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Major Obstacle (major + obstacle)
Selected AbstractsTopical tacrolimus in the management of atopic dermatitis in JapanDERMATOLOGIC THERAPY, Issue 2 2006Masutaka Furue ABSTRACT:, Atopic dermatitis (AD) is a common, chronic, relapsing, severely pruritic, eczematous skin disease. Topical steroids are the mainstay of treatment. However, the adverse effects of steroids on hormonal function are the major obstacle for their use as long-term topical therapy. Topical calcineurin inhibitors, such as tacrolimus, not only complement existing treatment options but also overcome some of the drawbacks of topical steroid therapy and fulfill the long-term needs of patients in preventing disease progression. Short- and long-term efficacy and safety of topical tacrolimus has been widely recognized and it is also accepted as a first-line treatment for the inflammation of AD. In order to reduce the possible long-term adverse effects, it is important to monitor the clinical dose in daily clinics. [source] Ploidy mosaicism in well-developed nuclear transplants produced by transfer of adult somatic cell nuclei to nonenucleated eggs of medaka (Oryzias latipes)DEVELOPMENT GROWTH & DIFFERENTIATION, Issue 9 2007Elena Kaftanovskaya Chromosomal abnormalities such as ploidy mosaicism have constituted a major obstacle to the successful nuclear transfer of adult somatic cell nuclei in lower vertebrates to date. Euploid mosaicism has been reported previously in well-developed amphibian transplants. Here, we investigated ploidy mosaicisms in well-developed transplants of adult somatic cell nuclei in medaka fish (Oryzias latipes). Donor nuclei from primary cultured cells from the adult caudal fin of a transgenic strain carrying the green fluorescent protein gene (GFP) were transferred to recipient nonenucleated eggs of a wild-type strain to produce 662 transplants. While some of the transplants developed beyond the body formation stage and several hatched, all exhibited varying degrees of abnormal morphology, limited growth and subsequent death. Twenty-one transplants, 19 embryos and two larvae, were selected for chromosomal analysis; all were well-developed 6-day-old or later embryonic stages exhibiting slight morphological abnormalities and the same pattern of GFP expression as that of the donor strain. In addition, all exhibited various levels of euploid mosaicism with haploid-diploid, haploid-triploid or haploid-diploid-triploid chromosome sets. No visible chromosomal abnormalities were observed. Thus, euploid mosaicism similar to that observed in amphibians was confirmed in well-developed nuclear transplants of fish. [source] The mechanisms that underlie glucose sensing during hypoglycaemia in diabetesDIABETIC MEDICINE, Issue 5 2008R. McCrimmon Abstract Hypoglycaemia is a frequent and greatly feared side-effect of insulin therapy, and a major obstacle to achieving near-normal glucose control. This review will focus on the more recent developments in our understanding of the mechanisms that underlie the sensing of hypoglycaemia in both non-diabetic and diabetic individuals, and how this mechanism becomes impaired over time. The research focus of my own laboratory and many others is directed by three principal questions. Where does the body sense a falling glucose? How does the body detect a falling glucose? And why does this mechanism fail in Type 1 diabetes? Hypoglycaemia is sensed by specialized neurons found in the brain and periphery, and of these the ventromedial hypothalamus appears to play a major role. Neurons that react to fluctuations in glucose use mechanisms very similar to those that operate in pancreatic B- and A-cells, in particular in their use of glucokinase and the KATP channel as key steps through which the metabolic signal is translated into altered neuronal firing rates. During hypoglycaemia, glucose-inhibited (GI) neurons may be regulated by the activity of AMP-activated protein kinase. This sensing mechanism is disturbed by recurrent hypoglycaemia, such that counter-regulatory defence responses are triggered at a lower glucose level. Why this should occur is not yet known, but it may involve increased metabolism or fuel delivery to glucose-sensing neurons or alterations in the mechanisms that regulate the stress response. [source] Recent advances in treatment of youth with Type 1 diabetes: better care through technologyDIABETIC MEDICINE, Issue 11 2001W. V. Tamborlane Abstract While treatment of Type 1 diabetes mellitus (T1DM) in children and adolescents is especially difficult, recent technological advances have provided new therapeutic options to clinicians and patients. The urgency to achieve strict diabetes control and the introduction of new and improved insulin pumps have been accompanied by a marked increase in use of continuous subcutaneous insulin infusion (CSII) therapy in youth with diabetes. Results of clinical outcome studies indicate that CSII provides a safe and effective alternative to multiple daily injection (MDI) therapy, even when employed in a regular clinic setting in a large number of children. The safety and efficacy of CSII is further enhanced by the introduction of lispro and aspart insulin. The sharper peaks and shorter duration of action of these very rapid-acting insulin analogues provides a means to achieve better control of post-prandial hyperglycaemia with less late post-prandial and nocturnal hypoglycaemia. Glargine insulin, a soluble and essentially peakless long-acting insulin analogue, may provide a better basal insulin for MDI regimens, but there are limited published data with this agent in children with T1DM. A number of systems for pulmonary delivery of insulin are in development and preliminary results of Phase III studies have been promising. Like CSII, inhaled insulin allows the child to take bolus insulin doses before each meal without having to take a premeal injection. A major obstacle to effective treatment is that self-monitoring of three to four blood glucose levels a day often misses the marked glycaemic excursions that characterize T1DM in young patients. On the other hand, new continuous glucose sensing systems provide a wealth of data that can be used to optimize basal and bolus therapy, regardless of how insulin is administered. Even more important, we may finally be at the threshold of development of a practically applicable artificial pancreas. Diabet. Med. 18, 864,870 (2001) [source] Upregulation