramphenicol were detected. Most isolates were resistant to amoxicillin/clavulanic acid (74 [58 Enterobacter and 16 Klebsiella]) or to ampicillin (80 [55/25]). Other resistances were less frequent: nitrofurantoin (13 isolates [12/1]), tetracycline (6 [5/1]), co-trimoxazole (3 [3/0]), cefotaxime (1 [1/0]), and streptomycin (2 [1/1]). Multiresistant isolates to two (56 [41/15]), three (10 E. cloacae isolates), four (one E. cloacae and one K. pneumoniae isolate), and five (two E. cloacae isolates) chemotherapeutic agents were also detected. The presence of potential pathogens points to marketed fresh produce, which often is eaten raw, as a risk factor for consumer health. In addition, these results support the usefulness of these bacterial species as indicators of the spreading of antibiotic resistances into the environment, particularly in the food chain, and suggest their role as carriers of resistance determinants from farms to consumers, which may constitute an additional "silent" food safety concern. Therefore, there is a need to improve the hygienic quality of marketed fresh

  14. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry for fast and accurate identification of clinically relevant Aspergillus species.

    PubMed

    Alanio, A; Beretti, J-L; Dauphin, B; Mellado, E; Quesne, G; Lacroix, C; Amara, A; Berche, P; Nassif, X; Bougnoux, M-E

    2011-05-01

    New Aspergillus species have recently been described with the use of multilocus sequencing in refractory cases of invasive aspergillosis. The classical phenotypic identification methods routinely used in clinical laboratories failed to identify them adequately. Some of these Aspergillus species have specific patterns of susceptibility to antifungal agents, and misidentification may lead to inappropriate therapy. We developed a matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS)-based strategy to adequately identify Aspergillus species to the species level. A database including the reference spectra of 28 clinically relevant species from seven Aspergillus sections (five common and 23 unusual species) was engineered. The profiles of young and mature colonies were analysed for each reference strain, and species-specific spectral fingerprints were identified. The performance of the database was then tested on 124 clinical and 16 environmental isolates previously characterized by partial sequencing of the β-tubulin and calmodulin genes. One hundred and thirty-eight isolates of 140 (98.6%) were correctly identified. Two atypical isolates could not be identified, but no isolate was misidentified (specificity: 100%). The database, including species-specific spectral fingerprints of young and mature colonies of the reference strains, allowed identification regardless of the maturity of the clinical isolate. These results indicate that MALDI-TOF MS is a powerful tool for rapid and accurate identification of both common and unusual species of Aspergillus. It can give better results than morphological identification in clinical laboratories.

  15. Development of Two Molecular Approaches for Differentiation of Clinically Relevant Yeast Species Closely Related to Candida guilliermondii and Candida famata

    PubMed Central

    Feng, Xiaobo; Wu, Jingsong; Ling, Bo; Yang, Xianwei; Liao, Wanqing

    2014-01-01

    The emerging pathogens Candida palmioleophila, Candida fermentati, and Debaryomyces nepalensis are often misidentified as Candida guilliermondii or Candida famata in the clinical laboratory. Due to the significant differences in antifungal susceptibilities and epidemiologies among these closely related species, a lot of studies have focused on the identification of these emerging yeast species in clinical specimens. Nevertheless, limited tools are currently available for their discrimination. Here, two new molecular approaches were established to distinguish these closely related species. The first approach differentiates these species by use of restriction fragment length polymorphism analysis of partial internal transcribed spacer 2 (ITS2) and large subunit ribosomal DNA with the enzymes BsaHI and XbaI in a double digestion. The second method involves a multiplex PCR based on the intron size differences of RPL18, a gene coding for a protein component of the large (60S) ribosomal subunit, and species-specific amplification. These two methods worked well in differentiation of these closely related yeast species and have the potential to serve as effective molecular tools suitable for laboratory diagnoses and epidemiological studies. PMID:24951804

  16. Development of two molecular approaches for differentiation of clinically relevant yeast species closely related to Candida guilliermondii and Candida famata.

    PubMed

    Feng, Xiaobo; Wu, Jingsong; Ling, Bo; Yang, Xianwei; Liao, Wanqing; Pan, Weihua; Yao, Zhirong

    2014-09-01

    The emerging pathogens Candida palmioleophila, Candida fermentati, and Debaryomyces nepalensis are often misidentified as Candida guilliermondii or Candida famata in the clinical laboratory. Due to the significant differences in antifungal susceptibilities and epidemiologies among these closely related species, a lot of studies have focused on the identification of these emerging yeast species in clinical specimens. Nevertheless, limited tools are currently available for their discrimination. Here, two new molecular approaches were established to distinguish these closely related species. The first approach differentiates these species by use of restriction fragment length polymorphism analysis of partial internal transcribed spacer 2 (ITS2) and large subunit ribosomal DNA with the enzymes BsaHI and XbaI in a double digestion. The second method involves a multiplex PCR based on the intron size differences of RPL18, a gene coding for a protein component of the large (60S) ribosomal subunit, and species-specific amplification. These two methods worked well in differentiation of these closely related yeast species and have the potential to serve as effective molecular tools suitable for laboratory diagnoses and epidemiological studies.

  17. Vacuum phenomenon: Clinical relevance.

    PubMed

    Gohil, Ishan; Vilensky, Joel A; Weber, Edward C

    2014-04-01

    Vacuum phenomenon (VP) is an anatomical entity of potential confusion in the diagnosis and evaluation of joint pathology. Observation of this phenomenon has been demonstrated on basic radiographs, computed tomography, and magnetic resonance imaging. Although VP is most often associated with degenerative joint disease, it is observed with other pathologies. Two problematic scenarios can occur: a false-positive diagnosis of serious pathology instead of benign VP and a false-negative diagnosis of benign VP with a more serious underlying process Despite this potential for confusion, criteria for distinguishing VP from other causes of joint pain and for evaluating a suspected case of VP have not been fully established. We reviewed the literature to determine underlying mechanism, symptomology, associated pathologies, and clinical importance of VP. The formation of VP can be explained by gas solubility, pressure-volume relationships, and human physiology. CT, GRE-MRI, and multipositional views are the best imaging studies to view VP. Although most cases of VP are benign, it can be associated with clinical signs and symptoms. VP outside the spine is an underreported finding on imaging studies. VP should be on the differential diagnosis for joint pain, especially in the elderly. We have proposed criteria for diagnosing VP and generated a basic algorithm for its workup. Underreporting of this phenomenon shows a lack of awareness of VP on the part of physicians. By identifying true anatomic VP, we can prevent harm from suboptimal treatment of patients.

  18. [Clinical research VI. Clinical relevance].

    PubMed

    Talavera, Juan O; Rivas-Ruiz, Rodolfo

    2011-01-01

    Usually, in clinical practice the maneuver selected is the one that achieves a favorable outcome with a direct percentage of superiority of at least 10 %, or when the number needed to treat is approximately equal to 10. While this percentage difference is practical for estimating the magnitude of an association, we need to differentiate the impact measures (attributable risk, preventable fraction), measures of association (RR, OR, HR), and frequency measures (incidence and prevalence) applicable when the outcome is nominal. And we must identify ways to measure the strength of association and the magnitude of the association when the outcome variable is quantitative. It is not uncommon to interpret the measures of association as if they were impact measures. For example, for a RR of 0.68, it is common to assume a 32 % reduction of the outcome, but we must consider that this is a relative reduction, which comes from relations of 0.4/0.6, 0.04/0.06, or 0.00004/0.00006. However the direct reduction is 20 % (60 % - 40 %), 2 %, and 2 per 100,000, respectively. Therefore, to estimate the impact of a maneuver it is important to have the direct difference and/or NNT.

  19. Efficient Identification of Clinically Relevant Candida Yeast Species by Use of an Assay Combining Panfungal Loop-Mediated Isothermal DNA Amplification with Hybridization to Species-Specific Oligonucleotide Probes▿

    PubMed Central

    Inácio, João; Flores, Orfeu; Spencer-Martins, Isabel

    2008-01-01

    The occurrence of invasive mycoses has progressively increased in recent years. Yeasts of the genus Candida remain the leading etiologic agents of those infections. Early identification of opportunistic yeasts may contribute significantly to improved disease management and the selection of appropriate antifungal therapy. We developed a rapid and reliable molecular identification system for clinically relevant yeasts that makes use of nonspecific primers to amplify a region of the 26S rRNA gene, followed by reverse hybridization of the digoxigenin-labeled products to a panel of species-specific oligonucleotide probes arranged on a nylon membrane macroarray format. DNA amplification was achieved by the recently developed loop-mediated isothermal DNA amplification technology, a promising option for the development of improved laboratory diagnostic kits. The newly developed method was successful in distinguishing among the major clinically relevant yeasts associated with bloodstream infections by using simple, rapid, and cost-effective procedures and equipment. PMID:18077626

  20. Clinical Relevance of Nontuberculous Mycobacteria, Oman

    PubMed Central

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

    2009-01-01

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

  1. Valerian: No Evidence for Clinically Relevant Interactions

    PubMed Central

    Nieber, Karen; Kraft, Karin

    2014-01-01

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

  2. [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.

  3. Women with epilepsy: clinically relevant issues

    PubMed Central

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

    2016-01-01

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

    PubMed Central

    Simmon, Keith E.; Fisher, Mark A.

    2012-01-01

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

  5. Fetal magnetocardiography: clinical relevance and feasibility

    NASA Astrophysics Data System (ADS)

    ter Brake, H. J. M.; Rijpma, A. P.; Stinstra, J. G.; Borgmann, J.; Holland, H. J.; Krooshoop, H. J. G.; Peters, M. J.; Flokstra, J.; Quartero, H. W. P.; Rogalla, H.

    2002-03-01

    We investigated the feasibility of a high- Tc SQUID system for fetal magnetocardiography (fetal MCG) aiming at a system without a magnetically shielded room and cooled by a cryocooler. The targeted SQUID resolution was 50 fT/√Hz (1-100 Hz). The research was performed along three lines: environmental noise suppression, cooling and low- Tc experiments. Environmental noise can be suppressed by forming second-order gradiometers from individual magnetometers. Concerning cooling, we investigated the applicability of commercially available coolers. In the low- Tc experiments, the medical relevance of fetal MCG was clearly shown. However, they also indicated that, in order to fully exploit the medical potential, the targeted resolution has to be 10 fT/√Hz. This increased resolution, in combination with the required high reliability of the sensors, will be hard to realize in high- Tc technology. This paper describes the results of the project and discusses the feasibility of a clinical system.

  6. [Sports cardiology : Overview of relevant clinical topics].

    PubMed

    Laszlo, R; Scharhag, J; Burgstahler, C; Striegel, H; Steinacker, J M

    2017-01-23

    Physical activity is nowadays an established therapeutic principle concerning primary and secondary prevention of cardiovascular diseases; therefore, in internal sports medicine various aspects go beyond basic cardiological knowledge and require special medical expertise (sports cardiology). Acute cardiac risk is increased during physical activity; therefore, physical activity should be individually phased under consideration of the whole clinical situation. Physical training results in a functional adaptation of the cardiovascular system. Moreover, a structural adaptation can also be observed in competitive athletes but a differentiation between athlete's heart and cardiomyopathy is sometimes challenging. Preparticipation screening verifiably reduces the incidence of sudden cardiac death in athletes. Respective recommendations for the required diagnostics have been published and statutory health insurances are increasingly more willing to bear the incurred costs. Statistically, doping is more frequent in performance-orientated leisure time sports than in competitive sports. Drugs which are relevant for doping have partially irreversible cardiac side effects.

  7. HUPO initiatives relevant to clinical proteomics.

    PubMed

    Hanash, Sam

    2004-04-01

    The past few years have seen a tremendous interest in the potential of proteomics to address unmet needs in biomedicine. Such unmet needs include more effective strategies for early disease detection and monitoring and more effective therapies, in addition to developing a better understanding of disease pathogenesis. Proteomics is particularly suited for investigating biological fluids to identify disease-related alterations and to develop molecular signatures for disease processes. However, much of the effort undertaken in clinical proteomics to date represents either demonstrations of principles or relatively small-scale studies when compared with genomics effort and accomplishments or more pertinently when contrasted with the tremendous untapped potential of clinical proteomics. Clearly, we are in the early stages. What seems to be urgently needed is an organized effort to build a solid foundation for proteomics that includes developing a much needed infrastructure with adequate resources. The Human Proteome Organization (HUPO) is fostering an organized international effort in proteomics that includes initiatives around organ systems and biological fluids that have disease relevance as well as development of proteomics resources.

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

    PubMed

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

    2015-01-01

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

  9. 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.

  10. [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.

  11. 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

  12. 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

  13. 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

  14. Clinical Relevance Of Systematic CRT Device Optimization.

    PubMed

    Lunati, Maurizio; Magenta, Giovanni; Cattafi, Giuseppe; Moreo, Antonella; Falaschi, Giacomo; Contardi, Danilo; Locati, Emanuela

    2014-01-01

    Cardiac Resynchronization Therapy (CRT) is known as a highly effective therapy in advanced heart failure patients with cardiac dyssynchrony. However, still one third of patients do not respond (or sub-optimally respond) to CRT. Among the many contributors for the high rate of non-responders, the lack of procedures dedicated to CRT device settings optimization (parameters to regulate AV synchrony and VV synchrony) is known as one of the most frequent. The most recent HF/CRT Guidelines do not recommend to carry-out optimization procedures in every CRT patient; they simply state those procedures "could be useful in selected patients", even though their role in improving response has not been proven. Echocardiography techniques still remain the gold-standard reference method to the purpose of CRT settings optimization. However, due to its severe limitations in the routine of CRT patients management (time and resource consuming, scarce reproducibility, inter and intra-operator dependency), echocardiography optimization is widely under-utilized in the real-world of CRT follow-up visits. As a consequence, device-based techniques have been developed to by-pass the need for repeated echo examinations to optimize CRT settings. In this report the available device-based optimization techniques onboard on CRT devices are shortly reviewed, with a specific focus on clinical outcomes observed in trials comparing these methods vs. clinical practice or echo-guided optimization methods. Particular emphasis is dedicated to hemodynamic methods and automaticity of optimization algorithms (making real the concept of "ambulatory CRT optimization"). In fact a hemodynamic-based approach combined with a concept of frequent re-optimization has been associated - although retrospectively - with a better clinical outcome on the long-term follow-up of CRT patients. Large randomized trials are ongoing to prospectively clarify the impact of automatic optimization procedures.

  15. Clinically relevant pharmacogenomic testing in pediatric practice.

    PubMed

    Korbel, Lindsey; George, Mathew; Kitzmiller, Joseph

    2014-08-01

    Clinicians and patients continue to convey interest in personalized medicine. The objective of personalized medicine is to improve healthcare by tailoring disease prevention, diagnosis, and treatment strategies for individuals based on their unique clinical history and genetic composition. This article offers an overview of pharmacogenomics, discusses caveats specific to pharmacogenomics in pediatric populations, provides evidence-based recommendations for pediatric clinicians, and offers insight regarding the future role of pharmacogenomics testing in pediatric medicine. Reviews of the current literature and thoughtful discussions are presented regarding the pharmacogenomics of antidepressants, codeine and oncologic, asthma, and immunomodulatory pharmacotherapies.

  16. 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.

  17. Clinically relevant advances in rheumatoid arthritis therapy.

    PubMed

    Müller-Ladner, Ulf; Neumann, Elena; Tarner, Ingo H

    2009-09-14

    Owing to the success of biologics in the treatment of rheumatoid arthritis (RA), several novel drugs have been introduced in the therapeutic armamentarium, although not all of them have been approved in all countries worldwide. Among the drugs are tumour necrosis factor (TNF) inhibitors such as certolizumab pegol and golimumab (the latter of which was the first TNF blocker shown to be effective in patients who had been unsuccessfully treated with other TNF blockers and which can be applied only once a month), and the interleukin-6 receptor antagonist tocilizumab, which not only opens up a completely new field of anti-inflammatory modulation of RA pathophysiology, but also highlights the challenge of novel potential side effects. Moreover, aside from clinical studies showing efficacy in the inhibition of osteoclast activation by the anti-RANKL (receptor activator of nuclear factor-kappa B ligand) antibody denosumab, an improved form of steroid application known as slow-release 'tempus tablet' for treatment of RA and several developments in the small-molecule area have been addressed by clinical trials.

  18. Melatonin and glucose metabolism: clinical relevance.

    PubMed

    Lardone, P J; Alvarez-Sanchez, Sanchez N; Guerrero, J M; Carrillo-Vico, A

    2014-01-01

    The role of melatonin in glucose homeostasis is an active area of investigation. There is a growing body of evidence suggesting a link between disturbances in melatonin production and impaired insulin, glucose, lipid metabolism, and antioxidant capacity. Furthermore, melatonin has been found to influence insulin secretion both in vivo and in vitro, and night-time melatonin levels are related to night-time insulin concentrations in patients with diabetes. In several recent studies, a single nucleotide polymorphism of the human melatonin receptor 1B has been described as being causally linked to an increased risk of developing type 2 diabetes. Taken together, these data suggest that endogenous as well as exogenous melatonin may play a role in diabetes and associated metabolic disturbances not only by regulating insulin secretion but also by providing protection against reactive oxygen species, considering pancreatic β-cells are particularly susceptible to oxidative stress because they possess only low-antioxidative capacity.

  19. 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

  20. Bed Bugs: Clinical Relevance and Control Options

    PubMed Central

    Dwyer, Dominic E.; Peñas, Pablo F.; Russell, Richard C.

    2012-01-01

    Summary: Since the late 1990s, bed bugs of the species Cimex lectularius and Cimex hemipterus have undergone a worldwide resurgence. These bed bugs are blood-sucking insects that readily bite humans. Cutaneous reactions may occur and can start out as small macular lesions that can develop into distinctive wheals of around 5 cm in diameter, which are accompanied by intense itching. Occasionally, bullous eruptions may result. If bed bugs are numerous, the patient can present with widespread urticaria or eythematous rashes. Often, bites occur in lines along the limbs. Over 40 pathogens have been detected in bed bugs, but there is no definitive evidence that they transmit any disease-causing organisms to humans. Anemia may result when bed bugs are numerous, and their allergens can trigger asthmatic reactions. The misuse of chemicals and other technologies for controlling bed bugs has the potential to have a deleterious impact on human health, while the insect itself can be the cause of significant psychological trauma. The control of bed bugs is challenging and should encompass a multidisciplinary approach utilizing nonchemical means of control and the judicious use of insecticides. For accommodation providers, risk management procedures should be implemented to reduce the potential of bed bug infestations. PMID:22232375

  1. Bed bugs: clinical relevance and control options.

    PubMed

    Doggett, Stephen L; Dwyer, Dominic E; Peñas, Pablo F; Russell, Richard C

    2012-01-01

    Since the late 1990s, bed bugs of the species Cimex lectularius and Cimex hemipterus have undergone a worldwide resurgence. These bed bugs are blood-sucking insects that readily bite humans. Cutaneous reactions may occur and can start out as small macular lesions that can develop into distinctive wheals of around 5 cm in diameter, which are accompanied by intense itching. Occasionally, bullous eruptions may result. If bed bugs are numerous, the patient can present with widespread urticaria or eythematous rashes. Often, bites occur in lines along the limbs. Over 40 pathogens have been detected in bed bugs, but there is no definitive evidence that they transmit any disease-causing organisms to humans. Anemia may result when bed bugs are numerous, and their allergens can trigger asthmatic reactions. The misuse of chemicals and other technologies for controlling bed bugs has the potential to have a deleterious impact on human health, while the insect itself can be the cause of significant psychological trauma. The control of bed bugs is challenging and should encompass a multidisciplinary approach utilizing nonchemical means of control and the judicious use of insecticides. For accommodation providers, risk management procedures should be implemented to reduce the potential of bed bug infestations.

  2. Chronic HCV infection: epidemiological and clinical relevance.

    PubMed

    Zaltron, S; Spinetti, A; Biasi, L; Baiguera, C; Castelli, F

    2012-01-01

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

  3. Chronic HCV infection: epidemiological and clinical relevance

    PubMed Central

    2012-01-01

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

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

    ERIC Educational Resources Information Center

    Blake, Margaret Lehman

    2006-01-01

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

  5. 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...

  6. Assay Platform for Clinically Relevant Metallo-β-lactamases

    PubMed Central

    2013-01-01

    Metallo-β-lactamases (MBLs) are a growing threat to the use of almost all clinically used β-lactam antibiotics. The identification of broad-spectrum MBL inhibitors is hampered by the lack of a suitable screening platform, consisting of appropriate substrates and a set of clinically relevant MBLs. We report procedures for the preparation of a set of clinically relevant metallo-β-lactamases (i.e., NDM-1 (New Delhi MBL), IMP-1 (Imipenemase), SPM-1 (São Paulo MBL), and VIM-2 (Verona integron-encoded MBL)) and the identification of suitable fluorogenic substrates (umbelliferone-derived cephalosporins). The fluorogenic substrates were compared to chromogenic substrates (CENTA, nitrocefin, and imipenem), showing improved sensitivity and kinetic parameters. The efficiency of the fluorogenic substrates was exemplified by inhibitor screening, identifying 4-chloroisoquinolinols as potential pan MBL inhibitors. PMID:23898798

  7. Antidrug Antibody Formation in Oncology: Clinical Relevance and Challenges.

    PubMed

    van Brummelen, Emilie M J; Ros, Willeke; Wolbink, Gertjan; Beijnen, Jos H; Schellens, Jan H M

    2016-10-01

    : In oncology, an increasing number of targeted anticancer agents and immunotherapies are of biological origin. These biological drugs may trigger immune responses that lead to the formation of antidrug antibodies (ADAs). ADAs are directed against immunogenic parts of the drug and may affect efficacy and safety. In other medical fields, such as rheumatology and hematology, the relevance of ADA formation is well established. However, the relevance of ADAs in oncology is just starting to be recognized, and literature on this topic is scarce. In an attempt to fill this gap in the literature, we provide an up-to-date status of ADA formation in oncology. In this focused review, data on ADAs was extracted from 81 clinical trials with biological anticancer agents. We found that most biological anticancer drugs in these trials are immunogenic and induce ADAs (63%). However, it is difficult to establish the clinical relevance of these ADAs. In order to determine this relevance, the possible effects of ADAs on pharmacokinetics, efficacy, and safety parameters need to be investigated. Our data show that this was done in fewer than 50% of the trials. In addition, we describe the incidence and consequences of ADAs for registered agents. We highlight the challenges in ADA detection and argue for the importance of validating, standardizing, and describing well the used assays. Finally, we discuss prevention strategies such as immunosuppression and regimen adaptations. We encourage the launch of clinical trials that explore these strategies in oncology.

  8. Symptoms and clinical relevance: a dilemma for clinical trials on prevention of venous thromboembolism.

    PubMed

    Bounameaux, Henri; Agnelli, Giancarlo

    2013-04-01

    The outcomes of thromboprophylactic trials have been debated for decades. Recently, the 9th edition of the American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines based their strong recommendations only on patient-important outcomes. Practically, symptoms were considered the crucial element. Consequently, studies that primarily aimed at reducing venographic thrombi were considered less pertinent than studies that focused on symptomatic thrombosis. In the present viewpoint, we challenge the argument that "symptomatic" and "clinically relevant" are interchangeable. In particular, the case is made that asymptomatic events may be clinically relevant and that asymptomatic venographically detected thrombosis is a clinically relevant surrogate outcome for fatal pulmonary embolism.

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

    PubMed Central

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

    2016-01-01

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

  10. Clinically relevant drug–drug interactions in oncology

    PubMed Central

    McLeod, Howard L

    1998-01-01

    Although anticancer agents are one of the most toxic classes of medication prescribed today, there is relatively little information available about clinically relevant drug–drug interactions. Pharmacokinetic drug interactions have been described, including alterations in absorption, catabolism, and excretion. For example, an increased bioavailability of 6-mercaptopurine has been observed when combined with either allopurinol or methotrexate, leading to increased toxicity in some patients. Induction of etoposide or teniposide clearance by anticonvulsants has also been described, resulting in a lower systemic exposure and risk for lower anticancer activity. Alterations in elimination of methotrexate has been observed with probenecid, presumably through competition for renal secretion. There are also several examples of pharmacodynamic interactions. The combination of 5-fluorouracil plus folinic acid results in more efficient inhibition of thymidylate synthase, a finding which is now utilized routinely in the treatment of colorectal cancer. Improvements in the in vitro and early clinical testing now allow a relatively high degree of prediction of potential clinical drug interactions, prior to observations of untoward drug effects. In conclusion, drug interactions among commonly used anticancer agents have been identified. Their clinical significance can have more impact than many other classes of medications due to the narrow therapeutic index of antineoplastic agents and the potential for lethal side-effects. It is only through prospective, preclinical and early clinical evaluation that the presence of clinically significant drug interactions can be identified and the information used to provide better therapy for this significant health problem. PMID:9663808

  11. Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance.

    PubMed

    Dinis-Oliveira, Ricardo Jorge

    2017-02-01

    Psilocybin and psilocin are controlled substances in many countries. These are the two main hallucinogenic compounds of the "magic mushrooms" and both act as agonists or partial agonists at 5-hydroxytryptamine (5-HT)2A subtype receptors. During the last few years, psilocybin and psilocin have gained therapeutic relevance but considerable physiological variability between individuals that can influence dose-response and toxicological profile has been reported. This review aims to discuss metabolism of psilocybin and psilocin, by presenting all major and minor psychoactive metabolites. Psilocybin is primarily a pro-drug that is dephosphorylated by alkaline phosphatase to active metabolite psilocin. This last is then further metabolized, psilocin-O-glucuronide being the main urinary metabolite with clinical and forensic relevance in diagnosis.

  12. Clinically-Relevant Cell Sources for TMJ Disc Engineering

    PubMed Central

    Johns, D.E.; Wong, M. E.; Athanasiou, K.A.

    2010-01-01

    Tissue-engineering of the temporomandibular joint (TMJ) disc aims to provide patients with TMJ disorders an option to replace diseased tissue with autologous, functional tissue. This study examined clinically-relevant cell sources by comparing costal chondrocytes, dermal fibroblasts, a mixture of the two, and TMJ disc cells in a scaffoldless tissue-engineering approach. It was hypothesized that all constructs would produce matrix relevant to the TMJ disc, but the mixture constructs were expected to appear most like the TMJ disc constructs. Costal chondrocyte and mixture constructs were morphologically and biochemically superior to the TMJ disc and dermal fibroblast constructs, and their compressive properties were not significantly different. Costal chondrocyte constructs produced almost 40 times more collagen and 800 times more glycosaminoglycans than TMJ constructs. This study demonstrates the ability of costal chondrocytes to produce extracellular matrix that may function in a TMJ disc replacement. PMID:18502963

  13. 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

  14. Hazelnut Allergens: Molecular Characterization, Detection, and Clinical Relevance.

    PubMed

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

    2016-11-17

    In last few years, special attention has been given to food-induced allergies, in which hazelnut allergy is highlighted. Hazelnut is one of the most commonly consumed tree nuts, being largely used by the food industry in a variety of processed foods. It has been regarded as a food with potential health benefits, but also as a source of allergens capable of inducing mild to severe allergic reactions in sensitized individuals. Considering the great number of reports addressing hazelnut allergens, with an estimated increasing trend, this review intends to assemble all the relevant information available so far on the following main issues: prevalence of tree nut allergy, clinical threshold levels, molecular characterization of hazelnut allergens (Cor a 1, Cor a 2, Cor a 8, Cor a 9, Cor a 10, Cor a 11, Cor a 12, Cor a 14, and Cor a TLP) and their clinical relevance, and methodologies for detection of hazelnut allergens in foods. A comprehensive overview of the current data about the molecular characterization of hazelnut allergens is presented, relating to biochemical classification and biological function with clinical importance. Recent advances in hazelnut allergen detection methodologies are summarized and compared, including all the novel protein-based and DNA-based approaches.

  15. [FeLV infection in the cat: clinically relevant aspects].

    PubMed

    Boretti, F S; Lutz, H; Hofmann-Lehmann, R

    2011-11-01

    The feline leukemia virus (FeLV) is a retrovirus of the domestic cat that was described almost 50 years ago. The FeLV-infection may lead to fatal diseases in domestic and small wild cats. The use of efficacious diagnostics assays and vaccines led to a reduction of the FeLV prevalence; however, FeLV still poses a problem for the cat presented with the infection. This article aims to describe recent developments in diagnostics and findings in the infection pathogenesis that are clinically relevant.

  16. 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

  17. Clinical relevance and biology of circulating tumor cells

    PubMed Central

    2011-01-01

    Most breast cancer patients die due to metastases, and the early onset of this multistep process is usually missed by current tumor staging modalities. Therefore, ultrasensitive techniques have been developed to enable the enrichment, detection, isolation and characterization of disseminated tumor cells in bone marrow and circulating tumor cells in the peripheral blood of cancer patients. There is increasing evidence that the presence of these cells is associated with an unfavorable prognosis related to metastatic progression in the bone and other organs. This review focuses on investigations regarding the biology and clinical relevance of circulating tumor cells in breast cancer. PMID:22114869

  18. Cervical ribs: identification on MRI and clinical relevance.

    PubMed

    Walden, Michael J; Adin, Mehmet E; Visagan, Ravindran; Viertel, Valentina G; Intrapiromkul, Jarunee; Maluf, Fernando; Patel, Neil V; Alluwaimi, Fatma; Lin, Doris; Yousem, David M

    2013-01-01

    To determine the prevalence of cervical ribs on cervical spine MRI and clinical relevance, we reviewed 2500 studies for cervical ribs and compression of neurovascular structures and compared to CT, when available. Brachial plexus or subclavian artery contact by cervical rib was identified on MRI and/or CT in 12 cases with diagnosis of thoracic outlet syndrome in one. Cervical ribs were identified on 1.2% (25/2083) of examinations, lower than on CT (2%), but MRI may offer equivalent anatomic explanation for patient symptoms.

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

    PubMed

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

    2015-11-01

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

  20. Endoplasmic reticulum stress in diabetes: New insights of clinical relevance.

    PubMed

    Balasubramanyam, Muthuswamy; Lenin, Raji; Monickaraj, Finny

    2010-04-01

    The endoplasmic reticulum (ER) is a cellular compartment responsible for multiple important cellular functions including the biosynthesis and folding of newly synthesized proteins destined for secretion, such as insulin. A myriad of pathological and physiological factors perturb ER function and cause dysregulation of ER homeostasis, leading to ER stress. Accumulating evidence suggests that ER stress plays a role in the pathogenesis of diabetes, contributing to pancreatic β-cell loss and insulin resistance. ER stress may also link obesity, inflammation and insulin resistance in type 2 diabetes. In this review, we address the transition from physiology to pathology, namely how and why the physiological UPR evolves to a proapoptotic ER stress response in diabetes and its complications. Special attention was given to elucidate how ER stress could explain some of the 'clinical paradoxes' such as secondary sulfonylurea failure, initial worsening of retinopathy during tight glycemic control, insulin resistance induced by protease inhibitors and other clinically relevant observations.

  1. Clinically relevant drug interactions with anti-Alzheimer's drugs.

    PubMed

    Caraci, Filippo; Sultana, Janet; Drago, Filippo; Spina, Edoardo

    2017-03-03

    The aging world population had led to an increase in the prevalence of Alzheimer's disease (AD). The drugs used to slow down the onset of AD, galantamine, donepezil, rivastigmine and memantine, are generally well-tolerated. However, drug interactions between these drugs and other drugs are an important aspect of patient safety that should be borne in mind, particularly given the high burden of polypharmacy in the elderly. The aim of this review is to provide an updated review of clinically significant drug-drug interactions concerning drugs approved for AD. PubMed was searched for relevant keywords. No time limit was imposed but only articles in English published in peer-reviewed journals were selected. Relevant literature was also identified from the references of identified articles. Further information was obtained from drug summary of product characteristics. The major pharmacokinetic interactions identified concerned fluoxetine, paroxetine and ketoconazole when used with galantamine or donepezil. On the other hand, the major potential pharmacodynamic interactions concerned anti-dementia drugs and general anesthesia agents, anti-cholinergic drugs, conventional antipsychotics and bradycardia-inducing drugs. In clinical practice memantine shows a lower potential for pharmacodynamic drug-drug interactions (DDIs) compared to other drug classes. In conclusion, the concomitant use of anti-dementia drugs with other drugs can have variable clinical effects, making appropriate prescribing of these drugs very challenging. A simple and coherent way of presenting evidence on complex drug interaction information from heterogenous sources to clinicians is needed in order for the voluminous data available to have an impact on clinical practice.

  2. Quantifying Clinical Relevance in the Treatment of Schizophrenia

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2008-06-01

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

  4. Laboratory Exercises to Teach Clinically Relevant Chemistry of Antibiotics

    PubMed Central

    Chelette, Candace T.

    2014-01-01

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

  5. Selective IgG subclass deficiency: quantification and clinical relevance.

    PubMed Central

    Jefferis, R; Kumararatne, D S

    1990-01-01

    Each of the four human IgG subclasses exhibits a unique profile of effector functions relevant to the clearance and elimination of infecting microorganisms. The quantitative response within each IgG subclass varies with the nature of the antigen, its route of entry and, presumably, the form in which it is presented to the immune system. This results in antibody responses to certain antigens being predominantly or exclusively of a single IgG subclass. An inability to produce antibody of the optimally protective isotype can result in a selective immunodeficiency state. This is particularly apparent for responses to certain bacterial carbohydrate antigens that are normally of IgG2 isotype. A failure to produce the appropriate specific antibody response may result in recurrent upper and/or lower respiratory tract infection. Careful patient investigation can identify such deficiencies and suggest appropriate clinical management. In this review we outline the biology and clinical relevance of the IgG subclasses and summarize current rational treatment approaches. PMID:2204502

  6. SELECTING RELEVANT TEST SPECIES FOR ECOLOGICAL RISK ASSESSMENTS FOR PESTICIDES

    EPA Science Inventory

    In many countries, numerous tests are required prior to chemical registration for the protection of human health and the environment from the unintended effects of chemical releases. The species used in these tests are quite often familiar to scientists, have an extensive histor...

  7. Microbial Transformations of Selenium Species of Relevance to Bioremediation

    PubMed Central

    Eswayah, Abdurrahman S.; Smith, Thomas J.

    2016-01-01

    Selenium species, particularly the oxyanions selenite (SeO32−) and selenate (SeO42−), are significant pollutants in the environment that leach from rocks and are released by anthropogenic activities. Selenium is also an essential micronutrient for organisms across the tree of life, including microorganisms and human beings, particularly because of its presence in the 21st genetically encoded amino acid, selenocysteine. Environmental microorganisms are known to be capable of a range of transformations of selenium species, including reduction, methylation, oxidation, and demethylation. Assimilatory reduction of selenium species is necessary for the synthesis of selenoproteins. Dissimilatory reduction of selenate is known to support the anaerobic respiration of a number of microorganisms, and the dissimilatory reduction of soluble selenate and selenite to nanoparticulate elemental selenium greatly reduces the toxicity and bioavailability of selenium and has a major role in bioremediation and potentially in the production of selenium nanospheres for technological applications. Also, microbial methylation after reduction of Se oxyanions is another potentially effective detoxification process if limitations with low reaction rates and capture of the volatile methylated selenium species can be overcome. This review discusses microbial transformations of different forms of Se in an environmental context, with special emphasis on bioremediation of Se pollution. PMID:27260359

  8. Clinical relevance of abnormal scintigraphic findings of adult equine ribs.

    PubMed

    Dahlberg, Jessica A; Ross, Michael W; Martin, Benson B; Davidson, Elizabeth J; Leitch, Midge

    2011-01-01

    Horses with cranial rib abnormalities may exhibit severe acute lameness and may have unusual gait deficits characterized by forelimb abduction during protraction at the walk. Horses with caudal rib abnormalities may resent being saddled and ridden. In a retrospective evaluation of 20 horses with a documented rib lesion, 25 sites of increased radiopharmaceutical uptake were found in one or more ribs. Thirteen (52%) scintigraphic lesions involved the first rib; four were located immediately dorsal to the sternal articulation, eight were near the costochondral junction and one was at the costovertebral junction. Six (24%) scintigraphic rib lesions involved ribs 2-8; one was located immediately dorsal to the sternal articulation, three were at the costovertebral junction and two were near the costochondral junction. Six (24%) scintigraphic rib lesions involved the mid-portion (five) or costovertebral junction (one) of ribs 9-18. The 20 horses were divided into three groups based on the clinical relevance of the scintigraphic findings. Group 1 (n=3) horses had clinical signs attributed to a rib abnormality; Group 2 (n=6) horses had a rib abnormality that was a plausible explanation for clinical signs; Group 3 (n=11) horses had clinical signs that could not be attributed to a rib abnormality. For horses with cranial rib abnormalities, a modified lateral scintigraphic image with the ipsilateral limb pulled caudally and a left (right) 45° caudal-right (left) radiograph facilitated the diagnosis.

  9. Pathobiology of human cerebrovascular malformations: basic mechanisms and clinical relevance.

    PubMed

    Gault, Judith; Sarin, Hemant; Awadallah, Nabil A; Shenkar, Robert; Awad, Issam A

    2004-07-01

    Cerebrovascular malformations affect more than 3% of the population, exposing them to a lifetime risk of hemorrhagic stroke, seizures, and focal neurological deficits. Cerebral cavernous malformations (CCMs) exhibit an immature vessel wall, a brittle hemorrhagic tendency, and epileptogenesis, whereas arteriovenous malformations (AVMs) lack capillary beds and manifest apoplectic bleeding under high-flow conditions. There are also more benign venous anomalies, capillary malformations, and lesions with mixed and transitional features. Advances have been made toward understanding the natural history, radiological and pathological correlates, and clinical management. Yet, mechanisms of lesion genesis and clinical manifestations remain largely unknown, and the clinical behavior in individual patients is highly unpredictable. Lesion pathogenesis likely involves abnormal assembly or maintenance of blood vessels, resulting in dysmorphic vessel phenotypes. Familial CCM disease is in part caused by mutations in a cytoskeletal-related protein that is likely integral to interendothelial cell connectivity and maturation of the vascular wall. Rare familial forms of AVM disease have been correlated with two different transforming growth factor-beta receptor components, possibly causing disturbance in signaling during vascular assembly. Relevance of these mechanisms to the more common and otherwise identical sporadic CCM and AVM lesions is being explored. In this report, basic mechanisms of vasculogenesis and angiogenesis and how they possibly relate to the common cerebrovascular malformation lesions are reviewed. Novel concepts are discussed related to the cellular, molecular, and genetic substrates in CCM and AVM as well as to how this knowledge can be applied to predict, explain, and possibly modify clinical disease manifestations.

  10. Epileptic activity in Alzheimer's disease: causes and clinical relevance.

    PubMed

    Vossel, Keith A; Tartaglia, Maria C; Nygaard, Haakon B; Zeman, Adam Z; Miller, Bruce L

    2017-04-01

    Epileptic activity is frequently associated with Alzheimer's disease; this association has therapeutic implications, because epileptic activity can occur at early disease stages and might contribute to pathogenesis. In clinical practice, seizures in patients with Alzheimer's disease can easily go unrecognised because they usually present as non-motor seizures, and can overlap with other symptoms of the disease. In patients with Alzheimer's disease, seizures can hasten cognitive decline, highlighting the clinical relevance of early recognition and treatment. Some evidence indicates that subclinical epileptiform activity in patients with Alzheimer's disease, detected by extended neurophysiological monitoring, can also lead to accelerated cognitive decline. Treatment of clinical seizures in patients with Alzheimer's disease with select antiepileptic drugs (AEDs), in low doses, is usually well tolerated and efficacious. Moreover, studies in mouse models of Alzheimer's disease suggest that certain classes of AEDs that reduce network hyperexcitability have disease-modifying properties. These AEDs target mechanisms of epileptogenesis involving amyloid β and tau. Clinical trials targeting network hyperexcitability in patients with Alzheimer's disease will identify whether AEDs or related strategies could improve their cognitive symptoms or slow decline.

  11. Sundowning in Dementia: Clinical Relevance, Pathophysiological Determinants, and Therapeutic Approaches

    PubMed Central

    Canevelli, Marco; Valletta, Martina; Trebbastoni, Alessandro; Sarli, Giuseppe; D’Antonio, Fabrizia; Tariciotti, Leonardo; de Lena, Carlo; Bruno, Giuseppe

    2016-01-01

    Sundowning means the emergence or worsening of neuropsychiatric symptoms (NPS) in the late afternoon or early evening. This syndrome has been recognized since a long time in the field of dementing illnesses and is well known among most of health-care providers involved in the assistance of people with dementia. Indeed, it represents a common manifestation among persons with dementia and is associated with several adverse outcomes (such as institutionalization, faster cognitive worsening, and greater caregiver burden). Its occurrence and phenotypic characteristics may be influenced by diverse neurobiological, psychosocial, and environmental determinants. Moreover, it may pose diagnostic challenges in relation to other common causes of behavioral disruptions. Beside these considerations, this phenomenon has so far drawn limited clinical and scientific interest compared to other specific NPS occurring in dementias, as indicated by the lack of commonly agreed definitions, specific screening/assessment tools, and robust estimates on its prevalence. Accordingly, no randomized controlled trial specifically investigating the effectiveness of pharmacological and non-pharmacological strategies in managing this condition among demented patients has been yet conducted. In the present narrative review, we present and discuss available evidence concerning sundowning occurring in people with dementia. A special focus is given to its definitions, pathophysiological determinants, and clinical relevance, as well as to the clinical and therapeutic approaches required for its management in the daily practice. PMID:28083535

  12. Development of clinically relevant implantable pressure sensors: perspectives and challenges.

    PubMed

    Clausen, Ingelin; Glott, Thomas

    2014-09-22

    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.

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

    PubMed Central

    Clausen, Ingelin; Glott, Thomas

    2014-01-01

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

  14. Clinical 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.

  15. Making the history of psychology clinically and philosophically relevant.

    PubMed

    Vande Kemp, Hendrika

    2002-08-01

    The author discusses ways to make the history of psychology course relevant for a clinical psychology doctoral program within a multidenominational Protestant theological seminary. She uses a personalist orientation to emphasize the need to integrate psychology, philosophy, and theology. She differentiates among the intrapersonal, interpersonal, impersonal, and transpersonal dimensions of experience. She illustrates the rich multidisciplinary historical roots of contemporary psychology by tracing the the history of the term psychology and examining its meanings in the existential psychology of Søren Kierkegaard and in the 19th-century novel. She includes brief histories of the "new psychology" and of the unconscious. She describes how she uses the field of psychotheological integration to illustrate principles of historiography and summarizes resources used to supplement traditional textbooks.

  16. 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

  17. [Relevance of nutrition knowledge on clinical practice: medical opinion survey].

    PubMed

    Alvares, Luísa; Moreira, Isabel; Oliveira, António

    2007-01-01

    Although previous studies show that physicians generally agree that nutrition knowledge is important for their daily clinical practice, several other studies report their poor knowledge of the subject. One of the strongest reasons given for this is the non-incorporation of Nutrition as a compulsory subject for the medical sciences degree. Dietary counselling and assessment of the patients' nutritional status don't seem to be systematic. The aim of this study is to asses how relevant physicians consider Nutrition to be in the successful running of a good practice. The study was undertaken at the general hospital of Vila Real/Peso da Régua (CHVR/PR) by distribution of a self- administered questionnaire to 153 of the physicians of the clinical body. Mean values were compared with the Student's t test and proportions with the Chi-square test. Of the 153 physicians, 108 replies were received (70,6%). Of these 108 replies, 53,3% consider nutrition knowledge important although 29,6% state their knowledge is poor. More than half say that Clinical Nutrition should be a compulsory subject of the Medical Sciences syllabus, and 99,1% deem it important to assess the patient's nutritional status. About 95% stated they provided written or verbal nutritional guidance, and most of the physicians had already sought the assistance of a nutritionist. This study shows that the clinical body of the CHVR/PR is aware of the importance nutrition knowledge has in their daily practice. It must be noted, though, that although almost one third of the physicians rate their nutrition knowledge poor, most of them provide nutritional guidance to their patients.

  18. 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

  19. Cashew Nut Allergy: Clinical Relevance and Allergen Characterisation.

    PubMed

    Mendes, Cíntia; Costa, Joana; Vicente, António A; Oliveira, Maria Beatriz P P; Mafra, Isabel

    2016-09-01

    Cashew plant (Anacardium occidentale L.) is the most relevant species of the Anacardium genus. It presents high economic value since it is widely used in human nutrition and in several industrial applications. Cashew nut is a well-appreciated food (belongs to the tree nut group), being widely consumed as snacks and in processed foods by the majority of world's population. However, cashew nut is also classified as a potent allergenic food known to be responsible for triggering severe and systemic immune reactions (e.g. anaphylaxis) in sensitised/allergic individuals that often demand epinephrine treatment and hospitalisation. So far, three groups of allergenic proteins have been identified and characterised in cashew nut: Ana o 1 and Ana o 2 (cupin superfamily) and Ana o 3 (prolamin superfamily), which are all classified as major allergens. The prevalence of cashew nut allergy seems to be rising in industrialised countries with the increasing consumption of this nut. There is still no cure for cashew nut allergy, as well as for other food allergies; thus, the allergic patients are advised to eliminate it from their diets. Accordingly, when carefully choosing processed foods that are commercially available, the allergic consumers have to rely on proper food labelling. In this sense, the control of labelling compliance is much needed, which has prompted the development of proficient analytical methods for allergen analysis. In the recent years, significant research advances in cashew nut allergy have been accomplished, which are highlighted and discussed in this review.

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

    PubMed Central

    Stefan, Hermann; Lopes da Silva, Fernando H.

    2012-01-01

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

  1. Clinical Relevance of Microparticles from Platelets and Megakaryocytes

    PubMed Central

    Italiano, Joseph E.; Mairuhu, Albert T.A.; Flaumenhaft, Robert

    2011-01-01

    Purpose of review Platelet microparticles were identified more than forty years ago and are the most abundant circulating microparticle subtype. Yet fundamental questions about their formation and role in human disease are just beginning to be understood at the cellular and molecular level. This review will address mechanisms of platelet microparticle generation and evaluate our current understanding of their clinical relevance. Recent findings New evidence indicates that the majority of CD41+ microparticles circulating in healthy individuals derive directly from megakaryocytes. CD41+ microparticles also form from activated platelets upon loss of cytoskeleton-membrane adhesion, which occurs in a multitude of disease states characterized by elevated platelet microparticle levels. More recent studies have demonstrated that platelet microparticles function as a transport and delivery system for bioactive molecules, participating in hemostasis and thrombosis, inflammation, malignancy infection transfer, angiogenesis, and immunity. The mechanism of platelet microparticle participation in specific disease entities such as rheumatoid arthritis has been elucidated. Summary Continued research into how platelet microparticles are generated and function as a transcellular delivery system will advance our basic understanding of microparticle physiology and may enable new strategies for treatment of select disease entities. PMID:20739880

  2. 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

  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. 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

  5. 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.

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

    PubMed Central

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

    2015-01-01

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

  7. [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.

  8. Predicting the presence and cover of management relevant invasive plant species on protected areas.

    PubMed

    Iacona, Gwenllian; Price, Franklin D; Armsworth, Paul R

    2016-01-15

    Invasive species are a management concern on protected areas worldwide. Conservation managers need to predict infestations of invasive plants they aim to treat if they want to plan for long term management. Many studies predict the presence of invasive species, but predictions of cover are more relevant for management. Here we examined how predictors of invasive plant presence and cover differ across species that vary in their management priority. To do so, we used data on management effort and cover of invasive plant species on central Florida protected areas. Using a zero-inflated multiple regression framework, we showed that protected area features can predict the presence and cover of the focal species but the same features rarely explain both. There were several predictors of either presence or cover that were important across multiple species. Protected areas with three days of frost per year or fewer were more likely to have occurrences of four of the six focal species. When invasive plants were present, their proportional cover was greater on small preserves for all species, and varied with surrounding household density for three species. None of the predictive features were clearly related to whether species were prioritized for management or not. Our results suggest that predictors of cover and presence can differ both within and across species but do not covary with management priority. We conclude that conservation managers need to select predictors of invasion with care as species identity can determine the relationship between predictors of presence and the more management relevant predictors of cover.

