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Sample records for late preclinical stage

  1. Late-Stage Caregiving

    Science.gov (United States)

    ... Caregiving Middle-Stage Caregiving Late-Stage Caregiving Behaviors Aggression & Anger Anxiety & Agitation Depression Hallucinations Memory Loss & Confusion Repetition Sleep Issues & Sundowning Suspicion & Delusions Wandering Abuse Start Here What You Need to Know Online ...

  2. [Impact of microdose clinical trials in the preclinical stage].

    Science.gov (United States)

    Kim, Soonih

    2014-01-01

    A microdose clinical trial may be useful as a safe early-phase exploratory study using doses as low as 100 μg or less for determination of the disposition of a candidate compound in humans in a short period of time. This may increase confidence in candidate compounds, especially those for which it is difficult to predict disposition based on the results of in vitro or preclinical studies. In this study, we examined microdose trials performed in the preclinical stage for two first-in-class compounds with a new mechanism of action. These compounds showed species difference in first pass metabolism in the digestive tract and liver, causing uncertainty in prediction of disposition in humans. For this reason, first-in-human microdose clinical trials were performed. The results showed that the two compounds had effective blood concentrations after oral administration at a dose of 100 mg qd. Administration of an extremely small dose of one (14)C-labeled compound permitted identification of major metabolites. No toxic metabolites were detected. The preclinical toxic dose was determined based on prediction of blood exposure at the estimated maximum clinical dose. For the other candidate compound, the findings of the microdose trial indicated a high bioavailability after oral administration and low hepatic clearance after intravenous administration. These results suggested only a small risk of a change in disposition in patients with hepatic disorder. The data obtained for the two compounds suggest that microdose clinical trials can be useful for improving the process of candidate selection in the preclinical stage.

  3. Genetic modification of risk assessment based on staging of preclinical type 1 diabetes in siblings of affected children.

    Science.gov (United States)

    Mrena, S; Savola, K; Kulmala, P; Reijonen, H; Ilonen, J; Akerblom, H K; Knip, M

    2003-06-01

    We set out to study the association between human leukocyte antigen-defined genetic disease susceptibility and the stage of preclinical type 1 diabetes and whether genetic predisposition affects the natural course of preclinical diabetes in initially nondiabetic siblings of affected children. A total of 701 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based on the initial number of disease-associated autoantibodies detectable close to the time of diagnosis of the index case: no prediabetes (no antibodies), early (one antibody specificity), advanced (two antibodies), and late prediabetes (three or more antibodies). Another classification system covering 659 siblings was based on a combination of the initial number of antibodies and the first-phase insulin response (FPIR) to iv glucose: no prediabetes (no antibodies), early (one antibody specificity, normal FPIR), advanced (two or more antibodies, normal FPIR), and late prediabetes (at least one antibody, reduced FPIR). Genetic susceptibility to type 1 diabetes was defined by human leukocyte antigen identity and DR and DQ genotypes. There was a higher proportion of siblings with late prediabetes initially among those with strong genetic disease susceptibility than among those with decreased genetic predisposition (16.7% vs. 0.5%; P siblings with no signs of prediabetes among those with genotypes conferring decreased risk (91.2% vs. 70.4% among those with high-risk DQB1 genotypes; P siblings than when combined with genetic susceptibility. Genetic susceptibility played a role in whether the initial prediabetic stage progressed (progression in 29.6% of the high-risk siblings compared with 6.6% of the siblings with DQB1 genotypes conferring decreased risk; P siblings of affected children.

  4. Late stage infection in sleeping sickness.

    Directory of Open Access Journals (Sweden)

    Hartwig Wolburg

    Full Text Available At the turn of the 19(th century, trypanosomes were identified as the causative agent of sleeping sickness and their presence within the cerebrospinal fluid of late stage sleeping sickness patients was described. However, no definitive proof of how the parasites reach the brain has been presented so far. Analyzing electron micrographs prepared from rodent brains more than 20 days after infection, we present here conclusive evidence that the parasites first enter the brain via the choroid plexus from where they penetrate the epithelial cell layer to reach the ventricular system. Adversely, no trypanosomes were observed within the parenchyma outside blood vessels. We also show that brain infection depends on the formation of long slender trypanosomes and that the cerebrospinal fluid as well as the stroma of the choroid plexus is a hostile environment for the survival of trypanosomes, which enter the pial space including the Virchow-Robin space via the subarachnoid space to escape degradation. Our data suggest that trypanosomes do not intend to colonize the brain but reside near or within the glia limitans, from where they can re-populate blood vessels and disrupt the sleep wake cycles.

  5. Functioning in early and late stages of schizophrenia

    Directory of Open Access Journals (Sweden)

    Leonardo Gazzi Costa

    2014-12-01

    Full Text Available INTRODUCTION: Schizophrenia is frequently associated with a debilitating course and prominent impairment in social and occupational functioning. Although the criteria for classification into stages have not been defined in the literature, illness duration and functioning seem to be good candidates.OBJECTIVE:To compare functioning of patients with schizophrenia at different stages of the disease (early vs. late and healthy sex- and age-matched controls.METHODS: This double-blinded, case-controlled study included 79 individuals: 23 patients with schizophrenia diagnosed up to 5 years earlier; 19 patients with schizophrenia diagnosed at least 20 years earlier; and healthy matched controls. Diagnoses were established using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV Axis I Disorder. Functioning was assessed using the Functioning Assessment Short Test (FAST.RESULTS: Patients in the early stage had significantly higher scores than healthy controls in total FAST and in autonomy, occupational functioning, cognitive functioning and interpersonal relationships. Individuals in the late stage had significantly poorer functioning than controls in all domains. The comparison of functioning between the two groups of patients revealed no significant differences, except in occupational functioning, in which late stage patients had a poorer performance.CONCLUSION: Functioning impairment in schizophrenia tends to remain stable despite illness duration. Therefore, functioning should be effectively assessed at an early stage, as illness duration alone may not be the most reliable criterion to stage patients with schizophrenia.

  6. Comorbidities and the Risk of Late-Stage Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Steven T. Fleming

    2006-01-01

    Full Text Available The degree to which comorbidities affect the diagnosis of prostate cancer is not clear. The purpose of this study was to determine how comorbidities affect the stage at which prostate cancer is diagnosed in elderly white and black men. We obtained data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute merged with Medicare claims data. For each patient, we estimated associations between stage of disease at diagnosis and each of the 27 comorbidities. The sample included 2,489 black and 2,587 white men with staged prostate cancer. Coronary artery disease, benign hypertension, and dyslipidemia reduced the odds of late-stage prostate cancer. A prior diagnosis of peripheral vascular disease, severe renal disease, or substance abuse increased the odds of being diagnosed with late-stage disease. The study shows some effect modification by race, particularly among white men with substance abuse, cardiac conduction disorders, and other neurologic conditions. The strongest predictors of late-stage prostate cancer diagnosis for both white and black men were age at diagnosis of at least 80 years and lack of PSA screening. Comorbidities do affect stage at diagnosis, although in different ways. Four hypotheses are discussed to explain these findings.

  7. OPHTHALMIC FINDINGS IN LATE STAGE SJOGREN-LARSSON SYNDROME.

    Science.gov (United States)

    Nanda, Tavish; Kovach, Jaclyn L

    2017-03-15

    To report spectral domain optical coherence tomography and fundus autofluorescence documentation of late stage macular findings associated with Sjogren-Larsson Syndrome in three adult siblings. Three adult siblings with Sjogren-Larsson Syndrome underwent ophthalmic examination and imaging. Crystalline maculopathy and subretinal deposits, presumably lipofuscin accumulation, with macular atrophy were present in varying degrees in all three adult siblings. In adults with Sjogren-Larsson Syndrome, crystalline retinopathy can progress to macular atrophy and the appearance of lipofuscin accumulation.

  8. Innovative financing for late-stage global health research and development: the Global Health Investment Fund.

    Science.gov (United States)

    Fitchett, Joseph Robert; Fan Li, Julia; Atun, Rifat

    2016-01-01

    Innovative financing strategies for global health are urgently needed to reinvigorate investment and new tools for impact. Bottleneck areas along the research and development (R&D) pipeline require particular attention, such as the transitions from preclinical discovery to clinical study, and product development to implementation and delivery. Successful organizations mobilizing and disbursing resources through innovating financing mechanisms include UNITAID, the Global Fund, and Gavi, the Vaccine Alliance. Although precise numbers are poorly documented, estimated investment in low-income settings falls seriously short of local need. This commentary discusses the newly established Global Health Investment Fund as a case study to support late-stage global health R&D. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Transcriptional analysis of late ripening stages of grapevine berry

    Science.gov (United States)

    2011-01-01

    Background The composition of grapevine berry at harvest is a major determinant of wine quality. Optimal oenological maturity of berries is characterized by a high sugar/acidity ratio, high anthocyanin content in the skin, and low astringency. However, harvest time is still mostly determined empirically, based on crude biochemical composition and berry tasting. In this context, it is interesting to identify genes that are expressed/repressed specifically at the late stages of ripening and which may be used as indicators of maturity. Results Whole bunches and berries sorted by density were collected in vineyard on Chardonnay (white cultivar) grapevines for two consecutive years at three stages of ripening (7-days before harvest (TH-7), harvest (TH), and 10-days after harvest (TH+10)). Microvinification and sensory analysis indicate that the quality of the wines made from the whole bunches collected at TH-7, TH and TH+10 differed, TH providing the highest quality wines. In parallel, gene expression was studied with Qiagen/Operon microarrays using two types of samples, i.e. whole bunches and berries sorted by density. Only 12 genes were consistently up- or down-regulated in whole bunches and density sorted berries for the two years studied in Chardonnay. 52 genes were differentially expressed between the TH-7 and TH samples. In order to determine whether these genes followed a similar pattern of expression during the late stages of berry ripening in a red cultivar, nine genes were selected for RT-PCR analysis with Cabernet Sauvignon grown under two different temperature regimes affecting the precocity of ripening. The expression profiles and their relationship to ripening were confirmed in Cabernet Sauvignon for seven genes, encoding a carotenoid cleavage dioxygenase, a galactinol synthase, a late embryogenesis abundant protein, a dirigent-like protein, a histidine kinase receptor, a valencene synthase and a putative S-adenosyl-L-methionine:salicylic acid carboxyl

  10. Transcriptional analysis of late ripening stages of grapevine berry

    Directory of Open Access Journals (Sweden)

    Guillaumie Sabine

    2011-11-01

    Full Text Available Abstract Background The composition of grapevine berry at harvest is a major determinant of wine quality. Optimal oenological maturity of berries is characterized by a high sugar/acidity ratio, high anthocyanin content in the skin, and low astringency. However, harvest time is still mostly determined empirically, based on crude biochemical composition and berry tasting. In this context, it is interesting to identify genes that are expressed/repressed specifically at the late stages of ripening and which may be used as indicators of maturity. Results Whole bunches and berries sorted by density were collected in vineyard on Chardonnay (white cultivar grapevines for two consecutive years at three stages of ripening (7-days before harvest (TH-7, harvest (TH, and 10-days after harvest (TH+10. Microvinification and sensory analysis indicate that the quality of the wines made from the whole bunches collected at TH-7, TH and TH+10 differed, TH providing the highest quality wines. In parallel, gene expression was studied with Qiagen/Operon microarrays using two types of samples, i.e. whole bunches and berries sorted by density. Only 12 genes were consistently up- or down-regulated in whole bunches and density sorted berries for the two years studied in Chardonnay. 52 genes were differentially expressed between the TH-7 and TH samples. In order to determine whether these genes followed a similar pattern of expression during the late stages of berry ripening in a red cultivar, nine genes were selected for RT-PCR analysis with Cabernet Sauvignon grown under two different temperature regimes affecting the precocity of ripening. The expression profiles and their relationship to ripening were confirmed in Cabernet Sauvignon for seven genes, encoding a carotenoid cleavage dioxygenase, a galactinol synthase, a late embryogenesis abundant protein, a dirigent-like protein, a histidine kinase receptor, a valencene synthase and a putative S

  11. Does posterior cingulate hypometabolism result from disconnection or local pathology across preclinical and clinical stages of Alzheimer's disease?

    Energy Technology Data Exchange (ETDEWEB)

    Teipel, Stefan [University of Rostock, Department of Psychosomatic Medicine, Rostock (Germany); DZNE, German Center for Neurodegenerative Diseases, Rostock (Germany); Alzheimer' s Disease Neuroimaging Initiative (United States); Grothe, Michel J. [DZNE, German Center for Neurodegenerative Diseases, Rostock (Germany); Alzheimer' s Disease Neuroimaging Initiative (United States)

    2016-03-15

    Posterior cingulate cortex (PCC) hypometabolism as measured by FDG PET is an indicator of Alzheimer's disease (AD) in prodromal stages, such as in mild cognitive impairment (MCI), and has been found to be closely associated with hippocampus atrophy in AD dementia.We studied the effects of local and remote atrophy and of local amyloid load on the PCC metabolic signal in patients with different preclinical and clinical stages of AD. We determined the volume of the hippocampus and PCC grey matter based on volumetric MRI scans, PCC amyloid load based on AV45 PET, and PCC metabolism based on FDG PET in 667 subjects participating in the Alzheimer's Disease Neuroimaging Initiative spanning the range from cognitively normal ageing through prodromal AD to AD dementia. In cognitively normal individuals and those with early MCI, PCC hypometabolism was exclusively associated with hippocampus atrophy, whereas in subjects with late MCI it was associated with both local and remote effects of atrophy as well as local amyloid load. In subjects with AD dementia, PCC hypometabolism was exclusively related to local atrophy. Our findings suggest that the effects of remote pathology on PCC hypometabolism decrease and the effects of local pathology increase from preclinical to clinical stages of AD, consistent with a progressive disconnection of the PCC from downstream cortical and subcortical brain regions. (orig.)

  12. Does posterior cingulate hypometabolism result from disconnection or local pathology across preclinical and clinical stages of Alzheimer's disease?

    International Nuclear Information System (INIS)

    Teipel, Stefan; Grothe, Michel J.

    2016-01-01

    Posterior cingulate cortex (PCC) hypometabolism as measured by FDG PET is an indicator of Alzheimer's disease (AD) in prodromal stages, such as in mild cognitive impairment (MCI), and has been found to be closely associated with hippocampus atrophy in AD dementia.We studied the effects of local and remote atrophy and of local amyloid load on the PCC metabolic signal in patients with different preclinical and clinical stages of AD. We determined the volume of the hippocampus and PCC grey matter based on volumetric MRI scans, PCC amyloid load based on AV45 PET, and PCC metabolism based on FDG PET in 667 subjects participating in the Alzheimer's Disease Neuroimaging Initiative spanning the range from cognitively normal ageing through prodromal AD to AD dementia. In cognitively normal individuals and those with early MCI, PCC hypometabolism was exclusively associated with hippocampus atrophy, whereas in subjects with late MCI it was associated with both local and remote effects of atrophy as well as local amyloid load. In subjects with AD dementia, PCC hypometabolism was exclusively related to local atrophy. Our findings suggest that the effects of remote pathology on PCC hypometabolism decrease and the effects of local pathology increase from preclinical to clinical stages of AD, consistent with a progressive disconnection of the PCC from downstream cortical and subcortical brain regions. (orig.)

  13. Novel dendritic cell-based vaccination in late stage melanoma.

    Science.gov (United States)

    Schneble, Erika J; Yu, Xianzhong; Wagner, T E; Peoples, George E

    2014-01-01

    Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that play an important role in stimulating an immune response of both CD4(+) T helper cells and CD8(+) cytotoxic T lymphocytes (CTLs). As such, DCs have been studied extensively in cancer immunotherapy for their capability to induce a specific anti-tumor response when loaded with tumor antigens. However, when the most relevant antigens of a tumor remain to be identified, alternative approaches are required. Formation of a dentritoma, a fused DC and tumor cells hybrid, is one strategy. Although initial studies of these hybrid cells are promising, several limitations interfere with its clinical and commercial application. Here we present early experience in clinical trials and an alternative approach to manufacturing this DC/tumor cell hybrid for use in the treatment of late stage and metastatic melanoma.

  14. Wilms tumour: prognostic factors, staging, therapy and late effects

    International Nuclear Information System (INIS)

    Kaste, Sue C.; Dome, Jeffrey S.; Babyn, Paul S.; Graf, Norbert M.; Grundy, Paul; Godzinski, Jan; Levitt, Gill A.; Jenkinson, Helen

    2008-01-01

    Wilms tumour is the most common malignant renal tumour in children. Dramatic improvements in survival have occurred as the result of advances in anaesthetic and surgical management, irradiation and chemotherapy. Current therapies are based on trials and studies primarily conducted by large multi-institutional cooperatives including the Societe Internationale d'Oncologie Pediatrique (SIOP) and the Children's Oncology Group (COG). The primary goals are to treat patients according to well-defined risk groups in order to achieve the highest cure rates, to decrease the frequency and intensity of acute and late toxicity and to minimize the cost of therapy. The SIOP trials and studies largely focus on the issue of preoperative therapy, whereas the COG trials and studies start with primary surgery. This paper reviews prognostic factors and staging systems for Wilms tumour and its current treatment with surgery and chemotherapy. Surgery remains a crucial part of treatment for nephroblastoma, providing local primary tumour control and adequate staging and possibly controlling the metastatic spread and central vascular extension of the disease. Partial nephrectomy, when technically feasible, seems reasonable not only in those with bilateral disease but also in those with unilateral disease where the patient has urological disorders or syndromes predisposing to malignancy. Partial nephrectomy, however, is frequently not sufficient for an anaplastic variant of tumour. The late effects for Wilms tumour and its treatment are also reviewed. The treatment of Wilms tumour has been a success story, and currently in excess of 80% of children diagnosed with Wilms tumour can look forward to long-term survival, with less than 20% experiencing serious morbidity at 20 years from diagnosis. The late complications are a consequence of the type and intensity of treatment required, which in turn reflects the nature and extent of the original tumour. Continual international trial development

  15. Wilms tumour: prognostic factors, staging, therapy and late effects

    Energy Technology Data Exchange (ETDEWEB)

    Kaste, Sue C. [St. Jude Children' s Research Hospital, Department of Radiological Sciences, Memphis, TN (United States); Dome, Jeffrey S. [St. Jude Children' s Research Hospital, Department of Oncology, Memphis, TN (United States); Babyn, Paul S. [Hospital for Sick Children, Department of Radiology, Toronto (Canada); Graf, Norbert M. [University Hospital of the Saarland, Clinic for Pediatric Oncology and Hematology, Homburg (Germany); Grundy, Paul [University of Alberta, Division of Pediatric Hematology, Oncology and Palliative Care, and Northern Alberta Children' s Cancer Program, Edmonton (Canada); Godzinski, Jan [Mother and Child Institute, Department of Oncological Surgery for Children and Adolescents, Warsaw (Poland); Levitt, Gill A. [Great Ormond Street Hospital for Sick Children NHS Trust, Paediatric Oncology, London (United Kingdom); Jenkinson, Helen [Birmingham Children' s Hospital NHS Trust, Oncology Department, Birmingham (United Kingdom)

    2008-01-15

    Wilms tumour is the most common malignant renal tumour in children. Dramatic improvements in survival have occurred as the result of advances in anaesthetic and surgical management, irradiation and chemotherapy. Current therapies are based on trials and studies primarily conducted by large multi-institutional cooperatives including the Societe Internationale d'Oncologie Pediatrique (SIOP) and the Children's Oncology Group (COG). The primary goals are to treat patients according to well-defined risk groups in order to achieve the highest cure rates, to decrease the frequency and intensity of acute and late toxicity and to minimize the cost of therapy. The SIOP trials and studies largely focus on the issue of preoperative therapy, whereas the COG trials and studies start with primary surgery. This paper reviews prognostic factors and staging systems for Wilms tumour and its current treatment with surgery and chemotherapy. Surgery remains a crucial part of treatment for nephroblastoma, providing local primary tumour control and adequate staging and possibly controlling the metastatic spread and central vascular extension of the disease. Partial nephrectomy, when technically feasible, seems reasonable not only in those with bilateral disease but also in those with unilateral disease where the patient has urological disorders or syndromes predisposing to malignancy. Partial nephrectomy, however, is frequently not sufficient for an anaplastic variant of tumour. The late effects for Wilms tumour and its treatment are also reviewed. The treatment of Wilms tumour has been a success story, and currently in excess of 80% of children diagnosed with Wilms tumour can look forward to long-term survival, with less than 20% experiencing serious morbidity at 20 years from diagnosis. The late complications are a consequence of the type and intensity of treatment required, which in turn reflects the nature and extent of the original tumour. Continual international trial

  16. New Breed of Mice May Improve Accuracy for Preclinical Testing of Cancer Drugs | FNLCR Staging

    Science.gov (United States)

    A new breed of lab animals, dubbed “glowing head mice,” may do a better job than conventional mice in predicting the success of experimental cancer drugs—while also helping to meet an urgent need for more realistic preclinical animal models. Th

  17. Network Disruption in the Preclinical Stages of Alzheimer's Disease: From Subjective Cognitive Decline to Mild Cognitive Impairment.

    Science.gov (United States)

    López-Sanz, David; Garcés, Pilar; Álvarez, Blanca; Delgado-Losada, María Luisa; López-Higes, Ramón; Maestú, Fernando

    2017-12-01

    Subjective Cognitive Decline (SCD) is a largely unknown state thought to represent a preclinical stage of Alzheimer's Disease (AD) previous to mild cognitive impairment (MCI). However, the course of network disruption in these stages is scarcely characterized. We employed resting state magnetoencephalography in the source space to calculate network smallworldness, clustering, modularity and transitivity. Nodal measures (clustering and node degree) as well as modular partitions were compared between groups. The MCI group exhibited decreased smallworldness, clustering and transitivity and increased modularity in theta and beta bands. SCD showed similar but smaller changes in clustering and transitivity, while exhibiting alterations in the alpha band in opposite direction to those showed by MCI for modularity and transitivity. At the node level, MCI disrupted both clustering and nodal degree while SCD showed minor changes in the latter. Additionally, we observed an increase in modular partition variability in both SCD and MCI in theta and beta bands. SCD elders exhibit a significant network disruption, showing intermediate values between HC and MCI groups in multiple parameters. These results highlight the relevance of cognitive concerns in the clinical setting and suggest that network disorganization in AD could start in the preclinical stages before the onset of cognitive symptoms.

  18. Effect of Tetracycline on Late-stage African trypanosomiasis in Rats ...

    African Journals Online (AJOL)

    Effect of Tetracycline on Late-stage African trypanosomiasis in Rats. T.O. Johnson, J.T. Ekanem. Abstract. The effect of tetracycline on late stage African trypanosomiasis was examined in an in vivo experiment using rats infected with Trypanosoma brucei brucei. Infected rats were treated on the 5th day of infection with ...

  19. Late Financial Distress Process Stages and Financial Ratios

    DEFF Research Database (Denmark)

    Sormunen, Nina; Laitinen, Teija

    2012-01-01

    stage affects the classification ability of single financial ratios and financial distress prediction models in short-term financial distress prediction. The study shows that the auditor's GC task could be supported by paying attention to the financial distress process stage. The implications...... of these findings for auditors and every stakeholder of business firms are considered....

  20. Impact of Urban Neighborhood Disadvantage on Late Stage Breast Cancer Diagnosis in Virginia.

    Science.gov (United States)

    DeGuzman, Pam Baker; Cohn, Wendy F; Camacho, Fabian; Edwards, Brandy L; Sturz, Vanessa N; Schroen, Anneke T

    2017-04-01

    Research suggests that residents of inner-city urban neighborhoods have higher rates of late stage cancer diagnosis. Identifying urban neighborhoods with high rates of both concentrated disadvantage and late stage cancer diagnosis may assist health care providers to target screening interventions to reduce disparities. The purposes of this study were to (1) create an index to evaluate concentrated disadvantage (CD) using non-racial measures of poverty, (2) determine the impact of neighborhood CD on late stage breast cancer diagnosis in US cities, and (3) to understand the role of obesity on this relationship. We used census block group- (CBG) level poverty indicators from five Virginia cities to develop the index. Breast cancer cases of women aged 18-65 who lived in the five cities were identified from the 2000-2012 Virginia Cancer Registry. A logistic regression model with random intercept was used to evaluate the impact of disadvantage on late stage breast cancer diagnosis. CBG-level maps were developed to geographically identify neighborhoods with both high rates of CD and late breast cancer staging. Over 900 CBGs and 6000 breast cases were included. Global fit of the concentrated disadvantage model was acceptable. The effect of disadvantage on late stage was significant (OR = 1.0083, p = 0.032). Inner-city poverty impacts risk of late stage breast cancer diagnosis. Area-level obesity is highly correlated with neighborhood poverty (ρ = 0.74, p diagnosis for urban poor and for minorities living in these underserved neighborhoods, but more study is needed to understanding the complex relationship between concentrated neighborhood poverty, obesity, and late stage diagnosis.

  1. Mechanisms of stage-transcending protection following immunization of mice with late liver stage-arresting genetically attenuated malaria parasites.

    Directory of Open Access Journals (Sweden)

    Brandon K Sack

    2015-05-01

    Full Text Available Malaria, caused by Plasmodium parasite infection, continues to be one of the leading causes of worldwide morbidity and mortality. Development of an effective vaccine has been encumbered by the complex life cycle of the parasite that has distinct pre-erythrocytic and erythrocytic stages of infection in the mammalian host. Historically, malaria vaccine development efforts have targeted each stage in isolation. An ideal vaccine, however, would target multiple life cycle stages with multiple arms of the immune system and be capable of eliminating initial infection in the liver, the subsequent blood stage infection, and would prevent further parasite transmission. We have previously shown that immunization of mice with Plasmodium yoelii genetically attenuated parasites (GAP that arrest late in liver stage development elicits stage-transcending protection against both a sporozoite challenge and a direct blood stage challenge. Here, we show that this immunization strategy engenders both T- and B-cell responses that are essential for stage-transcending protection, but the relative importance of each is determined by the host genetic background. Furthermore, potent anti-blood stage antibodies elicited after GAP immunization rely heavily on FC-mediated functions including complement fixation and FC receptor binding. These protective antibodies recognize the merozoite surface but do not appear to recognize the immunodominant merozoite surface protein-1. The antigen(s targeted by stage-transcending immunity are present in both the late liver stages and blood stage parasites. The data clearly show that GAP-engendered protective immune responses can target shared antigens of pre-erythrocytic and erythrocytic parasite life cycle stages. As such, this model constitutes a powerful tool to identify novel, protective and stage-transcending T and B cell targets for incorporation into a multi-stage subunit vaccine.

  2. Microbial landscape features in patients with generalized periodontitis at pre-clinical and radiological stage of its development

    Directory of Open Access Journals (Sweden)

    Vatamanyuk N.V.

    2014-11-01

    Full Text Available The paper presents the results of a comparative study of microbial landscape features in patients with generalized periodontitis at pre-clinical and radiological stage of its development in 42 patients. The purpose of the study is a comparative study of the composition of microbiocenosis of periodontal tissues in patients with chronic catarrhal gingivitis (CCG and chronic generalized periodontitis (CGP at an early stage of development and development studies of microbiological criteria for early emergence of the destructive process in periodontal structures. We found that the microflora isolated from dento-gingival grooves is of importance in diagnostics to identify the etiology of chronic generalized catarrhal gingivitis (CGCG and chronic generalized periodontitis in the early stages of its development. It was established that the presence of two or more types of fixed parodonto-pathogenic microorganisms in microbial association increases the likelihood of inflammatory and destructive events in periodontal tissues in patients with GCCG and is one of the reasons of is becoming CGP.

  3. Late stage and grave prognosis of esophageal cancer in Thailand.

    Science.gov (United States)

    Nun-Anan, Pongjarat; Vilaichone, Ratha-Korn

    2015-01-01

    Esophageal cancer is one of the major health concerns in Southeast Asian countries, including Thailand. However, only a limited number of studies have been reported from this region. This study was designed to evaluate the prevalence, clinical characteristics and survival rate of esophageal cancer in Thailand. Clinical information, histological features and endoscopic findings were collected from a tertiary care center in central region of Thailand between September 2011- November 2014 and reviewed. A total of 64 esophageal cancer patients including 58 men and 6 women with mean age of 62.6 years were enrolled. Common presenting symptoms were dysphagia (74%), dyspepsia (10%) and hematemesis (8%). Mean duration of symptoms prior to diagnosis was 72 days. Esophageal stenosis with contact bleeding was the most common endoscopic finding (55.6%). The location of cancer was found in proximal (16%), middle (50%) and distal (34%) esophagus. Squamous cell carcinoma was far more common histology than adenocarcinoma (84.2% vs 10.5%). However, esophageal adenocarcinoma was significantly more common than squamous cell carcinoma in distal area of esophagus (100% vs 22.9%; p=0.0001, OR=1.6, 95%CI=1.1-2.2). Esophageal cancer stages 3 and 4 accounted for 35.2% and 59.3% respectively. Overall 2-year survival rate was 20% and only 16% in metastatic patients. Most esophageal cancer patients in Thailand have squamous cell carcinoma and nearly all present at advanced stage with a grave prognosis. Screening of high risk individuals and early detection might be important keys to improve the survival rate and treatment outcome in Thailand.

  4. Endophenotypes for Age-Related Macular Degeneration: Extending Our Reach into the Preclinical Stages of Disease.

    Science.gov (United States)

    Gorin, Michael B; Weeks, Daniel E; Baron, Robert V; Conley, Yvette P; Ortube, Maria C; Nusinowitz, Steven

    2014-11-28

    The key to reducing the individual and societal burden of age-related macular degeneration (AMD)-related vision loss, is to be able to initiate therapies that slow or halt the progression at a point that will yield the maximum benefit while minimizing personal risk and cost. There is a critical need to find clinical markers that, when combined with the specificity of genetic testing, will identify individuals at the earliest stages of AMD who would benefit from preventive therapies. These clinical markers are endophenotypes for AMD, present in those who are likely to develop AMD, as well as in those who have clinical evidence of AMD. Clinical characteristics associated with AMD may also be possible endophenotypes if they can be detected before or at the earliest stages of the condition, but we and others have shown that this may not always be valid. Several studies have suggested that dynamic changes in rhodopsin regeneration (dark adaptation kinetics and/or critical flicker fusion frequencies) may be more subtle indicators of AMD-associated early retinal dysfunction. One can test for the relevance of these measures using genetic risk profiles based on known genetic risk variants. These functional measures may improve the sensitivity and specificity of predictive models for AMD and may also serve to delineate clinical subtypes of AMD that may differ with respect to prognosis and treatment.

  5. Imaging mass spectrometry (IMS) of cortical lipids from preclinical to severe stages of Alzheimer's disease.

    Science.gov (United States)

    Gónzalez de San Román, E; Manuel, I; Giralt, M T; Ferrer, I; Rodríguez-Puertas, R

    2017-09-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting millions of patients worldwide. Previous studies have demonstrated alterations in the lipid composition of lipid extracts from plasma and brain samples of AD patients. However, there is no consensus regarding the qualitative and quantitative changes of lipids in brains from AD patients. In addition, the recent developments in imaging mass spectrometry methods are leading to a new stage in the in situ analysis of lipid species in brain tissue slices from human postmortem samples. The present study uses the matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS), permitting the direct anatomical analysis of lipids in postmortem brain sections from AD patients, which are compared with the intensity of the lipid signal in samples from matched subjects with no neurological diseases. The frontal cortex samples from AD patients were classified in three groups based on Braak's histochemical criteria, ranging from non-cognitively impaired patients to those severely affected. The main results indicate a depletion of different sulfatide lipid species from the earliest stages of the disease in both white and gray matter areas of the frontal cortex. Therefore, the decrease in sulfatides in cortical areas could be considered as a marker of the disease, but may also indicate neurochemical modifications related to the pathogenesis of the disease. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Endophenotypes for Age-Related Macular Degeneration: Extending Our Reach into the Preclinical Stages of Disease

    Directory of Open Access Journals (Sweden)

    Michael B. Gorin

    2014-11-01

    Full Text Available The key to reducing the individual and societal burden of age-related macular degeneration (AMD-related vision loss, is to be able to initiate therapies that slow or halt the progression at a point that will yield the maximum benefit while minimizing personal risk and cost. There is a critical need to find clinical markers that, when combined with the specificity of genetic testing, will identify individuals at the earliest stages of AMD who would benefit from preventive therapies. These clinical markers are endophenotypes for AMD, present in those who are likely to develop AMD, as well as in those who have clinical evidence of AMD. Clinical characteristics associated with AMD may also be possible endophenotypes if they can be detected before or at the earliest stages of the condition, but we and others have shown that this may not always be valid. Several studies have suggested that dynamic changes in rhodopsin regeneration (dark adaptation kinetics and/or critical flicker fusion frequencies may be more subtle indicators of AMD-associated early retinal dysfunction. One can test for the relevance of these measures using genetic risk profiles based on known genetic risk variants. These functional measures may improve the sensitivity and specificity of predictive models for AMD and may also serve to delineate clinical subtypes of AMD that may differ with respect to prognosis and treatment.

  7. Failed magmatic eruptions: Late-stage cessation of magma ascent

    Science.gov (United States)

    Moran, S.C.; Newhall, C.; Roman, D.C.

    2011-01-01

    When a volcano becomes restless, a primary question is whether the unrest will lead to an eruption. Here we recognize four possible outcomes of a magmatic intrusion: "deep intrusion", "shallow intrusion", "sluggish/viscous magmatic eruption", and "rapid, often explosive magmatic eruption". We define "failed eruptions" as instances in which magma reaches but does not pass the "shallow intrusion" stage, i. e., when magma gets close to, but does not reach, the surface. Competing factors act to promote or hinder the eventual eruption of a magma intrusion. Fresh intrusion from depth, high magma gas content, rapid ascent rates that leave little time for enroute degassing, opening of pathways, and sudden decompression near the surface all act to promote eruption, whereas decreased magma supply from depth, slow ascent, significant enroute degassing and associated increases in viscosity, and impingement on structural barriers all act to hinder eruption. All of these factors interact in complex ways with variable results, but often cause magma to stall at some depth before reaching the surface. Although certain precursory phenomena, such as rapidly escalating seismic swarms or rates of degassing or deformation, are good indicators that an eruption is likely, such phenomena have also been observed in association with intrusions that have ultimately failed to erupt. A perpetual difficulty with quantifying the probability of eruption is a lack of data, particularly on instances of failed eruptions. This difficulty is being addressed in part through the WOVOdat database. Papers in this volume will be an additional resource for scientists grappling with the issue of whether or not an episode of unrest will lead to a magmatic eruption.

  8. Doppler Ultrasound Detection of Preclinical Changes in Foot Arteries in Early Stage of Type 2 Diabetes

    International Nuclear Information System (INIS)

    Leoniuk, Jolanta; Łukasiewicz, Adam; Szorc, Małgorzata; Sackiewicz, Izabela; Janica, Jacek; Łebkowska, Urszula

    2014-01-01

    There are few reports regarding the changes within the vessels in the initial stage of type 2 diabetes. The aim of this study was to estimate the hemodynamic and morphological parameters in foot arteries in type 2 diabetes subjects and to compare these parameters to those obtained in a control group of healthy volunteers. Ultrasound B-mode, color Doppler and pulse wave Doppler imaging of foot arteries was conducted in 37 diabetic patients and 36 non-diabetic subjects to determine their morphological (total vascular diameter and flow lumen diameter) and functional parameters (spectral analysis). In diabetic patients, the overall vascular diameter and wall thickness were statistically significantly larger when compared to the control group in the right dorsalis pedis artery (P=0.01; P=0.001), left dorsalis pedis artery (P=0.007; P=0.006), right posterior tibial artery (P=0.005; P=0.0005), and left posterior tibial artery (P=0.007; P=0.0002). No significant differences were observed in both groups in flow lumen diameters and blood flow parameters (PSV, EDV, PI, RI). In the diabetic group, the level of HbA1c positively correlated with flow resistance index in the right dorsalis pedis artery (r=0.38; P=0.02), right posterior tibial artery (r=0.38; P=0.02) and left posterior tibial artery (r=0.42; P=0.009). The pulsatility index within the dorsalis pedis artery decreased with increased trophic skin changes (r=–0.431, P=0.009). In the diabetic group, overall artery diameters larger than and flow lumina comparable to the control group suggest vessel wall thickening occurring in the early stage of diabetes. Doppler flow parameters are comparable in both groups. In the diabetic group, the level of HbA1c positively correlated with flow resistance index and negative correlation was observed between the intensity of trophic skin changes and the pulsatility index

  9. Factors influencing late stage of breast cancer at presentation in a district Hospital - Segamat Hospital, Johor.

    Science.gov (United States)

    Cheng, M L; Ling, D Y; Nanu P, K P; Nording, H; Lim, C H

    2015-06-01

    In Malaysia, late stage presentation of breast cancer (stage III or IV) has been a healthcare problem that varies geographically throughout the country. This study aims to understand the factors influencing late stage of breast cancer at presentation among Malaysian women in Segamat Hospital, Johor, which is a district hospital. A retrospective descriptive study was conducted on secondary data of all newly diagnosed breast cancer women from 1st August 2011 to 28th February 2014. Secondary data includes age, ethnicity, marital status, family history, education level, occupation, presenting symptom, duration of symptom, tumour size, tumour pathology, tumour grading, oestrogen, progesterone and HER-2 receptor status were collected and analysed using SPSS version 20.0.0. In total, data from 52 women was analysed and two women were excluded for incompleteness as these women defaulted. Late stage at presentation was 59.6% of all new cases (17.3% stage III and 42.3% stage IV). The commonest age group of all women diagnosed with breast cancer was in the 5th decade. Majority of them were Malay, married and housewives with no family history of breast cancer. The statistically significant factors associated with late stage at presentation include Malay ethnicity (p=0.019), presenting symptoms other than breast lump (p=0.047), and duration of breast lump more than 3 months (p=0.009). The study demonstrated presentation at late stage of breast cancer is a major health concern among Malaysian women in district hospital. This may be attributed to different sociocultural beliefs, strong belief in complementary and alternative medicine, lack of awareness, and difficult accessibility to healthcare services.

  10. The clinical study of interventional therapy of advanced and late staged carcinoma of digestive tract

    International Nuclear Information System (INIS)

    Liu Zengrong; Ren Shuiming; Luo Xiuzhen; Liu Fang; Liu Junxiang; Han Liping

    2003-01-01

    Objective: To evaluate the transarterial chemoembotherapy in the treatment of advanced or late staged digestive tract carcinoma. Methods: One hundred fifty-one patients with advanced or late staged digestive tract carcinoma (including 20 cases of esophageal carcinoma, 29 cases of cardia carcinoma, 71 cases of gastric carcinoma and 31 cases of large intestinal carcinoma) underwent super selective transarterial chemoembotherapy. Results: Interventions were successful. Symptoms were apparently improved in all cases. Decreased diameter of tumor was seen in all cases. Half-year survival rate was 95% (144/151); one year survival was 86% (130/150); two year survival rate was 66% (99/151); and three year survival rate was 29% (44/151). Conclusion: The transarterial chemoembotherapy is an effective treatment of advanced or late staged digestive tract carcinoma. In patients with metastases, the intervention is especially valuable for both primary and metastatic lesions

  11. Selection is stronger in early-versus-late stages of divergence in a Neotropical livebearing fish.

    Science.gov (United States)

    Ingley, Spencer J; Johnson, Jerald B

    2016-03-01

    How selection acts to drive trait evolution at different stages of divergence is of fundamental importance in our understanding of the origins of biodiversity. Yet, most studies have focused on a single point along an evolutionary trajectory. Here, we provide a case study evaluating the strength of divergent selection acting on life-history traits at early-versus-late stages of divergence in Brachyrhaphis fishes. We find that the difference in selection is stronger in the early-diverged population than the late-diverged population, and that trait differences acquired early are maintained over time. © 2016 The Author(s).

  12. Enantioselective Synthesis of (-)-Vallesine: Late-Stage C17-Oxidation via Complex Indole Boronation.

    Science.gov (United States)

    Antropow, Alyssa H; Garcia, Nicholas R; White, Kolby L; Movassaghi, Mohammad

    2018-06-04

    The first enantioselective total synthesis of (-)-vallesine via a strategy that features a late-stage regioselective C17-oxidation followed by a highly stereoselective transannular cyclization is reported. The versatility of this approach is highlighted by the divergent synthesis of the archetypal alkaloid of this family, (+)-aspidospermidine, and an A-ring-oxygenated derivative, (+)-deacetylaspidospermine, the precursor to (-)-vallesine, from a common intermediate.

  13. Noradrenergic Action in Prefrontal Cortex in the Late Stage of Memory Consolidation

    Science.gov (United States)

    Tronel, Sophie; Feenstra, Matthijs G. P.; Sara, Susan J.

    2004-01-01

    These experiments investigated the role of the noradrenergic system in the late stage of memory consolidation and in particular its action at beta receptors in the prelimbic region (PL) of the prefrontal cortex in the hours after training. Rats were trained in a rapidly acquired, appetitively motivated foraging task based on olfactory…

  14. Noradrenergic action in prefrontal cortex in the late stage of memory consolidation

    NARCIS (Netherlands)

    Tronel, Sophie; Feenstra, Matthijs G. P.; Sara, Susan J.

    2004-01-01

    These experiments investigated the role of the noradrenergic system in the late stage of memory consolidation and in particular its action at beta receptors in the prelimbic region (PL) of the prefrontal cortex in the hours after training. Rats were trained in a rapidly acquired, appetitively

  15. Late-stage diversification of biologically active pyridazinones via a direct C-H functionalization strategy.

    Science.gov (United States)

    Li, Wei; Fan, Zhoulong; Geng, Kaijun; Xu, Youjun; Zhang, Ao

    2015-01-14

    Divergent C-H functionalization reactions (arylation, carboxylation, olefination, thiolation, acetoxylation, halogenation, naphthylation) using a pyridazinone moiety as an internal directing group were successfully established. This approach offers a late-stage, ortho-selective diversification of a biologically active pyridazinone scaffold. Seven series of novel pyridazinone analogues were synthesized conveniently as the synthetic precursors of potential sortase A (SrtA) inhibitors.

  16. Increased prevalence of late stage T cell activation antigen (VLA-1) in active juvenile chronic arthritis

    DEFF Research Database (Denmark)

    Ødum, Niels; Morling, Niels; Platz, P

    1987-01-01

    The presence of activated T cells as judged from the reaction with monoclonal antibodies (MoAb) against (a) a late stage T cell activation antigen (VLA-1), (b) the interleukin 2 (IL2) receptor (CD25), and (c) four different HLA class II molecules (HLA-DR, DRw52, DQ, and DP) was studied in 15 pati...

  17. Ages and Career Stages: Considerations in Providing Support for Mid-Late Career Stage Doctoral Students

    Science.gov (United States)

    Robertson, Margaret J.

    2017-01-01

    This article raises two inter-related issues: firstly there is a correlation between the needs of doctoral students that are strongly related to age and career stage; and secondly, because these needs differ according to their demographic, the current discourse of developing work-readiness skills of doctoral students is misplaced for the growing…

  18. Skin denervation and its clinical significance in late-stage chronic kidney disease.

    Science.gov (United States)

    Chao, Chi-Chao; Wu, Vin-Cent; Tan, Chun-Hsiang; Wang, Yi-Mei; Tseng, Ming-Tsung; Wu, Pei-Chen; Lin, Yea-Huey; Lin, Whei-Min; Wu, Kwan-Dun; Hsieh, Sung-Tsang

    2011-02-01

    To investigate the skin innervation and its clinical significance in late-stage chronic kidney disease (CKD). Case series. National Taiwan University Hospital, Taipei, Taiwan. Forty consecutive nondiabetic patients with late-stage CKD (14 female and 26 male; mean [SD] age, 60.7 [12.3] years), including 2 cases with stage 3 CKD, 6 with stage 4 CKD, and 32 with stage 5 CKD, ie, end-stage kidney disease. Clinical evaluation of neurological deficits, nerve conduction study, autonomic function tests, and a 3-mm-diameter skin biopsy specimen taken from the distal leg. Quantitation of epidermal innervation, parameters of nerve conduction study, R-R interval variability, and sympathetic skin response. Clinically, 21 patients (52.5%) were symptomatic with paresthesia over the limbs or autonomic symptoms. The intraepidermal nerve fiber (IENF) density was markedly reduced in patients with CKD compared with age- and sex-matched controls (mean [SD], 2.8 [2.0] vs 8.6 [2.8] fibers/mm; P Skin denervation was observed in 27 patients (67.5%). Fifteen patients (37.5%) had abnormalities on nerve conduction studies, and 29 patients (72.5%) had abnormal results on autonomic function tests. By analysis with multiple regression models, the IENF density was negatively correlated with the duration of renal disease (P = .02). Additionally, the R-R interval variability at rest was linearly correlated with the IENF density (P = .02) and the absence of sympathetic skin responses at the soles was associated with reduced IENF density (P = .03). Small-fiber sensory and autonomic neuropathies constitute the major form of neuropathy in late-stage CKD. Furthermore, skin denervation was associated with the duration of renal disease.

  19. Late-stage pharmaceutical R&D and pricing policies under two-stage regulation.

    Science.gov (United States)

    Jobjörnsson, Sebastian; Forster, Martin; Pertile, Paolo; Burman, Carl-Fredrik

    2016-12-01

    We present a model combining the two regulatory stages relevant to the approval of a new health technology: the authorisation of its commercialisation and the insurer's decision about whether to reimburse its cost. We show that the degree of uncertainty concerning the true value of the insurer's maximum willingness to pay for a unit increase in effectiveness has a non-monotonic impact on the optimal price of the innovation, the firm's expected profit and the optimal sample size of the clinical trial. A key result is that there exists a range of values of the uncertainty parameter over which a reduction in uncertainty benefits the firm, the insurer and patients. We consider how different policy parameters may be used as incentive mechanisms, and the incentives to invest in R&D for marginal projects such as those targeting rare diseases. The model is calibrated using data on a new treatment for cystic fibrosis. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Disparity in Breast Cancer Late Stage at Diagnosis in Missouri: Does Rural Versus Urban Residence Matter?

    Science.gov (United States)

    Williams, Faustine; Thompson, Emmanuel

    2016-06-01

    Despite the fact that black women have a lower incidence of breast cancer compared to white women, black women experience higher death rates than any other group. We examined the stage of breast cancer presentation by race and geographic region using population-based breast cancer incidence in all 115 counties in the state of Missouri. We used 2003-2008 breast cancer incidence data from Missouri Cancer Registry and Research Center. County of residence was categorized as urban or rural using the rural-urban continuum code. We computed the conditional proportion of stage at diagnosis by race and metropolitan status and also used Pearson's chi-squared test with Yates' continuity correction to determine statistical significance of association. Results of the study indicate that a greater proportion of black women (38.8 %) compared to white women (30.2 %) were diagnosed with more advanced breast metastasis. Our results further suggest that stage at diagnosis depended on county of residence or metropolitan status (p = .04). Women living in non-metropolitan counties were slightly more likely to have late-stage breast cancer than their metropolitan counterparts (32.0 vs 30.7 %). Overall, black women had 1.5-fold increased odds of late-stage breast cancer diagnosis compared to their white counterparts (OR = 1.50; 95 % CI, 1.39, 1.63; p diagnosis among women living in non-metropolitan or rural counties was over 11 % higher compared with their metropolitan or urban counterpart. The current study corroborates previous findings that the risk of late-stage breast cancer diagnosis was higher among women residing in non-metropolitan rural counties.

  1. Relation between premorbid personality and patterns of emotion expression in mid- to late-stage dementia.

    Science.gov (United States)

    Magai, C; Cohen, C I; Culver, C; Gomberg, D; Malatesta, C

    1997-11-01

    Twenty-seven nursing home patients with mid- to late-stage dementia participated in a study of the relation between preillness personality, as indexed by attachment and emotion regulation style, and current emotional behavior. Preillness measures were completed by family members and current assessments of emotion were supplied by nursing home aides and family members; in addition, emotion was coded during a family visit using an objective coding system for facial emotion expressions. Attachment style was found to be related to the expression of positive affect, with securely attached individuals displaying more positive affect than avoidantly attached individuals. In addition, high ratings on premorbid hostility were associated with higher rates of negative affect and lower rates of positive affect. These findings indicate that premorbid aspects of personality show continuity over time, even in mid- to late-stage dementia.

  2. TRIM E3 ligases interfere with early and late stages of the retroviral life cycle.

    Directory of Open Access Journals (Sweden)

    Pradeep D Uchil

    2008-02-01

    Full Text Available Members of the TRIpartite interaction Motif (TRIM family of E3 ligases have been shown to exhibit antiviral activities. Here we report a near comprehensive screen for antiretroviral activities of 55 TRIM proteins (36 human, 19 mouse. We identified approximately 20 TRIM proteins that, when transiently expressed in HEK293 cells, affect the entry or release of human immunodeficiency virus 1 (HIV, murine leukemia virus (MLV, or avian leukosis virus (ALV. While TRIM11 and 31 inhibited HIV entry, TRIM11 enhanced N-MLV entry by interfering with Ref1 restriction. Strikingly, many TRIM proteins affected late stages of the viral life cycle. Gene silencing of endogenously expressed TRIM 25, 31, and 62 inhibited viral release indicating that they play an important role at late stages of the viral life cycle. In contrast, downregulation of TRIM11 and 15 enhanced virus release suggesting that these proteins contribute to the endogenous restriction of retroviruses in cells.

  3. Testing the correlation of fragmented pollen records of the middle and late Pleistocene temperate stages

    DEFF Research Database (Denmark)

    Kuneš, Petr; Odgaard, Bent Vad

    Quaternary temperate stages have long been described based on changing pollen abundances of various tree taxa in lacustrine sediments. Later, attempts have been made to assign such biostratigraphic units to distinct marine isotope stages (MIS). Existing continuous chronosequences from Southern...... records depends on site-to-site correlations. This comparison has often been performed on a visual basis, lacking clearly defined protocols and statements of underlying assumptions. Here I test the correlation of well and poorly known pollen records of the middle- and late-Pleistocene temperate stages...... from Northern-Central Europe and evaluate the usefulness of several numerical techniques. TWINSPAN analysis identifies groups of temperate stages based on presence/absence of their indicative taxa and may be useful for distinguishing between older and younger interglacials. Site-to-site sequence...

  4. Geographic Variations of Colorectal and Breast Cancer Late-Stage Diagnosis and the Effects of Neighborhood-Level Factors.

    Science.gov (United States)

    Lin, Yan; Wimberly, Michael C

    2017-04-01

    The purpose of this study was to examine the geographic variations of late-stage diagnosis in colorectal cancer (CRC) and breast cancer as well as to investigate the effects of 3 neighborhood-level factors-socioeconomic deprivation, urban/rural residence, and spatial accessibility to health care-on the late-stage risks. This study used population-based South Dakota cancer registry data from 2001 to 2012. A total of 4,878 CRC cases and 6,418 breast cancer cases were included in the analyses. Two-level logistic regression models were used to analyze the risk of late-stage CRC and breast cancer. For CRC, there was a small geographic variation across census tracts in late-stage diagnosis, and residing in isolated small rural areas was significantly associated with late-stage risk. However, this association became nonsignificant after adjusting for census-tract level socioeconomic deprivation. Socioeconomic deprivation was an independent predictor of CRC late-stage risk, and it explained the elevated risk among American Indians. No relationship was found between spatial accessibility and CRC late-stage risk. For breast cancer, no geographic variation in the late-stage diagnosis was observed across census tracts, and none of the 3 neighborhood-level factors was significantly associated with late-stage risk. Results suggested that socioeconomic deprivation, rather than spatial accessibility, contributed to CRC late-stage risks in South Dakota as a rural state. CRC intervention programs could be developed to target isolated small rural areas, socioeconomically disadvantaged areas, as well as American Indians residing in these areas. © 2016 National Rural Health Association.

  5. Evaluation of late stage iatrogenic extrahepatic bile duct stricture by using magnetic resonance cholangiopancreagraphy

    International Nuclear Information System (INIS)

    Sun Changjin; Zhou Xiangping; Liu Rongbo; Song Bin; Yan Zhihan; Chen Xian; Wang Wentao; Xiong Yan; Xu Minsheng; Gu Jianping

    2003-01-01

    Objective: To assess the role of magnetic resonance cholangiopancreagraphy (MRCP) in the preoperative evaluation of late stage iatrogenic extrahepatic bile duct stricture. Methods: Eighteen cases, which were diagnosed as late stage iatrogenic extrahepatic bile duct strictures only by MRCP and proved by surgery and pathology, were classified according to Bismuth classification and the surgical operation strategy was planed on the basis of MR cholangiopancreagraphic findings before surgery. The results were compared with surgery. Results: Diagnostic MR Cholangiopancreagrams were acquired in 18 patients. Among all 18 patients, the level of stricture was classified as Bismuth I in 3 patients, Bismuth II in 7 patients, Bismuth III in 3 patients, and Bismuth IV in 3 patients. A Bismuth II stricture was incorrectly classified as a Bismuth III lesion. On the basis of MR cholangiopancreagraphic findings, a surgical operation strategy can be planed. The therapeutic plan anticipated with MRCP matched the actually used procedure in 16 of 18 patients. conclusion: MRCP plays an important role in the evaluation of late stage iatrogenic extrahepatic bile duct stricture

  6. Numerical simulation of two-dimensional late-stage coarsening for nucleation and growth

    International Nuclear Information System (INIS)

    Akaiwa, N.; Meiron, D.I.

    1995-01-01

    Numerical simulations of two-dimensional late-stage coarsening for nucleation and growth or Ostwald ripening are performed at area fractions 0.05 to 0.4 using the monopole and dipole approximations of a boundary integral formulation for the steady state diffusion equation. The simulations are performed using two different initial spatial distributions. One is a random spatial distribution, and the other is a random spatial distribution with depletion zones around the particles. We characterize the spatial correlations of particles by the radial distribution function, the pair correlation functions, and the structure function. Although the initial spatial correlations are different, we find time-independent scaled correlation functions in the late stage of coarsening. An important feature of the late-stage spatial correlations is that depletion zones exist around particles. A log-log plot of the structure function shows that the slope at small wave numbers is close to 4 and is -3 at very large wave numbers for all area fractions. At large wave numbers we observe oscillations in the structure function. We also confirm the cubic growth law of the average particle radius. The rate constant of the cubic growth law and the particle size distribution functions are also determined. We find qualitatively good agreement between experiments and the present simulations. In addition, the present results agree well with simulation results using the Cahn-Hilliard equation

  7. Root Morphology Was Improved in a Late-Stage Vigor Super Rice Cultivar.

    Science.gov (United States)

    Huang, Min; Chen, Jiana; Cao, Fangbo; Jiang, Ligeng; Zou, Yingbin

    2015-01-01

    This study aimed to test the hypothesis that root morphology might be improved and consequently contributing to superior post-heading shoot growth and grain yield in late-stage vigor super rice. A pot experiment was carried out to compare yield attributes, shoot growth and physiological properties and root morphological traits between a late-stage vigor super rice cultivar (Y-liangyou 087) and an elite rice cultivar (Teyou 838). Grain yield and total shoot biomass were 7-9% higher in Y-liangyou 087 than in Teyou 838. Y-liangyou 087 had 60-64% higher post-heading shoot growth rate and biomass production than Teyou 838. Average relative chlorophyll concentration and net photosynthetic rate in flag leaves were 7-11% higher in Y-liangyou 087 than in Teyou 838 during heading to 25 days after heading. Y-liangyou 087 had 41% higher post-heading shoot N uptake but 17-25% lower root biomass and root-shoot ratio at heading and maturity than Teyou 838. Specific root length and length and surface area of fine roots were higher in Y-liangyou 087 than in Teyou 838 at heading and maturity by more than 15%. These results indicated that root-shoot relationships were well balanced during post-heading phase in the late-stage vigor super rice cultivar Y-liangyou 087 by improving root morphology including avoiding a too great root biomass and developing a large fine root system.

  8. Late-phase MSCT in the different stages of myocardial infarction: animal experiments

    International Nuclear Information System (INIS)

    Mahnken, Andreas H.; Bruners, Philipp; Kinzel, Sylvia; Katoh, Marcus; Muehlenbruch, Georg; Guenther, Rolf W.; Wildberger, Joachim E.

    2007-01-01

    The purpose of this study was to intraindividually evaluate myocardial late enhancement on multislice spiral computed tomography (MSCT) for the assessment of the different stages of myocardial infarction (MI) in comparison with magnetic resonance (MR) imaging. Reperfused MI was successfully induced in seven pigs. Delayed enhancement MR imaging and late-phase MSCT were performed on day 0 as well as 7, 28 and 90 days after the procedure. The pigs were sacrificed, and 2,3,5-triphenyltetrazolin-chloride (TTC) staining was acquired. MI size was compared between the different imaging techniques and over time applying Bland-Altman plots and multivariate analysis with repeated measures. On day 0 the mean MI size was 23.7 ± 11.8% of the left ventricular area on MSCT and 24.5 ± 10.6% on MR imaging. On day 90 infarct sizes decreased significantly to 16.9 ± 8.4% and 18.9 ± 8.0%, respectively (P 0.0019). On TTC staining the size of MI was 16.8 ± 8.2%. Bland-Altman plots showed a good agreement between MSCT and MR imaging with mean deviations ranging from -3.4% to -1.9%. No significant difference between MSCT and MR imaging was found. Myocardial late enhancement on MSCT correlates well with delayed enhancement MR imaging during the different stages of MI and allows for reliable assessment of reperfused MI during acute, subacute and chronic stages. (orig.)

  9. Unexpected HIMU-type late-stage volcanism on the Walvis Ridge

    Science.gov (United States)

    Homrighausen, S.; Hoernle, K.; Geldmacher, J.; Wartho, J.-A.; Hauff, F.; Portnyagin, M.; Werner, R.; van den Bogaard, P.; Garbe-Schönberg, D.

    2018-06-01

    Volcanic activity at many oceanic volcanoes, ridges and plateaus often reawakens after hiatuses of up to several million years. Compared to the earlier magmatic phases, this late-stage (rejuvenated/post-erosional) volcanism is commonly characterized by a distinct geochemical composition. Late-stage volcanism raises two hitherto unanswered questions: Why does volcanism restart after an extended hiatus and what is the origin of this volcanism? Here we present the first 40Ar/39Ar age and comprehensive trace element and Sr-Nd-Pb-Hf isotopic data from seamounts located on and adjacent to the Walvis Ridge in the South Atlantic ocean basin. The Walvis Ridge is the oldest submarine part of the Tristan-Gough hotspot track and is famous as the original type locality for the enriched mantle one (EM I) end member. Consistent with the bathymetric data, the age data indicates that most of these seamounts are 20-40 Myr younger than the underlying or nearby Walvis Ridge basement. The trace element and isotope data reveal a distinct compositional range from the EM I-type basement. The composition of the seamounts extend from the St. Helena HIMU (high time-integrated 238U/204Pb mantle with radiogenic Pb isotope ratios) end member to an enriched (E) Mid-Ocean-Ridge Basalt (MORB) type composition, reflecting a two-component mixing trend on all isotope diagrams. The EMORB end member could have been generated through mixing of Walvis Ridge EM I with normal (N) MORB source mantle, reflecting interaction of Tristan-Gough (EM I-type) plume melts with the upper mantle. The long volcanic quiescence and the HIMU-like geochemical signature of the seamounts are unusual for classical hotspot related late-stage volcanism, indicating that these seamounts are not related to the Tristan-Gough hotspot volcanism. Two volcanic arrays in southwestern Africa (Gibeon-Dicker Willem and Western Cape province) display similar ages to the late-stage Walvis seamounts and also have HIMU-like compositions

  10. Population risk factors for late-stage presentation of cervical cancer in sub-Saharan Africa.

    Science.gov (United States)

    Stewart, Tessa S; Moodley, Jennifer; Walter, Fiona M

    2018-04-01

    Cervical cancer is the most prevalent malignancy in sub-Saharan Africa (SSA) with many women only seeking professional help when they are experiencing symptoms, implying late-stage malignancy and higher mortality rates. This ecological study assesses population-level exposures of SSA women to the numerous risk factors for HPV infection and cervical cancer, against late-stage presentation of cervical cancer. A literature review revealed the relevant risk factors in SSA. Open-access databases were mined for variables closely representing each risk factor. A proxy for late-stage presentation was used (ratio of incidence-to-mortality, IMR), and gathered from IARC's GLOBOCAN 2012 database. Variables showing significant correlation to the IMR were used in stepwise multiple regression to quantify their effect on the IMR. Countries with high cervical cancer mortality rates relative to their incidence have an IMR nearer one, suggesting a larger proportion of late-stage presentation. Western Africa had the lowest median IMR (1.463), followed by Eastern Africa (IMR = 1.595) and Central Africa (IMR = 1.675), whereas Southern Africa had the highest median IMR (1.761). Variables selected for the final model explain 65.2% of changes seen in the IMR. Significant predictors of IMR were GDP (coefficient = 2.189 × 10 -6 , p = 0.064), HIV infection (-1.936 × 10 -3 , p = 0.095), not using a condom (-1.347 × 10 -3 , p = 0.013), high parity (-1.744 × 10 -2 , p = 0.008), and no formal education (-1.311 × 10 -3 , p < 0.001). Using an IMR enables identification of factors predicting late-stage cervical cancer in SSA including: GDP, HIV infection, not using a condom, high parity and no formal education. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. Visual information constrains early and late stages of spoken-word recognition in sentence context.

    Science.gov (United States)

    Brunellière, Angèle; Sánchez-García, Carolina; Ikumi, Nara; Soto-Faraco, Salvador

    2013-07-01

    Audiovisual speech perception has been frequently studied considering phoneme, syllable and word processing levels. Here, we examined the constraints that visual speech information might exert during the recognition of words embedded in a natural sentence context. We recorded event-related potentials (ERPs) to words that could be either strongly or weakly predictable on the basis of the prior semantic sentential context and, whose initial phoneme varied in the degree of visual saliency from lip movements. When the sentences were presented audio-visually (Experiment 1), words weakly predicted from semantic context elicited a larger long-lasting N400, compared to strongly predictable words. This semantic effect interacted with the degree of visual saliency over a late part of the N400. When comparing audio-visual versus auditory alone presentation (Experiment 2), the typical amplitude-reduction effect over the auditory-evoked N100 response was observed in the audiovisual modality. Interestingly, a specific benefit of high- versus low-visual saliency constraints occurred over the early N100 response and at the late N400 time window, confirming the result of Experiment 1. Taken together, our results indicate that the saliency of visual speech can exert an influence over both auditory processing and word recognition at relatively late stages, and thus suggest strong interactivity between audio-visual integration and other (arguably higher) stages of information processing during natural speech comprehension. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Is low survival for cancer in Eastern Europe due principally to late stage at diagnosis?

    Science.gov (United States)

    Minicozzi, Pamela; Walsh, Paul M; Sánchez, Maria-José; Trama, Annalisa; Innos, Kaire; Marcos-Gragera, Rafael; Dimitrova, Nadya; Botta, Laura; Johannesen, Tom B; Rossi, Silvia; Sant, Milena

    2018-04-01

    Cancer survival has persistently been shown to be worse for Eastern European and UK/Ireland patients than those of other European regions. This is often attributed to later stage at diagnosis. However, few stage-specific survival comparisons are available, so it is unclear whether poorer quality treatment or other factors also contribute. For the first time, European cancer registries have provided stage-at-diagnosis data to EUROCARE, enabling population-based stage-specific survival estimates across Europe. In this retrospective observational study, stage at diagnosis (as TNM, condensed TNM, or Extent of Disease) was analysed for patients (≥15 years) from 15 countries grouped into 4 regions (Northern Europe: Norway; Central Europe: Austria, France, Germany, Switzerland, The Netherlands; Southern Europe: Croatia, Italy, Slovenia, and Spain; and Eastern Europe: Bulgaria, Estonia, Lithuania, Poland, and Slovakia), diagnosed with 7 malignant cancers in 2000-2007, and followed to end of 2008. A new variable (reconstructed stage) was created which used all available stage information. Age-standardised 5-year relative survival (RS) by reconstructed stage was estimated and compared between regions. Excess risks of cancer death in the 5 years after diagnosis were also estimated, taking age, sex and stage into account. Low proportions of Eastern European patients were diagnosed with local stage cancers and high proportions with metastatic stage cancers. Stage-specific RS (especially for non-metastatic disease) was generally lower for Eastern European patients. After adjusting for age, sex, and stage, excess risks of death remained higher for Eastern European patients than for European patients in general. Late diagnosis alone does not explain worse cancer survival in Eastern Europe: greater risk of cancer death together with worse stage-specific survival suggest less effective care, probably in part because fewer resources are allocated to health care than in the rest of

  13. Relationship between early and late stages of information processing: an event-related potential study

    Directory of Open Access Journals (Sweden)

    Claudio Portella

    2012-11-01

    Full Text Available The brain is capable of elaborating and executing different stages of information processing. However, exactly how these stages are processed in the brain remains largely unknown. This study aimed to analyze the possible correlation between early and late stages of information processing by assessing the latency to, and amplitude of, early and late event-related potential (ERP components, including P200, N200, premotor potential (PMP and P300, in healthy participants in the context of a visual oddball paradigm. We found a moderate positive correlation among the latency of P200 (electrode O2, N200 (electrode O2, PMP (electrode C3, P300 (electrode PZ and the reaction time (RT. In addition, moderate negative correlation between the amplitude of P200 and the latencies of N200 (electrode O2, PMP (electrode C3, P300 (electrode PZ was found. Therefore, we propose that if the secondary processing of visual input (P200 latency occurs faster, the following will also happen sooner: discrimination and classification process of this input (N200 latency, motor response processing (PMP latency, reorganization of attention and working memory update (P300 latency, and RT. N200, PMP, and P300 latencies are also anticipated when higher activation level of occipital areas involved in the secondary processing of visual input rise (P200 amplitude.

  14. Drug Repositioning Discovery for Early- and Late-Stage Non-Small-Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Chien-Hung Huang

    2014-01-01

    Full Text Available Drug repositioning is a popular approach in the pharmaceutical industry for identifying potential new uses for existing drugs and accelerating the development time. Non-small-cell lung cancer (NSCLC is one of the leading causes of death worldwide. To reduce the biological heterogeneity effects among different individuals, both normal and cancer tissues were taken from the same patient, hence allowing pairwise testing. By comparing early- and late-stage cancer patients, we can identify stage-specific NSCLC genes. Differentially expressed genes are clustered separately to form up- and downregulated communities that are used as queries to perform enrichment analysis. The results suggest that pathways for early- and late-stage cancers are different. Sets of up- and downregulated genes were submitted to the cMap web resource to identify potential drugs. To achieve high confidence drug prediction, multiple microarray experimental results were merged by performing meta-analysis. The results of a few drug findings are supported by MTT assay or clonogenic assay data. In conclusion, we have been able to assess the potential existing drugs to identify novel anticancer drugs, which may be helpful in drug repositioning discovery for NSCLC.

  15. Relationship between early and late stages of information processing: an event-related potential study

    Science.gov (United States)

    Portella, Claudio; Machado, Sergio; Arias-Carrión, Oscar; Sack, Alexander T.; Silva, Julio Guilherme; Orsini, Marco; Leite, Marco Antonio Araujo; Silva, Adriana Cardoso; Nardi, Antonio E.; Cagy, Mauricio; Piedade, Roberto; Ribeiro, Pedro

    2012-01-01

    The brain is capable of elaborating and executing different stages of information processing. However, exactly how these stages are processed in the brain remains largely unknown. This study aimed to analyze the possible correlation between early and late stages of information processing by assessing the latency to, and amplitude of, early and late event-related potential (ERP) components, including P200, N200, premotor potential (PMP) and P300, in healthy participants in the context of a visual oddball paradigm. We found a moderate positive correlation among the latency of P200 (electrode O2), N200 (electrode O2), PMP (electrode C3), P300 (electrode PZ) and the reaction time (RT). In addition, moderate negative correlation between the amplitude of P200 and the latencies of N200 (electrode O2), PMP (electrode C3), P300 (electrode PZ) was found. Therefore, we propose that if the secondary processing of visual input (P200 latency) occurs faster, the following will also happen sooner: discrimination and classification process of this input (N200 latency), motor response processing (PMP latency), reorganization of attention and working memory update (P300 latency), and RT. N200, PMP, and P300 latencies are also anticipated when higher activation level of occipital areas involved in the secondary processing of visual input rise (P200 amplitude). PMID:23355929

  16. Root Morphology Was Improved in a Late-Stage Vigor Super Rice Cultivar.

    Directory of Open Access Journals (Sweden)

    Min Huang

    Full Text Available This study aimed to test the hypothesis that root morphology might be improved and consequently contributing to superior post-heading shoot growth and grain yield in late-stage vigor super rice. A pot experiment was carried out to compare yield attributes, shoot growth and physiological properties and root morphological traits between a late-stage vigor super rice cultivar (Y-liangyou 087 and an elite rice cultivar (Teyou 838. Grain yield and total shoot biomass were 7-9% higher in Y-liangyou 087 than in Teyou 838. Y-liangyou 087 had 60-64% higher post-heading shoot growth rate and biomass production than Teyou 838. Average relative chlorophyll concentration and net photosynthetic rate in flag leaves were 7-11% higher in Y-liangyou 087 than in Teyou 838 during heading to 25 days after heading. Y-liangyou 087 had 41% higher post-heading shoot N uptake but 17-25% lower root biomass and root-shoot ratio at heading and maturity than Teyou 838. Specific root length and length and surface area of fine roots were higher in Y-liangyou 087 than in Teyou 838 at heading and maturity by more than 15%. These results indicated that root-shoot relationships were well balanced during post-heading phase in the late-stage vigor super rice cultivar Y-liangyou 087 by improving root morphology including avoiding a too great root biomass and developing a large fine root system.

  17. Nifurtimox plus Eflornithine for late-stage sleeping sickness in Uganda: a case series.

    Directory of Open Access Journals (Sweden)

    Francesco Checchi

    2007-11-01

    Full Text Available We report efficacy and safety outcomes from a prospective case series of 31 late-stage T.b. gambiense sleeping sickness (Human African Trypanosomiasis, HAT patients treated with a combination of nifurtimox and eflornithine (N+E in Yumbe, northwest Uganda in 2002-2003, following on a previously reported terminated trial in nearby Omugo, in which 17 patients received the combination under the same conditions.Eligible sequential late-stage patients received 400 mg/Kg/day eflornithine (Ornidyl, Sanofi-Aventis for seven days plus 15 mg/Kg/day (20 mg for children <15 years old nifurtimox (Lampit, Bayer AG for ten days. Efficacy (primary outcome was monitored for 24 months post discharge. Clinical and laboratory adverse events (secondary outcome were monitored during treatment. All 31 patients were discharged alive, but two died post-discharge of non-HAT and non-treatment causes, and one was lost to follow-up. Efficacy ranged from 90.3% to 100.0% according to analysis approach. Five patients experienced major adverse events during treatment, and neutropenia was common (9/31 patients.Combined with the previous group of 17 trial patients, this case series yields a group of 48 patients treated with N+E, among whom no deaths judged to be treatment- or HAT-related, no treatment terminations and no relapses have been noted, a very favourable outcome in the context of late-stage disease. N+E could be the most promising combination regimen available for sleeping sickness, and deserves further evaluation.

  18. Prevalence of early and late stages of physiologic PVD in emmetropic elderly population.

    Science.gov (United States)

    Schwab, Christoph; Ivastinovic, Domagoj; Borkenstein, Andreas; Lackner, Eva-Maria; Wedrich, Andreas; Velikay-Parel, Michaela

    2012-05-01

    To investigate the early and late stages of posterior vitreous detachment (PVD) in the foveal area in correlation with age and gender. Three hundred and thirty-five emmetropic eyes of 271 Caucasian patients (216 women/119 men) were examined by optical coherence tomography (OCT) and ultrasound (US). Eyes were classified into groups according to the patients age (up to 69.9; 70-74.9; 75-79.9; over 80 years) and to the clinical findings [Vitreous state: Detached in US; Detached in OCT; Foveal adhesion (FA); Attached vitreous]. The mean age was 76 ± 8 ranging from 44 to 89 years in female and 72 ± 10 ranging from 46 to 87 years in male subjects. The vitreous was attached in 32% of all eyes, 18.5% had FA, 18.5% were detached in OCT and 68% were detached in US. While prevalence of FA decreases with increasing age, OCT-diagnosed detachments did not change significantly with age. Between the ages of 70 and 75, an increase in PVD rates occurred. The prevalence of PVD was similar in both genders. Women were significantly older than men in the late-stage PVD in the eyes. The use of OCT and US enabled us to detect a partial or total PVD in 80% of the eyes. A sudden increase in late-stage PVD between the ages of 70 and 75 was observed, correlating with the reported age prevalence of various macular diseases. In contrast to myopics, both genders of elderly emmetropics have a similar prevalence of PVD. © 2011 The Authors. Acta Ophthalmologica © 2011 Acta Ophthalmologica Scandinavica Foundation.

  19. Late-stage galaxy mergers in cosmos to z ∼ 1

    International Nuclear Information System (INIS)

    Lackner, C. N.; Silverman, J. D.; Salvato, M.; Kampczyk, P.; Kartaltepe, J. S.; Sanders, D.; Lee, N.; Capak, P.; Scoville, N.; Civano, F.; Halliday, C.; Ilbert, O.; Le Fèvre, O.; Jahnke, K.; Koekemoer, A. M.; Liu, C. T.; Sheth, K.; Toft, S.

