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Sample records for factor iiib generates

  1. Impact of lymph node ratio as a valuable prognostic factor in gallbladder carcinoma, focusing on stage IIIB gallbladder carcinoma

    PubMed Central

    Choi, Byung-Gwan; Kim, Choong-Young; Cho, Seung-Hyun; Kim, Hee-Joon; Koh, Yang-Seok; Kim, Jung-Chul; Cho, Chol-Kyoon; Kim, Hyun-Jong

    2013-01-01

    Purpose It is increasingly being recognized that the lymph node ratio (LNR) is an important prognostic factor for gallbladder carcinoma patients. The present study evaluated predictors of tumor recurrence and survival in a large, mono-institutional cohort of patients who underwent surgical resection for gallbladder carcinoma, focusing specifically on the prognostic value of lymph node (LN) status and of LNR in stage IIIB patients. Methods Between 2004 and 2011, 123 patients who underwent R0 radical resection for gallbladder carcinoma at the Chonnam National University Hwasun Hospital were reviewed retrospectively. Patients were staged according to the American Joint Committee on Cancer 7th edition, and prognostic factors affecting disease free survival, such as age, sex, comorbidity, body mass index, presence of preoperative symptoms, perioperative blood transfusion, postoperative complications, LN dissection, tumor size, differentiation, lymph-vascular invasion, perineural invasion, T stage, presence of LN involvement, N stage, numbers of positive LNs, LNR and implementation of adjuvant chemotherapy, were statistically analyzed. Results LN status was an important prognostic factor in patients undergoing curative resection for gallbladder carcinoma. The total number of LNs examined was implicated with prognosis, especially in N0 patients. LNR was a powerful predictor of disease free survival even after controlling for competing risk factors, in curative resected gallbladder cancer patients, and especially in stage IIIB patients. Conclusion LNR is confirmed as an independent prognostic factor in curative resected gallbladder cancer patients, especially in stage IIIB gallbladder carcinoma. PMID:23487246

  2. Cervical Cancer Stage IIIB

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Cervical Cancer Stage IIIB Add to My Pictures View / ... 1425x1326 View Download Large: 2850x2651 View Download Title: Cervical Cancer Stage IIIB Description: Stage IIIB cervical cancer; ...

  3. Figo IIIB squamous cell carcinoma of the cervix: an analysis of prognostic factors emphasizing the balance between external beam and intracavitary radiation therapy.

    PubMed

    Logsdon, M D; Eifel, P J

    1999-03-01

    To define patient, tumor, and treatment factors that influence the outcome of patients with FIGO Stage IIIB squamous cell carcinoma of the intact uterine cervix. The records of 1,096 patients treated with radiation therapy between 1960 and 1993 for FIGO Stage IIIB squamous cell carcinoma of the intact uterine cervix were reviewed retrospectively. Of these, 983 (90%) were treated with curative intent and 113 were treated only to achieve palliation of symptoms. Of 907 patients who completed the intended curative treatment, 641 (71%) were treated with a combination of external beam irradiation (EBRT) and intracavitary irradiation (ICRT) and 266 (29%) were treated with EBRT only. The median duration of treatment for these 907 patients was 51 days. Between 1966 and 1980, only 52% of patients who completed treatment with curative intent received ICRT, compared with 92% of patients treated during 1981-1993, an increase that reflects an evolution in the philosophy of treatment for advanced tumors. In general, the intensity of ICRT correlated inversely with the dose of EBRT to the,central pelvis. Median follow-up of surviving patients was 134 months. For 983 patients treated with initial curative intent, disease-specific survival (DSS) was significantly worse for those who were < 40 years old, had experienced more than a 10% weight loss, or had a hemoglobin level < 10 g/dl before or during radiation therapy. Tumor factors that correlated with a relatively poor DSS were bilateral pelvic wall involvement, clinical tumor diameter > or = 8 cm, hydronephrosis, lower vaginal involvement, and evidence of lymph node metastases on lymphangiogram (p < 0.01 in all cases). For the 907 patients who completed treatment with curative intent, 641 who had ICRT had a DSS of 45% at 5 years, compared with 24% for those treated with EBRT alone (p < 0.0001). Those who received > 52 Gy of EBRT to the central pelvis had DSS rates of 27-34%, compared with 53% for patients treated with lower doses

  4. Type III-B rotaxane dendrimers.

    PubMed

    Ho, Watson K-W; Lee, Siu-Fung; Wong, Chi-Hin; Zhu, Xiao-Ming; Kwan, Chak-Shing; Chak, Chun-Pong; Mendes, Paula M; Cheng, Christopher H K; Leung, Ken Cham-Fai

    2013-11-28

    Type III-B first generation [3]rotaxane and second generation [4]rotaxane dendrimers have been synthesized via (1) a modified copper-catalyzed alkyne-azide cycloaddition (CuAAC), (2) Glaser-Hay's acetylenic oxidative homo-coupling, and (3) amide formation. The dendron does not reveal obvious cytotoxicities in L929 fibroblast cells. The rotaxane dendrimers can capture ammonia and are switchable both in solution and on surfaces.

  5. TATA-box DNA binding activity and subunit composition for RNA polymerase III transcription factor IIIB from Xenopus laevis.

    PubMed Central

    McBryant, S J; Meier, E; Leresche, A; Sharp, S J; Wolf, V J; Gottesfeld, J M

    1996-01-01

    The RNA polymerase III transcription initiation factor TFIIIB contains the TATA-box-binding protein (TBP) and polymerase III-specific TBP-associated factors (TAFs). Previous studies have shown that DNA oligonucleotides containing the consensus TATA-box sequence inhibit polymerase III transcription, implying that the DNA binding domain of TBP is exposed in TFIIIB. We have investigated the TATA-box DNA binding activity of Xenopus TFIIIB, using transcription inhibition assays and a gel mobility shift assay. Gel shift competition assays with mutant and nonspecific DNAs demonstrate the specificity of the TFIIIB-TATA box DNA complex. The apparent dissociation constant for this protein-DNA interaction is approximately 0.4 nM, similar to the affinity of yeast TBP for the same sequence. TFIIIB transcriptional activity and TATA-box binding activity cofractionate during a series of four ion-exchange chromatographic steps, and reconstituted transcription reactions demonstrate that the TATA-box DNA-protein complex contains TFIIIB TAF activity. Polypeptides with apparent molecular masses of 75 and 92 kDa are associated with TBP in this complex. These polypeptides were renatured after elution from sodium dodecyl sulfate-gels and tested individually and in combination for TFIIIB TAF activity. Recombinant TBP along with protein fractions containing the 75- and 92-kDa polypeptides were sufficient to reconstitute TFIIIB transcriptional activity and DNA binding activity, suggesting that Xenopus TFIIIB is composed of TBP along with these polypeptides. PMID:8756620

  6. Safety of a Four-factor Prothrombin Complex Concentrate Versus Plasma for Vitamin K Antagonist Reversal: An Integrated Analysis of Two Phase IIIb Clinical Trials.

    PubMed

    Milling, Truman J; Refaai, Majed A; Sarode, Ravi; Lewis, Brandon; Mangione, Antoinette; Durn, Billie L; Harman, Amy; Lee, Martin L; Goldstein, Joshua N

    2016-04-01

    Clinicians often need to rapidly reverse vitamin K antagonists (VKAs) in the setting of major hemorrhage or urgent need for surgery. Little is known about the safety profile of the traditional reversal agent, plasma, or the newly approved agent, four-factor prothrombin complex concentrate (4F-PCC), in a randomized setting. This is an integrated analysis of safety data from two clinical trials that evaluated 4F-PCC versus plasma for the treatment of patients requiring rapid VKA reversal for acute major bleeding or prior to an urgent surgical/invasive procedure. This descriptive analysis comprised adverse event (AE) data from two phase IIIb, randomized, controlled trials. The bleeding and surgical studies were performed across 36 and 33 sites, respectively, in nine countries, with the integrated analysis comprising 388 patients (4F-PCC, n = 191; plasma, n = 197) aged ≥ 18 years, who required VKA reversal due to major bleeding or prior to an urgent surgical/invasive procedure. Patients received either 4F-PCC, containing nonactivated factors II, VII, IX, and X and proteins C and S (Beriplex/Kcentra, CSL Behring) or plasma, both dosed according to baseline international normalized ratio and body weight. Patients were also to receive vitamin K1. AEs and serious AEs (SAEs) were assessed up to days 10 and 45, respectively. The proportion of patients with AEs (4F-PCC, 115/191 [60.2%]; plasma, 124/197 [62.9%]) and SAEs (4F-PCC, 54/191 [28.3%]; plasma, 49/197 [24.9%]) was similar between groups. The proportion of patients with thromboembolic events was also similar between groups (4F-PCC, 14/191 [7.3%]; plasma, 14/197 [7.1%]). There were 13 (6.8%) deaths in the 4F-PCC group and 13 (6.6%) in the plasma group. Fluid overload events occurred in more patients in the plasma group than the 4F-PCC group (25 [12.7%] and 9 [4.7%], respectively). These safety data represent the largest controlled assessment of a 4F-PCC to date. For patients requiring urgent VKA reversal, 4F-PCC had a

  7. IIIB or not IIIB: a previously unanswered question.

    PubMed

    Thibodeau, Jennifer T; Mishkin, Joseph D; Patel, Parag C; Mammen, Pradeep P A; Markham, David W; Drazner, Mark H

    2012-05-01

    The term New York Heart Association (NYHA) class IIIB has been used increasingly in clinical medicine, including as an inclusion criteria for many clinical trials assessing left ventricular assist devices (LVADs). Indeed, NYHA class IIIB is incorporated in the Food and Drug Administration's approved indication for the Heartmate II. However, on review of the medical literature, we found that there is no consensus definition of NYHA class IIIB. Until the ambiguity is resolved, we suggest that this designation not be used in clinical practice or by investigators leading clinical trials assessing therapies which convey substantial risk to patients and therefore require clarity in describing the enrolled patient population. With ongoing improvements in LVADs, this therapy will increasingly be considered in patients less sick than those who require inotropic support, providing urgency to establish a consensus system of classifying such patients who nevertheless fall within the spectrum of advanced heart failure. Herein we propose a modification of the standard NYHA classification system which can be used to fill this void.

  8. Intraoperative Type IIIb Endoleak after Endograft Deployment during EVAR.

    PubMed

    Moulakakis, Konstantinos G; Kakisis, John D; Geroulakos, George; Brountzos, Elias N

    2017-08-01

    Type IIIb endoleak usually occurs years after the initial endograft implantation, and the cause is the chronic fatigue of the endograft. This rare case describes a type IIIb endoleak, appearing immediately after deployment of a new generation low-profile stentgraft and highlights the diagnostic and treatment challenges associated with the type IIIb endoleak. A 74-year-old man underwent elective EVAR for an infrarenal abdominal aortic aneurysm. A type IIIb endoleak near to the flow divider due to a fabric defect was diagnosed. The endoleak was successfully treated by endovascular positioning of a converter stent graft followed by the occlusion of the left limb with an iliac occluder and a femoro-femoral crossover bypass surgery. The ultrasound scan after 4 weeks showed no sign of endoleak. Occurrence of a type IIIb endoleak immediately after deployment is extremely rare. Based on the convenience of the intraoperative procedure and the anatomic characteristics of the aneurysm, we assume that the fabric defect might have occurred during loading of the endograft and subsequent confinement in the delivery catheter. We cannot definitely rule out the possibility of fabric damage induced by low-pressure balloon instrumentation. In case of a suspicion of a type IIIb endoleak, bilateral balloon occlusion of both limbs followed by antergrade aortography will help to identify the leak. In case the defect is near to the flow divider, aortouniliac grafting followed by femoro-femoral crossover bypass surgery represents an alternative option to conversion to open surgical repair. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Mucopolysaccharidosis type IIIB (MPS IIIB) masquerading as a behavioural disorder.

    PubMed

    Brady, Jacqueline; Trehan, Aditi; Landis, Dennis; Toro, Camilo

    2013-05-08

    Inborn errors of metabolism (IEMs) that manifest primarily as psychiatric and behavioural symptoms in childhood are often mistaken for idiopathic primary psychiatric disorders. The pathophysiological basis of these symptoms may be overlooked until later in the disease course when neurological deficits become dominant; this results in a significant delay in establishing a proper diagnosis. To illustrate this, we describe two siblings who presented with behavioural issues and mild learning disabilities in childhood, and were consequently given multiple psychiatric diagnoses. In early adulthood, however, they manifested a rapid cognitive decline. Subsequent cranial MRI imaging revealed progressive brain iron accumulation in deep brain nuclei. Whole exome sequencing and biochemical investigation confirmed the diagnosis of mucopolysaccharidosis type IIIB. Their long diagnostic odyssey illustrates the importance of considering IEMs when assessing individuals with behavioural abnormalities and cognitive impairment.

  10. Classification of Epidermal Growth Factor Receptor Gene Mutation Status Using Serum Proteomic Profiling Predicts Tumor Response in Patients with Stage IIIB or IV Non-Small-Cell Lung Cancer.

    PubMed

    Yang, Lin; Tang, Chuanhao; Xu, Bin; Wang, Weixia; Li, Jianjie; Li, Xiaoyan; Qin, Haifeng; Gao, Hongjun; He, Kun; Song, Santai; Liu, Xiaoqing

    2015-01-01

    Epidermal growth factor receptor (EGFR) gene mutations in tumors predict tumor response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC). However, obtaining tumor tissue for mutation analysis is challenging. Here, we aimed to detect serum peptides/proteins associated with EGFR gene mutation status, and test whether a classification algorithm based on serum proteomic profiling could be developed to analyze EGFR gene mutation status to aid therapeutic decision-making. Serum collected from 223 stage IIIB or IV NSCLC patients with known EGFR gene mutation status in their tumors prior to therapy was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and ClinProTools software. Differences in serum peptides/proteins between patients with EGFR gene TKI-sensitive mutations and wild-type EGFR genes were detected in a training group of 100 patients; based on this analysis, a serum proteomic classification algorithm was developed to classify EGFR gene mutation status and tested in an independent validation group of 123 patients. The correlation between EGFR gene mutation status, as identified with the serum proteomic classifier and response to EGFR-TKIs was analyzed. Nine peptide/protein peaks were significantly different between NSCLC patients with EGFR gene TKI-sensitive mutations and wild-type EGFR genes in the training group. A genetic algorithm model consisting of five peptides/proteins (m/z 4092.4, 4585.05, 1365.1, 4643.49 and 4438.43) was developed from the training group to separate patients with EGFR gene TKI-sensitive mutations and wild-type EGFR genes. The classifier exhibited a sensitivity of 84.6% and a specificity of 77.5% in the validation group. In the 81 patients from the validation group treated with EGFR-TKIs, 28 (59.6%) of 47 patients whose matched samples were labeled as "mutant" by the classifier and 3 (8.8%) of 34 patients whose matched samples were labeled as "wild

  11. Cutaneous head and neck melanoma in OPTiM, a randomized phase 3 trial of talimogene laherparepvec versus granulocyte‐macrophage colony‐stimulating factor for the treatment of unresected stage IIIB/IIIC/IV melanoma

    PubMed Central

    Agarwala, Sanjiv S.; Ollila, David W.; Hallmeyer, Sigrun; Milhem, Mohammed; Amatruda, Thomas; Nemunaitis, John J.; Harrington, Kevin J.; Chen, Lisa; Shilkrut, Mark; Ross, Merrick; Kaufman, Howard L.

    2016-01-01

    Abstract Background Cutaneous head and neck melanoma has poor outcomes and limited treatment options. In OPTiM, a phase 3 study in patients with unresectable stage IIIB/IIIC/IV melanoma, intralesional administration of the oncolytic virus talimogene laherparepvec improved durable response rate (DRR; continuous response ≥6 months) compared with subcutaneous granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). Methods Retrospective review of OPTiM identified patients with cutaneous head and neck melanoma given talimogene laherparepvec (n = 61) or GM‐CSF (n = 26). Outcomes were compared between talimogene laherparepvec and GM‐CSF treated patients with cutaneous head and neck melanoma. Results DRR was higher for talimogene laherparepvec–treated patients than for GM‐CSF treated patients (36.1% vs 3.8%; p = .001). A total of 29.5% of patients had a complete response with talimogene laherparepvec versus 0% with GM‐CSF. Among talimogene laherparepvec–treated patients with a response, the probability of still being in response after 12 months was 73%. Median overall survival (OS) was 25.2 months for GM‐CSF and had not been reached with talimogene laherparepvec. Conclusion Treatment with talimogene laherparepvec was associated with improved response and survival compared with GM‐CSF in patients with cutaneous head and neck melanoma. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1752–1758, 2016 PMID:27407058

  12. Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the Phase III OPTiM trial

    PubMed Central

    Harrington, Kevin J; Andtbacka, Robert HI; Collichio, Frances; Downey, Gerald; Chen, Lisa; Szabo, Zsolt; Kaufman, Howard L

    2016-01-01

    Objectives Talimogene laherparepvec is the first oncolytic immunotherapy to receive approval in Europe, the USA and Australia. In the randomized, open-label Phase III OPTiM trial (NCT00769704), talimogene laherparepvec significantly improved durable response rate (DRR) versus granulocyte-macrophage colony-stimulating factor (GM-CSF) in 436 patients with unresectable stage IIIB–IVM1c melanoma. The median overall survival (OS) was longer versus GM-CSF in patients with earlier-stage melanoma (IIIB–IVM1a). Here, we report a detailed subgroup analysis of the OPTiM study in patients with IIIB–IVM1a disease. Patients and methods The patients were randomized (2:1 ratio) to intralesional talimogene laherparepvec or subcutaneous GM-CSF and were evaluated for DRR, overall response rate (ORR), OS, safety, benefit–risk and numbers needed to treat. Descriptive statistics were used for subgroup comparisons. Results Among 249 evaluated patients with stage IIIB–IVM1a melanoma, DRR was higher with talimogene laherparepvec compared with GM-CSF (25.2% versus 1.2%; P<0.0001). ORR was also higher in the talimogene laherparepvec arm (40.5% versus 2.3%; P<0.0001), and 27 patients in the talimogene laherparepvec arm had a complete response, compared with none in GM-CSF-treated patients. The incidence rates of exposure-adjusted adverse events (AE) and serious AEs were similar with both treatments. Conclusion The subgroup of patients with stage IIIB, IIIC and IVM1a melanoma (57.1% of the OPTiM intent-to-treat population) derived greater benefit in DRR and ORR from talimogene laherparepvec compared with GM-CSF. Talimogene laherparepvec was well tolerated. PMID:27895500

  13. Chemical vapor deposition of group IIIB metals

    DOEpatents

    Erbil, Ahmet

    1989-01-01

    Coatings of Group IIIB metals and compounds thereof are formed by chemical vapor deposition, in which a heat decomposable organometallic compound of the formula (I) ##STR1## where M is a Group IIIB metal, such as lanthanum or yttrium and R is a lower alkyl or alkenyl radical containing from 2 to about 6 carbon atoms, with a heated substrate which is above the decomposition temperature of the organometallic compound. The pure metal is obtained when the compound of the formula I is the sole heat decomposable compound present and deposition is carried out under nonoxidizing conditions. Intermetallic compounds such as lanthanum telluride can be deposited from a lanthanum compound of formula I and a heat decomposable tellurium compound under nonoxidizing conditions.

  14. Chemical vapor deposition of group IIIB metals

    DOEpatents

    Erbil, A.

    1989-11-21

    Coatings of Group IIIB metals and compounds thereof are formed by chemical vapor deposition, in which a heat decomposable organometallic compound of the formula given in the patent where M is a Group IIIB metal, such as lanthanum or yttrium and R is a lower alkyl or alkenyl radical containing from 2 to about 6 carbon atoms, with a heated substrate which is above the decomposition temperature of the organometallic compound. The pure metal is obtained when the compound of the formula 1 is the sole heat decomposable compound present and deposition is carried out under nonoxidizing conditions. Intermetallic compounds such as lanthanum telluride can be deposited from a lanthanum compound of formula 1 and a heat decomposable tellurium compound under nonoxidizing conditions.

  15. Intracranial gene delivery of LV-NAGLU vector corrects neuropathology in murine MPS IIIB.

    PubMed

    Di Domenico, Carmela; Villani, Guglielmo R D; Di Napoli, Daniele; Nusco, Edoardo; Calì, Gaetano; Nitsch, Lucio; Di Natale, Paola

    2009-06-01

    Mucopolysacccharidosis (MPS) IIIB is an inherited lysosomal storage disorder caused by the deficiency of alpha-N-acetylglucosaminidase (NAGLU). The disease is characterized by mild somatic features and severe neurological involvement with high mortality. Although several therapeutic approaches have been applied to the murine model of the disease, no effective therapy is available for patients. In this study, we used the lentiviral-NAGLU vector to deliver the functional human NAGLU gene into the brain of young adult MPS IIIB mice. We report the restoration of active enzyme with a sustained expression throughout a large portion of the brain, and a significantly improved behavioral performance of treated animals. Moreover, we analyzed the effect of therapy on the expression profile of some genes related to neurotrophic signaling molecules and inflammatory cytokines previously found altered in MPS IIIB mice. At 1 month from treatment, the level of cerebellin 1 (Cbln1) was decreased while the brain-derived neurotrophic factor (Bdnf) expression was increased, both reaching normal values. At 6 months from treatment a significant reduction in the expression of all the inflammation- and oxidative stress-related genes was observed, as well as the maintenance of the correction of the Bdnf gene expression. These results indicate that NAGLU delivery from intracerebral sources has the capacity to alleviate most disease manifestations in MPS IIIB mice; furthermore, Bdnf might be a response-to-therapy biomarker for MPS IIIB.

  16. CIMAvax EGF vaccine for stage IIIb/IV non-small cell lung carcinoma

    PubMed Central

    Cheng, Jian Y.; Kananathan, Ratnavelu

    2012-01-01

    This case report documents the use of the CIMAvax Epidermal Growth Factor vaccine regimen in a 54 y old female with stage IIIb non-small cell lung carcinoma. Even after 48 mo since diagnosis her ECOG performance remains at zero. Further, this report documents a reaction to the vaccine of grade 3 severity not previously documented. PMID:22906936

  17. Theory of type IIIb solar radio bursts

    NASA Technical Reports Server (NTRS)

    Smith, R. A.; De La Noe, J.

    1976-01-01

    During the initial space-time evolution of an electron beam injected into the corona, the strong beam-plasma interaction occurs at the head of the beam, leading to the amplification of a quasi-monochromatic large-amplitude plasma wave that stabilizes by trapping the beam particles. Oscillation of the trapped particles in the wave troughs amplifies sideband electrostatic waves. The sidebands and the main wave subsequently decay to observable transverse electromagnetic waves through the parametric decay instability. This process gives rise to the elementary striation bursts. Owing to velocity dispersion in the beam and the density gradient of the corona, the entire process may repeat at a finite number of discrete plasma levels, producing chains of elementary bursts. All the properties of the type IIIb bursts are accounted for in the context of the theory.

  18. 5'- and 3'-terminal nucleotides in the FGFR2 ISAR splicing element core have overlapping roles in exon IIIb activation and exon IIIc repression.

    PubMed

    Jones, R B; Carstens, R P; Luo, Y; McKeehan, W L

    2001-09-01

    The cell type-specific, mutually-exclusive alternative splicing of the fibroblast growth factor receptor 2 (FGFR2) pre-mRNA is tightly regulated. A sequence termed ISAR (intronic splicing activator and repressor) has been implicated as an important cis regulatory element in both activation of exon IIIb and repression of exon IIIc splicing in epithelial cells. In order to better understand how this single sequence could have dual roles, we transfected minigenes containing a series of 2-bp mutations in the 18 3'-most nucleotides of ISAR that we refer to as the ISAR core. Transfection of cells with dual-exon (IIIb and IIIc) minigenes revealed that mutation of terminal sequences of the core led to decreased exon IIIb inclusion and increased exon IIIc inclusion. Transfection of cells with single-exon IIIb minigenes and single-exon IIIc minigenes revealed that mutation of terminal sequences of the ISAR core led to decreased exon IIIb inclusion and increased exon IIIc inclusion, respectively. Nucleotides of the ISAR core responsible for exon IIIb activation appear to overlap very closely with those required for exon IIIc repression. We describe a model in which ISAR and a 5' intronic sequence known as IAS2 form a stem structure required for simultaneous exon IIIb activation and exon IIIc repression.

  19. The neurobehavioral phenotype in mucopolysaccharidosis Type IIIB: An exploratory study

    PubMed Central

    Shapiro, E.; King, K.; Ahmed, A.; Rudser, K.; Rumsey, R.; Yund, B.; Delaney, K.; Nestrasil, I.; Whitley, C.; Potegal, M.

    2016-01-01

    Objectives Our goal was to describe the neurobehavioral phenotype in mucopolysaccharidosis Type IIIB (MPS IIIB). Parents report that behavioral abnormalities are a major problem in MPS III posing serious challenges to parenting and quality-of-life for both patient and parent. Our previous research on MPS IIIA identified autistic symptoms, and a Klüver-Bucy-type syndrome as indicated by reduced startle and loss of fear associated with amygdala atrophy. We hypothesized that MPS IIIB would manifest similar attributes when assessed with the same neurobehavioral protocol. Methods Ten patients with MPS IIIB were compared with 9 MPS IIIA patients, all older than 6. 8 younger children with Hurler syndrome (1H) were chosen as a comparison group for the Risk Room procedure; MPS IH does not directly affect social/emotional function and these younger children were closer to the developmental level of the MPS IIIB group. To examine disease severity, cognitive ability was assessed. Four evaluations were used: the Risk Room procedure (to measure social-emotional characteristics, especially fear and startle responses), the Autism Diagnostic Observation Schedule (ADOS), the Sanfilippo Behavior Rating Scale (SBRS), and amygdala brain volumes calculated from manually-traced MRI images. Results The two groups are equivalent in severity and show severe cognitive impairment. On the ADOS, the MPS IIIB patients exhibited the same autistic features as IIIA. The IIIB means differed from MPS IH means on most measures. However, the IIIB group did not approach the Risk Room stranger, like the MPS IH group who kept their distance, but unlike the IIIA group who showed no fear of the stranger. On the SBRS, the MPS IIIB patients were described as more inattentive and more fearful, especially of new people than the MPS IIIA. Onsets of some disease characteristics appeared more closely spaced and slightly earlier in MPS IIIB than IIIA. Conclusions On most behavioral measures, MPS IIIB patients did

  20. Long-term Outcome after Radiotherapy for FIGO Stage IIIB and IVA Carcinoma of the Cervix

    SciTech Connect

    Yeung, Anamaria R.; Amdur, Robert J. . E-mail: amdurrj@shands.ufl.edu; Morris, Christopher G.; Morgan, Linda S.; Mendenhall, William M.

    2007-04-01

    Purpose: To report the long-term outcome after radiotherapy with curative intent for Stage IIIB and IVA carcinoma of the cervix. Methods and Materials: We retrospectively reviewed 91 patients treated with radiotherapy with curative intent at University of Florida between January 1980 and December 2003 for Stage IIIB (84 patients) or IVA (7 patients) carcinoma of the cervix. Results: The median follow-up of the surviving patients was 8.8 years. The 5- and 10-year estimates of local control, regional control, locoregional control, relapse-free survival, and overall survival were 53% and 53%, 55% and 47%, 34% and 29%, 30% and 26%, and 29% and 21%, respectively. Ninety percent of the recurrences occurred within 2 years of treatment. Of these, 60% of all failures were local, 29% were regional, and 11% were distant failures alone. Also, 17% of the failures were in the paraaortic nodes with no evidence of failure in the pelvis. Univariate and multivariate analyses were conducted with the endpoint of relapse-free or overall survival. No factor was statistically significant. Complications from therapy were scored using the Radiation Therapy Oncology Group grading system; the overall severe late complication rate was 13% (Grade 3-5). Conclusion: This series is one of the most mature of published reports. With long-term follow-up, approximately one-third of patients with Stage IIIB or IVA carcinoma of the cervix were cured, with a 13% complication rate.

  1. Persistence Factors of First-Generation Learners

    ERIC Educational Resources Information Center

    Braswell, Tawanda M.

    2010-01-01

    This dissertation utilized a qualitative narrative case study method to explore the unknown factors and elements of perseverance in spite of adversity and crisis. The study documented the lives of five African American women in order to describe, understand, and explain the central research question of how and why some first-generation learners…

  2. Endodontic management of dens invaginatus Type IIIb: Case series

    PubMed Central

    Martins, Jorge N. R.; da Costa, Rui Pereira; Anderson, Craig; Quaresma, Sérgio André; Corte-Real, Luís S. M.; Monroe, Adam D.

    2016-01-01

    Dens invaginatus may be seen as a developmental malformation. It is characterized by an invagination of the enamel and dentin, creating a lumen inside the affected tooth, which may extend as deep as the apical foramen. Oehlers Type IIIb is considered the most challenging clinical conditions. The purpose of this study is to discuss the nonsurgical endodontic management of vital and necrotic dens invaginatus Type IIIb cases. Due to the complex anatomical consideration of dens invaginatus Type IIIb, endodontic treatment is extremely technique sensitive. A conservative approach was used in a vital case to treat the invaginated lumen only, to preserve the vitality of the pulp, and a more invasive approach was used in a necrotic case to debride the lumen and necrotic pulp for proper disinfection of the root canal system. Although different, all the approaches were successful. The clinical signs and symptoms were resolved. The vital case remains vital after 19 months, and the recall radiographs were able to show satisfactory periapical healing both in vital and necrotic cases. Due to the highly complex anatomy of dens invaginatus Type IIIb, the decision of preserving the pulp vitality may not be related only to pulpal diagnosis but also to the technical requirements of the treatment. Although very technically sensitive, it may be possible to treat the invaginated lumen exclusively, while preserving the vitality of the pulp. Necrotic cases may require a more aggressive approach to achieve a favorable prognosis. PMID:28042276

  3. Endodontic management of dens invaginatus Type IIIb: Case series.

    PubMed

    Martins, Jorge N R; da Costa, Rui Pereira; Anderson, Craig; Quaresma, Sérgio André; Corte-Real, Luís S M; Monroe, Adam D

    2016-01-01

    Dens invaginatus may be seen as a developmental malformation. It is characterized by an invagination of the enamel and dentin, creating a lumen inside the affected tooth, which may extend as deep as the apical foramen. Oehlers Type IIIb is considered the most challenging clinical conditions. The purpose of this study is to discuss the nonsurgical endodontic management of vital and necrotic dens invaginatus Type IIIb cases. Due to the complex anatomical consideration of dens invaginatus Type IIIb, endodontic treatment is extremely technique sensitive. A conservative approach was used in a vital case to treat the invaginated lumen only, to preserve the vitality of the pulp, and a more invasive approach was used in a necrotic case to debride the lumen and necrotic pulp for proper disinfection of the root canal system. Although different, all the approaches were successful. The clinical signs and symptoms were resolved. The vital case remains vital after 19 months, and the recall radiographs were able to show satisfactory periapical healing both in vital and necrotic cases. Due to the highly complex anatomy of dens invaginatus Type IIIb, the decision of preserving the pulp vitality may not be related only to pulpal diagnosis but also to the technical requirements of the treatment. Although very technically sensitive, it may be possible to treat the invaginated lumen exclusively, while preserving the vitality of the pulp. Necrotic cases may require a more aggressive approach to achieve a favorable prognosis.

  4. Proper hepatic pedicle clamping during hepatectomy is associated with improved postoperative long-term prognosis in patients with AJCC stage IIIB hepatocellular carcinoma

    PubMed Central

    Guo, Lei; Zhang, Bo; Lin, Zhenhai; Zhang, Jubo; Ye, Qinghai

    2016-01-01

    Intermittent hepatic pedicle clamping (HPC) is often performed during hepatectomy. Whether it affects the long-term prognosis of hepatocellular carcinoma (HCC) patients is still controversial. This study evaluated the impact of HPC in patients with different stages of HCC. The study included 1401 patients who underwent hepatectomy in the primary cohort with 129 AJCC stage IIIB HCC patients; there were 80 AJCC stage IIIB HCC patients in the validation cohort. In each cohort, patients were placed in the long-term HPC (LTHPC) group or the short-term HPC (STHPC) group based on the cut-off time of HPC estimated by the receiver-operating characteristic (ROC) curve. Although HPC did not show significant effects on the prognosis of stage I–IIIA HCC patients in the primary cohort, 1−, 3−, and 5-year overall survival (OS) and recurrence-free survival (RFS) rates of stage IIIB HCC patients who received LTHPC (HPC time > 12 minutes) were significantly higher than those with STHPC (HPC time ≤ 12 minutes or received no HPC), similar in the validation cohort. Multivariate analysis demonstrated HPC time was an independent protective factor for RFS and OS in stage IIIB HCC patients. Herein, we report that proper HPC improved the postoperative prognosis of stage IIIB HCC patients and served as an independent protective factor. PMID:27027437

  5. Proper hepatic pedicle clamping during hepatectomy is associated with improved postoperative long-term prognosis in patients with AJCC stage IIIB hepatocellular carcinoma.

    PubMed

    Li, Xiaoqiang; Liu, Shuang; Li, Hui; Guo, Lei; Zhang, Bo; Lin, Zhenhai; Zhang, Jubo; Ye, Qinghai

    2016-04-26

    Intermittent hepatic pedicle clamping (HPC) is often performed during hepatectomy. Whether it affects the long-term prognosis of hepatocellular carcinoma (HCC) patients is still controversial. This study evaluated the impact of HPC in patients with different stages of HCC. The study included 1401 patients who underwent hepatectomy in the primary cohort with 129 AJCC stage IIIB HCC patients; there were 80 AJCC stage IIIB HCC patients in the validation cohort. In each cohort, patients were placed in the long-term HPC (LTHPC) group or the short-term HPC (STHPC) group based on the cut-off time of HPC estimated by the receiver-operating characteristic (ROC) curve. Although HPC did not show significant effects on the prognosis of stage I-IIIA HCC patients in the primary cohort, 1-, 3-, and 5-year overall survival (OS) and recurrence-free survival (RFS) rates of stage IIIB HCC patients who received LTHPC (HPC time > 12 minutes) were significantly higher than those with STHPC (HPC time ≤ 12 minutes or received no HPC), similar in the validation cohort. Multivariate analysis demonstrated HPC time was an independent protective factor for RFS and OS in stage IIIB HCC patients. Herein, we report that proper HPC improved the postoperative prognosis of stage IIIB HCC patients and served as an independent protective factor.

  6. Novel mutation detection of fibroblast growth factor receptor 1 (FGFR1) gene, FGFR2IIIa, FGFR2IIIb, FGFR2IIIc, FGFR3, FGFR4 gene for craniosynostosis: A prospective study in Asian Indian patient

    PubMed Central

    Barik, Mayadhar; Bajpai, Minu; Malhotra, Arun; Samantaray, Jyotish Chandra; Dwivedi, Sadananda; Das, Sambhunath

    2015-01-01

    Background: Craniosynostosis (CS) syndrome is an autosomal dominant condition classically combining craniosynostosis and non-syndromic craniosynostosis with digital anomalies of the hands and feet. The majority of cases are caused by heterozygous mutations in the third immunoglobulin-like domain (IgIII) of FGFR2, whilst a larger number of cases can be attributed to mutations outside this region of the protein. Aims: To find out the FGFR1, FGFR2, FGFR3 and FGFR4 gene in craniosynostosis syndrome. Settings and Design: A hospital based prospective study. Materials and Methods: Prospective analysis of clinical records of patients registered in CS clinic from December 2007 to January 2015 was done in patients between 4 months to 13 years of age. We have performed genetic findings in a three generation Indian family with Craniosynostosis syndrome. Results: We report for the first time the clinical and genetic findings in a three generation Indian family with Craniosynostosis syndrome caused by a heterozygous missense mutation, Thr 392 Thr and ser 311 try, located in the IgII domain of FGFR2. FGFR 3 and 4 gene basis syndrome was eponymously named. Genetic analysis demonstrated that 51/56 families to be unrelated. In FGFR3 gene 10/TM location of 1172 the nucleotide changes C>A, Ala 391 Glu 19/56 and Exon-19, 5q35.2 at conserved linker region the changes occurred pro 246 Arg in 25/56 families. Conclusions: Independent genetic origins, but phenotypic similarities in the 51 families add to the evidence supporting the theory of selfish spermatogonial selective advantage for this rare gain-of-function FGFR2 mutation. PMID:26557159

  7. Effectiveness of acupuncture on chronic prostatitis-chronic pelvic pain syndrome category IIIB patients: a prospective, randomized, nonblinded, clinical trial.

    PubMed

    Küçük, Eyüp Veli; Suçeken, Ferhat Yakup; Bindayı, Ahmet; Boylu, Ugur; Onol, Fikret Fatih; Gümüş, Eyüp

    2015-03-01

    To compare the acupuncture treatment and the medical treatment with antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs) on pain control, urinary symptoms, and quality of life of category IIIB chronic prostatitis-chronic pelvic pain syndrome (CP-CPPS). From November 2008 to May 2009, 54 male patients with category IIIB CP-CPPS were randomly divided into 2 groups: the medical treatment group (group 1, n = 28) and the acupuncture treatment group (group 2, n = 26). Group 1 took levofloxacin 500 mg daily and ibuprofen 200 mg twice a day for 6 weeks. In the acupuncture group (group 2), bilateral BL32 (Ciliao) and BL33 (Zhongliao) acupoints were used to stimulate the sacral nerve using an electrical pulse generator, twice a week for 7 weeks. The change in National Institutes of Health Chronic Prostatitis Symptom Index scores from the baseline to the end of the treatment was observed. The mean follow-up was 28 weeks from the baseline (range, 20-43 weeks). In acupuncture group, reduction of pain, urinary symptoms, quality of life, and total National Institutes of Health Chronic Prostatitis Symptom Index score was higher compared with the medical group. However the treatment of CP-CPPS is challenging and difficult for the urologists. This clinical study showed that the acupuncture treatment is a safe and effective treatment of category IIIB CP-CPPS. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Genetic relationships among Italian and Mexican maize-rhizosphere Burkholderia cepacia complex (BCC) populations belonging to Burkholderia cenocepacia IIIB and BCC6 group

    PubMed Central

    2011-01-01

    Background A close association between maize roots and Burkholderia cepacia complex (BCC) bacteria has been observed in different locations globally. In this study we investigated by MultiLocus Restriction Typing (MLRT) the genetic diversity and relationships among Burkholderia cenocepacia IIIB and BCC6 populations associated with roots of maize plants cultivated in geographically distant countries (Italy and Mexico), in order to provide new insights into their population structure, evolution and ecology. Results The 31 B. cenocepacia IIIB and 65 BCC6 isolates gave rise to 29 and 39 different restriction types (RTs), respectively. Two pairs of isolates of B. cenocepacia IIIB and BCC6, recovered from both Italian and Mexican maize rhizospheres, were found to share the same RT. The eBURST (Based Upon Related Sequence Types) analysis of MLRT data grouped all the B. cenocepacia IIIB isolates into four clonal complexes, with the RT-4-complex including the 42% of them, while the majority of the BCC6 isolates (94%) were grouped into the RT-104-complex. These two main clonal complexes included RTs shared by both Italian and Mexican maize rhizospheres and a clear relationship between grouping and maize variety was also found. Grouping established by eBURST correlated well with the assessment using unweighted-pair group method with arithmetic mean (UPGMA). The standardized index of association values obtained in both B. cenocepacia IIIB and BCC6 suggests an epidemic population structure in which occasional clones emerge and spread. Conclusions Taken together our data demonstrate a wide dispersal of certain B. cenocepacia IIIB and BCC6 isolates in Mexican and Italian maize rhizospheres. Despite the clear relationship found between the geographic origin of isolates and grouping, identical RTs and closely related isolates were observed in geographically distant regions. Ecological factors and selective pressure may preferably promote some genotypes within each local microbial

  9. Serum global metabolomics profiling reveals profound metabolic impairments in patients with MPS IIIA and MPS IIIB.

    PubMed

    Fu, Haiyan; Meadows, Aaron S; Pineda, Ricardo J; Mohney, Robert P; Stirdivant, Steve; McCarty, Douglas M

    2017-04-05

    The monogenic defects in specific lysosomal enzymes in mucopolysaccharidosis (MPS) III lead to lysosomal storage of glycosaminoglycans and complex CNS and somatic pathology, for which the detailed mechanisms remain unclear. In this study, serum samples from patients with MPS IIIA (age 2-9 yr) and MPS IIIB (2-13 yr) and healthy controls (age 2-9 yr) were assayed by global metabolomics profiling of 658 metabolites using mass spectrometry. Significant alterations were detected in 423 metabolites in all MPS III patients, of which 366 (86.5%) decreased and 57 (13.5%) increased. Similar profiles were observed when analyzing data from MPS IIIA and MPS IIIB samples separately, with only limited age variations in 36 metabolites. The observed metabolic disturbances in MPS III patients involve virtually all major pathways of amino acid (101/150), peptide (17/21), carbohydrate (19/23), lipid (221/325), nucleotide (15/25), energy (8/9), vitamins and co-factors (8/21), and xenobiotics (34/84) metabolism. Notably, detected serum metabolite decreases involved all key amino acids, all major neurotransmitter pathways, and broad neuroprotective compounds. The elevated metabolites are predominantly lipid derivatives, and also include cysteine metabolites and a fibrinogen peptide fragment, consistent with the status of oxidative stress and inflammation in MPS III. This study demonstrates that the lysosomal glycosaminoglycans storage triggers profound metabolic disturbances in patients with MPS III disorders, leading to severe functional depression of virtually all metabolic pathways, which emerge early during the disease progression. Serum global metabolomics profiling may provide an important and minimally invasive tool for better understanding the disease mechanisms and identification of potential biomarkers for MPS III.

  10. Sequence similarities among kappa IIIb chains of monoclonal human IgM kappa autoantibodies

    PubMed Central

    1984-01-01

    Light chains of the serologically and chemically defined V region sub- subgroup kappa IIIb are preferentially associated with several types of human IgM kappa (monoclonal) autoantibodies and are remarkably homologous in primary structure, as evidenced by partial amino acid sequence data. To establish the extent of homology among such proteins, we have determined the complete variable region (V) sequence of the light chains of four monoclonal IgM kappa autoantibodies, of which two (GAR and GOT) are rheumatoid factors (RFs), the third (SON) has anti- apo beta lipoprotein specificity, and the fourth (PIE) binds specifically to intermediate filaments. The region encoded by the V kappa segment gene (positions 1-95) in all four light (L) chains is virtually identical in sequence, differing by only one residue in the FR3 of protein SON and in the first CDR of protein GOT. Further, the CDR3 of kappa chain SON contains an additional residue (prolyl) located at the carboxyl-terminus of the V segment. The region encoded by the J gene (positions 96-108) is identical after position 96 for the two RFs GAR and GOT (J kappa 2), but different in proteins SON (J kappa 4) and PIE (J kappa 1). The amino acid residue at position 96, located in CDR3 at the site of combinatoriaL joining of the V kappa and J kappa gene segments and involved as a contacting residue in the hapten binding site, is different in all four light chains. These results demonstrate the extensive homology in sequence among light chains of IgM kappa autoantibodies and indicate that a particular V kappa germ line gene, kappa IIIb, is expressed as a phylogenetic response to certain self antigens or as part of a selection process by which these autoimmune responses are regulated. PMID:6432934

  11. Factors for Generating Initial Construction Schedules

    DTIC Science & Technology

    1991-09-01

    Switches 128/1600 Accessories 128/1700 Power Distribution 128/2000 Uninterruptible Power Systems 128/2100 Static Charger - Battery 128/2200 Motor-Generator...are not to be construed as an official Depart- ment of the Army position, unless so designated by other authorized documents. DESTROY THIS REPORT WHEN...0704-0188), Washington, DC 205M0. 1. AGENCY USE ONLY (Leave Blank) 2. REPORT DATE 3. REPORT TYPE AND DATES COVERED I September 1991 Final 4. TITLE AND

  12. A Scenario for the Fine Structures of Solar Type IIIb Radio Bursts Based on Electron Cyclotron Maser Emission

    NASA Astrophysics Data System (ADS)

    Wang, C. B.

    2015-06-01

    A scenario based on electron cyclotron maser (ECM) emission is proposed for the fine structures of solar radio emission. It is suggested that under certain conditions modulation of the ratio between the plasma frequency and electron gyro frequency by ultra-low-frequency waves, which is a key parameter for excitation of ECM instability, may lead to the intermittent emission of radio waves. As an example, the explanation for the observed fine-structure components in the solar Type IIIb bursts is discussed in detail. Three primary issues of Type IIIb bursts are addressed: (1) the physical mechanism that results in intermittent emission elements that form a chain in the dynamic spectrum of Type IIIb bursts, (2) the cause of split pairs (or double stria) and triple stria, and (3) why only IIIb-III bursts are observed in the events of fundamental harmonic pair emission whereas IIIb-IIIb or III-IIIb bursts are very rarely observed.

  13. Molecular defects in Sanfilippo syndrome type B (mucopolysaccharidosis IIIB).

    PubMed

    Beesley, C E; Jackson, M; Young, E P; Vellodi, A; Winchester, B G

    2005-01-01

    Sanfilippo syndrome type B (mucopolysaccharidosis IIIB) is an autosomal recessive disease that is caused by the deficiency of the lysosomal enzyme alpha-N-acetylglucosaminidase (NAGLU). NAGLU is involved in the degradation of the glycosaminoglycan (GAG) heparan sulphate, and a deficiency results in the accumulation of partially degraded GAGs inside lysosomes. Early clinical symptoms include hyperactivity, aggressiveness and delayed development, followed by progressive mental deterioration, although there are a small number of late-onset attenuated cases. The gene for NAGLU has been fully characterized and we report the molecular analysis of 18 Sanfilippo B families. In total, 34 of the 36 mutant alleles were characterized in this study and 20 different mutations were identified including 8 novel changes (R38W, V77G, 407-410del4, 703delT, A246P, Y335C, 1487delT, E639X). The four novel missense mutations were transiently expressed in Chinese hamster ovary cells and all were shown to decrease the NAGLU activity markedly, although A246P did produce 12.7% residual enzyme activity.