  9. The nocebo effect and its relevance for clinical practice

    PubMed Central

    Colloca, Luana; Miller, Franklin G.

    2011-01-01

    Negative expectations deriving from the clinical encounter can produce negative outcomes, known as nocebo effects. Specifically, research on the nocebo effect indicates that information disclosure about potential side effects can itself contribute to producing adverse effects. Neurobiological processes play a role in the nocebo effect and this paper provides a selective review of mechanistic research on the nocebo effect. Comparatively little attention has been directed to clinical studies and their implications for daily clinical practice. The nocebo response is influenced by the content and the way information is presented to patients in clinical trials in both the placebo as well as active treatment conditions. Nocebo effect adversely influences quality of life and therapy adherence, emphasizing the need for minimizing these responses to the extent possible. Evidence further indicates that the informed consent process in clinical trials may induce nocebo effects. This paper concludes with ethical directions for future patient-oriented research and routine practice. PMID:21862825

  10. 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.

  11. [Dose-response relation: relevance for clinical practice].

    PubMed

    Klinkhardt, U; Harder, S

    1998-12-15

    Dose-finding studies are performed routinely in patients and--if appropriate surrogate models exist--also in healthy volunteers. Such studies aim at establishing the optimal dose range for further clinical studies on the efficacy and the risk-benefit ratio of a new drug. The dose-response relationship of a drug is most often described by a sigmoidal curve. Its parameters include the mean effective dose, the maximal effect and the steepness. Interpretation of such curves should be done in the context of the intended clinical indications of the drug. The risk-benefit ratio of a drug can be assessed by overlapping the dose-response curve of wanted and unwanted clinical effects, again, any overlapping (which can be described e.g. by the therapeutic index) should be seen in the context of the indication and available therapeutic alternatives.

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

    PubMed

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

    2011-11-01

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

  13. Clinical relevance of sonographically estimated amniotic fluid volume: polyhydramnios.

    PubMed

    Sandlin, Adam T; Chauhan, Suneet P; Magann, Everett F

    2013-05-01

    Polyhydramnios is an excessive amount of amniotic fluid within the amniotic cavity. The etiology of polyhydramnios may be idiopathic, the consequence of fetal structural anomalies, or the consequence of various fetal and maternal conditions. The clinical importance of polyhydramnios is found in its association with adverse pregnancy outcomes and the risk of perinatal mortality. The antenatal management of polyhydramnios can be challenging as there are no formalized guidelines on the topic. The purpose of this review is to provide a literature-based overview on the subject of polyhydramnios in singleton pregnancies, demonstrate its clinical implications, and describe a practical approach to its management.

  14. Brain white matter tracts: functional anatomy and clinical relevance.

    PubMed

    Gerrish, Amy C; Thomas, Adam G; Dineen, Robert A

    2014-10-01

    Diffusion tensor imaging is increasingly available on clinical magnetic resonance scanners and can be acquired in a relatively short time. There has been an explosion of applications in the research field but the use to the practicing radiologist may seem obscure. This paper aims to highlight how diffusion tensor imaging can be used to prompt a dedicated neuroanatomical search for white matter lesions in clinical presentations relating to motor, sensory, language, and visuospatial deficits. The enhanced depiction of white matter tracts in the temporal stem is also highlighted, which is a region of importance in epilepsy surgery planning.

  15. A clinically relevant frailty index for aging rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Frailty is a clinical syndrome that is increasingly prevalent during aging. Frailty involves the confluence of reduced strength, speed, physical activity, and endurance, and it is associated with adverse health outcomes. Frailty indices have been developed to diagnose frailty in older adult populati...

  16. 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…

  17. The potential clinical relevance of visible particles in parenteral drugs.

    PubMed

    Doessegger, Lucette; Mahler, Hanns-Christian; Szczesny, Piotr; Rockstroh, Helmut; Kallmeyer, Georg; Langenkamp, Anja; Herrmann, Joerg; Famulare, Joseph

    2012-08-01

    Visible particulates (VP) are one subclass of defects seen during the final visual inspection of parenteral products and are currently one of the top ten reasons for recalls 1,2. The risk posed by particles is still unclear with limited experience reported in humans but remains an important consideration during the manufacture and use of parenteral products. From the experimental and clinical knowledge of the distribution of particulate matter in the body, clinical complications would include events occurring around parenteral administration e.g., as a result of mechanical pulmonary artery obstruction and injection site reaction, or sub-acute or chronic events e.g., granuloma. The challenge is to better understand the implication for patients of single vials with VP and align the risk with the probabilistic detection process used by manufacturers for accept/reject decisions of individual units of product.

  18. Classification of Clinically Relevant Microorganisms in Non-Medical Environments

    DTIC Science & Technology

    2007-11-02

    humans. S . aureus should always be considered a potential pathogen, while most strains of S . epidermidis are nonpathogenic and may even play a...pure culture. He named them Staphylococcus aureus because of their golden color. S . aureus remains one of the most important pathogens in clinical...settings largely due to the rapidity of its evolutionary response to treatment. The first antibiotic-resistant strains of S . aureus were isolated only

  19. 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

  20. [Clinical relevance of immunotyping of oncologic and hematologic diseases].

    PubMed

    Diehl, V; Pfreundschuh, M

    1987-06-01

    Progress in immunology and molecular biology have provided a better understanding of etiology, pathogenesis and biology of many oncological and hematological diseases. In clinical practice, certain new methods of immunotyping (IT) are of diagnostic importance in assigning undifferentiated tumors to lymphoid, epithelial or mesenchymal origin and in defining subgroups of leukemias and lymphomas. The demonstration of rearrangements of gene coding for immunoglobulins or T-cell receptors assigns hematological malignancies of early differentiation to the B- or T-cell lineage, discriminates between reactive lymphoid changes and clonal lymphoid expansion and detects persistent clonal growth after therapy. In certain clinical entities (e.g. ALL) the immunological subtypes are of importance for differential therapy. By means of IT new clinical entities have been defined (Ki-1-lymphoma, T gamma-lymphoproliferative, LFA-1-deficiency) and the pathomechanisms of others have been elucidated (Bernard-Soulier-disease Syndrome, Glanzmann-Nägeli thrombasthenia). Of immediate therapeutic importance is the identification by IT of receptors for specific hormones or biological response modifiers on malignant cells. In-vivo diagnosis by monoclonal antibodies opens a way to define more exactly the extent of malignant disease by scintigrams or NMR.

  1. 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

  2. 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

  3. Biomarkers for Early Detection of Clinically Relevant Prostate Cancer: A Multi-Institutional Validation Trial

    DTIC Science & Technology

    2015-10-01

    1 1 AWARD NUMBER: W81XWH-14-1-0596 TITLE: Biomarkers for Early Detection of Clinically Relevant Prostate Cancer. A Multi-Institutional...Validation Trial PRINCIPAL INVESTIGATOR: Jesse McKenney, MD CONTRACTING ORGANIZATION: Cleveland Clinic Foundation Cleveland, OH 44195 REPORT DATE...COVERED 30 Sep 2014 - 29 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Biomarkers for Early Detection of Clinically Relevant Prostate Cancer. A

  4. Phylogenetic Relationships Matter: Antifungal Susceptibility among Clinically Relevant Yeasts

    PubMed Central

    Schmalreck, A. F.; Becker, K.; Fegeler, W.; Czaika, V.; Ulmer, H.; Lass-Flörl, C.

    2014-01-01

    The objective of this study was 2-fold: to evaluate whether phylogenetically closely related yeasts share common antifungal susceptibility profiles (ASPs) and whether these ASPs can be predicted from phylogeny. To address this question, 9,627 yeast strains were collected and tested for their antifungal susceptibility. Isolates were reidentified by considering recent changes in taxonomy and nomenclature. A phylogenetic (PHYLO) code based on the results of multilocus sequence analyses (large-subunit rRNA, small-subunit rRNA, translation elongation factor 1α, RNA polymerase II subunits 1 and 2) and the classification of the cellular neutral sugar composition of coenzyme Q and 18S ribosomal DNA was created to group related yeasts into PHYLO groups. The ASPs were determined for fluconazole, itraconazole, and voriconazole in each PHYLO group. The majority (95%) of the yeast strains were Ascomycetes. After reclassification, a total of 23 genera and 54 species were identified, resulting in an increase of 64% of genera and a decrease of 5% of species compared with the initial identification. These taxa were assigned to 17 distinct PHYLO groups (Ascomycota, n = 13; Basidiomycota, n = 4). ASPs for azoles were similar among members of the same PHYLO group and different between the various PHYLO groups. Yeast phylogeny may be an additional tool to significantly enhance the assessment of MIC values and to predict antifungal susceptibility, thereby more rapidly initiating appropriate patient management. PMID:24366735

  5. 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.

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

    PubMed Central

    Scholz, Tomáš; Garcia, Hector H.; Kuchta, Roman; Wicht, Barbara

    2009-01-01

    Summary: Tapeworms (Cestoda) continue to be an important cause of morbidity in humans worldwide. Diphyllobothriosis, a human disease caused by tapeworms of the genus Diphyllobothrium, is the most important fish-borne zoonosis caused by a cestode parasite. Up to 20 million humans are estimated to be infected worldwide. Besides humans, definitive hosts of Diphyllobothrium include piscivorous birds and mammals, which represent a significant zoonotic reservoir. The second intermediate hosts include both freshwater and marine fish, especially anadromous species such as salmonids. The zoonosis occurs most commonly in countries where the consumption of raw or marinated fish is a frequent practice. Due to the increasing popularity of dishes utilizing uncooked fish, numerous cases of human infections have appeared recently, even in the most developed countries. As many as 14 valid species of Diphyllobothrium can cause human diphyllobothriosis, with D. latum and D. nihonkaiense being the most important pathogens. In this paper, all taxa from humans reported are reviewed, with brief information on their life history and their current distribution. Data on diagnostics, epidemiology, clinical relevance, and control of the disease are also summarized. The importance of reliable identification of human-infecting species with molecular tools (sequences of mitochondrial genes) as well as the necessity of epidemiological studies aimed at determining the sources of infections are pointed out. PMID:19136438

  7. Functional and clinical relevance of chondroitin sulfate proteoglycan 4.

    PubMed

    Campoli, Michael; Ferrone, Soldano; Wang, Xinhui

    2010-01-01

    The lack of effective conventional therapies for the treatment of advanced stage melanoma has stimulated interest in the development of novel strategies for the management of patients with malignant melanoma. Among them, immunotherapy has attracted much attention because of the potential role played by immunological events in the clinical course of melanoma. For many years, T cell-based immunotherapy has been emphasized in part because of the disappointing results of the monoclonal antibody (mAb)-based clinical trials conducted in the early 1980s and in part because of the postulated major role played by T cells in tumor growth control. More recently, mAb-based therapies have gained in popularity given their clinical and commercial success for a variety of malignant diseases. As a result, there has been increased interest in identifying and characterizing antibody-defined melanoma antigens. Among them, the chondroitin sulfate proteoglycan 4 (CSPG4), also known as high molecular weight-melanoma associated antigen (HMW-MAA) or melanoma chondroitin sulfate proteoglycan (MCSP), has attracted much attention in recent years because of the growing experimental evidence that it fulfills two requirements for immunotherapy to be therapeutically effective: (1) targeting of cancer stem cells (CSC) and (2) development of combinatorial therapies to counteract the escape mechanisms driven by the genetic instability of tumor cells. With this in mind, in this chapter, we have reviewed recent information related to the distribution of CSPG4 on various types of tumors, including CSC, its expression on pericytes in the tumor microenvironment, its recognition by T cells, its role in cell biology as well as the potential mechanisms underlying the ability of CSPG4-specific immunity to control malignant cell growth.

  8. 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.

  9. [Clinical research IV. Relevancy of the statistical test chosen].

    PubMed

    Talavera, Juan O; Rivas-Ruiz, Rodolfo

    2011-01-01

    When we look at the difference between two therapies or the association of a risk factor or prognostic indicator with its outcome, we need to evaluate the accuracy of the result. This assessment is based on a judgment that uses information about the study design and statistical management of the information. This paper specifically mentions the relevance of the statistical test selected. Statistical tests are chosen mainly from two characteristics: the objective of the study and type of variables. The objective can be divided into three test groups: a) those in which you want to show differences between groups or inside a group before and after a maneuver, b) those that seek to show the relationship (correlation) between variables, and c) those that aim to predict an outcome. The types of variables are divided in two: quantitative (continuous and discontinuous) and qualitative (ordinal and dichotomous). For example, if we seek to demonstrate differences in age (quantitative variable) among patients with systemic lupus erythematosus (SLE) with and without neurological disease (two groups), the appropriate test is the "Student t test for independent samples." But if the comparison is about the frequency of females (binomial variable), then the appropriate statistical test is the χ(2).

  10. Vitamin E-drug interactions: molecular basis and clinical relevance.

    PubMed

    Podszun, Maren; Frank, Jan

    2014-12-01

    Vitamin E (α-, β-, γ- and δ-tocopherol and -tocotrienol) is an essential factor in the human diet and regularly taken as a dietary supplement by many people, who act under the assumption that it may be good for their health and can do no harm. With the publication of meta-analyses reporting increased mortality in persons taking vitamin E supplements, the safety of the micronutrient was questioned and interactions with prescription drugs were suggested as one potentially underlying mechanism. Here, we review the evidence in the scientific literature for adverse vitamin E-drug interactions and discuss the potential of each of the eight vitamin E congeners to alter the activity of drugs. In summary, there is no evidence from animal models or randomised controlled human trials to suggest that the intake of tocopherols and tocotrienols at nutritionally relevant doses may cause adverse nutrient-drug interactions. Consumption of high-dose vitamin E supplements ( ≥  300 mg/d), however, may lead to interactions with the drugs aspirin, warfarin, tamoxifen and cyclosporine A that may alter their activities. For the majority of drugs, however, interactions with vitamin E, even at high doses, have not been observed and are thus unlikely.

  11. Clinically relevant study end points in rectal cancer.

    PubMed

    Fernandez-Martos, Carlos; Guerrero, Angel; Minsky, Bruce

    2012-01-01

    In rectal cancer currently there are no clearly validated early end points which can serve as surrogates for long-term clinical outcome such as local control and survival. However, the use of a variety of response rates (i.e. pathological complete response, downsizing the primary tumor, tumor regression grade (TRG), radiological response) as endpoints in early (phase II) clinical trials is common since objective response to therapy is an early indication of activity. Disease-free survival (DFS) has been proposed as the most appropriate end point in adjuvant trials and is one of the most frequently used in newer rectal cancer trials. Due to the devastating nature of local recurrence in locally advanced rectal cancer, local control (which is itself a subset of the overall DFS endpoint) is still considered an important endpoint. Recently, circumferential resection margin (CRM) has been proposed as novel early end point because the CRM status can account for effects on DFS and overall survival after chemoradiation, radiation (RT), or surgery alone. Consensus is needed to define the most appropriate end points in both early and phase III trials in locally advanced cancer.

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

    PubMed

    Sharman, J E; LaGerche, A

    2015-06-01

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

  13. 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.

  14. 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

  15. The Clinical Relevance of Anti-DFS70 Autoantibodies.

    PubMed

    Conrad, Karsten; Röber, Nadja; Andrade, Luis E C; Mahler, Michael

    2017-04-01

    Despite all the progress in the establishment of specific autoantibody assays, screening for antinuclear antibodies (ANA) by indirect immunofluorescence on HEp-2 cells for quality-oriented laboratory diagnosis of ANA associated rheumatic diseases (AARD) remains indispensable but is not without limitations. Recent data on the relevance of the dense fine speckled (DFS) pattern and anti-DFS70 antibodies disclosed novel possibilities to optimize the serological stepwise diagnostics of AARD. The DFS pattern on HEp-2 cells is well differentiated from the classic "homogeneous" ANA pattern associated with dsDNA antibodies. This is the most frequent pattern in high titer ANA-positive healthy persons. The most characteristic ANA specificity associated with DFS pattern is the anti-DFS70 antibody (synonym LEDGF antibody). The prevalence of anti-DFS70 antibodies in AARD patients is significantly lower compared with the prevalence in ANA-positive healthy persons. There is a negative association between anti-DFS70 antibodies and AARD, especially if no concomitant AARD-specific autoantibodies are found. Isolated anti-DFS70 antibodies are detectable in less than 1 % of AARD but are detectable in 2-22 % of healthy persons. In the presence of an isolated anti-DFS70 antibody, the posttest probability for AARD is reduced significantly. The significance of anti-DFS70 antibodies as a criterion that helps to exclude AARD is also confirmed by follow-up studies on anti-DFS70 antibodies of positive, healthy individuals, who did not develop any AARD during a 4 year observation period. Consequently, anti-DFS70 antibodies are valuable novel biomarkers for better interpretation of positive ANA in cases of negative AARD-associated autoantibodies and should be integrated in modified test algorithms to avoid unnecessary referrals and examinations of ANA-positive persons.

  16. MicroRNAs: Clinical Relevance in Colorectal Cancer.

    PubMed

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

    2015-11-25

    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.

  17. Adipose Tissue Dysfunction: Clinical Relevance and Diagnostic Possibilities.

    PubMed

    Schrover, I M; Spiering, W; Leiner, T; Visseren, F L J

    2016-04-01

    Adipose tissue dysfunction is defined as an imbalance between pro- and anti-inflammatory adipokines, causing insulin resistance, systemic low-grade inflammation, hypercoagulability, and elevated blood pressure. These can lead to cardiovascular disease and diabetes mellitus type 2. Although quantity of adipose tissue is an important determinant of adipose tissue dysfunction, it can be diagnosed in both obese and lean individuals. This implies that not only quantity of adipose tissue should be used as a measure for adipose tissue dysfunction. Instead, focus should be on measuring quality of adipose tissue, which can be done with diagnostic modalities ranging from anthropometric measurements to tissue biopsies and advanced imaging techniques. In daily clinical practice, high quantity of visceral adipose tissue (reflected in high waist circumference or adipose tissue imaging), insulin resistance, or presence of the metabolic syndrome are easy and low-cost diagnostic modalities to evaluate presence or absence of adipose tissue dysfunction.

  18. Clinically relevant copy number variations detected in cerebral palsy

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    1990-12-01

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

  20. 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

  1. Osteoarthritis: an update with relevance for clinical practice.

    PubMed

    Bijlsma, Johannes W J; Berenbaum, Francis; Lafeber, Floris P J G

    2011-06-18

    Osteoarthritis is thought to be the most prevalent chronic joint disease. The incidence of osteoarthritis is rising because of the ageing population and the epidemic of obesity. Pain and loss of function are the main clinical features that lead to treatment, including non-pharmacological, pharmacological, and surgical approaches. Clinicians recognise that the diagnosis of osteoarthritis is established late in the disease process, maybe too late to expect much help from disease-modifying drugs. Despite efforts over the past decades to develop markers of disease, still-imaging procedures and biochemical marker analyses need to be improved and possibly extended with more specific and sensitive methods to reliably describe disease processes, to diagnose the disease at an early stage, to classify patients according to their prognosis, and to follow the course of disease and treatment effectiveness. In the coming years, a better definition of osteoarthritis is expected by delineating different phenotypes of the disease. Treatment targeted more specifically at these phenotypes might lead to improved outcomes.

  2. [Drug interactions and clinical relevance: it all began with cheese].

    PubMed

    Carrillo Norte, Juan Antonio

    2012-04-01

    In a drug interaction, the effects of one drug can be increased or decreased or a quite new effect produced by the previous, concurrent or subsequent administration of another substance, including prescription and nonprescription drugs, food, tobacco or alcohol. The effect of the interaction can be desirable, inconsequential, or adverse. The increasing number of drugs available and the increasing use of multidrug therapeutic regimens enhance the potential for drug interactions. However, in clinical practice, most interactions are not significant or rarely of significance. It is when the interaction leads to adverse consequences that it comes to the attention of the patient and physician. Interactions may occur by pharmacokinetic or pharmacodynamics mechanisms. Pharmacokinetic interactions represent the modification of one substance (the interacting substance) on the ADME processes of absorption, distribution, metabolism or excretion of a drug (the index drug). Subsequently, it may lead to changes in the concentration of the index drug at the receptor sites. Drug interactions with a pharmacodynamic basis involve actions on the same receptor or physiological systems through either synergism or antagonism. Many drug interactions can be predicted if the pharmacodynamics effects, pharmacokinetic properties and mechanisms of action of the interacting agents are known. The most obvious interactions are those producing altered pharmacokinetic of drugs with a low therapeutic index (oral anticoagulants, antidiabetic drugs, digoxin, benzodiazepines and immunosuppressant and cytotoxic drugs).

  3. 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

  4. 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

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

    PubMed

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

    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.

  6. Clinical relevance of FASII bypass in Staphylococcus aureus.

    PubMed

    Gloux, Karine; Guillemet, Mélanie; Soler, Charles; Morvan, Claire; Halpern, David; Pourcel, Christine; Vu Thien, Hoang; Lamberet, Gilles; Gruss, Alexandra

    2017-02-13

    The need for new antimicrobials to treat bacterial infections has led to the use of fatty acid synthesis (FASII) enzymes as front-line targets. However, recent studies suggest that FASII inhibitors may not work against the opportunist pathogen Staphylococcus aureus, as environmental fatty acids favor emergence of multi-anti-FASII resistance. As fatty acids are abundant in the host, and one FASII inhibitor, triclosan, is widespread, we investigated whether fatty acid pools impact resistance in clinical and veterinary S. aureus isolates. Simple addition of fatty acids to screening medium led to a 50% increase in triclosan resistance, as tested in 700 isolates. Moreover, non-culturable triclosan-resistant fatty acid auxotrophs, which escape detection under routine conditions, were uncovered in primary patient samples. FASII bypass in selected isolates correlated with polymorphisms in acc and fabD loci. We conclude that fatty-acid-dependent strategies to escape FASII inhibition are common among S. aureus isolates and correlate with anti-FASII resistance and emergence of non-culturable variants.

  7. Uterine fibroid vascularization and clinical relevance to uterine fibroid embolization.

    PubMed

    Pelage, Jean-Pierre; Cazejust, Julien; Pluot, Etienne; Le Dref, Olivier; Laurent, Alexandre; Spies, James B; Chagnon, Sophie; Lacombe, Pascal

    2005-10-01

    Embolization has become a first-line treatment for symptomatic uterine fibroid tumors. Selective catheterization and embolization of both uterine arteries, which are the predominant source of blood flow to fibroid tumors in most cases, is the cornerstone of treatment. Although embolization for treatment of uterine fibroid tumors is widely accepted, great familiarity with the normal and variant pelvic arterial anatomy is needed to ensure the safety and success of the procedure. The uterine artery classically arises as a first or second branch of the anterior division of the internal iliac artery and is usually dilated in the presence of a uterine fibroid tumor. Angiography is used for comprehensive pretreatment assessment of the pelvic arterial anatomy; for noninvasive evaluation, Doppler ultrasonography, contrast material-enhanced magnetic resonance (MR) imaging, and MR angiography also may be used. After the uterine artery is identified, selective catheterization should be performed distal to its cervicovaginal branch. For targeted embolization of the perifibroid arterial plexus, injection of particles with diameters larger than 500 mum is generally recommended. Excessive embolization may injure normal myometrium, ovaries, or fallopian tubes and lead to uterine necrosis or infection or to ovarian failure. Incomplete treatment or additional blood supply to the tumor (eg, via an ovarian artery) may result in clinical failure. The common postembolization angiographic end point is occlusion of the uterine arterial branches to the fibroid tumor while antegrade flow is maintained in the main uterine artery.

  8. 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

  9. Does the dawn phenomenon have clinical relevance in normal pregnancy?

    PubMed Central

    Mandujano, Alicia; Thomas, Alicia; Presley, Larraine Huston; Amini, Saeid B.; de Mouzon, Sylvie Hauguel; Catalano, Patrick M.

    2014-01-01

    OBJECTIVE The dawn phenomenon is a transient rise in blood glucose between 4 and 6 AM that is attributed to the pulsatile release of pituitary growth hormone (GH). In pregnancy, GH is suppressed by placental GH. Hence, we hypothesize that there is no evidence for the dawn phenomenon in late pregnancy in healthy women. STUDY DESIGN Twenty glucose-tolerant women with singleton gestations between 28 weeks and 36 weeks 6 days’ gestation were recruited. The women were admitted overnight to the Clinical Research Unit and had continuous glucose monitoring. Insulin and GH were measured at 2-hour intervals from 8 PM to 8 AM. GH was grouped into times 1A (8–10 PM), 2A (12–2 AM), and 3A (4–8 AM) for changes over time. Further analysis was performed with time 1B (8 PM to 2 AM) and 2B (4–8 AM). Insulin was measured between 4 and 8 AM. RESULTS Plasma glucose decreased over time (P < .001). There were no significant changes in GH among times 1A, 2A, and 3A (P = .45) or times 1B and 2B (P = .12). Insulin concentrations increased after meals, but there were no changes from 4 AM (8.5 ± 1.4 μU/mL) through 8 AM (8.6 ± 1.1 μU/mL; P = .98). CONCLUSION Glucose and insulin concentrations show no increase from 4–8 AM; although there is variability in GH, there is no evidence for the dawn phenomenon in late pregnancy in healthy women. PMID:23583837

  10. [Ibogaine - structure, influence on human body, clinical relevance].

    PubMed

    Zdrojewicz, Zygmunt; Kuszczak, Bartłomiej; Olszak, Natalia

    2016-07-29

    Ibogaine is a natural chemical compound, which belongs to the indole alkaloid family. It can be naturally found within the root bark of african plant Tabernanthe iboga. Ibogaine plays a significant role among tribal cultures. Ibogaine, in small amount, causes reduction of hunger, thirst and exhaustion. In bigger amount, however, it can cause intensive visions. Other effects include reduction or complete disappearance of absitnence symptoms visible in people addicted to the nicotine, alcohol, methamphetamine, cocaine or opioids, what has been scientifically proven after the tests on animals and small groups of people. After oral application, 80% of ibogaine is subjected to the Odemethylation into noribogaine; main catalyzing enzyme is cytochrome CYP2D6. Research suggests, that ibogaine acts in many places within central nervous system. NMDA receptors seem to play main role in its anti-addiction properties. It is important to mention the side effects of the compound, which are cardiotoxicity and neurotoxicity, what makes it harder to use its beneficial properties. Because of this, Ibogaine is included among the dangerous substance. However, there are a few clinics in the world which specializes in the use of the compound in order to interrupt the sypmtoms acute opioid withdrawal syndrome as well as a substance benficial in curing other addictions. There is more hope with synthetic derivatives of ibogaine, which although are less toxic still keep their anti-addiction properties. The aim is to collect the available knowledge related to the structure and effects on human body of alkaloid Tabernanthe iboga and consider the possibility of commercial medical use.

  11. Clinical relevance of sarcopenia in patients with cirrhosis.

    PubMed

    Montano-Loza, Aldo J

    2014-07-07

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

  12. Clinical Relevance of Cranial Nerve Injury following Carotid Endarterectomy

    PubMed Central

    Fokkema, M.; de Borst, G.J.; Nolan, B.W.; Indes, J.; Buck, D.B.; Lo, R.C.; Moll, F.L.; Schermerhorn, M.L.

    2014-01-01

    Objectives The benefit of carotid endarterectomy (CEA) may be diminished by cranial nerve injury (CNI). Using a quality improvement registry, we aimed to identify the nerves affected, duration of symptoms (transient vs. persistent), and clinical predictors of CNI. Methods We identified all patients undergoing CEA in the Vascular Study Group of New England (VSGNE) between 2003 and 2011. Surgeon-observed CNI rate was determined at discharge (postoperative CNI) and at follow-up to determine persistent CNI (CNIs that persisted at routine follow-up visit). Hierarchical multivariable model controlling for surgeon and hospital was used to assess independent predictors for postoperative CNI. Results A total of 6,878 patients (33.8% symptomatic) were included for analyses. CNI rate at discharge was 5.6% (n = 382). Sixty patients (0.7%) had more than one nerve affected. The hypoglossal nerve was most frequently involved (n = 185, 2.7%), followed by the facial (n = 128, 1.9%), the vagus (n = 49, 0.7%), and the glossopharyngeal (n = 33, 0.5%) nerve. The vast majority of these CNIs were transient; only 47 patients (0.7%) had a persistent CNI at their follow-up visit (median 10.0 months, range 0.3–15.6 months). Patients with perioperative stroke (0.9%, n = 64) had significantly higher risk of CNI (n = 15, CNI risk 23.4%, p < .01). Predictors for CNI were urgent procedures (OR 1.6, 95% CI 1.2–2.1, p < .01), immediate re-exploration after closure under the same anesthetic (OR 2.0, 95% CI 1.3–3.0, p < .01), and return to the operating room for a neurologic event or bleeding (OR 2.3, 95% CI 1.4–3.8, p < .01), but not redo CEA (OR 1.0, 95% CI 0.5–1.9, p = .90) or prior cervical radiation (OR 0.9, 95% CI 0.3–2.5, p = .80). Conclusions As patients are currently selected in the VSGNE, persistent CNI after CEA is rare. While conditions of urgency and (sub)acute reintervention carried increased risk for postoperative CNI, a history of prior ipsilateral CEA or cervical

  13. Comparative Genomics of Bacillus species and its Relevance in Industrial Microbiology

    PubMed Central

    Sharma, Archana; Satyanarayana, T

    2013-01-01

    With the advent of high throughput sequencing platforms and relevant analytical tools, the rate of microbial genome sequencing has accelerated which has in turn led to better understanding of microbial molecular biology and genetics. The complete genome sequences of important industrial organisms provide opportunities for human health, industry, and the environment. Bacillus species are the dominant workhorses in industrial fermentations. Today, genome sequences of several Bacillus species are available, and comparative genomics of this genus helps in understanding their physiology, biochemistry, and genetics. The genomes of these bacterial species are the sources of many industrially important enzymes and antibiotics and, therefore, provide an opportunity to tailor enzymes with desired properties to suit a wide range of applications. A comparative account of strengths and weaknesses of the different sequencing platforms are also highlighted in the review. PMID:26217108

  14. 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

  15. 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

  16. Multiple system organ response induced by hyperoxia in a clinically relevant animal model of sepsis.

    PubMed

    Rodríguez-González, Raquel; Martín-Barrasa, José Luis; Ramos-Nuez, Ángela; Cañas-Pedrosa, Ana María; Martínez-Saavedra, María Teresa; García-Bello, Miguel Ángel; López-Aguilar, Josefina; Baluja, Aurora; Álvarez, Julián; Slutsky, Arthur S; Villar, Jesús

    2014-08-01

    Oxygen therapy is currently used as a supportive treatment in septic patients to improve tissue oxygenation. However, oxygen can exert deleterious effects on the inflammatory response triggered by infection. We postulated that the use of high oxygen concentrations may be partially responsible for the worsening of sepsis-induced multiple system organ dysfunction in an experimental clinically relevant model of sepsis. We used Sprague-Dawley rats. Sepsis was induced by cecal ligation and puncture. Sham-septic controls (n = 16) and septic animals (n = 32) were randomly assigned to four groups and placed in a sealed Plexiglas cage continuously flushed for 24 h with medical air (group 1), 40% oxygen (group 2), 60% oxygen (group 3), or 100% oxygen (group 4). We examined the effects of these oxygen concentrations on the spread of infection in blood, urine, peritoneal fluid, bronchoalveolar lavage, and meninges; serum levels of inflammatory biomarkers and reactive oxygen species production; and hematological parameters in all experimental groups. In cecal ligation and puncture animals, the use of higher oxygen concentrations was associated with a greater number of infected biological samples (P < 0.0001), higher serum levels of interleukin-6 (P < 0.0001), interleukin-10 (P = 0.033), and tumor necrosis factor-α (P = 0.034), a marked decrease in platelet counts (P < 0.001), and a marked elevation of reactive oxygen species serum levels (P = 0.0006) after 24 h of oxygen exposure. Oxygen therapy greatly influences the progression and clinical manifestation of multiple system organ dysfunction in experimental sepsis. If these results are extrapolated to humans, they suggest that oxygen therapy should be carefully managed in septic patients to minimize its deleterious effects.

  17. Self-Esteem and Dimensions of Clinically Relevant Behavior Among Ten Year Olds.

    ERIC Educational Resources Information Center

    Starr, Philip; Pearman, William A.

    Although self-concept has been linked with many behavioral variables, most studies do not deal with dependent variables which would provide an understanding of such clinically relevant behaviors as sociability, aggression, activity level, somatization, inhibition, and sleep disturbance. The relationship between self-esteem and clinically relevant…

  18. Frankincense Revisited, Part I: Comparative Analysis of Volatiles in Commercially Relevant Boswellia Species.

    PubMed

    Niebler, Johannes; Buettner, Andrea

    2016-05-01

    The genus Boswellia comprises many species which are famous for their production of frankincense, a fragrant gum resin. In the published literature, manifold studies on the volatiles and semivolatiles in individual samples of these gum resins exist, yet very few studies have investigated multiple samples. Contradictory results with regard to the volatile composition exist in literature. In this first part of the study, a large sample set (n = 46) of mostly commercially obtained gum resins and essential oils was investigated by solid-phase microextraction gas chromatography/mass spectrometry. A total of 216 compounds were identified or tentatively identified from the four commercially relevant species, namely B. sacra, B. serrata, B. papyrifera, and B. frereana, and the statistical evaluation of the resulting chemical profiles allowed a clear distinction between the species by their volatile profile. With only few exceptions, the designated species was found to be in accordance with the composition reported in reliable literature sources and detected in botanically identified samples. Chemotaxonomic marker substances were suggested to facilitate the differentiation of commercial gum resins or essential oils based on their volatile profile.

  19. Contact allergy to colophony. Clinical and experimental studies with emphasis on clinical relevance.

    PubMed

    Färm, G

    1998-01-01

    Colophony--also called rosin--is a material obtained from coniferous trees. It is used widely in many products, particularly because of its good tackifying properties. Colophony is also used in paper sizing to increase water resistance. Colophony may cause contact allergy, and around 5% of Swedish dermatitis patients show allergic reactions to colophony at patch testing. There are many case reports of colophony in different products causing contact dermatitis. Often, however, the clinical relevance of a positive patch-test reaction to colophony is difficult to evaluate. The principal aims of the present thesis were to study the prevalence of contact allergy to colophony and of skin disease in individuals with an occupational exposure to colophony; to study the prognosis of dermatitis in colophony-sensitive subjects, and to investigate the outcome of repeated open applications of colophony, thereby trying to elucidate the clinical relevance of contact allergy to colophony. Employees of a tall-oil rosin (colophony) factory (n = 180), and of an opera company where colophony was used in dancers' rosin, mascara and wig glues (n = 132), were interviewed, examined and patch tested. 3.9% and 2% of these two groups respectively had a positive patch test to colophony. More than every fourth participant showed some kind of skin disease, but only few cases were related to work. Eighty-three patients with previously diagnosed contact allergy to colophony were followed-up 72% showed a positive patch-test reaction to colophony at re-testing. Around one third had hand eczema. There was no significant correlation between colophony exposure and current hand eczema. Adhesive bandages containing colophony and zinc oxide (ZnO), colophony and mixes of colophony and ZnO, were tested in 7 colophony-sensitive subjects to see whether addition of zinc oxide inhibited elicitation of allergic dermatitis to colophony, which has been proposed. No difference in reactivity between colophony and

  20. 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

  1. Caldora penicillata gen. nov., comb. nov. (Cyanobacteria), a pantropical marine species with biomedical relevance

    PubMed Central

    Engene, Niclas; Tronholm, Ana; Salvador-Reyes, Lilibeth A.; Luesch, Hendrik; Paul, Valerie J.

    2015-01-01

    Many tropical marine cyanobacteria are prolific producers of bioactive secondary metabolites with ecological relevance and promising pharmaceutical applications. One species of chemically rich, tropical marine cyanobacteria that was previously identified as Symploca hydnoides or Symploca sp. corresponds to the traditional taxonomic definition of Phormidium penicillatum. In this study, we clarified the taxonomy of this biomedically and ecologically important cyanobacterium by comparing recently collected specimens with the original type material and the taxonomic description of P. penicillatum. Molecular phylogenetic analyses of the 16S rRNA gene and the 16S-23S ITS regions showed that P. penicillatum formed an independent clade sister to the genus Symploca, and distantly related to Phormidium and Lyngbya. We propose the new genus Caldora for this clade, with Caldora penicillata comb. nov. as the type species and designate as the epitype the recently collected strain FK13-1. Furthermore, the production of bioactive secondary metabolites among various geographically dispersed collections of C. penicillata showed that this species consistently produced the metabolite dolastatin 10 and/or the related compound symplostatin 1, which appear to be robust autapomorphic characters and chemotaxonomic markers for this taxon. PMID:26327714

  2. Intraductal papillary mucinous neoplasms of the pancreas: reporting clinically relevant features.

    PubMed

    Del Chiaro, Marco; Verbeke, Caroline

    2016-11-22

    Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas can exhibit a wide spectrum of macroscopic and microscopic appearances. This not only causes occasional difficulties for the reporting pathologist in distinguishing these tumours from other lesions, but is also relevant clinically. As evidence accumulates, it becomes clear that multiple macroscopic and histological features of these neoplasms are relevant to the risk for malignant transformation and, consequently, of prime importance for clinical patient management. The need for detailed reporting is therefore increasing. This review discusses the panoply of gross and microscopic features of IPMN as well as the recommendations from recent consensus meetings regarding the pathology reporting on this tumour entity.

  3. Prevalence and clinical relevance of helminth co-infections among tuberculosis patients in urban Tanzania

    PubMed Central

    Hella, Jerry; Said, Khadija; Kamwela, Lujeko; Sasamalo, Mohamed; Maroa, Thomas; Chiryamkubi, Magreth; Mhalu, Grace; Schindler, Christian; Reither, Klaus; Knopp, Stefanie; Utzinger, Jürg; Gagneux, Sébastien; Fenner, Lukas

    2017-01-01

    Background Helminth infections can negatively affect the immunologic host control, which may increase the risk of progression from latent Mycobacterium tuberculosis infection to tuberculosis (TB) disease and alter the clinical presentation of TB. We assessed the prevalence and determined the clinical relevance of helminth co-infection among TB patients and household contact controls in urban Tanzania. Methodology Between November 2013 and October 2015, we enrolled adult (≥18 years) sputum smear-positive TB patients and household contact controls without TB during an ongoing TB cohort study in Dar es Salaam, Tanzania. We used Baermann, FLOTAC, Kato-Katz, point-of-care circulating cathodic antigen, and urine filtration to diagnose helminth infections. Multivariable logistic regression models with and without random effects for households were used to assess for associations between helminth infection and TB. Principal findings A total of 597 TB patients and 375 household contact controls were included. The median age was 33 years and 60.2% (585/972) were men. The prevalence of any helminth infection among TB patients was 31.8% (190/597) and 25.9% (97/375) among controls. Strongyloides stercoralis was the predominant helminth species (16.6%, 161), followed by hookworm (9.0%, 87) and Schistosoma mansoni (5.7%, 55). An infection with any helminth was not associated with TB (adjusted odds ratio (aOR) 1.26, 95% confidence interval (CI): 0.88–1.80, p = 0.22), but S. mansoni infection was (aOR 2.15, 95% CI: 1.03–4.45, p = 0.040). Moreover, S. mansoni infection was associated with lower sputum bacterial load (aOR 2.63, 95% CI: 1.38–5.26, p = 0.004) and tended to have fewer lung cavitations (aOR 0.41, 95% CI: 0.12–1.16, p = 0.088). Conclusions/Significance S. mansoni infection was an independent risk factor for active TB and altered the clinical presentation in TB patients. These findings suggest a role for schistosomiasis in modulating the pathogenesis of human TB

  4. Germination of Spores of Astrobiologically Relevant Bacillus Species in High-Salinity Environments

    NASA Astrophysics Data System (ADS)

    Nagler, Katja; Julius, Christina; Moeller, Ralf

    2016-07-01

    In times of increasing space exploration and search for extraterrestrial life, new questions and challenges for planetary protection, aiming to avoid forward contamination of different planets or moons with terrestrial life, are emerging. Spore-forming bacteria such as Bacillus species have a high contamination potential due to their spores' extreme resistance, enabling them to withstand space conditions. Spores require liquid water for their conversion into a growing cell (i.e., spore germination and subsequent growth). If present, water on extraterrestrial planets or moons is likely to be closely associated with salts (e.g., in salty oceans or brines), thus constituting high-salinity environments. Spores of Bacillus subtilis can germinate despite very high salt concentrations, although salt stress does exert negative effects on this process. In this study, germination and metabolic reactivation ("outgrowth") of spores of five astrobiologically relevant Bacillus species (B. megaterium, B. pumilus SAFR-032, B. nealsonii, B. mojavensis, and B. vallismortis) in high salinity (≤3.6 M NaCl) were investigated. Spores of different species exhibited different germination and outgrowth capabilities in high salinity, which strongly depended on germination conditions, especially the exact composition of the medium. In this context, a new "universal" germination trigger for Bacillus spores, named KAGE (KCl, L-alanine, D-glucose, ectoine), was identified, which will be very useful for future comparative germination and outgrowth studies on different Bacillus species. Overall, this study yielded interesting new insights on salt stress effects on spore germination and points out the difficulty of predicting the potential of spores to contaminate salty environments on extraterrestrial celestial bodies.

  5. Intestinal microbiota in metabolic diseases: from bacterial community structure and functions to species of pathophysiological relevance.

    PubMed

    Clavel, Thomas; Desmarchelier, Charles; Haller, Dirk; Gérard, Philippe; Rohn, Sascha; Lepage, Patricia; Daniel, Hannelore

    2014-07-01

    The trillions of bacterial cells that colonize the mammalian digestive tract influence both host physiology and the fate of dietary compounds. Gnotobionts and fecal transplantation have been instrumental in revealing the causal role of intestinal bacteria in energy homeostasis and metabolic dysfunctions such as type-2 diabetes. However, the exact contribution of gut bacterial metabolism to host energy balance is still unclear and knowledge about underlying molecular mechanisms is scant. We have previously characterized cecal bacterial community functions and host responses in diet-induced obese mice using omics approaches. Based on these studies, we here discuss issues on the relevance of mouse models, give evidence that the metabolism of cholesterol-derived compounds by gut bacteria is of particular importance in the context of metabolic disorders and that dominant species of the family Coriobacteriaceae are good models to study these functions.

  6. Campylobacter species in animal, food, and environmental sources, and relevant testing programs in Canada.

    PubMed

    Huang, Hongsheng; Brooks, Brian W; Lowman, Ruff; Carrillo, Catherine D

    2015-10-01

    Campylobacter species, particularly thermophilic campylobacters, have emerged as a leading cause of human foodborne gastroenteritis worldwide, with Campylobacter jejuni, Campylobacter coli, and Campylobacter lari responsible for the majority of human infections. Although most cases of campylobacteriosis are self-limiting, campylobacteriosis represents a significant public health burden. Human illness caused by infection with campylobacters has been reported across Canada since the early 1970s. Many studies have shown that dietary sources, including food, particularly raw poultry and other meat products, raw milk, and contaminated water, have contributed to outbreaks of campylobacteriosis in Canada. Campylobacter spp. have also been detected in a wide range of animal and environmental sources, including water, in Canada. The purpose of this article is to review (i) the prevalence of Campylobacter spp. in animals, food, and the environment, and (ii) the relevant testing programs in Canada with a focus on the potential links between campylobacters and human health in Canada.

  7. 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.

  8. Interaction of human serum albumin and its clinically relevant modification with oligoribonucleotides.

    PubMed

    Gerasimova, Yuliya V; Erchenko, Irina A; Shakirov, Makhmut M; Godovikova, Tatyana S

    2008-08-15

    Human serum albumin (HSA) was shown to mediate oligoribonucleotide cleavage. Nonenzymatic glycation of HSA decreased the ribonuclease-like activity of the protein. According to (31)P NMR data, both native and glycated albumins induced hydrolysis of RNA molecule through 2',3'-cyclophosphate intermediates. A feasible mechanism of RNA hydrolysis by native albumin and its clinically relevant modification was discussed.

  9. 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…

  10. 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…

  11. 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

  12. A software system to collect expert relevance ratings of medical record items for specific clinical tasks.

    PubMed

    Harvey, H Benjamin; Krishnaraj, Arun; Alkasab, Tarik K

    2014-02-28

    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.

  13. 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.

  14. FAST Real Time PCR for control of intra-species recycling in aquaculture feed, focused to the most relevant fish species farmed in Europe.

    PubMed

    Espiñeira, Montserrat; Vieites, Juan M

    2016-08-01

    Recent regulations in animal feed composition prohibit intra-species recycling, the recycling of one given animal species to the same species, in order to avoid potential safety risks to human and animal health. These regulations have generated the need of their control in aquaculture by effective and specific analytical techniques. To date, most studies of species identification and detection in feedstuffs are focused on land species, but few studies are focused on species composition in fish feed. The present work describes five methodologies based in Real Time PCR for detection of the most relevant fish species farmed in Europe: gilthead sea bream (Sparus aurata); sea bass (Dicentrarchus labrax); turbot (Scophthalmus maximus); rainbow trout (Onchorynchus mykiss); and salmon (Salmo salar), in order to guarantee the intra-species recycling regulation in aquaculture feedstuffs.

  15. Photoinactivation of Eight Health-Relevant Bacterial Species: Determining the Importance of the Exogenous Indirect Mechanism.

    PubMed

    Maraccini, Peter A; Wenk, Jannis; Boehm, Alexandria B

    2016-05-17

    It is presently unknown to what extent the endogenous direct, endogenous indirect, and exogenous indirect mechanisms contribute to bacterial photoinactivation in natural surface waters. In this study, we investigated the importance of the exogenous indirect mechanism by conducting photoinactivation experiments with eight health-relevant bacterial species (Bacteroides thetaiotaomicron, Campylobacter jejuni, Enterococcus faecalis, Escherichia coli K12, E. coli O157:H7, Salmonella enterica serovar Typhimurium LT2, Staphylococcus aureus, and Streptococcus bovis). We used three synthetic photosensitizers (methylene blue, rose bengal, and nitrite) and two model natural photosensitizers (Suwannee River natural organic matter and dissolved organic matter isolated from a wastewater treatment wetland) that generated singlet oxygen and hydroxyl radical. B. thetaiotaomicron had larger first order rate constants than all other organisms under all conditions tested. The presence of the synthetic photosensitizers generally enhanced photoinactivation of Gram-positive facultative anaerobes (Ent. faecalis, Staph. aureus, and Strep. bovis). Among Gram-negative bacteria, only methylene blue with E. coli K12 and rose bengal with C. jejuni showed an enhancing effect. The presence of model natural photosensitizers either reduced or did not affect photoinactivation rate constants. Our findings highlight the importance of the cellular membrane and photosensitizer properties in modulating the contribution of the exogenous indirect mechanism to the overall bacterial photoinactivation.

  16. MICS-Asia II: Model intercomparison and evaluation of ozone and relevant species

    NASA Astrophysics Data System (ADS)

    Han, Z.; Sakurai, T.; Ueda, H.; Carmichael, G. R.; Streets, D.; Hayami, H.; Wang, Z.; Holloway, T.; Engardt, M.; Hozumi, Y.; Park, S. U.; Kajino, M.; Sartelet, K.; Fung, C.; Bennet, C.; Thongboonchoo, N.; Tang, Y.; Chang, A.; Matsuda, K.; Amann, M.