    2014-01-01

    The role of major mergers in galaxy and black hole formation is not well-constrained. To help address this, we develop an automated method to identify late-stage galaxy mergers before coalescence of the galactic cores. The resulting sample of mergers is distinct from those obtained using pair-finding and morphological indicators. Our method relies on median-filtering of high-resolution images to distinguish two concentrated galaxy nuclei at small separations. This method does not rely on low surface brightness features to identify mergers, and is therefore reliable to high redshift. Using mock images, we derive statistical contamination and incompleteness corrections for the fraction of late-stage mergers. The mock images show that our method returns an uncontaminated (<10%) sample of mergers with projected separations between 2.2 and 8 kpc out to z∼1. We apply our new method to a magnitude-limited (m FW 814 <23) sample of 44,164 galaxies from the COSMOS HST/ACS catalog. Using a mass-complete sample with logM ∗ /M ⊙ >10.6 and 0.25late-stage mergers. Correcting for incompleteness and contamination, the fractional merger rate increases strongly with redshift as r merge ∝(1+z) 3.8±0.9 , in agreement both with earlier studies and with dark matter halo merger rates. Separating the sample into star-forming and quiescent galaxies shows that the merger rate for star-forming galaxies increases strongly with redshift, (1+z) 4.5±1.3 , while the merger rate for quiescent galaxies is consistent with no evolution, (1+z) 1.1±1.2 . The merger rate also becomes steeper with decreasing stellar mass. Limiting our sample to galaxies with spectroscopic redshifts from zCOSMOS, we find that the star formation rates and X-ray selected active galactic nucleus (AGN) activity in likely late-stage mergers are higher by factors of ∼2 relative to those of a control sample. Combining our sample with more widely separated pairs, we find that 8

  20. Late Pleistocene lithostratigraphy and sequences in the southwestern Mesopotamia (Argentina): Evidences of the last interglacial stage

    Science.gov (United States)

    Ernesto, Brunetto; Soledad, Ferrero Brenda; Ignacio, Noriega Jorge

    2015-03-01

    The aim of this paper is to show the stratigraphic record of the Late Pleistocene corresponding to the distal region of the Paraná River basin. It displays sedimentological, paleontological and geochronological evidences that characterise the last interglacial-glacial cycle. In particular, strong environmental records are shown for the Last Interglacial Stage (LIS). Salto Ander Egg Formation (SAEF) is defined as a new lithostratigraphic unit representative of the Late Pleistocene in southwestern Mesopotamia. This unit is formed of complex fluvial deposits, which contains a heterogeneous collection of sub-environments, of ages ranging from 120 to 60 ky BP. The clast-supported gravel facies containing sparse boulders indicate high flow during a humid climate. The large and middle-scale architectures of fluvial sedimentary bodies evidence the relationship between the sediment accommodation and the sea level oscillations. Three sub-sequences identified in the succession suggest a transgressive trend during the MIS5e, a highstand stage in MIS5c, and a minor transgressive cycle during MIS3. A Brazilian faunal association collected at the bottom of the sequence and sedimentological interpretations display wet and warm climatic conditions, typical of tropical or subtropical environments. Such environmental conditions are characteristic of the maximum of the last interglacial stage (MIS5e) and show a signal stronger than the signal of the current interglacial stage. All these data show a direct correlation between the increases of paleodischarges and the elevation of the sea level. The whole sequence is completed with transitional swampy deposits, accumulated probably during the MIS3/MIS2 transition, and the typical loess of the Tezanos Pinto Formation, mantled during the Last Maximum Glacial.

  1. Sociodemographic Factors and Late-stage Diagnosis of Breast Cancer in India: A Hospital-based Study

    OpenAIRE

    Sathwara, Jignasa Amrutlal; Balasubramaniam, Ganesh; Bobdey, Saurabh C; Jain, Aanchal; Saoba, Sushama

    2017-01-01

    Context: Breast cancer (BC) is one of the major causes of cancer mortality in India. Late-stage diagnosis of BC is associated with poor survival. Identification of factors affecting late presentation of the disease could be an effective step to reduce BC mortality. Aims: To study the association of sociodemographic factors with BC stage at diagnosis. Settings and Design: The study is a retrospective analysis from the case records from a single institution. Subjects and Methods: Data for the y...

  2. Cognitive adaptation theory and quality of life in late-stage cancer patients.

    Science.gov (United States)

    Christianson, Heidi Fowell; Weis, Jo M; Fouad, Nadya A

    2013-01-01

    In this study, the question of whether using slightly illusionary, positive attributions of self, control, and meaning (e.g., cognitive adaptation theory), in the face of disconfirmatory evidence, facilitates quality of life in late-stage cancer patients was examined. Eighty late-stage cancer patients (Mean age = 59.7, SD = 12.5; 48.8% male, 51.2% female; varying cancer diagnoses) who recently failed or refused first line anti-neoplastic treatment completed questionnaires assessing meaning, control, self-esteem, and optimism, as well as physical and psychological quality of life. Findings suggest that greater self-esteem, control, and meaning predicted physical and psychological quality of life, with physical quality of life being influenced by control beliefs and psychological quality of life influenced by self-esteem. Optimism independently predicted physical quality of life and neither mediated nor moderated the relationship between cognitive adaptation and quality of life. Findings suggest that slightly positive, illusionary beliefs of self, control, and meaning predicted quality of life even in the presence of clear, disconfirmatory environmental evidence.

  3. Development of the Japanese version of the Quality of Life in Late-stage Dementia Scale.

    Science.gov (United States)

    Nagata, Yuma; Tanaka, Hiroyuki; Ishimaru, Daiki; Uematsu, Masayasu; Naito, Yasuo; Nishikawa, Takashi

    2018-03-01

    Until now, there has been no instrument to measure the quality of life (QoL) of patients with severe dementia in Japan. The purpose of this study was to translate the Quality of Life in Late-stage Dementia Scale and to evaluate the reliability and validity of the Japanese version (QUALID-J). We translated the Quality of Life in Late-stage Dementia into Japanese with permission from the original authors. We assessed a total of 70 dementia patients (14 men, 56 women; mean age: 87.4 ± 7.9 years) with the QUALID-J. The test-retest and inter-rater reliability of the QUALID-J was significant. With regard to the criterion-related validity, the correlation coefficient for the total score between the QUALID-J and Quality of Life for Alzheimer's Disease was -0.287 (P quality of life scale for severe dementia. This scale finally enables an adequate assessment of the quality of life of patients with severe dementia in Japan, which has not been possible until now. © 2018 Japanese Psychogeriatric Society.

  4. New, but slow – technical newness challenges late stage development speed

    DEFF Research Database (Denmark)

    Smed, Marie; Salomo, Søren; Getz, Kenneth A.

    2014-01-01

    The down-stream processes where new product prospects undergo pilot testing and adjustments before market launch can have significant impact on development speed. Previous literature has primarily pointed to firm traits as influential factors to speed. However, product specific measures such as t......The down-stream processes where new product prospects undergo pilot testing and adjustments before market launch can have significant impact on development speed. Previous literature has primarily pointed to firm traits as influential factors to speed. However, product specific measures...... such as technical innovativeness may be a critical factor when going through the crucial late stages of development. We have limited knowledge of the relation between product newness and the speed of NPD, and how this may be related to firm size and partnering strategies during development. Combining product traits...... with firm resources relevant to late stage development speed can enrich our understanding of time-tomarket in the aim of improving this crucial measure of NPD. The research model is tested on a dataset of all new drug developments approved for the US market 2000-2010. The results show that newness...

  5. The development of an intervention to manage pain in people with late-stage osteoarthritis

    Directory of Open Access Journals (Sweden)

    Tina Kruger-Jakins

    2016-06-01

    Full Text Available Background: Osteoarthritis (OA is one of the most common musculoskeletal conditions worldwide, affecting the functional abilities of millions of people. Arthroplasty is recommended as a successful treatment option for late-stage OA. However, in South Africa there are extensive waiting lists for OA-related arthroplasty in government hospitals. This has negative consequences for patients having to cope for long periods of time with chronic pain and its impact. Alternative treatment methods in the form of physiotherapy-led exercise and education programmes focusing on pain, disability, self-efficacy, physical function and health-related quality of life have had good impact in populations elsewhere. Objectives: To develop an exercise and education intervention based on the current literature and by doing a field survey in a South African population. Results: A combined educational approach, with a strong focus on the physical aspects of exercise in particular, was adopted for the intervention in order to improve function and manage the disability associated with OA. Conclusion: This paper reports on the process and development of an intervention for use in South Africans with late-stage OA awaiting arthroplasty. Keywords: Hip/knee osteoarthritis, arthroplasty, joint replacement, bio-psychosocial intervention, waiting list, physiotherapy, exercise, education, chronic pain

  6. Thrombopoietin has a differentiative effect on late-stage human erythropoiesis.

    Science.gov (United States)

    Liu, W; Wang, M; Tang, D C; Ding, I; Rodgers, G P

    1999-05-01

    To further explore the mechanism of the effect of thrombopoietin (TPO) on erythropoiesis, we used a two-phase culture system to investigate the effect of TPO on late-stage human erythroid lineage differentiation. In serum-free suspension and semisolid cultures of human peripheral blood derived erythroid progenitors, TPO alone did not produce benzidine-positive cells. However, in serum-containing culture, TPO alone stimulated erythroid cell proliferation and differentiation, demonstrated by erythroid colony formation, production of benzidine-positive cells and haemoglobin (Hb) synthesis. Monoclonal anti-human erythropoietin antibody and anti-human erythropoietin receptor antibody completely abrogated the erythroid differentiative ability of TPO in the serum-containing systems. This implied that binding of EPO and EPO-R was essential for erythropoiesis and the resultant signal transduction may be augmented by the signals emanating from TPO-c-Mpl interaction. Experiment of withdrawal of TPO further demonstrated the involvement of TPO in late-stage erythropoiesis. RT-PCR results showed that there was EPO-R but not c-Mpl expression on developing erythroblasts induced by TPO in serum-containing system. Our results establish that TPO affects not only the proliferation of erythroid progenitors but also the differentiation of erythroid progenitors to mature erythroid cells.

  7. Management of postural sensory conflict and dynamic balance control in late-stage Parkinson's disease.

    Science.gov (United States)

    Colnat-Coulbois, S; Gauchard, G C; Maillard, L; Barroche, G; Vespignani, H; Auque, J; Perrin, P P

    2011-10-13

    Parkinson's disease (PD) is known to affect postural control, especially in situations needing a change in balance strategy or when a concurrent task is simultaneously performed. However, few studies assessing postural control in patients with PD included homogeneous population in late stage of the disease. Thus, this study aimed to analyse postural control and strategies in a homogeneous population of patients with idiopathic advanced (late-stage) PD, and to determine the contribution of peripheral inputs in simple and more complex postural tasks, such as sensory conflicting and dynamic tasks. Twenty-four subjects with advanced PD (duration: median (M)=11.0 years, interquartile range (IQR)=4.3 years; Unified Parkinson's Disease Rating Scale (UPDRS): M "on-dopa"=13.5, IQR=7.8; UPDRS: M "off-dopa"=48.5, IQR=16.8; Hoehn and Yahr stage IV in all patients) and 48 age-matched healthy controls underwent static (SPT) and dynamic posturographic (DPT) tests and a sensory organization test (SOT). In SPT, patients with PD showed reduced postural control precision with increased oscillations in both anterior-posterior and medial-lateral planes. In SOT, patients with PD displayed reduced postural performances especially in situations in which visual and vestibular cues became predominant to organize balance control, as was the ability to manage balance in situations for which visual or proprioceptive inputs are disrupted. In DPT, postural restabilization strategies were often inefficient to maintain equilibrium resulting in falls. Postural strategies were often precarious, postural regulation involving more hip joint than ankle joint in patients with advanced PD than in controls. Difficulties in managing complex postural situations, such as sensory conflicting and dynamic situations might reflect an inadequate sensory organization suggesting impairment in central information processing. Copyright © 2011. Published by Elsevier Ltd.

  8. Cyclostratigraphic calibration of the Famennian stage (Late Devonian, Illinois Basin, USA)

    Science.gov (United States)

    Pas, Damien; Hinnov, Linda; Day, James E. (Jed); Kodama, Kenneth; Sinnesael, Matthias; Liu, Wei

    2018-04-01

    The Late Devonian biosphere was affected by two of the most severe biodiversity crises in Earth's history, the Kellwasser and Hangenberg events near the Frasnian-Famennian (F-F) and the Devonian-Carboniferous (D-C) boundaries, respectively. Current hypotheses for the causes of the Late Devonian extinctions are focused on climate changes and associated ocean anoxia. Testing these hypotheses has been impeded by a lack of sufficient temporal resolution in paleobiological, tectonic and climate proxy records. While there have been recent advances in astronomical calibration that have improved the accuracy of the Frasnian time scale and part of the Famennian, the time duration of the entire Famennian Stage remains poorly constrained. During the Late Devonian, a complete Late Frasnian-Early Carboniferous succession of deep-shelf deposits accumulated in the epieric sea in Illinois Basin of the central North-American mid-continent. A record of this sequence is captured in three overlapping cores (H-30, Sullivan and H-32). The H-30 core section spans the F-F boundary; the Sullivan section spans almost all of the Famennian and the H-32 section sampled spans the interval of the Upper Famennian and the D-C boundary. To have the best chance of capturing Milankovitch cycles, 2000 rock samples were collected at minimum 5-cm-interval across the entire sequence. Magnetic susceptibility (MS) was measured on each sample and the preservation of climatic information into the MS signal was verified through geochemical analyses and low-temperature magnetic susceptibility acquisition. To estimate the duration of the Famennian Stage, we applied multiple spectral techniques and tuned the MS signal using the highly stable 405 kyr cycle for Sullivan and the obliquity cycle for the H-30 and H-32 cores. Based on the correlation between the cores we constructed a Famennian floating astronomical time scale, which indicates a duration of 13.5 ± 0.5 myr. An uncertainty of 0.5 myr was estimated for

  9. Important Late-Stage Symbiotic Role of the Sinorhizobium meliloti Exopolysaccharide Succinoglycan.

    Science.gov (United States)

    Arnold, Markus F F; Penterman, Jon; Shabab, Mohammed; Chen, Esther J; Walker, Graham C

    2018-07-01

    Sinorhizobium meliloti enters into beneficial symbiotic interactions with Medicago species of legumes. Bacterial exopolysaccharides play critical signaling roles in infection thread initiation and growth during the early stages of root nodule formation. After endocytosis of S. meliloti by plant cells in the developing nodule, plant-derived nodule-specific cysteine-rich (NCR) peptides mediate terminal differentiation of the bacteria into nitrogen-fixing bacteroids. Previous transcriptional studies showed that the intensively studied cationic peptide NCR247 induces expression of the exo genes that encode the proteins required for succinoglycan biosynthesis. In addition, genetic studies have shown that some exo mutants exhibit increased sensitivity to the antimicrobial action of NCR247. Therefore, we investigated whether the symbiotically active S. meliloti exopolysaccharide succinoglycan can protect S. meliloti against the antimicrobial activity of NCR247. We discovered that high-molecular-weight forms of succinoglycan have the ability to protect S. meliloti from the antimicrobial action of the NCR247 peptide but low-molecular-weight forms of wild-type succinoglycan do not. The protective function of high-molecular-weight succinoglycan occurs via direct molecular interactions between anionic succinoglycan and the cationic NCR247 peptide, but this interaction is not chiral. Taken together, our observations suggest that S. meliloti exopolysaccharides not only may be critical during early stages of nodule invasion but also are upregulated at a late stage of symbiosis to protect bacteria against the bactericidal action of cationic NCR peptides. Our findings represent an important step forward in fully understanding the complete set of exopolysaccharide functions during legume symbiosis. IMPORTANCE Symbiotic interactions between rhizobia and legumes are economically important for global food production. The legume symbiosis also is a major part of the global nitrogen

  10. Influence of cigarette smoking on hormone and lipid metabolism in women in late reproductive stage

    Directory of Open Access Journals (Sweden)

    Szkup M

    2018-01-01

    Full Text Available Małgorzata Szkup,1 Anna Jurczak,2 Beata Karakiewicz,3 Artur Kotwas,3 Jacek Kopeć,4 Elżbieta Grochans1 1Department of Nursing, 2Department of Clinical Nursing, 3Department of Public Health, Pomeranian Medical University in Szczecin, Szczecin, Poland; 4School of Population and Public Health, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada Background: The aim of the study was to analyze lipid and hormone metabolism, body mass index (BMI, and age parameters in late reproductive stage women in relation to cigarette smoking.Methods: The study enrolled 345 healthy late reproductive stage women living in Poland; 13.33% were smokers. The first part of the study assessed lipid metabolism (total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL], and triglycerides and hormone metabolism (estradiol [E2], follicle-stimulating hormone [FSH], and anti-Müllerian hormone [AMH] levels in women in the early phase of the follicular menstrual cycle. The second part of study was carried out using the diagnostic survey method, with a standardized questionnaire (Primary Care Evaluation of Mental Disorders [PRIME-MD] and the authors’ own research tools.Results: The women were aged 42.3±4.5 years (mean ± SD. The BMI (24.8±4.04 kg/m2 did not differ significantly between the groups. The women who smoked cigarettes had a statistically significantly (p<0.05 lower level of HDL as well as higher LDL and triglyceride levels (p<0.05. Differences were also shown in hormone levels: non-smoking participants had statistically significantly higher levels of E2 and FSH (p<0.05. In the group of non-smoking women, age was a predictor exerting a significant positive impact on the levels of total cholesterol, LDL, triglycerides, and AMH (p<0.05. BMI contributed to a decline in HDL and triglyceride levels. In the group of smoking women, age significantly positively influenced the level of E2, and negatively influenced AMH

  11. Risk factors for late-stage HIV disease presentation at initial HIV diagnosis in Durban, South Africa.

    Directory of Open Access Journals (Sweden)

    Paul K Drain

    Full Text Available After observing persistently low CD4 counts at initial HIV diagnosis in South Africa, we sought to determine risk factors for late-stage HIV disease presentation among adults.We surveyed adults prior to HIV testing at four outpatient clinics in Durban from August 2010 to November 2011. All HIV-infected adults were offered CD4 testing, and late-stage HIV disease was defined as a CD4 count <100 cells/mm(3. We used multivariate regression models to determine the effects of sex, emotional health, social support, distance from clinic, employment, perceived barriers to receiving healthcare, and foregoing healthcare to use money for food, clothing, or housing ("competing needs to healthcare" on presentation with late-stage HIV disease.Among 3,669 adults screened, 830 were enrolled, newly-diagnosed with HIV and obtained a CD4 result. Among those, 279 (33.6% presented with late-stage HIV disease. In multivariate analyses, participants who lived ≥5 kilometers from the test site [adjusted odds ratio (AOR 2.8, 95% CI 1.7-4.7], reported competing needs to healthcare (AOR 1.7, 95% CI 1.2-2.4, were male (AOR 1.7, 95% CI 1.2-2.3, worked outside the home (AOR 1.5, 95% CI 1.1-2.1, perceived health service delivery barriers (AOR 1.5, 95% CI 1.1-2.1, and/or had poor emotional health (AOR 1.4, 95% CI 1.0-1.9 had higher odds of late-stage HIV disease presentation.Independent risk factors for late-stage HIV disease presentation were from diverse domains, including geographic, economic, demographic, social, and psychosocial. These findings can inform various interventions, such as mobile testing or financial assistance, to reduce the risk of presentation with late-stage HIV disease.

  12. Causes and outcome of late referral of children who develop end-stage kidney disease.

    Science.gov (United States)

    Kennedy, Sean E; Bailey, Rohan; Kainer, Gad

    2012-03-01

    This study aims to characterise the timing of referral to a paediatric nephrology unit of children who develop end-stage kidney disease (ESKD). This study also aims to determine whether late referral (LR) influences outcomes and to explore factors that may lead to LR. A retrospective case review of all incident patients with ESKD who received renal replacement therapy (RRT) at a single paediatric centre. Time between referral to a paediatric nephrologist and commencement of RRT, demographic and clinical data were collated. Estimated glomerular filtration rate (eGFR) at referral was calculated using height and creatinine. LR was defined as having an eGFR ≤ 30 mL/min/1.73 m(2) when first seen by a paediatric nephrologist. RRT was initiated for 74 patients Children referred before age 1 year (41%) had a more prolonged course before ESKD. Median (interquartile range) eGFR at referral of children > 1 year was 27.2 (9.0-52.0) mL/min/1.73 m(2) . Twenty-two (55%) of these children were referred late (LR) with an eGFR ≤ 30 mL/min/1.73 m(2) . LR patients were more likely to have glomerulonephritis or haemolytic uraemic syndrome and to live in a remote or outer regional area. LR patients had higher urea, lower haemoglobin and were more likely to receive haemodialysis via a vascular catheter. A significant proportion of children who develop ESKD are referred late to nephrology units with potentially preventable complications. Aetiology of renal disease and geographic isolation contribute to LR. © 2011 The Authors. Journal of Paediatrics and Child Health © 2011 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

  13. Late-Stage Vortical Structures and Eddy Motions in a Transitional Boundary Layer

    International Nuclear Information System (INIS)

    Xiao-Bing, Liu; Zheng-Qing, Chen; Chao-Qun, Liu

    2010-01-01

    A high-order direct numerical simulation of flow transition over a flat-plate at a free stream Mach number 0.5 is carried out. Formation and development of three-dimensional vortical structures, typically shown as A-vortices, hairpin vortices and ring-like vortices, are observed. Numerical results show that there is a strong downdraft motion of fluid excited by every ring-like vortex in the late-stage of the transition process. At two sides of the vortical structure centerline, the downdraft motions induced by the ring-like vortex and the rotating legs superimpose. This is responsible for the appearance of a high-speed streak associated with the positive spike observed in a previous investigation and the appearance of a high-shear layer in the near wall region. (fundamental areas of phenomenology(including applications))

  14. Lower limb lymphedema: experiences and perceptions of cancer patients in the late palliative stage.

    Science.gov (United States)

    Frid, Marianne; Strang, Peter; Friedrichsen, Maria J; Johansson, Karin

    2006-01-01

    Lower limb lymphedema (LLL) is a common but neglected problem in palliative cancer patients. No studies have focused on these patients' experiences of lymphedema. The aims of this study were to explore patients' experiences regarding LLL and how they manage to deal with this in the late palliative stage. Thirteen patients with cancer-related LLL were included to satisfy a maximum variation sampling strategy. Interviews were analyzed using a qualitative phenomenographic method. LLL influenced the patients' thoughts about the future. Body image was often strongly influenced. Interactions with other persons were perceived as both positive and negative, and a range of coping strategies were expressed. LLL can exert a considerable influence on the physical experiences and the psychosocial situation of cancer patients in palliative care. Areas in need of increased education, attention, and further research are highlighted.

  15. Cholinergic systems are essential for late-stage maturation and refinement of motor cortical circuits

    Science.gov (United States)

    Ramanathan, Dhakshin S.; Conner, James M.; Anilkumar, Arjun A.

    2014-01-01

    Previous studies reported that early postnatal cholinergic lesions severely perturb early cortical development, impairing neuronal cortical migration and the formation of cortical dendrites and synapses. These severe effects of early postnatal cholinergic lesions preclude our ability to understand the contribution of cholinergic systems to the later-stage maturation of topographic cortical representations. To study cholinergic mechanisms contributing to the later maturation of motor cortical circuits, we first characterized the temporal course of cortical motor map development and maturation in rats. In this study, we focused our attention on the maturation of cortical motor representations after postnatal day 25 (PND 25), a time after neuronal migration has been accomplished and cortical volume has reached adult size. We found significant maturation of cortical motor representations after this time, including both an expansion of forelimb representations in motor cortex and a shift from proximal to distal forelimb representations to an extent unexplainable by simple volume enlargement of the neocortex. Specific cholinergic lesions placed at PND 24 impaired enlargement of distal forelimb representations in particular and markedly reduced the ability to learn skilled motor tasks as adults. These results identify a novel and essential role for cholinergic systems in the late refinement and maturation of cortical circuits. Dysfunctions in this system may constitute a mechanism of late-onset neurodevelopmental disorders such as Rett syndrome and schizophrenia. PMID:25505106

  16. Leptospirosis-associated acute kidney injury: penicillin at the late stage is still controversial.

    Science.gov (United States)

    Daher, E F; Silva, G B; de Abreu, K L S; Mota, R M S; Batista, D V; Rocha, N A; Araújo, S M H A; Libório, A B

    2012-08-01

    Some antimicrobial agents are active in vitro against Leptospiras. The use of penicillins at the late stage of leptospirosis is still controversial. We aimed to evaluate the use of penicillin in patients with leptospirosis-associated acute kidney injury (AKI). A retrospective study was conducted of patients with leptospirosis admitted to two hospitals in Fortaleza city, Brazil, between 1985 and 2008. AKI was defined according to the RIFLE and AKIN classifications. Patients were divided in two groups according to whether they were treated with a penicillin or not. Two hundred and eighty-seven patients were included, with an average age of 36·8±15·6 years and mostly male (80·8%). One hundred and twelve patients (39%) received a penicillin. Patients treated with a penicillin were younger (32±14 years vs. 39±16 years, P=0·0002) and had a shorter hospital stay (8·4±5·0 vs. 11±7·7 days, Ppenicillin group (111±21 vs. 119±22 mmHg, P=0·04). AKI, need of dialysis and renal recovery at the time of hospital discharge were more frequent in patients who did not use a penicillin (Ppenicillin, remains controversial. The main benefit of using penicillin in the present study was a reduction in the length of hospital stay and fewer complications, such as AKI, but its use was not associated with a decrease in mortality. On balance of risks and benefits, we recommend the use of penicillin in late-stage leptospirosis. © 2011 Blackwell Publishing Ltd.

  17. Is Travel Time to Colonoscopy Associated With Late-Stage Colorectal Cancer Among Medicare Beneficiaries in Iowa?

    Science.gov (United States)

    Charlton, Mary E; Matthews, Kevin A; Gaglioti, Anne; Bay, Camden; McDowell, Bradley D; Ward, Marcia M; Levy, Barcey T

    2016-09-01

    Colorectal cancer (CRC) screening has been shown to decrease the incidence of late-stage colorectal cancer, yet a substantial proportion of Americans do not receive screening. Those in rural areas may face barriers to colonoscopy services based on travel time, and previous studies have demonstrated lower screening among rural residents. Our purpose was to assess factors associated with late-stage CRC, and specifically to determine if longer travel time to colonoscopy was associated with late-stage CRC among an insured population in Iowa. SEER-Medicare data were used to identify individuals ages 65 to 84 years old diagnosed with CRC in Iowa from 2002 to 2009. The distance between the centroid of the ZIP code of residence and the ZIP code of colonoscopy was computed for each individual who had continuous Medicare fee-for-service coverage for a 3- to 4-month period prior to diagnosis, and a professional claim for colonoscopy within that time frame. Demographic characteristics and travel times were compared between those diagnosed with early- versus late-stage CRC. Also, demographic differences between those who had colonoscopy claims identified within 3-4 months prior to diagnosis (81%) were compared to patients with no colonoscopy claims identified (19%). A total of 5,792 subjects met inclusion criteria; 31% were diagnosed with early-stage versus 69% with late-stage CRC. Those divorced or widowed (vs married) were more likely to be diagnosed with late-stage CRC (OR: 1.20, 95% CI: 1.06-1.37). Travel time was not associated with diagnosis of late-stage CRC. Among a Medicare-insured population, there was no relationship between travel time to colonoscopy and disease stage at diagnosis. It is likely that factors other than distance to colonoscopy present more pertinent barriers to screening in this insured population. Additional research should be done to determine reasons for nonadherence to screening among those with access to CRC screening services, given that over

  18. [Endocrinology of cancer and age: early and late stages of ontogenesis].

    Science.gov (United States)

    Berstein, L M

    2017-01-01

    Processes important for hormone-mediated carcinogenesis are present on different, even very early, ontogenesis stages. Early shifts in hormone-metabolic status often display opposite correlations with the risk of most common age-associated non-communicable pathologies (namely, hormone-dependent cancers and cardiovascular diseases). Additional known contradiction is the raise of reproductive system tumors incidence in the age associated with lower production of mitogenic hormones. Consequently, one should take into account production of steroids in target tissues themselves, recognize the importance of progenotoxic effect, which, apart from mitogenic function, is characteristic for estrogens and their derivatives, as well as the role of endocrine-genotoxic switchings forming so called basic triad, which is born under the influence of age-associated endocrine shifts and environmental factors. Aside from steroids-related system of increased cancer risk, attention should be paid to non-steroid ones (in particular insulin resistance- and inflammatory cytokines-associated), with their close connection to immune system functional state, low-grade chronic inflammation, obesity phenotype, and pro-/anti-inflammatory lipid factors ratio. In total, it confirms and importance of timely preventive interventions on both ontogenesis stages, early and late ones, which are often separated by several decades.

  19. Two consecutive pregnancies in early and late stage of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Sarafov, Stayko; Doitchinova, Maryana; Karagiozova, Zhvka; Slancheva, Boriana; Dengler, Reinhard; Petri, Susanne; Kollewe, Katja

    2009-01-01

    There are few reports on pregnancies in sporadic and familial amyotrophic lateral sclerosis (ALS). We report on a young woman with sporadic ALS who gave birth twice during the course of her disease. The first pregnancy occurred 13 months after the onset of symptoms, and one month after diagnosis. The pregnancy was uncomplicated and resulted in vaginal delivery of a healthy boy. Fifteen months later, when she was already bed-ridden, she became pregnant again. She received a percutaneous endoscopic gastrostomy in the 21st gestational week and underwent early Caesarean section in the 34th week of gestation. The child was ventilated for 72 h in a neonatological unit. The patient was tracheotomized and ventilated two months later, i.e. 47 months after symptom onset, and died nine months later from gastrointestinal haemorrhage. Her two children have developed without abnormalities to date. This case confirms that pregnancies in early-stage ALS can develop normally and may result in uncomplicated vaginal delivery. Pregnancies in late stages may be critical for mother and child, and early delivery by Caesarean section may become necessary although neonatal outcome can be good.

  20. Emotional conflict occurs at a late stage: evidence from the paired-picture paradigm

    Directory of Open Access Journals (Sweden)

    Pan Fada

    2016-01-01

    Full Text Available The present study used paired-picture paradigm, where either congruent or incongruent emotional expressions were presented side by side to measure the neural correlates underlying the processing of emotional conflict effect. Event-related potentials were recorded while participants identified whether the valences of the paired-picture were consistent or not. The results showed that incongruent and congruent picture pairs both elicited larger N2 (210-310 ms amplitudes than neutral pairs. In contrast, the conflict picture pairs elicited a larger conflict slow potential (conflict SP, 700-1000 ms than did the positive and neutral picture pairs. There was no significant difference in conflict SP amplitudes between incongruent and congruent picture pairs (i.e., the mean amplitudes of negative and positive picture pairs. The results demonstrated that emotional information was identified and processed during the stage from about 210 ms to 310 ms. However, the emotional conflict effect did not appear until late stage (700-1000 ms. These results supported the distributed attention theory of emotions (DATE.

  1. A loss of profilin-1 in late-stage oral squamous cell carcinoma.

    Science.gov (United States)

    Adami, Guy R; O'Callaghan, Thomas N; Kolokythas, Antonia; Cabay, Robert J; Zhou, Yalu; Schwartz, Joel L

    2017-08-01

    The genes for PFN1 and TMSB4 are both highly expressed in oral tissue and both encode actin monomer binding proteins thought to play a role in cell motility and possibly other crucial parts of tumor progression. Oral brush cytology of epithelium from oral squamous cell carcinoma (OSCC) was used to measure PFN1 and TMSB4 mRNA in OSCC, while immunohistochemical analysis of tissue was used to check protein levels. High but variable expression of mRNAs encoding these two proteins was observed suggesting they may contribute to tumor characteristics in a subset of OSCCs. Both proteins were highly expressed in normal appearing basal epithelium, in the cytoplasm, and perinuclear area, while expression was minimal in upper epithelial layers. In OSCCs, expression of these proteins varied. In tumors classified as later stage, based on size and/or lymph node involvement, PFN1 levels were lower in tumor epithelium. A control gene, KRT13, showed expression in normal differentiated basal and suprabasal oral mucosa epithelial cells and as reported was lost in OSCC cells. Loss of PFN1 in tumor cells has been associated with lymph node invasion and metastasis in other tumor types, strengthening the argument that the protein has the potential to be a tumor suppressor in late-stage OSCC. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. IL-6 is Upregulated in Late-Stage Disease in Monkeys Experimentally Infected with Trypanosoma brucei rhodesiense

    Directory of Open Access Journals (Sweden)

    Dawn Nyawira Maranga

    2013-01-01

    Full Text Available The management of human African trypanosomiasis (HAT is constrained by lack of simple-to-use diagnostic, staging, and treatment tools. The search for novel biomarkers is, therefore, essential in the fight against HAT. The current study aimed at investigating the potential of IL-6 as an adjunct parameter for HAT stage determination in vervet monkey model. Four adult vervet monkeys (Chlorocebus aethiops were experimentally infected with Trypanosoma brucei rhodesiense and treated subcuratively at 28 days after infection (dpi to induce late stage disease. Three noninfected monkeys formed the control group. Cerebrospinal fluid (CSF and blood samples were obtained at weekly intervals and assessed for various biological parameters. A typical HAT-like infection was observed. The late stage was characterized by significant (P<0.05 elevation of CSF IL-6, white blood cell count, and total protein starting 35 dpi with peak levels of these parameters coinciding with relapse parasitaemia. Brain immunohistochemical staining revealed an increase in brain glial fibrillary acidic protein expression indicative of reactive astrogliosis in infected animals which were euthanized in late-stage disease. The elevation of IL-6 in CSF which accompanied other HAT biomarkers indicates onset of parasite neuroinvasion and show potential for use as an adjunct late-stage disease biomarker in the Rhodesian sleeping sickness.

  3. Physiological and Biochemical Characteristics in Flag Leaves of the C Liangyou Series of Hybrid Rice Combinations at Late Growth Stages

    Directory of Open Access Journals (Sweden)

    Wen-bang TANG

    2010-12-01

    Full Text Available The contents of chlorophyll, soluble sugars, soluble proteins and thiobarbituric acid reaction substance (TBARS, chlorophyll fluorescence parameters, net photosynthetic rate as well as the activities of superoxide dismutase (SOD and peroxidase (POD of flag leaves at the late growth stages were studied by using C Liangyou series of hybrid rice combinitions as material and Shanyou 63 as control. The C Liangyou series of hybrid rice combinations used in the experiment included C Liangyou 396, C Liangyou 87, C Liangyou 755 and C Liangyou 34, which all used C815S as male sterile line. The contents of chlorophyll, soluble sugars and soluble proteins in flag leaves of the C Liangyou series combinations at the late growth stages were higher than those of the control, whereas the TBARS content was lower than that of the control. The activities of SOD and POD were significantly higher than those of the control on the 7th day after heading, and then decreased slowly. FPSII value and qP value of flag leaves decreased at the late growth stages, and these two parameters in flag leaves of the C Liangyou series combinations were higher than those of the control, while the qN value increased at the late growth stages and was lower than that of the control. The net photosynthetic rate of flag leaves at the late growth stage was higher compared with the control. These results suggest that slow senescence and strong photosynthetic capability in flag leaves at the late growth stages are the physiological basis of the C Liangyou series combinations.

  4. Consequences of Late-Stage Non-Small-Cell Lung Cancer Cachexia on Muscle Metabolic Processes.

    Science.gov (United States)

    Murton, Andrew J; Maddocks, Matthew; Stephens, Francis B; Marimuthu, Kanagaraj; England, Ruth; Wilcock, Andrew

    2017-01-01

    The loss of muscle is common in patients with advanced non-small-cell lung cancer (NSCLC) and contributes to the high morbidity and mortality of this group. The exact mechanisms behind the muscle loss are unclear. To investigate this, 4 patients with stage IV NSCLC who met the clinical definitions for sarcopenia and cachexia were recruited, along with 4 age-matched healthy volunteers. After an overnight fast, biopsy specimens were obtained from the vastus lateralis, and the key components associated with inflammation and the control of muscle protein, carbohydrate, and fat metabolism were assessed. Compared with the healthy volunteers, significant increases in mRNA levels for interleukin-6 and NF-κB signaling and lower intramyocellular lipid content in slow-twitch fibers were observed in NSCLC patients. Although a significant decrease in phosphorylation of the mechanistic target of rapamycin (mTOR) signaling protein 4E-BP1 (Ser 65 ) was observed, along with a trend toward reduced p70 S6K (Thr 389 ) phosphorylation (P = .06), no difference was found between groups for the mRNA levels of MAFbx (muscle atrophy F box) and MuRF1 (muscle ring finger protein 1), chymotrypsin-like activity of the proteasome, or protein levels of multiple proteasome subunits. Moreover, despite decreases in intramyocellular lipid content, no robust changes in mRNA levels for key proteins involved in insulin signaling, glycolysis, oxidative metabolism, or fat metabolism were observed. These findings suggest that examining the contribution of suppressed mTOR signaling in the loss of muscle mass in late-stage NSCLC patients is warranted and reinforces our need to understand the potential contribution of impaired fat metabolism and muscle protein synthesis in the etiology of cancer cachexia. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. MR Analysis of the Transverse Ligament in the Late Stage of Whiplash Injury

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    Krakenes, J.; Nordli, H.; Moen, G. [Haukeland Univ. Hospital, Bergen (Norway). Section of Neuroradiology; Kaale, B.R. [Firda Medical Center, Sandane (Norway); Rorvik, J. [Haukeland Univ. Hospital, Bergen (Norway). Dept. of Radiology; Gilhus, N.E. [Haukeland Univ. Hospital, Bergen (Norway). Dept. of Neurology

    2003-11-01

    Purpose: To analyse and classify structural changes in the transverse ligament in the late stage of whiplash injury by use of high-resolution MRI, and to evaluate the reliability of our classification. Material and Methods: Ninety-two whiplash-injured (2-9 years previously, mean 6 years) and 30 non-injured individuals underwent proton-weighted MR imaging of the craniovertebral junction in three orthogonal planes. Structural changes in the transverse ligaments were graded twice (grades 1-3) based on increased signal, independently by 3 radiologists with a 4-month interval. Inter- and intraobserver statistics were calculated by ordinary and weighted kappa (K). Results: Image quality was excellent in 109 cases and slightly reduced in 13. Twenty-two out of 30 ligaments in the control group were classified as normal (73%) compared with only 32 out of 92 in the injured group (36%). Two or all 3 observers agreed in their grading in 101 out of 122 ligaments (83%). Intraobserver agreement (weighted K) was fair to good (0.33-0.73). Pair-wise interobserver agreement was fair (0.24-0.39). Reasons for divergent grading were insufficient knowledge of normal variations, low signal intensity in the peridental soft tissue obscuring the ligament and interpretation flaw. Conclusion: Whiplash trauma can damage the transverse ligament. By use of high-resolution proton-weighted MR images such lesions can be detected and classified. The reliability of this classification still needs improvement.

  6. MR Analysis of the Transverse Ligament in the Late Stage of Whiplash Injury

    International Nuclear Information System (INIS)

    Krakenes, J.; Nordli, H.; Moen, G.; Rorvik, J.; Gilhus, N.E.

    2003-01-01

    Purpose: To analyse and classify structural changes in the transverse ligament in the late stage of whiplash injury by use of high-resolution MRI, and to evaluate the reliability of our classification. Material and Methods: Ninety-two whiplash-injured (2-9 years previously, mean 6 years) and 30 non-injured individuals underwent proton-weighted MR imaging of the craniovertebral junction in three orthogonal planes. Structural changes in the transverse ligaments were graded twice (grades 1-3) based on increased signal, independently by 3 radiologists with a 4-month interval. Inter- and intraobserver statistics were calculated by ordinary and weighted kappa (K). Results: Image quality was excellent in 109 cases and slightly reduced in 13. Twenty-two out of 30 ligaments in the control group were classified as normal (73%) compared with only 32 out of 92 in the injured group (36%). Two or all 3 observers agreed in their grading in 101 out of 122 ligaments (83%). Intraobserver agreement (weighted K) was fair to good (0.33-0.73). Pair-wise interobserver agreement was fair (0.24-0.39). Reasons for divergent grading were insufficient knowledge of normal variations, low signal intensity in the peridental soft tissue obscuring the ligament and interpretation flaw. Conclusion: Whiplash trauma can damage the transverse ligament. By use of high-resolution proton-weighted MR images such lesions can be detected and classified. The reliability of this classification still needs improvement

  7. VMAT2 identified as a regulator of late-stage β-cell differentiation.

    Science.gov (United States)

    Sakano, Daisuke; Shiraki, Nobuaki; Kikawa, Kazuhide; Yamazoe, Taiji; Kataoka, Masateru; Umeda, Kahoko; Araki, Kimi; Mao, Di; Matsumoto, Shirou; Nakagata, Naomi; Andersson, Olov; Stainier, Didier; Endo, Fumio; Kume, Kazuhiko; Uesugi, Motonari; Kume, Shoen

    2014-02-01

    Cell replacement therapy for diabetes mellitus requires cost-effective generation of high-quality, insulin-producing, pancreatic β cells from pluripotent stem cells. Development of this technique has been hampered by a lack of knowledge of the molecular mechanisms underlying β-cell differentiation. The present study identified reserpine and tetrabenazine (TBZ), both vesicular monoamine transporter 2 (VMAT2) inhibitors, as promoters of late-stage differentiation of Pdx1-positive pancreatic progenitor cells into Neurog3 (referred to henceforth as Ngn3)-positive endocrine precursors. VMAT2-controlled monoamines, such as dopamine, histamine and serotonin, negatively regulated β-cell differentiation. Reserpine or TBZ acted additively with dibutyryl adenosine 3',5'-cyclic AMP, a cell-permeable cAMP analog, to potentiate differentiation of embryonic stem (ES) cells into β cells that exhibited glucose-stimulated insulin secretion. When ES cell-derived β cells were transplanted into AKITA diabetic mice, the cells reversed hyperglycemia. Our protocol provides a basis for the understanding of β-cell differentiation and its application to a cost-effective production of functional β cells for cell therapy.

  8. Creb1 regulates late stage mammalian lung development via respiratory epithelial and mesenchymal-independent mechanisms

    Science.gov (United States)

    Antony, N.; McDougall, A. R.; Mantamadiotis, T.; Cole, T. J.; Bird, A. D.

    2016-01-01

    During mammalian lung development, the morphological transition from respiratory tree branching morphogenesis to a predominantly saccular architecture, capable of air-breathing at birth, is dependent on physical forces as well as molecular signaling by a range of transcription factors including the cAMP response element binding protein 1 (Creb1). Creb1−/− mutant mice exhibit complete neonatal lethality consistent with a lack of lung maturation beyond the branching phase. To further define its role in the developing mouse lung, we deleted Creb1 separately in the respiratory epithelium and mesenchyme. Surprisingly, we found no evidence of a morphological lung defect nor compromised neonatal survival in either conditional Creb1 mutant. Interestingly however, loss of mesenchymal Creb1 on a genetic background lacking the related Crem protein showed normal lung development but poor neonatal survival. To investigate the underlying requirement for Creb1 for normal lung development, Creb1−/− mice were re-examined for defects in both respiratory muscles and glucocorticoid hormone signaling, which are also required for late stage lung maturation. However, these systems appeared normal in Creb1−/− mice. Together our results suggest that the requirement of Creb1 for normal mammalian lung morphogenesis is not dependent upon its expression in lung epithelium or mesenchyme, nor its role in musculoskeletal development. PMID:27150575

  9. The radiocesium dynamics in the Fukushima forests at the late stage after deposition

    Science.gov (United States)

    Yoschenko, Vasyl; Takase, Tsugiko; Nanba, Kenji; Konoplev, Alexei; Onda, Yuichi

    2017-04-01

    Forests cover about 2/3 of the territory of Areas 2 and 3 in the Fukushima prefecture. This territory was heavily contaminated with radiocesium released from the Fukushima Dai-Ichi Nuclear Power Plant in March 2011. The extensive decontamination measures aimed to prepare the return of population have been scheduled and are being implemented at the agricultural and residential lands at this territory. However, these measures will be not applied in the large scale in the Fukushima forests. The current radiocesium levels in wood at this territory exceed the Japanese standards for wood; thus, after return of population, the Fukushima forests may remain excluded from the economical use. Understanding of the further dynamics of radiocesium in the forest ecosystems is necessary for elaboration of the strategy concerning the radioactive contaminated Fukushima forests. In March 2011 radiocesium was intercepted by the tree canopies and then, at the early stage after the accident, was effectively transported to the soil surface with precipitation and litterfall, and partly translocated to wood forming the current levels. The general trend was the decrease of the radiocesium inventory in the aboveground forest biomass. After redistribution in the root-inhabited soil layer radiocesium became available for uptake into the trees through the roots. From the Chernobyl experience, the further levels of radiocesium in the forest ecosystem compartments at the late stage may increase or decrease depending on the intensities of the root uptake and removal fluxes. In the Fukushima forests, the stage of the root uptake has begun recently, and the parameters of the root uptake have not been studied well for the varieties of species, forest types and soil conditions. Our study is aimed to monitoring and modelling of the radiocesium redistribution in the Fukushima forests after the removal of its initial deposition from the tree canopies. The study has been performed since May 2014 at

  10. Definition, age, and correlation of the Clarence Series stages in New Zealand (late Early to early Late Cretaceous)

    International Nuclear Information System (INIS)

    Crampton, J.S.; Tulloch, A.J.; Wilson, G.J.; Ramezani, J.; Speden, I.G.

    2004-01-01

    The New Zealand local Clarence Series spans the Lower/Upper Cretaceous boundary and includes three stages, in ascending order, the Urutawan, Motuan, and Ngaterian. All three were defined originally from a type section at Motu Falls, Raukumara Peninsula. To address problems with their original definitions and to improve correlations between the New Zealand time-scale and Global Chronostratigraphic Scale, four key sections have been re-studied: the Motu Falls and adjacent Te Waka sections, and the Coverham and Seymour sections in the Clarence valley, Marlborough. The sections contain locally abundant macrofossils and have been sampled at a reconnaissance level for dinoflagellates. In addition, a middle Motuan tuff bed in the Motu Falls section has yielded a zircon U-Pb age of 101.6 ± 0.2 Ma, and an upper Ngaterian basalt flow in the Seymour section has yielded a plagioclase Ar/Ar age of 96.1 ± 0.6 Ma. The older of these dates allows, for the first time, direct age correlation of Clarence Series stages that are based on marine strata in eastern New Zealand, with non-marine rocks in the west. Thus, the Stitts Tuff, at the base of the Pororari Group in the western South Island, is shown to be middle Motuan. Based on the new data, we emend the definitions of the Clarence Series stages. The base of the Urutawan is defined using the lowest occurrence of the inoceramid bivalve Mytiloides ipuanus in the Motu Falls section. The base of the Motuan is defined using the lowest occurrence of the bivalve Aucellina euglypha in the same section. The base of the Ngaterian is defined using the lowest occurrence of the inoceramid 'I.' tawhanus in the Te Waka section. In all three cases, the placements of the lowest occurrence datums are subject to uncertainties that can only be resolved by further biostratigraphic and/or taxonomic study. Based on biostratigraphic data and the new radiometric dates, the following international correlations are proposed: Urutawan Stage = lower

  11. The Relationship between Neighborhood Immigrant Composition, Limited English Proficiency, and Late-Stage Colorectal Cancer Diagnosis in California

    Directory of Open Access Journals (Sweden)

    Cynthia M. Mojica

    2015-01-01

    Full Text Available Despite the availability of effective early detection technologies, more than half (61% of colorectal cancers in the United States and 55% in California are identified at an advanced stage. Data on colorectal cancer patients (N=35,030 diagnosed from 2005 to 2007 were obtained from the California Cancer Registry. Multivariate analyses found a relationship among neighborhood concentration of recent immigrants, neighborhood rates of limited English proficiency, and late-stage colorectal cancer diagnosis. Hispanics living in neighborhoods with a greater percentage of recent immigrants (compared to the lowest percentage had greater odds (OR 1.57, 95% CI 1.22, 2.02 of late-stage diagnosis whereas Hispanics living in neighborhoods with the highest percentage of limited English proficiency (compared to the lowest percentage had lower odds (OR .71, 95% CI .51, .99 of late-stage diagnosis. These relationships were not observed for other ethnic groups. Results highlight the complex relationship among race/ethnicity, neighborhood characteristics, and colorectal cancer stage at diagnosis.

  12. Concept and benefits of the Inverted Classroom method for a competency-based biochemistry course in the pre-clinical stage of a human medicine course of studies.

    Science.gov (United States)

    Kühl, Susanne J; Toberer, Matthias; Keis, Oliver; Tolks, Daniel; Fischer, Martin R; Kühl, Michael

    2017-01-01

    Background: Medical students often have a problem recognising the relevance of basic science subjects for their later professional work in the pre-clinical stage of their studies. This can lead to a lower motivation to learn biochemical content and dissatisfaction in the courses amongst the students. Alternative teaching methods such as the Inverted Classroom (IC) method can address this deficiency. The goal of this study was: to analyse the motivation and satisfaction of the students in a biochemistry seminar through the use of the e-learning-based IC method, to investigate the acceptance against the IC teaching method in biochemistry, and to compare the learning success achieved using the IC approach with that of a traditional course. We also investigated how a biochemistry course in the pre-clinical stage of a human medicine course of studies can be successfully organised according to the IC method. Furthermore, we examined the benefits of the IC method over conventional teaching formats. Method: The IC method was implemented in accordance with the guidelines of the GMA committee "New Media" [30] in a biochemistry seminar for two student IC intervention groups with 42 students. A part of the factual knowledge from the on-site phase in the form of teaching videos together with self-learning control tasks were provided online before the seminar for both IC intervention groups. Exporting content to the self-learning phase creates new free time in the on-site phase, during which the content can be critically considered and processed and additional competency-based learning objectives can be taught. Identical biochemistry teaching content was taught in parallel control groups (14 student groups with n=299 students), but no material was handed out beforehand for a self-learning phase. These students only received the materials after the on-site phase. Motivation and satisfaction as well as the acceptance for the teaching methods were recorded by questionnaires, the

  13. Concept and benefits of the Inverted Classroom method for a competency-based biochemistry course in the pre-clinical stage of a human medicine course of studies

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    Kühl, Susanne J.

    2017-08-01

    Full Text Available Background: Medical students often have a problem recognising the relevance of basic science subjects for their later professional work in the pre-clinical stage of their studies. This can lead to a lower motivation to learn biochemical content and dissatisfaction in the courses amongst the students. Alternative teaching methods such as the Inverted Classroom (IC method can address this deficiency. The goal of this study was: We also investigated how a biochemistry course in the pre-clinical stage of a human medicine course of studies can be successfully organised according to the IC method. Furthermore, we examined the benefits of the IC method over conventional teaching formats. Method: The IC method was implemented in accordance with the guidelines of the GMA committee “New Media” in a biochemistry seminar for two student IC intervention groups with 42 students. A part of the factual knowledge from the on-site phase in the form of teaching videos together with self-learning control tasks were provided online before the seminar for both IC intervention groups. Exporting content to the self-learning phase creates new free time in the on-site phase, during which the content can be critically considered and processed and additional competency-based learning objectives can be taught. Identical biochemistry teaching content was taught in parallel control groups (14 student groups with n=299 students, but no material was handed out beforehand for a self-learning phase. These students only received the materials after the on-site phase. Motivation and satisfaction as well as the acceptance for the teaching methods were recorded by questionnaires, the acquisition of knowledge by MC exams.Results: On a Likert scale from 1 (strongly disagree to 6 (strongly agree, the students in the IC intervention groups could be seen to be much more motivated (5.53 than students in the control group (4.01. Students in the IC intervention groups also recognised the

  14. Rural-Urban Differences in Late-Stage Breast Cancer: Do Associations Differ by Rural-Urban Classification System?

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    Pruitt, Sandi L; Eberth, Jan M; Morris, E Scott; Grinsfelder, David B; Cuate, Erica L

    2016-01-01

    Introduction Rural residence is associated with later stage of breast cancer diagnosis in some but not all prior studies. The lack of a standardized definition of rural residence may contribute to these mixed findings. We characterize and compare multiple definitions of rural vs. non-rural residence to provide guidance regarding choice of measures and to further elucidate rural disparities in breast cancer stage at diagnosis. Methods We used Texas Cancer Registry data of 120,738 female breast cancer patients ≥50 years old diagnosed between 1995–2009. We defined rural vs. non-rural residence using 7 different measures and examined their agreement using Kappa statistics. Measures were defined at various geographic levels: county, ZIP code, census tract, and census block group. Late-stage was defined as regional or distant disease. For each measure, we tested the association of rural residence and late-stage cancer with unadjusted and adjusted logistic regression. Covariates included: age; patient race/ethnicity; diagnosis year; census block group-level mammography capacity; and census tract-level percent poverty, percent Hispanic, and percent Black. Results We found moderate to high levels of agreement between measures of rural vs. non-rural residence. For 72.9% of all patients, all 7 definitions agreed as to rural vs. non-rural residence. Overall, 6 of 7 definitions demonstrated an adverse association between rural residence and late-stage disease in unadjusted and adjusted models (Adjusted OR Range = 1.09–1.14). Discussion Our results document a clear rural disadvantage in late-stage breast cancer. We contribute to the heterogeneous literature by comparing varied measures of rural residence. We recommend use of the census tract-level Rural Urban Commuting Area Codes in future cancer outcomes research where small area data are available. PMID:27158685

  15. Penicillin at the late stage of leptospirosis: a randomized controlled trial

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    Costa Everaldo

    2003-01-01

    Full Text Available There is evidence that an early start of penicillin reduces the case-fatality rate of leptospirosis and that chemoprophylaxis is efficacious in persons exposed to the sources of leptospira. The existent data, however, are inconsistent regarding the benefit of introducing penicillin at a late stage of leptospirosis. The present study was developed to assess whether the introduction of penicillin after more than four days of symptoms reduces the in-hospital case-fatality rate of leptospirosis. A total of 253 patients aged 15 to 76 years with advanced leptospirosis, i.e., more than four days of symptoms, admitted to an infectious disease hospital located in Salvador, Brazil, were selected for the study. The patients were randomized to one of two treatment groups: with intravenous penicillin, 6 million units day (one million unit every four hours for seven days (n = 125 and without (n = 128 penicillin. The main outcome was death during hospitalization. The case-fatality rate was approximately twice as high in the group treated with penicillin (12%; 15/125 than in the comparison group (6.3%; 8/128. This difference pointed in the opposite direction of the study hypothesis, but was not statistically significant (p = 0.112. Length of hospital stay was similar between the treatment groups. According to the results of the present randomized clinical trial initiation of penicillin in patients with severe forms of leptospirosis after at least four days of symptomatic leptospirosis is not beneficial. Therefore, more attention should be directed to prevention and earlier initiation of the treatment of leptospirosis.

  16. Crevasse-squeeze ridge corridors: Diagnostic features of late-stage palaeo-ice stream activity

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    Evans, David J. A.; Storrar, Robert D.; Rea, Brice R.

    2016-04-01

    A 200-km-long and 10-km-wide linear assemblage of till-filled geometrical ridges on the bed of the Maskwa palaeo-ice stream of the late Wisconsinan southwest Laurentide Ice Sheet are interpreted as crevasse-squeeze ridges (CSR) developed during internal flow unit reorganization, immediately prior to ice stream shutdown. Ridge orientations are predominantly orientated WNW-ESE, with a subordinate WSW-ENE alignment, both indicative of ice fracture development transverse to former ice stream flow, as indicated by NNE-SSW aligned MSGL. Subglacial till injection into basal and/or full depth, mode I and II crevasses occurred at the approximate centreline of the ice stream, in response to extension and fracturing. Landform preservation indicates that this took place during the final stages of ice streaming, immediately prior to ice stream shutdown. This linear zone of ice fracturing therefore likely represents the narrowing of the fast-flowing trunk, similar to the plug flow identified in some surging valley glaciers. Lateral drag between the final active flow unit and the slower moving ice on either side is likely recorded by the up-ice bending of the CSR limbs. The resulting CSR corridor, here related to an individual ice stream flow unit, constitutes a previously unreported style of crevasse infilling and contrasts with two existing CSR patterns: (1) wide arcuate zones of CSRs related to widespread fracturing within glacier surge lobes; and (2) narrow concentric arcs of CSRs and recessional push moraines related to submarginal till deformation at active temperate glacier lobes.

  17. Late-stage alteration and tin-tungsten mineralization in the Khuntan Batholith, northern Thailand

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    Yokart, B.; Barr, S. M.; Williams-Jones, A. E.; Macdonald, A. S.

    2003-07-01

    The Khuntan Batholith is part of the Triassic-Jurassic eastern marginal belt of the Northern Thailand Granite Province. Most of the batholith consists of coarse-grained, porphyritic to megacrystic biotite-muscovite granite (Huai Mae San unit). However, the southeastern part, called the Muang Yao unit, consists of coarse- to medium-grained muscovite and muscovite-tourmaline granite and is associated with Sn-W mineralization. The Huai Mae San granite has S-type petrological features typical of batholiths in the eastern marginal belt, which formed in a syn-collisional setting. The more silicic Muang Yao granite differs chemically from felsic S-type granite, for example in extreme Rb-Y-Nb enrichment and Ba-Sr-Zr depletion, probably as a result of late-stage fluid alteration. Vein-hosted deposits of cassiterite, scheelite, and wolframite associated with minor sulfides occur in both the Muang Yao granite and adjacent metamorphic rocks. Fluid-inclusion studies indicate that both aqueous and aqueous-carbonic fluids of low salinity (0-8 wt% equiv. NaCl) were involved in vein formation, and were subject to pressure fluctuation between essentially lithostatic and hydrostatic conditions. Dilution of magmatic hydrous fluid by influx of meteoric water may explain the anomalously low salinity. Oxygen isotope data support a primary magmatic origin for the fluid, and indicate temperatures of ca. 400 °C for ore deposition. The three vein-type Sn-W deposits of this study represent a spectrum from an endogranite vein system to proximal-intermediate vein systems of magmatic-hydrothermal origin.

  18. Biomarkers for early and late stage chronic allograft nephropathy by proteogenomic profiling of peripheral blood.

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    Sunil M Kurian

    2009-07-01

    Full Text Available Despite significant improvements in life expectancy of kidney transplant patients due to advances in surgery and immunosuppression, Chronic Allograft Nephropathy (CAN remains a daunting problem. A complex network of cellular mechanisms in both graft and peripheral immune compartments complicates the non-invasive diagnosis of CAN, which still requires biopsy histology. This is compounded by non-immunological factors contributing to graft injury. There is a pressing need to identify and validate minimally invasive biomarkers for CAN to serve as early predictors of graft loss and as metrics for managing long-term immunosuppression.We used DNA microarrays, tandem mass spectroscopy proteomics and bioinformatics to identify genomic and proteomic markers of mild and moderate/severe CAN in peripheral blood of two distinct cohorts (n = 77 total of kidney transplant patients with biopsy-documented histology.Gene expression profiles reveal over 2400 genes for mild CAN, and over 700 for moderate/severe CAN. A consensus analysis reveals 393 (mild and 63 (moderate/severe final candidates as CAN markers with predictive accuracy of 80% (mild and 92% (moderate/severe. Proteomic profiles show over 500 candidates each, for both stages of CAN including 302 proteins unique to mild and 509 unique to moderate/severe CAN.This study identifies several unique signatures of transcript and protein biomarkers with high predictive accuracies for mild and moderate/severe CAN, the most common cause of late allograft failure. These biomarkers are the necessary first step to a proteogenomic classification of CAN based on peripheral blood profiling and will be the targets of a prospective clinical validation study.

  19. The association between bullying and early stages of suicidal ideation in late adolescents in Greece

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    Araya Ricardo

    2011-02-01

    Full Text Available Abstract Background Bullying in schools has been associated with suicidal ideation but the confounding effect of psychiatric morbidity has not always been taken into account. Our main aim was to test the association between bullying behavior and early stages of suicidal ideation in a sample of Greek adolescents and to examine whether this is independent of the presence of psychiatric morbidity, including sub-threshold symptoms. Methods 5614 pupils 16-18 years old and attending 25 senior high schools were screened in the first phase and a stratified random sample of 2431 were selected for a detailed interview at the second phase. Psychiatric morbidity and suicidal ideation were assessed with the revised Clinical Interview Schedule (CIS-R while bullying was assessed with the revised Olweus bully/victim questionnaire. Results Victims of bullying behavior were more likely to express suicidal ideation. This association was particularly strong for those who were bullied on a weekly basis and it was independent of the presence of psychiatric morbidity (Odds Ratio: 7.78; 95% Confidence Interval: 3.05 - 19.90. In contrast, being a perpetrator ("bullying others" was not associated with this type of ideation after adjustment. These findings were similar in both boys and girls, although the population impact of victimization in the prevalence of suicidal ideation was potentially higher for boys. Conclusions The strong cross-sectional association between frequent victimization and suicidal ideation in late adolescence offers an opportunity for identifying pupils in the school setting that are in a higher risk for exhibiting suicidal ideation.

  20. Geographical, temporal and racial disparities in late-stage prostate cancer incidence across Florida: A multiscale joinpoint regression analysis

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    Goovaerts Pierre

    2011-12-01

    Full Text Available Abstract Background Although prostate cancer-related incidence and mortality have declined recently, striking racial/ethnic differences persist in the United States. Visualizing and modelling temporal trends of prostate cancer late-stage incidence, and how they vary according to geographic locations and race, should help explaining such disparities. Joinpoint regression is increasingly used to identify the timing and extent of changes in time series of health outcomes. Yet, most analyses of temporal trends are aspatial and conducted at the national level or for a single cancer registry. Methods Time series (1981-2007 of annual proportions of prostate cancer late-stage cases were analyzed for non-Hispanic Whites and non-Hispanic Blacks in each county of Florida. Noise in the data was first filtered by binomial kriging and results were modelled using joinpoint regression. A similar analysis was also conducted at the state level and for groups of metropolitan and non-metropolitan counties. Significant racial differences were detected using tests of parallelism and coincidence of time trends. A new disparity statistic was introduced to measure spatial and temporal changes in the frequency of racial disparities. Results State-level percentage of late-stage diagnosis decreased 50% since 1981; a decline that accelerated in the 90's when Prostate Specific Antigen (PSA screening was introduced. Analysis at the metropolitan and non-metropolitan levels revealed that the frequency of late-stage diagnosis increased recently in urban areas, and this trend was significant for white males. The annual rate of decrease in late-stage diagnosis and the onset years for significant declines varied greatly among counties and racial groups. Most counties with non-significant average annual percent change (AAPC were located in the Florida Panhandle for white males, whereas they clustered in South-eastern Florida for black males. The new disparity statistic indicated

  1. Geographical, temporal and racial disparities in late-stage prostate cancer incidence across Florida: a multiscale joinpoint regression analysis.

    Science.gov (United States)

    Goovaerts, Pierre; Xiao, Hong

    2011-12-05

    Although prostate cancer-related incidence and mortality have declined recently, striking racial/ethnic differences persist in the United States. Visualizing and modelling temporal trends of prostate cancer late-stage incidence, and how they vary according to geographic locations and race, should help explaining such disparities. Joinpoint regression is increasingly used to identify the timing and extent of changes in time series of health outcomes. Yet, most analyses of temporal trends are aspatial and conducted at the national level or for a single cancer registry. Time series (1981-2007) of annual proportions of prostate cancer late-stage cases were analyzed for non-Hispanic Whites and non-Hispanic Blacks in each county of Florida. Noise in the data was first filtered by binomial kriging and results were modelled using joinpoint regression. A similar analysis was also conducted at the state level and for groups of metropolitan and non-metropolitan counties. Significant racial differences were detected using tests of parallelism and coincidence of time trends. A new disparity statistic was introduced to measure spatial and temporal changes in the frequency of racial disparities. State-level percentage of late-stage diagnosis decreased 50% since 1981; a decline that accelerated in the 90's when Prostate Specific Antigen (PSA) screening was introduced. Analysis at the metropolitan and non-metropolitan levels revealed that the frequency of late-stage diagnosis increased recently in urban areas, and this trend was significant for white males. The annual rate of decrease in late-stage diagnosis and the onset years for significant declines varied greatly among counties and racial groups. Most counties with non-significant average annual percent change (AAPC) were located in the Florida Panhandle for white males, whereas they clustered in South-eastern Florida for black males. The new disparity statistic indicated that the spatial extent of racial disparities reached a

  2. Montessori-based activities among persons with late-stage dementia: Evaluation of mental and behavioral health outcomes.

    Science.gov (United States)

    Wilks, Scott E; Boyd, P August; Bates, Samantha M; Cain, Daphne S; Geiger, Jennifer R

    2017-01-01

    Objectives Literature regarding Montessori-based activities with older adults with dementia is fairly common with early stages of dementia. Conversely, research on said activities with individuals experiencing late-stage dementia is limited because of logistical difficulties in sampling and data collection. Given the need to understand risks and benefits of treatments for individuals with late-stage dementia, specifically regarding their mental and behavioral health, this study sought to evaluate the effects of a Montessori-based activity program implemented in a long-term care facility. Method Utilizing an interrupted time series design, trained staff completed observation-based measures for 43 residents with late-stage dementia at three intervals over six months. Empirical measures assessed mental health (anxiety, psychological well-being, quality of life) and behavioral health (problem behaviors, social engagement, capacity for activities of daily living). Results Group differences were observed via repeated measures ANOVA and paired-samples t-tests. The aggregate, longitudinal results-from baseline to final data interval-for the psychological and behavioral health measures were as follows: problem behaviors diminished though not significantly; social engagement decreased significantly; capacities for activities of daily living decreased significantly; quality of life increased slightly but not significantly; anxiety decreased slightly but not significantly; and psychological well-being significantly decreased. Conclusion Improvements observed for quality of life and problem behaviors may yield promise for Montessori-based activities and related health care practices. The rapid physiological and cognitive deterioration from late-stage dementia should be considered when interpreting these results.

  3. Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages

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    Meng Yang

    2017-05-01

    Full Text Available Abstract Background Solid tumors residing in tissues and organs leave footprints in circulation through circulating tumor cells (CTCs and circulating tumor DNAs (ctDNA. Characterization of the ctDNA portraits and comparison with tumor DNA mutational portraits may reveal clinically actionable information on solid tumors that is traditionally achieved through more invasive approaches. Methods We isolated ctDNAs from plasma of patients of 103 lung cancer and 74 other solid tumors of different tissue origins. Deep sequencing using the Guardant360 test was performed to identify mutations in 73 clinically actionable genes, and the results were associated with clinical characteristics of the patient. The mutation profiles of 37 lung cancer cases with paired ctDNA and tumor genomic DNA sequencing were used to evaluate clonal representation of tumor in circulation. Five lung cancer cases with longitudinal ctDNA sampling were monitored for cancer progression or response to treatments. Results Mutations in TP53, EGFR, and KRAS genes are most prevalent in our cohort. Mutation rates of ctDNA are similar in early (I and II and late stage (III and IV cancers. Mutation in DNA repair genes BRCA1, BRCA2, and ATM are found in 18.1% (32/177 of cases. Patients with higher mutation rates had significantly higher mortality rates. Lung cancer of never smokers exhibited significantly higher ctDNA mutation rates as well as higher EGFR and ERBB2 mutations than ever smokers. Comparative analysis of ctDNA and tumor DNA mutation data from the same patients showed that key driver mutations could be detected in plasma even when they were present at a minor clonal population in the tumor. Mutations of key genes found in the tumor tissue could remain in circulation even after frontline radiotherapy and chemotherapy suggesting these mutations represented resistance mechanisms. Longitudinal sampling of five lung cancer cases showed distinct changes in ctDNA mutation portraits that

  4. Requirement of vasculogenesis and blood circulation in late stages of liver growth in zebrafish

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    Wohland Thorsten

    2008-09-01

    Full Text Available Abstract Background Early events in vertebrate liver development have been the major focus in previous studies, however, late events of liver organogenesis remain poorly understood. Liver vasculogenesis in vertebrates occurs through the interaction of endoderm-derived liver epithelium and mesoderm-derived endothelial cells (ECs. In zebrafish, although it has been found that ECs are not required for liver budding, how and when the spatio-temporal pattern of liver growth is coordinated with ECs remains to be elucidated. Results To study the process of liver development and vasculogenesis in vivo, a two-color transgenic zebrafish line Tg(lfabf:dsRed; elaA:EGFP was generated and named LiPan for liver-specific expression of DsRed RFP and exocrine pancreas-specific expression of GFP. Using the LiPan line, we first followed the dynamic development of liver from live embryos to adult and showed the formation of three distinct yet connected liver lobes during development. The LiPan line was then crossed with Tg(fli1:EGFPy1 and vascular development in the liver was traced in vivo. Liver vasculogenesis started at 55–58 hpf when ECs first surrounded hepatocytes from the liver bud surface and then invaded the liver to form sinusoids and later the vascular network. Using a novel non-invasive and label-free fluorescence correction spectroscopy, we detected blood circulation in the liver starting at ~72 hpf. To analyze the roles of ECs and blood circulation in liver development, both cloche mutants (lacking ECs and Tnnt2 morphants (no blood circulation were employed. We found that until 70 hpf liver growth and morphogenesis depended on ECs and nascent sinusoids. After 72 hpf, a functional sinusoidal network was essential for continued liver growth. An absence of blood circulation in Tnnt2 morphants caused defects in liver vasculature and small liver. Conclusion There are two phases of liver development in zebrafish, budding and growth. In the growth phase

  5. Characterisation of the Broadly-Specific O-Methyl-transferase JerF from the Late Stages of Jerangolid Biosynthesis

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    Steffen Friedrich

    2016-10-01

    Full Text Available We describe the characterisation of the O-methyltransferase JerF from the late stages of jerangolid biosynthesis. JerF is the first known example of an enzyme that catalyses the formation of a non-aromatic, cyclic methylenolether. The enzyme was overexpressed in E. coli and the cell-free extracts were used in bioconversion experiments. Chemical synthesis gave access to a series of substrate surrogates that covered a broad structural space. Enzymatic assays revealed a broad substrate tolerance and high regioselectivity of JerF, which makes it an attractive candidate for an application in chemoenzymatic synthesis with particular usefulness for late stage application on 4-methoxy-5,6-dihydro-2H-pyran-2-one-containing natural products.

  6. Pharmacophore mapping in the laulimalide series: total synthesis of a vinylogue for a late-stage metathesis diversification strategy.

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    Wender, Paul A; Hilinski, Michael K; Skaanderup, Philip R; Soldermann, Nicolas G; Mooberry, Susan L

    2006-08-31

    An efficient synthesis of the macrocyclic core of laulimalide with a pendant vinyl group at C20 is described, allowing for late-stage introduction of various side chains through a selective and efficient cross metathesis diversification step. Representative analogues reported herein are the first to contain modifications to only the side chain dihydropyran of laulimalide and des-epoxy laulimalide. This step-economical strategy enables the rapid synthesis of new analogues using alkenes as an inexpensive, abundantly available diversification feedstock.

  7. Highly Convergent Total Synthesis of (+)-Lithospermic Acid via a Late-Stage Intermolecular C–H Olefination

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    Wang, Dong-Hui; Yu, Jin-Quan

    2011-01-01

    The total synthesis of (+)-lithospermic acid is reported, which exploits two successive C–H activation reactions as the key steps. Rh-catalyzed carbene C–H insertion reaction using Davies’ catalyst built the dihydrobenzofuran core, and a late-stage intermolecular C–H olefination coupled the olefin unit with the dihydrobenzofuran core to construct the molecule in a highly convergent manner. PMID:21443224

  8. [Effect of Supportan on nutritional status and immune function of late-staged gastric cancer patients undergoing chemotherapy].

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    Zhong, Hai-jun; Ying, Jie-er; Ma, Sheng-lin

    2006-09-01

    To evaluate the effect of Supportan, an enteral nutrition (EN) specific for tumor patients, on the nutritional status and immune function of late-staged gastric cancer patients undergoing chemotherapy. Sixty-six late-staged gastric cancer patients undergoing chemotherapy were randomly divided into EN group (n=33) and control group (n=33). During chemotherapy, the patients in EN group received Supportan and the patients in the control group received basic diet. On the 14th day before chemotherapy and after chemotherapy, nutritional status and cell immune indicators were evaluated. As for nutrition indicators, there were no significant differences in EN group before and after chemotherapy (P > 0.05). Total protein, hemoglobin, prealbumin and transferrin significantly decreased after chemotherapy compared with those before chemotherapy in the control group (Pnutrition in EN group were superior to that in the control group, however, the differences were not statistically significant. The incidences of nausea, vomiting and marrow inhibition in Supportan group was lower compared with those in the control group, but with no significant difference. Supportan can prevent malnutrition of the late-staged gastric cancer patients undergoing chemotherapy, and improve immune function and alleviate adverse effects of chemotherapy.