  14. Bortezomib in Treating Patients With Stage IIIB or Stage IV Lung Cancer

    ClinicalTrials.gov

    2014-08-04

    Adenocarcinoma of the Lung; Bronchoalveolar Cell Lung Cancer; Non-small Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  15. Formulation, development, and optimization of a novel octyldodecanol-based nanoemulsion for transdermal delivery of ceramide IIIB

    PubMed Central

    Su, Runping; Yang, Li; Wang, Yue; Yu, Shanshan; Guo, Yu; Deng, Jiayu; Zhao, Qianqian; Jin, Xiangqun

    2017-01-01

    This research aimed to develop and optimize a nanoemulsion-based formulation containing ceramide IIIB using phase-inversion composition for transdermal delivery. The effects of ethanol, propylene glycol (PG), and glycerol in octyldodecanol and Tween 80 systems on the size of the nanoemulsion region in the phase diagrams were investigated using water titration. Subsequently, ceramide IIIB loading was kept constant (0.05 wt%), and the proposed formulation and conditions were optimized via preliminary screening and experimental design. Factors such as octyldodecanol/(Tween 80:glycerol) weight ratio, water content, temperature, addition rate, and mixing rate were investigated in the preliminary screening experiment. Response surface methodology was employed to study the effect of water content (30%–70%, w/w), mixing rate (400–720 rpm), temperature (20°C–60°C), and addition rate (0.3–1.8 mL/min) on droplet size and polydispersity index. The mathematical model showed that the optimum formulation and conditions for preparation of ceramide IIIB nanoemulsion with desirable criteria were a temperature of 41.49°C, addition rate of 1.74 mL/min, water content of 55.08 wt%, and mixing rate of 720 rpm. Under optimum formulation conditions, the corresponding predicted response values for droplet size and polydispersity index were 15.51 nm and 0.12, respectively, which showed excellent agreement with the actual values (15.8 nm and 0.108, respectively), with no significant (P>0.05) differences. PMID:28860748

  16. Exploratory Factor Analysis, Theory Generation, and Scientific Method

    ERIC Educational Resources Information Center

    Haig, Brian D.

    2005-01-01

    This article examines the methodological foundations of exploratory factor analysis (EFA) and suggests that it is properly construed as a method for generating explanatory theories. In the first half of the article it is argued that EFA should be understood as an abductive method of theory generation that exploits an important precept of…

  17. Cytokines, neurotrophins, and oxidative stress in brain disease from mucopolysaccharidosis IIIB.

    PubMed

    Villani, Guglielmo R D; Gargiulo, Nadia; Faraonio, Raffaella; Castaldo, Sigismondo; Gonzalez Y Reyero, Enrico; Di Natale, Paola

    2007-02-15

    Mucopolysaccharidosis IIIB (MPS IIIB; Sanfilippo syndrome type B) is characterized by profound neurological deterioration. Because a murine model of MPS IIIB disease is available, we focused on analysis of gene expression in the brain and cerebellum of 7-month-old MPS IIIB mice by pathway-specific filter microarrays designed to probe apoptotic-related, neurotrophic signalling molecules and inflammatory cytokines and receptors. Moreover, we extended the analysis with real-time PCR performed at 1, 3, 7 months after birth. Bdnf was down-regulated in the brain but up-regulated in the cerebellum at 7 months of age, both at RNA and at protein levels. Cbln1 presented a threefold increase in the oldest brains while remaining unaltered in the cerebellum. Ccl3, Casp11, gp91(phox), p67(phox), and p47(phox) showed an increased expression in both brain and cerebellum at each examined time point. Ccl3, in particular, exhibited in both organs and at all times tested approximately a tenfold increase in its expression. Insofar as p47(phox), p67(phox), and gp91(phox) are all components of the phagocyte NADPH oxidase, our results suggest the possible involvement of the reactive oxygen species in the genesis of neurodegeneration in MPS IIIB disease.

  18. Endovascular Repair of Type IIIb Endoleak With the Amplatzer Septal Occluder.

    PubMed

    McWilliams, Richard G; Chan, Tze Yuan; Smout, Jonathan; Torella, Francesco; Fisher, Robert K

    2017-04-01

    To report the successful treatment of a type IIIb endoleak with an Amplatzer Septal Occluder. A 76-year-old man was found to have a type IIIb endoleak in the proximal body component of a fenestrated graft at 4-year surveillance imaging; the leak was associated with rapid aneurysm growth. The anatomy of the graft and position of the fabric defect precluded treatment by relining with a secondary endograft. The defect was demonstrated with catheter angiography, sized with an angioplasty balloon, and repaired using an Amplatzer Septal Occluder. Follow-up imaging at 6 months showed no endoleak and marked reduction in the aneurysm size. The Amplatzer Septal Occluder may be considered as an option for managing type IIIb endoleaks.

  19. Exploratory Factor Analysis, Theory Generation, and Scientific Method.

    PubMed

    Haig, Brian D

    2005-01-01

    This article examines the methodological foundations of exploratory factor analysis (EFA) and suggests that it is properly construed as a method for generating explanatory theories. In the first half of the article it is argued that EFA should be understood as an abductive method of theory generation that exploits an important precept of scientific inference known as the principle of the common cause. This characterization of the inferential nature of EFA coheres well with its interpretation as a latent variable method. The second half of the article outlines a broad theory of scientific method in which abductive reasoning figures prominently. It then discusses a number of methodological features of EFA in the light of that method. Specifically, it is argued that EFA helps researchers generate theories with genuine explanatory merit; that factor indeterminacy is a methodological challenge for both EFA and confirmatory factor analysis, but that the challenge can be satisfactorily met in each case; and, that EFA, as a useful method of theory generation, can be profitably employed in tandem with confirmatory factor analysis and other methods of theory evaluation.

  20. Thrombin generation in rheumatoid arthritis: dependence on plasma factor composition.

    PubMed

    Undas, Anetta; Gissel, Matthew; Kwasny-Krochin, Beata; Gluszko, Piotr; Mann, Kenneth G; Brummel-Ziedins, Kathleen E

    2010-08-01

    Growing evidence indicates that rheumatoid arthritis (RA) is associated with an increased risk for thromboembolic cardiovascular events. We investigated thrombin generation profiles in RA patients and their dependence on plasma factor/inhibitor composition. Plasma factor (F) compositions (II, V, VII, VIII, IX, X), antithrombin and free tissue factor pathway inhibitor (TFPI) from 46 consecutive RA patients with no cardiovascular events (39 female, 7 male, aged 57 [range, 23-75] years; DAS28 [Disease Activity Score] 5.2 +/- 1.1) were compared with those obtained in age- and sex-matched apparently healthy controls. Using each individual's plasma coagulation protein composition, tissue factor-initiated thrombin generation was assessed both computationally and empirically. RA patients had higher fibrinogen (4.18 [IQR 1.09] vs. 2.56 [0.41] g/l, p<0.0001), FVIII (226 +/- 40 vs. 113 +/- 15%, p<0.001), PC (107 [16] vs. 100 [14]%, p<0.001), and free TFPI levels (22.3 [2.2] vs. 14.7 [2.1] ng/ml, p<0.001). DAS28, but not age, RA duration, or C-reactive protein, was associated with FV, FVIII, FIX, FX, antithrombin, and free TFPI (r from 0.27 to 0.48, p<0.05). Intergroup comparison of computational thrombin generation profiles showed that in RA patients, maximum thrombin levels (p=0.01) and the rate of thrombin formation (p<0.0001) were higher, whereas the initiation phase of thrombin generation (p<0.0001) and the time to maximum thrombin levels (p<0.0001) were longer. Empirical reconstructions of the populations reproduced the thrombin generation profiles generated by the computational model. Simulations of thrombin formation suggest that blood plasma composition, i.e. a marked increase in FVIII, somewhat counterbalanced by free TFPI, contributes to the prothrombotic phenotype in RA patients.

  1. RADGEN: A radiation exchange factor generator for rod bundles

    SciTech Connect

    Rector, D.R.

    1987-10-01

    The RADGEN computer program has been developed at Pacific Northwest Laboratory (PNL) to generate input required for the thermal radiation models used in the COBRA-SFS (Spent Fuel Storage) computer program. The COBRA-SFS program uses radiation exchange factors to describe the net amount of energy transferred from each surface to every other surface in an enclosure. The RADGEN program generates radiation exchange factors for arrays of rods on a square or triangular pitch as well as open channel geometries. This report describes the input requirements for the RADGEN code, which may be executed in a batch or interactive mode, and outlines the solution procedure used to obtain the exchange factors. 4 refs., 25 figs., 13 tabs.

  2. A SCENARIO FOR THE FINE STRUCTURES OF SOLAR TYPE IIIb RADIO BURSTS BASED ON ELECTRON CYCLOTRON MASER EMISSION

    SciTech Connect

    Wang, C. B.

    2015-06-10

    A scenario based on electron cyclotron maser (ECM) emission is proposed for the fine structures of solar radio emission. It is suggested that under certain conditions modulation of the ratio between the plasma frequency and electron gyro frequency by ultra-low-frequency waves, which is a key parameter for excitation of ECM instability, may lead to the intermittent emission of radio waves. As an example, the explanation for the observed fine-structure components in the solar Type IIIb bursts is discussed in detail. Three primary issues of Type IIIb bursts are addressed: (1) the physical mechanism that results in intermittent emission elements that form a chain in the dynamic spectrum of Type IIIb bursts, (2) the cause of split pairs (or double stria) and triple stria, and (3) why only IIIb–III bursts are observed in the events of fundamental harmonic pair emission whereas IIIb–IIIb or III–IIIb bursts are very rarely observed.

  3. Tissue factor-driven thrombin generation and inflammation in atherosclerosis.

    PubMed

    ten Cate, Hugo

    2012-05-01

    The transmembrane receptor tissue factor is a prominent protein expressed at macrophages and smooth muscle cells within human atherosclerotic lesions. While many coagulation proteins are detectable in atherosclerosis, a locally active thrombin and fibrin generating molecular machinery may be instrumental in manipulating cellular functions involved in atherogenesis. These include inflammation, angiogenesis and cell proliferation. Indeed, many experimental studies in mice show a correlation between hypercoagulability and increased atherosclerosis. In mice, the amount of atherosclerosis and/or the plaque phenotype, appear to be modifiable by specific anticoagulant interventions. While attempts to vary tissue factor level in the vasculature does not directly reduce plaque burden, the overexpression of tissue factor pathway inhibitor attenuates thrombogenicity and neo intima formation in mice. Moreover, inhibition of factor Xa or thrombin with novel selective agents, including rivaroxaban and dabigatran, inhibits inflammation associated with atherosclerosis in apoE(-/-) mice. The potential to modify a complex chronic disease like atherosclerosis with novel selective anticoagulants merits further clinical study.

  4. Isolated Limb Perfusion With Melphalan in Treating Patients With Stage IIIB-IV Melanoma or Sarcoma

    ClinicalTrials.gov

    2015-07-22

    Basal Cell Carcinoma of the Skin; Eccrine Carcinoma of the Skin; Recurrent Adult Soft Tissue Sarcoma; Recurrent Melanoma; Recurrent Skin Cancer; Squamous Cell Carcinoma of the Skin; Stage III Adult Soft Tissue Sarcoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Melanoma

  5. Selected Findings from Phase III-B. BTES. Beginning Teacher Evaluation Study. Supplement. Preliminary Version.

    ERIC Educational Resources Information Center

    Fisher, Charles W.; And Others

    This series of six papers concerning the Beginning Teacher Evaluation Study (BTES) starts with Teaching Behaviors, Academic Learning Time and Student Achievement: An Overview of Phase III-B of the Beginning Teacher Evaluation Study by the project director, Charles Fisher. As an introduction, it describes a model of classroom instruction based on…

  6. Long-term clinical course of a patient with mucopolysaccharidosis type IIIB

    PubMed Central

    Kim, Ja Hye; Chi, Yang Hyun; Kim, Gu-Hwan; Yoo, Han-Wook

    2016-01-01

    Mucopolysaccharidosis type III (MPS III) is a rare genetic disorder caused by lysosomal storage of heparan sulfate. MPS IIIB results from a deficiency in the enzyme alpha-N-acetyl-D-glucosaminidase (NAGLU). Affected patients begin showing behavioral changes, progressive profound mental retardation, and severe disability from the age of 2 to 6 years. We report a patient with MPS IIIB with a long-term follow-up duration. He showed normal development until 3 years. Subsequently, he presented behavioral changes, sleep disturbance, and progressive motor dysfunction. He had been hospitalized owing to recurrent pneumonia and epilepsy with severe cognitive dysfunction. The patient had compound heterozygous c.1444C>T (p.R482W) and c.1675G>T (p.D559Y) variants of NAGLU. Considering that individuals with MPS IIIB have less prominent facial features and skeletal changes, evaluation of long-term clinical course is important for diagnosis. Although no effective therapies for MPS IIIB have been developed yet, early and accurate diagnosis can provide important information for family planning in families at risk of the disorder. PMID:28018442

  7. Negative pressure wound therapy for Gustilo Anderson grade IIIb open tibial fractures

    PubMed Central

    Park, Chul Hyun; Shon, Oog Jin; Kim, Gi Beom

    2016-01-01

    Background: Traditionally, Gustilo Anderson grade IIIb open tibial fractures have been treated by initial wide wound debridement, stabilization of fracture with external fixation, and delayed wound closure. The purpose of this study is to evaluate the clinical and radiological results of staged treatment using negative pressure wound therapy (NPWT) for Gustilo Anderson grade IIIb open tibial fractures. Materials and Methods: 15 patients with Gustilo Anderson grade IIIb open tibial fractures, treated using staged protocol by a single surgeon between January 2007 and December 2011 were reviewed in this retrospective study. The clinical results were assessed using a Puno scoring system for severe open fractures of the tibia at the last followup. The range of motion (ROM) of the knee and ankle joints and postoperative complication were evaluated at the last followup. The radiographic results were assessed using time to bone union, coronal and sagittal angulations and a shortening at the last followup. Results: The mean score of Puno scoring system was 87.4 (range 67–94). The mean ROM of the knee and ankle joints was 121.3° (range 90°–130°) and 37.7° (range 15°–50°), respectively. Bone union developed in all patients and the mean time to union was 25.3 weeks (range 16–42 weeks). The mean coronal angulation was 2.1° (range 0–4°) and sagittal was 2.7° (range 1–4°). The mean shortening was 4.1 mm (range 0–8 mm). Three patients had partial flap necrosis and 1 patient had total flap necrosis. There was no superficial and deep wound infection. Conclusion: Staged treatment using NPWT decreased the risks of infection and requirement of flap surgeries in Gustilo Anderson grade IIIb open tibial fractures. Therefore, staged treatment using NPWT could be a useful treatment option for Gustilo Anderson grade IIIb open tibial fractures. PMID:27746498

  8. The Comparative Characteristic of Components in the Iiib-Iii Pairs According to the Observation Data Obtained by Radio Telescope URAN-2

    NASA Astrophysics Data System (ADS)

    Brazhenko, A. I.; Melnik, V. N.; Konovalenko, A. A.; Dorovskiy, V. V.; Vashchishin, R. V.; Frantsuzenko, A. V.; Rucker, G.

    In this paper we analyze the properties of type IIIb and type III bursts in IIIb-III pairs observed by radio telescope URAN-2 at frequencies 16-32 MHz. We discuss pro and contra of harmonic phenomenon of decameter IIIb-III pairs.

  9. Results of a conservative treatment combining induction (neoadjuvant) and consolidation chemotherapy, hormonotherapy, and external and interstitial irradiation in 98 patients with locally advanced breast cancer (IIIA-IIIB)

    SciTech Connect

    Jacquillat, C.; Baillet, F.; Weil, M.; Auclerc, G.; Housset, M.; Auclerc, M.; Sellami, M.; Jindani, A.; Thill, L.; Soubrane, C.

    1988-05-15

    Ninety-eight patients with locally advanced breast cancer (Stage IIIA-IIIB) were entered into a pilot study combining intensive induction (neoadjuvant) chemotherapy (VTMFAP) with or without hormonochemotherapy, external and interstitial radiotherapy, and consolidation chemotherapy with or without hormonochemotherapy. Tumor regression over 50% was observed in 91% patients after chemotherapy, and complete clinical remission occurred in 100% patients after irradiation. The rate of local relapse is 13%. The 3-year disease-free survival is 62% and 3-year global survival is 77%. Initial chemotherapeutic tumor regression greater than 75% is the main predictive factor for disease-free survival.

  10. Developing the Next Generation Shell Buckling Design Factors and Technologies

    NASA Technical Reports Server (NTRS)

    Hilburger, Mark W.

    2012-01-01

    NASA s Shell Buckling Knockdown Factor (SBKF) Project was established in the spring of 2007 by the NASA Engineering and Safety Center (NESC) in collaboration with the Constellation Program and Exploration Systems Mission Directorate. The SBKF project has the current goal of developing less-conservative, robust shell buckling design factors (a.k.a. knockdown factors) and design and analysis technologies for light-weight stiffened metallic launch vehicle (LV) structures. Preliminary design studies indicate that implementation of these new knockdown factors can enable significant reductions in mass and mass-growth in these vehicles and can help mitigate some of NASA s LV development and performance risks. In particular, it is expected that the results from this project will help reduce the reliance on testing, provide high-fidelity estimates of structural performance, reliability, robustness, and enable increased payload capability. The SBKF project objectives and approach used to develop and validate new design technologies are presented, and provide a glimpse into the future of design of the next generation of buckling-critical launch vehicle structures.

  11. Link community detection using generative model and nonnegative matrix factorization.

    PubMed

    He, Dongxiao; Jin, Di; Baquero, Carlos; Liu, Dayou

    2014-01-01

    Discovery of communities in complex networks is a fundamental data analysis problem with applications in various domains. While most of the existing approaches have focused on discovering communities of nodes, recent studies have shown the advantages and uses of link community discovery in networks. Generative models provide a promising class of techniques for the identification of modular structures in networks, but most generative models mainly focus on the detection of node communities rather than link communities. In this work, we propose a generative model, which is based on the importance of each node when forming links in each community, to describe the structure of link communities. We proceed to fit the model parameters by taking it as an optimization problem, and solve it using nonnegative matrix factorization. Thereafter, in order to automatically determine the number of communities, we extend the above method by introducing a strategy of iterative bipartition. This extended method not only finds the number of communities all by itself, but also obtains high efficiency, and thus it is more suitable to deal with large and unexplored real networks. We test this approach on both synthetic benchmarks and real-world networks including an application on a large biological network, and compare it with two highly related methods. Results demonstrate the superior performance of our approach over competing methods for the detection of link communities.

  12. Link Community Detection Using Generative Model and Nonnegative Matrix Factorization

    PubMed Central

    He, Dongxiao; Jin, Di; Baquero, Carlos; Liu, Dayou

    2014-01-01

    Discovery of communities in complex networks is a fundamental data analysis problem with applications in various domains. While most of the existing approaches have focused on discovering communities of nodes, recent studies have shown the advantages and uses of link community discovery in networks. Generative models provide a promising class of techniques for the identification of modular structures in networks, but most generative models mainly focus on the detection of node communities rather than link communities. In this work, we propose a generative model, which is based on the importance of each node when forming links in each community, to describe the structure of link communities. We proceed to fit the model parameters by taking it as an optimization problem, and solve it using nonnegative matrix factorization. Thereafter, in order to automatically determine the number of communities, we extend the above method by introducing a strategy of iterative bipartition. This extended method not only finds the number of communities all by itself, but also obtains high efficiency, and thus it is more suitable to deal with large and unexplored real networks. We test this approach on both synthetic benchmarks and real-world networks including an application on a large biological network, and compare it with two highly related methods. Results demonstrate the superior performance of our approach over competing methods for the detection of link communities. PMID:24489803

  13. Negative pressure wound therapy in grade IIIB tibial fractures: fewer infections and fewer flap procedures?

    PubMed

    Schlatterer, Daniel R; Hirschfeld, Adam G; Webb, Lawrence X

    2015-05-01

    Grade IIIB open tibia fractures are devastating injuries. Some clinicians advocate wound closure or stable muscle flap coverage within 72 hours to limit complications such as infection. Negative pressure wound therapy was approved by the FDA in 1997 and has become an adjunct for many surgeons in treating these fractures. Opinions vary regarding the extent to which negative pressure wound therapy contributes to limb salvage. Evidence-based practice guidelines are limited for use of negative pressure wound therapy in Grade IIIB tibia fractures. This systematic literature review of negative pressure wound therapy in Grade IIIB tibia fractures may substantiate current use and guide future studies. We sought to answer the following: (1) Does the use of negative pressure would therapy compared with gauze dressings lead to fewer infections? (2) Does it allow flap procedures to be performed safely beyond 72 hours without increased infection rates? (3) Is it associated with fewer local or free flap procedures? We conducted a systematic review of six large databases (through September 1, 2013) for studies reporting use of negative pressure wound therapy in Grade IIIB open tibia fractures, including information regarding infection rates and soft tissue reconstruction. The systematic review identified one randomized controlled trial and 12 retrospective studies: four studies compared infection rates between negative pressure wound therapy and gauze dressings, 10 addressed infection rates with extended use, and six reported on flap coverage rates in relation to negative pressure wound therapy use beyond 72 hours. None of the 13 studies was eliminated owing to lack of study quality. Negative pressure wound therapy showed a decrease in infection rates over rates for gauze dressings in two of four studies (5.4% [two of 35] versus 28% [seven of 25], and 8.4% [14 of 166] versus 20.6% [13 of 63]), an equivalent infection rate in one study (15% [eight of 53] versus 14% [five of 16

  14. Zenith Cook limb type IIIB endoleak causing aneurysm rupture five years after EVAR.

    PubMed

    Mezes, Peter; Sallam, Morad; Diamantopoulos, Athanasios; Taylor, Peter; Ahmed, Irfan

    2015-06-01

    Type III endoleaks are rare late complications of endovascular abdominal aortic aneurysm repair. The aneurysm sac is pressurised either through disconnection of modular components (type IIIA) or a defect in the graft fabric (type IIIB). We report the endovascular treatment of a ruptured infrarenal aortic aneurysm five years after elective endovascular abdominal aortic aneurysm repair caused by a type IIIB endoleak secondary to probable graft material erosion of the contralateral limb. This is the first report of a late aneurysm rupture caused by fabric defect in a Cook Zenith limb. The case highlights the potential serious consequences of minimal migration of the device and the importance of landing the proximal fixation in healthy aorta. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  15. Implant Materials Generate Different Peri-implant Inflammatory Factors

    PubMed Central

    Olivares-Navarrete, Rene; Hyzy, Sharon L.; Slosar, Paul J.; Schneider, Jennifer M.; Schwartz, Zvi

    2015-01-01

    Study Design. An in vitro study examining factors produced by human mesenchymal stem cells on spine implant materials. Objective. The aim of this study was to examine whether the inflammatory microenvironment generated by cells on titanium-aluminum-vanadium (Ti-alloy, TiAlV) surfaces is affected by surface microtexture and whether it differs from that generated on poly-ether-ether-ketone (PEEK). Summary of Background Data. Histologically, implants fabricated from PEEK have a fibrous connective tissue surface interface whereas Ti-alloy implants demonstrate close approximation with surrounding bone. Ti-alloy surfaces with complex micron/submicron scale roughness promote osteoblastic differentiation and foster a specific cellular environment that favors bone formation whereas PEEK favors fibrous tissue formation. Methods. Human mesenchymal stem cells were cultured on tissue culture polystyrene, PEEK, smooth TiAlV, or macro-/micro-/nano-textured rough TiAlV (mmnTiAlV) disks. Osteoblastic differentiation and secreted inflammatory interleukins were assessed after 7 days. Fold changes in mRNAs for inflammation, necrosis, DNA damage, or apoptosis with respect to tissue culture polystyrene were measured by low-density polymerase chain reaction array. Data were analyzed by analysis of variance, followed by Bonferroni's correction of Student's t-test. Results. Cells on PEEK upregulated mRNAs for chemokine ligand-2, interleukin (IL) 1β, IL6, IL8, and tumor necrosis factor. Cells grown on the mmnTiAlV had an 8-fold reduction in mRNAs for toll-like receptor-4. Cells grown on mmnTiAlV had reduced levels of proinflammatory interleukins. Cells on PEEK had higher mRNAs for factors strongly associated with cell death/apoptosis, whereas cells on mmnTiAlV exhibited reduced cytokine factor levels. All results were significant (P < 0.05). Conclusion. These results suggest that fibrous tissue around PEEK implants may be due to several factors: reduced osteoblastic differentiation of

  16. The Next Generation of Transcription Factor Binding Site Prediction

    PubMed Central

    Mathelier, Anthony; Wasserman, Wyeth W.

    2013-01-01

    Finding where transcription factors (TFs) bind to the DNA is of key importance to decipher gene regulation at a transcriptional level. Classically, computational prediction of TF binding sites (TFBSs) is based on basic position weight matrices (PWMs) which quantitatively score binding motifs based on the observed nucleotide patterns in a set of TFBSs for the corresponding TF. Such models make the strong assumption that each nucleotide participates independently in the corresponding DNA-protein interaction and do not account for flexible length motifs. We introduce transcription factor flexible models (TFFMs) to represent TF binding properties. Based on hidden Markov models, TFFMs are flexible, and can model both position interdependence within TFBSs and variable length motifs within a single dedicated framework. The availability of thousands of experimentally validated DNA-TF interaction sequences from ChIP-seq allows for the generation of models that perform as well as PWMs for stereotypical TFs and can improve performance for TFs with flexible binding characteristics. We present a new graphical representation of the motifs that convey properties of position interdependence. TFFMs have been assessed on ChIP-seq data sets coming from the ENCODE project, revealing that they can perform better than both PWMs and the dinucleotide weight matrix extension in discriminating ChIP-seq from background sequences. Under the assumption that ChIP-seq signal values are correlated with the affinity of the TF-DNA binding, we find that TFFM scores correlate with ChIP-seq peak signals. Moreover, using available TF-DNA affinity measurements for the Max TF, we demonstrate that TFFMs constructed from ChIP-seq data correlate with published experimentally measured DNA-binding affinities. Finally, TFFMs allow for the straightforward computation of an integrated TF occupancy score across a sequence. These results demonstrate the capacity of TFFMs to accurately model DNA

  17. Generation of monoclonal antibody targeting fibroblast growth factor receptor 3.

    PubMed

    Gorbenko, Olena; Ovcharenko, Galyna; Klymenko, Tetyana; Zhyvoloup, Olexandr; Gaman, Nadia; Volkova, Darija; Gout, Ivan; Filonenko, Valeriy

    2009-08-01

    Fibroblast growth factor receptor 3 (FGFR3) is a member of the FGFR family of receptor tyrosine kinases, whose function has been implicated in diverse biological processes, including cell proliferation, differentiation, survival, and tumorigenesis. Deregulation of FGFR3 signaling has been implicated with human pathologies, including cancer. Activating mutations in FGFR3 gene are frequently detected in bladder cancer, multiple myeloma, and noninvasive papillary urothelial cell carcinomas, while the overexpression of the receptor is observed in thyroid lymphoma and bladder cancer. The main aim of this study was to generate hybridoma clones producing antibody that could specifically recognize FGFR3/S249C mutant, but not the wild-type FGFR. To achieve this, we used for immunization bacterially expressed fragment of FGFR3 corresponding to loops II-III of the extracellular domain (GST-His/FGFR3/S249C-LII-III), which possesses oncogenic mutation at Ser249 detected in at least 50% of bladder cancers. Primary ELISA screening allowed us to isolate several hybridoma clones that showed specificity towards FGFR3/S249C, but not FGFR3wt protein. Unfortunately, these clones were not stable during single-cell cloning and expansion and lost the ability to recognize specifically FGFR3/S249C. However, this study allowed us to generate several monoclonal antibodies specific towards both FGFR3wt and FGFR3/S249C recombinant proteins. Produced hybridomas secreted MAbs that were specific in Western blotting towards bacterially expressed FGFR3wt and FGFR3/S249C, as well as the full-length receptors ectopically expressed in Sf21 and HEK293 cells. Moreover, transiently expressed wild-type and oncogenic forms of FGFR were efficiently immunoprecipitated with selected antibodies from the lysates of infected Sf21 and transiently transfected HEK293. In summary, generated antibodies should be useful as tools for examining the expression pattern and biological functions of FGFR3 in normal and

  18. Mucopolysaccharidosis IIIB confers enhanced neonatal intracranial transduction by AAV8 but not by 5, 9 or rh10

    PubMed Central

    Gilkes, J A; Bloom, M D; Heldermon, C D

    2016-01-01

    Sanfilippo syndrome type B (mucopolysaccharidosis IIIB, MPS IIIB) is a lysosomal storage disease resulting from deficiency of N-acetyl-glucosaminidase (NAGLU) activity. To determine the possible therapeutic utility of recombinant adeno-associated virus (rAAV) in early gene therapy-based interventions, we performed a comprehensive assessment of transduction and biodistribution profiles of four central nervous system (CNS) administered rAAV serotypes, -5, -8, -9 and -rh10. To simulate optimal earliest treatment of the disease, each rAAV serotype was injected into the CNS of neonatal MPS IIIB and control animals. We observed marked differences in biodistribution and transduction profiles between the serotypes and this differed in MPS IIIB compared with healthy control mice. Overall, in control mice, all serotypes performed comparably, although some differences were observed in certain focal areas. In MPS IIIB mice, AAV8 was more efficient than AAV5, -9 and -rh10 for gene delivery to most structures analyzed, including the cerebral cortex, hippocampus and thalamus. Noteworthy, the pattern of biodistribution within the CNS varied by serotype and genotype. Interestingly, AAV8 also produced the highest green fluorescent protein intensity levels compared with any other serotype and demonstrated improved transduction in NAGLU compared with control brains. Importantly, we also show leakage of AAV8, -9 and -rh10, but not AAV5, from CNS parenchyma to systemic organs. Overall, our data suggest that AAV8 represents the best therapeutic gene transfer vector for early intervention in MPS IIIB. PMID:26674264

  19. High duty factor plasma generator for CERN's Superconducting Proton Linac.

    PubMed

    Lettry, J; Kronberger, M; Scrivens, R; Chaudet, E; Faircloth, D; Favre, G; Geisser, J-M; Küchler, D; Mathot, S; Midttun, O; Paoluzzi, M; Schmitzer, C; Steyaert, D

    2010-02-01

    CERN's Linac4 is a 160 MeV linear accelerator currently under construction. It will inject negatively charged hydrogen ions into CERN's PS-Booster. Its ion source is a noncesiated rf driven H(-) volume source directly inspired from the one of DESY and is aimed to deliver pulses of 80 mA of H(-) during 0.4 ms at a 2 Hz repetition rate. The Superconducting Proton Linac (SPL) project is part of the luminosity upgrade of the Large Hadron Collider. It consists of an extension of Linac4 up to 5 GeV and is foreseen to deliver protons to a future 50 GeV synchrotron (PS2). For the SPL high power option (HP-SPL), the ion source would deliver pulses of 80 mA of H(-) during 1.2 ms and operate at a 50 Hz repetition rate. This significant upgrade motivates the design of the new water cooled plasma generator presented in this paper. Its engineering is based on the results of a finite element thermal study of the Linac4 H(-) plasma generator that identified critical components and thermal barriers. A cooling system is proposed which achieves the required heat dissipation and maintains the original functionality. Materials with higher thermal conductivity are selected and, wherever possible, thermal barriers resulting from low pressure contacts are removed by brazing metals on insulators. The AlN plasma chamber cooling circuit is inspired from the approach chosen for the cesiated high duty factor rf H(-) source operating at SNS.

  20. Generation and characterization of transgenic mice expressing cobra venom factor.

    PubMed

    Andrä, Jörg; Halter, Roman; Kock, Michael A; Niemann, Heiner; Vogel, Carl-Wilhelm; Paul, Dieter

    2002-10-01

    Cobra venom factor (CVF), the anticomplementary protein in cobra venom, activates the alternative complement pathway, eventually leading to complement consumption. Here, we describe the development of a transgenic mouse model for CVF. We generated a DNA construct containing the full-length cDNA for single-chain pre-pro-CVF. Expression of CVF was controlled by the alpha(1)-antitrypsin promoter to achieve liver-specific expression. Linearized DNA was microinjected into murine ovary cells (strain CD(2)F(1) (BALB/cxDBA/2J)) and the newborn mice were analyzed for stable integration of CVF DNA. After establishing the transgene, mice were propagated in a BALB/c background. The CVF mRNA was detected in the liver and, in some animals, in the kidney. CVF protein was detected in small amounts in the serum. Serum complement hemolytic activity in CVF-transgenic mice was virtually absent. The concentration of plasma C3 was significantly reduced. The CVF-transgenic animals show no unusual phenotype. They provide an animal model to study the effect of long-term complement depletion by continued activation, as well as the role of complement in host immune response and pathogenesis of disease.

  1. Hyperactive behaviour in the mouse model of mucopolysaccharidosis IIIB in the open field and home cage environments.

    PubMed

    Langford-Smith, A; Malinowska, M; Langford-Smith, K J; Wegrzyn, G; Jones, S; Wynn, R; Wraith, J E; Wilkinson, F L; Bigger, B W

    2011-08-01

    Mucopolysaccharidosis IIIB (MPS IIIB) is a lysosomal storage disorder characterized by severe behavioural disturbances and progressive loss of cognitive and motor function. There is no effective treatment, but behavioural testing is a valuable tool to assess neurodegeneration and the effect of novel therapies in mouse models of disease. Several groups have evaluated behaviour in this model, but the data are inconsistent, often conflicting with patient natural history. We hypothesize that this discrepancy could be due to differences in open field habituation and home cage behaviour. Eight-month-old wild-type and MPS IIIB mice were tested in a 1-h open field test, performed 1.5 h after lights on, and a 24-h home cage behaviour test performed after 24 h of acclimatization. In the 1-h test, MPS IIIB mice were hyperactive, with increased rapid exploratory behaviour and reduced immobility time. No differences in anxiety were seen. Over the course of the test, differences became more pronounced with maximal effects at 1 h. The 24-hour home cage test was less reliable. There was evidence of increased hyperactivity in MPS IIIB mice, however, immobility was also increased, suggesting a level of inconsistency in this test. Performance of open field analysis within 1-2 h after lights on is probably critical to achieving maximal success as MPS IIIB mice have a peak in activity around this time. The open field test effectively identifies hyperactive behaviour in MPS IIIB mice and is a significant tool for evaluating effects of therapy on neurodegeneration. © 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

  2. Cue Set Stimulation as a Factor in Human Response Generation.

    ERIC Educational Resources Information Center

    Petelle, John L.

    The hypotheses that there will be a significant difference (1) in the number of responses generated according to economic issues, (2) in the number of responses generated according to social issues, (3) in the number of responses generated between the category of economic issues and the category of social issues, (4) in cue ranking by response…

  3. Type IIIb Endoleak and Relining: A Mathematical Model of Distraction Forces.

    PubMed

    Swaelens, Charles; Poole, Robert J; Torella, Francesco; McWilliams, Richard G; England, Andrew; Fisher, Robert K

    2016-04-01

    To examine the changes in distraction force following relining of a conventional abdominal aortic stent-graft with a type IIIb endoleak using the Nellix endovascular sealing device compared to a unilateral stent-graft. Relining is often used to repair type IIIb endoleaks, but the consequences to graft stability are unknown. A mathematical model was constructed based on pressure and volume flow through the stent-grafts, incorporating recognized distraction force equations. Steady flow was presumed at peak systolic pressures to calculate the maximum distraction force, with gravity ignored. Distraction forces for 28- to 36-mm-diameter stent-graft bodies with 16-mm limbs were calculated and compared to forces following relining with single and double Nellix devices or the Renu unilateral device. Distraction forces for the 28-, 32-, and 36-mm stent-grafts prior to relining were 5.99, 10.21, and 14.99 N, respectively. Similar forces were reported after relining with bilateral Nellix devices (5.86, 10.08, and 14.86 N, respectively). However, use of a unilateral Nellix increased the distraction forces to 9.92, 14.14, and 18.92 N, respectively. These were comparable to the increase observed after relining with a Renu unilateral stent-graft (9.87, 14.09, and 18.86 N, respectively). The proportional increase in distraction force for a unilateral relining ranged from 26% to 66%, with the greatest increase noted in the smaller diameter main bodies. Relining a stent-graft with a type IIIb endoleak using bilateral Nellix devices does not increase the distraction force. However, a unilateral Nellix device or the Renu system could theoretically increase the distraction force by up to 66%, potentially risking migration and type Ia endoleak. In clinical practice, these results suggest that a relining with bilateral Nellix may have benefits over the Renu unilateral stent-graft. © The Author(s) 2016.

  4. The Murine Model of Mucopolysaccharidosis IIIB Develops Cardiopathies over Time Leading to Heart Failure

    PubMed Central

    De Pasquale, Valeria; Cocchiaro, Pasquale; Paciello, Orlando; Avallone, Luigi; Belfiore, Maria Paola; Iacobellis, Francesca; Di Napoli, Daniele; Magliulo, Fabio; Perrino, Cinzia; Trimarco, Bruno; Esposito, Giovanni; Di Natale, Paola; Pavone, Luigi Michele

    2015-01-01

    Mucopolysaccharidosis (MPS) IIIB is a lysosomal disease due to the deficiency of the enzyme α-N-acetylglucosaminidase (NAGLU) required for heparan sulfate (HS) degradation. The disease is characterized by mild somatic features and severe neurological disorders. Very little is known on the cardiac dysfunctions in MPS IIIB. In this study, we used the murine model of MPS IIIB (NAGLU knockout mice, NAGLU-/-) in order to investigate the cardiac involvement in the disease. Echocardiographic analysis showed a marked increase in left ventricular (LV) mass, reduced cardiac function and valvular defects in NAGLU-/- mice as compared to wild-type (WT) littermates. The NAGLU-/- mice exhibited a significant increase in aortic and mitral annulus dimension with a progressive elongation and thickening of anterior mitral valve leaflet. A severe mitral regurgitation with reduction in mitral inflow E-wave-to-A-wave ratio was observed in 32-week-old NAGLU-/- mice. Compared to WT mice, NAGLU-/- mice exhibited a significantly lower survival with increased mortality observed in particular after 25 weeks of age. Histopathological analysis revealed a significant increase of myocardial fiber vacuolization, accumulation of HS in the myocardial vacuoles, recruitment of inflammatory cells and collagen deposition within the myocardium, and an increase of LV fibrosis in NAGLU-/- mice compared to WT mice. Biochemical analysis of heart samples from affected mice showed increased expression levels of cardiac failure hallmarks such as calcium/calmodulin-dependent protein kinase II, connexin43, α-smooth muscle actin, α-actinin, atrial and brain natriuretic peptides, and myosin heavy polypeptide 7. Furthermore, heart samples from NAGLU-/- mice showed enhanced expression of the lysosome-associated membrane protein-2 (LAMP2), and the autophagic markers Beclin1 and LC3 isoform II (LC3-II). Overall, our findings demonstrate that NAGLU-/- mice develop heart disease, valvular abnormalities and cardiac

  5. Novel pathologic findings associated with urinary retention in a mouse model of mucopolysaccharidosis type IIIB.

    PubMed

    Gografe, Sylvia I; Sanberg, Paul R; Chamizo, Wilfredo; Monforte, Hector; Garbuzova-Davis, Svitlana

    2009-04-01

    Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome type B) is a metabolic disorder with devastating clinical characteristics starting in early childhood and leading to premature death. A knockout mouse strain was developed that models this disease. Mice of the strain B6.129S6- Naglu(tm1Efn)/J are invaluable for investigating pathogenesis and possible treatment modalities. However, the mouse strain also exhibits some objectionable phenotypic features. One such feature, urinary retention, not only is atypical of human MPS IIIB but often leads to early termination of experiments due to animal welfare concerns. The aim of this study was to investigate abnormalities associated with the urinary retention. Necropsies were performed on 9-mo-old mice; urinalysis, hematology and blood chemistry parameters were evaluated, and urogenital specimens were microscopically examined. Histopathologic examinations of urinary tract specimens proved illuminating regarding pathology in the urinary tract. A large mononuclear cell infiltrate was discovered in mutant mice of both sexes, more pronounced in females compared with male mice. The infiltrate comprises of large rounded or polygonal cells with generous variably vacuolated, granular eosinophilic cytoplasm and small round vesicular nuclei. These cells were present throughout and expand the interstitium of the lower urinary tract. Either this results in extrinsic compression of the lumen of the urethra, eventually leading to obstructive uropathy, bladder hyperdistension, and urinary retention or possibly interferes with the neurogenic component of micturition needs to be further investigated. The novel finding of an unexpected mononuclear cell infiltrate in the urinary tract in the knockout mice B6.129S6- Naglu(tm1Efn)/J is reported.

  6. Novel Pathologic Findings Associated with Urinary Retention in a Mouse Model of Mucopolysaccharidosis Type IIIB

    PubMed Central

    Gografe, Sylvia I; Sanberg, Paul R; Chamizo, Wilfredo; Monforte, Hector; Garbuzova-Davis, Svitlana

    2009-01-01

    Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome type B) is a metabolic disorder with devastating clinical characteristics starting in early childhood and leading to premature death. A knockout mouse strain was developed that models this disease. Mice of the strain B6.129S6- Naglutm1Efn/J are invaluable for investigating pathogenesis and possible treatment modalities. However, the mouse strain also exhibits some objectionable phenotypic features. One such feature, urinary retention, not only is atypical of human MPS IIIB but often leads to early termination of experiments due to animal welfare concerns. The aim of this study was to investigate abnormalities associated with the urinary retention. Necropsies were performed on 9-mo-old mice; urinalysis, hematology and blood chemistry parameters were evaluated, and urogenital specimens were microscopically examined. Histopathologic examinations of urinary tract specimens proved illuminating regarding pathology in the urinary tract. A large mononuclear cell infiltrate was discovered in mutant mice of both sexes, more pronounced in females compared with male mice. The infiltrate comprises of large rounded or polygonal cells with generous variably vacuolated, granular eosinophilic cytoplasm and small round vesicular nuclei. These cells were present throughout and expand the interstitium of the lower urinary tract. Either this results in extrinsic compression of the lumen of the urethra, eventually leading to obstructive uropathy, bladder hyperdistension, and urinary retention or possibly interferes with the neurogenic component of micturition needs to be further investigated. The novel finding of an unexpected mononuclear cell infiltrate in the urinary tract in the knockout mice B6.129S6- Naglutm1Efn/J is reported. PMID:19389305

  7. Inhibition of fibroblast growth factor receptor 2 attenuates proliferation and invasion of pancreatic cancer

    PubMed Central

    Matsuda, Yoko; Yoshimura, Hisashi; Suzuki, Taeko; Uchida, Eiji; Naito, Zenya; Ishiwata, Toshiyuki

    2014-01-01

    The alternative splicing of the extracellular domain of fibroblast growth factor receptor (FGFR)-2 generates the IIIb and IIIc isoforms. Expression of FGFR-2 IIIb correlates with vascular endothelial growth factor-A (VEGF-A) expression and venous invasion of pancreatic ductal adenocarcinoma (PDAC). By contrast, FGFR-2 IIIc expression correlates with faster development of liver metastasis after surgery, and increased proliferation rates and invasion of the cancer. In this study, we analyzed the expression and roles of total FGFR-2 (both isoforms) to determine the effectiveness of FGFR-2-targeting therapy for PDAC. Immunohistochemically, FGFR-2 was highly expressed in 25/48 (52.1%) PDAC cases, and correlated with advanced stage cancer. In FISH analysis, FGFR2 was amplified in 3/7 PDAC cell lines. We stably transfected an FGFR-2 shRNA targeting the IIIb and IIIc isoforms into FGFR2-amplified PDAC cells. The proliferation rates, migration, and invasion of FGFR-2-shRNA-transfected cells were lower than those of control cells in vitro. In response to FGF-2, FGFR-2-shRNA-transfected cells showed decreased phosphorylation of ERK compared with control cells. The FGFR-2-shRNA-transfected cells also expressed lower levels of vascular endothelial growth factor-A than control cells, and formed smaller s.c. tumors in nude mice. These findings suggest that FGFR-2 is a therapeutic target for inhibition in PDAC. PMID:24975163

  8. Epilepsy and electrophysiological findings in polish twins with glycogenosis type IIIb.

    PubMed

    Kroczka, Sławomir; Biedroń, Agnieszka; Kaciński, Marek

    2014-07-01

    Glycogen storage diseases are rare genetic disorders, mostly autosomal recessively inherited. Abnormal accumulation is because of the lack of one of the enzymes involved in glycogen metabolism. Neurological manifestation of the diseases involves muscle weakness and hypoglycemia-induced seizures. In this article, we present a history of twin sisters with unusual coincidence of glycogenosis type IIIb and epilepsy. Hypoglycemic background of seizures and organic changes of the central nervous system were excluded. Since the introduction of antiepileptic treatment, the patients have been seizure-free; however, paroxysmal electroencephalographic (EEG) changes have persisted. A high-protein and low-carbohydrate diet has protected them against hypoglycemia.

  9. Electrophysiological and Histological Characterization of Rod-Cone Retinal Degeneration and Microglia Activation in a Mouse Model of Mucopolysaccharidosis Type IIIB

    PubMed Central

    Tse, Dennis Y.; Lotfi, Parisa; Simons, David L.; Sardiello, Marco; Wu, Samuel M.

    2015-01-01

    Sanfilippo syndrome Type B or Mucopolysaccharidosis IIIB (MPS IIIB) is a neurodegenerative autosomal recessive lysosomal storage disorder in which patients suffer severe vision loss from associated retinopathy. Here we sought to study the underlying retinal functional and morphological changes associated with MPS IIIB disease progression using the established model of MPS IIIB, the B6.129S6-Naglu(tm1Efn)/J mouse line. Electroretinogram (ERG) was recorded from MPS IIIB and wild-type (WT) mice at the age of 28 and 46 weeks, and retinal tissues were subsequently collected for immunohistochemistry analysis. At the 28th week, rod a- and b-wave amplitudes were significantly diminished in MPS IIIB compared to WT mice. The cone a- and b-waves of MPS IIIB mice were not significantly different from those of the control at the 28th week but were significantly diminished at the 46th week, when MPS IIIB mice showed a major loss of rods and rod bipolar cells in both central and peripheral regions and a minor loss of cones in the periphery. Activation of microglia and neovascularization were also detected in the MPS IIIB retina. The new findings that cones and rod bipolar cells also undergo degeneration, and that retinal microglia are activated, will inform future development of therapeutic strategies. PMID:26607664

  10. Factors determining waste generation in Spanish towns and cities.

    PubMed

    Prades, Miriam; Gallardo, Antonio; Ibàñez, Maria Victoria

    2015-01-01

    This paper analyzes the generation and composition of municipal solid waste in Spanish towns and cities with more than 5000 inhabitants, which altogether account for 87% of the Spanish population. To do so, the total composition and generation of municipal solid waste fractions were obtained from 135 towns and cities. Homogeneity tests revealed heterogeneity in the proportions of municipal solid waste fractions from one city to another. Statistical analyses identified significant differences in the generation of glass in cities of different sizes and in the generation of all fractions depending on the hydrographic area. Finally, linear regression models and residuals analysis were applied to analyze the effect of different demographic, geographic, and socioeconomic variables on the generation of waste fractions. The conclusions show that more densely populated towns, a hydrographic area, and cities with over 50,000 inhabitants have higher waste generation rates, while certain socioeconomic variables (people/car) decrease that generation. Other socioeconomic variables (foreigners and unemployment) show a positive and null influence on that waste generation, respectively.