    Eight regional Eulerian chemical transport models (CTMs) are compared with each other and with an extensive set of observations including ground-level concentrations from EANET, ozone soundings from JMA and vertical profiles from the TRACE-P experiment to evaluate the models' abilities in simulating O 3 and relevant species (SO 2, NO, NO 2, HNO 3 and PAN) in the troposphere of East Asia and to look for similarities and differences among model performances. Statistical analysis is conducted to help estimate the consistency and discrepancy between model simulation and observation in terms of various species, seasons, locations, as well as altitude ranges. In general, all models show a good skill of simulating SO 2 for both ground level and the lower troposphere, although two of the eight models systematically overpredict SO 2 concentration. The model skills for O 3 vary largely with region and season. For ground-level O 3, model results are best correlated with observations in July 2001. Comparing with O 3 soundings measured in the afternoon reveals the best consistency among models in March 2001 and the largest disparity in O 3 magnitude in July 2001, although most models produce the best correlation in July as well. In terms of the statistics for the four flights of TRACE-P experiment, most models appear to be able to accurately capture the variability in the lower troposphere. The model performances for NO x are relatively poor, with lower correlation and with almost all models tending to underpredict NO x levels, due to larger uncertainties in either emission estimates or complex chemical mechanism represented. All models exhibit larger RMSE at altitudes <2 km than 2-5.5 km, mainly due to a consistent tendency of these models towards underprediction of the magnitude of intense plumes that often originate from near surface. Relatively lower correlation at altitudes 2-5.5 km may be attributed to the models' limitation in representing convection or potential

  17. 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

  18. Clinical manipulation of mineral trioxide aggregate: lessons from the construction industry and their relevance to clinical practice.

    PubMed

    Ha, William N; Kahler, Bill; Walsh, Laurence J

    2015-01-01

    Mineral trioxide aggregate (MTA) is based on ordinary Portland cement (with added radiopaque agents) and, thus, shares many of its features. Although MTA is reported to be difficult to handle clinically, concrete materials made using Portland cement are the foundation of the construction industry. In this paper, we summarize important lessons from the construction literature that are relevant to the successful use of MTA in clinical practice, including behaviour during storage, susceptibility to acidic environments, the effects of exposure of the setting material to moisture and interactions with substances that may interfere with the speed of setting and the quality of the end product.

  19. Minimal residual disease detection in mantle cell lymphoma: technical aspects and clinical relevance.

    PubMed

    Pott, Christiane

    2011-07-01

    The prognostic impact of minimal residual disease (MRD) has been demonstrated for several hematologic malignancies. While in acute lymphoblastic leukemias MRD assessment by polymerase chain reaction (PCR)-based methods has been established as an important tool for clinical risk assessment and is part of clinical management, data demonstrating a prognostic value of MRD in mantle cell lymphoma (MCL) were sparse and results from randomized trials have been published only recently. In the present review technical aspects of different MRD detection methods are discussed, as well as the prognostic relevance of MRD in the context of clinical trials in patients with MCL. Furthermore, recommendations are given for workflow and useful implication of MRD in future clinical trials design.

  20. Rapid Identification of Candida Species and Other Clinically Important Yeast Species by Flow Cytometry†

    PubMed Central

    Page, Brent T.; Kurtzman, Cletus P.

    2005-01-01

    Two rapid diagnostic assays, utilizing two different Luminex flow cytometry methods, were developed for identification of clinically important ascomycetous yeast species. Direct hybridization and allele-specific primer extension methods were both successful in establishing a DNA-based assay that can rapidly and accurately identify Candida albicans, Candida krusei, Candida parapsilosis, Candida glabrata, and Candida tropicalis as well as other clinical species. The direct hybridization assay was designed to identify a total of 19 ascomycetous yeast species, and the allele-specific primer extension assay was designed to identify a total of 34 species. Probes were validated against 438 strains representing 303 species. From culture to identification, the allele-specific primer extension method takes 8 h and the direct hybridization method takes less than 5 h to complete. These assays represent comprehensive, rapid tests that are well suited for the clinical laboratory. PMID:16145099

  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.

  2. 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

  3. 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.

  4. Evaluation of Luminex xTAG fungal analyte-specific reagents for rapid identification of clinically relevant fungi.

    PubMed

    Babady, N Esther; Miranda, Edwin; Gilhuley, Kathleen A

    2011-11-01

    Invasive fungal infections (IFI) remain a serious threat to immunocompromised hosts. Current diagnostic methods, including fungal culture and antigen detection, are slow and often lack specificity. Rapid diagnostic tools with increased sensitivity and specificity could improve the care of patients with IFI. Recently, Luminex Molecular Diagnostics (Toronto, Canada) developed 23 analyte-specific reagents (ASRs) for the detection of the most common clinically relevant fungi. This study's objective was to evaluate the sensitivity and specificity of a subset of these ASRs for fungal isolates and clinical specimens. Previously characterized fungal and bacterial isolates (n = 110), blood culture specimens (n = 34), and respiratory specimens (n = 44) were tested using either a Candida 7-plex panel (Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis, Candida lusitaniae, Candida guilliermondii, and Candida krusei) or a mold 11-plex panel (Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Scedosporium prolificans, Scedosporium apiospermum, Fusarium oxysporum/Fusarium solani, Rhizopus arrhizus, Rhizopus microsporus, Mucor indicus, and Cunninghamella bertholletiae). The Candida 7-plex panel correctly identified all Candida isolates as confirmed by fungal culture and biochemical tests, for a sensitivity and specificity of 100%. The mold 11-plex panel correctly identified all mold isolates tested except for A. niger. Fungal isolates of Rhizopus and Mucor species were not detected, either, although they could represent species other than those targeted by the ASRs. Further evaluation will be necessary to confirm the sensitivities of some of the mold ASRs. Implementation of these ASRs will allow same-day detection of fungal DNA in clinical specimens.

  5. 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.

  6. Using mixed methods to identify and answer clinically relevant research questions.

    PubMed

    Shneerson, Catherine L; Gale, Nicola K

    2015-06-01

    The need for mixed methods research in answering health care questions is becoming increasingly recognized because of the complexity of factors that affect health outcomes. In this article, we argue for the value of using a qualitatively driven mixed method approach for identifying and answering clinically relevant research questions. This argument is illustrated by findings from a study on the self-management practices of cancer survivors and the exploration of one particular clinically relevant finding about higher uptake of self-management in cancer survivors who had received chemotherapy treatment compared with those who have not. A cross-sectional study generated findings that formed the basis for the qualitative study, by informing the purposive sampling strategy and generating new qualitative research questions. Using a quantitative research component to supplement a qualitative study can enhance the generalizability and clinical relevance of the findings and produce detailed, contextualized, and rich answers to research questions that would be unachievable through quantitative or qualitative methods alone.

  7. Establishing a clinically relevant cutoff to the Dependency Scale from the dimensional clinical personality inventory.

    PubMed

    Carvalho, Lucas de F; Pianowski, Giselle; Filho, Nelson H

    2017-02-03

    The Clinical Dimensional Personality Inventory (IDCP) is a 163-item self-report tool developed for the assessment of 12 dimensions of personality pathology. One of the scales comprising the instrument-the Dependency scale-is intended to provide psychometric information on traits closely related to the Dependent Personality Disorder (DPD). In the present study, we used both Item Response Theory modeling and Receiver Operating Characteristic curve analysis to establishing a clinically meaningful cutoff for the IDCP Dependency Scale. Participants were 2.481 adults, comprised by outpatients diagnosed with DPD, outpatients diagnosed with other PDs, and adults from the general population. The Wright's item map graphing technique revealed that outpatients were located at the very high levels in the latent scale continuum of the Dependency Scale, with a very large effect size for the mean difference between patients and non-patients. The ROC curve analysis supported a cutoff at 2.3 points in the Dependency Scale, which yielded 0.86 of sensitivity and 0.79 of specificity. Findings from the present investigation suggest the IDCP Dependency Scale is useful as a screening tool of the core features of the DPD. We address potential clinical applications for the instrument, and discuss limitations from the present study.

  8. Molecular weight and galloylation affect grape seed extract constituents’ ability to cross-link dentin collagen in clinically relevant time

    PubMed Central

    Liu, Yi; Bai, Xinyan; Li, Shaohua; Liu, Ying; Keightley, Andrew; Wang, Yong

    2015-01-01

    Objective To investigate the relationship between the structures of polyphenolic compounds found in grape seed extract (GSE) and their activity in cross-linking dentin collagen in clinically relevant settings. Methods Representative monomeric and dimeric GSE constituents including (+)-catechin (pCT), (−)-catechin (CT), (−)-epicatechin (EC), (−)-epigallocatechin (EGC), (−)-epicatechin gallate (ECG), (−)-epigallocatechin gallate (EGCG), procyanidin B2 and a pCT-pCT dimer were purchased or synthesized. GSE was separated into low (PALM) and high molecular weight (PAHM) fractions. Human molars were processed into dentin films and beams. After demineralization, 11 groups of films (n=5) were treated for 1 min with the aforementioned reagents (1 wt% in 50/50 ethanol/water) and 1 group remained untreated. The films were studied by Fourier transform infrared spectroscopy (FTIR) followed by a quantitative mass spectroscopy-based digestion assay. Tensile properties of demineralized dentin beams were evaluated (n=7) after treatments (2h and 24h) with selective GSE species that were found to protect dentin collagen from collagenase. Results Efficacy of GSE constituents in cross-linking dentin collagen was dependent on molecular size and galloylation. Non-galloylated species with degree of polymerization up to two, including pCT, CT, EC, EGC, procyanidin B2 and pCT-pCT dimer were not active. Galloylated species were active starting from monomeric form, including ECG, EGCG, PALM, GSE and PAHM. PALM induced the best overall improvement in tensile properties of dentin collagen. Significance Identification under clinically relevant settings of structural features that contribute to GSE constituents’ efficacy in stabilizing demineralized dentin matrix has immediate impact on optimizing GSE’s use in dentin bonding. PMID:25958268

  9. Emergence of Rare Species of Nontuberculous Mycobacteria as Potential Pathogens in Saudi Arabian Clinical Setting

    PubMed Central

    Varghese, Bright; Enani, Mushira; Shoukri, Mohammed; AlThawadi, Sahar; AlJohani, Sameera; Al- Hajoj, Sahal

    2017-01-01

    Background Clinical relevance of nontuberculous mycobacteria (NTM) is increasing worldwide including in Saudi Arabia. A high species diversity of NTM’s has been noticed in a recent study. However, the identification in diagnostic laboratories is mostly limited to common species. The impact of NTM species diversity on clinical outcome is so far neglected in most of the clinical settings. Methodology/Principal Findings During April 2014 to September 2015, a nationwide collection of suspected NTM clinical isolates with clinical and demographical data were carried out. Primary identification was performed by commercial line probe assays. Isolates identified up to Mycobacterium species level by line probe assays only were included and subjected to sequencing of 16S rRNA, rpoB, hsp65 and 16S-23S ITS region genes. The sequence data were subjected to BLAST analysis in GenBank and Ez-Taxon databases. Male Saudi nationals were dominated in the study population and falling majorly into the 46–59 years age group. Pulmonary cases were 59.3% with a surprising clinical relevance of 75% based on American Thoracic Society guidelines. Among the 40.7% extra-pulmonary cases, 50% of them were skin infections. The identification revealed 16 species and all of them are reporting for the first time in Saudi Arabia. The major species obtained were Mycobacterium monascence (18.5%), M. cosmeticum (11.1%), M. kubicae (11.1%), M. duvalli (7.4%), M.terrae (7.4%) and M. triplex (7.4%). This is the first report on clinical relevance of M. kubicae, M. tusciae, M.yongonense, M. arupense and M.iranicum causing pulmonary disease and M. monascence, M. duvalli, M. perigrinum, M. insubricum, M. holsaticum and M. kyorinense causing various extra-pulmonary diseases in Saudi Arabia. Ascites caused by M. monascence and cecum infection by M. holsaticum were the rarest incidents. Conclusions/Significance To the first time in the country, clinical significance of various rare NTM’s are well explored and

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

    PubMed Central

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

    2015-01-01

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

  11. Mercury methylation rates for geochemically relevant Hg(II) species in sediments.

    PubMed

    Jonsson, Sofi; Skyllberg, Ulf; Nilsson, Mats B; Westlund, Per-Olof; Shchukarev, Andrey; Lundberg, Erik; Björn, Erik

    2012-11-06

    Monomethylmercury (MeHg) in fish from freshwater, estuarine, and marine environments is a major global environmental issue. Mercury levels in biota are mainly controlled by the methylation of inorganic mercuric mercury (Hg(II)) to MeHg in water, sediments, and soils. There is, however, a knowledge gap concerning the mechanisms and rates of methylation of specific geochemical Hg(II) species. Such information is crucial for a better understanding of variations in MeHg concentrations among ecosystems and, in particular, for predicting the outcome of currently proposed measures to mitigate mercury emissions and reduce MeHg concentrations in fish. To fill this knowledge gap we propose an experimental approach using Hg(II) isotope tracers, with defined and geochemically important adsorbed and solid Hg(II) forms in sediments, to study MeHg formation. We report Hg(II) methylation rate constants, k(m), in estuarine sediments which span over 2 orders of magnitude depending on chemical form of added tracer: metacinnabar (β-(201)HgS(s)) < cinnabar (α-(199)HgS(s)) < Hg(II) reacted with mackinawite (≡FeS-(202)Hg(II)) < Hg(II) bonded to natural organic matter (NOM-(196)Hg(II)) < a typical aqueous tracer ((198)Hg(NO(3))(2)(aq)). We conclude that a combination of thermodynamic and kinetic effects of Hg(II) solid-phase dissolution and surface desorption control the Hg(II) methylation rate in sediments and cause the large observed differences in k(m)-values. The selection of relevant solid-phase and surface-adsorbed Hg(II) tracers will therefore be crucial to achieving biogeochemically accurate estimates of ambient Hg(II) methylation rates.

  12. 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

  13. 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.

  14. 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

  15. Antifungal drug resistance among Candida species: mechanisms and clinical impact.

    PubMed

    Sanguinetti, Maurizio; Posteraro, Brunella; Lass-Flörl, Cornelia

    2015-06-01

    The epidemiology of Candida infections has changed in recent years. Although Candida albicans is still the main cause of invasive candidiasis in most clinical settings, a substantial proportion of patients is now infected with non-albicans Candida species. The various Candida species vary in their susceptibility to the most commonly used antifungal agents, and the intrinsic resistance to antifungal therapy seen in some species, along with the development of acquired resistance during treatment in others, is becoming a major problem in the management of Candida infection. A better understanding of the mechanisms and clinical impact of antifungal drug resistance is essential for the efficient treatment of patients with Candida infection and for improving treatment outcomes. Herein, we report resistance to the azoles and echinocandins among Candida species.

  16. 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

  17. Empathy and alteration: the ethical relevance of a phenomenological species concept.

    PubMed

    Meacham, Darian

    2014-10-01

    The debate over the ethics of radically, technologically altering the capacities and traditional form of the human body is rife with appeals to and dismissals of the importance of the integrity of the human species. Species-integrist arguments can be found in authors as varied as Annas, Fukuyama, Habermas, and Agar. However, the ethical salience of species integrity is widely contested by authors such as Buchanan, Daniels, Fenton, and Juengst. This article proposes a Phenomenological approach to the question of species-integrity, arguing in favor of a phenomenon of species-recognition that carries an ethical pull. Building on Husserl's Phenomenological account of empathy and the lived-body, as well as Schopenhauer's concept of compassion as an ethical urphenomenon, I develop a "Phenomenological species concept" (PSC), which I argue has the ethical significance that biological species concepts do not. The PSC reorients the debate over human alteration and species integrity.

  18. The pulsed light inactivation of veterinary relevant microbial biofilms and the use of a RTPCR assay to detect parasite species within biofilm structures

    PubMed Central

    Garvey, M.; Coughlan, G.; Murphy, N.; Rowan, N.

    2016-01-01

    The presence of pathogenic organisms namely parasite species and bacteria in biofilms in veterinary settings, is a public health concern in relation to human and animal exposure. Veterinary clinics represent a significant risk factor for the transfer of pathogens from housed animals to humans, especially in cases of wound infection and the shedding of faecal matter. This study aims to provide a means of detecting veterinary relevant parasite species in bacterial biofilms, and to provide a means of disinfecting these biofilms. A real time PCR assay was utilized to detect parasite DNA in Bacillus cereus biofilms on stainless steel and PVC surfaces. Results show that both Cryptosporidium and Giardia attach to biofilms in large numbers (100-1000 oo/cysts) in as little as 72 hours. Pulsed light successfully inactivated all test species (Listeria, Salmonella, Bacillus, Escherichia) in planktonic and biofilm form with an increase in inactivation for every increase in UV dose. PMID:26862516

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

    PubMed

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

    2016-06-01

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

  20. 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

  1. 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

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

    PubMed Central

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

    2012-01-01

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

  3. 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.

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

    PubMed

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

    2015-06-01

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

  5. Carbon dioxide production during cardiopulmonary bypass: pathophysiology, measure and clinical relevance.

    PubMed

    Ranucci, Marco; Carboni, Giovanni; Cotza, Mauro; de Somer, Filip

    2017-01-01

    Carbon dioxide production during cardiopulmonary bypass derives from both the aerobic metabolism and the buffering of lactic acid produced by tissues under anaerobic conditions. Therefore, carbon dioxide removal monitoring is an important measure of the adequacy of perfusion and oxygen delivery. However, routine monitoring of carbon dioxide removal is not widely applied. The present article reviews the main physiological and pathophysiological sources of carbon dioxide, the available techniques to assess carbon dioxide production and removal and the clinically relevant applications of carbon dioxide-related variables as markers of the adequacy of perfusion during cardiopulmonary bypass.

  6. 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.

  7. 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

  8. Clinically Relevant Cognitive Impairment in Middle-Aged Adults With Childhood-Onset Type 1 Diabetes

    PubMed Central

    Nunley, Karen A.; Ryan, Christopher M.; Jennings, J. Richard; Aizenstein, Howard J.; Zgibor, Janice C.; Costacou, Tina; Boudreau, Robert M.; Miller, Rachel; Orchard, Trevor J.; Saxton, Judith A.

    2015-01-01

    OBJECTIVE The aim of this study was to investigate the presence and correlates of clinically relevant cognitive impairment in middle-aged adults with childhood-onset type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS During 2010–2013, 97 adults diagnosed with T1D and aged <18 years (age and duration 49 ± 7 and 41 ± 6 years, respectively; 51% female) and 138 similarly aged adults without T1D (age 49 ± 7 years; 55% female) completed extensive neuropsychological testing. Biomedical data on participants with T1D were collected periodically since 1986–1988. Cognitive impairment status was based on the number of test scores ≥1.5 SD worse than demographically appropriate published norms: none, mild (only one test), or clinically relevant (two or more tests). RESULTS The prevalence of clinically relevant cognitive impairment was five times higher among participants with than without T1D (28% vs. 5%; P < 0.0001), independent of education, age, or blood pressure. Effect sizes were large (Cohen d 0.6–0.9; P < 0.0001) for psychomotor speed and visuoconstruction tasks and were modest (d 0.3–0.6; P < 0.05) for measures of executive function. Among participants with T1D, prevalent cognitive impairment was related to 14-year average A1c >7.5% (58 mmol/mol) (odds ratio [OR] 3.0; P = 0.009), proliferative retinopathy (OR 2.8; P = 0.01), and distal symmetric polyneuropathy (OR 2.6; P = 0.03) measured 5 years earlier; higher BMI (OR 1.1; P = 0.03); and ankle-brachial index ≥1.3 (OR 4.2; P = 0.01) measured 20 years earlier, independent of education. CONCLUSIONS Clinically relevant cognitive impairment is highly prevalent among these middle-aged adults with childhood-onset T1D. In this aging cohort, chronic hyperglycemia and prevalent microvascular disease were associated with cognitive impairment, relationships shown previously in younger populations with T1D. Two additional potentially modifiable risk factors for T1D-related cognitive impairment, vascular health and BMI

  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. Promoting culturally competent chronic pain management using the clinically relevant continuum model.

    PubMed

    Monsivais, Diane B

    2011-06-01

    This article reviews the culture of biomedicine and current practices in pain management education, which often merge to create a hostile environment for effective chronic pain care. Areas of cultural tensions in chronic pain frequently involve the struggle to achieve credibility regarding one's complaints of pain (or being believed that the pain is real) and complying with pain medication protocols. The clinically relevant continuum model is presented as a framework allowing providers to approach care from an evidence-based, culturally appropriate (patient centered) perspective that takes into account the highest level of evidence available, provider expertise, and patient preferences and values.

  11. Emerging Bacterial Infection: Identification and Clinical Significance of Kocuria Species

    PubMed Central

    Palange, Padmavali; Vaish, Ritu; Bhatti, Adnan Bashir; Kale, Vinod; Kandi, Maheshwar Reddy; Bhoomagiri, Mohan Rao

    2016-01-01

    Recently there have been reports of gram-positive cocci which are morphologically similar to both Staphylococci and the Micrococci. These bacteria have been identified as Kocuria species with the help of automated identification system and other molecular methods including 16S rRNA (ribosomal ribonucleic acid) evaluation. Kocuria belongs to the family Micrococcaceae which also includes Staphylococcus species and Micrococcus species. Isolation and clinical significance of these bacteria from human specimens warrant great caution as it does not necessarily confirm infection due to their ubiquitous presence, and as a normal flora of skin and mucous membranes in human and animals. Most clinical microbiology laboratories ignore such bacteria as laboratory and specimen contaminants. With increasing reports of infections associated with these bacteria, it is now important for clinical microbiologists to identify and enumerate the virulence and antibiotic susceptibility patterns of such bacteria and assist clinicians in improving the patient care and management. We review the occurrence and clinical significance of Kocuria species. PMID:27630804

  12. Nurses in the clinical area: relevance of a PhD.

    PubMed

    Wilkes, Lesley M; Mohan, Shantala

    2008-01-01

    This project aimed to explore the application and relevance of a PhD to nurses working in the clinical area. The complexity of nursing practice requires clinical nurses to be competent as investigators and professional leaders who could help structure nursing practice in more efficient ways. Research proposes that a PhD offers Limited employment opportunities, is mainly research oriented and tends to direct a nurse away from the clinical field. A mixed method study design utilising surveys and interviews was chosen to collect data for this study. Participants were nurses with a doctoral degree working/having worked in a clinical area after obtaining their PhD Nurses were recruited through student databases from Australian universities that offer doctoral degrees in nursing and also by using a snowball sampling technique. The majority of the 19 nurses who participated in the study had: varied expectation of doing a PhD; maintained their clinical positions after obtaining their doctoral degree, considered that the degree helped them to obtain better jobs/promotions and acknowledged the value of the PhD in patient care, in improving research and informing health policy. This study has exposed the positive aspects of completing a PhD and identifies its constructive application in the clinical area. It is essential to provide support and opportunities for nurses working in the clinical area to pursue doctoral degrees in order to enable them to enhance knowledge and build confidence and leadership skills and contribute to the improvement of nursing practice and the continued development of the profession.

  13. 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.

  14. 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

  15. The association between clinically relevant anxiety and other non-motor symptoms in Parkinson's disease.

    PubMed

    Jiang, Si-Ming; Yuan, Yong-Sheng; Tong, Qing; Zhang, Li; Xu, Qin-Rong; Ding, Jian; Zhang, Ke-Zhong

    2015-11-01

    Anxiety disorders in patients with Parkinson's disease (PD) are often missed due to an overlap with other non-motor symptoms. The relationships between anxiety and other non-motor symptoms in PD still remain unclear. We used the Hamilton anxiety rating scale and the Non-motor Symptoms Questionnaire to measure anxiety and the complex range of non-motor symptoms in 99 PD patients. The relationships between anxiety and other PD-related non-motor symptoms were examined through regression analyses. 25 % of PD patients were diagnosed with clinically relevant anxiety. Non-motor symptoms were more prominent in patients with anxiety. Depression, urinary disorders, and sleep disruption were the factors most likely to influence anxiety in PD. Our findings have revealed a strong interplay between anxiety and other non-motor symptoms of PD and have highlighted the need for a holistic approach towards the clinical treatment of this disabling condition.

  16. Less than meets the eye: reappraising the clinical relevance of attentional bias in addiction.

    PubMed

    Christiansen, Paul; Schoenmakers, Tim M; Field, Matt

    2015-05-01

    Recent years have seen an explosion of interest in attentional bias in addiction, particularly its clinical relevance. Specifically, numerous articles claimed to demonstrate either that (1) attentional bias measured in treatment settings could predict subsequent relapse to substance use, or (2) direct modification of attentional bias reduced substance use and improved treatment outcomes. In this paper, we critically evaluate empirical studies that investigated these issues. We show that the evidence regarding both of these claims is decidedly mixed, and that many of the studies that appear to yield positive findings have serious methodological and statistical limitations. We contend that the available literature suggests that attentional bias for drug cues fluctuates within individuals because it is an output of the underlying motivational state at that moment in time, but there is no convincing evidence that it exerts a causal influence on substance use. Future research should make use of experience sampling methodology to characterise the clinical significance of fluctuations in attentional bias over time.

  17. 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.

  18. 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

  19. 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

  20. 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.

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

    PubMed

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

    2016-06-01

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

  2. COMPLEMENTARY APPROACHES TO THE DETERMINATION OF ARSENIC SPECIES RELEVANT TO CONCENTRATED ANIMAL FEEDING OPERATIONS

    EPA Science Inventory

    Ion-exchange chromatography is the most often used analytical approach for arsenic

    speciation, due to the weak-acid nature of several of its species. However, no single

    technique can determine all potentially occurring arsenic species, especially in complex

    e...

  3. Colonization, pathogenicity, host susceptibility, and therapeutics for Staphylococcus aureus: what is the clinical relevance?

    PubMed

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

    2012-03-01

    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.

  4. 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.

  5. Nicotine at clinically relevant concentrations affects atrial inward rectifier potassium current sensitive to acetylcholine.

    PubMed

    Bébarová, Markéta; Matejovič, Peter; Švecová, Olga; Kula, Roman; Šimurdová, Milena; Šimurda, Jiří

    2017-02-03

    Nicotine abuse is associated with variety of diseases including arrhythmias, most often atrial fibrillation (AF). Altered inward rectifier potassium currents including acetylcholine-sensitive current I K(Ach) are known to be related to AF pathogenesis. Since relevant data are missing, we aimed to investigate I K(Ach) changes at clinically relevant concentrations of nicotine. Experiments were performed by the whole cell patch clamp technique at 23 ± 1 °C on isolated rat atrial myocytes. Nicotine was applied at following concentrations: 4, 40 and 400 nM; ethanol at 20 mM (∼0.09%). Nicotine at 40 and 400 nM significantly activated constitutively active component of I K(Ach) with the maximum effect at 40 nM (an increase by ∼100%); similar effect was observed at -110 and -50 mV. Changes at 4 nM nicotine were negligible on average. Coapplication of 40 nM nicotine and 20 mM ethanol (which is also known to activate this current) did not show cumulative effect. In the case of acetylcholine-induced component of I K(Ach), a dual effect of nicotine and its correlation with the current magnitude in control were apparent: the current was increased by nicotine in the cells showing small current in control and vice versa. The effect of 40 and 400 nM nicotine on acetylcholine-induced component of I K(Ach) was significantly different at -110 and -50 mV. We conclude that nicotine at clinically relevant concentrations significantly increased constitutively active component of I K(Ach) and showed a dual effect on its acetylcholine-induced component, similarly as ethanol. Synchronous application of nicotine and ethanol did not cause additive effect.

  6. Occurrence of Ochroconis and Verruconis Species in Clinical Specimens from the United States

    PubMed Central

    Giraldo, Alejandra; Sutton, Deanna A.; Samerpitak, Kittipan; de Hoog, G. Sybren; Wiederhold, Nathan P.; Guarro, Josep

    2014-01-01

    Ochroconis is a dematiaceous fungus able to infect immunocompetent people. Recently, the taxonomy of the genus has been reevaluated, and the most relevant species, Ochroconis gallopava, was transferred to the new genus Verruconis. Due to the important clinical implications of these fungi and based on the recent classification, it was of interest to know the spectra of Ochroconis and Verruconis species in clinical samples received in a reference laboratory in the United States. A set of 51 isolates was identified morphologically and molecularly based on sequence analyses of the nuclear ribosomal RNA (nrRNA), actin, and β-tubulin genes. Verruconis gallopava was the most common species (68.6%), followed by Ochroconis mirabilis (21.5%). One isolate of Ochroconis cordanae was found, being reported for the first time in a clinical setting. The most common anatomical site of isolation was the lower respiratory tract (58.8%), followed by superficial and deep tissues at similar frequencies (21.6 and 19.6%, respectively). Interestingly, three new species were found, which are Ochroconis olivacea and Ochroconis ramosa from clinical specimens and Ochroconis icarus of an environmental origin. The in vitro antifungal susceptibilities of eight antifungal drugs against the Ochroconis isolates revealed that terbinafine and micafungin were the most active drugs. PMID:25232157

  7. [Differential diagnosis of medically relevant flea species and their significance in dermatology].

    PubMed

    Beck, W; Clark, H H

    1997-10-01

    Different flea species may infest humans temporarily. Such arthropods should be considered as a possible cause of erythematous and pruritic papules and nodules of unclear origin. Bites from animal fleas can be seen in people with close contact to domestic or wild animals. This dermatosis may often be misdiagnosed. Several flea species including Pulex irritans, Ctenocephalides canis, Ctenocephalides felis, Ceratophyllus gallinae, Ceratophyllus columbae and Archaeopsylla erinacei may infest human skin, causing symptoms. Flea bite-allergy and the role of various flea species as disease vectors are also discussed.

  8. Cladosporium Species Recovered from Clinical Samples in the United States

    PubMed Central

    Sutton, Deanna A.; Martin-Vicente, Adela; Cano-Lira, José F.; Wiederhold, Nathan; Guarro, Josep

    2015-01-01

    Cladosporium species are ubiquitous, saprobic, dematiaceous fungi, only infrequently associated with human and animal opportunistic infections. We have studied a large set of Cladosporium isolates recovered from clinical samples in the United States to ascertain the predominant species there in light of recent taxonomic changes in this genus and to determine whether some could possibly be rare potential pathogens. A total of 92 isolates were identified using phenotypic and molecular methods, which included sequence analysis of the internal transcribed spacer (ITS) region and a fragment of the large subunit (LSU) of the nuclear ribosomal DNA (rDNA), as well as fragments of the translation elongation factor 1 alpha (EF-1α) and actin (Act) genes. The most frequent species was Cladosporium halotolerans (14.8%), followed by C. tenuissimum (10.2%), C. subuliforme (5.7%), and C. pseudocladosporioides (4.5%). However, 39.8% of the isolates did not correspond to any known species and were deemed to comprise at least 17 new lineages for Cladosporium. The most frequent anatomic site of isolation was the respiratory tract (54.5%), followed by superficial (28.4%) and deep tissues and fluids (14.7%). Species of the two recently described cladosporiumlike genera Toxicocladosporium and Penidiella are reported for the first time from clinical samples. In vitro susceptibility testing of 92 isolates against nine antifungal drugs showed a variety of results but high activity overall for the azoles, echinocandins, and terbinafine. PMID:26179305

  9. Complete Genome Sequences for 35 Biothreat Assay-Relevant Bacillus Species

    DOE PAGES

    Johnson, Shannon L.; Daligault, Hajnalka E.; Davenport, Karen W.; ...

    2015-04-30

    In 2011, the Association of Analytical Communities (AOAC) International released a list of Bacillus strains relevant to biothreat molecular detection assays. Presented in this document are the complete and annotated genome assemblies for the 15 strains listed on the inclusivity panel, as well as the 20 strains listed on the exclusivity panel.

  10. Photoactivated disinfection of Streptococcus intermedius through dentin disc at clinically relevant intervals: an in vitro study.

    PubMed

    Bonstein, Tammy; Mikulski, Lynn M; Bush, Mary A; Bush, Peter J

    2010-10-01

    In this present study we have tested the impact of porfimer sodium (Photofrin, AXCAN PHARMA Inc., Quebec, Canada) photoactivated disinfection (PD) on cells of Streptococcus intermedius in suspension. In order to provide basic data to support future clinical studies of PD in dentistry the study used exposure to Quartz-tungsten-halogen (QTH) dental curing light for clinically relevant time periods to activate Photofrin and measured its effectiveness under a variety of conditions including activation through dentin hard tissue. S. intermedius was grown in planktonic suspension for 48h. Nine groups were formed: three control groups (1-3) and six experimental groups (4-9). Groups 4-6 tested the use of Photofrin treatment combined with QTH light at various intervals of irradiation (5, 15 and 60s). Groups 7-9 were similar to groups 4-6 with the exception that irradiation commenced through a dentin disc. Following treatment, bacteria were plated. Colony counts were measured following 72h incubation at 37 degrees C. Statistical analysis was carried out by one-way ANOVA at a 95% confidence level. A significant reduction in S. intermedius colony counts was observed for all experimental groups and one control group. The reduction in numbers of colonies in the experimental groups varied from 79.28 to 99.40% with an average of 94.61%. Reduction in viable bacterial cells indicated a strong relationship between power density and irradiation interval. When curing light energy density was lower due to the irradiation through the 1mm dentin disc, prolonged irradiation interval enhanced bacterial kill. In conclusion, where direct irradiation is not possible for PD treatment, irradiation through dentin may still be done successfully within a clinically relevant interval.

  11. Food authentication of commercially-relevant shrimp and prawn species: from classical methods to Foodomics.

    PubMed

    Ortea, Ignacio; Pascoal, Ananías; Cañas, Benito; Gallardo, José M; Barros-Velázquez, Jorge; Calo-Mata, Pilar

    2012-08-01

    Although seafood species identification has traditionally relied on morphological analysis, sometimes this is difficult to apply for the differentiation among penaeid shrimps owing to their phenotypic similarities and to the frequent removal of external carapace during processing. The objective of this review is to provide an updated and extensive overview on the molecular methods for shrimp and prawn species authentication, in which several omics approaches based on protein and DNA analysis are described. DNA-based methods include the amplification by PCR of different genes, commonly the mitochondrial 16S ribosomal RNA and cytochrome oxidase I genes. A recently described method based on RFLP coupled to PCR turned out to be particularly interesting for species differentiation and origin identification. Protein analysis methods for the characterization and detection of species-specific peptides are also summarized, emphasizing some novel proteomics-based approaches, such as phyloproteomics, peptide fragmentation, and species-specific peptide detection by HPLC coupled to multiple reaction monitoring (MRM) MS, the latter representing the fastest method described to date for species authentication in food.

  12. Update on cardiovascular safety of PPARgamma agonists and relevance to medicinal chemistry and clinical pharmacology.

    PubMed

    Ciudin, Andreea; Hernandez, Cristina; Simó, Rafael

    2012-01-01

    Peroxisome proliferator-activator receptors (PPARs) are now known as members of the nuclear hormonereceptor superfamily of ligand-activated transcription factors that regulate gene expression in response to nutritional and physiological stimuli. PPARγ plays a crucial role in glucose homeostasis and it is involved in the regulation of lipid metabolism and adipocyte differentiation and function. From all the PAARγ ligands, the thiazolidindiones (TZDs) are of most clinical importance. Rosiglitazone and pioglitazone have been largely used so far in the clinical practice. They provide similar effects on glycemic control, as well as a range of similar adverse effects, such as weight gain, fluid retention, and increased risk of hearth failure, which seem to be PPARγ mediated. Interestingly, they differ on their effect on lipid and cardiovascular safety profile, indicating a PPARγ-independent mechanism. Indeed, rosiglitazone was recently withdrawn in Europe and its use has been restricted in USA as a consequence of increased risk of cardiovascular events in type 2 diabetic patients. This review is focused on the cardiovascular effects of rosiglitazone and pioglitazone as representative members of PPARγ ligands, because they were widely evaluated in many clinical trials and experimental studies and data obtained from these studies are relevant from medicinal chemistry and clinical pharmacology point of view. Finally, an overview on the development of selective PPARγ modulators and/or dual PPARα/γ agonists will be given. These new approaches might provide anti-hyperglycemic efficacy without the associated undesirable side-effects. However, further experimental and clinical studies evaluating the theoretical benefit and safety of this therapeutic strategy are needed.

  13. Prophage carriage and diversity within clinically relevant strains of Clostridium difficile.

    PubMed

    Shan, Jinyu; Patel, Krusha V; Hickenbotham, Peter T; Nale, Janet Y; Hargreaves, Katherine R; Clokie, Martha R J

    2012-09-01

    Prophages are encoded in most genomes of sequenced Clostridium difficile strains. They are key components of the mobile genetic elements and, as such, are likely to influence the biology of their host strains. The majority of these phages are not amenable to propagation, and therefore the development of a molecular marker is a useful tool with which to establish the extent and diversity of C. difficile prophage carriage within clinical strains. To design markers, several candidate genes were analyzed including structural and holin genes. The holin gene is the only gene present in all sequenced phage genomes, conserved at both terminals, with a variable mid-section. This allowed us to design two sets of degenerate PCR primers specific to C. difficile myoviruses and siphoviruses. Subsequent PCR analysis of 16 clinical C. difficile ribotypes showed that 15 of them are myovirus positive, and 2 of them are also siphovirus positive. Antibiotic induction and transmission electron microscope analysis confirmed the molecular prediction of myoviruses and/or siphovirus presence. Phylogenetic analysis of the holin sequences identified three groups of C. difficile phages, two within the myoviruses and a divergent siphovirus group. The marker also produced tight groups within temperate phages that infect other taxa, including Clostridium perfringens, Clostridium botulinum, and Bacillus spp., which suggests the potential application of the holin gene to study prophage carriage in other bacteria. This study reveals the high incidence of prophage carriage in clinically relevant strains of C. difficile and correlates the molecular data to the morphological observation.

  14. Prophage Carriage and Diversity within Clinically Relevant Strains of Clostridium difficile

    PubMed Central

    Shan, Jinyu; Patel, Krusha V.; Hickenbotham, Peter T.; Nale, Janet Y.; Hargreaves, Katherine R.

    2012-01-01

    Prophages are encoded in most genomes of sequenced Clostridium difficile strains. They are key components of the mobile genetic elements and, as such, are likely to influence the biology of their host strains. The majority of these phages are not amenable to propagation, and therefore the development of a molecular marker is a useful tool with which to establish the extent and diversity of C. difficile prophage carriage within clinical strains. To design markers, several candidate genes were analyzed including structural and holin genes. The holin gene is the only gene present in all sequenced phage genomes, conserved at both terminals, with a variable mid-section. This allowed us to design two sets of degenerate PCR primers specific to C. difficile myoviruses and siphoviruses. Subsequent PCR analysis of 16 clinical C. difficile ribotypes showed that 15 of them are myovirus positive, and 2 of them are also siphovirus positive. Antibiotic induction and transmission electron microscope analysis confirmed the molecular prediction of myoviruses and/or siphovirus presence. Phylogenetic analysis of the holin sequences identified three groups of C. difficile phages, two within the myoviruses and a divergent siphovirus group. The marker also produced tight groups within temperate phages that infect other taxa, including Clostridium perfringens, Clostridium botulinum, and Bacillus spp., which suggests the potential application of the holin gene to study prophage carriage in other bacteria. This study reveals the high incidence of prophage carriage in clinically relevant strains of C. difficile and correlates the molecular data to the morphological observation. PMID:22706062

  15. Mutation databases for inherited renal disease: are they complete, accurate, clinically relevant, and freely available?

    PubMed

    Savige, Judy; Dagher, Hayat; Povey, Sue

    2014-07-01

    This study examined whether gene-specific DNA variant databases for inherited diseases of the kidney fulfilled the Human Variome Project recommendations of being complete, accurate, clinically relevant and freely available. A recent review identified 60 inherited renal diseases caused by mutations in 132 genes. The disease name, MIM number, gene name, together with "mutation" or "database," were used to identify web-based databases. Fifty-nine diseases (98%) due to mutations in 128 genes had a variant database. Altogether there were 349 databases (a median of 3 per gene, range 0-6), but no gene had two databases with the same number of variants, and 165 (50%) databases included fewer than 10 variants. About half the databases (180, 54%) had been updated in the previous year. Few (77, 23%) were curated by "experts" but these included nine of the 11 with the most variants. Even fewer databases (41, 12%) included clinical features apart from the name of the associated disease. Most (223, 67%) could be accessed without charge, including those for 50 genes (40%) with the maximum number of variants. Future efforts should focus on encouraging experts to collaborate on a single database for each gene affected in inherited renal disease, including both unpublished variants, and clinical phenotypes.

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

    Prosperini, Luca; Pozzilli, Carlo

    2013-01-01

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

  18. Polanyi's tacit knowing and the relevance of epistemology to clinical medicine.

    PubMed

    Henry, Stephen G

    2010-04-01

    Most clinicians take for granted a simple, reductionist understanding of medical knowledge that is at odds with how they actually practice medicine; routine medical decisions incorporate more complicated kinds of information than most standard accounts of medical reasoning suggest. A better understanding of the structure and function of knowledge in medicine can lead to practical improvements in clinical medicine. This understanding requires some familiarity with epistemology, the study of knowledge and its structure, in medicine. Michael Polanyi's theory of tacit knowing is advanced as the basis for developing a more accurate understanding of medical knowledge. Tacit knowing, which explores the taken-for-granted background knowledge that underlies all human knowing, is explained in detail with a focus on its relevance for clinical medicine. The implications of recognizing tacit knowing in medicine and medical decisions are discussed. These include the ability to explain the importance of the clinical encounter in medical practice, mechanisms for analysing patient and doctor as persons, and the need for humility given the uncertainty that the tacit dimension injects into all medical decisions. This more robust medical epistemology allows clinicians to better articulate the nature and importance of patient-centred care, to avoid pitfalls inherent in reductionist approaches to medical knowledge, and to think more clearly about the relationships between medicine and health care at the individual and population levels.

  19. Studies of ion species separation in ICF-relevant plasmas at OMEGA

    NASA Astrophysics Data System (ADS)

    Rinderknecht, Hans; Wilks, Scott; Amendt, Peter; Ross, Steve; Park, Hye-Sook; Gatu Johnson, Maria; Frenje, Johan; Li, Chikang; Seguin, Fredrick; Sio, Hong; Petrasso, Richard; Rosenberg, Michael; Forrest, Chad; Glebov, Vladimir; Stoeckl, Christian; Sangster, Craig; Zylstra, Alex; Hoffman, Nelson; Kwan, Tom; Larroche, Olivier

    2015-11-01

    Plasmas produced in high-energy density (HED) and inertial confinement fusion (ICF) experiments generally contain multiple ion species, which allows for multiple-ion species dynamics that are not simulated in typical single-ion fluid hydro codes. In implosions of D3He-gas filled thin-glass spheres on the OMEGA laser facility, comprehensive nuclear diagnostics were used to infer the composition of the fuel during nuclear production, demonstrating that the deuterium fraction was reduced during the implosion of the fuel. Hydrodynamic simulations including an ion diffusion model indicate that pressure, temperature, and potential gradients drive diffusive separation of the ion species, producing better agreement with the experiments than standard hydrodynamic codes. The results of fully kinetic (Vlasov-Fokker-Planck and PIC) simulations confirm the importance of multi-species dynamics to the evolution of these experiments. Implications for multi-species (DT) cryogenic implosions on the National Ignition Facility will be addressed. This work was partially supported by the US DOE, NLUF, LLE, and GA.

  20. Talaromyces atroroseus, a New Species Efficiently Producing Industrially Relevant Red Pigments

    PubMed Central

    Frisvad, Jens C.; Yilmaz, Neriman; Thrane, Ulf; Rasmussen, Kasper Bøwig; Houbraken, Jos; Samson, Robert A.

    2013-01-01

    Some species of Talaromyces secrete large amounts of red pigments. Literature has linked this character to species such as Talaromyces purpurogenus, T. albobiverticillius, T. marneffei, and T. minioluteus often under earlier Penicillium names. Isolates identified as T. purpurogenus have been reported to be interesting industrially and they can produce extracellular enzymes and red pigments, but they can also produce mycotoxins such as rubratoxin A and B and luteoskyrin. Production of mycotoxins limits the use of isolates of a particular species in biotechnology. Talaromyces atroroseus sp. nov., described in this study, produces the azaphilone biosynthetic families mitorubrins and Monascus pigments without any production of mycotoxins. Within the red pigment producing clade, T. atroroseus resolved in a distinct clade separate from all the other species in multigene phylogenies (ITS, β-tubulin and RPB1), which confirm its unique nature. Talaromyces atroroseus resembles T. purpurogenus and T. albobiverticillius in producing red diffusible pigments, but differs from the latter two species by the production of glauconic acid, purpuride and ZG–1494α and by the dull to dark green, thick walled ellipsoidal conidia produced. The type strain of Talaromyces atroroseus is CBS 133442 PMID:24367630

  1. The Soil Microbiota Harbors a Diversity of Carbapenem-Hydrolyzing β-Lactamases of Potential Clinical Relevance.

    PubMed

    Gudeta, Dereje Dadi; Bortolaia, Valeria; Amos, Greg; Wellington, Elizabeth M H; Brandt, Kristian K; Poirel, Laurent; Nielsen, Jesper Boye; Westh, Henrik; Guardabassi, Luca

    2015-10-19

    The origin of carbapenem-hydrolyzing metallo-β-lactamases (MBLs) acquired by clinical bacteria is largely unknown. We investigated the frequency, host range, diversity, and functionality of MBLs in the soil microbiota. Twenty-five soil samples of different types and geographical origins were analyzed by antimicrobial selective culture, followed by phenotypic testing and expression of MBL-encoding genes in Escherichia coli, and whole-genome sequencing of MBL-producing strains was performed. Carbapenemase activity was detected in 29 bacterial isolates from 13 soil samples, leading to identification of seven new MBLs in presumptive Pedobacter roseus (PEDO-1), Pedobacter borealis (PEDO-2), Pedobacter kyungheensis (PEDO-3), Chryseobacterium piscium (CPS-1), Epilithonimonas tenax (ESP-1), Massilia oculi (MSI-1), and Sphingomonas sp. (SPG-1). Carbapenemase production was likely an intrinsic feature in Chryseobacterium and Epilithonimonas, as it occurred in reference strains of different species within these genera. The amino acid identity to MBLs described in clinical bacteria ranged between 40 and 69%. Remarkable features of the new MBLs included prophage integration of the encoding gene (PEDO-1), an unusual amino acid residue at a key position for MBL structure and catalysis (CPS-1), and overlap with a putative OXA β-lactamase (MSI-1). Heterologous expression of PEDO-1, CPS-1, and ESP-1in E. coli significantly increased the MICs of ampicillin, ceftazidime, cefpodoxime, cefoxitin, and meropenem. Our study shows that MBL producers are widespread in soil and include four genera that were previously not known to produce MBLs. The MBLs produced by these bacteria are distantly related to MBLs identified in clinical samples but constitute resistance determinants of clinical relevance if acquired by pathogenic bacteria.

  2. The Soil Microbiota Harbors a Diversity of Carbapenem-Hydrolyzing β-Lactamases of Potential Clinical Relevance

    PubMed Central

    Gudeta, Dereje Dadi; Bortolaia, Valeria; Amos, Greg; Wellington, Elizabeth M. H.; Brandt, Kristian K.; Poirel, Laurent; Nielsen, Jesper Boye; Westh, Henrik

    2015-01-01

    The origin of carbapenem-hydrolyzing metallo-β-lactamases (MBLs) acquired by clinical bacteria is largely unknown. We investigated the frequency, host range, diversity, and functionality of MBLs in the soil microbiota. Twenty-five soil samples of different types and geographical origins were analyzed by antimicrobial selective culture, followed by phenotypic testing and expression of MBL-encoding genes in Escherichia coli, and whole-genome sequencing of MBL-producing strains was performed. Carbapenemase activity was detected in 29 bacterial isolates from 13 soil samples, leading to identification of seven new MBLs in presumptive Pedobacter roseus (PEDO-1), Pedobacter borealis (PEDO-2), Pedobacter kyungheensis (PEDO-3), Chryseobacterium piscium (CPS-1), Epilithonimonas tenax (ESP-1), Massilia oculi (MSI-1), and Sphingomonas sp. (SPG-1). Carbapenemase production was likely an intrinsic feature in Chryseobacterium and Epilithonimonas, as it occurred in reference strains of different species within these genera. The amino acid identity to MBLs described in clinical bacteria ranged between 40 and 69%. Remarkable features of the new MBLs included prophage integration of the encoding gene (PEDO-1), an unusual amino acid residue at a key position for MBL structure and catalysis (CPS-1), and overlap with a putative OXA β-lactamase (MSI-1). Heterologous expression of PEDO-1, CPS-1, and ESP-1in E. coli significantly increased the MICs of ampicillin, ceftazidime, cefpodoxime, cefoxitin, and meropenem. Our study shows that MBL producers are widespread in soil and include four genera that were previously not known to produce MBLs. The MBLs produced by these bacteria are distantly related to MBLs identified in clinical samples but constitute resistance determinants of clinical relevance if acquired by pathogenic bacteria. PMID:26482314

  3. Skin autofluorescence, a non-invasive marker of advanced glycation end products: clinical relevance and limitations.

    PubMed

    Da Moura Semedo, Cidila; Webb, M'Balu; Waller, Helen; Khunti, Kamlesh; Davies, Melanie

    2017-01-31

    Advanced glycation end products (AGEs) are protein-bound compounds derived from glycaemic and oxidative stress that contain fluorescent properties, which can be non-invasively measured as skin autofluorescence (SAF) by the AGE Reader. SAF has been demonstrated to be a biomarker of cumulative skin AGEs and potentially may be a better predictor for the development of chronic complications and mortality in diabetes than glycated haemoglobin A1c. However, there are several confounding factors that should be assessed prior to its broader application: these include presence of other fluorescent compounds in the skin that might be measured (eg, fluorophores), skin pigmentation and use of skin creams. The aim of this article is to provide a theoretical background of this newly developed method, evaluate its clinical relevance and discuss the potential confounding factors that need further analysis.