  9. The CD3-zeta chimeric antigen receptor overcomes TCR Hypo-responsiveness of human terminal late-stage T cells.

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    Gunter Rappl

    Full Text Available Adoptive therapy of malignant diseases with tumor-specific cytotoxic T cells showed remarkable efficacy in recent trials. Repetitive T cell receptor (TCR engagement of target antigen, however, inevitably ends up in hypo-responsive cells with terminally differentiated KLRG-1(+ CD57(+ CD7(- phenotype limiting their therapeutic efficacy. We here revealed that hypo-responsiveness of CMV-specific late-stage CD8(+ T cells is due to reduced TCR synapse formation compared to younger cells. Membrane anchoring of TCR components contributes to T cell hypo-responsiveness since dislocation of galectin-3 from the synapse by swainsonine restored both TCR synapse formation and T cell response. Transgenic expression of a CD3-zeta signaling chimeric antigen receptor (CAR recovered hypo-responsive T cells to full effector functions indicating that the defect is restricted to TCR membrane components while synapse formation of the transgenic CAR was not blocked. CAR engineered late-stage T cells released cytokines and mediated redirected cytotoxicity as efficiently as younger effector T cells. Our data provide a rationale for TCR independent, CAR mediated activation in the adoptive cell therapy to avoid hypo-responsiveness of late-stage T cells upon repetitive antigen encounter.

  10. Pramipexole but not imipramine or fluoxetine reverses the "depressive-like" behaviour in a rat model of preclinical stages of Parkinson's disease.

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    Berghauzen-Maciejewska, Klemencja; Kuter, Katarzyna; Kolasiewicz, Wacław; Głowacka, Urszula; Dziubina, Anna; Ossowska, Krystyna; Wardas, Jadwiga

    2014-09-01

    Depression is a frequent comorbid disorder in Parkinson's disease and may antedate its motor symptoms. However, mechanisms underlying Parkinson's disease-associated depression are unknown and its current medication is insufficient. The aim of the present study was to compare antidepressant-like effects of imipramine, fluoxetine and pramipexole in a model of preclinical stages of Parkinson's disease in rats. 6-Hydroxydopamine was bilaterally injected into the ventrolateral region of the caudate-putamen in rats. This treatment induced moderate decreases in the levels of dopamine and its metabolites in the caudate-putamen, nucleus accumbens and frontal cortex and reduced the density of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta and ventral tegmental area. The lesion increased immobility measured in the forced swimming test without influencing locomotor activity. Chronic (13 days) administration of pramipexole (1mg/kg sc/twice a day) reversed prolongation of the immobility time in lesioned animals but did not stimulate their locomotion. Chronic pramipexole activated dopaminergic transmission in the brain structures which might contribute to its effectiveness in the forced swimming test. In contrast, the 13-day administration of imipramine (10mg/kg ip/day) and fluoxetine (10mg/kg ip/day) did not shorten the immobility time in lesioned rats but reduced their locomotion. The present study indicates that already a moderate lesion of dopaminergic neurons induces "depressive-like" behaviour in animals which is reversed by chronic administration of the antiparkinsonian drug, pramipexole. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Midlife Eriksonian Psychosocial Development: Setting the Stage for Cognitive and Emotional Health in Late Life

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    Malone, Johanna C.; Liu, Sabrina R.; Vaillant, George E.; Rentz, Dorene M.; Waldinger, Robert J.

    2017-01-01

    Erikson’s (1950) model of adult psychosocial development outlines the significance of successful involvement within one’s relationships, work, and community for healthy aging. He theorized that the consequences of not meeting developmental challenges included stagnation and emotional despair. Drawing on this model, the present study uses prospective longitudinal data to examine how the quality of assessed Eriksonian psychosocial development in midlife relates to late-life cognitive and emotional functioning. In particular we were interested to see whether late-life depression mediated the relationship between Eriksonian development and specific domains of cognitive functioning (i.e., executive functioning and memory). Participants were 159 men from the over 75 year longitudinal Study of Adult Development. The sample was comprised of men from both higher and lower socio-economic strata. Eriksonian psychosocial development was coded from men’s narrative responses to interviews between the ages of 30–47 (Vaillant and Milofsky, 1980). In late life (ages 75–85) men completed a performance - based neuropsychological assessment measuring global cognitive status, executive functioning, and memory. In addition depressive symptomatology was assessed using the Geriatric Depression Scale. Our results indicated that higher midlife Eriksonian psychosocial development was associated with stronger global cognitive functioning and executive functioning, and lower levels of depression three to four decades later. There was no significant association between Eriksonian development and late-life memory. Late-life depression mediated the relationship between Eriksonian development and both global cognition and executive functioning. All of these results controlled for highest level of education and adolescent intelligence. Findings have important implications for understanding the lasting benefits of psychosocial engagement in mid-adulthood for late-life cognitive and

  12. Management of Early- and Late-Stage Rheumatoid Arthritis: Are Physiotherapy Students' Intended Behaviours Consistent with Canadian Best Practice Guidelines?

    Science.gov (United States)

    Lineker, Sydney C.; Hallett, Christina; Tumber, Jake; Fernando, Nalin; Hul, Magdalena

    2012-01-01

    ABSTRACT Purpose: This study examined whether physiotherapy students in a problem-based learning (PBL) curriculum intend to implement best practices for management of clients with rheumatoid arthritis (RA). Method: Physiotherapy students (n=49) completed a subsection of the ACREU Primary Care Survey to evaluate the concordance between intended behaviours and Canadian best practices for early- and late-stage RA, before and after completing the relevant PBL content. Changes in scores were assessed using McNemar's test for dependent proportions. Results: Most students indicated that they would recommend treatments or referrals for physiotherapy/exercise, education, and occupational therapy or joint protection pre- and post-PBL (>83% and >95%, respectively). Post-PBL, more students recommended referral to a rheumatologist and disease-modifying anti-rheumatic drugs (DMARDs) for both early and late RA; however, the increase was significant only for early RA (p=0.013 and 0.031 for referral to rheumatologist and DMARDs, respectively). More students recommended psychosocial support at both stages of RA post-PBL (early RA: pstudents recommended DMARDs post-PBL, only 8 students in total made this recommendation (16%), and fewer students considered use of non-steroidal anti-inflammatory drugs. Most students (94%) did not recommend referral to a surgeon for early or late RA. Conclusion: Intended behaviour of physiotherapy students was more consistent with Canadian best practice guidelines for managing clients with early- and late-stage RA following the PBL curriculum. Further study is required to determine whether the students were less aware of best practices related to pharmacologic interventions and timely referral to appropriate specialists, or whether they considered these issues to be outside their scope of practice. PMID:23729962

  13. Content of Diabetes-Associated Autoantibodies against Islet Autoantigens (IA-2A, GADA, IAA and the Level of Different Cytokines in Children and Adolescents on the Pre-Clinical and Early Clinical Stages of Type 1 Diabetes Mellitus Development

    Directory of Open Access Journals (Sweden)

    V.V. Popova

    2015-03-01

    Full Text Available The article provides the data on the immunological mechanisms of type 1 diabetes mellitus (T1DM on the preclinical and early clinical stages of disease formation on the basis of studying the features of T1DM pathogenesis, monitoring the process of autoimmune destruction of insulin-producing β-cells by determining the content of diabetes-associated auto-antibodies (the incidence and titers dynamics, the study of the characteristics of cytokine secretion on the pre-clinical stage of T1DM development in children and adolescents. Introduction of new approaches to pre-clinical diagnosis of T1DM allowed determine the group of marker-positive children with burdened heredity and predictable risk of disease development. The study involved 450 healthy normoglycemic children and adolescents aged from 7 to 15 years old. It was revealed that 94 (26.7 % of 366 children with burdened hereditary by at least two-fold determination of DAAb had an increased DAAb titer, mainly GADA and IA-2A, the clinical debut of T1DM manifested in 49 (52.1 % of them from 6 months to 12 years (30.9 ± 3.2 months. T1DM developed in the same period in a child, that was 0.8 % of the 272 (73.3 % DAAb-negative children. There was determined a formula of combined incidence and values of simultaneously elevated DAAb titers to islet autoantigens, namely IA-2A + GADA, which are predictor of the duration of T1DM pre-clinical stage and debut occurrence. It has been also established a disturbance of cytokine production (increased level of pro-inflammatory cytokines IL-1α, IL-6 and FNO-α, IL-8 and IL-16 while reduced concentration of IL-4 in blood plasma as a key factor in the T1DM pathogenesis that causes the debut occurrence, and aggressiveness of its course.

  14. MANTLE-CRUST INTERACTION AT THE LATE STAGE OF EVOLUTION OF HERCYNIAN ALTAI COLLISION SYSTEM, WESTERN PART OF CAOB

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    S. V. Khromykh

    2017-01-01

    Full Text Available Altai collision system of Hercynides was formed in Late Paleozoic as a result of oblique collision of Siberian continent and Kazakhstan composed terrane [Vladimirov et al., 2003; 2008; Xiao et al., 2010]. At the late stages of its evolution (time interval from 310–300 to 280–270 Ma the huge different mafic and felsic magmatism occurred at the territory (Fig. 1 [Vladimirov et al., 2008; Khromykh et al., 2011, 2013, 2014, 2016; Kotler et al., 2015; Sokolova et al., 2016]. It is evident about increased thermal gradient in lithosphere and about significant role of mantle and active manifestation of mantle-crust interactions. Some magmatic complexes may be considered as indicators of mantle-crust interaction processes.

  15. deep-orange and carnation define distinct stages in late endosomal biogenesis in Drosophila melanogaster

    OpenAIRE

    Sriram, V.; Krishnan, K.S.; Mayor, Satyajit

    2003-01-01

    Endosomal degradation is severely impaired in primary hemocytes from larvae of eye color mutants of Drosophila. Using high resolution imaging and immunofluorescence microscopy in these cells, products of eye color genes, deep-orange (dor) and carnation (car), are localized to large multivesicular Rab7-positive late endosomes containing Golgi-derived enzymes. These structures mature into small sized Dor-negative, Car-positive structures, which subsequently fuse to form tubular lysosomes. Defec...

  16. Probe into the origin, development and evolution model of shelf desertizational environment in the last stage of Late Pleistocene

    Science.gov (United States)

    Yu, Hong-Jun; Liu, Jing-Pu; Shan, Qiu-Mei

    1998-12-01

    Based on study of China's shelf paleoenvironment, this paper summarises the definition of shelf desertization that occurred in the last stage of Late Pleistocene, and discusses the background of its formation and evolution process. Study of shallow layer profiler records and core data revealed that cold-dry aeolian erosion was the major exogenic force on the exposed shelf. Under the prevailing paleo-winter monsoon, part of the exposed marine stratum disintegrated into sand and then desertization occurred. The fine sediments were blown away and deposited on the leeward to form derivative loess deposits.

  17. How Receptive Are Patients With Late Stage Cancer to Rehabilitation Services and What Are the Sources of Their Resistance?

    Science.gov (United States)

    Cheville, Andrea L; Rhudy, Lori; Basford, Jeffrey R; Griffin, Joan M; Flores, Ann Marie

    2017-02-01

    To describe the proportion and characteristics of patients with late stage cancer that are and are not receptive to receiving rehabilitation services, and the rationale for their level of interest. Prospective mixed-methods study. Comprehensive cancer center in a quaternary medical center. Adults with stage IIIC or IV non-small cell or extensive stage small cell lung cancer (N=311). Not applicable. Telephone-acquired responses to the administration of (1) the Activity Measure for Post Acute Care Computer Adaptive Test (AM-PAC-CAT); (2) numerical rating scales for pain, dyspnea, fatigue, general emotional distress, and distress associated with functional limitations; (3) a query regarding receptivity to receipt of rehabilitation services, and (4) a query about rationale for nonreceptivity. Overall, 99 (31.8%) of the study's 311 participants expressed interest in receiving rehabilitation services: 38 at the time of enrollment and an additional 61 during at least 1 subsequent contact. Participants expressing interest were more likely to have a child as primary caregiver (18.18% vs 9.91%, P=.04) and a musculoskeletal comorbidity (42.4% vs 31.6%, P=.05). Function-related distress was highly associated with receptivity, as were lower AM-PAC-CAT scores. Reasons provided for lack of interest in receiving services included a perception of their limited benefit, being too busy, and prioritization below more pressing tasks/concerns. One-third of patients with late stage lung cancer are likely to be interested in receiving rehabilitation services despite high levels of disability and related distress. These findings suggest that patient misperception of the role of rehabilitation services may be a barrier to improved function and quality of life. Efforts to educate patients on the benefits of rehabilitation and to more formally integrate rehabilitation as part of comprehensive care may curb these missed opportunities. Copyright © 2016. Published by Elsevier Inc.

  18. Use of ultrasonography to identify late-stage maturity in rainbow trout Oncorhynchus mykiss

    Science.gov (United States)

    Morphometric measurements by ultrasonography has been used to determine gonad and follicle size in many species of fish for purposes of identifying sex and estimating stage of maturation. We have been using a portable ultrasound system (SonoSite MicroMaxx, L25e/13-6 MHz transducer) to identify fem...

  19. A case of late-stage lymphogranuloma venereum in a woman in Europe.

    Science.gov (United States)

    Lázaro, Maria Jesus; López, Patricia Mejuto; Vall-Mayans, Marti; Fernández, Beatriz Lorenzana; Rodríguez-Guardado, Azucena

    2013-10-01

    Lymphogranuloma venereum is caused by Chlamydia trachomatis serovars L1-L3. The third stage of the disease leads to chronic progressive lymphangitis. The first European case of elephantiasic enlargement of the female genitalia caused by C. trachomatis L2 serovar in decades is reported.

  20. Late-stage development of the Bryant Canyon turbidite pathway on the Louisiana continental slope

    Science.gov (United States)

    Twichell, David C.; Nelson, Hans; Damuth, John E.

    2000-01-01

    GLORIA sidescan imagery, multibeam bathymetry, seismic profiles, and piston cores (3–5 m penetration) reveal the near-surface geology of the Bryant Canyon turbidite pathway on the continental margin of Louisiana. This pathway extends from the continental shelf edge, across the continental slope, to a deep-sea fan on the continental rise. The pathway is narrow (thalweg no longer has a continuous down-slope gradient. Some mini-basin floors along the pathway are now more than 500 m deeper than their basin’s spill point. We propose a 6-stage conceptual model to explain our observations for the evolution of a mini-basin along this turbidite pathway. In this model, an active channel feeds sand to a mini-basin (Stabe B). Once the mini-basin is filled, the sand deposit is entrenched by a bypass channel (Stage C). When the turbidite system shuts off, salt migration oversteepens the mini-basin walls (Stage D) which collapse and create a layer of mass-transport deposits on the mini-basin floor (Stage E). The depositional succession is capped by a layer of highstand hemipelagic drape (Stage F). The Bryant Canyon turbidite pathway provides a recent example of a large turbidite pathway in the Gulf of Mexico that crosses an area of active salt tectonics thus providing a conceptual model for older systems in similar settings. In Bryant Canyon, thick turbidite sands presumably are found in mini-basins however, they are sealed by thick, fine-grained, mass-transport deposits which terminate mini-basin turbidite deposition cycles. The importance of mass-transport deposits in basins along this turbidite pathway is in startling contrast to the Trinity-Brazos pathway whose shallow subsurface expression is virtually free of mass-transport deposits and has undergone minimal deformation by salt movement.

  1. Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014

    Science.gov (United States)

    Schneider, Lon S.; Mangialasche, Francesca; Andreasen, Niels; Feldman, Howard; Giacobini, Ezio; Jones, Roy; Mantua, Valentina; Mecocci, Patrizia; Pani, Luca; Winblad, Bengt; Kivipelto, Miia

    2014-01-01

    The modern era of drug development for Alzheimer’s disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer’s disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here we review the development of treatments for Alzheimer’s disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer’s disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild to moderate Alzheimer’s disease criteria, recently extending to early or prodromal Alzheimer disease or ‘mild cognitive impairment due to Alzheimer’s disease’, for drugs considered to be disease modifying. The duration of trials has remained at 6 to 12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities

  2. The role of singing familiar songs in encouraging conversation among people with middle to late stage Alzheimer's disease.

    Science.gov (United States)

    Dassa, Ayelet; Amir, Dorit

    2014-01-01

    Language deficits in people with Alzheimer's disease (AD) manifest, among other things, in a gradual deterioration of spontaneous speech. People with AD tend to speak less as the disease progresses and their speech becomes confused. However, the ability to sing old tunes sometimes remains intact throughout the disease. The purpose of this study was to explore the role of singing familiar songs in encouraging conversation among people with middle to late stage AD. Six participants attended group music therapy sessions over a one-month period. Using content analysis, we qualitatively examined transcriptions of verbal and sung content during 8 group sessions for the purpose of understanding the relationship between specific songs and conversations that occurred during and following group singing. Content analysis revealed that songs from the participants' past-elicited memories, especially songs related to their social and national identity. Analyses also indicated that conversation related to the singing was extensive and the act of group singing encouraged spontaneous responses. After singing, group members expressed positive feelings, a sense of accomplishment, and belonging. Carefully selecting music from the participants' past can encourage conversation. Considering the failure in spontaneous speech in people with middle to late stage AD, it is important to emphasize that group members' responses to each other occurred spontaneously without the researcher's encouragement. © the American Music Therapy Association 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  3. Salmonella enterica serovar Enteritidis enterocolitis during late stages of gestation induces an adverse pregnancy outcome in the murine model.

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    Mariángeles Noto Llana

    Full Text Available Foodborne diseases caused by Salmonella enterica serovar Enteritidis (S. Enteritidis are a significant health problem. Pregnancy, state of immunological tolerance, is a predisposing condition for the development of infections with intracellular pathogens. Salmonella species can cause pregnancy complications such as chorioamnionitis, transplacental fetal infection, pre term labor, abortions, neonatal and maternal septicemia. However, the specific mechanisms by which Salmonella infections trigger these alterations are not clear. In the present work, using a self-limiting enterocolitis murine model, we show that the ingestion of a low dose of S. Enteritidis at late stages of pregnancy (day 15 of gestation is sufficient to induce massive maternal infection. We found that Salmonella infection leads to 40% of pre term delivery, 33% of abortion and fetal growth restriction. Placental dysfunction during S. Enteritidis enterocolitis was confirmed through cellular infiltration and hypoxia markers (MPO activity and COX-1 and COX-2 expression, respectively. Apoptosis in placental tissue due to Salmonella infection was also evident at day 18 of gestation when investigated by morphometric procedure, DNA fragmentation and Fas/FasL expression. Also, the expression of IFN-γ, TNF-α, IL-17 and IL-10 was up regulated in response to Salmonella not only in placenta, but also in amniotic fluid and maternal serum. Altogether, our results demonstrate that S. Enteritidis enterocolitis during late stages of gestation causes detrimental effect on pregnancy outcome.

  4. Non-Catalytic Functions of Pyk2 and Fyn Regulate Late Stage Adhesion in Human T Cells

    Science.gov (United States)

    Houtman, Jon C. D.

    2012-01-01

    T cell activation drives the protective immune response against pathogens, but is also critical for the development of pathological diseases in humans. Cytoskeletal changes are required for downstream functions in T cells, including proliferation, cytokine production, migration, spreading, and adhesion. Therefore, investigating the molecular mechanism of cytoskeletal changes is crucial for understanding the induction of T cell-driven immune responses and for developing therapies to treat immune disorders related to aberrant T cell activation. In this study, we used a plate-bound adhesion assay that incorporated near-infrared imaging technology to address how TCR signaling drives human T cell adhesion. Interestingly, we observed that T cells have weak adhesion early after TCR activation and that binding to the plate was significantly enhanced 30–60 minutes after receptor activation. This late stage of adhesion was mediated by actin polymerization but was surprisingly not dependent upon Src family kinase activity. By contrast, the non-catalytic functions of the kinases Fyn and Pyk2 were required for late stage human T cell adhesion. These data reveal a novel TCR-induced signaling pathway that controls cellular adhesion independent of the canonical TCR signaling cascade driven by tyrosine kinase activity. PMID:23300847

  5. Overexpression of feline tripartite motif-containing 25 interferes with the late stage of feline leukemia virus replication.

    Science.gov (United States)

    Koba, Ryota; Oguma, Keisuke; Sentsui, Hiroshi

    2015-06-02

    Tripartite motif-containing 25 (TRIM25) regulates various cellular processes through E3 ubiquitin ligase activity. Previous studies have revealed that the expression of TRIM25 is induced by type I interferon and that TRIM25 is involved in the host cellular innate immune response against retroviral infection. Although retroviral infection is prevalent in domestic cats, the roles of feline TRIM25 in the immune response against these viral infections are poorly understood. Because feline TRIM25 is expected to modulate the infection of feline leukemia virus (FeLV), we investigated its effects on early- and late-stage FeLV replication. This study revealed that ectopic expression of feline TRIM25 in HEK293T cells reduced viral protein levels leading to the inhibition of FeLV release. Our findings show that feline TRIM25 has a potent antiviral activity and implicate an antiviral mechanism whereby feline TRIM25 interferes with late-stage FeLV replication. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Theta oscillations are sensitive to both early and late conflict processing stages: effects of alcohol intoxication.

    Science.gov (United States)

    Kovacevic, Sanja; Azma, Sheeva; Irimia, Andrei; Sherfey, Jason; Halgren, Eric; Marinkovic, Ksenija

    2012-01-01

    Prior neuroimaging evidence indicates that decision conflict activates medial and lateral prefrontal and parietal cortices. Theoretical accounts of cognitive control highlight anterior cingulate cortex (ACC) as a central node in this network. However, a better understanding of the relative primacy and functional contributions of these areas to decision conflict requires insight into the neural dynamics of successive processing stages including conflict detection, response selection and execution. Moderate alcohol intoxication impairs cognitive control as it interferes with the ability to inhibit dominant, prepotent responses when they are no longer correct. To examine the effects of moderate intoxication on successive processing stages during cognitive control, spatio-temporal changes in total event-related theta power were measured during Stroop-induced conflict. Healthy social drinkers served as their own controls by participating in both alcohol (0.6 g/kg ethanol for men, 0.55 g/kg women) and placebo conditions in a counterbalanced design. Anatomically-constrained magnetoencephalography (aMEG) approach was applied to complex power spectra for theta (4-7 Hz) frequencies. The principal generator of event-related theta power to conflict was estimated to ACC, with contributions from fronto-parietal areas. The ACC was uniquely sensitive to conflict during both early conflict detection, and later response selection and execution stages. Alcohol attenuated theta power to conflict across successive processing stages, suggesting that alcohol-induced deficits in cognitive control may result from theta suppression in the executive network. Slower RTs were associated with attenuated theta power estimated to ACC, indicating that alcohol impairs motor preparation and execution subserved by the ACC. In addition to their relevance for the currently prevailing accounts of cognitive control, our results suggest that alcohol-induced impairment of top-down strategic processing

  7. Effect of chicory seed extract on glucose tolerance test (GTT and metabolic profile in early and late stage diabetic rats

    Directory of Open Access Journals (Sweden)

    Ali Ahadi

    2012-10-01

    Full Text Available Background and purpose of the study The goal was to evaluate and compare the effects of aqueous extract of the seeds of chicory, Cichorium intybus L., on glucose tolerance test (GTT and blood biochemical indices of experimentally-induced hyperglycemic rats.MethodsLate stage and early stage of Type 2 diabetes mellitus (T2DM were induced in rats by streptozotocin (STZ and a combination of STZ and niacinamide (NIA/STZ, respectively. Within each group, one subgroup received daily i. p. injections of chicory extract (125 mg/kg body weight, for 28 days. Body weight and fasting blood sugar (FBS were measured weekly. Blood was analyzed for glycosylated hemoglobin (HbA1c and sera for alanine aminotransferase (ALT, aspartate aminotransferase (AST, nitric oxide (NO, triacylglycerol (TG, total cholesterol (TC, total protein, and insulin on days 10 and 28 after treatment. Intraperitoneal glucose tolerance test (IPGTT along with insulin determination was performed on a different set of rats in which the chicory-treated groups received the extract for 10 days.ResultsDuring 4 weeks of treatment, chicory prevented body-weight loss and decreased FBS. ALT activities and levels of TG, TC and HbA1c decreased, and concentration of NO increased in the chicory treated groups (p < 0.05. Unlike late-stage diabetes, fasting serum insulin concentrations were higher and GTT pattern approximated to normal in chicory-treated earlystage diabetic rats.ConclusionsChicory appeared to have short-term (about 2 hours, as far as GTT is concerned and longterm (28 days, in this study effects on diabetes. Chicory may be useful as a natural dietary supplement for slowing down the pace of diabetes progress, and delaying the development of its complications.

  8. ERP evidence for own-age effects on late stages of processing sad faces.

    Science.gov (United States)

    Fölster, Mara; Werheid, Katja

    2016-08-01

    Faces convey important information on interaction partners, such as their emotional state and age. Faces of the same age are, according to recent research, preferentially processed. The aim of the present study was to investigate whether the neural processes underlying this own-age effect are influenced by the emotional expression of the face, and to explore possible explanations such as the frequency or quality of contact to own-age versus other-age groups. Event-related potentials were recorded while 19 younger (18-30 years) and 19 older (64-86 years) observers watched younger and older sad and happy faces. Sad but not happy faces elicited higher late positive potential amplitudes for own-age than for other-age faces. This own-age effect was significant for older, but not for younger, observers, and correlated with the quality of contact with the own-age versus the other-age group. This pattern suggests that sad own-age faces are motivationally more relevant.

  9. deep-orange and carnation define distinct stages in late endosomal biogenesis in Drosophila melanogaster.

    Science.gov (United States)

    Sriram, V; Krishnan, K S; Mayor, Satyajit

    2003-05-12

    Endosomal degradation is severely impaired in primary hemocytes from larvae of eye color mutants of Drosophila. Using high resolution imaging and immunofluorescence microscopy in these cells, products of eye color genes, deep-orange (dor) and carnation (car), are localized to large multivesicular Rab7-positive late endosomes containing Golgi-derived enzymes. These structures mature into small sized Dor-negative, Car-positive structures, which subsequently fuse to form tubular lysosomes. Defective endosomal degradation in mutant alleles of dor results from a failure of Golgi-derived vesicles to fuse with morphologically arrested Rab7-positive large sized endosomes, which are, however, normally acidified and mature with wild-type kinetics. This locates the site of Dor function to fusion of Golgi-derived vesicles with the large Rab7-positive endocytic compartments. In contrast, endosomal degradation is not considerably affected in car1 mutant; fusion of Golgi-derived vesicles and maturation of large sized endosomes is normal. However, removal of Dor from small sized Car-positive endosomes is slowed, and subsequent fusion with tubular lysosomes is abolished. Overexpression of Dor in car1 mutant aggravates this defect, implicating Car in the removal of Dor from endosomes. This suggests that, in addition to an independent role in fusion with tubular lysosomes, the Sec1p homologue, Car, regulates Dor function.

  10. Resolving RAD51C function in late stages of homologous recombination

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    Kuznetsov Sergey G

    2007-06-01

    Full Text Available Abstract DNA double strand breaks are efficiently repaired by homologous recombination. One of the last steps of this process is resolution of Holliday junctions that are formed at the sites of genetic exchange between homologous DNA. Although various resolvases with Holliday junctions processing activity have been identified in bacteriophages, bacteria and archaebacteria, eukaryotic resolvases have been elusive. Recent biochemical evidence has revealed that RAD51C and XRCC3, members of the RAD51-like protein family, are involved in Holliday junction resolution in mammalian cells. However, purified recombinant RAD51C and XRCC3 proteins have not shown any Holliday junction resolution activity. In addition, these proteins did not reveal the presence of a nuclease domain, which raises doubts about their ability to function as a resolvase. Furthermore, oocytes from infertile Rad51C mutant mice exhibit precocious separation of sister chromatids at metaphase II, a phenotype that reflects a defect in sister chromatid cohesion, not a lack of Holliday junction resolution. Here we discuss a model to explain how a Holliday junction resolution defect can lead to sister chromatid separation in mouse oocytes. We also describe other recent in vitro and in vivo evidence supporting a late role for RAD51C in homologous recombination in mammalian cells, which is likely to be resolution of the Holliday junction.

  11. Influence of late-stage chronic kidney disease on overall survival in patients with upper tract urothelial carcinoma following radical nephroureterectomy

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    Sheng-Chen Wen

    2015-06-01

    Conclusion: Patients with late-stage CKD had a higher risk of having poor OS. Patients with concomitant bladder tumor had a greater risk of having bladder cancer recurrence despite primary tumor stage. Concomitant bladder tumor, however, had no effect on OS and CSS in this study.

  12. Renal cell carcinoma in India demonstrates early age of onset & a late stage of presentation

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    Shalini Agnihotri

    2014-01-01

    Full Text Available Background & objectives: Clinical spectrum of most of the diseases in developing countries is different from the west. Similarly whether renal cell carcinomas (RCC in a developing country like India is seen in the same spectrum in relation to the age at presentation as in the west is not described in the literature. This study was carried out to investigate the spectrum of RCC in India with regards to age of onset, stage at presentation and survival. Methods: Patients with renal tumour, treated between January 2000 to December 2012 in a tertiary care hospital in north India, were analyzed for age at presentation, clinical features and histopathological characteristics. Clinical diagnosis was made by contrast enhanced computerized tomography (CECT scans and/or magnetic resonance imaging (MRI. Renal masses diagnosed as angiomyolipoma, infective masses and hydatid cysts were excluded from the analysis. Impact of various age groups on gender, tumour size, TNM stage, Fuhrman grade, histopathological subtypes, lymph node, inferior vena cava (IVC involvement and survival was analyzed. Patients were grouped in five age groups i.e. ≤39, 40-49, 50-59, 60-69 and more than 70 yr of age. Results: Of the total 617 patients with 617 renal tumours (2 patients had bilateral tumours but only the larger tumour was considered clinically suspected as RCC, 586 had epithelial cell tumour and the remaining 31 had non epithelial cell tumour. The mean tumour size was 8.08±3.5 cm (median 7, range 1-25 cm. Tumour of less than 4 cm size was present in only 10.4 per cent patients. The mean age at diagnosis was 55.15±13.34 (median 56, range 14-91 yr years. A total of 30.03 per cent of renal tumours presented in patients younger than 50 yr of age. Though there was no difference in stage, Fuhrman′s grade, IVC involvement and lymph nodal spread among various age groups, younger patients had higher proportion of non clear cell RCC and only 48.59 per cent of them presented

  13. Regulation of ITAM adaptor molecules and their receptors by inhibition of calcineurin-NFAT signalling during late stage osteoclast differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Zawawi, M.S.F. [Universiti Sains Malaysia (USM) (Malaysia); Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005 (Australia); Dharmapatni, A.A.S.S.K.; Cantley, M.D. [Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005 (Australia); McHugh, K.P. [University of Florida, College of Dentistry, Fl (United States); Haynes, D.R. [Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005 (Australia); Crotti, T.N., E-mail: tania.crotti@adelaide.edu.au [Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005 (Australia)

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer Calcineurin/NFAT inhibitors FK506 and VIVIT treated human PBMC derived osteoclasts in vitro. Black-Right-Pointing-Pointer Differential regulation of ITAM receptors and adaptor molecules by calcineurin/NFAT inhibitors. Black-Right-Pointing-Pointer FK506 and VIVIT suppress ITAM factors during late phase osteoclast differentiation. -- Abstract: Osteoclasts are specialised bone resorptive cells responsible for both physiological and pathological bone loss. Osteoclast differentiation and activity is dependent upon receptor activator NF-kappa-B ligand (RANKL) interacting with its receptor RANK to induce the transcription factor, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). The immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway has been identified as a co-stimulatory pathway in osteoclasts. Osteoclast-associated receptor (OSCAR) and triggering receptor expressed in myeloid cells (TREM2) are essential receptors that pair with adaptor molecules Fc receptor common gamma chain (FcR{gamma}) and DNAX-activating protein 12 kDa (DAP12) respectively to induce calcium signalling. Treatment with calcineurin-NFAT inhibitors, Tacrolimus (FK506) and the 11R-VIVIT (VIVIT) peptide, reduces NFATc1 expression consistent with a reduction in osteoclast differentiation and activity. This study aimed to investigate the effects of inhibiting calcineurin-NFAT signalling on the expression of ITAM factors and late stage osteoclast genes including cathepsin K (CathK), Beta 3 integrin ({beta}3) and Annexin VIII (AnnVIII). Human peripheral blood mononuclear cells (PBMCs) were differentiated with RANKL and macrophage-colony stimulating factor (M-CSF) over 10 days in the presence or absence of FK506 or VIVIT. Osteoclast formation (as assessed by tartrate resistant acid phosphatase (TRAP)) and activity (assessed by dentine pit resorption) were significantly reduced with treatment. Quantitative real

  14. Leishmania infantum nicotinamidase is required for late-stage development in its natural sand fly vector, Phlebotomus perniciosus.

    Science.gov (United States)

    Gazanion, Elodie; Seblova, Veronika; Votypka, Jan; Vergnes, Baptiste; Garcia, Déborah; Volf, Petr; Sereno, Denis

    2012-04-01

    Leishmania infantum nicotinamidase, encoded by the Lipnc1 gene, converts nicotinamide into nicotinicacid to ensure Nicotinamide–Adenine–Dinucleotide (NAD+) biosynthesis. We were curious to explore the role of this enzyme during L. infantum development in its natural sand fly vector, Phlebotomus perniciosus (Diptera, Phlebotominae), using null mutants with a deleted Lipnc1 gene. The null mutants developed as well as the wild type L. infantum at the early time points post their ingestion within the bloodmeal. In contrast, once the blood meal digestion was completed, the null mutants were unable to develop further and establish late-stage infections. Data highlight the importance of the nicotinamide degradation pathway for Leishmania development in sand flies. They indicate that the endogenous nicotinamidase is essential for Leishmania development in the sand fly after the blood meal has been digested and the remnants defecated.

  15. Live Imaging of Meiosis I in Late-Stage Drosophila melanogaster Oocytes.

    Science.gov (United States)

    Hughes, Stacie E; Hawley, R Scott

    2017-01-01

    Drosophila melanogaster has been studied for a century as a genetic model to understand recombination, chromosome segregation, and the basic rules of inheritance. However, it has only been about 25 years since the events that occur during nuclear envelope breakdown, spindle assembly, and chromosome orientation during D. melanogaster female meiosis I were first visualized by fixed cytological methods (Theurkauf and Hawley, J Cell Biol 116:1167-1180, 1992). Although these fixed cytological studies revealed many important details about the events that occur during meiosis I, they failed to elucidate the timing or order of these events. The development of protocols for live imaging of meiotic events within the oocyte has enabled collection of real-time information on the kinetics and dynamics of spindle assembly, as well as the behavior of chromosomes during prometaphase I. Here, we describe a method to visualize spindle assembly and chromosome movement during meiosis I by injecting fluorescent dyes to label microtubules and DNA into stage 12-14 oocytes. This method enables the events during Drosophila female meiosis I, such as spindle assembly and chromosome movement, to be observed in vivo, regardless of genetic background, with exceptional spatial and temporal resolution.

  16. Sociocultural Barriers Related to Late-Stage Presentation of Breast Cancer in Morocco.

    Science.gov (United States)

    Soliman, Ann A; Khouchani, Mouna; Renne, Elisha P

    2018-04-23

    Breast cancer is the most prevalent cancer affecting women globally and in Morocco, where more than one fourth of patients are diagnosed at advanced stages. This study aimed to investigate sociocultural barriers that contribute to delayed presentation and diagnosis of breast cancer among women in Marrakesh, Morocco. Qualitative interviews were conducted with 25 breast cancer patients who received care at the CHU Mohammed VI Hospital in Marrakesh to elicit barriers to diagnosis and treatment and ease of access to care. Interviews with breast cancer patients revealed several themes regarding structural and sociocultural barriers to initial diagnosis and treatment. Structural barriers included high treatment-associated costs for patients and their families, burden of transportation to central treatment centers, and limited access to appropriate health care resources. Sociocultural barriers included perceived attack on one's identity associated with breast cancer diagnosis and treatment, influence of the local community, and ideas of faith, spirituality, and conception of death. Findings from this study can help identify areas for improved access and education of patients in order to improve breast cancer diagnostic and treatment efforts and enhance opportunities for early detection.

  17. SU-E-T-381: Radio-Dynamic Therapy (RDT) for the Treatment of Late-Stage Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Ma, C; Chen, L; Price, R [Fox Chase Cancer Center, Philadelphia, PA (United States); Zhang, Q [Wu Xi Yi Ren Tumor Hosiptal, Wuxi, Jiangsu (China); Zeng, J; Xu, K; Sun, Q [Wuxi Yiren Cancer Hospital, Wuxi, Jiangsu (China)

    2014-06-01

    Purpose: Photo-dynamic therapy (PDT) is an effective treatment modality because of the preferential absorption of photosensitizing agent in tumor cells than in surrounding normal tissues. A limitation of PDT for cancer therapy is the finite penetration of laser light to activate the targeting agent in deep-seated tumors. Radio-dynamic therapy (RDT) is designed to overcome this problem by the combination of high-energy (up to 45MV) photon beams and photo/radio-sensitizers. This work investigates the feasibility of PDT for late-stage cancer patients who are no longer respond to conventional therapies available. Methods: The high-energy photon beams are generated using a LA45 RaceTrack Microtron (Top Grade Medical, Beijing, China). The targeting agent investigated is 5- aminolevulinic acid (5-ALA). Both in vitro cell lines and in vivo animal models have been used to investigate the mechanisms of RDT and its therapeutic effects and normal tissue toxicities. Oral 5-ALA (30-60 mg/kg) was administered 4-6 hours before the radiation treatment and the total radiation dose varied between 0.1-4.0Gy in 1-4 fractions. Clinical trials are initiated in China for late-stage cancer patients targeting both primary tumors utilizing localized therapies such as 3DCRT/IMRT and metastases using TBI. Results: There is clear correlation between the cell death and the 5-ALA concentration/radiation dose. The therapeutic effect of RDT is demonstrated using an animal model where the volume of parotid tumors for the RT only group continued to grow after 3Gy irradiation while the RDT group showed a complete response with the same radiation dose. The preliminary clinical results showed encouraging clinical outcome. Conclusion: RDT is a novel treatment technique that may be developed into an effective cancer treatment modality. Further studies on the mechanisms of RDT and its potential clinical applications are warranted.

  18. SU-E-T-381: Radio-Dynamic Therapy (RDT) for the Treatment of Late-Stage Cancers

    International Nuclear Information System (INIS)

    Ma, C; Chen, L; Price, R; Zhang, Q; Zeng, J; Xu, K; Sun, Q

    2014-01-01

    Purpose: Photo-dynamic therapy (PDT) is an effective treatment modality because of the preferential absorption of photosensitizing agent in tumor cells than in surrounding normal tissues. A limitation of PDT for cancer therapy is the finite penetration of laser light to activate the targeting agent in deep-seated tumors. Radio-dynamic therapy (RDT) is designed to overcome this problem by the combination of high-energy (up to 45MV) photon beams and photo/radio-sensitizers. This work investigates the feasibility of PDT for late-stage cancer patients who are no longer respond to conventional therapies available. Methods: The high-energy photon beams are generated using a LA45 RaceTrack Microtron (Top Grade Medical, Beijing, China). The targeting agent investigated is 5- aminolevulinic acid (5-ALA). Both in vitro cell lines and in vivo animal models have been used to investigate the mechanisms of RDT and its therapeutic effects and normal tissue toxicities. Oral 5-ALA (30-60 mg/kg) was administered 4-6 hours before the radiation treatment and the total radiation dose varied between 0.1-4.0Gy in 1-4 fractions. Clinical trials are initiated in China for late-stage cancer patients targeting both primary tumors utilizing localized therapies such as 3DCRT/IMRT and metastases using TBI. Results: There is clear correlation between the cell death and the 5-ALA concentration/radiation dose. The therapeutic effect of RDT is demonstrated using an animal model where the volume of parotid tumors for the RT only group continued to grow after 3Gy irradiation while the RDT group showed a complete response with the same radiation dose. The preliminary clinical results showed encouraging clinical outcome. Conclusion: RDT is a novel treatment technique that may be developed into an effective cancer treatment modality. Further studies on the mechanisms of RDT and its potential clinical applications are warranted

  19. Kelch-like ECT2-interacting protein KLEIP regulates late-stage pulmonary maturation via Hif-2α in mice

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    Nicole Woik

    2014-06-01

    Full Text Available Respiratory distress syndrome (RDS caused by preterm delivery is a major clinical problem with limited mechanistic insight. Late-stage embryonic lung development is driven by hypoxia and the hypoxia-inducible transcription factors Hif-1α and Hif-2α, which act as important regulators for lung development. Expression of the BTB-and kelch-domain-containing (BTB-kelch protein KLEIP (Kelch-like ECT2-interacting protein; also named Klhl20 is controlled by two hypoxia response elements, and KLEIP regulates stabilization and transcriptional activation of Hif-2α. Based on the available data, we hypothesized an essential role for KLEIP in murine lung development and function. Therefore, we have performed a functional, histological, mechanistic and interventional study in embryonic and neonatal KLEIP−/− mice. Here, we show that about half of the KLEIP−/− neonates die due to respiratory failure that is caused by insufficient aeration, reduced septal thinning, reduced glycogenolysis, type II pneumocyte immaturity and reduced surfactant production. Expression analyses in embryonic day (E 18.5 lungs identified KLEIP in lung capillaries, and showed strongly reduced mRNA and protein levels for Hif-2α and VEGF; such reduced levels are associated with embryonic endothelial cell apoptosis and lung bleedings. Betamethasone injection in pregnant females prevented respiratory failure in KLEIP−/− neonates, normalized lung maturation, vascularization, aeration and function, and increased neonatal Hif-2α expression. Thus, the experimental study shows that respiratory failure in KLEIP−/− neonates is determined by insufficient angiocrine Hif-2α–VEGF signaling and that betamethasone activates this newly identified signaling cascade in late-stage embryonic lung development.

  20. The genomic landscape at a late stage of stickleback speciation: High genomic divergence interspersed by small localized regions of introgression.

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    Mark Ravinet

    2018-05-01

    Full Text Available Speciation is a continuous process and analysis of species pairs at different stages of divergence provides insight into how it unfolds. Previous genomic studies on young species pairs have revealed peaks of divergence and heterogeneous genomic differentiation. Yet less known is how localised peaks of differentiation progress to genome-wide divergence during the later stages of speciation in the presence of persistent gene flow. Spanning the speciation continuum, stickleback species pairs are ideal for investigating how genomic divergence builds up during speciation. However, attention has largely focused on young postglacial species pairs, with little knowledge of the genomic signatures of divergence and introgression in older stickleback systems. The Japanese stickleback species pair, composed of the Pacific Ocean three-spined stickleback (Gasterosteus aculeatus and the Japan Sea stickleback (G. nipponicus, which co-occur in the Japanese islands, is at a late stage of speciation. Divergence likely started well before the end of the last glacial period and crosses between Japan Sea females and Pacific Ocean males result in hybrid male sterility. Here we use coalescent analyses and Approximate Bayesian Computation to show that the two species split approximately 0.68-1 million years ago but that they have continued to exchange genes at a low rate throughout divergence. Population genomic data revealed that, despite gene flow, a high level of genomic differentiation is maintained across the majority of the genome. However, we identified multiple, small regions of introgression, occurring mainly in areas of low recombination rate. Our results demonstrate that a high level of genome-wide divergence can establish in the face of persistent introgression and that gene flow can be localized to small genomic regions at the later stages of speciation with gene flow.

  1. The genomic landscape at a late stage of stickleback speciation: High genomic divergence interspersed by small localized regions of introgression.

    Science.gov (United States)

    Ravinet, Mark; Yoshida, Kohta; Shigenobu, Shuji; Toyoda, Atsushi; Fujiyama, Asao; Kitano, Jun

    2018-05-01

    Speciation is a continuous process and analysis of species pairs at different stages of divergence provides insight into how it unfolds. Previous genomic studies on young species pairs have revealed peaks of divergence and heterogeneous genomic differentiation. Yet less known is how localised peaks of differentiation progress to genome-wide divergence during the later stages of speciation in the presence of persistent gene flow. Spanning the speciation continuum, stickleback species pairs are ideal for investigating how genomic divergence builds up during speciation. However, attention has largely focused on young postglacial species pairs, with little knowledge of the genomic signatures of divergence and introgression in older stickleback systems. The Japanese stickleback species pair, composed of the Pacific Ocean three-spined stickleback (Gasterosteus aculeatus) and the Japan Sea stickleback (G. nipponicus), which co-occur in the Japanese islands, is at a late stage of speciation. Divergence likely started well before the end of the last glacial period and crosses between Japan Sea females and Pacific Ocean males result in hybrid male sterility. Here we use coalescent analyses and Approximate Bayesian Computation to show that the two species split approximately 0.68-1 million years ago but that they have continued to exchange genes at a low rate throughout divergence. Population genomic data revealed that, despite gene flow, a high level of genomic differentiation is maintained across the majority of the genome. However, we identified multiple, small regions of introgression, occurring mainly in areas of low recombination rate. Our results demonstrate that a high level of genome-wide divergence can establish in the face of persistent introgression and that gene flow can be localized to small genomic regions at the later stages of speciation with gene flow.

  2. HLA-B8 association with late-stage melanoma – an immunological lesson?

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    Andersen Mads

    2006-03-01

    Full Text Available Abstract Background Differences in HLA allele frequencies between the diseased and healthy populations may signify efficient immune responses, a notion that has been successfully tested for infectious diseases or for association with genetic elements involved in a distinct type of immunity. This retrospective study is intended to detect differences in MHC class I carrier frequencies of advanced melanoma patients compared to healthy bone marrow donors. Methods The HLA-A and -B carrier frequencies of 748 stage IV melanoma patients retrieved from serotyping at 6 different centers in Germany were compared using a chi-square test to 13,386 fully HLA typed bone marrow donors registered in the German national bone marrow donor registry. Results The comparison of HLA carrier frequencies in advanced cancer patients with healthy bone marrow donors revealed a significant decrease in HLA-B8 carrier frequencies, which was also apparent in patients with advanced disease compared to patients with loco-regional disease. Conclusion The data suggest that protective immune responses restricted to distinct MHC class I molecules may be operational in a subset of melanoma patients, which is the prerequisite for a large scale screen for the corresponding epitopes. Alternatively, the known association of the ancestral haplotype HLA-A1, -B8 and -DR3 with genetic elements such as distinct TNF-α alleles might have a protective effect on disease progression. In any case, identification of the cause of protection within this patient subset might lead to a significant improvement in the efficacy of current immunotherapeutic approaches.

  3. The development of self-regulated learning during the pre-clinical stage of medical school: a comparison between a lecture-based and a problem-based curriculum.

    Science.gov (United States)

    Lucieer, Susanna M; van der Geest, Jos N; Elói-Santos, Silvana M; de Faria, Rosa M Delbone; Jonker, Laura; Visscher, Chris; Rikers, Remy M J P; Themmen, Axel P N

    2016-03-01

    Society expects physicians to always improve their competencies and to be up to date with developments in their field. Therefore, an important aim of medical schools is to educate future medical doctors to become self-regulated, lifelong learners. However, it is unclear if medical students become better self-regulated learners during the pre-clinical stage of medical school, and whether students develop self-regulated learning skills differently, dependent on the educational approach of their medical school. In a cross-sectional design, we investigated the development of 384 medical students' self-regulated learning skills with the use of the Self-Regulation of Learning Self-Report Scale. Next, we compared this development in students who enrolled in two distinct medical curricula: a problem-based curriculum and a lectured-based curriculum. Analysis showed that more skills decreased than increased during the pre-clinical stage of medical school, and that the difference between the curricula was mainly caused by a decrease in the skill evaluation in the lecture-based curriculum. These findings seem to suggest that, irrespective of the curriculum, self-regulated learning skills do not develop during medical school.

  4. Modelling the enigmatic Late Pliocene Glacial Event - Marine Isotope Stage M2

    Science.gov (United States)

    Dolan, Aisling M.; Haywood, Alan M.; Hunter, Stephen J.; Tindall, Julia C.; Dowsett, Harry J.; Hill, Daniel J.; Pickering, Steven J.

    2015-01-01

    The Pliocene Epoch (5.2 to 2.58 Ma) has often been targeted to investigate the nature of warm climates. However, climate records for the Pliocene exhibit significant variability and show intervals that apparently experienced a cooler than modern climate. Marine Isotope Stage (MIS) M2 (~ 3.3 Ma) is a globally recognisable cooling event that disturbs an otherwise relatively (compared to present-day) warm background climate state. It remains unclear whether this event corresponds to significant ice sheet build-up in the Northern and Southern Hemisphere. Estimates of sea level for this interval vary, and range from modern values to estimates of 65 m sea level fall with respect to present day. Here we implement plausible M2 ice sheet configurations into a coupled atmosphere–ocean climate model to test the hypothesis that larger-than-modern ice sheet configurations may have existed at M2. Climate model results are compared with proxy climate data available for M2 to assess the plausibility of each ice sheet configuration. Whilst the outcomes of our data/model comparisons are not in all cases straight forward to interpret, there is little indication that results from model simulations in which significant ice masses have been prescribed in the Northern Hemisphere are incompatible with proxy data from the North Atlantic, Northeast Arctic Russia, North Africa and the Southern Ocean. Therefore, our model results do not preclude the possibility of the existence of larger ice masses during M2 in the Northern or Southern Hemisphere. Specifically they are not able to discount the possibility of significant ice masses in the Northern Hemisphere during the M2 event, consistent with a global sea-level fall of between 40 m and 60 m. This study highlights the general need for more focused and coordinated data generation in the future to improve the coverage and consistency in proxy records for M2, which will allow these and future M2 sensitivity tests to be interrogated

  5. A circulating microrna profile is associated with late-stage neovascular age-related macular degeneration.

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    Felix Grassmann

    Full Text Available Age-related macular degeneration (AMD is the leading cause of severe vision impairment in Western populations over 55 years. A growing number of gene variants have been identified which are strongly associated with an altered risk to develop AMD. Nevertheless, gene-based biomarkers which could be dysregulated at defined stages of AMD may point toward key processes in disease mechanism and thus may support efforts to design novel treatment regimens for this blinding disorder. Circulating microRNAs (cmiRNAs which are carried by nanosized exosomes or microvesicles in blood plasma or serum, have been recognized as valuable indicators for various age-related diseases. We therefore aimed to elucidate the role of cmiRNAs in AMD by genome-wide miRNA expression profiling and replication analyses in 147 controls and 129 neovascular AMD patients. We identified three microRNAs differentially secreted in neovascular (NV AMD (hsa-mir-301-3p, pcorrected = 5.6*10-5, hsa-mir-361-5p, pcorrected = 8.0*10-4 and hsa-mir-424-5p, pcorrected = 9.6*10-3. A combined profile of the three miRNAs revealed an area under the curve (AUC value of 0.727 and was highly associated with NV AMD (p = 1.2*10-8. To evaluate subtype-specificity, an additional 59 AMD cases with pure unilateral or bilateral geographic atrophy (GA were analyzed for microRNAs hsa-mir-301-3p, hsa-mir-361-5p, and hsa-mir-424-5p. While we found no significant differences between GA AMD and controls neither individually nor for a combined microRNAs profile, hsa-mir-424-5p levels remained significantly higher in GA AMD when compared to NV (pcorrected<0.005. Pathway enrichment analysis on genes predicted to be regulated by microRNAs hsa-mir-301-3p, hsa-mir-361-5p, and hsa-mir-424-5p, suggests canonical TGFβ, mTOR and related pathways to be involved in NV AMD. In addition, knockdown of hsa-mir-361-5p resulted in increased neovascularization in an in vitro angiogenesis assay.

  6. RPA and XPA interaction with DNA structures mimicking intermediates of the late stages in nucleotide excision repair.

    Science.gov (United States)

    Krasikova, Yuliya S; Rechkunova, Nadejda I; Maltseva, Ekaterina A; Lavrik, Olga I

    2018-01-01

    Replication protein A (RPA) and the xeroderma pigmentosum group A (XPA) protein are indispensable for both pathways of nucleotide excision repair (NER). Here we analyze the interaction of RPA and XPA with DNA containing a flap and different size gaps that imitate intermediates of the late NER stages. Using gel mobility shift assays, we found that RPA affinity for DNA decreased when DNA contained both extended gap and similar sized flap in comparison with gapped-DNA structure. Moreover, crosslinking experiments with the flap-gap DNA revealed that RPA interacts mainly with the ssDNA platform within the long gap and contacts flap in DNA with a short gap. XPA exhibits higher affinity for bubble-DNA structures than to flap-gap-containing DNA. Protein titration analysis showed that formation of the RPA-XPA-DNA ternary complex depends on the protein concentration ratio and these proteins can function as independent players or in tandem. Using fluorescently-labelled RPA, direct interaction of this protein with XPA was detected and characterized quantitatively. The data obtained allow us to suggest that XPA can be involved in the post-incision NER stages via its interaction with RPA.

  7. RPA and XPA interaction with DNA structures mimicking intermediates of the late stages in nucleotide excision repair.

    Directory of Open Access Journals (Sweden)

    Yuliya S Krasikova

    Full Text Available Replication protein A (RPA and the xeroderma pigmentosum group A (XPA protein are indispensable for both pathways of nucleotide excision repair (NER. Here we analyze the interaction of RPA and XPA with DNA containing a flap and different size gaps that imitate intermediates of the late NER stages. Using gel mobility shift assays, we found that RPA affinity for DNA decreased when DNA contained both extended gap and similar sized flap in comparison with gapped-DNA structure. Moreover, crosslinking experiments with the flap-gap DNA revealed that RPA interacts mainly with the ssDNA platform within the long gap and contacts flap in DNA with a short gap. XPA exhibits higher affinity for bubble-DNA structures than to flap-gap-containing DNA. Protein titration analysis showed that formation of the RPA-XPA-DNA ternary complex depends on the protein concentration ratio and these proteins can function as independent players or in tandem. Using fluorescently-labelled RPA, direct interaction of this protein with XPA was detected and characterized quantitatively. The data obtained allow us to suggest that XPA can be involved in the post-incision NER stages via its interaction with RPA.

  8. Symptoms and quality of life in late stage Parkinson syndromes: a longitudinal community study of predictive factors.

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    Irene J Higginson

    Full Text Available BACKGROUND: Palliative care is increasingly offered earlier in the cancer trajectory but rarely in Idiopathic Parkinson's Disease(IPD, Progressive Supranuclear Palsy(PSP or Multiple System Atrophy(MSA. There is little longitudinal data of people with late stage disease to understand levels of need. We aimed to determine how symptoms and quality of life of these patients change over time; and what demographic and clinical factors predicted changes. METHODS: We recruited 82 patients into a longitudinal study, consenting patients with a diagnosis of IPD, MSA or PSP, stages 3-5 Hoehn and Yahr(H&Y. At baseline and then on up to 3 occasions over one year, we collected self-reported demographic, clinical, symptom, palliative and quality of life data, using Parkinson's specific and generic validated scales, including the Palliative care Outcome Scale (POS. We tested for predictors using multivariable analysis, adjusting for confounders. FINDINGS: Over two thirds of patients had severe disability, over one third being wheelchair-bound/bedridden. Symptoms were highly prevalent in all conditions - mean (SD of 10.6(4.0 symptoms. More than 50% of the MSA and PSP patients died over the year. Over the year, half of the patients showed either an upward (worsening, 24/60 or fluctuant (8/60 trajectory for POS and symptoms. The strongest predictors of higher levels of symptoms at the end of follow-up were initial scores on POS (AOR 1.30; 95%CI:1.05-1.60 and being male (AOR 5.18; 95% CI 1.17 to 22.92, both were more predictive than initial H&Y scores. INTERPRETATION: The findings point to profound and complex mix of non-motor and motor symptoms in patients with late stage IPD, MSA and PSP. Symptoms are not resolved and half of the patients deteriorate. Palliative problems are predictive of future symptoms, suggesting that an early palliative assessment might help screen for those in need of earlier intervention.

  9. Effect of chicory seed extract on glucose tolerance test (GTT and metabolic profile in early and late stage diabetic rats

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    Ghamarian Abdolreza

    2012-10-01

    Full Text Available Abstract Background and purpose of the study The goal was to evaluate and compare the effects of aqueous extract of the seeds of chicory, Cichorium intybus L., on glucose tolerance test (GTT and blood biochemical indices of experimentally-induced hyperglycemic rats. Methods Late stage and early stage of Type 2 diabetes mellitus (T2DM were induced in rats by streptozotocin (STZ and a combination of STZ and niacinamide (NIA/STZ, respectively. Within each group, one subgroup received daily i. p. injections of chicory extract (125 mg/kg body weight, for 28 days. Body weight and fasting blood sugar (FBS were measured weekly. Blood was analyzed for glycosylated hemoglobin (HbA1c and sera for alanine aminotransferase (ALT, aspartate aminotransferase (AST, nitric oxide (NO, triacylglycerol (TG, total cholesterol (TC, total protein, and insulin on days 10 and 28 after treatment. Intraperitoneal glucose tolerance test (IPGTT along with insulin determination was performed on a different set of rats in which the chicory-treated groups received the extract for 10 days. Results During 4 weeks of treatment, chicory prevented body-weight loss and decreased FBS. ALT activities and levels of TG, TC and HbA1c decreased, and concentration of NO increased in the chicory treated groups (p Conclusions Chicory appeared to have short-term (about 2 hours, as far as GTT is concerned and long-term (28 days, in this study effects on diabetes. Chicory may be useful as a natural dietary supplement for slowing down the pace of diabetes progress, and delaying the development of its complications.

  10. Dynamics of waterflooding massive oil deposits in the Chechen Ingush ASSR, including fissured reservoirs in the late stages of development

    Energy Technology Data Exchange (ETDEWEB)

    Tatashev, K.Kh.; Soboleva, G.N.; Tagunova, A.V.

    1979-01-01

    In 1956 in the Chechen Ingush ASSR a number of massive oil deposits located in fissured cavernous Upper Cretaceous limestone were developed. The deposits were developed by water-oil displacement from the edges and pericline toward the dome of the structure using the natural water pressure drive as well as artificial marginal flooding. The great oil-bearing capacity, the good hydrodynamic link with the deposit, the close magnitude of oil viscosity and water under the layer conditions and the significant difference in their density (0.4-0.5 g/cm/sup 3/) practically guarantees pistonlike oil displacement. Based on the deposit's geologic-physical characteristics, the late stage of development may be characterized by noncontinuous time and a sharp increase in well waterflooding to maintain full flooding. However, the data obtained from working the field suggest that a sharp increase in waterflooding will be substituted by a slow increase, by stabilization and possibly even a decrease in the percentage of water over the last 3-6 years. This occurred in a number of cases where measures were taken to limit the liquid flow, to periodically operate the well with isolated waterflooding and pereclinal perforation at intervals. This also occurred in a number of cases where the rate of fluid yield was naturally lowered by decreasing the number of producing wells due to waterflooding and disengagement. To more completely extract the oil from relatively low permeable areas of the deposits and to develop them in the later stages, it is useful to use a slow tempo once all wells have been brought to perclinal interval operation.

  11. Comparison of NH4+-N and NO3--N nutrition in hybrid and conventional rice at the late growth stage

    International Nuclear Information System (INIS)

    Yang Xiaoe; Sun Xi

    1990-01-01

    The difference of NH 4 + -N/NO 3 - -N nutrition between hybrid and conventional rice varieties at the late growth stage was studied by using 15 N-tracer technique. The results showed that the nitrate fertilizer utilization efficiency by the hybrid rice after anthesis was 7.8% higher than that by the ordinary rice variety, and the nitrate fertilizer recovery fraction by the former was 13.2% greater than that by the latter. The varietal difference in NO 3 - -N uptake and utilization was almost twice as that in NH 4 + -N. It was also showed that 15 N distribution in ear of the hybrid rice was about 20% greater than that of the conventional variety, but there were no obvious differences between NO 3 - -N and NH 4 + -N. However, 15 N distribution in the lower node leaves and root was found to be significant higher with NO 3 - -N than that with NH 4 + -N in both rice varieties, particularly in the hybrid rice. Compared with NH 4 + -N, NO 3 - -N top-dressing before anthesis was observed to have much greater positive effects on the uptake of calcium and magnesium and the growth of the superficial root and the grain yield of the tested rice varieties, especially of the hybrid rice

  12. Distribution of elastic fibers in the head and neck: a histological study using late-stage human fetuses

    Science.gov (United States)

    Kinoshita, Hideaki; Umezawa, Takashi; Omine, Yuya; Kasahara, Masaaki; Rodríguez-Vázquez, José Francisco; Murakami, Gen

    2013-01-01

    There is little or no information about the distribution of elastic fibers in the human fetal head. We examined this issue in 15 late-stage fetuses (crown-rump length, 220-320 mm) using aldehyde-fuchsin and elastica-Masson staining, and we used the arterial wall elastic laminae and external ear cartilages as positive staining controls. The posterior pharyngeal wall, as well as the ligaments connecting the laryngeal cartilages, contained abundant elastic fibers. In contrast with the sphenomandibular ligament and the temporomandibular joint disk, in which elastic fibers were partly present, the discomalleolar ligament and the fascial structures around the pterygoid muscles did not have any elastic fibers. In addition, the posterior marginal fascia of the prestyloid space did contain such fibers. Notably, in the middle ear, elastic fibers accumulated along the tendons of the tensor tympani and stapedius muscles and in the joint capsules of the ear ossicle articulations. Elastic fibers were not seen in any other muscle tendons or vertebral facet capsules in the head and neck. Despite being composed of smooth muscle, the orbitalis muscle did not contain any elastic fibers. The elastic fibers in the sphenomandibular ligament seemed to correspond to an intermediate step of development between Meckel's cartilage and the final ligament. Overall, there seemed to be a mini-version of elastic fiber distribution compared to that in adults and a different specific developmental pattern of connective tissues. The latter morphology might be a result of an adaptation to hypoxic conditions during development. PMID:23560235

  13. A Hybrid Fault-Tolerant Strategy for Severe Sensor Failure Scenarios in Late-Stage Offshore DFIG-WT

    Directory of Open Access Journals (Sweden)

    Wei Li

    2017-12-01

    Full Text Available As the phase current sensors and rotor speed/position sensor are prone to fail in the late stage of an offshore doubly-fed induction generator based wind turbine (DFIG-WT, this paper investigates a hybrid fault-tolerant strategy for a severe sensor failure scenario. The phase current sensors in the back-to-back (BTB converter and the speed/position sensor are in the faulty states simultaneously. Based on the 7th-order doubly-fed induction generator (DFIG dynamic state space model, the extended Kalman filter (EKF algorithm is applied for rotor speed and position estimation. In addition, good robustness of this sensorless control algorithm to system uncertainties and measurement disturbances is presented. Besides, a single DC-link current sensor based phase current reconstruction scheme is utilized for deriving the phase current information according to the switching states. A duty ratio adjustment strategy is proposed to avoid missing the sampling points in a switching period, which is simple to implement. Furthermore, the additional active time of the targeted nonzero switching states is complemented so that the reference voltage vector remains in the same position as that before duty ratio adjustment. The validity of the proposed hybrid fault-tolerant sensorless control strategy is demonstrated by simulation results in Matlab/Simulink2017a by considering harsh operating environments.

  14. Acute paretic syndrome in juvenile White Leghorn chickens resembles late stages of acute inflammatory demyelinating polyneuropathies in humans

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    Preisinger Rudolf

    2010-01-01

    Full Text Available Abstract Background Sudden limb paresis is a common problem in White Leghorn flocks, affecting about 1% of the chicken population before achievement of sexual maturity. Previously, a similar clinical syndrome has been reported as being caused by inflammatory demyelination of peripheral nerve fibres. Here, we investigated in detail the immunopathology of this paretic syndrome and its possible resemblance to human neuropathies. Methods Neurologically affected chickens and control animals from one single flock underwent clinical and neuropathological examination. Peripheral nervous system (PNS alterations were characterised using standard morphological techniques, including nerve fibre teasing and transmission electron microscopy. Infiltrating cells were phenotyped immunohistologically and quantified by flow cytometry. The cytokine expression pattern was assessed by quantitative real-time PCR (qRT-PCR. These investigations were accomplished by MHC genotyping and a PCR screen for Marek's disease virus (MDV. Results Spontaneous paresis of White Leghorns is caused by cell-mediated, inflammatory demyelination affecting multiple cranial and spinal nerves and nerve roots with a proximodistal tapering. Clinical manifestation coincides with the employment of humoral immune mechanisms, enrolling plasma cell recruitment, deposition of myelin-bound IgG and antibody-dependent macrophageal myelin-stripping. Disease development was significantly linked to a 539 bp microsatellite in MHC locus LEI0258. An aetiological role for MDV was excluded. Conclusions The paretic phase of avian inflammatory demyelinating polyradiculoneuritis immunobiologically resembles the late-acute disease stages of human acute inflammatory demyelinating polyneuropathy, and is characterised by a Th1-to-Th2 shift.

  15. Temporal and spatial variation of habitat conditions in the zonation of vegetation in the late stages of lake overgrowth

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    Stanisław Kłosowski

    2014-01-01

    Full Text Available The water and substrate properties in the vegetation zones characteristic of the late stages of lake overgrowth were determined. It was demonstrated that the spatial distribution of plant communities conformed with the spatial gradient of habitat conditions. With regard to water properties the largest differences between the zones were found in Mg2+, Ca2+, electrolytic conductivity and NH4+. In the case of substrate the zones differed significantly in Ca2+, total Fe and organic matter content. The water properties varied greatly during the vegetative season in the successive zones. The temporal changes often proceeded at a different level of a given component or factor in most zones. The differences between the zones were, however, maintained. It appears that the plant communities can alter their habitats to a large extent. In the lake studied, the invasion of raised and transitional bog vegetation was observed. The process of dystrophy proceeded from the terrestrialized peripheral parts of the lake to the centre of the lake.

  16. The Kepler Dichotomy in Planetary Disks: Linking Kepler Observables to Simulations of Late-stage Planet Formation

    Science.gov (United States)

    Moriarty, John; Ballard, Sarah

    2016-11-01

    NASA’s Kepler Mission uncovered a wealth of planetary systems, many with planets on short-period orbits. These short-period systems reside around 50% of Sun-like stars and are similarly prevalent around M dwarfs. Their formation and subsequent evolution is the subject of active debate. In this paper, we simulate late-stage, in situ planet formation across a grid of planetesimal disks with varying surface density profiles and total mass. We compare simulation results with observable characteristics of the Kepler sample. We identify mixture models with different primordial planetesimal disk properties that self-consistently recover the multiplicity, radius, period and period ratio, and duration ratio distributions of the Kepler planets. We draw three main conclusions. (1) We favor a “frozen-in” narrative for systems of short-period planets, in which they are stable over long timescales, as opposed to metastable. (2) The “Kepler dichotomy,” an observed phenomenon of the Kepler sample wherein the architectures of planetary systems appear to either vary significantly or have multiple modes, can naturally be explained by formation within planetesimal disks with varying surface density profiles. Finally, (3) we quantify the nature of the “Kepler dichotomy” for both GK stars and M dwarfs, and find that it varies with stellar type. While the mode of planet formation that accounts for high multiplicity systems occurs in 24% ± 7% of planetary systems orbiting GK stars, it occurs in 63% ± 16% of planetary systems orbiting M dwarfs.

  17. Distribution of elastic fibers in the head and neck: a histological study using late-stage human fetuses.

    Science.gov (United States)

    Kinoshita, Hideaki; Umezawa, Takashi; Omine, Yuya; Kasahara, Masaaki; Rodríguez-Vázquez, José Francisco; Murakami, Gen; Abe, Shinichi

    2013-03-01

    There is little or no information about the distribution of elastic fibers in the human fetal head. We examined this issue in 15 late-stage fetuses (crown-rump length, 220-320 mm) using aldehyde-fuchsin and elastica-Masson staining, and we used the arterial wall elastic laminae and external ear cartilages as positive staining controls. The posterior pharyngeal wall, as well as the ligaments connecting the laryngeal cartilages, contained abundant elastic fibers. In contrast with the sphenomandibular ligament and the temporomandibular joint disk, in which elastic fibers were partly present, the discomalleolar ligament and the fascial structures around the pterygoid muscles did not have any elastic fibers. In addition, the posterior marginal fascia of the prestyloid space did contain such fibers. Notably, in the middle ear, elastic fibers accumulated along the tendons of the tensor tympani and stapedius muscles and in the joint capsules of the ear ossicle articulations. Elastic fibers were not seen in any other muscle tendons or vertebral facet capsules in the head and neck. Despite being composed of smooth muscle, the orbitalis muscle did not contain any elastic fibers. The elastic fibers in the sphenomandibular ligament seemed to correspond to an intermediate step of development between Meckel's cartilage and the final ligament. Overall, there seemed to be a mini-version of elastic fiber distribution compared to that in adults and a different specific developmental pattern of connective tissues. The latter morphology might be a result of an adaptation to hypoxic conditions during development.

  18. The role of the amygdala during emotional processing in Huntington's disease: from pre-manifest to late stage disease.

    Science.gov (United States)

    Mason, Sarah L; Zhang, Jiaxiang; Begeti, Faye; Guzman, Natalie Valle; Lazar, Alpar S; Rowe, James B; Barker, Roger A; Hampshire, Adam

    2015-04-01

    Deficits in emotional processing can be detected in the pre-manifest stage of Huntington's disease and negative emotion recognition has been identified as a predictor of clinical diagnosis. The underlying neuropathological correlates of such deficits are typically established using correlative structural MRI studies. This approach does not take into consideration the impact of disruption to the complex interactions between multiple brain circuits on emotional processing. Therefore, exploration of the neural substrates of emotional processing in pre-manifest HD using fMRI connectivity analysis may be a useful way of evaluating the way brain regions interrelate in the period prior to diagnosis. We investigated the impact of predicted time to disease onset on brain activation when participants were exposed to pictures of faces with angry and neutral expressions, in 20 pre-manifest HD gene carriers and 23 healthy controls. On the basis of the results of this initial study went on to look at amygdala dependent cognitive performance in 79 Huntington's disease patients from a cross-section of disease stages (pre-manifest to late disease) and 26 healthy controls, using a validated theory of mind task: "the Reading the Mind in the Eyes Test" which has been previously been shown to be amygdala dependent. Psychophysiological interaction analysis identified reduced connectivity between the left amygdala and right fusiform facial area in pre-manifest HD gene carriers compared to controls when viewing angry compared to neutral faces. Change in PPI connectivity scores correlated with predicted time to disease onset (r=0.45, pneural networks underlying social cognition and emotional processing can be detected prior to clinical diagnosis in Huntington's disease. Connectivity between the amygdala and other brain regions is impacted by the disease process in pre-manifest HD and may therefore be a useful way of identifying participants who are approaching a clinical diagnosis

  19. Age-dependent role for Ras-GRF1 in the late stages of adult neurogenesis in the dentate gyrus.

    Science.gov (United States)

    Darcy, Michael J; Trouche, Stéphanie; Jin, Shan-Xue; Feig, Larry A

    2014-03-01

    The dentate gyrus of the hippocampus plays a pivotal role in pattern separation, a process required for the behavioral task of contextual discrimination. One unique feature of the dentate gyrus that contributes to pattern separation is adult neurogenesis, where newly born neurons play a distinct role in neuronal circuitry. Moreover,the function of neurogenesis in this brain region differs in adolescent and adult mice. The signaling mechanisms that differentially regulate the distinct steps of adult neurogenesis in adolescence and adulthood remain poorly understood. We used mice lacking RASGRF1(GRF1), a calcium-dependent exchange factor that regulates synaptic plasticity and participates in contextual discrimination performed by mice, to test whether GRF1 plays a role in adult neurogenesis.We show Grf1 knockout mice begin to display a defect in neurogenesis at the onset of adulthood (~2 months of age), when wild-type mice first acquire the ability to distinguish between closely related contexts. At this age, young hippocampal neurons in Grf1 knockout mice display severely reduced dendritic arborization. By 3 months of age, new neuron survival is also impaired. BrdU labeling of new neurons in 2-month-old Grf1 knockout mice shows they begin to display reduced survival between 2 and 3 weeks after birth, just as new neurons begin to develop complex dendritic morphology and transition into using glutamatergic excitatory input. Interestingly, GRF1 expression appears in new neurons at the developmental stage when GRF1 loss begins to effect neuronal function. In addition, we induced a similar loss of new hippocampal neurons by knocking down expression of GRF1 solely in new neurons by injecting retrovirus that express shRNA against GRF1 into the dentate gyrus. Together, these findings show that GRF1 expressed in new neurons promotes late stages of adult neurogenesis. Overall our findings show GRF1 to be an age-dependent regulator of adult hippocampal neurogenesis, which

  20. Principal component analysis of the Norwegian version of the quality of life in late-stage dementia scale.

    Science.gov (United States)

    Mjørud, Marit; Kirkevold, Marit; Røsvik, Janne; Engedal, Knut

    2014-01-01

    To investigate which factors the Quality of Life in Late-Stage Dementia (QUALID) scale holds when used among people with dementia (pwd) in nursing homes and to find out how the symptom load varies across the different severity levels of dementia. We included 661 pwd [mean age ± SD, 85.3 ± 8.6 years; 71.4% women]. The QUALID and the Clinical Dementia Rating (CDR) scale were applied. A principal component analysis (PCA) with varimax rotation and Kaiser normalization was applied to test the factor structure. Nonparametric analyses were applied to examine differences of symptom load across the three CDR groups. The mean QUALID score was 21.5 (±7.1), and the CDR scores of the three groups were 1 in 22.5%, 2 in 33.6% and 3 in 43.9%. The results of the statistical measures employed were the following: Crohnbach's α of QUALID, 0.74; Bartlett's test of sphericity, p Kaiser-Meyer-Olkin measure, 0.77. The PCA analysis resulted in three components accounting for 53% of the variance. The first component was 'tension' ('facial expression of discomfort', 'appears physically uncomfortable', 'verbalization suggests discomfort', 'being irritable and aggressive', 'appears calm', Crohnbach's α = 0.69), the second was 'well-being' ('smiles', 'enjoys eating', 'enjoys touching/being touched', 'enjoys social interaction', Crohnbach's α = 0.62) and the third was 'sadness' ('appears sad', 'cries', 'facial expression of discomfort', Crohnbach's α 0.65). The mean score on the components 'tension' and 'well-being' increased significantly with increasing severity levels of dementia. Three components of quality of life (qol) were identified. Qol decreased with increasing severity of dementia. © 2013 S. Karger AG, Basel.