  11. A type III-B CRISPR-Cas effector complex mediating massive target DNA destruction

    PubMed Central

    Han, Wenyuan; Li, Yingjun; Deng, Ling; Feng, Mingxia; Peng, Wenfang; Hallstrøm, Søren; Zhang, Jing; Peng, Nan; Liang, Yun Xiang; White, Malcolm F.

    2017-01-01

    Abstract The CRISPR (clustered regularly interspaced short palindromic repeats) system protects archaea and bacteria by eliminating nucleic acid invaders in a crRNA-guided manner. The Sulfolobus islandicus type III-B Cmr–α system targets invading nucleic acid at both RNA and DNA levels and DNA targeting relies on the directional transcription of the protospacer in vivo. To gain further insight into the involved mechanism, we purified a native effector complex of III-B Cmr–α from S. islandicus and characterized it in vitro. Cmr–α cleaved RNAs complementary to crRNA present in the complex and its ssDNA destruction activity was activated by target RNA. The ssDNA cleavage required mismatches between the 5΄-tag of crRNA and the 3΄-flanking region of target RNA. An invader plasmid assay showed that mutation either in the histidine-aspartate acid (HD) domain (a quadruple mutation) or in the GGDD motif of the Cmr–2α protein resulted in attenuation of the DNA interference in vivo. However, double mutation of the HD motif only abolished the DNase activity in vitro. Furthermore, the activated Cmr–α binary complex functioned as a highly active DNase to destroy a large excess DNA substrate, which could provide a powerful means to rapidly degrade replicating viral DNA. PMID:27986854

  12. Molecular characterization of MPS IIIA, MPS IIIB and MPS IIIC in Tunisian patients.

    PubMed

    Ouesleti, S; Brunel, V; Ben Turkia, H; Dranguet, H; Miled, A; Miladi, N; Ben Dridi, M F; Lavoinne, A; Saugier-Veber, P; Bekri, S

    2011-11-20

    Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) is a progressive disorder in which patients are characterized by severe central nervous system degeneration together with mild somatic disease. MPS III results from a deficiency in one of the four enzymes involved in the heparan sulfate degradation, with sulfamidase (SGSH), α-N-acetylglucosaminidase (NAGLU), acetyl-coenzyme A: α-glucosaminide N-acetyltransferase (HGSNAT), and N-acetylglucosamine-6-sulfatase (GNS) being deficient respectively in MPS IIIA, MPS IIIB, MPS IIIC and MPS IIID. Mutation screening using PCR reaction/sequencing analysis on genomic DNA fragments was performed in seven Tunisian index cases with MPS IIIA, three with MPS IIIB and two with MPS IIIC. QMPSF (Quantitative Multiplex PCR of Short fluorescent Fragments) analysis was developed for the detection of genomic deletions and duplications in the SGSH gene. These approaches allowed the identification of 11 mutations, 8 of them were novel including a mutation involving the start codon (p.Met1?), one small duplication (p.Leu11AlafsX22), one small deletion (p.Val361SerfsX52) and a large deletion of exon 1 to exon 5 in the SGSH gene, one missense mutation (p.Pro604Leu) and one nonsense mutation (p.Tyr558X) in the NAGLU gene and, finally, one missense mutation (p.Trp627Cys) and one nonsense mutation (p.Trp403X) in the HGSNAT gene. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. Lymphangiogenesis in cervical cancer evaluated by expression of the VEGF-C gene in clinical stage IB-IIIB

    PubMed Central

    Franc, Magdalena; Kachel-Flis, Agata; Michalski, Bogdan; Fila-Daniłow, Anna; Mazurek, Urszula; Michalska, Anna; Kuczerawy, Ilona; Skrzypulec-Plinta, Violetta

    2015-01-01

    Introduction The aim of the present study was to evaluate the profile of VEGF-C gene expression in particular stages of cervical cancer (IB-IIIB) and to estimate the correlation between VEGF-C mRNA quantity profile and clinical stage. Material and methods Material for molecular analysis consisted of cervical cancer tissue specimens collected from 38 women (10, 15, 13 cases were classified as IB, IIB and IIIB, respectively). The control group was composed of normal cervical tissues collected from 10 women who underwent hysterectomy for non-oncological reasons. The number of VEGF-C mRNA copies in particular groups was estimated by the reverse transcription quantitative polymerase chain reaction (RT-qPCR) method. Results In the control group the average number of mRNA copies was 134 ± 36 (median: 106), in a group with stage IB it was 16 077 ± 7090 (median: 580), for stage IIB – 35 019 ± 8945 (median: 40 870). The highest number of mRNA VEGF-C copies was derived in a group of patients with cervical cancer of stage IIIB. The average quantity was 56 155 ± 12 470, whereas median 55 981. A statistically significantly higher level of VEGF-C gene expression was disclosed in cervical cancer specimens with stage IIB and IIIB than in the control group. In stage IIIB, the VEGF-C gene expression was significantly higher than in specimens derived from individuals in stage IB. Conclusions In squamous cell carcinoma of the uterine cervix of stage IB-IIIB genes involved in lymphangiogenesis, especially VEGF-C, are expressed, which expression increases as the clinical stage of cervical cancer is higher. PMID:26327898

  14. Neutrophil biology and the next generation of myeloid growth factors.

    PubMed

    Dale, David C

    2009-01-01

    Neutrophils are the body's critical phagocytic cells for defense against bacterial and fungal infections; bone marrow must produce approximately 10 x 10(9) neutrophils/kg/d to maintain normal blood neutrophil counts. Production of neutrophils depends on myeloid growth factors, particularly granulocyte colony-stimulating factor (G-CSF). After the original phase of development, researchers modified these growth factors to increase their size and delay renal clearance, increase their biologic potency, and create unique molecules for business purposes. Pegylated G-CSF is a successful product of these efforts. Researchers have also tried to identify small molecules to serve as oral agents that mimic the parent molecules, but these programs have been less successful. In 2006, the European Medicines Agency established guidelines for the introduction of new biologic medicinal products claimed to be similar to reference products that had previously been granted marketing authorization in the European community, called bio-similars. Globally, new and copied versions of G-CSF and other myeloid growth factors are now appearing. Some properties of the myeloid growth factors are similar to other agents, offering opportunities for the development of alternative drugs and treatments. For example, recent research shows that hematopoietic progenitor cells can be mobilized with a chemokine receptor antagonist, chemotherapy, G-CSF, and granulocyte macrophage colony-stimulating factor. Advances in neutrophil biology coupled with better understanding and development of myeloid growth factors offer great promise for improving the care of patients with cancer and many other disorders.

  15. A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study).

    PubMed

    Yoshioka, H; Azuma, K; Yamamoto, N; Takahashi, T; Nishio, M; Katakami, N; Ahn, M J; Hirashima, T; Maemondo, M; Kim, S W; Kurosaki, M; Akinaga, S; Park, K; Tsai, C M; Tamura, T; Mitsudomi, T; Nakagawa, K

    2015-10-01

    A previous randomized phase II study demonstrated that the addition of a c-Met inhibitor tivantinib to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib might prolong progression-free survival (PFS) in patients with previously treated, nonsquamous nonsmall-cell lung cancer (NSCLC). On a subset analysis, the survival benefit was greater in patients with wild-type EGFR (WT-EGFR) than in those with activating EGFR mutations. Herein, this phase III study compared overall survival (OS) between Asian nonsquamous NSCLC patients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group). A total of 460 NSCLC patients were planned to be randomized to the tivantinib or placebo group. Primary end point was OS. Secondary end points were PFS, tumor response, and safety. Tissue was collected for biomarker analysis, including c-Met and HGF expression. Enrollment was stopped when 307 patients were randomized, following the Safety Review Committee's recommendation based on an imbalance in the interstitial lung disease (ILD) incidence between the groups. ILD developed in 14 patients (3 deaths) and 6 patients (0 deaths) in the tivantinib and the placebo groups, respectively. In the enrolled patients, median OS was 12.7 and 11.1 months in the tivantinib and the placebo groups, respectively [hazard ratio (HR) = 0.891, P = 0.427]. Median PFS was 2.9 and 2.0 months in the tivantinib and the placebo groups, respectively (HR = 0.719, P = 0.019). The commonly observed grade ≥ 3 adverse events in the tivantinib group were neutropenia (24.3%), leukopenia (18.4%), febrile neutropenia (13.8%), and anemia (13.2%). This study was prematurely terminated due to the increased ILD incidence in the tivantinib group. Although this study lacked statistical power because of the premature termination and did not demonstrate an improvement in OS, our results suggest that tivantinib plus erlotinib might improve PFS than

  16. FGFR2IIIb-MAPK Activity Is Required for Epithelial Cell Fate Decision in the Lower Müllerian Duct

    PubMed Central

    Terakawa, Jumpei; Rocchi, Altea; Serna, Vanida A.; Bottinger, Erwin P.; Graff, Jonathan M.

    2016-01-01

    Cell fate of lower Müllerian duct epithelium (MDE), to become uterine or vaginal epithelium, is determined by the absence or presence of ΔNp63 expression, respectively. Previously, we showed that SMAD4 and runt-related transcription factor 1 (RUNX1) were independently required for MDE to express ΔNp63. Here, we report that vaginal mesenchyme directs vaginal epithelial cell fate in MDE through paracrine activation of fibroblast growth factor (FGF) receptor-MAPK pathway. In the developing reproductive tract, FGF7 and FGF10 were enriched in vaginal mesenchyme, whereas FGF receptor 2IIIb was expressed in epithelia of both the uterus and vagina. When Fgfr2 was inactivated, vaginal MDE underwent uterine cell fate, and this differentiation defect was corrected by activation of MEK-ERK pathway. In vitro, FGF10 in combination with bone morphogenetic protein 4 and activin A (ActA) was sufficient to induce ΔNp63 in MDE, and ActA was essential for induction of RUNX1 through SMAD-independent pathways. Accordingly, inhibition of type 1 receptors for activin in neonatal mice induced uterine differentiation in vaginal epithelium by down-regulating RUNX1, whereas conditional deletion of Smad2 and Smad3 had no effect on vaginal epithelial differentiation. In conclusion, vaginal epithelial cell fate in MDE is induced by FGF7/10-MAPK, bone morphogenetic protein 4-SMAD, and ActA-RUNX1 pathway activities, and the disruption in any one of these pathways results in conversion from vaginal to uterine epithelial cell fate. PMID:27164167

  17. Advanced stage IIIB cancer of the cervix treatment by hyperthermia and radiation.

    PubMed

    Hornback, N B; Shupe, R E; Shidnia, H; Marshall, C U; Lauer, T

    1986-02-01

    Treatment records of patients with primary untreated Stage IIIB carcinoma of the cervix treated at Indiana University Department of Radiation Oncology from November 1964 through January 1979 were reviewed. During this period, 79 patients were treated; 46 received external therapy using cobalt-60, 15 received a 25-MV photon beam, and 18 received a 25-MV photon beam followed by 45 min of 434-MHz microwave hyperthermia producing central tumor core temperatures of 39.5 to 41.5 degrees C. All patients received similar doses of radiation using combination intracavitary radioactive isotopes and external therapy. Patients who received heat therapy in combination with radiation therapy did not have increased acute or chronic complications of normal tissues. Local tumor control was superior when regional heat therapy was given; however, long-term absolute survival rates were not affected as the survival rate at 5 years was not statistically different in any of the three treatment groups.

  18. RNA-activated DNA cleavage by the Type III-B CRISPR–Cas effector complex

    PubMed Central

    Estrella, Michael A.; Kuo, Fang-Ting; Bailey, Scott

    2016-01-01

    The CRISPR (clustered regularly interspaced short palindromic repeat) system is an RNA-guided immune system that protects prokaryotes from invading genetic elements. This system represents an inheritable and adaptable immune system that is mediated by multisubunit effector complexes. In the Type III-B system, the Cmr effector complex has been found to cleave ssRNA in vitro. However, in vivo, it has been implicated in transcription-dependent DNA targeting. We show here that the Cmr complex from Thermotoga maritima can cleave an ssRNA target that is complementary to the CRISPR RNA. We also show that binding of a complementary ssRNA target activates an ssDNA-specific nuclease activity in the histidine–aspartate (HD) domain of the Cmr2 subunit of the complex. These data suggest a mechanism for transcription-coupled DNA targeting by the Cmr complex and provide a unifying mechanism for all Type III systems. PMID:26848046

  19. Advanced stage IIIB cancer of the cervix treatment by hyperthermia and radiation

    SciTech Connect

    Hornback, N.B.; Shupe, R.E.; Shidnia, H.; Marshall, C.U.; Lauer, T.

    1986-02-01

    Treatment records of patients with primary untreated Stage IIIB carcinoma of the cervix treated at Indiana University Department of Radiation Oncology from November 1964 through January 1979 were reviewed. During this period, 79 patients were treated; 46 received external therapy using cobalt-60, 15 received a 25-MV photon beam, and 18 received a 25-MV photon beam followed by 45 min of 434-MHz microwave hyperthermia producing central tumor core temperatures of 39.5 to 41.5 degrees C. All patients received similar doses of radiation using combination intracavitary radioactive isotopes and external therapy. Patients who received heat therapy in combination with radiation therapy did not have increased acute or chronic complications of normal tissues. Local tumor control was superior when regional heat therapy was given; however, long-term absolute survival rates were not affected as the survival rate at 5 years was not statistically different in any of the three treatment groups.

  20. Exopolysaccharides produced by Burkholderia cenocepacia recA lineages IIIA and IIIB.

    PubMed

    Chiarini, Luigi; Cescutti, Paola; Drigo, Laura; Impallomeni, Giuseppe; Herasimenka, Yury; Bevivino, Annamaria; Dalmastri, Claudia; Tabacchioni, Silvia; Manno, Graziana; Zanetti, Flavio; Rizzo, Roberto

    2004-08-01

    Clinical and environmental strains of Burkholderia cenocepacia belonging to the recA lineages IIIA and IIIB were examined for exopolysaccharide (EPS) production. The exopolysaccharides structure was determined using mainly gas chromatography coupled to mass spectrometry and NMR spectroscopy. All the strains produced Cepacian, a highly branched polysaccharide constituted of a heptasaccharide repeating unit, composed of one rhamnose, one glucose, one glucuronic acid, one mannose and three galactose residues. This polymer is the most common exopolysaccharide produced by strains of the Burkholderia cepacia (Bcc) complex. One clinical strain produced also another polysaccharide constituted of three galactose units and one 3-deoxy-D-manno-2-octulosonic acid residues, a polymer that was previously isolated from two strains of B. cepacia genomovar I and B. cenocepacia IIIA.

  1. Coenzyme A Binding to the Aminoglycoside Acetyltransferase (3)-IIIb Increases Conformational Sampling of Antibiotic Binding Site

    SciTech Connect

    Hu, Xiaohu; Norris, Adrianne; Baudry, Jerome Y; Serpersu, Engin H

    2011-01-01

    NMR spectroscopy experiments and molecular dynamics simulations were performed to describe the dynamic properties of the aminoglycoside acetyltransferase (3)-IIIb (AAC) in its apo and coenzyme A (CoASH) bound forms. The {sup 15}N-{sup 1}H HSQC spectra indicate a partial structural change and coupling of the CoASH binding site with another region in the protein upon the CoASH titration into the apo enzyme. Molecular dynamics simulations indicate a significant structural and dynamic variation of the long loop in the antibiotic binding domain in the form of a relatively slow (250 ns), concerted opening motion in the CoASH enzyme complex and that binding of the CoASH increases the structural flexibility of the loop, leading to an interchange between several similar equally populated conformations.

  2. A Qualitative Study of Recovery from Type III-B and III-C Tibial Fractures

    PubMed Central

    Shauver, Melissa S.; Aravind, Maya S.; Chung, Kevin C.

    2011-01-01

    The literature has shown that long-term outcomes for both below-knee amputation and reconstruction following type III-B and III-C tibial fracture are poor. Yet, patients often report satisfaction with their treatment and/or outcomes. The aim of this study is to explore the relationship between patient outcomes and satisfaction after open tibial fractures via qualitative methodology. Twenty patients who were treated for open tibial fractures at one institution were selected using purposeful sampling and interviewed in-person in a semi-structured manner. Data were analyzed using grounded theory methodology. Despite reporting marked physical and psychosocial deficits, participants relayed high satisfaction. We hypothesize that the use adaptive coping techniques successfully reduces stress, which leads to an increase in coping self-efficacy that results in the further use of adaptive coping strategies, culminating in personal growth. This stress reduction and personal growth leads to satisfaction despite poor functional and emotional outcomes. PMID:20948418

  3. Literature Review: Factors Affecting the Development of Generation X and Millennials. Societal Factors Affecting Education.

    ERIC Educational Resources Information Center

    Denham, Thomas J.; adbow, Nancy

    Generation X, or "Xers," refers to those born in the United States between 1960 and 1980 and Generation Y, also known as "Millennials," refers to those born between 1980 and 2000. An examination of these two generations is important to educators as the new generation of Millennials begins to access higher education. A large and…

  4. Radiation Therapy, Chemotherapy, and Soy Isoflavones in Treating Patients With Stage IIIA-IIIB Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2017-05-23

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Bronchoalveolar Cell Lung Cancer; Large Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  5. Chemoradiation Therapy and Ipilimumab in Treating Patients With Stages IB2-IIB or IIIB-IVA Cervical Cancer

    ClinicalTrials.gov

    2017-09-28

    Cervical Adenocarcinoma; Cervical Adenosquamous Carcinoma; Cervical Squamous Cell Carcinoma, Not Otherwise Specified; Positive Para-Aortic Lymph Node; Positive Pelvic Lymph Node; Stage IB2 Cervical Cancer; Stage II Cervical Cancer; Stage IIA Cervical Cancer; Stage IIB Cervical Cancer; Stage IIIB Cervical Cancer; Stage IVA Cervical Cancer

  6. Metabolome profiling to understand the defense response to sugar beet (Beta vulgaris) to Rhizoctonia solani AG 2-2 IIIB

    USDA-ARS?s Scientific Manuscript database

    Rhizoctonia crown and root rot, caused by Rhizoctonia solani Kühn AG 2-2 IIIB, is an important disease of sugar beet (Beta vulgaris L.). The molecular processes that mediate sugar beet resistance to R. solani are largely unknown and identifying the metabolites associated with R. solani infection ma...

  7. Nivolumab After Combined Modality Therapy in Treating Patients With High Risk Stage II-IIIB Anal Cancer

    ClinicalTrials.gov

    2017-09-04

    Anal Basaloid Carcinoma; Anal Canal Cloacogenic Carcinoma; Anal Margin Squamous Cell Carcinoma; Stage II Anal Canal Cancer AJCC v6 and v7; Stage III Anal Canal Cancer AJCC v6 and v7; Stage IIIA Anal Canal Cancer AJCC v6 and v7; Stage IIIB Anal Canal Cancer AJCC v6 and v7

  8. Exploring First Generation African American Graduate Students: Motivating Factors for Pursuing a Doctoral Degree

    ERIC Educational Resources Information Center

    Adams, Stephanie G.

    2011-01-01

    The purpose for conducting the study was to examine the factors that motivate African-American first-generation students to pursue doctoral education at a four-year public university. There has been little research on the influence academic or nonacademic factors have on first-generation graduate student motivation. Similarly, little research…

  9. Exploring First Generation African American Graduate Students: Motivating Factors for Pursuing a Doctoral Degree

    ERIC Educational Resources Information Center

    Adams, Stephanie G.

    2011-01-01

    The purpose for conducting the study was to examine the factors that motivate African-American first-generation students to pursue doctoral education at a four-year public university. There has been little research on the influence academic or nonacademic factors have on first-generation graduate student motivation. Similarly, little research…

  10. The prognostic impact of supraclavicular lymph node in N3-IIIB stage non-small cell lung cancer patients treated with definitive concurrent chemo-radiotherapy

    PubMed Central

    Oh, Dongryul; Ahn, Yong Chan; Park, Hee Chul; Lim, Do Hoon; Noh, Jae Myoung; Cho, Won Kyung; Pyo, Hongryull

    2017-01-01

    Background This study aimed to investigate the prognostic impact of supraclavicular lymph node (SCN) metastasis in patients who were treated with definitive chemoradiotherapy for N3-IIIB stage non-small cell lung cancer (NSCLC). Results The 2- and 5-year overall survival (OS) rates were 57.3% and 35.7% in patients without SCN metastasis and 56.4% and 26.7% in patients with SCN metastasis, respectively. The median OS was 34 months in both groups. There was no significant difference in OS between the two groups (p = 0.679). The 2- and 5-year progression-free survival (PFS) rates were 24.1% and 12.6% in patients without SCN metastasis and 18.0% and 16.0% in patients with SCN metastasis, respectively. Patients without SCN metastasis had slightly longer median PFS (10 months vs. 8 months), but the difference was not statistically significant (p = 0.223). In multivariate analysis, SCN metastasis was not a significant factor for OS (p = 0.391) and PFS (p = 0.149). Materials and Methods This retrospective analysis included 204 consecutive patients who were treated with chemoradiotherapy for N3-IIIB stage NSCLC between May 2003 and December 2012. A median RT dose of 66 Gy was administered over 6.5 weeks. Of these, 119 patients (58.3%) had SCN metastasis and 85 (41.7%) had another type of N3 disease: mediastinal N3 nodes in 84 patients (98.8%) and contralateral hilar node in one (1.2%). The patients were divided into two groups according to SCN metastasis. Conclusions SCN metastasis does not compromise treatment outcomes compared to other mediastinal metastasis in the setting of definitive chemoradiotherapy. PMID:28415687

  11. The prognostic impact of supraclavicular lymph node in N3-IIIB stage non-small cell lung cancer patients treated with definitive concurrent chemo-radiotherapy.

    PubMed

    Oh, Dongryul; Ahn, Yong Chan; Park, Hee Chul; Lim, Do Hoon; Noh, Jae Myoung; Cho, Won Kyung; Pyo, Hongryull

    2017-05-30

    This study aimed to investigate the prognostic impact of supraclavicular lymph node (SCN) metastasis in patients who were treated with definitive chemoradiotherapy for N3-IIIB stage non-small cell lung cancer (NSCLC). The 2- and 5-year overall survival (OS) rates were 57.3% and 35.7% in patients without SCN metastasis and 56.4% and 26.7% in patients with SCN metastasis, respectively. The median OS was 34 months in both groups. There was no significant difference in OS between the two groups (p = 0.679). The 2- and 5-year progression-free survival (PFS) rates were 24.1% and 12.6% in patients without SCN metastasis and 18.0% and 16.0% in patients with SCN metastasis, respectively. Patients without SCN metastasis had slightly longer median PFS (10 months vs. 8 months), but the difference was not statistically significant (p = 0.223). In multivariate analysis, SCN metastasis was not a significant factor for OS (p = 0.391) and PFS (p = 0.149). This retrospective analysis included 204 consecutive patients who were treated with chemoradiotherapy for N3-IIIB stage NSCLC between May 2003 and December 2012. A median RT dose of 66 Gy was administered over 6.5 weeks. Of these, 119 patients (58.3%) had SCN metastasis and 85 (41.7%) had another type of N3 disease: mediastinal N3 nodes in 84 patients (98.8%) and contralateral hilar node in one (1.2%). The patients were divided into two groups according to SCN metastasis. SCN metastasis does not compromise treatment outcomes compared to other mediastinal metastasis in the setting of definitive chemoradiotherapy.

  12. Factors associated with the satisfaction of millennial generation dental residents.

    PubMed

    Lam, Hwai-Tai C; O'Toole, Terry G; Arola, Patricia E; Kashner, T Michael; Chang, Barbara K

    2012-11-01

    Data from the 2010 Learners' Perceptions Survey (LPS) administered through the Office of Academic Affiliations, Department of Veterans Affairs (VA) were analyzed to identify factors associated with dental residents' satisfaction with the VA as a clinical training environment. Satisfaction scores were linked to clinic workloads, dental procedure complexity levels, staffing patterns, and facility infrastructure data to explore conditions that may improve residents' satisfaction. Findings supported the construct validity of the LPS survey data and underscored the importance of maintaining optimal ratios of attending dentists, dental assistants, and administrative staff to residents so that each trainee will have opportunities to perform an adequate level of dental workload. As programs strive to improve the quality of graduate dental education, findings from this study are vital for setting curriculum design guidelines and for providing infrastructure support for dental resident education.

  13. Historical and contemporary factors generate unique butterfly communities on islands

    PubMed Central

    Vodă, Raluca; Dapporto, Leonardo; Dincă, Vlad; Shreeve, Tim G.; Khaldi, Mourad; Barech, Ghania; Rebbas, Khellaf; Sammut, Paul; Scalercio, Stefano; Hebert, Paul D. N.; Vila, Roger

    2016-01-01

    The mechanisms shaping island biotas are not yet well understood mostly because of a lack of studies comparing eco-evolutionary fingerprints over entire taxonomic groups. Here, we linked community structure (richness, frequency and nestedness) and genetic differentiation (based on mitochondrial DNA) in order to compare insular butterfly communities occurring over a key intercontinental area in the Mediterranean (Italy-Sicily-Maghreb). We found that community characteristics and genetic structure were influenced by a combination of contemporary and historical factors, and among the latter, connection during the Pleistocene had an important impact. We showed that species can be divided into two groups with radically different properties: widespread taxa had high dispersal capacity, a nested pattern of occurrence, and displayed little genetic structure, while rare species were mainly characterized by low dispersal, high turnover and genetically differentiated populations. These results offer an unprecedented view of the distinctive butterfly communities and of the main processes determining them on each studied island and highlight the importance of assessing the phylogeographic value of populations for conservation. PMID:27353723

  14. Historical and contemporary factors generate unique butterfly communities on islands

    NASA Astrophysics Data System (ADS)

    Vodă, Raluca; Dapporto, Leonardo; Dincă, Vlad; Shreeve, Tim G.; Khaldi, Mourad; Barech, Ghania; Rebbas, Khellaf; Sammut, Paul; Scalercio, Stefano; Hebert, Paul D. N.; Vila, Roger

    2016-06-01

    The mechanisms shaping island biotas are not yet well understood mostly because of a lack of studies comparing eco-evolutionary fingerprints over entire taxonomic groups. Here, we linked community structure (richness, frequency and nestedness) and genetic differentiation (based on mitochondrial DNA) in order to compare insular butterfly communities occurring over a key intercontinental area in the Mediterranean (Italy-Sicily-Maghreb). We found that community characteristics and genetic structure were influenced by a combination of contemporary and historical factors, and among the latter, connection during the Pleistocene had an important impact. We showed that species can be divided into two groups with radically different properties: widespread taxa had high dispersal capacity, a nested pattern of occurrence, and displayed little genetic structure, while rare species were mainly characterized by low dispersal, high turnover and genetically differentiated populations. These results offer an unprecedented view of the distinctive butterfly communities and of the main processes determining them on each studied island and highlight the importance of assessing the phylogeographic value of populations for conservation.

  15. Factors that influence the generation of autobiographical memory conjunction errors.

    PubMed

    Devitt, Aleea L; Monk-Fromont, Edwin; Schacter, Daniel L; Addis, Donna Rose

    2016-01-01

    The constructive nature of memory is generally adaptive, allowing us to efficiently store, process and learn from life events, and simulate future scenarios to prepare ourselves for what may come. However, the cost of a flexibly constructive memory system is the occasional conjunction error, whereby the components of an event are authentic, but the combination of those components is false. Using a novel recombination paradigm, it was demonstrated that details from one autobiographical memory (AM) may be incorrectly incorporated into another, forming AM conjunction errors that elude typical reality monitoring checks. The factors that contribute to the creation of these conjunction errors were examined across two experiments. Conjunction errors were more likely to occur when the corresponding details were partially rather than fully recombined, likely due to increased plausibility and ease of simulation of partially recombined scenarios. Brief periods of imagination increased conjunction error rates, in line with the imagination inflation effect. Subjective ratings suggest that this inflation is due to similarity of phenomenological experience between conjunction and authentic memories, consistent with a source monitoring perspective. Moreover, objective scoring of memory content indicates that increased perceptual detail may be particularly important for the formation of AM conjunction errors.

  16. Factors that influence the generation of autobiographical memory conjunction errors

    PubMed Central

    Devitt, Aleea L.; Monk-Fromont, Edwin; Schacter, Daniel L.; Addis, Donna Rose

    2015-01-01

    The constructive nature of memory is generally adaptive, allowing us to efficiently store, process and learn from life events, and simulate future scenarios to prepare ourselves for what may come. However, the cost of a flexibly constructive memory system is the occasional conjunction error, whereby the components of an event are authentic, but the combination of those components is false. Using a novel recombination paradigm, it was demonstrated that details from one autobiographical memory may be incorrectly incorporated into another, forming autobiographical memory conjunction errors that elude typical reality monitoring checks. The factors that contribute to the creation of these conjunction errors were examined across two experiments. Conjunction errors were more likely to occur when the corresponding details were partially rather than fully recombined, likely due to increased plausibility and ease of simulation of partially recombined scenarios. Brief periods of imagination increased conjunction error rates, in line with the imagination inflation effect. Subjective ratings suggest that this inflation is due to similarity of phenomenological experience between conjunction and authentic memories, consistent with a source monitoring perspective. Moreover, objective scoring of memory content indicates that increased perceptual detail may be particularly important for the formation of autobiographical memory conjunction errors. PMID:25611492

  17. A Review of Operational Water Consumption and Withdrawal Factors for Electricity Generating Technologies

    SciTech Connect

    Macknick, Jordan; Newmark, Robin; Heath, Garvin; Hallett, K. C.

    2011-03-01

    This report provides estimates of operational water withdrawal and water consumption factors for electricity generating technologies in the United States. Estimates of water factors were collected from published primary literature and were not modified except for unit conversions. The presented water factors may be useful in modeling and policy analyses where reliable power plant level data are not available.

  18. Factors Influencing the First-Year Persistence of First Generation College Students.

    ERIC Educational Resources Information Center

    Duggan, Michael

    The factors that influence the first-year persistence of first generation college students at four-year institutions were studied using data from the Beginning Postsecondary Students (BPS) database. The BPS is a longitudinal study of first-time students in the 1995 National Postsecondary Student Aid Study. First generation students are those whose…

  19. Circadian rhythm and suprachiasmatic nucleus alterations in the mouse model of mucopolysaccharidosis IIIB.

    PubMed

    Canal, Maria M; Wilkinson, Fiona L; Cooper, Jonathan D; Wraith, J Ed; Wynn, Rob; Bigger, Brian W

    2010-06-19

    Mucopolysaccharidosis IIIB (MPSIIIB) is a lysosomal storage disease characterised by progressive central nervous system degeneration in patients, with death usually in the late teens. Serious behavioural problems have been reported in children at the early stages of the disease, such as hyperactivity and severe sleep disturbances, which suggest alterations in circadian rhythms. We investigated the circadian rhythm of locomotor activity of young and old MPSIIIB mice, under a 24-h light-dark (LD) cycle and under constant darkness (DD), and also examined neuropeptide expression in the suprachiasmatic nucleus (SCN), site of the principal biological pacemaker. We show that MPSIIIB mice have higher activity levels during the light (resting) phase of the LD cycle, together with weaker circadian rhythms, and a longer active phase due to a late peak of activity, in both LD and DD. In addition, young MPSIIIB mice showed shorter phase delays in response to a light pulse in DD. Increased lysosomal storage, neuroinflammation and changes in the expression of Arginine Vasopressin and Vasointestinal Polypeptide, two circadian neuropeptides, were observed in the SCN, which may be in part responsible for the changes in circadian behaviour observed in MPSIIIB mice. These findings suggest an alteration of the circadian system in MPSIIIB mice, and may inform better clinical management of circadian, sleep and behavioural disturbances in patients with MPSIII. Copyright 2010 Elsevier B.V. All rights reserved.

  20. RIP Input Tables From Wapdeg For La Design Selection: Enhanced Design Alternative Iiib

    SciTech Connect

    K.G. Mon; K.G. Mast; J.H. Lee

    1999-07-01

    The purpose of this calculation is to document the Waste Package Degradation (WAPDEG) version 3.09 (CRWMS M&O 1998b. 'Software Routine Report for WAPDEG' (Version 3.09)) simulations used to analyze degradation and failure of 2-cm thick titanium grade 7 corrosion resistant material (CRM) drip shields as well as degradation and failure of the waste packages over which they are placed. The waste packages are composed of two corrosion resistant materials (CRM) barriers. The outer barrier is composed of 2 cm of Alloy 22 and the inner barrier is composed of 1.5 cm of titanium grade 7. The WAPDEG simulation results are post-processed into tables of drip shield/waste package degradation time histories suitable for use as input into the Integrated Probabilistic Simulator for Environmental Systems (RIP) version 5.19.01 (Golder Associates 1998) computer code. This calculation supports Performance Assessment analysis of the License Application Design Selection (LADS) Enhanced Design Alternative IIIb.

  1. Effectiveness of composition based on oxidized dextran in the treatment of grade IIIB skin burns.

    PubMed

    Shkurupy, V A; Karpov, M A; Troitskii, A V; Arkhipov, S A; Neshchadim, D V

    2015-03-01

    Grade IIIB skin burns were treated with a composition based on oxidized dextran with a molecular weight of 40 kDa (oxidation of 7% glucose residues). On day 32 after burn infliction and from the start of the treatment, the area of skin defect in rats was 30% less than in the group without treatment and by 2.3 times less than in rats treated with panthenol. In rats treated with dextran-based composition or panthenol, the eschar was absent on day 21 after the start of the treatment; by day 32, we found cells of surface epithelium, hair follicles, and sebaceous glands above the scar tissue that were absent in untreated animals; in rats treated with the composition, their number was higher by 2.5 times than in animals treated with panthenol. Treatment with the composition increased volume density (by 2.5 times) and numerical density (by more than 3 times) of blood vessels in the wound and reduced signs of inflammation and fibroplastic activity of fibroblasts in comparison with the corresponding parameters in untreated animals or animals treated with panthenol.

  2. One-stage emergency treatment of open grade IIIB tibial shaft fractures with bone loss.

    PubMed

    Tropet, Y; Garbuio, P; Obert, L; Jeunet, L; Elias, B

    2001-02-01

    The purpose of this study was to report the authors' experience with emergency reconstruction of severe tibial shaft fractures. Five male patients were admitted to the emergency room with a grade IIIB open tibial shaft fracture with bone loss (average age, 33 years; age range, 18-65 years). Injuries were the result of motorcycle accidents (N = 2), pedestrian accidents (N = 1), gunshot wound (N = 1), and paragliding fall (N = 1). Primary emergent one-stage management for all patients consisted of administration of antibiotics, debridement, stabilization by locked intramedullary nailing, bone grafting from the iliac crest, and coverage using free muscle flaps (four latissimus dorsi and one gracilis). The average follow-up was 21 months (range, 8 months-3.5 years). Partial weight bearing with no immobilization was started at 3 months, and full weight bearing began 5 months after trauma. No angular complications and no nonunions were observed. There was one case of superficial infection without osteitis. All fractures healed within 6 months in 4 patients and within 10 months in 1 patient. At the last follow-up examination, ankle and knee motion was normal and no pain was noted, except for 1 patient who had associated lesions (ankle motion reduced by 50%). Aggressive emergency management of severe open tibial fractures provides good results. It improves end results markedly, not only by reducing tissue loss from infection, but also reducing healing and rehabilitation times.

  3. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer.

    PubMed

    Butts, Charles; Murray, Nevin; Maksymiuk, Andrew; Goss, Glenwood; Marshall, Ernie; Soulières, Denis; Cormier, Yvon; Ellis, Peter; Price, Allan; Sawhney, Ravinder; Davis, Mary; Mansi, Janine; Smith, Colum; Vergidis, Dimitrios; Ellis, Paul; MacNeil, Mary; Palmer, Martin

    2005-09-20

    To evaluate the effect of BLP25 liposome vaccine (L-BLP25) on survival and toxicity in patients with stage IIIB and IV non-small-cell lung cancer (NSCLC). Secondary objectives included health-related quality of life (QOL) and immune responses elicited by L-BLP25. Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 and stable or responding stage IIIB or IV NSCLC after any first-line chemotherapy were prestratified by stage and randomly assigned to either L-BLP25 plus best supportive care (BSC) or BSC alone. Patients in the L-BLP25 arm received a single intravenous dose of cyclophosphamide 300 mg/m2 followed by eight weekly subcutaneous immunizations with L-BLP25 (1,000 microg). Subsequent immunizations were administered at 6-week intervals. The survival results indicate a median survival time of 4.4 months longer for patients randomly assigned to the L-BLP25 arm (88 patients) compared with patients assigned to the BSC arm (83 patients; adjusted hazard ratio [HR] = 0.739; 95% CI, 0.509 to 1.073; P = .112). The greatest effect was observed in stage IIIB locoregional (LR) patients, for whom the median survival time for the L-BLP25 arm has not yet been reached compared with 13.3 months for the BSC arm (adjusted HR = 0.524; 95% CI, 0.261 to 1.052; P = .069). No significant toxicity was observed. QOL was maintained longer in patients on the L-BLP25 arm. L-BLP25 maintenance therapy in patients with advanced NSCLC is feasible with minimal toxicity. The survival difference of 4.4 months observed with the vaccine did not reach statistical significance. In the subgroup of patients with stage IIIB LR disease, a strong trend in 2-year survival in favor of L-BLP25 was observed.

  4. PET/CT surveillance detects asymptomatic recurrences in stage IIIB and IIIC melanoma patients: a prospective cohort study.

    PubMed

    Madu, Max F; Timmerman, Pieter; Wouters, Michel W J M; van der Hiel, Bernies; van der Hage, Jos A; van Akkooi, Alexander C J

    2017-02-20

    AJCC stage IIIB and IIIC melanoma patients are at risk for disease relapse or progression. The advent of effective systemic therapies has made curative treatment of progressive disease a possibility. As resection of oligometastatic disease can confer a survival benefit and as immunotherapy is possibly most effective in a low tumor load setting, there is a likely benefit to early detection of progression. The aim of this pilot study was to evaluate a PET/computed tomography (CT) surveillance schedule for resected stage IIIB and IIIC melanoma. From 1-2015, stage IIIB and IIIC melanoma patients at our institution underwent 6-monthly surveillance with PET/CT, together with 3-monthly S100B assessment. When symptoms or elevated S100B were detected, an additional PET/CT was performed. Descriptive statistics were used to evaluate outcomes for this surveillance schedule. Fifty-one patients were followed up, 27 patients developed a recurrence before surveillance imaging, five were detected by an elevated S100B, and one patient was not scanned according to protocol. Eighteen patients were included. Thirty-two scans were acquired. Eleven relapses were suspected on PET/CT. Ten scans were true positive, one case was false positive, and one case was false negative. All recurrences detected by PET/CT were asymptomatic at that time, with a normal range of S100B. The number of scans needed to find one asymptomatic relapse was 3.6. PET/CT surveillance imaging seems to be an effective strategy for detecting asymptomatic recurrence in stage IIIB and IIIC melanoma patients in the first year after complete surgical resection.

  5. Combination Chemotherapy and Peripheral Blood Stem Cell Transplant Followed By Aldesleukin and Sargramostim in Treating Patients With Inflammatory Stage IIIB or Metastatic Stage IV Breast Cancer

    ClinicalTrials.gov

    2017-06-16

    Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; Inflammatory Breast Cancer; Male Breast Cancer; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage IIIB Breast Cancer; Stage IV Breast Cancer

  6. Phospholipid-esterified eicosanoids are generated in agonist-activated human platelets and enhance tissue factor-dependent thrombin generation.

    PubMed

    Thomas, Christopher P; Morgan, Lloyd T; Maskrey, Benjamin H; Murphy, Robert C; Kühn, Hartmut; Hazen, Stanley L; Goodall, Alison H; Hamali, Hassan A; Collins, Peter W; O'Donnell, Valerie B

    2010-03-05

    Here, a group of specific lipids, comprising phosphatidylethanolamine (PE)- or phosphatidylcholine (PC)-esterified 12S-hydroxyeicosatetraenoic acid (12S-HETE), generated by 12-lipoxygenase was identified and characterized. 12S-HETE-PE/PCs were formed within 5 min of activation by thrombin, ionophore, or collagen. Esterified HETE levels generated in response to thrombin were 5.85 +/- 1.42 (PE) or 18.35 +/- 4.61 (PC), whereas free was 65.5 +/- 17.6 ng/4 x 10(7) cells (n = 5 separate donors, mean +/- S.E.). Their generation was stimulated by triggering protease-activated receptors-1 and -4 and signaling via Ca(2+) mobilization secretory phospholipase A2, platelet-activating factor-acetylhydrolase, src tyrosine kinases, and protein kinase C. Stable isotope labeling showed that they form predominantly by esterification that occurs on the same time scale as free acid generation. Unlike free 12S-HETE that is secreted, esterified HETEs remain cell-associated, with HETE-PEs migrating to the outside of the plasma membrane. 12-Lipoxygenase inhibition attenuated externalization of native PE and phosphatidylserine and HETE-PEs. Platelets from a patient with the bleeding disorder, Scott syndrome, did not externalize HETE-PEs, and liposomes supplemented with HETE-PC dose-dependently enhanced tissue factor-dependent thrombin generation in vitro. This suggests a role for these novel lipids in promoting coagulation. Thus, oxidized phospholipids form by receptor/agonist mechanisms, not merely as an undesirable consequence of vascular and inflammatory disease.

  7. Relationship between short activated partial thromboplastin times, thrombin generation, procoagulant factors and procoagulant phospholipid activity.

    PubMed

    Mina, Ashraf; Favaloro, Emmanuel J; Koutts, Jerry

    2012-04-01

    Short activated partial thromboplastin times (APTTs) are associated with thrombosis. However, what short APTTs actually represent in terms of possible mechanistic pathways is not well characterized. We have assessed thrombin generation as compared with levels of procoagulant factor (fibrinogen, V, VIII, IX, XI and XII) activities, von Willebrand factor level and activity using collagen binding, as well as procoagulant phospholipid activity, in 113 consecutive samples exhibiting a short APTT compared with an equal number of age-matched and sex-matched samples yielding a normal APTT. We found a significant difference in peak thrombin generation, velocity index and area under the curve between the two groups, and that thrombin generation markers correlated with the APTT, procoagulant phospholipid activity and several procoagulant clotting factors. We conclude that short APTTs represent a procoagulant milieu, as represented by heightened thrombin generation and several other heightened procoagulant activities, which may help explain the association with thrombosis.

  8. Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial.

    PubMed

    Tardieu, Marc; Zérah, Michel; Gougeon, Marie-Lise; Ausseil, Jérome; de Bournonville, Stéphanie; Husson, Béatrice; Zafeiriou, Dimitrios; Parenti, Giancarlo; Bourget, Philippe; Poirier, Béatrice; Furlan, Valérie; Artaud, Cécile; Baugnon, Thomas; Roujeau, Thomas; Crystal, Ronald G; Meyer, Christian; Deiva, Kumaran; Heard, Jean-Michel

    2017-09-01

    Mucopolysaccharidosis type IIIB syndrome (also known as Sanfilippo type B syndrome) is a lysosomal storage disease resulting in progressive deterioration of cognitive acquisition after age 2-4 years. No treatment is available for the neurological manifestations of the disease. We sought to assess the safety and efficacy of a novel intracerebral gene therapy. Local regulatory authorities in France allowed inclusion of up to four children in this phase 1/2 study. Treatment was 16 intraparenchymal deposits (four in the cerebellum) of a recombinant adenoassociated viral vector serotype 2/5 (rAAV2/5) encoding human α-N-acetylglucosaminidase (NAGLU) plus immunosuppressive therapy. We assessed tolerance, neurocognitive progression, brain growth, NAGLU enzymatic activity in CSF, and specific anti-NAGLU immune response for 30 months after surgery. This trial is registered with EudraCT, number 2012-000856-33, and the International Standard Clinical Trial Registry, number ISRCTN19853672. Of seven eligible children, the four youngest, from France (n=2), Italy (n=1), and Greece (n=1), aged 20, 26, 30, and 53 months, were included between February, 2012, and February, 2014. 125 adverse events were recorded, of which 117 were treatment emergent and included six classified as severe, but no suspected unexpected serious adverse drug reactions were seen. Vector genomes were detected in blood for 2 days after surgery. Compared with the natural history of mucopolysaccharidosis type III syndromes, neurocognitive progression was improved in all patients, with the youngest patient having function close to that in healthy children. Decrease in developmental quotient was -11·0 points in patient one, -23·0 in patient two, -29·0 in patient three, and -17·0 in patient four, compared with -37·7 in the natural history of the disease. NAGLU activity was detected in lumbar CSF and was 15-20% of that in unaffected children. Circulating T lymphocytes that proliferated and produced tumour

  9. Thrombin generation in acute coronary syndrome and stable coronary artery disease: dependence on plasma factor composition.

    PubMed

    Brummel-Ziedins, K; Undas, A; Orfeo, T; Gissel, M; Butenas, S; Zmudka, K; Mann, K G

    2008-01-01

    Acute coronary syndrome (ACS) is associated with thrombin formation, triggered by ruptured or eroded coronary atheroma. We investigated whether thrombin generation based on circulating coagulation protein levels, could distinguish between acute and stable coronary artery disease (CAD). Plasma coagulation factor (F) compositions from 28 patients with ACS were obtained after onset of chest pain. Similar data were obtained from 25 age- and sex-matched patients with stable CAD. All individuals took aspirin. Patients on anticoagulant therapy were excluded. The groups were similar in demographic characteristics, comorbidities and concomitant treatment. Using each individual's coagulation protein composition, tissue factor (TF) initiated thrombin generation was assessed both computationally and empirically. TF pathway inhibitor (TFPI), antithrombin (AT), factor II (FII) and FVIII differed significantly (P < 0.01) between the groups, with levels of FII, FVIII and TFPI higher and AT lower in ACS patients. When thrombin generation profiles from individuals in each group were compared, simulated maximum thrombin levels (P < 0.01) and rates (P < 0.01) were 50% higher with ACS while the initiation phases of thrombin generation were shorter. Empirical reconstructions of the populations reproduced the thrombin generation profiles generated by the computational model. The differences between the thrombin generation profiles for each population were primarily dependent upon the collective contribution of AT, FII and FVIII. Simulations of thrombin formation based on plasma composition can discriminate between acute and stable CAD.