  4. Clinical relevance associated to the analysis of circulating tumour cells in patients with solid tumours.

    PubMed

    Serrano Fernádez, María José; Alvarez Merino, Juan Carlos; Martínez Zubiaurre, Iñigo; Fernández García, Ana; Sánchez Rovira, Pedro; Lorente Acosta, José Antonio

    2009-10-01

    The distant growth of tumour cells escaping from primary tumours, a process termed metastasis, represents the leading cause of death among patients affected by malignant neoplasias from breast and colon. During the metastasis process, cancer cells liberated from primary tumour tissue, also termed circulating tumour cells (CTCs), travel through the circulatory and/or lymphatic systems to reach distant organs. The early detection and the genotypic and phenotypic characterisation of such CTCs could represent a powerful diagnostic tool of the disease, and could also be considered an important predictive and prognostic marker of disease progression and treatment response. In this article we discuss the potential relevance in the clinic of monitoring CTCs from patients suffering from solid epithelial tumours, with emphasis on the impact of such analyses as a predictive marker for treatment response.

  5. In vivo photoacoustic and fluorescence cystography using clinically relevant dual modal indocyanine green.

    PubMed

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

    2014-10-21

    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.

  6. Fungal-bacterial interactions and their relevance to oral health: linking the clinic and the bench.

    PubMed

    Diaz, Patricia I; Strausbaugh, Linda D; Dongari-Bagtzoglou, Anna

    2014-01-01

    High throughput sequencing has accelerated knowledge on the oral microbiome. While the bacterial component of oral communities has been extensively characterized, the role of the fungal microbiota in the oral cavity is largely unknown. Interactions among fungi and bacteria are likely to influence oral health as exemplified by the synergistic relationship between Candida albicans and oral streptococci. In this perspective, we discuss the current state of the field of fungal-bacterial interactions in the context of the oral cavity. We highlight the need to conduct longitudinal clinical studies to simultaneously characterize the bacterial and fungal components of the human oral microbiome in health and during disease progression. Such studies need to be coupled with investigations using disease-relevant models to mechanistically test the associations observed in humans and eventually identify fungal-bacterial interactions that could serve as preventive or therapeutic targets for oral diseases.

  7. Fungal-bacterial interactions and their relevance to oral health: linking the clinic and the bench

    PubMed Central

    Diaz, Patricia I.; Strausbaugh, Linda D.; Dongari-Bagtzoglou, Anna

    2014-01-01

    High throughput sequencing has accelerated knowledge on the oral microbiome. While the bacterial component of oral communities has been extensively characterized, the role of the fungal microbiota in the oral cavity is largely unknown. Interactions among fungi and bacteria are likely to influence oral health as exemplified by the synergistic relationship between Candida albicans and oral streptococci. In this perspective, we discuss the current state of the field of fungal-bacterial interactions in the context of the oral cavity. We highlight the need to conduct longitudinal clinical studies to simultaneously characterize the bacterial and fungal components of the human oral microbiome in health and during disease progression. Such studies need to be coupled with investigations using disease-relevant models to mechanistically test the associations observed in humans and eventually identify fungal-bacterial interactions that could serve as preventive or therapeutic targets for oral diseases. PMID:25120959

  8. 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

  9. Taxonomy, biology, and clinical aspects of Fusarium species.

    PubMed Central

    Nelson, P E; Dignani, M C; Anaissie, E J

    1994-01-01

    There are several taxonomic systems available for identifying Fusarium species. The philosophy used in each taxonomic system is discussed as well as problems encountered in working with Fusarium species in culture. Fusarium species are toxigenic, and the mycotoxins produced by these organisms are often associated with animal and human diseases. The implications for the association of the carcinogens, fumonisins, produced by Fusarium moniliforme and other Fusarium species with human diseases are discussed. Foreign-body-associated fusarial infection such as keratitis in contact lens wearers, onychomycosis, skin infections, and disseminated multiorgan infections are discussed. Disseminated fusarial hyalohyphomycosis has emerged as a significant, usually fatal infection in the immunocompromised host. Successful outcome is determined by the degree of immunosuppression, the extent of the infection, and the presence of a removable focus such as an indwelling central venous catheter. These infections may be clinically suspected on the basis of a constellation of clinical and laboratory findings, which should lead to prompt therapy, probably with one of the newer antifungal agents. Perhaps the use of such agents or the use of colony-stimulating factors may improve the outcome of this devastating infection. However, until new approaches for treatment develop, effective preventive measures are urgently needed. Images PMID:7834602

  10. 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.

  11. Molecular driver alterations and their clinical relevance in cancer of unknown primary site.

    PubMed

    Löffler, Harald; Pfarr, Nicole; Kriegsmann, Mark; Endris, Volker; Hielscher, Thomas; Lohneis, Philipp; Folprecht, Gunnar; Stenzinger, Albrecht; Dietel, Manfred; Weichert, Wilko; Krämer, Alwin

    2016-07-12

    Cancer of unknown primary (CUP) is defined as metastatic solid malignancy where no primary tumor is detected despite appropriate staging. About 90% of CUP represent adenocarcinoma or undifferentiated carcinoma. Since therapy regimens are only modestly effective, identification of the molecular landscape of these neoplasms might be a promising approach to direct CUP therapy and aid in tumor classification. We screened a cohort of 128 patients with adenocarcinoma or undifferentiated carcinoma meeting the definition of CUP. Massive parallel multigene sequencing of 50 genes, which had been selected due to their relevance as oncogenic drivers or druggable molecular targets could ultimately be performed on samples from 55 patients for whom complete clinical datasets were also available. Overall, 60 tumor-specific mutations and 29 amplifications/deletions, as revealed by coverage analysis, were detected in 46 cases (84%). The most frequently mutated genes were TP53 (30 cases, 55%), KRAS (9 cases, 16%), CDKN2A (5 cases, 9%), and SMAD4 (5 cases, 9%). The most frequently deleted gene was CDKN2A (8 cases, 15%). KRAS and CDKN2A mutations significantly correlated with poor progression-free survival (PFS) and, in case of KRAS, overall survival (OS). WIldtype TP53 and female sex defined a relatively favorable category, with favorable PFS and OS. 8 cases (15%) harbored mutations that may be targetable by currently approved drugs. Taken together, Mutations of relevant driver genes are present in the vast majority of CUP tumors. Some of them impact on prognosis and a subset is putatively druggable.

  12. 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

  13. 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

  14. Power to detect clinically relevant carry-over in a series of cross-over studies.

    PubMed

    Putt, Mary E

    2006-08-15

    The potential for carry-over effects is an important consideration in the design of any cross-over study, and can cause an investigator to abandon the design altogether. In cross-over studies, carry-over is the lingering effect of a treatment into the subsequent period. Carry-over effects are differences in the extent of the carry-over between the treatments under consideration. It is well known that the test for carry-over effects in individual studies has low power. Empirical evidence of carry-over effects, or the absence of carry-over effects, could be useful for investigators considering the design. Here we develop methods for expressing the power to detect carry-over as a function of the power to detect a clinically relevant treatment effect. Our results suggest that for two-treatment, two-period cross-over studies the power to detect clinically relevant carry-over effects is often less than 15 per cent, and the number of studies needed to differentiate this effect from the type I error rate of 10 per cent is prohibitive. For the three-treatment three-period cross-over design, the power to detect carry-over effects was larger than for the two-period study, but still approached the type I error rate in a number of cases. Unequivocal conclusions about the absence of carry-over effects based on collections of hypothesis tests appear unlikely. Similar findings are presented for bioequivalence studies. For bioequivalence studies, small carry-over effects (e.g. 12.5 per cent of the treatment effect) can seriously inflate the type I error rate, particularly when the power to detect equivalence is high.

  15. Clinical relevance of the ROC and free-response paradigms for comparing imaging system efficacies.

    PubMed

    Chakraborty, D P

    2010-01-01

    Observer performance studies are widely used to assess medical imaging systems. Unlike technical/engineering measurements observer performance include the entire imaging chain and the radiologist. However, the widely used receiver operating characteristic (ROC) method ignores lesion localisation information. The free-response ROC (FROC) method uses the location information to appropriately reward or penalise correct or incorrect localisations, respectively. This paper describes a method for improving the clinical relevance of FROC studies. The method consists of assigning appropriate risk values to the different lesions that may be present on a single image. A high-risk lesion is one that is critical to detect and act upon, and is assigned a higher risk value than a low-risk lesion, one that is relatively innocuous. Instead of simply counting the number of lesions that are detected, as is done in conventional FROC analysis, a risk-weighted count is used. This has the advantage of rewarding detections of high-risk lesions commensurately more than detections of lower risk lesions. Simulations were used to demonstrate that the new method, termed case-based analysis, results in a higher figure of merit for an expert who detects more high-risk lesions than a naive observer who detects more low-risk lesions, even though both detect the same total number of lesions. Conventional free-response analysis is unable to distinguish between the two types of observers. This paper also comments on the issue of clinical relevance of ROC analysis vs. FROC for tasks that involve lesion localisation.

  16. 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.

  17. 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

  18. Comparative Inter-Species Pharmacokinetics of Phenoxyacetic Acid Herbicides and Related Organic Acids. Evidence that the Dog is Not a Relevant Species for Evaluation of Human Health Risk.

    SciTech Connect

    Timchalk, Chuck

    2004-07-15

    findings suggest that for new structurally similar organic acids, a limited comparative species (rat vs. dog) pharmacokinetic analysis early in the toxicology evaluation process may provide important insight into the relevance of the dog. In summary, the substantial difference between the pharmacokinetics of phenoxyacetic acids and related organic acids in dogs relative to other species, including humans, questions the relevance of using dog toxicity data for the extrapolation of human health risk.

  19. 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

  20. Time-Domain Simulations of Transient Species in Experimentally Relevant Environments

    SciTech Connect

    Ueltschi, Tyler W.; Fischer, Sean A.; Apra, Edoardo; Tarnovsky, Alexander N.; Govind, Niranjan; El-Khoury, Patrick Z.; Hess, Wayne P.

    2016-02-04

    Simulating the spectroscopic properties of short-lived thermal and photochemical reaction intermediates and products is a challenging task, as these species often feature atypical molecular and electronic structures. The complex environments in which such species typically reside in practice add further complexity to the problem. Herein, we tackle this problem in silico using ab initio molecular dynamics (AIMD) simulations, employing iso-CHBr3, namely H(Br)C-Br-Br, as a prototypical system. This species was chosen because it features both a non-conventional C-Br-Br bonding pattern, as well as a strong dependence of its spectral features on the local environment in which it resides, as illustrated in recent experimental reports. The spectroscopic properties of iso-CHBr3 were measured by several groups that captured this transient intermediate in the photochemistry of CHBr3 in the gas phase, in rare gas matrices at 5K, and in solution under ambient laboratory conditions. We simulate the UV-Vis and IR spectra of iso-CHBr3 in all three media, including a Ne cluster (64 atoms) and a methylcyclohexane cage (14 solvent molecules) representative of the matrix isolated and solvated species. We exclusively perform fully quantum mechanical static and dynamic simulations. By comparing our condensed phase simulations to their experimental analogues, we stress the importance of (i) conformational sampling, even at cryogenic temperatures, and (ii) using a fully quantum mechanical description of both solute and bath to properly account for the experimental observables.

  1. Clinical significance of Bacillus species isolated from blood cultures.

    PubMed

    Weber, D J; Saviteer, S M; Rutala, W A; Thomann, C A

    1989-06-01

    To determine the clinical significance of blood isolates of Bacillus, we reviewed all blood cultures obtained at North Carolina Memorial Hospital between 1981 and 1985. Over the five-year study period the number of patients (incidence per 10,000 hospital admissions) from whom Bacillus was isolated increased from 4.97 in 1981 to 12.5 in 1985. The incidence per 1,000 blood cultures also increased from 1.12 in 1981 to 2.33 in 1985. Review of the medical records of 78 of the 95 patients (82%) with positive cultures allowed retrospective classification of five isolates (6.4%) as clinically significant, 33 isolates (42.3%) as possibly significant, and 40 isolates (51.3%) as nonsignificant. Underlying diseases in patients with clinically significant Bacillus bacteremia included burn trauma in two, leukemia in one, carcinoma in one, and gastrointestinal hemorrhage in one. All isolates judged to be clinically significant and the majority of possibly significant isolates were B cereus. We conclude that the isolation of Bacillus species from blood cultures is clinically significant in 5% to 10% of cases, that the incidence of Bacillus bacteremia is increasing, and that burn trauma should be added to the list of conditions known to predispose to clinically significant Bacillus bacteremia.

  2. The Clinical Relevance of Antifibrillarin (anti-U3-RNP) Autoantibodies in Systemic Sclerosis.

    PubMed

    Tall, F; Dechomet, M; Riviere, S; Cottin, V; Ballot, E; Tiev, K P; Montin, R; Morin, C; Chantran, Y; Grange, C; Jullien, D; Ninet, J; Chretien, P; Cabane, J; Fabien, N; Johanet, C

    2017-01-01

    Systemic sclerosis (SSc) is a heterogeneous autoimmune disease associated with several antinuclear autoantibodies useful to diagnosis and prognosis. The aim of the present multicentric study was to determine the clinical relevance of antifibrillarin autoantibodies (AFA) in patients with SSc. The clinical features of 37 patients with SSc positive for AFA (AFA+) and 139 SSc patients without AFA (AFA-) were collected retrospectively from medical records to enable a comparison between AFA- and AFA+ patients. Antifibrillarin autoantibodies were screened by an indirect immunofluorescence technique using HEp2 cells and identified by an in-house Western blot technique and/or an EliA test. Comparing AFA+ and AFA- patients, AFA+ patients were significantly younger at disease onset (36.9 versus 42.9; P = 0.02), more frequently male (P = 0.02) and of Afro-Caribbean descent (65% versus 7.7%; P < 0.001). At diagnosis, the Rodnan skin score evaluating the cutaneous manifestations was higher (13.3 versus 8.7; P = 0.01) and myositis was also more common in the AFA+ group (31.4% versus 12.2%; P < 0.01). Patients with AFA+ were not associated with diffuse cutaneous SSc or with lung involvement and no difference in survival was observed. Antifibrillarin autoantibodies are associated with patients of Afro-Caribbean origin and can identify patients with SSc who are younger at disease onset and display a higher prevalence of myositis.

  3. 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.

  4. In vivo radiosensitization efficacy of KU-2285 and etanidazole at clinically relevant low radiation doses

    SciTech Connect

    Oya, Natsuo; Shibamoto, Yuta; Sasai, Keisuke; Abe, Mitsuyuki; Sugiyama, Taketoshi )

    1993-12-01

    The in vivo radiosensitization efficacy of KU-2285 (a fluorinated nitroimidazole derivative) at clinically relevant low radiation doses (2-4 Gy) was compared with that of etanidazole using four types of assays with EMT6, SCCVII, and C[sup 3]H mammary tumors. The in vivo-in vitro cytokinesis-block micronucleus assay and the chromosomal aberration assay were used to assess the sensitizing effect at single doses of 2-4 Gy. After in vivo treatment for tumors, tumor cells were cultured in the presence of cytochalasin B for the former assay or demecolcine for the latter assay, and the micronucleus frequency in binucleate cells and the chromosomal frequency in metaphase cells were evaluated after 42 hr and 3 hr of culture. In addition, an in vivo-in vitro colony assay and a growth delay assay were performed using fractionated irradiation regimens (4 Gy [times] 5). The sensitizer enhancement ratio for 100-400 mg/kg of KU-2285 was between 1.12 and 1.42. KU-2285 was a more efficient sensitizer than etanidazole in 3 of 9 experiments and as efficient as etanidazole in the remaining six experiments. Both the micronucleus assay and the chromosomal aberration assay appeared to be very useful in evaluating the in vivo sensitizing effect at low radiation doses. KU-2285 had a definite radiosensitizing effect even at low radiation doses, and clinical trials of KU-2285 may be warranted. 23 refs., 5 figs., 1 tab.

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

    PubMed

    Grimwade, David; Ivey, Adam; Huntly, Brian J P

    2016-01-07

    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.

  6. 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.

  7. 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.

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

    PubMed Central

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

    2009-01-01

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

  9. Integrative Analysis of Cellular Morphometric Context Reveals Clinically Relevant Signatures in Lower Grade Glioma⋆

    PubMed Central

    Han, Ju; Wang, Yunfu; Cai, Weidong; Borowsky, Alexander; Parvin, Bahram; Chang, Hang

    2016-01-01

    Integrative analysis based on quantitative representation of whole slide images (WSIs) in a large histology cohort may provide predictive models of clinical outcome. On one hand, the efficiency and effectiveness of such representation is hindered as a result of large technical variations (e.g., fixation, staining) and biological heterogeneities (e.g., cell type, cell state) that are always present in a large cohort. On the other hand, perceptual interpretation/validation of important multivariate phenotypic signatures are often difficult due to the loss of visual information during feature transformation in hyperspace. To address these issues, we propose a novel approach for integrative analysis based on cellular morphometric context, which is a robust representation of WSI, with the emphasis on tumor architecture and tumor heterogeneity, built upon cellular level morphometric features within the spatial pyramid matching (SPM) framework. The proposed approach is applied to The Cancer Genome Atlas (TCGA) lower grade glioma (LGG) cohort, where experimental results (i) reveal several clinically relevant cellular morphometric types, which enables both perceptual interpretation/validation and further investigation through gene set enrichment analysis; and (ii) indicate the significantly increased survival rates in one of the cellular morphometric context subtypes derived from the cellular morphometric context. PMID:28018994

  10. Cell death and cell death responses in liver disease: mechanisms and clinical relevance.

    PubMed

    Luedde, Tom; Kaplowitz, Neil; Schwabe, Robert F

    2014-10-01

    Hepatocellular death is present in almost all types of human liver disease and is used as a sensitive parameter for the detection of acute and chronic liver disease of viral, toxic, metabolic, or autoimmune origin. Clinical data and animal models suggest that hepatocyte death is the key trigger of liver disease progression, manifested by the subsequent development of inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Modes of hepatocellular death differ substantially between liver diseases. Different modes of cell death such as apoptosis, necrosis, and necroptosis trigger specific cell death responses and promote progression of liver disease through distinct mechanisms. In this review, we first discuss molecular mechanisms by which different modes of cell death, damage-associated molecular patterns, and specific cell death responses contribute to the development of liver disease. We then review the clinical relevance of cell death, focusing on biomarkers; the contribution of cell death to drug-induced, viral, and fatty liver disease and liver cancer; and evidence for cell death pathways as therapeutic targets.

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

    PubMed Central

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

    2013-01-01

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

  12. 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

  13. 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

  14. Clinical Relevance of Sleep Duration: Results from a Cross-Sectional Analysis Using NHANES

    PubMed Central

    Cepeda, M. Soledad; Stang, Paul; Blacketer, Clair; Kent, Justine M.; Wittenberg, Gayle M.

    2016-01-01

    Study Objectives: To assess the clinical relevance of sleep duration, hours slept were compared by health status, presence of insomnia, and presence of depression, and the association of sleep duration with BMI and cardiovascular risk was quantified. Methods: Cross-sectional analysis of subjects in the US National Health and Nutrition Examination Surveys using adjusted linear and logistic regressions. Results: A total of 22,281 adults were included, 37% slept ≤ 6 hours, 36% were obese, and 45% reported cardiovascular conditions. Mean sleep duration was 6.87 hours. Better health was associated with more hours of sleep. Subjects with poor health reported sleeping 46 min, (95% CI −56.85 to −35.67) less than subjects with excellent health. Individuals with depression (vs. not depressed) reported 40 min less sleep, (95% CI −47.14 to −32.85). Individuals with insomnia (vs. without insomnia) reported 39 min less sleep, (95% CI −56.24 to −22.45). Duration of sleep was inversely related to BMI; for every additional hour of sleep, there was a decrease of 0.18 kg/m2 in BMI, (95% CI −0.30 to −0.06). The odds of reporting cardiovascular problems were 6.0% lower for every hour of sleep (odds ratio = 0.94, 95% CI [0.91 to 0.97]). Compared with subjects who slept ≤ 6 h, subjects who slept more had lower odds of reporting cardiovascular problems, with the exception of subjects ≥ 55 years old who slept ≥ 9 hours. Conclusions: Long sleep duration is associated with better health. The fewer the hours of sleep, the greater the BMI and reported cardiovascular disease. A difference of 30 minutes of sleep is associated with substantive impact on clinical well-being. Citation: Cepeda MS, Stang P, Blacketer C, Kent JM, Wittenberg GM. Clinical relevance of sleep duration: results from a cross-sectional analysis using NHANES. J Clin Sleep Med 2016;12(6):813–819. PMID:26951419

  15. Development of Microcomputer Methods for Analysis and Simulation of Clinical Pharmacokinetic Data Relevant to New Drug Development.

    DTIC Science & Technology

    1985-08-02

    interpretation, and simulation of pharmacokinetic data, dose - response kinetic data, and other data relevant to new drug development, for use with the Tektronix...Statistical Programs for Clinical Pharmacological Problems; Keywords: Clinical Pharmacokinetics, Dose - Response Relations, Pharmakinetic Simulation, Non-Parametric Statistics, Mefloquine, Microcomputer Graphics, Tektronix 4052.

  16. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2014-03-01

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

  18. Molecular driver alterations and their clinical relevance in cancer of unknown primary site

    PubMed Central

    Endris, Volker; Hielscher, Thomas; Lohneis, Philipp; Folprecht, Gunnar; Stenzinger, Albrecht; Dietel, Manfred

    2016-01-01

    Cancer of unknown primary (CUP) is defined as metastatic solid malignancy where no primary tumor is detected despite appropriate staging. About 90% of CUP represent adenocarcinoma or undifferentiated carcinoma. Since therapy regimens are only modestly effective, identification of the molecular landscape of these neoplasms might be a promising approach to direct CUP therapy and aid in tumor classification. We screened a cohort of 128 patients with adenocarcinoma or undifferentiated carcinoma meeting the definition of CUP. Massive parallel multigene sequencing of 50 genes, which had been selected due to their relevance as oncogenic drivers or druggable molecular targets could ultimately be performed on samples from 55 patients for whom complete clinical datasets were also available. Overall, 60 tumor-specific mutations and 29 amplifications/deletions, as revealed by coverage analysis, were detected in 46 cases (84%). The most frequently mutated genes were TP53 (30 cases, 55%), KRAS (9 cases, 16%), CDKN2A (5 cases, 9%), and SMAD4 (5 cases, 9%). The most frequently deleted gene was CDKN2A (8 cases, 15%). KRAS and CDKN2A mutations significantly correlated with poor progression-free survival (PFS) and, in case of KRAS, overall survival (OS). WIldtype TP53 and female sex defined a relatively favorable category, with favorable PFS and OS. 8 cases (15%) harbored mutations that may be targetable by currently approved drugs. Taken together, Mutations of relevant driver genes are present in the vast majority of CUP tumors. Some of them impact on prognosis and a subset is putatively druggable. PMID:27322425

  19. [Biological role and clinical relevance of central and peripheral circadian clocks].

    PubMed

    Husse, J; Leliavski, A; Oster, H

    2013-03-01

    In most species--from cyanobacteria to humans--genetically encoded circadian clocks have evolved to adapt behavioral and physiological processes to environmental changes brought about by the Earth's rotation. Clock disruption, e. g. by shift work, can lead to circadian misalignment, promoting the development of metabolic, immune and cognitive dysfunction. In mammals, a central circadian pacemaker residing in the suprachiasmatic nuclei of the hypothalamus resets subordinate, but semi-independent cellular clocks in tissues such as liver, kidney, adrenal, and many brain areas. Peripheral clocks regulate various endocrine, metabolic and immune processes, whereas central oscillators modulate basic as well as higher brain functions. For the clinical practice it is of major importance to be aware of these physiological rhythms in order to correctly interpret laboratory data and other disease symptoms. Chronomedical therapies can reduce side effects and increase efficacy by optimizing the timing of treatment or directly affect disease state by restoring internal circadian synchrony.

  20. Aspergillus fumigatus-Related Species in Clinical Practice

    PubMed Central

    Lamoth, Frédéric

    2016-01-01

    Aspergillus fumigatus is the main etiologic agent of invasive aspergillosis (IA). Other Aspergillus species belonging to the section Fumigati (A. fumigatus complex) may occasionally be the cause of IA. These strains are often misidentified, as they cannot be distinguished from A. fumigatus by conventional morphological analysis and sequencing methods. This lack of recognition may have important consequences as these A. fumigatus-related species often display some level of intrinsic resistance to azoles and other antifungal drugs. A. lentulus, A. udagawae, A. viridinutans, and A. thermomutatus (Neosartorya pseudofischeri) have been associated with refractory cases of IA. Microbiologists should be able to suspect the presence of these cryptic species behind a putative A. fumigatus isolate on the basis of some simple characteristics, such as defect in sporulation and/or unusual antifungal susceptibility profile. However, definitive species identification requires specific sequencing analyses of the beta-tubulin or calmodulin genes, which are not available in most laboratories. Multiplex PCR assays or matrix-assisted laser desorption ionization – time-of-flight mass spectrometry (MALDI-TOF MS) gave promising results for rapid and accurate distinction between A. fumigatus and other Aspergillus spp. of the section Fumigati in clinical practice. Improved diagnostic procedures and antifungal susceptibility testing may be helpful for the early detection and management of these particular IA cases. PMID:27242710

  1. A guideline for the identification of environmentally relevant, ionizable organic molecule species.

    PubMed

    Schaffer, Mario; Licha, Tobias

    2014-05-01

    An increasing number of organic compounds detected today in the aquatic environment are ionizable and, therefore, partially or permanently charged (ionic) under the pH conditions encountered in these systems. For evaluating their environmental behavior, which strongly depends on the charge state, the identification of functional groups together with their correct assignment of the respective acidic or basic dissociation constants (pKa) is essential. Despite the growing concern and increasing awareness for ionizable compounds, contradicting and/or confusing information regarding their acid/base properties can be regularly found in the literature, especially when complex structures are encountered. Therefore, we provide a simplified, general, and comprehensive guideline for the identification of ionizable functional groups in organic compounds combined with the correct assignment of their respective pKa values. Beside the explicit definition of basic terms, several tables with more than 30 of the most frequently encountered ionizable compound classes, including their typical pKa value ranges are the centerpiece of the proposed procedure. The straight forward application of the guideline is successfully shown for several environmentally relevant compounds as example.

  2. Evidence, Mechanism, and Clinical Relevance of the Transdifferentiation from Lung Adenocarcinoma to Squamous Cell Carcinoma.

    PubMed

    Hou, Shenda; Zhou, Shiyu; Qin, Zhen; Yang, Liu; Han, Xiangkun; Yao, Shun; Ji, Hongbin

    2017-03-08

    Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct subtypes of non-small-cell lung carcinoma. Interestingly, approximately 4% to 9% of human non-small-cell lung carcinoma tumors contain mixed adenomatous and squamous pathologies in a single lesion, clinically termed adenosquamous cell carcinoma. More important, these two different pathological components frequently share identical oncogenic mutations, indicative of a potential transition. Indeed, recent data have provided convincing evidence in supporting the ADC to SCC transdifferentiation in lungs. In the liver kinase B1 (official name STK11)-deficient mouse model, lung ADC can progressively transdifferentiate to SCC through pathologically mixed adenosquamous cell carcinoma as the intermediate status. Mechanistic studies further identify essential roles of extracellular matrix remodeling and metabolic reprogramming during this phenotypic transition. Small molecular compounds, including lysyl oxidase inhibitors and reactive oxygen species-inducing reagents such as phenformin, significantly accelerate the transition from lung ADC to SCC and thus confer lung tumors with drug resistance. Consistent with these findings, recent clinical studies have shown that epidermal growth factor receptor-mutant lung ADC can transdifferentiate to SCC in relapsed cancer patients. Together, these data support that this phenotypic transition from lung ADC to SCC might represent a novel mechanism for drug resistance. This review will summarize our current understanding of the transdifferentiation from lung ADC to SCC.

  3. 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.

  4. 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".

  5. Social and clinically-relevant cardiovascular risk factors in Asian Americans adults: NHANES 2011-2014.

    PubMed

    Echeverria, Sandra E; Mustafa, Mehnaz; Pentakota, Sri Ram; Kim, Soyeon; Hastings, Katherine G; Amadi, Chioma; Palaniappan, Latha

    2017-02-17

    Little evidence exists examining cardiovascular risk factors among Asian Americans and how social determinants such as nativity status and education pattern risk in the United States (U.S.) context. We used the National Health and Nutrition Examination Survey, which purposely oversampled Asian Americans from 2011 to 2014, and examined prevalence of Type II diabetes, smoking and obesity for Asian Americans (n=1363) and non-Latino Whites (n=4121). We classified Asian Americans as U.S. or foreign-born and by years in the U.S. Obesity status was based on standard body mass index (BMI) cut points of ≥30kg/m(2) and Asian-specific cut points (BMI≥25kg/m(2)) that may be more clinically relevant for this population. We fit separate logistic regression models for each outcome using complex survey design methods and tested for the joint effect of race, nativity and education on each outcome. Diabetes and obesity prevalence (applying Asian-specific BMI cut points) were higher among Asian Americans when compared to non-Latino Whites but smoking prevalence was lower. These patterns remained in fully adjusted models and showed small increases with longer duration in the U.S. Joint effects models showed higher odds of prevalent Type II diabetes and obesity (Asian-specific) for foreign-born Asians, regardless of years in the U.S. and slightly higher risk for lowe ducation, when compared to non-Latino Whites with high education. Smoking models showed significant interaction effects between race and education for non-Latino Whites only. Our study supports the premise that social as well as clinical factors should be considered when developing health initiatives for Asian Americans.

  6. Clinical relevance of multiple respiratory virus detection in adult patients with acute respiratory illness.

    PubMed

    Choi, Seong-Ho; Chung, Jin-Won; Kim, Hye Ryoun

    2015-04-01

    Because increasing numbers of nasopharyngeal swab specimens from adult patients with acute respiratory illness (ARI) are being tested by respiratory virus (RV) multiplex reverse transcriptase PCR (RVM-RT-PCR), multiple RV detection (MRVD) is being encountered more frequently. However, the clinical relevance of MRVD in adult patients has rarely been evaluated. The clinical characteristics of hospitalized adult patients with ARI and MRVD by RVM-RT-PCR tests were compared to those of patients with single RV detection (SRVD) during a single year at a tertiary care center. MRVD was observed in 26 of the 190 adult patients (13.7%). The patients with MRVD had a higher incidence of chronic lung disease than the patients with SRVD (34.6% versus 15.9%, crude odds ratio [OR]=2.81, 95% confidence interval [CI]=1.13 to 6.98, P=0.03). Although the former were more likely than the latter to receive mechanical ventilation (19.2% versus 6.7%, crude OR=3.31, 95% CI=1.05 to 10.47, P=0.049), the length of hospital stay (median, 7 versus 6.5 days; P=0.66), and the in-hospital mortality rate (7.7% versus 4.3%, crude OR=1.87, 95% CI=0.37 to 9.53, P=0.35) were not different between the two groups. In multivariate analysis, chronic lung disease was associated with MRVD (adjusted OR=3.08, 95% CI=1.12 to 8.46, P=0.03). In summary, it was not uncommon to encounter adult patients with ARI and MRVD by RVM-RT-PCR tests of nasopharyngeal swab specimens. MRVD was associated with chronic lung disease rather than the severity of the ARI.

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

    PubMed Central

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

    2014-01-01

    clinically relevant genetic profiling of CTCs. PMID:24489774

  8. 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

  9. Toxicity of aqueous vanadium to zooplankton and phytoplankton species of relevance to the athabasca oil sands region.

    PubMed

    Schiffer, Stephanie; Liber, Karsten

    2017-03-01

    Vanadium (V) is an abundant trace metal present in bitumen from the Athabasca Oil Sands (AOS) region in Alberta, Canada. The upgrading of bitumen can result in the production of large volumes of a carbonaceous material referred to as petroleum coke that contains V at elevated levels compared to the native bitumen. Previous studies have shown that coke has the capacity to leach ecotoxicologically relevant levels of V into water it contacts, yet limited data are available on the toxicity of aqueous V to planktonic organisms. Therefore, this study set out to evaluate the acute and chronic toxicity of V (as vanadate oxyanions) to freshwater zooplankton and phytoplankton species that are either commonly-used laboratory species, or species more regionally-representative of northern Alberta. Four cladoceran (2-d and 21-d tests) and two algal (3-d tests) species were exposed to V to obtain both acute and chronic toxicity estimates. Acute V toxicity (LC50s) ranged from 0.60mgV/L for Ceriodaphnia quadrangula to 2.17mgV/L for Daphnia pulex. Chronic toxicity estimates (EC50s) for cladoceran survival and reproduction were nearly identical within species and ranged from a low of 0.13 to a high of 0.46mgV/L for Daphnia dentifera and D. pulex, respectively. The lack of sublethal V toxicity in daphnia suggests a direct mechanism of toxicity through ion imbalance. Growth inhibition (EC50) of green algae occurred at concentrations of 3.24 and 4.12mgV/L for Pseudokirchneriella subcapitata and Scenedesmus quadricauda, respectively. Overall, cladocerans were more sensitive to V than green algae, with survival of the field-collected D. dentifera being approximately 2.5 to 3.5 times more sensitive to acute and chronic V exposure than the standard test species D. pulex. However, there were no significant differences in V toxicity between the field-collected cladocerans Simocephalus serrulatus and C. quadrangula, compared to the respective standard species D. pulex and Ceriodaphnia dubia

  10. Characterization of Iron-Imido Species Relevant for N-Group Transfer Chemistry

    PubMed Central

    Iovan, Diana A.; Betley, Theodore A.

    2016-01-01

    A sterically accessible tert-butyl-substituted dipyrrinato di-iron(II) complex [(tBuL)FeCl]2 possessing two bridging chloride atoms was synthesized from the previously reported solvento adduct. Upon treatment with aryl azides, the formation of high-spin FeIII species was confirmed by 57Fe Mössbauer spectroscopy. Crystallographic characterization revealed two possible oxidation products: (1) a terminal iron iminyl from aryl azides bearing ortho isopropyl substituents, (tBuL)FeCl(•NC6H3-2,6-iPr2); or (2) a bridging di-iron imido arising from reaction with 3,5-bis(trifluoromethyl)aryl azide, [(tBuL)FeCl]2(μ-NC6H3-3,5-(CF3)2). Similar to the previously reported (ArL)FeCl(•NC6H4-4-tBu), the monomeric iron imido is best described as a high-spin FeIII antiferromagnetically coupled to an iminyl radical, affording an S = 2 spin state as confirmed by SQUID magnetometry. The di-iron imido possesses an S = 0 ground state, arising from two high-spin FeIII centers weakly antiferromagnetically coupled through the bridging imido ligand. The terminal iron iminyl complex undergoes facile decomposition via intra- or intermolecular hydrogen-atom abstraction (HAA) from an imido aryl ortho isopropyl group, or from 1,4-cyclohexadiene, respectively. The bridging di-iron imido is a competent N-group transfer reagent to cyclic internal olefins as well as styrene. Although solid-state magnetometry indicates an antiferromagnetic interaction between the two iron centers (J = −108.7 cm−1) in [(tBuL)FeCl]2(μ-NC6H3-3,5-(CF3)2), we demonstrate that in solution the bridging imido can facilitate HAA as well as dissociate into a terminal iminyl species, which then can promote HAA. In situ monitoring reveals the di-iron bridging imido is a catalytically competent intermediate, one of several iron complexes observed in the amination of C–H bond substrates or styrene aziridination. PMID:26788747

  11. A clinically relevant model of perinatal global ischemic brain damage in rats.

    PubMed

    Yang, Ting; Zhuang, Lei; Terrando, Niccolò; Wu, Xinmin; Jonhson, Mark R; Maze, Mervyn; Ma, Daqing

    2011-04-06

    We have designed a clinically relevant model of perinatal asphyxia providing intrapartum hypoxia in rats. On gestation day 22 SD rats were anesthetized and the uterine horns were exteriorized and placed in a water bath at 37°C for up to 20min. After this, pups were delivered from the uterus and manually stimulated to initiate breathing in an incubator at 37°C for 1 h in air. Brains were harvested and stained with cresyl violet, caspase-3, and TUNEL to detect morphological and apoptotic changes on postnatal days (PND) 1, 3, and 7. Separate cohorts were maintained until PND 50 and tested for learning and memory using Morris water maze (WM). Survival rate was decreased with longer hypoxic time, and 100% mortality was noted when hypoxia time was beyond 18min. Apoptosis was increased with the duration of hypoxia with neuronal loss and cell shrinkage in the CA1 of hippocampus. The time taken for the juveniles to locate the hidden platform during WM was increased in animals subjected to hypoxia. These data demonstrate that perinatal ischemic injury leads to neuronal death in the hippocampus and long-lasting cognitive dysfunction. This model mimics hypoxic ischemic encephalopathy in humans and may be appropriate for investigating therapeutic interventions.

  12. 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.

  13. Clinically-relevant chemotherapy interactions with complementary and alternative medicines in patients with cancer.

    PubMed

    Yap, Kevin Yi-Lwern; See, Cheng Shang; Chan, Alexandre

    2010-01-01

    Complementary and alternative medicines (CAMs), in particular herbal medicines, are commonly used by cancer patients in conjunction with chemotherapy treatment for their anticancer properties and supportive care. However, the effects of many of these herbs are not well-documented due to limited studies done on them. Severe herb-drug interactions (HDIs) have been recorded in some cases, and failure to recognize these harmful HDIs can lead to dire consequences in cancer patients. This study discusses clinically-relevant interactions between anticancer drugs (ACDs) and herbs classified into 7 categories: cancer treatment and prevention, immune-system-related, alopecia, nausea and vomiting, peripheral neuropathy and pain, inflammation, and fatigue. Some promising patents which contain these herbs and thus may manifest these interactions are also presented in this article. Pharmacokinetic interactions involved mainly induction or inhibition of the cytochrome P450 isozymes and p-glycoprotein, while pharmacodynamic interactions were related to increased risks of central nervous system-related effects, hepatotoxicity and bleeding, among others. Clinicians should be vigilant when treating cancer patients who take CAMs with concurrent chemotherapy since they face a high risk of HDIs. These HDIs can be minimized or avoided by selecting herb-drug pairs which are less likely to interact. Furthermore, close monitoring of pharmacological effects and plasma drug levels should be carried out to avoid toxicity and ensure adequate chemotherapeutic coverage in patients with cancer.

  14. 3D Culture as a Clinically Relevant Model for Personalized Medicine.

    PubMed

    Fong, Eliza Li Shan; Toh, Tan Boon; Yu, Hanry; Chow, Edward Kai-Hua

    2017-03-01

    Advances in understanding many of the fundamental mechanisms of cancer progression have led to the development of molecular targeted therapies. While molecular targeted therapeutics continue to improve the outcome for cancer patients, tumor heterogeneity among patients, as well as intratumoral heterogeneity, limits the efficacy of these drugs to specific patient subtypes, as well as contributes to relapse. Thus, there is a need for a more personalized approach toward drug development and diagnosis that takes into account the diversity of cancer patients, as well as the complex milieu of tumor cells within a single patient. Three-dimensional (3D) culture systems paired with patient-derived xenografts or patient-derived organoids may provide a more clinically relevant system to address issues presented by personalized or precision medical approaches. In this review, we cover the current methods available for applying 3D culture systems toward personalized cancer research and drug development, as well as key challenges that must be addressed in order to fully realize the potential of 3D patient-derived culture systems for cancer drug development. Greater implementation of 3D patient-derived culture systems in the cancer research field should accelerate the development of truly personalized medical therapies for cancer patients.

  15. Registered nurses' ideas of physical science concepts relevant to their clinical practice

    NASA Astrophysics Data System (ADS)

    Wilkes, Lesley M.; Batts, Judith E.

    1996-09-01

    Experience in teaching science to nurses has raised the question of whether nurses' expressions of their understanding of concepts in physical science are adequate for professional practice. Nurses' descriptions of physical science concepts relevant to their practice must be explicated before educators can develop strategies to enhance nurses' learning of science. A cross-sectional study was undertaken to establish registered nurses' conceptions of physical science in their clinical practice. Data were collected using a multiple choice question survey, field work and focused interviews. Six categories of conceptions emerged from data analysis. Of the three which related to complexity of understanding “association” and “definition” were predominant and related in the main, to two of the three contextual categories “instrumentation/equipment” and “procedure.” There were few examples of the other two categories of “elaboration” and “body processes.” We argue that the conceptions held by the nurses were not adequate to allow them to fulfil their roles as professional practitioners in health care.

  16. Is the mouse a clinically relevant model for human fertilization failures?

    PubMed

    Neuber, E; Powers, R D

    2000-01-01

    This study compares failed fertilization oocytes from patients participating in an in-vitro fertilization (IVF) programme with failed fertilization oocytes from B6SJLF(1)/J mice, in order to characterize and describe the distribution of DNA in oocytes that do not undergo normal fertilization. Our goal is to evaluate the mouse IVF system as a model to gain insight into reasons for human fertilization failures. All oocytes were stained with the vital fluorescent dye, Hoechst 33342, which rapidly stains double-stranded DNA. Of the 237 human oocytes that had been scored as failed fertilization by brightfield microscopy, 61 (25.7%) showed the presence of at least one spermatozoon within the oocyte cytoplasm. In contrast, out of 69 failed fertilization mouse oocytes, only one oocyte showed the presence of a spermatozoon within its cytoplasm. Mouse failed fertilization oocytes exhibited a significantly lower internal sperm rate (P < 0.0001) than human failed fertilization oocytes. Human failed fertilization oocytes show a higher incidence of sperm penetration, but the cytoplasm fails to support pronuclear development, whereas, at least in this strain, mouse failed fertilization oocytes arise from an inability of the spermatozoa to penetrate the oocyte. This study suggests that the mouse is not a clinically relevant model for human fertilization failures.

  17. Polymorphisms in drug-metabolizing enzymes: What is their clinical relevance and why do they exist?

    SciTech Connect

    Nebert, D.W.

    1997-02-01

    The beautiful report by Sachse in this issue of the journal represents the culmination of 2 decades of increasingly exciting work on the {open_quotes}debrisoquine oxidation polymorphism,{close_quotes} one of dozens of pharmacogenetic or ecogenetic polymorphisms that have been shown to have an important impact on innumerable clinical diseases. Pharmacogenetics is the study of the hereditary basis of the differences in responses to drugs. Ecogenetics is the broader field of interindividual differences in response to all environmental chemical and physical agents (e.g., heavy metals, insecticides, compounds formed during combustion, and UV radiation). It is now clear that each of us has his or her own {open_quotes}individual fingerprint{close_quotes} of unique alleles encoding the so-called drug-metabolizing enzymes (DMEs) and the receptors that regulate these enzymes. In this invited editorial, I first introduce the current thinking in the field of DME (and DME-receptor) research and how DMEs have evolved from animal-plant interactions. I then describe the debrisoquine oxidation polymorphism, as well as two other relevant DME polymorphisms; show the relationship between these polymorphisms and human disease; provide examples of synergistic effects caused by the combination of two DME polymorphisms; and discuss the ethical considerations of such research. Last, I speculate on why these allelic frequencies of the DME genes might exist in human populations in the first place. 35 refs.

  18. Dose-dependent cytotoxicity of clinically relevant cobalt nanoparticles and ions on macrophages in vitro.

    PubMed

    Kwon, Young-Min; Xia, Zhidao; Glyn-Jones, Sion; Beard, David; Gill, Harinderjit S; Murray, David W

    2009-04-01

    Despite the satisfactory short-term implant survivorship of metal-on-metal hip resurfacing arthroplasty, periprosthetic soft-tissue masses such as pseudotumours are being increasingly reported. Cytotoxic effects of cobalt or chromium have been suggested to play a role in its aetiology. The aim of this study was to investigate the effects of clinically relevant metal nanoparticles and ions on the viability of macrophages in vitro. A RAW 264.7 murine macrophage cell line was cultured in the presence of either: (1) cobalt, chromium and titanium nanoparticles sized 30-35 nm; or (2) cobalt sulphate and chromium chloride. Two methods were used to quantify cell viability: Alamar Blue assay and Live/Dead assay. The cytotoxicity was observed only with cobalt. Cobalt nanoparticles and ions demonstrated dose-dependent cytotoxic effects on macrophages in vitro: the cytotoxic concentrations of nanoparticles and ions were 1 x 10(12) particles ml(-1) and 1000 microM, respectively. The high concentration of cobalt nanoparticles required for cytotoxicity of macrophages in vitro suggests that increased production of cobalt nanoparticles in vivo, due to excessive MoM implant wear, may lead to local adverse biological effects. Therefore, cytotoxicity of high concentrations of metal nanoparticles phagocytosed by macrophages located in the periprosthetic tissues may be an important factor in pathogenesis of pseudotumours.

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

    PubMed

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

    2012-02-21

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

  20. A LINEAR ACTUATED TORSIONAL DEVICE TO REPLICATE CLINICALLY RELEVANT SPIRAL FRACTURES IN LONG BONES

    PubMed Central

    Edwards, W. Brent; Troy, Karen L.

    2012-01-01

    To better understand the mechanisms underlying spiral fracture we would like to carry out biomechanical tests of long bones loaded in torsion to failure. A device was fabricated to perform torsional tests of long bones using a single-axis linear actuator. The principal operation of the device was to transform the vertical displacement of a material testing machine’s linear actuator into rotational movement using a spur gear and rack system. Accuracy and precision of the device were quantified using cast-acrylic rods with known torque-rotation behavior. Cadaveric experimentation was used to replicate a clinically relevant spiral fracture in eleven human proximal tibiae; strain gage data were recorded for a single specimen. The device had an experimental error less than 0.2 Nm and was repeatable to within 0.3%. Strain gage data were in line with those expected from pure torsion and the cadaveric tibiae illustrated spiral fractures at ultimate torque and rotation values of 130.6 ± 53.2 Nm and 8.3 ± 1.5°, respectively. Ultimate torque was highly correlated with DXA assessed bone mineral density (r = 0.87; p<0.001). The device presented is applicable to any torsional testing of long bone when only a single-axis linear actuator is available. PMID:23025174

  1. A linear-actuated torsional device to replicate clinically relevant spiral fractures in long bones.

    PubMed

    Edwards, W Brent; Troy, Karen L

    2012-09-01

    To better understand the mechanisms underlying spiral fracture we would like to carry out biomechanical tests of long bones loaded in torsion to failure. A device was fabricated to perform torsional tests of long bones using a single-axis linear actuator. The principal operation of the device was to transform the vertical displacement of a material testing machine's linear actuator into rotational movement using a spur gear and rack system. Accuracy and precision of the device were quantified using cast-acrylic rods with known torque-rotation behavior. Cadaveric experimentation was used to replicate a clinically relevant spiral fracture in eleven human proximal tibiae; strain-gage data were recorded for a single specimen. The device had an experimental error of less than 0.2 Nm and was repeatable to within 0.3%. Strain gage data were in line with those expected from pure torsion and the cadaveric tibiae illustrated spiral fractures at ultimate torque and rotation values of 130.6 +/- 53.2 Nm and 8.3 +/- 1.5 degrees, respectively. Ultimate torque was highly correlated with DXA assessed bone mineral density (r = 0.87; p < 0.00 1). The device presented is applicable to any torsional testing of long bone when only a single-axis linear actuator is available.