of glycolytic enzymes in proteins secreted from human colon cancer cells with 5-fluorouracil resistanceELECTROPHORESIS, Issue 12 2009Young-Kyoung Shin Abstract 5-Fluorouracil (5-FU) is the most commonly used chemotherapeutic agent for colorectal cancer (CRC). However, resistance to this drug is a major obstacle in CRC chemotherapy. Accurate prediction of response to 5-FU would avoid unnecessary chemotherapy and allow the selection of other effective drugs. To identify a candidate predictor of 5-FU resistance, we isolated secreted proteins that were up- or downregulated in a 5-FU-resistant cancer cell line, compared with the parent cell line (SNU-C4), using a stable isotope-coded labeling protocol. For validating the clinical applicability of this method, levels of the identified proteins were determined in the sera of 46 patients treated with 5-FU. In total, 238 proteins with molecular weights ranging from 50 to 75,kDa were identified. Among these, 45 and 35 secreted proteins were up- and downregulated in the 5-FU-resistant cell line, respectively. We observed significant upregulation of glycolytic enzymes, including glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase M2 (PK-M2), transketolase, and NADP(+)-dependent malic enzyme 1. In particular, the level of PK-M2, a key enzyme in the glycolytic pathway, showed an increasing tendency in both sera and tissues from CRC patients displaying no response to 5-FU-based chemotherapy (progressive and stable disease cases), compared with that in complete or partial responders to 5-FU-based chemotherapy; however, it did not reach the statistical significance. In conclusion, increasing pattern of PK-M2 observed with 5-FU resistance induced in vitro and in sera and tissues from CRC patients displaying poor response to 5-FU-based chemotherapy suggest the relevance of dysregulated glycolysis and 5-FU-resistant CRC. [source] Family member presence during resuscitation in the emergency department: An Australian perspectiveEMERGENCY MEDICINE AUSTRALASIA, Issue 4 2004Bernice Redley Abstract Objective: The practice of family member presence during resuscitation in the ED has attracted widespread attention over the last few decades. Despite the recommendations of international organizations, clinical staff remain reluctant to engage in this practice in many EDs. This paper separates the evidence from opinion to determine the current state of knowledge about this practice. Methods: A search strategy was developed and used to locate research based publications, which were subsequently reviewed for the strength of evidence providing the basis for recommendations. Results: The literature was examined to reveal what patients and their family members want; the outcomes of family presence during resuscitation for patients and their family members; staff views and practices regarding family presence during resuscitation. Findings suggest that providing the opportunity to be with their critically ill family member is both important to and beneficial for families, however, disparity in staff views has been identified as a major obstacle to family presence during resuscitation. Examination of published guidelines and staff practices described in the literature revealed consistent elements. Conclusion: Although critics point to the lack of rigour in this body of literature, the current state of knowledge suggests merit in pursuing future research to examine and measure effects of family member presence during resuscitation on patients, family members and healthcare providers. [source] Targeted inhibition of IL-10-secreting CD25, Treg via p38 MAPK suppression in cancer immunotherapyEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2010Kozo Ohkusu-Tsukada Abstract Cancer-induced immunotolerance mediated by inducible Treg (iTreg) is a major obstacle to cancer immunotherapy. In a basic study of immunotolerance, injection of an endogenous superantigen, i.e. the minor lymphocyte stimulatory (Mls)-1a, into specific TCR V,8.1-Tg mice enabled generation of anergic CD25, iTreg, the immunosuppressive function of which was maintained by IL-10 production via p38-MAPK activation. Interestingly, although p38-chemical inhibitor (p38-inhibitor) is capable of breaking CD25, iTreg-induced immunotolerance, the p38-inhibitor had hardly any immunotolerance breaking effect when CD25+ Treg were present, suggesting that depletion of CD25+ Treg is necessary for p38-inhibitor to be effective. Peptide OVA323,339iv.- injection into its specific TCR-Tg (OT-II) mice also induced adaptive tolerance by iTreg. Peptide immunotherapy with p38-inhibitor after CD25+ Treg-depletion was performed in an OVA-expressing lymphoma E.G7-bearing tolerant model established by adoptive transfer of OT-II CD25, iTreg, which resulted in suppression of tumor growth. Similarly, the antitumor immunity induced by peptide immunotherapy in colon carcinoma CT26-bearing mice, in which the number of IL-10-secreting iTreg is increased, was augmented by treatment with p38-inhibitor after CD25+ Treg-depletion and resulted in inhibition of tumor progression. These results suggest that simultaneous inhibition of two distinct Treg-functions may be important to the success of cancer immunotherapy. [source] Heterologous expression of nonribosomal peptide synthetases in B. subtilis: construction of a bi-functional B. subtilis/E. coli shuttle vector systemFEMS MICROBIOLOGY LETTERS, Issue 2 2002Sascha Doekel Abstract A major obstacle in investigating the biosynthesis of pharmacologically important peptide antibiotics is the heterologous expression of the giant biosynthetic genes. Recently, the genetically engineered strain Bacillus subtilis KE30 has been reported as an excellent surrogate host for the heterologous expression of an entire nonribosomal peptide synthetase (NRPS) gene cluster. In this study, we expand the applicability of this strain, by the development of four Escherichia coli/B. subtilis shuttle expression vectors. Comparative overproduction of hybrid NRPS proteins derived from both organisms revealed a significant beneficial effect of overproducing proteins in B. subtilis KE30 as underlined by the production of stable nondegradative proteins, as well as the formation of active phosphopantetheinylated holo-proteins. [source] Reference Minerals for the Microanalysis of Light ElementsGEOSTANDARDS & GEOANALYTICAL RESEARCH, Issue 2-3 2001M. Darby Dyar tourmaline; danburite; spodumène; muscovite; isotopes The quantitative