  10. S-100B: a stronger prognostic biomarker than LDH in stage IIIB-C melanoma.

    PubMed

    Wevers, K P; Kruijff, S; Speijers, M J; Bastiaannet, E; Muller Kobold, A C; Hoekstra, H J

    2013-08-01

    In melanoma patients with nodal macrometastases, the distinction between good and poor prognosis is based on the presence of primary melanoma ulceration or metastatic involvement of 4 or more lymph nodes in the 7th edition of the American Joint Committee on Cancer (AJCC) classification. We hypothesized that biomarkers would increase the accurateness of staging in these patients. The aim was to assess and compare the prognostic impact of biomarkers S-100B and LDH and to determine the best timing of their measurement in stage IIIB-C melanoma. A total of 119 patients underwent therapeutic lymph node dissection (TLND) for nodal macrometastases with serum S-100B and LDH level measurements preoperatively. In 75 of them, S-100B and LDH were also measured on postoperative days 1 and 2. S-100B and LDH levels on days 0, 1, and 2 were compared for their association with disease-free survival (DFS) and disease-specific survival (DSS). At a median follow-up of 17 (range 1-89) months, S-100B levels at all time points were associated with DFS. In multivariable analysis, preoperative S-100B and S-100B measured on day 2 showed the strongest association with DFS (hazard ratio [HR] 2.55, P = 0.007 and HR 3.80, P = 0.01). For DSS, the preoperative S-100B level was the strongest independent predictor (HR 2.81, P = 0.01). LDH measurements showed a significant association with DSS in univariate analysis only when measured preoperatively (HR 2.46, P = 0.01). In multivariable analysis, LDH measurement was not associated with melanoma prognosis. The S-100B level measured preoperatively is, in contrast to LDH, one of the most important independent predictors of melanoma prognosis in patients undergoing TLND for nodal macrometastases.

  11. Biochemical, histological and functional correction of mucopolysaccharidosis type IIIB by intra-cerebrospinal fluid gene therapy.

    PubMed

    Ribera, Albert; Haurigot, Virginia; Garcia, Miguel; Marcó, Sara; Motas, Sandra; Villacampa, Pilar; Maggioni, Luca; León, Xavier; Molas, Maria; Sánchez, Víctor; Muñoz, Sergio; Leborgne, Christian; Moll, Xavier; Pumarola, Martí; Mingozzi, Federico; Ruberte, Jesús; Añor, Sònia; Bosch, Fatima

    2015-04-01

    Gene therapy is an attractive tool for the treatment of monogenic disorders, in particular for lysosomal storage diseases (LSD) caused by deficiencies in secretable lysosomal enzymes in which neither full restoration of normal enzymatic activity nor transduction of all affected cells are necessary. However, some LSD such as Mucopolysaccharidosis Type IIIB (MPSIIIB) are challenging because the disease's main target organ is the brain and enzymes do not efficiently cross the blood-brain barrier even if present at very high concentration in circulation. To overcome these limitations, we delivered AAV9 vectors encoding for α-N-acetylglucosaminidase (NAGLU) to the Cerebrospinal Fluid (CSF) of MPSIIIB mice with the disease already detectable at biochemical, histological and functional level. Restoration of enzymatic activity in Central Nervous System (CNS) resulted in normalization of glycosaminoglycan content and lysosomal physiology, resolved neuroinflammation and restored the pattern of gene expression in brain similar to that of healthy animals. Additionally, transduction of the liver due to passage of vectors to the circulation led to whole-body disease correction. Treated animals also showed reversal of behavioural deficits and extended lifespan. Importantly, when the levels of enzymatic activity were monitored in the CSF of dogs following administration of canine NAGLU-coding vectors to animals that were either naïve or had pre-existing immunity against AAV9, similar levels of activity were achieved, suggesting that CNS efficacy would not be compromised in patients seropositive for AAV9. Our studies provide a strong rationale for the clinical development of this novel therapeutic approach as the treatment for MPSIIIB.

  12. Three-dimensional surface grid generation for calculation of thermal radiation shape factors

    NASA Technical Reports Server (NTRS)

    Aly, Hany M.

    1992-01-01

    A technique is described to generate three dimensional surface grids suitable for calculating shape factors for thermal radiative heat transfer. The surface under consideration is approximated by finite triangular elements generated in a special manner. The grid is generated by dividing the surface into a two dimensional array of nodes. Each node is defined by its coordinates. Each set of four adjacent nodes is used to construct two triangular elements. Each triangular element is characterized by the vector representation of its vertices. Vector algebra is used to calculate all desired geometric properties of grid elements. The properties are used to determine the shape factor between the element and an area element in space. The grid generation can be graphically displayed using any software with three dimensional features. DISSPLA was used to view the grids.

  13. Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation

    PubMed Central

    Stopa, Jack D.; Neuberg, Donna; Puligandla, Maneka; Furie, Bruce; Zwicker, Jeffrey I.

    2017-01-01

    BACKGROUND: Protein disulfide isomerase (PDI) is required for thrombus formation. We previously demonstrated that glycosylated quercetin flavonoids such as isoquercetin inhibit PDI activity and thrombus formation in animal models, but whether extracellular PDI represents a viable anticoagulant target in humans and how its inhibition affects blood coagulation remain unknown. METHODS: We evaluated effects of oral administration of isoquercetin on platelet-dependent thrombin generation in healthy subjects and patients with persistently elevated anti-phospholipid antibodies. RESULTS: Following oral administration of 1,000 mg isoquercetin to healthy adults, the measured peak plasma quercetin concentration (9.2 μM) exceeded its IC50 for inhibition of PDI by isoquercetin in vitro (2.5 ± 0.4 μM). Platelet-dependent thrombin generation decreased by 51% in the healthy volunteers compared with baseline (P = 0.0004) and by 64% in the anti-phospholipid antibody cohort (P = 0.015) following isoquercetin ingestion. To understand how PDI affects thrombin generation, we evaluated substrates of PDI identified using an unbiased mechanistic-based substrate trapping approach. These studies identified platelet factor V as a PDI substrate. Isoquercetin blocked both platelet factor Va and thrombin generation with an IC50 of ~5 μM. Inhibition of PDI by isoquercetin ingestion resulted in a 53% decrease in the generation of platelet factor Va (P = 0.001). Isoquercetin-mediated inhibition was reversed with addition of exogenous factor Va. CONCLUSION: These studies show that oral administration of isoquercetin inhibits PDI activity in plasma and diminishes platelet-dependent thrombin generation predominantly by blocking the generation of platelet factor Va. These pharmacodynamic and mechanistic observations represent an important step in the development of a novel class of antithrombotic agents targeting PDI. TRIAL REGISTRATION: Clinicaltrials.gov (NCT01722669) FUNDING: National Heart

  14. One-Time Password Generation and Two-Factor Authentication Using Molecules and Light.

    PubMed

    Naren, Gaowa; Li, Shiming; Andréasson, Joakim

    2017-03-02

    Herein, we report the first example of one-time password (OTP) generation and two-factor authentication (2FA) using a molecular approach. OTPs are passwords that are valid for one entry only. For the next login session, a new, different password is generated. This brings the advantage that any undesired recording of a password will not risk the security of the authentication process. Our molecular realization of the OTP generator is based on a photochromic molecular triad where the optical input required to set the triad to the fluorescent form differs depending on the initial isomeric state.

  15. Long-term results for Stage IIIB cervical cancer patients receiving external beam radiotherapy combined with either HDR (252)Cf or HDR (60)Co intracavitary brachytherapy.

    PubMed

    Ulinskas, K; Janulionis, E; Valuckas, K P; Samerdokiene, V; Atkocius, V; Rivard, M J

    2016-01-01

    The aim of this work was to compare the long-term curative effects and complications of patients diagnosed with cervical cancer International Federation of Gynecology and Obstetrics IIIB (n = 430) as treated with Californium-252 ((252)Cf) or cobalt-60 ((60)Co) intracavitary brachytherapy (ICBT) combined with external beam radiotherapy (EBRT). Cervical cancer cases with a history of treatment with (252)Cf or (60)Co ICBT combined with EBRT were selected from the Lithuanian National Cancer Institute database. Complications and second primary malignancies were compared in both patients groups. Estimates of the 5-, 10-, and 15-year overall survival and disease-free survival rates were computed with the Kaplan-Meier method and a Cox proportional hazards model applied using STATA software. At 5, 10, and 15 years, the overall survival rates were 46.9%, 39.3%, and 34.6% for the (252)Cf group and 35.4%, 26.9%, and 22.5% for the (60)Co group (p = 0.004), respectively. The disease-free survival rates were 42.1%, 35.0%, and 31.0% for the (252)Cf group and 32.0%, 25.1%, and 21.4% for the (60)Co group (p = 0.009), respectively. Histopathologic type of adenocarcinoma increased the risk of death for the (252)Cf group (hazard ratio 3.62). Histopathologic tumor type (hazard ratio 7.48) and recurrence (hazard ratio 2.83) were factors that statistically and significantly influenced the patient prognosis for the (60)Co group. Applying (252)Cf ICBT with EBRT was effective for International Federation of Gynecology and Obstetrics IIIB cervical cancer patients. Moreover, long-term followup data demonstrated higher survival rates in patients treated with (252)Cf ICBT than (60)Co ICBT. Complications in patients treated with neutron ICBT were not more frequent or severe than those treated with (60)Co ICBT. Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

  16. Comparison of Retention Factors between First-Generation and Second- and Third-Generation College Students and Development of the Likelihood of Success Model

    ERIC Educational Resources Information Center

    Williams, Gerri Brown

    2009-01-01

    The purpose of this study was to compare the retention factors between first-generation college students and second- and third-generation college students in the postsecondary educational setting. This study examined the differences in the preselected retention factors: faculty-student interaction, college mentor, academic support, residential…

  17. A Systematic Review of Outcomes and Complications of Reconstruction and Amputation for Type IIIB and IIIC Fractures of the Tibia

    PubMed Central

    Saddawi-Konefka, Daniel; Kim, Hyungjin Myra; Chung, Kevin C.

    2015-01-01

    Background The question of whether to recommend amputation or salvage after IIIB and IIIC tibial fractures remains unanswered. The purpose of this study is to conduct a systematic review to derive evidence-based recommendation concerning primary amputation versus limb salvage for IIIB and IIIC open tibial fractures. Methods Articles from Medline, Cinahl and Embase that met pre-determined criteria were included. Outcomes of interest included: hospital stay duration, complications, rehabilitation time, quality of life, limb function, pain, and return to work data. Pooling of statistical data was performed when possible. Results We reviewed 1,947 articles, and 28 observational studies were included. Length of hospital stay was 56.9 days for salvage patients and 63.7 days for amputees. The most common complications after salvage attempt were osteomyelitis (17.9%), nonunion (15.5%), secondary amputation (7.3%) and flap failure (5.8%). Rehabilitation time for salvaged patients was reported as time to union (10.2 months) and time to full weight-bearing (8.1 months). Pain, quality of life and limb function outcomes were assessed differently among studies and could not be combined. Percent of patients who returned to work was 63.5% for salvage patients and 73% for amputees. Conclusions The current literature offers no evidence to support superior outcomes of either limb salvage or primary amputation for IIIB and IIIC tibial fractures. When outcomes are similar between two treatment strategies, economic analysis that incorporates cost and preference (utility) may define an optimal treatment strategy to guide physicians and patients. PMID:19050533

  18. Robot-assisted laparoscopic retroperitoneal lymph node dissection for stage IIIb mixed germ cell testicular cancer after chemotherapy.

    PubMed

    Lee, Sang Hyub; Kim, Dong Soo; Chang, Sung-Goo; Jeon, Seung Hyun

    2015-07-01

    Laparoscopic retroperitoneal lymph node dissection, especially when performed with the da Vinci Surgical System (Intuitive Surgical), has shown excellent cosmetic results with similar oncologic outcomes to those of open surgery. In this study, we present a case of robot-assisted retroperitoneal lymph node dissection performed in an 18-year-old man who was diagnosed with a stage IIIb mixed germ cell tumor and who was initially treated with radical orchiectomy, followed by chemotherapy. This case shows that robot-assisted retroperitoneal lymph node dissection is technically feasible, safe, and cosmetically favorable, even when performed on patients with high-stage disease or after chemotherapy.

  19. Generation Y Student-Teachers' Motivational Factors: Retention Implications for K-12 Educational Leaders

    ERIC Educational Resources Information Center

    Bontempo, Brian

    2010-01-01

    Generation Y represents a growing number of student-teachers who will impact the future of educational practice, yet little research has been conducted for this demographic group. The purpose of this mixed-method study was to identify motivational factors of neophyte teachers and the retention implications these findings had on Kindergarten…

  20. Factors That Relate to the Persistence of First-Generation Undergraduate Students in a Public University

    ERIC Educational Resources Information Center

    Thachil, Shoba Anne

    2013-01-01

    This study examined factors that relate to the persistence of first-generation undergraduate students in a 4-year public university in the Southeastern United States. Results were analyzed from a 2011 two-part survey: CARES-I (College Assessment of Readiness for Entering Students-Intent) and CARES-A (College Assessment of Readiness for Entering…

  1. Factors That Relate to the Persistence of First-Generation Undergraduate Students in a Public University

    ERIC Educational Resources Information Center

    Thachil, Shoba Anne

    2013-01-01

    This study examined factors that relate to the persistence of first-generation undergraduate students in a 4-year public university in the Southeastern United States. Results were analyzed from a 2011 two-part survey: CARES-I (College Assessment of Readiness for Entering Students-Intent) and CARES-A (College Assessment of Readiness for Entering…

  2. Implementation of human factors considerations in a coal fired generating station control room

    SciTech Connect

    Higginbotham, J.W.

    1985-04-01

    Fossil fueled generating station control room design has followed a basically classical approach until recent years. However, as technological advances occurred and were retrofitted into these control rooms, some clashes occurred between the environment and the equipment which negatively impacted the operator's effectiveness. One utility's approach toward implementing the incorporation of new technology devices and of solving the resulting human factors problems is discussed.

  3. Factors Influencing College Decision-Making for First-Generation Appalachian Students

    ERIC Educational Resources Information Center

    Wood, Kristy Lynn

    2012-01-01

    This investigation determined the degree of importance for selected personal-psychological, academic, peer, financial, and family factors influencing the decision to attend college by first-generation, Appalachian (FGA) sophomore students. Outcomes were further related to the degree of academic and social integration in college and the likelihood…

  4. Biodemographic and sociocultural factors in two generations of families from six Polish rural and urban populations.

    PubMed

    Wolański, N

    1994-01-01

    There were investigated 6967 families from 6 rural regions, under industrialization, and industrialized urban regions. In the grandparents generation there were taken into account 10 traits (an education level, a mating radius, and a stature) and in parents generation 17 traits (the mentioned-above ones and a number of family members, a flat size, incomes, an employees No., a life mode, smoking etc. Numerical characteristics of traits have been calculated jointly and separately in six populations, matrices of correlation have been constructed and moreover factorial analysis have been carried out, as a result of which 8 rotated factors have been obtained. The highest cultural mobility (increase in the level of education) from generation to generation occurs in the population of textile industry town Lódź. The highest improvement of biological status, the increase in mating radius and high incomes are characteristic for this regions, too. On the other side are villages with low culture mobility (not large increase in education level), slight improvement of biological status, almost no migrations, overcrowded flats and low income per family member. The relations between pairs of traits appear to vary largely in several populations. Generally is a high correlation between the education level of the same family members in both generations. The has been stated negative correlation between grandfather stature both of the mother and the father lines, with occurring of positive assortative mating in the couples of two generations. In both investigated generations there is the positive assortative mating, but the negative correlation in the stature between grandfathers of the mother and the father lines. The grandparents education level is correlated with their and their offsprings stature. The duration of holidays is one of the best (closely correlated with others) indicators of life mode, and partially of a given family living conditions, too. 8 hidden factors have been

  5. Kinetic Modeling Sheds Light on the Mode of Action of Recombinant Factor VIIa on Thrombin Generation

    DTIC Science & Technology

    2011-01-01

    Haemost 2004;2:402–13. [20] Brummel Ziedins K, Rivard GE, Pouliot RL, Butenas S, Gissel M, Parhami-Seren B, et al. Factor VIIa replacement therapy in...coagulopathy in a porcine trauma model. J Trauma 2010;68:1151–7. [25] Gallistl S, Cvirn G, Muntean W . Recombinant factor VIIa does not induce...VIIa-induced thrombin generation in plasmas deficient in factors VIII, IX, XI. J Thromb Haemost 2006;4:192–200. [27] Streif W , Paes B, Berry L, Andrew

  6. Effect of Sugar Beet Variety and Nonhost Plant on Rhizoctonia solani AG2-2IIIB Soil Inoculum Potential Measured in Soil DNA Extracts.

    PubMed

    Schulze, Sascha; Koch, Heinz-Josef; Märländer, Bernward; Varrelmann, Mark

    2016-09-01

    A direct soil DNA extraction method from soil samples (250 g) was applied for detection of the soilborne sugar-beet-infecting pathogen Rhizoctonia solani anastomosis group (AG) 2-2IIIB using a newly developed real-time polymerase chain reaction assay that showed specificity to AG2-2IIIB when tested against various R. solani AG. The assay showed a good relation between cycle threshold and amount of AG2-2IIIB sclerotia detected in three spiked field soils and was also able to detect the pathogen in naturally infested field soil samples. A field trial was conducted to quantify R. solani AG2-2IIIB soil inoculum potential (IP) before and after growing a susceptible and a resistant sugar beet variety as well as after subsequent growth of an expected nonhost winter rye. Plants of the susceptible sugar beet variety displayed a higher disease severity. A more than sixfold increase of the R. solani AG2-2IIIB soil IP was observed in contrast to the resistant variety that resulted in a constant IP. Growing winter rye significantly reduced soil IP to the initial level at sowing. Further research is required to better understand the interaction between disease occurrence and soil IP as well as the environmental influence on IP development.

  7. Influence of single nucleotide polymorphisms on thrombin generation in factor V Leiden heterozygotes.

    PubMed

    Segers, O; Simioni, P; Tormene, D; Castoldi, E

    2014-03-03

    Carriership of the factor V (FV) Leiden mutation increases the risk of venous thromboembolism (VTE) ~4-fold, but the individual risk of each FV Leiden carrier depends on several co-inherited risk and protective factors. Under the hypothesis that thrombin generation might serve as an intermediate phenotype to identify genetic modulators of VTE risk, we enrolled 188 FV Leiden heterozygotes (11 with VTE) and determined the following parameters: thrombin generation in the absence and presence of activated protein C (APC); plasma levels of prothrombin, factor X, antithrombin, protein S and tissue factor pathway inhibitor; and the genotypes of 24 SNPs located in the genes encoding these coagulation factors and inhibitors. Multiple regression analysis was subsequently applied to identify the (genetic) determinants of thrombin generation. The endogenous thrombin potential (ETP) showed a striking inter-individual variability among different FV Leiden carriers and, especially when measured in the presence of APC, correlated with VTE risk. Several SNPs in the F2 (rs1799963, rs3136516), F10 (rs693335), SERPINC1 (rs2227589), PROS1 (Heerlen polymorphism) and TFPI (rs5940) genes significantly affected the ETP-APC and/or the ETP+APC in FV Leiden carriers. Most of these SNPs have shown an association with VTE risk in conventional epidemiological studies, suggesting that the genetic dissection of thrombin generation leads to the detection of clinically relevant SNPs. In conclusion, we have identified several SNPs that modulate thrombin generation in FV Leiden heterozygotes. These SNPs may help explain the large variability in VTE risk observed among different FV Leiden carriers.

  8. The impact of major surgery on blood coagulation factors and thrombin generation.

    PubMed

    Horne, McDonald K; Merryman, Paula K; Cullinane, Ann M; Nghiem, Khanh; Alexander, H Richard

    2007-09-01

    We studied the blood coagulation system of 14 patients with metastatic malignancies before and after they had undergone major surgery. In addition to measuring a battery of coagulation factors, we assessed the function of the system with assays of whole blood thrombin generation. With the exceptions of factor VIII (fVIII), which increased, and fibrinogen and fIX, which did not change, the activities of all the pro- and anticoagulant proteins were significantly lower postoperatively. However, the thrombin generating capacity of the system was relatively preserved. Although the integral of thrombin activity over time was lower after surgery, the mean peak thrombin concentration was unchanged and the time to clot formation was shortened. Similar changes could be reproduced by lowering the concentrations of pro- and anticoagulant factors together in control blood samples. Therefore, simultaneous reductions in pro- and anticoagulant proteins postoperatively worked to maintain the functional integrity of the blood coagulation system. 2007 Wiley-Liss, Inc

  9. Generations.

    PubMed

    Chambers, David W

    2005-01-01

    Groups naturally promote their strengths and prefer values and rules that give them an identity and an advantage. This shows up as generational tensions across cohorts who share common experiences, including common elders. Dramatic cultural events in America since 1925 can help create an understanding of the differing value structures of the Silents, the Boomers, Gen Xers, and the Millennials. Differences in how these generations see motivation and values, fundamental reality, relations with others, and work are presented, as are some applications of these differences to the dental profession.

  10. [Amputation or reconstruction of IIIB and IIIC open tibial fracture. Decision criteria in the acute phase and late functional outcome].

    PubMed

    Seekamp, A; Regel, G; Ruffert, S; Ziegler, M; Tscherne, H

    1998-05-01

    In IIIB and IIIC type open tibial fractures (according to Gustilo) the primary decision that has to be made regarding therapy is wether or not the limb can be salvaged. To standardize the criteria for amputation different salvage scores have been established in recent years. In this study the Hannover Fracture Scale (HFS), the Predictive Salvage Index (PSI), the Mangled Extremity Severity Score (MESS) and the NISSSA score were evaluated regarding their clinical relevance. When ROC Analysis was performed for all these scores in our patients the HFS revealed the highest sensitivity (0.91), but low specificity (0.71). The highest specificity was noted for the MESS (0.97), which in parallel showed the lowest sensitivity (0.59). In general it seems to be essential to make the right decision initially in order to avoid secondary amputation. All the scores mentioned here appear to be helpful in decision making. Salvaged limbs in IIIB and IIIC fractures presented a comparable good outcome, whereas salvaged IIIC injuries with a high score presented an outcome which was as bad as in secondary amputations. Secondary amputated patients required not only significant longer hospitalization but also resulted in poor outcome compared with the patients having received reconstruction or primary amputation.

  11. Treatment of stage IIIB cervical cancer with Californium-252 fast-neutron brachytherapy and external photon therapy

    SciTech Connect

    Gallion, H.H.; Maruyama, Y.; van Nagell, J.R. Jr.; Donaldson, E.S.; Rowley, K.C.; Yoneda, J.; Beach, J.L.; Powell, D.E.; Kryscio, R.J.

    1987-05-15

    From January 1977 to July 1984, 32 patients with Stage IIIB cervical cancer were treated at the University of Kentucky Medical Center by a combination of outpatient neutron brachytherapy and external pelvic radiation. These patients received 4500 to 5000 rad external photon therapy and two or three outpatient Californium-252 (252Cf) implants, plus sidewall boost irradiation. Treatment results were compared retrospectively to those obtained in a historical control group of patients with Stage IIIB cervical cancer treated with external radiation and conventional photon brachytherapy from 1972 to 1976. Local or regional tumor recurrence developed in 53% of patients treated with neutron therapy and an additional 9% experienced distant metastases. Thirty-eight percent of patients remain free of disease 12 to 96 months (mean, 51 months) after therapy. The 2-year and 5-year survival rates of patients treated with neutron therapy were 53% and 36%, which were not significantly different than those obtained with photon brachytherapy (2-year survival, 61%; 5-year survival, 34%). Complications of neutron therapy were minimal and included proctitis (19%) and vaginal stenosis (9%). There were no cases of enteric fistulae. Outpatient neutron brachytherapy was cost effective and was well tolerated by patients.

  12. Treatment of stage IIIB cervical cancer with Californium-252 fast-neutron brachytherapy and external photon therapy.

    PubMed

    Gallion, H H; Maruyama, Y; van Nagell, J R; Donaldson, E S; Rowley, K C; Yoneda, J; Beach, J L; Powell, D E; Kryscio, R J

    1987-05-15

    From January 1977 to July 1984, 32 patients with Stage IIIB cervical cancer were treated at the University of Kentucky Medical Center by a combination of outpatient neutron brachytherapy and external pelvic radiation. These patients received 4500 to 5000 rad external photon therapy and two or three outpatient Californium-252 (252Cf) implants, plus sidewall boost irradiation. Treatment results were compared retrospectively to those obtained in a historical control group of patients with Stage IIIB cervical cancer treated with external radiation and conventional photon brachytherapy from 1972 to 1976. Local or regional tumor recurrence developed in 53% of patients treated with neutron therapy and an additional 9% experienced distant metastases. Thirty-eight percent of patients remain free of disease 12 to 96 months (mean, 51 months) after therapy. The 2-year and 5-year survival rates of patients treated with neutron therapy were 53% and 36%, which were not significantly different than those obtained with photon brachytherapy (2-year survival, 61%; 5-year survival, 34%). Complications of neutron therapy were minimal and included proctitis (19%) and vaginal stenosis (9%). There were no cases of enteric fistulae. Outpatient neutron brachytherapy was cost effective and was well tolerated by patients.

  13. A novel mutation (c.200T>C) in the NAGLU gene of a Korean patient with mucopolysaccharidosis IIIB.

    PubMed

    Kim, Young-Eun; Park, Hyung-Doo; Jang, Mi-Ae; Ki, Chang-Seok; Lee, Soo-Youn; Kim, Jong-Won; Cho, Sung Yoon; Jin, Dong-Kyu

    2013-05-01

    Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disorder (LSD) caused by abnormalities of the enzyme α-N-acetylglucosaminidase (NAGLU) that is required for degradation of heparan sulfate. The patient in this study was a 4-yr-old boy. He presented with normal height and weight, pectus carinatum, and multiple persistent Mongolian spots on his back. He had mild dysmorphic features with prominent speech developmental delays and, to a lesser extent, motor developmental delays. The cetylpyridinium chloride precipitation test revealed excessive mucopolysacchariduria (657.2 mg glycosaminoglycan/g creatinine; reference range, <175 mg glycosaminoglycan/g creatinine). Thin layer chromatography showed urinary heparan sulfate excretion. NAGLU enzyme activity was significantly decreased in leukocytes (not detected; reference range, 0.9-1.51 nmol/hr/mg protein) as well as in plasma (0.14 nmol/hr/mg protein; reference range, 22.3-60.9 nmol/hr/mg protein). PCR and direct sequencing analysis of the NAGLU gene showed that the patient was a compound heterozygote for 2 mutations: c.200T>C (p.L67P) and c.1444C>T (p.R482W). The c.200T>C mutation was a novel finding. This is the first report of a Korean patient with MPS IIIB who was confirmed by molecular genetic analyses and biochemical investigation.

  14. Factors influencing municipal solid waste generation in China: a multiple statistical analysis study.

    PubMed

    Liu, Chen; Wu, Xin-wu

    2011-04-01

    A relationship between the waste production and socio-economic factors is essential in waste management. In the present study, the factors influencing municipal solid waste generation in China were investigated by multiple statistical analysis. Twelve items were chosen for investigation: GDP, per capita GDP, urban population, the proportion of urban population, the area of urban construction, the area of paved roads, the area of urban gardens and green areas, the number of the large cities, annual per capita disposable income of urban households, annual per capita consumption expenditure of urban households, total energy consumption and annual per capital consumption for households. Two methodologies from multiple statistical analysis were selected; specifically principal components analysis (PCA) and cluster analysis (CA). Three new dimensions were identified by PCA: component 1: economy and urban development; component 2: energy consumption; and component 3: urban scale. The three components together accounted for 99.1% of the initial variance. The results show that economy and urban development are important items influencing MSW generation. The proportion of urban population and urban population had the highest loadings in all factors. The relationship between growth of gross domestic product (GDP) and production of MSW was not as clear-cut as often assumed in China, a situation that is more likely to apply to developed countries. Energy consumption was another factor considered in our study of MSW generation. In addition, the annual MSW quantity variation was investigated by cluster analysis.

  15. Physical factors limiting the spectral extent and band gap dependence of supercontinuum generation.

    PubMed

    Kolesik, M; Katona, G; Moloney, J V; Wright, E M

    2003-07-25

    Based on simulations of femtosecond pulse propagation in water we elucidate the physical factors that limit the attainable spectral extent of supercontinuum generation in bulk media. In contrast to the standard scenario, where arrest of self-focusing collapse by multiphoton absorption and plasma defocusing are viewed as imposing a limit to supercontinuum broadening, we show that linear chromatic dispersion also plays a major role. This insight provides an intuitive explanation of the observed band gap dependence of the attainable supercontinuum generation in condensed media.

  16. SEATIDE Analysis Process. Volume IIIB. Cruise Missile - Concept Generation and Screening Model (CM-CGSM). Appendices A - B.

    DTIC Science & Technology

    1974-01-01

    s t ics of Var ious Wal leye Components and Confi gurations in the Subson ic , T ranson ic , and Supersonic Flight Reg ions ” , U. S. Naval...f t ) 100 , 000 . 0 5 R range (f t ) 1 , 000 , 000 . 0 6 W mass ( Ibm) 1,000 . 0 7 “tB ideal veloci ty ( f t / s e c ) 1, 000. 0 V 3 . 2 NEWTON ...RAPHSON PROCEDURE ~ Newton -Raphson procedure is used in several instances to solve a non- l inear equation fo r the independent variable

  17. Europium-activated phosphors containing oxides of rare-earth and group-IIIB metals and method of making the same

    DOEpatents

    Comanzo, Holly Ann; Setlur, Anant Achyut; Srivastava, Alok Mani

    2006-04-04

    Europium-activated phosphors comprise oxides of at least a rare-earth metal selected from the group consisting of gadolinium, yttrium, lanthanum, and combinations thereof and at least a Group-IIIB metal selected from the group consisting of aluminum, gallium, indium, and combinations thereof. A method for making such phosphors comprises adding at least a halide of at least one of the selected Group-IIIB metals in a starting mixture. The method further comprises firing the starting mixture in an oxygen-containing atmosphere. The phosphors produced by such a method exhibit improved absorption in the UV wavelength range and improved quantum efficiency.

  18. Europium-activated phosphors containing oxides of rare-earth and group-IIIB metals and method of making the same

    DOEpatents

    Comanzo, Holly Ann; Setlur, Anant Achyut; Srivastava, Alok Mani; Manivannan, Venkatesan

    2004-07-13

    Europium-activated phosphors comprise oxides of at least a rare-earth metal selected from the group consisting of gadolinium, yttrium, lanthanum, and combinations thereof and at least a Group-IIIB metal selected from the group consisting of aluminum, gallium, indium, and combinations thereof. A method for making such phosphors comprises adding at least a halide of at least one of the selected Group-IIIB metals in a starting mixture. The method further comprises firing the starting mixture in an oxygen-containing atmosphere. The phosphors produced by such a method exhibit improved absorption in the UV wavelength range and improved quantum efficiency.

  19. Delayed Type IIIb endoleak secondary to graft fabric tear 7 years following implantation of a Medtronic Talent endovascular aortic device: A case report and review of the literature.

    PubMed

    Kansal, Vinay; Nagpal, Sudhir

    2016-01-01

    To report a rare case of delayed Type IIIb endoleak secondary to fabric tear following implantation of a Medtronic Talent endovascular device. A 83-year old gentleman underwent elective endovascular aneurysm repair for infrarenal abdominal aortic aneurysm with a Medtronic bifurcated stent graft in 2008. Seven years after the initial repair, imaging surveillance revealed significant endoleak and brisk aneurysm sac expansion due to Type IIIb endoleak secondary to endograft limb fabric tear. This case illustrates the imperative role of imaging surveillance in detection of long-term endovascular aneurysm repair complications. Furthermore, we discuss exclusion of the graft tear with aortouniiliac stent grafting as the treatment for this complication.

  20. Thrombin generation in chronic obstructive pulmonary disease: dependence on plasma factor composition.

    PubMed

    Undas, Anetta; Jankowski, Milosz; Kaczmarek, Przemysław; Sladek, Krzysztof; Brummel-Ziedins, Kathleen

    2011-10-01

    Chronic obstructive pulmonary disease (COPD) is associated with an increased risk for thromboembolic events. We investigated thrombin generation profiles in COPD patients and their dependence on plasma factor/inhibitor composition. Factors (f) (fII, fV, fVII, fVIII, fIX, fX), antithrombin, protein C (PC) and free tissue factor pathway inhibitor (fTFPI) from 60 COPD patients (aged 64.2 ± 10.1 years; a mean forced expiratory volume in 1 second [FEV(1)], 55.6 ± 15.8% of predicted values) were compared with those for 43 controls matched for age, sex, weight and smoking. Patients receiving anticoagulation were excluded. Using each individual's plasma coagulation protein composition, tissue factor-initiated thrombin generation was assessed computationally. COPD patients had higher fII (115 ± 16 vs 102 ± 10%, p < 0.0001), fV (114 ± 19 vs 102 ± 12%, p = 0.0002), fVII (111 ± 15 vs 102 ± 17%, p = 0.002), fVIII (170 ± 34 vs 115 ± 27%, p < 0.0001), and fIX (119 ± 21 vs 107 ± 17%, p = 0.003), and lower fTFPI (17.7 ± 3.2 vs 18.9 ± 3.2 ng/ml, p = 0.047) compared with controls, while fX, antithrombin, and PC were similar in both groups. Computational thrombin generation profiles showed that compared with controls, COPD patients had higher maximum thrombin levels (+28.3%, p < 0.0001), rates of thrombin generation (+46.1%, p < 0.0001) and total thrombin formation (+14.4%, p < 0.001), together with shorter initiation phase of thrombin generation (p < 0.0001) and the time to maximum thrombin levels (p < 0.0001). Thrombin generation profiles in COPD patients can be normalized via correction of fII, fVIII , fIX and TFPI. The severity of COPD and inflammatory markers were not associated with thrombin generation profiles. Prothrombotic phenotype in COPD patients is largely driven by increased prothrombin, fVIII, fIX, and lower fTFPI. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. Factors involved in the generation and replication of rhabdovirus defective T particles.

    PubMed Central

    Holland, J J; Villarreal, L P; Breindl, M

    1976-01-01

    Previous indications that cloned B virions might be genetically predisposed to generate a particular defective T particle are shown to be inaccurate. T particle generation was found to be a much more random process than was previously believed. We show that the previously observed generation of particular sizes of T particles by B virion pools is due to the random generation of T particles during preparation of first-passage pools of cloned B virions, and these breed true during the additional passages needed to produce visible quantities of T particles. It is also shown that different host cell lines selectively amplify different T particles, suggesting a strong role of host cell factors in T particle replication. Surprisingly, our line of HeLa cells did not generate or replicate detectable T particles of vesicular stomatitis virus (VSV) Indiana after either serial undiluted passage or direct addition of T particles, even though the added T particles strongly interfered with B virion replication. In contrast to VSV, rabies virus generates large amounts of T particles during the first passage of cloned B virions, and every rabies-infected baby hamster kidney-21 cell culture evolves into a persistent carrier state. We find that T particle RNA is biologically inactive although T particle nucleocapsid ribonucleoprotein replicates and interferes in cells coinfected with B virions. Efforts to study the mechanism of T particle generation by in vitro attempts to generate T particles or modify their size (using sheared ribonucleoprotein or chemical or UV mutagenesis) were unsuccessful. The kinetics of UV and nitrous acid inactivation of T particles indicate a smaller target size relative to B virions, even after correcting for lengths of RNA molecules. The intercalating dye proflavine does not photosensitize VSV B virions or T particles when present during replication, indicating that there is little or no RNA base pairing in the helical nucleocapsids of either. PMID

  2. Generational status and social factors predicting initiation of partnered sexual activity among Latino/a youth.

    PubMed

    Cabral, Patricia; Wallander, Jan L; Song, Anna V; Elliott, Marc N; Tortolero, Susan R; Reisner, Sari L; Schuster, Mark A

    2017-02-01

    Examine the longitudinal association of generational status (first = child and parent born outside the United States; second = child born in the United States, parent born outside the United States; third = child and parent born in the United States) and parent and peer social factors considered in 5th grade with subsequent oral, vaginal, and anal intercourse initiation by 7th and 10th grade among Latino/a youth. Using data from Latino/a participants (N = 1,790) in the Healthy Passages™ study, the authors measured generational status (first = 18.4%, second = 57.3%, third-generation = 24.3%) and parental (i.e., monitoring, involvement, nurturance) and peer (i.e., friendship quality, social interaction, peer norms) influences in 5th grade and oral, vaginal, and anal intercourse initiation by 7th and 10th (retention = 89%) grade. Among girls, parental monitoring, social interaction, friendship quality, and peer norms predicted sexual initiation. Among boys, parental involvement, social interaction, and peer norms predicted sexual initiation (ps < .05). When ≥1 friend was perceived to have initiated sexual intercourse, third-generation Latinas were more than twice as likely as first- and second-generation Latinas (ps < .05) to initiate vaginal intercourse by 10th grade and almost 5 times as likely as first-generation Latinas to initiate oral intercourse by 7th grade. Among Latina youth, generational status plays a role in social influences on vaginal and oral intercourse initiation. Moreover, Latinas and Latinos differ in which social influences predict sexual intercourse initiation. Preventive efforts for Latino/a youth may need to differ by gender and generational status. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  3. Factors associated with involvement in nonmetropolitan LGBTQ organizations: Proximity? Generativity? Minority stress? Social location?

    PubMed

    Paceley, Megan S; Oswald, Ramona Faith; Hardesty, Jennifer L

    2014-01-01

    Little is known about involvement in LGBTQ organizations. Factors associated with involvement in nonmetropolitan LGBTQ organizations were examined using logistic regression and survey data from 426 LGBTQ individuals residing in a nonmetropolitan region. Involvement was examined in five types of organizations (professional, social/recreational, religious, political, and community center/charity). The same model testing proximity, generativity, minority stress, and social location hypotheses was repeated for each organization type. Results demonstrate that the generativity hypothesis is most strongly supported. Indeed, emotional attachment to the LGBTQ community significantly increased the odds of involvement in every type of organization. However, the factors associated with involvement otherwise differed by organization type. Implications for organizational leaders are discussed.

  4. Learning a generative model of images by factoring appearance and shape.

    PubMed

    Le Roux, Nicolas; Heess, Nicolas; Shotton, Jamie; Winn, John

    2011-03-01

    Computer vision has grown tremendously in the past two decades. Despite all efforts, existing attempts at matching parts of the human visual system's extraordinary ability to understand visual scenes lack either scope or power. By combining the advantages of general low-level generative models and powerful layer-based and hierarchical models, this work aims at being a first step toward richer, more flexible models of images. After comparing various types of restricted Boltzmann machines (RBMs) able to model continuous-valued data, we introduce our basic model, the masked RBM, which explicitly models occlusion boundaries in image patches by factoring the appearance of any patch region from its shape. We then propose a generative model of larger images using a field of such RBMs. Finally, we discuss how masked RBMs could be stacked to form a deep model able to generate more complicated structures and suitable for various tasks such as segmentation or object recognition.

  5. Different Recovery Profiles of Coagulation Factors, Thrombin Generation, and Coagulation Function After Hemorrhagic Shock in Pigs

    DTIC Science & Technology

    2012-06-06

    Different recovery profiles of coagulation factors, thrombin generation, and coagulation function after hemorrhagic shock in pigs Wenjun Z. Martini ...Defense. Address for reprints: Wenjun Z. Martini , PhD, The US Army Institute of Surgical Research, 3698 Chambers Pass, Ft. Sam Houston, San Antonio, TX...ELEMENT NUMBER 6. AUTHOR(S) Martini W. Z., Cortez D. S., Dubick M. A., Blackbourne L. H., 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7

  6. Generation of flat viewing zone in DFVZ autostereoscopic multiview 3D display by weighting factor

    NASA Astrophysics Data System (ADS)

    Kim, Sung-Kyu; Yoon, Seon-Kyu; Yoon, Ky-Hyuk

    2013-05-01

    A new method is introduced to reduce three crosstalk problems and the brightness variation in 3D image by means of the dynamic fusion of viewing zones (DFVZ) using weighting factor. The new method effectively generates the flat viewing zone at the center of viewing zone. The new type autostereoscopic 3D display can give less brightness variation of 3D image when observer moves.

  7. Generation of hyaline cartilaginous tissue from mouse adult dermal fibroblast culture by defined factors

    PubMed Central

    Hiramatsu, Kunihiko; Sasagawa, Satoru; Outani, Hidetatsu; Nakagawa, Kanako; Yoshikawa, Hideki; Tsumaki, Noriyuki

    2011-01-01

    Repair of cartilage injury with hyaline cartilage continues to be a challenging clinical problem. Because of the limited number of chondrocytes in vivo, coupled with in vitro de-differentiation of chondrocytes into fibrochondrocytes, which secrete type I collagen and have an altered matrix architecture and mechanical function, there is a need for a novel cell source that produces hyaline cartilage. The generation of induced pluripotent stem (iPS) cells has provided a tool for reprogramming dermal fibroblasts to an undifferentiated state by ectopic expression of reprogramming factors. Here, we show that retroviral expression of two reprogramming factors (c-Myc and Klf4) and one chondrogenic factor (SOX9) induces polygonal chondrogenic cells directly from adult dermal fibroblast cultures. Induced cells expressed marker genes for chondrocytes but not fibroblasts, i.e., the promoters of type I collagen genes were extensively methylated. Although some induced cell lines formed tumors when subcutaneously injected into nude mice, other induced cell lines generated stable homogenous hyaline cartilage–like tissue. Further, the doxycycline-inducible induction system demonstrated that induced cells are able to respond to chondrogenic medium by expressing endogenous Sox9 and maintain chondrogenic potential after substantial reduction of transgene expression. Thus, this approach could lead to the preparation of hyaline cartilage directly from skin, without generating iPS cells. PMID:21293062

  8. Factors Related to Upper Gastrointestinal Symptom Generation in 2275 Helicobacter pylori Seroprevalent Adults.

    PubMed

    Lee, Sang Pyo; Lee, Sun-Young; Kim, Jeong Hwan; Sung, In-Kyung; Park, Hyung Seok; Shim, Chan Sup

    2017-06-01

    Upper gastrointestinal (UGI) symptoms are common; however, the role of Helicobacter pylori and gastric corpus atrophy in the generation of these symptoms is controversial. The aim of this study was to determine the risk factors for UGI symptoms in adults in an endemic area of H. pylori infection. Korean adults who completed questionnaires on the day of serum anti-H. pylori IgG and pepsinogen (PG) assays before UGI endoscopy were included. Gastric corpus atrophy was based on the criteria of a serum PG I/II ratio <3.0 and a PG I <70 ng/ml. Of the 2275 included subjects, 723 (31.8%) had at least one UGI symptom. A total of 374 (16.4%) subjects had multiple symptoms without significant correlations between the symptoms (λ < 0.2). The H. pylori serology assay was positive in 1382 (60.7%) subjects, and gastric corpus atrophy was present in 291 (12.8%). Neither H. pylori seropositivity (p = 0.077) nor gastric corpus atrophy (p = 0.138) was related to the presence of UGI symptoms. Female gender and smoking were independent risk factors for heartburn and upper abdominal pain (all p < 0.001). Furthermore, female gender was the only independent risk factor for multiple UGI symptoms (p < 0.001), globus sensation (p < 0.001), early satiety (p < 0.001), epigastric soreness (p = 0.001), and chest discomfort (p = 0.003). In an H. pylori seroprevalent population, female gender is the most common risk factor followed by smoking for UGI symptom generation. Neither H. pylori seropositivity nor gastric corpus atrophy is an independent risk factor for UGI symptom generation.

  9. Third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer.

    PubMed

    Pirker, Robert

    2016-03-01

    Patients with epidermal growth factor receptor (EGFR) mutation-positive nonsmall cell lung cancer (NSCLC) develop resistance during therapy with EGFR tyrosine kinase inhibitors (TKIs). In about half of the patients, this resistance is because of the emergence of the T790M mutation. Third-generation TKIs are active against EGFR-activating mutations and the T790M resistance mutation and have only limited efficacy against wild-type EGFR. Here we review the current status of the clinical development of these novel TKIs. Third-generation TKIs in clinical development include osimertinib, rociletinib, and HM61713. Osimertinib and rociletinib have shown clinical efficacy in phase I/II trials in patients who had acquired resistance to first- or second-generation TKIs. Both TKIs are currently further evaluated in phase III trials as first-line or second-line therapy in patients with advanced EGFR mutation-positive NSCLC. HM61713 is in early clinical development. Third-generation EGFR TKIs have shown activity in patients with acquired resistance to first- and second-generation EGFR TKIs and may further improve clinical outcome in patients with advanced EGFR mutation-positive NSCLC.

  10. A global fouling factor methodology for analyzing steam generator thermal performance degradation

    SciTech Connect

    Kreider, M.A.; White, G.A.; Varrin, R.D. Jr.

    1998-06-01

    Over the past few years, steam generator (SG) thermal performance degradation has led to decreased plant efficiency and power output at numerous PWR nuclear power plants with recirculating-type SGs. The authors have developed and implemented methodologies for quantitatively evaluating the various sources of SG performance degradation, both internal and external to the SG pressure boundary. These methodologies include computation of the global fouling factor history, evaluation of secondary deposit thermal resistance using deposit characterization data, and consideration of pressure loss causes unrelated to the tube bundle, such as hot-leg temperature streaming and SG moisture separator fouling. In order to evaluate the utility of the global fouling factor methodology, the authors performed case studies for a number of PWR SG designs. Key results from two of these studies are presented here. In tandem with the fouling-factor analyses, a study evaluated for each plant the potential causes of pressure loss. The combined results of the global fouling factor calculations and the pressure-loss evaluations demonstrated two key points: (1) that the available thermal margin against fouling, which can vary substantially from plant to plant, has an important bearing on whether a given plant exhibits losses in electrical generating capacity, and (2) that a wide variety of causes can result in SG thermal performance degradation.