  2. A clinically relevant model of osteoinduction: a process requiring calcium phosphate and BMP/Wnt signalling

    PubMed Central

    Eyckmans, J; Roberts, S J; Schrooten, J; Luyten, F P

    2010-01-01

    Abstract In this study, we investigated a clinically relevant model of in vivo ectopic bone formation utilizing human periosteum derived cells (HPDCs) seeded in a Collagraft™ carrier and explored the mechanisms by which this process is driven. Bone formation occurred after eight weeks when a minimum of one million HPDCs was loaded on Collagraft™ carriers and implanted subcutaneously in NMRI nu/nu mice. De novo bone matrix, mainly secreted by the HPDCs, was found juxta-proximal of the calcium phosphate (CaP) granules suggesting that CaP may have triggered the ‘osteoinductive program’. Indeed, removal of the CaP granules by ethylenediaminetetraacetic acid decalcification prior to cell seeding and implantation resulted in loss of bone formation. In addition, inhibition of endogenous bone morphogenetic protein and Wnt signalling by overexpression of the secreted antagonists Noggin and Frzb, respectively, also abrogated osteoinduction. Proliferation of the engrafted HPDCs was strongly reduced in the decalcified scaffolds or when seeded with adenovirus-Noggin/Frzb transduced HPDCs indicating that cell division of the engrafted HPDCs is required for the direct bone formation cascade. These data suggest that this model of bone formation is similar to that observed during physiological intramembranous bone development and may be of importance when investigating tissue engineering strategies. PMID:19538476

  3. 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

    2014-10-06

    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.

  4. Reactive oxygen species in Hevea brasiliensis latex and relevance to Tapping Panel Dryness.

    PubMed

    Zhang, Yi; Leclercq, Julie; Montoro, Pascal

    2016-11-29

    Environmental stress can lead to oxidative stress resulting from an increase in reactive oxygen species (ROS) and involves redox adjustments. Natural rubber is synthesized in laticifers, which is a non-photosynthetic tissue particularly prone to oxidative stress. This paper reviews the current state of knowledge on the ROS production and ROS-scavenging systems in laticifers. These regulations have been the subject of intense research into a physiological syndrome, called Tapping Panel Dryness (TPD), affecting latex production in Hevea brasiliensis In order to prevent TPD occurrence, monitoring thiol content appeared to be a crucial factor of latex diagnosis. Thiols, ascorbate and γ-tocotrienol are the major antioxidants in latex. They are involved in membrane protection from ROS and likely have an effect on the quality of raw rubber. Some transcription factors might play a role in the redox regulatory network in Hevea, in particular ethylene response factors, which have been the most intensively studied given the role of ethylene on rubber production. Current challenges for rubber research and development with regard to redox systems will involve improving antioxidant capacity using natural genetic variability.

  5. 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.

  6. Drug resistance & virulence determinants in clinical isolatesof Enterococcus species

    PubMed Central

    Fernandes, Sanal C.; Dhanashree, B.

    2013-01-01

    Background & objectives: Enterococci are the leading cause of nosocomial infections, and are thus a persisting clinical problem globally. We undertook this study to determine the virulence factors and the antibiotic resistance in Enterococcus clinical isolates. Methods: One hundred and fifty Enterococcus isolates obtained from various clinical specimens were speciated biochemically and subjected to antibiotic susceptibility testing using Kirby-Bauer disk diffusion method. Resistance to vancomycin was determined by using agar screen method. Haemolysin and gelatinase productions were detected using 5 per cent sheep blood agar and 12 per cent gelatin agar, respectively. Results: Among the 150 Enterococcus isolates, 84 (56%) were E. faecalis. 51(34%) E. faecium, and 15 (10%) were other Enterococcus spp. Haemolysin production was seen among 123 (82%) isolates while 61 (40.6%) isolates produced gelatinase. Nearly 50 per cent of the isolates showed high level aminoglycoside resistance (HLAR). A total of 13 (8.6%) isolates showed vancomycin resistance, of which 11(7.3%) had an MIC >8 μg/ml. Interpretation & conclusions: Presence of VRE was found to be low among the isolates studied. However, occurrence of VRE along with HLAR calls for regular detection of vancomycin resistance promptly and accurately to recognize VRE colonization and infection. Early detection of VRE and HLAR along with their virulence trait will help in preventing the establishment and spread of multidrug resistant Enterococcus species. PMID:23760387

  7. Pulsed light for the inactivation of fungal biofilms of clinically important pathogenic Candida species.

    PubMed

    Garvey, Mary; Andrade Fernandes, Joao Paulo; Rowan, Neil

    2015-07-01

    Microorganisms are naturally found as biofilm communities more than planktonic free-floating cells; however, planktonic culture remains the current model for microbiological studies, such as disinfection techniques. The presence of fungal biofilms in the clinical setting has a negative impact on patient mortality, as Candida biofilms have proved to be resistant to biocides in numerous in vitro studies; however, there is limited information on the effect of pulsed light on sessile communities. Here we report on the use of pulsed UV light for the effective inactivation of clinically relevant Candida species. Fungal biofilms were grown by use of a CDC reactor on clinically relevant surfaces. Following a maximal 72 h formation period, the densely populated biofilms were exposed to pulsed light at varying fluences to determine biofilm sensitivity to pulsed-light inactivation. The results were then compared to planktonic cell inactivation. High levels of inactivation of C. albicans and C. parapsilosis biofilms were achieved with pulsed light for both 48 and 72 h biofilm structures. The findings suggest that pulsed light has the potential to provide a means of surface decontamination, subsequently reducing the risk of infection to patients. The research described herein deals with an important aspect of disease prevention and public health.

  8. Comprehensive Genomic Profiling of Advanced Penile Carcinoma Suggests a High Frequency of Clinically Relevant Genomic Alterations

    PubMed Central

    Pal, Sumanta K.; Wang, Kai; Palma, Norma A.; Sanford, Eric; Bailey, Mark; He, Jie; Elvin, Julia A.; Chmielecki, Juliann; Squillace, Rachel; Dow, Edward; Morosini, Deborah; Buell, Jamie; Yelensky, Roman; Lipson, Doron; Frampton, Garrett M.; Howley, Peter; Ross, Jeffrey S.; Stephens, Philip J.; Miller, Vincent A.

    2016-01-01

    Background. Advanced penile squamous cell carcinoma (PSCC) is associated with poor survival due to the aggressiveness of the disease and lack of effective systemic therapies. Comprehensive genomic profiling (CGP) was performed to identify clinically relevant genomic alterations (CRGAs). Materials and Methods. DNA was extracted from 40 μm of formalin-fixed, paraffin-embedded sections in patients with advanced PSCC. CGP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of 692× for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. CRGAs were defined as genomic alterations (GAs) linked to targeted therapies on the market or under evaluation in mechanism-driven clinical trials. Results. Twenty male patients with a median age of 60 years (range, 46–87 years) were assessed. Seventeen (85%) cases were stage IV and three cases (15%) were stage III. CGP revealed 109 GAs (5.45 per tumor), 44 of which were CRGAs (2.2 per tumor). At least one CRGA was detected in 19 (95%) cases, and the most common CRGAs were CDKN2A point mutations and homozygous deletion (40%), NOTCH1 point mutations and rearrangements (25%), PIK3CA point mutations and amplification (25%), EGFR amplification (20%), CCND1 amplification (20%), BRCA2 insertions/deletions (10%), RICTOR amplifications (10%), and FBXW7 point mutations (10%). Conclusion. CGP identified CRGAs in patients with advanced PSCC, including EGFR amplification and PIK3CA alterations, which can lead to the rational administration of targeted therapy and subsequent benefit for these patients. Implications for Practice: Few treatment options exist for patients with advanced penile squamous cell carcinoma (PSCC). Outcomes are dismal with platinum-based chemotherapy, with median survival estimated at 1 year or less across multiple series. Biological studies of patients with PSCC to date have principally focused on human papillomavirus status

  9. 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.

  10. Observed inter-camera variability of clinically relevant performance characteristics for Siemens Symbia gamma cameras.

    PubMed

    Kappadath, S Cheenu; Erwin, William D; Wendt, Richard E

    2006-11-28

    We conducted an evaluation of the intercamera (i.e., between cameras) variability in clinically relevant performance characteristics for Symbia gamma cameras (Siemens Medical Solutions, Malvern, PA) based on measurements made using nine separate systems. The significance of the observed intercamera variability was determined by comparing it to the intracamera (i.e., within a single camera) variability. Measurements of performance characteristics were based on the standards of the National Electrical Manufacturers Association and reports 6, 9, 22, and 52 from the American Association of Physicists in Medicine. All measurements were performed using 99mTc (except 57Co used for extrinsic resolution) and low-energy, high-resolution collimation. Of the nine cameras, four have crystals 3/8 in. thick and five have crystals 5/8 in. thick. We evaluated intrinsic energy resolution, intrinsic and extrinsic spatial resolution, intrinsic integral and differential flood uniformity over the useful field-of-view, count rate at 20% count loss, planar sensitivity, single-photon emission computed tomography (SPECT) resolution, and SPECT integral uniformity. The intracamera variability was estimated by repeated measurements of the performance characteristics on a single system. The significance of the observed intercamera variability was evaluated using the two-tailed F distribution. The planar sensitivity of the gamma cameras tested was found be variable at the 99.8% confidence level for both the 3/8-in. and 5/8-in. crystal systems. The integral uniformity and energy resolution were found to be variable only for the 5/8-in. crystal systems at the 98% and 90% confidence level, respectively. All other performance characteristics tested exhibited no significant variability between camera systems. The measured variability reported here could perhaps be used to define nominal performance values of Symbia gamma cameras for planar and SPECT imaging.

  11. New clinically relevant, orthotopic mouse models of human chondrosarcoma with spontaneous metastasis

    PubMed Central

    2010-01-01

    Background Chondrosarcoma responds poorly to adjuvant therapy and new, clinically relevant animal models are required to test targeted therapy. Methods Two human chondrosarcoma cell lines, JJ012 and FS090, were evaluated for proliferation, colony formation, invasion, angiogenesis and osteoclastogenesis. Cell lines were also investigated for VEGF, MMP-2, MMP-9, and RECK expression. JJ012 and FS090 were injected separately into the mouse tibia intramedullary canal or tibial periosteum. Animal limbs were measured, and x-rayed for evidence of tumour take and progression. Tibias and lungs were harvested to determine the presence of tumour and lung metastases. Results JJ012 demonstrated significantly higher proliferative capacity, invasion, and colony formation in collagen I gel. JJ012 conditioned medium stimulated endothelial tube formation and osteoclastogenesis with a greater potency than FS090 conditioned medium, perhaps related to the effects of VEGF and MMP-9. In vivo, tumours formed in intratibial and periosteal groups injected with JJ012, however no mice injected with FS090 developed tumours. JJ012 periosteal tumours grew to 3 times the non-injected limb size by 7 weeks, whereas intratibial injected limbs required 10 weeks to achieve a similar tumour size. Sectioned tumour tissue demonstrated features of grade III chondrosarcoma. All JJ012 periosteal tumours (5/5) resulted in lung micro-metastases, while only 2/4 JJ012 intratibial tumours demonstrated metastases. Conclusions The established JJ012 models replicate the site, morphology, and many behavioural characteristics of human chondrosarcoma. Local tumour invasion of bone and spontaneous lung metastasis offer valuable assessment tools to test the potential of novel agents for future chondrosarcoma therapy. PMID:20584302

  12. Exercise hemorheology as a three acts play with metabolic actors: is it of clinical relevance?

    PubMed

    Brun, Jean-Frédéric

    2002-01-01

    Hemorheological effects of exercise are a triphasic phenomenon including: (a) short-term effects (hyperviscosity mostly due to fluid shifts and alterations of erythrocyte rigidity and aggregability); (b) middle-term effects (i.e., the reversal of acute effects due to plasma volume expansion (autohemodilution) that lowers both plasma viscosity and hematocrit; (c) long-term effects that further improve blood fluidity, parallel with the classical training-induced hormonal and metabolic alterations. Red cell rheology during these 3 stages is affected by white cells and oxidant stress. On the other hand, most metabolic and hormonal alterations play a role in exercise-induced hemorheological changes: among them, blood lactate appears to have opposite effects according to the training status, since it generally impairs erythrocyte fluidity while it improves it in some subgroups of highly trained athletes, a difference that could be related to membrane monocarboxylate transporter status. Body composition (mostly hydration status and the amount of fat mass) as well as its major hormonal regulating system (the growth-hormone-IGF-I axis) are both markedly modified by training and these modifications are correlated with hemorheology. Nutritional disturbances affecting caloric and proteic intake, lipids, iron, zinc, etc. also modulate the hemorheologic effects of exercise. The overtraining syndrome represents a situation of unbalance between body's possibilities, nutrition, and work load, and is associated with metabolic, hormonal, immunologic and hemorheologic disturbances. The clinical relevance of these data is underlined by studies showing that exercise training in patients suffering from metabolic and/or cardiovascular disorders (such as the insulin resistance syndrome) results in a parallel improvement of metabolism, risk factors, blood rheology and fitness. Hemorheological measurements require to be studied, at least as sensitive markers of training, and possibly as

  13. 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.

  14. Pancreatic Steatosis Demonstrated at MR Imaging in the General Population: Clinical Relevance

    PubMed Central

    Berthold, Friederike; Mayerle, Julia; Völzke, Henry; Reeder, Scott B.; Rathmann, Wolfgang; Lerch, Markus M.; Hosten, Norbert; Hegenscheid, Katrin; Meffert, Peter J.

    2015-01-01

    Purpose To determine the relationship between pancreatic fat content and type 2 diabetes and prediabetes. Materials and Methods From the prospective population-based Study of Health in Pomerania (SHIP), 1367 volunteers (563 men, 678 women; median age, 50 years) underwent whole-body magnetic resonance (MR) imaging at 1.5 T, which included multiecho chemical shift–encoded acquisition of the abdomen. SHIP was approved by the institutional review board, and written informed consent was obtained from all participants. The proton density fat fraction (PDFF) was calculated after correction for T1 bias, T2* bias, multipeak spectral complexity of fat, and noise bias. On the basis of oral glucose tolerance test results, participants were grouped into those with normal glucose tolerance (n = 740), those with prediabetes (n = 431), and those with confirmed type 2 diabetes but without medication (n = 70). PDFF was assessed in the pancreatic head, body, and tail. Multivariable regression analysis was conducted to investigate possible relationships of PDFF with demographic factors, behavioral factors, and laboratory data associated with the metabolic syndrome. Results In all subjects, the mean unadjusted pancreatic fat content was 4.4% (head, 4.6%; body, 4.9%; tail, 3.9%; being unequally distributed, P < .001). There was no significant difference in pancreatic PDFF among subjects with normal glucose tolerance, prediabetes, and type 2 diabetes (P = .980). Pancreatic PDFF showed a positive association with age and body mass index and a negative association with serum lipase activity (P < .001). Conclusion The presence of pancreatic fat is not related to prediabetes or diabetes, which suggests that it has little clinical relevance for an individual’s glycemic status. © RSNA, 2015 Online supplemental material is available for this article. PMID:25658037

  15. 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.

  16. 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

  17. Quantity and clinical relevance of circulating endothelial progenitor cells in human ovarian cancer

    PubMed Central

    2010-01-01

    Background Circulating bone marrow-derived endothelial progenitor cells (EPCs) have been reported to participate in tumor angiogenesis and growth; however, the role of circulating EPCs in tumor progression is controversial. The role of circulating EPCs in ovarian cancer progression and angiogenesis has not yet been investigated. Methods The number of circulating EPCs in the peripheral blood in 25 healthy volunteers and 42 patients with ovarian cancer was determined by flow cytometry. EPCs were defined by co-expression of CD34 and vascular endothelial growth factor receptor 2 (VEGFR2). In addition, we determined CD34 and VEGFR2 mRNA levels by real-time reverse transcription-polymerase chain reaction. Plasma levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) were determined by enzyme-linked immunosorbent assay. Results Circulating levels of EPCs were significantly increased in ovarian cancer patients, correlating with tumor stage and residual tumor size. Higher levels of EPCs were detected in patients with stage III and IV ovarian cancer than in patients with stage I and II disease. After excision of the tumor, EPCs levels rapidly declined. Residual tumor size greater than 2 cm was associated with significantly higher levels of EPCs. In addition, high circulating EPCs correlated with poor overall survival. Pretreatment CD34 mRNA levels were not significantly increased in ovarian cancer patients compared with healthy controls; however, VEGFR2 expression was increased, and plasma levels of VEGF and MMP-9 were also elevated. Conclusions Our results demonstrate the clinical relevance of circulating EPCs in ovarian cancer. EPCs may be a potential biomarker to monitor ovarian cancer progression and angiogenesis and treatment response. PMID:20334653

  18. Resistance to antibiotics of clinical relevance in the fecal microbiota of Mexican wildlife.

    PubMed

    Cristóbal-Azkarate, Jurgi; Dunn, Jacob C; Day, Jennifer M W; Amábile-Cuevas, Carlos F

    2014-01-01

    There are a growing number of reports of antibiotic resistance (ATBR) in bacteria living in wildlife. This is a cause for concern as ATBR in wildlife represents a potential public health threat. However, little is known about the factors that might determine the presence, abundance and dispersion of ATBR bacteria in wildlife. Here, we used culture and molecular methods to assess ATBR in bacteria in fecal samples from howler monkeys (Alouatta palliata), spider monkeys (Ateles geoffroyi), tapirs (Tapirus bairdii) and felids (jaguars, Panthera onca; pumas, Puma concolor; jaguarundis, Puma yagouaroundi; and ocelots, Leopardus pardalis) living freely in two regions of the Mexican state of Veracruz under different degrees of human influence. Overall, our study shows that ATBR is commonplace in bacteria isolated from wildlife in southeast Mexico. Most of the resistances were towards old and naturally occurring antibiotics, but we also observed resistances of potential clinical significance. We found that proximity to humans positively affected the presence of ATBR and that ATBR was higher in terrestrial than arboreal species. We also found evidence suggesting different terrestrial and aerial routes for the transmission of ATBR between humans and wildlife. The prevalence and potential ATBR transfer mechanisms between humans and wildlife observed in this study highlight the need for further studies to identify the factors that might determine ATBR presence, abundance and distribution.

  19. Resistance to Antibiotics of Clinical Relevance in the Fecal Microbiota of Mexican Wildlife

    PubMed Central

    Cristóbal-Azkarate, Jurgi; Dunn, Jacob C.; Day, Jennifer M. W.; Amábile-Cuevas, Carlos F.

    2014-01-01

    There are a growing number of reports of antibiotic resistance (ATBR) in bacteria living in wildlife. This is a cause for concern as ATBR in wildlife represents a potential public health threat. However, little is known about the factors that might determine the presence, abundance and dispersion of ATBR bacteria in wildlife. Here, we used culture and molecular methods to assess ATBR in bacteria in fecal samples from howler monkeys (Alouatta palliata), spider monkeys (Ateles geoffroyi), tapirs (Tapirus bairdii) and felids (jaguars, Panthera onca; pumas, Puma concolor; jaguarundis, Puma yagouaroundi; and ocelots, Leopardus pardalis) living freely in two regions of the Mexican state of Veracruz under different degrees of human influence. Overall, our study shows that ATBR is commonplace in bacteria isolated from wildlife in southeast Mexico. Most of the resistances were towards old and naturally occurring antibiotics, but we also observed resistances of potential clinical significance. We found that proximity to humans positively affected the presence of ATBR and that ATBR was higher in terrestrial than arboreal species. We also found evidence suggesting different terrestrial and aerial routes for the transmission of ATBR between humans and wildlife. The prevalence and potential ATBR transfer mechanisms between humans and wildlife observed in this study highlight the need for further studies to identify the factors that might determine ATBR presence, abundance and distribution. PMID:25233089

  20. Impact of plasma jet vacuum ultraviolet radiation on reactive oxygen species generation in bio-relevant liquids

    SciTech Connect

    Jablonowski, H.; Hammer, M. U.; Reuter, S.; Bussiahn, R.; Weltmann, K.-D.; Woedtke, Th. von

    2015-12-15

    Plasma medicine utilizes the combined interaction of plasma produced reactive components. These are reactive atoms, molecules, ions, metastable species, and radiation. Here, ultraviolet (UV, 100–400 nm) and, in particular, vacuum ultraviolet (VUV, 10–200 nm) radiation generated by an atmospheric pressure argon plasma jet were investigated regarding plasma emission, absorption in a humidified atmosphere and in solutions relevant for plasma medicine. The energy absorption was obtained for simple solutions like distilled water (dH{sub 2}O) or ultrapure water and sodium chloride (NaCl) solution as well as for more complex ones, for example, Rosewell Park Memorial Institute (RPMI 1640) cell culture media. As moderate stable reactive oxygen species, hydrogen peroxide (H{sub 2}O{sub 2}) was studied. Highly reactive oxygen radicals, namely, superoxide anion (O{sub 2}{sup •−}) and hydroxyl radicals ({sup •}OH), were investigated by the use of electron paramagnetic resonance spectroscopy. All species amounts were detected for three different treatment cases: Plasma jet generated VUV and UV radiation, plasma jet generated UV radiation without VUV part, and complete plasma jet including all reactive components additionally to VUV and UV radiation. It was found that a considerable amount of radicals are generated by the plasma generated photoemission. From the experiments, estimation on the low hazard potential of plasma generated VUV radiation is discussed.

  1. Impact of plasma jet vacuum ultraviolet radiation on reactive oxygen species generation in bio-relevant liquids

    NASA Astrophysics Data System (ADS)

    Jablonowski, H.; Bussiahn, R.; Hammer, M. U.; Weltmann, K.-D.; von Woedtke, Th.; Reuter, S.

    2015-12-01

    Plasma medicine utilizes the combined interaction of plasma produced reactive components. These are reactive atoms, molecules, ions, metastable species, and radiation. Here, ultraviolet (UV, 100-400 nm) and, in particular, vacuum ultraviolet (VUV, 10-200 nm) radiation generated by an atmospheric pressure argon plasma jet were investigated regarding plasma emission, absorption in a humidified atmosphere and in solutions relevant for plasma medicine. The energy absorption was obtained for simple solutions like distilled water (dH2O) or ultrapure water and sodium chloride (NaCl) solution as well as for more complex ones, for example, Rosewell Park Memorial Institute (RPMI 1640) cell culture media. As moderate stable reactive oxygen species, hydrogen peroxide (H2O2) was studied. Highly reactive oxygen radicals, namely, superoxide anion (O2•-) and hydroxyl radicals (•OH), were investigated by the use of electron paramagnetic resonance spectroscopy. All species amounts were detected for three different treatment cases: Plasma jet generated VUV and UV radiation, plasma jet generated UV radiation without VUV part, and complete plasma jet including all reactive components additionally to VUV and UV radiation. It was found that a considerable amount of radicals are generated by the plasma generated photoemission. From the experiments, estimation on the low hazard potential of plasma generated VUV radiation is discussed.

  2. 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.

  3. 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.

  4. Clinically relevant depression in old age: An international study with populations from Canada, Latin America and Eastern Europe.

    PubMed

    Ylli, Alban; Miszkurka, Malgorzata; Phillips, Susan P; Guralnik, Jack; Deshpande, Nandini; Zunzunegui, Maria Victoria

    2016-07-30

    Our aim is to assess cross-national variations in prevalence of clinically relevant depression and to examine the relationships of social and health factors with depression in five diverse populations of older adults, from Canada, Brazil, Colombia and Albania. We used the data from the International Mobility in Aging Study. Clinically relevant depression was defined as a score of ≥16 on the Center for Epidemiologic Study Depression Scale (CES-D). Poisson regressions with robust covariance correction were used to estimate prevalence ratios associated with potential risk factors. Prevalence of clinically relevant depression across research sites varied widely, being consistently higher in women than in men. It was lowest in men from Brazil (6.3%) and highest in women from Albania (46.6%). Low education and insufficient income, living alone, multiple chronic conditions, and poor physical performance were all significantly associated with depression prevalence. Poor physical performance was more strongly associated with depression in men than in women. Similar factors are associated with clinically relevant depression among men and women and across research sites. The large variation in depression prevalence population rates is unexplained by the classical individual factors considered in the study suggesting the impact of country characteristics on depression among older populations.

  5. Clinically relevant variants - identifying, collecting, interpreting, and disseminating: the 2013 annual scientific meeting of the Human Genome Variation Society.

    PubMed

    Stanley, Christine M; Sunyaev, Shamil R; Greenblatt, Marc S; Oetting, William S

    2014-04-01

    The dramatic advances in genetic sequencing technologies used in research laboratories are now entering the clinic, and applications of whole-genome and whole-exome sequencing to disease diagnosis, predisposition, and treatment will soon be commonplace. However, the standards and methods for identifying clinically relevant variants are currently being debated and defined. Multiple agencies worldwide have recognized that we have reached an exciting and critical transition point into the clinic, and many important issues are being discussed that impact how genetic variation data in the clinic will be interpreted and used. The 2013 annual scientific meeting of the Human Genome Variation Society (HGVS) had as its main theme the discovery, interpretation, and dissemination of clinically relevant DNA variants. The meeting featured the continuously developing technology of databasing genetic variation and computational tools for allelic variant discovery. Attention was given to curating and integrating these data with clinical findings, including approaches to distinguish between functional alleles underlying clinical phenotypes and benign sequence variants and making data sources interoperable and functional for clinical diagnostic utility, citing examples in specific diseases.

  6. Relevance of risk predictions derived from a chronic species sensitivity distribution with cadmium to aquatic populations and ecosystems

    USGS Publications Warehouse

    Mebane, C.A.

    2010-01-01

    Criteria to protect aquatic life are intended to protect diverse ecosystems, but in practice are usually developed from compilations of single-species toxicity tests using standard test organisms that were tested in laboratory environments. Species sensitivity distributions (SSDs) developed from these compilations are extrapolated to set aquatic ecosystem criteria. The protectiveness of the approach was critically reviewed with a chronic SSD for cadmium comprising 27 species within 21 genera. Within the data set, one genus had lower cadmium effects concentrations than the SSD fifth percentile-based criterion, so in theory this genus, the amphipod Hyalella, could be lost or at least allowed some level of harm by this criteria approach. However, population matrix modeling projected only slightly increased extinction risks for a temperate Hyalella population under scenarios similar to the SSD fifth percentile criterion. The criterion value was further compared to cadmium effects concentrations in ecosystem experiments and field studies. Generally, few adverse effects were inferred from ecosystem experiments at concentrations less than the SSD fifth percentile criterion. Exceptions were behavioral impairments in simplified food web studies. No adverse effects were apparent in field studies under conditions that seldom exceeded the criterion. At concentrations greater than the SSD fifth percentile, the magnitudes of adverse effects in the field studies were roughly proportional to the laboratory-based fraction of species with adverse effects in the SSD. Overall, the modeling and field validation comparisons of the chronic criterion values generally supported the relevance and protectiveness of the SSD fifth percentile approach with cadmium. ?? 2009 Society for Risk Analysis.

  7. Species characterization and minimum inhibitory concentration patterns of Brachyspira species isolates from swine with clinical disease.

    PubMed

    Clothier, Kristin A; Kinyon, Joann M; Frana, Timothy S; Naberhaus, Nadine; Bower, Leslie; Strait, Erin L; Schwartz, Kent

    2011-11-01

    Typhlocolitis and dysentery due to Brachyspira hyodysenteriae infection represent an economically important disease syndrome in growing pigs. Largely disappearing from U.S. swine herds in the late 1990 s and early 2000s, Brachyspira-associated disease and bacterial isolation from swine with clinical disease has increased in the last several years, and non-B. hyodysenteriae isolates are commonly identified. Antimicrobial resistance has been demonstrated in Brachyspira spp. isolates from Europe and Asia, and may be the reason for the resurgence in U.S. herds. Seventy-nine clinical isolates identified at the Iowa State University Veterinary Diagnostic Lab were tested with multiple polymerase chain reaction assays to establish species identity, and evaluated for minimum inhibitory concentrations (MICs) using an agar dilution method against lincomycin, gentamicin, valnemulin, tiamulin, salinomycin, and carbadox. Only 38.0% of isolates could be confirmed as the known pathogens B. hyodysenteriae (30.4%) or Brachyspira pilosicoli (7.6%). Twenty of the 79 isolates (25.3%) were identified as Brachyspira murdochii, and 13.9% could not be identified to species. The MIC values were consistently high against lincomycin and moderately high against gentamicin. The remaining antimicrobials had MICs that were at the low end of the test ranges. Brachyspira murdochii and Brachyspira spp. had significantly greater MIC values against several of these drugs than other Brachyspira spp. examined. The increased incidence of these less definitively characterized Brachyspira species with increased MIC values to commonly prescribed antimicrobials may, at least in part, explain the increased prevalence and severity of this disease complex in recent years. Further research is necessary to understand these changes.

  8. The relationship between immediate relevant basic science knowledge and clinical knowledge: physiology knowledge and transthoracic echocardiography image interpretation.

    PubMed

    Nielsen, Dorte Guldbrand; Gotzsche, Ole; Sonne, Ole; Eika, Berit

    2012-10-01

    Two major views on the relationship between basic science knowledge and clinical knowledge stand out; the Two-world view seeing basic science and clinical science as two separate knowledge bases and the encapsulated knowledge view stating that basic science knowledge plays an overt role being encapsulated in the clinical knowledge. However, resent research has implied that a more complex relationship between the two knowledge bases exists. In this study, we explore the relationship between immediate relevant basic science (physiology) and clinical knowledge within a specific domain of medicine (echocardiography). Twenty eight medical students in their 3rd year and 45 physicians (15 interns, 15 cardiology residents and 15 cardiology consultants) took a multiple-choice test of physiology knowledge. The physicians also viewed images of a transthoracic echocardiography (TTE) examination and completed a checklist of possible pathologies found. A total score for each participant was calculated for the physiology test, and for all physicians also for the TTE checklist. Consultants scored significantly higher on the physiology test than did medical students and interns. A significant correlation between physiology test scores and TTE checklist scores was found for the cardiology residents only. Basic science knowledge of immediate relevance for daily clinical work expands with increased work experience within a specific domain. Consultants showed no relationship between physiology knowledge and TTE interpretation indicating that experts do not use basic science knowledge in routine daily practice, but knowledge of immediate relevance remains ready for use.

  9. 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

  10. SU-E-T-185: Clinically-Relevant Investigation of Flattening Filter Free Skin Dose

    SciTech Connect

    Guy, C; Karki, K; Sharma, M; Kim, S

    2015-06-15

    Purpose: Flattening-filter-free (FFF) beams are increasingly used for small-field treatments due to inherent advantages like higher MU efficiency and reduced treatment time and scatter dose. Removal of the flattening-filter increases the electron contamination and low-energy x-rays. As such, surface-dose characteristics are different from traditional flattened (FF) beams. The goal of this work is to investigate surface dose of 6/10 MV FFF and FF beams under conditions representative of emerging complex techniques like small-field stereotactic treatments which use small fields formed with multi-leaf-collimators (MLCs) at closer SSDs. Methods: A parallel-plate PTW Markus-chamber (N23343) placed in custom air- and water-equivalent phantoms was used to measure surface-dose at 2/3/4/6/8/10/20/30 cm{sup 2} field sizes, at 80/90/100 cm source-to-surface distances, and at fields defined by jaws and MLCs. The effect of dose rate (600 and 1400/2400 MU/min) was also investigated at 100 cm SSD. Measurements were performed on TrueBeam linac (Varian Medical Systems, Palo Alto, CA) for 6X/6XFFF/10X/10XFFF beam energies. Results: No dose-rate dependence was seen for FFF skin-dose. Air-phantom measurements were, on average, 5±3% larger than for water-phantom measurements. With SSD increase from 80 to 100 cm, skin-dose decreased by an average of 3.9±2.5%. FFF beams were found to be more sensitive to SSD changes in comparison to FF beams. The difference in skin dose between MLC- and jaw-fields was less variable with field size for FFF compared to FF beams. 10 MV beams showed greater difference in FFF-to-FF ratio, 50% (jaws) and 22% (MLC), between the largest and smallest field sizes compared to 6 MV beams, 30% (jaws) and 9% (MLC). Conclusion: Under clinically-relevant conditions, surface dose for FFF beams was higher at small field size (<10 cm), lower at largest field size (30 cm), more sensitive to SSD changes, and had less variation with field size compared to dose for FF beams.

  11. More Than Just Light: Clinical Relevance of Light Perception in the Nosocomial Pathogen Acinetobacter baumannii and Other Members of the Genus Acinetobacter.

    PubMed

    Ramírez, María Soledad; Müller, Gabriela Leticia; Pérez, Jorgelina Fernanda; Golic, Adrián Ezequiel; Mussi, María Alejandra

    2015-11-01

    A summary of the major findings concerning light modulation in Acinetobacter baumannii, which governs aspects related to the success of this microorganism as a nosocomial pathogen, is presented. Particularly, the evidence shows that light modulates the ability of the bacteria to persist in the environment, its virulence against eukaryotic hosts and even susceptibility to certain antibiotics. The light signal is sensed through different mechanisms, in some cases involving specialized photoreceptors of the BLUF-type, whereas in others, directly by a photosensitizer molecule. We also provide new data concerning the genomic context of BLUF-domain containing proteins within the genus Acinetobacter, as well as further insights into the mechanism of light-mediated reduction in susceptibility to antibiotics. The overall information points toward light being a crucial stimulus in the lifestyle of members of the genus Acinetobacter as well as in other clinically relevant species, such as members of the ESKAPE group, playing therefore an important role in the clinical settings.

  12. 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.

  13. Microbiological quality of ready-to-eat salads: an underestimated vehicle of bacteria and clinically relevant antibiotic resistance genes.

    PubMed

    Campos, Joana; Mourão, Joana; Pestana, Nazaré; Peixe, Luísa; Novais, Carla; Antunes, Patrícia

    2013-09-16

    The increase demand for fresh vegetables is causing an expansion of the market for minimally processed vegetables along with new recognized food safety problems. To gain further insight on this topic we analyzed the microbiological quality of Portuguese ready-to-eat salads (RTS) and their role in the spread of bacteria carrying acquired antibiotic resistance genes, food products scarcely considered in surveillance studies. A total of 50 RTS (7 brands; split or mixed leaves, carrot, corn) were collected in 5 national supermarket chains in Porto region (2010). They were tested for aerobic mesophilic counts, coliforms and Escherichia coli counts as well as for the presence of Salmonella and Listeria monocytogenes. Samples were also plated in different selective media with/without antibiotics before and after enrichment. The E. coli, other coliforms and Enterococcus recovered were characterized for antibiotic resistance profiles and clonality with phenotypic and genetic approaches. A high number of RTS presented poor microbiological quality (86%--aerobic mesophilic counts, 74%--coliforms, 4%--E. coli), despite the absence of screened pathogens. In addition, a high diversity of bacteria (species and clones) and antibiotic resistance backgrounds (phenotypes and genotypes) were observed, mostly with enrichment and antibiotic selective media. E. coli was detected in 13 samples (n=78; all types and 4 brands; phylogenetic groups A, B1 and D; none STEC) with resistance to tetracycline [72%; tet(A) and/or tet(B)], streptomycin (58%; aadA and/or strA-strB), sulfamethoxazole (50%; sul1 and/or sul2), trimethoprim (50%; dfrA1 or dfrA12), ampicillin (49%; blaTEM), nalidixic acid (36%), ciprofloxacin (5%) or chloramphenicol (3%; catA). E. coli clones, including the widespread group D/ST69, were detected in different samples from the same brand or different brands pointing out to a potential cross-contamination. Other clinically relevant resistance genes were detected in 2 Raoultella

  14. 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…

  15. 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.

  16. Use of 16S rRNA gene for identification of a broad range of clinically relevant bacterial pathogens.

    PubMed

    Srinivasan, Ramya; Karaoz, Ulas; Volegova, Marina; MacKichan, Joanna; Kato-Maeda, Midori; Miller, Steve; Nadarajan, Rohan; Brodie, Eoin L; Lynch, Susan V

    2015-01-01

    According to World Health Organization statistics of 2011, infectious diseases remain in the top five causes of mortality worldwide. However, despite sophisticated research tools for microbial detection, rapid and accurate molecular diagnostics for identification of infection in humans have not been extensively adopted. Time-consuming culture-based methods remain to the forefront of clinical microbial detection. The 16S rRNA gene, a molecular marker for identification of bacterial species, is ubiquitous to members of this domain and, thanks to ever-expanding databases of sequence information, a useful tool for bacterial identification. In this study, we assembled an extensive repository of clinical isolates (n = 617), representing 30 medically important pathogenic species and originally identified using traditional culture-based or non-16S molecular methods. This strain repository was used to systematically evaluate the ability of 16S rRNA for species level identification. To enable the most accurate species level classification based on the paucity of sequence data accumulated in public databases, we built a Naïve Bayes classifier representing a diverse set of high-quality sequences from medically important bacterial organisms. We show that for species identification, a model-based approach is superior to an alignment based method. Overall, between 16S gene based and clinical identities, our study shows a genus-level concordance rate of 96% and a species-level concordance rate of 87.5%. We point to multiple cases of probable clinical misidentification with traditional culture based identification across a wide range of gram-negative rods and gram-positive cocci as well as common gram-negative cocci.

  17. Use of 16S rRNA Gene for Identification of a Broad Range of Clinically Relevant Bacterial Pathogens

    PubMed Central

    Srinivasan, Ramya; Karaoz, Ulas; Volegova, Marina; MacKichan, Joanna; Kato-Maeda, Midori; Miller, Steve; Nadarajan, Rohan; Brodie, Eoin L.; Lynch, Susan V.

    2015-01-01

    According to World Health Organization statistics of 2011, infectious diseases remain in the top five causes of mortality worldwide. However, despite sophisticated research tools for microbial detection, rapid and accurate molecular diagnostics for identification of infection in humans have not been extensively adopted. Time-consuming culture-based methods remain to the forefront of clinical microbial detection. The 16S rRNA gene, a molecular marker for identification of bacterial species, is ubiquitous to members of this domain and, thanks to ever-expanding databases of sequence information, a useful tool for bacterial identification. In this study, we assembled an extensive repository of clinical isolates (n = 617), representing 30 medically important pathogenic species and originally identified using traditional culture-based or non-16S molecular methods. This strain repository was used to systematically evaluate the ability of 16S rRNA for species level identification. To enable the most accurate species level classification based on the paucity of sequence data accumulated in public databases, we built a Naïve Bayes classifier representing a diverse set of high-quality sequences from medically important bacterial organisms. We show that for species identification, a model-based approach is superior to an alignment based method. Overall, between 16S gene based and clinical identities, our study shows a genus-level concordance rate of 96% and a species-level concordance rate of 87.5%. We point to multiple cases of probable clinical misidentification with traditional culture based identification across a wide range of gram-negative rods and gram-positive cocci as well as common gram-negative cocci. PMID:25658760

  18. Use of 16S rRNA gene for identification of a broad range of clinically relevant bacterial pathogens

    DOE PAGES

    Srinivasan, Ramya; Karaoz, Ulas; Volegova, Marina; ...

    2015-02-06

    According to World Health Organization statistics of 2011, infectious diseases remain in the top five causes of mortality worldwide. However, despite sophisticated research tools for microbial detection, rapid and accurate molecular diagnostics for identification of infection in humans have not been extensively adopted. Time-consuming culture-based methods remain to the forefront of clinical microbial detection. The 16S rRNA gene, a molecular marker for identification of bacterial species, is ubiquitous to members of this domain and, thanks to ever-expanding databases of sequence information, a useful tool for bacterial identification. In this study, we assembled an extensive repository of clinical isolates (n =more » 617), representing 30 medically important pathogenic species and originally identified using traditional culture-based or non-16S molecular methods. This strain repository was used to systematically evaluate the ability of 16S rRNA for species level identification. To enable the most accurate species level classification based on the paucity of sequence data accumulated in public databases, we built a Naïve Bayes classifier representing a diverse set of high-quality sequences from medically important bacterial organisms. We show that for species identification, a model-based approach is superior to an alignment based method. Overall, between 16S gene based and clinical identities, our study shows a genus-level concordance rate of 96% and a species-level concordance rate of 87.5%. We point to multiple cases of probable clinical misidentification with traditional culture based identification across a wide range of gram-negative rods and gram-positive cocci as well as common gram-negative cocci.« less

  19. Use of 16S rRNA gene for identification of a broad range of clinically relevant bacterial pathogens

    SciTech Connect

    Srinivasan, Ramya; Karaoz, Ulas; Volegova, Marina; MacKichan, Joanna; Kato-Maeda, Midori; Miller, Steve; Nadarajan, Rohan; Brodie, Eoin L.; Lynch, Susan V.; Heimesaat, Markus M.

    2015-02-06

    According to World Health Organization statistics of 2011, infectious diseases remain in the top five causes of mortality worldwide. However, despite sophisticated research tools for microbial detection, rapid and accurate molecular diagnostics for identification of infection in humans have not been extensively adopted. Time-consuming culture-based methods remain to the forefront of clinical microbial detection. The 16S rRNA gene, a molecular marker for identification of bacterial species, is ubiquitous to members of this domain and, thanks to ever-expanding databases of sequence information, a useful tool for bacterial identification. In this study, we assembled an extensive repository of clinical isolates (n = 617), representing 30 medically important pathogenic species and originally identified using traditional culture-based or non-16S molecular methods. This strain repository was used to systematically evaluate the ability of 16S rRNA for species level identification. To enable the most accurate species level classification based on the paucity of sequence data accumulated in public databases, we built a Naïve Bayes classifier representing a diverse set of high-quality sequences from medically important bacterial organisms. We show that for species identification, a model-based approach is superior to an alignment based method. Overall, between 16S gene based and clinical identities, our study shows a genus-level concordance rate of 96% and a species-level concordance rate of 87.5%. We point to multiple cases of probable clinical misidentification with traditional culture based identification across a wide range of gram-negative rods and gram-positive cocci as well as common gram-negative cocci.

  20. 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

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

    PubMed

    Frantzi, Maria; Bhat, Akshay; Latosinska, Agnieszka

    2014-03-29

    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.

  2. Effect of endothelin receptor antagonists on clinically relevant outcomes after experimental subarachnoid hemorrhage: a systematic review and meta-analysis

    PubMed Central

    Laban, Kamil G; Vergouwen, Mervyn DI; Dijkhuizen, Rick M; Sena, Emily S; Macleod, Malcolm R; Rinkel, Gabriel JE; van der Worp, H Bart

    2015-01-01

    In clinical trials, endothelin receptor antagonists (ETRAs) reduced vasospasm but did not improve functional outcome after subarachnoid hemorrhage (SAH). We assessed the effects of treatment with ETRAs on clinically relevant outcomes in animal studies modelling SAH by performing a systematic review of the literature for controlled animal studies of ETRAs for the treatment of SAH. Primary outcomes were neurobehavioral outcomes and case fatality. Secondary outcomes were cerebral vasospasm and cerebral blood flow. Summary estimates were calculated using normalized mean difference random effects meta-analysis. We included 27 studies (55 experiments, 639 animals). Neurobehavioral scores were reported in none of the experiments, and case fatality in 8 (15%). Treatment with ETRAs was associated with a pooled odds ratio for case fatality of 0.61 (95% confidence interval (CI), 0.27 to 1.39); a 54% increase (95% CI, 39 to 69) in cerebral arterial diameter; and a 93% increase (95% CI, 58 to 129) in cerebral blood flow. We conclude that there is no evidence from animal studies that treatment with an ETRA improves clinically relevant outcomes after SAH. The reduction in cerebral vasospasm observed in animal studies is consistent with that observed in clinical trials, an effect that is not associated with better functional outcome in patients. PMID:25944590

  3. Evaluation of regional and whole gut motility using the wireless motility capsule: relevance in clinical practice

    PubMed Central

    Tran, Khoa; Brun, Rita

    2012-01-01

    The wireless motility capsule (WMC) is an ambulatory noninvasive and nonradioactive diagnostic sensor that continuously samples intraluminal pH, temperature, and pressure as it moves through the gastrointestinal (GI) tract. This review summarizes the data obtained in clinical trials with the WMC and discusses its role in clinical practice. The United States Food and Drug Administration has approved the SmartPill GI monitoring system for the evaluation of gastric emptying time in patients with suspected gastroparesis, the evaluation of colonic transit time in patients with suspected chronic constipation, and for the characterization of pressure profiles from the antrum and duodenum. Clinical studies have shown that WMC-measured GI transit times can distinguish patients with motility abnormalities similarly to conventional testing. However, the WMC offers the advantage of providing a full GI-tract profile, enabling the detection of multiregional GI transit abnormalities in patients with suspected upper or lower GI dysmotility. The WMC also characterizes pressure profiles of the GI tract and impaired pressure profile limits are reported for the antrum and duodenum. In comparison with manometry, interpretations of pressure measurements obtained by the WMC are limited by an inability to detect a peristaltic pressure wave front, and further investigation is required to develop clinical applications. Clinical studies with the WMC indicated that it should be considered for the evaluation of regional and whole gut transit time in patients with suspected upper or lower dysmotility, particularly if there are concerns about multiregional dysmotility. PMID:22778790

  4. Antibiotic resistance - is resistance detected by surveillance relevant to predicting resistance in the clinical setting?

    PubMed

    Karlowsky, James A; Sahm, Daniel F

    2002-10-01

    Local, regional, national and global surveillance initiatives have several important functions, which include identifying shifts in antibiotic resistance, detecting the emergence of new resistance mechanisms and monitoring the impact of changes made to empiric prescribing, infection control and public health guidelines. Although the need for surveillance is indubitable and its use in the treatment of individual patients important, it cannot unequivocally predict outcomes in patients with infections. Treatment regimens for individual patients with suspected or demonstrated infections should be developed following consideration of symptoms, laboratory findings and relevant medical history, and in the context of appropriate local and widespread antibiotic resistance trends.

  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. Clinically-Relevant Cutaneous Lesions by Nitrogen Mustard: Useful Biomarkers of Vesicants Skin Injury in SKH-1 Hairless and C57BL/6 Mice

    PubMed Central

    Tewari-Singh, Neera; Jain, Anil K.; Inturi, Swetha; White, Carl W.; Agarwal, Rajesh

    2013-01-01

    A paucity of clinically applicable biomarkers to screen therapies in laboratory is a limitation in the development of countermeasures against cutaneous injuries by chemical weapon, sulfur mustard (SM), and its analog nitrogen mustard (NM). Consequently, we assessed NM-caused progression of clinical cutaneous lesions; notably, skin injury with NM is comparable to SM. Exposure of SKH-1 hairless and C57BL/6 (haired) mice to NM (3.2 mg) for 12–120 h caused clinical sequelae of toxicity, including microblister formation, edema, erythema, altered pigmentation, wounding, xerosis and scaly dry skin. These toxic effects of NM were similar in both mouse strains, except that wounding and altered pigmentation at 12–24 h and appearance of dry skin at 24 and 72 h post-NM exposure were more pronounced in C57BL/6 compared to SKH-1 mice. Conversely, edema, erythema and microblister formation were more prominent in SKH-1 than C57BL/6 mice at 24–72 h after NM exposure. In addition, 40–60% mortality was observed following 120 h of NM exposure in the both mouse strains. Overall, these toxic effects of NM are comparable to those reported in humans and other animal species with SM, and thus represent clinically-relevant cutaneous injury endpoints in screening and optimization of therapies for skin injuries by vesicating agents. PMID:23826320

  9. Putting the Pieces Together: Clinically Relevant Genetic and Genomic Resources for Hospitalists and Neonatologists.

    PubMed

    Miller, Rebecca; Khromykh, Alina; Babcock, Holly; Jenevein, Callie; Solomon, Benjamin D

    2017-02-01

    Genetic conditions are individually rare but are common in aggregate, and they often present in the neonatal and early pediatric periods. These conditions are often severe, can be difficult to diagnose and manage, and may heavily affect patients, families, health care systems, and society. Because of recent technological advances, the availability and uptake of genetic and genomic testing are increasing rapidly. However, there is a dearth of trained geneticists and genetic counselors to help guide and explain these conditions and relevant tests. To help hospitalists, neonatologists, and related practitioners navigate this complex and evolving field, we have compiled a list of free (mostly Web-based) resources relevant to the diagnosis and management of genetic conditions and related disorders. These resources, which we describe individually, can be useful for nongeneticist clinicians, and some also include material that can be used to explain concepts and conditions to patients or families. The resources presented are divided into the following categories (which overlap): general information, databases of genetic conditions, resources that can help generate differential diagnoses, databases of genetic testing laboratories (to help with logistics of ordering tests), information on newborn screening, and other resources. We also include a separate list of helpful textbooks and manuals. We conclude with 2 examples describing how some of these resources would be used by a pediatric hospitalist or neonatologist during the inpatient management of a child with a suspected genetic condition.