determination of light element concentrations in geological specimens represents a major analytical challenge as the electron probe is generally not suited to this task. With the development of new in situ analytical techniques, and in particular the increasing use of secondary ion mass spectrometry, the routine determination of Li, Be and B contents has become a realistic goal. However, a major obstacle to the development of this research field is the critical dependence of SIMS on the availability of well characterized, homogeneous reference materials that are closely matched in matrix (composition and structure) to the sample being studied. Here we report the first results from a suite of large, gem crystals which cover a broad spectrum of minerals in which light elements are major constituents. We have characterized these materials using both in situ and wet chemical techniques. The samples described here are intended for distribution to geochemical laboratories active in the study of light elements. Further work is needed before reference values for these materials can be finalized, but the availability of this suite of materials represents a major step toward the routine analysis of the light element contents of geological specimens. La détermination quantitative des concentrations en éléments légers dans les échantillons géologiques représente un défi analytique majeur, la sonde électronique ne convenant généralement pas pour ce travail. Avec le développement de nouvelles techniques analytiques in situ, en particulier l'utilisation grandissante de la spectrométrie ionique secondaire, la détermination en routine des teneurs en Li, Be et B est devenue un objectif réaliste. Toutefois, un obstacle majeur dans le développement de cette recherche subsiste : la technique SIMS est dépendante de la disponibilité de matériaux de référence bien caractérisés et homogènes proches en composition et en structure de l'échantillon étudié. Nous rapportons ici les premiers résultats obtenus à partie d'un groupe de grands cristaux de qualité gemme recouvrant un large spectre de minéraux composés essentiellement d'éléments légers. Nous avons caractérisé ces matériaux en utilisant à la fois des techniques in situ et par voie humide. Les échantillons décrits ici vont être distribués dans les laboratoires de géochimie spécialisés dans l'étude des éléments légers. Avant la conclusion des valeurs de référence de ces matériaux, des travaux ultérieurs seront nécessaires, mais la disponibilité de l'ensemble de ces matériaux représente une étape importante vers l'analyse en routine des teneurs en éléments légers d'échantillons géologiques. [source] Diabetes mellitus and geriatric syndromesGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 2 2009Atsushi Araki Diabetes mellitus is associated with an increased prevalence and incidence of geriatric syndrome: functional disabilities, depression, fall, urinary incontinence, malnutrition and cognitive impairment. Geriatric syndrome not only leads to frailty, loss of independence and low quality of life, but also becomes a major obstacle in the treatment and care of diabetic people. The risk factors or contributing factors of geriatric symptoms are micro- and macrovascular complications, age-rated comorbid disease and aging per se. Comprehensive geriatric assessment of geriatric syndrome, including basic activities of daily living, instrumental activities of daily living, gait and balance, visual acuity, the Mini-Mental State Examination, depression scores, history and risk of fall, urination and nutrition, should be performed as part of the care of elderly diabetic patients, in particular old-old patients. Because geriatric syndromes are multifactorial and share risk factors, diabetic people with any geriatric symptoms should be treated with a common concentric strategy, such as supervised exercise therapy including muscle-strengthening training, psychological support, social support for adherence, and good glycemic control with avoidance of hypoglycemia. [source] Octamer 4 (Oct4) mediates chemotherapeutic drug resistance in liver cancer cells through a potential Oct4,AKT,ATP-binding cassette G2 pathway,HEPATOLOGY, Issue 2 2010Xiao Qi Wang Chemoresistance presents a major obstacle to the efficacy of chemotherapeutic treatment of cancers. Using chemotherapeutic drugs to select drug-resistant cancer cells in hepatocellular carcinoma (HCC) and several other cancer cell lines, we demonstrate that chemoresistant cells displayed cancer stem cell features, such as increased self-renewal ability, cell motility, multiple drug resistance, and tumorigenicity. Octamer 4 (Oct4) messenger RNA (mRNA) levels were dramatically increased in chemoresistant cancer cells due to DNA demethylation regulation of Oct4. By functional study, Oct4 overexpression enhanced whereas Oct4 knockdown reduced liver cancer cell resistance to chemotherapeutic drugs in vitro and in xenograft tumors. It is known that the Oct4-TCL1-AKT pathway acts on embryonic stem cells and cancer stem cells in cell proliferation through inhibition of apoptosis. We further demonstrate that Oct4 overexpression induced activation of TCL1, AKT, and ABCG2 to mediate chemoresistance, which can be overcome by addition of the PI3K/AKT inhibitor; therefore, a direct pathway of Oct4-TCL1-AKT-ABCG2 or a combination of Oct4-TCL1-AKT with the AKT-ABCG2 pathway could be a potential new mechanism involved in liver cancer cell chemoresistance. Moreover, the clinical significance of the Oct4-AKT-ABCG2 pathway can be demonstrated in HCC patients, with a strong correlation of expression patterns in human HCC tumors. The role of the Oct4-AKT-ABCG2 axis in cancer cell chemoresistant machinery suggests that AKT pathway inhibition (PI3K inhibitors) not only inhibits cancer cell proliferation, but may also enhance chemosensitivity by target potential chemoresistant cells. Conclusion: Oct4, a transcriptional factor of pluripotent cells, can mediate chemoresistance through a potential Oct4-AKT-ABCG2 pathway. (HEPATOLOGY 2010;) [source] Prevalence of drug resistance and importance of viral load measurements in Honduran HIV-infected patients failing antiretroviral treatmentHIV MEDICINE, Issue 2 2010W Murillo Objective The Honduran HIV/AIDS Program began to scale up access to HIV therapy in 2002. Up to May 2008, more than 6000 patients received combination antiretroviral therapy (cART). As HIV drug resistance is the major obstacle for effective treatment, the