  11. The Management of Soft Tissue and Bone Loss in Type IIIB and IIIC Pediatric Open Tibia Fractures.

    PubMed

    Laine, Jennifer C; Cherkashin, Alexander; Samchukov, Mikhail; Birch, John G; Rathjen, Karl E

    2016-01-01

    Type III B and C open tibia fractures in children pose a challenge to the orthopaedic surgeon. Limb salvage is the initial goal for the majority of patients, but managing soft-tissue defects and bone loss can be a challenge. The purpose of this study was to evaluate the use of circular external fixation in the management of these injuries. In this retrospective review, we examined children with type IIIB and IIIC open tibial fractures treated with circular external fixation and soft-tissue coverage between 1990 and 2010. Chart review included: mechanism and severity of injury, degree of bone and soft-tissue loss, technique and duration of external fixation, additional procedures, clinical and radiographic outcomes, and complications. Eight patients were identified whose average age at the time of injury was 10.4 years (range, 3.8 to 15.3 y). There were 7 type IIIB and 1 type IIIC fractures. All patients received free or rotational soft-tissue flaps. Average bone loss was 5.4 cm (range, 0 to 12 cm). Three techniques of circular external fixation were used, including: (1) static stabilization to allow for soft-tissue coverage and fracture healing, (2) acute shortening with plan for later limb lengthening, and (3) stabilization of the extremity for soft-tissue coverage and intended bone transport. Seven of 8 limbs were salvaged. Of those 7, all were followed to skeletal maturity and ambulating without assistive devices at final follow-up. Three patients had a clinically relevant leg-length discrepancy (≥2 cm). Four of 8 patients required secondary or contralateral procedures. Pediatric type IIIB and IIIC tibia fractures are limb-threatening injuries that require dynamic thinking and management as the bone and soft-tissue injuries evolve. We have proposed a general algorithm to guide the treatment of these severe injuries. In our experience, circular external fixation, in conjunction with this algorithm, provides the appropriate stability and environment for managing

  12. Improvement of force factor of magnetostrictive vibration power generator for high efficiency

    SciTech Connect

    Kita, Shota Ueno, Toshiyuki; Yamada, Sotoshi

    2015-05-07

    We develop high power magnetostrictive vibration power generator for battery-free wireless electronics. The generator is based on a cantilever of parallel beam structure consisting of coil-wound Galfenol and stainless plates with permanent magnet for bias. Oscillating force exerted on the tip bends the cantilever in vibration yields stress variation of Galfenol plate, which causes flux variation and generates voltage on coil due to the law of induction. This generator has advantages over conventional, such as piezoelectric or moving magnet types, in the point of high efficiency, highly robust, and low electrical impedance. Our concern is the improvement of energy conversion efficiency dependent on the dimension. Especially, force factor, the conversion ratio of the electromotive force (voltage) on the tip velocity in vibration, has an important role in energy conversion process. First, the theoretical value of the force factor is formulated and then the validity was verified by experiments, where we compare four types of prototype with parameters of the dimension using 7.0 × 1.5 × 50 mm beams of Galfenol with 1606-turn wound coil. In addition, the energy conversion efficiency of the prototypes depending on load resistance was measured. The most efficient prototype exhibits the maximum instantaneous power of 0.73 W and energy of 4.7 mJ at a free vibration of frequency of 202 Hz in the case of applied force is 25 N. Further, it was found that energy conversion efficiency depends not only on the force factor but also on the damping (mechanical loss) of the vibration.

  13. Improvement of force factor of magnetostrictive vibration power generator for high efficiency

    NASA Astrophysics Data System (ADS)

    Kita, Shota; Ueno, Toshiyuki; Yamada, Sotoshi

    2015-05-01

    We develop high power magnetostrictive vibration power generator for battery-free wireless electronics. The generator is based on a cantilever of parallel beam structure consisting of coil-wound Galfenol and stainless plates with permanent magnet for bias. Oscillating force exerted on the tip bends the cantilever in vibration yields stress variation of Galfenol plate, which causes flux variation and generates voltage on coil due to the law of induction. This generator has advantages over conventional, such as piezoelectric or moving magnet types, in the point of high efficiency, highly robust, and low electrical impedance. Our concern is the improvement of energy conversion efficiency dependent on the dimension. Especially, force factor, the conversion ratio of the electromotive force (voltage) on the tip velocity in vibration, has an important role in energy conversion process. First, the theoretical value of the force factor is formulated and then the validity was verified by experiments, where we compare four types of prototype with parameters of the dimension using 7.0 × 1.5 × 50 mm beams of Galfenol with 1606-turn wound coil. In addition, the energy conversion efficiency of the prototypes depending on load resistance was measured. The most efficient prototype exhibits the maximum instantaneous power of 0.73 W and energy of 4.7 mJ at a free vibration of frequency of 202 Hz in the case of applied force is 25 N. Further, it was found that energy conversion efficiency depends not only on the force factor but also on the damping (mechanical loss) of the vibration.

  14. Operational water consumption and withdrawal factors for electricity generating technologies: a review of existing literature

    NASA Astrophysics Data System (ADS)

    Macknick, J.; Newmark, R.; Heath, G.; Hallett, K. C.

    2012-12-01

    This report provides estimates of operational water withdrawal and water consumption factors for electricity generating technologies in the United States. Estimates of water factors were collected from published primary literature and were not modified except for unit conversions. The water factors presented may be useful in modeling and policy analyses where reliable power plant level data are not available. Major findings of the report include: water withdrawal and consumption factors vary greatly across and within fuel technologies, and water factors show greater agreement when organized according to cooling technologies as opposed to fuel technologies; a transition to a less carbon-intensive electricity sector could result in either an increase or a decrease in water use, depending on the choice of technologies and cooling systems employed; concentrating solar power technologies and coal facilities with carbon capture and sequestration capabilities have the highest water consumption values when using a recirculating cooling system; and non-thermal renewables, such as photovoltaics and wind, have the lowest water consumption factors. Improved power plant data and further studies into the water requirements of energy technologies in different climatic regions would facilitate greater resolution in analyses of water impacts of future energy and economic scenarios. This report provides the foundation for conducting water use impact assessments of the power sector while also identifying gaps in data that could guide future research.

  15. Conversion of open tibial IIIb to IIIa fractures using intentional temporary deformation and the Taylor Spatial Frame.

    PubMed

    Sharma, H; Nunn, T

    2013-08-01

    The closure of small-to-moderate-sized soft tissue defects in open tibial fractures can be successfully achieved with acute bony shortening. In some instances, it may be possible to close soft tissue envelope defects by preserving length and intentionally creating a deformity of the limb. As the soft tissue is now able to close, this manoeuvre converts an open IIIb to IIIa fracture. This obviates the need for soft tissue reconstructive procedures such as flaps and grafts, which have the potential to cause donor-site morbidity and may fail. In this article, the authors demonstrate the technique for treating anterior medial soft tissue defects by deforming the bone at the fracture site, permitting temporary malalignment and closure of the wound. After healing of the envelope, the malalignment is gradually corrected with the use of the Taylor Spatial Frame. We present two such cases and discuss the technical indications and challenges of managing such cases.

  16. Draft genome sequence of the sugar beet pathogen Rhizoctonia solani AG2-2IIIB strain BBA69670.

    PubMed

    Wibberg, Daniel; Andersson, Louise; Rupp, Oliver; Goesmann, Alexander; Pühler, Alfred; Varrelmann, Mark; Dixelius, Christina; Schlüter, Andreas

    2016-03-20

    Rhizoctonia solani is a widespread plant pathogenic fungus featuring a broad host range including several economically important crops. Accordingly, genome analyses of R. solani isolates are important to uncover their pathogenic potential. Draft genome sequences for four R. solani isolates representing three of the 14 R. solani anastomosis groups (AGs) are available. Here, we present the first draft genome sequence for an R. solani AG2-2IIIB isolate that is pathogenic on sugar beet. The fungal genome was assembled in 2065 scaffolds consisting of 5826 contigs amounting to a size of about 52 Mb which is larger than any other R. solani isolate known today. Genes potentially encoding cellulolytic, lignolytic and pectinolytic enzymes were identified.

  17. Examining Involvement as a Critical Factor: Perceptions from First Generation and Non-First Generation College Students

    ERIC Educational Resources Information Center

    Davenport, Mona Yvette

    2010-01-01

    This study tested the perceptions of involvement components (Non-Academic Facility Usage, Intra-Racial Relations, Campus and Charleston Involvement, Faculty Interaction, Academic Facility Usage, Inter-Racial Relations, Cultural Center Usage, and Athletic Facilities Usage) for first generation and non-first generation African American and Hispanic…

  18. Examining Involvement as a Critical Factor: Perceptions from First Generation and Non-First Generation College Students

    ERIC Educational Resources Information Center

    Davenport, Mona Yvette

    2010-01-01

    This study tested the perceptions of involvement components (Non-Academic Facility Usage, Intra-Racial Relations, Campus and Charleston Involvement, Faculty Interaction, Academic Facility Usage, Inter-Racial Relations, Cultural Center Usage, and Athletic Facilities Usage) for first generation and non-first generation African American and Hispanic…

  19. Docetaxel, Cisplatin, Pegfilgrastim, and Erlotinib Hydrochloride in Treating Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2017-07-28

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Bronchoalveolar Cell Lung Cancer; Large Cell Lung Cancer; Non-small Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  20. Pathological and biochemical studies of mucopolysaccharidosis type IIIB (Sanfilippo syndrome type B) in juvenile emus (Dromaius novaehollandiae).

    PubMed

    Palmieri, C; Giger, U; Wang, P; Pizarro, M; Shivaprasad, H L

    2015-01-01

    Mucopolysaccharidosis (MPS) type IIIB was diagnosed in 14 juvenile emus (Dromaius novaehollandiae), ages 3 weeks to 6 months, based on pathological and biochemical analyses. The animals had a history of neurological signs or sudden death; one of the birds with neurological signs and 3 others experienced acute hemoabdomen. Histopathologically, neuronal swelling and vacuolation in the cerebrum, cerebellum, brainstem, and spinal cord (80%-92%); retina (100%); autonomic ganglia of the intestine (71%); gizzard (50%); adrenal gland (27%); and ear (50%) were noted in affected but not healthy emus. Cytoplasmic vacuoles were also observed in the pancreas, liver, intestine, adrenal glands, and kidneys. The intracytoplasmic inclusions were periodic acid-Schiff and Luxol Fast Blue positive, consistent with a storage disease. Foamy macrophages infiltrated the liver, intestine, tunica media of the aorta, and spleen. By transmission electron microscopy, typical lamellated cytoplasmic bodies were detected in neurons of the brain and retina, while electron-dense bodies consistent with glycosaminoglycan inclusions were observed in hepatocytes and/or hepatic macrophages. The livers of the 2 affected emus studied contained large amounts of heparan sulfate, which is suggestive of MPS type III. Compared with normal controls, hepatic and serum α-N-acetylglucosaminidase activity was very low (<8% of control), while other enzyme activities were normal to increased in the 2 affected emus studied. Moreover, affected emus were homozygous for a 2-bp deletion in the NAGLU gene. This study characterizes the pathology of MPS type IIIB in emus, which is one of the rare inborn errors in birds, showing the homology of this condition to Sanfilippo syndrome in humans.

  1. Chemoradiotherapy followed by consolidation chemotherapy involving paclitaxel and carboplatin and in FIGO stage IIIB/IVA cervical cancer patients

    PubMed Central

    2017-01-01

    Objective To evaluate the efficacy and toxicity of paclitaxel plus carboplatin (TC)-based concurrent chemoradiotherapy (CCRT) followed by consolidation chemotherapy in the International Federation of Gynecology and Obstetrics (FIGO) stage IIIB/IVA cervical cancer patients. Methods We reviewed the medical records of FIGO stage IIIB/IVA cervical cancer patients (n=30) who had been intended to be treated with TC-based CCRT followed by consolidation chemotherapy (TC-CCRT-group) from April 2012–May 2016. Patients who had been treated with CCRT involving a single platinum agent (CCRT-group; n=52) or definitive radiotherapy alone (RT-group; n=74) from January 1997–September 2012 were also identified and used as historical controls. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. Results Of the 30 patients included in the TC-CCRT-group, 22 patients (73.3%) completed the planned TC-based CCRT. The most frequently observed acute grade 3/4 hematological toxicities were leukopenia and neutropenia, and diarrhea was the most common acute grade 3/4 non-hematological toxicity. After a median follow-up of 35 months, 9 patients (30.0%) had developed recurrent disease. The patients’ estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 67.9% and 90.8%, respectively. In comparisons with historical control groups, the survival outcomes of TC-CCRT-group was significantly superior to CCRT-group in terms of OS (p=0.011) and significantly superior to RT-group in terms of both PFS (p=0.009) and OS (p<0.001). Conclusion TC-based CCRT followed by consolidation chemotherapy is safe and effective. A randomized controlled study needs to be conducted to further evaluate the efficacy of this multimodal approach in this patient population. PMID:27958682

  2. Clotting factor VIII (FVIII) and thrombin generation in camel plasma: A comparative study with humans

    PubMed Central

    Abdel Gader, Abdel Galil M.; Al Momen, Abdul Karim M.; Alhaider, Abdulqader; Brooks, Marjory B.; Catalfamo, James L.; Al Haidary, Ahmed A.; Hussain, Mansour F.

    2013-01-01

    The objective of this study was to characterize the highly elevated levels of clotting factor VIII (FVIII) in camel plasma. Whole blood was collected from healthy camels and factor VIII clotting activity (FVIII:C) assays were conducted using both the clotting and the chromogenic techniques. The anticoagulant citrate phosphate dextrose adenine (CPDA) produced the highest harvest of FVIII:C, the level of plasma factor VIII, compared to heparin:saline and heparin:CPDA anticoagulants. Camel FVIII can be concentrated 2 to 3 times in cryoprecipitate. There was a significant loss of camel FVIII when comparing levels of FVIII in camel plasma after 1 h of incubation at 37°C (533%), 40°C (364%), and 50°C (223%). Thrombin generation of camel plasma is comparable to that of human plasma. It was concluded that camel plasma contains very elevated levels of FVIII:C, approaching 8 times the levels in human plasma, and that these elevated levels could not be attributed to excessive thrombin generation. Unlike human FVIII:C, camel FVIII:C is remarkably heat stable. Taken together, these unique features of camel FVIII could be part of the physiological adaptation of hemostasis of the Arabian camel in order to survive in the hot desert environment. PMID:24082408

  3. Generating a robust statistical causal structure over 13 cardiovascular disease risk factors using genomics data.

    PubMed

    Yazdani, Azam; Yazdani, Akram; Samiei, Ahmad; Boerwinkle, Eric

    2016-04-01

    Understanding causal relationships among large numbers of variables is a fundamental goal of biomedical sciences and can be facilitated by Directed Acyclic Graphs (DAGs) where directed edges between nodes represent the influence of components of the system on each other. In an observational setting, some of the directions are often unidentifiable because of Markov equivalency. Additional exogenous information, such as expert knowledge or genotype data can help establish directionality among the endogenous variables. In this study, we use the method of principle component analysis to extract information across the genome in order to generate a robust statistical causal network among phenotypes, the variables of primary interest. The method is applied to 590,020 SNP genotypes measured on 1596 individuals to generate the statistical causal network of 13 cardiovascular disease risk factor phenotypes. First, principal component analysis was used to capture information across the genome. The principal components were then used to identify a robust causal network structure, GDAG, among the phenotypes. Analyzing a robust causal network over risk factors reveals the flow of information in direct and alternative paths, as well as determining predictors and good targets for intervention. For example, the analysis identified BMI as influencing multiple other risk factor phenotypes and a good target for intervention to lower disease risk.

  4. Generating Pedestrian Trajectories Consistent with the Fundamental Diagram Based on Physiological and Psychological Factors

    PubMed Central

    Narang, Sahil; Best, Andrew; Curtis, Sean; Manocha, Dinesh

    2015-01-01

    Pedestrian crowds often have been modeled as many-particle system including microscopic multi-agent simulators. One of the key challenges is to unearth governing principles that can model pedestrian movement, and use them to reproduce paths and behaviors that are frequently observed in human crowds. To that effect, we present a novel crowd simulation algorithm that generates pedestrian trajectories that exhibit the speed-density relationships expressed by the Fundamental Diagram. Our approach is based on biomechanical principles and psychological factors. The overall formulation results in better utilization of free space by the pedestrians and can be easily combined with well-known multi-agent simulation techniques with little computational overhead. We are able to generate human-like dense crowd behaviors in large indoor and outdoor environments and validate the results with captured real-world crowd trajectories. PMID:25875932

  5. Radiotherapy treatment planning with dynamic wedges--an algorithm for generating wedge factors and beam data.

    PubMed

    Thomas, S J; Foster, K R

    1995-09-01

    If the jaws of a linear accelerator are moved under computer control during irradiation, dose distributions similar to those with wedge filters can be produced. Varian linear accelerators utilize this effect to give a 'dynamic wedge', using segmented treatment tables (STTs). An algorithm is described to generate the dose per monitor unit at any point in a beam, using the STT values. Dynamically wedged beams are modelled as the superposition of static asymmetric beams, using an algorithm based on beam data measured for symmetric beams. Predictions of wedge factors, depth doses and profiles generated using the algorithm are compared with measurements. Good agreement is found between predictions and measurements. The calculation time is typically 5 ms/dose point on a PC with a 486DX processor.

  6. Converting cell fates: generating hematopoietic stem cells de novo via transcription factor reprogramming.

    PubMed

    Daniel, Michael G; Lemischka, Ihor R; Moore, Kateri

    2016-04-01

    Even though all paradigms of stem cell therapy and regenerative medicine emerged from the study of hematopoietic stem cells (HSCs), the inability to generate these cells de novo or expand them in vitro persists. Initial efforts to obtain these cells began with the use of embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) technologies, but these strategies have yet to yield fully functional cells. Subsequently, more recent approaches involve transcription factor (TF) overexpression to reprogram PSCs and various somatic cells. The induction of pluripotency with just four TFs by Yamanaka informs our ability to convert cell fates and demonstrates the feasibility of utilizing terminally differentiated cells to generate cells with multilineage potential. In this review, we discuss the recent efforts undertaken using TF-based reprogramming strategies to convert several cell types into HSCs. © 2016 New York Academy of Sciences.

  7. A Progenitor Cell Expressing Transcription Factor RORγt Generates All Human Innate Lymphoid Cell Subsets.

    PubMed

    Scoville, Steven D; Mundy-Bosse, Bethany L; Zhang, Michael H; Chen, Li; Zhang, Xiaoli; Keller, Karen A; Hughes, Tiffany; Chen, Luxi; Cheng, Stephanie; Bergin, Stephen M; Mao, Hsiaoyin C; McClory, Susan; Yu, Jianhua; Carson, William E; Caligiuri, Michael A; Freud, Aharon G

    2016-05-17

    The current model of murine innate lymphoid cell (ILC) development holds that mouse ILCs are derived downstream of the common lymphoid progenitor through lineage-restricted progenitors. However, corresponding lineage-restricted progenitors in humans have yet to be discovered. Here we identified a progenitor population in human secondary lymphoid tissues (SLTs) that expressed the transcription factor RORγt and was unique in its ability to generate all known ILC subsets, including natural killer (NK) cells, but not other leukocyte populations. In contrast to murine fate-mapping data, which indicate that only ILC3s express Rorγt, these human progenitor cells as well as human peripheral blood NK cells and all mature ILC populations expressed RORγt. Thus, all human ILCs can be generated through an RORγt(+) developmental pathway from a common progenitor in SLTs. These findings help establish the developmental signals and pathways involved in human ILC development.

  8. Oxidatively generated base modifications in DNA: Not only carcinogenic risk factor but also regulatory mark?

    PubMed

    Seifermann, Marco; Epe, Bernd

    2017-06-01

    The generation of DNA modifications in cells is in most cases accidental and associated with detrimental consequences such as increased mutation rates and an elevated risk of malignant transformation. Accordingly, repair enzymes involved in the removal of the modifications have primarily a protective function. Among the well-established exceptions of this rule are 5-methylcytosine and uracil, which are generated in DNA enzymatically under controlled conditions and fulfill important regulatory functions in DNA as epigenetic marks and in antibody diversification, respectively. More recently, considerable evidence has been obtained that also 8-oxo-7,8-dihydroguanine (8-oxoG), a frequent pro-mutagenic DNA modification generated by endogenous or exogenous reactive oxygen species (ROS), has distinct roles in the regulation of both transcription and signal transduction. Thus, the activation of transcription by the estrogen receptor, NF-κB, MYC and other transcription factors was shown to depend on the presence of 8-oxoG in the promoter regions and its recognition by the DNA repair glycosylase OGG1. The lysine-specific histone demethylase LSD1, which produces H2O2 as a by-product, was indentified as a local generator of 8-oxoG in some of these cases. In addition, a complex of OGG1 with the excised free substrate base was demonstrated to act as a guanine nucleotide exchange factor (GEF) for small GTPases such as Ras, Rac and Rho, thus stimulating signal transduction. The various findings and intriguing novel mechanisms suggested will be described and compared in this review. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Performance of the new 2011 ACR/EULAR remission criteria with tocilizumab using the phase IIIb study TAMARA as an example and their comparison with traditional remission criteria

    PubMed Central

    Iking-Konert, Christof; Aringer, Martin; Wollenhaupt, Jürgen; Mosch, Thomas; Tuerk, Stefan; Feist, Eugen; Burmester, Gerd R

    2011-01-01

    Background Remission is the established goal in rheumatoid arthritis (RA) treatment. Although originally defined by a disease activity score in 28 joints (DAS28) <2.6, more stringent criteria may imply the absence of disease activity. The 2011 ACR/EULAR remission criteria provide the newest and most stringent definition of remission. Objectives To evaluate post hoc the remission by ACR/EULAR criteria and compare the criteria with the conventional DAS28 in TAMARA, an open-label phase IIIb tocilizumab (TCZ) trial including patients with active RA receiving inadequate disease-modifying antirheumatic drugs (DMARDs) or tumour necrosis factor α (TNFα) inhibitor treatment. Results 286 patients were enrolled, 99.7% of patients were receiving a conventional DMARD and 41.6% had TNFα inhibitor pretreatment. Baseline mean DAS28 of 6.0 ± 1.0 fell to 2.6 ± 1.5 at week 24. DAS28 <2.6 was achieved by 47.6% at week 24. Remission rates with the new ACR/EULAR Boolean-based criteria for clinical studies were 15.0% after 12 weeks and 20.3% after 24 weeks. Of note, 13.5% of patients with previous TNFα blocker inadequate response still achieved remission according to the new ACR/EULAR criteria after 24 weeks. Clinical Disease Activity Index and Simplified Disease Activity Index remission rates were 24.1% and 25.2%, respectively. Conclusions Under the definition of the new stringent 2011 ACR/EULAR remission criteria, patients with active RA despite DMARD treatment and even after inadequate response to TNFα inhibitors, receiving TCZ showed significant rates of remission. Similar remission rates were achieved, when clinical practice criteria, not inclusive of acute phase reactants, were used. PMID:21875873

  10. Performance of the new 2011 ACR/EULAR remission criteria with tocilizumab using the phase IIIb study TAMARA as an example and their comparison with traditional remission criteria.

    PubMed

    Iking-Konert, Christof; Aringer, Martin; Wollenhaupt, Jürgen; Mosch, Thomas; Tuerk, Stefan; Feist, Eugen; Burmester, Gerd R

    2011-11-01

    Remission is the established goal in rheumatoid arthritis (RA) treatment. Although originally defined by a disease activity score in 28 joints (DAS28) <2.6, more stringent criteria may imply the absence of disease activity. The 2011 ACR/EULAR remission criteria provide the newest and most stringent definition of remission. To evaluate post hoc the remission by ACR/EULAR criteria and compare the criteria with the conventional DAS28 in TAMARA, an open-label phase IIIb tocilizumab (TCZ) trial including patients with active RA receiving inadequate disease-modifying antirheumatic drugs (DMARDs) or tumour necrosis factor α (TNFα) inhibitor treatment. 286 patients were enrolled, 99.7% of patients were receiving a conventional DMARD and 41.6% had TNFα inhibitor pretreatment. Baseline mean DAS28 of 6.0 ± 1.0 fell to 2.6 ± 1.5 at week 24. DAS28 <2.6 was achieved by 47.6% at week 24. Remission rates with the new ACR/EULAR Boolean-based criteria for clinical studies were 15.0% after 12 weeks and 20.3% after 24 weeks. Of note, 13.5% of patients with previous TNFα blocker inadequate response still achieved remission according to the new ACR/EULAR criteria after 24 weeks. Clinical Disease Activity Index and Simplified Disease Activity Index remission rates were 24.1% and 25.2%, respectively. Under the definition of the new stringent 2011 ACR/EULAR remission criteria, patients with active RA despite DMARD treatment and even after inadequate response to TNFα inhibitors, receiving TCZ showed significant rates of remission. Similar remission rates were achieved, when clinical practice criteria, not inclusive of acute phase reactants, were used.

  11. Inhibition of tissue factor pathway inhibitor increases the sensitivity of thrombin generation assay to procoagulant microvesicles.

    PubMed

    Gheldof, Damien; Mullier, François; Chatelain, Bernard; Dogné, Jean-Michel; Chatelain, Christian

    2013-07-01

    Patients with cancer have a seven-fold to 10-fold increased risk of developing venous thromboembolism (VTE). Circulating microvesicles could be a predictive biomarker for VTE in cancer. Thrombin generation assay (TGA) is a useful technique to detect procoagulant activity of microvesicles. However, TGA suffers from a lack of sensitivity due to the presence of tissue factor pathway inhibitor (TFPI) in plasma. The aim of the study was to improve the sensitivity of TGA to tissue factor by limiting the interference of TFPI. Serial dilutions of MDA-MB231 cells were incubated for 45 min at 37°C to generate microvesicles. Samples were then centrifuged and supernatants that contain microvesicles were used for TGA. Normal pooled plasma was incubated with inhibitor of TFPI or was diluted twice to decrease plasma level of TFPI. Lagtime was used as a surrogate marker of TGA to detect procoagulant activity of microvesicles. Inhibition of TFPI decreased twice the cell concentration needed for a significant reduction of lagtime and decreased 2.4-fold the intraassay variability. Plasma dilution had no impact on the TGA sensitivity when TGA was triggered by microvesicles derived from MDA-MB-231. Thrombin generation is a very sensitive method to study the procoagulant activity of tissue factor bearing microvesicles. The sensitivity can be increased by inhibition of TFPI with specific monoclonal antibody against its Kunitz domain I. A two times plasma dilution is an interesting cheaper alternative to study the procoagulant activity of microvesicles by TGA with a good sensitivity, especially when low plasma quantities are available.

  12. Colonization with third-generation cephalosporin-resistant Enterobacteriaceae on hospital admission: prevalence and risk factors.

    PubMed

    Hamprecht, A; Rohde, A M; Behnke, M; Feihl, S; Gastmeier, P; Gebhardt, F; Kern, W V; Knobloch, J K; Mischnik, A; Obermann, B; Querbach, C; Peter, S; Schneider, C; Schröder, W; Schwab, F; Tacconelli, E; Wiese-Posselt, M; Wille, T; Willmann, M; Seifert, H; Zweigner, J

    2016-10-01

    The objectives of this study were to prospectively assess the rectal carriage rate of third-generation cephalosporin-resistant Enterobacteriaceae (3GCREB) in non-ICU patients on hospital admission and to investigate resistance mechanisms and risk factors for carriage. Adult patients were screened for 3GCREB carriage at six German tertiary care hospitals in 2014 using rectal swabs or stool samples. 3GCREB isolates were characterized by phenotypic and molecular methods. Each patient answered a questionnaire about potential risk factors for colonization with MDR organisms (MDROs). Univariable and multivariable risk factor analyses were performed to identify factors associated with 3GCREB carriage. Of 4376 patients, 416 (9.5%) were 3GCREB carriers. Escherichia coli was the predominant species (79.1%). ESBLs of the CTX-M-1 group (67.3%) and the CTX-M-9 group (16.8%) were the most frequent β-lactamases. Five patients (0.11%) were colonized with carbapenemase-producing Enterobacteriaceae. The following risk factors were significantly associated with 3GCREB colonization in the multivariable analysis (P < 0.05): centre; previous MDRO colonization (OR = 2.12); antibiotic use within the previous 6 months (OR = 2.09); travel outside Europe (OR = 2.24); stay in a long-term care facility (OR = 1.33); and treatment of gastroesophageal reflux disease (GERD) (OR = 1.22). To our knowledge, this is the largest admission prevalence study of 3GCREB in Europe. The observed prevalence of 9.5% 3GCREB carriage was higher than previously reported and differed significantly among centres. In addition to previously identified risk factors, the treatment of GERD proved to be an independent risk factor for 3GCREB colonization. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. A Survey of Combat Models for Use in CARF (Combat Active Replacement Factor) Value Generation

    DTIC Science & Technology

    1985-03-01

    requirements for the degree of MASTER OF SCIENCE IN CPERATIONS RESEARCH from the NAVAL POSTGRADUATE SCHOOL darch 1985 Author: tv Approved by :... - n Z ...GENERATION OF A WARTIME ACTIVE REPLACEMENT FACTOR (WARF) 65 A. THE PREPROCESSER ................. 66 B. THE COMBAT SAMPLE GEERATOR (COSAGE) MODEL 66 C. THE...en -T,, , -T T L T 17, V 7777% T -T T K 97 7 Ř 7 T W 71 T 7 - Z W.; ., . 7. , II. THE CARF GENERA7ION SYSTEM TODAY The previous and current CARF

  14. Generation of mouse ES cell lines engineered for the forced induction of transcription factors

    PubMed Central

    Correa-Cerro, Lina S.; Piao, Yulan; Sharov, Alexei A.; Nishiyama, Akira; Cadet, Jean S.; Yu, Hong; Sharova, Lioudmila V.; Xin, Li; Hoang, Hien G.; Thomas, Marshall; Qian, Yong; Dudekula, Dawood B.; Meyers, Emily; Binder, Bernard Y.; Mowrer, Gregory; Bassey, Uwem; Longo, Dan L.; Schlessinger, David; Ko, Minoru S. H.

    2011-01-01

    Here we report the generation and characterization of 84 mouse ES cell lines with doxycycline-controllable transcription factors (TFs) which, together with the previous 53 lines, cover 7–10% of all TFs encoded in the mouse genome. Global gene expression profiles of all 137 lines after the induction of TFs for 48 hrs can associate each TF with the direction of ES cell differentiation, regulatory pathways, and mouse phenotypes. These cell lines and microarray data provide building blocks for a variety of future biomedical research applications as a community resource. PMID:22355682

  15. Factors affecting the appreciation generated through applying human factors/ergonomics (HFE) principles to systems of work.

    PubMed

    So, R H Y; Lam, S T

    2014-01-01

    This retrospective study examined the levels of appreciation (applause) given by clients to Human Factors/Ergonomic (HFE) specialists after they have modified the systems of work. Thirteen non-academic projects were chosen because the HFE interventions involved changed the way workers work at their workplaces. Companies involved range from multi-national corporations and military organizations with thousands of employees to small trading companies with less than 10 employees. In 5 cases the HFE recommendations were fully adopted and well appreciated. In 4 they were largely ignored and not appreciated, with partial adoption and some appreciation in the other 4 cases. Three factors that predict appreciation were identified: (i) alignment between the benefits HFE can provide and the project's key performance indices; (ii) awareness of HFE among the client's senior management; and (iii) a team organization appropriate for applying HFE recommendations. Having an HFE specialist on the client's side can greatly increase levels of appreciation, but lack of such a specialist will not affect levels of appreciation. A clear contractual requirement for HFE intervention does not promote appreciation significantly, but its absence can greatly reduce levels of appreciation. These relationships are discussed using the Kano's model of quality. Means to generate greater appreciation of the benefits of HFE are discussed.

  16. Subspecies IIIa and IIIb Salmonellae are defective for colonization of murine models of salmonellosis compared to Salmonella enterica subsp. I serovar typhimurium.

    PubMed

    Katribe, Erin; Bogomolnaya, Lydia M; Wingert, Heather; Andrews-Polymenis, Helene

    2009-04-01

    Non-subspecies I salmonellae are commensals of cold-blooded vertebrates and cause sporadic disease in mammals. The reasons why non-subspecies I salmonellae do not circulate in populations of warm-blooded vertebrates, but instead only cause occasional disease in this niche, are unknown. We examined the ability of Salmonella enterica subsp. IIIa (subsp. arizonae) and subsp. IIIb (subsp. diarizonae) isolates to grow competitively with subspecies I (serovar Typhimurium) ATCC 14028 in vitro, to colonize Salmonella-sensitive BALB/c mice, and to persist in the intestine of Salmonella-resistant CBA/J mice in competitive infections. Subspecies IIIa had severely reduced intestinal colonization, intestinal persistence, and systemic spread in mice. Subspecies IIIa is nonmotile on swarming agar and thus may also have reduced motility under viscous conditions in vivo. Surprisingly, subspecies IIIb colonizes the intestinal tract of BALB/c mice normally yet does not spread systemically. Subspecies IIIb colonization of the intestine of CBA/J mice is reduced late in infection. In order to understand why these isolates do not colonize systemic sites, we determined that subspecies IIIa and IIIb are not internalized well and do not replicate in J774-A.1 murine macrophages, despite normal adherence to these cells. We further show that selected effectors of both type III secretion systems 1 and 2 are secreted by subspecies IIIa and IIIb in vitro but that each of these isolates secretes a different combination of effectors. We outline the phenotypic differences between these subspecies and subspecies I and provide a possible explanation for the inability of these strains to spread systemically in murine models.

  17. X4-tropic human immunodeficiency virus IIIB utilizes CXCR4 as coreceptor, as distinct from R5X4-tropic viruses.

    PubMed

    Islam, Salequl; Hoque, Sheikh Ariful; Adnan, Nihad; Tanaka, Atsushi; Jinno-Oue, Atsushi; Hoshino, Hiroo

    2013-06-01

    Human immunodeficiency viruses initiate infections via CCR5 coreceptors and then change their tropism to C-X-C chemokine receptor type 4 (CXCR4), this change being associated with rapid disease progression. HIV-1IIIB, a widely described pure X4-tropic strain, is distinct from R5X4-tropic viruses. In this study, the requirement for amino terminal regions (NTRs) of CXCR4 for entry of HIV-1IIIB virus into host cells was examined and compared to that of R5X4-tropic viruses. CXCR4 and its deletion mutant (CXCR4ΔNTR23; first 23 amino acids removed from NTR) were amplified to examine their coreceptor activities. NP-2/CD4/CXCR4 and NP-2/CD4/CXCR4ΔNTR23 cell lines were prepared accordingly. Indirect immune fluorescence assay (IFA), PCR, and reverse transcriptase (RT) activity were used to compare the process of infection of host cells by HIV-1IIIB virus, one R5-tropic and five other R5X4-tropic viruses. All the R5X4-tropic HIVs were found to utilize both CCR5 and CXCR4 but unable to use CXCR4ΔNTR23 as coreceptors. In contrast, X4-tropic HIV-1IIIB was found to preferentially infect through CXCR4ΔNTR23. Viral antigens in infected NP-2/CD4/CXCR4ΔNTR23 cells were detected by IFA and confirmed by detection of proviral DNA and by performing RT assays on the spent cell-supernatants. In dual tropic viruses, deletion of 23 amino acids from NTR abrogates the coreceptor activity of CXCR4. This observation demonstrates that NTR of CXCR4 have an obligatory coreceptor role for dual tropic viruses. However, HIV-1IIIB may have different requirements for NTR than R5X4 viruses or may infect host cells independent of NTR of CXCR4.

  18. Platelet factor 4 enhances generation of activated protein C in vitro and in vivo.

    PubMed

    Slungaard, Arne; Fernandez, Jose A; Griffin, John H; Key, Nigel S; Long, Janel R; Piegors, Donald J; Lentz, Steven R

    2003-07-01

    Platelet factor 4 (PF4), an abundant platelet alpha-granule protein, accelerates in vitro generation of activated protein C (APC) by soluble thrombin/thrombomodulin (TM) complexes up to 25-fold. To test the hypothesis that PF4 similarly stimulates endothelium-associated TM, we assessed the influence of human PF4 on thrombin-dependent APC generation by cultured endothelial monolayers. APC generated in the presence of 1 to 100 microg PF4 was up to 5-fold higher than baseline for human umbilical vein endothelial cells, 10-fold higher for microvascular endothelial cells, and unaltered for blood outgrowth endothelial cells. In an in vivo model, cynomolgus monkeys (n = 6, each serving as its own control) were infused with either PF4 (7.5 mg/kg) or vehicle buffer, then with human thrombin (1.0 microg/kg/min) for 10 minutes. Circulating APC levels (baseline 3 ng/mL) peaked at 10 minutes, when PF4-treated and vehicle-treated animals had APC levels of 67 +/- 5 ng/mL and 39 +/- 2 ng/mL, respectively (P <.001). The activated partial thromboplastin time (APTT; baseline, 28 seconds) increased maximally by 27 +/- 6 seconds in PF4-treated animals and by 9 +/- 1 seconds in control animals at 30 minutes (P <.001). PF4-dependent increases in circulating APC and APTT persisted more than 2-fold greater than that of controls from 10 through 120 minutes (P < or =.04). All APTT prolongations were essentially reversed by monoclonal antibody C3, which blocks APC activity. Thus, physiologically relevant concentrations of PF4 stimulate thrombin-dependent APC generation both in vitro by cultured endothelial cells and in vivo in a primate thrombin infusion model. These findings suggest that PF4 may play a previously unsuspected physiologic role in enhancing APC generation.

  19. Isolated and Passive Power Factor Correction AC/DC Converter for Radioisotope Stirling Generators

    NASA Astrophysics Data System (ADS)

    Garrigos, A.; Blanes, J. M.; Gutierrez, R.; Lizan, J. L.; Carrasco, J. A.; Maset, E.; Montalban, G.; Sanchis-Kilders, E.; Ejea, J. B.; Ferreres, A.

    2014-08-01

    A power processing system is described for low voltage, large inductance, single-phase alternator. This kind of electrical machine appears in Radioisotope Stirling Generators (RSG) as the electrical part attached to the thermodynamic system. The proposed power conditioning system splits into two independent stages; the front-end rectifier performs power factor control by adding a series capacitor in the AC side that forms a resonant filter with the alternator parasitic inductance. Further, the rectifier, thanks to the alternator inductance, behaves as a constant current source that supplies a current-fed, zero-voltage, zero-current push-pull stage. This approach takes advantage of all parasitic elements. Finally, some discussion about linear shunt and reconfigurable power factor filter is provided.

  20. The Impact of Local and Regional Disease Extent on Overall Survival in Patients With Advanced Stage IIIB/IV Non-Small Cell Lung Carcinoma

    SciTech Connect

    Higginson, Daniel S.; Chen, Ronald C.; Tracton, Gregg; Morris, David E.; Halle, Jan; Rosenman, Julian G.; Stefanescu, Mihaela; Pham, Erica; Socinski, Mark A.; Marks, Lawrence B.

    2012-11-01

    Purpose: Patients with advanced stage IIIB or stage IV non-small cell lung carcinoma are typically treated with initial platinum-based chemotherapy. A variety of factors (eg, performance status, gender, age, histology, weight loss, and smoking history) are generally accepted as predictors of overall survival. Because uncontrolled pulmonary disease constitutes a major cause of death in these patients, we hypothesized that clinical and radiographic factors related to intrathoracic disease at diagnosis may be prognostically significant in addition to conventional factors. The results have implications regarding the selection of patients for whom palliative thoracic radiation therapy may be of most benefit. Methods and Materials: We conducted a pooled analysis of 189 patients enrolled at a single institution into 9 prospective phase II and III clinical trials involving first-line, platinum-based chemotherapy. Baseline clinical and radiographic characteristics before trial enrollment were analyzed as possible predictors for subsequent overall survival. To assess the relationship between anatomic location and volume of disease within the thorax and its effect on survival, the pre-enrollment computed tomography images were also analyzed by contouring central and peripheral intrapulmonary disease. Results: On univariate survival analysis, multiple pulmonary-related factors were significantly associated with worse overall survival, including pulmonary symptoms at presentation (P=.0046), total volume of intrathoracic disease (P=.0006), and evidence of obstruction of major bronchi or vessels on prechemotherapy computed tomography (P<.0001). When partitioned into central and peripheral volumes, central (P<.0001) but not peripheral (P=.74) disease was associated with worse survival. On multivariate analysis with known factors, pulmonary symptoms (hazard ratio, 1.46; P=.042), central disease volume (hazard ratio, 1.47; P=.042), and bronchial/vascular compression (hazard ratio, 1

  1. Factors Associated With Electronic Cigarette Users' Device Preferences and Transition From First Generation to Advanced Generation Devices.

    PubMed

    Yingst, Jessica M; Veldheer, Susan; Hrabovsky, Shari; Nichols, Travis T; Wilson, Stephen J; Foulds, Jonathan

    2015-10-01

    Electronic cigarettes (e-cigs) are becoming increasingly popular but little is known about how e-cig users' transition between the different device types and what device characteristics and preferences may influence the transition. Four thousand four hundred twenty-one experienced e-cig users completed an online survey about their e-cig use, devices, and preferences. Participants included in analysis were ever cigarette smokers who used an e-cig at least 30 days in their lifetime and who reported the type of their first and current e-cig device and the nicotine concentration of their liquid. Analyses focused on transitions between "first generation" devices (same size as a cigarette with no button) and "advanced generation" devices (larger than a cigarette with a manual button) and differences between current users of each device type. Most e-cig users (n = 2603, 58.9%) began use with a first generation device, and of these users, 63.7% subsequently transitioned to current use of an advanced generation device. Among users who began use with an advanced generation device (n = 1818, 41.1%), only 5.7% transitioned to a first generation device. Seventy-seven percent of current advanced generation e-cig users switched to their current device in order to obtain a "more satisfying hit." Battery capabilities and liquid flavor choices also influenced device choice. E-cig users commonly begin use with a device shaped like a cigarette and transition to a larger device with a more powerful battery, a button for manual activation and a wider choice of liquid flavors. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  2. Enhancing factors of electricity generation in a microbial fuel cell using Geobacter sulfurreducens.

    PubMed

    Kim, Mi-Sun; Cha, Jaehwan; Kim, Dong-Hoon

    2012-10-01

    In this study, we investigated various cultural and operational factors to enhance electricity generation in a microbial fuel cell (MFC) using Geobacter sulfurreducens. The pure culture of G. sulfurreducens was cultivated using various substrates including acetate, malate, succinate, and butyrate, with fumarate as an electron acceptor. Cell growth was observed only in acetate-fed medium, when the cell concentrations increased 4-fold for 3 days. A high acetate concentration suppressed electricity generation. As the acetate concentration was increased from 5 to 20 mM, the power density dropped from 16 to 13 mW/m2, whereas the coulombic efficiency (CE) declined by about half. The immobilization of G. sulfurreducens on the anode considerably reduced the enrichment period from 15 to 7 days. Using argon gas to create an anaerobic condition in the anode chamber led to increased pH, and electricity generation subsequently dropped. When the plain carbon paper cathode was replaced by Pt-coated carbon paper (0.5 mg Pt/cm2), the CE increased greatly from 39% to 83%.

  3. Asymmetry Factors Shaping Regular and Irregular Bursting Rhythms in Central Pattern Generators

    PubMed Central

    Elices, Irene; Varona, Pablo

    2017-01-01

    Central Pattern Generator (CPG) circuits are neural networks that generate rhythmic motor patterns. These circuits are typically built of half-center oscillator subcircuits with reciprocally inhibitory connections. Another common property in many CPGs is the remarkable rich spiking-bursting dynamics of their constituent cells, which balance robustness and flexibility to generate their joint coordinated rhythms. In this paper, we use conductance-based models and realistic connection topologies inspired by the crustacean pyloric CPG to address the study of asymmetry factors shaping CPG bursting rhythms. In particular, we assess the role of asymmetric maximal synaptic conductances, time constants and gap-junction connectivity to establish the regularity of half-center oscillator based CPGs. We map and characterize the synaptic parameter space that lead to regular and irregular bursting activity in these networks. The analysis indicates that asymmetric configurations display robust regular rhythms and that large regions of both regular and irregular but coordinated rhythms exist as a function of the asymmetry in the circuit. Our results show that asymmetry both in the maximal conductances and in the temporal dynamics of mutually inhibitory neurons can synergistically contribute to shape wide regimes of regular spiking-bursting activity in CPGs. Finally, we discuss how a closed-loop protocol driven by a regularity goal can be used to find and characterize regular regimes when there is not time to perform an exhaustive search, as in most experimental studies. PMID:28261081

  4. Rapid and efficient generation of oligodendrocytes from human induced pluripotent stem cells using transcription factors

    PubMed Central

    Ehrlich, Marc; Mozafari, Sabah; Glatza, Michael; Starost, Laura; Velychko, Sergiy; Hallmann, Anna-Lena; Cui, Qiao-Ling; Schambach, Axel; Kim, Kee-Pyo; Bachelin, Corinne; Marteyn, Antoine; Hargus, Gunnar; Johnson, Radia Marie; Antel, Jack; Sterneckert, Jared; Zaehres, Holm; Schöler, Hans R.; Baron-Van Evercooren, Anne; Kuhlmann, Tanja

    2017-01-01

    Rapid and efficient protocols to generate oligodendrocytes (OL) from human induced pluripotent stem cells (iPSC) are currently lacking, but may be a key technology to understand the biology of myelin diseases and to develop treatments for such disorders. Here, we demonstrate that the induction of three transcription factors (SOX10, OLIG2, NKX6.2) in iPSC-derived neural progenitor cells is sufficient to rapidly generate O4+ OL with an efficiency of up to 70% in 28 d and a global gene-expression profile comparable to primary human OL. We further demonstrate that iPSC-derived OL disperse and myelinate the CNS of Mbpshi/shi Rag−/− mice during development and after demyelination, are suitable for in vitro myelination assays, disease modeling, and screening of pharmacological compounds potentially promoting oligodendroglial differentiation. Thus, the strategy presented here to generate OL from iPSC may facilitate the studying of human myelin diseases and the development of high-throughput screening platforms for drug discovery. PMID:28246330

  5. Asymmetry Factors Shaping Regular and Irregular Bursting Rhythms in Central Pattern Generators.

    PubMed

    Elices, Irene; Varona, Pablo

    2017-01-01

    Central Pattern Generator (CPG) circuits are neural networks that generate rhythmic motor patterns. These circuits are typically built of half-center oscillator subcircuits with reciprocally inhibitory connections. Another common property in many CPGs is the remarkable rich spiking-bursting dynamics of their constituent cells, which balance robustness and flexibility to generate their joint coordinated rhythms. In this paper, we use conductance-based models and realistic connection topologies inspired by the crustacean pyloric CPG to address the study of asymmetry factors shaping CPG bursting rhythms. In particular, we assess the role of asymmetric maximal synaptic conductances, time constants and gap-junction connectivity to establish the regularity of half-center oscillator based CPGs. We map and characterize the synaptic parameter space that lead to regular and irregular bursting activity in these networks. The analysis indicates that asymmetric configurations display robust regular rhythms and that large regions of both regular and irregular but coordinated rhythms exist as a function of the asymmetry in the circuit. Our results show that asymmetry both in the maximal conductances and in the temporal dynamics of mutually inhibitory neurons can synergistically contribute to shape wide regimes of regular spiking-bursting activity in CPGs. Finally, we discuss how a closed-loop protocol driven by a regularity goal can be used to find and characterize regular regimes when there is not time to perform an exhaustive search, as in most experimental studies.