  10. 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

  11. Cardiovascular risk assessment in patients with rheumatoid arthritis: The relevance of clinical, genetic and serological markers.

    PubMed

    López-Mejías, Raquel; Castañeda, Santos; González-Juanatey, Carlos; Corrales, Alfonso; Ferraz-Amaro, Iván; Genre, Fernanda; Remuzgo-Martínez, Sara; Rodriguez-Rodriguez, Luis; Blanco, Ricardo; Llorca, Javier; Martín, Javier; González-Gay, Miguel A

    2016-11-01

    Cardiovascular disease (CV) is the most common cause of premature mortality in patients with rheumatoid arthritis (RA). This is the result of an accelerated atherosclerotic process. Adequate CV risk stratification has special relevance in RA to identify patients at risk of CV disease. However, current CV risk screening and management strategies underestimate the actual CV risk in RA. Consequently, the search for additional tools that may help to identify those patients at high CV risk has become a key objective in the last years. In this regard, non-invasive surrogates, such as carotid ultrasonography, have been found to be excellent predictors of future CV events. In addition, several studies have revealed the relevance of a genetic component in the development of CV disease in RA patients. Besides an association with HLA-DRB1* shared epitope alleles other gene polymorphisms located inside and outside the HLA seem to influence the risk of cardiovascular disease in RA. Moreover, serum levels of some metabolic syndrome-related biomarkers, adipokines such as adiponectin and biomarkers of endothelial cell activation and inflammation such as Osteoprotegerin and Asymmetric dimethylarginine have recently been found useful for the prediction of CV disease in these patients. An update of the current knowledge on these potential markers, especially focused on new genetic and serological biomarkers is shown in this review.

  12. Lack of Clinical Relevance of ANA and ASMA Positivity in Patients with Liver Transplantation without a History of Autoimmune Diseases.

    PubMed

    Pellegrini, Lucienne; Parrilli, Gianpaolo; Santonicola, Antonella; Cinquanta, Luigi; Caputo, Cesare; Ciacci, Carolina; Zingone, Fabiana

    2017-01-01

    The relevance of isolated autoimmunity elevation in orthotopic liver transplantation (OLT) patients is unknown. Our aim was to analyse how serum autoantibodies change in time and to evaluate their clinical relevance in OLT patients. Patients were invited to provide samples to evaluate ANA, AMA, ASMA, and LKM at the time of enrolment (T0), after 6 months (T6), and after 12 months (T12). We included 114 patients in the study (76% males, median age 62.5 years), finding isolated elevation of at least one serum antibody in up to 80% of them. We described fluctuating positive autoantibodies in the one year of observation, with only 45.6% of patients positive for ANA and less than 2% positive for ASMA, at all three times. Isolated elevation of tissue antibodies was not related to gender, age, HCC at transplant, early rejection, cause of transplantation, immunotherapy taken, and age at the time of the study. We did not detect a higher prevalence of positive autoimmunity in patients with signs of liver injury. ANA and ASMA evaluation in patients with liver transplantation and no history of autoimmune disease has no clinical relevance, since it varies in time and is not related to any risk factors or liver injury. Routine autoimmunity evaluation should be avoided.

  13. Lack of Clinical Relevance of ANA and ASMA Positivity in Patients with Liver Transplantation without a History of Autoimmune Diseases

    PubMed Central

    Pellegrini, Lucienne; Parrilli, Gianpaolo; Santonicola, Antonella; Cinquanta, Luigi; Caputo, Cesare

    2017-01-01

    The relevance of isolated autoimmunity elevation in orthotopic liver transplantation (OLT) patients is unknown. Our aim was to analyse how serum autoantibodies change in time and to evaluate their clinical relevance in OLT patients. Patients were invited to provide samples to evaluate ANA, AMA, ASMA, and LKM at the time of enrolment (T0), after 6 months (T6), and after 12 months (T12). We included 114 patients in the study (76% males, median age 62.5 years), finding isolated elevation of at least one serum antibody in up to 80% of them. We described fluctuating positive autoantibodies in the one year of observation, with only 45.6% of patients positive for ANA and less than 2% positive for ASMA, at all three times. Isolated elevation of tissue antibodies was not related to gender, age, HCC at transplant, early rejection, cause of transplantation, immunotherapy taken, and age at the time of the study. We did not detect a higher prevalence of positive autoimmunity in patients with signs of liver injury. ANA and ASMA evaluation in patients with liver transplantation and no history of autoimmune disease has no clinical relevance, since it varies in time and is not related to any risk factors or liver injury. Routine autoimmunity evaluation should be avoided. PMID:28337446

  14. 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…

  15. ClinVar: public archive of interpretations of clinically relevant variants.

    PubMed

    Landrum, Melissa J; Lee, Jennifer M; Benson, Mark; Brown, Garth; Chao, Chen; Chitipiralla, Shanmuga; Gu, Baoshan; Hart, Jennifer; Hoffman, Douglas; Hoover, Jeffrey; Jang, Wonhee; Katz, Kenneth; Ovetsky, Michael; Riley, George; Sethi, Amanjeev; Tully, Ray; Villamarin-Salomon, Ricardo; Rubinstein, Wendy; Maglott, Donna R

    2016-01-04

    ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) at the National Center for Biotechnology Information (NCBI) is a freely available archive for interpretations of clinical significance of variants for reported conditions. The database includes germline and somatic variants of any size, type or genomic location. Interpretations are submitted by clinical testing laboratories, research laboratories, locus-specific databases, OMIM®, GeneReviews™, UniProt, expert panels and practice guidelines. In NCBI's Variation submission portal, submitters upload batch submissions or use the Submission Wizard for single submissions. Each submitted interpretation is assigned an accession number prefixed with SCV. ClinVar staff review validation reports with data types such as HGVS (Human Genome Variation Society) expressions; however, clinical significance is reported directly from submitters. Interpretations are aggregated by variant-condition combination and assigned an accession number prefixed with RCV. Clinical significance is calculated for the aggregate record, indicating consensus or conflict in the submitted interpretations. ClinVar uses data standards, such as HGVS nomenclature for variants and MedGen identifiers for conditions. The data are available on the web as variant-specific views; the entire data set can be downloaded via ftp. Programmatic access for ClinVar records is available through NCBI's E-utilities. Future development includes providing a variant-centric XML archive and a web page for details of SCV submissions.

  16. 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'…

  17. Anti-Aß immunotherapy in Alzheimer's disease; relevance of transgenic mouse studies to clinical trials

    PubMed Central

    Wilcock, Donna M.; Colton, Carol A.

    2009-01-01

    Therapeutic approaches to the treatment of Alzheimer's disease are focused primarily on the Aß peptide which aggregates to form amyloid deposits in the brain. The amyloid hypothesis states that amyloid is the precipitating factor that results in the other pathologies of Alzheimer's, namely neurofibrillary tangles and neurodegeneration, as well as the clinical dementia. One such therapy that has attracted significant attention is anti-Aß immunotherapy. First described in 1999, immunotherapy uses anti-Aß antibodies to lower brain amyloid levels. Active immunization, in which Aß is combined with an adjuvant to stimulate an immune response producing antibodies and passive immunization, in which antibodies are directly injected, were shown to lower brain amyloid levels and improve cognition in multiple transgenic mouse models. Mechanisms of action were studied in these mice and revealed a complex set of mechanisms that depended on the type of antibody used. When active immunization advanced to clinical trials a subset of patients developed meningoencephalitis; an event not predicted in mouse studies. However, it was suspected that a T-cell response due to the type of adjuvant used was the cause of the meningoencephalitis and studies in mice indicated alternative methods of vaccination. Passive immunization has also advanced to phase III clinical trials on the basis of successful transgenic mouse studies. Reports from the active immunization clinical trial indicated that, indeed, amyloid levels in brain were reduced. While APP transgenic mouse models are useful in studying amyloid pathology these mice do not generate significant tau pathology or neuron loss. Continued development of new mouse models that do generate all of these pathologies will be critical in more accurately testing therapeutics and predicting the clinical outcome of such therapeutics. PMID:19096156

  18. Comparison and optimization of two MALDI-TOF MS platforms for the identification of medically relevant yeast species.

    PubMed

    Pence, M A; McElvania TeKippe, E; Wallace, M A; Burnham, C-A D

    2014-10-01

    The rapid identification of yeast is essential for the optimization of antifungal therapy. The objective of our study was to evaluate two matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) platforms, the bioMérieux VITEK MS (IVD Knowledgebase v.2.0) and Bruker Biotyper (software version 3.1), for the rapid identification of medically relevant yeast. One hundred and seventeen isolates, representing six genera and 18 species, were analyzed using multiple direct smear methods to optimize identification. Sequence analysis was the gold standard for comparison. Isolates were analyzed with VITEK MS using the direct smear method +/- a 25 % formic acid on-plate extraction. For Biotyper, isolates were analyzed using direct smear without formic acid, and with 25 % and 100 % formic acid on-plate extractions. When all methods were included, VITEK MS correctly identified 113 (96.6 %) isolates after 24 h with one misidentification, and Biotyper correctly identified 77 (65.8 %) isolates using a threshold of ≥2.0 with no misidentifications. Using a revised threshold of ≥1.7, Biotyper correctly identified 103 (88.0 %) isolates, with 3 (2.6 %) misidentifications. For both platforms, the number of identifications was significantly increased using a formic acid overlay (VITEK MS, p < 0.01; Biotyper, p < 0.001), and reducing the Biotyper threshold from ≥2.0 to ≥1.7 significantly increased the rate of identification (p < 0.001). The data in this study demonstrate that the direct smear method with on-plate formic acid extraction can be used for yeast identification on both MS platforms, and more isolates are identified using the VITEK MS system (p < 0.01).

  19. Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry

    PubMed Central

    Bassani-Sternberg, Michal; Bräunlein, Eva; Klar, Richard; Engleitner, Thomas; Sinitcyn, Pavel; Audehm, Stefan; Straub, Melanie; Weber, Julia; Slotta-Huspenina, Julia; Specht, Katja; Martignoni, Marc E.; Werner, Angelika; Hein, Rüdiger; H. Busch, Dirk; Peschel, Christian; Rad, Roland; Cox, Jürgen; Mann, Matthias; Krackhardt, Angela M.

    2016-01-01

    Although mutations may represent attractive targets for immunotherapy, direct identification of mutated peptide ligands isolated from human leucocyte antigens (HLA) on the surface of native tumour tissue has so far not been successful. Using advanced mass spectrometry (MS) analysis, we survey the melanoma-associated immunopeptidome to a depth of 95,500 patient-presented peptides. We thereby discover a large spectrum of attractive target antigen candidates including cancer testis antigens and phosphopeptides. Most importantly, we identify peptide ligands presented on native tumour tissue samples harbouring somatic mutations. Four of eleven mutated ligands prove to be immunogenic by neoantigen-specific T-cell responses. Moreover, tumour-reactive T cells with specificity for selected neoantigens identified by MS are detected in the patient's tumour and peripheral blood. We conclude that direct identification of mutated peptide ligands from primary tumour material by MS is possible and yields true neoepitopes with high relevance for immunotherapeutic strategies in cancer. PMID:27869121

  20. HIV/AIDS Indicators for Clinical Care Quality Assessment: Relevance and Utility Assessed by Health Professionals.

    PubMed

    Catumbela, Emanuel Castro Cassoco; Santos, Cristina; Freitas, Alberto; Costa, Carlos; Sarmento, António; Costa Pereira, Altamiro

    2016-06-01

    Introdução: Após a realização de uma revisão sistemática sobre indicadores de qualidade para avaliar os cuidados clínicos prestados a doentes com infecção VIH/ SIDA, procuramos avaliar a relevância e utilidade clínica prática desses indicadores, do ponto de vista dos médicos especialistas em doenças infecciosas, incluindo VIH/ SIDA. Material e Métodos: Este é um estudo observacional, transversal, em que foram selecionados, por conveniência, os médicos que trabalham em um Departamento de Doenças Infecciosas de um hospital central, para responder a dois questionários, com um conjunto básico de indicadores, selecionando aqueles mais relevantes e úteis para a avaliação dos cuidados clínicos para avaliação do atendimento clínico prestado aos doentes com infeção por VIH/SIDA. A escala do tipo Likert foi utilizada para classificar os indicadores. Resultados: Onze dos treze médicos preencheram os dois questionários. A partir da lista inicial de 53 indicadores de qualidade, 21 foram identificados como os mais relevantes e úteis para avaliar os cuidados clínicos prestados a doentes com infeção por VIH/SIDA. A consistência interna para a relevância clínica, em cada domínio de indicadores foi quanto à relevância clínica – sinais clínicos (p = 0,971), terapêutica (p = 0,900), prognóstico (p = 0,820) e diagnóstico (p = 0,733) e quanto à utilidade prática – diagnóstico (p = 0,934), sinais clínicos (p = 0,964), exames laboratoriais (p = 0,947), terapêutica (p = 0,583) e prognóstico (p = 0,368). Discussão: No processo de avaliação da relevância clínica e utilidade prática dos indicadores de qualidade de cuidados prestados a doentes com infeção por VIH/SIDA, descobrimos que a maioria dos médicos concorda que os indicadores dos domínios de diagnóstico, sinais e sintomas clínicos são os mais importantes para avaliar a qualidade dos cuidados clínicos prestados a doentes com infeção por VIH/SIDA. Conclusão: Este

  1. High throughput estimation of functional cell activities reveals disease mechanisms and predicts relevant clinical outcomes.

    PubMed

    Hidalgo, Marta R; Cubuk, Cankut; Amadoz, Alicia; Salavert, Francisco; Carbonell-Caballero, José; Dopazo, Joaquin

    2017-01-17

    Understanding the aspects of the cell functionality that account for disease or drug action mechanisms is a main challenge for precision medicine. Here we propose a new method that models cell signaling using biological knowledge on signal transduction. The method recodes individual gene expression values (and/or gene mutations) into accurate measurements of changes in the activity of signaling circuits, which ultimately constitute high-throughput estimations of cell functionalities caused by gene activity within the pathway. Moreover, such estimations can be obtained either at cohort-level, in case/control comparisons, or personalized for individual patients. The accuracy of the method is demonstrated in an extensive analysis involving 5640 patients from 12 different cancer types. Circuit activity measurements not only have a high diagnostic value but also can be related to relevant disease outcomes such as survival, and can be used to assess therapeutic interventions.

  2. Spectrometric determination of clinically relevant fatty acids in the blood serum

    NASA Astrophysics Data System (ADS)

    Kalinin, A. V.; Krasheninnikov, V. N.; Sviridov, A. P.; Titov, V. N.

    2016-12-01

    The content of fatty acid (FA) triglycerides in food and biological media is predicting traditionally using gas and liquid chromatographic methods. Named techniques aren't available for clinical labs due to their complexity. So, our objective was to develop the method and apparatus for rapid assay of a few clinically important FA as the saturated palmitic, mono unsaturated oleic and others in serum using near infrared spectrometer. As a result, the applicability of the FT spectrometer in the wavelength range of 0.9 -1.8 μ to analyze these FA in serum without sample preparation was confirmed. Besides, measurement specifications were determined and a correlations of the absorption spectra and contents of total triglycerides and cholesterol, palmitic, oleic, linoleic and arachidonic FA in serum were established

  3. Attentional bias toward infant faces - Review of the adaptive and clinical relevance.

    PubMed

    Lucion, Marta Knijnik; Oliveira, Vanessa; Bizarro, Lisiane; Bischoff, Adrianne Rahde; Silveira, Patricia Pelufo; Kauer-Sant'Anna, Marcia

    2017-04-01

    Human survival depends on care received early in life. Infants need to capture adults' attention to have their basic needs met. Therefore, infant stimuli are prioritized by the attention system in adults, resulting in an attentional bias toward infant faces. We conducted a systematic review of the literature on behavioral measures of attentional bias toward infant faces. PubMed, PsycINFO, and ISI Web of Knowledge databases were used. The review suggests the existence of a measurable attentional bias toward infant faces and a positive correlation between attentional bias toward infant distress and the quality of mother-infant relationship. Depressive symptoms and breastfeeding modulate this behavior in women. Parental status and sex also influence the attentional prioritization of infant faces. Evidence indicates that differences in attentional bias are associated with clinical symptoms and variations in maternal behavior, reinforcing the potential use of attentional bias as a behavioral marker of clinical outcomes.

  4. Ultrasound in sports medicine: relevance of emerging techniques to clinical care of athletes.

    PubMed

    Yim, Eugene Sun; Corrado, Gianmichael

    2012-08-01

    The applications of ultrasound in managing the clinical care of athletes have been expanding over the past decade. This review provides an analysis of the research that has been published regarding the use of ultrasound in athletes and focuses on how these emerging techniques can impact the clinical management of athletes by sports medicine physicians. Electronic database literature searches were performed using the subject terms 'ultrasound' and 'athletes' from the years 2003 to 2012. The following databases were searched: PubMed, Web of Science, Cochrane Library, CINAHL, and SPORTDiscus™. The search produced 617 articles in total, with a predominance of articles focused on cardiac and musculoskeletal ultrasound. 266 of the studies involved application of ultrasound in evaluating the cardiovascular properties of athletes, and 151 studies involved musculoskeletal ultrasound. Other applications of ultrasound included abdominal, vascular, bone density and volume status. New techniques in echocardiography have made significant contributions to the understanding of the physiological changes that occur in the athlete's heart in response to the haemodynamic stress associated with different types of activity. The likely application of these techniques will be in managing athletes with hypertrophic cardiomyopathy, and the techniques are near ready for application into clinical practice. These techniques are highly specialized, however, and will require referral to dedicated laboratories to influence the clinical management of athletes. Investigation of aortic root pathology and pulmonary vascular haemodynamics are also emerging, but will require additional studies with larger numbers and outcomes analysis to validate their clinical utility. Some of these techniques are relatively simple, and thus hold the potential to enter clinical management in a point-of-care fashion. Musculoskeletal ultrasound has demonstrated a number of diagnostic and therapeutic techniques

  5. Relevance of basic research to clinical data: good answers, wrong questions!

    PubMed

    Ben-Ari, Yehezkel; Holmes, Gregory L

    2008-01-01

    Do early seizures beget seizures later in life? Clinical data and experimental observations seem to answer that question differently, with a no and a yes, respectively, which may stem from an inadequate readout of what experimental data actually do tell us and a possible simplification of what clinical data indicate. Using specific experimental examples, it is possible to show that in the developing brain, seizures do produce long-lasting alterations of neuronal excitability, although ongoing seizures are not observed in adults. The findings suggest that the long-lasting changes in developmental programs and network activity that seizures induce do not necessarily lead to epilepsy, unless other events that remain to be identified occur.

  6. Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus.

    PubMed

    Sommese, Linda; Zullo, Alberto; Mancini, Francesco Paolo; Fabbricini, Rossella; Soricelli, Andrea; Napoli, Claudio

    2017-01-06

    Epigenetics is involved in the altered expression of gene networks that underlie insulin resistance and insufficiency. Major genes controlling β-cell differentiation and function, such as PAX4, PDX1, and GLP1 receptor, are epigenetically controlled. Epigenetics can cause insulin resistance through immunomediated pro-inflammatory actions related to several factors, such as NF-kB, osteopontin, and Toll-like receptors. Hereafter, we provide a critical and comprehensive summary on this topic with a particular emphasis on translational and clinical aspects. We discuss the effect of epigenetics on β-cell regeneration for cell replacement therapy, the emerging bioinformatics approaches for analyzing the epigenetic contribution to type 2 diabetes mellitus (T2DM), the epigenetic core of the transgenerational inheritance hypothesis in T2DM, and the epigenetic clinical trials on T2DM. Therefore, prevention or reversion of the epigenetic changes occurring during T2DM development may reduce the individual and societal burden of the disease.

  7. Endpoint measures in the mdx mouse relevant for muscular dystrophy pre-clinical studies

    PubMed Central

    Kobayashi, Yvonne M.; Rader, Erik P.; Crawford, Robert W.; Campbell, Kevin P.

    2011-01-01

    Loss of mobility influences the quality of life for patients with neuromuscular diseases. Common measures of mobility and chronic muscle damage are the six-minute walk test and serum creatine kinase. Despite extensive pre-clinical studies of therapeutic approaches, characterization of these measures is incomplete. To address this, a six-minute ambulation assay, serum creatine kinase, and myoglobinuria were investigated for the mdx mouse, a dystrophinopathy mouse model commonly used in pre-clinical studies. Mdx mice ambulated shorter distances than normal controls, a disparity accentuated after mild exercise. An asymmetric pathophysiology in mdx mice was unmasked with exercise, and peak measurements of serum creatine kinase and myoglobinuria were identified. Our data highlights the necessity to consider asymmetric pathology and timing of biomarkers when testing potential therapies for muscular dystrophy. PMID:22154712

  8. 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.

  9. Occult hepatitis C virus infection and its relevance in clinical practice.

    PubMed

    Pham, Tram Nq; Michalak, Tomasz I

    2011-12-01

    Hepatitis C virus (HCV) can persist in the liver, lymphoid (immune) cells, and serum of individuals long after an apparently complete therapy-induced or a spontaneous resolution of hepatitis C. This essential asymptomatic infection, called secondary occult HCV infection (OCI), usually occurs in anti-HCV antibody reactive individuals with normal liver function tests. This infection has been identified when the nucleic acid amplification assays of enhanced sensitivity were applied for the detection of HCV genome and its replication. In addition to the secondary OCI, a form of low-level HCV-RNA-positive infection of unknown etiology coinciding with moderately elevated serum liver enzymes and progressing in the absence of anti-HCV detectable by standard clinical assays has been reported. Because of its undefined origin, it can be termed cryptogenic OCI. In this review, the general characteristics of OCI, the ways of its detection and associated controversies, and the potential clinical implications of its existence will be concisely outlined.

  10. [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.

  11. 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.

  12. 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.

  13. Biomarkers for Early Detection of Clinically Relevant Prostate Cancer: A Multi-Institutional Validation Trial

    DTIC Science & Technology

    2015-10-01

    diagnosed with early stage prostate cancer a critical need exists for molecular assays that accurately distinguish aggressive prostate cancer from those...their ability to distinguish aggressive cancers from indolent cancers. We have established agreements with three commercial companies to analyze their...in clinical practice to predict aggressive disease. The accuracy of each biomarker for predicting short- and long-term progression will be

  14. Clinically Relevant Variants Identified in Thoracic Aortic Aneurysm Patients by Research Exome Sequencing

    PubMed Central

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

    2016-01-01

    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

  15. Congenital anomalies of the IVC—embryological perspective and clinical relevance

    PubMed Central

    Ghandour, Abed; Partovi, Sasan; Karuppasamy, Karunakaravel

    2016-01-01

    With the increased use of cross-sectional imaging, systemic venous anomalies are more frequently being recognized in asymptomatic patients. Accurate characterization of systemic venous anomalies plays a major role in the appropriate selection of a surgical approach or interventional procedure. In this article, we review common and uncommon inferior vena cava (IVC) anomalies. We describe the embryological basis and clinical implications of these anomalies, particularly from an interventional radiology perspective. We also discuss the complications and treatments of these anomalies. PMID:28123970

  16. Direct oral anticoagulants and antiplatelet agents. Clinical relevance and options for laboratory testing.

    PubMed

    Sibbing, D; Spannagl, M

    2014-01-01

    Oral anticoagulants and platelet receptor blockers are widely used in clinical practice with the aim of reducing the risk of thrombotic complications in patients with cardiovascular diseases. Their regular intake and adequate antithrombotic action is vital and this is way numerous assays have been developed for laboratory testing and monitoring of these agents. Available assays can be stratified into pharmacokinetic and pharmacodynamic assays. Such assays are increasingly used in clinical routine and their daily use is triggered by the advent of the novel direct oral anticoagulants (DOACs) as an alternative for vitamin K antagonist (VKA) treatment, which are dabigatran, rivaroxaban and apixaban, and by the advent of prasugrel or ticagrelor as an alternative for clopidogrel with regard to platelet P2Y12 receptor inhibition. In this review the most important and most commonly used laboratory assays are summarized as well as their clinical implications with the focus on DOACs as an alternative for VKAs and the different P2Y12 receptor blockers for antiplatelet treatment.

  17. [Residual pocket depth after periodontal regenerative procedures. Clinical relevance and interpretation of meta-analyses data].

    PubMed

    Schmidlin, Patrick R; Hauri, Dimitri; Krähenmann, Michael A; Puhan, Milo A; Attin, Thomas

    2009-01-01

    Meta-analyses allow to combine results systematically and to obtain more precise quantitative results on the efficacy of a therapy. For the clinician, the comparison of two therapy modalities is particularly of interest. Several meta-analyses exist in the field of periodontal regenerative procedures. The problem is that the results are difficult to interpret for the clinician. It is only the clinical effect that can indicate the superiority of a certain treatment modality, e.g. remaining periodontal pockets. The aim of the present systematic review was the re-evaluation of studies of existing meta-analyses and to determine the probability of remaining periodontal pockets of more than 3 respectively 5 mm after active therapy. The probability of remaining periodontal pockets over 3 respectively 5 mm was significantly higher after periodontal flap procedure without regenerative procedures, compared to guided tissue regeneration (GTR) or the use of enamel matrix derivatives. Moreover, the probability of remaining pockets over 3 mm was with GTR on average 57% and with the use of enamel maxtrix derivatives 74%. Using the cut-off value of 5 mm this probability was reduced to 8 and 17%, respectively. A new clinical attachment that was less than 50% of the original level was to be expected in 29% (GTR) and 15% using enamel matrix derivatives. This statistical interpretation permits not only the clinician, but also the patient to compare the efficacy of the different treatment modalities using the probability of primary clinical effect outcomes.

  18. A Closer Look at Seborrheic Keratoses: Patient Perspectives, Clinical Relevance, Medical Necessity, and Implications for Management

    PubMed Central

    2017-01-01

    The author sought to discover why seborrheic keratoses that are not symptomatic or clinically suspicious are not considered therapeutically important to most clinicians. The author conducted an office-based, observational study examining how the diagnosis of asymptomatic seborrheic keratoses personally affects patients and what these patients think concerning treatment. Many patients reported being bothered by the diagnosis of seborrheic keratoses, even when told it’s not cancerous, and indicated an interest in its treatment. Lack of insurance coverage for the treatment of non-symptomatic seborrheic keratoses may be the primary reason clinicians do not consider seborrheic keratoses therapeutically important, as clinicians often find the discussion of “self payment” with their patients to be awkward. Furthermore, patients may not understand the implications that “lack of medical necessity” may have on their treatment options. The author describes a clinical approach that may better serve patients and clinicians through the compartmentalization of asymptomatic seborrheic keratoses treatment as a cosmetic procedure within the clinical practice model. PMID:28360965

  19. Clinical Relevance of Coronary Fractional Flow Reserve: Art-of-state

    PubMed Central

    Adiputra, Yohanes; Chen, Shao-Liang

    2015-01-01

    Objective: The objective was to delineate the current knowledge of fractional flow reserve (FFR) in terms of definition, features, clinical applications, and pitfalls of measurement of FFR. Data Sources: We searched database for primary studies published in English. The database of National Library of Medicine (NLM), MEDLINE, and PubMed up to July 2014 was used to conduct a search using the keyword term “FFR”. Study Selection: The articles about the definition, features, clinical application, and pitfalls of measurement of FFR were identified, retrieved, and reviewed. Results: Coronary pressure-derived FFR rapidly assesses the hemodynamic significance of individual coronary artery lesions and can readily be performed in the catheterization laboratory. The use of FFR has been shown to effectively guide coronary revascularization procedures leading to improved patient outcomes. Conclusions: FFR is a valuable tool to determine the functional significance of coronary stenosis. It combines physiological and anatomical information, and can be followed immediately by percutaneous coronary intervention (PCI) if necessary. The technique of FFR measurement can be performed easily, rapidly, and safely in the catheterization laboratory. By systematic use of FFR in dubious stenosis and multi-vessel disease, PCI can be made an even more effective and better treatment than it is currently. The current clinical evidence for FFR should encourage cardiologists to use this tool in the catheterization laboratory. PMID:25963364

  20. Can anaerobes be acid fast? A novel, clinically relevant acid fast anaerobe

    PubMed Central

    Jump, Robin; Canaday, David H.; Wnek, Maria D.; SenGupta, Dhruba J.; McQuiston, John R.; Bell, Melissa

    2016-01-01

    Introduction: Anaerobic acid fast bacilli (AFB) have not been previously reported in clinical microbiology. This is the second case report of a novel anaerobic AFB causing disease in humans. Case presentation: An anaerobic AFB was isolated from an abdominal wall abscess in a 64–year-old Caucasian diabetic male, who underwent distal pancreatectomy and splenectomy for resection of a pancreatic neuroendocrine tumour. The isolated bacteria were gram-variable and acid-fast, consisting of small irregular rods. The 16S rRNA gene sequence analysis showed that the isolate is a novel organism described in the literature only once before. The organism was studied at the CDC (Centers for Disease Control and Prevention) by the same group that worked with the isolates from the previous report; their findings suggest that the strain belongs to the suborder Corynebacterineae. Conclusion: This is the fifth reported case of an anaerobic AFB involved in clinical disease; its microbiological features and 16S RNA sequence are identical to previously reported cases. Clinical disease with this organism seems to be associated with recent history of surgery and abscess formation in deep soft tissues. Acquisition from surgical material is uncertain but seems unlikely. PMID:28348766

  1. Enhancing clinically-relevant shoulder function assessment using only essential movements.

    PubMed

    Pichonnaz, C; Lécureux, E; Bassin, J-P; Duc, C; Farron, A; Aminian, K; Jolles, B M; Gleeson, N

    2015-03-01

    Kinematic functional evaluation with body-worn sensors provides discriminative and responsive scores after shoulder surgery, but the optimal movements' combination has not yet been scientifically investigated. The aim of this study was the development of a simplified shoulder function kinematic score including only essential movements. The P Score, a seven-movement kinematic score developed on 31 healthy participants and 35 patients before surgery and at 3, 6 and 12 months after shoulder surgery, served as a reference. Principal component analysis and multiple regression were used to create simplified scoring models. The candidate models were compared to the reference score. ROC curve for shoulder pathology detection and correlations with clinical questionnaires were calculated. The B-B Score (hand to the Back and hand upwards as to change a Bulb) showed no difference to the P Score in time*score interaction (P > .05) and its relation with the reference score was highly linear (R(2) > .97). Absolute value of correlations with clinical questionnaires ranged from 0.51 to 0.77. Sensitivity was 97% and specificity 94%. The B-B and reference scores are equivalent for the measurement of group responses. The validated simplified scoring model presents practical advantages that facilitate the objective evaluation of shoulder function in clinical practice.

  2. Multicenter Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry Study for Identification of Clinically Relevant Nocardia spp.

    PubMed Central

    Blosser, Sara J.; Drake, Steven K.; Andrasko, Jennifer L.; Henderson, Christina M.; Kamboj, Kamal; Antonara, Stella; Mijares, Lilia; Conville, Patricia; Frank, Karen M.; Harrington, Susan M.; Balada-Llasat, Joan-Miquel

    2016-01-01

    This multicenter study analyzed Nocardia spp., including extraction, spectral acquisition, Bruker matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) identification, and score interpretation, using three Nocardia libraries, the Bruker, National Institutes of Health (NIH), and The Ohio State University (OSU) libraries, and compared the results obtained by each center. A standardized study protocol, 150 Nocardia isolates, and NIH and OSU Nocardia MALDI-TOF MS libraries were distributed to three centers. Following standardized culture, extraction, and MALDI-TOF MS analysis, isolates were identified using score cutoffs of ≥2.0 for species/species complex-level identification and ≥1.8 for genus-level identification. Isolates yielding a score of <2.0 underwent a single repeat extraction and analysis. The overall score range for all centers was 1.3 to 2.7 (average, 2.2 ± 0.3), with common species generally producing higher average scores than less common ones. Score categorization and isolate identification demonstrated 86% agreement between centers; 118 of 150 isolates were correctly identified to the species/species complex level by all centers. Nine strains (6.0%) were not identified by any center, and six (4.0%) of these were uncommon species with limited library representation. A categorical score discrepancy among centers occurred for 21 isolates (14.0%). There was an overall benefit of 21.2% from repeat extraction of low-scoring isolates and a center-dependent benefit for duplicate spotting (range, 2 to 8.7%). Finally, supplementation of the Bruker Nocardia MALDI-TOF MS library with both the OSU and NIH libraries increased the genus-level and species-level identification by 18.2% and 36.9%, respectively. Overall, this study demonstrates the ability of diverse clinical microbiology laboratories to utilize MALDI-TOF MS for the rapid identification of clinically relevant Nocardia spp. and to implement MALDI-TOF MS

  3. Molecular Tools for Cryptic "Candida" Species Identification with Applications in a Clinical Laboratory

    ERIC Educational Resources Information Center

    Gamarra, Soledad; Dudiuk, Catiana; Mancilla, Estefania; Vera Garate, Maria Veronica; Guerrero, Sergio; Garcia-Effron, Guillermo

    2013-01-01

    "Candida" spp. includes more than 160 species but only 20 species pose clinical problems. "C. albicans" and "C. parapsilosis" account for more than 75% of all the fungemias worldwide. In 1995 and 2005, one "C. albicans" and two "C. parapsilosis"-related species were described, respectively. Using…

  4. The prevalence and clinical relevance of hyperkalaemia in calves with neonatal diarrhoea.

    PubMed

    Trefz, Florian M; Lorch, Annette; Feist, Melanie; Sauter-Louis, Carola; Lorenz, Ingrid

    2013-03-01

    One hundred and twenty-four calves with neonatal diarrhoea were investigated in order to assess the prevalence of hyperkalaemia and the associated clinical signs. Hyperkalaemia (potassium concentration >5.8mmol/L) was recognized in 42 (34%) calves and was more closely associated with dehydration than with decreases in base excess or venous blood pH. In 75 calves with normal blood concentrations of D-lactate (i.e. ⩽3.96mmol/L), K concentrations were moderately correlated with base excess values (r=-0.48, P<0.001). In contrast, no significant correlation was observed in 49 calves with elevated D-lactate. Only three hyperkalaemic calves had bradycardia and a weak positive correlation was found between heart rate and K concentrations (r=0.22, P=0.014). Ten of the 124 calves had cardiac arrhythmia and of these seven had hyperkalaemia indicating that cardiac arrhythmia had a low sensitivity (17%) but a high specificity (96%) as a predictor of hyperkalaemia. In a subset of 34 calves with base excess values ⩽-5mmol/L and D-lactate concentrations <5mmol/L (of which 22 had hyperkalaemia), changes in posture/ability to stand could be mainly explained by elevations of K concentrations (P<0.001) and to a lesser extent by increases in L-lactate concentrations (P=0.024). Skeletal muscle weakness due to hyperkalaemia alongside hypovolaemia may produce a clinical picture that is similar to that in calves with marked D-lactic acidosis. However, since reductions in the strength of the palpebral reflex are closely correlated with D-lactate concentrations, a prompt palpebral reflex can assist the clinical prediction of hyperkalaemia in calves presenting with a distinct impairment in their ability to stand (specificity 99%, sensitivity 29%).

  5. Technetium-99m hexamethyl propylene amine oxime granulocyte scintigraphy in Crohn's disease: diagnostic and clinical relevance.

    PubMed Central

    Sciarretta, G; Furno, A; Mazzoni, M; Basile, C; Malaguti, P

    1993-01-01

    Scintigraphy with autologous granulocytes labelled by technetium-99m hexamethyl, propylene amine oxime (99mTc-HMPAO) was performed in 103 Crohn's disease patients and 52 healthy controls. In 31 patients endoscopic and histologic activity was compared with scan activity index. In the 98 patients with a positive scan, the extent of Crohn's disease, assessed by scintigraphy, was compared with that evaluated by small bowel x ray or colonoscopy with biopsies. In 48 patients, Crohn's disease activity index, activity index, simple index, erythrocyte sedimentation rate, C-reactive protein were correlated with the scan results. In 16 patients the five parameters and scan were repeated after treatment with methyl-prednisolone (10 cases), enteral nutrition (3), and 5-acetylsalicylic acid (3). The results showed that 99mTc-HMPAO granulocyte scan had a 95% sensitivity and 100% specificity to detect active inflammation; it correctly showed an abscess or a fistula in all the 24 cases found. The correlation between histological inflammatory activity and scan activity index was highly significant (r = 0.85; p < 0.01), less significant (r = 0.65; p < 0.01) between endoscopy and scan activity index. The evaluation for the extent of Crohn's disease by scan was completely correct in the small bowel (100%) and 93% correct in the large bowel. No correlation was seen between the three clinical activity parameters and scanning; in more than 80% of the cases in remission on the basis of a clinical or laboratory index, scintigraphy remained positive. Medical treatment was effective on the clinical indices but not on the active inflammation in the ileum, whereas it led to a negative scan in 5/11 cases in the large intestine. Scintigraphy with 99mTc-HMPAO granulocyte plays an important part in Crohn's disease for the diagnosis of complications, for activity and assessment of the extent, and for the treatment results evaluation. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8244102

  6. 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.

  7. 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

  8. Systematic protein-protein interaction mapping for clinically relevant human GPCRs.

    PubMed

    Sokolina, Kate; Kittanakom, Saranya; Snider, Jamie; Kotlyar, Max; Maurice, Pascal; Gandía, Jorge; Benleulmi-Chaachoua, Abla; Tadagaki, Kenjiro; Oishi, Atsuro; Wong, Victoria; Malty, Ramy H; Deineko, Viktor; Aoki, Hiroyuki; Amin, Shahreen; Yao, Zhong; Morató, Xavier; Otasek, David; Kobayashi, Hiroyuki; Menendez, Javier; Auerbach, Daniel; Angers, Stephane; Pržulj, Natasa; Bouvier, Michel; Babu, Mohan; Ciruela, Francisco; Jockers, Ralf; Jurisica, Igor; Stagljar, Igor

    2017-03-15

    G-protein-coupled receptors (GPCRs) are the largest family of integral membrane receptors with key roles in regulating signaling pathways targeted by therapeutics, but are difficult to study using existing proteomics technologies due to their complex biochemical features. To obtain a global view of GPCR-mediated signaling and to identify novel components of their pathways, we used a modified membrane yeast two-hybrid (MYTH) approach and identified interacting partners for 48 selected full-length human ligand-unoccupied GPCRs in their native membrane environment. The resulting GPCR interactome connects 686 proteins by 987 unique interactions, including 299 membrane proteins involved in a diverse range of cellular functions. To demonstrate the biological relevance of the GPCR interactome, we validated novel interactions of the GPR37, serotonin 5-HT4d, and adenosine ADORA2A receptors. Our data represent the first large-scale interactome mapping for human GPCRs and provide a valuable resource for the analysis of signaling pathways involving this druggable family of integral membrane proteins.

  9. 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

  10. 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.

  11. Occult Hepatitis C Virus Infection and Its Relevance in Clinical Practice

    PubMed Central

    Pham, Tram NQ; Michalak, Tomasz I

    2012-01-01

    Hepatitis C virus (HCV) can persist in the liver, lymphoid (immune) cells, and serum of individuals long after an apparently complete therapy-induced or a spontaneous resolution of hepatitis C. This essential asymptomatic infection, called secondary occult HCV infection (OCI), usually occurs in anti-HCV antibody reactive individuals with normal liver function tests. This infection has been identified when the nucleic acid amplification assays of enhanced sensitivity were applied for the detection of HCV genome and its replication. In addition to the secondary OCI, a form of low-level HCV-RNA-positive infection of unknown etiology coinciding with moderately elevated serum liver enzymes and progressing in the absence of anti-HCV detectable by standard clinical assays has been reported. Because of its undefined origin, it can be termed cryptogenic OCI. In this review, the general characteristics of OCI, the ways of its detection and associated controversies, and the potential clinical implications of its existence will be concisely outlined. PMID:25755384

  12. 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

    2016-01-04

    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.

  13. 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).

  14. A Comparative Analysis of Drug-Induced Hepatotoxicity in Clinically Relevant Situations

    PubMed Central

    Thiel, Christoph; Cordes, Henrik; Fabbri, Lorenzo; Aschmann, Hélène Eloise; Baier, Vanessa; Atkinson, Francis; Blank, Lars Mathias; Kuepfer, Lars

    2017-01-01

    Drug-induced toxicity is a significant problem in clinical care. A key problem here is a general understanding of the molecular mechanisms accompanying the transition from desired drug effects to adverse events following administration of either therapeutic or toxic doses, in particular within a patient context. Here, a comparative toxicity analysis was performed for fifteen hepatotoxic drugs by evaluating toxic changes reflecting the transition from therapeutic drug responses to toxic reactions at the cellular level. By use of physiologically-based pharmacokinetic modeling, in vitro toxicity data were first contextualized to quantitatively describe time-resolved drug responses within a patient context. Comparatively studying toxic changes across the considered hepatotoxicants allowed the identification of subsets of drugs sharing similar perturbations on key cellular processes, functional classes of genes, and individual genes. The identified subsets of drugs were next analyzed with regard to drug-related characteristics and their physicochemical properties. Toxic changes were finally evaluated to predict both molecular biomarkers and potential drug-drug interactions. The results may facilitate the early diagnosis of adverse drug events in clinical application. PMID:28151932

  15. Evaluation of Immunogenicity of Nivolumab Monotherapy and Its Clinical Relevance in Patients With Metastatic Solid Tumors.

    PubMed

    Agrawal, Shruti; Statkevich, Paul; Bajaj, Gaurav; Feng, Yan; Saeger, Sally; Desai, Dharmesh D; Park, Jong-Soon; Waxman, Ian M; Roy, Amit; Gupta, Manish

    2017-03-01

    Nivolumab is a fully human IgG4 monoclonal antibody targeting the programmed death-1 (PD-1) receptor that blocks interactions between PD-1 and its ligands on tumor cells to prevent T-cell exhaustion in patients with cancer. It has demonstrated efficacy in multiple tumor types, including melanoma, non-small-cell lung cancer, and renal cell carcinoma. This analysis assessed the immunogenicity of nivolumab and its impact on pharmacokinetics, safety, and efficacy in patients with solid tumors enrolled in 6 clinical studies. The incidence and prevalence of antidrug antibodies (ADAs) were determined by validated electrochemiluminescence assays in samples collected during nivolumab treatment and up to 100 days after the last dose. Confirmed positive samples from the 6 studies were also tested for presence of neutralizing antibodies (NAbs). Among 1086 nivolumab-treated patients, 138 patients (12.7%) were ADA positive (relative to baseline), only 3 (0.3%) of whom were persistently positive for ADA, and 9 (0.8%) were NAb positive at 1 time point. The presence of ADAs was not associated with hypersensitivity, infusion reactions, or loss of efficacy and had minimal impact on nivolumab clearance. Additionally, the presence of NAbs was not associated with loss of efficacy. In conclusion, immunogenicity of nivolumab is not clinically meaningful.

  16. 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.

  17. 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.

  18. A Comparative Analysis of Drug-Induced Hepatotoxicity in Clinically Relevant Situations.

    PubMed

    Thiel, Christoph; Cordes, Henrik; Fabbri, Lorenzo; Aschmann, Hélène Eloise; Baier, Vanessa; Smit, Ines; Atkinson, Francis; Blank, Lars Mathias; Kuepfer, Lars

    2017-02-01

    Drug-induced toxicity is a significant problem in clinical care. A key problem here is a general understanding of the molecular mechanisms accompanying the transition from desired drug effects to adverse events following administration of either therapeutic or toxic doses, in particular within a patient context. Here, a comparative toxicity analysis was performed for fifteen hepatotoxic drugs by evaluating toxic changes reflecting the transition from therapeutic drug responses to toxic reactions at the cellular level. By use of physiologically-based pharmacokinetic modeling, in vitro toxicity data were first contextualized to quantitatively describe time-resolved drug responses within a patient context. Comparatively studying toxic changes across the considered hepatotoxicants allowed the identification of subsets of drugs sharing similar perturbations on key cellular processes, functional classes of genes, and individual genes. The identified subsets of drugs were next analyzed with regard to drug-related characteristics and their physicochemical properties. Toxic changes were finally evaluated to predict both molecular biomarkers and potential drug-drug interactions. The results may facilitate the early diagnosis of adverse drug events in clinical application.

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

    PubMed Central

    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

  20. Tissue Engineered Bone Grafts: Biological Requirements, Tissue Culture and Clinical Relevance

    PubMed Central

    Fröhlich, Mirjam; Grayson, Warren L.; Wan, Leo Q.; Marolt, Darja; Drobnic, Matej; Vunjak-Novakovic, Gordana

    2009-01-01

    The tremendous need for bone tissue in numerous clinical situations and the limited availability of suitable bone grafts are driving the development of tissue engineering approaches to bone repair. In order to engineer viable bone grafts, one needs to understand the mechanisms of native bone development and fracture healing, as these processes should ideally guide the selection of optimal conditions for tissue culture and implantation. Engineered bone grafts have been shown to have capacity for osteogenesis, osteoconduction, osteoinduction and osteointegration - functional connection between the host bone and the graft. Cells from various anatomical sources in conjunction with scaffolds and osteogenic factors have been shown to form bone tissue in vitro. The use of bioreactor systems to culture cells on scaffolds before implantation further improved the quality of the resulting bone grafts. Animal studies confirmed the capability of engineered grafts to form bone and integrate with the host tissues. However, the vascularization of bone remains one of the hurdles that need to be overcome if clinically sized, fully viable bone grafts are to be engineered and implanted. We discuss here the biological guidelines for tissue engineering of bone, the bioreactor cultivation of human mesenchymal stem cells on three-dimensional scaffolds, and the need for vascularization and functional integration of bone grafts following implantation. PMID:19075755

  1. 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.

  2. Morphogenetic fields within the human dentition: A new, clinically relevant synthesis of an old concept☆

    PubMed Central

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

    2009-01-01

    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

  3. 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

  4. 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.

  5. 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

  6. European edition of the NCCN clinical practice guidelines: relevance of the translation and adaptation into Spanish.

    PubMed

    Guillem, V; Camps, C; Carrato, A; Díaz-Rubio, E; Gascón, P

    2017-03-01

    The NCCN-evidence-based oncology guidelines are consensus-based management documents, to ensure that all patients receive the most appropriate diagnosis, treatment and support services to achieve the best results. However, the use of these guidelines for decision-making by physicians in Spain is sometimes controversial, as treatments or diagnostic procedures are recommended which might not be authorised in our country, or other management options may exist. In March 2015, the ECO Foundation reached an agreement to translate and adapt the NCCN's clinical practice guidelines in oncology for the Spanish sector. Consequently, ECO is the first European organization to reach an agreement of this type with the NCCN. This agreement will allow all agents involved in managing the cancer patients to have available guidelines that are adapted to the specific needs of Spain.

  7. Detection of clinically relevant genotypes of vancomycin-resistant enterococci in nosocomial surveillance specimens by PCR.

    PubMed

    Jayaratne, P; Rutherford, C

    1999-06-01

    This study evaluated a PCR method for the rapid detection of clinically significant genotypes of vancomycin-resistant enterococci (VRE) in nosocomial surveillance specimens. Detection of the vanA and vanB genes by multiplex PCR using 657 specimens that showed presumptive growth of VRE on bile esculin azide agar containing 6 mg of vancomycin/liter was compared to the conventional method. The diagnostic values for the PCR compared to the phenotypic method were as follows: 99.8% specificity, 95.4% sensitivity, 98.8% positive predictive value, and 99.3% negative predictive value. The average cost per test for PCR is $8.26, compared to $9.45 for the phenotypic method. The average turnaround time for detecting a VRE is 48 h for PCR, compared to 96 h for the conventional method.