purpose of this study was to assess the prevalence of antiretroviral drug resistance in Honduran HIV-1-infected individuals. Methods We collected samples from 138 individuals (97 adults and 41 children) on cART with virological, immunological or clinical signs of treatment failure. HIV-1 pol sequences were obtained using an in-house method. Resistance mutations were identified according to the 2007 International AIDS Society (IAS)-USA list and predicted susceptibility to cART was scored using the anrs algorithm. Results Resistance mutations were detected in 112 patients (81%), 74% in adults and 98% in children. Triple-, dual- and single-class drug resistance was documented in 27%, 43% and 11% of the study subjects, respectively. Multiple logistic regression showed that resistance was independently associated with type of treatment failure [virological failure (odds ratio (OR)=1) vs. immunological failure (OR=0.11; 95% confidence interval (CI) 0.030,0.43) vs. clinical failure (OR=0.037; 95% CI 0.0063,0.22)], route of transmission (OR=42.8; 95% CI 3.73,491), and years on therapy (OR=1.81; 95% CI 1.11,2.93). Conclusion The prevalence of antiretroviral resistance was high in Honduran HIV-infected patients with signs of treatment failure. A majority of study subjects showed dual- or triple-class resistance to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors and protease inhibitors. Virologically defined treatment failure was a strong predictor of resistance, indicating that viral load testing is needed to correctly identify patients with treatment failure attributable to resistance. [source] Peptide-,2-microglobulin-major histocompatibility complex expressing cells are potent antigen-presenting cells that can generate specific T cellsIMMUNOLOGY, Issue 1 2007Sonja Obermann Summary Adoptive T-cell therapy represents a promising therapeutic approach for the treatment of cancer. Successful adoptive immunotherapy depends on the ex vivo priming and expansion of antigen-specific T cells. However, the in vitro generation of adequate numbers of functional antigen-specific T cell remains a major obstacle. It is important to develop efficient and reproducible methods to generate high numbers of antigen-specific T cells for adoptive T-cell transfer. We have developed a new artificial antigen-presenting cell (aAPC) by transfection of major histocompatibility (MHC) class I negative Daudi cells with a peptide-,2-microglobulin,MHC fusion construct (single-chain aAPC) ensuring presentation of the peptide,MHC complex of interest. Using this artificial antigen-presenting cell, we could generate up to 9·2 × 108 antigen-specific cytotoxic CD8+ T cells from 10 ml blood. In vitro generated T cells lysed endogenously presented antigens. Direct comparison of the single-chain aAPC with autologous monocyte-derived dendritic cells demonstrated that these cells were equally efficient in stimulation of T cells. Finally, we were able to generate antigen-specific T cell lines from perpheral blood mononuclear cells of patients receiving cytotoxic chemotherapy. The use of single-chain aAPC represent a promising option for the generation of antigen-specific CD8+ T cells, which could be used for adoptive T-cell therapy. [source] Association of genomic imbalances with drug resistance and thermoresistance in human gastric carcinoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2003Holger Tönnies Abstract Therapy resistance is the major obstacle to advances in successful cancer treatment. To characterize chromosomal alterations associated with different types of acquired MDR and thermoresistance, we applied CGH to compare a unique panel of human gastric carcinoma cells consisting of the parental, drug-sensitive and thermosensitive cancer cell line EPG85-257P, the atypical MDR variant EPG85-257RNOV, the classical MDR subline EPG85-257RDB and their thermoresistant counterparts EPG85-257P-TR, EPG85-257RNOV-TR and EPG85-257RDB-TR. CGH with genomic DNA prepared from these cell lines as probes successfully identified genomic gains and/or losses in chromosomal regions encoding putative genes associated with drug resistance and/or thermoresistance. These genes included various members of the families of ABC transporters and molecular chaperones. The importance of these cell variant-specific genomic imbalances in the development of MDR and thermoresistance is discussed and remains to be elucidated. © 2002 Wiley-Liss, Inc. [source] Possible impacts of anthropogenic and natural aerosols on Australian climate: a reviewINTERNATIONAL JOURNAL OF CLIMATOLOGY, Issue 4 2009Leon D. Rotstayn Abstract A review is presented of the aerosol,climate interaction with specific focus on the Australian region. The uncertainties associated with this interaction are much larger than those associated with greenhouse gases or other forcing agents, and are currently a major obstacle in climate-change research. However, new research suggests that aerosol effects are of comparable importance to greenhouse gases as a driver of recent climate trends in the Southern Hemisphere, including Australia. A significant new result from climate modelling is that anthropogenic aerosol over Asia affects meridional temperature gradients and atmospheric circulation, and may have caused an increase in rainfall over north-western Australia. Global ocean circulation provides another mechanism whereby aerosol changes in the Northern Hemisphere can affect climate in the Southern Hemisphere, suggesting an urgent need for further targeted studies using coupled ocean-atmosphere global climate models. To better model climate variability and climate change in the Australian region, more research is needed into the sources of aerosol and their precursors, their atmospheric distributions and transformations, and how to incorporate these processes robustly in global climate models (GCMs). The following priorities are suggested for further research in Australia linking aerosol observations and modelling: natural aerosol over the Southern Ocean, tropical biomass-burning aerosol in Indonesia and Australia, secondary organic aerosol (SOA) from volatile organic compounds (VOCs), wind-blown dust and modulation of rainfall by anthropogenic aerosol. Copyright © 2008 Royal Meteorological Society [source] Role of the MRP1/ABCC1 Multidrug Transporter Protein in CancerIUBMB LIFE, Issue 12 2007Marcia Munoz Abstract Multidrug resistance is a major obstacle to cancer treatment and leads to poor prognosis