  6. Generation of induced pluripotent stem cells from buffalo (Bubalus bubalis) fetal fibroblasts with buffalo defined factors.

    PubMed

    Deng, Yanfei; Liu, Qingyou; Luo, Chan; Chen, Shibei; Li, Xiangping; Wang, Caizhu; Liu, Zhenzhen; Lei, Xiaocan; Zhang, Huina; Sun, Hongliang; Lu, Fenghua; Jiang, Jianrong; Shi, Deshun

    2012-09-01

    Ectopically, expression of defined factors could reprogram mammalian somatic cells into induced pluripotent stem cells (iPSCs), which initiates a new strategy to obtain pluripotent stem cell lines. Attempts have been made to generate buffalo pluripotent stem cells by culturing primary germ cells or inner cell mass, but the efficiency is extremely low. Here, we report a successful method to reprogram buffalo fetal fibroblasts (BFFs) into pluripotent stem cells [buffalo induced pluripotent stem cell (biPSCs)] by transduction of buffalo defined factors (Oct4, Sox2, Klf4, and c-Myc) using retroviral vectors. The established biPSCs displayed typical morphological characteristics of pluripotent stem cells, normal karyotype, positive staining of alkaline phosphatase, and expressed pluripotent markers including Oct4, Sox2, Nanog, Lin28, E-Cadherin, SSEA-1, SSEA-4, TRA-1-81, STAT3, and FOXD3. They could form embryoid bodies (EBs) in vitro and teratomas after injecting into the nude BALB/C mice, and 3 germ layers were identified in the EBs and teratomas. Methylation assay revealed that the promoters of Oct4 and Nanog were hypomethylated in biPSCs compared with BFFs and pre-biPSCs, while the promoters of Sox2 and E-Cadherin were hypomethylated in both BFFs and biPSCs. Further, inhibiting p53 expression by coexpression of SV40 large T antigen and buffalo defined factors in BFFs or treating BFFs with p53 inhibitor pifithrin-a (PFT) could increase the efficiency of biPSCs generation up to 3-fold, and nuclear transfer embryos reconstructed with biPSCs could develop to blastocysts. These results indicate that BFFs can be reprogrammed into biPSCs by buffalo defined factors, and the generation efficiency of biPSCs can be increased by inhibition of p53 expression. These efforts will provide a feasible approach for investigating buffalo stem cell signal pathways, establishing buffalo stem cell lines, and producing genetic modification buffaloes in the future.

  7. Maternal haemoglobin levels and cardio-metabolic risk factors in childhood: the Generation R study.

    PubMed

    Welten, M; Gaillard, R; Hofman, A; de Jonge, L L; Jaddoe, V W V

    2015-05-01

    To assess whether variations in maternal haemoglobin levels during pregnancy are associated with cardio-metabolic risk factors in school age children. Population-based prospective cohort study. Rotterdam, The Netherlands, 2002-2012. Mothers and children (n = 5002) participating in the Generation R Study. We obtained maternal haemoglobin levels during early pregnancy (median gestational age 14.6 weeks [95% range 10.3, 25.3]) from venous blood samples. Maternal anaemia and elevated haemoglobin levels were based on World Health Organization criteria. We measured childhood cardio-metabolic risk factors at age 6 years. Cardio-metabolic risk factors included body mass index, total fat mass percentage, android/gynoid fat mass ratio, systolic and diastolic blood pressure, left ventricular mass, and blood levels of cholesterol, insulin and C-peptide. Maternal haemoglobin levels were not associated with childhood body mass index, total fat mass percentage, android/gynoid fat mass ratio, systolic blood pressure, cholesterol or insulin levels. Compared with children with normal maternal haemoglobin levels, children from anaemic mothers had slightly higher diastolic blood pressures (difference 0.70 mmHg, 95% CI 0.12, 1.29) and lower C-peptide levels (difference factor 0.93, 95% CI 0.88, 0.98), and children of mothers with elevated haemoglobin levels had lower left ventricular masses (difference -1.08 g, 95% CI -1.88, -0.29). These associations attenuated after adjustment for multiple testing and were not consistent within linear models. These results do not strongly support the hypothesis that variations in maternal haemoglobin levels during pregnancy influence cardio-metabolic risk factors in childhood. © 2014 Royal College of Obstetricians and Gynaecologists.

  8. Factors Influencing the Use of Second-Generation Antipsychotics in Children with Psychosis.

    PubMed

    Ramachandran, Sujith; Banahan, Benjamin F; Bentley, John P; West-Strum, Donna S; Patel, Amit S

    2016-08-01

    In 2011, the U.S. Department of Health and Human Services sent a letter to state Medicaid directors explaining the need for oversight of psychiatric prescriptions for children with mental health disorders. The National Committee for Quality Alliance proposed 3 quality measures for rating managed care organizations (MCOs) that involve use of second-generation or atypical antipsychotics in children. In order to ensure appropriate use and to effectively manage the use of second-generation antipsychotics in children, MCOs need to better understand the factors that influence medication treatment decisions for children. To (a) determine how patient-level and physician-level factors influence decisions to prescribe second-generation antipsychotics to children (aged under 18 years) diagnosed with psychosis and (b) evaluate how the influence of these factors may differ between primary care providers and psychiatrists. This study employed a cross-sectional survey of 193 primary care providers and psychiatrists. A web-based patient simulation survey using a fractional factorial design was administered via a commercial vendor. Respondents were presented with simulated patient profiles described by various levels of factors considered to be essential to decision making. Respondents were asked to make treatment recommendations for each profile evaluated. In addition to treatment recommendations, demographics and beliefs about products were measured. Modified Poisson regression accounting for multilevel data was used to identify the factors that significantly affect treatment recommendations. Psychiatrists were more likely to recommend second-generation antipsychotics than primary care practitioners (unadjusted RR = 1.36, 95% CI = 1.23-1.51). Social factors such as foster status or parental concern were not found to be significant predictors of prescribing second-generation antipsychotics. The percentage of a provider's patients using second-generation antipsychotics (RR = 1

  9. Factors Associated With Electronic Cigarette Users’ Device Preferences and Transition From First Generation to Advanced Generation Devices

    PubMed Central

    Veldheer, Susan; Hrabovsky, Shari; Nichols, Travis T.; Wilson, Stephen J.; Foulds, Jonathan

    2015-01-01

    Introduction: Electronic cigarettes (e-cigs) are becoming increasingly popular but little is known about how e-cig users’ transition between the different device types and what device characteristics and preferences may influence the transition. Methods: Four thousand four hundred twenty-one experienced e-cig users completed an online survey about their e-cig use, devices, and preferences. Participants included in analysis were ever cigarette smokers who used an e-cig at least 30 days in their lifetime and who reported the type of their first and current e-cig device and the nicotine concentration of their liquid. Analyses focused on transitions between “first generation” devices (same size as a cigarette with no button) and “advanced generation” devices (larger than a cigarette with a manual button) and differences between current users of each device type. Results: Most e-cig users (n = 2603, 58.9%) began use with a first generation device, and of these users, 63.7% subsequently transitioned to current use of an advanced generation device. Among users who began use with an advanced generation device (n = 1818, 41.1%), only 5.7% transitioned to a first generation device. Seventy-seven percent of current advanced generation e-cig users switched to their current device in order to obtain a “more satisfying hit.” Battery capabilities and liquid flavor choices also influenced device choice. Conclusion: E-cig users commonly begin use with a device shaped like a cigarette and transition to a larger device with a more powerful battery, a button for manual activation and a wider choice of liquid flavors. PMID:25744966

  10. Generation and characterization of monoclonal antibodies against the transcription factor Nkx6.1.

    PubMed

    Pedersen, Inger L; Klinck, Rasmus; Hecksher-Sorensen, Jacob; Zahn, Stefan; Madsen, Ole D; Serup, Palle; Jorgensen, Mette C

    2006-05-01

    We present the generation of a panel of monoclonal antibodies (F55A10, F55A12, F64A6B4, and F65A2) against the homeodomain transcription factor Nkx6.1, one of the essential transcription factors that regulates the multistep differentiation process of precursor cells into endocrine beta-cells in the pancreas. Expression of Nkx6.1 can be detected in developing pancreatic epithelium and in adult insulin-producing beta-cells, making this transcription factor a unique beta-cell marker. For production of monoclonal antibodies, RBF mice were immunized with a GST-Nkx6.1 fusion protein containing a 66-amino acid C-terminal fragment of rat Nkx6.1. Four clones were established as stable hybridoma cell lines and the produced antibodies were of the mouse IgG1/kappa subtype. When applied for immunohistochemistry on frozen sections of adult mouse pancreas, monoclonal antibodies stain specifically the beta-cells in the endocrine islets of Langerhans with patterns comparable to that of a previously produced polyclonal rabbit serum. Monoclonal antibodies can be divided into two groups that appear to recognize different epitopes, as determined by competition ELISA. The presented antibodies are useful tools for the further characterization of the role and function of Nkx6.1 in pancreatic development, especially for use in double-labeling experiments with existing polyclonal rabbit antibodies.

  11. Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI

    PubMed Central

    Tucker, Erik I.; Marzec, Ulla M.; White, Tara C.; Hurst, Sawan; Rugonyi, Sandra; McCarty, Owen J. T.; Gailani, David; Hanson, Stephen R.

    2009-01-01

    The protease thrombin is required for normal hemostasis and pathologic thrombogenesis. Since the mechanism of coagulation factor XI (FXI)–dependent thrombus growth remains unclear, we investigated the contribution of FXI to thrombus formation in a primate thrombosis model. Pretreatment of baboons with a novel anti–human FXI monoclonal antibody (aXIMab; 2 mg/kg) inhibited plasma FXI by at least 99% for 10 days, and suppressed thrombin-antithrombin (TAT) complex and β-thromboglobulin (βTG) formation measured immediately downstream from thrombi forming within collagen-coated vascular grafts. FXI inhibition with aXIMab limited platelet and fibrin deposition in 4-mm diameter grafts without an apparent increase in D-dimer release from thrombi, and prevented the occlusion of 2-mm diameter grafts without affecting template bleeding times. In comparison, pretreatment with aspirin (32 mg/kg) prolonged bleeding times but failed to prevent graft occlusion, supporting the concept that FXI blockade may offer therapeutic advantages over other antithrombotic agents in terms of bleeding complications. In whole blood, aXIMab prevented fibrin formation in a collagen-coated flow chamber, independent of factor XII and factor VII. These data suggest that endogenous FXI contributes to arterial thrombus propagation through a striking amplification of thrombin generation at the thrombus luminal surface. PMID:18945968

  12. Socioeconomic and Sociodemographic Factors Associated with Asthma Related Outcomes in Early Childhood: The Generation R Study

    PubMed Central

    Hafkamp-de Groen, Esther; Sonnenschein-van der Voort, Agnes M. M.; Mackenbach, Johan P.; Duijts, Liesbeth; Jaddoe, Vincent W. V.; Moll, Henriëtte A.; Hofman, Albert; de Jongste, Johan C.; Raat, Hein

    2013-01-01

    Rationale Few studies have analyzed the association of socioeconomic and sociodemographic factors with asthma related outcomes in early childhood, including Fraction of exhaled Nitric Oxide (FeNO) and airway resistance (Rint). We examined the association of socioeconomic and sociodemographic factors with wheezing, asthma, FeNO and Rint at age 6 years. Additionally, the role of potential mediating factors was studied. Methods The study included 6717 children participating in The Generation R Study, a prospective population-based cohort study. Data on socioeconomic and sociodemographic factors, wheezing and asthma were obtained by questionnaires. FeNO and Rint were measured at the research center. Statistical analyses were performed using logistic and linear regression models. Results At age 6 years, 9% (456/5084) of the children had wheezing symptoms and 7% (328/4953) had asthma. Children from parents with financial difficulties had an increased risk of wheezing (adjusted Odds Ratio (aOR) = 1.63, 95% Confidence Interval (CI):1.18–2.24). Parental low education, paternal unemployment and child's male sex were associated with asthma, independent of other socioeconomic or sociodemographic factors (aOR = 1.63, 95% CI:1.24–2.15, aOR = 1.85, 95% CI:1.11–3.09, aOR = 1.58, 95% CI:1.24–2.01, respectively). No socioeconomic or gender differences in FeNO were found. The risks of wheezing, asthma, FeNO and Rint measurements differed between ethnic groups (p<0.05). Associations between paternal unemployment, child's sex, ethnicity and asthma related outcomes remained largely unexplained. Conclusions This study showed differences between the socioeconomic and sociodemographic correlates of wheezing and asthma compared to the correlates of FeNO and Rint at age 6 years. Several socioeconomic and sociodemographic factors were independently associated with wheezing and asthma. Child's ethnicity was the only factor independently associated with FeNO. We

  13. Immunogenicity of HIV-1 IIIB and SHIV 89.6P Tat and Tat toxoids in rhesus macaques: induction of humoral and cellular immune responses.

    PubMed

    Richardson, Max W; Mirchandani, Jyotika; Silvera, Peter; Régulier, Emmanuel G; Capini, Christelle; Bojczuk, Paul M; Hu, Jason; Gracely, Edward J; Boyer, Jean D; Khalili, Kamel; Zagury, Jean-François; Lewis, Mark G; Rappaport, Jay

    2002-09-01

    This study compared immune responses in rhesus macaques immunized with unmodified HIV-1 IIIB Tat, SHIV89.6P Tat, and carboxymethylated IIIB and 89.6P Tat toxoids. Immunization with either IIIB or 89.6P preparation induced high titer and broadly crossreactive serum anti-Tat IgG that recognized HIV-1 subtype-E and SIVmac251 Tat. However, the response was delayed, and titers were lower in 89.6P vaccination groups. Serum anti-Tat IgG recognized peptides corresponding to the amino-terminus, basic domain, and carboxy-terminal region. Cellular proliferative responses to Tat toxoids corresponding to the immunogen were evident in vitro in both IIIB and 89.6P groups. Crossreactive proliferative responses were observed in IIIB groups in response to stimulation with 89.6P or SIVmac251 Tat toxoids, but were much less prevalent in 89.6P groups. The truncated 86 amino acid IIIB Tat appears to be more immunogenic than the 102 amino acid 89.6P Tat with respect to both humoral and cellular immune responses, and may be a better vaccine component. Despite induction of robust humoral and cellular immune responses (including both CD4+ and CD8+ T-cell responses) to Tat, all animals were infected upon intravenous challenge with 30 MID(50) of SHIV89.6P and outcome of vaccine groups was not different from controls. Sequencing both Tat exons from serum viral RNA revealed no evidence of escape mutants. These results suggest that with intravenous SHIV89.6P challenge in rhesus macaques, precipitous CD4+ T-cell decline overwhelms potentially protective immune responses. Alternatively, Tat specific CD8+ T-cell responses may not appropriately recognize infected cells in vivo in this model. In view of evidence demonstrating Tat specific CTLs in the SIV model and in humans infected with HIV-1, results in this pathogenic SHIV model may not apparently predict the efficacy of this approach in human studies. The potency and cross-reactivity of these immune responses confirm Tat toxoid as an excellent

  14. Structural specificity in a FGF7-affinity purified heparin octasaccharide required for formation of a complex with FGF7 and FGFR2IIIb.

    PubMed

    Luo, Yongde; Ye, Sheng; Kan, Mikio; McKeehan, Wallace L

    2006-04-15

    Variations in sulfation of heparan sulfate (HS) affect interaction with FGF, FGFR, and FGF-HS-FGFR signaling complexes. Whether structurally distinct HS motifs are at play is unclear. Here we used stabilized recombinant FGF7 as a bioaffinity matrix to purify size-defined heparin oligosaccharides. We show that only 0.2%-4% of 6 to 14 unit oligosaccharides, respectively, have high affinity for FGF7 based on resistance to salt above 0.6M NaCl. The high affinity fractions exhibit highest specific activity for interaction with FGFR2IIIb and formation of complexes of FGF7-HS-FGFR2IIIb. The majority fractions with moderate (0.30-0.6M NaCl), low (0.14-0.30M NaCl) or no affinity at 0.14M NaCl for FGF7 supported no complex formation. The high affinity octasaccharide mixture exhibited predominantly 7- and 8-sulfated components (7,8-S-OctaF7) and formed FGF7-HS-FGFR2IIIb complexes with highest specific activity. Deduced disaccharide analysis indicated that 7,8-S-OctaF7 comprised of DeltaHexA2SGlcN6S in a 2:1 ratio to a trisulfated and a variable unsulfated or monosulfated disaccharide. The inactive octasaccharides with moderate affinity for FGF7 were much more heterogenous and highly sulfated with major components containing 11 or 12 sulfates comprised of predominantly trisulfated disaccharides. This suggests that a rare undersulfated motif in which sulfate groups are specifically distributed has highest affinity for FGF7. The same motif also exhibits structural requirements for high affinity binding to dimers of FGFR2IIIb prior to binding FGF7 to form FGF7-HS-FGFR2IIIb complexes. In contrast, the majority of more highly sulfated HS motifs likely play FGFR-independent roles in stability and control of access of FGF7 to FGFR2IIIb in the tissue matrix. Copyright (c) 2005 Wiley-Liss, Inc.

  15. Factors impacting stemflow generation in a European beech forest: Individual tree versus neighborhood properties

    NASA Astrophysics Data System (ADS)

    Metzger, Johanna Clara; Germer, Sonja; Hildebrandt, Anke

    2017-04-01

    identified the different factors, individual and neighborhood, which significantly explain stemflow amount per tree. Preliminary results show, that the main impact on stemflow in our heterogeneous beech forest is due to individual tree diameter at breast height, while neighborhood factors have a smaller influence. This work defines the most important factors for stemflow fluxes, using easy-to-acquire tree and stand information, which allows the robust extrapolation of stemflow measurements and the generation of a spatially discrete pattern of stemflow input to the soil. Because of the high local and temporal concentration of precipitation, stemflow fluxes could be a key factor in forest soil water dynamics. On the long run, the results shall enable us to directly link soil water content measurements with estimated stemflow volumes for individual trees to trace stemflow fluxes into and through the soil.

  16. Effective factors on twisted terahertz radiation generation in a rippled plasma

    NASA Astrophysics Data System (ADS)

    Sobhani, Hassan; Dadar, Elham; Feili, Sahar

    2017-02-01

    Based on the beating of two Laguerre-Gaussian laser beams in a rippled plasma medium, the effective factors such as plasma density, Gouy phase and orbital angular momentums of input lasers on the output twisted terahertz radiation are investigated. As a result, the amplitude of the generated vortex terahertz radiation is an increasing function of plasma density. The vortex terahertz intensity is strongly dependent on the orbital angular momentum of the input lasers. The terahertz output amplitude increases by decreasing the orbital angular momentum of the Laguerre-Gaussian input lasers. Here, by employing a suitably ripple wavenumber, the destroyer effect of the relative Gouy phase of the input lasers is removed, and perfect phase matching is satisfied.

  17. Kinetic Model Facilitates Analysis of Fibrin Generation and Its Modulation by Clotting Factors: Implications for Hemostasis-Enhancing Therapies

    DTIC Science & Technology

    2014-01-01

    investigating its potential as a hemostatic agent in trauma and surgery.6,7 These applications necessitate a detailed understanding of fibrin ...facilitates analysis of fibrin generation and its modulation by clotting factors: implications for hemostasis-enhancing therapies† Alexander Y...ability of the suggested molecular mechanisms to account for fibrin generation and degradation kinetics in diverse, physiologically relevant in vitro

  18. Factors Influencing the Creation of a Wiki Culture for Knowledge Management in a Cross-Generational Organizational Setting

    ERIC Educational Resources Information Center

    Macro, Kenneth L., Jr.

    2011-01-01

    Initiatives within organizations that promote sharing of knowledge may be hampered by generational differences. Research on relationships between generations and technology-based knowledge sharing campaigns provides little managerial guidance for practitioners. The purpose of this ethnographic study was to identify the factors that influence the…

  19. Modeling and analysis of PM2.5 generation for key factors identification in China

    NASA Astrophysics Data System (ADS)

    Xia, Dehong; Jiang, Binfan; Xie, Yulei

    2016-06-01

    Recently, the PM2.5 pollution in China has occurred frequently and caused widely concern. In order to identify the key factors for PM2.5 generation, the formation characteristics of PM2.5 would be revealed. A property of electric neutrality of PM2.5 was proposed under the least-energy principle and verified through electricity-charge calculation in this paper. It indicated that PM2.5 is formed by the effect of electromagnetic force, including the effect of ionic bond, hydrogen bond and polarization. According to the analysis of interactive forces among different chemical components, a simulation model is developed for describing the random process of PM2.5 generation. In addition, an orthogonal test with two levels and four factors has been designed and carried out through the proposed model. From the text analysis, PM2.5 would be looser and suspend longer in atmosphere due to Organic Compound (OC) existing (OC can reduce about 67% of PM2.5 density). Considering that NH4+ is the only cation in the main chemical components of PM2.5, it would be vital for anions (such as SO42- and NO3-) to aggregate together for facilitating PM2.5 growing. Therefore, in order to relieve PM2.5 pollution, control strategies for OC and NH4+ would be enhanced by government through improving the quality of oils and solvent products, decreasing the amount of nitrogenous fertilizer utilization, or changing the fertilizing environment from dry condition to wet condition.

  20. Recent Development of the Second and Third Generation Irreversible Epidermal Growth Factor Receptor Inhibitors.

    PubMed

    Han, Weiwei; Du, Yongli

    2017-07-01

    Recent reports suggested that essential directions for new lung cancer, breast carcinoma therapies, as well as the roomier realm of targeted cancer therapies were provided through targeting the epidermal growth factor receptor (EGFR). Patients who carrying non-small cell lung carcinoma (NSCLC) with activating mutations in EGFR initially respond well to the EGFR inhibitors erlotinib and gefitinib, which were located the active site of the EGFR kinase and designed to act as competitive inhibitors of combining with the ATP. However, patients who were treated with the erlotinib and gefitinib will relapse because of the emergence of drug-resistant mutations, with T790M mutations accounting for approximately 60% of all resistance. In order to overcome drug resistance, Pharmaceutical chemistry experts recently devoted great endeavors to the development of second-generation irreversible selective inhibitors which covalently modify Cys797 or Cys773 at the ATP binding cleft. Nevertheless, these inhibitors have not reached ideal effect of experts in patients with T790M positive mutation and apparently because of the dose-limiting toxicities associated with inhibition of wild type EGFR. A novel class of 'third generation' EGFR TKIs have been developed that is sensitising and T790M mutant-specific whilst sparing WT EGFR, representing a significant breakthrough in the treatment in NSCLC patients with acquired resistance harboring these genotypes. Herein, we provides an overview of the second and third generation inhibitors currently approved, in clinical trial and also encompasses novel structures of discovery. This review mainly focuses on drug resistance, their mechanisms of action, development of structure-activity relationships and binding modes. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

  1. Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor

    PubMed Central

    Sahu, Ravi P.; Ocana, Jesus A.; Harrison, Kathleen A.; Ferracini, Matheus; Touloukian, Christopher E.; Al-Hassani, Mohammed; Sun, Louis; Loesch, Mathew; Murphy, Robert C.; Althouse, Sandra K.; Perkins, Susan M.; Speicher, Paul J.; Tyler, Douglas S.; Konger, Raymond L.; Travers, Jeffrey B.

    2014-01-01

    Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated non-enzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or cyclooxygenase-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Further, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation. PMID:25304264

  2. The Generation of Superficial Cortical Layers Is Regulated by Levels of the Transcription Factor Pax6

    PubMed Central

    Manuel, Martine; Price, David J.

    2011-01-01

    The ventricular zone (VZ) of the embryonic dorsal telencephalon is a major site for generating cortical projection neurons. The transcription factor Pax6 is highly expressed in apical progenitors (APs) residing in the VZ from the earliest stages of corticogenesis. Previous studies mainly focused on Pax6−/− mice have implicated Pax6 in regulating cortical progenitor proliferation, neurogenesis, and formation of superficial cortical layers. We analyzed the developing cortex of PAX77 transgenic mice that overexpress Pax6 in its normal domains of expression. We show that Pax6 overexpression increases cell cycle length of APs and drives the system toward neurogenesis. These effects are specific to late stages of corticogenesis, when superficial layer neurons are normally generated, in cortical regions that express Pax6 at the highest levels. The number of superficial layer neurons is reduced in postnatal PAX77 mice, whereas radial migration and lamina specification of cortical neurons are not affected by Pax6 overexpression. Conditional deletion of Pax6 in cortical progenitors at midstages of corticogenesis, by using a tamoxifen-inducible Emx1-CreER line, affected both numbers and specification of late-born neurons in superficial layers of the mutant cortex. Our analyses suggest that correct levels of Pax6 are essential for normal production of superficial layers of the cortex. PMID:20413449

  3. Methods and analysis of factors impact on the efficiency of the photovoltaic generation

    NASA Astrophysics Data System (ADS)

    Tianze, Li; Xia, Zhang; Chuan, Jiang; Luan, Hou

    2011-02-01

    First of all, the thesis elaborates two important breakthroughs which happened In the field of the application of solar energy in the 1950s.The 21st century the development of solar photovoltaic power generation will have the following characteristics: the continued high growth of industrial development, the significantly reducing cost of the solar cell, the large-scale high-tech development of photovoltaic industries, the breakthroughs of the film battery technology, the rapid development of solar PV buildings integration and combined to the grids. The paper makes principles of solar cells the theoretical analysis. On the basis, we study the conversion efficiency of solar cells, find the factors impact on the efficiency of the photovoltaic generation, solve solar cell conversion efficiency of technical problems through the development of new technology, and open up new ways to improve the solar cell conversion efficiency. Finally, the paper connecting with the practice establishes policies and legislation to the use of encourage renewable energy, development strategy, basic applied research etc.

  4. Stress generation in adolescence: Contributions from five-factor model (FFM) personality traits and childhood maltreatment.

    PubMed

    Kushner, Shauna C; Bagby, R Michael; Harkness, Kate L

    2017-04-01

    Youth with depression are theorized to generate stress in their lives because of a complex interaction between their personal characteristics and their chronic environmental context. Using a moderated regression approach, we provided a novel test of this hypothesis by examining whether adolescent 5-factor model personality traits moderate the associations between early emotional, physical, and sexual maltreatment and life events experienced in the past 6 months. Participants in this cross-sectional study were 110 adolescents (M = 16.24, SD = 1.53, age range = 13-17, 74.5% female) with major depressive disorder. The relation of physical maltreatment to dependent interpersonal life events was moderated by extraversion. Among physically maltreated youth, dependent interpersonal events were positively associated with extraversion. Further, the relation of sexual maltreatment to independent events were moderated by extraversion and agreeableness. Among sexually maltreated youth, independent events were negatively associated with extraversion and positively associated with agreeableness. The observed vulnerability-risk interactions are discussed in terms of their implications for understanding the role of stress generation mechanisms in an integrated model of depression. (PsycINFO Database Record

  5. Factors that increase the electric field of the dielectric barrier ozone generators

    NASA Astrophysics Data System (ADS)

    Ganea, I.; Morar, R.

    2017-05-01

    The dielectric barrier discharge cell (DBDC), also called ozone cell, is the main component of the ozone generators widely used. When the cell is powered with a high voltage value (> 5 kV) in the dielectric gas, arises a high intensity electric field that influences ozone generation processes by silent discharge also called dielectric barrier discharge. The intensity of the electric field depends by a number of factors such as the constructive form of the cell, the cell sizes, the value and the waveform of the supply voltage, the type of insulators used as dielectric barrier. The insulators which constituting the dielectric barrier, influence the intensity of the electric field through the dielectric constant of the liquid or solid shows the values of intensity electrical fields from ozone cells, with plane electrodes and ozone cells with cylindrical electrodes. The paper presents a graphic variation of the electric field from the gap and the dielectric barrier of cells with plane electrodes and cylindrical collinear electrodes. Experimental research highlights current-voltage characteristic for several types of dielectrics. Distilled water was highlighted as dielectric with the best results.

  6. Generation and gene expression profiling of 48 transcription-factor-inducible mouse embryonic stem cell lines

    PubMed Central

    Yamamizu, Kohei; Sharov, Alexei A.; Piao, Yulan; Amano, Misa; Yu, Hong; Nishiyama, Akira; Dudekula, Dawood B.; Schlessinger, David; Ko, Minoru S. H.

    2016-01-01

    Mouse embryonic stem cells (ESCs) can differentiate into a wide range – and possibly all cell types in vitro, and thus provide an ideal platform to study systematically the action of transcription factors (TFs) in cell differentiation. Previously, we have generated and analyzed 137 TF-inducible mouse ESC lines. As an extension of this “NIA Mouse ESC Bank,” we generated and characterized 48 additional mouse ESC lines, in which single TFs in each line could be induced in a doxycycline-controllable manner. Together, with the previous ESC lines, the bank now comprises 185 TF-manipulable ESC lines (>10% of all mouse TFs). Global gene expression (transcriptome) profiling revealed that the induction of individual TFs in mouse ESCs for 48 hours shifts their transcriptomes toward specific differentiation fates (e.g., neural lineages by Myt1 Isl1, and St18; mesodermal lineages by Pitx1, Pitx2, Barhl2, and Lmx1a; white blood cells by Myb, Etv2, and Tbx6, and ovary by Pitx1, Pitx2, and Dmrtc2). These data also provide and lists of inferred target genes of each TF and possible functions of these TFs. The results demonstrate the utility of mouse ESC lines and their transcriptome data for understanding the mechanism of cell differentiation and the function of TFs. PMID:27150017

  7. Development of a Semi-Autonomous Underwater Vehicle for Intervention Missions (SAUVIM Phase III-B)

    DTIC Science & Technology

    2009-03-20

    Annual Announcement of the July 11, 1996 Commerce Business Daily, and the project officially began on August 1, 1997 with an 18-month, $2.237 million...whole set of the new SAUVIM upgrades to the AdCom members. In general , during every site visit, each SAUVIM research group gave a presentation of...trajectory generation , although they are not completely independent of each other. Path planning is a computation and optimization of a collision-free

  8. Generation of Induced Neuronal Cells by the Single Reprogramming Factor ASCL1

    PubMed Central

    Chanda, Soham; Ang, Cheen Euong; Davila, Jonathan; Pak, ChangHui; Mall, Moritz; Lee, Qian Yi; Ahlenius, Henrik; Jung, Seung Woo; Südhof, Thomas C.; Wernig, Marius

    2014-01-01

    Summary Direct conversion of nonneural cells to functional neurons holds great promise for neurological disease modeling and regenerative medicine. We previously reported rapid reprogramming of mouse embryonic fibroblasts (MEFs) into mature induced neuronal (iN) cells by forced expression of three transcription factors: ASCL1, MYT1L, and BRN2. Here, we show that ASCL1 alone is sufficient to generate functional iN cells from mouse and human fibroblasts and embryonic stem cells, indicating that ASCL1 is the key driver of iN cell reprogramming in different cell contexts and that the role of MYT1L and BRN2 is primarily to enhance the neuronal maturation process. ASCL1-induced single-factor neurons (1F-iN) expressed mature neuronal markers, exhibited typical passive and active intrinsic membrane properties, and formed functional pre- and postsynaptic structures. Surprisingly, ASCL1-induced iN cells were predominantly excitatory, demonstrating that ASCL1 is permissive but alone not deterministic for the inhibitory neuronal lineage. PMID:25254342

  9. Transition of historial tube flaps to free flap for 2-stage total knee arthroplasty in a patient with a history of Gustilo grade IIIB tibia fracture.

    PubMed

    Spence, Sean A; Doren, Erin L; Dayicioglu, Deniz; Bernasek, Thomas

    2014-06-01

    We report the case of a 56-year-old patient who had posttraumatic bilateral knee arthritis and underwent sequential bilateral total knee arthroplasty (TKA). The left knee joint required 2-stage reconstruction: a free flap for enhanced soft-tissue coverage and then left knee TKA. Uniquely, at age 16 years this patient sustained a left tibia grade IIIB high-energy crush injury in a car crash and underwent reconstruction with multiple pedicle tube flaps and transfer of soft tissues. Most of that reconstruction was done between the ages of 16 and 19. At age 56 years, staged TKA was performed. To our knowledge, this is the first report of a knee reconstructed with pedicle tube flaps for a grade IIIB tibial fracture, followed years later by free-flap coverage before TKA. This report offers insights and treatment recommendations through long-term follow-up of a unique case and a historical perspective on how reconstructive options have evolved.

  10. Delayed Type IIIb endoleak secondary to graft fabric tear 7 years following implantation of a Medtronic Talent endovascular aortic device: A case report and review of the literature

    PubMed Central

    Kansal, Vinay; Nagpal, Sudhir

    2016-01-01

    Objectives: To report a rare case of delayed Type IIIb endoleak secondary to fabric tear following implantation of a Medtronic Talent endovascular device. Methods: A 83-year old gentleman underwent elective endovascular aneurysm repair for infrarenal abdominal aortic aneurysm with a Medtronic bifurcated stent graft in 2008. Results: Seven years after the initial repair, imaging surveillance revealed significant endoleak and brisk aneurysm sac expansion due to Type IIIb endoleak secondary to endograft limb fabric tear. Conclusions: This case illustrates the imperative role of imaging surveillance in detection of long-term endovascular aneurysm repair complications. Furthermore, we discuss exclusion of the graft tear with aortouniiliac stent grafting as the treatment for this complication. PMID:27708782

  11. Porphyromonas gingivalis Uses Specific Domain Rearrangements and Allelic Exchange to Generate Diversity in Surface Virulence Factors

    PubMed Central

    Dashper, Stuart G.; Mitchell, Helen L.; Seers, Christine A.; Gladman, Simon L.; Seemann, Torsten; Bulach, Dieter M.; Chandry, P. Scott; Cross, Keith J.; Cleal, Steven M.; Reynolds, Eric C.

    2017-01-01

    Porphyromonas gingivalis is a keystone pathogen of chronic periodontitis. The virulence of P. gingivalis is reported to be strain related and there are currently a number of strain typing schemes based on variation in capsular polysaccharide, the major and minor fimbriae and adhesin domains of Lys-gingipain (Kgp), amongst other surface proteins. P. gingivalis can exchange chromosomal DNA between strains by natural competence and conjugation. The aim of this study was to determine the genetic variability of P. gingivalis strains sourced from international locations over a 25-year period and to determine if variability in surface virulence factors has a phylogenetic basis. Whole genome sequencing was performed on 13 strains and comparison made to 10 previously sequenced strains. A single nucleotide polymorphism-based phylogenetic analysis demonstrated a shallow tri-lobed phylogeny. There was a high level of reticulation in the phylogenetic network, demonstrating extensive horizontal gene transfer between the strains. Two highly conserved variants of the catalytic domain of the major virulence factor the Kgp proteinase (KgpcatI and KgpcatII) were found. There were three variants of the fourth Kgp C-terminal cleaved adhesin domain. Specific variants of the cell surface proteins FimA, FimCDE, MfaI, RagAB, Tpr, and PrtT were also identified. The occurrence of all these variants in the P. gingivalis strains formed a mosaic that was not related to the SNP-based phylogeny. In conclusion P. gingivalis uses domain rearrangements and genetic exchange to generate diversity in specific surface virulence factors. PMID:28184216

  12. Bipartite recognition of target RNAs activates DNA cleavage by the Type III-B CRISPR–Cas system

    PubMed Central

    Elmore, Joshua R.; Sheppard, Nolan F.; Ramia, Nancy; Deighan, Trace; Li, Hong; Terns, Rebecca M.; Terns, Michael P.

    2016-01-01

    CRISPR–Cas systems eliminate nucleic acid invaders in bacteria and archaea. The effector complex of the Type III-B Cmr system cleaves invader RNAs recognized by the CRISPR RNA (crRNA ) of the complex. Here we show that invader RNAs also activate the Cmr complex to cleave DNA. As has been observed for other Type III systems, Cmr eliminates plasmid invaders in Pyrococcus furiosus by a mechanism that depends on transcription of the crRNA target sequence within the plasmid. Notably, we found that the target RNA per se induces DNA cleavage by the Cmr complex in vitro. DNA cleavage activity does not depend on cleavage of the target RNA but notably does require the presence of a short sequence adjacent to the target sequence within the activating target RNA (rPAM [RNA protospacer-adjacent motif]). The activated complex does not require a target sequence (or a PAM) in the DNA substrate. Plasmid elimination by the P. furiosus Cmr system also does not require the Csx1 (CRISPR-associated Rossman fold [CARF] superfamily) protein. Plasmid silencing depends on the HD nuclease and Palm domains of the Cmr2 (Cas10 superfamily) protein. The results establish the Cmr complex as a novel DNA nuclease activated by invader RNAs containing a crRNA target sequence and a rPAM. PMID:26848045

  13. CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120IIIB binding to the cell surface

    PubMed Central

    Martínez-Muñoz, Laura; Barroso, Rubén; Dyrhaug, Sunniva Y.; Navarro, Gemma; Lucas, Pilar; Soriano, Silvia F.; Vega, Beatriz; Costas, Coloma; Muñoz-Fernández, M. Ángeles; Santiago, César; Frade, José Miguel Rodríguez; Franco, Rafael; Mellado, Mario

    2014-01-01

    CCR5 and CXCR4, the respective cell surface coreceptors of R5 and X4 HIV-1 strains, both form heterodimers with CD4, the principal HIV-1 receptor. Using several resonance energy transfer techniques, we determined that CD4, CXCR4, and CCR5 formed heterotrimers, and that CCR5 coexpression altered the conformation of both CXCR4/CXCR4 homodimers and CD4/CXCR4 heterodimers. As a result, binding of the HIV-1 envelope protein gp120IIIB to the CD4/CXCR4/CCR5 heterooligomer was negligible, and the gp120-induced cytoskeletal rearrangements necessary for HIV-1 entry were prevented. CCR5 reduced HIV-1 envelope-induced CD4/CXCR4-mediated cell-cell fusion. In nucleofected Jurkat CD4 cells and primary human CD4+ T cells, CCR5 expression led to a reduction in X4 HIV-1 infectivity. These findings can help to understand why X4 HIV-1 strains infection affect T-cell types differently during AIDS development and indicate that receptor oligomerization might be a target for previously unidentified therapeutic approaches for AIDS intervention. PMID:24778234

  14. Myosin IIIB uses an actin-binding motif in its espin-1 cargo to reach the tips of actin protrusions.

    PubMed

    Merritt, Raymond C; Manor, Uri; Salles, Felipe T; Grati, M'hamed; Dose, Andrea C; Unrath, William C; Quintero, Omar A; Yengo, Christopher M; Kachar, Bechara

    2012-02-21

    Myosin IIIA (MYO3A) targets actin protrusion tips using a motility mechanism dependent on both motor and tail actin-binding activity [1]. We show that myosin IIIB (MYO3B) lacks tail actin-binding activity and is unable to target COS7 cell filopodia tips, yet is somehow able to target stereocilia tips. Strikingly, when MYO3B is coexpressed with espin-1 (ESPN1), a MYO3A cargo protein endogenously expressed in stereocilia [2], MYO3B targets and carries ESPN1 to COS7 filopodia tips. We show that this tip localization is lost when we remove the ESPN1 C terminus actin-binding site. We also demonstrate that, like MYO3A [2], MYO3B can elongate filopodia by transporting ESPN1 to the polymerizing end of actin filaments. The mutual dependence of MYO3B and ESPN1 for tip localization reveals a novel mechanism for the cell to regulate myosin tip localization via a reciprocal relationship with cargo that directly participates in actin binding for motility. Our results are consistent with a novel form of motility for class III myosins that requires both motor and tail domain actin-binding activity and show that the actin-binding tail can be replaced by actin-binding cargo. This study also provides a framework to better understand the late-onset hearing loss phenotype in patients with MYO3A mutations.

  15. CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120IIIB binding to the cell surface.

    PubMed

    Martínez-Muñoz, Laura; Barroso, Rubén; Dyrhaug, Sunniva Y; Navarro, Gemma; Lucas, Pilar; Soriano, Silvia F; Vega, Beatriz; Costas, Coloma; Muñoz-Fernández, M Ángeles; Santiago, César; Rodríguez Frade, José Miguel; Franco, Rafael; Mellado, Mario

    2014-05-13

    CCR5 and CXCR4, the respective cell surface coreceptors of R5 and X4 HIV-1 strains, both form heterodimers with CD4, the principal HIV-1 receptor. Using several resonance energy transfer techniques, we determined that CD4, CXCR4, and CCR5 formed heterotrimers, and that CCR5 coexpression altered the conformation of both CXCR4/CXCR4 homodimers and CD4/CXCR4 heterodimers. As a result, binding of the HIV-1 envelope protein gp120IIIB to the CD4/CXCR4/CCR5 heterooligomer was negligible, and the gp120-induced cytoskeletal rearrangements necessary for HIV-1 entry were prevented. CCR5 reduced HIV-1 envelope-induced CD4/CXCR4-mediated cell-cell fusion. In nucleofected Jurkat CD4 cells and primary human CD4(+) T cells, CCR5 expression led to a reduction in X4 HIV-1 infectivity. These findings can help to understand why X4 HIV-1 strains infection affect T-cell types differently during AIDS development and indicate that receptor oligomerization might be a target for previously unidentified therapeutic approaches for AIDS intervention.

  16. Coal-fired MHD combustor development project: Phase IIIB. First quarterly technical progress report, 13 January-30 April 1982

    SciTech Connect

    1982-05-20

    The first quarterly technical progress report of the Coal-Fired MHD Combustor Development Project (Phase IIIB) presents the accomplishments during the period 13 January to 30 April, 1982. The scope of work covered by this quarterly report relates to those tasks associated with preparing the TRW 20 MW/sub t/ MHD coal combustor for delivery to AERL for integrated power tests and the work associated with the preliminary design of a 50 MW/sub t/ coal-fired combustor. Progress during this reporting period is described. All new 20 MW/sub t/ hardware was designed and fabricated. Interface coordination meetings were conducted with AERL and DOE. Interface control drawings were completed and a 20 MW/sub t/ coal combustion User's manual was delivered to AERL. The User's manual contained a shipping plan, a crew training plan, an assembly manual, interface documentation and recommended operating procedures. Facility/combustor set-up was completed and the pre-delivery 20 MW/sub t/ coal combustor qualification test series was completed. The 50 MW/sub t/ coal-fired MHD combustor preliminary designs were finalized and the DOE preliminary design review (PDR) was successfully completed.

  17. Definitive radiotherapy with concurrent oncothermia for stage IIIB non-small-cell lung cancer: A case report

    PubMed Central

    YEO, SEUNG-GU

    2015-01-01

    Hyperthermia enhances the susceptibility of tumors to radiotherapy (RT) and chemotherapy. Oncothermia, also known as electro-hyperthermia, is a new treatment modality developed to overcome the problems of traditional hyperthermia by selectively delivering energy to the malignant tissues. The present study reports the outcome of combined oncothermia and RT in a 75-year-old patient with stage IIIB non-small-cell lung cancer (NSCLC). Due to the advanced age and the performance status of the patient, the combination of systemic chemotherapy and RT was deemed infeasible; therefore, the patient instead decided to undergo oncothermia concurrently with definitive RT. The RT was administered at a dose of 64.8 Gy in 36 fractions using a three-dimensional conformal plan technique. Oncothermia was started concomitantly with RT and was performed for 60 min per session, two sessions per week, for a total of 12 sessions. No severe toxicities developed, with the exception of mild odynophagia, which resolved soon after the treatments. Follow-up computed tomography showed complete tumor response, and the patient was alive with no evidence of the disease 18 months after the completion of the treatment. In conclusion, the present case report suggests that oncothermia combined with RT, with the former possessing radiosensitizing potential and no additional toxicities, may be a promising alternative for advanced-age and/or frail patients with locally advanced NSCLC. PMID:26622391

  18. Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery.

    PubMed

    Fu, Haiyan; Meadows, Aaron S; Ware, Tierra; Mohney, Robert P; McCarty, Douglas M

    2017-03-01

    Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disease with complex CNS and somatic pathology due to a deficiency in α-N-acetylglucosaminidase (NAGLU). Using global metabolic profiling by mass spectrometry targeting 361 metabolites, this study detected significant decreases in 225 and increases in six metabolites in serum samples from 7-month-old MPS IIIB mice, compared to wild-type (WT) mice. The metabolic disturbances involve virtually all major pathways of amino acid, peptide (58/102), carbohydrate (18/28), lipid (111/139), nucleotide (12/24), energy (2/9), vitamin and cofactor (11/16), and xenobiotic (11/28) metabolism. Notably, the reduced metabolites included eight essential amino acids, vitamins (C, E, B2, and B6), and neurotransmitters (serotonin, glutamate, aspartate, tryptophan, and N-acetyltyrosine). The metabolic impairments appear to emerge early during disease progression before the age of 2 months. Importantly, the restoration of NAGLU activity with an intravenous (i.v.) injection of rAAV9-hNAGLU vector led to near-complete correction of all serum metabolite abnormalities, with 201 (87%) metabolites normalized and 30 (13%) over-corrected. While the mechanisms are unclear, our data demonstrate that the lack of NAGLU activity triggers profound functional metabolic disturbances in MPS IIIB. These metabolic impairments respond well to a systemic rAAV9-hNAGLU gene delivery, supporting the surrogate biomarker potential of serum metabolomic profiles for MPS IIIB therapies. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  19. The Mammalian Neuronal Sodium Channel Blocker μ-Conotoxin BuIIIB has a Structured N-terminus that Influences Potency

    PubMed Central

    Kuang, Zhihe; Zhang, Min-Min; Gupta, Kallol; Gajewiak, Joanna; Gulyas, Jozsef; Balaram, Padmanabhan; Rivier, Jean E.; Olivera, Baldomero M.; Yoshikami, Doju; Bulaj, Grzegorz; Norton, Raymond S.