  1. Immunization with 60 kD Ro peptide produces different stages of preclinical autoimmunity in a Sjögren's syndrome model among multiple strains of inbred mice.

    Science.gov (United States)

    Kurien, B T; Dsouza, A; Igoe, A; Lee, Y J; Maier-Moore, J S; Gordon, T; Jackson, M; Scofield, R H

    2013-07-01

    Sjögren's syndrome is a chronic illness manifested characteristically by immune injury to the salivary and lacrimal glands, resulting in dry mouth/eyes. Anti-Ro [Sjögren's syndrome antigen A (SSA)] and anti-La [Sjögren's syndrome antigen B (SSB)] autoantibodies are found frequently in Sjögren's subjects as well as in individuals who will go on to develop the disease. Immunization of BALB/c mice with Ro60 peptides results in epitope spreading with anti-Ro and anti-La along with lymphocyte infiltration of salivary glands similar to human Sjögren's. In addition, these animals have poor salivary function/low saliva volume. In this study, we examined whether Ro-peptide immunization produces a Sjögren's-like illness in other strains of mice. BALB/c, DBA-2, PL/J, SJL/J and C57BL/6 mice were immunized with Ro60 peptide-274. Sera from these mice were studied by immunoblot and enzyme-linked immunosorbent assay for autoantibodies. Timed salivary flow was determined after pharmacological stimulation, and salivary glands were examined pathologically. We found that SJL/J mice had no immune response to the peptide from Ro60, while C57BL/6 mice produced antibodies that bound the peptide but had no epitope spreading. PL/J mice had epitope spreading to other structures of Ro60 as well as to La, but like C57BL/6 and SJL/J had no salivary gland lymphocytic infiltration and no decrement of salivary function. DBA-2 and BALB/c mice had infiltration but only BALB/c had decreased salivary function. The immunological processes leading to a Sjögren's-like illness after Ro-peptide immunization were interrupted in a stepwise fashion in these differing mice strains. These data suggest that this is a model of preclinical disease with genetic control for epitope spreading, lymphocytic infiltration and glandular dysfunction. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

  2. Dynamics of natural rehabilitation of Cs 137 soil contamination at the late stage due to the Chernobyl NPP accident

    International Nuclear Information System (INIS)

    Germenchuk, M.G.; Zhukova, O.M.; Tretyakevich, S.S.; Koreniak, A.P.

    2006-01-01

    precipitation at a late stage after the Chernobyl accident is defined by radioactive disintegration of Cs 137, resulting 80% EDP decrease for 1993-2003. To assess an external irradiation dose of inhabitants of settlements which are in zone of radioactive contamination, it is possible to use a value of the transition factor, obtained by results of measurements on observation sites of a network of radiating monitoring NSEM, without making EDP measurement in every radioactive contamination zone settlements. (authors)

  3. Physicians' experiences of caring for late-stage HIV patients in the post-HAART era: challenges and adaptations.

    Science.gov (United States)

    Karasz, Alison; Dyche, Larry; Selwyn, Peter

    2003-11-01

    As medical treatment for AIDS has become more complex, the need for good palliative and end-of-life care has also increased for patients with advanced disease. Such care is often inadequate, especially among low-income, ethnic minority patients. The current study investigated physicians' experiences with caring for dying HIV patients in an underserved, inner city community in the Bronx, NY. The goals of the study included: (1) to investigate the barriers to effective end-of-life care for HIV patients; and (2) to examine physicians' experiences of role hindrance and frustration in caring for dying patients in the era of HAART. Qualitative, open-ended interviews were conducted with 16 physicians. Physicians identified two core, prescriptive myths shaping their care for patients with HIV. The 'Good Doctor Myth' equates good medical care with the delivery of efficacious biomedical care. The role of the physician is defined as technical curer, while the patient's role is limited to consultation and compliance. The 'Good Death Myth' envisions an ideal death which is acknowledged, organized, and pain free: the role of the physician is defined as that of comforter and supporter in the dying process. Role expectations associated with these myths were often disappointed. First, late-stage patients refused to adhere to treatment and were thus dying "unnecessarily." Second, patients often refused to acknowledge, accept, or plan for the end of life and as a result died painful, chaotic deaths. These realities presented intense psychological and practical challenges for providers. Adaptive coping included both behavioral and cognitive strategies. Successful adaptation resulted in "positive engagement," experienced by participants as a continuing sense of fascination, gratification, and joy. Less successful adaptation could result in detachment or anger. Participants believed that engagement had a powerful impact on patient care. Working with dying HIV patients in the post

  4. Older patients with late-stage COPD: Their illness experiences and involvement in decision-making regarding mechanical ventilation and noninvasive ventilation.

    Science.gov (United States)

    Jerpseth, Heidi; Dahl, Vegard; Nortvedt, Per; Halvorsen, Kristin

    2018-02-01

    To explore the illness experiences of older patients with late-stage chronic obstructive pulmonary disease and to develop knowledge about how patients perceive their preferences to be taken into account in decision-making processes concerning mechanical ventilation and/or noninvasive ventilation. Decisions about whether older patients with late-stage chronic obstructive pulmonary disease will benefit from noninvasive ventilation treatment or whether the time has come for palliative treatment are complicated, both medically and ethically. Knowledge regarding patients' values and preferences concerning ventilation support is crucial yet often lacking. Qualitative design with a hermeneutic-phenomenological approach. The data consist of qualitative in-depth interviews with 12 patients from Norway diagnosed with late-stage chronic obstructive pulmonary disease. The data were analysed within the three interpretative contexts described by Kvale and Brinkmann. The participants described their lives as fragile and burdensome, frequently interrupted by unpredictable and frightening exacerbations. They lacked information about their diagnosis and prognosis and were often not included in decisions about noninvasive ventilation or mechanical ventilation. Findings indicate that these patients are highly vulnerable and have complex needs in terms of nursing care and medical treatment. Moreover, they need access to proactive advanced care planning and an opportunity to discuss their wishes for treatment and care. To provide competent care for these patients, healthcare personnel must be aware of how patients experience being seriously ill. Advanced care planning and shared decision-making should be initiated alongside the curative treatment. © 2017 John Wiley & Sons Ltd.

  5. A cross-sectional study of inpatients with late stage of dementia in Southeast China and the associations between biochemical parameters and apolipoprotein E genotypes

    Directory of Open Access Journals (Sweden)

    Jiang B

    2018-01-01

    Full Text Available Bin Jiang,1,2,* Xue-Ping Zhang,3,* Mei-Fang Chen,3 Zheng Wang,3 Ming-Xue Zhao,3 Bin-Hua Chen,3 Hong-Lei Li1 1Department of Neurology and Research Center of Neurology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 2Department of Neurology, The First Affiliated Hospital of Xiamen University, Xiamen, 3The Seventh People’s Hospital of Hangzhou, Mental Health Center of Zhejiang University School of Medicine, Hangzhou, People’s Republic of China *These authors contributed equally to this work Background: The purpose of this study was to analyze the disease distribution of patients in the late stage of dementia through a cross-sectional investigation and to clarify the association between apolipoprotein E (APOE genotypes and the serum levels of total cholesterol, total triglycerides, and blood glucose in the late-stage Alzheimer’s disease (AD patients.Methods: Patients who were in the late stage of dementia in a mental health center were enrolled in this study. A broad battery of neuropsychological tests and neuroimaging was applied to make the diagnosis. The APOE genotype was determined by the multiplex amplification refractory mutation system polymerase chain reaction. The association between APOE genotype and the blood level of biochemical parameters was studied.Results: A total of 155 patients were enrolled in this study. The majority of patients had AD (67.8%, followed by vascular dementia (15.5%, mixed dementia (9%, and others (7.7%. The APOE ε4 allele frequency was significantly different in the different groups. The serum level of total cholesterol (TC in APOE ε4 carriers was higher than in non-carriers (P<0.05. No statistically significant differences were found in the blood glucose and triglycerides (TG levels between these two groups.Conclusion: To our knowledge, this is the first paper to study the characteristics of late-stage dementia in hospital patients in Southeast China. We found that the

  6. Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology

    International Nuclear Information System (INIS)

    Wendel, Marco; Kolatkar, Anand; Honnatti, Meghana; Cho, Edward H; Marrinucci, Dena; Kuhn, Peter

    2012-01-01

    Circulating tumor cell (CTC) counts are an established prognostic marker in metastatic prostate, breast and colorectal cancer, and recent data suggest a similar role in late stage non-small cell lung cancer (NSCLC). However, due to sensitivity constraints in current enrichment-based CTC detection technologies, there are few published data about CTC prevalence rates and morphologic heterogeneity in early-stage NSCLC, or the correlation of CTCs with disease progression and their usability for clinical staging. We investigated CTC counts, morphology and aggregation in early stage, locally advanced and metastatic NSCLC patients by using a fluid-phase biopsy approach that identifies CTCs without relying on surface-receptor-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. HD-CTCs were analyzed in blood samples from 78 chemotherapy-naïve NSCLC patients. 73% of the total population had a positive HD-CTC count (>0 CTC in 1 mL of blood) with a median of 4.4 HD-CTCs mL −1 (range 0–515.6) and a mean of 44.7 (±95.2) HD-CTCs mL −1 . No significant difference in the medians of HD-CTC counts was detected between stage IV (n = 31, range 0–178.2), stage III (n = 34, range 0–515.6) and stages I/II (n = 13, range 0–442.3). Furthermore, HD-CTCs exhibited a uniformity in terms of molecular and physical characteristics such as fluorescent cytokeratin intensity, nuclear size, frequency of apoptosis and aggregate formation across the spectrum of staging. Our results demonstrate that despite stringent morphologic inclusion criteria for the definition of HD-CTCs, the HD-CTC assay shows high sensitivity in the detection and characterization of both early- and late-stage lung cancer CTCs. Extensive studies are warranted to investigate the prognostic value of CTC profiling in early-stage lung cancer. This finding has implications for the design of extensive studies examining screening, therapy and

  7. Transcriptomic analysis of the late stages of grapevine (Vitis vinifera cv. Cabernet Sauvignon) berry ripening reveals significant induction of ethylene signaling and flavor pathways in the skin.

    Science.gov (United States)

    Cramer, Grant R; Ghan, Ryan; Schlauch, Karen A; Tillett, Richard L; Heymann, Hildegarde; Ferrarini, Alberto; Delledonne, Massimo; Zenoni, Sara; Fasoli, Marianna; Pezzotti, Mario

    2014-12-19

    Grapevine berry, a nonclimacteric fruit, has three developmental stages; the last one is when berry color and sugar increase. Flavors derived from terpenoid and fatty acid metabolism develop at the very end of this ripening stage. The transcriptomic response of pulp and skin of Cabernet Sauvignon berries in the late stages of ripening between 22 and 37 °Brix was assessed using whole-genome micorarrays. The transcript abundance of approximately 18,000 genes changed with °Brix and tissue type. There were a large number of changes in many gene ontology (GO) categories involving metabolism, signaling and abiotic stress. GO categories reflecting tissue differences were overrepresented in photosynthesis, isoprenoid metabolism and pigment biosynthesis. Detailed analysis of the interaction of the skin and pulp with °Brix revealed that there were statistically significantly higher abundances of transcripts changing with °Brix in the skin that were involved in ethylene signaling, isoprenoid and fatty acid metabolism. Many transcripts were peaking around known optimal fruit stages for flavor production. The transcript abundance of approximately two-thirds of the AP2/ERF superfamily of transcription factors changed during these developmental stages. The transcript abundance of a unique clade of ERF6-type transcription factors had the largest changes in the skin and clustered with genes involved in ethylene, senescence, and fruit flavor production including ACC oxidase, terpene synthases, and lipoxygenases. The transcript abundance of important transcription factors involved in fruit ripening was also higher in the skin. A detailed analysis of the transcriptome dynamics during late stages of ripening of grapevine berries revealed that these berries went through massive transcriptional changes in gene ontology categories involving chemical signaling and metabolism in both the pulp and skin, particularly in the skin. Changes in the transcript abundance of genes involved in

  8. The Role of Neighborhood Characteristics in Late Stage Melanoma Diagnosis among Hispanic Men in California, Texas, and Florida, 1996–2012

    Directory of Open Access Journals (Sweden)

    Valerie M. Harvey

    2017-01-01

    Full Text Available Background. Hispanics diagnosed with cutaneous melanoma are more likely to present at advanced stages but the reasons for this are unknown. We identify census tracts at high risk for late stage melanoma diagnosis (LSMD and examine the contextual predictors of LSMD in California, Texas, and Florida. Methods. We conducted a cross-sectional study using geocoded state cancer registry data. Using hierarchical multilevel logistic regression models we estimated ORs and 95% confidence intervals for the impact of socioeconomic, Hispanic ethnic concentration, index of dissimilarity, and health resource availability measures on LSMD. Results. We identified 12,493 cases. In California, late stage cases were significantly more likely to reside within census tracts composed mostly of Hispanics and immigrants. In Texas, LSMD was associated with residence in areas of socioeconomic deprivation and a higher proportion of immigrants. In Florida, living in areas of low education attainment, high levels of poverty, and a high percentage of Hispanic residents was significantly associated with LSMD. Residential segregation did not independently affect LSMD. Conclusion. The influence of contextual predictors on LSMD varied in magnitude and strength by state, highlighting both the cosegregation of social adversity and poverty and the complexity of their interactions.

  9. Intake of key micronutrients and food groups in patients with late-stage age-related macular degeneration compared with age-sex-matched controls.

    Science.gov (United States)

    Gopinath, Bamini; Liew, Gerald; Russell, Joanna; Cosatto, Victoria; Burlutsky, George; Mitchell, Paul

    2017-08-01

    Knowledge of the risk factor profile of patients presenting with late-stage age-related macular degeneration (AMD) could help identify the most frequent modifiable AMD precursors among people who are referred for treatment. We aimed to assess dietary behaviours by comparing adjusted mean intakes of micronutrients and major food groups (fruits, vegetables, fish) among patients with AMD and a sample of age-sex-matched controls. Cross-sectional analysis of 480 late AMD cases and 518 population-based age-sex-matched controls with no AMD signs. AMD cases (aged 60+ years) were those presenting for treatment to a hospital eye clinic in Sydney, Australia, during 2012-2015. The comparator group were obtained from a cohort study (Blue Mountains Eye Study; Sydney, Australia) during 2002-2009. Dietary intake was assessed using a semiquantitative food-frequency questionnaire. AMD lesions were assessed from retinal photographs. After multivariable adjustment, patients with late-stage AMD compared with controls had significantly lower intakes of vitamin E (7.4 vs 9.8 mg/day; p<0.0001), beta-carotene (6232 vs 7738 μg/day; p<0.0001), vitamin C (161 vs 184 mg/day; p=0.0002) and folate (498.3 vs 602 μg/day; p<0.0001); but had higher intakes of zinc (13.0 vs 11.9 mg/day; p<0.0001). A significantly lower proportion of patients with late AMD met the recommended intake of vegetables than controls: 52.9% versus 64.5%; p=0.0002. This study showed significant differences in intakes of vitamins C and E, beta-carotene, folate and vegetables between patients with late-stage AMD and healthy controls, and thus has provided a better understanding of the nutritional intake of patients presenting with advanced AMD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  10. Correlation of Ventricular Arrhythmogenesis with Neuronal Remodeling of Cardiac Postganglionic Parasympathetic Neurons in the Late Stage of Heart Failure after Myocardial Infarction.

    Science.gov (United States)

    Zhang, Dongze; Tu, Huiyin; Wang, Chaojun; Cao, Liang; Muelleman, Robert L; Wadman, Michael C; Li, Yu-Long

    2017-01-01

    Introduction: Ventricular arrhythmia is a major cause of sudden cardiac death in patients with chronic heart failure (CHF). Our recent study demonstrates that N-type Ca 2+ currents in intracardiac ganglionic neurons are reduced in the late stage of CHF rats. Rat intracardiac ganglia are divided into the atrioventricular ganglion (AVG) and sinoatrial ganglion. Only AVG nerve terminals innervate the ventricular myocardium. In this study, we tested the correlation of electrical remodeling in AVG neurons with ventricular arrhythmogenesis in CHF rats. Methods and Results: CHF was induced in male Sprague-Dawley rats by surgical ligation of the left coronary artery. The data from 24-h continuous radiotelemetry ECG recording in conscious rats showed that ventricular tachycardia/fibrillation (VT/VF) occurred in 3 and 14-week CHF rats but not 8-week CHF rats. Additionally, as an index for vagal control of ventricular function, changes of left ventricular systolic pressure (LVSP) and the maximum rate of left ventricular pressure rise (LV dP/dt max ) in response to vagal efferent nerve stimulation were blunted in 14-week CHF rats but not 3 or 8-week CHF rats. Results from whole-cell patch clamp recording demonstrated that N-type Ca 2+ currents in AVG neurons began to decrease in 8-week CHF rats, and that there was also a significant decrease in 14-week CHF rats. Correlation analysis revealed that N-type Ca 2+ currents in AVG neurons negatively correlated with the cumulative duration of VT/VF in 14-week CHF rats, whereas there was no correlation between N-type Ca 2+ currents in AVG neurons and the cumulative duration of VT/VF in 3-week CHF. Conclusion: Malignant ventricular arrhythmias mainly occur in the early and late stages of CHF. Electrical remodeling of AVG neurons highly correlates with the occurrence of ventricular arrhythmias in the late stage of CHF.

  11. Reducing by half the percentage of late-stage presentation for breast and cervix cancer over 4 years: a pilot study of clinical downstaging in Sarawak, Malaysia.

    Science.gov (United States)

    Devi, B C R; Tang, T S; Corbex, M

    2007-07-01

    The registry of the Oncology Departmental in Sarawak General Hospital showed that 79% of nasopharyngeal, 77% of breast and 70% of cervix cancer patients were diagnosed at an advanced stage (stages III and IV) for year 1993. Hence, a low cost Early Cancer Surveillance Program was started in 1994, with the intent of downstaging these three most common cancers in Sarawak. The program consisted of (i) training health staff in hospital and rural clinics to improve their skills in early cancer detection, (ii) raising public awareness through pamphlets, posters and sensitization by health staff. Data analysis revealed that the program achieved downstaging in two of the cancers. Breast cancer in stage III and IV was reduced from 60% (1994) to 35% (1998) (P < 0.0001) and cervical cancer in stage III and IV from 60% (1994) to 26% (1998) (P < 0.0001). No reduction was observed for nasopharyngeal cancer at 88% (1994) to 91% (1998). The overall cost of this program was late stage (III and IV) where screening programs meet important difficulties. Our data analyses revealed important shortcomings in the PAP smear screening program where inadequate groups of women were screened. It resulted in a pick up rate of only 5% of the cases. This finding confirmed the need for the simple and complementary downstaging approach.

  12. Late-stage, primary open-angle glaucoma in Europe: social and health care maintenance costs and quality of life of patients from 4 countries

    DEFF Research Database (Denmark)

    Thygesen, J.; Aagren, M.; Arnavielle, S.

    2008-01-01

    OBJECTIVE: The purpose of this study was to estimate costs and quality of life (QoL) of late-stage glaucoma patients in 4 European countries. METHODS: Retrospective review of medical charts of patients with POAG who were followed in a low-vision or vision rehabilitation center in one of 4 countries......) and use of resources including: the number of visits to rehabilitation centers, visits to hospital and non-hospital specialists, the use of low-vision devices, medication, tests, and the use of hired home help. The costs associated with resource use were calculated from the perspective of a third...

  13. Replay of conditioned stimuli during late REM and stage N2 sleep influences affective tone rather than emotional memory strength.

    Science.gov (United States)

    Rihm, Julia S; Rasch, Björn

    2015-07-01

    Emotional memories are reprocessed during sleep, and it is widely assumed that this reprocessing occurs mainly during rapid eye movement (REM) sleep. In support for this notion, vivid emotional dreams occur mainly during REM sleep, and several studies have reported emotional memory enhancement to be associated with REM sleep or REM sleep-related parameters. However, it is still unknown whether reactivation of emotional memories during REM sleep strengthens emotional memories. Here, we tested whether re-presentation of emotionally learned stimuli during REM sleep enhances emotional memory. In a split-night design, participants underwent Pavlovian conditioning after the first half of the night. Neutral sounds served as conditioned stimuli (CS) and were either paired with a negative odor (CS+) or an odorless vehicle (CS-). During sound replay in subsequent late REM or N2 sleep, half of the CS+ and half of the CS- were presented again. In contrast to our hypothesis, replay during sleep did not affect emotional memory as measured by the differentiation between CS+ and CS- in expectancy, arousal and valence ratings. However, replay unspecifically decreased subjective arousal ratings of both emotional and neutral sounds and increased positive valence ratings also for both CS+ and CS- sounds, respectively. These effects were slightly more pronounced for replay during REM sleep. Our results suggest that re-exposure to previously conditioned stimuli during late sleep does not affect emotional memory strength, but rather influences the affective tone of both emotional and neutral memories. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Potts shunt in a child with end-stage pulmonary hypertension after late repair of ventricular septal defect

    DEFF Research Database (Denmark)

    Petersen, Cecilie; Helvind, Morten; Jensen, Tim

    2013-01-01

    We report on a 10-year-old boy with medically refractory pulmonary arterial hypertension (PAH) and end-stage right heart failure after closure of a ventricular septal defect. The boy was a candidate for lung transplantation (LTX), but an alternative option was to create an Eisenmenger physiology ...

  15. Sulforaphene in Raphanus sativus L. var. caudatus Alef increased in late-bolting stage as well as anticancer activity

    Directory of Open Access Journals (Sweden)

    Piman Pocasap

    2017-11-01

    Conclusions: The reproductive parts (flower, pod, and dry seed of Raphanus sativus have the greatest isothiocyanate concentration, evidenced by a sulforaphene concentration higher than the sulforaphane. This result should inform the selection of the most appropriate harvesting stage and plant part for use as a potential chemopreventive agent.

  16. Neural-Dural Transition at the Thoracic and Lumbar Spinal Nerve Roots: A Histological Study of Human Late-Stage Fetuses

    Directory of Open Access Journals (Sweden)

    Kwang Ho Cho

    2016-01-01

    Full Text Available Epidural blocks have been used extensively in infants. However, little histological information is available on the immature neural-dural transition. The neural-dural transition was histologically investigated in 12 late-stage (28–30 weeks fetuses. The dural sheath of the spinal cord was observed to always continue along the nerve roots with varying thicknesses between specimens and segments, while the dorsal root ganglion sheath was usually very thin or unclear. Immature neural-dural transitions were associated with effective anesthesia. The posterior radicular artery was near the dorsal root ganglion and/or embedded in the nerve root, whereas the anterior radicular artery was separated from the nearest nerve root. The anterior radicular artery was not associated with the dural sheath but with thin mesenchymal tissue. The numbers of radicular arteries tended to become smaller in larger specimens. Likewise, larger specimens of the upper thoracic and lower lumbar segments did not show the artery. Therefore, elimination of the radicular arteries to form a single artery of Adamkiewicz was occurring in late-stage fetuses. The epidural space was filled with veins, and the loose tissue space extended ventrolaterally to the subpleural tissue between the ribs. Consequently, epidural blocks in infants require special attention although immature neural-dural transitions seemed to increase the effect.

  17. Distribution of Cathepsin K in Late Stage of Tooth Germ Development and Its Function in Degrading Enamel Matrix Proteins in Mouse.

    Directory of Open Access Journals (Sweden)

    Tao Jiang

    Full Text Available Cathepsin K (CTSK is a member of cysteine proteinase family, and is predominantly expressed in osteoclastsfor degradationof bone matrix proteins. Given the similarity in physical properties of bone and dental mineralized tissues, including enamel, dentin and cementum, CTSK is likely to take part in mineralization process during odontogenesis. On the other hand, patients with pycnodysostosis caused by mutations of the CTSK gene displayedmultipledental abnormalities, such as hypoplasia of the enamel, obliterated pulp chambers, hypercementosis and periodontal disease. Thereforeitis necessary to study the metabolic role of CTSK in tooth matrix proteins. In this study, BALB/c mice at embryonic day 18 (E18, post-natal day 1 (P1, P5, P10 and P20 were used (5 mice at each time pointfor systematic analyses of CTSK expression in the late stage of tooth germ development. We found that CTSK was abundantly expressed in the ameloblasts during secretory and maturation stages (P5 and P10 by immunohistochemistry stainings.During dentinogenesis, the staining was also intense in the mineralization stage (P5 and P10,but not detectable in the early stage of dentin formation (P1 and after tooth eruption (P20.Furthermore, through zymography and digestion test in vitro, CTSK was proved to be capable of hydrolyzing Emdogain and also cleaving Amelogenininto multiple products. Our resultsshed lights on revealing new functions of CTSK and pathogenesis of pycnodysostosis in oral tissues.

  18. Gamma ray heating rates due to chromium isotopes in stellar core during late stages of high mass stars (>10M⊙

    Directory of Open Access Journals (Sweden)

    Nabi Jameel-Un

    2017-01-01

    Full Text Available Gamma ray heating rates are thought to play a crucial role during the pre-supernova stage of high mass stars. Gamma ray heating rates, due to β±-decay and electron (positron capture on chromium isotopes, are calculated using proton-neutron quasiparticle random phase approximation theory. The electron capture significantly affects the lepton fraction (Ye and accelerates the core contraction. The gamma rays emitted as a result of weak processes heat the core and tend to hinder the cooling and contraction due to electron capture and neutrino emission. The emitted gamma rays tend to produce enormous entropy and set the convection to play its role at this stage. The gamma heating rates, on 50-60Cr, are calculated for the density range 10 < ρ (g.cm-3 < 1011 and temperature range 107 < T (K < 3.0×1010.

  19. Decoupling of stream and vegetation solutes during the late stages of weathering: insights from elemental and Mg isotope trends at the Luquillo Critical Zone Observatory, Puerto Rico

    Science.gov (United States)

    Chapela Lara, M.; Schuessler, J. A.; Buss, H. L.; McDowell, W. H.

    2017-12-01

    During the evolution of the critical zone, the predominant source of nutrients to the vegetation changes from bedrock weathering to atmospheric inputs and biological recycling. In parallel, the architecture of the critical zone changes with time, promoting a change in water flow regime from near-surface porous flow during early weathering stages to more complex flow regimes modulated by clay-rich regolith during the late stages of weathering. As a consequence of these two concurrent processes, we can expect the predominant sources and pathways of solutes to the streams to also change during critical zone evolution. If this is true, we would observe a decoupling between the solutes used by the vegetation and those that determine the composition of the streams during the late stages of weathering, represented by geomorphically stable tropical settings. To test these hypotheses, we are analyzing the elemental and Mg isotopic composition of regolith and streams at the humid tropical Luquillo Critical Zone Observatory. We aim to trace the relative contributions of the surficial, biologically mediated pathways and the deeper, weathering controlled nutrient pathways. We also investigate the role of lithology on the solute decoupling between the vegetation and the stream, by examining two similar headwater catchments draining two different bedrocks (andesitic volcaniclastic and granitic). Our preliminary elemental and Mg isotope results are consistent with atmospheric inputs in the upper 2 m of regolith in both lithologies and with bedrock weathering at depth. During a short storm event ( 6 h), a headwater stream draining volcaniclastic bedrock showed a large variation in Mg and δ26Mg, correlated with total suspended solids, while another similar headwater granitic stream showed a much narrower variation. A larger stream draining volcaniclastic bedrock showed changes in Mg concentration in response to rain during the same storm event, but did not change in δ26Mg

  20. Glial alterations from early to late stages in a model of Alzheimer's disease: Evidence of autophagy involvement in Aβ internalization.

    Science.gov (United States)

    Pomilio, Carlos; Pavia, Patricio; Gorojod, Roxana Mayra; Vinuesa, Angeles; Alaimo, Agustina; Galvan, Veronica; Kotler, Monica Lidia; Beauquis, Juan; Saravia, Flavia

    2016-02-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease without effective therapy. Brain amyloid deposits are classical histopathological hallmarks that generate an inflammatory reaction affecting neuronal and glial function. The identification of early cell responses and of brain areas involved could help to design new successful treatments. Hence, we studied early alterations of hippocampal glia and their progression during the neuropathology in PDAPP-J20 transgenic mice, AD model, at 3, 9, and 15 months (m) of age. At 3 m, before deposits formation, microglial Iba1+ cells from transgenic mice already exhibited signs of activation and larger soma size in the hilus, alterations appearing later on stratum radiatum. Iba1 immunohistochemistry revealed increased cell density and immunoreactive area in PDAPP mice from 9 m onward selectively in the hilus, in coincidence with prominent amyloid Congo red + deposition. At pre-plaque stages, GFAP+ astroglia showed density alterations while, at an advanced age, the presence of deposits was associated with important glial volume changes and apparently being intimately involved in amyloid degradation. Astrocytes around plaques were strongly labeled for LC3 until 15 m in Tg mice, suggestive of increased autophagic flux. Moreover, β-Amyloid fibrils internalization by astrocytes in in vitro conditions was dependent on autophagy. Co-localization of Iba1 with ubiquitin or p62 was exclusively found in microglia contacting deposits from 9 m onward, suggesting torpid autophagy. Our work characterizes glial changes at early stages of the disease in PDAPP-J20 mice, focusing on the hilus as an especially susceptible hippocampal subfield, and provides evidence that glial autophagy could play a role in amyloid processing at advanced stages. © 2015 Wiley Periodicals, Inc.

  1. Accuracy of repeated measurements of late-night salivary cortisol to screen for early-stage recurrence of Cushing's disease following pituitary surgery.

    Science.gov (United States)

    Danet-Lamasou, Marie; Asselineau, Julien; Perez, Paul; Vivot, Alexandre; Nunes, Marie-Laure; Loiseau, Hugues; San-Galli, François; Cherifi-Gatta, Blandine; Corcuff, Jean-Benoît; Tabarin, Antoine

    2015-02-01

    The performance of late-night salivary cortisol (LNSC) to accurately screen for postoperative recurrence of Cushing's disease (CD) at an early stage is unknown. The aim of this study was to compare the accuracy of multiple sampling strategies to suggest the optimal number of LNSC samples needed for diagnosing post-surgical recurrences of CD at an early stage. Retrospective analysis in a single centre. Thirty-six patients in surgical remission of CD had successive measurements of LNSC, defined as 'sequences', using a locally modified RIA assay as part of long-term follow-up (69·2 ± 10·6 months). Patients underwent an extensive biochemical evaluation within 3 months before or after a sequence of saliva sampling and were classified as being in remission or in early-stage recurrence. The accuracy of three diagnostic strategies combining two, three or four LNSC results from a sequence was estimated using areas under the ROC curves (AUC), sensitivity, specificity and predictive values. Forty-four sequences of LNSC measurements were available. Fifty-two percent of sequences were performed during early-stage recurrence. The intrasequence variability of LNSC was higher during recurrence than during remission (medians of SDs: 2·1 vs 0·5 nm; P recurrence of CD. However, due to a major within-patient variability of LNSC from 1 day to another, a screening strategy using three or four samples collected on successive days may be recommended to detect early-stage recurrence of CD with a high accuracy. © 2014 John Wiley & Sons Ltd.

  2. Rates of oxygen uptake increase independently of changes in heart rate in late stages of development and at hatching in the green iguana, Iguana iguana.

    Science.gov (United States)

    Sartori, Marina R; Abe, Augusto S; Crossley, Dane A; Taylor, Edwin W

    2017-03-01

    Oxygen consumption (VO 2 ), heart rate (f H ), heart mass (M h ) and body mass (M b ) were measured during embryonic incubation and in hatchlings of green iguana (Iguana iguana). Mean f H and VO 2 were unvarying in early stage embryos. VO 2 increased exponentially during the later stages of embryonic development, doubling by the end of incubation, while f H was constant, resulting in a 2.7-fold increase in oxygen pulse. Compared to late stage embryos, the mean inactive level of VO 2 in hatchlings was 1.7 fold higher, while f H was reduced by half resulting in a further 3.6 fold increase in oxygen pulse. There was an overall negative correlation between mean f H and VO 2 when data from hatchlings was included. Thus, predicting metabolic rate as VO 2 from measurements of f H is not possible in embryonic reptiles. Convective transport of oxygen to supply metabolism during embryonic incubation was more reliably indicated as an index of cardiac output (CO i ) derived from the product of f H and M h . However, a thorough analysis of factors determining rates of oxygen supply during development and eclosion in reptiles will require cannulation of blood vessels that proved impossible in the present study, to determine oxygen carrying capacity by the blood and arteriovenous oxygen content difference (A-V diff), plus patterns of blood flow. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Impact of TBI on late effects in children treated by megatherapy for Stage IV neuroblastoma. A study of the French Society of Pediatric oncology

    International Nuclear Information System (INIS)

    Flandin, Isabelle; Hartmann, Olivier; Michon, Jean; Pinkerton, Ross; Coze, Carole; Stephan, Jean Louis; Fourquet, Bernard; Valteau-Couanet, Dominique; Bergeron, Christophe; Philip, Thierry; Carrie, Christian

    2006-01-01

    Purpose: To determine the contribution of total body irradiation (TBI) to late sequelae in children treated with high-dose chemotherapy and autologous bone marrow transplantation for Stage IV neuroblastoma. Patients and Methods: We compared two populations that were similar with regard to age, stage, pre-autologous bone marrow transplantation chemotherapy (CT) regimen, period of treatment, and follow-up (12 years). The TBI group (n = 32) received TBI as part of the megatherapy procedure (1982-1993), whereas the CT group (n 30) received conditioning without TBI (1985-1992). Analysis 12 years later focused on growth, weight and corpulence (body mass index) delay; hormonal deficiencies; liver, kidney, heart, ear, eye, and dental sequelae; school performance; and the incidence of secondary tumors. Results: Impact of TBI was most marked in relation to growth and weight delay, although the mean delay was not severe, probably because of treatment with growth hormones. Other consequences of TBI were thyroid insufficiency, cataracts, and a high incidence of secondary tumors. Hearing loss and dental agenesis were more prominent in the group treated with CT alone. No differences were observed in school performance. Conclusion: The most frequent side effects of TBI were cataracts, thyroid insufficiency, and growth delay, but more worrying is the risk of secondary tumors. Because of the young mean age of patients and the toxicity of TBI regimens without any survival advantage, regimens without TBI are preferable in the management of Stage IV neuroblastoma

  4. Late-stage anhydrite-gypsum-siderite-dolomite-calcite assemblages record the transition from a deep to a shallow hydrothermal system in the Schwarzwald mining district, SW Germany

    Science.gov (United States)

    Burisch, Mathias; Walter, Benjamin F.; Gerdes, Axel; Lanz, Maximilian; Markl, Gregor

    2018-02-01

    The majority of hydrothermal vein systems of economic interest occur at relatively shallow crustal levels, although many of them formed at significantly greater depths. Their present position is a consequence of uplift and erosion. Although, many aspects of their formation are well constrained, the temporal chemical evolution of such systems during uplift and erosion is still poorly understood. These vein minerals comprise calcite, dolomite-ankerite, siderite-magnesite, anhydrite and gypsum forming the last gangue assemblages in Jurassic and Tertiary sulphide-fluorite-quartz-barite veins of the Schwarzwald mining district, SW Germany. Mineral textures of samples from nine localities reveal that in these sequences, mineral precipitation follows a recurring pattern: early calcite is followed by anhydrite or gypsum, siderite and/or dolomite. This succession may repeat up to three times. In-situ (LA-ICP-MS) U-Pb age dating of 15 carbonates from three subsequent generations of the late-stage vein assemblage yield robust ages between 20 and 0.6 Ma. Each mineral sequence forms in a distinctive period of about 2-5 Ma. These ages clearly relate these late-stage mineral phases to the youngest geological episode of the Schwarzwald, which is associated with the Cenozoic Rhine Graben rifting and basement uplift. Based on thermodynamic modelling, the formation of the observed mineral assemblages required an deeply sourced Mg-, Fe- and SO4-rich fluid (b), which was episodically mixed with a shallow crustal HCO3-rich fluid (a). As a consequence of fluid mixing, concentrations of Mg, Fe and SO4 temporarily increased and initiated the formation of the observed sulphate-carbonate mineral sequences. This discontinuous large-scale vertical fluid mixing was presumably directly related to episodes of active tectonics associated with the Cenozoic strike-slip regime of the Upper Rhine Graben. Analogously, episodic fluid mixing is a major key in the formation of older (Jurassic to early

  5. Preface [11. Pacific Rim conference on stellar astrophysics: Physics and chemistry of the late stages of stellar evolution, Hong Kong (China), 14-17 December 2015

    International Nuclear Information System (INIS)

    Kwok, Sun; Leung, Kam Ching

    2016-01-01

    Stellar mass loss is now widely recognized to have a significant impact on stellar evolution. Mass loss on the asymptotic giant branch (AGB) allows stars with initial masses under 8 solar masses to avoid the fate of going supernovae. Over 95% of stars in our Galaxy will evolve through the planetary nebulae phase to end up as white dwarfs instead of neutron stars or black holes. Massive stars undergo mass loss both in the blue and red phases of evolution and create new classes of stars such as Wolf-Rayet stars and luminous blue variables. The circumstellar matter ejected by these mass loss processes becomes new laboratories to study the physical and chemical processes of interstellar matter. The interaction between different phases of mass loss (with variable mass loss rates, ejection speeds, and directions) leads to spectacular morphological transformation of the circumstellar nebulae. The circumstellar nebulae are also sites of molecular and solid-state synthesis. Close to 100 molecular species and a variety of solids, including minerals and complex organics, have been detected in circumstellar envelopes. Since the dynamical time scale of the ejection puts an upper limit on the chemical time scale, we are witnessing a rapid synthesis of chemical species in an extremely low-density environment, creating new challenges to our understanding of chemical reactions. Effects of mass loss are not limited to single stars. Mass loss by one component of a binary system allows mass transfer to occur at separations beyond the Roche Lobe limit. Accreted wind materials on the surface of a degenerate star can lead to periodic outbursts through H-shell burning. When both components are losing mass, we have interesting dynamical systems such as symbiotic novae. The theme of this conference is “Physics and Chemistry of the Late Stages of Stellar Evolution”. We try to bring together experts in different fields to exchange ideas in the hope of solving the many unsolved problems in

  6. Forecasting cracked collectors on anticlinal type structures at late stage of exploration in oil and gas area

    Science.gov (United States)

    Hasanov, M. A.; Aleksandrov, B. L.; Eljayev, A. S.; Ezirbaev, T. B.; Gatsaeva, S. S.

    2017-10-01

    The possibility of using complex information on morphological parameters of structures, block porosity and the reservoir pressure gradient over previously explored deposits for the development of a multidimensional equation for estimating secondary porosity is considered. This is examined by the example of reservoirs with secondary (fractured) porosity of the Upper Cretaceous carbonate deposits of the Tersko-Sunzhenskaya oil and gas bearing region of the Ciscaucasia. The use of this equation makes it possible to predict the magnitude of the secondary porosity on the anticlinal structures, which are newly discovered by seismic methods at a later stage of exploration in the relevant oil and gas region, as a quantitative criterion that predicts the presence of a trap.

  7. Bovine lactoferricin B induces apoptosis of human gastric cancer cell line AGS by inhibition of autophagy at a late stage.

    Science.gov (United States)

    Pan, W-R; Chen, P-W; Chen, Y-L S; Hsu, H-C; Lin, C-C; Chen, W-J

    2013-01-01

    Gastric cancer is one of the most common malignant cancers, with poor prognosis and high mortality rates worldwide. Therefore, development of an effective therapeutic method without side effects is an urgent need. It has been reported that cationic antimicrobial peptides can selectively bind to negatively charged prokaryotic and cancer cell membranes and exert cytotoxicity without causing severe drug resistance. In the current study, we prepared a series of peptide fragments derived from bovine lactoferrin and evaluated their anticancer potency toward the gastric cancer cell line AGS. Cell viability assay revealed that a 25-AA peptide fragment, lactoferricin B25 (LFcinB25), exhibited the most potent anticancer capability against AGS cells. Lactoferricin B25 selectively inhibited AGS cell growth in a dose-dependent manner, exhibiting a half-maximal inhibitory concentration (IC50) value of 64 μM. Flow cytometry showed a notable increment of the sub-G1 populations of the cell cycle, indicating the induction of apoptosis by LFcinB25. Western blot analysis further revealed that upon LFcinB25 treatment for 2 to 6h, apoptosis-related caspases-3, 7, 8, 9, and poly(ADP-ribose) polymerase (PARP) were cleaved and activated, whereas autophagy-related LC3-II and beclin-1 were concomitantly increased. Thus, both apoptosis and autophagy are involved in the early stage of LFcinB25-induced cell death of AGS cells. However, upon treatment with LFcinB25 for 12 to 24h, LC3-II began to decrease, whereas cleaved beclin-1 increased in a time-dependent manner, suggesting that consecutive activation of caspases cleaved beclin-1 to inhibit autophagy, thus enhancing apoptosis at the final stage. These findings provide support for future application of LFcinB25 as a potential therapeutic agent for gastric cancer. Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  8. Nurses' role and care practices in decision-making regarding artificial ventilation in late stage pulmonary disease.

    Science.gov (United States)

    Jerpseth, Heidi; Dahl, Vegard; Nortvedt, Per; Halvorsen, Kristin

    2017-11-01

    Decisions regarding whether or not to institute mechanical ventilation during the later stages of chronic obstructive pulmonary disease is challenging both ethically, emotionally and medically. Caring for these patients is a multifaceted process where nurses play a crucial role. Research question and design: We have investigated how nurses experienced their own role in decision-making processes regarding mechanical ventilation in later stages of chronic obstructive pulmonary disease and how they consider the patients' role in these processes. We applied a qualitative approach, with six focus-group interviews of nurses (n = 26). Ethical considerations: The Regional Committees for Medical and Health Research Ethics approved the study. Voluntary informed consent was obtained. The nurses found themselves operating within a cure-directed treatment culture wherein they were unable to stand up for the caring values. They perceived their roles and responsibilities in decision-making processes regarding mechanical ventilation to patients as unclear and unsatisfactory. They also experienced inadequate interdisciplinary cooperation. Lack of communication skills, the traditional hierarchical hospital culture together with operating in a medical-orientated treatment culture where caring values is rated as less important might explain the nurses' absence in participation in the decision about mechanical ventilation. To be able to advocate for the patients' and their own right to be included in decision-making processes, nurses need an awareness of their own responsibilities. This requires personal courage, leadership who are capable of organising common interpersonal meetings and willingness on the part of the physicians to include and value the nurses' participation in decision-making processes.

  9. Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Katrina L Paumier

    Full Text Available Parkinson's disease (PD pathology is characterized by the formation of intra-neuronal inclusions called Lewy bodies, which are comprised of alpha-synuclein (α-syn. Duplication, triplication or genetic mutations in α-syn (A53T, A30P and E46K are linked to autosomal dominant PD; thus implicating its role in the pathogenesis of PD. In both PD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of protein aggregates (i.e., α-syn and neurodegeneration. Characterization of the timing and nature of symptomatic dysfunction is important for understanding the impact of α-syn on disease progression. Furthermore, this knowledge is essential for identifying pathways and molecular targets for therapeutic intervention. To this end, we examined various functional and morphological endpoints in the transgenic mouse model expressing the human A53T α-syn variant directed by the mouse prion promoter at specific ages relating to disease progression (2, 6 and 12 months of age. Our findings indicate A53T mice develop fine, sensorimotor, and synaptic deficits before the onset of age-related gross motor and cognitive dysfunction. Results from open field and rotarod tests show A53T mice develop age-dependent changes in locomotor activity and reduced anxiety-like behavior. Additionally, digigait analysis shows these mice develop an abnormal gait by 12 months of age. A53T mice also exhibit spatial memory deficits at 6 and 12 months, as demonstrated by Y-maze performance. In contrast to gross motor and cognitive changes, A53T mice display significant impairments in fine- and sensorimotor tasks such as grooming, nest building and acoustic startle as early as 1-2 months of age. These mice also show significant abnormalities in basal synaptic transmission, paired-pulse facilitation and long-term depression (LTD. Combined, these data indicate the A53T model exhibits early- and late-onset behavioral and synaptic

  10. Behavioral Characterization of A53T Mice Reveals Early and Late Stage Deficits Related to Parkinson’s Disease

    Science.gov (United States)

    Paumier, Katrina L.; Sukoff Rizzo, Stacey J.; Berger, Zdenek; Chen, Yi; Gonzales, Cathleen; Kaftan, Edward; Li, Li; Lotarski, Susan; Monaghan, Michael; Shen, Wei; Stolyar, Polina; Vasilyev, Dmytro; Zaleska, Margaret; D. Hirst, Warren; Dunlop, John

    2013-01-01

    Parkinson's disease (PD) pathology is characterized by the formation of intra-neuronal inclusions called Lewy bodies, which are comprised of alpha-synuclein (α-syn). Duplication, triplication or genetic mutations in α-syn (A53T, A30P and E46K) are linked to autosomal dominant PD; thus implicating its role in the pathogenesis of PD. In both PD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of protein aggregates (i.e., α-syn) and neurodegeneration. Characterization of the timing and nature of symptomatic dysfunction is important for understanding the impact of α-syn on disease progression. Furthermore, this knowledge is essential for identifying pathways and molecular targets for therapeutic intervention. To this end, we examined various functional and morphological endpoints in the transgenic mouse model expressing the human A53T α-syn variant directed by the mouse prion promoter at specific ages relating to disease progression (2, 6 and 12 months of age). Our findings indicate A53T mice develop fine, sensorimotor, and synaptic deficits before the onset of age-related gross motor and cognitive dysfunction. Results from open field and rotarod tests show A53T mice develop age-dependent changes in locomotor activity and reduced anxiety-like behavior. Additionally, digigait analysis shows these mice develop an abnormal gait by 12 months of age. A53T mice also exhibit spatial memory deficits at 6 and 12 months, as demonstrated by Y-maze performance. In contrast to gross motor and cognitive changes, A53T mice display significant impairments in fine- and sensorimotor tasks such as grooming, nest building and acoustic startle as early as 1–2 months of age. These mice also show significant abnormalities in basal synaptic transmission, paired-pulse facilitation and long-term depression (LTD). Combined, these data indicate the A53T model exhibits early- and late-onset behavioral and synaptic impairments

  11. Titanium zoning and diffusion chronometry reveal dynamic and late-stage quartz growth in the Youngest Toba Tuff, Indonesia

    Science.gov (United States)

    Tierney, C. R.; Reid, M. R.; Burns, D. H.; Costa Rodriguez, F.; Chesner, C. A.

    2017-12-01

    The enormous 74 ka Youngest Toba Tuff (YTT) ejected 2800 km3 of compositionally zoned (68-77 wt.% SiO2) ignimbrite and co-ignimbrite ash. Titanium zoning within YTT quartz records a dynamic growth history, and sometimes concludes with a final growth stage under different conditions. We investigated the timescales of quartz growth using diffusion chronometry, and determined whether the last stage of crystallization was the result of a discrete and chamber-wide magmatic event. This work offers insight into the dynamics and timescales of storage and remobilization of voluminous silicic magmas - an important consideration for hazards assessment. High-resolution (1 µm steps) hyperspectral CL was mapped from 5-20 quartz crystals from each of five pumices spanning the YTT compositional spectrum. CL intensity was calibrated to Ti concentration via EPMA, and numerically modeled time-dependent diffusional relaxation curves where fit to concentration profiles across zone boundaries. CL-bright/high-Ti rims are found in quartz from all samples, but become less common and have lower Ti concentrations with increasing host pumice silica content (e.g., 70 ppm vs 50 ppm). Some large crystals contain distinct CL-bright interior zones with similar Ti concentration to the rims. Onset of growth of CL-bright rims commenced between 15 and 100 years before eruption, and interior bands between 30 and 1500 years. Neither rim nor interior ages correlate significantly with host pumice silica. Rim growth on quartz evidently occurred closer to eruption than a previous estimate of several decades to centuries for quartz from a single YTT pumice (Matthews et al., 2012). The similar timing for the onset of high-Ti quartz rim growth across all samples suggests a marked and temporally discrete magmatic event in the years to decades prior to eruption and may be recording the chamber-wide influence of magmatic recharge or remobilization. High-Ti interior zones likely record older recharge events that

  12. Exposure to nature gardens has time-dependent associations with mood improvements for people with mid- and late-stage dementia: Innovative practice.

    Science.gov (United States)

    White, Piran Cl; Wyatt, Jonathan; Chalfont, Garuth; Bland, J Martin; Neale, Christopher; Trepel, Dominic; Graham, Hilary

    2017-01-01

    Exposure to green space and nature has a potential role to play in the care of people with dementia, with possible benefits including improved mood and slower disease progression. In this observational study at a dementia care facility in the UK, we used carer-assessed measures to evaluate change in mood of residents with mid- to late-stage dementia following exposure to a nature garden. We found that exposure to nature was associated with a beneficial change in patient mood. There was a non-linear relationship between time spent outdoors and mood outcome. Improvements in patient mood were associated with relatively short duration exposures to nature, and no additional measureable increases in mood were found with exposures beyond 80-90 minutes duration. Whilst further investigation is required before causality can be determined, these results raise important questions for policy about the integration of outdoor space into the design of dementia care facilities and programmes.

  13. The severity of late rectal and recto-sigmoid complications related to fraction size in irradiation treatment of carcinoma cervix stage III B

    International Nuclear Information System (INIS)

    Deore, S.M.; Shrivastava, S.K.; Viswanathan, P.S.; Dinshaw, K.A.; Tata Memorial Hospital, Bombay

    1991-01-01

    A retrospective analysis of late rectal and recto-sigmoid complications was carried out of the 203 patients with stage III B carcinoma of uterine cervix, treated using radiation therapy alone during January 1979 to December 1983. The patients were treated with a combination of external irradiation and single intracavitary insertion. External irradiation was randomised to one of the four different fractionation regimes having dose per fraction of 2 Gy, 3 Gy, 4 Gy and 5.4 Gy, delivering with five fractions/week, three fractions/week, two fractions/week and one fraction/week, respectively. The total doses in four different regimens were adjusted using the TDF model. There were 39 cases of late radiation induced rectal and recto-sigmoid complications. The complication rate was correlated with the dose per fraction and TDFs delivered in each regimen. The complication rate of 8.2% for 2 Gy per fraction was increased to 33.33% for 5.4 Gy per fraction. It was found that there is strong correlation (P [de

  14. Landscape Features Impact on Soil Available Water, Corn Biomass, and Gene Expression during the Late Vegetative Stage

    Directory of Open Access Journals (Sweden)

    Stephanie Hansen

    2013-07-01

    Full Text Available Crop yields at summit positions of rolling landscapes often are lower than backslope yields. The differences in plant response may be the result of many different factors. We examined corn ( L. plant productivity, gene expression, soil water, and nutrient availability in two landscape positions located in historically high (backslope and moderate (summit and shoulder yielding zones to gain insight into plant response differences. Growth characteristics, gene expression, and soil parameters (water and N and P content were determined at the V12 growth stage of corn. At tassel, plant biomass, N content, C isotope discrimination (Δ, and soil water was measured. Soil water was 35% lower in the summit and shoulder compared with the lower backslope plots. Plants at the summit had 16% less leaf area, biomass, and N and P uptake at V12 and 30% less biomass at tassel compared with plants from the lower backslope. Transcriptome analysis at V12 indicated that summit and shoulder-grown plants had 496 downregulated and 341 upregulated genes compared with backslope-grown plants. Gene set and subnetwork enrichment analyses indicated alterations in growth and circadian response and lowered nutrient uptake, wound recovery, pest resistance, and photosynthetic capacity in summit and shoulder-grown plants. Reducing plant populations, to lessen demands on available soil water, and applying pesticides, to limit biotic stress, may ameliorate negative water stress responses.

  15. Redox Variations in Early Solar System Materials and Implications for Late Stage Planetary Accretion and Planet Formation

    Science.gov (United States)

    Righter, K.

    2017-01-01

    Oxygen fugacity plays an important role in determining the detailed physical and chemical aspects of planets and their building blocks. Basic chemical properties such as the amount of oxidized Fe in a mantle (as FeO), the nature of alloying elements in the core (S, C, H, O, Si), and the solubility of various volatile elements in the silicate and metallic portions of embryos and planets can influence physical properties such as the size of the core, the liquidus and solidus of the mantle and core, and the speciation of volatile compounds contributing to atmospheres. This paper will provide an overview of the range of fO2 variation observed in primitive and differentiated materials that may have participated in accretion (cosmic dust, Star-dust and meteorites), a comparison to observations of planetary fO2 (Mercury, Mars and Earth), and a discus-sion of timing of variation of fO2 within both early and later accreted materials. This overview is meant to promote discussion and interaction between students of these two stages of planet formation to identify areas where more work is needed.

  16. Disruption of visual awareness during the attentional blink is reflected by selective disruption of late-stage neural processing

    Science.gov (United States)

    Harris, Joseph A.; McMahon, Alex R.; Woldorff, Marty G.

    2015-01-01

    Any information represented in the brain holds the potential to influence behavior. It is therefore of broad interest to determine the extent and quality of neural processing of stimulus input that occurs with and without awareness. The attentional blink is a useful tool for dissociating neural and behavioral measures of perceptual visual processing across conditions of awareness. The extent of higher-order visual information beyond basic sensory signaling that is processed during the attentional blink remains controversial. To determine what neural processing at the level of visual-object identification occurs in the absence of awareness, electrophysiological responses to images of faces and houses were recorded both within and outside of the attentional blink period during a rapid serial visual presentation (RSVP) stream. Electrophysiological results were sorted according to behavioral performance (correctly identified targets versus missed targets) within these blink and non-blink periods. An early index of face-specific processing (the N170, 140–220 ms post-stimulus) was observed regardless of whether the subject demonstrated awareness of the stimulus, whereas a later face-specific effect with the same topographic distribution (500–700 ms post-stimulus) was only seen for accurate behavioral discrimination of the stimulus content. The present findings suggest a multi-stage process of object-category processing, with only the later phase being associated with explicit visual awareness. PMID:23859644

  17. Immunospecific immunoglobulins and IL-10 as markers for Trypanosoma brucei rhodesiense late stage disease in experimentally infected vervet monkeys

    DEFF Research Database (Denmark)

    Ngotho, Maina; Kagira, J.M.; Jensen, Henrik Michael Elvang

    2009-01-01

    and 140 days post-infection (dpi) respectively. Matched serum and CSF samples were obtained at regular intervals and immunospecific IgM, immunoglobulin G (IgG) and IL-10 were quantified by ELISA. RESULTS: There was no detectable immunospecific IgM and IgG in the CSF before 49 dpi. CSF IgM and Ig......OBJECTIVE: To determine the usefulness of IL-10 and immunoglobulin M (IgM) as biomarkers for staging HAT in vervet monkeys, a useful pathogenesis model for humans. METHODS: Vervet monkeys were infected with Trypanosoma brucei rhodesiense and subsequently given sub-curative and curative treatment 28...... curative treatment was given. After curative treatment, there was rapid and significant drop in serum IgM and IL-10 concentration as well as CSF WCC. However, the CSF IgM and IgG remained detectable to the end of the study. CONCLUSIONS: Serum and CSF concentrations of immunospecific IgM and CSF IgG changes...

  18. Late Stage of Corneal Decompensation Caused by Progressive Keratoconus: Can We Treat It and Save the Cornea?

    Directory of Open Access Journals (Sweden)

    Igor Knezović

    2015-01-01

    Full Text Available Aim. To report a case of 40-year-old male with progressive bilateral keratoconus who had undergone transepithelial phototherapeutic keratectomy (TE-PTK and corneal collagen cross-linking (CXL using hypoosmolar riboflavin solution in a same day procedure. Methods. Eye examination showed that UCDVA on both eyes was 0,01 according to Snellen charts, and slit lamp biomicroscopy showed paracentral diffuse intrastromal corneal haze. Anterior OCT marked stromal hyperreflective zones and localized paracentral thinning of the cornea. Scheimpflug tomography noted keratoconus stages III-IV on both eyes. After 40/35 microns TE-PTK, a CXL was performed for 30 minutes using hypoosmolar riboflavin solution. The left eye was treated first and the right eye 1 month after. Follow-up period was 10 months. Results. One month after the treatment both eyes showed improvement in corneal topography and the UCDVA was better. Eight months after the treatment BSCVA improved to 0,6 in both eyes using Rose K2 contact lenses and remained stable. Conclusion. TE-PTK and CXL using hypotonic riboflavin solution as a same day procedure have been shown to be a safe and promising method in this case of progressive keratoconus. It was necessary to consider certain parameters that could influence the safety and the final outcome of this combined protocol.

  19. Anti-Inflammatory Effects of the Mediterranean Diet in the Early and Late Stages of Atheroma Plaque Development

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    Rosa Casas

    2017-01-01

    Full Text Available Objective. To evaluate the long-term effects of a Mediterranean diet (MeDiet intervention on the plasma concentrations of inflammatory and plaque stability-related molecules in elderly people at high risk for cardiovascular disease. Design and Setting. 66 participants from primary care centers affiliated with the Hospital Clinic of Barcelona were randomized into 3 groups: MeDiet plus extra virgin olive oil (EVOO or nuts and a low-fat diet (LFD. At baseline and at 3 and 5 years, we evaluated the changes in the plasma concentrations of 24 inflammatory biomarkers related to the different stages of the atherosclerotic process by Luminex®. Results. At 3 and 5 years, both MeDiet groups showed a significant reduction of IL-6, IL-8, MCP-1, and MIP-1β (P<0.05; all compared to LFD. IL-1β, IL-5, IL-7, IL-12p70, IL-18, TNF-α, IFN-γ, GCSF, GMCSF, and ENA78 (P<0.05; all only decreased in the MeDiet+EVOO group and E-selectin and sVCAM-1 (P<0.05; both in the MeDiet+nuts group. Conclusions. Long-term adherence to MeDiet decreases the plasma concentrations of inflammatory biomarkers related to different steps of atheroma plaque development in elderly persons at high cardiovascular risk.

  20. Gaining power and precision by using model-based weights in the analysis of late stage cancer trials with substantial treatment switching.

    Science.gov (United States)

    Bowden, Jack; Seaman, Shaun; Huang, Xin; White, Ian R

    2016-04-30

    In randomised controlled trials of treatments for late-stage cancer, it is common for control arm patients to receive the experimental treatment around the point of disease progression. This treatment switching can dilute the estimated treatment effect on overall survival and impact the assessment of a treatment's benefit on health economic evaluations. The rank-preserving structural failure time model of Robins and Tsiatis (Comm. Stat., 20:2609-2631) offers a potential solution to this problem and is typically implemented using the logrank test. However, in the presence of substantial switching, this test can have low power because the hazard ratio is not constant over time. Schoenfeld (Biometrika, 68:316-319) showed that when the hazard ratio is not constant, weighted versions of the logrank test become optimal. We present a weighted logrank test statistic for the late stage cancer trial context given the treatment switching pattern and working assumptions about the underlying hazard function in the population. Simulations suggest that the weighted approach can lead to large efficiency gains in either an intention-to-treat or a causal rank-preserving structural failure time model analysis compared with the unweighted approach. Furthermore, violation of the working assumptions used in the derivation of the weights only affects the efficiency of the estimates and does not induce bias or inflate the type I error rate. The weighted logrank test statistic should therefore be considered for use as part of a careful secondary, exploratory analysis of trial data affected by substantial treatment switching. ©2015 The Authors. Statistics inMedicine Published by John Wiley & Sons Ltd.

  1. Distribution of calcifying and silicifying phytoplankton in relation to environmental and biogeochemical parameters during the late stages of the 2005 North East Atlantic Spring Bloom

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    K. Leblanc

    2009-10-01

    Full Text Available The late stage of the North East Atlantic (NEA spring bloom was investigated during June 2005 along a transect section from 45 to 66° N between 15 and 20° W in order to characterize the contribution of siliceous and calcareous phytoplankton groups and describe their distribution in relation to environmental factors. We measured several biogeochemical parameters such as nutrients, surface trace metals, algal pigments, biogenic silica (BSi, particulate inorganic carbon (PIC or calcium carbonate, particulate organic carbon, nitrogen and phosphorus (POC, PON and POP, respectively, as well as transparent exopolymer particles (TEP. Results were compared with other studies undertaken in this area since the JGOFS NABE program. Characteristics of the spring bloom generally agreed well with the accepted scenario for the development of the autotrophic community. The NEA seasonal diatom bloom was in the late stages when we sampled the area and diatoms were constrained to the northern part of our transect, over the Icelandic Basin (IB and Icelandic Shelf (IS. Coccolithophores dominated the phytoplankton community, with a large distribution over the Rockall-Hatton Plateau (RHP and IB. The Porcupine Abyssal Plain (PAP region at the southern end of our transect was the region with the lowest biomass, as demonstrated by very low Chla concentrations and a community dominated by picophytoplankton. Early depletion of dissolved silicic acid (DSi and increased stratification of the surface layer most likely triggered the end of the diatom bloom, leading to coccolithophore dominance. The chronic Si deficiency observed in the NEA could be linked to moderate Fe limitation, which increases the efficiency of the Si pump. TEP closely mirrored the distribution of both biogenic silica at depth and prymnesiophytes in the surface layer suggesting the sedimentation of the diatom bloom in the form of aggregates, but the relative contribution of diatoms and

  2. Tendon Interposition and Ligament Reconstruction with ECRL Tendon in the Late Stages of Kienböck’s Disease: A Cadaver Study

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    Nazım Karalezli

    2013-01-01

    Full Text Available Background. The optimal surgical treatment for Kienböck’s disease with stages IIIB and IV remains controversial. A cadaver study was carried out to evaluate the use of coiled extensor carpi radialis longus tendon for tendon interposition and a strip obtained from the same tendon for ligament reconstruction in the late stages of Kienböck’s disease. Methods. Coiled extensor carpi radialis longus tendon was used to fill the cavity of the excised lunate, and a strip obtained from this tendon was sutured onto itself after passing through the scaphoid and the triquetrum acting as a ligament to preserve proximal row integrity. Biomechanical tests were carried out in order to evaluate this new ligamentous reconstruction. Results. It was biomechanically confirmed that the procedure was effective against axial compression and distributed the upcoming mechanical stress to the distal row. Conclusion. Extensor carpi radialis longus tendon has not been used for tendon interposition and ligament reconstruction in the treatment of this disease before. In view of the biomechanical data, the procedure seems to be effective for the stabilization of scaphoid and carpal bones.

  3. [The clinical and microbiological characteristics of oropharyngeal candidiasis in the HIV-infected patients at the late stages of the disease].

    Science.gov (United States)

    Charushin, A O; Elovikov, A M; Charushina, I P; Vorob'eva, N N; Katretskaya, G G

    Oropharyngeal candidiasis in 512 HIV-infected patients at the late stages of the disease was studied with special reference to the clinical and microbiological characteristics of this condition. The diagnosis was established based on the results of the clinical and microbiological examination of the patients including investigation of the tissue samples taken from the oral cavity and the throat with the use of the device specially developed for this purpose. It was shown that the disease existed in various clinical forms the most common of which were monocomponent pathology represented by pseudomembranous candidiasis in 37.5±2.14% of the patients, the two-component mixed form (pseudomembranous candidiasis with concomitant angular chelitis) diagnosed in 27.5±1.97% cases, and the ternary form (the combination of pseudomembranous candidiasis, acute atrophic process, and angular chelitis) documented in 11.9±1.43% patients. The main clinical features of the disease included the combination of its various forms, multiple localization of the pathological process, and its polymorphous manifestations. Changes in the clinical course of oropharyngeal candidiasis associated with the progression of HIV from the 4A to the 4B stage were detected for the first time. They were shown to be accompanied by variations in the species composition and concentration of fungal flora in the crypts of the palatine tonsils and its sensitivity to fluconazole therapy.

  4. Cuprizone decreases intermediate and late-stage progenitor cells in hippocampal neurogenesis of rats in a framework of 28-day oral dose toxicity study

    International Nuclear Information System (INIS)

    Abe, Hajime; Tanaka, Takeshi; Kimura, Masayuki; Mizukami, Sayaka; Saito, Fumiyo; Imatanaka, Nobuya; Akahori, Yumi; Yoshida, Toshinori; Shibutani, Makoto

    2015-01-01

    Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600 mg/kg body weight/day for 28 days. In the subgranular zone (SGZ), 600 mg/kg CPZ increased the number of cleaved caspase-3 + apoptotic cells. At ≥ 120 mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at ≥ 120 mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥ 120 mg/kg decreased phosphorylated TRKB + interneurons, although the number of reelin + interneurons was unchanged. At 600 mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells. - Highlights: • Effect of 28-day CPZ exposure on hippocampal neurogenesis was examined in rats. • CPZ suppressed intermediate neurogenesis and late-stage neurogenesis in the dentate gyrus. • CPZ suppressed BDNF signals to interneurons by decrease of cholinergic

  5. Differential gene expression in soybean leaf tissues at late developmental stages under drought stress revealed by genome-wide transcriptome analysis.

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    Dung Tien Le

    Full Text Available The availability of complete genome sequence of soybean has allowed research community to design the 66 K Affymetrix Soybean Array GeneChip for genome-wide expression profiling of soybean. In this study, we carried out microarray analysis of leaf tissues of soybean plants, which were subjected to drought stress from late vegetative V6 and from full bloom reproductive R2 stages. Our data analyses showed that out of 46,093 soybean genes, which were predicted with high confidence among approximately 66,000 putative genes, 41,059 genes could be assigned with a known function. Using the criteria of a ratio change > = 2 and a q-value<0.05, we identified 1458 and 1818 upregulated and 1582 and 1688 downregulated genes in drought-stressed V6 and R2 leaves, respectively. These datasets were classified into 19 most abundant biological categories with similar proportions. There were only 612 and 463 genes that were overlapped among the upregulated and downregulated genes, respectively, in both stages, suggesting that both conserved and unconserved pathways might be involved in regulation of drought response in different stages of plant development. A comparative expression analysis using our datasets and that of drought stressed Arabidopsis leaves revealed the existence of both conserved and species-specific mechanisms that regulate drought responses. Many upregulated genes encode either regulatory proteins, such as transcription factors, including those with high homology to Arabidopsis DREB, NAC, AREB and ZAT/STZ transcription factors, kinases and two-component system members, or functional proteins, e.g. late embryogenesis-abundant proteins, glycosyltransferases, glycoside hydrolases, defensins and glyoxalase I family proteins. A detailed analysis of the GmNAC family and the hormone-related gene category showed that expression of many GmNAC and hormone-related genes was altered by drought in V6 and/or R2 leaves. Additionally, the downregulation of

  6. Cuprizone decreases intermediate and late-stage progenitor cells in hippocampal neurogenesis of rats in a framework of 28-day oral dose toxicity study

    Energy Technology Data Exchange (ETDEWEB)

    Abe, Hajime; Tanaka, Takeshi; Kimura, Masayuki; Mizukami, Sayaka [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193 (Japan); Saito, Fumiyo; Imatanaka, Nobuya; Akahori, Yumi [Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004 (Japan); Yoshida, Toshinori [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Shibutani, Makoto, E-mail: mshibuta@cc.tuat.ac.jp [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan)

    2015-09-15

    Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600 mg/kg body weight/day for 28 days. In the subgranular zone (SGZ), 600 mg/kg CPZ increased the number of cleaved caspase-3{sup +} apoptotic cells. At ≥ 120 mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at ≥ 120 mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥ 120 mg/kg decreased phosphorylated TRKB{sup +} interneurons, although the number of reelin{sup +} interneurons was unchanged. At 600 mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells. - Highlights: • Effect of 28-day CPZ exposure on hippocampal neurogenesis was examined in rats. • CPZ suppressed intermediate neurogenesis and late-stage neurogenesis in the dentate gyrus. • CPZ suppressed BDNF signals to interneurons by decrease of

  7. Effect of late-stage therapy on disease progression in AAV-mediated rescue of photoreceptor cells in the retinoschisin-deficient mouse.

    Science.gov (United States)

    Janssen, Andreas; Min, Seok H; Molday, Laurie L; Tanimoto, Naoyuki; Seeliger, Mathias W; Hauswirth, William W; Molday, Robert S; Weber, Bernhard H F

    2008-06-01

    Proof-of-concept for a successful adeno-associated virus serotype 5 (AAV5)-mediated gene therapy in X-linked juvenile retinoschisis (XLRS) has been demonstrated in an established mouse model for this condition. The initial studies concentrated on early time-points of treatment. In this study, we aimed to explore the consequences of single subretinal injections administered at various stages of more advanced disease. By electroretinogram (ERG), functional improvement in treated versus untreated eyes is found to be significant in retinoschisin-deficient mice injected at the time-points of 15 days (P15), 1 month (PM1), and 2 months (PM2) after birth. In mice treated at 7 months after birth (PM7), an age previously shown to exhibit advanced retinal disease, ERG responses reveal no beneficial effects of vector treatment. Generally, functional rescue is paralleled by sustained retinoschisin expression and significant photoreceptor survival relative to untreated eyes. Quantitative measures of photoreceptors and peanut agglutinin-labeled ribbon synapses demonstrate rescue effects even in mice injected as late as PM7. Taken together, AAV5-mediated gene replacement is beneficial in slowing disease progression in murine XLRS. In addition, we show the effectiveness of rescue efforts even if treatment is delayed until advanced signs of disease have developed. Human XLRS patients might benefit from these findings, which suggest that the effectiveness of treatment appears not to be restricted to the early stages of the disease, and that treatment may prove to be valuable even when administered at more advanced stages.

  8. Dementia and severity of parkinsonism determines the handicap of patients in late-stage Parkinson's disease: the Barcelona-Lisbon cohort.

    Science.gov (United States)

    Coelho, M; Marti, M J; Sampaio, C; Ferreira, J J; Valldeoriola, F; Rosa, M M; Tolosa, E

    2015-02-01

    Handicap has not been explored as a patient-centred outcome measure in Parkinson's disease (PD). The clinical features and medication use in late stages of PD (LS-PD) were reported previously. Handicap, medical conditions, use of healthcare resources and the impact of LS-PD upon caregivers were characterized in a cross-sectional study of LS-PD stages 4 or 5 of Hoehn and Yahr (H&Y). Handicap was measured using the London Handicap Scale (LHS: 0, maximal handicap; 1, no handicap). The mean LHS score in 50 patients was 0.33 (SD ±0.15). The presence of dementia, the Unified Parkinson's Disease Rating Scale part I score and the H&Y stage in 'off' independently predicted the LHS score (adjusted R(2) = 0.62; P = 0.000). Comorbidities and past medical conditions were frequent. Thirty-five patients lived at their house. Forty-five received unpaid care. Mean visits to the family doctor in the preceding 6 months were 2.2 (SD ±3.0) and to a neurologist 1.7 (SD ±1.0). Use of other health resources was low. Unpaid caregivers spent much time with patients and reported a high burden. Handicap could be measured in LS-PD and the LHS was easily completed by patients and caregivers. The high handicap in our cohort was mostly driven by the presence of dementia, behavioural complaints and the severity of non-dopaminergic motor features. Patients visited doctors infrequently and made low use of health resources, whilst unpaid caregivers reported a high burden. © 2014 EAN.

  9. Propofol exposure during late stages of pregnancy impairs learning and memory in rat offspring via the BDNF-TrkB signalling pathway.