  8. Biomarkers of ALI/ARDS: pathogenesis, discovery, and relevance to clinical trials.

    PubMed

    Janz, David R; Ware, Lorraine B

    2013-08-01

    Despite the high incidence and poor prognosis of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), it remains challenging to identify patients who are at highest risk of developing these syndromes, differentiate these syndromes from other causes of acute respiratory failure, and accurately prognosticate once the diagnosis is made. The identification and validation of biological markers of ALI has the potential to ameliorate these challenges by facilitating studies of therapies aimed at prevention, identifying patients more accurately that have ALI so they can benefit from evidence-based therapies and enrollment in clinical trials, and determining which patients are unlikely to have a positive outcome to guide therapeutic choices and trials of experimental rescue therapies. This article reviews the current state of biomarker research in ALI/ARDS. New methodologies for identification of novel biomarkers of ALI, including metabolomics, proteomics, gene expression, and genetic studies are also discussed.

  9. The statistical crisis in science: how is it relevant to clinical neuropsychology?

    PubMed

    Gelman, Andrew; Geurts, Hilde M

    2017-01-11

    There is currently increased attention to the statistical (and replication) crisis in science. Biomedicine and social psychology have been at the heart of this crisis, but similar problems are evident in a wide range of fields. We discuss three examples of replication challenges from the field of social psychology and some proposed solutions, and then consider the applicability of these ideas to clinical neuropsychology. In addition to procedural developments such as preregistration and open data and criticism, we recommend that data be collected and analyzed with more recognition that each new study is a part of a learning process. The goal of improving neuropsychological assessment, care, and cure is too important to not take good scientific practice seriously.

  10. Gain-of-Function Research and the Relevance to Clinical Practice.

    PubMed

    Kilianski, Andy; Nuzzo, Jennifer B; Modjarrad, Kayvon

    2016-05-01

    The ongoing moratorium on gain-of-function (GOF) research with highly pathogenic avian influenza virus, severe acute respiratory syndrome coronavirus, and Middle East respiratory syndrome coronavirus has drawn attention to the current debate on these research practices and the potential benefits and risks they present. While much of the discussion has been steered by members of the microbiology and policy communities, additional input from medical practitioners will be highly valuable toward developing a broadly inclusive policy that considers the relative value and harm of GOF research. This review attempts to serve as a primer on the topic for the clinical community by providing a historical context for GOF research, summarizing concerns about its risks, and surveying the medical products that it has yielded.

  11. 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

  12. 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

  13. 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

  14. 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

  15. Enteropathogen infections in canine puppies: (Co-)occurrence, clinical relevance and risk factors.

    PubMed

    Duijvestijn, Mirjam; Mughini-Gras, Lapo; Schuurman, Nancy; Schijf, Wim; Wagenaar, Jaap A; Egberink, Herman

    2016-11-15

    Laboratory confirmation of the causative agent(s) of diarrhoea in puppies may allow for appropriate treatment. The presence of potential pathogens however, does not prove a causal relationship with diarrhoea. The aim of this study was to identify specific enteropathogens in ≤12 month old puppies with and without acute diarrhoea and to assess their associations with clinical signs, putative risk factors and pathogen co-occurrence. Faecal samples from puppies with (n=113) and without (n=56) acute diarrhoea were collected and screened for Canine Parvovirus (CPV), Canine Coronavirus (CCoV), Salmonella spp., Campylobacter spp., Clostridium perfringens, Clostridium difficile, β-hemolytic Eschericha coli (hEC), Giardia spp., Toxocara spp., Cystoisospora spp., and Cyniclomyces guttulatus. One or more pathogens were detected in 86.5% of diarrhoeic puppies and in 77.8% of asymptomatic puppies. Significant positive associations were found between CPV and CCoV, CPV and Cystoisospora spp., Toxocara spp. and hEC, Giardia spp. and C. guttulatus. Only CPV and CCoV were significantly associated with diarrhoea, hEC with a subset of puppies that had diarrhoea and severe clinical signs. CPV was more prevalent in puppies under 3 months of age. Puppies from high-volume dog breeders were significantly at increased risk for CPV (OR 4.20), CCoV (OR 4.50) and Cystoisospora spp. (OR 3.60). CCoV occurred significantly more often in winter (OR 3.35), and CPV in winter (OR 3.78) and spring (OR 4.72) as compared to summer. We conclude that routine screening for CPV, CCoV and hEC is recommended in puppies with acute diarrhoea, especially if they are under 3 months of age and originate from high-volume dog breeders. Routine screening for other pathogens may lead to less conclusive results.

  16. Clinical relevance of polymorphonuclear (PMN-) elastase determination in semen and serum during infertility investigation.

    PubMed

    Eggert-Kruse, W; Zimmermann, K; Geissler, W; Ehrmann, A; Boit, R; Strowitzki, T

    2009-08-01

    The polymorphonuclear (PMN) elastase is secreted by activated granulocytes and is widely used as a marker of male accessory gland infection. However, the clinical value of routine determination of seminal plasma (SP) PMN elastase in asymptomatic patients during infertility investigation has not clearly been established and not much is known about the significance of PMN-elastase levels in serum as a potential biochemical determinant associated with infection/inflammation of the male genital tract. This prospective study included a total of 221 asymptomatic males from unselected subfertile couples, to evaluate the relationship of (i) serum and (ii) same-day SP PMN elastase concentrations with established semen quality parameters, including sperm functional capacity, local antisperm antibodies (ASA), seminal leucocytes, and the outcome of semen cultures including typical sexually transmitted disease pathogens, and a potential association with patients' medical history and results of clinical andrological examination. Furthermore, couples were followed up for subsequent fertility (controlled for female infertility factors). The concentrations of PMN elastase in serum and in SP were not significantly related to semen quality [with regard to microscopic (e.g. count, motility, morphology) as well as biochemical parameters, and also to local ASA of the IgG- or IgA-class]. There was no strong relationship with sperm functional capacity. No significant relationship with the outcome of the microbial screening was found. PMN-elastase levels in serum and SP were not significantly correlated and there was no association with subsequent fertility. Therefore, the value of routine determination of PMN elastase in semen and/or serum samples, particularly when used as a single parameter to screen for subclinical infection/inflammation in males under infertility investigation is limited.

  17. Clinically relevant enhancement of human sperm motility using compounds with reported phosphodiesterase inhibitor activity

    PubMed Central

    Tardif, Steve; Madamidola, Oladipo A.; Brown, Sean G.; Frame, Lorna; Lefièvre, Linda; Wyatt, Paul G.; Barratt, Christopher L.R.; Martins Da Silva, Sarah J.

    2014-01-01

    order to reduce variability and increase the number of cells available for simultaneous examination of multiple compounds. During Phase 2 testing, semen samples from 23 patients attending for either routine diagnostic andrology assessment or IVF/ICSI were prepared and exposed to selected compounds. Additionally, 48 aliquots of prepared samples, surplus to clinical use, were examined from IVF (n = 32) and ICSI (n = 16) patients to further determine the effects of selected compounds under clinical conditions of treatment. Effects of compounds on sperm motility were assessed by computer-assisted sperm analysis. A modified Kremer test using methyl cellulose was used to assess sperm functional ability to penetrate into viscous media. Sperm acrosome integrity and induction of apoptosis were assessed using the acrosomal content marker PSA-FITC and annexin V kit, respectively. MAIN RESULTS AND THE ROLE OF CHANCE In Phase 1, six compounds were found to have a strong effect on poor motility samples with a magnitude of response of ≥60% increase in percentage total motility. Under capacitating and non-capacitating conditions, these compounds significantly (P ≤ 0.05) increased the percentage of total and progressive motility. Furthermore, these compounds enhanced penetration into a cervical mucus substitute (P ≤ 0.05). Finally, the AR was not significantly induced and these compounds did not significantly increase the externalization of phosphatidylserine (P = 0.6, respectively). In general, the six compounds maintained the stimulation of motility over long periods of time (180 min) and their effects were still observed after their removal. In examinations of clinical samples, there was a general observation of a more significant stimulation of sperm motility in samples with lower baseline motility. In ICSI samples, compounds #26, #37 and #38 were the most effective at significantly increasing total motility (88, 81 and 79% of samples, respectively) and progressive motility

  18. Relevance of biofilm formation and virulence of different species of coagulase-negative staphylococci to public health.

    PubMed

    Osman, K M; Abd El-Razik, K A; Marie, H S H; Arafa, A

    2015-10-01

    The ability of biofilm formation seems to play an essential role in the virulence of coagulase-negative staphylococci (CNS). The present work aimed to: (a) evaluate the biofilm-forming ability of different strains of CNS field isolates; (b) evaluate their virulence potential through the assessment of the Madin-Darby canine kidney (MDCK) cytotoxicity assay; (c) determine the frequency of biofilm-associated genes among these CNS isolates. Biofilm markers associated with biofilm formation and MDCK cells cytotoxicity were compared to find possible associations with pathogenicity. CNS isolates (n = 94) belonging to 11 different species were tested for slime production using the tube test (TA) and the Congo red agar plate test (CRA), while the presence of icaA and icaD genes were evaluated by d-PCR. Two points were addressed for the first time: (1) the specific relationship between slime phenotype and icaD gene expression; (2) the specific relationship between slime phenotype, icaAD genes, and MDCK cytotoxicity. The proportion of biofilm-positive/icaD-positive versus biofilm-positive/icaD-negative strains was 9:0 and 9:0 (81.8%) by the TA and CRA, which clearly indicates that icaD was a more reliable gene to be accounted for in the biofilm formation. MDCK recorded a higher proportion than that recorded by the CRA and TA results (MDCK-positive/icaD-positive versus MDCK-positive/icaD-negative 10:0, 90.9%). Evaluation of the ica operon, CRA plate test, TA, and MDCK can contribute to the high clinical impact in the management of antibiotic therapy, in infections associated with devices in veterinary medicine, the dairy industry, and food processing.

  19. Myeloid-derived suppressor cells: general characteristics and relevance to clinical management of pancreatic cancer.

    PubMed

    Goedegebuure, P; Mitchem, J B; Porembka, M R; Tan, M C B; Belt, B A; Wang-Gillam, A; Gillanders, W E; Hawkins, W G; Linehan, D C

    2011-07-01

    Recent studies describe a heterogeneous population of cells of the myeloid lineage, termed myeloid derived suppressor cells (MDSC), which are observed with increased prevalence in the peripheral blood and tumor microenvironment of cancer patients, including pancreatic cancer. Accumulation of MDSC in the peripheral circulation has been related to extent of disease, and correlates with stage. MDSC have primarily been implicated in promoting tumor growth by suppressing antitumor immunity. There is also compelling evidence MDSC are also involved in angiogenesis and metastatic spread. Two main subsets of MDSC have been identified in cancer patients: a monocytic subset, characterized by expression of CD14, and a granulocytic subset characterized by expression of CD15. Both subsets of MDSC actively suppress host immunity through a variety of mechanisms including production of reactive oxygen species and arginase. Just as in humans, accumulation of monocytic and granulocytic MDSC has been noted in the bone marrow, spleen, peripheral circulation, and tumors of tumor bearing mice. Successful targeting of MDSC in mice is associated with improved immune responses, delayed tumor growth, improved survival, and increased efficacy of vaccine therapy. By further elucidating mechanisms of MDSC recruitment and maintenance in the tumor environment, strategies could be developed to reverse immune tolerance to tumor. We discuss here what is currently known about MDSC as well as some potential strategies targeting MDSC in the context of our work on pancreatic cancer and recent literature. Due to the number of new reports on MDSC, the most pertinent ones have been selected.

  20. 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.

  1. 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

  2. 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.

  3. The clinical relevance of complex regional pain syndrome type I: The Emperor's New Clothes.

    PubMed

    Borchers, Andrea T; Gershwin, M Eric

    2017-01-01

    The management of patients with chronic pain is a nearly daily challenge to rheumatologists, neurologists, orthopedic surgeons, pain specialists and indeed a issue in nearly every clinical practice. Among the myriad of causes of pain are often included a unique syndrome, generally referred to as complex regional pain syndrome type I (CRPS). Unfortunately CRPS I has become a catch all phase and there are serious questions on whether it exists at all; this has led to an extraordinary number of poorly defined diagnostic criteria. It has also led to an etiologic quagmire that includes features as diverse as autoimmunity to simple trauma. These, in turn, have led to overdiagnosis and often overzealous use of pain medications, including narcotics. In a previous paper, we raised the issue of whether CRPS type I reflected a valid diagnosis. Indeed, the diagnostic criteria for CRPS I, and therefore the diagnosis itself, is unreliable for a number of reasons: 1) the underlying pathophysiology of the signs and symptoms of CPRS I are not biologically plausible; 2) there are no consistent laboratory or imaging testing available; 3) the signs and symptoms fluctuate over time without a medical explanation; 4) the definitions of most studies are derived from statistical analysis with little consideration to required sample size, i.e. power calculations; 5) interobserver reliability in the assessment of the signs and symptoms are often only fair to moderate, and agreement on the diagnosis of "CRPS I" is poor. Even physicians who still believe in the concept of "CRPS I" admit that it is vastly overdiagnosed and has become a diagnosis of last resort, often without a complete differential diagnosis and an alternative explanation. Finally, one of the most convincing arguments that there is no clinical entity as "CRPS I" comes from the enormous heterogeneity in sign and symptom profiles and the heterogeneity of pathophysiological mechanisms postulated. This observation is underscored by

  4. 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

  5. Pathophysiology and clinical relevance of pulmonary remodelling in pulmonary hypertension due to left heart diseases.

    PubMed

    Dupuis, Jocelyn; Guazzi, Marco

    2015-04-01

    Pulmonary hypertension (PH) in left heart disease, classified as group II, is the most common form of PH that occurs in approximately 60% of cases of reduced and preserved left ventricular ejection fraction. Although relatively much is known about hemodynamic stages (passive or reactive) and their consequences on the right ventricle (RV) there is no consensus on the best hemodynamic definition of group II PH. In addition, the main pathways that lead to lung capillary injury and impaired biology of small artery remodelling processes are largely unknown. Typical lung manifestations of an increased pulmonary pressure and progressive RV-pulmonary circulation uncoupling are an abnormal alveolar capillary gas diffusion, impaired lung mechanics (restriction), and exercise ventilation inefficiency. Of several classes of pulmonary vasodilators currently clinically available, oral phosphodiesterase 5 inhibition, because of its strong selectivity for targeting the cyclic guanosine monophosphate pathway in the pulmonary circulation, is increasingly emerging as an attractive opportunity to reach hemodynamic benefits, reverse capillary injury, and RV remodelling, and improve functional capacity. Guanylate cyclase stimulators offer an additional intriguing opportunity but the lack of selectivity and systemic effects might preclude some of the anticipated benefits on the pulmonary circulation. Future trials will determine whether new routes of pharmacologic strategy aimed at targeting lung structural and vascular remodelling might affect morbidity and mortality in left heart disease populations. We believe that this therapeutic goal rather than a pure hemodynamic effect might ultimately emerge as an important challenge for the clinician.

  6. Progressive muscle proteome changes in a clinically relevant pig model of Duchenne muscular dystrophy

    PubMed Central

    Fröhlich, Thomas; Kemter, Elisabeth; Flenkenthaler, Florian; Klymiuk, Nikolai; Otte, Kathrin A.; Blutke, Andreas; Krause, Sabine; Walter, Maggie C.; Wanke, Rüdiger; Wolf, Eckhard; Arnold, Georg J.

    2016-01-01

    Duchenne muscular dystrophy (DMD) is caused by genetic deficiency of dystrophin and characterized by massive structural and functional changes of skeletal muscle tissue, leading to terminal muscle failure. We recently generated a novel genetically engineered pig model reflecting pathological hallmarks of human DMD better than the widely used mdx mouse. To get insight into the hierarchy of molecular derangements during DMD progression, we performed a proteome analysis of biceps femoris muscle samples from 2-day-old and 3-month-old DMD and wild-type (WT) pigs. The extent of proteome changes in DMD vs. WT muscle increased markedly with age, reflecting progression of the pathological changes. In 3-month-old DMD muscle, proteins related to muscle repair such as vimentin, nestin, desmin and tenascin C were found to be increased, whereas a large number of respiratory chain proteins were decreased in abundance in DMD muscle, indicating serious disturbances in aerobic energy production and a reduction of functional muscle tissue. The combination of proteome data for fiber type specific myosin heavy chain proteins and immunohistochemistry showed preferential degeneration of fast-twitch fiber types in DMD muscle. The stage-specific proteome changes detected in this large animal model of clinically severe muscular dystrophy provide novel molecular readouts for future treatment trials. PMID:27634466

  7. [Digital breast tomosynthesis : technical principles, current clinical relevance and future perspectives].

    PubMed

    Hellerhoff, K

    2010-11-01

    In recent years digital full field mammography has increasingly replaced conventional film mammography. High quality imaging is guaranteed by high quantum efficiency and very good contrast resolution with optimized dosing even for women with dense glandular tissue. However, digital mammography remains a projection procedure by which overlapping tissue limits the detectability of subtle alterations. Tomosynthesis is a procedure developed from digital mammography for slice examination of breasts which eliminates the effects of overlapping tissue and allows 3D imaging of breasts. A curved movement of the X-ray tube during scanning allows the acquisition of many 2D images from different angles. Subseqently, reconstruction algorithms employing a shift and add method improve the recognition of details at a defined level and at the same time eliminate smear artefacts due to overlapping structures. The total dose corresponds to that of conventional mammography imaging. The technical procedure, including the number of levels, suitable anodes/filter combinations, angle regions of images and selection of reconstruction algorithms, is presently undergoing optimization. Previous studies on the clinical value of tomosynthesis have examined screening parameters, such as recall rate and detection rate as well as information on tumor extent for histologically proven breast tumors. More advanced techniques, such as contrast medium-enhanced tomosynthesis, are presently under development and dual-energy imaging is of particular importance.

  8. Clinical relevance of epigenetic dysregulation in chronic kidney disease-associated cardiovascular disease.

    PubMed

    Zawada, Adam M; Rogacev, Kyrill S; Heine, Gunnar H

    2013-07-01

    Across the spectrum of clinical medicine, the field of epigenetics has gained substantial scientific interest in recent years. Epigenetics refers to modifications in gene expression which are not explained by changes in DNA sequence. Classical components of epigenetic regulation comprise DNA methylation, histone modifications and RNA interference. In chronic kidney disease (CKD), several features of uraemia, such as hyperhomocysteinemia and inflammation, may contribute to changes in epigenetic gene regulation. It has been suggested that these changes may affect genes related to cardiovascular disease. Thereby, a uraemia-associated disturbance in epigenetic regulation may contribute to the substantial increase in cardiovascular morbidity in CKD patients. The present review aims to summarize current knowledge of epigenetic dysregulation in cardiovascular disease from a nephrological perspective, with a special focus on DNA methylation. We first describe the impact of altered epigenetic regulation in non-CKD-associated arteriosclerosis, and next characterize uraemic features which may affect epigenetic gene regulation in the context of cardiovascular disease. Finally, we conclude that substantial additional work is needed before epigenetic regulatory mechanisms may become therapeutic targets in CKD-associated cardiovascular disease.

  9. Phosphoprotein Stability in Clinical Tissue and Its Relevance for Reverse Phase Protein Microarray Technology

    PubMed Central

    Espina, Virginia; Mueller, Claudius; Liotta, Lance A.

    2013-01-01

    Phosphorylated proteins reflect the activity of specific cell signaling nodes in biological kinase protein networks. Cell signaling pathways can be either activated or deactivated depending on the phosphorylation state of the constituent proteins. The state of these kinase pathways reflects the in vivo activity of the cells and tissue at any given point in time. As such, cell signaling pathway information can be extrapolated to infer which phosphorylated proteins/pathways are driving an individual tumor’s growth. Reverse Phase Protein Microarrays (RPMA) are a sensitive and precise platform that can be applied to the quantitative measurement of hundreds of phosphorylated signal proteins from a small sample of tissue. Pre-analytical variability originating from tissue procurement and preservation may cause significant variability and bias in downstream molecular analysis. Depending on the ex vivo delay time in tissue processing, and the manner of tissue handling, protein biomarkers such as signal pathway phosphoproteins will be elevated or suppressed in a manner that does not represent the biomarker levels at the time of excision. Consequently, assessment of the state of these kinase networks requires stabilization, or preservation, of the phosphoproteins immediately post tissue procurement. We have employed reverse phase protein microarray analysis of phosphoproteins to study the factors influencing stability of phosphoproteins in tissue following procurement. Based on this analysis we have established tissue procurement guidelines for clinical research with an emphasis on quantifying phosphoproteins by RPMA. PMID:21901591

  10. Endoscopic Pancreas Fluid Collection: Methods and Relevance for Clinical Care and Translational Science.

    PubMed

    Hart, Phil A; Topazian, Mark; Raimondo, Massimo; Cruz-Monserrate, Zobeida; Fisher, William E; Lesinski, Gregory B; Steen, Hanno; Conwell, Darwin L

    2016-09-01

    Pancreatic secretions have an important role in the regulation of a normal nutritional state but can be altered owing to a variety of pathophysiological mechanisms in the context of exocrine pancreatic disease. The development of an endoscopic technique for collection of pancreatic fluid, termed endoscopic pancreatic function testing, has led to improved understanding of these alterations and is particularly helpful to characterize chronic pancreatitis. In addition, investigators have found endoscopically collected pancreatic fluid to be a valuable biofluid for the purposes of translational science. Techniques such as proteomic, cytokine, genetic mutation, DNA methylation, and microRNA analyses, among others, can be utilized to gain a better understanding of the molecular characteristics of chronic pancreatitis and other pancreatic diseases. Endoscopic collection of pancreatic fluid is safe and relatively straightforward, permitting opportunities for longitudinal analysis of these translational markers throughout the course of disease. This manuscript summarizes our current knowledge of pancreatic fluid, with an emphasis on proper techniques for sample collection and handling, its clinical utility, and preliminary observations in translational science.

  11. 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.

  12. Clinicians' emotional responses and Psychodynamic Diagnostic Manual adult personality disorders: A clinically relevant empirical investigation.

    PubMed

    Gazzillo, Francesco; Lingiardi, Vittorio; Del Corno, Franco; Genova, Federica; Bornstein, Robert F; Gordon, Robert M; McWilliams, Nancy

    2015-06-01

    The aim of this study is to explore the relationship between level of personality organization and type of personality disorder as assessed with the categories in the Psychodynamic Diagnostic Manual (PDM; PDM Task Force, 2006) and the emotional responses of treating clinicians. We asked 148 Italian clinicians to assess 1 of their adult patients in treatment for personality disorders with the Psychodiagnostic Chart (PDC; Gordon & Bornstein, 2012) and the Personality Diagnostic Prototype (PDP; Gazzillo, Lingiardi, & Del Corno, 2012) and to complete the Therapist Response Questionnaire (TRQ; Betan, Heim, Zittel-Conklin, & Westen, 2005). The patients' level of overall personality pathology was positively associated with helpless and overwhelmed responses in clinicians and negatively associated with positive emotional responses. A parental and disengaged response was associated with the depressive, anxious, and dependent personality disorders; an exclusively parental response with the phobic personality disorder; and a parental and criticized response with narcissistic disorder. Dissociative disorder evoked a helpless and parental response in the treating clinicians whereas somatizing disorder elicited a disengaged reaction. An overwhelmed and disengaged response was associated with sadistic and masochistic personality disorders, with the latter also associated with a parental and hostile/criticized reaction; an exclusively overwhelmed response with psychopathic patients; and a helpless response with paranoid patients. Finally, patients with histrionic personality disorder evoked an overwhelmed and sexualized response in their clinicians whereas there was no specific emotional reaction associated with the schizoid and the obsessive-compulsive disorders. Clinical implications of these findings were discussed.

  13. Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance.

    PubMed

    Avgeris, Margaritis; Mavridis, Konstantinos; Scorilas, Andreas

    2012-04-01

    Tissue kallikrein (KLK1) and kallikrein-related peptidases (KLK2-15) comprise a family of 15 highly conserved secreted serine proteases with similar structural characteristics and a wide spectrum of functional properties. Both gene expression and protein activity of KLKs are rigorously controlled at various levels via diverse mechanisms, including extensive steroid hormone regulation, to exert their broad physiological role. Nevertheless, deregulated expression, secretion, and function of KLK family members has been observed in several pathological conditions and, particularly, in endocrine-related human malignancies, including those of the prostate, breast, and ovary. The cancer-related abnormal activity of KLKs upon substrates such as growth factors, cell adhesion molecules, cell surface receptors, and extracellular matrix proteins facilitate both tumorigenesis and disease progression to the advanced stages. The well-documented relationship between KLK status and the clinical outcome of cancer patients has led to their identification as promising diagnostic, prognostic, and treatment response monitoring biomarkers for these complex disease entities. The main objective of this review is to summarize the existing knowledge concerning the role of KLKs in prostate, breast, and ovarian cancers and to highlight their continually evolving biomarker capabilities that can provide significant benefits for the management of cancer patients.

  14. [The lower trapezius muscle island flap. Anatomic principles and clinical relevance].

    PubMed

    Haas, F; Pierer, G; Weiglein, A; Moshammer, H; Schwarzl, F; Scharnagl, E

    1999-01-01

    Up to now, there is no uniform anatomic description neither of the branches of the subclavian artery nor of the pedicle of the lower myocutaneous trapezius flap. A dissection study was carried out on 140 necks in 70 cadavers. Variations of the subclavian artery and its branches, vessel diameter at different levels, the course of the pedicle under the levator scapulae muscle, the arc of rotation of the island flap, and the variations of the segmental intercostal branches to the lower part of the trapezius muscle were examined. Results of this study enable us to suggest a new nomenclature for the branches of the subclavian artery, a proper pedicle definition, and a technique for safe flap elevation. The lower trapezius island flap is a thin and pliable myocutaneous flap with a constant pedicle which ensures safe flap elevation. This flap has the potential for a wider acceptance due to minor donor site morbidity, large arc of rotation, and an ample range of clinical applications in the head and neck area as an island flap as well as a free flap.

  15. Laser tumor thermotherapy: Is there a clinically relevant effect on the immune system?

    NASA Astrophysics Data System (ADS)

    Tranberg, Karl-G.

    2006-02-01

    Laser thermotherapy is interesting from an immunological point of view since it can reduce tumor volume without causing immunosuppression at the same time as it may induce and/or enhance tumor immunity. In a rat liver tumor model, we have demonstrated that laser thermotherapy 1) is superior to surgical resection, 2) gives a strong rejection immunity associated with an immune cellular response of tumor-infiltrating macrophages and CD8 lymphocytes, 3) results in pronounced suppression of the growth of a simultaneous untreated tumor (distant bystander effect), 4) produces an increased anti-tumor lymphocyte proliferative response in tumor-draining and systemic lymph nodes and spleen, and 5) results in increased HSP70 immunoreactivity in tumors and tumor-infiltrating macrophages. Thus, the evidence for a laser-induced immunologic effect in tumor-bearing rats is strong. Some observations suggest that laser thermotherapy may be used for inducing favorable immunologic effects also in patients. Thus, we have shown a laser-induced bystander effect in a patient with malignant melanoma. In patients with breast cancer we have shown that laser thermotherapy induces intratumoral infiltration of immunocompetent cells like CD68 macrophages and CD8 lymphocytes. Laser thermotherapy is likely to be beneficial mainly when tumor burden is small, that is, when treatment is performed with curative intent, either with laser alone or together with surgical resection. For optimal effect, it appears likely that thermotherapy should be combined with other therapies. Most likely, a clinically meaningful effect can only be proven in prospective randomized studies comparing thermotherapy with other methods, particularly surgical resection.

  16. Differential Effectiveness of Clinically-Relevant Analgesics in a Rat Model of Chemotherapy-Induced Mucositis

    PubMed Central

    Whittaker, Alexandra L.; Lymn, Kerry A.; Wallace, Georgia L.; Howarth, Gordon S.

    2016-01-01

    Chemotherapy-induced intestinal mucositis is characterized by pain and a pro-inflammatory tissue response. Rat models are frequently used in mucositis disease investigations yet little is known about the presence of pain in these animals, the ability of analgesics to ameliorate the condition, or the effect that analgesic administration may have on study outcomes. This study investigated different classes of analgesics with the aim of determining their analgesic effects and impact on research outcomes of interest in a rat model of mucositis. Female DA rats were allocated to 8 groups to include saline and chemotherapy controls (n = 8). Analgesics included opioid derivatives (buprenorphine; 0.05mg/kg and tramadol 12.5mg/kg) and NSAID (carprofen; 15mg/kg) in combination with either saline or 5-Fluorouracil (5-FU; 150mg/kg). Research outcome measures included daily clinical parameters, pain score and gut histology. Myeloperoxidase assay was performed to determine gut inflammation. At the dosages employed, all agents had an analgesic effect based on behavioural pain scores. Jejunal myeloperoxidase activity was significantly reduced by buprenorphine and tramadol in comparison to 5-FU control animals (53%, p = 0.0004 and 58%, p = 0.0001). Carprofen had no ameliorating effect on myeloperoxidase levels. None of the agents reduced the histological damage caused by 5-FU administration although tramadol tended to increase villus length even when administered to healthy animals. These data provide evidence that carprofen offers potential as an analgesic in this animal model due to its pain-relieving efficacy and minimal effect on measured parameters. This study also supports further investigation into the mechanism and utility of opioid agents in the treatment of chemotherapy-induced mucositis. PMID:27463799

  17. Tendon and Ligament Regeneration and Repair: Clinical Relevance and Developmental Paradigm

    PubMed Central

    Tuan, Rocky S.

    2014-01-01

    Tendon and ligament (T/L) are dense connective tissues connecting bone to muscle and bone to bone, respectively. Similar to other musculoskeletal tissues, T/L arise from the somitic mesoderm, but they are derived from a recently discovered somitic compartment, the syndetome. The adjacent sclerotome and myotome provide inductive signals to the interposing syndetome, thereby upregulating the expression of the transcription factor Scleraxis, which in turn leads to further tenogenic and ligamentogenic differentiation. These advances in the understanding of T/L development have been sought to provide a knowledge base for improving the healing of T/L injuries, a common clinical challenge due to the intrinsically poor natural healing response. Specifically, the three most common tendon injuries involve tearing of the rotator cuff of the shoulder, the flexor tendon of the hand, and the Achilles tendon. At present, injuries to these tissues are treated by surgical repair and/or conservative approaches, including biophysical modalities such as physical rehabilitation and cryotherapy. Unfortunately, the healing tissue forms fibrovascular scar and possesses inferior mechanical and biochemical properties as compared to native T/L. Therefore, tissue engineers have sought to improve upon the natural healing response by augmenting the injured tissue with cells, scaffolds, bioactive agents, and mechanical stimulation. These strategies show promise, both in vitro and in vivo, for improving T/L healing. However, several challenges remain in restoring full T/L function following injury, including uncertainties over the optimal combination of these biological agents as well how to best deliver tissue engineered elements to the injury site. A greater understanding of the molecular mechanisms involved in T/L development and natural healing, coupled with the capability of producing complex biomaterials to deliver multiple growth factors with high spatiotemporal resolution and specificity

  18. Clinical and immunological relevance of anti-neuronal antibodies in celiac disease with neurological manifestations

    PubMed Central

    Caio, Giacomo; Giorgio, Roberto De; Venturi, Alessandro; Giancola, Fiorella; Latorre, Rocco; Boschetti, Elisa; Serra, Mauro; Ruggeri, Eugenio; Volta, Umberto

    2015-01-01

    Aim: To assess anti-neuronal antibodies (NA) prevalence and their correlation with neurological disorders and bowel habits in celiac disease (CD) patients. Background: Neurological manifestations are estimated to occur in about 10% of celiac disease patients and NA to central nervous system (CNS) and enteric nervous system (ENS) are found in a significant proportion of them. Little is known about the clinical and immunological features in CD patients with neurological manifestations. Patients and methods: NA to CNS and ENS were investigated in 106 CD patients and in 60 controls with autoimmune disorders by indirect immunofluorescence on rat / primate cerebellar cortex and intestinal (small and large bowel) sections. Results: IgG NA to CNS (titer 1:50 - 1:400) were positive in 23 celiacs (21%), being more frequently detected in those with neurological disorders that in those without neurological dysfunction (49% vs. 8%, P< 0.0001). Of the 26 celiacs (24%) with IgG NA to ENS, 11 out of 12 with an antibody titer > 1:200 had severe constipation. Only one patient with cerebellar ataxia and intestinal sub-occlusion was positive for NA to CNS and ENS. NA to CNS and ENS were found in 7% and 5% of controls, respectively. Conclusion: In CD the positivity of NA to CNS can be regarded as a marker of neurological manifestations. High titer NA to ENS are associated with severe constipation. The demonstration of NA to CNS and ENS suggests an immune-mediated pathogenesis leading to central neural impairment as well as gut dysfunction (hence constipation), respectively. PMID:25926940

  19. CLINICAL AND BIOLOGICAL RELEVANCE OF EZH2 IN TRIPLE NEGATIVE BREAST CANCER

    PubMed Central

    Hussein, Yaser R.; Sood, Anil K.; Bandyopadhyay, Sudeshna; Albashiti, Bassam; Semaan, Assaad; Nahleh, Zeina; Roh, Juwon; Han, Hee Dong; Lopez-Berestein, Gabriel; Ali-Fehmi, Rouba

    2014-01-01

    The polycomb group protein, enhancer of zeste homolog 2 (EZH2), is a transcriptional repressor involved in cell cycle regulation and has been linked to aggressive breast cancer. We examined the clinical and biological significance of EZH2 expression in triple-negative breast cancers. Tissue microarrays were constructed with invasive breast cancer cases and stained with EZH2, cytokeratin 5/6, epidermal growth factor receptor 1(EGFR) and p53. The expression of these markers was correlated with clinicopathologic variables and patients’ outcome. Furthermore, in vivo EZH2 gene silencing was achieved using siRNA incorporated into chitosan nanoparticles. Out of 261 cases of invasive breast cancer, high expression of EZH2 was detected in 87 (33%) cases, and it was strongly associated with a triple-negative breast cancer phenotype (P<.001) compared to all other non-triple negative breast cancers. Furthermore, high EZH2 was significantly associated with high histologic grade (P=.01), estrogen receptor negativity (P<.001), progesterone receptor negativity (P<.001), EGFR positivity (P=.04), and high p53 expression (P<.001). Survival analysis demonstrated that patients with high EZH2 had a poorer overall survival, compared to those with low EZH2 (P=.03), and it retained its significance as an independent prognostic factor (P=.02). In addition, EZH2 gene silencing resulted in significant reduction in tumor growth (P<.01) in the orthotopic MB-231 mouse model of breast carcinoma. Our results show that high EZH2 expression is significantly associated with triple-negative breast cancer and decreased survival. EZH2 may represent a potential therapeutic target for this aggressive disease, which warrants further investigation. PMID:22436627

  20. Biliary atresia-polysplenia syndrome: surgical and clinical relevance in liver transplantation.

    PubMed Central

    Varela-Fascinetto, G; Castaldo, P; Fox, I J; Sudan, D; Heffron, T G; Shaw, B W; Langnas, A N

    1998-01-01

    OBJECTIVE: To review a single center's 10-year experience with liver transplantation (LTx) for the biliary atresia-polysplenia syndrome (BA-PS) and to define surgical and clinical guidelines for its management. SUMMARY BACKGROUND DATA: BA is the most common indication for pediatric liver transplantation (LTx) and is associated with PS in 12% of cases. Only a few studies of LTx for BA-PS have been reported, and the optimal management of BA-PS patients undergoing LTx has yet to be determined. METHODS: From July 1985 to September 1995, 166 liver transplants were performed in 130 patients with BA and were included in the study. The malformations most commonly associated with BA-PS, surgical techniques used to overcome these anomalies, and surgical pitfalls that could have contributed to the outcome were characterized. Actuarial 10-year patient and graft survival for patients undergoing LTx for BA-PS were calculated and compared to those with isolated BA. RESULTS: Ten patients (7.8%) with BA had associated PS. An additional patient with PS without BA was included in the study. The diagnosis of PS was unknown before the transplantation in 72% of cases. Thirteen liver transplants were performed in these 11 patients. Modifications of the usual surgical technique were used to overcome the complex anatomy encountered. There was no association between the type of anomaly and the outcome, nor were there any significant differences in patient survival (72% vs. 73.5%, p = 0.79) or graft survival (56.4% vs. 54.6%, p = 0.54). CONCLUSIONS: The association of BA with various anomalies should be considered a spectrum that may vary widely from patient to patient. The finding of two or more of these malformations in a patient awaiting transplantation should lead the surgeon to look systematically for other associated anomalies. With some special surgical considerations, the outcome in BA-PS patients should not differ from those with isolated BA. Images Figure 3. PMID:9563550

  1. Clinical relevance of urinary angiotensinogen and renin as potential biomarkers in patients with overt proteinuria.

    PubMed

    Jang, Hye Ryoun; Jeon, Junseok; Park, Ji Hyeon; Lee, Jung Eun; Huh, Wooseong; Oh, Ha Young; Kim, Yoon-Goo

    2014-11-01

    Urinary angiotensinogen (AGT) and renin have been reported to reflect the intrarenal renin-angiotensin system (RAS) activity. However, the adequacy and clinical significance of these markers have not been evaluated in overtly proteinuric patients. In patients with biopsy-proven glomerulonephritis, plasma and urinary AGT and renin were analyzed. A cohort of 75 patients treated with RAS inhibitors was followed for 1 year. Among the 207 patients, 105 had subnephrotic and 102 had nephrotic-range proteinuria. Mean age, estimated glomerular filtration rate (eGFR), and urinary protein-to-creatinine ratio (P/Cr) of all patients were 48 years, 79.7 mL/min/1.73 m(2), and 5.66 mg/mg, respectively. Both natural logarithm of urinary AGT/creatinine (ln [urinary AGT/Cr]) and ln (urinary renin/Cr) showed positive correlations with urinary P/Cr. There was a positive correlation between ln (urinary AGT/Cr) and ln (urinary renin/Cr). Ln (urinary renin/Cr) was not affected by ln (plasma renin) regardless of the degree of proteinuria. The treatment response to RAS inhibitors was greatest in patients with high urinary AGT and renin. However, the predictive value of those parameters was no longer present when the values were adjusted by the degree of proteinuria. Ln (urinary renin/Cr) and initial eGFR were independently associated with the changes in renal function for 1 year. Ln (urinary AGT/Cr) was associated with persistent overt proteinuria after 1 year. Our study suggests that urinary renin may be a better marker in heavy proteinuria, and the treatment response to RAS inhibitors may be enhanced in patients with high urinary renin and AGT. Further studies will be necessary to explore the value of urinary AGT and renin.

  2. Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product-Drug Interaction.

    PubMed

    Gufford, Brandon T; Chen, Gang; Vergara, Ana G; Lazarus, Philip; Oberlies, Nicholas H; Paine, Mary F

    2015-09-01

    Women at high risk of developing breast cancer are prescribed selective estrogen response modulators, including raloxifene, as chemoprevention. Patients often seek complementary and alternative treatment modalities, including herbal products, to supplement prescribed medications. Milk thistle preparations, including silibinin and silymarin, are top-selling herbal products that may be consumed by women taking raloxifene, which undergoes extensive first-pass glucuronidation in the intestine. Key constituents in milk thistle, flavonolignans, were previously shown to be potent inhibitors of intestinal UDP-glucuronosyl transferases (UGTs), with IC50s ≤ 10 μM. Taken together, milk thistle preparations may perpetrate unwanted interactions with raloxifene. The objective of this work was to evaluate the inhibitory effects of individual milk thistle constituents on the intestinal glucuronidation of raloxifene using human intestinal microsomes and human embryonic kidney cell lysates overexpressing UGT1A1, UGT1A8, and UGT1A10, isoforms highly expressed in the intestine that are critical to raloxifene clearance. The flavonolignans silybin A and silybin B were potent inhibitors of both raloxifene 4'- and 6-glucuronidation in all enzyme systems. The Kis (human intestinal microsomes, 27-66 µM; UGT1A1, 3.2-8.3 µM; UGT1A8, 19-73 µM; and UGT1A10, 65-120 µM) encompassed reported intestinal tissue concentrations (20-310 µM), prompting prediction of clinical interaction risk using a mechanistic static model. Silibinin and silymarin were predicted to increase raloxifene systemic exposure by 4- to 5-fold, indicating high interaction risk that merits further evaluation. This systematic investigation of the potential interaction between a widely used herbal product and chemopreventive agent underscores the importance of understanding natural product-drug interactions in the context of cancer prevention.

  3. Lack of clinically relevant drug–drug interactions when dalcetrapib is co-administered with ezetimibe

    PubMed Central

    Derks, Michael; Abt, Markus; Phelan, Mary

    2010-01-01

    AIMS Dalcetrapib, which targets cholesteryl ester transfer protein activity, is in development for prevention of cardiovascular events. Because dalcetrapib will likely be prescribed with other lipid-modifying therapies such as ezetimibe, a study was performed to investigate potential pharmacokinetic interactions between dalcetrapib and ezetimibe. Lipids changes and tolerability were secondary endpoints. METHODS Co-administration of dalcetrapib 900 mg (higher than the phase III dose) with ezetimibe was investigated in a three period, three treatment crossover study in healthy males: 7 days of dalcetrapib, 7 days of dalcetrapib plus ezetimibe, 7 days of ezetimibe alone. A full pharmacokinetic profile was performed on day 7 of each treatment. RESULTS Co-administration of dalcetrapib with ezetimibe was associated with minimal changes in dalcetrapib exposure compared with dalcetrapib alone. Least squares mean ratio (LSMR) (90% confidence interval) was 93.6 (87.1, 100.7) for AUC(0,24 h) and 99.0 (85.2, 115.0) for Cmax. Ezetimibe exposure was reduced with co-administration of ezetimibe with dalcetrapib compared with ezetimibe alone: LSMR 80.3 (74.6, 86.4) for AUC(0,24 h) and 88.9 (80.9, 99.9) for Cmax for total ezetimibe. High-density lipoprotein cholesterol increases associated with co-administration of dalcetrapib with ezetimibe (+29.8%) were comparable with those with dalcetrapib alone (+25.6%), while the reduction in low-density lipoprotein cholesterol with co-administration (−35.9%) was greater than with ezetimibe alone (−20.9%). Dalcetrapib was generally well tolerated when administered alone and when co-administered with ezetimibe. CONCLUSION Co-administration of dalcetrapib with ezetimibe was not associated with clinically significant changes in pharmacokinetic parameters or tolerability and did not diminish the lipid effects of either drug. PMID:21175438

  4. Out-of-Field Dose Equivalents Delivered by Passively Scattered Therapeutic Proton Beams for Clinically Relevant Field Configurations

    SciTech Connect

    Wroe, Andrew Clasie, Ben; Kooy, Hanne; Flanz, Jay; Schulte, Reinhard; Rosenfeld, Anatoly

    2009-01-01

    Purpose: Microdosimetric measurements were performed at Massachusetts General Hospital, Boston, MA, to assess the dose equivalent external to passively delivered proton fields for various clinical treatment scenarios. Methods and Materials: Treatment fields evaluated included a prostate cancer field, cranial and spinal medulloblastoma fields, ocular melanoma field, and a field for an intracranial stereotactic treatment. Measurements were completed with patient-specific configurations of clinically relevant treatment settings using a silicon-on-insulator microdosimeter placed on the surface of and at various depths within a homogeneous Lucite phantom. The dose equivalent and average quality factor were assessed as a function of both lateral displacement from the treatment field edge and distance downstream of the beam's distal edge. Results: Dose-equivalent value range was 8.3-0.3 mSv/Gy (2.5-60-cm lateral displacement) for a typical prostate cancer field, 10.8-0.58 mSv/Gy (2.5-40-cm lateral displacement) for the cranial medulloblastoma field, 2.5-0.58 mSv/Gy (5-20-cm lateral displacement) for the spinal medulloblastoma field, and 0.5-0.08 mSv/Gy (2.5-10-cm lateral displacement) for the ocular melanoma field. Measurements of external field dose equivalent for the stereotactic field case showed differences as high as 50% depending on the modality of beam collimation. Average quality factors derived from this work ranged from 2-7, with the value dependent on the position within the phantom in relation to the primary beam. Conclusions: This work provides a valuable and clinically relevant comparison of the external field dose equivalents for various passively scattered proton treatment fields.

  5. [18F]FDG in recurrent breast cancer: diagnostic performances, clinical impact and relevance of induced changes in management.

    PubMed

    Grahek, Dany; Montravers, Françoise; Kerrou, Khaldoun; Aide, Nicolas; Lotz, Jean-Pierre; Talbot, Jean-Noël

    2004-02-01

    Prognosis and management of patients with recurrent breast cancer depend on the spread of the disease. The aim of this study was to evaluate the performance of fluorine-18 fluorodeoxyglucose gamma camera positron emission tomography (FDG-GPET) in detecting breast cancer recurrence, its clinical impact and the relevance of induced changes in management. Patients (n = 134) with suspicion of recurrence either clinically or on conventional imaging (suspected recurrence: SR) or with an isolated increase in tumour marker levels (occult recurrence: OR) underwent FDG-GPET on a coincidence gamma camera. The reference standard for evaluation of accuracy, either histology (n = 26) or follow-up for 1 year (n = 49), was available in 75 (56%) patients. A questionnaire was sent to the referring clinician to evaluate the impact of FDG on management. Responses were obtained for 75 patients. Information regarding both approaches was available for 46 patients (46/134 = 34%). At the patient level, the sensitivity of FDG-GPET was 84%, significantly higher than the 63% sensitivity for conventional modalities, and the specificity was 78% versus 61%. The values for FDG-GPET were 81% and 86% respectively in the SR group and 90% and 73% respectively in the OR group, without any significant difference between these settings. The rate of change in management was 44% overall, 43% in the SR group and 45% in the OR group. Within the two groups, intermodality (major) changes were more frequent than intramodality (minor) changes. In the 46 patients for whom both approaches were available, 93% of management modifications were relevant (validated by biopsy or clinical follow-up). The results of this retrospective study show that FDG-GPET has an important role to play in patient management by confirming and evaluating the extent of recurrence or by localising occult recurrence.

  6. In-vivo longitudinal MRI study: an assessment of melanoma brain metastases in a clinically relevant mouse model.

    PubMed

    Henry, Mariama N; Chen, Yuhua; McFadden, Catherine D; Simedrea, Felicia C; Foster, Paula J

    2015-04-01

    Brain metastases are an important clinical problem. Few animal models exist for melanoma brain metastases; many of which are not clinically relevant. Longitudinal MRI was implemented to examine the development of tumors in a clinically relevant mouse model of melanoma brain metastases. Fifty thousand human metastatic melanoma (A2058) cells were injected intracardially into nude mice. Three Tesla MRI was performed using a custom-built gradient insert coil and a mouse solenoid head coil. Imaging was performed on consecutive days at four time points. Tumor burden and volumes of metastases were measured from balanced steady-state free precession image data. Metastases with a disrupted blood-tumor barrier were identified from T1-weighted spin echo images acquired after administration of gadopentetic acid (Gd-DTPA). Metastases permeable to Gd-DTPA showed signal enhancement. The number of enhancing metastases was determined by comparing balanced steady-state free precession images with T1-weighted spin echo images. After the final imaging session, ex-vivo permeability and histological analyses were carried out. Imaging showed that both enhancing and nonenhancing brain metastases coexist in the brain, and that most metastases switched from the nonenhancing to the enhancing phenotype. Small numbers of brain metastases were enhancing when first detected by MRI and remained enhancing, whereas other metastases remained nonenhancing to Gd-DTPA throughout the experiment. No clear relationship existed between the permeability of brain metastases and size, brain location and age. Longitudinal in-vivo MRI is key to studying the complex and dynamic processes of metastasis and changes in the blood-tumor barrier permeability, which may lead to a better understanding of the variable responses of brain metastases to treatments.