    2014-01-01

    Among the μ-conotoxins that block vertebrate voltage-gated sodium channels (VGSCs), some have been shown to be potent analgesics following systemic administration in mice. We have determined the solution structure of a new representative of this family, μ-BuIIIB, and established its disulfide connectivities by direct mass spectrometric collision induced dissociation fragmentation of the peptide with disulfides intact. The major oxidative folding product adopts a 1-4/2-5/3-6 pattern with the following disulfide bridges: Cys5-Cys17, Cys6-Cys23 and Cys13-Cys24. The solution structure reveals that the unique N-terminal extension in μ-BuIIIB, which is also present in μ-BuIIIA and μ-BuIIIC but absent in other μ-conotoxins, forms part of a short α-helix encompassing Glu3 to Asn8. This helix is packed against the rest of the toxin and stabilized by the Cys5-Cys17 and Cys6-Cys23 disulfide bonds. As such, the side chain of Val1 is located close to the aromatic rings of Trp16 and His20, which are located on the canonical helix that displays several residues found to be essential for VGSC blockade in related μ-conotoxins. Mutations of residues 2 and 3 in the N-terminal extension enhanced the potency of μ-BuIIIB for NaV1.3. One analog, [d-Ala2]BuIIIB, showed a 40-fold increase, making it the most potent peptide blocker of this channel characterized to date and thus a useful new tool with which to characterize this channel. Based on previous results for related μ-conotoxins, the dramatic effects of mutations at the N-terminus were unanticipated, and suggest that further gains in potency might be achieved by additional modifications of this region. PMID:23557677

  20. Explanatory factors for first and second-generation non-western women's inadequate prenatal care utilisation: a prospective cohort study.

    PubMed

    Boerleider, Agatha W; Manniën, Judith; van Stenus, Cherelle M V; Wiegers, Therese A; Feijen-de Jong, Esther I; Spelten, Evelien R; Devillé, Walter L J M

    2015-04-21

    Little research into non-western women's prenatal care utilisation in industrialised western countries has taken generational differences into account. In this study we examined non-western women's prenatal care utilisation and its explanatory factors according to generational status. Data from 3300 women participating in a prospective cohort of primary midwifery care clients (i.e. women with no complications or no increased risk for complications during pregnancy, childbirth and the puerperium who receive maternity care by autonomous midwives) in the Netherlands (the DELIVER study) was used. Gestational age at entry and the total number of prenatal visits were aggregated into an index. The extent to which potential factors explained non-western women's prenatal care utilisation was assessed by means of blockwise logistic regression analyses and percentage changes in odds ratios. The unadjusted odds of first and second-generation non-western women making inadequate use of prenatal care were 3.26 and 1.96 times greater than for native Dutch women. For the first generation, sociocultural factors explained 43% of inadequate prenatal care utilisation, socioeconomic factors explained 33% and demographic and pregnancy factors explained 29%. For the second generation, sociocultural factors explained 66% of inadequate prenatal care utilisation. Irrespective of generation, strategies to improve utilisation should focus on those with the following sociocultural characteristics (not speaking Dutch at home, no partner or a first-generation non-Dutch partner). For the first generation, strategies should also focus on those with the following demographic, pregnancy and socioeconomic characteristics (aged ≤ 19 or ≥ 36, unplanned pregnancies, poor obstetric histories (extra-uterine pregnancy, molar pregnancy or abortion), a low educational level, below average net household income and no supplementary insurance.

  1. Hepatic artery reconstruction first for the treatment of hilar cholangiocarcinoma bismuth type IIIB with contralateral arterial invasion: a novel technical strategy

    PubMed Central

    de Santibañes, Eduardo; Ardiles, Victoria; Alvarez, Fernando A; Pekolj, Juan; Brandi, Claudio; Beskow, Axel

    2012-01-01

    Background En-bloc liver resection with the extrahepatic bile duct is mandatory to obtain tumour-free surgical margins and better long-term outcomes in hilar cholangiocarcinoma (CC). One of the most important criteria for irresectability is local extensive invasion to major vessels. As hilar CC Bismuth type IIIB often requires a major left hepatic resection, the invasion of the right hepatic artery (RHA) usually contraindicates this procedure. Methods The authors describe a novel technique that allowed an oncological resection in two patients with hilar CC Bismuth type IIIB and contralateral arterial invasion. Arterial reconstruction between the posterior branch of the RHA and the left hepatic artery (LHA) was performed as the first surgical step. Once arterial vascular flow was restored, a left trisectionectomy with caudate lobe resection and portal vein reconstruction was performed. Results In both patients an R0 resection was achieved. Both patients made a full recovery and were discharged within 14 days of surgery. Both patients remain free of disease at 18 months. Conclusions This new technique allows a R0 resection to be achieved in patients with Bismuth type IIIB hilar CC with contralateral arterial involvement. PMID:22151454

  2. Hepatic artery reconstruction first for the treatment of hilar cholangiocarcinoma bismuth type IIIB with contralateral arterial invasion: a novel technical strategy.

    PubMed

    de Santibañes, Eduardo; Ardiles, Victoria; Alvarez, Fernando A; Pekolj, Juan; Brandi, Claudio; Beskow, Axel

    2012-01-01

    En-bloc liver resection with the extrahepatic bile duct is mandatory to obtain tumour-free surgical margins and better long-term outcomes in hilar cholangiocarcinoma (CC). One of the most important criteria for irresectability is local extensive invasion to major vessels. As hilar CC Bismuth type IIIB often requires a major left hepatic resection, the invasion of the right hepatic artery (RHA) usually contraindicates this procedure. The authors describe a novel technique that allowed an oncological resection in two patients with hilar CC Bismuth type IIIB and contralateral arterial invasion. Arterial reconstruction between the posterior branch of the RHA and the left hepatic artery (LHA) was performed as the first surgical step. Once arterial vascular flow was restored, a left trisectionectomy with caudate lobe resection and portal vein reconstruction was performed. In both patients an R0 resection was achieved. Both patients made a full recovery and were discharged within 14 days of surgery. Both patients remain free of disease at 18 months. This new technique allows a R0 resection to be achieved in patients with Bismuth type IIIB hilar CC with contralateral arterial involvement. © 2011 International Hepato-Pancreato-Biliary Association.

  3. Mutation Scanning of D1705 and D1709 in the RNAse IIIb Domain of MicroRNA Processing Enzyme Dicer in Cutaneous Melanoma.

    PubMed

    Sand, Michael; Bechara, Falk G; Skrygan, Marina; Sand, Daniel; Gambichler, Thilo; Bromba, Michael; Stockfleth, Eggert; Hessam, Schapoor

    2016-07-01

    Since the discovery of microRNAs (miRNAs) there have been performed several studies showing perturbations in the expression of miRNAs and the miRNA expression machinery in cutaneous melanoma. Dicer, a pivotal cytosolic enzyme of miRNA maturation has shown to be affected by both somatic and germline mutations in a variety of cancers. Recent studies have shown that recurrent somatic mutations of Dicer frequently affect the metal-ion-binding sites D1709 and D1705 of its RNase IIIb domain, therefore called hot spot mutations. The present study investigates metal-ion-binding sites D1709 and D1705 of the Dicer RNase IIIb domain in cutaneous melanomas and melanoma metastasis by Sanger sequencing. All investigated samples showed wildtype sequence and no single mutation was detected. The miRNA processing enzyme Dicer of melanoma and melanoma metastasis does not appear to be affected by mutation in the metal-ion-binding sites D1709 and D1705 of its RNase IIIb domain.

  4. Concomitant cisplatin plus radiotherapy and high-dose-rate brachytherapy versus radiotherapy alone for stage IIIB epidermoid cervical cancer: a randomized controlled trial.

    PubMed

    Zuliani, Antonio Carlos; Esteves, Sergio Carlos Barros; Teixeira, Luiz Carlos; Teixeira, Júlio César; de Souza, Gustavo Antonio; Sarian, Luis Otávio

    2014-02-20

    The benefits of chemoradiotherapy (CRT) for cervical cancer compared with radiation (RT) alone seem to diminish in later-stage disease. However, these modalities have not been directly compared for disease-free interval (DFI) and overall survival (OS) of women with stage IIIB cervical cancer. We conducted a randomized controlled clinical trial comparing DFI and OS of 147 women with stage IIIB squamous cervical cancer who received either cisplatin plus RT (CRT) or RT alone (72 patients in the CRT group and 75 patients in the RT-only group). The CRT group had significantly better DFI (hazard ratio [HR], 0.52; 95% CI, 0.29 to 0.93; P = .02). However, patients in the CRT group did not have significantly better OS than those in the RT-only group (HR, 0.67; 95% CI, 0.38 to 1.17; P = .16). Toxicity was graded according to criteria of the Radiation Therapy Oncology Group. The organs affected (excluding hematologic effects) did not differ significantly between groups. Also, late toxicity events and organs affected were not significantly disproportionate between the study groups. For stage IIIB cervical cancer, the addition of cisplatin offers a small but significant benefit in DFI, with acceptable toxicity.

  5. Phase II Study of a HER-2/neu (HER2) Intracellular Domain (ICD) Peptide-Based Vaccine Administered to Stage IIIB and IV HER2 Positive Breast Cancer Patients Receiving Trastuzumab Monotherapy

    DTIC Science & Technology

    2008-05-01

    Intracellular Domain (ICD) Peptide - Based Vaccine Administered to Stage IIIB and IV HER2 Positive Breast Cancer Patients Receiving Trastuzumab...To) 27 APR 2007 - 26 APR 2008 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Phase II Study of a HER-2/neu (HER2) Intracellular Domain (ICD) Peptide ...intracellular domain (ICD) peptide -based vaccine while receiving maintenance trastuzumab. Patients enrolled will be HER2 overexpressing stage IIIB and IV

  6. Plasma factor and inhibitor composition contributes to thrombin generation dynamics in patients with acute or previous cerebrovascular events

    PubMed Central

    Gissel, Matthew; Undas, Anetta; Slowik, Agnieszka; Mann, Kenneth G.; Brummel-Ziedins, Kathleen E.

    2010-01-01

    Introduction More than 80% of cerebrovascular events are ischemic and largely thromboembolic by nature. We evaluated whether plasma factor composition and thrombin generation dynamics might be a contributor to the thrombotic phenotype of ischemic cerebrovascular events. Materials and Methods We studied (1) 100 patients with acute ischemic stroke (n=50) or transient ischemic attack (TIA) (n=50) within the first 24 hours from symptom onset, and (2) 100 individuals 1 to 4 years following ischemic stroke (n=50) or TIA (n=50). The tissue factor pathway to thrombin generation was simulated with a mathematical model using plasma levels of clotting factors (F)II, V, VII, VIII, IX, X, antithrombin and free tissue factor pathway inhibitor (TFPI). Results The plasma levels of free TFPI, FII, FVIII, and FX were higher, while antithrombin was lower, in the acute patients compared to the previous event group (all p≤0.02). Thrombin generation during acute events was enhanced, with an 11% faster maximum rate, a 15% higher maximum level and a 26% larger total production (all p<0.01). The increased thrombin generation in acute patients was determined by higher FII and lower antithrombin, while increased free TFPI mediated this effect. When the groups are classified by etiology, all stroke sub-types except cardioembolic have increased TFPI and decreased AT and total thrombin produced. Conclusion Augmented thrombin generation in acute stroke/TIA is to some extent determined by altered plasma levels of coagulation factors. PMID:20709367

  7. Cave spiders choose optimal environmental factors with respect to the generated entropy when laying their cocoon

    NASA Astrophysics Data System (ADS)

    Chiavazzo, Eliodoro; Isaia, Marco; Mammola, Stefano; Lepore, Emiliano; Ventola, Luigi; Asinari, Pietro; Pugno, Nicola Maria

    2015-01-01

    The choice of a suitable area to spiders where to lay eggs is promoted in terms of Darwinian fitness. Despite its importance, the underlying factors behind this key decision are generally poorly understood. Here, we designed a multidisciplinary study based both on in-field data and laboratory experiments focusing on the European cave spider Meta menardi (Araneae, Tetragnathidae) and aiming at understanding the selective forces driving the female in the choice of the depositional area. Our in-field data analysis demonstrated a major role of air velocity and distance from the cave entrance within a particular cave in driving the female choice. This has been interpreted using a model based on the Entropy Generation Minimization - EGM - method, without invoking best fit parameters and thanks to independent lab experiments, thus demonstrating that the female chooses the depositional area according to minimal level of thermo-fluid-dynamic irreversibility. This methodology may pave the way to a novel approach in understanding evolutionary strategies for other living organisms.

  8. Cave spiders choose optimal environmental factors with respect to the generated entropy when laying their cocoon

    PubMed Central

    Chiavazzo, Eliodoro; Isaia, Marco; Mammola, Stefano; Lepore, Emiliano; Ventola, Luigi; Asinari, Pietro; Pugno, Nicola Maria

    2015-01-01

    The choice of a suitable area to spiders where to lay eggs is promoted in terms of Darwinian fitness. Despite its importance, the underlying factors behind this key decision are generally poorly understood. Here, we designed a multidisciplinary study based both on in-field data and laboratory experiments focusing on the European cave spider Meta menardi (Araneae, Tetragnathidae) and aiming at understanding the selective forces driving the female in the choice of the depositional area. Our in-field data analysis demonstrated a major role of air velocity and distance from the cave entrance within a particular cave in driving the female choice. This has been interpreted using a model based on the Entropy Generation Minimization - EGM - method, without invoking best fit parameters and thanks to independent lab experiments, thus demonstrating that the female chooses the depositional area according to minimal level of thermo-fluid-dynamic irreversibility. This methodology may pave the way to a novel approach in understanding evolutionary strategies for other living organisms. PMID:25556697

  9. The impact of thrombin generation and rotation thromboelastometry on assessment of severity of factor XI deficiency.

    PubMed

    Livnat, Tami; Shenkman, Boris; Martinowitz, Uri; Zivelin, Ariella; Dardik, Rima; Tamarin, Ilia; Mansharov, Rachel; Budnik, Ivan; Salomon, Ophira

    2015-08-01

    The phenotype of bleeding in patients with severe FXI deficiency is unpredictable and unlike other bleeding disorders, it is not directly correlated with levels of FXI. In this study we analyzed whether the global coagulation assays can serve as a clinical tool in predicting bleeding tendency in patients with severe FXI deficiency undergoing surgery, taking into account the large inter-individual variability of FXI levels and genotypes. Thrombin generation (TG) was measured in 39 platelet-poor plasma with or without tissue factor (TF) and in the presence or absence of corn trypsin inhibitor (CTI). Rotation thromboelastometry (ROTEM) was performed with fresh whole blood of 26 patients applying NATEM and INTEM tests. TG induced by recalcification can distinguish between bleeding and non-bleeding patients with severe FXI deficiency particularly among those with FXI activity of 2-20IU/dl. The addition of TF or TF and CTI to the TG assay masked the ability to differentiate between XI activity, genotype as well as bleeding and non-bleeding patients. ROTEM assays failed to distinguish bleeding from non-bleeding patients but could do so between different FXI activity levels and genotypes. In conclusion, in the current study we found a sensitive tool to distinguish between bleeding and non-bleeding patients. In order to recommend TG as a predictive tool for treatment tailoring, a larger patient group is required.

  10. Review of Operational Water Consumption and Withdrawal Factors for Electricity Generating Technologies

    SciTech Connect

    Macknick, J.; Newmark, R.; Heath, G.; Hallett, K. C.

    2011-03-01

    Various studies have attempted to consolidate published estimates of water use impacts of electricity generating technologies, resulting in a wide range of technologies and values based on different primary sources of literature. The goal of this work is to consolidate the various primary literature estimates of water use during the generation of electricity by conventional and renewable electricity generating technologies in the United States to more completely convey the variability and uncertainty associated with water use in electricity generating technologies.

  11. Using a Chimney to Make a Sandwich: Salvage of a Multibranched Thoracoabdominal Aortic Endograft with a Type IIIb Endoleak.

    PubMed

    Misskey, Jonathan; Johnson, Steven; Baxter, Keith; Gagnon, Joel

    2015-11-01

    The advent of branched and fenestrated aortic endografts has facilitated the treatment of increasingly complex aortic pathology. The management of complications and endoleaks involving the branches and fenestrations of these grafts represents an increasingly significant clinical and technical challenge. A 79-year-old woman developed a rare type IIIb endoleak from a tear in the graft fabric immediately posterior to the celiac axis branch 3 years after the placement of an off-the-shelf branched endograft for a type II thoracoabdominal aortic aneurysm. The patient presented urgently with abdominal pain and a maximal aneurysm diameter of 15.3 cm. The operative plan was to create a chimney graft completely within the original branched endograft to cover the defect and maintain celiac branch flow. The celiac trunk was accessed from a left axillary approach and access for the main endograft body was achieved via the left femoral artery. Two balloon-expandable covered stents were deployed from the celiac branch extending into the main endograft as a chimney and molded to 2 aortic extension cuffs to cover the fabric defect. The resultant configuration was a modified-sandwich graft within the original stent graft and resulted in successful exclusion of the endoleak. Postoperative imaging at 1, 6, and 12 months has demonstrated continued patency of the celiac trunk, no further endoleak, and a 16-mm reduction in aneurysm size. The chimney technique was successfully applied as an endovascular option to salvage a multibranched endograft with a significant and anatomically unfavorable defect. Careful follow-up and additional clinical study are required to clarify the role of off-the-shelf solutions in complex endoleak management. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. The association of Fcgamma receptor IIIb genetic polymorphism and susceptibility to periodontitis in Taiwanese individuals.

    PubMed

    Ho, Ya-Ping; Yang, Yi-Hsin; Ho, Kun-Yen; Wu, Yi-Min; Tsai, Chi-Cheng

    2010-02-01

    The allelic polymorphism of FcgammaRIIIb, the neutrophil-specific receptor involved in the phagocytosis of immunoglobulin G-opsonized bacteria, has functionally distinct capacities that are important in host defence mediated by neutrophils. The aim of this study was to identify whether the polymorphism of FcgammaRIIIb is associated with periodontitis in Taiwanese individuals. This case-control study included of 93 aggressive periodontitis (AgP) patients, 372 chronic periodontitis (CP) patients and 158 healthy controls (HC). The FcgammaRIIIb genotypes were determined by PCR using allele-specific primers. The risk for periodontitis associated with genotypes was calculated as the odds ratio (OR). A significant difference was observed in the distribution of the FcgammaRIIIb genotype between either AgP and HC, or AgP and CP, but not between CP and HC. The OR for carriage of the NA2 allele (NA1NA2+NA2NA2 versus NA1NA1) in AgP was 3.27 [95% confidence interval (CI)=1.57-7.51, p=0.0027] and 2.94 (95% CI=1.49-6.48, p=0.0037), as compared with HC and CP. After adjusting for possible confounding factors, the association was still significant. The results of the present study suggest that subjects carrying at least one copy of the FcgammaRIIIb-NA2 allele might be associated with susceptibility to AgP. However, the clinical implications of the FcgammaRIIIb allelic polymorphism should be determined by further studies.

  13. International Normalized Ratio (INR), coagulation factor activities and calibrated automated thrombin generation - influence of 24 h storage at ambient temperature.

    PubMed

    Christensen, T D; Jensen, C; Larsen, T B; Maegaard, M; Christiansen, K; Sørensen, B

    2010-04-01

    International Normalized Ratio (INR) measurements are used to monitor oral anticoagulation therapy with coumarins. Single coagulation factor activities and calibrated automated thrombin (CAT) generation are considered as more advanced methods for evaluating overall haemostatic capacity. The aims were to assess the variability of INR, coagulation factor activities, and CAT, during 24 h of storage of blood samples at ambient temperature. A total of 24 patients on stable coumarin treatment were followed prospectively for 6 weeks. INR was analyzed at 0, 6 and 24 h after blood sampling and 1-stage clotting activity of coagulation factors II, VII, IX, and X as well as CAT generation was recorded after 0 and 24 h respectively. Statistical analyses included Bland-Altman plot, 95% limits of agreement, and a variability test using a mixed effect model. The level of INR remained statistically unchanged from 0 to 6 and 24 h of storage. Coagulation factor activities and CAT revealed no significant difference induced by 24 h of storage, although the limits of agreement were wide. Patients' individual INR, coagulation factor activities, and CAT generation were not significantly influenced by 24 h storage of blood samples, but for the CAT generation analyses a trend toward time dependency was detected.

  14. The Multigenerational Workforce within Two-Year Public Community Colleges: A Study of Generational Factors Affecting Employee Learning and Interaction

    ERIC Educational Resources Information Center

    Starks, Florida Elizabeth

    2014-01-01

    The purpose of this quantitative study is to broaden multigenerational workforce research involving factors affecting employee learning and interaction by using a population of Baby Boomer, Generation X, and Millennial faculty and staff age cohorts employed at two-year public community college organizations. Researchers have studied…

  15. A Continuum of Persistence: Low-Income and First-Generation College Students' Perceptions of Critical Factors for Postsecondary Success

    ERIC Educational Resources Information Center

    Ganuza Hoaglund, Zoila M.

    2014-01-01

    The purpose of this study was to explore similarities and differences among low-income and first-generation (LIFG) students' perceptions of influential academic, psychosocial, and contextual factors that shaped their persistence at different stages at the postsecondary level. This study consisted of 29 LIFG students from a large, urban research…

  16. Dependent Personality Disorder: Comparing an Expert Generated and Empirically Derived Five-Factor Model Personality Disorder Count

    ERIC Educational Resources Information Center

    Miller, Joshua D.; Lynam, Donald R.

    2008-01-01

    Assessment of the "Diagnostic and Statistical Manual of Mental Disorders" (4th Ed.; "DSM-IV") personality disorders (PDs) using five-factor model (FFM) prototypes and counts has shown substantial promise, with a few exceptions. Miller, Reynolds, and Pilkonis suggested that the expert-generated FFM dependent prototype might be misspecified in…

  17. The Multigenerational Workforce within Two-Year Public Community Colleges: A Study of Generational Factors Affecting Employee Learning and Interaction

    ERIC Educational Resources Information Center

    Starks, Florida Elizabeth

    2014-01-01

    The purpose of this quantitative study is to broaden multigenerational workforce research involving factors affecting employee learning and interaction by using a population of Baby Boomer, Generation X, and Millennial faculty and staff age cohorts employed at two-year public community college organizations. Researchers have studied…

  18. Early pregnancy maternal and fetal angiogenic factors and fetal and childhood growth: the Generation R Study.

    PubMed

    Bergen, N E; Bouwland-Both, M I; Steegers-Theunissen, R P M; Hofman, A; Russcher, H; Lindemans, J; Jaddoe, V W V; Steegers, E A P

    2015-06-01

    What are the effects of maternal and fetal soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) concentrations on fetal and childhood growth patterns? An angiogenic profile that is characterized by both low early pregnancy maternal sFlt-1 and PlGF concentrations and higher sFlt-1 concentrations, lower PlGF concentrations or a higher sFlt-1:PlGF ratio in umbilical cord blood is associated with a reduced fetal and childhood growth. An imbalance in maternal and fetal sFlt-1 and PlGF concentrations has been suggested to affect pregnancy outcomes. However, their effects on longitudinal fetal and childhood growth remain largely unknown. This study was performed in 5980 mothers and 4108 of their children, participating in the Generation R Study; a population-based prospective cohort study from fetal life onwards in Rotterdam, the Netherlands (2001-2005). Blood samples were obtained from mothers in early and mid-pregnancy and from the umbilical vein at delivery. Fetal and childhood growth characteristics (weight and length) were measured repeatedly by ultrasound and physical examinations until the age of 6 years. We assessed the associations of maternal and fetal angiogenic factors with fetal and childhood growth using repeated measurement regression models. Logistic regression models were used to determine associations between angiogenic factors and small for gestational age at birth (SGA). Compared with early pregnancy maternal sFlt-1 concentrations in the lowest quintile, early pregnancy maternal sFlt-1 concentrations in the highest quintile were associated with a higher fetal weight growth resulting in a higher birthweight (difference in birthweight 0.33 standard deviation score (SDS); 95% Confidence Interval (CI) 0.25-0.41), a lower risk of SGA (Odds Ratio (OR) 0.36; 95% CI 0.27-0.48) and a subsequent higher weight growth until the age of 6 years. Early pregnancy maternal PlGF concentrations in the lowest quintile were associated with a

  19. Effect of BAX499 aptamer on tissue factor pathway inhibitor function and thrombin generation in models of hemophilia

    PubMed Central

    Gissel, Matthew; Orfeo, Thomas; Foley, Jonathan H; Butenas, Saulius

    2012-01-01

    Summary Introduction In hemophilia, thrombin generation is significantly suppressed due to decreased factor (F)X activation. Clinical studies and experiments with transgenic mice have suggested that the severity of hemophilia is substantially reduced by tissue factor pathway inhibitor (TFPI) deficiency. Methods We evaluated the effect of TFPI antagonist aptamer BAX499 (formerly ARC19499) on TFPI function in purified systems and on thrombin generation and clot formation in plasma and blood. Results BAX499 effectively neutralized TFPI inhibition of FXa and FXa dependent inhibition of TF/FVIIa by TFPI. BAX499 did not inhibit FXa or TF/FVIIa when used up to 500 nM. In the synthetic coagulation proteome with TFPI at its mean physiologic concentration, BAX499 at 1 – 10 nM increased thrombin generation triggered with 5 pM relipidated TF in a concentration-dependent manner. In severe hemophilia A or B models using the synthetic coagulation proteome, the addition of BAX499 at 5 nM increased thrombin generation to the levels observed in normal control. Thrombin generation measured in induced hemophilia B plasma required ~100 nM BAX499 to restore thrombin levels to those seen in untreated plasma. In induced hemophilia B whole blood, BAX499 repaired the clotting time but failed to appreciably impact the propagation phase of thrombin generation. Conclusion These data suggest that inhibition of TFPI by BAX499 may have potential for hemophilia treatment but requires further study in blood-based hemophilia systems. PMID:22951415

  20. Wind Power predictability a risk factor in the design, construction and operation of Wind Generation Turbines

    NASA Astrophysics Data System (ADS)

    Thiesen, J.; Gulstad, L.; Ristic, I.; Maric, T.

    2010-09-01

    Summit: The wind power predictability is often a forgotten decision and planning factor for most major wind parks, both onshore and offshore. The results of the predictability are presented after having examined a number of European offshore and offshore parks power predictability by using three(3) mesoscale model IRIE_GFS and IRIE_EC and WRF. Full description: It is well known that the potential wind production is changing with latitude and complexity in terrain, but how big are the changes in the predictability and the economic impacts on a project? The concept of meteorological predictability has hitherto to some degree been neglected as a risk factor in the design, construction and operation of wind power plants. Wind power plants are generally built in places where the wind resources are high, but these are often also sites where the predictability of the wind and other weather parameters is comparatively low. This presentation addresses the question of whether higher predictability can outweigh lower average wind speeds with regard to the overall economy of a wind power project. Low predictability also tends to reduce the value of the energy produced. If it is difficult to forecast the wind on a site, it will also be difficult to predict the power production. This, in turn, leads to increased balance costs and a less reduced carbon emission from the renewable source. By investigating the output from three(3) mesoscale models IRIE and WRF, using ECMWF and GFS as boundary data over a forecasting period of 3 months for 25 offshore and onshore wind parks in Europe, the predictability are mapped. Three operational mesoscale models with two different boundary data have been chosen in order to eliminate the uncertainty with one mesoscale model. All mesoscale models are running in a 10 km horizontal resolution. The model output are converted into "day a head" wind turbine generation forecasts by using a well proven advanced physical wind power model. The power models

  1. Updated greenhouse gas and criteria air pollutant emission factors and their probability distribution functions for electricity generating units

    SciTech Connect

    Cai, H.; Wang, M.; Elgowainy, A.; Han, J.

    2012-07-06

    Greenhouse gas (CO{sub 2}, CH{sub 4} and N{sub 2}O, hereinafter GHG) and criteria air pollutant (CO, NO{sub x}, VOC, PM{sub 10}, PM{sub 2.5} and SO{sub x}, hereinafter CAP) emission factors for various types of power plants burning various fuels with different technologies are important upstream parameters for estimating life-cycle emissions associated with alternative vehicle/fuel systems in the transportation sector, especially electric vehicles. The emission factors are typically expressed in grams of GHG or CAP per kWh of electricity generated by a specific power generation technology. This document describes our approach for updating and expanding GHG and CAP emission factors in the GREET (Greenhouse Gases, Regulated Emissions, and Energy Use in Transportation) model developed at Argonne National Laboratory (see Wang 1999 and the GREET website at http://greet.es.anl.gov/main) for various power generation technologies. These GHG and CAP emissions are used to estimate the impact of electricity use by stationary and transportation applications on their fuel-cycle emissions. The electricity generation mixes and the fuel shares attributable to various combustion technologies at the national, regional and state levels are also updated in this document. The energy conversion efficiencies of electric generating units (EGUs) by fuel type and combustion technology are calculated on the basis of the lower heating values of each fuel, to be consistent with the basis used in GREET for transportation fuels. On the basis of the updated GHG and CAP emission factors and energy efficiencies of EGUs, the probability distribution functions (PDFs), which are functions that describe the relative likelihood for the emission factors and energy efficiencies as random variables to take on a given value by the integral of their own probability distributions, are updated using best-fit statistical curves to characterize the uncertainties associated with GHG and CAP emissions in life

  2. Factor XIa and Thrombin Generation Are Elevated in Patients with Acute Coronary Syndrome and Predict Recurrent Cardiovascular Events

    PubMed Central

    Loeffen, Rinske; van Oerle, René; Leers, Mathie P. G.; Kragten, Johannes A.; Crijns, Harry; Spronk, Henri M. H.; ten Cate, Hugo

    2016-01-01

    Objective In acute coronary syndrome (ACS) cardiac cell damage is preceded by thrombosis. Therefore, plasma coagulation markers may have additional diagnostic relevance in ACS. By using novel coagulation assays this study aims to gain more insight into the relationship between the coagulation system and ACS. Methods We measured plasma thrombin generation, factor XIa and D-dimer levels in plasma from ACS (n = 104) and non-ACS patients (n = 42). Follow-up measurements (n = 73) were performed at 1 and 6 months. Associations between coagulation markers and recurrent cardiovascular events were calculated by logistic regression analysis. Results Thrombin generation was significantly enhanced in ACS compared to non-ACS patients: peak height 148±53 vs. 122±42 nM. There was a significantly diminished ETP reduction (32 vs. 41%) and increased intrinsic coagulation activation (25 vs. 7%) in ACS compared to non-ACS patients. Furthermore, compared to non-ACS patients factor XIa and D-dimer levels were significantly elevated in ACS patients: 1.9±1.1 vs. 1.4±0.7 pM and 495(310–885) vs. 380(235–540) μg/L. Within the ACS spectrum, ST-elevated myocardial infarction patients had the highest prothrombotic profile. During the acute event, thrombin generation was significantly increased compared to 1 and 6 months afterwards: peak height 145±52 vs. 100±44 vs. 98±33 nM. Both peak height and factor XIa levels on admission predicted recurrent cardiovascular events (OR: 4.9 [95%CI 1.2–20.9] and 4.5 [1.1–18.9]). Conclusion ACS patients had an enhanced prothrombotic profile, demonstrated by an increased thrombin generation potential, factor XIa and D-dimer levels. This study is the first to demonstrate the positive association between factor XIa, thrombin generation and recurrent cardiovascular events. PMID:27419389

  3. Validation of the French version of the marijuana craving questionnaire (MCQ) generates a two-factor model.

    PubMed

    Chauchard, Emeline; Goutaudier, Nelly; Heishman, Stephen J; Gorelick, David A; Chabrol, Henri

    2015-01-01

    Craving is a major issue in drug addiction, and a target for drug treatment. The Marijuana Craving Questionnaire-Short Form (MCQ-SF) is a useful tool for assessing cannabis craving in clinical and research settings. To validate the French version of the MCQ-SF (FMCQ-SF). Young adult cannabis users not seeking treatment (n = 679) completed the FMCQ-SF and questionnaires assessing their frequency of cannabis use and craving, cannabis use disorder criteria, and alcohol use. Confirmatory factor analysis of the four-factor FMCQ-SF model did not fit the data well. Exploratory factor analysis suggested a two-factor solution ("pleasure", characterized by planning and expectation of positive effects, and "release of tension", characterized by relief from anxiety, nervousness, or tension) with good psychometric properties. This two-factor model showed good internal and convergent validity and correlated with cannabis abuse and dependence and with frequency of cannabis use and craving. Validation of the FMCQ-SF generated a two-factor model, different from the four-factor solution generated in English language studies. Considering that craving plays an important role in withdrawal and relapse, this questionnaire should be useful for French-language addiction professionals.

  4. Generation Y New Zealand Registered Nurses' views about nursing work: a survey of motivation and maintenance factors.

    PubMed

    Jamieson, Isabel; Kirk, Ray; Wright, Sarah; Andrew, Cathy

    2015-07-01

    The aim of this article was to report on the analysis of qualitative, open text data, received from a national on-line survey of what factors Generation Y New Zealand Registered Nurses wish to change about nursing and consideration of the potential policy and practice impacts of these requests on their retention. Prior to the economic recession of 2007-2010, the growing shortage of nurses in New Zealand presented a serious concern for the healthcare workforce. Given the ageing New Zealand nursing workforce, an ageing population and the increasing demands for health care, it is imperative that issues of retention of Generation Y nurses are resolved prior to the imminent retirement of more experienced nurses. A descriptive exploratory approach using a national wide, on-line survey, eliciting both quantitative and qualitative data was used. The survey, conducted from August 2009-January 2010, collected data from Generation Y New Zealand Registered Nurses (n = 358) about their views about nursing, work and career. Herzberg's Motivation-Hygiene theory was used as the framework for the analysis of the open text data. The factors that nurses wanted changed were skewed towards Herzberg's hygiene-maintenance factors rather than motivating factors. This is of concern because hygiene-maintenance factors are considered to be dissatisfiers that are likely to push workers to another employment option.

  5. Bioelectrical impedance phase angle in clinical practice: implications for prognosis in stage IIIB and IV non-small cell lung cancer.

    PubMed

    Gupta, Digant; Lammersfeld, Carolyn A; Vashi, Pankaj G; King, Jessica; Dahlk, Sadie L; Grutsch, James F; Lis, Christopher G

    2009-01-28

    A frequent manifestation of advanced lung cancer is malnutrition, timely identification and treatment of which can lead to improved patient outcomes. Bioelectrical impedance analysis (BIA) is an easy-to-use and non-invasive technique to evaluate changes in body composition and nutritional status. We investigated the prognostic role of BIA-derived phase angle in advanced non-small cell lung cancer (NSCLC). A case series of 165 stages IIIB and IV NSCLC patients treated at our center. The Kaplan Meier method was used to calculate survival. Cox proportional hazard models were constructed to evaluate the prognostic effect of phase angle, independent of stage at diagnosis and prior treatment history. 93 were males and 72 females. 61 had stage IIIB disease at diagnosis while 104 had stage IV. The median phase angle was 5.3 degrees (range = 2.9 - 8). Patients with phase angle 5.3 had 12.4 months (95% CI: 10.5 to 18.7; n = 84); (p = 0.02). After adjusting for age, stage at diagnosis and prior treatment history we found that every one degree increase in phase angle was associated with a relative risk of 0.79 (95% CI: 0.64 to 0.97, P = 0.02). We found BIA-derived phase angle to be an independent prognostic indicator in patients with stage IIIB and IV NSCLC. Nutritional interventions targeted at improving phase angle could potentially lead to an improved survival in patients with advanced NSCLC.

  6. A GLP-Compliant Toxicology and Biodistribution Study: Systemic Delivery of an rAAV9 Vector for the Treatment of Mucopolysaccharidosis IIIB

    PubMed Central

    Meadows, Aaron S.; Duncan, F. Jason; Camboni, Marybeth; Waligura, Kathryn; Montgomery, Chrystal; Zaraspe, Kimberly; Naughton, Bartholomew J.; Bremer, William G.; Shilling, Christopher; Walker, Christopher M.; Bolon, Brad; Flanigan, Kevin M.; McBride, Kim L.; McCarty, Douglas M.; Fu, Haiyan

    2015-01-01

    No treatment is currently available for mucopolysaccharidosis (MPS) IIIB, a neuropathic lysosomal storage disease due to defect in α-N-acetylglucosaminidase (NAGLU). In preparation for a clinical trial, we performed an IND-enabling GLP-toxicology study to assess systemic rAAV9-CMV-hNAGLU gene delivery in WT C57BL/6 mice at 1 × 1014 vg/kg and 2 × 1014 vg/kg (n = 30/group, M:F = 1:1), and non-GLP testing in MPS IIIB mice at 2 × 1014 vg/kg. Importantly, no adverse clinical signs or chronic toxicity were observed through the 6 month study duration. The rAAV9-mediated rNAGLU expression was rapid and persistent in virtually all tested CNS and somatic tissues. However, acute liver toxicity occurred in 33% (5/15) WT males in the 2 × 1014 vg/kg cohort, which was dose-dependent, sex-associated, and genotype-specific, likely due to hepatic rNAGLU overexpression. Interestingly, a significant dose response was observed only in the brain and spinal cord, whereas in the liver at 24 weeks postinfection (pi), NAGLU activity was reduced to endogenous levels in the high dose cohort but remained at supranormal levels in the low dose group. The possibility of rAAV9 germline transmission appears to be minimal. The vector delivery resulted in transient T-cell responses and characteristic acute antibody responses to both AAV9 and rNAGLU in all rAAV9-treated animals, with no detectable impacts on tissue transgene expression. This study demonstrates a generally safe and effective profile, and may have identified the upper dosing limit of rAAV9-CMV-hNAGLU via systemic delivery for the treatment of MPS IIIB. PMID:26684447

  7. Novel morphological features for prediction of distal thoracic aortic enlargement after thoracic endovascular aortic repair of DeBakey IIIb aortic dissection.

    PubMed

    Ge, Yang Yang; Xue, Yan; Guo, Wei; Zhang, Hong Peng; Liu, Xiao Ping; Xiong, Jiang; Jia, Xin; Ma, Xiao Hui; Wang, Li Jun

    2017-09-05

    To assess the novel morphological features for DeBakey IIIb aortic dissection in predicting distal thoracic aortic enlargement after thoracic endovascular aortic repair (TEVAR). Sixty-seven patients who underwent TEVAR for DeBakey IIIb aortic dissection between January 2011 and December 2013 at our center were divided based on preoperative computer tomography angiography (CTA) features into 3 groups: I (n = 27) and III (n = 9), with true and false lumen, respectively, coursing closely along thoracic vertebral bodies; and II, spiral configuration (n = 31). Distal thoracic aortic enlargement was determined using pre- and postoperative CTA images. At median 12.2 (interquartile range, 4.3-26.6) months, 12 patients developed distal thoracic aortic enlargement, with estimated cumulative incidence tending to increase from categories I to III (P for trend < .01). Categories II and III vs. I had more frequently concave location of primary entry tear (P < .01), larger dissection length and height index (L/Hi) (P = .05), and greater number of abdominal small branches involved preoperatively (P = .03), with otherwise similar baseline characteristics; and significantly greater total aortic diameter increase and lower false lumen regression up to 24 months, and lower true lumen expansion up to 12 months. In multivariable regression analysis, categories II and III were independently associated with distal thoracic aortic enlargement (hazard ratio, 19.95 [95% confidence interval, 2.14-186.09]; 41.23 [3.61-470.22], respectively) after adjustment for Society of Vascular Surgery score, preoperative maximum total aortic diameter, L/Hi, and number of abdominal small branches involved preoperatively. The CTA-based morphological features described in this study might improve preoperative risk stratification of DeBakey IIIb aortic dissection, with categories II and III having higher risk of distal thoracic aortic enlargement after TEVAR. Copyright © 2017. Published by Elsevier Inc.

  8. Preferred transduction with AAV8 and AAV9 via thalamic administration in the MPS IIIB model: A comparison of four rAAV serotypes

    PubMed Central

    Gilkes, J.A.; Bloom, M.D.; Heldermon, C.D.

    2015-01-01

    Sanfilippo syndrome type B (MPS IIIB) is a lysosomal storage disease caused by a deficiency of N-acetyl-glucosaminidase (NAGLU) activity. Since early therapeutic intervention is likely to yield the most efficacious results, we sought to determine the possible therapeutic utility of rAAV in early gene therapy based interventions. Currently, the application of recombinant adeno-associated virus (AAV) vectors is one of the most widely used gene transfer systems, and represents a promising approach in the treatment of MPS IIIB. From a translational standpoint, a minimally invasive, yet highly efficient method of vector administration is ideal. The thalamus is thought to be the switchboard for signal relay in the central nervous system (CNS) and therefore represents an attractive target. To identify an optimal AAV vector for early therapeutic intervention, and establish whether thalamic administration represents a feasible therapeutic approach, we performed a comprehensive assessment of transduction and biodistribution profiles of four green fluorescent protein (GFP) bearing rAAV serotypes, -5, -8, -9 and -rh10, administered bilaterally into the thalamus. Of the four serotypes compared, AAV8 and -9 proved superior to AAV5 and -rh10 both in biodistribution and transduction efficiency profiles. Genotype differences in transduction efficiency and biodistribution patterns were also observed. Importantly, we conclude that AAV8 and to a lesser extent, AAV9 represent preferable candidates for early gene therapy based intervention in the treatment of MPS IIIB. We also highlight the feasibility of thalamic rAAV administration, and conclude that this method results in moderate rAAV biodistribution with limited treatment capacity, thus suggesting a need for alternate methods of vector delivery. PMID:27014573

  9. Preferred transduction with AAV8 and AAV9 via thalamic administration in the MPS IIIB model: A comparison of four rAAV serotypes.

    PubMed

    Gilkes, J A; Bloom, M D; Heldermon, C D

    2016-03-01

    Sanfilippo syndrome type B (MPS IIIB) is a lysosomal storage disease caused by a deficiency of N-acetyl-glucosaminidase (NAGLU) activity. Since early therapeutic intervention is likely to yield the most efficacious results, we sought to determine the possible therapeutic utility of rAAV in early gene therapy based interventions. Currently, the application of recombinant adeno-associated virus (AAV) vectors is one of the most widely used gene transfer systems, and represents a promising approach in the treatment of MPS IIIB. From a translational standpoint, a minimally invasive, yet highly efficient method of vector administration is ideal. The thalamus is thought to be the switchboard for signal relay in the central nervous system (CNS) and therefore represents an attractive target. To identify an optimal AAV vector for early therapeutic intervention, and establish whether thalamic administration represents a feasible therapeutic approach, we performed a comprehensive assessment of transduction and biodistribution profiles of four green fluorescent protein (GFP) bearing rAAV serotypes, -5, -8, -9 and -rh10, administered bilaterally into the thalamus. Of the four serotypes compared, AAV8 and -9 proved superior to AAV5 and -rh10 both in biodistribution and transduction efficiency profiles. Genotype differences in transduction efficiency and biodistribution patterns were also observed. Importantly, we conclude that AAV8 and to a lesser extent, AAV9 represent preferable candidates for early gene therapy based intervention in the treatment of MPS IIIB. We also highlight the feasibility of thalamic rAAV administration, and conclude that this method results in moderate rAAV biodistribution with limited treatment capacity, thus suggesting a need for alternate methods of vector delivery.

  10. Subcutaneous Abatacept vErsus Intravenous Abatacept: A Phase IIIb Noninferiority Study in Patients With an Inadequate Response to Methotrexate

    PubMed Central

    Genovese, M C; Covarrubias, A; Leon, G; Mysler, E; Keiserman, M; Valente, R; Nash, P; Simon-Campos, J A; Porawska, W; Box, J; Legerton, C; Nasonov, E; Durez, P; Aranda, R; Pappu, R; Delaet, I; Teng, J; Alten, R

    2011-01-01

    Objective To compare the efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept. Methods In this phase IIIb double-blind, double-dummy, 6-month study, patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus an IV loading dose [∼10 mg/kg] on day 1) or IV abatacept (∼10 mg/kg) on days 1, 15, and 29 and every 4 weeks thereafter. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at month 6. Other efficacy end points, immunogenicity, and safety were also assessed. Results Of 1,457 patients, 693 of 736 (94.2%) treated with SC abatacept and 676 of 721 (93.8%) treated with IV abatacept completed 6 months. At month 6, 76.0% (95% confidence interval 72.9, 79.2) of SC abatacept–treated patients versus 75.8% (95% confidence interval 72.6, 79.0) of IV abatacept–treated patients achieved an ACR20 response (estimated difference between groups 0.3% [95% confidence interval –4.2, 4.8]), confirming noninferiority of SC abatacept to IV abatacept. Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept–treated groups. The proportions of adverse events (AEs) and serious AEs over 6 months were 67.0% and 4.2%, respectively, in the SC abatacept–treated group and 65.2% and 4.9%, respectively, in the IV abatacept–treated group, with comparable frequencies of serious infections, malignancies, and autoimmune events between groups. SC injection site reactions (mostly mild) occurred in 19 SC abatacept (IV placebo)–treated patients (2.6%) and 18 IV abatacept (SC placebo)–treated patients (2.5%). Abatacept-induced antibodies occurred in 1.1% of SC abatacept–treated patients and 2

  11. Behavioural risk factors in two generations of non-Western migrants: do trends converge towards the host population?

    PubMed

    Hosper, Karen; Nierkens, Vera; Nicolaou, Mary; Stronks, Karien

    2007-01-01

    Migrant mortality does not conform to a single pattern of convergence towards prevalence rates in the host population. To understand better how migrant mortality develops, it is necessary to further investigate how the underlying behavioural determinants change following migration. We studied whether the prevalence of behavioural risk factors over two generations of Turkish and Moroccan migrants converge towards the prevalence rates in the Dutch population. From a random sample from the population register of Amsterdam, 291 Moroccan and 505 Turkish migrants, aged 15-30, participated in a structured interview that included questions on smoking, alcohol consumption, physical inactivity and weight/height. Data from the Dutch population were available from Statistics Netherlands. By calculating age-adjusted Odds Ratio's, prevalence rates among both generations were compared with prevalence rates in the host population for men and women separately. We found indications of convergence across generations towards the prevalence rates in the host population for smoking in Turkish men, for overweight in Turkish and Moroccan women and for physical inactivity in Turkish women. Alcohol consumption, however, remained low in all subgroups and did not converge towards the higher rates in the host population. In addition, we found a reversed trend among Turkish women regarding smoking: the second generation smoked significantly more, while the first generation did not differ from ethnic Dutch. In general, behavioural risk factors in two generations of non-Western migrants in the Netherlands seem to converge towards the prevalence rates in the Dutch population. However, some subgroups and risk factors showed a different pattern.