    Science.gov (United States)

    Zhong, Liang; Luo, Foquan; Zhao, Weilu; Feng, Yunlin; Wu, Liuqin; Lin, Jiamei; Liu, Tianyin; Wang, Shengqiang; You, Xuexue; Zhang, Wei

    2016-10-01

    The brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) (BDNF-TrkB) signalling pathway plays a crucial role in regulating learning and memory. Synaptophysin provides the structural basis for synaptic plasticity and depends on BDNF processing and subsequent TrkB signalling. Our previous studies demonstrated that maternal exposure to propofol during late stages of pregnancy impaired learning and memory in rat offspring. The purpose of this study is to investigate whether the BDNF-TrkB signalling pathway is involved in propofol-induced learning and memory impairments. Propofol was intravenously infused into pregnant rats for 4 hrs on gestational day 18 (E18). Thirty days after birth, learning and memory of offspring was assessed by the Morris water maze (MWM) test. After the MWM test, BDNF and TrkB transcript and protein levels were measured in rat offspring hippocampus tissues using real-time PCR (RT-PCR) and immunohistochemistry (IHC), respectively. The levels of phosphorylated-TrkB (phospho-TrkB) and synaptophysin were measured by western blot. It was discovered that maternal exposure to propofol on day E18 impaired spatial learning and memory of rat offspring, decreased mRNA and protein levels of BDNF and TrkB, and decreased the levels of both phospho-TrkB and synaptophysin in the hippocampus. Furthermore, the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) reversed all of the observed changes. Treatment with 7,8-DHF had no significant effects on the offspring that were not exposed to propofol. The results herein indicate that maternal exposure to propofol during the late stages of pregnancy impairs spatial learning and memory of offspring by disturbing the BDNF-TrkB signalling pathway. The TrkB agonist 7,8-DHF might be a potential therapy for learning and memory impairments induced by maternal propofol exposure. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular

  10. The change of metabotropic glutamate receptor 5 expression level in rats with late-stage traumatic brain injury and the therapeutic effect of taurine

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    Ying CAI

    2016-08-01

    Full Text Available Objective To investigate the change of metabotropic glutamate receptor 5 (mGluR5 expression level in rats with late-stage (the 7th day traumatic brain injury (TBI and the role of taurine. Methods The left cerebral TBI rat models were made by using lateral fluid percussion method. A total of 30 specific pathogen free (SPF male Sprague-Dawley (SD rats were randomly divided into 3 groups: sham operation group (control group, TBI model group (TBI group and taurine treatment group (taurine group. Wet and dry weight method was used to measure the brain water content. Real-time fluorescent quantitative polymerase chain reaction (PCR and Western blotting were used to detect the change of mRNA and protein expression of aquaporin 4 (AQP4 and mGluR5 in each group.  Results Compared with control group, the brain water content (t = 4.893, P = 0.002, AQP4 mRNA (t = 6.523, P = 0.000 and protein (t = 4.366, P = 0.008 expression were upregulated, while mGluR5 mRNA (t = 5.776, P = 0.001 and protein (t = 3.945, P = 0.014 expression were downregulated in TBI group. After taurine treatment, the brain water content (t = 2.151, P = 0.140, AQP4 mRNA (t = 1.144,P = 0.432 and protein (t = 0.367, P = 0.804 decreased to normal, while mGluR5 mRNA (t = 1.824, P = 0.216 and protein (t = 1.185, P = 0.414 increased to normal. Correlation analysis showed brain water content was negatively correlated with mGluR5 mRNA (r = -0.617, P = 0.014 and mGluR5 protein (r = -0.665, P = 0.007, while it was positively correlated with AQP4 protein (r = 0.658, P = 0.008.  Conclusions Taurine can significantly increase the mGluR5 expression level of brain issue in the late-stage (the 7th day of TBI and decline brain edema and brain water content. It may be a potential protective agent as an inhibitory neurotransmitter. DOI: 10.3969/j.issn.1672-6731.2016.08.008

  11. Late Gadolinium Enhancement Amount as an Independent Risk Factor for the Incidence of Adverse Cardiovascular Events in Patients with Stage C or D Heart Failure

    Directory of Open Access Journals (Sweden)

    Tong Liu

    2016-10-01

    Full Text Available Background Myocardial fibrosis (MF is a risk factor for poor prognosis in dilated cardiomyopathy (DCM. Late gadolinium enhancement (LGE of the myocardium on cardiac magnetic resonance (CMR represents MF. We examined whether the LGE amount increases the incidence of adverse cardiovascular events in patients with stage C or D heart failure (HF. Methods Eighty-four consecutive patients with stage C or D HF, either ischemic or non-ischemic, were enrolled. Comprehensive clinical and CMR evaluations were performed. All patients were followed up for a composite endpoint of cardiovascular death, heart transplantation, and cardiac resynchronization therapy with defibrillator (CRT-D.Results LGE was present in 79.7% of the end-stage HF patients. LGE distribution patterns were mid-wall, epi-myocardial, endo-myocardial, and the morphological patterns were patchy, transmural, and diffuse. During the average follow-up of 544 days, 13 (15.5% patients had endpoint events: 7 patients cardiac death, 2 patients heart transplantation, and 4 patients underwent CRT-D implantation. On univariate analysis, LGE quantification on cardiac magnetic resonance, blood urine nitrogen, QRS duration on electrocardiogram, left ventricular end-diastolic diameter (LVEDD and left ventricular end-diastolic volume (LVEDV on CMR had the strongest associations with the composite endpoint events. However, on multivariate analysis for both Model I (after adjusting for age, sex, and body mass index and Model II (after adjusting for age, sex, BMI, renal function, QRS duration and atrial fibrillation on electrocardiogram, the etiology of HF, LVEF, CMR-LVEDD and CMR-LVEDV, LGE amount was a significant risk factor for composite endpoint events (Model I 6SD HR 1.037, 95%CI 1.005-1.071, p=0.022; Model II 6SD HR 1.045, 95%CI 1.001-1.084, p=0.022. Conclusion LGE amount from high-scale threshold on CMR increased the incidence of adverse cardiovascular events for patients in either stage C or D HF.

  12. The mycorrhiza-dependent defensin MtDefMd1 of Medicago truncatula acts during the late restructuring stages of arbuscule-containing cells.

    Directory of Open Access Journals (Sweden)

    Marian Uhe

    Full Text Available Different symbiotic and pathogenic plant-microbe interactions involve the production of cysteine-rich antimicrobial defensins. In Medicago truncatula, the expression of four MtDefMd genes, encoding arbuscular mycorrhiza-dependent defensins containing an N-terminal signal peptide and exhibiting some differences to non-symbiotic defensins, raised over the time of fungal colonization. Whereas the MtDefMd1 and MtDefMd2 promoters were inactive in cells containing young arbuscules, cells with fully developed arbuscules displayed different levels of promoter activities, indicating an up-regulation towards later stages of arbuscule formation. MtDefMd1 and MtDefMd2 expression was absent or strongly down-regulated in mycorrhized ram1-1 and pt4-2 mutants, known for defects in arbuscule branching or premature arbuscule degeneration, respectively. A ~97% knock-down of MtDefMd1/MtDefMd2 expression did not significantly affect arbuscule size. Although overexpression of MtDefMd1 in arbuscule-containing cells led to an up-regulation of MtRam1, encoding a key transcriptional regulator of arbuscule formation, no morphological changes were evident. Co-localization of an MtDefMd1-mGFP6 fusion with additional, subcellular markers revealed that this defensin is associated with arbuscules in later stages of their life-cycle. MtDefMd1-mGFP6 was detected in cells with older arbuscules about to collapse, and ultimately in vacuolar compartments. Comparisons with mycorrhized roots expressing a tonoplast marker indicated that MtDefMd1 acts during late restructuring processes of arbuscule-containing cells, upon their transition into a post-symbiotic state.

  13. Characterization of fluid inclusions from mineralized pegmatites of the Damara Belt, Namibia: insight into late-stage fluid evolution and implications for mineralization

    Science.gov (United States)

    Ashworth, Luisa; Kinnaird, Judith Ann; Nex, Paul Andrew Martin; Erasmus, Rudolph Marthinus; Przybyłowicz, Wojciech Józef

    2018-05-01

    Mineralized NYF and LCT pegmatites occur throughout the northeast-trending Neoproterozoic Damara Belt, Namibia. Mineralization in the pegmatites varies geographically, from the northeast, where they are enriched in Li-Be, to the southwest, where they also contain notable Sn and U. Similar fluid inclusion populations occur throughout the pegmatites, regardless of their respective metal enrichments, and primary fluid inclusion textures were destroyed by continued fluid activity. Pseudosecondary to secondary inclusions are aqueo-carbonic, carbonic, and aqueous in composition, and have been divided into five types. The earliest populations are saline (>26.3 eq. wt.% NaCl), homogenizing at temperatures in excess of 300 °C. Their carbonic phase is composed of CO2, with minor CH4, and micro-elemental mapping indicates they contain trace metals, including Ca, Fe, Zn, Cu, and K. Type 3 inclusions formed later, homogenize at 325 °C, and are less saline, with a carbonic phase composed of CO2. Type 4 carbonic inclusions are composed of pure CO2, and represent the latest stages of fluid evolution, while Type 5 aqueous inclusions are believed to be unrelated to the crystallization of the pegmatites, and rather the result of regional Cretaceous magmatism, or the ingress of meteoric water. The similarities in fluid inclusion populations observed in the pegmatites suggest that differences in mineralization were driven by magma composition rather than fluid activity alone, however saline fluids facilitated the enrichment and deposition of metals during the late stages of crystallization. Furthermore, the similarities between fluid inclusion populations in different pegmatites suggests they share a similar fluid evolution.

  14. THREE-DIMENSIONAL GEOMETRY OF A CURRENT SHEET IN THE HIGH SOLAR CORONA: EVIDENCE FOR RECONNECTION IN THE LATE STAGE OF THE CORONAL MASS EJECTIONS

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Ryun-Young [College of Science, George Mason University, 4400 University Drive, Fairfax, VA 22030 (United States); Vourlidas, Angelos [The Johns Hopkins University, Applied Physics Laboratory, Laurel, MD 20723 (United States); Webb, David, E-mail: rkwon@gmu.edu [ISR, Boston College, Chestnut Hill, MA (United States)

    2016-07-20

    Motivated by the standard flare model, ray-like structures in the wake of coronal mass ejections (CMEs) have been often interpreted as proxies of the reconnecting current sheet connecting the CME with the postflare arcade. We present the three-dimensional properties of a post-CME ray derived from white light images taken from three different viewing perspectives on 2013 September 21. By using a forward modeling method, the direction, cross section, and electron density are determined within the heliocentric distance range of 5–9 R {sub ⊙}. The width and depth of the ray are 0.42 ± 0.08 R {sub ⊙} and 1.24 ± 0.35 R {sub ⊙}, respectively, and the electron density is (2.0 ± 0.5) × 10{sup 4} cm{sup 3}, which seems to be constant with height. Successive blobs moving outward along the ray are observed around 13 hr after the parent CME onset. We model the three-dimensional geometry of the parent CME with the Gradual Cylindrical Shell model and find that the CME and ray are coaxial. We suggest that coaxial post-CME rays, seen in coronagraph images, with successive formation of blobs could be associated with current sheets undergoing magnetic reconnection in the late stage of CMEs.

  15. Sensorless Control of Late-Stage Offshore DFIG-WT with FSTP Converters by Using EKF to Ride through Hybrid Faults

    Directory of Open Access Journals (Sweden)

    Wei Li

    2017-11-01

    Full Text Available A hybrid fault scenario in a late-stage offshore doubly-fed induction generator (DFIG-based wind turbine (DFIG-WT with converter open-circuit fault and position sensor failure is investigated in this paper. An extended Kalman filter (EKF-based sensorless control strategy is utilized to eliminate the encoder. Based on the detailed analysis of the seventh-order dynamic state space model of DFIG, along with the input voltage signals and measured current signals, the EKF algorithm for DFIG is designed to estimate the rotor speed and position. In addition, the bridge arm open circuit in the back-to-back (BTB power converter of DFIG is taken as a commonly-encountered fault due to the fragility of semiconductor switches. Four-switch three-phase (FSTP topology-based fault-tolerant converters are employed for post-fault operation by considering the minimization of switching losses and reducing the circuit complexity. Moreover, a simplified space vector pulse width modulation (SVPWM technique is proposed to reduce the computational burden, and a voltage balancing scheme is put forward to increase the DC-bus voltage utilization rate. Simulation studies are carried out in MATLAB/Simulink2017a (MathWorks, Natick, MA, USA to demonstrate the validity of the proposed hybrid fault-tolerant strategy for DFIG-WT, with the wind speed fluctuation, measurement noises and grid voltage sag taken into consideration.

  16. FORMATION OF THE SHORT-LIVED RADIONUCLIDE 36Cl IN THE PROTOPLANETARY DISK DURING LATE-STAGE IRRADIATION OF A VOLATILE-RICH RESERVOIR

    International Nuclear Information System (INIS)

    Jacobsen, Benjamin; Yin Qingzhu; Matzel, Jennifer; Hutcheon, Ian D.; Ramon, Erick C.; Weber, Peter K.; Krot, Alexander N.; Nagashima, Kazuhide; Ishii, Hope A.; Ciesla, Fred J.

    2011-01-01

    Short-lived radionuclides (SLRs) in the early solar system provide fundamental insight into protoplanetary disk evolution. We measured the 36 Cl- 36 S-isotope abundance in wadalite ( 36 Cl (τ 1/2 ∼ 3 x 10 5 yr) in the early solar system. Its presence, initial abundance, and the noticeable decoupling from 26 Al raise serious questions about the origin of SLRs. The inferred initial 36 Cl abundance for wadalite, corresponding to a 36 Cl/ 35 Cl ratio of (1.81 ± 0.13) x 10 -5 , is the highest 36 Cl abundance ever reported in any early solar system material. The high level of 36 Cl in wadalite and the absence of 26 Al ( 26 Al/ 27 Al ≤ 3.9 x 10 -6 ) in co-existing grossular (1) unequivocally support the production of 36 Cl by late-stage solar energetic particle irradiation in the protoplanetary disk and (2) indicates that the production of 36 Cl, recorded by wadalite, is unrelated to the origin of 26 Al and other SLRs ( 10 Be, 53 Mn) recorded by primary minerals of CAIs and chondrules. We infer that 36 Cl was largely produced by irradiation of a volatile-rich reservoir in an optically thin protoplanetary disk adjacent to the region in which the CV chondrite parent asteroid accreted while the Sun was a weak T Tauri star. Subsequently, 36 Cl accreted into the Allende CV chondrite together with condensed water ices.

  17. Interleukin-4 enhances trafficking and functional activities of GM-CSF-stimulated mouse myeloid-derived dendritic cells at late differentiation stage

    International Nuclear Information System (INIS)

    Yin, Shu-Yi; Wang, Chien-Yu; Yang, Ning-Sun

    2011-01-01

    Mouse bone marrow-derived dendritic cells (BMDCs) are being employed as an important model for translational research into the development of DC-based therapeutics. For such use, the localization and specialized mobility of injected BMDCs within specific immune tissues are known to define their immunity and usefulness in vivo. In this study, we demonstrate that IL-4, a key driving factor for in vitro propagation and differentiation of BMDCs, when added during a late culture stage can enhance the in vivo trafficking activity of granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced BMDCs. It suggests that the temporal control of IL-4 stimulation during the in vitro generation of DCs drastically affects the DC trafficking efficiency in vivo. With this modification of IL-4 stimulation, we also show that much less cytokine was needed to generate BMDCs with high purity and yield that secrete a high level of cytokines and possess a good capacity to induce proliferation of allogeneic CD4 + T cells, as compared to the conventional method that uses a continuous supplement of GM-CSF and IL-4 throughout cultivation. These results provide us with an important know-how for differentiation of BMDCs from myeloid stem cells, and for use of other immune cells in related medical or stem cell applications.

  18. Endoscope-Assisted and Controlled Argus II Epiretinal Prosthesis Implantation in Late-Stage Retinitis Pigmentosa: A Report of 2 Cases.

    Science.gov (United States)

    Özmert, Emin; Demirel, Sibel

    2016-01-01

    Several different approaches for restoring sight in subjects who are blind due to outer retinal degeneration are currently under investigation, including stem cell therapy, gene therapy, and visual prostheses. Although many different types of visual prostheses have shown promise, to date, the Argus II Epiretinal Prosthesis System, developed in a clinical setting over the course of 10 years, is the world's first and only retinal prosthesis that has been approved by the United States Food and Drug Administration (FDA) and has been given the CE-Mark for sale within the European Economic Area (EEA). The incidence of serious adverse events from Argus II implantation decreased over time after minor changes in the implant design and improvements in the surgical steps used for the procedure had been made. In order to further decrease the scleral incision-related complications and enhance the assessment of the tack position and the contact between the array and the inner macular surface, we used an ophthalmic endoscope during the regular course of Argus II implantation surgery in 2 patients with late-stage retinitis pigmentosa in an attempt to improve the anatomical and functional outcomes.

  19. Endoscope-Assisted and Controlled Argus II Epiretinal Prosthesis Implantation in Late-Stage Retinitis Pigmentosa: A Report of 2 Cases

    Directory of Open Access Journals (Sweden)

    Emin Özmert

    2016-12-01

    Full Text Available Several different approaches for restoring sight in subjects who are blind due to outer retinal degeneration are currently under investigation, including stem cell therapy, gene therapy, and visual prostheses. Although many different types of visual prostheses have shown promise, to date, the Argus II Epiretinal Prosthesis System, developed in a clinical setting over the course of 10 years, is the world’s first and only retinal prosthesis that has been approved by the United States Food and Drug Administration (FDA and has been given the CE-Mark for sale within the European Economic Area (EEA. The incidence of serious adverse events from Argus II implantation decreased over time after minor changes in the implant design and improvements in the surgical steps used for the procedure had been made. In order to further decrease the scleral incision-related complications and enhance the assessment of the tack position and the contact between the array and the inner macular surface, we used an ophthalmic endoscope during the regular course of Argus II implantation surgery in 2 patients with late-stage retinitis pigmentosa in an attempt to improve the anatomical and functional outcomes.

  20. Interleukin-4 enhances trafficking and functional activities of GM-CSF-stimulated mouse myeloid-derived dendritic cells at late differentiation stage

    Energy Technology Data Exchange (ETDEWEB)

    Yin, Shu-Yi, E-mail: in_shuyi@hotmail.com [Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC (China); Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan, ROC (China); Taiwan International Graduate Program (TIGP), Molecular and Biological Agricultural Sciences Program, Academia Sinica, Taipei, Taiwan, ROC (China); Wang, Chien-Yu, E-mail: sallywang1973@hotmail.com [Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC (China); Yang, Ning-Sun, E-mail: nsyang@gate.sinica.edu.tw [Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC (China); Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan, ROC (China); Taiwan International Graduate Program (TIGP), Molecular and Biological Agricultural Sciences Program, Academia Sinica, Taipei, Taiwan, ROC (China)

    2011-09-10

    Mouse bone marrow-derived dendritic cells (BMDCs) are being employed as an important model for translational research into the development of DC-based therapeutics. For such use, the localization and specialized mobility of injected BMDCs within specific immune tissues are known to define their immunity and usefulness in vivo. In this study, we demonstrate that IL-4, a key driving factor for in vitro propagation and differentiation of BMDCs, when added during a late culture stage can enhance the in vivo trafficking activity of granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced BMDCs. It suggests that the temporal control of IL-4 stimulation during the in vitro generation of DCs drastically affects the DC trafficking efficiency in vivo. With this modification of IL-4 stimulation, we also show that much less cytokine was needed to generate BMDCs with high purity and yield that secrete a high level of cytokines and possess a good capacity to induce proliferation of allogeneic CD4{sup +}T cells, as compared to the conventional method that uses a continuous supplement of GM-CSF and IL-4 throughout cultivation. These results provide us with an important know-how for differentiation of BMDCs from myeloid stem cells, and for use of other immune cells in related medical or stem cell applications.

  1. MRI assessment of the alar ligaments in the late stage of whiplash injury - a study of structural abnormalities and observer agreement

    Energy Technology Data Exchange (ETDEWEB)

    Krakenes, J.; Moen, G.; Nordli, H. [Section of Neuroradiology, Department of Radiology, Haukeland University Hospital, University of Bergen Medical School (Norway); Kaale, B.R. [Firda Medical Centre, Sandane (Norway); Gilhus, N.E. [Department of Neurology, Haukeland University Hospital, University of Bergen Medical School (Norway); Rorvik, J. [Department of Radiology, Haukeland University Hospital, University of Bergen Medical School (Norway)

    2002-07-01

    Our aim was to characterise and classify structural changes in the alar ligaments in the late stage of whiplash injuries by use of a new MRI protocol, and to evaluate the reliability and the validity of this classification. We studied 92 whiplash-injured and 30 uninjured individuals who underwent proton density-weighted MRI of the craniovertebral junction in three orthogonal planes. Changes in the alar ligaments (grades 0-3) based on the ratio between the high signal area and the total cross-sectional area were rated twice at a 4-month interval, independently by three radiologists. Inter- and intraobserver statistics were calculated by ordinary and weighted kappa. Cases classified differently were reviewed to identify potential causes for disagreement. The alar ligaments were satisfactorily demonstrated in all cases (244 ligaments in 122 individuals). The lesions, 2-9 years after the injury, varied from small high-signal spots to high signal throughout the cross-sectional area. Signal was highest near the condylar insertion in 82 of 94 ligaments, indicating a lesion near that insertion, and near the dental insertion in eight, indicating a medial lesion. No grade 2 or 3 lesion was found in the control group. At least two observers assigned the same grade to 214 ligaments (87.7%) on the second occasion. In 30 ligaments (12.3%) this agreement was not obtained. Pair-wise interobserver agreement (weighted kappa) was fair to moderate (0.31-0.54) in the first grading, improving to moderate (0.49-0.57) in the second. Intraobserver agreement (weighted kappa) was moderate to good (0.43-0.70). Whiplash trauma can cause permanent damage to the alar ligaments, which can be shown by high-resolution proton density-weighted MRI. Reliability of classification of alar ligament lesions needs to be improved. (orig.)

  2. MRI assessment of the alar ligaments in the late stage of whiplash injury - a study of structural abnormalities and observer agreement

    International Nuclear Information System (INIS)

    Krakenes, J.; Moen, G.; Nordli, H.; Kaale, B.R.; Gilhus, N.E.; Rorvik, J.

    2002-01-01

    Our aim was to characterise and classify structural changes in the alar ligaments in the late stage of whiplash injuries by use of a new MRI protocol, and to evaluate the reliability and the validity of this classification. We studied 92 whiplash-injured and 30 uninjured individuals who underwent proton density-weighted MRI of the craniovertebral junction in three orthogonal planes. Changes in the alar ligaments (grades 0-3) based on the ratio between the high signal area and the total cross-sectional area were rated twice at a 4-month interval, independently by three radiologists. Inter- and intraobserver statistics were calculated by ordinary and weighted kappa. Cases classified differently were reviewed to identify potential causes for disagreement. The alar ligaments were satisfactorily demonstrated in all cases (244 ligaments in 122 individuals). The lesions, 2-9 years after the injury, varied from small high-signal spots to high signal throughout the cross-sectional area. Signal was highest near the condylar insertion in 82 of 94 ligaments, indicating a lesion near that insertion, and near the dental insertion in eight, indicating a medial lesion. No grade 2 or 3 lesion was found in the control group. At least two observers assigned the same grade to 214 ligaments (87.7%) on the second occasion. In 30 ligaments (12.3%) this agreement was not obtained. Pair-wise interobserver agreement (weighted kappa) was fair to moderate (0.31-0.54) in the first grading, improving to moderate (0.49-0.57) in the second. Intraobserver agreement (weighted kappa) was moderate to good (0.43-0.70). Whiplash trauma can cause permanent damage to the alar ligaments, which can be shown by high-resolution proton density-weighted MRI. Reliability of classification of alar ligament lesions needs to be improved. (orig.)

  3. Evaluation of Different Antiretroviral Drug Protocols on Naturally Infected Feline Immunodeficiency Virus (FIV Cats in the late Phase of the Asymptomatic Stage of Infection

    Directory of Open Access Journals (Sweden)

    Paola B. Pisano

    2012-05-01

    Full Text Available The aim of this study was to evaluate the efficacy of the antiretrovirals: Zidovudine (ZDV alone; ZDV + Recombinant Human Interferon-α (rHuIFN-α; ZDV + Lamivudine (3TC and ZDV + valproic acid (Valp on naturally feline immunodeficiency virus (FIV-infected cats, in the late phase of the asymptomatic stage of infection. The follow-up was performed over one year, through clinical evaluation and the determination of viral loads and CD4+/CD8+ ratios. Neurological signs were studied by visual and auditory evoked potentials (VEP, AEP and the responses were abnormal in 80% of the FIV-infected cats. After one year, an improvement in VEP and AEP was observed in the ZDV + Valp group and a worsening in the group receiving ZDV + rHuIFN-α. The CD4+/CD8+ ratio showed a significant increase (both intra and inter-groups only in ZDV and ZDV + 3TC, between their pre-treatment and one year values, as well as among the other groups. Viral load only showed a significant decrease in ZDV and ZDV + 3TC groups, when comparing the values at one year of treatment vs. pre-treatment values and when the different groups were compared. In addition, the viral load decrease was significantly more pronounced in the ZDV + 3TC vs. ZDV group. We conclude that ZDV and ZDV + 3TC produce significant reductions in viral load and stimulate a recovery of the CD4+/CD8+ ratio, compared with the other protocols. It is clear that the addition of 3TC resulted in a greater reduction in viral load than use of ZDV as a single drug. Therefore, the combination ZDV + 3TC could be more effective than the sole use of ZDV.

  4. Comparison of the effectiveness of ''late'' and ''early'' prophylactic cranial irradiation in patients with limited-stage small cell lung cancer

    International Nuclear Information System (INIS)

    Sas-Korczynska, Beata; Korzeniowski, Stanislaw; Wojcik, Ewa

    2010-01-01

    Purpose: to evaluate the effectiveness of timing of application of prophylactic cranial irradiation (PCI) in patients with small cell lung cancer in limited stage of disease (LS SCLC). Patients and methods: between 1995 and 2004, 129 patients with LS SCLC were treated within two consecutive phase II studies assessing different schedules of combined treatment. All patients received chemotherapy and concurrent thoracic radiotherapy. In 86 patients (66.7%) who developed complete response in the thorax, PCI was performed either after chemoradiotherapy (''late'' PCI, n = 45 [52.4%]) or during chemoradiotherapy (''early'' PCI, n = 41 [47.7%]). In the latter case, PCI was given immediately after the end of thoracic radiotherapy and prior to the last cycles of chemotherapy to a total dose of 30 Gy in 2-Gy fractions to the whole brain. The results were evaluated with regard to 4-year rates of overall survival, disease-free survival, and brain metastases-free survival. Additionally, the prognostic role of PCI application and its time delay in relation to survival rates and incidence of brain metastases was estimated. Results: the 4-year survival rates were 25.5% for overall survival, 26.8% for disease-free survival, and 67.8% for brain metastases-free survival. During the observation period, 32 patients (24.8%) developed brain metastases, which occured in 20 of 43 patients (46.5%) without and only in twelve out of 86 patients (14%) with PCI. The 4-year brain metastases-free survival rates were 81.8%, if PCI was applied, versus 32.2%, if no such procedure was used (for p = 0.0000). The timing of PCI appeared to be an important factor in terms of decreasing the incidence of brain metastases. Conclusion: PCI significantly decreases the incidence of brain metastases and delays their development in patients with LS SCLC. ''Early'' PCI is more effective than PCI applied after combined therapy. (orig.)

  5. Analysis of in-field control and late toxicity for adults with early-stage Hodgkin's disease treated with chemotherapy followed by radiotherapy

    International Nuclear Information System (INIS)

    Chronowski, Gregory M.; Wilder, Richard B.; Tucker, Susan L.; Ha, Chul S.; Younes, Anas; Fayad, Luis; Rodriguez, Maria A.; Hagemeister, Fredrick B.; Barista, Ibrahim; Cabanillas, Fernando; Cox, James D.

    2003-01-01

    chemotherapy for bulky nodal disease, the 5-year IF control rates were 99% and 92%, respectively (p=0.0006). The 15-year actuarial risks of coronary artery disease requiring surgical intervention and of solid tumors were 4.1% and 16.8%, respectively. There was a trend toward a greater risk of solid tumors in patients who received extended-field RT rather than involved-field or regional RT (p=0.08). Conclusions: In patients with nonbulky disease, induction chemotherapy followed by RT to a median dose of 40.0 Gy resulted in excellent IF control, regardless of the chemotherapeutic regimen used, the fact that only 1-2 cycles of chemotherapy were delivered, and the response to chemotherapy. There was a trend toward a higher incidence of solid tumors in patients who received consolidation RT to both sides rather than only one side of the diaphragm. Ongoing Phase III trials will help clarify whether lower RT doses and smaller RT fields after chemotherapy can maintain the IF control seen in our study, but with a lower incidence of late complications in patients with Stage I or II Hodgkin's disease

  6. Analysis of in-field control and late toxicity for adults with early-stage Hodgkin's disease treated with chemotherapy followed by radiotherapy.

    Science.gov (United States)

    Chronowski, Gregory M; Wilder, Richard B; Tucker, Susan L; Ha, Chul S; Younes, Anas; Fayad, Luis; Rodriguez, Maria A; Hagemeister, Fredrick B; Barista, Ibrahim; Cabanillas, Fernando; Cox, James D

    2003-01-01

    -year IF control rates were 99% and 92%, respectively (p = 0.0006). The 15-year actuarial risks of coronary artery disease requiring surgical intervention and of solid tumors were 4.1% and 16.8%, respectively. There was a trend toward a greater risk of solid tumors in patients who received extended-field RT rather than involved-field or regional RT (p = 0.08). In patients with nonbulky disease, induction chemotherapy followed by RT to a median dose of 40.0 Gy resulted in excellent IF control, regardless of the chemotherapeutic regimen used, the fact that only 1-2 cycles of chemotherapy were delivered, and the response to chemotherapy. There was a trend toward a higher incidence of solid tumors in patients who received consolidation RT to both sides rather than only one side of the diaphragm. Ongoing Phase III trials will help clarify whether lower RT doses and smaller RT fields after chemotherapy can maintain the IF control seen in our study, but with a lower incidence of late complications in patients with Stage I or II Hodgkin's disease.

  7. Factores asociados al estadio clínico avanzado en el inicio de la terapia antirretroviral Factors associated to late clinical stage at the initiation of antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Eduardo Warley

    2012-10-01

    Full Text Available A fin de evaluar la frecuencia y posibles factores asociados a la presencia de estadio clínico avanzado al inicio de terapia antirretroviral (ECAITA, efectuamos un análisis retrospectivo de datos de dos cohortes prospectivas de pacientes infectados por HIV que iniciaron terapia antirretroviral (sin tratamiento anterior entre 2005 y 2009. Se analizaron las historias clínicas de 264 pacientes, 123 mujeres (46.6% y 141 hombres (53.4%. La mediana de edad fue de 37.7 años. Observamos ECAITA en 132 casos (50%, de los cuales 102 (77.2% se asociaron a diagnóstico tardío de infección por HIV y 30 (22.8% a pacientes con diagnóstico previo no retenidos en el cuidado clínico de la salud. La mediana de células CD4 fue 120/ml y de carga viral 58 038 copias/ml. El recuento de células CD4 era inferior a 200 cel/ml en 174 pacientes (71.3%. Los hombres presentaron ECAITA con mayor frecuencia que las mujeres (59.8% vs. 40.2%, en quienes el diagnóstico se realizó durante el control de un embarazo en el 25.2% de los casos. Consumo elevado de alcohol (p 0.006, ser soltero (p 0.04 y nivel de educación menor al secundario completo (p 0.008 se asociaron a ECAITA en el análisis bivariado. Ser de sexo masculino (p 0.003 fue el único factor asociado tanto en el análisis bivariado como en el multivariado. Nuestros datos refuerzan la necesidad de expandir el testeo para HIV y deberían impulsar a definir acciones programáticas que promuevan el ingreso precoz al cuidado de la infección por HIV.In order to evaluate the frequency of a late clinical stage in HIV infected patients at onset of antiretroviral therapy (LART and to identify possible associated factors, we performed a retrospective analysis of data reported in two prospective cohorts of HIV infected patients who started antiretroviral therapy for the first time between 2005 and 2009. Medical records of 265 patients -123 women (46.6% and 141 men, median age 37.7 years old- were analyzed. LART was

  8. Origin of pegmatites and fluids at Ponta Negra (RJ, Brazil) during late- to post-collisional stages of the Gondwana Assembly

    Science.gov (United States)

    Bongiolo, Everton Marques; Renac, Christophe; Piza, Patricia d'Almeida de Toledo; Schmitt, Renata da Silva; Mexias, André Sampaio

    2016-01-01

    The Ponta Negra Pegmatites (PNP), part of a pegmatitic province in Rio de Janeiro State, Brazil, crop out along an intensely deformed, medium- to high-grade metamorphic area that is proximal to a crustal-scale thrust zone developed during the Brasiliano/Pan-African Orogeny. Fieldwork shows that the pegmatites formed in two distinct stages: (i) syn-collisional leucosome veins (Group I) conformable with the tectonic foliation of the gneissic host rocks and (ii) late- to post-collisional dykes (Group II) that cross-cut the same tectonic foliation at a high angle. In this paper, we use geochemistry of whole-rock and mineral separates (alkali-feldspar and biotite), fluid inclusion microthermometry and stable isotopic (δ18O, δD, δ13C) determinations on minerals (quartz, alkali-feldspar, biotite and magnetite) and fluid inclusions to provide insights into the composition of the pegmatite-forming melts, associated fluids, and their geotectonic significance. U-Pb SHRIMP dating of the Cajú syenogranite was performed to evaluate and compare the timing of magmatic events along the Cabo Frio Tectonic Domain as this is the closest post-collisional pluton to the studied pegmatites. The calculated temperature for the Group I syn-collisional veins (740 °C) is similar to previous estimates for the peak metamorphic conditions in the study area. Variations in the temperature of the Group II pegmatite dykes obtained from stable isotopes (380 to 720 °C), and microthermometric data from primary fluid inclusions with traces of N2 (Th = 280 to 360 °C), may reflect the thermodynamics of the pegmatite crystallization, exsolution textures and isotopic exchange. The composition of fluids in equilibrium within the pegmatite dykes consists of magmatic and metamorphic components. The minimum pressures calculated for the emplacement of the pegmatites are equivalent to a shallow crustal depth between 1.7 and 3.5 km, which corresponds to the exhumation of the orogen since the emplacement of

  9. NCI Pediatric Preclinical Testing Consortium

    Science.gov (United States)

    NCI has awarded grants to five research teams to participate in its Pediatric Preclinical Testing Consortium, which is intended to help to prioritize which agents to pursue in pediatric clinical trials.

  10. Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

    Science.gov (United States)

    Dubois, Bruno; Hampel, Harald; Feldman, Howard H; Scheltens, Philip; Aisen, Paul; Andrieu, Sandrine; Bakardjian, Hovagim; Benali, Habib; Bertram, Lars; Blennow, Kaj; Broich, Karl; Cavedo, Enrica; Crutch, Sebastian; Dartigues, Jean-François; Duyckaerts, Charles; Epelbaum, Stéphane; Frisoni, Giovanni B; Gauthier, Serge; Genthon, Remy; Gouw, Alida A; Habert, Marie-Odile; Holtzman, David M; Kivipelto, Miia; Lista, Simone; Molinuevo, José-Luis; O'Bryant, Sid E; Rabinovici, Gil D; Rowe, Christopher; Salloway, Stephen; Schneider, Lon S; Sperling, Reisa; Teichmann, Marc; Carrillo, Maria C; Cummings, Jeffrey; Jack, Cliff R

    2016-03-01

    During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations. Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  11. Apple juice improved behavioral but not cognitive symptoms in moderate-to-late stage Alzheimer's disease in an open-label pilot study.

    Science.gov (United States)

    Remington, Ruth; Chan, Amy; Lepore, Alicia; Kotlya, Elizabeth; Shea, Thomas B

    2010-06-01

    Preclinical studies demonstrate that apple juice exerts multiple beneficial effects including reduction of central nervous system oxidative damage, suppression of Alzheimer's disease (AD) hallmarks, improved cognitive performance, and organized synaptic signaling. Herein, we initiated an open-label clinical trial in which 21 institutionalized individuals with moderate-to-severe AD consumed 2 4-oz glasses of apple juice daily for 1 month. Participants demonstrated no change in the Dementia Rating Scale, and institutional caregivers reported no change in Alzheimer's Disease Cooperative Study (ADCS)-Activities of Daily Living (ADL) in this brief study. However, caregivers reported an approximate 27% (P Inventory, with the largest changes in anxiety, agitation, and delusion. This pilot study suggests that apple juice may be a useful supplement, perhaps to augment pharmacological approaches, for attenuating the decline in mood that accompanies progression of AD, which may also reduce caregiver burden.

  12. The Influence of Developmental Stage on the Relationship Between Severity of Late Effects of Anticancer Therapy and Perceived Quality of Life of Childhood Cancer Survivors

    Czech Academy of Sciences Publication Activity Database

    Blatný, Marek; Jelínek, Martin; Sobotková, Veronika; Kepák, T.

    2013-01-01

    Roč. 3, August (2013), s. 1-5 ISSN 2158-2440 R&D Projects: GA ČR(CZ) GAP407/11/2421 Institutional support: RVO:68081740 Keywords : childhood cancer survivors * quality of life * late effects * age differences Subject RIV: AN - Psychology http://sgo.sagepub.com/content/3/3/2158244013500678

  13. Early renin-angiotensin system intervention is more beneficial than late intervention in delaying end-stage renal disease in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Schievink, B; Kröpelin, T; Mulder, S

    2016-01-01

    AIMS: To develop and validate a model to simulate progression of diabetic kidney disease (DKD) from early onset until end-stage renal disease (ESRD), and to assess the effect of renin-angiotensin system (RAS) intervention in early, intermediate and advanced stages of DKD. METHODS: We used data from...

  14. Preclinical models in radiation oncology

    Directory of Open Access Journals (Sweden)

    Kahn Jenna

    2012-12-01

    Full Text Available Abstract As the incidence of cancer continues to rise, the use of radiotherapy has emerged as a leading treatment modality. Preclinical models in radiation oncology are essential tools for cancer research and therapeutics. Various model systems have been used to test radiation therapy, including in vitro cell culture assays as well as in vivo ectopic and orthotopic xenograft models. This review aims to describe such models, their advantages and disadvantages, particularly as they have been employed in the discovery of molecular targets for tumor radiosensitization. Ultimately, any model system must be judged by its utility in developing more effective cancer therapies, which is in turn dependent on its ability to simulate the biology of tumors as they exist in situ. Although every model has its limitations, each has played a significant role in preclinical testing. Continued advances in preclinical models will allow for the identification and application of targets for radiation in the clinic.

  15. Stages and Behaviors

    Science.gov (United States)

    ... Caregiving Middle-Stage Caregiving Late-Stage Caregiving Behaviors Aggression & Anger Anxiety & Agitation Depression Hallucinations Memory Loss & Confusion Repetition Sleep Issues & Sundowning Suspicion & Delusions Wandering Abuse Start Here What You Need to Know Online ...

  16. Early-Stage Caregiving

    Science.gov (United States)

    ... Caregiving Middle-Stage Caregiving Late-Stage Caregiving Behaviors Aggression & Anger Anxiety & Agitation Depression Hallucinations Memory Loss & Confusion Repetition Sleep Issues & Sundowning Suspicion & Delusions Wandering Abuse Start Here What You Need to Know Online ...

  17. Specific Antibody Production by Blood B Cells is Retained in Late Stage Drug-naïve HIV-infected Africans

    Directory of Open Access Journals (Sweden)

    Lydie Béniguel

    2004-01-01

    Full Text Available Unseparated peripheral blood mononuclear cells (PBMCs obtained from drug-naïve African individuals living in a context of multi-infections and presenting with high viral load (VL, were cultured in vitro and tested for their ability to produce antibodies (Abs reacting with HIV-1 antigens. Within these PBMCs, circulating B cells were differentiated in vitro and produced IgG Abs against not only ENV, but also GAG and POL proteins. Under similar experimental conditions, HAART treated patients produced Abs to ENV proteins only. The in vitro antibody production by drug-naïve individuals' PBMCs depended on exogenous cytokines (IL-2 and IL-10 but neither on the re-stimulation of reactive cells in cultures by purified HIV-1-gp 160 antigen nor on the re-engagement of CD40 surface molecules. Further, it was not abrogated by the addition of various monoclonal Abs (mAbs to co-stimulatory molecules. This suggests that the in vitro antibody production by drug-naïve individuals' PBMCs resulted from the maturation of already envelope and core antigen-primed, differentiated B cells, presumably pre-plasma cells, which are not known to circulate at homeostasy. As in vitro produced Abs retained the capacity of binding antigen and forming complexes, this study provides pre-clinical support for functional humoral responses despite major HIV- and other tropical pathogen-induced B cell perturbations.

  18. Preclinical electrogastrography in experimental pigs

    Science.gov (United States)

    Květina, Jaroslav; Varayil, Jithinraj Edakkanambeth; Ali, Shahzad Marghoob; Kuneš, Martin; Bureš, Jan; Tachecí, Ilja; Rejchrt, Stanislav; Kopáčová, Marcela

    2010-01-01

    Surface electrogastrography (EGG) is a non-invasive means of recording gastric myoelectric activity or slow waves from cutaneous leads placed over the stomach. This paper provides a comprehensive review of preclinical EGG. Our group recently set up and worked out the methods for EGG in experimental pigs. We gained our initial experience in the use of EGG in assessment of porcine gastric myoelectric activity after volume challenge and after intragastric administration of itopride and erythromycin. The mean dominant frequency in pigs is comparable with that found in humans. EGG in experimental pigs is feasible. Experimental EGG is an important basis for further preclinical projects in pharmacology and toxicology. PMID:21217873

  19. Preclinical Pharmacokinetic/Pharmacodynamic Modeling and Simulation in the Pharmaceutical Industry: An IQ Consortium Survey Examining the Current Landscape

    OpenAIRE

    Schuck, Edgar; Bohnert, Tonika; Chakravarty, Arijit; Damian-Iordache, Valeriu; Gibson, Christopher; Hsu, Cheng-Pang; Heimbach, Tycho; Krishnatry, Anu Shilpa; Liederer, Bianca M; Lin, Jing; Maurer, Tristan; Mettetal, Jerome T; Mudra, Daniel R; Nijsen, Marjoleen JMA; Raybon, Joseph

    2015-01-01

    The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses, ~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its...

  20. Effects of late winter pruning at different phenological stages on vine yield components and berry composition in La Rioja, North-central Spain

    Directory of Open Access Journals (Sweden)

    Wei Zheng

    2017-11-01

    Significance and impact of the study: The outcomes of this research open a door for the winegrowers to realize the yield control in a simple way. Also, for those who only pursue wines of top quality (regardless of production, a very late winter pruning might provide them with high-quality grapes. Moreover, as can be seen obviously from our results, viticulturists could postpone the budburst date to whatever extent they wish thus reducing the risk of spring frost injury to zero, though this point is not our focus in the study.

  1. Homeobox protein MSX-1 inhibits expression of bone morphogenetic protein 2, bone morphogenetic protein 4, and lymphoid enhancer-binding factor 1 via Wnt/β-catenin signaling to prevent differentiation of dental mesenchymal cells during the late bell stage.

    Science.gov (United States)

    Feng, Xiao-Yu; Wu, Xiao-Shan; Wang, Jin-Song; Zhang, Chun-Mei; Wang, Song-Lin

    2018-02-01

    Homeobox protein MSX-1 (hereafter referred to as MSX-1) is essential for early tooth-germ development. Tooth-germ development is arrested at bud stage in Msx1 knockout mice, which prompted us to study the functions of MSX-1 beyond this stage. Here, we investigated the roles of MSX-1 during late bell stage. Mesenchymal cells of the mandibular first molar were isolated from mice at embryonic day (E)17.5 and cultured in vitro. We determined the expression levels of β-catenin, bone morphogenetic protein 2 (Bmp2), Bmp4, and lymphoid enhancer-binding factor 1 (Lef1) after knockdown or overexpression of Msx1. Our findings suggest that knockdown of Msx1 promoted expression of Bmp2, Bmp4, and Lef1, resulting in elevated differentiation of odontoblasts, which was rescued by blocking the expression of these genes. In contrast, overexpression of Msx1 decreased the expression of Bmp2, Bmp4, and Lef1, leading to a reduction in odontoblast differentiation. The regulation of Bmp2, Bmp4, and Lef1 by Msx1 was mediated by the Wnt/β-catenin signaling pathway. Additionally, knockdown of Msx1 impaired cell proliferation and slowed S-phase progression, while overexpression of Msx1 also impaired cell proliferation and prolonged G1-phase progression. We therefore conclude that MSX-1 maintains cell proliferation by regulating transition of cells from G1-phase to S-phase and prevents odontoblast differentiation by inhibiting expression of Bmp2, Bmp4, and Lef1 at the late bell stage via the Wnt/β-catenin signaling pathway. © 2017 Eur J Oral Sci.

  2. Comparative Cost-Effectiveness of Drugs in Early versus Late Stages of Cancer : Review of the Literature and a Case Study in Breast Cancer

    NARCIS (Netherlands)

    Dvortsin, Evgeni; Gout-Zwart, Judith; Eijssen, Ernst-Lodewijk Marie; van Brussel, Jan; Postma, Maarten J.

    2016-01-01

    Background Many oncological drugs that are being used in the adjuvant setting were first submitted for reimbursement in the metastatic stage, with differences in incremental cost-effectiveness ratios (ICERs) in both settings having potential implications for reimbursement and pricing. The aim of

  3. Preclinical diagnosis of Alzheimer's disease: Prevention or prediction?

    Directory of Open Access Journals (Sweden)

    Ricardo Nitrini

    Full Text Available Abstract The diagnosis of Alzheimer's disease (AD for cases with dementia may be too late to allow effective treatment. Criteria for diagnosis of preclinical AD suggested by the Alzheimer's Association include the use of molecular and structural biomarkers. Preclinical diagnosis will enable testing of new drugs and forms of treatment toward achieving successful preventive treatment. But what are the advantages for the individual? To know that someone who is cognitively normal is probably going to develop AD's dementia when there is no effective preventive treatment is definitely not good news. A research method whereby volunteers are assigned to receive treatment or placebo without knowing whether they are in the control or at-risk arm of a trial would overcome this potential problem. If these new criteria are used wisely they may represent a relevant milestone in the search for a definitive treatment for AD.

  4. Spatial reversal learning in preclinical scrapie-inoculated mice.

    Science.gov (United States)

    Lysons, A M; Woollard, S J

    1996-04-10

    Acquisition and reversal of a two-choice spatial discrimination were tested in scrapie-inoculated mice. Both acquisition and reversal were normal in mice tested 138 and 103 days prior to the onset of clinical symptoms. At 65 days before onset of clinical symptoms, scrapie-inoculated mice required more trails to criterion in reversal learning, but this effect was not significant in a second experiment (68 days preclinical) and was transient: no effect was seen 33 days before symptoms. However, the course of reversal learning was abnormal in all three late preclinical groups (68, 65 and 33 days before symptoms). Reversal learning in these three groups was characterized by a rapid extinction of the original discrimination, followed by a period, absent in controls, during which performance showed no further improvement. This effect corresponds in time of onset to the appearance of characteristic neuropathological features.

  5. The influence of late-stage pupal irradiation and increased irradiated: un-irradiated male ratio on mating competitiveness of the malaria mosquito Anopheles arabiensis Patton.

    Science.gov (United States)

    Helinski, M E H; Knols, B G J

    2009-06-01

    Competitiveness of released males in genetic control programmes is of critical importance. In this paper, we explored two scenarios to compensate for the loss of mating competitiveness after pupal stage irradiation in males of the malaria mosquito Anopheles arabiensis. First, competition experiments with a higher ratio of irradiated versus un-irradiated males were performed. Second, pupae were irradiated just prior to emergence and male mating competitiveness was determined. Males were irradiated in the pupal stage with a partially or fully-sterilizing dose of 70 or 120 Gy, respectively. Pupae were irradiated aged 20-26 h (young) as routinely performed, or the pupal stage was artificially prolonged by cooling and pupae were irradiated aged 42-48 h (old). Irradiated males competed at a ratio of 3:1:1 to un-irradiated males for mates in a large cage design. At the 3:1 ratio, the number of females inseminated by males irradiated with 70 Gy as young pupae was similar to the number inseminated by un-irradiated males for the majority of the replicates. At 120 Gy, significantly fewer females were inseminated by irradiated than by un-irradiated males. The irradiation of older pupae did not result in a significantly improved male mating competitiveness compared to the irradiation of young pupae. Our findings indicate that the loss of competitiveness after pupal stage irradiation can be compensated for by a threefold increase of irradiated males, but only for the partially-sterilizing dose. In addition, cooling might be a useful tool to facilitate handling processes of large numbers of mosquitoes in genetic control programmes.

  6. Sequence-dependent toxicity and small bowel mucosal injury in neonatal mice treated with low doses of 5-azacytidine and X-irradiation at the late organogenesis stage

    International Nuclear Information System (INIS)

    Schmahl, W.

    1983-01-01

    A combined treatment of pregnant mice on day 12 of gestation with both azacytidine and X-irradiation in low doses induces sequence-dependent histological effects. These effects, in turn, induce different symptomatic signs if evaluated either prenatally or neonatally. In the azacytidine treatment/X-irradiation sequence the malformations of the fetal forebrain are predominant. Consequently, these dams show a high incidence in the stillbirth rate. Conversely, the X-irradiation/azacytidine treatment schedule leads only to a mild brain hypoplasia, and does not cause an increased stillbirth rate. In these offspring, however, a severe impairment of small bowel epithelial proliferation capacity was found. This is linked to an outstanding neonatal mortality within 48 h after birth. The pathogenesis of these sequence-dependent effects can be attributed to a selective vulnerability of cells in different stages of the generation cycle. This comprises a high degree of cytolethality affecting the S/G 2 -stage cells in azacytidine/X-irradiation treatment and the G 1 /S-stage cells in the reverse combinations (Schmahl 1979). The present observations show the validity of a teratological assay in providing a detailed analysis of the cell kinetic responses after combined noxious influences. (orig.)

  7. Glial Alterations From Early to Late Stages in a Model of Alzheimer’s Disease: Evidence of Autophagy Involvement in Aβ Internalization

    Science.gov (United States)

    Pomilio, Carlos; Pavia, Patricio; Gorojod, Roxana Mayra; Vinuesa, Angeles; Alaimo, Agustina; Galvan, Veronica; Kotler, Monica Lidia; Beauquis, Juan; Saravia, Flavia

    2017-01-01

    Alzheimer’s disease (AD) is a progressive neurodegenerative disease without effective therapy. Brain amyloid deposits are classical histopathological hallmarks that generate an inflammatory reaction affecting neuronal and glial function. The identification of early cell responses and of brain areas involved could help to design new successful treatments. Hence, we studied early alterations of hippocampal glia and their progression during the neuropathology in PDAPP-J20 transgenic mice, AD model, at 3, 9, and 15 months (m) of age. At 3 m, before deposits formation, microglial Iba1 + cells from transgenic mice already exhibited signs of activation and larger soma size in the hilus, alterations appearing later on stratum radiatum. Iba1 immunohistochemistry revealed increased cell density and immunoreactive area in PDAPP mice from 9 m onward selectively in the hilus, in coincidence with prominent amyloid Congo red + deposition. At pre-plaque stages, GFAP+ astroglia showed density alterations while, at an advanced age, the presence of deposits was associated with important glial volume changes and apparently being intimately involved in amyloid degradation. Astrocytes around plaques were strongly labeled for LC3 until 15 m in Tg mice, suggestive of increased autophagic flux. Moreover, β-Amyloid fibrils internalization by astrocytes in in vitro conditions was dependent on autophagy. Co-localization of Iba1 with ubiquitin or p62 was exclusively found in microglia contacting deposits from 9 m onward, suggesting torpid autophagy. Our work characterizes glial changes at early stages of the disease in PDAPP-J20 mice, focusing on the hilus as an especially susceptible hippocampal subfield, and provides evidence that glial autophagy could play a role in amyloid processing at advanced stages. PMID:26235241

  8. Case series of infants presenting with end stage retinopathy of prematurity to two tertiary eye care facilities in Mexico: underlying reasons for late presentation.

    Science.gov (United States)

    Zepeda-Romero, Luz C; Meza-Anguiano, Alonso; Barrera-de León, Juan C; Angulo-Castellanos, Eusebio; Ramirez-Ortiz, Marco A; Gutiérrez-Padilla, José A; Gilbert, Clare E

    2015-06-01

    To describe the characteristics of infants with bilateral Stage 4b or 5 ROP (i.e. with subtotal or total retinal detachment) who presented to eye departments in two major cities in Mexico, to identify reasons why they may have become blind in order to recommend how programs could be improved. A large case-series of infants with Stage 4b or 5 ROP in both eyes confirmed by ultrasound who attended the ROP Clinic, Hospital Civil de Guadalajara from September 2010 to November 2012, and the Department of Ophthalmology, Hospital Infantil de Mexico Federico Gomez from December 2011 to December 2012 were identified from the diagnostic databases of each hospital. Mothers of infants in Guadalajara had a telephone interview. 89/94 eligible infants were included in the study, 48 in Guadalajara and 41 in Mexico City. Cases came from 22 of the 32 states in Mexico. Half of the infants attending Guadalajara 24/48 (50 %) had been cared for in NICUs without ROP screening programs and were not examined. Among the 24 infants cared for in NICUs with ROP programs, 7/24 (29.1 %) mothers reported that their infant had not been examined while in the NICU, and a further 9/24 (37.5 %) were either not referred for screening after discharge or they did not attend. Two infants had failed laser treatment. Strategies and resources to prevent end stage ROP have not been firmly established in Mexico. There is an urgent need to expand the coverage and quality of ROP programs, to ensure that existing screening guidelines are better adhered to, and to improve communication with parents.

  9. USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE

    Science.gov (United States)

    Langbaum, Jessica B.S.; Fleisher, Adam S.; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T.; Caselli, Richard J.; Tariot, Pierre N.; Reiman, Eric M.

    2014-01-01

    Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of or completely prevent clinical decline. Here, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how these advances have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research. PMID:23752908

  10. Biosafety preclinical trials of xenogenic, Allogeniec and autologous progenitor cells from fat tissue

    OpenAIRE

    Melikhova, Vs; Saburina, I.; Repin, V.; Novikova, N.; Murashev, A.; Orlov, A.

    2008-01-01

    Due to wide spread of new methods of regenerative medicine on basis of stem cells it has become increasingly necessary to establish standards of techniques using them. Preclinical trial of a new technology after receiving preliminary experiment results is a primary stage of its adoption. We carried out the experiments to assess biosafety of autogenous, allergenic and xenogeneic cultures of human and rat cells in models under standard preclinical experiments conditions used in a presentday pha...

  11. Late Embryogenesis Abundant Proteins

    NARCIS (Netherlands)

    Shih, M.D.; Hoekstra, F.A.; Hsing, Y.I.C.

    2008-01-01

    During the late maturation stage of seed development, water content decreases greatly. One of the most striking characteristics of mature orthodox seeds is their ability to withstand severe desiccation. Mechanisms of plant drought/desiccation tolerance have been studied by numerous groups, and a

  12. In vitro induced regulatory T cells are unique from endogenous regulatory T cells and effective at suppressing late stages of ongoing autoimmunity.

    Directory of Open Access Journals (Sweden)

    Thanh-Long M Nguyen

    Full Text Available Strategies to boost the numbers and functions of regulatory T cells (Tregs are currently being tested as means to treat autoimmunity. While Tregs have been shown to be effective in this role, strategies to manipulate Tregs to effectively suppress later stages of ongoing diseases need to be established. In this study, we evaluated the ability of TGF-β-induced Tregs (iTregs specific for the major self-antigen in autoimmune gastritis to suppress established autoimmune gastritis in mice. When transferred into mice during later stages of disease, iTregs demethylated the Foxp3 promoter, maintained Foxp3 expression, and suppressed effector T cell proliferation. More importantly, these iTregs were effective at stopping disease progression. Untreated mice had high numbers of endogenous Tregs (enTregs but these were unable to stop disease progression. In contrast, iTregs, were found in relatively low numbers in treated mice, yet were effective at stopping disease progression, suggesting qualitative differences in suppressor functions. We identified several inhibitory receptors (LAG-3, PD-1, GARP, and TNFR2, cytokines (TGF-β1 and IL12p35, and transcription factors (IRF4 and Tbet expressed at higher levels by iTregs compared to enTregs isolated form mice with ongoing disease, which likely accounts for superior suppressor ability in this disease model. These data support efforts to use iTregs in therapies to treat establish autoimmunity, and show that iTregs are more effective than enTregs at suppressing inflammation in this disease model.

  13. A glass fiber-reinforced composite - bioactive glass cranioplasty implant: A case study of an early development stage implant removed due to a late infection.

    Science.gov (United States)

    Posti, Jussi P; Piitulainen, Jaakko M; Hupa, Leena; Fagerlund, Susanne; Frantzén, Janek; Aitasalo, Kalle M J; Vuorinen, Ville; Serlo, Willy; Syrjänen, Stina; Vallittu, Pekka K

    2015-03-01

    This case study describes the properties of an early development stage bioactive glass containing fiber-reinforced composite calvarial implant with histology that has been in function for two years and three months. The patient is a 33-year old woman with a history of substance abuse, who sustained a severe traumatic brain injury later unsuccessfully treated with an autologous bone flap and a custom-made porous polyethylene implant. She was thereafter treated with developmental stage glass fiber-reinforced composite - bioactive glass implant. After two years and three months, the implant was removed due to an implant site infection. The implant was analyzed histologically, mechanically, and in terms of chemistry and dissolution of bioactive glass. Mechanical integrity of the load bearing fiber-reinforced composite part of the implant was not affected by the in vivo period. Bioactive glass particles demonstrated surface layers of hydroxyapatite like mineral and dissolution, and related increase of pH was considerably less after two and three months period than that for fresh bioactive glass. There was a difference in the histology of the tissues inside the implant areas near to the margin of the implant that absorbed blood during implant installation surgery, showed fibrous tissue with blood vessels, osteoblasts, collagenous fibers with osteoid formation, and tiny clusters of more mature hard tissue. In the center of the implant, where there was less absorbed blood, only fibrous tissue was observed. This finding is in line with the combined positron emission tomography - computed tomography examination with (18F)-fluoride marker, which demonstrated activity of the mineralizing bone by osteoblasts especially at the area near to the margin of the implant 10 months after implantation. Based on these promising reactions found in the bioactive glass containing fiber-reinforced composite implant that has been implanted for two years and three months, calvarial

  14. Atom-Economical Dimerization Strategy by the Rhodium-Catalyzed Addition of Carboxylic Acids to Allenes: Protecting-Group-Free Synthesis of Clavosolide A and Late-Stage Modification.

    Science.gov (United States)

    Haydl, Alexander M; Breit, Bernhard

    2015-12-14

    Natural products of polyketide origin with a high level of symmetry, in particular C2 -symmetric diolides as a special macrolactone-based product class, often possess a broad spectrum of biological activity. An efficient route to this important structural motif was developed as part of a concise and highly convergent synthesis of clavosolide A. This strategy features an atom-economic "head-to-tail" dimerization by the stereoselective rhodium-catalyzed addition of carboxylic acids to terminal allenes with the simultaneous construction of two new stereocenters. The excellent efficiency and selectivity with which the C2 -symmetric core structures were obtained are remarkable considering the outcome under classical dimerization conditions. Furthermore, this approach facilitates late-stage modification and provides ready access to potential new lead structures. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Kinetics of telencephalic neural cell proliferation during the fetal regeneration period following a single X-irradiation at the late organogenesis stage. Pt. 2

    International Nuclear Information System (INIS)

    Schmahl, W.

    1983-01-01

    Autoradiographic studies were conducted at the cerebral hemispheres of mouse embryos X-irradiated on day 12 of gestation and of normal litter mates during the subsequent developmental period. By counting the percentage of labeled mitoses the generation time, the potential doubling time, the growth fraction, as well as the length of the individuall cell cycle stages of the neuroblast cells were determined. A continuous increase of generation time was found in the normal brains, concomitant with a latero-medial gradient in telencephalic wall differentiation progress. After X-irradiation this normal differentiation pattern still prevails, but with some marked topographical pecularities. The most important finding was a significant lengthening of the generation time at the medially situated rudiments of the ventricular zone and, similarly at the heterotopic cell islets located within the intermediary zone. Concomitant with this effect, which was seen mainly on days 15 and 17 of gestation, there was a marked increase of mitotic time of these special neuroblasts. The latter finding was regarded as a random event only, which has no causal relationship to the pathogenesis of the heterotopic islets or similar overgrowth anomalies after X-irradiation. In spite of the long generation time of these histological pecularities, they make a considerable contribution to the regeneration of the injured telencephalic wall: up to day 15 gestation the heterotopias had a growth fraction of nearly 1.0(=100 %), whereas the percentage of proliferating cells within the orthotopic remainders of the ventricular zone was only 44%. (orig.)

  16. Paired carbon stable-isotope records for the Cenomanian Stage (100.5 -93.9 Ma): correlation tool and Late Cretaceous pCO2 record?

    Science.gov (United States)

    Jarvis, Ian; Gröcke, Darren; Laurin, Jiří; Selby, David; Roest-Ellis, Sascha; Miles, Andrew; Lignum, John; Gale, Andrew; Kennedy, Jim

    2016-04-01

    Carbon stable-isotope stratigraphy of marine carbonates (δ13Ccarb) provides remarkable insights into past variation in the global carbon cycle, and has become firmly established as a powerful global correlation tool. Continuous δ13Ccarb time series are becoming increasingly available for much of the geological record, including the Upper Cretaceous. However, our knowledge of stratigraphic variation in the carbon isotopic composition of sedimentary organic matter (δ13Corg) is much poorer, and is generally restricted to organic-rich sedimentary successions and/or key boundary intervals. Close coupling exists between the global isotopic composition of the reduced and oxidised carbon reservoirs on geological time scales, but the stratigraphic resolution of most long-term δ13Corg Mesozoic records is inadequate to identify leads and lags in the responses of the two reservoirs to carbon cycle perturbations. Cenomanian times (100.5-93.9 Ma) represent perhaps the best documented episode of eustatic rise in sea level in Earth history and the beginning of the Late Mesozoic thermal maximum, driving global expansion of epicontinental seas and the onset of widespread pelagic and hemipelagic carbonate deposition. Significant changes occurred in global stable-isotope records, including two prominent perturbations of the carbon cycle - the Mid-Cenomanian Event I (MCEI; ~96.5-96.2 Ma) and Oceanic Anoxic Event 2 (OAE2; ~94.5-93.8 Ma). OAE2, one of two truly global Cretaceous OAEs, was marked by the widespread deposition of black shales, and a global positive carbon stable-isotope excursion of 2.0 - 2.5‰ δ13Ccarb, and up to 7‰ in the sulphur-bound phytane biomarker. MCEI, by contrast, shows a English Chalk reference section at Folkestone, and correlate the carbon-isotope events between England, France, Germany and Italy. Comparison of the Vergons δ13Ccarb vs. δ13Corg profiles demonstrates similar medium-term stratigraphic variation, but significant differences in both short

  17. Tacrolimus (FK506 suppresses TREM-1 expression at an early but not at a late stage in a murine model of fungal keratitis.

    Directory of Open Access Journals (Sweden)

    Weilan Huang

    Full Text Available To investigate the efficacy and mechanism of tacrolimus(FK506, which is a novel macrolide immunosuppressant, in inhibiting triggering receptor expressed on myeloid cells-1 (TREM-1 expression in a murine keratitis model induced by Aspergillus fumigatus.TREM-1 was detected in 11 fungus-infected human corneas by quantitative real-time PCR (qRT-PCR. RAW264.7 macrophages were divided into four groups, which received treatment with zymosan (100 µg/ml, zymosan (100 µg/ml + mTREM-1/Fc protein (1 µg/ml, or zymosan (100 µg/ml + FK506 (20 µM or negative-control treatment. After this treatment, the expression of TREM-1, interleukin-1β (IL-1β and tumor necrosis factor α (TNFα was assayed using qRT-PCR and ELISA. The mouse model of fungal keratitis was created by intrastromal injection with Aspergillus fumigatus, and the mice were divided into 2 groups: group A received vehicle eye drops 4 times each day, and group B received 4 doses of FK506 eye drops each day. Corneal damage was evaluated by clinical scoring and histologic examination,and myeloperoxidase (MPO protein levels were also detected by ELISA. The expression of TREM-1, IL-1β and TNFα was then determined at different time points using qRT-PCR and ELISA.TREM-1 expression dramatically increased in the human corneas with fungal keratitis. In contrast, FK506 reduced the expression of TREM-1, IL-1β and TNFα in RAW264.7 macrophages stimulated with zymosan. In the mouse model, at day 1 post-infection, the corneal score of the FK506-treated group was lower than that of the control, and polymorphonuclear neutrophil (PMN infiltration was diminished. TREM-1, IL-1β and TNFα expression was significantly reduced at the same time point. However, the statistically significant differences in cytokine expression, clinical scores and infiltration disappeared at 5 days post-infection.FK506 may inhibit the inflammation induced by fungi and alleviate the severity of corneal damage at an early stage of

  18. The genesis of the newly discovered giant Wuben magmatic Fe-Ti oxide deposit in the Emeishan Large Igneous Province: a product of the late-stage redistribution and sorting of crystal slurries

    Science.gov (United States)

    Bai, Zhong-Jie; Zhong, Hong; Zhu, Wei-Guang; Hu, Wen-Jun; Chen, Cai-Jie

    2018-04-01

    A giant Fe-Ti oxide deposit hosted by the Wuben mafic intrusion has recently been discovered in the Pan-Xi area of the Emeishan Large Igneous Province (ELIP). The evolved compositions of the gangue minerals within the Fe-Ti oxide ores indicate that they formed during later stages of magma differentiation than those within the neighboring Panzhihua intrusion or other ore-bearing intrusions in this area. The rocks from the Wuben intrusion and MZb of the Panzhihua intrusion contain compositionally similar silicate minerals and have similar titanomagnetite/ilmenite ratios, suggesting that the former is related to and probably connected to the latter by subsurface magmatic conduits. This indicates that unconsolidated minerals that formed in the MZb flowed as crystal slurries into the Wuben magma chamber during the later stages of evolution of the parental magma. The later secondary enrichment of Fe-Ti oxides by mechanical redistribution and the sorting of crystals as a result of density and size differences generated the Wuben massive Fe-Ti oxide bodies. The ilmenite was commonly saturated in the magma at late stage of differentiation in the ELIP, thereby the associated deposit contains much higher contents of ilmenite. This indicates that future exploration for Fe-Ti oxide mineralization in the ELIP should not merely focus on the lower parts of large layered intrusions but should also include nearby relatively small intrusions or even the upper parts of large intrusions, especially as ilmenite-enriched Fe-Ti oxide deposits may have greater economic value than ilmenite-poor deposits.

  19. Late Toxicity and Patient Self-Assessment of Breast Appearance/Satisfaction on RTOG 0319: A Phase 2 Trial of 3-Dimensional Conformal Radiation Therapy-Accelerated Partial Breast Irradiation Following Lumpectomy for Stages I and II Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Chafe, Susan, E-mail: susan.chafe@albertahealthservices.ca [Department of Radiation Oncology, Cross Cancer Institute-University of Alberta, Edmonton, Alberta (Canada); Moughan, Jennifer [Department of Radiation Oncology, RTOG Statistical Center, Philadelphia, Pennsylvania (United States); McCormick, Beryl [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Wong, John [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland (United States); Pass, Helen [Womens' Breast Center, Stamford Hospital, Stamford, Connecticut (United States); Rabinovitch, Rachel [Department of Radiation Oncology, University of Colorado Denver, Aurora, Colorado (United States); Arthur, Douglas W. [Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia (United States); Petersen, Ivy [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); White, Julia [Department of Radiation Oncology, Ohio State University, Columbus, Ohio (United States); Vicini, Frank A. [Michigan Healthcare Professionals/21st Century Oncology, Farmington Hills, Michigan (United States)

    2013-08-01

    Purpose: Late toxicities and cosmetic analyses of patients treated with accelerated partial breast irradiation (APBI) on RTOG 0319 are presented. Methods and Materials: Patients with stages I to II breast cancer ≤3 cm, negative margins, and ≤3 positive nodes were eligible. Patients received three-dimensional conformal external beam radiation therapy (3D-CRT; 38.5 Gy in 10 fractions twice daily over 5 days). Toxicity and cosmesis were assessed by the patient (P), the radiation oncologist (RO), and the surgical oncologist (SO) at 3, 6, and 12 months from the completion of treatment and then annually. National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, was used to grade toxicity. Results: Fifty-two patients were evaluable. Median follow-up was 5.3 years (range, 1.7-6.4 years). Eighty-two percent of patients rated their cosmesis as good/excellent at 1 year, with rates of 64% at 3 years. At 3 years, 31 patients were satisfied with the treatment, 5 were not satisfied but would choose 3D-CRT again, and none would choose standard radiation therapy. The worst adverse event (AE) per patient reported as definitely, probably, or possibly related to radiation therapy was 36.5% grade 1, 50% grade 2, and 5.8% grade 3 events. Grade 3 AEs were all skin or musculoskeletal-related. Treatment-related factors were evaluated to potentially establish an association with observed toxicity. Surgical bed volume, target volume, the number of beams used, and the use of bolus were not associated with late cosmesis. Conclusions: Most patients enrolled in RTOG 0319 were satisfied with their treatment, and all would choose to have the 3D-CRT APBI again.

  20. Compositionally heterogeneous podiform chromitite in the Shetland Ophiolite Complex (Scotland): Implications for chromitite petrogenesis and late-stage alteration in the upper mantle portion of a supra-subduction zone ophiolite

    Science.gov (United States)

    Derbyshire, E. J.; O'Driscoll, B.; Lenaz, D.; Gertisser, R.; Kronz, A.

    2013-03-01

    The mantle sequence of the ~ 492 Ma Shetland Ophiolite Complex (SOC; Scotland) contains abundant compositionally heterogeneous podiform chromitite bodies enclosed in elongate dunite lenses in the vicinity of the petrological Moho. Chromitite petrogenesis and late-stage alteration events recorded in these seams are examined here using petrography, mineral chemistry and crystal structural data. The resistant nature of Cr-spinel to serpentinisation and other late-stage alteration means that primary igneous compositions are preserved in unaltered crystal cores. Chromitite mineralogy and texture from five sampled localities at The Viels, Hagdale, Harold's Grave, Nikka Vord and Cliff reveal significant inter-pod chemical heterogeneity. The Cr-spinel mineral chemistry is consistent with supra-subduction zone melt extraction from the SOC peridotites. The occurrence of chromitite seams in the centres of the dunite lenses combined with variable Cr-spinel compositions at different chromitite seam localities supports a model of chromitite formation from spatially (and temporally?) fluctuating amounts of melt-rock interaction through channelised and/or porous melt flow. Pervasive serpentinisation of the SOC has led to the almost complete replacement of the primary (mantle) silicate mineral assemblages with serpentine (lizardite with minor chrysotile and antigorite). Magmatic sulphide (e.g., pentlandite) in dunite and chromitite is locally converted to reduced Ni-sulphide varieties (e.g., heazlewoodite and millerite). A post-serpentinisation (prograde) oxidisation event is recorded in the extensively altered Cliff chromitite seams in the west of the studied area, where chromitite Cr-spinel is extensively altered to ferritchromit. The ferritchromit may comprise > 50% of the volume of the Cliff Cr-spinels and contain appreciable quantities of 1-2 μm inclusions of sperrylite (PtAs2) and Ni-arsenide, signifying the coeval formation of these minerals with ferritchromit at

  1. Late stages of solar type protostars

    International Nuclear Information System (INIS)

    Winkler, K.H.A.

    1978-05-01

    A consistent hydrodynamical and radiative transfer calculation in spherical symmetry for a 1 M protostar is presented. The calculation starts with Larson's initial conditions and continues until almost all the material has fallen onto a hydrostatic core with a large outer convection zone. The innermost percent of the mass is partially degenerate. Due to the numerical technique used, the radius of the hydrostatic core is determined with a high degree of accuracy. (orig.) [de

  2. Relationship between damage clustering and mortality in systemic lupus erythematosus in early and late stages of the disease: cluster analyses in a large cohort from the Spanish Society of Rheumatology Lupus Registry.

    Science.gov (United States)

    Pego-Reigosa, José María; Lois-Iglesias, Ana; Rúa-Figueroa, Íñigo; Galindo, María; Calvo-Alén, Jaime; de Uña-Álvarez, Jacobo; Balboa-Barreiro, Vanessa; Ibáñez Ruan, Jesús; Olivé, Alejandro; Rodríguez-Gómez, Manuel; Fernández Nebro, Antonio; Andrés, Mariano; Erausquin, Celia; Tomero, Eva; Horcada Rubio, Loreto; Uriarte Isacelaya, Esther; Freire, Mercedes; Montilla, Carlos; Sánchez-Atrio, Ana I; Santos-Soler, Gregorio; Zea, Antonio; Díez, Elvira; Narváez, Javier; Blanco-Alonso, Ricardo; Silva-Fernández, Lucía; Ruiz-Lucea, María Esther; Fernández-Castro, Mónica; Hernández-Beriain, José Ángel; Gantes-Mora, Marian; Hernández-Cruz, Blanca; Pérez-Venegas, José; Pecondón-Español, Ángela; Marras Fernández-Cid, Carlos; Ibáñez-Barcelo, Mónica; Bonilla, Gema; Torrente-Segarra, Vicenç; Castellví, Iván; Alegre, Juan José; Calvet, Joan; Marenco de la Fuente, José Luis; Raya, Enrique; Vázquez-Rodríguez, Tomás Ramón; Quevedo-Vila, Víctor; Muñoz-Fernández, Santiago; Otón, Teresa; Rahman, Anisur; López-Longo, Francisco Javier

    2016-07-01

    To identify patterns (clusters) of damage manifestations within a large cohort of SLE patients and evaluate the potential association of these clusters with a higher risk of mortality. This is a multicentre, descriptive, cross-sectional study of a cohort of 3656 SLE patients from the Spanish Society of Rheumatology Lupus Registry. Organ damage was ascertained using the Systemic Lupus International Collaborating Clinics Damage Index. Using cluster analysis, groups of patients with similar patterns of damage manifestations were identified. Then, overall clusters were compared as well as the subgroup of patients within every cluster with disease duration shorter than 5 years. Three damage clusters were identified. Cluster 1 (80.6% of patients) presented a lower amount of individuals with damage (23.2 vs 100% in clusters 2 and 3, P Cluster 2 (11.4% of patients) was characterized by musculoskeletal damage in all patients. Cluster 3 (8.0% of patients) was the only group with cardiovascular damage, and this was present in all patients. The overall mortality rate of patients in clusters 2 and 3 was higher than that in cluster 1 (P clusters. Both in early and late stages of the disease, there was a significant association of these clusters with an increased risk of mortality. Physicians should pay special attention to the early prevention of damage in these two systems. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. Late Budgets

    DEFF Research Database (Denmark)

    Andersen, Asger Lau; Lassen, David Dreyer; Nielsen, Lasse Holbøll Westh

    are negative rather than positive; and when there is divided government. We test the hypotheses of the model using a unique data set of late budgets for US state governments, based on dates of budget approval collected from news reports and a survey of state budget o¢ cers for the period 1988...