  7. Pasteurella caballi, a new species from equine clinical specimens.

    PubMed Central

    Schlater, L K; Brenner, D J; Steigerwalt, A G; Moss, C W; Lambert, M A; Packer, R A

    1989-01-01

    The name Pasteurella caballi is proposed for a group of organisms represented by 29 strains isolated from respiratory and other infections in horses. P. caballi strains are gram-negative, oxidase-positive, nonmotile, fermentative rods with the key characteristics of the genus Pasteurella. These strains differed from other Pasteurella species in that all were aerogenic and catalase negative, and some strains produced acid from myo-inositol and L-rhamnose. The levels of DNA relatedness of 28 P. caballi strains with labeled DNA from the proposed type strain averaged 91 and 85% (hydroxyapatite method at 55 and 70 degrees C). P. caballi was 13 to 53% related to strains representing 22 other species of the family Pasteurellaceae. The guanine-plus-cytosine content of the DNA of four strains was 41 to 42 mol%. The type strain is 83851 (=ATCC 49197). PMID:2584369

  8. Duration-dependent effects of clinically relevant oral alendronate doses on cortical bone toughness in beagle dogs.

    PubMed

    Burr, David B; Liu, Ziyue; Allen, Matthew R

    2015-02-01

    Bisphosphonates (BPs) have been shown to significantly reduce bone toughness in vertebrae within one year when given at clinical doses to dogs. Although BPs also reduce toughness in the cortical bone when given at high doses, their effect on cortical bone material properties when given at clinical doses is less clear. In part, this may be due to the use of small sample sizes that were powered to demonstrate differences in bone mineral density rather than the bone's material properties. Our lab has conducted several studies in which dogs were treated with alendronate at a clinically relevant dose. The goal of this study was to examine these published and unpublished data collectively to determine whether there is a significant time-dependent effect of alendronate on toughness of the cortical bone. This analysis seemed particularly relevant given the recent occurrence of atypical femoral fractures in humans. Differences in the toughness of ribs taken from dogs derived from five separate experiments were measured. The dogs were orally administered saline (CON, 1ml/kg/day) or alendronate (ALN) at a clinical dose (0.2mg/kg/day). Treatment duration ranged from 3months to 3years. Groups were compared using ANOVA, and time trends analyzed with linear regression analysis. Linear regressions of the percent difference in toughness between CON and ALN at each time point revealed a significant reduction in toughness with longer exposure to ALN. The downward trend was primarily driven by a downward trend in post-yield toughness, whereas toughness in the pre-yield region was not changed relative to CON. These data suggest that a longer duration of treatment with clinical doses of ALN results in deterioration of cortical bone toughness in a time-dependent manner. As the duration of treatment is lengthened, the cortical bone exhibits increasingly brittle behavior. This may be important in assessing the role that long-term BP treatments play in the risk of atypical fractures of the

  9. [First Argentine consensus guidelines for in vitro antimicrobial susceptibility testing of clinically relevant anaerobic bacteria in humans/ Anaerobic Subcommittee of the Asociación Argentina de Microbiología].

    PubMed

    Legaria, María C; Bianchini, Hebe M; Castello, Liliana; Carloni, Graciela; Di Martino, Ana; Fernández Canigia, Liliana; Litterio, Mirta; Rollet, Raquel; Rossetti, Adelaida; Predari, Silvia C

    2011-01-01

    Through time, anaerobic bacteria have shown good susceptibility to clinically useful antianaerobic agents. Nevertheless, the antimicrobial resistance profile of most of the anaerobic species related to severe infections in humans has been modified in the last years and different kinds of resistance to the most active agents have emerged, making their effectiveness less predictable. With the aim of finding an answer and for the purpose of facilitating the detection of anaerobic antimicrobial resistance, the Anaerobic Subcommittee of the Asociación Argentina de Microbiología developed the First Argentine consensus guidelines for in vitro antimicrobial susceptibility testing of clinically relevant anaerobic bacteria in humans. This document resulted from the compatibilization of the Clinical and Laboratory Standards Institute recommendations, the international literature and the work and experience of the Subcommittee. The Consensus document provides a brief taxonomy review, and exposes why and when anaerobic antimicrobial susceptibility tests should be conducted, and which antimicrobial agents can be used according to the species involved. The recommendations on how to perform, read and interpret in vitro anaerobic antimicrobial susceptibility tests with each method are exposed. Finally, the antibiotic susceptibility profile, the classification of antibiotics according to their in vitro activities, the natural and acquired mechanisms of resistance, the emerging resistance and the regional antibiotic resistance profile of clinically relevant anaerobic species are shown.

  10. Expanded national database collection and data coverage in the FINDbase worldwide database for clinically relevant genomic variation allele frequencies

    PubMed Central

    Viennas, Emmanouil; Komianou, Angeliki; Mizzi, Clint; Stojiljkovic, Maja; Mitropoulou, Christina; Muilu, Juha; Vihinen, Mauno; Grypioti, Panagiota; Papadaki, Styliani; Pavlidis, Cristiana; Zukic, Branka; Katsila, Theodora; van der Spek, Peter J.; Pavlovic, Sonja; Tzimas, Giannis; Patrinos, George P.

    2017-01-01

    FINDbase (http://www.findbase.org) is a comprehensive data repository that records the prevalence of clinically relevant genomic variants in various populations worldwide, such as pathogenic variants leading mostly to monogenic disorders and pharmacogenomics biomarkers. The database also records the incidence of rare genetic diseases in various populations, all in well-distinct data modules. Here, we report extensive data content updates in all data modules, with direct implications to clinical pharmacogenomics. Also, we report significant new developments in FINDbase, namely (i) the release of a new version of the ETHNOS software that catalyzes development curation of national/ethnic genetic databases, (ii) the migration of all FINDbase data content into 90 distinct national/ethnic mutation databases, all built around Microsoft's PivotViewer (http://www.getpivot.com) software (iii) new data visualization tools and (iv) the interrelation of FINDbase with DruGeVar database with direct implications in clinical pharmacogenomics. The abovementioned updates further enhance the impact of FINDbase, as a key resource for Genomic Medicine applications. PMID:27924022

  11. Clinical relevance of the proposed sexual addiction diagnostic criteria: relation to the Sexual Addiction Screening Test-Revised.

    PubMed

    Carnes, Patrick J; Hopkins, Tiffany A; Green, Bradley A

    2014-01-01

    The present article examines and compares the various diagnostic rubrics proposed to codify symptoms of sexual addiction, and then briefly summarizes the ongoing controversy on whether sexual addiction is a valid construct. Using the diagnostic criteria proposed by , the prevalence rate of each criterion is examined in terms of scores on the Sexual Addiction Screening Test-Revised scales (). Differences in diagnostic criteria endorsement associated with sex, sexual orientation, and setting were also explored. Results from a clinical sample of men and women seeking treatment for sexual addiction demonstrated clinical relevance of the criteria, in that all but 3 criteria are endorsed at more than 50% of participants screening positive for sexual addiction on the Sexual Addiction Screening Test-Revised. Sex differences were also noted for endorsement rates of several of the criteria. Finally, several proposed criteria may pose a higher clinical threshold and thus be utilized by clinicians to identify patients with increased pathology. Results are discussed in the context of existing diagnostic frameworks across etiological perspectives.

  12. Evaluation of an Instructional Model to Teach Clinically Relevant Medicinal Chemistry in a Campus and a Distance Pathway

    PubMed Central

    Galt, Kimberly A.

    2008-01-01

    Objectives To evaluate an instructional model for teaching clinically relevant medicinal chemistry. Methods An instructional model that uses Bloom's cognitive and Krathwohl's affective taxonomy, published and tested concepts in teaching medicinal chemistry, and active learning strategies, was introduced in the medicinal chemistry courses for second-professional year (P2) doctor of pharmacy (PharmD) students (campus and distance) in the 2005-2006 academic year. Student learning and the overall effectiveness of the instructional model were assessed. Student performance after introducing the instructional model was compared to that in prior years. Results Student performance on course examinations improved compared to previous years. Students expressed overall enthusiasm about the course and better understood the value of medicinal chemistry to clinical practice. Conclusion The explicit integration of the cognitive and affective learning objectives improved student performance, student ability to apply medicinal chemistry to clinical practice, and student attitude towards the discipline. Testing this instructional model provided validation to this theoretical framework. The model is effective for both our campus and distance-students. This instructional model may also have broad-based applications to other science courses. PMID:18483599

  13. Expanded national database collection and data coverage in the FINDbase worldwide database for clinically relevant genomic variation allele frequencies.

    PubMed

    Viennas, Emmanouil; Komianou, Angeliki; Mizzi, Clint; Stojiljkovic, Maja; Mitropoulou, Christina; Muilu, Juha; Vihinen, Mauno; Grypioti, Panagiota; Papadaki, Styliani; Pavlidis, Cristiana; Zukic, Branka; Katsila, Theodora; van der Spek, Peter J; Pavlovic, Sonja; Tzimas, Giannis; Patrinos, George P

    2017-01-04

    FINDbase (http://www.findbase.org) is a comprehensive data repository that records the prevalence of clinically relevant genomic variants in various populations worldwide, such as pathogenic variants leading mostly to monogenic disorders and pharmacogenomics biomarkers. The database also records the incidence of rare genetic diseases in various populations, all in well-distinct data modules. Here, we report extensive data content updates in all data modules, with direct implications to clinical pharmacogenomics. Also, we report significant new developments in FINDbase, namely (i) the release of a new version of the ETHNOS software that catalyzes development curation of national/ethnic genetic databases, (ii) the migration of all FINDbase data content into 90 distinct national/ethnic mutation databases, all built around Microsoft's PivotViewer (http://www.getpivot.com) software (iii) new data visualization tools and (iv) the interrelation of FINDbase with DruGeVar database with direct implications in clinical pharmacogenomics. The abovementioned updates further enhance the impact of FINDbase, as a key resource for Genomic Medicine applications.

  14. Clinically relevant determinants of body composition, function and nutritional status as mortality predictors in lung cancer patients.

    PubMed

    Kovarik, Miroslav; Hronek, Miloslav; Zadak, Zdenek

    2014-04-01

    Lung cancer belongs to the type of tumors with a relatively high frequency of malnutrition, sarcopenia and cachexia, severe metabolic syndromes related to impairment of physical function and quality of life, resistance to therapy and short survival. Inexpensive and accessible methods of evaluating changes in body composition, physical function and nutrition status are for this reason of great importance for clinical practice to enable the early identification, monitoring, preventing and treatment of these nutritional deficiencies. This could lead to improved outcomes in the quality of life, physical performance and survival of patients with lung cancer. The aim of this article is to summarize the recent knowledge for the use of such methods, their predictability for patient outcomes and an association with other clinically relevant parameters, specifically with lung cancer patients, because such an article collectively describing their practical application in clinical practice is lacking. The interest of this article is in the use of anthropometry, handgrip dynamometry, bioelectrical impedance analysis derived phase angle and nutritional screening questionnaires in lung cancer patients.

  15. Comprehensive genomic profiling of inflammatory breast cancer cases reveals a high frequency of clinically relevant genomic alterations.

    PubMed

    Ross, Jeffrey S; Ali, Siraj M; Wang, Kai; Khaira, Depinder; Palma, Norma A; Chmielecki, Juliann; Palmer, Gary A; Morosini, Deborah; Elvin, Julia A; Fernandez, Sandra V; Miller, Vincent A; Stephens, Philip J; Cristofanilli, Massimo

    2015-11-01

    Inflammatory breast cancer (IBC) is a distinct clinicopathologic entity that carries a worse prognosis relative to non-IBC breast cancer even when matched for standard biomarkers (ER/PR/HER2). The objective of this study was to identify opportunities for benefit from targeted therapy, which are not currently identifiable in the standard workup for advanced breast cancer. Comprehensive genomic profiling on 53 IBC formalin-fixed paraffin-embedded specimens (mean, 800× + coverage) using the hybrid capture-based FoundationOne assay. Academic and community oncology clinics. From a series of 2208 clinical cases of advanced/refractory invasive breast cancers, 53 cases with IBC were identified. The presence of clinically relevant genomic alterations (CRGA) in IBC and responses to targeted therapies. CRGA were defined as genomic alterations (GA) associated with on label targeted therapies and targeted therapies in mechanism-driven clinical trials. For the 44 IBCs with available biomarker data, 19 (39 %) were ER-/PR-/HER2- (triple-negative breast cancer, TNBC). For patients in which the clinical HER2 status was known, 11 (25 %) were HER2+ with complete (100 %) concordance with ERBB2 (HER2) amplification detected by the CGP assay. The 53 sequenced IBC cases harbored a total of 266 GA with an average of 5.0 GA/tumor (range 1-15). At least one alteration associated with an FDA approved therapy or clinical trial was identified in 51/53 (96 %) of cases with an average of 2.6 CRGA/case. The most frequently altered genes were TP53 (62 %), MYC (32 %), PIK3CA (28 %), ERBB2 (26 %), FGFR1 (17 %), BRCA2 (15 %), and PTEN (15 %). In the TNBC subset of IBC, 8/19 (42 %) showed MYC amplification (median copy number 8X, range 7-20) as compared to 9/32 (28 %) in non-TNBC IBC (median copy number 7X, range 6-21). Comprehensive genomic profiling uncovered a high frequency of GA in IBC with 96 % of cases harboring at least 1 CRGA. The clinical benefit of selected targeted

  16. Acetaldehyde at clinically relevant concentrations inhibits inward rectifier potassium current I(K1) in rat ventricular myocytes.

    PubMed

    Bébarová, M; Matejovič, P; Šimurdová, M; Šimurda, J

    2015-01-01

    Considering the effects of alcohol on cardiac electrical behavior as well as the important role of the inward rectifier potassium current I(K1) in arrhythmogenesis, this study was aimed at the effect of acetaldehyde, the primary metabolite of ethanol, on I(K1) in rat ventricular myocytes. Acetaldehyde induced a reversible inhibition of I(K1) with IC(50) = 53.7+/-7.7 microM at -110 mV; a significant inhibition was documented even at clinically-relevant concentrations (at 3 microM by 13.1+/-3.0 %). The inhibition was voltage-independent at physiological voltages above -90 mV. The I(K1) changes under acetaldehyde may contribute to alcohol-induced alterations of cardiac electrophysiology, especially in individuals with a genetic defect of aldehyde dehydrogenase where the acetaldehyde level may be elevated.

  17. Clinical relevance of novel Otarine herpesvirus-3 in California sea lions (Zalophus californianus): lymphoma, esophageal ulcers, and strandings.

    PubMed

    Venn-Watson, Stephanie; Benham, Celeste; Gulland, Frances M; Smith, Cynthia R; St Leger, Judy; Yochem, Pam; Nollens, Hendrik; Blas-Machado, Uriel; Saliki, Jeremiah; Colegrove, Katie; Wellehan, James Fx; Rivera, Rebecca

    2012-12-12

    Herpesviruses have been recognized in marine mammals, but their clinical relevance is not always easy to assess. A novel otarine herpesvirus-3 (OtHV3) was detected in a geriatric California sea lion (Zalophus californianus), and using a newly developed quantitative PCR assay paired with histology, OtHV3 was associated with esophageal ulcers and B cell lymphoblastic lymphoma in this animal. The prevalence and quantities of OtHV3 were then determined among buffy coats from 87 stranded and managed collection sea lions. Stranded sea lions had a higher prevalence of OtHV3 compared to managed collection sea lions (34.9% versus 12.5%; p = 0.04), and among the stranded sea lions, yearlings were most likely to be positive. Future epidemiological studies comparing the presence and viral loads of OtHV3 among a larger population of California sea lions with and without lymphoid neoplasia or esophageal ulcers would help elucidate the relevance of OtHV3-associated pathologies to these groups.

  18. Clinical relevance of novel Otarine herpesvirus-3 in California sea lions (Zalophus californianus): lymphoma, esophageal ulcers, and strandings

    PubMed Central

    2012-01-01

    Herpesviruses have been recognized in marine mammals, but their clinical relevance is not always easy to assess. A novel otarine herpesvirus-3 (OtHV3) was detected in a geriatric California sea lion (Zalophus californianus), and using a newly developed quantitative PCR assay paired with histology, OtHV3 was associated with esophageal ulcers and B cell lymphoblastic lymphoma in this animal. The prevalence and quantities of OtHV3 were then determined among buffy coats from 87 stranded and managed collection sea lions. Stranded sea lions had a higher prevalence of OtHV3 compared to managed collection sea lions (34.9% versus 12.5%; p = 0.04), and among the stranded sea lions, yearlings were most likely to be positive. Future epidemiological studies comparing the presence and viral loads of OtHV3 among a larger population of California sea lions with and without lymphoid neoplasia or esophageal ulcers would help elucidate the relevance of OtHV3-associated pathologies to these groups. PMID:23234600

  19. SU-E-T-789: Validation of 3DVH Accuracy On Quantifying Delivery Errors Based On Clinical Relevant DVH Metrics

    SciTech Connect

    Ma, T; Kumaraswamy, L

    2015-06-15

    Purpose: Detection of treatment delivery errors is important in radiation therapy. However, accurate quantification of delivery errors is also of great importance. This study aims to evaluate the 3DVH software’s ability to accurately quantify delivery errors. Methods: Three VMAT plans (prostate, H&N and brain) were randomly chosen for this study. First, we evaluated whether delivery errors could be detected by gamma evaluation. Conventional per-beam IMRT QA was performed with the ArcCHECK diode detector for the original plans and for the following modified plans: (1) induced dose difference error up to ±4.0% and (2) control point (CP) deletion (3 to 10 CPs were deleted) (3) gantry angle shift error (3 degree uniformly shift). 2D and 3D gamma evaluation were performed for all plans through SNC Patient and 3DVH, respectively. Subsequently, we investigated the accuracy of 3DVH analysis for all cases. This part evaluated, using the Eclipse TPS plans as standard, whether 3DVH accurately can model the changes in clinically relevant metrics caused by the delivery errors. Results: 2D evaluation seemed to be more sensitive to delivery errors. The average differences between ECLIPSE predicted and 3DVH results for each pair of specific DVH constraints were within 2% for all three types of error-induced treatment plans, illustrating the fact that 3DVH is fairly accurate in quantifying the delivery errors. Another interesting observation was that even though the gamma pass rates for the error plans are high, the DVHs showed significant differences between original plan and error-induced plans in both Eclipse and 3DVH analysis. Conclusion: The 3DVH software is shown to accurately quantify the error in delivered dose based on clinically relevant DVH metrics, where a conventional gamma based pre-treatment QA might not necessarily detect.

  20. Viability of primary osteoblasts after treatment with tenofovir alafenamide: Lack of cytotoxicity at clinically relevant drug concentrations

    PubMed Central

    Callebaut, Christian; Liu, Yang; Babusis, Darius; Ray, Adrian; Miller, Michael; Kitrinos, Kathryn

    2017-01-01

    Tenofovir alafenamide (TAF) is a phosphonoamidate prodrug of the nucleotide HIV reverse transcriptase inhibitor tenofovir (TFV). TAF is approved for the treatment of HIV-1 infection as part of the single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and TAF. When dosed once-daily, TAF results in approximately 90% lower levels of plasma TFV and a 4-fold increase in intracellular TFV-diphosphate (TFV-DP) in PBMCs compared with the TFV prodrug tenofovir disoproxil fumarate (TDF). Several antiretrovirals, including TDF, have been associated with bone mineral density decreases in patients; the effect of clinically relevant TAF concentrations on primary osteoblast viability was therefore assessed in vitro. Studies in PBMCs determined that a 2-hour TAF exposure at concentrations similar to human plasma Cmax achieved intracellular TFV-DP levels comparable to those observed after the maximum recommended human dose of 25 mg TAF. Comparable intracellular TFV-DP levels were achieved in primary osteoblasts with 2-hour TAF exposure daily for 3 days at concentrations similar to those used for PBMCs (100–400 nM). No change in cell viability was observed in either primary osteoblasts or PBMCs. The mean TAF CC50 in primary osteoblasts after 3 days of daily 2-hour pulses was >500 μM, which is >1033 times higher than the TAF maximum recommended human dose plasma Cmax. In summary, primary osteoblasts were not preferentially loaded by TAF compared with PBMCs, with comparable TFV-DP levels achieved in both cell types. Furthermore, there was no impact on osteoblast cell viability at clinically relevant TAF concentrations. PMID:28182625

  1. Standing chromosomal variation in Lake Whitefish species pairs: the role of historical contingency and relevance for speciation.

    PubMed

    Dion-Côté, Anne-Marie; Symonová, Radka; Lamaze, Fabien C; Pelikánová, Šárka; Ráb, Petr; Bernatchez, Louis

    2017-01-01

    The role of chromosome changes in speciation remains a debated topic, although demographic conditions associated with divergence should promote their appearance. We tested a potential relationship between chromosome changes and speciation by studying two Lake Whitefish (Coregonus clupeaformis) lineages that recently colonized postglacial lakes following allopatry. A dwarf limnetic species evolved repeatedly from the normal benthic species, becoming reproductively isolated. Lake Whitefish hybrids experience mitotic and meiotic instability, which may result from structurally divergent chromosomes. Motivated by this observation, we test the hypothesis that chromosome organization differs between Lake Whitefish species pairs using cytogenetics. While chromosome and fundamental numbers are conserved between the species (2n = 80, NF = 98), we observe extensive polymorphism of subtle karyotype traits. We describe intrachromosomal differences associated with heterochromatin and repetitive DNA, and test for parallelism among three sympatric species pairs. Multivariate analyses support the hypothesis that differentiation at the level of subchromosomal markers mostly appeared during allopatry. Yet we find no evidence for parallelism between species pairs among lakes, consistent with colonization effect or postcolonization differentiation. The reported intrachromosomal polymorphisms do not appear to play a central role in driving adaptive divergence between normal and dwarf Lake Whitefish. We discuss how chromosomal differentiation in the Lake Whitefish system may contribute to the destabilization of mitotic and meiotic chromosome segregation in hybrids, as documented previously. The chromosome structures detected here are still difficult to sequence and assemble, demonstrating the value of cytogenetics as a complementary approach to understand the genomic bases of speciation.

  2. Species-specific differences in adaptive phenotypic plasticity in an ecologically relevant trophic trait: hypertrophic lips in Midas cichlid fishes.

    PubMed

    Machado-Schiaffino, Gonzalo; Henning, Frederico; Meyer, Axel

    2014-07-01

    The spectacular species richness of cichlids and their diversity in morphology, coloration, and behavior have made them an ideal model for the study of speciation and adaptive evolution. Hypertrophic lips evolved repeatedly and independently in African and Neotropical cichlid radiations. Cichlids with hypertrophic lips forage predominantly in rocky crevices and it has been hypothesized that mechanical stress caused by friction could result in larger lips through phenotypic plasticity. To test the influence of the environment on the size and development of lips, we conducted a series of breeding and feeding experiments on Midas cichlids. Full-sibs of Amphilophus labiatus (thick-lipped) and Amphilophus citrinellus (thin-lipped) each were split into a control group which was fed food from the water column and a treatment group whose food was fixed to substrates. We found strong evidence for phenotypic plasticity on lip area in the thick-lipped species, but not in the thin-lipped species. Intermediate phenotypic values were observed in hybrids from thick- and thin-lipped species reared under "control" conditions. Thus, both a genetic, but also a phenotypic plastic component is involved in the development of hypertrophic lips in Neotropical cichlids. Moreover, species-specific adaptive phenotypic plasticity was found, suggesting that plasticity is selected for in recent thick-lipped species.

  3. Theoretical studies of nonadiabatic and spin-forbidden processes: Investigations of the reactions and spectroscopy of radical species relevant to combustion reactions and diagnostics

    SciTech Connect

    Yarkony, D.R.

    1993-12-01

    This research program focusses on studies of spin-forbidden and electronically nonadiabatic processes involving radical species relevant to combustion reactions and combustion diagnostics. To study the electronic structure aspects of these processes a unique and powerful system of electronic structure programs, developed over the past nine years, the BROOKLYN codes, is employed. These programs enable the authors to address questions basic to the understanding of elementary combustion processes not tractable using more standard quantum chemistry codes.

  4. Identification of clinically relevant Corynebacterium strains by Api Coryne, MALDI-TOF-mass spectrometry and molecular approaches.

    PubMed

    Alibi, S; Ferjani, A; Gaillot, O; Marzouk, M; Courcol, R; Boukadida, J

    2015-09-01

    We evaluated the Bruker Biotyper matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry (MS) for the identification of 97 Corynebacterium clinical in comparison to identification strains by Api Coryne and MALDI-TOF-MS using 16S rRNA gene and hypervariable region of rpoB genes sequencing as a reference method. C. striatum was the predominant species isolated followed by C. amycolatum. There was an agreement between Api Coryne strips and MALDI-TOF-MS identification in 88.65% of cases. MALDI-TOF-MS was unable to differentiate C. aurimucosum from C. minutissimum and C. minutissimum from C. singulare but reliably identify 92 of 97 (94.84%) strains. Two strains remained incompletely identified to the species level by MALDI-TOF-MS and molecular approaches. They belonged to Cellulomonas and Pseudoclavibacter genus. In conclusion, MALDI-TOF-MS is a rapid and reliable method for the identification of Corynebacterium species. However, some limits have been noted and have to be resolved by the application of molecular methods.

  5. Clinical significance of Aeromonas species isolated from patients with diarrhea.

    PubMed

    Moyer, N P

    1987-11-01

    A total of 248 strains of Aeromonas spp. were isolated from 3,334 human fecal specimens submitted to a state public health laboratory over a 2-year period to be cultured for enteric pathogens. Cary-Blair transport medium, blood ampicillin agar, and alkaline peptone water enrichment provided optimal recovery of Aeromonas spp. A questionnaire requesting clinical and epidemiological information was sent to physicians, who submitted stool samples for testing, with each laboratory report for 107 consecutive stool isolates of Aeromonas spp. The 56 questionnaires which were completed and returned were analyzed to determine the seasonal distribution of illness and the age and sex distribution of patients; characteristic symptoms; and predisposing factors for gastrointestinal disease caused by Aeromonas spp. It was concluded that some A. hydrophila, A. sobria, and A. caviae strains are capable of causing diarrhea and that antibiotic therapy and the drinking of untreated water are significant risk factors for susceptible hosts.

  6. Clinical significance of Aeromonas species isolated from patients with diarrhea.

    PubMed Central

    Moyer, N P

    1987-01-01

    A total of 248 strains of Aeromonas spp. were isolated from 3,334 human fecal specimens submitted to a state public health laboratory over a 2-year period to be cultured for enteric pathogens. Cary-Blair transport medium, blood ampicillin agar, and alkaline peptone water enrichment provided optimal recovery of Aeromonas spp. A questionnaire requesting clinical and epidemiological information was sent to physicians, who submitted stool samples for testing, with each laboratory report for 107 consecutive stool isolates of Aeromonas spp. The 56 questionnaires which were completed and returned were analyzed to determine the seasonal distribution of illness and the age and sex distribution of patients; characteristic symptoms; and predisposing factors for gastrointestinal disease caused by Aeromonas spp. It was concluded that some A. hydrophila, A. sobria, and A. caviae strains are capable of causing diarrhea and that antibiotic therapy and the drinking of untreated water are significant risk factors for susceptible hosts. PMID:3693537

  7. Secretion by the nasal salt glands of two insectivorous lizard species is initiated by an ecologically relevant dietary ion, chloride.

    PubMed

    Hazard, Lisa C; Lechuga, Claudia; Zilinskis, Stephanie

    2010-08-01

    Salt glands are used by some vertebrates to excrete hyperosmotic NaCl or KCl solutions in response to dietary salt loads. Control of secretion varies across taxa; some secrete in response to osmotic challenges while others secrete in response to specific dietary ions. We hypothesized that differences in control could be related to different diet-related selective pressures on herbivorous, marine, and insectivorous species. We studied control of secretion and flexibility of cation (sodium or potassium) and anion (chloride or bicarbonate) secretion in two insectivorous lizard species, Schneider's skinks (Eumeces schneideri, Scincidae) and green anoles (Anolis carolinensis, Polychrotidae). Lizards were injected daily for four days with combinations of cations (potassium, sodium, and histidine control) and anions (chloride and acetate control), isoosmotic saline, or sham injection. Secretions were collected daily and analyzed for sodium, potassium, and chloride. Both species secreted only in response to chloride; sodium appeared to have a slight inhibitory effect. Regardless of cation load, skinks secreted a combination of potassium and sodium, while anoles secreted solely potassium. In both species, total cation secretion was matched closely by chloride; very little bicarbonate was secreted. As predicted, secretion in insectivorous lizards was initiated by the dietary ion ecologically most important for these species, chloride, which otherwise cannot be excreted without significant water loss (unlike the cations, which may be excreted as insoluble urate salts). This gives further support to the hypothesis that ecological factors drive the evolution of control mechanisms in lizard salt glands.

  8. Identification of Species of Nontuberculous Mycobacteria Clinical Isolates from 8 Provinces of China

    PubMed Central

    Lian, Lulu; Jiang, Yi; Huang, Mingxiang; Tan, Yunhong; Zhang, Jingrui; Yu, Qin; Liu, Jiao; Dong, Haiyan; Lu, Bing

    2016-01-01

    Pulmonary diseases caused by nontuberculous mycobacteria (NTM) are increasing in incidence and prevalence worldwide. In this study, we identified NTM species of the clinical isolates from 8 provinces in China, in order to preliminarily provide some basic scientific data in the different species and distribution of NTM related to pulmonary disease in China. A total of 523 clinical isolates from patients with tuberculosis (TB) diagnosed clinically from 2005 to 2012 were identified to the species using conventional and molecular methods, including multilocus PCR, rpoB and hsp65 PCR-PRA, hsp65, rpoB, and 16S-23S internal transcribed spacer region sequencing. The isolates were identified into 3 bacterium genera, including NTM, Gordonia bronchialis, and Nocardia farcinica, and, for the 488 NTM isolates, 27 species were identified. For all the 27 species of NTM which were found to cause pulmonary infections in humans, the most prevalent species was M. intracellulare, followed by M. avium and M. abscessus. And seven other species were for the first time identified in patients with TB in China. NTM species identification is very important for distinguishing between tuberculosis and NTM pulmonary diseases, and the species diversity drives the creation of diverse and integrated identification methods with higher accuracy and efficacy. PMID:27882322

  9. Identification of Species of Nontuberculous Mycobacteria Clinical Isolates from 8 Provinces of China.

    PubMed

    Liu, Haican; Lian, Lulu; Jiang, Yi; Huang, Mingxiang; Tan, Yunhong; Zhao, Xiuqin; Zhang, Jingrui; Yu, Qin; Liu, Jiao; Dong, Haiyan; Lu, Bing; Wu, Yimou; Wan, Kanglin

    2016-01-01

    Pulmonary diseases caused by nontuberculous mycobacteria (NTM) are increasing in incidence and prevalence worldwide. In this study, we identified NTM species of the clinical isolates from 8 provinces in China, in order to preliminarily provide some basic scientific data in the different species and distribution of NTM related to pulmonary disease in China. A total of 523 clinical isolates from patients with tuberculosis (TB) diagnosed clinically from 2005 to 2012 were identified to the species using conventional and molecular methods, including multilocus PCR, rpoB and hsp65 PCR-PRA, hsp65, rpoB, and 16S-23S internal transcribed spacer region sequencing. The isolates were identified into 3 bacterium genera, including NTM, Gordonia bronchialis, and Nocardia farcinica, and, for the 488 NTM isolates, 27 species were identified. For all the 27 species of NTM which were found to cause pulmonary infections in humans, the most prevalent species was M. intracellulare, followed by M. avium and M. abscessus. And seven other species were for the first time identified in patients with TB in China. NTM species identification is very important for distinguishing between tuberculosis and NTM pulmonary diseases, and the species diversity drives the creation of diverse and integrated identification methods with higher accuracy and efficacy.

  10. Efficient, Long-term Hepatic Gene Transfer Using Clinically Relevant HDAd Doses by Balloon Occlusion Catheter Delivery in Nonhuman Primates

    PubMed Central

    Brunetti-Pierri, Nicola; Stapleton, Gary E; Law, Mark; Breinholt, John; Palmer, Donna J; Zuo, Yu; Grove, Nathan C; Finegold, Milton J; Rice, Karen; Beaudet, Arthur L; Mullins, Charles E; Ng, Philip

    2008-01-01

    Helper-dependent adenoviral vectors (HDAd) are devoid of all viral coding sequences and are thus an improvement over early generation Ad because they can provide long-term transgene expression in vivo without chronic toxicity. However, high vector doses are required to achieve efficient hepatic transduction by systemic intravenous injection, and this unfortunately results in dose-dependent acute toxicity. To overcome this important obstacle, we have developed a minimally invasive method to preferentially deliver HDAd into the liver of nonhuman primates. Briefly, a balloon occlusion catheter was percutaneously positioned in the inferior vena cava to occlude hepatic venous outflow. HDAd was injected directly into the occluded liver via a percutaneously placed hepatic artery catheter. Compared to systemic vector injection, this approach resulted in substantially higher hepatic transduction efficiency using clinically relevant low vector doses and was accompanied by mild-to-moderate acute but transient toxicities. Transgene expression was sustained for up to 964 days. These results suggest that our minimally invasive method of delivery can significantly improve the vector's therapeutic index and may be a first step toward clinical application of HDAd for liver-directed gene therapy. PMID:19050700

  11. Establishing a Clinically Relevant Large Animal Model Platform for TBI Therapy Development: Using Cyclosporin A as a Case Study

    PubMed Central

    Margulies, Susan S.; Kilbaugh, Todd; Sullivan, Sarah; Smith, Colin; Propert, Kathleen; Byro, Melissa; Saliga, Kristen; Costine, Beth A.; Duhaime, Ann-Christine

    2015-01-01

    We have developed the first immature large animal translational treatment trial of a pharmacologic intervention for traumatic brain injury (TBI) in children. The preclinical trial design includes multiple doses of the intervention in two different injury types (focal and diffuse) to bracket the range seen in clinical injury and uses two post-TBI delays to drug administration. Cyclosporin A (CsA) was used as a case study in our first implementation of the platform because of its success in multiple preclinical adult rodent TBI models and its current use in children for other indications. Tier 1 of the therapy development platform assessed the short-term treatment efficacy after 24 h of agent administration. Positive responses to treatment were compared with injured controls using an objective effect threshold established prior to the study. Effective CsA doses were identified to study in Tier 2. In the Tier 2 paradigm, agent is administered in a porcine intensive care unit utilizing neurological monitoring and clinically relevant management strategies, and intervention efficacy is defined as improvement in longer term behavioral endpoints above untreated injured animals. In summary, this innovative large animal preclinical study design can be applied to future evaluations of other agents that promote recovery or repair after TBI. PMID:25904045

  12. MALDI imaging mass spectrometry reveals multiple clinically relevant masses in colorectal cancer using large-scale tissue microarrays.

    PubMed

    Hinsch, Andrea; Buchholz, Malte; Odinga, Sinje; Borkowski, Carina; Koop, Christina; Izbicki, Jacob R; Wurlitzer, Marcus; Krech, Till; Wilczak, Waldemar; Steurer, Stefan; Jacobsen, Frank; Burandt, Eike-Christian; Stahl, Phillip; Simon, Ronald; Sauter, Guido; Schlüter, Hartmut

    2017-01-24

    For identification of clinically relevant masses to predict status, grade, relapse and prognosis of colorectal cancer we applied MALDI imaging mass spectrometry (IMS) to a tissue micro array (TMA) containing formalin-fixed and paraffin-embedded tissue samples from 349 patients. Analysis of our MALDI-IMS data revealed 27 different m/z signals associated with epithelial structures. Comparison of these signals showed significant association with status, grade and Ki-67 labeling index. 15 out of 27 IMS signals revealed a significant association with survival. For 7 signals (m/z 654, 776, 788, 904, 944, 975, and 1013) the absence, and for 8 signals (m/z 643, 678, 836, 886, 898, 1095, 1459, and 1477) the presence was associated with decreased life expectancy, including 5 masses (m/z 788, 836, 904, 944, and 1013) that provided prognostic information independently from the established prognosticators pT and pN. Combination of these 5 masses resulted in a 3-step classifier that provided prognostic information superior to univariate analysis. In addition, a total of 19 masses were associated with tumor stage, grade, metastasis, and cell proliferation. Our data demonstrate the suitability of combining IMS and large-scale TMAs to simultaneously identify and validate clinically useful molecular marker.

  13. Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury.

    PubMed

    Rizzo, Alicia N; Sammani, Saad; Esquinca, Adilene E; Jacobson, Jeffrey R; Garcia, Joe G N; Letsiou, Eleftheria; Dudek, Steven M

    2015-12-01

    Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), an illness characterized by life-threatening vascular leak, is a significant cause of morbidity and mortality in critically ill patients. Recent preclinical studies and clinical observations have suggested a potential role for the chemotherapeutic agent imatinib in restoring vascular integrity. Our prior work demonstrates differential effects of imatinib in mouse models of ALI, namely attenuation of LPS-induced lung injury but exacerbation of ventilator-induced lung injury (VILI). Because of the critical role of mechanical ventilation in the care of patients with ARDS, in the present study we pursued an assessment of the effectiveness of imatinib in a "two-hit" model of ALI caused by combined LPS and VILI. Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNF-α levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In subsequent experiments focusing on its protective role in LPS-induced lung injury, imatinib attenuated ALI when given 4 h after LPS, suggesting potential therapeutic effectiveness when given after the onset of injury. Mechanistic studies in mouse lung tissue and human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-κB expression and activation. Overall, these results further characterize the therapeutic potential of imatinib against inflammatory vascular leak.

  14. Establishing a Clinically Relevant Large Animal Model Platform for TBI Therapy Development: Using Cyclosporin A as a Case Study.

    PubMed

    Margulies, Susan S; Kilbaugh, Todd; Sullivan, Sarah; Smith, Colin; Propert, Kathleen; Byro, Melissa; Saliga, Kristen; Costine, Beth A; Duhaime, Ann-Christine

    2015-05-01

    We have developed the first immature large animal translational treatment trial of a pharmacologic intervention for traumatic brain injury (TBI) in children. The preclinical trial design includes multiple doses of the intervention in two different injury types (focal and diffuse) to bracket the range seen in clinical injury and uses two post-TBI delays to drug administration. Cyclosporin A (CsA) was used as a case study in our first implementation of the platform because of its success in multiple preclinical adult rodent TBI models and its current use in children for other indications. Tier 1 of the therapy development platform assessed the short-term treatment efficacy after 24 h of agent administration. Positive responses to treatment were compared with injured controls using an objective effect threshold established prior to the study. Effective CsA doses were identified to study in Tier 2. In the Tier 2 paradigm, agent is administered in a porcine intensive care unit utilizing neurological monitoring and clinically relevant management strategies, and intervention efficacy is defined as improvement in longer term behavioral endpoints above untreated injured animals. In summary, this innovative large animal preclinical study design can be applied to future evaluations of other agents that promote recovery or repair after TBI.

  15. Combined effect of clinically relevant doses of emitefur, a new 5-fluorouracil derivative, and radiation in murine tumours.

    PubMed Central

    Shibamoto, Y.; Murata, R.; Miyauchi, S.; Hirohashi, M.; Takagi, T.; Sasai, K.; Shibata, T.; Oya, N.; Takahashi, M.

    1996-01-01

    We investigated the combined effect of radiation and clinically relevant doses of emitefur (BOF-A2), a newly developed anti-cancer agent consisting of a masked form of 5-fluorouracil (5-FU) and a potent inhibitor of 5-FU degradation, in two types of murine tumours. In preliminary pharmacokinetic studies, the area under the curve for 5-FU in plasma, after administration of 12.5 mg kg-1 and 25 mg kg-1 emitefur in mice, appeared to be similar to that obtained on the first day and that on the seventh day, respectively, after starting administration of 400-600 mg day-1 in humans. These doses (12.5 and 25 mg kg-1) of emitefur were evaluated either alone or in combination with single (15 Gy), five-fraction (4 Gy each) or ten-fraction (2.8 Gy each) irradiation using a tumour growth delay assay for SCCVII tumours and in combination with four-fraction (5 Gy each) irradiation using an in vivo-in vitro assay for EMT6 tumours. The anti-tumour and radiation-enhancing effects of 12.5 mg kg-1 emitefur were not significant in any except the ten-fraction experiment. On the other hand, multiple doses of 25 mg kg-1 emitefur given either alone or in combination with radiation produced marked effects. The mean tumour growth delay time (the time to double in volume for treated tumours minus that for untreated tumours) was 8.1 days for five administrations of 25 mg kg-1 emitefur. 10.4 days for five fractions of 4 Gy and 22.1 days for five treatments with the combination of the two. Thus, the increase in growth delay afforded by this combination was at least additive. The effect of four fractions of 5 Gy with 25 mg kg-1 emitefur in EMT6 tumours was lower than that of four fractions of 7.5 Gy, but the effect of five fractions of 4 Gy with this dose of emitefur in SCCVII tumours was similar to the effect of five fractions of 6 Gy, and the effect of ten fractions of 2.8 Gy with 25 mg kg-1 emitefur was much higher than that of ten fractions of 4.2 Gy. In conclusion, emitefur given either alone

  16. The relevance of "non-criteria" clinical manifestations of antiphospholipid syndrome: 14th International Congress on Antiphospholipid Antibodies Technical Task Force Report on Antiphospholipid Syndrome Clinical Features.

    PubMed

    Abreu, Mirhelen M; Danowski, Adriana; Wahl, Denis G; Amigo, Mary-Carmen; Tektonidou, Maria; Pacheco, Marcelo S; Fleming, Norma; Domingues, Vinicius; Sciascia, Savino; Lyra, Julia O; Petri, Michelle; Khamashta, Munther; Levy, Roger A

    2015-05-01

    The purpose of this task force was to critically analyze nine non-criteria manifestations of APS to support their inclusion as APS classification criteria. The Task Force Members selected the non-criteria clinical manifestations according to their clinical relevance, that is, the patient-important outcome from clinician perspective. They included superficial vein thrombosis, thrombocytopenia, renal microangiopathy, heart valve disease, livedo reticularis, migraine, chorea, seizures and myelitis, which were reviewed by this International Task Force collaboration, in addition to the seronegative APS (SN-APS). GRADE system was used to evaluate the quality of evidence of medical literature of each selected item. This critical appraisal exercise aimed to support the debate regarding the clinical picture of APS. We found that the overall GRADE analysis was very low for migraine and seizures, low for superficial venous thrombosis, thrombocytopenia, chorea, longitudinal myelitis and the so-called seronegative APS and moderate for APS nephropathy, heart valve lesions and livedo reticularis. The next step can be a critical redefinition of an APS gold standard, for instance derived from the APS ACTION registry that will include not only current APS patients but also those with antiphospholipid antibodies not meeting current classification criteria.

  17. Vasopressin in Preeclampsia: A Novel Very-Early Human Pregnancy Biomarker and Clinically-Relevant Mouse Model

    PubMed Central

    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.

    2014-01-01

    Preeclampsia, a cardiovascular disorder of late pregnancy, is characterized as a low-renin hypertensive state relative to normotensive pregnancy. As other non-pregnant low-renin hypertensive disorders often exhibit and are occasionally dependent upon elevated arginine vasopressin (AVP) secretion, we hypothesized a possible use for plasma AVP measurements in the prediction of preeclampsia. Copeptin is an inert pro-segment of AVP that is secreted in a 1:1 molar ratio and exhibits a substantially longer biological half-life than 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, BMI, chronic essential hypertension, twin gestation, diabetes, 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 6th 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/hr) is sufficient to phenocopy preeclampsia in C57BL/6J mice, causing pregnancy-specific hypertension, renal glomerular endotheliosis, proteinuria, and intrauterine growth restriction. These data (1) implicate AVP release as a novel predictive biomarker for preeclampsia very early in pregnancy, (2) identify chronic AVP infusion as a novel and clinically-relevant model of preeclampsia in mice, and are (3) consistent with a potential causative role for AVP in preeclampsia in humans. PMID:25001273

  18. Latrodectism: variations in clinical manifestations provoked by Latrodectus species of spiders.

    PubMed

    Maretić, Z

    1983-01-01

    The clinical picture caused by the bite of Latrodectus spp. is described, including the patient's general condition with agonizing pains, cramps, spasms, motor unrest, boardlike abdomen, "facies latrodectismica", sweating, oliguria, hypertension, anxiety, mental excitation and an extended convalescence. The notorious biters are mainly L. mactans, L. variolus, L. hesperus, L. tredecimguttatus, L. hasselti, L. indistinctus and L. menavodi, all of which appear to provoke somewhat similar clinical pictures. For some species, however, there is limited data and for the toxicity of some spiders, such as L. rhodesiensis, no data are available, However, it would appear that the clinical manifestations of the venom are similar in all species.

  19. A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity

    SciTech Connect

    Kostadinova, Radina; Boess, Franziska; Suter, Laura; Weiser, Thomas; Singer, Thomas; Roth, Adrian

    2013-04-01

    Drug-induced liver injury (DILI) is the major cause for liver failure and post-marketing drug withdrawals. Due to species-specific differences in hepatocellular function, animal experiments to assess potential liabilities of drug candidates can predict hepatotoxicity in humans only to a certain extent. In addition to animal experimentation, primary hepatocytes from rat or human are widely used for pre-clinical safety assessment. However, as many toxic responses in vivo are mediated by a complex interplay among different cell types and often require chronic drug exposures, the predictive performance of hepatocytes is very limited. Here, we established and characterized human and rat in vitro three-dimensional (3D) liver co-culture systems containing primary parenchymal and non-parenchymal hepatic cells. Our data demonstrate that cells cultured on a 3D scaffold have a preserved composition of hepatocytes, stellate, Kupffer and endothelial cells and maintain liver function for up to 3 months, as measured by the production of albumin, fibrinogen, transferrin and urea. Additionally, 3D liver co-cultures maintain cytochrome P450 inducibility, form bile canaliculi-like structures and respond to inflammatory stimuli. Upon incubation with selected hepatotoxicants including drugs which have been shown to induce idiosyncratic toxicity, we demonstrated that this model better detected in vivo drug-induced toxicity, including species-specific drug effects, when compared to monolayer hepatocyte cultures. In conclusion, our results underline the importance of more complex and long lasting in vitro cell culture models that contain all liver cell types and allow repeated drug-treatments for detection of in vivo-relevant adverse drug effects. - Highlights: ► 3D liver co-cultures maintain liver specific functions for up to three months. ► Activities of Cytochrome P450s remain drug- inducible accross three months. ► 3D liver co-cultures recapitulate drug-induced liver toxicity

  20. Effect of Transmission Setting and Mixed Species Infections on Clinical Measures of Malaria in Malawi

    PubMed Central

    Bruce, Marian C.; Macheso, Allan; Kelly-Hope, Louise A.; Nkhoma, Standwell; McConnachie, Alex; Molyneux, Malcolm E.

    2008-01-01

    Background In malaria endemic regions people are commonly infected with multiple species of malaria parasites but the clinical impact of these Plasmodium co-infections is unclear. Differences in transmission seasonality and transmission intensity between endemic regions have been suggested as important factors in determining the effect of multiple species co-infections. Principal Findings In order to investigate the impact of multiple-species infections on clinical measures of malaria we carried out a cross-sectional community survey in Malawi, in 2002. We collected clinical and parasitological data from 2918 participants aged >6 months, and applied a questionnaire to measure malaria morbidity. We examined the effect of transmission seasonality and intensity on fever, history of fever, haemoglobin concentration ([Hb]) and parasite density, by comparing three regions: perennial transmission (PT), high intensity seasonal transmission (HIST) and low intensity seasonal transmission (LIST). These regions were defined using multi-level modelling of PCR prevalence data and spatial and geo-climatic measures. The three Plasmodium species (P. falciparum, P. malariae and P. ovale) were randomly distributed amongst all children but not adults in the LIST and PT regions. Mean parasite density in children was lower in the HIST compared with the other two regions. Mixed species infections had lower mean parasite density compared with single species infections in the PT region. Fever rates were similar between transmission regions and were unaffected by mixed species infections. A history of fever was associated with single species infections but only in the HIST region. Reduced mean [Hb] and increased anaemia was associated with perennial transmission compared to seasonal transmission. Children with mixed species infections had higher [Hb] in the HIST region. Conclusions Our study suggests that the interaction of Plasmodium co-infecting species can have protective effects against