for the patient. Multidrug resistance-associated protein 1 (MRP1) transports a wide range of therapeutic agents as well as diverse physiological substrates and may play a role in the development of drug resistance in several cancers including those of the lung, breast and prostate, as well as childhood neuroblastoma. The majority of patients with neuroblastoma present with widely disseminated disease at diagnosis and despite intensive treatment, the prognosis for such patients is dismal. There is increasing evidence that MRP1 is a MYCN target gene involved in the development of multidrug resistance in neuroblastoma. Given the importance of MRP1 overexpression in neuroblastoma, MRP1 inhibition may be a clinically relevant approach to improving patient outcome in this disease. [source] Users' views of prison health services: a qualitative studyJOURNAL OF ADVANCED NURSING, Issue 3 2007Louise Condon Abstract Title. Users' views of prison health services: a qualitative study. Aim., This paper is a report of a study of the views of prisoners about health services provided in prisons. Background., Prison provides an opportunity for a ,hard to reach' group to access health services, primarily those provided by nurses. Prisoners typically have high health and social needs, but the views and experiences of prisoners about health services in prison have not been widely researched. Method., Semi-structured interviews were carried out with 111 prisoners in purposively selected 12 prisons in England in 2005. Interviews covered both prisoners' views of health services and their own ways of caring for their health in prison. Interviews were analysed to develop a conceptual framework and identify dominant themes. Findings., Prisoners considered health services part of a personal prison journey, which began at imprisonment and ended on release. For those who did not access health services outside prison, imprisonment improved access to both mental and physical health services. Prisoners identified accessing services, including those provided by nurses, confidentiality, being seen as a ,legitimate' patient and living with a chronic condition as problems within the prison healthcare system. At all points along the prison healthcare journey, the prison regime could conflict with optimal health care. Conclusion., Lack of autonomy is a major obstacle to ensuring that prisoners' health needs are fully met. Their views should be considered when planning, organizing and delivering prison health services. Further research is needed to examine how nurses can ensure a smooth journey through health care for prisoners. [source] Cardiotoxicity of doxorubicin/paclitaxel combination in rats: Effect of sequence and timing of administrationJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 2 2004Sherif Y. Saad Abstract The higher incidence of cardiotoxicity of doxorubicin (DOX)/paclitaxel (PTX) combination compared with DOX alone remains to be a major obstacle against effective chemotherapeutic treatment. We investigated the effect of sequence and time interval between administration of both drugs on the severity of cardiotoxicity of the combination. Male Wistar rats were divided into seven groups. DOX was administeded intraperitoneally (ip) at a single dose of 5 mg kg,1 every other 2 days, 2 doses per week for a total cumulative dose of 20 mg kg,1. PTX was administered by an ip route at a dose of 20 mg kg,1 every other 2 days. Both drugs were injected either alone or sequentially in combination. In one case, DOX preceded PTX by 30 min and 24 h and in the other case, PTX preceded DOX by 30 min and 24 h. Cardiotoxicity was evaluated by both biochemical and histopathological examination, 48 h after the last DOX dose. DOX-induced cardiotoxicity was manifested by abnormal biochemical changes including marked increases in serum creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-Px), and aspartate aminotransferase (AST) activity levels. Myocardial tissue from DOX-treated rats showed significant increases in malondialdehyde (MDA) production and total nitrate/nitrite (NOx) levels, parallel with depletion of "endogenous antioxidant reserve," including GSH contents and GSH-Px activity level. PTX treatment produced significant changes in the biochemical parameters measured by a lower magnitude than those changes produced by DOX alone. Combination of both drugs resulted in aggravation of DOX-induced cardiotoxicity regardless the sequence and time interval between administration of either drug. Administration of PTX 30 min and 24 h after DOX treatment showed exaggeration of combination-induced cardiotoxicity compared with the reverse sequence. This exacerbation was manifested by much more pronounced changes in serum and cardiac tissue parameters measured. Histopathological examination of ventricles of rat's heart revealed that DOX treatment produced myo-cytolysis and myocardial necrosis. Administration of PTX following DOX treatment showed extensive myocardial necrosis compared with those rats treated with either DOX alone or the reverse sequence of administration. Moreover, rats treated with PTX 24 h after DOX treatment showed exaggeration of the combination-induced cardiotoxicity. In conclusion, PTX might synergistically aggravate DOX-induced cardiotoxicity. The effect might be much more pronounced with those rats treated with PTX 24 h after DOX treatment. © 2004 Wiley Periodicals, Inc. J Biochem Mol Toxicol 18:78,86, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20012 [source] Trafficking and localization of platinum complexes in cisplatin-resistant cell lines monitored by fluorescence-labeled platinum,JOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2005Xing-Jie Liang Cisplatin is a chemotherapeutic agent commonly used in the treatment of a wide variety of malignant tumors. Resistance to cisplatin represents a major obstacle to effective cancer therapy because clinically significant levels of resistance quickly emerge after treatment. Based on previous studies indicating abnormal plasma membrane protein trafficking in cisplatin-resistant (CP-r) cells, Fluorescence (Alexa Fluor)-labeled cisplatin was used to determine whether this defect altered the trafficking and localization of cisplatin by comparing drug sensitive KB-3-1 and KB-CP-r cells. Alexa Fluor,cisplatin was readily internalized and localized throughout the KB-3-1 cells, but overall fluorescence decreased in KB-CP-r cells, as detected by flow cytometry (FACS) and confocal microscopy. Only punctate cytoplasmic staining was observed in KB-CP-r cells with less fluorescence observed in the nucleus. Colocalization experiments with a Golgi-selective stain indicate the involvement of Golgi-like vesicles in initial intracellular processing of Alexa Fluor conjugated cisplatin complexes. As detected using an antibody to Alexa Fluor,cisplatin, cisplatin complex-binding proteins (CCBPs) were reduced in membrane fractions of single-step cisplatin-resistant KB-CP.5 cells, and increased in the cytoplasm of KB-CP.5 cells compared to KB-3-1 cells. CCBPs localized to lower density fractions in KB-CP.5 cells than in KB-3-1 cells as determined by iodixanol gradient centrifugation. In summary, inappropriate trafficking of CCBPs might explain resistance to cisplatin in cultured cancer cells, presumably because membrane binding proteins for cisplatin are not properly located on the cell surface in these cells, but are instead trapped in low density vesicles within the cytoplasm. © 2004 Wiley-Liss, Inc. [source] Effects of the past and the present on species distribution: land-use history and demography of wintergreenJOURNAL OF ECOLOGY, Issue 2 2000Kathleen Donohue Summary 1,Past land use can have long-term effects on plant species' distributional patterns if alterations in resources and environmental conditions have persistent effects on population demography (environmental change) and/or if plants are intrinsically limited in their colonization ability (historical factors). 2,We evaluated the role of environmental alteration vs. historical factors in controlling distributional patterns of Gaultheria procumbens, a woody, clonal understorey species with a pronounced restriction to areas that have never been ploughed, and near absence from adjoining areas that were ploughed in the 19th century. The demographic study was conducted in scrub oak and hardwood plant communities on an extensive sand plain, where it was possible to control for the effect of variation in environment prior to land use. 3,The observed demographic effects were contrary to the hypothesis that persistent environmental alteration depressed demographic performance and limited the distribution of G. procumbens. We observed no overall effect of land-use history on stem density, stem recruitment or flower production. In fact, some aspects of performance were enhanced in previously ploughed areas. Populations in previously ploughed areas exhibited less stem mortality in scrub oak transitions, an increase in germination, seedling longevity and proportion of potentially reproductive stems in both plant communities, a trend for slower observed rates of population decline in both plant communities, and a higher projected rate of population growth in the scrub oak transitions. Thus, particularly in scrub oak communities, the lower abundance of G. procumbens in formerly ploughed than in unploughed areas contrasted with its performance. 4,The limited occurrence of G. procumbens in formerly farmed areas was explained instead by its slow intrinsic growth rate, coupled with limited seedling establishment. Lateral population extension occurred exclusively through vegetative growth, allowing a maximum expansion of 43 cm year,1. 5,We conclude that inherent limitations in the colonizing ability of some plant species may present a major obstacle in the restoration or recovery of plant communities on intensively disturbed sites, even in the absence of persistent environmental effects that depress population growth. [source] Using hospital administrative data to evaluate the knowledge-to-action gap in pressure ulcer preventive careJOURNAL OF EVALUATION IN CLINICAL PRACTICE, Issue 2 2009Pieter Van Herck Msc RN Abstract Rationale, aims and objectives, Issues of overuse, underuse and misuse are paramount and lead to avoidable morbidity and mortality. Although evidence-based practice is advocated, the widespread implementation of this kind of practice remains a challenge. This is also the case for evidence-based practice related to the prevention of pressure ulcers, which varies widely in process and outcome in Belgian hospital care. One major obstacle to bridging this knowledge-to-action gap is data availability. We propose using large-scale hospital administrative data combined with the latest evidence-based methods as part of the solution to this problem. Method, To test our proposal, we applied this approach to pressure ulcer prevention, using an administrative dataset with regard to 6030 patients in 22 Belgian hospitals as a sample of nationally available data. Methods include a systematic review approach, evidence grading, recommendations formulation, algorithm construction, programming of the rule set and application on the database. Results, We found that Belgian hospitals frequently failed to provide appropriate prevention care. Significant levels of underuse, up to 28.4% in pressure ulcer prevention education and 17.5% in the use of dynamic systems mattresses, were detected. Figures for overuse were mostly not significant. Misuse couldn't be assessed. Conclusions, These results demonstrate that this approach can indeed be successfully used to bridge the knowledge-to-action gap in medical practice, by implementing an innovative method to assess underuse and overuse in hospital care. The integrative use of administrative data and clinical applications should be replicated in other patient groups, other datasets and other countries. [source] Future Prospects for Biomarkers of Alcohol Consumption and Alcohol-Induced DisordersALCOHOLISM, Issue 6 2010Willard M. Freeman The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis, treatment, and research of alcohol abuse and alcoholism. Successful development of a biomarker that allows for accurate assessment of alcohol intake and drinking patterns would not only be a major advance in clinical care but also a valuable research tool. A number of advances have been made in testing the validity of proposed biomarkers as well as in identifying potential new biomarkers through systems biology approaches. This commentary will examine the definition of a biomarker of heavy drinking, the types of potential biomarkers, the steps in biomarker development, the current state of biomarker development, and critical obstacles for the field. The challenges in developing biomarkers for alcohol treatment and research are similar to those found in other fields. However, the alcohol research