  4. Preclinical models for obesity research

    Directory of Open Access Journals (Sweden)

    Perry Barrett

    2016-11-01

    Full Text Available A multi-dimensional strategy to tackle the global obesity epidemic requires an in-depth understanding of the mechanisms that underlie this complex condition. Much of the current mechanistic knowledge has arisen from preclinical research performed mostly, but not exclusively, in laboratory mouse and rat strains. These experimental models mimic certain aspects of the human condition and its root causes, particularly the over-consumption of calories and unbalanced diets. As with human obesity, obesity in rodents is the result of complex gene–environment interactions. Here, we review the traditional monogenic models of obesity, their contemporary optogenetic and chemogenetic successors, and the use of dietary manipulations and meal-feeding regimes to recapitulate the complexity of human obesity. We critically appraise the strengths and weaknesses of these different models to explore the underlying mechanisms, including the neural circuits that drive behaviours such as appetite control. We also discuss the use of these models for testing and screening anti-obesity drugs, beneficial bio-actives, and nutritional strategies, with the goal of ultimately translating these findings for the treatment of human obesity.

  5. Ethical Considerations of Preclinical Testing

    Directory of Open Access Journals (Sweden)

    Allen Goldenthal

    2015-12-01

    Full Text Available The numbers of animal tests being conducted are on a sharp incline.  Much of this increase is directly due to our ability to generate transgenic models and knock-outs, thereby increasing the validity of the animal model but not necessarily correlating directly with any translational medical benefits to the human counterpart.  In spite of our best efforts, there still exist species differences that prevent the application directly from animal to human, and in some examples having a completely different and adverse effect from that seen in the animal model. There are several ways in which we can improve the opportunity for a positive test outcome and at the same time reduce the animal usage which is associated with our current animal testing practices. The benefit of the 3R’s is that they encourage us not only to avoid wastage of life but that they require us to provide considerable foresight and extrapolated thought before directly engaging in the preclinical testing phase.

  6. Preclinical studies of dendrimer prodrugs.

    Science.gov (United States)

    Kojima, Chie

    2015-01-01

    Dendrimers are synthetic macromolecules with well-defined structures bearing a wide variety of functional groups on their periphery. These groups can be used to conjugate bioactive molecules such as drugs, ligands and imaging agents. Dendrimer prodrugs can be used to improve the water solubility and pharmacokinetic properties of the corresponding free drugs. This article summarizes preclinical studies pertaining to the use of drug-dendrimer conjugates as dendrimer prodrugs for the treatments of various diseases, including cancer and inflammatory diseases. A wide range of anticancer drugs have been conjugated to dendrimers via biodegradable linkers. The side effects of the parent drugs can be markedly reduced using dendrimer prodrugs, with some drugs showing improved efficacy. Anti-inflammatory agents have also been conjugated to dendrimers and used to treat a number of inflammatory diseases. Drug-dendrimer conjugates are preferable to drug-dendrimer complexes, where the use of degradable linkers is critical to the release of the drug. Polyethylene glycol and/or ligands can be added to a dendrimer prodrug, which is useful for the targeting of affected tissues. Imaging probes can also be incorporated into dendrimer prodrugs for the simultaneous delivery of therapeutic and diagnostic agents as 'theranostics.'

  7. Cardiac safety implications of hNav1.5 blockade and a framework for preclinical evaluation

    Directory of Open Access Journals (Sweden)

    Gul eErdemli

    2012-01-01

    Full Text Available The human cardiac sodium channel (hNav1.5, encoded by the SCN5A gene is critical for action potential generation and propagation in the heart. Drug-induced sodium channel inhibition decreases the rate of cardiomyocyte depolarization and consequently conduction velocity and can have serious implications for cardiac safety. Genetic mutations in hNav1.5 have also been linked to a number of cardiac diseases. Therefore, off-target hNav1.5 inhibition may be considered a risk marker for a drug candidate. Given the potential safety implications for patients and the costs of late stage drug development, detection and mitigation of hNav1.5 liabilities early in drug discovery and development becomes important. In this review, we describe a preclinical strategy to identify hNav1.5 liabilities that incorporates in vitro, in vivo, and in silico techniques and the application of this information in the integrated risk assessment at different stages of drug discovery and development.

  8. Reirradiation of normal tissues: Preclinical radiobiological data; Reirradiation des tissus sains: donnees radiobiologiques precliniques

    Energy Technology Data Exchange (ETDEWEB)

    Bourgier, C.; Vozenin, M.C.; Deutsch, E. [Departement de radiotherapie et laboratoire Upres EA2710, institut Gustave-Roussy, 94 - Villejuif (France)

    2010-10-15

    Reirradiation represent an unfrequent particular clinical situation. The risk/benefit ratio assessment must be taken into account, considering both clinical and dosimetric aspects. There is a relatively limited amount of preclinical data available to date and clinicians should cautiously perform re-irradiations in selected indications. This review summarizes the experimental data available on reirradiation of normal tissues, the consequences on early and late toxicities as well as the intrinsic limitations of these models. (authors)

  9. Late Raphael

    OpenAIRE

    Henry, Tom F. K.; Joannides, Paul; González Mozo, Ana; Martín, Bruno

    2012-01-01

    Exhibition catalogue (co-authored with P. Joannides) in English, Spanish and French by the Museo del Prado and the Musée du Louvre, 2012. English edition, publisher: Museo Nacional del Prado (ISBN 978-84-8480-237-2). 382 pages, of which 300 were co-authored with P. Joannides. This publication was the catalogue of the major exhibtion of Raphael's late work which was at the Prado and the Louvre in 2012-13. The exhibition was seen by more than 650,000 visitors, and was widely reviewed in the int...

  10. The Economics of Reproducibility in Preclinical Research.

    Directory of Open Access Journals (Sweden)

    Leonard P Freedman

    2015-06-01

    Full Text Available Low reproducibility rates within life science research undermine cumulative knowledge production and contribute to both delays and costs of therapeutic drug development. An analysis of past studies indicates that the cumulative (total prevalence of irreproducible preclinical research exceeds 50%, resulting in approximately US$28,000,000,000 (US$28B/year spent on preclinical research that is not reproducible-in the United States alone. We outline a framework for solutions and a plan for long-term improvements in reproducibility rates that will help to accelerate the discovery of life-saving therapies and cures.

  11. Melatonin and breast cancer: Evidences from preclinical and human studies.

    Science.gov (United States)

    Kubatka, Peter; Zubor, Pavol; Busselberg, Dietrich; Kwon, Taeg Kyu; Adamek, Mariusz; Petrovic, Daniel; Opatrilova, Radka; Gazdikova, Katarina; Caprnda, Martin; Rodrigo, Luis; Danko, Jan; Kruzliak, Peter

    2018-02-01

    The breast cancer affects women with high mortality and morbidity worldwide. The risk is highest in the most developed world but also is markedly rising in the developing countries. It is well documented that melatonin has a significant anti-tumor activities demonstrated on various cancer types in a plethora of preclinical studies. In breast cancer, melatonin is capable to disrupt estrogen-dependent cell signaling, resulting in a reduction of estrogen-stimulated cells, moreover, it's obvious neuro-immunomodulatory effect in organism was described. Several prospective studies have demonstrated the inverse correlation between melatonin metabolites and the risk of breast cancer. This correlation was confirmed by observational studies that found lower melatonin levels in breast cancer patients. Moreover, clinical studies have showed that circadian disruption of melatonin synthesis, specifically night shift work, is linked to increased breast cancer risk. In this regard, proper light/dark exposure with more selective use of light at night along with oral supplementation of melatonin may have benefits for high-risk women. The results of current preclinical studies, the mechanism of action, and clinical efficacy of melatonin in breast cancer are reviewed in this paper. Melatonin alone or in combined administration seems to be appropriate drug for the treatment of early stages of breast cancer with documented low toxicity over a wide range of doses. These and other issues are also discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Preclinical Studies for Cartilage Repair

    Science.gov (United States)

    Hurtig, Mark B.; Buschmann, Michael D.; Fortier, Lisa A.; Hoemann, Caroline D.; Hunziker, Ernst B.; Jurvelin, Jukka S.; Mainil-Varlet, Pierre; McIlwraith, C. Wayne; Sah, Robert L.; Whiteside, Robert A.

    2011-01-01

    Investigational devices for articular cartilage repair or replacement are considered to be significant risk devices by regulatory bodies. Therefore animal models are needed to provide proof of efficacy and safety prior to clinical testing. The financial commitment and regulatory steps needed to bring a new technology to clinical use can be major obstacles, so the implementation of highly predictive animal models is a pressing issue. Until recently, a reductionist approach using acute chondral defects in immature laboratory species, particularly the rabbit, was considered adequate; however, if successful and timely translation from animal models to regulatory approval and clinical use is the goal, a step-wise development using laboratory animals for screening and early development work followed by larger species such as the goat, sheep and horse for late development and pivotal studies is recommended. Such animals must have fully organized and mature cartilage. Both acute and chronic chondral defects can be used but the later are more like the lesions found in patients and may be more predictive. Quantitative and qualitative outcome measures such as macroscopic appearance, histology, biochemistry, functional imaging, and biomechanical testing of cartilage, provide reliable data to support investment decisions and subsequent applications to regulatory bodies for clinical trials. No one model or species can be considered ideal for pivotal studies, but the larger animal species are recommended for pivotal studies. Larger species such as the horse, goat and pig also allow arthroscopic delivery, and press-fit or sutured implant fixation in thick cartilage as well as second look arthroscopies and biopsy procedures. PMID:26069576

  13. Recommendations for Benchmarking Preclinical Studies of Nanomedicines.

    Science.gov (United States)

    Dawidczyk, Charlene M; Russell, Luisa M; Searson, Peter C

    2015-10-01

    Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small-molecule drug therapy for cancer and to achieve both therapeutic and diagnostic functions in the same platform. Preclinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of preclinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of preclinical trials and propose a protocol for benchmarking that we recommend be included in in vivo preclinical studies of drug-delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. ©2015 American Association for Cancer Research.

  14. Resveratrol: A review of preclinical studies for human cancer prevention

    International Nuclear Information System (INIS)

    Athar, Mohammad; Back, Jung Ho; Tang Xiuwei; Kim, Kwang Ho; Kopelovich, Levy; Bickers, David R.; Kim, Arianna L.

    2007-01-01

    The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol's anticancer effects to support its potential as an anticancer agent in human populations

  15. Cued memory decline in biomarker-defined preclinical Alzheimer disease.

    Science.gov (United States)

    Papp, Kathryn V; Rentz, Dorene M; Mormino, Elizabeth C; Schultz, Aaron P; Amariglio, Rebecca E; Quiroz, Yakeel; Johnson, Keith A; Sperling, Reisa A

    2017-04-11

    To determine whether a decline in cued recall is observable in the preclinical stage of Alzheimer disease (AD) in clinically normal older adults with elevated β-amyloid (Aβ) burden on PET imaging. Clinically normal older adults underwent baseline neuroimaging (PET to assess Aβ +/- status and MRI) and annual neuropsychological testing. Cox proportional hazards models were used to assess the relative risk of cued memory decline (drop of 1, 2, 3, or 4 points on the total score of the Free and Cued Selective Reminding Test) in relation to neuroimaging measures, functional status, age, sex, and education. A total of 276 older adults (Clinical Dementia Rating = 0, mean Mini-Mental State Examination score = 29 ± 1.06) were followed up for a mean of 3.6 ± 1.2 years. Despite the infrequency of cued memory decline (only 19% of participants scored ≤46/48 in total recall by year 3), Aβ + participants were 3.55 times (95% confidence interval = 1.77-7.12) more likely to exhibit decline in total recall (≤46/48) compared with their Aβ - peers. Furthermore, Aβ + participants who scored ≤46/48 had smaller hippocampal volumes ( t = 3.37, p = 0.001) and evidence of early functional decline, i.e., greater risk of progression to global Clinical Dementia Rating of 0.5 (χ 2 = 14.30, p recall. Cued memory decline in healthy older adults may be particularly indicative of Aβ-related decline during the preclinical stage of AD and useful for identifying Aβ + clinically normal individuals at greatest risk of short-term clinical progression. © 2017 American Academy of Neurology.

  16. Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer's Disease.

    Science.gov (United States)

    Gomar, Jesus J; Conejero-Goldberg, Concepcion; Davies, Peter; Goldberg, Terry E

    2016-01-01

    The earliest stage of preclinical Alzheimer's disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood. To examine dynamic interrelationships between Aβ42 and tau in preclinical AD. We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n = 14); and 3) Aβ42 levels consistently abnormal (n = 18). In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = -0.60; p = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.

  17. Exploring Late Globalization

    DEFF Research Database (Denmark)

    Turcan, Romeo V.

    2016-01-01

    literature on late globalization from sociocultural and economic perspectives. It illustrates in a vignette the character and features of late globalization observable in the withdrawal from foreign locations or deinternationalization of universities, as late globalizing entitis. The paper discusses...

  18. Establishment of a large panel of patient-derived preclinical models of human renal cell carcinoma

    OpenAIRE

    Lang, Herv?; B?raud, Claire; Bethry, Audrey; Danilin, Sabrina; Lindner, V?ronique; Coquard, Catherine; Rothhut, Sylvie; Massfelder, Thierry

    2016-01-01

    The objective of the present work was to establish a large panel of preclinical models of human renal cell carcinoma (RCC) directly from patients, faithfully reproducing the biological features of the original tumor. RCC tissues (all stages/subtypes) were collected for 8 years from 336 patients undergoing surgery, xenografted subcutaneously in nude mice, and serially passaged into new mice up to 13 passages. Tissue samples from the primary tumor and tumors grown in mice through passages were ...

  19. The Alzheimer’s Prevention Initiative composite cognitive test score: Sample size estimates for the evaluation of preclinical Alzheimer’s disease treatments in presenilin 1 E280A mutation carriers

    Science.gov (United States)

    Ayutyanont, Napatkamon; Langbaum, Jessica B.; Hendrix, Suzanne B.; Chen, Kewei; Fleisher, Adam S.; Friesenhahn, Michel; Ward, Michael; Aguirre, Camilo; Acosta-Baena, Natalia; Madrigal, Lucìa; Muñoz, Claudia; Tirado, Victoria; Moreno, Sonia; Tariot, Pierre N.; Lopera, Francisco; Reiman, Eric M.

    2014-01-01

    sensitive single test item to track preclinical AD decline in ADAD mutation carriers and evaluate preclinical AD treatments. This API composite cognitive test score will be used as the primary endpoint in the first API trial in cognitively unimpaired ADAD carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset AD, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytical approaches. PMID:24816373

  20. Late toxicity results of the GORTEC 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems

    International Nuclear Information System (INIS)

    Denis, Fabrice; Garaud, Pascal; Bardet, Etienne; Alfonsi, Marc; Sire, Christian; Germain, Thierry; Bergerot, Philippe; Rhein, Beatrix; Tortochaux, Jacques; Oudinot, Patrick; Calais, Gilles

    2003-01-01

    Purpose: To prospectively assess 5-year late toxicity in patients treated by concomitant radiochemotherapy for locally advanced oropharynx carcinoma using three different toxicity scales. Methods and Materials: A total of 226 patients were entered in a Phase III multicenter, randomized trial comparing radiotherapy alone (70 Gy in 35 fractions: Arm A) with concomitant radiochemotherapy (70 Gy in 35 fractions with three cycles of a 4-day regimen containing carboplatin and 5-fluorouracil: Arm B). Five living patients, free of local or distant recurrences, could not be evaluated for late toxicity. Forty-four patients were eligible for late toxicity with a median follow-up of 5 years. Late toxicity was evaluated by the radiation oncologist using a large questionnaire containing 120 mixed items of three scales (NCI-CTC, LENT/SOMA, and RTOG). The data were then transposed on separate scales using corresponding grades. Results: The 5-year overall survival rate was 22% in Arm B and 16% in Arm A (p=0.05). The 5-year locoregional control rate was 48% in Arm B and 25% in Arm A (p=0.002). The spinal cord was not affected by the concomitant adjunct of chemotherapy, and no deaths were caused by late toxicity. Using the three late toxicity scales, 100% of the patients treated with the combined modality (Arm B) developed one or more late complications vs. 94% in the radiotherapy-alone arm (Arm A). The difference was not statistically significant. The most commonly damaged organs (all Grade 1-4) were the salivary glands (100% in Arm B vs. 82% in Arm A, p<0.05), skin (78% vs. 47%, p<0.05), teeth (67% vs. 18%, p<0.05), mucosa (59% vs. 63% p = not significant), and mandible (44% vs. 12%, p<0.05). One or more Grade 3-4 complications occurred in 82% of the patients in Arm B vs. 47% in Arm A (p=0.02) but concerned only the teeth. The correlation between the RTOG and LENT/SOMA scale and between the NCI-CTC and LENT/SOMA scale were low for Grade 1-4 toxicity (near 30%). The transposability

  1. Modeling the Western Diet for Preclinical Investigations.

    Science.gov (United States)

    Hintze, Korry J; Benninghoff, Abby D; Cho, Clara E; Ward, Robert E

    2018-05-01

    Rodent models have been invaluable for biomedical research. Preclinical investigations with rodents allow researchers to investigate diseases by using study designs that are not suitable for human subjects. The primary criticism of preclinical animal models is that results are not always translatable to humans. Some of this lack of translation is due to inherent differences between species. However, rodent models have been refined over time, and translatability to humans has improved. Transgenic animals have greatly aided our understanding of interactions between genes and disease and have narrowed the translation gap between humans and model animals. Despite the technological innovations of animal models through advances in genetics, relatively little attention has been given to animal diets. Namely, developing diets that replicate what humans eat will help make animal models more relevant to human populations. This review focuses on commonly used rodent diets that are used to emulate the Western dietary pattern in preclinical studies of obesity and type 2 diabetes, nonalcoholic liver disease, maternal nutrition, and colorectal cancer.

  2. Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

    Directory of Open Access Journals (Sweden)

    Carlo Abbate

    2014-01-01

    Full Text Available Objective. We describe a case of dementia with Lewy bodies (DLB that presented long-lasting preclinical complex polymodal hallucinations. Background. Few studies have deeply investigated the characteristics of hallucinations in DLB, especially in the preclinical phase. Moreover, the clinical phenotype of mild cognitive impairment-(MCI- DLB is poorly understood. Methods. The patient was followed for 4 years and a selective phenomenological and cognitive study was performed at the predementia stage. Results. The phenomenological study showed the presence of hypnagogic and hypnopompic hallucinations that allowed us to make a differential diagnosis between DLB and Charles Bonnet syndrome (CBS. The neuropsychological evaluation showed a multiple domain without amnesia MCI subtype with prefrontal dysexecutive, visuoperceptual, and visuospatial impairments and simultanagnosia, which has not previously been reported in MCI-DLB. Conclusions. This study extends the prognostic value of hallucinations for DLB to the preclinical phases. It supports and refines the MCI-DLB concept and identifies simultanagnosia as a possible early cognitive marker. Finally, it confirms an association between hallucinations and visuoperceptual impairments at an intermediate stage of the disease course and strongly supports the hypothesis that hallucinations in the earliest stages of DLB may reflect a narcolepsy-like REM-sleep disorder.

  3. Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

    Science.gov (United States)

    Abbate, Carlo; Trimarchi, Pietro Davide; Inglese, Silvia; Viti, Niccolò; Cantatore, Alessandra; De Agostini, Lisa; Pirri, Federico; Marino, Lorenza; Bagarolo, Renzo

    2014-01-01

    Objective. We describe a case of dementia with Lewy bodies (DLB) that presented long-lasting preclinical complex polymodal hallucinations. Background. Few studies have deeply investigated the characteristics of hallucinations in DLB, especially in the preclinical phase. Moreover, the clinical phenotype of mild cognitive impairment-(MCI-) DLB is poorly understood. Methods. The patient was followed for 4 years and a selective phenomenological and cognitive study was performed at the predementia stage. Results. The phenomenological study showed the presence of hypnagogic and hypnopompic hallucinations that allowed us to make a differential diagnosis between DLB and Charles Bonnet syndrome (CBS). The neuropsychological evaluation showed a multiple domain without amnesia MCI subtype with prefrontal dysexecutive, visuoperceptual, and visuospatial impairments and simultanagnosia, which has not previously been reported in MCI-DLB. Conclusions. This study extends the prognostic value of hallucinations for DLB to the preclinical phases. It supports and refines the MCI-DLB concept and identifies simultanagnosia as a possible early cognitive marker. Finally, it confirms an association between hallucinations and visuoperceptual impairments at an intermediate stage of the disease course and strongly supports the hypothesis that hallucinations in the earliest stages of DLB may reflect a narcolepsy-like REM-sleep disorder. PMID:24868122

  4. Identification of Cells at Early and Late Stages of Polarization During Odontoblast Differentiation Using pOBCol3.6GFP and pOBCol2.3GFP Transgenic Mice

    Science.gov (United States)

    Balic, Anamaria; Aguila, H. Leonardo; Mina, Mina

    2010-01-01

    Transgenic mouse lines in which GFP expression is under the control of tissue-and stage specific promoters have provided powerful experimental tools for identification and isolation of cells at specific stage of differentiation along a lineage. In the present study we used primary cell cultures derived from the dental pulp from pOBCol3.6GFP and pOBCol2.3GFP transgenic mice as a model to develop markers for early stages of odontoblast differentiation from progenitor cells. We analyzed the temporal and spatial expression of 2.3-GFP and 3.6-GFP during in vitro mineralization. Using FACS to separate cells based on GFP expression, we obtained relatively homogenous sub-populations of cells and analyzed their dentinogenic potentials and their progression into odontoblasts. Our observations showed that these transgenes were activated before the onset of matrix deposition and in cells at different stages of polarization. The 3.6-GFP transgene was activated in cells in early stages of polarization whereas the 2.3-GFP transgene was activated at a later stage of polarization just before or at the time of formation of secretory odontoblast. PMID:20728593

  5. The Alzheimer's prevention initiative composite cognitive test score: sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers.

    Science.gov (United States)

    Ayutyanont, Napatkamon; Langbaum, Jessica B S; Hendrix, Suzanne B; Chen, Kewei; Fleisher, Adam S; Friesenhahn, Michel; Ward, Michael; Aguirre, Camilo; Acosta-Baena, Natalia; Madrigal, Lucìa; Muñoz, Claudia; Tirado, Victoria; Moreno, Sonia; Tariot, Pierre N; Lopera, Francisco; Reiman, Eric M

    2014-06-01

    have identified a composite cognitive test score representing multiple cognitive domains that, compared to the most sensitive single test item, has improved power to track preclinical Alzheimer's disease decline in autosomal dominant Alzheimer's disease mutation carriers and to evaluate preclinical Alzheimer's disease treatments. This API composite cognitive test score will be used as the primary end point in the first API trial in cognitively unimpaired autosomal dominant Alzheimer's disease carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset Alzheimer's disease, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytic approaches. © Copyright 2014 Physicians Postgraduate Press, Inc.

  6. Stage design

    International Nuclear Information System (INIS)

    Shacter, J.

    1975-01-01

    A method is described of cycling gases through a plurality of diffusion stages comprising the steps of admitting the diffused gases from a first diffusion stage into an axial compressor, simultaneously admitting the undiffused gases from a second diffusion stage into an intermediate pressure zone of said compressor corresponding in pressure to the pressure of said undiffused gases, and then admitting the resulting compressed mixture of diffused and undiffused gases into a third diffusion stage

  7. Preclinical and clinical safety studies on DNA vaccines.

    NARCIS (Netherlands)

    Schalk, Johanna A C; Mooi, Frits R; Berbers, Guy A M; Aerts, Leon A G J M van; Ovelgönne, Hans; Kimman, Tjeerd G

    2007-01-01

    DNA vaccines are based on the transfer of genetic material, encoding an antigen, to the cells of the vaccine recipient. Despite high expectations of DNA vaccines as a result of promising preclinical data their clinical utility remains unproven. However, much data is gathered in preclinical and

  8. Staging Mobilities

    DEFF Research Database (Denmark)

    Jensen, Ole B.

    and lived as people are “staging themselves” (from below). Staging mobilities is a dynamic process between “being staged” (for example, being stopped at traffic lights) and the “mobile staging” of interacting individuals (negotiating a passage on the pavement). Staging Mobilities is about the fact...

  9. Developing Potential Candidates of Preclinical Preeclampsia

    Directory of Open Access Journals (Sweden)

    Sandra Founds

    2015-11-01

    Full Text Available The potential for developing molecules of interest in preclinical preeclampsia from candidate genes that were discovered on gene expression microarray analysis has been challenged by limited access to additional first trimester trophoblast and decidual tissues. The question of whether these candidates encode secreted proteins that may be detected in maternal circulation early in pregnancy has been investigated using various proteomic methods. Pilot studies utilizing mass spectrometry based proteomic assays, along with enzyme linked immunosorbent assays (ELISAs, and Western immunoblotting in first trimester samples are reported. The novel targeted mass spectrometry methods led to robust multiple reaction monitoring assays. Despite detection of several candidates in early gestation, challenges persist. Future antibody-based studies may lead to a novel multiplex protein panel for screening or detection to prevent or mitigate preeclampsia.

  10. Common pitfalls in preclinical cancer target validation.

    Science.gov (United States)

    Kaelin, William G

    2017-07-01

    An alarming number of papers from laboratories nominating new cancer drug targets contain findings that cannot be reproduced by others or are simply not robust enough to justify drug discovery efforts. This problem probably has many causes, including an underappreciation of the danger of being misled by off-target effects when using pharmacological or genetic perturbants in complex biological assays. This danger is particularly acute when, as is often the case in cancer pharmacology, the biological phenotype being measured is a 'down' readout (such as decreased proliferation, decreased viability or decreased tumour growth) that could simply reflect a nonspecific loss of cellular fitness. These problems are compounded by multiple hypothesis testing, such as when candidate targets emerge from high-throughput screens that interrogate multiple targets in parallel, and by a publication and promotion system that preferentially rewards positive findings. In this Perspective, I outline some of the common pitfalls in preclinical cancer target identification and some potential approaches to mitigate them.

  11. Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data

    Energy Technology Data Exchange (ETDEWEB)

    Jorge, S.E.D.C.; Kobayashi, S.S.; Costa, D.B. [Harvard Medical School, Beth Israel Deaconess Medical Center, Department of Medicine, Division of Hematology/Oncology, Boston, MA (United States)

    2014-09-05

    Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC.

  12. Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data

    International Nuclear Information System (INIS)

    Jorge, S.E.D.C.; Kobayashi, S.S.; Costa, D.B.

    2014-01-01

    Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC

  13. Preclinical deposition of pathological prion protein in muscle of experimentally infected primates.

    Directory of Open Access Journals (Sweden)

    Susanne Krasemann

    Full Text Available Prion diseases are transmissible fatal neurodegenerative disorders affecting humans and animals. A central step in disease progression is the accumulation of a misfolded form (PrP(Sc of the host encoded prion protein (PrP(C in neuronal and non-neuronal tissues. The involvement of peripheral tissues in preclinical states increases the risk of accidental transmission. On the other hand, detection of PrP(Sc in non-neuronal easy-accessible compartments such as muscle may offer a novel diagnostic tool. Primate models have proven invaluable to investigate prion diseases. We have studied the deposition of PrP(Sc in muscle and central nervous system of rhesus monkeys challenged with sporadic Creutzfeldt-Jakob disease (sCJD, variant CJD (vCJD and bovine spongiform encephalopathy (BSE in preclinical and clinical stage using biochemical and morphological methods. Here, we show the preclinical presence of PrP(Sc in muscle and central nervous system of rhesus monkeys experimentally infected with vCJD.

  14. LATE VISION: PROCESSES AND EPISTEMIC STATUS

    Directory of Open Access Journals (Sweden)

    Athanassios eRaftopoulos

    2011-12-01

    Full Text Available In this paper, I examine the processes that occur in late vision and address the problem of whether late vision should be construed as a properly speaking perceptual stage, or as a thought-like discursive stage. Specifically, I argue that late vision, its (partly conceptual nature notwithstanding, neither is constituted by nor does it implicate what I call pure thoughts, that is, propositional structures that are formed in the cognitive areas of the brain through, and participate in, discursive reasoning and inferences. At the same time, the output of late vision, namely an explicit belief concerning the identity and category membership of an object (that is, a recognitional belief or its features, eventually enters into discursive reasoning. Using Jackendoff’s distinction between visual awareness, which characterizes perception, and visual understanding, which characterizes pure thought, I claim that the contents of late vision belong to visual awareness and not to visual understanding and that although late vision implicates beliefs, either implicit or explicit, these beliefs are hybrid visual/conceptual constructs and not pure thoughts. Distinguishing between these hybrid representations and pure thoughts and delineating the nature of the representations of late vision lays the ground for examining, among other things, the process of conceptualization that occurs in visual processing and the way concepts modulate perceptual content affecting either its representational or phenomenal character. I also do not discuss the epistemological relations between the representations of late vision and the perceptual judgments they ‘support’, or ‘guide’ or ‘render possible’ or ‘evidence’ or ‘entitle’. However, the specification of the epistemology of late vision lays the ground for attacking that problem as well.

  15. Trading stages

    DEFF Research Database (Denmark)

    Steiner, Uli; Tuljapurkar, Shripad; Coulson, Tim

    2012-01-01

    Interest in stage-and age structured models has recently increased because they can describe quantitative traits such as size that are left out of age-only demography. Available methods for the analysis of effects of vital rates on lifespan in stage-structured models have not been widely applied ...... examples. Much of our approach relies on trading of time and mortality risk in one stage for time and risk in others. Our approach contributes to the new framework of the study of age- and stage-structured biodemography....

  16. Biomarker clusters are differentially associated with longitudinal cognitive decline in late midlife

    Science.gov (United States)

    Racine, Annie M.; Koscik, Rebecca L.; Berman, Sara E.; Nicholas, Christopher R.; Clark, Lindsay R.; Okonkwo, Ozioma C.; Rowley, Howard A.; Asthana, Sanjay; Bendlin, Barbara B.; Blennow, Kaj; Zetterberg, Henrik; Gleason, Carey E.; Carlsson, Cynthia M.

    2016-01-01

    The ability to detect preclinical Alzheimer’s disease is of great importance, as this stage of the Alzheimer’s continuum is believed to provide a key window for intervention and prevention. As Alzheimer’s disease is characterized by multiple pathological changes, a biomarker panel reflecting co-occurring pathology will likely be most useful for early detection. Towards this end, 175 late middle-aged participants (mean age 55.9 ± 5.7 years at first cognitive assessment, 70% female) were recruited from two longitudinally followed cohorts to undergo magnetic resonance imaging and lumbar puncture. Cluster analysis was used to group individuals based on biomarkers of amyloid pathology (cerebrospinal fluid amyloid-β42/amyloid-β40 assay levels), magnetic resonance imaging-derived measures of neurodegeneration/atrophy (cerebrospinal fluid-to-brain volume ratio, and hippocampal volume), neurofibrillary tangles (cerebrospinal fluid phosphorylated tau181 assay levels), and a brain-based marker of vascular risk (total white matter hyperintensity lesion volume). Four biomarker clusters emerged consistent with preclinical features of (i) Alzheimer’s disease; (ii) mixed Alzheimer’s disease and vascular aetiology; (iii) suspected non-Alzheimer’s disease aetiology; and (iv) healthy ageing. Cognitive decline was then analysed between clusters using longitudinal assessments of episodic memory, semantic memory, executive function, and global cognitive function with linear mixed effects modelling. Cluster 1 exhibited a higher intercept and greater rates of decline on tests of episodic memory. Cluster 2 had a lower intercept on a test of semantic memory and both Cluster 2 and Cluster 3 had steeper rates of decline on a test of global cognition. Additional analyses on Cluster 3, which had the smallest hippocampal volume, suggest that its biomarker profile is more likely due to hippocampal vulnerability and not to detectable specific volume loss exceeding the rate of normal

  17. Accumulation of Mitochondrial DNA Common Deletion Since The Preataxic Stage of Machado-Joseph Disease.

    Science.gov (United States)

    Raposo, Mafalda; Ramos, Amanda; Santos, Cristina; Kazachkova, Nadiya; Teixeira, Balbina; Bettencourt, Conceição; Lima, Manuela

    2018-04-21

    Molecular alterations reflecting pathophysiologic changes thought to occur many years before the clinical onset of Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3), a late-onset polyglutamine disorder, remain unidentified. The absence of molecular biomarkers hampers clinical trials, which lack sensitive measures of disease progression, preventing the identification of events occurring prior to clinical onset. Our aim was to analyse the mtDNA content and the amount of the common deletion (m.8482_13460del4977) in a cohort of 16 preataxic MJD mutation carriers, 85 MJD patients and 101 apparently healthy age-matched controls. Relative expression levels of RPPH1, MT-ND1 and MT-ND4 genes were assessed by quantitative real-time PCR. The mtDNA content was calculated as the difference between the expression levels of a mitochondrial gene (MT-ND1) and a nuclear gene (RPPH1); the amount of mtDNA common deletion was calculated as the difference between expression levels of a deleted (MT-ND4) and an undeleted (MT-ND1) mitochondrial genes. mtDNA content in MJD carriers was similar to that of healthy age-matched controls, whereas the percentage of the common deletion was significantly increased in MJD subjects, and more pronounced in the preclinical stage (p < 0.05). The BCL2/BAX ratio was decreased in preataxic carriers compared to controls, suggesting that the mitochondrial-mediated apoptotic pathway is altered in MJD. Our findings demonstrate for the first time that accumulation of common deletion starts in the preclinical stage. Such early alterations provide support to the current understanding that any therapeutic intervention in MJD should start before the overt clinical phenotype.

  18. Progressive loss of sensitivity to growth control by retinoic acid and transforming growth factor-beta at late stages of human papillomavirus type 16-initiated transformation of human keratinocytes.

    Science.gov (United States)

    Creek, K E; Geslani, G; Batova, A; Pirisi, L

    1995-01-01

    . We next studied the effect of TGF-beta 1 and TGF-beta 2 on the proliferation of early to late passage HKc/HPVa6, HKc/GFI and HKc/DR. While early passage HKc/HPV16 were as sensitive as normal HKc to growth inhibition by TGF-beta 1 and TGF-beta 2, the cells became increasingly resistant to TGF-beta during in vitro progression, with the proliferation of HKc/DR being virtually unaffected by TGF-beta 1 or TGF-beta 2 treatment. Overall, loss of growth inhibition by RA parallels loss of TGF-beta sensitivity.(ABSTRACT TRUNCATED AT 400 WORDS)

  19. LATE NEUROSYPHILIS: TRENDS AND CHALLENGES.

    Directory of Open Access Journals (Sweden)

    Ivan Dimitrov

    2015-09-01

    Full Text Available Background: Syphilis is not only a disease of historical importance. It has been recognized that nowadays, in the era of AIDS, it still remains a serious challenge. For the last two decades there has been a resumption of neurosyphilis cases. This has revived the interest in the diagnostic and therapeutic challenges that the disease presents to clinical practice and to healthcare systems. Material/Methods: We present the overall picture of newly registered cases of syphilis in Varna municipality between 2009 and 2013, and report a case of neurosyphilis diagnosed at the first clinic of neurological diseases of St. Marina University Hospital during this period. Results: For the 5-year period, newly registered cases of syphilis in Varna have shown a tendency towards a decrease. Patients were typically in the early stages of the disease, primary and secondary. Late manifestations dropped from 29 in 2009 to 0 in 2010, but increased again to 15 in 2013. Only 1 case of neurosyphilis was registered during the 5-year period, in 2013. Conclusions: Neurological syndromes observed in cases of late neurosyphilis, presenting in different clinical forms, require a broad spectrum of differential diagnoses. Attention in everyday clinical practice should be focused on these cases which, though rare, are of high medical and social importance. Clinical cases of late neurosyphilis are often atypical and the early consideration of serologic tests or even biopsy may be of critical importance.

  20. Preclinical Alzheimer disease and risk of falls.

    Science.gov (United States)

    Stark, Susan L; Roe, Catherine M; Grant, Elizabeth A; Hollingsworth, Holly; Benzinger, Tammie L; Fagan, Anne M; Buckles, Virginia D; Morris, John C

    2013-07-30

    We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aβ₄₂, tau, and phosphorylated tau. We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Aβ₄₂ and CSF phosphorylated tau/Aβ₄₂, after adjustment for common fall risk factors. The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01-6.45], p = 0.05) and of CSF biomarker ratios (p risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes.

  1. [Preclinical horizon of depression in adults].

    Science.gov (United States)

    Jiménez-Báez, María Valeria; Márquez-González, Horacio; Monsreal-Góngora, Juan Leonardo; Góngora-González, Gonzalo; Sandoval-Jurado, Luis; Boquer-Hernández, Rubén

    2016-01-01

    Identify factors related to preclinical depression in healthy adults, their risk factors and concordance with family doctor diagnostic. Case-control study in adult from family medicine consulting room. Beck inventory for depression was applied. The correlation between depression and the diagnosis by the family physician was evaluated. Odds ratio (OR) was determined. Involved 138 patients randomly from four family medicine units (FMU) in the Northern Region of Quintana Roo, Mexico. The mean age 34.9 ± 11.4 years, 55.8% women, prevalence for depression was 26.1%. Being male OR: 3.76; 95% CI: 1.69-8.36, under 30 years OR: 2.76; 95% CI: 1.27-5.99, low socioeconomic status (SES) OR: 2.11; 95% CI: 0.97-4.59 and be married OR: 3.22; 95% CI: 1.41.-7.36 had depression risk. Diagnosis by the family physician and inventory Beck. Kappa Index 0.2, 95% CI: -0057-0176; p = 0.05. Almost a third of young adults have some depression degree in family medicine consulting room, it is necessary a depression screening for male patients, low SES, married, and under 30 years old, attending medical consultation familiar, for a early diagnosis and improve prognosis.

  2. Time management for preclinical safety professionals.

    Science.gov (United States)

    Wells, Monique Y

    2010-08-01

    A survey about time management in the workplace was distributed to obtain a sense of the level of job satisfaction among preclinical safety professionals in the current economic climate, and to encourage reflection upon how we manage time in our work environment. Roughly equal numbers of respondents (approximately 32%) identified themselves as management or staff, and approximately 27% indicated that they are consultants. Though 45.2% of respondents indicated that time management is very challenging for the profession in general, only 36.7% find it very challenging for themselves. Ten percent of respondents view time management to be exceedingly challenging for themselves. Approximately 34% of respondents indicated that prioritization of tasks was the most challenging aspect of time management for them. Focusing on an individual task was the second most challenging aspect (26%), followed equally by procrastination and delegation of tasks (12.4%). Almost equal numbers of respondents said that they would (35.2%) or might (33.3%) undertake training to improve their time management skills. Almost equal numbers of participants responded "perhaps" (44.6%) or "yes" (44.2%) to the question of whether management personnel should be trained in time management.

  3. Detection of preclinical Parkinson's disease with PET

    International Nuclear Information System (INIS)

    Brooks, D.J.

    1991-01-01

    Putamen 18F-dopa uptake of patients with Parkinson's disease (PD) is reduced by at least 35% at onset of symptoms; therefore, positron-emission tomography (PET) can be used to detect preclinical disease in clinically unaffected twins and relatives of patients with PD. Three out of 6 monozygotic and 2 out of 3 dizygotic unaffected PD co-twins have shown reduced putamen 18F-dopa uptake to date. In addition, an intact sibling and a daughter of 1 of 4 siblings with PD both had low putamen 18F-dopa uptake. These preliminary findings suggest there may be a familial component to the etiology of PD. PET can also be used to detect underlying nigral pathology in patients with isolated tremor and patients who become rigid taking dopamine-receptor blocking agents (DRBAs). Patients with familial essential tremor have normal, and those with isolated rest tremor have consistently low, putamen 18F-dopa uptake. Drug-induced parkinsonism is infrequently associated with underlying nigral pathology

  4. Quetiapine: recent developments in preclinical research

    Directory of Open Access Journals (Sweden)

    Marco Orsetti

    2010-03-01

    Full Text Available Quetiapine (QTP is an atypical antipsychotic labelled for the treatment of patients with schizophrenia, bipolar mania and bipolar depression. Nevertheless, QTP has been tried across multiple diagnosis categories and seems to be used, among other atypical antipsychotics, in clinical practice for an expanding range of disorders such as major depression, substance abuse disorders, anxiety disorders, and borderline personality disorders. The present review focuses on papers which investigated the molecular mechanism(s of QTP antidepressant effect. In particular, preclinical studies performed by coupling the chronic mild stress, an animal model of human depression with Affymetrix microarray technology, revealed that chronic QTP administration prevented the stress-induced up- or down-regulation of 42 genes involved in the central nervous system development or having a crucial role for viability of neural cells, like regulation of signal transduction, inorganic ion transport, membrane organisation, and neurite morphogenesis. Among these, Ptgs2, Hes5, Plcb1, Senp2, Gad1, and Marcks are presumably the effectors of the QTP clinical efficacy.

  5. Preclinical animal anxiety research - flaws and prejudices.

    Science.gov (United States)

    Ennaceur, Abdelkader; Chazot, Paul L

    2016-04-01

    The current tests of anxiety in mice and rats used in preclinical research include the elevated plus-maze (EPM) or zero-maze (EZM), the light/dark box (LDB), and the open-field (OF). They are currently very popular, and despite their poor achievements, they continue to exert considerable constraints on the development of novel approaches. Hence, a novel anxiety test needs to be compared with these traditional tests, and assessed against various factors that were identified as a source of their inconsistent and contradictory results. These constraints are very costly, and they are in most cases useless as they originate from flawed methodologies. In the present report, we argue that the EPM or EZM, LDB, and OF do not provide unequivocal measures of anxiety; that there is no evidence of motivation conflict involved in these tests. They can be considered at best, tests of natural preference for unlit and/or enclosed spaces. We also argued that pharmacological validation of a behavioral test is an inappropriate approach; it stems from the confusion of animal models of human behavior with animal models of pathophysiology. A behavioral test is developed to detect not to produce symptoms, and a drug is used to validate an identified physiological target. In order to overcome the major methodological flaws in animal anxiety studies, we proposed an open space anxiety test, a 3D maze, which is described here with highlights of its various advantages over to the traditional tests.

  6. Nephrogenic systemic fibrosis: late skin manifestations

    DEFF Research Database (Denmark)

    Bangsgaard, Nannie; Marckmann, Peter; Rossen, Kristian

    2009-01-01

    BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a serious disease that occurs in patients with severe renal disease and is believed to be caused by gadolinium-containing contrast agents. A detailed description of the late skin manifestations of NSF is important to help dermatologists...... and nephrologists recognize the disease. OBSERVATIONS: We studied 17 patients with NSF late in the disease. All patients showed epidermal atrophy and hairlessness of the affected regions, primarily the lower legs. Affected areas were symmetrically distributed and hyperpigmented in most cases. Eleven patients showed......: This descriptive case series of patients with NSF gives a detailed clinical picture of the skin manifestations late in the disease. It demonstrates that the clinical picture in the late stage has a varied presentation and that NSF has a significant effect on the quality of life....

  7. Preclinical efficacy and safety of herbal formulation for management ...

    African Journals Online (AJOL)

    Preclinical efficacy and safety of herbal formulation for management of wounds. ... The effects of the treatments on rate of wound closure, epithelialisation time ... inflammation and better tissue remodeling for rats treated with herbal product.

  8. The role of radiolabelled compounds in preclinical drug development

    International Nuclear Information System (INIS)

    Hawkins, D.R.

    1988-01-01

    The role of radiolabelled compounds in the development of new drugs is discussed, with particular reference to their use in toxicological, metabolic and pharmacokinetic studies for the pre-clinical safety evaluation of new drugs. (U.K.)

  9. Personality in Late Midlife

    DEFF Research Database (Denmark)

    Mortensen, Erik Lykke; Flensborg-Madsen, Trine; Molbo, Drude

    2014-01-01

    To analyze associations in late midlife between sex, age, education and social class, and the Big Five personality traits; to analyze associations between personality traits and cognitive ability in late midlife; and to evaluate how these associations are influenced by demographic factors....

  10. Rigor or mortis: best practices for preclinical research in neuroscience.

    Science.gov (United States)

    Steward, Oswald; Balice-Gordon, Rita

    2014-11-05

    Numerous recent reports document a lack of reproducibility of preclinical studies, raising concerns about potential lack of rigor. Examples of lack of rigor have been extensively documented and proposals for practices to improve rigor are appearing. Here, we discuss some of the details and implications of previously proposed best practices and consider some new ones, focusing on preclinical studies relevant to human neurological and psychiatric disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. El registro más completo de un Hoplophorini (Xenarthra: Glyptodontidae para los Pisos/Edades Chapadmalalense-Marplatense (Plioceno tardío-Pleistoceno temprano The most complete record of a Hoplophorini (Xenarthra: Glyptodontidae for the Chapadmalalan-Marplatan Stages (Late Pliocene-Early Pleistocene

    Directory of Open Access Journals (Sweden)

    Alfredo E Zurita

    2011-06-01

    Full Text Available Los Glyptodontidae del Neógeno tardío (Pisos/Edades Chapadmalalense-Marplatense; ca. 3.9-1.8 Ma constituyen un grupo escasamente conocido, en tanto la mayoría de los registros están limitados a restos aislados de la coraza dorsal y/o caudal. Las únicas excepciones están representadas por Paraglyptodon chapalmalensis (Ameghino in Rovereto, un fósil guía para el Chapadmalalense superior, y el Plohophorini Plohophorus figuratus Ameghino. Por otro lado, los "Hoplophorinae" Hoplophorini son gliptodontes que tienen sus primeros registros durante los Pisos Huayqueriense (Mioceno tardío y "Araucanense" (Mioceno tardío-Plioceno, pero están prácticamente ausentes durante los Pisos Chapadmalalense-Marplatense (Plioceno-Pleistoceno temprano. Posteriormente, los Hoplophorini (Neosclerocalyptus Paula Couto son, junto con Glyptodon Owen, los Glyptodontidae de registro más frecuente en el Pleistoceno de América del Sur. En esta contribución damos a conocer el primer registro de un Hoplophorini de antigüedad Chapadmalalense, asignado al género Eosclerocalyptus C. Ameghino (Eosclerocalyptus cf. E. lineatus. Este nuevo material, representado por una coraza dorsal, fue exhumado de la sección superior de la Fm. Chapadmalal, Mar del Plata, provincia de Buenos Aires. Desde una perspectiva morfológica, esta coraza presenta un tamaño intermedio entre E. tapinocephalus Cabrera, E. proximus (Moreno & Mercerat y Neosclerocalyptus Paula Couto. Junto con cf. Paraglyptodon chapalmalensis y Plohophorus figuratus Ameghino, estos registros representan los Glyptodontidae Pliocenos más completos que se conocen; a su vez, completa parcialmente la distribución estratigráfica de los Glyptodontidae Hoplophorini.The late Neogene (Chapadmalalan-Marplatan Stages; ca. 3.9-1.8 Ma Glyptodontidae from southern South America are poorly known since most of the record are limited to remains of the dorsal and/or caudal armour. In this sense, the exceptions are represented

  12. Study partners should be required in preclinical Alzheimer's disease trials.

    Science.gov (United States)

    Grill, Joshua D; Karlawish, Jason

    2017-12-06

    In an effort to intervene earlier in Alzheimer's disease (AD), clinical trials are testing promising candidate therapies in preclinical disease. Preclinical AD trial participants are cognitively normal, functionally independent, and autonomous decision-makers. Yet, like AD dementia trials, preclinical trials require dual enrollment of a participant and a knowledgeable informant, or study partner. The requirement of dyadic enrollment is a barrier to recruitment and may present unique ethical challenges. Despite these limitations, the requirement should continue. Study partners may be essential to ensure participant safety and wellbeing, including overcoming distress related to biomarker disclosure and minimizing risk for catastrophic reactions and suicide. The requirement may maximize participant retention and ensure data integrity, including that study partners are the source of data that will ultimately instruct whether a new treatment has a clinical benefit and meaningful impact on the population health burden associated with AD. Finally, study partners are needed to ensure the scientific and clinical value of trials. Preclinical AD will represent a new model of care, in which persons with no symptoms are informed of probable cognitive decline and eventual dementia. The rationale for early diagnosis in symptomatic AD is equally applicable in preclinical AD-to minimize risk, maximize quality of life, and ensure optimal planning and communication. Family members and other sources of support will likely be essential to the goals of this new model of care for preclinical AD patients and trials must instruct this clinical practice.

  13. Prevalence and associated factors of late HIV diagnosis in north ...

    African Journals Online (AJOL)

    Information regarding age, sex, WHO stage, type of opportunistic condition, HIV testing service and on diagnosis CD4 counts were all collected. On diagnosis CD4 counts <200cells/µl was coded as Late HIV diagnosis. The proportion of with Late HIV diagnosis was calculated and logistic regression modal was used to ...

  14. Staging atmospheres

    DEFF Research Database (Denmark)

    Bille, Mikkel; Bjerregaard, Peter; Sørensen, Tim Flohr

    2015-01-01

    The article introduces the special issue on staging atmospheres by surveying the philosophical, political and anthropological literature on atmosphere, and explores the relationship between atmosphere, material culture, subjectivity and affect. Atmosphere seems to occupy one of the classic...

  15. Do stages of dentistry training affect anxiety provoking situations ...

    African Journals Online (AJOL)

    Getting diagnosis wrong, help in faint episode, not developing radiograph properly and coping with children were the anxiety provoking situations that showed statistically significant difference in the 3 studied training stages of dentistry. Bonferroni post‑hoc analysis significant difference was in the preclinical and clinical ...

  16. A Metadata Analysis of Oxidative Stress Etiology in Preclinical Amyotrophic Lateral Sclerosis: Benefits of Antioxidant Therapy

    Directory of Open Access Journals (Sweden)

    Leila Bond

    2018-01-01

    Full Text Available Oxidative stress, induced by an imbalance of free radicals, incites neurodegeneration in Amyotrophic Lateral Sclerosis (ALS. In fact, a mutation in antioxidant enzyme superoxide dismutase 1 (SOD1 accounts for 20% of familial ALS cases. However, the variance among individual studies examining ALS oxidative stress clouds corresponding conclusions. Therefore, we construct a comprehensive, temporal view of oxidative stress and corresponding antioxidant therapy in preclinical ALS by mining published quantitative experimental data and performing metadata analysis of 41 studies. In vitro aggregate analysis of innate oxidative stress inducers, glutamate and hydrogen peroxide, revealed 70–90% of cell death coincides to inducer exposure equivalent to 30–50% peak concentration (p < 0.05. A correlative plateau in cell death suggests oxidative stress impact is greatest in early-stage neurodegeneration. In vivo SOD1-G93A transgenic ALS mouse aggregate analysis of heat shock proteins (HSPs revealed HSP levels are 30% lower in muscle than spine (p < 0.1. Overall spine HSP levels, including HSP70, are mildly upregulated in SOD1-G93A mice compared to wild type, but not significantly (p > 0.05. Thus, innate HSP compensatory responses to oxidative stress are simply insufficient, a result supportive of homeostatic system instability as central to ALS etiology. In vivo aggregate analysis of antioxidant therapy finds SOD1-G93A ALS mouse survival duration significantly increases by 11.2% (p << 0.001 but insignificantly decreases onset age by 2%. Thus, the aggregate antioxidant treatment effect on survival in preclinical ALS is not sufficient to overcome clinical heterogeneity, which explains the literature disparity between preclinical and clinical antioxidant survival benefit. The aggregate effect sizes on preclinical ALS survival and onset illustrate that present antioxidants, alone, are not sufficient to halt ALS, which underscores its multi-factorial nature

  17. A Dual-Stage Two-Phase Model of Selective Attention

    Science.gov (United States)

    Hubner, Ronald; Steinhauser, Marco; Lehle, Carola

    2010-01-01

    The dual-stage two-phase (DSTP) model is introduced as a formal and general model of selective attention that includes both an early and a late stage of stimulus selection. Whereas at the early stage information is selected by perceptual filters whose selectivity is relatively limited, at the late stage stimuli are selected more efficiently on a…

  18. A case of late-onset oligomeganephronia

    Directory of Open Access Journals (Sweden)

    Rafael José Vargas Alves

    2012-12-01

    Full Text Available A 33-year old caucasian man was investigated for pain in the right flank, proteinuria, hemathuria and an elevated serum creatinine level. He also presented an abnormal ultrasonography, which revealed asymmetric kidneys. Through renal biopsy, the diagnosis of oligomeganephronia (OMN was confirmed. OMN is a very rare form of renal hypoplasia, and late-onset in adulthood is even rarer. In the pediatric population, OMN leads to end-stage-renal-failure(ESRF in a few years. This is the sixth case related in the literature of a late-onset OMN who have not yet developed ESRF.

  19. Recent developments in preclinical toxicological pathology

    International Nuclear Information System (INIS)

    Finch, John M.

    2005-01-01

    In the late nineteenth century, microscopists developed a quaint method for examining the fine structure of biological specimens: paraffin embedding and staining with hematoxylin and eosin. This ancient technology is here to stay for the foreseeable future, because it can and does reveal the truth about biological processes. However, the role of pathology is developing with ever greater worldwide interaction between pathologists, and better communication and agreeing of international standards. Furthermore, recent techniques including immunohistochemistry, electron microscopy and image analysis complement the traditional tried and tested tools. There is also in toxicologic pathology a willingness to use pathology methods and skills in new contexts, drug discovery in particular. But even in these days of genetic modification, proteomics and high throughput screening, pathologists continue to rely on dyes extracted from a Central American logwood used in Mexico before the Spanish invasion in 1520

  20. Challenges for Preclinical Investigations of Human Biofield Modalities

    Science.gov (United States)

    Gronowicz, Gloria; Bengston, William

    2015-01-01

    Preclinical models for studying the effects of the human biofield have great potential to advance our understanding of human biofield modalities, which include external qigong, Johrei, Reiki, therapeutic touch, healing touch, polarity therapy, pranic healing, and other practices. A short history of Western biofield studies using preclinical models is presented and demonstrates numerous and consistent examples of human biofields significantly affecting biological systems both in vitro and in vivo. Methodological issues arising from these studies and practical solutions in experimental design are presented. Important questions still left unanswered with preclinical models include variable reproducibility, dosing, intentionality of the practitioner, best preclinical systems, and mechanisms. Input from the biofield practitioners in the experimental design is critical to improving experimental outcomes; however, the development of standard criteria for uniformity of practice and for inclusion of multiple practitioners is needed. Research in human biofield studies involving preclinical models promises a better understanding of the mechanisms underlying the efficacy of biofield therapies and will be important in guiding clinical protocols and integrating treatments with conventional medical therapies. PMID:26665042

  1. Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease.

    Science.gov (United States)

    Ng, Kok Pin; Pascoal, Tharick A; Mathotaarachchi, Sulantha; Chung, Chang-Oh; Benedet, Andréa L; Shin, Monica; Kang, Min Su; Li, Xiaofeng; Ba, Maowen; Kandiah, Nagaendran; Rosa-Neto, Pedro; Gauthier, Serge

    2017-05-09

    To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD). We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [ 18 F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [ 18 F]fluorodeoxyglucose (FDG) PET. Individuals with preclinical AD with higher NPI scores had higher [ 18 F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction. The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

  2. Late stages of massive star evolution and nucleosynthesis

    International Nuclear Information System (INIS)

    Nomoto, Ken'ichi; Hashimoto, Masa-aki.

    1986-01-01

    The evolution of massive stars in the mass range of 8 to 25 M solar mass is reviewed. The effect of electron degeneracy on the gravothermal nature of stars is discussed. Depending on the stellar mass, the stars form three types of cores, namely, non-degenerate, semi-degenerate, and strongly degenerate cores. The evolution for these cases is quite distinct from each other and leads to the three different types of final fate. It is suggested that our helium star model, which is equivalent to a 25 M solar mass star, will form a relatively small mass iron core despite the faster 12 C(α,γ) 16 O reaction. 50 refs., 21 figs

  3. Recent Simulations of the Late Stages Growth of Jupiter

    Science.gov (United States)

    Lissauer, Jack J.; D'Angelo, Gennaro; Hubickyj, Olenka

    2012-01-01

    Presented by Lissauer et al. (2009, Icarus 199, 338) are used to test the model of capture of Jupiter's irregular satellites within proto-Jupiter's distended and thermally-supported envelope. We find such capture highly unlikely, since the envelope shrinks too slowly for a large number of moons to be retained, and many of those that would be retained would orbit closer to the planet than do the observed Jovian irregulars. Our calculations do not address (and therefore do not exclude) the possibility that the irregular satellites were captured as a result of gas drag within a circumjovian disk. Support for this research from NASA Outer Planets Research Program is gratefully acknowledged.

  4. Capitellocondylar total elbow replacement in late-stage rheumatoid arthritis

    DEFF Research Database (Denmark)

    Ovesen, Janne; Olsen, Bo Sanderhoff; Johannsen, Hans Viggo

    2012-01-01

    of instability. Other complications included 2 maltracking elbows, 2 triceps tendon ruptures, 2 cases of operative olecranon bursitis, and 2 ulnar nerve palsies. One elbow showed radiolucent lines of more than 1 mm in the circumference of the ulnar component; none of the other elbows showed any signs...

  5. Diagnosis of Late Stage, Early Onset, Small Fiber Polyneuropathy

    Science.gov (United States)

    2016-10-01

    definition 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a. REPORT U...War Illness, chronic widespread pain, chronic multisymptom illness, small- fiber polyneuropathy, case definition 3. ACCOMPLISHMENTS: What were the...Registry (RPDR), cross-check with electronic medical records, advertisement , contact with patient advocacy groups and Veterans’ Service

  6. Late Relapses in Stage I Testicular Cancer Patients on Surveillance

    DEFF Research Database (Denmark)

    Mortensen, Mette Saksø; Lauritsen, Jakob; Kier, Maria Gry Gundgaard

    2016-01-01

    Cancer (DaTeCa) database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We estimated survival and relapse probabilities and compared the results using log-rank tests and Cox regression analyses. We compared differences in patient characteristics by using χ(2), Fisher exact, and Mann-Whitney tests...... no significant differences in patient characteristics at orchiectomy or relapse. Limitations include retrospective design and exclusion of patients who had been offered adjuvant therapy. CONCLUSIONS: The risk of VLR is minimal, and the patients carry a good prognosis. Patient characteristics of CS-1 surveillance...

  7. Characterizing Debris Disks in the Late Stages of Planet Formation

    Science.gov (United States)

    White, Jacob

    2018-01-01

    The planet formation process shapes the morphology and grain size distribution of circumstellar disks, encoding the formation history of a given system. Remnants of planet formation, such as comets and asteroids, collisionally evolve and can replenish the dust and small solids that would otherwise be cleared on short timescales. These grains are observed through reprocessed starlight at submm to cm wavelengths.The spectrum of the mm/cm emission reveals details of the grain population. However, one confounding parameter in studying these grains around stars is the stars themselves. The emission from stars in the mm/cm is nontrivial and generally not well-constrained. I will present examples of debris systems (HD 141569 and Fomalhaut) studied by ALMA and the VLA, in which unconstrained stellar emission may be contributing to the observed flux densities. Such contamination in turn biases the inferred emission from the disk and the corresponding dust properties. In some cases, the behavior of the observed A/B stars can exhibit an emission profile that has similarities to that of the Sun's mm/cm emission, although the same processes are not thought to necessarily occur in the atmospheres of massive stars.To address the uncertainty in stellar emission at mm/cm wavelengths, we present ongoing radio observations (JCMT, SMA, VLA) of Sirius A, which is a bright, nearby star with no known debris. We seek to use this system to set an observationally determined standard for stellar atmosphere modeling and debris disk studies around A stars, as well as to take the first step toward characterizing potential intrinsic uncertainty in stellar emission at these wavelengths. This talk will highlight the effort to characterize stellar atmospheres through a project known as MESAS (Measuring the Emission of Stellar Atmospheres at Submillimeter/millimeter wavelengths) which is imperative to the success of current and future debris disk studies.

  8. Antibiotics in late clinical development.

    Science.gov (United States)

    Fernandes, Prabhavathi; Martens, Evan

    2017-06-01

    Most pharmaceutical companies have stopped or have severely limited investments to discover and develop new antibiotics to treat the increasing prevalence of infections caused by multi-drug resistant bacteria, because the return on investment has been mostly negative for antibiotics that received marketing approved in the last few decades. In contrast, a few small companies have taken on this challenge and are developing new antibiotics. This review describes those antibiotics in late-stage clinical development. Most of them belong to existing antibiotic classes and a few with a narrow spectrum of activity are novel compounds directed against novel targets. The reasons for some of the past failures to find new molecules and a path forward to help attract investments to fund discovery of new antibiotics are described. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Theory of mind and empathy in preclinical and clinical Huntington's disease.

    Science.gov (United States)

    Adjeroud, Najia; Besnard, Jérémy; El Massioui, Nicole; Verny, Christophe; Prudean, Adriana; Scherer, Clarisse; Gohier, Bénédicte; Bonneau, Dominique; Allain, Philippe

    2016-01-01

    We investigated cognitive and affective Theory of Mind (ToM) and empathy in patients with premanifest and manifest Huntington's disease (HD). The relationship between ToM performance and executive skills was also examined. Sixteen preclinical and 23 clinical HD patients, and 39 healthy subjects divided into 2 control groups were given a French adaptation of the Yoni test (Shamay-Tsoory, S.G., Aharon-Peretz, J. (2007). Dissociable prefrontal networks for cognitive and affective theory of mind: a lesion study. Neuropsychologia, 45(3), 3054-67) that examines first- and second-order cognitive and affective ToM processing in separate conditions with a physical control condition. Participants were also given questionnaires of empathy and cognitive tests which mainly assessed executive functions (inhibition and mental flexibility). Clinical HD patients made significantly more errors than their controls in the first- and second-order cognitive and affective ToM conditions of the Yoni task, but exhibited no empathy deficits. However, there was no evidence that ToM impairment was related to cognitive deficits in these patients. Preclinical HD patients were unimpaired in ToM tasks and empathy measures compared with their controls. Our results are consistent with the idea that impaired affective and cognitive mentalizing emerges with the clinical manifestation of HD, but is not necessarily part of the preclinical stage. Furthermore, these impairments appear independent of executive dysfunction and empathy. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  10. Characterization of novel preclinical dose distributions for micro irradiator

    International Nuclear Information System (INIS)

    Kodra, J; Miles, D; Yoon, S W; Kirsch, D G; Oldham, M

    2017-01-01

    This work explores and demonstrates the feasibility of utilizing new 3D printing techniques to implement advanced micro radiation therapy for pre-clinical small animal studies. 3D printed blocks and compensators were designed and printed from a strong x-ray attenuating material at sub-millimeter resolution. These techniques enable a powerful range of new preclinical treatment capabilities including grid therapy, lattice therapy, and IMRT treatment. At small scales, verification of these treatments is exceptionally challenging, and high resolution 3D dosimetry (0.5mm 3 ) is an essential capability to characterize and verify these capabilities, Here, investigate the 2D and 3D dosimetry of several novel pre-clinical treatments using a combination of EBT film and Presage/optical-CT 3D dosimetry in rodent-morphic dosimeters. (paper)

  11. Characterization of novel preclinical dose distributions for micro irradiator

    Science.gov (United States)

    Kodra, J.; Miles, D.; Yoon, S. W.; Kirsch, D. G.; Oldham, M.

    2017-05-01

    This work explores and demonstrates the feasibility of utilizing new 3D printing techniques to implement advanced micro radiation therapy for pre-clinical small animal studies. 3D printed blocks and compensators were designed and printed from a strong x-ray attenuating material at sub-millimeter resolution. These techniques enable a powerful range of new preclinical treatment capabilities including grid therapy, lattice therapy, and IMRT treatment. At small scales, verification of these treatments is exceptionally challenging, and high resolution 3D dosimetry (0.5mm3) is an essential capability to characterize and verify these capabilities, Here, investigate the 2D and 3D dosimetry of several novel pre-clinical treatments using a combination of EBT film and Presage/optical-CT 3D dosimetry in rodent-morphic dosimeters.

  12. Preclinical animal research on therapy dosimetry with dual isotopes

    International Nuclear Information System (INIS)

    Konijnenberg, Mark W.; Jong, Marion de

    2011-01-01

    Preclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of sublethal damage, and repopulation during or after the therapy. Models for radiation response of preclinical tumour models after peptide receptor radionuclide therapy based on the linear quadratic model are presented. The accuracy of the radiation dose is very important for observation of dose-effects. Uncertainties in the radiation dose estimation arise from incomplete assay of the kinetics, low accuracy in volume measurements and absorbed dose S-values for stylized models instead of the actual animal geometry. Normal dose uncertainties in the order of 20% might easily make the difference between seeing a dose-effect or missing it altogether. This is true for the theoretical case of a homogeneous tumour type behaving in vivo in the same way as its cells do in vitro. Heterogeneity of tumours induces variations in clonogenic cell density, radiation sensitivity, repopulation capacity and repair kinetics. The influence of these aspects are analysed within the linear quadratic model for tumour response to radionuclide therapy. Preclinical tumour models tend to be less heterogenic than the clinical conditions they should represent. The results of various preclinical radionuclide therapy experiments for peptide receptor radionuclide therapy are compared to the outcome of theoretical models and the influence of increased heterogeneity is analysed when the results of preclinical research is transferred to the clinic. When the radiation dose and radiobiology of the tumour response is known well enough it may be possible to leave the current phenomenological approach in preclinical radionuclide therapy and start basing these experiments on radiation dose. Then the use of a gamma ray

  13. Preclinical animal research on therapy dosimetry with dual isotopes

    Energy Technology Data Exchange (ETDEWEB)

    Konijnenberg, Mark W.; Jong, Marion de [Nuclear Medicine Department, Erasmus MC, Rotterdam (Netherlands)

    2011-06-15

    Preclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of sublethal damage, and repopulation during or after the therapy. Models for radiation response of preclinical tumour models after peptide receptor radionuclide therapy based on the linear quadratic model are presented. The accuracy of the radiation dose is very important for observation of dose-effects. Uncertainties in the radiation dose estimation arise from incomplete assay of the kinetics, low accuracy in volume measurements and absorbed dose S-values for stylized models instead of the actual animal geometry. Normal dose uncertainties in the order of 20% might easily make the difference between seeing a dose-effect or missing it altogether. This is true for the theoretical case of a homogeneous tumour type behaving in vivo in the same way as its cells do in vitro. Heterogeneity of tumours induces variations in clonogenic cell density, radiation sensitivity, repopulation capacity and repair kinetics. The influence of these aspects are analysed within the linear quadratic model for tumour response to radionuclide therapy. Preclinical tumour models tend to be less heterogenic than the clinical conditions they should represent. The results of various preclinical radionuclide therapy experiments for peptide receptor radionuclide therapy are compared to the outcome of theoretical models and the influence of increased heterogeneity is analysed when the results of preclinical research is transferred to the clinic. When the radiation dose and radiobiology of the tumour response is known well enough it may be possible to leave the current phenomenological approach in preclinical radionuclide therapy and start basing these experiments on radiation dose. Then the use of a gamma ray

  14. Academic performance in Iranian medical students during the pre-clinical stage

    OpenAIRE

    Davoudi, Farnoush; Esmaeeli, Shooka; AhmadzadAsl, Masoud; Nojomi, Marzieh

    2017-01-01

    Background: Better understanding of factors associated with medical school performance is necessary to improve admission processes and to help students succeed in their career. This study follows a group of Iranian med students during their first 2.5 years of medical education, to evaluate their academic success in accordance with their demographic, cognitive and non-cognitive characteristics. Methods: 143 of 200 matriculants of Iran University of Medical Sciences medical school in 2010, were...

  15. Molecular and cellular profiling of systemic sclerosis and its preclinical stages

    NARCIS (Netherlands)

    Cossu, Marta

    2017-01-01

    The development of unrestrained fibrosis in the skin and internal organs is the hallmark of systemic sclerosis (SSc). Nevertheless, it is known that fibrosis is preceded by vascular and immune modifications. On the basis of SSc-specific autoantibodies and nailfold capillary lesions it is possible to

  16. Cognitive impairment in the preclinical stage of dementia in FTD-3 CHMP2B mutation carriers

    DEFF Research Database (Denmark)

    Stokholm, Jette; Teasdale, Thomas W; Johannsen, Peter

    2013-01-01

    -3). Subjects were assessed with neuropsychological tests in 2002, 2005 and 2010. RESULTS: Cross-sectional analyses showed that the mutation carriers scored lower on tests of psychomotor speed, working memory, executive functions and verbal memory than a control group consisting of not-at-risk family...... members and spouses. Longitudinal analyses showed a gradual decline in psychomotor speed, working memory capacity and global executive measures in the group of non-demented mutation carriers that was not found in the control group. In contrast, there were no significant group differences in domain scores...

  17. Kinetic modeling in pre-clinical positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Kuntner, Claudia [AIT Austrian Institute of Technology GmbH, Seibersdorf (Austria). Biomedical Systems, Health and Environment Dept.

    2014-07-01

    Pre-clinical positron emission tomography (PET) has evolved in the last few years from pure visualization of radiotracer uptake and distribution towards quantification of the physiological parameters. For reliable and reproducible quantification the kinetic modeling methods used to obtain relevant parameters of radiotracer tissue interaction are important. Here we present different kinetic modeling techniques with a focus on compartmental models including plasma input models and reference tissue input models. The experimental challenges of deriving the plasma input function in rodents and the effect of anesthesia are discussed. Finally, in vivo application of kinetic modeling in various areas of pre-clinical research is presented and compared to human data.

  18. The basics of preclinical drug development for neurodegenerative disease indications.

    Science.gov (United States)

    Steinmetz, Karen L; Spack, Edward G

    2009-06-12

    Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and

  19. The basics of preclinical drug development for neurodegenerative disease indications

    Directory of Open Access Journals (Sweden)

    Spack Edward G

    2009-06-01

    Full Text Available Abstract Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s. Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot

  20. Late onset endophthalmitis

    Directory of Open Access Journals (Sweden)

    Abdulaziz AlHadlaq

    2016-04-01

    Full Text Available We report an extremely rare presentation of late-onset endophthalmitis in a young adult patient with an unexposed Ahmed tube implant. The implant was inserted 11 years prior to presentation. There was no history of trauma or any obvious exposure on clinical examination and the tube plate was filled with purulent material. After aqueous and vitreous tap, the patient underwent intracameral, intravitreal subconjunctival antibiotic injections and was started on systemic antibiotics with good response. Endophthalmitis associated with tube drainage device can present as late as 11 years and even without an unexposed tube.

  1. Lateness to School Remediation Game

    Science.gov (United States)

    Ugwuegbulam, Charles N.; Ibrahim, Haj. Naheed

    2015-01-01

    Primary and secondary school in Nigeria encourage punctuality to school yet a good number of the learners came late to school. This is especially true in the case of day students. Learners who come late to school are usually punished in one way or the other yet the lateness to school phenomenon still persist. Lateness to school behaviour affects…

  2. Advanced Pre-clinical Research Approaches and Models to Studying Pediatric Anesthetic Neurotoxicity

    Directory of Open Access Journals (Sweden)

    Cheng eWang

    2012-10-01

    Full Text Available Advances in pediatric and obstetric surgery have resulted in an increase in the duration and complexity of anesthetic procedures. A great deal of concern has recently arisen regarding the safety of anesthesia in infants and children. Because of obvious limitations, it is not possible to thoroughly explore the effects of anesthetic agents on neurons in vivo in human infants or children. However, the availability of some advanced pre-clinical research approaches and models, such as imaging technology both in vitro and in vivo, stem cell and nonhuman primate experimental models, have provided potentially invaluable tools for examining the developmental effects of anesthetic agents. This review discusses the potential application of some sophisticaled research approaches, e.g., calcium imaging, in stem cell-derived in vitro models, especially human embryonic neural stem cells, along with their capacity for proliferation and their potential for differentiation, to dissect relevant mechanisms underlying the etiology of the neurotoxicity associated with developmental exposures to anesthetic agents. Also, this review attempts to discuss several advantages for using the developing rhesus monkey models (in vivo, when combined with dynamic molecular imaging approaches, in addressing critical issues related to the topic of pediatric sedation/anesthesia. These include the relationships between anesthetic-induced neurotoxicity, dose response, time-course and developmental stage at time of exposure (in vivo studies, serving to provide the most expeditious platform toward decreasing the uncertainty in extrapolating pre-clinical data to the human condition.

  3. Lymphoma: current status of clinical and preclinical imaging with radiolabeled antibodies

    Energy Technology Data Exchange (ETDEWEB)

    England, Christopher G. [University of Wisconsin School of Medicine and Public Health, Department of Medical Physics, Madison, WI (United States); Rui, Lixin [University of Wisconsin School of Medicine and Public Health, Department of Medicine, Madison, WI (United States); University of Wisconsin School of Medicine and Public Health, Carbone Cancer Center, Madison, WI (United States); Cai, Weibo [University of Wisconsin School of Medicine and Public Health, Department of Medical Physics, Madison, WI (United States); University of Wisconsin School of Medicine and Public Health, Carbone Cancer Center, Madison, WI (United States); University of Wisconsin School of Medicine and Public Health, Department of Radiology, Madison, WI (United States)

    2017-03-15

    Lymphoma is a complex disease that arises from cells of the immune system with an intricate pathology. While lymphoma may be classified as Hodgkin or non-Hodgkin, each type of tumor is genetically and phenotypically different and highly invasive tissue biopsies are the only method to investigate these differences. Noninvasive imaging strategies, such as immunoPET, can provide a vital insight into disease staging, monitoring treatment response in patients, and dose planning in radioimmunotherapy. ImmunoPET imaging with radiolabeled antibody-based tracers may also assist physicians in optimizing treatment strategies and enhancing patient stratification. Currently, there are two common biomarkers for molecular imaging of lymphoma, CD20 and CD30, both of which have been considered for investigation in preclinical imaging studies. In this review, we examine the current status of both preclinical and clinical imaging of lymphoma using radiolabeled antibodies. Additionally, we briefly investigate the role of radiolabeled antibodies in lymphoma therapy. As radiolabeled antibodies play critical roles in both imaging and therapy of lymphoma, the development of novel antibodies and the discovery of new biomarkers may greatly affect lymphoma imaging and therapy in the future. (orig.)

  4. Lymphoma: current status of clinical and preclinical imaging with radiolabeled antibodies

    International Nuclear Information System (INIS)

    England, Christopher G.; Rui, Lixin; Cai, Weibo

    2017-01-01

    Lymphoma is a complex disease that arises from cells of the immune system with an intricate pathology. While lymphoma may be classified as Hodgkin or non-Hodgkin, each type of tumor is genetically and phenotypically different and highly invasive tissue biopsies are the only method to investigate these differences. Noninvasive imaging strategies, such as immunoPET, can provide a vital insight into disease staging, monitoring treatment response in patients, and dose planning in radioimmunotherapy. ImmunoPET imaging with radiolabeled antibody-based tracers may also assist physicians in optimizing treatment strategies and enhancing patient stratification. Currently, there are two common biomarkers for molecular imaging of lymphoma, CD20 and CD30, both of which have been considered for investigation in preclinical imaging studies. In this review, we examine the current status of both preclinical and clinical imaging of lymphoma using radiolabeled antibodies. Additionally, we briefly investigate the role of radiolabeled antibodies in lymphoma therapy. As radiolabeled antibodies play critical roles in both imaging and therapy of lymphoma, the development of novel antibodies and the discovery of new biomarkers may greatly affect lymphoma imaging and therapy in the future. (orig.)

  5. Late-onset Huntington's disease: diagnostic and prognostic considerations.

    Science.gov (United States)

    Koutsis, Georgios; Karadima, Georgia; Kladi, Athina; Panas, Marios

    2014-07-01

    To address diagnostic and prognostic issues in patients with late-onset Huntington's disease (HD). We analyzed a cohort of 41 late-onset (≥60 years) HD patients and compared them to 39 late-onset patients referred for HD testing that were negative for the HD-expansion and to 290 usual-onset (20-59 years) HD patients. Disease severity was assessed by the Total Functional Capacity Scale. Late-onset HD comprised 11.5% of our HD cohort. In total, 70.7% of late-onset HD patients had positive family history compared to 15.4% of late-onset expansion-negative patients (p < 0.001). Clinical features at onset or presentation could not usefully distinguish between late-onset expansion-positive and negative patients, excepting hemichorea, which was absent from the HD group (p = 0.024). Chorea was the first clinical feature in 53.7% and a presenting feature in 90.2% of late-onset HD. The mutation hit rate for late-onset patients was 51.3%, lower than in usual-onset patients (p = 0.04). Frequencies of chorea, cognitive impairment and psychiatric manifestations at onset or presentation were not significantly different between late-onset and usual-onset HD patients. Gait unsteadiness however was more common at presentation in late-onset HD (p = 0.007). Late-onset HD patients reached a severe stage of illness on average 2.8 years earlier than usual-onset HD patients (p = 0.046). A positive family history suggestive of HD, although absent in a third of patients, remains a helpful clue in diagnosing late-onset HD. Prognosis of late-onset HD in terms of Total Functional Capacity appears no better and shows a trend of being somewhat less favorable compared to usual-onset HD. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Late effecten van kankerbehandeling

    NARCIS (Netherlands)

    Langeveld, Nelia E.

    2004-01-01

    In dit artikel wordt ingegaan op de lange termijn effecten van kanker op de kinderleeftijd. Vervolgens wordt een kort overzicht gegeven van de belangrijkste late gevolgen die kunnen optreden na een oncologische behandeling met radio- en/of chemotherapie toegepast in de kinderleeftijd. Er wordt kort

  7. Late-modern hipsters

    DEFF Research Database (Denmark)

    Andersen, Bjørn Schiermer

    2014-01-01

    The article deals with the cultural significance of a new figure in late-modern Western culture: the hipster. The current hipster culture, so I argue, can be used as a magnifying glass that makes impending changes to our conception of culture and of cultural development visible. It ushers...

  8. Big Java late objects

    CERN Document Server

    Horstmann, Cay S

    2012-01-01

    Big Java: Late Objects is a comprehensive introduction to Java and computer programming, which focuses on the principles of programming, software engineering, and effective learning. It is designed for a two-semester first course in programming for computer science students.

  9. Stress, Burnout and Coping Strategies in Preclinical Medical Students

    Science.gov (United States)

    Fares, Jawad; Al Tabosh, Hayat; Saadeddin, Zein; El Mouhayyar, Christopher; Aridi, Hussam

    2016-01-01

    It is acknowledged that physicians do not seek the same expert aid for themselves as they would offer their patients. In their preclinical years, medical students appear to espouse comparable behavior. To many, medicine is described as a never-ending path that places the student under heavy stress and burnout from the beginning, leaving him/her vulnerable and with insufficient coping methods. Hence, the objective of this study is to 1) explore the prevalence of stress and burnout among preclinical medical students, and 2) propose solutions to decrease stress and burnout and improve medical education in the preclinical years. A detailed scholarly research strategy using Google Scholar, Scopus, Embase, MEDLINE and PubMed was implemented to highlight key themes that are relevant to preclinical medical students’ stress and burnout. Stress varied among different samples of medical students and ranged between 20.9% and 90%. Conversely, burnout ranged between 27% and 75%. Methods that help in reducing the incidence of stress and burnout by promoting strategies that focus on personal engagement, extracurricular activities, positive reinterpretation and expression of emotion, student-led mentorship programs, evaluation systems, career counseling and life coaching should be adopted. PMID:27042604

  10. Perspective: Recommendations for benchmarking pre-clinical studies of nanomedicines

    Science.gov (United States)

    Dawidczyk, Charlene M.; Russell, Luisa M.; Searson, Peter C.

    2015-01-01

    Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small molecule drug therapy for cancer, and to achieve both therapeutic and diagnostic functions in the same platform. Pre-clinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of pre-clinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of pre-clinical trials and propose a protocol for benchmarking that we recommend be included in in vivo pre-clinical studies of drug delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. PMID:26249177

  11. Preclinical animal research on therapy dosimetry with dual isotopes

    NARCIS (Netherlands)

    M.W. Konijnenberg (Mark); M. de Jong (Marion)

    2011-01-01

    textabstractPreclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of

  12. A preclinical mouse model of invasive lobular breast cancer metastasis

    NARCIS (Netherlands)

    Doornebal, Chris W.; Klarenbeek, Sjoerd; Braumuller, Tanya M.; Klijn, Christiaan N.; Ciampricotti, Metamia; Hau, Cheei-Sing; Hollmann, Markus W.; Jonkers, Jos; de Visser, Karin E.

    2013-01-01

    Metastatic disease accounts for more than 90% of cancer-related deaths, but the development of effective antimetastatic agents has been hampered by the paucity of clinically relevant preclinical models of human metastatic disease. Here, we report the development of a mouse model of spontaneous

  13. Stress, Burnout and Coping Strategies in Preclinical Medical Students.

    Science.gov (United States)

    Fares, Jawad; Al Tabosh, Hayat; Saadeddin, Zein; El Mouhayyar, Christopher; Aridi, Hussam

    2016-02-01

    It is acknowledged that physicians do not seek the same expert aid for themselves as they would offer their patients. In their preclinical years, medical students appear to espouse comparable behavior. To many, medicine is described as a never-ending path that places the student under heavy stress and burnout from the beginning, leaving him/her vulnerable and with insufficient coping methods. Hence, the objective of this study is to 1) explore the prevalence of stress and burnout among preclinical medical students, and 2) propose solutions to decrease stress and burnout and improve medical education in the preclinical years. A detailed scholarly research strategy using Google Scholar, Scopus, Embase, MEDLINE and PubMed was implemented to highlight key themes that are relevant to preclinical medical students' stress and burnout. Stress varied among different samples of medical students and ranged between 20.9% and 90%. Conversely, burnout ranged between 27% and 75%. Methods that help in reducing the incidence of stress and burnout by promoting strategies that focus on personal engagement, extracurricular activities, positive reinterpretation and expression of emotion, student-led mentorship programs, evaluation systems, career counseling and life coaching should be adopted.

  14. Nanotechnology and nuclear medicine; research and preclinical applications.

    Science.gov (United States)

    Assadi, Majid; Afrasiabi, Kolsoom; Nabipour, Iraj; Seyedabadi, Mohammad

    2011-01-01

    The birth of nanotechnology in human society was around 2000 years ago and soon found applications in various fields. In this article, we highlight the current status of research and preclinical applications and also future prospects of nanotechnology in medicine and in nuclear medicine. The most important field is cancer. A regular nanotechnology training program for nuclear medicine physicians may be welcome.

  15. Subjective and Objective Evaluation of PBL Outcomes in Preclinical ...

    African Journals Online (AJOL)

    Subjective and Objective Evaluation of PBL Outcomes in Preclinical Medical Students. ... ABSTRACT: Problem based learning curriculum is widely recognized as a progressive, learner-centered, active learning approach and is currently used in the entire medical curriculum in over 10% of medical schools worldwide.

  16. Image-guided drug delivery: preclinical applications and clinical translation

    NARCIS (Netherlands)

    Ojha, Tarun; Rizzo, Larissa; Storm, Gerrit; Kiessling, Fabian; Lammers, Twan Gerardus Gertudis Maria

    2015-01-01

    Image-guided drug delivery refers to the combination of drug targeting and imaging. Preclinically, image-guided drug delivery can be used for several different purposes, including for monitoring biodistribution, target site accumulation, off-target localization, drug release and drug efficacy.

  17. Development of computational small animal models and their applications in preclinical imaging and therapy research

    NARCIS (Netherlands)

    Xie, Tianwu; Zaidi, Habib

    The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal

  18. 77 FR 71194 - Draft Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy...

    Science.gov (United States)

    2012-11-29

    ...] Draft Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy... Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products,'' dated November... Evaluation (CBER), Office of Cellular, Tissue, and Gene Therapies (OCTGT). The product areas covered by this...

  19. Preclinical Cancer Chemoprevention Studies Using Animal Model of Inflammation-Associated Colorectal Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Takuji [Cytopatholgy Division, Tohkai Cytopathology Institute, Cancer Research and Prevention (TCI-CaRP), 5-1-2 Minami-uzura, Gifu 500-8285 (Japan); Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan)

    2012-07-16

    Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described.

  20. Diagnostic and prognostic role of semantic processing in preclinical Alzheimer's disease.

    Science.gov (United States)

    Venneri, Annalena; Jahn-Carta, Caroline; Marco, Matteo De; Quaranta, Davide; Marra, Camillo

    2018-06-13

    Relatively spared during most of the timeline of normal aging, semantic memory shows a subtle yet measurable decline even during the pre-clinical stage of Alzheimer's disease. This decline is thought to reflect early neurofibrillary changes and impairment is detectable using tests of language relying on lexical-semantic abilities. A promising approach is the characterization of semantic parameters such as typicality and age of acquisition of words, and propositional density from verbal output. Seminal research like the Nun Study or the analysis of the linguistic decline of famous writers and politicians later diagnosed with Alzheimer's disease supports the early diagnostic value of semantic processing and semantic memory. Moreover, measures of these skills may play an important role for the prognosis of patients with mild cognitive impairment.

  1. Sedimentology, geochemistry and OSL dating of the alluvial succession in the northern Gujarat alluvial plain (western India) - A record to evaluate the sensitivity of a semiarid fluvial system to the climatic and tectonic forcing since the late Marine Isotopic Stage 3

    Science.gov (United States)

    Bhattacharya, Falguni; Shukla, Anil D.; Patel, R. C.; Rastogi, B. K.; Juyal, Navin

    2017-11-01

    The alluvial successions in the northern Gujarat alluvial plain (western India) have been investigated for reconstructing the climatic fluctuations during the last 40 ka. Alluvial architecture and geochemical proxies indicate prevalence of a strengthened Indian Summer Monsoon (ISM) with fluctuations between the late Marine Isotopic Stage 3 (MIS 3; 37 ka) to the early MIS 2 (27 ka). A gradual onset of aridity (declining ISM) after 27 ka with peak aridity at 22 ka is observed. A gradual strengthening of ISM at around 18 and > 12 ka followed by a short reversal in ISM intensity between 12 and 11 ka, is attributed to the Younger-Dryas (YD) cooling event. The aeolian sand sheet dated to 6 and 3.5 ka represents the onset of regional aridity. Following this, a short-lived humid phase was observed after 2 ka, which includes the Medieval Warm Period (MWP). The study suggests that the variability in the ISM to the latitudinal migration of the Inter Tropical Convergence Zone was caused by insolation-driven cooling and warming events in the North Atlantic. The incision of the valley fill alluvium occurred in two distinct phases. The older incision phase occurred after 11 ka and before 6 ka, whereas the younger incision phase that led to the development of present day topography is bracketed between 3.5 ka and before 1 ka. The older incision phase is ascribed to the early to mid-Holocene enhanced ISM (climatically driven), whereas the younger incision seems to be modulated by the activation of basement faults (tectonically driven).

  2. Cortical hypometabolism and hypoperfusion in Parkinson's disease is extensive: probably even at early disease stages

    DEFF Research Database (Denmark)

    Borghammer, Per; Chakravarty, Mallar; Jonsdottir, Kristjana Yr

    2010-01-01

    independent samples of PD patients. We compared SPECT CBF images of 32 early-stage and 33 late-stage PD patients with that of 60 matched controls. We also compared PET FDG images from 23 late-stage PD patients with that of 13 controls. Three different normalization methods were compared: (1) GM normalization...

  3. Late-Onset Asthma

    DEFF Research Database (Denmark)

    Ulrik, Charlotte Suppli

    2017-01-01

    Late-onset asthma is common, associated with poor outcome, underdiagnosed and undertreated, possibly due to the modifying effect of ageing on disease expression. Although the diagnostic work-up in elderly individuals suspected of having asthma follows the same steps as in younger individuals (case......, to objectively confirm asthma. If necessary, a trial of oral or inhaled corticosteroid might be necessary. Asthma can be diagnosed when increased airflow variability is identified in a symptomatic patient, and if the patient does not have a history of exposure, primarily smoking, known to cause chronic...... obstructive pulmonary disease, the diagnosis is asthma even if the patient does not have fully reversible airflow obstruction. Pharmacological therapy in patients with late-onset asthma follows international guidelines, including treatment with the lowest effective dose of inhaled corticosteroid to minimize...

  4. A systematic review of methodology applied during preclinical anesthetic neurotoxicity studies: important issues and lessons relevant to the design of future clinical research.

    Science.gov (United States)

    Disma, Nicola; Mondardini, Maria C; Terrando, Niccolò; Absalom, Anthony R; Bilotta, Federico

    2016-01-01

    Preclinical evidence suggests that anesthetic agents harm the developing brain thereby causing long-term neurocognitive impairments. It is not clear if these findings apply to humans, and retrospective epidemiological studies thus far have failed to show definitive evidence that anesthetic agents are harmful to the developing human brain. The aim of this systematic review was to summarize the preclinical studies published over the past decade, with a focus on methodological issues, to facilitate the comparison between different preclinical studies and inform better design of future trials. The literature search identified 941 articles related to the topic of neurotoxicity. As the primary aim of this systematic review was to compare methodologies applied in animal studies to inform future trials, we excluded a priori all articles focused on putative mechanism of neurotoxicity and the neuroprotective agents. Forty-seven preclinical studies were finally included in this review. Methods used in these studies were highly heterogeneous-animals were exposed to anesthetic agents at different developmental stages, in various doses and in various combinations with other drugs, and overall showed diverse toxicity profiles. Physiological monitoring and maintenance of physiological homeostasis was variable and the use of cognitive tests was generally limited to assessment of specific brain areas, with restricted translational relevance to humans. Comparison between studies is thus complicated by this heterogeneous methodology and the relevance of the combined body of literature to humans remains uncertain. Future preclinical studies should use better standardized methodologies to facilitate transferability of findings from preclinical into clinical science. © 2015 John Wiley & Sons Ltd.

  5. Late Babylonian Astrology

    Science.gov (United States)

    Steele, John M.

    The last five centuries BC saw the development of several new forms of astrology in Babylonia. Key to these new astrological techniques was the invention of the zodiac in about 400 BC. These new forms of astrology include personal horoscopes, astral medicine, and the exploitation of geometrical relationships between the position of heavenly bodies. Several Late Babylonian astrological doctrines were later adopted within Greek astrology.

  6. Late Palaeozoic plants.

    Science.gov (United States)

    Feng, Zhuo

    2017-09-11

    Land plants are one of the major constituents of terrestrial ecosystems on Earth, and play an irreplaceable role in human activities today. If we are to understand the extant plants, it is imperative that we have some understanding of the fossil plants from the deep geological past, particularly those that occurred during their early evolutionary history, in the late Palaeozoic. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Late somatic effects

    International Nuclear Information System (INIS)

    Gilbert, E.S.

    1989-01-01

    Late effects are by definition effects that occur at least one year, and in most cases decades, after the time of exposure. The late effects considered in this chapter are limited to latent cancer incidence and mortality, and benign thyroid disease. A model is provided for estimating risks of late effects resulting from the radiation exposure likely to be received in the event of a nuclear power plant accident. It is assumed that exposure to high-LET radiation would be negligible in such an accident, and thus only risks from low-LET exposure are evaluated. Separate estimates are provided for risks of leukemia, bone cancer, lung cancer, gastrointestinal cancers, thyroid cancer, skin cancer, and the residual group of all other cancers; estimates of leukemia and other cancers due to in utero exposure are also provided. Risks are expressed in absolute terms as the number of cancer deaths (or cases) per million persons exposed to a particular dose. Because the time of death is also important in assessing the impact of an accident, and because the quality of life after the occurrence of cancer will often be reduced, the number of years of life lost and the number of years of life lived after the occurrence of cancer are also estimated

  8. WE-H-206-00: Advances in Preclinical Imaging

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2016-06-15

    Lihong V. Wang: Photoacoustic tomography (PAT), combining non-ionizing optical and ultrasonic waves via the photoacoustic effect, provides in vivo multiscale functional, metabolic, and molecular imaging. Broad applications include imaging of the breast, brain, skin, esophagus, colon, vascular system, and lymphatic system in humans or animals. Light offers rich contrast but does not penetrate biological tissue in straight paths as x-rays do. Consequently, high-resolution pure optical imaging (e.g., confocal microscopy, two-photon microscopy, and optical coherence tomography) is limited to penetration within the optical diffusion limit (∼1 mm in the skin). Ultrasonic imaging, on the contrary, provides fine spatial resolution but suffers from both poor contrast in early-stage tumors and strong speckle artifacts. In PAT, pulsed laser light penetrates tissue and generates a small but rapid temperature rise, which induces emission of ultrasonic waves due to thermoelastic expansion. The ultrasonic waves, orders of magnitude less scattering than optical waves, are then detected to form high-resolution images of optical absorption at depths up to 7 cm, conquering the optical diffusion limit. PAT is the only modality capable of imaging across the length scales of organelles, cells, tissues, and organs (up to whole-body small animals) with consistent contrast. This rapidly growing technology promises to enable multiscale biological research and accelerate translation from microscopic laboratory discoveries to macroscopic clinical practice. PAT may also hold the key to label-free early detection of cancer by in vivo quantification of hypermetabolism, the quintessential hallmark of malignancy. Learning Objectives: To understand the contrast mechanism of PAT To understand the multiscale applications of PAT Benjamin M. W. Tsui: Multi-modality molecular imaging instrumentation and techniques have been major developments in small animal imaging that has contributed significantly

  9. WE-H-206-00: Advances in Preclinical Imaging

    International Nuclear Information System (INIS)

    2016-01-01

    Lihong V. Wang: Photoacoustic tomography (PAT), combining non-ionizing optical and ultrasonic waves via the photoacoustic effect, provides in vivo multiscale functional, metabolic, and molecular imaging. Broad applications include imaging of the breast, brain, skin, esophagus, colon, vascular system, and lymphatic system in humans or animals. Light offers rich contrast but does not penetrate biological tissue in straight paths as x-rays do. Consequently, high-resolution pure optical imaging (e.g., confocal microscopy, two-photon microscopy, and optical coherence tomography) is limited to penetration within the optical diffusion limit (∼1 mm in the skin). Ultrasonic imaging, on the contrary, provides fine spatial resolution but suffers from both poor contrast in early-stage tumors and strong speckle artifacts. In PAT, pulsed laser light penetrates tissue and generates a small but rapid temperature rise, which induces emission of ultrasonic waves due to thermoelastic expansion. The ultrasonic waves, orders of magnitude less scattering than optical waves, are then detected to form high-resolution images of optical absorption at depths up to 7 cm, conquering the optical diffusion limit. PAT is the only modality capable of imaging across the length scales of organelles, cells, tissues, and organs (up to whole-body small animals) with consistent contrast. This rapidly growing technology promises to enable multiscale biological research and accelerate translation from microscopic laboratory discoveries to macroscopic clinical practice. PAT may also hold the key to label-free early detection of cancer by in vivo quantification of hypermetabolism, the quintessential hallmark of malignancy. Learning Objectives: To understand the contrast mechanism of PAT To understand the multiscale applications of PAT Benjamin M. W. Tsui: Multi-modality molecular imaging instrumentation and techniques have been major developments in small animal imaging that has contributed significantly

  10. Coping – Late Side Effects

    Science.gov (United States)

    Cancer treatment can cause late side effects that may not show up for months or years after treatment. These late effects may include heart and lung problems, bone loss, eye and hearing changes, lymphedema, and other problems

  11. Prediction of antibiotic resistance: time for a new preclinical paradigm?

    DEFF Research Database (Denmark)

    Sommer, Morten Otto Alexander; Munck, Christian; Toft-Kehler, Rasmus Vendler

    2017-01-01

    Predicting the future is difficult, especially for evolutionary processes that are influenced by numerous unknown factors. Still, this is what is required of drug developers when they assess the risk of resistance arising against a new antibiotic candidate during preclinical development. In this ......Predicting the future is difficult, especially for evolutionary processes that are influenced by numerous unknown factors. Still, this is what is required of drug developers when they assess the risk of resistance arising against a new antibiotic candidate during preclinical development....... In this Opinion article, we argue that the traditional procedures that are used for the prediction of antibiotic resistance today could be markedly improved by including a broader analysis of bacterial fitness, infection dynamics, horizontal gene transfer and other factors. This will lead to more informed...

  12. Division of volcanic activity cycles in the late mesozoic in South Jiangxi and North Guangdong

    International Nuclear Information System (INIS)

    Li Qinglong; Wu Jianhua

    1999-01-01

    Based on stratigraphical unconformity, rock association, fossil assemblage, isotope age and tectonic features, the volcanic activity in late Mesozoic in south Jiangxi and north Guandong can be divided into four cycles: Yutian volcanic activity cycle, Lianhuazhai volcanic activity cycle. Banshi volcanic activity cycle and Nanxiong volcanic activity cycle. Yutian volcanic cycle which occurs in middle Jurassic epoch is the bimodal rock association composed of rhyolite and basalt. Lianhuazhai volcanic cycle which occurs in late Jurassic epoch is unimodal rock association composed of rhyolite. Banshi volcanic cycle occurs from the late stage of early Cretaceous to the early stage of late Cretaceous epoch. There are two types of rock associations related to this cycle: unimodal rock association composed of rhyolite or basalt and bimodal rock association composed of rhyolite and basalt. Nanxiong volcanic activity cycle which occurred in late stage of late Cretaceous epoch is the unimodal rock association composed of basalt which is the interlayer of the red sedimentary series

  13. Applications of the Preclinical Molecular Imaging in Biomedicine: Gene Therapy

    International Nuclear Information System (INIS)

    Collantes, M.; Peñuelas, I.

    2014-01-01

    Gene therapy constitutes a promising option for efficient and targeted treatment of several inherited disorders. Imaging techniques using ionizing radiation as PET or SPECT are used for non-invasive monitoring of the distribution and kinetics of vector-mediated gene expression. In this review the main reporter gene/reporter probe strategies are summarized, as well as the contribution of preclinical models to the development of this new imaging modality previously to its application in clinical arena. [es

  14. Multimodal imaging of bone metastases: From preclinical to clinical applications

    Directory of Open Access Journals (Sweden)

    Stephan Ellmann

    2015-10-01

    Full Text Available Metastases to the skeletal system are commonly observed in cancer patients, highly affecting the patients' quality of life. Imaging plays a major role in detection, follow-up, and molecular characterisation of metastatic disease. Thus, imaging techniques have been optimised and combined in a multimodal and multiparametric manner for assessment of complementary aspects in osseous metastases. This review summarises both application of the most relevant imaging techniques for bone metastasis in preclinical models and the clinical setting.

  15. Identification of new treatments for epilepsy: issues in preclinical methodology

    Science.gov (United States)

    Galanopoulou, Aristea S.; Buckmaster, Paul S.; Staley, Kevin J.; Moshé, Solomon L.; Perucca, Emilio; Engel, Jerome; Löscher, Wolfgang; Noebels, Jeffrey L.; Pitkänen, Asla; Stables, James; White, Steve H.; O’Brien, Terence J.; Simonato, Michele

    2013-01-01

    Summary Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (a) new symptomatic anti-seizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (b) disease modifying treatments that prevent or ameliorate the epileptogenic state, and (c) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, i.e. age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical anti-epilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis and comorbidities. PMID:22292566

  16. Identification of new epilepsy treatments: issues in preclinical methodology.

    Science.gov (United States)

    Galanopoulou, Aristea S; Buckmaster, Paul S; Staley, Kevin J; Moshé, Solomon L; Perucca, Emilio; Engel, Jerome; Löscher, Wolfgang; Noebels, Jeffrey L; Pitkänen, Asla; Stables, James; White, H Steve; O'Brien, Terence J; Simonato, Michele

    2012-03-01

    Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (1) new symptomatic antiseizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (2) disease-modifying treatments that prevent or ameliorate the process of epileptogenesis, and (3) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, that is, age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome, or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical antiepilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis, and comorbidities. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

  17. A cost-effective simulation curriculum for preclinical endodontics.

    Science.gov (United States)

    Pileggi, Roberta; Glickman, Gerald N

    2004-02-01

    A challenge in contemporary dental education is to achieve a smooth transition from preclinical teaching environments to patient-care clinics in a cost-effective manner. The preclinical endodontic courses at The University of Texas, Dental Branch at Houston provide a unique learning environment that enables the student to perform endodontic treatment on extracted teeth in a typodont, and be involved in diagnosis and treatment-planning discussions. The specially designed stone typodont used has built-in radiographic capability, and is mounted at each chair in the clinic. During each preclinical session, students are assigned clinical cubicles and proper aseptic protocol is followed. Students are required to wear gloves, masks and eyewear, and place a rubber dam during treatment. Written self-assessment evaluations based upon prescribed criteria are utilised; feedback is given by faculty composed of both full-time endodontists and graduate students who periodically rotate and are calibrated on a regular basis. In the lecture phase, clinical case scenarios are presented to reinforce concepts of diagnosis and emergency care and to help integrate endodontics with other disciplines; a Socratic-like teaching style is established by the faculty facilitator to create an environment for developing critical-thinking and problem-solving skills. The overall feedback from graduating students has been very positive. Advantages of this format are an easier transition to patient management, a more keen interest in specialsation and a perceived increase in levels of confidence.

  18. Preclinical experimental stress studies: protocols, assessment and comparison.

    Science.gov (United States)

    Bali, Anjana; Jaggi, Amteshwar Singh

    2015-01-05

    Stress is a state of threatened homeostasis during which a variety of adaptive processes are activated to produce physiological and behavioral changes. Preclinical models are pivotal for understanding these physiological or pathophysiological changes in the body in response to stress. Furthermore, these models are also important for the development of novel pharmacological agents for stress management. The well described preclinical stress models include immobilization, restraint, electric foot shock and social isolation stress. Stress assessment in animals is done at the behavioral level using open field, social interaction, hole board test; at the biochemical level by measuring plasma corticosterone and ACTH; at the physiological level by measuring food intake, body weight, adrenal gland weight and gastric ulceration. Furthermore the comparison between different stressors including electric foot shock, immobilization and cold stressor is described in terms of intensity, hormonal release, protein changes in brain, adaptation and sleep pattern. This present review describes these preclinical stress protocols, and stress assessment at different levels. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Is medical students' moral orientation changeable after preclinical medical education?

    Science.gov (United States)

    Lin, Chaou-Shune; Tsou, Kuo-Inn; Cho, Shu-Ling; Hsieh, Ming-Shium; Wu, Hsi-Chin; Lin, Chyi-Her

    2012-03-01

    Moral orientation can affect ethical decision-making. Very few studies have focused on whether medical education can change the moral orientation of the students. The purpose of the present study was to document the types of moral orientation exhibited by medical students, and to study if their moral orientation was changed after preclinical education. From 2007 to 2009, the Mojac scale was used to measure the moral orientation of Taiwan medical students. The students included 271 first-year and 109 third-year students. They were rated as a communitarian, dual, or libertarian group and followed for 2 years to monitor the changes in their Mojac scores. In both first and third-year students, the dual group after 2 years of preclinical medical education did not show any significant change. In the libertarian group, first and third-year students showed a statistically significant increase from a score of 99.4 and 101.3 to 103.0 and 105.7, respectively. In the communitarian group, first and third-year students showed a significant decline from 122.8 and 126.1 to 116.0 and 121.5, respectively. During the preclinical medical education years, students with communitarian orientation and libertarian orientation had changed in their moral orientation to become closer to dual orientation. These findings provide valuable hints to medical educators regarding bioethics education and the selection criteria of medical students for admission.

  20. Operação de Glenn bidirecional no tratamento estagiado da síndrome de hipoplasia do coração esquerdo: resultados imediatos e tardios Bidirectional Glenn procedure in the staged treatment of hypoplastic left heart syndrome: early and late results

    Directory of Open Access Journals (Sweden)

    Luciana da Fonseca

    2005-03-01

    technique. METHOD: From March 1998 to February 2004, 15 patients who had been previously submitted to the Norwood procedure underwent elective partial cavopulmonary anastomosis. Ages ranged from 2 to 6 months (mean 3.46±0.83 months, Six were male. Ministernotomy was performed in 11 (73.3% patients. In order to obtain adequate initial blood oxygenation, an accessory 3 mm PTFE shunt was useed in nine patients and the right ventricle-pulmonary artery tube was maintained in one case. Clinical and echocardiographic follow-up was obtained in all patients. RESULTS: Hospital survival was 86.6%, with one early death caused by surgical bleeding and another due to hypoxemia. Postoperative echocardiogram showed some early blood flow in PTFE shunt, and its closure in long-term follow-up.There were two late deaths, one due to tracheostomy complications and another due to infectious meningitis. Seven patients, who are waiting third stage, are doing well clinically. Four patients already undergone the third stage, successfully. The echocardiograms of 11 late survival patients showed good right ventricular function, no tricuspid regurgitation and good cavopulmonary blood flow over a 2.5-years mean follow-up time. CONCLUSIONS: The Glenn procedure in HLHS resulted in a low mortality rate and satisfactory long-term outcomes, and can be performed using the ministernotomy technique. An acessory source of systemic-pulmonary flow in very small infants seems to improve the oxygen saturation.

  1. Late induced abortion.

    Science.gov (United States)

    Savage, W

    1990-09-01

    In the UK in 1988, 13.3% of abortions were performed at 13 weeks' gestation or later. Reasons for this delay, in addition to the diagnosis through amniocentesis of a fetal abnormality, include late recognition of pregnancy, a change of mind about completing the pregnancy, a failure of primary care physicians to entertain the diagnosis of pregnancy, travel or financial problems, and referral difficulties and scheduling delays. Women with little education and very young women are most likely to present for late abortions. From 13-16 weeks, dilatation and evacuation is the safest method of pregnancy termination. The procedure can be made easier through preparation of the cervix with a prostaglandin pessary or Foley catheter. After 16 weeks, an instillation method is recommended; prostaglandin administration can be intro- or extra-amniotic. Complication rates at 13-19 weeks are 14.5/1000 for vaginal methods of abortion and 7.2/1000 for prostaglandin methods. The risk of complications is 3 times higher for women who have 2nd-trimester abortions through the National Health Service. Although it is not realistic to expect that late abortions ever can be eliminated, improved sex education and contraceptive reliability as well as reforms in the National Health Service could reduce the number substantially. To reduce delay, it is suggested that the National Health Service set up satellite day care units and 1-2 central units in each region to deal quickly with midtrimester abortions. Delays would be further reduced by legislation to allow abortion on request in at least the 1st trimester of pregnancy.

  2. Late Washing efficiency

    International Nuclear Information System (INIS)

    Morrissey, M.F.

    1992-01-01

    Interim Waste Technology has demonstrated the Late Washing concept on the Experimental Laboratory Filter (ELF) at TNX. In two tests, washing reduced the [NO 2 - ] from 0.08 M to approximately 0.01 M on slurries with 2 year equivalent radiation exposures and 9.5 wt. % solids. For both washes, the [NO 2 - ] decreased at rates near theoretical for a constant volume stirred vessel, indicating approximately l00% washing efficiency. Permeate flux was greater than 0.05 gpm/ft 2 for both washes at a transmembrane pressure of 50 psi and flow velocity of 9 ft/sec

  3. Late-onset hypogonadism

    Directory of Open Access Journals (Sweden)

    Piotr Dudek

    2017-06-01

    Full Text Available In Poland, the number of men over the age of 50 years exceeds 6 million. It is estimated that about 2-6% of this population develops symptoms of late-onset hypogonadism (LOH. In men, testosterone deficiency increases slightly with age. LOH is a clinically and biochemically defined disease of older men with serum testosterone level below the reference parameters of younger healthy men and with symptoms of testosterone deficiency, manifested by pronounced disturbances of quality of life and harmful effects on multiple organ systems. Testosterone replacement therapy may give several benefits regarding body composition, metabolic control, and psychological and sexual parameters.

  4. Early and late motherhood

    DEFF Research Database (Denmark)

    Christoffersen, Mogens; Lausten, Mette

    2009-01-01

    The study investigates parental child rearing methods, structural factors relating to the family during adolescence geographic segregation, individual resource deficits and social background of first time late live births among 32 to 37 years old women and compare to teenagers before becoming...... economic and social gradient for first-time teenage mothers. Teenagers who had experienced family separation or who were formerly in out-of-home care in particular had an increased risk of early childbearing. Results showed that teenage mothers were in every respect in a more disadvantaged position than...

  5. Theoretical Exploration of the Neural Bases of Behavioural Disinhibition, Apathy and Executive Dysfunction in Preclinical Alzheimer's Disease in People with Down's Syndrome: Potential Involvement of Multiple Frontal-Subcortical Neuronal Circuits

    Science.gov (United States)

    Ball, S. L.; Holland, A. J.; Watson, P. C.; Huppert, F. A.

    2010-01-01

    Background: Recent research has suggested a specific impairment in frontal-lobe functioning in the preclinical stages of Alzheimer's disease (AD) in people with Down's syndrome (DS), characterised by prominent changes in personality or behaviour. The aim of the current paper is to explore whether particular kinds of change (namely executive…

  6. Better late than never

    DEFF Research Database (Denmark)

    Womack, Molly C; Christensen-Dalsgaard, Jakob; Hoke, Kim L

    2016-01-01

    Most vertebrates have evolved a tympanic middle ear that enables effective hearing of airborne sound on land. Although inner ears develop during the tadpole stages of toads, tympanic middle ear structures are not complete until months after metamorphosis, potentially limiting the sensitivity of p...

  7. WE-E-BRE-04: Dual Focal Spot Dose Painting for Precision Preclinical Radiobiological Investigations

    Energy Technology Data Exchange (ETDEWEB)

    Stewart, J; Lindsay, P [Princess Margaret Cancer Centre, Toronto (Canada); University of Toronto, Toronto (Canada); Jaffray, D [Princess Margaret Cancer Centre, Toronto (Canada); The Techna Institute for the Advancement of Technology for Health, Toronto (Canada)

    2014-06-15

    Purpose: Recent progress in small animal radiotherapy systems has provided the foundation for delivering the heterogeneous, millimeter scale dose distributions demanded by preclinical radiobiology investigations. Despite advances in preclinical dose planning, delivery of highly heterogeneous dose distributions is constrained by the fixed collimation systems and large x-ray focal spot common in small animal radiotherapy systems. This work proposes a dual focal spot dose optimization and delivery method with a large x-ray focal spot used to deliver homogeneous dose regions and a small focal spot to paint spatially heterogeneous dose regions. Methods: Two-dimensional dose kernels were measured for a 1 mm circular collimator with radiochromic film at 10 mm depth in a solid water phantom for the small and large x-ray focal spots on a recently developed small animal microirradiator. These kernels were used in an optimization framework which segmented a desired dose distribution into low- and high-spatial frequency regions for delivery by the large and small focal spot, respectively. For each region, the method determined an optimal set of stage positions and beam-on times. The method was demonstrated by optimizing a bullseye pattern consisting of 0.75 mm radius circular target and 0.5 and 1.0 mm wide rings alternating between 0 and 2 Gy. Results: Compared to a large focal spot technique, the dual focal spot technique improved the optimized dose distribution: 69.2% of the optimized dose was within 0.5 Gy of the intended dose for the large focal spot, compared to 80.6% for the dual focal spot method. The dual focal spot design required 14.0 minutes of optimization, and will require 178.3 minutes for automated delivery. Conclusion: The dual focal spot optimization and delivery framework is a novel option for delivering conformal and heterogeneous dose distributions at the preclinical level and provides a new experimental option for unique radiobiological investigations

  8. WE-E-BRE-04: Dual Focal Spot Dose Painting for Precision Preclinical Radiobiological Investigations

    International Nuclear Information System (INIS)

    Stewart, J; Lindsay, P; Jaffray, D

    2014-01-01

    Purpose: Recent progress in small animal radiotherapy systems has provided the foundation for delivering the heterogeneous, millimeter scale dose distributions demanded by preclinical radiobiology investigations. Despite advances in preclinical dose planning, delivery of highly heterogeneous dose distributions is constrained by the fixed collimation systems and large x-ray focal spot common in small animal radiotherapy systems. This work proposes a dual focal spot dose optimization and delivery method with a large x-ray focal spot used to deliver homogeneous dose regions and a small focal spot to paint spatially heterogeneous dose regions. Methods: Two-dimensional dose kernels were measured for a 1 mm circular collimator with radiochromic film at 10 mm depth in a solid water phantom for the small and large x-ray focal spots on a recently developed small animal microirradiator. These kernels were used in an optimization framework which segmented a desired dose distribution into low- and high-spatial frequency regions for delivery by the large and small focal spot, respectively. For each region, the method determined an optimal set of stage positions and beam-on times. The method was demonstrated by optimizing a bullseye pattern consisting of 0.75 mm radius circular target and 0.5 and 1.0 mm wide rings alternating between 0 and 2 Gy. Results: Compared to a large focal spot technique, the dual focal spot technique improved the optimized dose distribution: 69.2% of the optimized dose was within 0.5 Gy of the intended dose for the large focal spot, compared to 80.6% for the dual focal spot method. The dual focal spot design required 14.0 minutes of optimization, and will require 178.3 minutes for automated delivery. Conclusion: The dual focal spot optimization and delivery framework is a novel option for delivering conformal and heterogeneous dose distributions at the preclinical level and provides a new experimental option for unique radiobiological investigations

  9. Second-generation magnesium scaffold Magmaris: device design and preclinical evaluation in a porcine coronary artery model.

    Science.gov (United States)

    Waksman, Ron; Zumstein, Philine; Pritsch, Martin; Wittchow, Eric; Haude, Michael; Lapointe-Corriveau, Capucine; Leclerc, Guy; Joner, Michael

    2017-07-20

    The second-generation drug-eluting absorbable magnesium scaffold Magmaris, recently introduced for the treatment of obstructive coronary atherosclerotic lesions, suggests a good safety profile, but preclinical assessment is important for predicting clinical performance. The aim of the present study was to assess subacute and long-term safety as well as pharmacokinetic properties of the Magmaris compared with a current-generation metallic DES and an approved BRS in porcine and rabbit animal models. Ninety Magmaris scaffolds were implanted into non-diseased porcine and rabbit models. A bioresorbable vascular scaffold (Absorb) and a permanent drug-eluting stent (XIENCE Xpedition) served as controls. Scanning electron microscopy showed increased endothelialisation and decreased thrombus formation at three and 28 days in the Magmaris group compared with the Absorb group. In the XIENCE group, inflammation exceeded the level in the Magmaris group at 365 and 730 days. Neointimal growth was greater in the Magmaris group than in the XIENCE group. Late lumen loss decreased over time in both groups. Optical coherence tomography (OCT) showed stable luminal dimensions in both the Magmaris and XIENCE groups. Pharmacokinetic studies demonstrated a retarded elution profile in the Magmaris group with 69.4% of sirolimus released at 90 days. Preclinical results suggest that the Magmaris has a favourable safety profile with advanced healing relative to benchmark, low acute thrombogenicity, and absence of excessive lumen loss up to two years. These results support clinical application of Magmaris for human use.

  10. Radiotherapy in early stage dupuytren's contracture

    International Nuclear Information System (INIS)

    Adamietz, B.; Sauer, R.; Gruenert, J.

    2001-01-01

    Purpose: In early stage Dupuytren's contracture radiotherapy was applied to prevent disease progression. Long-term results and late toxicity of this treatment were evaluated in a retrospective analysis. Patients and Methods: Between 1982 and 1994, 99 patients (176 hands) received orthovoltage radiotherapy, which consisted of two courses with 5 x 3 Gy (total dose: 30 Gy, daily fractionated; 120 kV, 4 mm Al), separated by a 6 to 8-week pause. The Dupuytren's contracture was staged according to the classification of Tubiana et al. The long-term outcome was analyzed at last follow-up between July and November 1999. The median follow-up was 10 years (range 7-18 years). Late toxicity was assessed using the LENT-SOMA criteria. Results: In Stage N 84% and Stage N/I 67% of cases remained stable. 65% of the cases in Stage I and 83% in Stage II showed progressive nodules and cords. In case of progression we saw no complications after a second radiotherapy or salvage operation. Conclusion: Radiotherapy effectively prevents disease progression for early stage Dupuytren's contracture (Stage N, N/I). Moreover, in case of disease progression despite radiotherapy salvage surgery is still feasible. (orig.) [de

  11. Chronic radiation-induced leukemogenesis: alterations of hematopoietic progenitor repair functions during preclinical phases

    International Nuclear Information System (INIS)

    Seed, T.M.; Kaspar, L.V.; Grdina, D.J.; Frazier, M.E.

    1987-01-01

    Chronic exposure to low daily doses of whole-body gamma irradiation elicits a high incidence of myeloid leukemia (ML) and related myeloproliferative diseases (MPD) in beagles. Previously, the authors identified and partially characterized a four-phase sequence of evolving MPD as a consequence of chronic radiation exposure. With a focus on preclinical alterations in granulocyte/monocyte-committed stem cells, they have identified two critical events in the process: (i) an early event, involving the coupling of acquired radioresistance of the stem cell with renewed proliferative capacity; and (ii) a late event, involving acquired autocrine functions and associated change in stem cell clonality. In terms of the early event, repair-associated parameters are currently being examined on the cellular level by both split-dose and low dose-rate-type assays with survival enhancement used as the measured end point. On the molecular level, these parameters are examined by microfluorometric alkaline elution assays with DNA damage and repair used as end points

  12. Can anti-vascular endothelial growth factor antibody reverse radiation necrosis? A preclinical investigation.

    Science.gov (United States)

    Duan, Chong; Perez-Torres, Carlos J; Yuan, Liya; Engelbach, John A; Beeman, Scott C; Tsien, Christina I; Rich, Keith M; Schmidt, Robert E; Ackerman, Joseph J H; Garbow, Joel R

    2017-05-01

    Anti-vascular endothelial growth factor (anti-VEGF) antibodies are a promising new treatment for late time-to-onset radiation-induced necrosis (RN). We sought to evaluate and validate the response to anti-VEGF antibody in a mouse model of RN. Mice were irradiated with the Leksell Gamma Knife Perfexion™ and then treated with anti-VEGF antibody, beginning at post-irradiation (PIR) week 8. RN progression was monitored via anatomic and diffusion MRI from weeks 4-12 PIR. Standard histology, using haematoxylin and eosin (H&E), and immunohistochemistry staining were used to validate the response to treatment. After treatment, both post-contrast T1-weighted and T2-weighted image-derived lesion volumes decreased (P < 0.001), while the lesion volumes for the control group increased. The abnormally high apparent diffusion coefficient (ADC) for RN also returned to the ADC range for normal brain following treatment (P < 0.001). However, typical RN pathology was still present histologically. Large areas of focal calcification were observed in ~50% of treated mouse brains. Additionally, VEGF and hypoxia-inducible factor 1-alpha (HIF-1α) were continually upregulated in both the anti-VEGF and control groups. Despite improvements observed radiographically following anti-VEGF treatment, lesions were not completely resolved histologically. The subsequent calcification and the continued upregulation of VEGF and HIF-1α merit further preclinical/clinical investigation.

  13. Late-Modern Symbolism

    DEFF Research Database (Denmark)

    Andersen, Bjørn Schiermer

    2015-01-01

    Through analysis of key texts, I seek to demonstrate the explanative potential of Durkheim’s sociology of religion in the present context. I critically readdress the idea, found in his early work, that modernity is characterized by a rupture with pre-modern forms of solidarity. First, I investigate...... the ways in which Durkheim sets up a stark distinction between the pre-modern and the modern in his early work, and how this distinction is further cemented by his orthodox critique of the modern economy and its negative effects on social life. Second, I show how another timeless and positive understanding...... of “mechanical” solidarity is to be found behind the “symbolist” template crystalizing in Durkheim’s late work. Third, I develop this template for a modern context by critically addressing and removing other obstacles and prejudices on Durkheim’s part....

  14. Late somatic effects

    International Nuclear Information System (INIS)

    Gilbert, E.

    1985-01-01

    A model is provided for estimating risks of late effects resulting from low-LET radiation exposure likely to be received in the event of a nuclear power plant accident. Separate estimates are provided for risks of leukemia, cancers of the bones, lungs, gastrointestinal tract, thyroid, skin, and the residual group of all other cancers; estimates of leukemia and other cancers due to in utero exposure are also provided. Risks are expressed in absolute terms as the number of cancer deaths (or cases) per million persons exposed to a particular dose. In addition, the number of years of life lost and the number of years of life lived after the occurrence of cancer are also estimated. The model used in the earlier Reactor Safety Study has been modified to reflect additional epidemiological data and these changes are described in detail. 37 references, 1 figure, 13 tables

  15. Evaluation of Aerosol Delivery of Nanosuspension for Pre-clinical Pulmonary Drug Delivery

    Directory of Open Access Journals (Sweden)

    Chiang Po-Chang

    2009-01-01

    Full Text Available Abstract Asthma and chronic obstructive pulmonary disease (COPD are pulmonary diseases that are characterized by inflammatory cell infiltration, cytokine production, and airway hyper-reactivity. Most of the effector cells responsible for these pathologies reside in the lungs. One of the most direct ways to deliver drugs to the target cells is via the trachea. In a pre-clinical setting, this can be achieved via intratracheal (IT, intranasal (IN, or aerosol delivery in the desired animal model. In this study, we pioneered the aerosol delivery of a nanosuspension formulation in a rodent model. The efficiency of different dosing techniques and formulations to target the lungs were compared, and fluticasone was used as the model compound. For the aerosol particle size determination, a ten-stage cascade impactor was used. The mass median aerodynamic diameter (MMAD was calculated based on the percent cumulative accumulation at each stage. Formulations with different particle size of fluticasone were made for evaluation. The compatibility of regular fluticasone suspension and nanosuspension for aerosol delivery was also investigated. The in vivo studies were conducted on mice with optimized setting. It was found that the aerosol delivery of fluticasone with nanosuspension was as efficient as intranasal (IN dosing, and was able to achieve dose dependent lung deposition.

  16. The late Cainozoic East Antarctic ice sheet

    International Nuclear Information System (INIS)

    Colhoun, E.A.

    1999-01-01

    A review, mainly of East Antarctic late Cainozoic (post 40 Ma) geological and geomorphological evidence, supports the hypothesis of the continuous presence of an ice sheet, of about the present size, since the late Miocene. Evidence is presented and the view advanced that, during the late Wisconsin maximum of isotope stage 2, ice was not nearly as thick or extensive over the continental shelf as required by the model of 'maximum' Antarctic glaciation. Some of the factors influencing the contribution of Antarctica to post-glacial sea-level rise are discussed. It is considered that Antarctica's contribution was probably considerably less than previously estimated. The dating of marine and freshwater sequences in the Vestfold and Bunger Hills is consistent with deglaciation around the Pleistocene Holocene boundary, after the Late Wisconsin maximum. A date of ∼25 ka BP from permafrost in the Larsemann Hills means that either the Larsemann Hills were not glaciated during the Late Wisconsin or the ice failed to erode much of the permafrost surface. The degree of weathering of rock and glacial drifts in the Vestfold, Larsemann and Bunger Hills suggests a long time for formation, perhaps considerably longer than indicated by the dated marine and freshwater sediment sequences. Cosmogenic isotope dating in the Vestfold Hills has provided equivocal ages for deglaciation. While the results could indicate deglaciation before 80 ka BP, they do not confirm such early deglaciation. If the ice cover was thin and failed to remove the previous rock exposure profile, then the assays could predate the last ice advance. Weathered iron crust fragments in the till suggest little erosion. The raised beaches of the oases are Holocene. Assuming they have been produced by post Late Wisconsin isostatic uplift and by the Holocene transgression, calculations show that the Antarctic continental ice sheet could not have been more than ∼500 m thicker in the inner shelf-coastal zone. The

  17. Preclinical evaluation of strontium-containing bioactive bone cement

    Energy Technology Data Exchange (ETDEWEB)

    Li, Zhaoyang, E-mail: lizy@hku.hk [School of Materials Science and Engineering, Tianjin University, Tianjin 300072 (China); Tianjin Key Laboratory of Composite and Functional Materials, Tianjin 300072 (China); Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong (China); Yuan, Ning [Department of Laboratory Medicine, Tianjin Chest Hospital, Tianjin 300051 (China); Lam, Raymond Wing Moon [Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong (China); Cui, Zhenduo; Yang, Xianjin [School of Materials Science and Engineering, Tianjin University, Tianjin 300072 (China); Tianjin Key Laboratory of Composite and Functional Materials, Tianjin 300072 (China); Lu, William Weijia, E-mail: wwlu@hku.hk [Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong (China)

    2013-12-01

    Strontium (Sr) has become more attractive for orthopaedic applications as they can simultaneously stimulate bone formation and prevent bone loss. A Sr-containing bioactive bone cement (Sr-BC) has been designed to fix osteoporotic bone fracture. Sr is a trace element, so the safety of containing Sr is concerned when Sr-BC is implanted in human body. The preclinical assessment of biocompatibility of Sr-BC was conducted according to ISO 10993 standards. MTT assay showed that this bioactive bone cement was non-toxic to mouse fibroblasts, and it met the basic requirement for the orthopaedic implant. The three independent genetic toxicity studies including Ames, chromosome aberration and bone marrow micronucleus assays demonstrated absence of genotoxic components in Sr-BC, which reassured the safety concerns of this novel bone cement. The muscle implantation results in present study were also encouraging. The acute inflammation around the cement was observed at 1 week post-implantation; however, no significant difference was observed between control and Sr-BC groups. These responses may be attributed to the presence of the foreign body, but the tissue healed after 12 weeks implantation. In summary, the above preclinical results provide additional assurance for the safety of this implant. Sr-BC can be used as a potential alternative to the traditional bone cement. - Highlights: • Strontium-containing bioactive bone cement (Sr-BC) was designed. • The biocompatibility of Sr-BC was evaluated according ISO 10993 standards. • Preclinical results provide additional assurance for the safety of Sr-BC.

  18. Preclinical evaluation of strontium-containing bioactive bone cement

    International Nuclear Information System (INIS)

    Li, Zhaoyang; Yuan, Ning; Lam, Raymond Wing Moon; Cui, Zhenduo; Yang, Xianjin; Lu, William Weijia

    2013-01-01

    Strontium (Sr) has become more attractive for orthopaedic applications as they can simultaneously stimulate bone formation and prevent bone loss. A Sr-containing bioactive bone cement (Sr-BC) has been designed to fix osteoporotic bone fracture. Sr is a trace element, so the safety of containing Sr is concerned when Sr-BC is implanted in human body. The preclinical assessment of biocompatibility of Sr-BC was conducted according to ISO 10993 standards. MTT assay showed that this bioactive bone cement was non-toxic to mouse fibroblasts, and it met the basic requirement for the orthopaedic implant. The three independent genetic toxicity studies including Ames, chromosome aberration and bone marrow micronucleus assays demonstrated absence of genotoxic components in Sr-BC, which reassured the safety concerns of this novel bone cement. The muscle implantation results in present study were also encouraging. The acute inflammation around the cement was observed at 1 week post-implantation; however, no significant difference was observed between control and Sr-BC groups. These responses may be attributed to the presence of the foreign body, but the tissue healed after 12 weeks implantation. In summary, the above preclinical results provide additional assurance for the safety of this implant. Sr-BC can be used as a potential alternative to the traditional bone cement. - Highlights: • Strontium-containing bioactive bone cement (Sr-BC) was designed. • The biocompatibility of Sr-BC was evaluated according ISO 10993 standards. • Preclinical results provide additional assurance for the safety of Sr-BC

  19. Collaborative learning in pre-clinical dental hygiene education.

    Science.gov (United States)

    Mueller-Joseph, Laura J; Nappo-Dattoma, Luisa

    2013-04-01

    Dental hygiene education continues to move beyond mastery of content material and skill development to learning concepts that promote critical-thinking and problem-solving skills. The purpose of this research was to evaluate the effectiveness of collaborative learning and determine the growth in intellectual development of 54 first-year dental hygiene students. The control group used traditional pre-clinical teaching and the experimental group used collaborative pedagogy for instrument introduction. All students were subjected to a post-test evaluating their ability to apply the principles of instrumentation. Intellectual development was determined using pre- and post-tests based on the Perry Scheme of Intellectual Development. Student attitudes were assessed using daily Classroom Assessment Activities and an end-of-semester departmental course evaluation. Findings indicated no significant difference between collaborative learning and traditional learning in achieving pre-clinical competence as evidenced by the students' ability to apply the principles of instrumentation. Advancement in intellectual development did not differ significantly between groups. Value added benefits of a collaborative learning environment as identified by the evaluation of student attitudes included decreased student reliance on authority, recognition of peers as legitimate sources of learning and increased self-confidence. A significant difference in student responses to daily classroom assessments was evident on the 5 days a collaborative learning environment was employed. Dental hygiene students involved in a pre-clinical collaborative learning environment are more responsible for their own learning and tend to have a more positive attitude toward the subject matter. Future studies evaluating collaborative learning in clinical dental hygiene education need to investigate the cost/benefit ratio of the value added outcomes of collaborative learning.

  20. Preclinical Science Regarding Cannabinoids as Analgesics: An Overview

    Directory of Open Access Journals (Sweden)

    ME Lynch

    2005-01-01

    Full Text Available Modern pharmacology of cannabinoids began in 1964 with the isolation and partial synthesis of delta-9-tetrahydrocannabinol, the main psychoactive agent in herbal cannabis. Since then, potent antinociceptive and antihyperalgesic effects of cannabinoid agonists in animal models of acute and chronic pain; the presence of cannabinoid receptors in pain-processing areas of the brain, spinal cord and periphery; and evidence supporting endogenous modulation of pain systems by cannabinoids has provided support that cannabinoids exhibit significant potential as analgesics. The present article presents an overview of the preclinical science.

  1. Late Carboniferous to Late Permian carbon isotope stratigraphy

    DEFF Research Database (Denmark)

    Buggisch, Werner; Krainer, Karl; Schaffhauser, Maria

    2015-01-01

    An integrated study of the litho-, bio-, and isotope stratigraphy of carbonates in the Southern Alps was undertaken in order to better constrain δ13C variations during the Late Carboniferous to Late Permian. The presented high resolution isotope curves are based on 1299 δ13Ccarb and 396 δ13Corg...

  2. Preclinical QSP Modeling in the Pharmaceutical Industry: An IQ Consortium Survey Examining the Current Landscape

    Science.gov (United States)

    Wu, Fan; Bansal, Loveleena; Bradshaw‐Pierce, Erica; Chan, Jason R.; Liederer, Bianca M.; Mettetal, Jerome T.; Schroeder, Patricia; Schuck, Edgar; Tsai, Alice; Xu, Christine; Chimalakonda, Anjaneya; Le, Kha; Penney, Mark; Topp, Brian; Yamada, Akihiro

    2018-01-01

    A cross‐industry survey was conducted to assess the landscape of preclinical quantitative systems pharmacology (QSP) modeling within pharmaceutical companies. This article presents the survey results, which provide insights on the current state of preclinical QSP modeling in addition to future opportunities. Our results call attention to the need for an aligned definition and consistent terminology around QSP, yet highlight the broad applicability and benefits preclinical QSP modeling is currently delivering. PMID:29349875

  3. Decreasing Irradiated Rat Lung Volume Changes Dose-Limiting Toxicity From Early to Late Effects

    Energy Technology Data Exchange (ETDEWEB)

    Veen, Sonja J. van der; Faber, Hette; Ghobadi, Ghazaleh [Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Brandenburg, Sytze [KVI Center for Advanced Radiation Research, University of Groningen, Groningen (Netherlands); Langendijk, Johannes A. [Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Coppes, Robert P. [Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Luijk, Peter van, E-mail: p.van.luijk@umcg.nl [Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands)

    2016-01-01

    Purpose: Technological developments in radiation therapy result in smaller irradiated volumes of normal tissue. Because the risk of radiation therapy-induced toxicity generally depends on irradiated volume, changing volume could change the dose-limiting toxicity of a treatment. Recently, in our rat model, we found that early radiation-induced lung dysfunction (RILD) was closely related to irradiated volume dependent vascular remodeling besides inflammation. The exact relationship between early and late RILD is still unknown. Therefore, in this preclinical study we investigated the dose-volume relationship of late RILD, assessed its dependence on early and late pathologies and studied if decreasing irradiated volume changed the dose-limiting toxicity. Methods and Materials: A volume of 25%, 32%, 50%, 63%, 88%, or 100% of the rat lung was irradiated using protons. Until 26 weeks after irradiation, respiratory rates were measured. Macrovascular remodeling, pulmonary inflammation, and fibrosis were assessed at 26 weeks after irradiation. For all endpoints dose-volume response curves were made. These results were compared to our previously published early lung effects. Results: Early vascular remodeling and inflammation correlated significantly with early RILD. Late RILD correlated with inflammation and fibrosis, but not with vascular remodeling. In contrast to the early effects, late vascular remodeling, inflammation and fibrosis showed a primarily dose but not volume dependence. Comparison of respiratory rate increases early and late after irradiation for the different dose-distributions indicated that with decreasing irradiated volumes, the dose-limiting toxicity changed from early to late RILD. Conclusions: In our rat model, different pathologies underlie early and late RILD with different dose-volume dependencies. Consequently, the dose-limiting toxicity changed from early to late dysfunction when the irradiated volume was reduced. In patients, early and late

  4. Utilization of blended learning to teach preclinical endodontics.

    Science.gov (United States)

    Maresca, Cristina; Barrero, Carlos; Duggan, Dereck; Platin, Enrique; Rivera, Eric; Hannum, Wallace; Petrola, Frank

    2014-08-01

    Blended learning (BL) is the integration of classroom learning with an online environment. The purpose of this study was to determine whether dental students who experienced BL in a preclinical endodontic course demonstrated better manual skills, conceptual knowledge, and learning experience compared to those experiencing traditional learning. All eighty-one students (100 percent) in a preclinical endodontics course agreed to participate and were assigned to either the traditional or BL group. A root canal procedure was used to determine the level of manual skills gained by each group. Pre- and post-intervention quizzes were given to all students to evaluate conceptual knowledge gained, and the students' perspectives on the methods were evaluated with a survey. The BL group scored better than the traditional group on the manual skills exercise at a statistically significant level (p=0.0067). There were no differences in the post-intervention quiz scores between the two groups, and the students' opinions were positive regarding BL. With BL, the students were able to learn and demonstrate dental skills at a high level.

  5. Left ventricular remodeling in preclinical experimental mitral regurgitation of dogs.

    Science.gov (United States)

    Dillon, A Ray; Dell'Italia, Louis J; Tillson, Michael; Killingsworth, Cheryl; Denney, Thomas; Hathcock, John; Botzman, Logan

    2012-03-01

    Dogs with experimental mitral regurgitation (MR) provide insights into the left ventricular remodeling in preclinical MR. The early preclinical left ventricular (LV) changes after mitral regurgitation represent progressive dysfunctional remodeling, in that no compensatory response returns the functional stroke volume (SV) to normal even as total SV increases. The gradual disease progression leads to mitral annulus stretch and enlargement of the regurgitant orifice, further increasing the regurgitant volume. Remodeling with loss of collagen weave and extracellular matrix (ECM) is accompanied by stretching and hypertrophy of the cross-sectional area and length of the cardiomyocyte. Isolated ventricular cardiomyocytes demonstrate dysfunction based on decreased cell shortening and reduced intracellular calcium transients before chamber enlargement or decreases in contractility in the whole heart can be clinically appreciated. The genetic response to increased end-diastolic pressure is down-regulation of genes associated with support of the collagen and ECM and up-regulation of genes associated with matrix remodeling. Experiments have not demonstrated any beneficial effects on remodeling from treatments that decrease afterload via blocking the renin-angiotensin system (RAS). Beta-1 receptor blockade and chymase inhibition have altered the progression of the LV remodeling and have supported cardiomyocyte function. The geometry of the LV during the remodeling provides insight into the importance of regional differences in responses to wall stress. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. Subjective memory complaints in preclinical autosomal dominant Alzheimer disease.

    Science.gov (United States)

    Norton, Daniel J; Amariglio, Rebecca; Protas, Hillary; Chen, Kewei; Aguirre-Acevedo, Daniel C; Pulsifer, Brendan; Castrillon, Gabriel; Tirado, Victoria; Munoz, Claudia; Tariot, Pierre; Langbaum, Jessica B; Reiman, Eric M; Lopera, Francisco; Sperling, Reisa A; Quiroz, Yakeel T

    2017-10-03

    To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD). We examined self-reported and study partner-based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried the PSEN-1 E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing. Self-reported SMC were greater in carriers than noncarriers ( p = 0.02). Study partner-based SMC did not differ between groups ( p = 0.21), but in carriers increased with age ( r = 0.66, p < 0.001) and decreased with hippocampal volume ( r = -0.35, p = 0.08). Cognitively unimpaired PSEN-1 carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset. © 2017 American Academy of Neurology.

  7. Cognitive reserve and lifestyle: moving towards preclinical Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Eider M Arenaza-Urquijo

    2015-08-01

    Full Text Available The large majority of neuroimaging studies in Alzheimer’s disease (AD patients have supported the idea that lifestyle factors may protect against the clinical manifestations of AD rather than influence AD neuropathological processes (the cognitive reserve hypothesis. This evidence argues in favor of the hypothesis that lifestyle factors act as moderators between AD pathology and cognition, i.e. through indirect compensatory mechanisms. In this review, we identify emerging evidence in cognitively normal older people that relate lifestyle factors to established AD neuroimaging biomarkers. While some of these investigations are in agreement with the compensatory view of cognitive reserve, other studies have revealed new clues on the neural mechanisms underlying beneficial effects of lifestyle factors on the brain. Specifically, they provide novel evidence suggesting direct effects of lifestyle factors on AD neuropathological processes. Here, we review current findings on the effects of lifestyle factors on AD neuroimaging biomarkers in cognitively normal older people. We propose a tentative theoretical model where lifestyle factors may act via direct neuroprotective and/or indirect compensatory pathways. Importantly, we suggest that neuroprotective mechanisms may have a major role during early stages and compensatory pathways in later stages of the disease. In the absence of an effective treatment for AD and considering the potential of lifestyle factors in AD prevention, understanding the neural mechanisms underlying lifestyle effects on the brain seems crucial. We hope to provide an integrative view that may help to better understand the complex effects of lifestyle factors on AD neuropathological processes, starting from the preclinical stage.

  8. The late administration of surfactant

    African Journals Online (AJOL)

    HMD and 4 as having congenital pneumonia. Overall there was a significant and sustained improvement ... 3 infants weighing> 2 400 g with congenital pneumonia responded to a single delayed dose of SRT. Late SRT is ..... pneumonia and meconium aspiration syndrome.' It does not appear that late SRT compromised the ...

  9. Automated NREM Sleep Staging Using the Electro-oculogram

    NARCIS (Netherlands)

    Garcia-Molina, G.; Abtahi, S.F.; Lagares-Lemos, M.

    2012-01-01

    Automatic sleep staging from convenient and unobtrusive sensors hasreceived considerable attention lately because this can enable a large range of potential applications in the clinical and consumer fields. In this paper the focus is on achieving non REM sleep staging from ocular electrodes. From

  10. Prostate cancer staging

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000397.htm Prostate cancer staging To use the sharing features on this ... trials you may be able to join How Prostate Cancer Staging is Done Initial staging is based on ...

  11. Preliminary study for small animal preclinical hadrontherapy facility

    Energy Technology Data Exchange (ETDEWEB)

    Russo, G. [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); Pisciotta, P., E-mail: pietro.pisciotta@ibfm.cnr.it [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, Catania (Italy); Cirrone, G.A.P.; Romano, F. [National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, Catania (Italy); Cammarata, F.; Marchese, V.; Forte, G.I.; Lamia, D.; Minafra, L.; Bravatá, V. [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); Acquaviva, R. [University of Catania, Catania (Italy); Gilardi, M.C. [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); Cuttone, G. [National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, Catania (Italy)

    2017-02-21

    Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and

  12. Preliminary study for small animal preclinical hadrontherapy facility

    Science.gov (United States)

    Russo, G.; Pisciotta, P.; Cirrone, G. A. P.; Romano, F.; Cammarata, F.; Marchese, V.; Forte, G. I.; Lamia, D.; Minafra, L.; Bravatá, V.; Acquaviva, R.; Gilardi, M. C.; Cuttone, G.

    2017-02-01

    Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and

  13. Preliminary study for small animal preclinical hadrontherapy facility

    International Nuclear Information System (INIS)

    Russo, G.; Pisciotta, P.; Cirrone, G.A.P.; Romano, F.; Cammarata, F.; Marchese, V.; Forte, G.I.; Lamia, D.; Minafra, L.; Bravatá, V.; Acquaviva, R.; Gilardi, M.C.; Cuttone, G.

    2017-01-01

    Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and

  14. Feasibility of Primary Tumor Culture Models and Preclinical Prediction Assays for Head and Neck Cancer: A Narrative Review

    International Nuclear Information System (INIS)

    Dohmen, Amy J. C.; Swartz, Justin E.; Van Den Brekel, Michiel W. M.; Willems, Stefan M.; Spijker, René; Neefjes, Jacques; Zuur, Charlotte L.

    2015-01-01

    Primary human tumor culture models allow for individualized drug sensitivity testing and are therefore a promising technique to achieve personalized treatment for cancer patients. This would especially be of interest for patients with advanced stage head and neck cancer. They are extensively treated with surgery, usually in combination with high-dose cisplatin chemoradiation. However, adding cisplatin to radiotherapy is associated with an increase in severe acute toxicity, while conferring only a minor overall survival benefit. Hence, there is a strong need for a preclinical model to identify patients that will respond to the intended treatment regimen and to test novel drugs. One of such models is the technique of culturing primary human tumor tissue. This review discusses the feasibility and success rate of existing primary head and neck tumor culturing techniques and their corresponding chemo- and radiosensitivity assays. A comprehensive literature search was performed and success factors for culturing in vitro are debated, together with the actual value of these models as preclinical prediction assay for individual patients. With this review, we aim to fill a gap in the understanding of primary culture models from head and neck tumors, with potential importance for other tumor types as well

  15. Feasibility of Primary Tumor Culture Models and Preclinical Prediction Assays for Head and Neck Cancer: A Narrative Review

    Directory of Open Access Journals (Sweden)

    Amy J. C. Dohmen

    2015-08-01

    Full Text Available Primary human tumor culture models allow for individualized drug sensitivity testing and are therefore a promising technique to achieve personalized treatment for cancer patients. This would especially be of interest for patients with advanced stage head and neck cancer. They are extensively treated with surgery, usually in combination with high-dose cisplatin chemoradiation. However, adding cisplatin to radiotherapy is associated with an increase in severe acute toxicity, while conferring only a minor overall survival benefit. Hence, there is a strong need for a preclinical model to identify patients that will respond to the intended treatment regimen and to test novel drugs. One of such models is the technique of culturing primary human tumor tissue. This review discusses the feasibility and success rate of existing primary head and neck tumor culturing techniques and their corresponding chemo- and radiosensitivity assays. A comprehensive literature search was performed and success factors for culturing in vitro are debated, together with the actual value of these models as preclinical prediction assay for individual patients. With this review, we aim to fill a gap in the understanding of primary culture models from head and neck tumors, with potential importance for other tumor types as well.

  16. Feasibility of Primary Tumor Culture Models and Preclinical Prediction Assays for Head and Neck Cancer: A Narrative Review

    Energy Technology Data Exchange (ETDEWEB)

    Dohmen, Amy J. C., E-mail: a.dohmen@nki.nl [Department of Head and Neck Surgery and Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam 1066 CX (Netherlands); Department of Cell Biology, the Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam 1066 CX (Netherlands); Swartz, Justin E. [Department of Otorhinolaryngology-Head and Neck Surgery, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3508 GA (Netherlands); Van Den Brekel, Michiel W. M. [Department of Head and Neck Surgery and Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam 1066 CX (Netherlands); Willems, Stefan M. [Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3508 GA (Netherlands); Spijker, René [Medical library, Academic Medical Center, Amsterdam 1100 DE (Netherlands); Dutch Cochrane Centre, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3508 GA (Netherlands); Neefjes, Jacques [Department of Cell Biology, the Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam 1066 CX (Netherlands); Zuur, Charlotte L. [Department of Head and Neck Surgery and Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam 1066 CX (Netherlands)

    2015-08-28

    Primary human tumor culture models allow for individualized drug sensitivity testing and are therefore a promising technique to achieve personalized treatment for cancer patients. This would especially be of interest for patients with advanced stage head and neck cancer. They are extensively treated with surgery, usually in combination with high-dose cisplatin chemoradiation. However, adding cisplatin to radiotherapy is associated with an increase in severe acute toxicity, while conferring only a minor overall survival benefit. Hence, there is a strong need for a preclinical model to identify patients that will respond to the intended treatment regimen and to test novel drugs. One of such models is the technique of culturing primary human tumor tissue. This review discusses the feasibility and success rate of existing primary head and neck tumor culturing techniques and their corresponding chemo- and radiosensitivity assays. A comprehensive literature search was performed and success factors for culturing in vitro are debated, together with the actual value of these models as preclinical prediction assay for individual patients. With this review, we aim to fill a gap in the understanding of primary culture models from head and neck tumors, with potential importance for other tumor types as well.