field must reach a competitive level of rigor and organization. We recommend that NIAAA consider taking a leadership role in organizing investigators in the field and providing a common set of clinical specimens for biomarker validation studies. [source] Soil properties, but not plant nutrients (N, P, K) interact with chemically induced resistance against powdery mildew in barleyJOURNAL OF PLANT NUTRITION AND SOIL SCIENCE, Issue 3 2003Joachim Wiese Abstract Chemically induced resistance is a promising method of plant protection against diseases, which can be triggered by systemically acting chemical inducers such as BTH (benzo(1, 2, 3)thiadiazole-carbothioic-acid-S-methylester). BTH is commercially distributed as a 50,% formulation, called Bion®. The uncertain success of Bion® application in controlling infection by powdery mildew is a major obstacle in using induced resistance for plant protection in agriculture. This study aimed to investigate the effect of soil properties, selected macronutrients (N, P, and K), and addition of organic matter on induced resistance and to identify possible factors responsible for the high variability of BTH effect under field conditions. A pot experiment under open-air conditions was set up using the pathosystem Hordeum vulgare cv. Ingrid / Blumeria graminis f. sp. hordei race A6. The different soils strongly affected the resistance of barley plants against powdery mildew after BTH treatment. The infection of barley by powdery mildew was lower than on all other soils when grown on an acid forest soil which was limed up to pH 4.9, even after BTH treatment. A reproducible induction of pathogen resistance by BTH was shown only on a mineral soil (Kleinlinden) with a negligible C content. Application of N, P, and K did not consistently affect the induction of resistance by BTH. The addition of green manure and compost led to an enhanced variability of resistance induction on the soil "Kleinlinden". Possible effects of soil microflora on resistance induction are discussed. Bodeneigenschaften, aber nicht Pflanzennährstoffe (N, P, K) interagieren mit der chemisch induzierten Resistenz gegen Gerstenmehltau in Gerste Chemisch induzierte Resistenz ist eine viel versprechende Methode im Pflanzenschutz, welche durch systemisch wirkende Substanzen wie BTH (Benzo(1, 2, 3)-thiadiazolcarbothion-Säure- S -Methylester) induziert werden kann. BTH ist die wirksame Komponente des kommerziell erhältlichen Produkts Bion®. Allerdings ist die Wirksicherheit von Bion® im Feld gering, wodurch die Anwendung des Produkts im Pflanzenschutz eingeschränkt ist. Das Ziel der vorliegenden Arbeit war es, den Einfluss verschiedener Böden, ausgewählter Makronährstoffe (N, P und K) und des Zusatzes von organischem Material zum Boden auf die induzierte Resistenz zu untersuchen und Faktoren zu identifizieren, die für die unsichere BTH-Wirkung im Feld verantwortlich sind. Dafür wurden Gefäßexperimente unter freilandähnlichen Bedingungen durchgeführt. In diesen wurde das Pathosystem Hordeum vulgare cv. Ingrid / Blumeria graminis f. sp. hordei Stamm A6 verwendet. Es wurde ein starker Einfluss des Bodens auf die Resistenz der Gerste gegen Gerstenmehltau nach BTH-Behandlung ermittelt. Die Mehltauinfektion von Gerste, welche auf einem sauren Waldboden kultiviert wurde, der auf einen pH-Wert von 4, 9 aufgekalkt worden war, war niedriger als auf allen anderen Böden, selbst nach BTH-Behandlung. Eine reproduzierbare Induktion der Pathogenresistenz durch BTH konnte nur auf einem Mineralboden mit vernachlässigbarem C-Gehalt gezeigt werden. Die Ernährung mit N, P und K hatte keinen konsistenten Einfluss auf die Resistenzinduktion mittels BTH. Der Zusatz von Kompost und Gründünger zum Boden ,Kleinlinden" erhöhte die Variabilität der Resistenzinduktion. Der mögliche Einfluss der Bodenmikroflora auf die Resistenzinduktion wird diskutiert. [source] Liver transplantation for hepatocellular carcinoma: Analysis of survival according to the intention-to-treat principle and dropout from the waiting listLIVER TRANSPLANTATION, Issue 10 2002Francis Y. Yao MD A major obstacle for orthotopic liver transplantation (OLT) as treatment for hepatocellular carcinoma (HCC) is tumor growth resulting in dropout from the waiting list for OLT. There is a paucity of data on survival according to intention-to-treat analysis and the rate of dropout from the waiting list for OLT among patients with HCC. To further evaluate these issues, we analyzed the outcome of 46 consecutive patients with HCC listed for OLT between January 1998 and January 2001. Exclusion criteria for OLT were tumor size greater than 5 cm for one to three lesions or four lesions or greater of any size. Twenty-one patients underwent OLT. There were 11 dropouts because of tumor progression and six deaths, including three deaths after dropout. Kaplan-Meier 1- and 2-year intention-to-treat survival rates were 91.7% and 72.6%, respectively. Monthly dropout rates were 0% from 0 to 3 months, 1.5% from 3 to 6 months, 1.0% from 6 to 9 months, 4.9% from 9 to 12 months, and 5.6% from 12 to 15 months. One dropout occurred beyond 15 months among 4 patients remaining at risk. Cumulative probabilities for dropout at 6, 12, and 24 months were 7.3%, 25.3%, and 43.6%, respectively. Predictors for dropout included two or three tumor nodules or a solitary lesion greater than 3 cm at initial presentation and previous hepatic resection. Our results support recent changes in the scheme of organ allocation aimed at reducing the dropout rate and improving outcome for patients with HCC awaiting OLT. [source] Long-term cisapride treatment improves diabetic gastroparesis but not glycaemic controlALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 7 2002B. Braden Background: In patients with diabetic gastroparesis, delayed food delivery to the intestine may become a major obstacle to post-prandial glycaemic control. Aim: To investigate whether cisapride accelerates gastric emptying in the long term or improves diabetes control in patients with diabetic gastroparesis. Methods: Eighty-five patients with long-standing insulin-dependent diabetes mellitus (glycosylated haemoglobin (HbA1c) > 7.0%), dyspepsia and diabetic neuropathy were tested for impaired gastric emptying of solids by the 13C-octanoate breath test. Nineteen of these patients with severe diabetic gastroparesis (i.e. t1/2 > 170 min) were randomly treated with 10 mg cisapride t.d.s. (n=9) or placebo (n=10) for 12 months. Thereafter, the breath