  17. PHARMACOLOGICAL IN VITRO MODELS IN PRE-CLINICAL DRUG TESTING - EXAMPLE OF hSERT TRANSFECTED HUMAN EMBRYONIC KIDNEY CELLS

    Directory of Open Access Journals (Sweden)

    Mihajlo Jakovljević

    2012-06-01

    Full Text Available Preclinical drug testing should be considered an important stage during examinations of its efficiency and safety in any likely indication observed. Purpose of the process is acquisition of substantial amount of particular drug-related data before approaching clinical trials in humans. Historical preclinical testing relied on available testing in microbe cultures and animal models. During recent decades laboratory techniques of human cell lines cultivation have been developed and improved. These provide unique possibility of drug acting mechanism testing in a simplified environment lacking basic homeostatic mechanisms. Some examples of these are measuring drug impact to biochemical transport, signaling or anabolic processes. Humane cell lines of embrional kidney 293 are an example of easy-to-grow and disseminate and quite endurable cell line. This methodological article notices some of the details of HEK293 cells cultivation and breading. We took transfection as an example of in vitro model creation for drug testing. Transfection refers to gene introduction into HEK293 cellular genome in order to achieve membrane expression of coded protein. In our case it would be human serotonin transporter. Article contains description of one particular methodological approach in measuring human serotonin transporter expression. The role and importance of serotonin pump in affective disorders genesis was already widely recognized. Aim of the paper was to emphasize feasibility of cell cultivation and its advantages in comparison with alternative traditional methods.

  18. Gratkorn - A new late Middle Miocene vertebrate fauna from Styria (Late Sarmatian, Austria)

    Science.gov (United States)

    Gross, M.; Böhme, M.; Prieto, J.

    2009-04-01

    Integrated stratigraphic approaches provide precise correlations of global standard stages with regional Paratethys stages. Nevertheless, higher resolution stratigraphic matching of terrestrial deposits remains challenging due to the lack of a practical continental biostratigraphy. The mostly used tool for biostratigraphic correlation of non-marine deposits in the Old World is still the concept of Neogene Mammal-zones (MN-zones). However, at higher biostratigraphic resolution (reptiles (scincids, lacertids, gekkonids, anguids, varanids, colubrids, testudinids, emydids), birds (coliiformes), rodents and lagomorphs (cricetids, glirids, eomyids, sciurids, castorids), insectivores and chiropterans (erinaceids, soricids, talpids), and large mammals (suids, tragulids, moschids, cervids, ?palaeomerycids, equids, chalicotheriids, rhinos, proboscidians, carnivors). Litho- and biostratigraphy (terrestrial gastropods) as well as magnetostratigraphic data and the sequence stratigraphic and geodynamic frame indicate an age of 12-12.2 Ma (early Late Sarmatian s.str., chron 5An.1n) for the locality. Therefore, Gratkorn is one of richest and most complete fauna of the late Middle Miocene of Central Europe and will be confidentially one of the key faunas for a high-resolution continental biostratigraphy and the comprehension of the faunal succession and interchanges near the Middle/Late Miocene transition. Acknowledgements This is a preliminary overview of the Gratkorn vertebrate fauna. Several taxa are still under investigation. We are especially grateful to Gudrun Daxner-Höck, Ursula Göhlich (both Natural History Museum Vienna) and Getrud Rössner (University of Munich) for their comments to the rodents, ruminants, proboscidians and bird remains. References Böhme, M., Ilg, A., Winklhofer, M. 2008. Late Miocene "washhouse" climate in Europe.- Earth and Planetary Science Letters, 275: 393-401. Gross, M., 2008. A limnic ostracod fauna from the surroundings of the Central

  19. 7 CFR 920.112 - Late payments.

    Science.gov (United States)

    2010-01-01

    ... Miscellaneous Provisions § 920.112 Late payments. Pursuant to § 920.41(a), interest will be charged at a 1.5 percent monthly simple interest rate. Assessments for kiwifruit shall be deemed late if not received... late charge will be assessed when payment becomes 30 days late. Interest and late payment charges shall...

  20. Magnetic particle imaging: from proof of principle to preclinical applications

    Science.gov (United States)

    Knopp, T.; Gdaniec, N.; Möddel, M.

    2017-07-01

    Tomographic imaging has become a mandatory tool for the diagnosis of a majority of diseases in clinical routine. Since each method has its pros and cons, a variety of them is regularly used in clinics to satisfy all application needs. Magnetic particle imaging (MPI) is a relatively new tomographic imaging technique that images magnetic nanoparticles with a high spatiotemporal resolution in a quantitative way, and in turn is highly suited for vascular and targeted imaging. MPI was introduced in 2005 and now enters the preclinical research phase, where medical researchers get access to this new technology and exploit its potential under physiological conditions. Within this paper, we review the development of MPI since its introduction in 2005. Besides an in-depth description of the basic principles, we provide detailed discussions on imaging sequences, reconstruction algorithms, scanner instrumentation and potential medical applications.

  1. Pediatric Blood Pressure and Adult Preclinical Markers of Cardiovascular Disease

    Science.gov (United States)

    Magnussen, Costan G.; Smith, Kylie J.

    2016-01-01

    A high blood pressure level in adults is considered the single most important modifiable risk factor for global disease burden, especially those of cardiovascular (CV) origin such as stroke and ischemic heart disease. Because blood pressure levels have been shown to persist from childhood to adulthood, elevations in pediatric levels have been hypothesized to lead to increased CV burden in adulthood and, as such, might provide a window in the life course where primordial and primary prevention could be focused. In the absence of substantive data directly linking childhood blood pressure levels to overt adult CV disease, this review outlines the available literature that examines the association between pediatric blood pressure and adult preclinical markers of CV disease. PMID:27168729

  2. Preclinical tests of an android based dietary logging application.

    Science.gov (United States)

    Kósa, István; Vassányi, István; Pintér, Balázs; Nemes, Márta; Kámánné, Krisztina; Kohut, László

    2014-01-01

    The paper describes the first, preclinical evaluation of a dietary logging application developed at the University of Pannonia, Hungary. The mobile user interface is briefly introduced. The three evaluation phases examined the completeness and contents of the dietary database and the time expenditure of the mobile based diet logging procedure. The results show that although there are substantial individual differences between various dietary databases, the expectable difference with respect to nutrient contents is below 10% on typical institutional menu list. Another important finding is that the time needed to record the meals can be reduced to about 3 minutes daily especially if the user uses set-based search. a well designed user interface on a mobile device is a viable and reliable way for a personalized lifestyle support service.

  3. Evolution of strategies to improve preclinical cardiac safety testing.

    Science.gov (United States)

    Gintant, Gary; Sager, Philip T; Stockbridge, Norman

    2016-07-01

    The early and efficient assessment of cardiac safety liabilities is essential to confidently advance novel drug candidates. This article discusses evolving mechanistically based preclinical strategies for detecting drug-induced electrophysiological and structural cardiotoxicity using in vitro human ion channel assays, human-based in silico reconstructions and human stem cell-derived cardiomyocytes. These strategies represent a paradigm shift from current approaches, which rely on simplistic in vitro assays that measure blockade of the Kv11.1 current (also known as the hERG current or IKr) and on the use of non-human cells or tissues. These new strategies have the potential to improve sensitivity and specificity in the early detection of genuine cardiotoxicity risks, thereby reducing the likelihood of mistakenly discarding viable drug candidates and speeding the progression of worthy drugs into clinical trials.

  4. Preclinical Murine Models for Lung Cancer: Clinical Trial Applications

    Directory of Open Access Journals (Sweden)

    Amelia Kellar

    2015-01-01

    Full Text Available Murine models for the study of lung cancer have historically been the backbone of preliminary preclinical data to support early human clinical trials. However, the availability of multiple experimental systems leads to debate concerning which model, if any, is best suited for a particular therapeutic strategy. It is imperative that these models accurately predict clinical benefit of therapy. This review provides an overview of the current murine models used to study lung cancer and the advantages and limitations of each model, as well as a retrospective evaluation of the uses of each model with respect to accuracy in predicting clinical benefit of therapy. A better understanding of murine models and their uses, as well as their limitations may aid future research concerning the development and implementation of new targeted therapies and chemotherapeutic agents for lung cancer.

  5. Pre-clinical MR elastography: Principles, techniques, and applications

    Science.gov (United States)

    Bayly, P. V.; Garbow, J. R.

    2018-06-01

    Magnetic resonance elastography (MRE) is a method for measuring the mechanical properties of soft tissue in vivo, non-invasively, by imaging propagating shear waves in the tissue. The speed and attenuation of waves depends on the elastic and dissipative properties of the underlying material. Tissue mechanical properties are essential for biomechanical models and simulations, and may serve as markers of disease, injury, development, or recovery. MRE is already established as a clinical technique for detecting and characterizing liver disease. The potential of MRE for diagnosing or characterizing disease in other organs, including brain, breast, and heart is an active research area. Studies involving MRE in the pre-clinical setting, in phantoms and artificial biomaterials, in the mouse, and in other mammals, are critical to the development of MRE as a robust, reliable, and useful modality.

  6. Rationale for nebivolol/valsartan combination for hypertension: review of preclinical and clinical data.

    Science.gov (United States)

    Giles, Thomas D; Cockcroft, John R; Pitt, Bertram; Jakate, Abhijeet; Wright, Harold M

    2017-09-01

    : To treat hypertension, combining two or more antihypertensive drugs from different classes is often necessary. β-Blockers and renin-angiotensin-aldosterone system inhibitors, when combined, have been deemed 'less effective' based on partially overlapping mechanisms of action and limited evidence. Recently, the single-pill combination (SPC) of nebivolol (Neb) 5 mg - a vasodilatory β1-selective antagonist/β3 agonist - and valsartan 80 mg, an angiotensin II receptor blocker, was US Food and Drug Administration-approved for hypertension. Pharmacological profiles of Neb and valsartan, alone and combined, are well characterized. In addition, a large 8-week randomized trial in stages I-II hypertensive patients (N = 4161) demonstrated greater blood pressure-reducing efficacy for Neb/valsartan SPCs than component monotherapies with comparable tolerability. In a biomarkers substudy (N = 805), Neb/valsartan SPCs prevented valsartan-induced increases in plasma renin, and a greater reduction in plasma aldosterone was observed with the highest SPC dose vs. valsartan 320 mg/day. This review summarizes preclinical and clinical evidence supporting Neb/valsartan as an efficacious and well tolerated combination treatment for hypertension.

  7. Preclinical evaluation of invariant natural killer T cells in the 5T33 multiple myeloma model.

    Directory of Open Access Journals (Sweden)

    Haneen Nur

    Full Text Available Immunomodulators have been used in recent years to reactivate host anti-tumor immunity in several hematological malignancies. This report describes the effect of activating natural killer T (NKT cells by α-Galactosylceramide (α-GalCer in the 5T33MM model of multiple myeloma (MM. NKT cells are T lymphocytes, co-expressing T and NK receptors, while invariant NKT cells (iNKTs also express a unique semi-invariant TCR α-chain. We followed iNKT numbers during the development of the disease in both 5T33MM mice and MM patients and found that their numbers dropped dramatically at the end stage of the disease, leading to a loss of total IFN-γ secretion. We furthermore observed that α-GalCer treatment significantly increased the survival of 5T33MM diseased mice. Taken together, our data demonstrate for the first time the possibility of using a preclinical murine MM model to study the effects of α-GalCer and show promising results of α-GalCer treatment in a low tumor burden setting.

  8. Learning style preferences among pre-clinical medical students

    Directory of Open Access Journals (Sweden)

    Aye Aye Mon

    2014-02-01

    Full Text Available Generally, different students employ different learning styles dur-ing their studies and medical students are exposed to diverse methods of teaching. Therefore, understanding students’ learning style preference is an important consideration for a high quality and effective teaching and learning process.The aim of the study was to study the variation of learning styles among pre-clinical medical students of SEGi University, Malaysia. A cross-sectional study was performed by using VARK (Visual, Audio, Reading and Kinaesthetic questionnaire version 7.2 to assess the learning style preference of 98 (n=98 pre-clinical medical students in SEGi University. The questionnaire consists of 16 items which identify four different learning styles: visual, aural, reading/writing and kin-esthetic. Descriptive statistics were used to identify the learning styles of students. 61 students preferred multimodal as their learning style, out of which 43 (70% of them were female stu-dents and 18 (30% were male students. 37 students preferred unimodal as their learning style out of which 22 (59% of them were female students and 15 (41% were male students. In addi-tion, female students had more diverse preferences than male students by having 10 out of the other 11 possible combinations in multimodal learning style of preference, whereas the male stu-dents only had 5 out of the 11 combinations. In this study, there was no significant gender difference in the percentages of males and female students who preferred unimodal and multimodal styles of information presentation (P= 0.263; α=0.05. To con-clude, the majority of students of both genders had chosen quad-modal as their learning style preference. The results of this study can provide useful information for improving the quality of the teaching and learning experiences of students.

  9. Functional network integrity presages cognitive decline in preclinical Alzheimer disease.

    Science.gov (United States)

    Buckley, Rachel F; Schultz, Aaron P; Hedden, Trey; Papp, Kathryn V; Hanseeuw, Bernard J; Marshall, Gad; Sepulcre, Jorge; Smith, Emily E; Rentz, Dorene M; Johnson, Keith A; Sperling, Reisa A; Chhatwal, Jasmeer P

    2017-07-04

    To examine the utility of resting-state functional connectivity MRI (rs-fcMRI) measurements of network integrity as a predictor of future cognitive decline in preclinical Alzheimer disease (AD). A total of 237 clinically normal older adults (aged 63-90 years, Clinical Dementia Rating 0) underwent baseline β-amyloid (Aβ) imaging with Pittsburgh compound B PET and structural and rs-fcMRI. We identified 7 networks for analysis, including 4 cognitive networks (default, salience, dorsal attention, and frontoparietal control) and 3 noncognitive networks (primary visual, extrastriate visual, motor). Using linear and curvilinear mixed models, we used baseline connectivity in these networks to predict longitudinal changes in preclinical Alzheimer cognitive composite (PACC) performance, both alone and interacting with Aβ burden. Median neuropsychological follow-up was 3 years. Baseline connectivity in the default, salience, and control networks predicted longitudinal PACC decline, unlike connectivity in the dorsal attention and all noncognitive networks. Default, salience, and control network connectivity was also synergistic with Aβ burden in predicting decline, with combined higher Aβ and lower connectivity predicting the steepest curvilinear decline in PACC performance. In clinically normal older adults, lower functional connectivity predicted more rapid decline in PACC scores over time, particularly when coupled with increased Aβ burden. Among examined networks, default, salience, and control networks were the strongest predictors of rate of change in PACC scores, with the inflection point of greatest decline beyond the fourth year of follow-up. These results suggest that rs-fcMRI may be a useful predictor of early, AD-related cognitive decline in clinical research settings. © 2017 American Academy of Neurology.

  10. Vaginal bleeding in late pregnancy

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000627.htm Vaginal bleeding in late pregnancy To use the sharing ... JavaScript. One out of 10 women will have vaginal bleeding during their 3rd trimester. At times, it ...

  11. Cohort Profile: The Danish Testicular Cancer Late Treatment Effects Cohort (DaTeCa-LATE

    Directory of Open Access Journals (Sweden)

    Michael Kreiberg

    2018-02-01

    Full Text Available The cohort was set up in order to analyze late effects in long-term testicular cancer survivors (TCS and to contribute to the design of future follow-up programs addressing and potentially preventing late effects. Data for this cross-sectional study were collected between January 1, 2014, and December 31, 2016, among living Danish TCS and 60% agreed to participate in the cohort (N = 2,572. Mean time since testicular cancer (TC diagnosis was 18 years (range 7–33 and mean age of participants was 53 years (range 25–95. Data consist of results of a questionnaire with patient reported outcomes which covers a broad range of items on late-effects. The study also included data obtained through linkages to Danish registries, a biobank, and clinical data from hospital files and pathology reports originating from the Danish Testicular Cancer Database (DaTeCa. The treatment during the observation period has been nearly the same for all stages of TC and is in agreement with today’s standard treatment, this allows for interesting analysis with a wide timespan. We have extensive data on non-responders and are able to validate our study findings. Data from a Danish reference population (N = 162,283 allow us to compare our findings with a Danish background population. The cohort can easily be extended to access more outcomes, or include new TCS. A limitation of the present study is the cross-sectional design and despite the large sample size, The Danish Testicular Cancer Late Treatment Effects Cohort (DaTeCa-LATE lacks statistical power to study very rare late effects. Since it was voluntary to participate in the study we have some selection bias, for instance, we lack responders who were not in a paired relationship, but we would still argue that this cohort of TCSs is representative for TCSs in Denmark.Collaboration and data accessResearches interested in collaboration with the DaTeCa-LATE study group please contact Professor Gedske Daugaard

  12. Between Stage and Screen

    NARCIS (Netherlands)

    Tornqvist, Egil

    1996-01-01

    Ingmar Bergman is worldwide known as a film and stage director. Yet no-one has attempted to compare his stage and screen activities. In Between stage and screen Egil Tornqvist examines formal and thematical correspondences and differences between a number of Bergman's stage, screen, and radio

  13. Summary Stage 2018 - SEER

    Science.gov (United States)

    Access this manual of codes and coding instructions for the summary stage field for cases diagnosed January 1, 2018 and forward. 2018 version applies to every site and/or histology combination, including lymphomas and leukemias. Historically, also called General Staging, California Staging, and SEER Staging.

  14. Late prematurity: a systematic review

    Directory of Open Access Journals (Sweden)

    Luís Carlos Machado Júnior

    2014-06-01

    Full Text Available Objective: this study aimed to review the literature regarding late preterm births (34 weeks to 36 weeks and 6 days of gestation in its several aspects. Sources: the MEDLINE, LILACS, and Cochrane Library databases were searched, and the references of the articles retrieved were also used, with no limit of time. Data synthesis: numerous studies showed a recent increase in late preterm births. In all series, late preterm comprised the majority of preterm births. Studies including millions of births showed a strong association between late preterm birth and neonatal mortality. A higher mortality in childhood and among young adults was also observed. Many studies found an association with several neonatal complications, and also with long-term disorders and sequelae: breastfeeding problems, cerebral palsy, asthma in childhood, poor school performance, schizophrenia, and young adult diabetes. Some authors propose strategies to reduce late preterm birth, or to improve neonatal outcome: use of antenatal corticosteroids, changes in some of the guidelines for early delivery in high-risk pregnancies, and changes in neonatal care for this group. Conclusions: numerous studies show greater mortality and morbidity in late preterm infants compared with term infants, in addition to long-term disorders. More recent studies evaluated strategies to improve the outcomes of these neonates. Further studies on these strategies are needed.

  15. Late effects from hadron therapy

    Energy Technology Data Exchange (ETDEWEB)

    Blakely, Eleanor A.; Chang, Polly Y.

    2004-06-01

    Successful cancer patient survival and local tumor control from hadron radiotherapy warrant a discussion of potential secondary late effects from the radiation. The study of late-appearing clinical effects from particle beams of protons, carbon, or heavier ions is a relatively new field with few data. However, new clinical information is available from pioneer hadron radiotherapy programs in the USA, Japan, Germany and Switzerland. This paper will review available data on late tissue effects from particle radiation exposures, and discuss its importance to the future of hadron therapy. Potential late radiation effects are associated with irradiated normal tissue volumes at risk that in many cases can be reduced with hadron therapy. However, normal tissues present within hadron treatment volumes can demonstrate enhanced responses compared to conventional modes of therapy. Late endpoints of concern include induction of secondary cancers, cataract, fibrosis, neurodegeneration, vascular damage, and immunological, endocrine and hereditary effects. Low-dose tissue effects at tumor margins need further study, and there is need for more acute molecular studies underlying late effects of hadron therapy.

  16. Dynamic Penile Corpora Cavernosa Reconstruction Using Bilateral Innervated Gracilis Muscles: A Preclinical Investigation.

    Science.gov (United States)

    Yin, Zhuming; Liu, Liqiang; Xue, Bingjian; Fan, Jincai; Chen, Wenlin; Liu, Zheng

    2018-03-07

    Prosthesis-assisted penile reconstruction has been performed extensively to restore a cosmetically acceptable phallus. However, a large number of patients will undergo revision surgery for various prosthesis-related complications. To develop a 1-stage prosthesis-free dynamic cavernosa reconstruction method using bilateral innervated gracilis muscles and to investigate the feasibility and reliability of the surgical design. 10 fresh cadavers were dissected to assess the availability of bilateral gracilis muscles for functional cavernosa rebuilding. 11 mongrel female dogs were involved in the penile reconstruction surgery. The neophallus consisted of bilateral gracilis muscles as the neo-cavernosa, a right gracilis skin flap as the neourethra, and a lower abdominal flap with an anterior rectus sheath as the skin envelope and neo-tunica albuginea. The function and structure of the neo-phalli were assessed 7 months postoperatively. The neurovascular pedicle length of the gracilis muscles and the volume of the gracilis venter musculi were measured in the cadaveric investigation. The average dimensions of the canine neo-phalli at rest and during electrostimulated erection were obtained and the muscular fatigue-resistant curve was drawn. Histologic evaluations also were performed. The neurovascular pedicle length and volume of the gracilis muscles were sufficient to yield a nearly normal appearance of the neo-cavernosa in the cadaveric and animal studies. The muscular fatigue-resistant curve demonstrated adequate length, stiffness, and duration of erection of the neo-phalli to accomplish normal coitus. Histologic evaluations showed an intact neourethra and nearly normal muscle structure in the inner layer of the canine neo-cavernosa, except for significantly increased amount of collagen fibers and type I/III collagen ratio in the outer layer of the neo-cavernosa. The percentage of type II (fatigue-prone) muscle fibers did not change significantly. Our preclinical

  17. Two-dimensional inverse planning and delivery with a preclinical image guided microirradiator

    International Nuclear Information System (INIS)

    Stewart, James M. P.; Lindsay, Patricia E.; Jaffray, David A.

    2013-01-01

    Purpose: Recent advances in preclinical radiotherapy systems have provided the foundation for scaling many of the elements of clinical radiation therapy practice to the dimensions and energy demanded in small animal studies. Such systems support the technical capabilities to accurately deliver highly complex dose distributions, but methods to optimize and deliver such distributions remain in their infancy. This study developed an optimization method based on empirically measured two-dimensional dose kernel measurements to deliver arbitrary planar dose distributions on a recently developed small animal radiotherapy platform.Methods: A two-dimensional dose kernel was measured with repeated radiochromic film measurements for the circular 1 mm diameter fixed collimator of the small animal radiotherapy system at 1 cm depth in a solid water phantom. This kernel was utilized in a sequential quadratic programming optimization framework to determine optimal beam positions and weights to deliver an arbitrary desired dose distribution. The positions and weights were then translated to a set of stage motions to automatically deliver the optimized dose distribution. End-to-end efficacy of the framework was quantified through five repeated deliveries of two dosimetric challenges: (1) a 5 mm radius bullseye distribution, and (2) a “sock” distribution contained within a 9 × 13 mm bounding box incorporating rectangular, semicircular, and exponentially decaying geometric constructs and a rectangular linear dose gradient region. These two challenges were designed to gauge targeting, geometric, and dosimetric fidelity.Results: Optimization of the bullseye and sock distributions required 2.1 and 5.9 min and utilized 50 and 77 individual beams for delivery, respectively. Automated delivery of the resulting optimized distributions, validated using radiochromic film measurements, revealed an average targeting accuracy of 0.32 mm, and a dosimetric delivery error along four line

  18. Late toxicity in breast cancer radiotherapy

    International Nuclear Information System (INIS)

    Gonzalez Coletti, F.; Rafailovici, L.; Filomia, M.L.; Chiozza, J.; Dosoretz, B.

    2008-01-01

    Full text: The aim of this study is to describe and classify chronic complications due to radiotherapy in breast cancer. Also the impact of radiotherapy on the quality of life of patients is evaluated. Materials and methods: 50 patients with breast cancer at early stages (78% in situ, 22% I and II) treated with radiotherapy in breast volume plus boost (45/50 Gy + 18/20 Gy) with a follow up over 5 years. Acute toxicities were found retrospectively and chronic toxicities were assessed though physical examination and review of complementary studies. To facilitate data collection, pre printed forms were used. Bibliographic searches were made. Results: 10% received chemotherapy and 64% tamoxifen. The predominant chronic toxicity were found in skin (66%), although grade I and II (hyperpigmentation 26%, dryness 22%, telangiectasia 10% fibrosis, 4%, other 4%). A 50% of the patients showed hypoesthesia in ipsilateral upper limb. The other toxicities were presented in low rate and magnitude: mastodynia 16%; actinic pneumonitis 4%, pyrosis 4%, Tachycardia 2%, among others. Of the patients with acute toxicity, only 30% were grade III. The 70% of the patients had a positive impact of radiotherapy on quality of life. Conclusions: We found low rates and degrees of late toxicity. It was noticed a relationship between acute and chronic toxicity, because those who presented adverse effects during treatment developed late effects. It reflects the importance of integrating monitoring as part of radiation treatment. It should be adopted a single score of late toxicity measurement to unify data from different series. (authors) [es

  19. Late-presenting congenital diaphragmatic hernia

    Directory of Open Access Journals (Sweden)

    Raashid Hamid

    2014-01-01

    Full Text Available Background: This study was undertaken to highlight the clinical profile, misdiagnosis, surgical treatment,and prognosis of late-presenting congenital diaphragmatic hernia (CDH cases in a tertiary level hospital. Patients and Methods: This retrospective study included all the babies and children >1 month of age with CDH who were admitted in our Hospital (Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India during the period between January 2008 and December 2013. Babies with age <1 month were excluded from the study. Data regarding clinical profile, operative records, and follow-up was reviewed and analysed statistically. Results: A total of 20 patients were included in this study. The clinical picture ranged from respiratory distress (13 patients to non-specific gastrointestinal complaints (5 patients. In two patients, CDH was misdiagnosed as pneumothorax and had got chest tube inserted in other hospitals before referral to this tertiary care centre. In 14 patients chest, X-ray revealed the diagnosis of CDH and in remaining five patients (including the two patients with misdiagnosis further investigations were undertaken to establish the diagnosis. Age ranged from 45 days to 17 years with an average age of 58.9 months. There were 12 male and 8 female patients. In all the 20 patients, surgical procedures were undertaken with the retrieval of herniated contents from the thoracic cavity and repair of the diaphragmatic defect. There was no mortality in our series. All the 20 patients were followed-up for a period ranging from 6 months to 5 years (median 3.1 years. Conclusions: Late-presenting CDH can have diverse clinical presentation. Late diagnosis and misdiagnosis can result in significant morbidity and potential mortality if these cases are not managed properly at an appropriate stage. Outcome is favourable if these patients are expeditiously identified and surgically repaired.

  20. Late neurotoxicity after nasopharyngeal carcinoma treatment

    International Nuclear Information System (INIS)

    Siala, W.; Mnejja, W.; Daoud, J.; Khabir, A.; Boudawara, T.; Ben Mahfoudh, K.; Ghorbel, A.; Frikha, M.

    2009-01-01

    Purpose A retrospective analysis of risk factors for late neurological toxicity after nasopharyngeal carcinoma radiotherapy. Patients and methods Between 1993 and 2004, 239 patients with non metastatic nasopharyngeal carcinoma were treated by radiotherapy associated or not to chemotherapy. Radiotherapy was delivered with two modalities: hyperfractionated for 82 patients and conventional fractionation for 157 patients. We evaluated the impact of tumour stage, age, gender, radiotherapy schedule and chemotherapy on neurological toxicity. Results After a mean follow-up of 107 months (35-176 months), 21 patients (8.8%) developed neurological complications, such as temporal necrosis in nine cases, brain stem necrosis in five cases, optics nerve atrophy in two cases and myelitis in one case. Five- and ten-year free of toxicity survival was 95 and 84% respectively. Young patients had greater risk of temporal necrosis, and hyperfractionated radiotherapy was associated with a significantly higher risk of neurological complications (14.6% vs 5.7%, p = 0.02). On multivariate analysis, hyperfractionation and age were insignificant. Conclusion Late neurological toxicity after radiotherapy for nasopharyngeal carcinoma was rare. Younger age and hyperfractionation were considered as risk factors of neurological toxicity in our study

  1. Reversing resistance to vascular-disrupting agents by blocking late mobilization of circulating endothelial progenitor cells.

    Science.gov (United States)

    Taylor, Melissa; Billiot, Fanny; Marty, Virginie; Rouffiac, Valérie; Cohen, Patrick; Tournay, Elodie; Opolon, Paule; Louache, Fawzia; Vassal, Gilles; Laplace-Builhé, Corinne; Vielh, Philippe; Soria, Jean-Charles; Farace, Françoise

    2012-05-01

    The prevailing concept is that immediate mobilization of bone marrow-derived circulating endothelial progenitor cells (CEP) is a key mechanism mediating tumor resistance to vascular-disrupting agents (VDA). Here, we show that administration of VDA to tumor-bearing mice induces 2 distinct peaks in CEPs: an early, unspecific CEP efflux followed by a late yet more dramatic tumor-specific CEP burst that infiltrates tumors and is recruited to vessels. Combination with antiangiogenic drugs could not disrupt the early peak but completely abrogated the late VDA-induced CEP burst, blunted bone marrow-derived cell recruitment to tumors, and resulted in striking antitumor efficacy, indicating that the late CEP burst might be crucial to tumor recovery after VDA therapy. CEP and circulating endothelial cell kinetics in VDA-treated patients with cancer were remarkably consistent with our preclinical data. These findings expand the current understanding of vasculogenic "rebounds" that may be targeted to improve VDA-based strategies. Our findings suggest that resistance to VDA therapy may be strongly mediated by late, rather than early, tumor-specific recruitment of CEPs, the suppression of which resulted in increased VDA-mediated antitumor efficacy. VDA-based therapy might thus be significantly enhanced by combination strategies targeting late CEP mobilization. © 2012 AACR

  2. Chemical and radiation induced late dominant lethal effects in mice

    International Nuclear Information System (INIS)

    Favor, J.; Crenshaw, J.W. Jr.; Soares, E.R.

    1978-01-01

    Although theoretically expected, experimental data to date have not shown dominant lethal expression to occur throughout the developmental period. Specifically, late post-implantation effects have not been demonstrated. The authors routinely use an experimental technique in which parental females mated to mutagenically treated males are allowed to give birth and wean their litter, and their uterine horns are then inspected for uterine scars indicative of live and dead embryos. In a number of experiments in which males were mutagenically treated with either chemicals or X-irradiation, a discrepancy was observed between the number of live embryos as determined by the scar technique and the number of live observed at birth, suggesting the possibility of embryonic losses at a late stage in development. Initial analyses showed that mutagenic treatment increased the percentage of these late losses. These differences were statistically significant in 2 of 3 analyses. Factors affecting statistical significance and an understanding of dominant lethal mutations are discussed. (Auth.)

  3. Preclinical incorporation dosimetry of (+)-[18F) flubatine in piglets

    International Nuclear Information System (INIS)

    Sattler, B.; Patt, M.; Sabri, O.; Kranz, M.; Donat, C.K.; Deuther-Conrad, W.; Fischer, S.; Brust, P.; Sattler, T.; Smits, R.; Hoepping, A.; Steinbach, J.

    2015-01-01

    Full text of publication follows. Aim: (+)-[ 18 F] flubatine is the mirror image isomer of (-)-[ 18 F] flubatine, which is successfully used for neuroimaging of alpha4beta2 nAChRs with PET. To assess the radiation risk by this new radiotracer, biodistribution, organ doses (OD) and the effective dose (ED) were investigated in a preclinical trials using piglets. Method: whole body dosimetry of (+)-[ 18 F] flubatine was performed in 3 female piglets (age: 43 ± 1.2 days, weight: 14 ± 1.0 kg). The animals were narcotized using 20 mg/kg Ketamine, 2 mg/kg Azaperone; 1.5% Isoflurane in 70% N 2 O/30% O 2 and sequentially PET-imaged up to 5 hours post i.v. injection of 183.5 ± 9.0 MBq on a SIEMENS Biograph16 PET/CT-system on 7 bed positions (BP) per frame, 1.5 to 6 min/BP, CT-attenuation correction (AC) and iterative reconstruction. All relevant organs were defined by volumes of interest. Exponential curves were fitted to the time-activity-data (%ID/g, and %ID/organ). Time- and mass-scales were adapted to the human order of magnitude. The ODs were calculated using the adult male model with OLINDA. The ED was calculated using tissue weighting factors as published in the ICRP103. Results: The highest OD was received by the urinary bladder (71.7 ± 26.3 μSv/MBq), the kidneys (45.1 ± 6.5 μSv/MBq) and the brain (32.3 ± 3.24 μSv/MBq). The highest contribution to the ED was by the urinary bladder (2.9 ± 1.1 μSv/MBq), the lungs (1.7 ± 0.02 μSv/MBq) and the red marrow (1.4 ± 0.1μSv/MBq). According to this data, the ED to humans is 14.3 ± 0.3 μSv/MBq. Conclusion: considering 40% underestimation of the ED to humans by preclinical dosimetry [1] the expected ED to humans after 300 MBq i.v. is 7.2 mSv, which is about the ED by (-)-[ 18 F]flubatine (6.8 mSv/300 MBq) and well within the range of what other 18 F-labeled compounds cause to humans. This risk assessment encourages to transfer (+)-[F 18 ] flubatine from preclinical to clinical study phases and to further develop

  4. Biological soil crust response to late season prescribed fire in a Great Basin juniper woodland

    Science.gov (United States)

    Steven D. Warren; Larry L. St.Clair; Jeffrey R. Johansen; Paul Kugrens; L. Scott Baggett; Benjamin J. Bird

    2015-01-01

    Expansion of juniper on U.S. rangelands is a significant environmental concern. Prescribed fire is often recommended to control juniper. To that end, a prescribed burn was conducted in a Great Basin juniper woodland. Conditions were suboptimal; fire did not encroach into mid- or late-seral stages and was patchy in the early-seral stage. This study evaluated the effects...

  5. Relationships between Psychosocial Development and Personality Disorder Symptomatology in Late Adolescents.

    Science.gov (United States)

    Johnson, Jeffrey G.

    1993-01-01

    Studied the extent to which psychosocial development thorough the first 5 stages of E. H. Erikson's theory of personality development is associated with personality disorder symptoms, using 106 undergraduates. Negative resolutions of stages one through five may predict the presence of personality disorder symptomatology during late adolescence.…

  6. Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling

    Science.gov (United States)

    Le Bihan, Amélie; Angulo-Barturen, Iñigo; Binkert, Christoph; Boss, Christoph; Brun, Reto; Brunner, Ralf; Buchmann, Stephan; Dechering, Koen J.; Delves, Michael; Ewerling, Sonja; Ferrer, Santiago; Fischli, Christoph; Gamo–Benito, Francisco Javier; Heidmann, Bibia; Jiménez-Díaz, María Belén; Leroy, Didier; Martínez, Maria Santos; Meyer, Solange; Moehrle, Joerg J.; Noviyanti, Rintis; Sanz, Laura María; Sauerwein, Robert W.; Scheurer, Christian; Schleiferboeck, Sarah; Sinden, Robert; Snyder, Christopher; Straimer, Judith; Wirjanata, Grennady; Marfurt, Jutta; Weller, Thomas; Clozel, Martine; Wittlin, Sergio

    2016-01-01

    Background Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. Method and Findings The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3–4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11–16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23–39). The compound’s preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as

  7. Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

    Science.gov (United States)

    Le Bihan, Amélie; de Kanter, Ruben; Angulo-Barturen, Iñigo; Binkert, Christoph; Boss, Christoph; Brun, Reto; Brunner, Ralf; Buchmann, Stephan; Burrows, Jeremy; Dechering, Koen J; Delves, Michael; Ewerling, Sonja; Ferrer, Santiago; Fischli, Christoph; Gamo-Benito, Francisco Javier; Gnädig, Nina F; Heidmann, Bibia; Jiménez-Díaz, María Belén; Leroy, Didier; Martínez, Maria Santos; Meyer, Solange; Moehrle, Joerg J; Ng, Caroline L; Noviyanti, Rintis; Ruecker, Andrea; Sanz, Laura María; Sauerwein, Robert W; Scheurer, Christian; Schleiferboeck, Sarah; Sinden, Robert; Snyder, Christopher; Straimer, Judith; Wirjanata, Grennady; Marfurt, Jutta; Price, Ric N; Weller, Thomas; Fischli, Walter; Fidock, David A; Clozel, Martine; Wittlin, Sergio

    2016-10-01

    Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under

  8. Does student performance on preclinical OSCEs relate to clerkship grades?

    Directory of Open Access Journals (Sweden)

    Margot Chima

    2016-06-01

    Full Text Available Background: Objective structured clinical examinations (OSCEs have been used to assess the clinical competence and interpersonal skills of healthcare professional students for decades. However, the relationship between preclinical (second year or M2 OSCE grades and clerkship performance had never been evaluated, until it was explored to provide information to educators at the University of Nebraska Medical Center (UNMC. In addition, the relationship between M2 OSCE communication scores (which is a portion of the total score and third-year (M3 Internal Medicine (IM clerkship OSCE scores was also explored. Lastly, conflicting evidence exists about the relationship between the amount of previous clinical experience and OSCE performance. Therefore, the relationship between M3 IM clerkship OSCE scores and the timing of the clerkship in the academic year was explored. Methods: Data from UNMC M2 OSCEs and M3 IM clerkship OSCEs were obtained for graduates of the 2013 and 2014 classes. Specifically, the following data points were collected: M2 fall OSCE total, M2 fall OSCE communication; M2 spring OSCE total, M2 spring OSCE communication; and M3 IM clerkship OSCE total percentages. Data were organized by class, M3 IM clerkship OSCE performance, and timing of the clerkship. Microsoft Excel and SPSS were used for data organization and analysis. Results: Of the 245 records, 229 (93.5% had data points for all metrics of interest. Significant differences between the classes of 2013 and 2014 existed for average M2 spring total, M2 spring communication, and M3 IM clerkship OSCEs. Retrospectively, there were no differences in M2 OSCE performances based on how students scored on the M3 IM clerkship OSCE. M3 IM clerkship OSCE performance improved for those students who completed the clerkship last in the academic year. Conclusions: There were inconsistencies in OSCE performances between the classes of 2013 and 2014, but more information is needed to determine if

  9. Does student performance on preclinical OSCEs relate to clerkship grades?

    Science.gov (United States)

    Chima, Margot; Dallaghan, Gary Beck

    2016-01-01

    Objective structured clinical examinations (OSCEs) have been used to assess the clinical competence and interpersonal skills of healthcare professional students for decades. However, the relationship between preclinical (second year or M2) OSCE grades and clerkship performance had never been evaluated, until it was explored to provide information to educators at the University of Nebraska Medical Center (UNMC). In addition, the relationship between M2 OSCE communication scores (which is a portion of the total score) and third-year (M3) Internal Medicine (IM) clerkship OSCE scores was also explored. Lastly, conflicting evidence exists about the relationship between the amount of previous clinical experience and OSCE performance. Therefore, the relationship between M3 IM clerkship OSCE scores and the timing of the clerkship in the academic year was explored. Data from UNMC M2 OSCEs and M3 IM clerkship OSCEs were obtained for graduates of the 2013 and 2014 classes. Specifically, the following data points were collected: M2 fall OSCE total, M2 fall OSCE communication; M2 spring OSCE total, M2 spring OSCE communication; and M3 IM clerkship OSCE total percentages. Data were organized by class, M3 IM clerkship OSCE performance, and timing of the clerkship. Microsoft Excel and SPSS were used for data organization and analysis. Of the 245 records, 229 (93.5%) had data points for all metrics of interest. Significant differences between the classes of 2013 and 2014 existed for average M2 spring total, M2 spring communication, and M3 IM clerkship OSCEs. Retrospectively, there were no differences in M2 OSCE performances based on how students scored on the M3 IM clerkship OSCE. M3 IM clerkship OSCE performance improved for those students who completed the clerkship last in the academic year. There were inconsistencies in OSCE performances between the classes of 2013 and 2014, but more information is needed to determine if this is because of testing variability or heterogeneity

  10. Preclinical imaging characteristics and quantification of Platinum-195m SPECT

    Energy Technology Data Exchange (ETDEWEB)

    Aalbersberg, E.A.; Wit-van der Veen, B.J. de; Vegt, E.; Vogel, Wouter V. [The Netherlands Cancer Institute (NKI-AVL), Department of Nuclear Medicine, Amsterdam (Netherlands); Zwaagstra, O.; Codee-van der Schilden, K. [Nuclear Research and Consultancy Group (NRG), Petten (Netherlands)

    2017-08-15

    In vivo biodistribution imaging of platinum-based compounds may allow better patient selection for treatment with chemo(radio)therapy. Radiolabeling with Platinum-195m ({sup 195m}Pt) allows SPECT imaging, without altering the chemical structure or biological activity of the compound. We have assessed the feasibility of {sup 195m}Pt SPECT imaging in mice, with the aim to determine the image quality and accuracy of quantification for current preclinical imaging equipment. Enriched (>96%) {sup 194}Pt was irradiated in the High Flux Reactor (HFR) in Petten, The Netherlands (NRG). A 0.05 M HCl {sup 195m}Pt-solution with a specific activity of 33 MBq/mg was obtained. Image quality was assessed for the NanoSPECT/CT (Bioscan Inc., Washington DC, USA) and U-SPECT{sup +}/CT (MILabs BV, Utrecht, the Netherlands) scanners. A radioactivity-filled rod phantom (rod diameter 0.85-1.7 mm) filled with 1 MBq {sup 195m}Pt was scanned with different acquisition durations (10-120 min). Four healthy mice were injected intravenously with 3-4 MBq {sup 195m}Pt. Mouse images were acquired with the NanoSPECT for 120 min at 0, 2, 4, or 24 h after injection. Organs were delineated to quantify {sup 195m}Pt concentrations. Immediately after scanning, the mice were sacrificed, and the platinum concentration was determined in organs using a gamma counter and graphite furnace - atomic absorption spectroscopy (GF-AAS) as reference standards. A 30-min acquisition of the phantom provided visually adequate image quality for both scanners. The smallest visible rods were 0.95 mm in diameter on the NanoSPECT and 0.85 mm in diameter on the U-SPECT{sup +}. The image quality in mice was visually adequate. Uptake was seen in the kidneys with excretion to the bladder, and in the liver, blood, and intestine. No uptake was seen in the brain. The Spearman correlation between SPECT and gamma counter was 0.92, between SPECT and GF-AAS it was 0.84, and between GF-AAS and gamma counter it was0.97 (all p < 0

  11. Restoflex--a revolutionary change in preclinical practice for restorative dentistry and endodontics.

    Science.gov (United States)

    Jain, Shweta; Khaiser, Imran M; Thakur, Sophia; Jain, Shikha

    2014-05-01

    Preclinical exercises are very important for the dental students in order to master various dental techniques. The objective of this article is to introduce a new preclinical working model named Restoflex. It is especially designed for the students to carry out various restorative and endodontic procedures in an environment that closely simulate clinical situations. This will help them to provide a smooth transition from preclinical environment to the clinical one. It would also mean an increased confidence level and the efficiency with which the students would deal with their cases.

  12. Seven Stages of Alzheimer's

    Science.gov (United States)

    ... Disease > Stages Overview What Is Dementia? What Is Alzheimer's? Younger/Early Onset Facts and Figures Know the 10 Signs Stages Inside the Brain: An Interactive Tour Risk Factors Diagnosis Treatments Myths Clinical Studies Research Brain Donation ...

  13. Ovarian Cancer Stage II

    Science.gov (United States)

    ... peritoneal cancer; the first panel (stage IIA) shows cancer inside both ovaries that has spread to the uterus and fallopian tube. The second panel (stage IIB) shows cancer inside both ovaries that has spread to the colon. The third ...

  14. Cervical Cancer Stage IIIB

    Science.gov (United States)

    ... by the cancer. This blockage can cause the kidney to enlarge or stop working. Stage IIIB cervical cancer. Topics/Categories: Anatomy -- Gynecologic Cancer Types -- Cervical Cancer Staging Type: Color, ...

  15. Breast cancer staging

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000911.htm Breast cancer staging To use the sharing features on this ... Once your health care team knows you have breast cancer , they will do more tests to stage it. ...

  16. Identification and preclinical testing of novel antiepileptic compounds.

    Science.gov (United States)

    Meldrum, B S

    1997-01-01

    Procedures for identifying novel antiepileptic drugs (AEDs) are changing and need to change more. Widespread reliance on two primary screens has led to the identification of novel compounds that resemble either phenytoin (suppressing high-frequency repetitive firing in cultured neurons and prolonging inactivation of voltage-dependent sodium channels identified by the maximal electroshock test) or benzodiazepines (potentiating the inhibitory effect of gamma-aminobutyric acid (GABA), identified by the threshold pentylenetetrazol test). Advances in molecular neurobiology have identified specific molecular targets (subunits of ion channels, neurotransmitter receptors, and transporters) and have made them available in a form permitting high-throughput screening. AEDs can be designed to interact with specific sites on the target molecules. Alternatively, the molecular screens can be used to identify active components in natural products, including folk remedies. Preclinical in vivo screens can be improved by using animals with genetic or acquired epilepsies that have similar modifications in the properties of the target molecules as do human epilepsy syndromes. Future work is likely to define molecular targets for AEDs that will block or reverse chronic epileptogenesis.

  17. Guidance for Methods Descriptions Used in Preclinical Imaging Papers

    Directory of Open Access Journals (Sweden)

    David Stout

    2013-10-01

    Full Text Available Preclinical molecular imaging is a rapidly growing field, where new imaging systems, methods, and biological findings are constantly being developed or discovered. Imaging systems and the associated software usually have multiple options for generating data, which is often overlooked but is essential when reporting the methods used to create and analyze data. Similarly, the ways in which animals are housed, handled, and treated to create physiologically based data must be well described in order that the findings be relevant, useful, and reproducible. There are frequently new developments for metabolic imaging methods. Thus, specific reporting requirements are difficult to establish; however, it remains essential to adequately report how the data have been collected, processed, and analyzed. To assist with future manuscript submissions, this article aims to provide guidelines of what details to report for several of the most common imaging modalities. Examples are provided in an attempt to give comprehensive, succinct descriptions of the essential items to report about the experimental process.

  18. Visualization, imaging and new preclinical diagnostics in radiation oncology

    International Nuclear Information System (INIS)

    Cyran, Clemens C; Reiser, Maximilian F; Belka, Claus; Niyazi, Maximilian; Paprottka, Philipp M; Eisenblätter, Michel; Clevert, Dirk A; Rist, Carsten; Nikolaou, Konstantin; Lauber, Kirsten; Wenz, Frederik; Hausmann, Daniel

    2014-01-01

    Innovative strategies in cancer radiotherapy are stimulated by the growing knowledge on cellular and molecular tumor biology, tumor pathophysiology, and tumor microenvironment. In terms of tumor diagnostics and therapy monitoring, the reliable delineation of tumor boundaries and the assessment of tumor heterogeneity are increasingly complemented by the non-invasive characterization of functional and molecular processes, moving preclinical and clinical imaging from solely assessing tumor morphology towards the visualization of physiological and pathophysiological processes. Functional and molecular imaging techniques allow for the non-invasive characterization of tissues in vivo, using different modalities, including computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, positron emission tomography (PET) and optical imaging (OI). With novel therapeutic concepts combining optimized radiotherapy with molecularly targeted agents focusing on tumor cell proliferation, angiogenesis, and cell death, the non-invasive assessment of tumor microcirculation and tissue water diffusion, together with strategies for imaging the mechanisms of cellular injury and repair is of particular interest. Characterizing the tumor microenvironment prior to and in response to irradiation will help to optimize the outcome of radiotherapy. These novel concepts of personalized multi-modal cancer therapy require careful pre-treatment stratification as well as a timely and efficient therapy monitoring to maximize patient benefit on an individual basis. Functional and molecular imaging techniques are key in this regard to open novel opportunities for exploring and understanding the underlying mechanisms with the perspective to optimize therapeutic concepts and translate them into a personalized form of radiotherapy in the near future

  19. Preclinical and Clinical Effects of Mistletoe against Breast Cancer

    Directory of Open Access Journals (Sweden)

    Mohsen Marvibaigi

    2014-01-01

    Full Text Available Breast cancer is among the most frequent types of cancer in women worldwide. Current conventional treatment options are accompanied by side effects. Mistletoe is amongst the important herbal medicines traditionally used as complementary remedies. An increasing number of studies have reported anticancer activity of mistletoe extracts on breast cancer cells and animal models. Some recent evidence suggests that cytotoxic activity of mistletoe may be mediated through different mechanisms. These findings provide a good base for clinical trials. Various studies on mistletoe therapy for breast cancer patients revealed similar findings concerning possible benefits on survival time, health-related quality of life (HRQoL, remission rate, and alleviating adverse reactions to conventional therapy. This review provides an overview of the recent findings on preclinical experiments and clinical trials of mistletoe for its cytotoxic and antitumor activity and its effect on HRQoL in breast cancer patients. Moreover, studies investigating molecular and cellular mechanisms underlying antitumor activity of mistletoe are discussed in this paper. The analyzed trials provided evidence that there might be a combination of pharmacological and motivational aspects mediated by the mistletoe extract application which may contribute to the clinical benefit and positive outcome such as improved HRQoL and self-regulation in breast cancer patients.

  20. Pre-Clinical Models of Diffuse Intrinsic Pontine Glioma

    Directory of Open Access Journals (Sweden)

    Oren J Becher

    2015-07-01

    Full Text Available Diffuse Intrinsic Pontine Glioma (DIPG is a rare and incurable brain tumor that arises in the brainstem of children predominantly between the ages of six and eight. Its intricate morphology and involvement of normal pons tissue precludes surgical resection, and the standard of care today remains fractionated radiation alone. In the past 30 years, there have been no significant advances made in the treatment of DIPG. This is largely because we lack good models of DIPG and therefore have little biological basis for treatment. In recent years however, due to increased biopsy and acquisition of autopsy specimens, research is beginning to unravel the genetic and epigenetic drivers of DIPG. Insight gleaned from these studies has led to improvements in approaches to both model these tumors in the lab, as well as to potentially treat them in the clinic. This review will detail the initial strides towards modeling DIPG in animals, which included allograft and xenograft rodent models using non-DIPG glioma cells. Important advances in the field came with the development of in vitro cell and in vivo xenograft models derived directly from autopsy material of DIPG patients or from human embryonic stem cells. Lastly, we will summarize the progress made in the development of genetically engineered mouse models of DIPG. Cooperation of studies incorporating all of these modeling systems to both investigate the unique mechanisms of gliomagenesis in the brainstem and to test potential novel therapeutic agents in a preclinical setting will result in improvement in treatments for DIPG patients.

  1. Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

    Science.gov (United States)

    Voorhees, Jaymie R.; Rohlman, Diane S.; Lein, Pamela J.; Pieper, Andrew A.

    2017-01-01

    Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally. PMID:28149268

  2. Can cancer researchers accurately judge whether preclinical reports will reproduce?

    Directory of Open Access Journals (Sweden)

    Daniel Benjamin

    2017-06-01

    Full Text Available There is vigorous debate about the reproducibility of research findings in cancer biology. Whether scientists can accurately assess which experiments will reproduce original findings is important to determining the pace at which science self-corrects. We collected forecasts from basic and preclinical cancer researchers on the first 6 replication studies conducted by the Reproducibility Project: Cancer Biology (RP:CB to assess the accuracy of expert judgments on specific replication outcomes. On average, researchers forecasted a 75% probability of replicating the statistical significance and a 50% probability of replicating the effect size, yet none of these studies successfully replicated on either criterion (for the 5 studies with results reported. Accuracy was related to expertise: experts with higher h-indices were more accurate, whereas experts with more topic-specific expertise were less accurate. Our findings suggest that experts, especially those with specialized knowledge, were overconfident about the RP:CB replicating individual experiments within published reports; researcher optimism likely reflects a combination of overestimating the validity of original studies and underestimating the difficulties of repeating their methodologies.

  3. 'Muscle-sparing' statins: preclinical profiles and future clinical use.

    Science.gov (United States)

    Pfefferkorn, Jeffrey A

    2009-03-01

    Coronary heart disease (CHD) is a leading cause of death in the US, and hypercholesterolemia is a key risk factor for this disease. The current standard of care for treating hypercholesterolemia is the use of HMG-CoA reductase inhibitors, also known as statins, which block the rate-limiting step of cholesterol biosynthesis. In widespread clinical use, statins have proven safe and effective for both primary prevention of CHD and secondary prevention of coronary events. Results from several recent clinical trials have demonstrated that increasingly aggressive cholesterol-lowering therapy might offer additional protection against CHD compared with less aggressive treatment standards. While higher doses of current statin therapies are capable of achieving these more aggressive treatment goals, in certain cases statin-induced myalgia, the muscle pain or weakness that sometimes accompanies high-dose statin therapy, limits patient compliance with a treatment regimen. To address this limitation, efforts have been undertaken to develop highly hepatoselective statins that are capable of delivering best-in-class efficacy with minimized risk of dose-limiting myalgia. In this review, the preclinical and early clinical data for these next generation statins are discussed.

  4. Improving treatment of neurodevelopmental disorders: recommendations based on preclinical studies.

    Science.gov (United States)

    Homberg, Judith R; Kyzar, Evan J; Stewart, Adam Michael; Nguyen, Michael; Poudel, Manoj K; Echevarria, David J; Collier, Adam D; Gaikwad, Siddharth; Klimenko, Viktor M; Norton, William; Pittman, Julian; Nakamura, Shun; Koshiba, Mamiko; Yamanouchi, Hideo; Apryatin, Sergey A; Scattoni, Maria Luisa; Diamond, David M; Ullmann, Jeremy F P; Parker, Matthew O; Brown, Richard E; Song, Cai; Kalueff, Allan V

    2016-01-01

    Neurodevelopmental disorders (NDDs) are common and severely debilitating. Their chronic nature and reliance on both genetic and environmental factors makes studying NDDs and their treatment a challenging task. Herein, the authors discuss the neurobiological mechanisms of NDDs, and present recommendations on their translational research and therapy, outlined by the International Stress and Behavior Society. Various drugs currently prescribed to treat NDDs also represent a highly diverse group. Acting on various neurotransmitter and physiological systems, these drugs often lack specificity of action, and are commonly used to treat multiple other psychiatric conditions. There has also been relatively little progress in the development of novel medications to treat NDDs. Based on clinical, preclinical and translational models of NDDs, our recommendations cover a wide range of methodological approaches and conceptual strategies. To improve pharmacotherapy and drug discovery for NDDs, we need a stronger emphasis on targeting multiple endophenotypes, a better dissection of genetic/epigenetic factors or "hidden heritability," and a careful consideration of potential developmental/trophic roles of brain neurotransmitters. The validity of animal NDD models can be improved through discovery of novel (behavioral, physiological and neuroimaging) biomarkers, applying proper environmental enrichment, widening the spectrum of model organisms, targeting developmental trajectories of NDD-related behaviors and comorbid conditions beyond traditional NDDs. While these recommendations cannot be addressed all in once, our increased understanding of NDD pathobiology may trigger innovative cross-disciplinary research expanding beyond traditional methods and concepts.

  5. DNA nanomaterials for preclinical imaging and drug delivery.

    Science.gov (United States)

    Jiang, Dawei; England, Christopher G; Cai, Weibo

    2016-10-10

    Besides being the carrier of genetic information, DNA is also an excellent biological organizer to establish well-designed nanostructures in the fields of material engineering, nanotechnology, and biomedicine. DNA-based materials represent a diverse nanoscale system primarily due to their predictable base pairing and highly regulated conformations, which greatly facilitate the construction of DNA nanostructures with distinct shapes and sizes. Integrating the emerging advancements in bioconjugation techniques, DNA nanostructures can be readily functionalized with high precision for many purposes ranging from biosensors to imaging to drug delivery. Recent progress in the field of DNA nanotechnology has exhibited collective efforts to employ DNA nanostructures as smart imaging agents or delivery platforms within living organisms. Despite significant improvements in the development of DNA nanostructures, there is limited knowledge regarding the in vivo biological fate of these intriguing nanomaterials. In this review, we summarize the current strategies for designing and purifying highly-versatile DNA nanostructures for biological applications, including molecular imaging and drug delivery. Since DNA nanostructures may elicit an immune response in vivo, we also present a short discussion of their potential toxicities in biomedical applications. Lastly, we discuss future perspectives and potential challenges that may limit the effective preclinical and clinical employment of DNA nanostructures. Due to their unique properties, we predict that DNA nanomaterials will make excellent agents for effective diagnostic imaging and drug delivery, improving patient outcome in cancer and other related diseases in the near future. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Preclinical evaluation of molecular-targeted anticancer agents for radiotherapy

    International Nuclear Information System (INIS)

    Krause, Mechthild; Zips, Daniel; Thames, Howard D.; Kummermehr, Johann; Baumann, Michael

    2006-01-01

    The combination of molecular-targeted agents with irradiation is a highly promising avenue for cancer research and patient care. Molecular-targeted agents are in themselves not curative in solid tumours, whereas radiotherapy is highly efficient in eradicating tumour stem cells. Recurrences after high-dose radiotherapy are caused by only one or few surviving tumour stem cells. Thus, even if a novel agent has the potential to kill only few tumour stem cells, or if it interferes in mechanisms of radioresistance of tumours, combination with radiotherapy may lead to an important improvement in local tumour control and survival. To evaluate the effects of novel agents combined with radiotherapy, it is therefore necessary to use experimental endpoints which reflect the killing of tumour stem cells, in particular tumour control assays. Such endpoints often do not correlate with volume-based parameters of tumour response such as tumour regression and growth delay. This calls for radiotherapy specific research strategies in the preclinical testing of novel anti-cancer drugs, which in many aspects are different from research approaches for medical oncology

  7. Novel technology to prepare oral formulations for preclinical safety studies.

    Science.gov (United States)

    Niwa, Toshiyuki; Hashimoto, Naofumi

    2008-02-28

    A novel method to prepare oral formulations, normally suspended dosage form, for preclinical safety studies in animals has been developed using a rotation/revolution mixer. Small hard balls made of zirconia were added to the mixing process to evaluate effectiveness in making a high quality suspension. The driving with balls loaded in the cylindrical container (vessel) of the mixer was quite efficient in dispersing and milling the particles of the active pharmaceutical ingredient (API) in an aqueous medium. The API powder and a small amount of oral aqueous medium (vehicle) were successfully mixed by the spinning motion of the balls in the vessel as though the paste-like suspension was kneaded with a mortar and pestle. It was found that the milled suspension with the mean size of 10-20microm could be prepared, in addition finer milling of less than 10microm could be achieved by selecting the material of vessel. Optimum driving conditions including mixing time, size and quantity of balls, and the standard operational procedure was established using compounds varying in physicochemical properties. The particle size and quantitative analysis by HPLC showed that the resultant suspension was well-milled and highly homogeneous with the nearly intended concentration of API. The proposed method established by this experiment could be applied to the actual safety studies in the real preparation scale of oral suspension.

  8. Robotic Anterior and Midline Skull Base Surgery: Preclinical Investigations

    International Nuclear Information System (INIS)

    O'Malley, Bert W.; Weinstein, Gregory S.

    2007-01-01

    Purpose: To develop a minimally invasive surgical technique to access the midline and anterior skull base using the optical and technical advantages of robotic surgical instrumentation. Methods and Materials: Ten experimental procedures focusing on approaches to the nasopharynx, clivus, sphenoid, pituitary sella, and suprasellar regions were performed on one cadaver and one live mongrel dog. Both the cadaver and canine procedures were performed in an approved training facility using the da Vinci Surgical Robot. For the canine experiments, a transoral robotic surgery (TORS) approach was used, and for the cadaver a newly developed combined cervical-transoral robotic surgery (C-TORS) approach was investigated and compared with standard TORS. The ability to access and dissect tissues within the various areas of the midline and anterior skull base were evaluated, and techniques to enhance visualization and instrumentation were developed. Results: Standard TORS approaches did not provide adequate access to the midline and anterior skull base; however, the newly developed C-TORS approach was successful in providing the surgical access to these regions of the skull base. Conclusion: Robotic surgery is an exciting minimally invasive approach to the skull base that warrants continued preclinical investigation and development

  9. Wireless Handheld Computers in the Preclinical Undergraduate Curriculum

    Directory of Open Access Journals (Sweden)

    Matt Jackson

    2003-02-01

    Full Text Available This report presents the results of a pilot project using wireless PDAs as teaching tools in an undergraduate medical curriculum. This technology was used to foster a transition from a passive to an interactive learning environment in the classroom and provided a solution for the implementation of computer-based exams for a large class. Wayne State Medical School recently provided model e570 Toshiba PocketPCs® (personal digital assistants or PDAs, network interface cards, and application software developed by CampusMobility® to 20 sophomore medical students. The pilot group of preclinical students used the PDAs to access web-based course content, for communication, scheduling, to participate in interactive teaching sessions, and to complete course evaluations. Another part of this pilot has been to utilize the PDAs for computer-based exams in a wireless environment. Server authentication that restricted access during the exams and a proctoring console to monitor and record the PDA screens will be described in this report. Results of a student satisfaction survey will be presented.

  10. Recent casualties of late globalization

    DEFF Research Database (Denmark)

    Turcan, Romeo V.

    2016-01-01

    In this essay I will expand my thoughts on universities as ‘late globalizers’ and the impact ‘being late’ has on university internationalization or globalization activities. In my earlier essay I viewed universities as ‘late globalizers’ and briefly introduced the impact of being ‘late’, e.g., wi.......g., withdrawal or de-internationalization of universities due to incompatibility between university autonomy and the context in the target country or universities unwillingness to compromise on their freedom and autonomy....

  11. Staging of Lung Cancer

    Science.gov (United States)

    ... LUNG CANCER MINI-SERIES #2 Staging of Lung Cancer Once your lung cancer is diagnosed, staging tells you and your health care provider about ... at it under a microscope. The stages of lung cancer are listed as I, II, III, and IV ...

  12. Cervical Cancer Stage IA

    Science.gov (United States)

    ... historical Searches are case-insensitive Cervical Cancer Stage IA Add to My Pictures View /Download : Small: 720x576 ... Large: 3000x2400 View Download Title: Cervical Cancer Stage IA Description: Stage IA1 and IA2 cervical cancer; drawing ...

  13. Ovarian Cancer Stage IIIC

    Science.gov (United States)

    ... Stage IIIC Description: Drawing of stage IIIC shows cancer inside both ovaries that has spread to the omentum. The cancer ... lymph nodes behind the peritoneum. In stage IIIC, cancer is found in one or both ovaries or fallopian tubes and has spread to the ...

  14. Cervical Cancer Stage IIIA

    Science.gov (United States)

    ... hyphen, e.g. -historical Searches are case-insensitive Cervical Cancer Stage IIIA Add to My Pictures View /Download : ... 1275x1275 View Download Large: 2550x2550 View Download Title: Cervical Cancer Stage IIIA Description: Stage IIIA cervical cancer; drawing ...

  15. Cervical Cancer Stage IVA

    Science.gov (United States)

    ... hyphen, e.g. -historical Searches are case-insensitive Cervical Cancer Stage IVA Add to My Pictures View /Download : ... 1575x1200 View Download Large: 3150x2400 View Download Title: Cervical Cancer Stage IVA Description: Stage IVA cervical cancer; drawing ...

  16. Cervical Cancer Stage IVB

    Science.gov (United States)

    ... hyphen, e.g. -historical Searches are case-insensitive Cervical Cancer Stage IVB Add to My Pictures View /Download : ... 1200x1305 View Download Large: 2400x2610 View Download Title: Cervical Cancer Stage IVB Description: Stage IVB cervical cancer; drawing ...

  17. Cervical Cancer Stage IB

    Science.gov (United States)

    ... hyphen, e.g. -historical Searches are case-insensitive Cervical Cancer Stage IB Add to My Pictures View /Download : ... 1613x1200 View Download Large: 3225x2400 View Download Title: Cervical Cancer Stage IB Description: Stage IB1 and IB2 cervical ...

  18. Late Jute seed production in cropland agroforestry system

    Directory of Open Access Journals (Sweden)

    Kazi Noor-E-Alam Jewel

    2015-12-01

    Full Text Available Farmers were not self-sufficient in jute seed production and cultivation to avoid use exotic jute seed from different resources. Though the conventional method of jute seed production was not enough to meet the demand of farmers because of shrinkage of jute seed production land. So, late jute seed production technique was applied in agroforestry systems at both established and newly developed orchards. The study was conducted in the selected three sites of Rangpur, Dinajpur and Faridpur. Both White (Corchorus capsularis L.cv. CVL-1 and Tossa (two popular cultivars, eg., Corchorus olitorius L. cv. O-9897, and cv. O-72 varieties were used for to evaluate the late jute seed production in cropland agroforestry in 2011- 2013. It was observed that 600 kg ha-1 to 725 kg ha-1 of jute seed was produced in different types of orchard plantation. Seeds from Litchi orchard showed the higher fiber yield (1051.11, 2511.11 and 3555.56 kg ha-1 at Rangpur, Dinajpur and Faridpur, respectively than the mango orchard. Nutrient contents of soil in three sits were improved significantly due to the cultivation of late jute seed production. Moreover, late jute seed production in early stages of orchard plantation was more profitable and late jute can be produced economically for five to seven years depending on the plantations type and age.

  19. Discrete β-adrenergic mechanisms regulate early and late erythropoiesis in erythropoietin-resistant anemia.

    Science.gov (United States)

    Hasan, Shirin; Mosier, Michael J; Szilagyi, Andrea; Gamelli, Richard L; Muthumalaiappan, Kuzhali

    2017-10-01

    Anemia of critical illness is resistant to exogenous erythropoietin. Packed red blood cells transfusions is the only treatment option, and despite related cost and morbidity, there is a need for alternate strategies. Erythrocyte development can be divided into erythropoietin-dependent and erythropoietin-independent stages. We have shown previously that erythropoietin-dependent development is intact in burn patients and the erythropoietin-independent early commitment stage, which is regulated by β1/β2-adrenergic mechanisms, is compromised. Utilizing the scald burn injury model, we studied erythropoietin-independent late maturation stages and the effect of β1/β2, β-2, or β-3 blockade in burn mediated erythropoietin-resistant anemia. Burn mice were randomized to receive daily injections of propranolol (nonselective β1/β2 antagonist), nadolol (long-acting β1/β2 antagonist), butoxamine (selective β2 antagonist), or SR59230A (selective β3 antagonist) for 6 days after burn. Total bone marrow cells were characterized as nonerythroid cells, early and late erythroblasts, nucleated orthochromatic erythroblasts and enucleated reticulocyte subsets using CD71, Ter119, and Syto-16 by flow cytometry. Multipotential progenitors were probed for MafB expressing cells. Although propranolol improved early and late erythroblasts, only butoxamine and selective β3-antagonist administrations were positively reflected in the peripheral blood hemoglobin and red blood cells count. While burn impeded early commitment and late maturation stages, β1/β2 antagonism increased the early erythroblasts through commitment stages via β2 specific MafB regulation. β3 antagonism was more effective in improving overall red blood cells through late maturation stages. The study unfolds novel β2 and β3 adrenergic mechanisms orchestrating erythropoietin resistant anemia after burn, which impedes both the early commitment stage and the late maturation stages, respectively. Copyright © 2017

  20. Harmonization in preclinical epilepsy research: A joint AES/ILAE translational initiative.

    Science.gov (United States)

    Galanopoulou, Aristea S; French, Jacqueline A; O'Brien, Terence; Simonato, Michele

    2017-11-01

    Among the priority next steps outlined during the first translational epilepsy research workshop in London, United Kingdom (2012), jointly organized by the American Epilepsy Society (AES) and the International League Against Epilepsy (ILAE), are the harmonization of research practices used in preclinical studies and the development of infrastructure that facilitates multicenter preclinical studies. The AES/ILAE Translational Task Force of the ILAE has been pursuing initiatives that advance these goals. In this supplement, we present the first reports of the working groups of the Task Force that aim to improve practices of performing rodent video-electroencephalography (vEEG) studies in experimental controls, generate systematic reviews of preclinical research data, and develop preclinical common data elements (CDEs) for epilepsy research in animals. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  1. Attitudes of Pre-Clinical and Clinical Medical Students to Psychiatry ...

    African Journals Online (AJOL)

    Attitudes of Pre-Clinical and Clinical Medical Students to Psychiatry. ... Nigerian Hospital Practice ... Abstract. Medical training provides an environment in which proper and professional attitudes towards psychiatric patients can be acquired.

  2. Degenerated human articular cartilage at autopsy represents preclinical osteoarthritic cartilage: comparison with clinically defined osteoarthritic cartilage

    NARCIS (Netherlands)

    van Valburg, A. A.; Wenting, M. J.; Beekman, B.; te Koppele, J. M.; Lafeber, F. P.; Bijlsma, J. W.

    1997-01-01

    To investigate whether macroscopically fibrillated human articular knee cartilage observed at autopsy can be considered an early, preclinical phase of osteoarthritis (OA). Histological and biochemical characteristics of 3 types of articular knee cartilage were compared: macroscopically degenerated

  3. The application of selective reaction monitoring confirms dysregulation of glycolysis in a preclinical model of schizophrenia

    NARCIS (Netherlands)

    D. Martins-de-Souza (Daniel); M. Alsaif (Murtada); A. Ernst (Agnes); L.W. Harris (Laura); N. Aerts (Nancy); I. Lenaerts (Ilse); P.J. Peeters (Pieter); K. Amess (Kevin); H. Rahmoune (Hassan); S. Bahn (Sabine); P.C. Guest (Paul)

    2012-01-01

    textabstractBackground: Establishing preclinical models is essential for novel drug discovery in schizophrenia. Most existing models are characterized by abnormalities in behavioral readouts, which are informative, but do not necessarily translate to the symptoms of the human disease. Therefore,

  4. Preclinical evaluation of radiolabeled DOTA-derivatized cyclic minigastrin analogs for targeting cholecystokinin receptor expressing malignancies.

    NARCIS (Netherlands)

    Guggenberg, E. von; Rangger, C.; Sosabowski, J.; Laverman, P.; Reubi, J.C.; Virgolini, I.J.; Decristoforo, C.

    2012-01-01

    PURPOSE: Targeting of cholecystokinin receptor expressing malignancies such as medullary thyroid carcinoma is currently limited by low in vivo stability of radioligands. To increase the stability, we have developed and preclinically evaluated two cyclic

  5. Circadian Activators Are Expressed Days before They Initiate Clock Function in Late Pacemaker Neurons from Drosophila.

    Science.gov (United States)

    Liu, Tianxin; Mahesh, Guruswamy; Houl, Jerry H; Hardin, Paul E

    2015-06-03

    Circadian pacemaker neurons in the Drosophila brain control daily rhythms in locomotor activity. These pacemaker neurons can be subdivided into early or late groups depending on whether rhythms in period (per) and timeless (tim) expression are initiated at the first instar (L1) larval stage or during metamorphosis, respectively. Because CLOCK-CYCLE (CLK-CYC) heterodimers initiate circadian oscillator function by activating per and tim transcription, a Clk-GFP transgene was used to mark when late pacemaker neurons begin to develop. We were surprised to see that CLK-GFP was already expressed in four of five clusters of late pacemaker neurons during the third instar (L3) larval stage. CLK-GFP is only detected in postmitotic neurons from L3 larvae, suggesting that these four late pacemaker neuron clusters are formed before the L3 larval stage. A GFP-cyc transgene was used to show that CYC, like CLK, is also expressed exclusively in pacemaker neurons from L3 larval brains, demonstrating that CLK-CYC is not sufficient to activate per and tim in late pacemaker neurons at the L3 larval stage. These results suggest that most late pacemaker neurons develop days before novel factors activate circadian oscillator function during metamorphosis. Copyright © 2015 the authors 0270-6474/15/358662-10$15.00/0.

  6. Late onset globoid cell leukodystrophy.

    OpenAIRE

    Grewal, R P; Petronas, N; Barton, N W

    1991-01-01

    A 29 year old male with onset of globoid cell leukodystrophy at age 14 is described. This is the first case of enzymatically confirmed globoid cell leukodystrophy with onset of symptoms after the age of ten. This patient is unique because of the late onset and slow progression and extends the clinical spectrum of globoid cell leukodystrophy.

  7. Late onset globoid cell leukodystrophy.

    Science.gov (United States)

    Grewal, R P; Petronas, N; Barton, N W

    1991-11-01

    A 29 year old male with onset of globoid cell leukodystrophy at age 14 is described. This is the first case of enzymatically confirmed globoid cell leukodystrophy with onset of symptoms after the age of ten. This patient is unique because of the late onset and slow progression and extends the clinical spectrum of globoid cell leukodystrophy.

  8. Early and Late Retirement Exits

    Science.gov (United States)

    Brougham, Ruby R.; Walsh, David A.

    2009-01-01

    The current study proposes that personal need fulfillment (relatedness, generativity, identity, growth, and finances) predicts early and late retirement intentions. The personal needs of 160 full-time older employees were measured by personal goals, job satisfactions, job characteristics, and intrinsic motivation. Results suggest that the personal…

  9. Late onset startle induced tics

    NARCIS (Netherlands)

    Tijssen, MAJ; Brown, P; Morris, HR; Lees, A

    1999-01-01

    Three cases of late onset Gilles de la Tourette's syndrome are presented. The motor ties were mainly induced by an unexpected startling stimulus, but the startle reflex was not exaggerated. The ties developed after physical trauma or a period of undue emotional stress. Reflex ties may occur in

  10. L