test, dyspeptic symptoms and HbA1c values were reassessed. Results: Half emptying times in nine patients with diabetic gastroparesis were significantly shortened by cisapride (175 ± 46 min vs. 227 ± 40 min; P < 0.03). Half emptying times in the 10 patients taking placebo did not change (205 ± 37 min vs. 211 ± 36 min, P=0.54). Cisapride significantly reduced dyspepsia (score: 4.1 ± 1.6 vs. 2.0 ± 0.5, P=0.002). HbA1c values after 12 months of treatment were not different (cisapride: 7.7 ± 0.4% vs. 7.6 ± 0.9%, P=0.76; placebo: 7.5 ± 0.6% vs. 7.6 ± 1.5%, P=0.89). Conclusions: Prokinetic treatment with cisapride accelerates gastric emptying of solids and improves dyspeptic symptoms in diabetic gastroparesis. Glycaemic control, however, is not affected by cisapride. [source] Opening an Occluded Subclavian Vein with a Screw-Like Flexible Hollow Guide-wire and VenoplastyPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 10 2007SETH JOSEPH WORLEY M.D. Patients with existing internal cardioverter defibrillators (ICDs) often require upgrading to a biventricular ICD for treatment of congestive heart failure (CHF). Placement of a left ventricular (LV) lead can be technically challenging in the best of circumstances. A subclavian vein stenosis or occlusion related to previously placed leads adds a major obstacle to a successful implant. We report a technique of implanting an LV lead from the same side as the existing ICD system despite complete occlusion of the subclavian vein. [source] Ex vivo generation of cytokine-induced killer cells (CD3+ CD56+) from post-stem cell transplant pediatric patients against autologous,Epstein,Barr virus,transformed lymphoblastoid cell linesPEDIATRIC TRANSPLANTATION, Issue 5 2007Sawang Petvises Abstract:, EBV-PTLDs affect as high as 20% of SCT recipients especially those with T-cell depleted grafts while high mortality rates were also noted. Adoptive allogeneic and autologous CTLs have a therapeutic potential in this setting. However, the process of expansion of these cells is tedious and time consuming in both allogeneic and autologous CTL generation. For the allogeneic SCT, another major obstacle is unavailability of donors especially in an unrelated SCT setting. The aim of the present study was therefore to investigate the efficacy of autologous CIK cells (CD3+ CD56+) against autologous EBV-LCLs from post-SCT pediatric patients. We could demonstrate that CIK cells can be generated within two wk and did show the significant cytotoxicity against autologous EBV-LCLs. CIK cells may provide a potent tool for use in post-transplantation adoptive immunotherapy. [source] Sidewall epitaxial lateral overgrowth of nonpolar a-plane GaN by metalorganic vapor phase epitaxyPHYSICA STATUS SOLIDI (C) - CURRENT TOPICS IN SOLID STATE PHYSICS, Issue 6 2008Daisuke Iida Abstract A major obstacle to achieving high-performance devices using nonpolar a-plane and m-plane GaN is the existence of high-density threading dislocations and stacking faults. Low-defect-density nonpolar plane GaN films were previously grown by sidewall epitaxial overgrowth using metalorganic vapor phase epitaxy [1, 2]. In this study, we control the growth-rate ratio of Ga-polar GaN to N-polar GaN by adjusting the V/III ratio. It is possible to grow GaN only from the N-face sidewall of grooves by maintaining a high V/III ratio, which reduces the number of coalescence regions on grooves and decreases the threading-dislocation density and stacking-fault density. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Surface Modification of Poly(propylene) Microporous Membrane to Improve Its Antifouling Characteristics in an SMBR: O2 Plasma TreatmentPLASMA PROCESSES AND POLYMERS, Issue 1 2008Hai-Yin Yu Abstract Fouling is the major obstacle in membrane processes applied in water and wastewater treatment. To improve the antifouling characteristics of PPHFMMs in an SMBR for wastewater treatment, the PPHFMMs were surface-modified by O2 low temperature plasma treatment. Structural and morphological changes on the membrane surface were characterized by XPS and FE-SEM. The change of surface wettability was monitored by contact angle measurements. Results of XPS clearly indicated that the plasma treatment introduced oxygen containing polar groups on the membrane surface. The static water contact angle of the modified membrane reduced obviously with the increase of plasma treatment time. The relative pure water flux for the modified membranes increased with plasma treatment time up to 1 min, then it decreased with further increase of plasma treatment time. Decreases in the tensile strength and the tensile elongation at break of the modified membranes were also observed. To assess the relation between the plasma treatment and the membrane fouling in an SMBR, filtration for activated sludge was carried out by using synthetic wastewater. After continuous operation in the SMBR for about 75 h, flux recovery were 8.7 and 12.3%, reduction of flux were 91.6 and 87.4% for the nascent and O2 plasma treated PPHFMM for 1 min, relative flux ratio for O2 plasma treated PPHFMM for 1 min was 49.9% higher than that of the nascent PPHFMM. [source] Customization: Impact on Product and Process PerformancePRODUCTION AND OPERATIONS MANAGEMENT, Issue 4 2005Vishwanath G. Hegde Manufacturing capability has often been viewed to be a major obstacle in achieving higher levels of customization. Companies follow various strategies ranging from equipment selection to order process management to cope with the challenges of increased customization. We examined how the customization process affects product performance and conformance in the context of a design-to-order (DTO) manufacturer of industrial components. Our competing risk hazard function model incorporates two thresholds, which we define as mismatch and manufacturing thresholds. Product performance was adversely affected when the degree of customization exceeded the mismatch threshold. Likewise, product conformance eroded when the degree of customization exceeded the manufacturing threshold. Relative sizes of the two thresholds have management implications for the subsequent investments to improve customization capabilities. Our research developed a rigorous framework to address two key questions relevant to the implementation of product customization: (1) what degrees of customization to offer, and (2) how to customize the product design process. [source] | |||||||||||||||||||||||||||||||||||||||||||||||||