  12. Identification of ciliary neurotrophic factor (CNTF) residues essential for leukemia inhibitory factor receptor binding and generation of CNTF receptor antagonists.

    PubMed Central

    Di Marco, A; Gloaguen, I; Graziani, R; Paonessa, G; Saggio, I; Hudson, K R; Laufer, R

    1996-01-01

    Ciliary neurotrophic factor (CNTF) drives the sequential assembly of a receptor complex containing the ligand-specific alpha-receptor subunit (CNTFR alpha) and the signal transducers gp130 and leukemia inhibitory factor receptor-beta (LIFR). The D1 structural motif, located at the beginning of the D-helix of human CNTF, contains two amino acid residues, F152 and K155, which are conserved among all cytokines that signal through LIFR. The functional importance of these residues was assessed by alanine mutagenesis. Substitution of either F152 or K155 with alanine was found to specifically inhibit cytokine interaction with LIFR without affecting binding to CNTFR alpha or gp130. The resulting variants behaved as partial agonists with varying degrees of residual bioactivity in different cell-based assays. Simultaneous alanine substitution of both F152 and K155 totally abolished biological activity. Combining these mutations with amino acid substitutions in the D-helix, which enhance binding affinity for the CNTFR alpha, gave rise to a potent competitive CNTF receptor antagonist. This protein constitutes a new tool for studies of CNTF function in normal physiology and disease. Images Fig. 1 Fig. 6 PMID:8799186

  13. Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer.

    PubMed

    Liao, Bin-Chi; Lin, Chia-Chi; Yang, James Chih-Hsin

    2015-03-01

    The first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, are effective as first-line treatment of advanced nonsmall cell lung cancer (NSCLC) harboring activating EGFR mutations (deletions in exon 19 and exon 21 L858R mutation). EGFR T790 M resistance mutation (EGFR T790 M) ultimately emerged in most of these patients. The second and third-generation EGFR-TKIs were designed to have more potent inhibition of EGFR and to overcome EGFR T790 M. This review describes the recent developments of these novel EGFR-TKIs. The second-generation EGFR-TKIs, afatinib and dacomitinib, irreversibly bind to the tyrosine kinase of EGFR and other ErbB-family members. Afatinib has been approved as first-line treatment of advanced NSCLC harboring activating EGFR mutations. Dacomitinib is under development. Third-generation EGFR-TKIs, AZD9291, CO-1686, and HM61713, inhibit both EGFR activating and resistance mutations, while sparing wild-type EGFR. In early-phase studies, these drugs demonstrated promising response rates against tumors with acquired EGFR T790 M. Second-generation EGFR-TKI, afatinib, is available as first-line treatment of advanced NSCLC harboring activating EGFR mutations. Third-generation EGFR-TKIs are under development for tumors harboring acquired EGFR T790 M.

  14. Contextual Factors Contributing to Ethnic Identity Development of Second-Generation Iranian American Adolescents

    ERIC Educational Resources Information Center

    Daha, Maryam

    2011-01-01

    The data drawn from interviews with 55 second-generation Iranian American adolescents revealed that pride in ancient Persian culture, the adolescents' physical characteristics, perceived stereotypes, and community point of reference all combined to affect ethnic identity as well as to reinforce a sense of ethnic loyalty. The contextual factors…

  15. Contextual Factors Contributing to Ethnic Identity Development of Second-Generation Iranian American Adolescents

    ERIC Educational Resources Information Center

    Daha, Maryam

    2011-01-01

    The data drawn from interviews with 55 second-generation Iranian American adolescents revealed that pride in ancient Persian culture, the adolescents' physical characteristics, perceived stereotypes, and community point of reference all combined to affect ethnic identity as well as to reinforce a sense of ethnic loyalty. The contextual factors…

  16. Viewing Generativity and Social Capital as Underlying Factors of Parent Involvement

    ERIC Educational Resources Information Center

    Stevens, Sharon; Patel, Nimisha

    2015-01-01

    Parent involvement in education is a multifaceted support that has many well-documented benefits for students of all ages. Parent involvement is also a common expression of generativity as defined in Erik Erikson's theory of psychosocial development. The activities parents engage in during their children's educational pursuits, as well as their…

  17. First-Generation Freshman College Students: Factors Impacting Retention for the Subsequent Year

    ERIC Educational Resources Information Center

    McLean, Laura Colson

    2013-01-01

    Against all odds, first-generation college students continue to enroll in postsecondary schools with aspirations of obtaining a bachelor's degree. Unfortunately, many have not successfully reached their goal, which in turn has affected retention rates of colleges and universities. There are programs that provide academic support and advising to…

  18. STT arthrodesis versus proximal row carpectomy for Lichtman stage IIIB Kienböck's disease: first results of an ongoing observational study.

    PubMed

    Hohendorff, Bernd; Mühldorfer-Fodor, Marion; Kalb, Karlheinz; van Schoonhoven, Jörg; Prommersberger, Karl-Josef

    2012-09-01

    Scapho-trapezial-trapezoidal (STT) arthrodesis and proximal row carpectomy (PRC) are used for the treatment of Lichtman stage IIIB Kienböck's disease. This study prospectively compares 1-year results of STT arthrodesis and PRC in Lichtman stage IIIB Kienböck's disease. Nineteen patients were operated: eight with STT arthrodesis and 11 with PRC. Preoperatively and 1-year postoperatively, mobility and grip strength were examined. Both DASH and Mayo Wrist Scores were obtained from the patients. In the STT arthrodesis group, mean extension/flexion worsened from 54 to 39 % of the opposite hand. Grip strength improved from 52.9 to 62.1 %. The DASH Score improved from 32.6 to 21.4, and the Mayo Wrist Score from 50.6 to 57.9. In the PRC group, extension/flexion decreased from 62.5 to 57.0 % of the opposite hand. Grip strength improved from 38.6 to 69.0 %, the DASH Score from 36.7 to 18.9, and the Mayo Wrist Score from 54.6 to 66.0. One year after operation, slightly better results were observed in patients with PRC compared to STT arthrodesis.

  19. Unreamed Intramedullary Nailing is a better alternative than External Fixator for Gustilo grade IIIB Tibial Fractures based on a meta-analysis.

    PubMed

    Zhang, F; Zhu, Y; Li, W; Chen, W; Tian, Y; Zhang, Y

    2016-06-01

    There remains a controversy between unreamed intramedullary nailing and external fixation to treat Gustilo grade IIIB tibial fractures. To evaluate the comparative effectiveness and safeness of both methods for this type of fracture, we performed this meta-analysis. Relevant original studies were searched in MEDLINE, EMBASE, China National Knowledge Infrastructure, and Cochrane Central Database (all through February 2014). Studies included in this meta-analysis had to compare the effectiveness or complications and provided sufficient data of interest. The patients treated by both methods were similar statistically in demography and injury mechanism. The Stata 11.0 was used to analyze all data. Six studies involving 163 participants were included. Unreamed intramedullary nailing was associated with reduced time to union (standardized mean difference, -1.14; 95% confidence interval, -2.04 to -0.24) and lower rates of superficial infection (odds ratio: 0.39; 95% confidence interval: 0.17-0.87) and malunion (odds ratio: 0.27; 95% confidence interval: 0.09-0.78). However, there were no significant differences in other adverse events including delayed union, non-union, deep infection, and fixation failure. The existing evidence supports unreamed intramedullary nailing to be a better method for treating Gustilo grade IIIB tibial fractures, and this might aid in the management of this sever injury. © The Finnish Surgical Society 2015.

  20. Therapeutic Efficacy of Bone Marrow Transplant, Intracranial AAV-mediated Gene Therapy, or Both in the Mouse Model of MPS IIIB

    PubMed Central

    Heldermon, Coy D; Ohlemiller, Kevin K; Herzog, Erik D; Vogler, Carole; Qin, Elizabeth; Wozniak, David F; Tan, Yun; Orrock, John L; Sands, Mark S

    2010-01-01

    Sanfilippo syndrome type B (MPS IIIB) is a lysosomal storage disease resulting from a deficiency of N-acetyl-glucosaminidase (NAGLU) activity. In an attempt to correct the disease in the murine model of MPS IIIB, neonatal mice were treated with intracranial AAV2/5-NAGLU (AAV), syngeneic bone marrow transplant (BMT), or both (AAV/BMT). All treatments resulted in some improvement in clinical phenotype. Adeno-associated viral (AAV) treatment resulted in improvements in lifespan, motor function, hearing, time to activity onset, and daytime activity level, but no reduction of lysosomal storage. BMT resulted in improved hearing by 9 months, and improved circadian measures, but had no effect on lifespan, motor function, or central nervous system (CNS) lysosomal storage. AAV/BMT treatment resulted in improvements in hearing, time to activity onset, motor function, and reduced CNS lysosomal storage, but had no effect on lifespan. Combination therapy compared to either therapy alone resulted in synergistic effects on hearing and CNS lysosomal inclusions but antagonistic effects on motor function and lifespan. AAV alone is more efficacious than BMT or AAV/BMT treatment for lifespan. BMT was the least efficacious treatment by all measures. CNS-directed AAV treatment alone appears to be the preferred treatment, combining the most efficacy with the least toxicity of the approaches assessed. PMID:20179679

  1. Alpha-1 proteinase inhibitor M358R reduces thrombin generation when displayed on the surface of cells expressing tissue factor.

    PubMed

    Gierczak, Richard F; Pepler, Laura; Bhagirath, Vinai; Liaw, Patricia C; Sheffield, William P

    2014-11-01

    The M358R variant of alpha-1-proteinase inhibitor (API) is a potent soluble inhibitor of thrombin. Previously we engineered AR-API M358R, a membrane-bound form of this protein and showed that it inhibited exogenous thrombin when expressed on transfected cells lacking tissue factor (TF). To determine the suitability of AR-API M358R for gene transfer to vascular cells to limit thrombogenicity, we tested the ability of AR-API M358R to inhibit endogenous thrombin generated in plasma via co-expression co-expressing it on the surface of cells expressing TF. Transfected AR-API M358R formed inhibitory complexes with thrombin following exposure of recalcified, defibrinated plasma to TF on T24/83 cells, but discontinuously monitored thrombin generation was unaffected. Similarly, AR-API M358R expression did not reduce continuously monitored thrombin generation by T24/83 cell suspensions exposed to recalcified normal plasma in a Thrombogram-Thrombinoscope-type thrombin generation assay (TGA); in contrast, 1 μM hirudin variant 3 or soluble API M358R abolished thrombin generation. Gene transfer of TF to HEK 293 conferred the ability to support TF-dependent thrombin generation on HEK 293 cells. Co-transfection of HEK 293 cells with a 9:1 excess of DNA encoding AR-API M358R to that encoding TF reduced peak thrombin generation approximately 3-fold compared to controls. These in vitro results suggest that surface display of API M358R inhibits thrombin generation when the tethered serpin is expressed in excess of TF, and suggest its potential to limit thrombosis in appropriate vascular beds in animal models. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Association of translation factor eEF1A with defective ribosomal products generates a signal for aggresome formation.

    PubMed

    Meriin, Anatoli B; Zaarur, Nava; Sherman, Michael Y

    2012-06-01

    Aggresome formation is initiated upon proteasome failure, and facilitates autophagic clearance of protein aggregates to protect cells from proteotoxicity. Here we demonstrate that proteasome inhibition generates a signaling event to trigger aggresome formation. In aggresome signaling, the cell senses a build-up of aberrant newly synthesized proteins. The translation elongation factor eEF1A associated with these species, and knockdown of this factor suppressed aggresome formation. We used the Legionella toxin SidI to distinguish between the function of eEF1A in translation and its novel function in the aggresome formation. In fact, although it strongly inhibited translation, this toxin had only a marginal effect on aggresome formation. Furthermore, SidI reduced the threshold of the aberrant ribosomal products for triggering aggresome formation. Therefore, eEF1A binds defective polypeptides released from ribosomes, which generates a signal that triggers aggresome formation.

  3. Generational differences in factors influencing job turnover among Japanese nurses: an exploratory comparative design.

    PubMed

    Takase, Miyuki; Oba, Keiko; Yamashita, Noriko

    2009-07-01

    Although nurse turnover is a serious problem, the fact that each nurse has different work-related needs/values, and leaves their job for different reasons makes it difficult for organisations to develop effective countermeasures against it. Understanding nurses' needs and the reasons for job turnover by the generation in which they were born may provide some feasible solutions. The purpose of the study was to identify specific work-related needs and values of nurses in three generations (born in 1946-1959, 1960-1974, 1975-present). The study also aimed to explore generation-specific reasons that might make nurses consider leaving the jobs. The study was conducted in three public hospitals in Japan. A convenience sample of 315 registered nurses participated in the study. A survey method was used to collect quantitative and qualitative data. Quantitative data were analysed by ANOVA, and qualitative data were analysed by content analysis. Nurses born between 1960 and 1974 embraced high needs and values in professional privileges such as autonomy and recognition, while those born after 1975 expressed low needs and values in the opportunities for clinical challenge. For nurses born between 1960 and 1974, the imbalance between their jobs and personal life made them consider leaving their jobs. For those born after 1975, losing the confidence to care made them consider turning over. Nurses born after 1960 tended to value economic return and job security more highly compared to those born between 1946 and 1959. Nurses in different generations have different sets of needs/values and reasons for job turnover. Understanding generation-specific needs and values of nurses may enable organisations and Nurse Managers to develop feasible and effective countermeasures to reduce nurse turnover.

  4. Concurrent Phosphorus Recovery and Energy Generation in Mediator-Less Dual Chamber Microbial Fuel Cells: Mechanisms and Influencing Factors

    PubMed Central

    Almatouq, Abdullah; Babatunde, Akintunde O.

    2016-01-01

    This study investigated the mechanism and key factors influencing concurrent phosphorus (P) recovery and energy generation in microbial fuel cells (MFC) during wastewater treatment. Using a mediator-less dual chamber microbial fuel cell operated for 120 days; P was shown to precipitate as struvite when ammonium and magnesium chloride solutions were added to the cathode chamber. Monitoring data for chemical oxygen demand (COD), pH, oxidation reduction potential (ORP) and aeration flow rate showed that a maximum 38% P recovery was achieved; and this corresponds to 1.5 g/L, pH > 8, −550 ± 10 mV and 50 mL/min respectively, for COD, pHcathode, ORP and cathode aeration flow rate. More importantly, COD and aeration flow rate were shown to be the key influencing factors for the P recovery and energy generation. Results further show that the maximum P recovery corresponds to 72 mW/m2 power density. However, the energy generated at maximum P recovery was not the optimum; this shows that whilst P recovery and energy generation can be concurrently achieved in a microbial fuel cell, neither can be at the optimal value. PMID:27043584

  5. Enhanced hemangioblast generation and improved vascular repair and regeneration from embryonic stem cells by defined transcription factors.

    PubMed

    Liu, Fang; Bhang, Suk Ho; Arentson, Elizabeth; Sawada, Atsushi; Kim, Chan Kyu; Kang, Inyoung; Yu, Jinsheng; Sakurai, Nagisa; Kim, Suk Hyung; Yoo, Judy Ji Woon; Kim, Paul; Pahng, Seong Ho; Xia, Younan; Solnica-Krezel, Lilianna; Choi, Kyunghee

    2013-01-01

    The fetal liver kinase 1 (FLK-1)(+) hemangioblast can generate hematopoietic, endothelial, and smooth muscle cells (SMCs). ER71/ETV2, GATA2, and SCL form a core transcriptional network in hemangioblast development. Transient coexpression of these three factors during mesoderm formation stage in mouse embryonic stem cells (ESCs) robustly enhanced hemangioblast generation by activating bone morphogenetic protein (BMP) and FLK-1 signaling while inhibiting phosphatidylinositol 3-kinase, WNT signaling, and cardiac output. Moreover, etsrp, gata2, and scl inhibition converted hematopoietic field of the zebrafish anterior lateral plate mesoderm to cardiac. FLK-1(+) hemangioblasts generated by transient coexpression of the three factors (ER71-GATA2-SCL [EGS]-induced FLK-1(+)) effectively produced hematopoietic, endothelial, and SMCs in culture and in vivo. Importantly, EGS-induced FLK-1(+) hemangioblasts, when codelivered with mesenchymal stem cells as spheroids, were protected from apoptosis and generated functional endothelial cells and SMCs in ischemic mouse hindlimbs, resulting in improved blood perfusion and limb salvage. ESC-derived, EGS-induced FLK-1(+) hemangioblasts could provide an attractive cell source for future hematopoietic and vascular repair and regeneration.

  6. Concurrent Phosphorus Recovery and Energy Generation in Mediator-Less Dual Chamber Microbial Fuel Cells: Mechanisms and Influencing Factors.

    PubMed

    Almatouq, Abdullah; Babatunde, Akintunde O

    2016-03-29

    This study investigated the mechanism and key factors influencing concurrent phosphorus (P) recovery and energy generation in microbial fuel cells (MFC) during wastewater treatment. Using a mediator-less dual chamber microbial fuel cell operated for 120 days; P was shown to precipitate as struvite when ammonium and magnesium chloride solutions were added to the cathode chamber. Monitoring data for chemical oxygen demand (COD), pH, oxidation reduction potential (ORP) and aeration flow rate showed that a maximum 38% P recovery was achieved; and this corresponds to 1.5 g/L, pH > 8, -550 ± 10 mV and 50 mL/min respectively, for COD, pH(cathode), ORP and cathode aeration flow rate. More importantly, COD and aeration flow rate were shown to be the key influencing factors for the P recovery and energy generation. Results further show that the maximum P recovery corresponds to 72 mW/m² power density. However, the energy generated at maximum P recovery was not the optimum; this shows that whilst P recovery and energy generation can be concurrently achieved in a microbial fuel cell, neither can be at the optimal value.

  7. Factors affecting eluation characteristics of sorption generators of technetium-99m

    NASA Astrophysics Data System (ADS)

    Skuridin, V. S.; Chernov, V. I.; Sadkin, V. L.; Stasyuk, E. S.; Varlamova, N. V.; Rogov, A. S.; Nesterov, E. A.; Ilina, E. A.; Larionova, L. A.; Medvedeva, A. A.

    2016-08-01

    The influence of the adsorbed mass of molybdenum on the width of eluation profiles of generators and the patterns of molybdenum distribution in the amount of chromatographic columns by scanning them on the germanium-gallium detector using collimating device are studied. The boundary conditions under which the maximum value of 99mTc yield from generators Ye = 1 are defined. After scanning the columns, it was found out that the degree of filling the columns with molybdenum Q and the value of its maximum adsorption depend naturally on the total weight of the adsorbed mass. In order to achieve the condition Ye = 1 the value of Q should be at least 85%.

  8. Factors affecting eluation characteristics of sorption generators of technetium-99m

    SciTech Connect

    Skuridin, V. S.; Sadkin, V. L.; Stasyuk, E. S.; Varlamova, N. V.; Rogov, A. S. Nesterov, E. A.; Ilina, E. A.; Larionova, L. A.; Chernov, V. I.; Medvedeva, A. A.

    2016-08-02

    The influence of the adsorbed mass of molybdenum on the width of eluation profiles of generators and the patterns of molybdenum distribution in the amount of chromatographic columns by scanning them on the germanium-gallium detector using collimating device are studied. The boundary conditions under which the maximum value of {sup 99m}Tc yield from generators Y{sub e} = 1 are defined. After scanning the columns, it was found out that the degree of filling the columns with molybdenum Q and the value of its maximum adsorption depend naturally on the total weight of the adsorbed mass. In order to achieve the condition Y{sub e} = 1 the value of Q should be at least 85%.

  9. Signaling and Transcription Factors during Inner Ear Development: The Generation of Hair Cells and Otic Neurons

    PubMed Central

    Gálvez, Héctor; Abelló, Gina; Giraldez, Fernando

    2017-01-01

    Integration between cell signals and bHLH transcription factors plays a prominent role during the development of hair cells of the inner ear. Hair cells are the sensory receptors of the inner ear, responsible for the mechano-transduction of sound waves into electrical signals. They derive from multipotent progenitors that reside in the otic placode. Progenitor commitment is the result of cell signaling from the surrounding tissues that result in the restricted expression of SoxB1 transcription factors, Sox2 and Sox3. In turn, they induce the expression of Neurog1 and Atoh1, two bHLH factors that specify neuronal and hair cell fates, respectively. Neuronal and hair cell development, however, do not occur simultaneously. Hair cell development is prevented during neurogenesis and prosensory stages, resulting in the delay of hair cell development with respect to neuron production. Negative interactions between Neurog1 and Atoh1, and of Atoh1 with other bHLH factors driven by Notch signaling, like Hey1 and Hes5, account for this delay. In summary, the regulation of Atoh1 and hair cell development relies on interactions between cell signaling and bHLH transcription factors that dictate cell fate and timing decisions during development. Interestingly, these mechanisms operate as well during hair cell regeneration after damage and during stem cell directed differentiation, making developmental studies instrumental for improving therapies for hearing impairment. PMID:28393066

  10. Risk factors for dating violence versus cohabiting violence: Results from the third generation of the Cambridge Study in Delinquent Development.

    PubMed

    Theobald, Delphine; Farrington, David P; Ttofi, Maria M; Crago, Rebecca V

    2016-10-01

    Dating violence is an important problem. Evidence suggests that women are more likely to perpetrate dating violence. The present study investigates the prevalence of dating violence compared with cohabiting violence in a community sample of men and women and assesses to what extent child and adolescent explanatory factors predict this behaviour. A secondary aim is to construct a risk score for dating violence based on the strongest risk factors. The Cambridge Study in Delinquent Development is a prospective longitudinal survey of 411 men (generation 2) born in the 1950s in an inner London area. Most recently, their sons and daughters [generation 3 (G3)] have been interviewed regarding their perpetration of dating and cohabiting violence, utilising the Conflict Tactics Scale. Risk factors were measured in four domains (family, parental, socio-economic and individual). A larger proportion of women than men perpetrated at least one act of violence towards their dating partner (36.4 vs 21.7%). There was a similar pattern for cohabiting violence (39.6 vs 21.4%). A number of risk factors were significantly associated with the perpetration of dating violence. For G3 women, these included a convicted father, parental conflict, large family size and poor housing. For G3 men, these included having a young father or mother, separation from the father before age 16, early school leaving, frequent truancy and having a criminal conviction. A risk score for both men and women, based on 10 risk factors, significantly predicted dating violence. Risk factors from four domains were important in predicting dating violence, but they were different for G3 men and women. It may be important to consider different risk factors and different risk assessments for male compared with female perpetration of dating violence. Early identification and interventions are recommended. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  11. Battling the "Hydra": Changing Operational Factors in 4th Generation War

    DTIC Science & Technology

    2007-11-02

    challenging us to change current doctrine and attempts to reduce war to algebraic formulae. Current Operational Doctrine Operational art, as advanced...over terrain -- the image and concept of ’classic’ war. A- 2 Armies turned to ’science," relying upon mathematical probabilities and algebraic formulae...Jominian war of algebraic formula and mathematical probabilities, vice accepting the 3d generation premise to cause and thrive within chaos. Lacking

  12. Complicating factors in safety testing of drug metabolites: Kinetic differences between generated and preformed metabolites

    SciTech Connect

    Prueksaritanont, Thomayant . E-mail: thomayant_prueksaritanont@merck.com; Lin, Jiunn H.; Baillie, Thomas A.

    2006-12-01

    This paper aims to provide a scientifically based perspective on issues surrounding the proposed toxicology testing of synthetic drug metabolites as a means of ensuring adequate nonclinical safety evaluation of drug candidates that generate metabolites considered either to be unique to humans or are present at much higher levels in humans than in preclinical species. We put forward a number of theoretical considerations and present several specific examples where the kinetic behavior of a preformed metabolite given to animals or humans differs from that of the corresponding metabolite generated endogenously from its parent. The potential ramifications of this phenomenon are that the results of toxicity testing of the preformed metabolite may be misleading and fail to characterize the true toxicological contribution of the metabolite when formed from the parent. It is anticipated that such complications would be evident in situations where (a) differences exist in the accumulation of the preformed versus generated metabolites in specific tissues, and (b) the metabolite undergoes sequential metabolism to a downstream product that is toxic, leading to differences in tissue-specific toxicity. Owing to the complex nature of this subject, there is a need to treat drug metabolite issues in safety assessment on a case-by-case basis, in which a knowledge of metabolite kinetics is employed to validate experimental paradigms that entail administration of preformed metabolites to animal models.

  13. Endogenous platelet factor 4 stimulates activated protein C generation in vivo and improves survival after thrombin or lipopolysaccharide challenge

    PubMed Central

    Mahmud, Shawn A.; Lambert, Michele P.; Poncz, Mortimer; Slungaard, Arne

    2007-01-01

    Pharmacologic infusion of activated protein C (APC) improves survival in severe sepsis, and platelet factor 4 (PF4) accelerates APC generation in a primate thrombin-infusion model. We now tested whether endogenous platelet PF4 content affects APC generation. Mice completely deficient in PF4 (mPF4−/−) had impaired APC generation and survival after thrombin infusion, similar to the impairment seen in heterozygote protein C–deficient (PC+/−) mice. Transgenic mice overexpressing human PF4 (hPF4+) had increased plasma APC generation. Overexpression of platelet PF4 compensated for the defect seen in PC+/− mice. In both a thrombin and a lipopolysaccharide (LPS) survival model, hPF4+ and PC+/−/hPF4+ mice had improved survival. Further, infusion of hPF4+ platelets improved survival of wild-type mice after an LPS challenge. These studies suggest that endogenous PF4 release may have biologic consequences for APC generation and survival in clinical sepsis. Infusions of PF4-rich platelets may be an effective strategy to improve outcome in this setting. PMID:17540840

  14. Endogenous platelet factor 4 stimulates activated protein C generation in vivo and improves survival after thrombin or lipopolysaccharide challenge.

    PubMed

    Kowalska, M Anna; Mahmud, Shawn A; Lambert, Michele P; Poncz, Mortimer; Slungaard, Arne

    2007-09-15

    Pharmacologic infusion of activated protein C (APC) improves survival in severe sepsis, and platelet factor 4 (PF4) accelerates APC generation in a primate thrombin-infusion model. We now tested whether endogenous platelet PF4 content affects APC generation. Mice completely deficient in PF4 (mPF4(-/-)) had impaired APC generation and survival after thrombin infusion, similar to the impairment seen in heterozygote protein C-deficient (PC(+/-)) mice. Transgenic mice overexpressing human PF4 (hPF4(+)) had increased plasma APC generation. Overexpression of platelet PF4 compensated for the defect seen in PC(+/-) mice. In both a thrombin and a lipopolysaccharide (LPS) survival model, hPF4(+) and PC(+/-)/hPF4(+) mice had improved survival. Further, infusion of hPF4(+) platelets improved survival of wild-type mice after an LPS challenge. These studies suggest that endogenous PF4 release may have biologic consequences for APC generation and survival in clinical sepsis. Infusions of PF4-rich platelets may be an effective strategy to improve outcome in this setting.

  15. Generation of embryos directly from embryonic stem cells by tetraploid embryo complementation reveals a role for GATA factors in organogenesis.

    PubMed

    Duncan, S A

    2005-12-01

    Gene targeting in ES (embryonic stem) cells has been used extensively to study the role of proteins during embryonic development. In the traditional procedure, this requires the generation of chimaeric mice by introducing ES cells into blastocysts and allowing them to develop to term. Once chimaeric mice are produced, they are bred into a recipient mouse strain to establish germline transmission of the allele of interest. Although this approach has been used very successfully, the breeding cycles involved are time consuming. In addition, genes that are essential for organogenesis often have roles in the formation of extra-embryonic tissues that are essential for early stages of post-implantation development. For example, mice lacking the GATA transcription factors, GATA4 or GATA6, arrest during gastrulation due to an essential role for these factors in differentiation of extra-embryonic endoderm. This lethality has frustrated the study of these factors during the development of organs such as the liver and heart. Extraembryonic defects can, however, be circumvented by generating clonal mouse embryos directly from ES cells by tetraploid complementation. Here, we describe the usefulness and efficacy of this approach using GATA factors as an example.

  16. Perceived Factors Influencing the Pursuit of Higher Education among First-Generation College Students

    ERIC Educational Resources Information Center

    Coy-Ogan, Lynne

    2009-01-01

    Students who are first in their families to pursue higher education are often less likely to receive the academic, social, and financial support needed to experience success when compared to students from college-educated families. This study examined the perceived differences among salient factors influencing the pursuit of higher education…

  17. Factors Related to Perceived Status in the Campus Community for First Generation Students at an HBCU

    ERIC Educational Resources Information Center

    Longmire-Avital, Buffie; Miller-Dyce, Cherrel

    2013-01-01

    Research that has examined the complexities of within-group difference as they related to socioeconomic diversity has been necessary to fully understand the myriad of factors that affected college experience, persistence, and graduation rates of Black students not just at predominately White institutions (PWI's), but also at the Historically Black…

  18. State-level Greenhouse Gas Emission Factors for Electricity Generation, Updated

    EIA Publications

    2001-01-01

    To assist reporters in estimating emissions and emission reductions, The Energy Information Administration (EIA) has made available in the instructions to Forms EIA-1605 and EIA-1605EZ emission coefficients for most commonly used fossil fuels and electricity. These coefficients were based on 1992 emissions and generation data. In 1999, updated coefficients were prepared based on the most recent data (1998) then available; however, the updated coefficients were not included in the instructions for the 1999 data year. This year, they have been updated again, but based on three years worth of data (1997, 1998, and 1999) rather than a single year.

  19. Environmental and sustainability factors associated with next-generation biofuels in the U.S.: what do we really know?

    PubMed

    Williams, Pamela R D; Inman, Daniel; Aden, Andy; Heath, Garvin A

    2009-07-01

    In this paper, we assess what is known or anticipated about environmental and sustainability factors associated with next-generation biofuels relative to the primary conventional biofuels (i.e., corn grain-based ethanol and soybean-based diesel) in the United States during feedstock production and conversion processes. Factors considered include greenhouse (GHG) emissions, air pollutant emissions, soil health and quality, water use and water quality, wastewater and solid waste streams, and biodiversity and land-use changes. Based on our review of the available literature, we find that the production of next-generation feedstocks in the U.S. (e.g., municipal solid waste, forest residues, dedicated energy crops, microalgae) are expected to fare better than corn-grain or soybean production on most of these factors, although the magnitude of these differences may vary significantly among feedstocks. Ethanol produced using a biochemical or thermochemical conversion platform is expected to result in fewer GHG and air pollutant emissions, but to have similar or potentially greater water demands and solid waste streams than conventional ethanol biorefineries in the U.S. However, these conversion-related differences are likely to be small, particularly relative to those associated with feedstock production. Modeling performed for illustrative purposes and to allow for standardized quantitative comparisons across feedstocks and conversion technologies generally confirms the findings from the literature. Despite current expectations, significant uncertainty remains regarding how well next-generation biofuels will fare on different environmental and sustainability factors when produced on a commercial scale in the U.S. Additional research is needed in several broad areas including quantifying impacts, designing standardized metrics and approaches, and developing decision-support tools to identify and quantify environmental trade-offs and ensure sustainable biofuels production.

  20. Generation and characterization of small single domain antibodies inhibiting human tumor necrosis factor receptor 1.

    PubMed

    Steeland, Sophie; Puimège, Leen; Vandenbroucke, Roosmarijn E; Van Hauwermeiren, Filip; Haustraete, Jurgen; Devoogdt, Nick; Hulpiau, Paco; Leroux-Roels, Geert; Laukens, Debby; Meuleman, Philip; De Vos, Martine; Libert, Claude

    2015-02-13

    The cytokine TNF is a well known drug target for several inflammatory diseases such as Crohn disease. Despite the great success of TNF blockers, therapy could be improved because of high costs and side effects. Selective inhibition of TNF receptor (TNFR) 1 signaling holds the potential to greatly reduce the pro-inflammatory activity of TNF, thereby preserving the advantageous immunomodulatory signals mediated by TNFR2. We generated a selective human TNFR1 inhibitor based on Nanobody (Nb) technology. Two anti-human TNFR1 Nbs were linked with an anti-albumin Nb to generate Nb Alb-70-96 named "TNF Receptor-One Silencer" (TROS). TROS selectively binds and inhibits TNF/TNFR1 and lymphotoxin-α/TNFR1 signaling with good affinity and IC50 values, both of which are in the nanomolar range. Surface plasmon resonance analysis reveals that TROS competes with TNF for binding to human TNFR1. In HEK293T cells, TROS strongly reduces TNF-induced gene expression, like IL8 and TNF, in a dose-dependent manner; and in ex vivo cultured colon biopsies of CD patients, TROS inhibits inflammation. Finally, in liver chimeric humanized mice, TROS antagonizes inflammation in a model of acute TNF-induced liver inflammation, reflected in reduced human IL8 expression in liver and reduced IL6 levels in serum. These results demonstrate the considerable potential of TROS and justify the evaluation of TROS in relevant disease animal models of both acute and chronic inflammation and eventually in patients.

  1. Review of factors impacting emission/concentration of cooking generated particulate matter.

    PubMed

    Amouei Torkmahalleh, Mehdi; Gorjinezhad, Soudabeh; Unluevcek, Hediye Sumru; Hopke, Philip K

    2017-05-15

    Studies have shown that exposure to particulate matter (PM) emitted while cooking is related to adverse human health effects. The level of PM emissions during cooking varies with several factors. This study reviewed controlled studies available in the cooking PM emissions literature, and found that cooking method, type and quality of the energy (heating) source, burner size, cooking pan, cooking oil, food, additives, source surface area, cooking temperature, ventilation and position of the cooking pan on the stove are influential factors affecting cooking PM emission rates and resulting concentrations. Opportunities to reduce indoor PM concentrations during cooking are proposed. Minor changes in cooking habits and manner might result in a substantial reduction in the cook's exposure to the cooking PM. Finally, the need for additional studies is discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Impact of Prophylactic Cranial Irradiation Timing on Brain Relapse Rates in Patients With Stage IIIB Non-Small-Cell Lung Carcinoma Treated With Two Different Chemoradiotherapy Regimens

    SciTech Connect

    Topkan, Erkan; Parlak, Cem; Kotek, Ayse; Yuksel, Oznur; Cengiz, Mustafa; Ozsahin, Mahmut; Pehlivan, Berrin

    2012-07-15

    Purpose: To retrospectively assess the influence of prophylactic cranial irradiation (PCI) timing on brain relapse rates in patients treated with two different chemoradiotherapy (CRT) regimens for Stage IIIB non-small-cell lung cancer (NSCLC). Methods and Materials: A cohort of 134 patients, with Stage IIIB NSCLC in recursive partitioning analysis Group 1, was treated with PCI (30 Gy at 2 Gy/fr) following one of two CRT regimens. Regimen 1 (n = 58) consisted of three cycles of induction chemotherapy (ICT) followed by concurrent CRT (C-CRT). Regimen 2 (n = 76) consisted of immediate C-CRT during thoracic radiotherapy. Results: At a median follow-up of 27.6 months (range, 7.2-40.4), 65 patients were alive. Median, progression-free, and brain metastasis-free survival (BMFS) times for the whole study cohort were 23.4, 15.4, and 23.0 months, respectively. Median survival time and the 3-year survival rate for regimens 1 and 2 were 19.3 vs. 26.1 months (p = 0.001) and 14.4% vs. 34.4% (p < .001), respectively. Median time from the initiation of primary treatment to PCI was 123.2 (range, 97-161) and 63.4 (range, 55-74) days for regimens 1 and 2, respectively (p < 0.001). Overall, 11 (8.2%) patients developed brain metastasis (BM) during the follow-up period: 8 (13.8%) in regimen 1 and 3 (3.9%) in regimen 2 (p = 0.03). Only 3 (2.2%) patients developed BM at the site of first failure, and for 2 of them, it was also the sole site of recurrence. Median BMFS for regimens 1 and 2 were 17.4 (13.5-21.3) vs. 26.0 (22.9-29.1 months), respectively (p < 0.001). Conclusion: These results suggest that in Stage IIIB NSCLC patients treated with PCI, lower BM incidence and longer survival rates result from immediate C-CRT rather than ITC-first regimens. This indicates the benefit of earlier PCI use without delay because of induction protocols.

  3. Source segregation of food waste in office areas: Factors affecting waste generation rates and quality.

    PubMed

    Edjabou, Maklawe Essonanawe; Boldrin, Alessio; Scheutz, Charlotte; Astrup, Thomas Fruergaard

    2015-12-01

    Existing legislation mandates that the amount of waste being recycled should be increased. Among others, in its Resource Strategy Plan, the Danish Government decided that at least 60% of food waste generated by the service sector, including in office areas, should be source-sorted and collected separately by 2018. To assess the achievability of these targets, source-sorted food waste and residual waste from office areas was collected and weighed on a daily basis during 133 working days. Waste composition analyses were conducted every week to investigate the efficiency of the source-sorting campaign and the purity of the source-sorted food waste. The moisture content of source-sorted food waste and residual waste fractions, and potential methane production from source-sorted food waste, was also investigated. Food waste generation equated to 23 ± 5 kg/employee/year, of which 20 ± 5 kg/employee/year was source-sorted, with a considerably high purity of 99%. Residual waste amounted to 10 ± 5 kg/employee/year and consisted mainly of paper (29 ± 13%), plastic (23 ± 9%) and missorted food waste (24 ± 16%). The moisture content of source-sorted food waste was significantly higher (8%) than missorted food waste, and the methane potential of source-sorted food waste was 463 ± 42 mL CH4/g VS. These results show that food waste in office areas offers promising potential for relatively easily collectable and pure source-sorted food waste, suggesting that recycling targets for food waste could be achieved with reasonable logistical ease in office areas.

  4. Three generations of epidermal growth factor receptor tyrosine kinase inhibitors developed to revolutionize the therapy of lung cancer

    PubMed Central

    Zhang, Haijun

    2016-01-01

    Lung cancer, ~80%–85% of which is non-small-cell lung cancer (NSCLC), is the leading cause of cancer-related mortality worldwide. Sensitizing mutations in epidermal growth factor receptor (EGFR) gene (EGFRm+), such as exon 19 deletions and exon 21 L858R point mutations, are the most important drivers in NSCLC patients. In this respect, small-molecule EGFR tyrosine kinase inhibitors (TKIs) have been designed and developed, which launched the era of targeted, personalized and precise medicine for lung cancer. Patients with EGFRm+ could achieve good responses to the treatment with the first-generation EGFR TKIs, such as erlotinib and gefitinib. However, most patients develop acquired drug resistance mostly driven by the T790M mutation occurring within exon 20. Although the second-generation EGFR TKIs, such as afatinib, dacomitinib and neratinib, demonstrated promising activity against T790M in preclinical models, they have failed to overcome resistance in patients due to dose-limiting toxicity. Recently, the third-generation EGFR TKIs have shown to be effective against cell lines and murine models harboring T790M mutations while sparing wild-type EGFR, which represents a promising breakthrough approach in overcoming T790M-mediated resistance in NSCLC patients. This article provides a comprehensive review of the therapy revolution for NSCLC with three generations of EGFR TKIs. PMID:27920501

  5. The Inflammatory Cytokine Tumor Necrosis FactorGenerates an Autocrine Tumor-Promoting Network in Epithelial Ovarian Cancer Cells

    PubMed Central

    Kulbe, Hagen; Thompson, Richard; Wilson, Julia L.; Robinson, Stephen; Hagemann, Thorsten; Fatah, Rewas; Gould, David; Ayhan, Ayse; Balkwill, Frances

    2009-01-01

    Constitutive expression of the inflammatory cytokine tumor necrosis factor-α (TNF-α) is characteristic of malignant ovarian surface epithelium. We investigated the hypothesis that this autocrine action of TNF-α generates and sustains a network of other mediators that promote peritoneal cancer growth and spread. When compared with two ovarian cancer cell lines that did not make TNF-α, constitutive production of TNF-α was associated with greater release of the chemokines CCL2 and CXCL12, the cytokines interleukin-6 (IL-6) and macrophage migration-inhibitory factor (MIF), and the angiogenic factor vascular endothelial growth factor (VEGF). TNF-α production was associated also with increased peritoneal dissemination when the ovarian cancer cells were xenografted. We next used RNA interference to generate stable knockdown of TNF-α in ovarian cancer cells. Production of CCL2, CXCL12, VEGF, IL-6, and MIF was decreased significantly in these cells compared with wild-type or mock-transfected cells, but in vitro growth rates were unaltered. Tumor growth and dissemination in vivo were significantly reduced when stable knockdown of TNF-α was achieved. Tumors derived from TNF-α knockdown cells were noninvasive and well circumscribed and showed high levels of apoptosis, even in the smallest deposits. This was reflected in reduced vascularization of TNF-α knockdown tumors. Furthermore, culture supernatants from such cells failed to stimulate endothelial cell growth in vitro. We conclude that autocrine production of TNF-α by ovarian cancer cells stimulates a constitutive network of other cytokines, angiogenic factors, and chemokines that may act in an autocrine/paracrine manner to promote colonization of the peritoneum and neovascularization of developing tumor deposits. PMID:17234767

  6. TRANSCRIPTION FACTOR Bmsage PLAYS A CRUCIAL ROLE IN SILK GLAND GENERATION IN SILKWORM, Bombyx mori.

    PubMed

    Xin, Hu-hu; Zhang, Deng-pan; Chen, Rui-ting; Cai, Zi-zheng; Lu, Yan; Liang, Shuang; Miao, Yun-gen

    2015-10-01

    Salivary gland secretion is altered in Drosophila embryos with loss of function of the sage gene. Saliva has a reduced volume and an increased electron density according to transmission electron microscopy, resulting in regions of tube dilation and constriction with intermittent tube closure. However, the precise functions of Bmsage in silkworm (Bombyx mori) are unknown, although its sequence had been deposited in SilkDB. From this, Bmsage is inferred to be a transcription factor that regulates the synthesis of silk fibroin and interacts with another silk gland-specific transcription factor, namely, silk gland factor-1. In this study, we introduced a germline mutation of Bmsage using the Cas9/sgRNA system, a genome-editing technology, resulting in deletion of Bmsage from the genome of B. mori. Of the 15 tested samples, seven displayed alterations at the target site. The mutagenesis efficiency was about 46.7% and there were no obvious off-target effects. In the screened homozygous mutants, silk glands developed poorly and the middle and posterior silk glands (MSG and PSG) were absent, which was significantly different from the wild type. The offspring of G0 mosaic silkworms had indel mutations causing 2- or 9-bp deletions at the target site, but exhibited the same abnormal silk gland structure. Mutant larvae containing different open-reading frames of Bmsage had the same silk gland phenotype. This illustrated that the mutant phenotype was due to Bmsage knockout. We conclude that Bmsage participates in embryonic development of the silk gland. © 2015 Wiley Periodicals, Inc.

  7. Third-Generation Tyrosine Kinase Inhibitors Targeting Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer.

    PubMed

    Barnes, Tristan A; O'Kane, Grainne M; Vincent, Mark David; Leighl, Natasha B

    2017-01-01

    Sensitizing mutations in the epidermal growth factor receptor (EGFR) predict response to EGFR tyrosine kinase inhibitors (TKIs) and both first- and second-generation TKIs are available as first-line treatment options in patients with advanced EGFR-mutant non-small cell lung cancer. Eventual resistance develops with multiple mechanisms identifiable both upon repeat biopsy and in plasma circulating tumor DNA. The T790M gatekeeper mutation is responsible for almost 60% of cases. A number of third-generation TKIs are in clinical development, and osimertinib has been approved by the US Food and Drug Administration for the treatment of patients with EGFR T790M mutant lung cancer after failure of initial EGFR kinase therapy. Resistance mechanisms are being identified to these novel agents, and the treatment landscape of EGFR-mutant lung cancer continues to evolve. The sequence of EGFR TKIs may change in the future and combination therapies targeting resistance appear highly promising.

  8. Thrombin generation and fibrin clot formation under hypothermic conditions: an in vitro evaluation of tissue factor initiated whole blood coagulation

    PubMed Central

    Whelihan, Matthew F.; Kiankhooy, Armin; Brummel-Ziedins, Kathleen

    2015-01-01

    Background Despite trauma-induced hypothermic coagulopathy being familiar in the clinical setting, empirical experimentation concerning this phenomenon is lacking. In this study we investigated the effects of hypothermia on thrombin generation, clot formation and global hemostatic functions in an in vitro environment using a whole blood model and thromboelastography (TEG) which can recapitulate hypothermia. Methods Blood was collected from healthy individuals through venipuncture and treated with corn trypsin inhibitor, to block the contact pathway. Coagulation was initiated with 5pM tissue factor at temperatures 37°C, 32°C, and 27°C. Reactions were quenched over time with soluble and insoluble components of each time point analyzed for thrombin generation, fibrinogen consumption, factor (f)XIII activation and fibrin deposition. Global coagulation potential was evaluated through TEG. Results Data showed that thrombin generation in samples at 37°C and 32°C had comparable rates while 27°C had a much lower rate (39.2 ± 1.1 and 43 ± 2.4 nM/min vs 28.6 ± 4.4 nM/min, respectively). Fibrinogen consumption and fXIII activation were highest at 37°C followed by 32°C and 27°C (13.8 ± 2.9 percent/min vs 7.8 ± 1.8 percent/min, respectively). Fibrin formation as seen through clot weights also followed this trend. TEG data showed clot formation was fastest in samples at 37°C and lowest at 27°C. Maximum clot strength was similar for each temperature. Also, percent lysis of clots was highest at 37°C followed by 32°C and then 27°C. Conclusions Induced hypothermic conditions directly affect the rate of thrombin generation and clot formation while global clot stability remains intact. PMID:24331944

  9. Thrombin generation and fibrin clot formation under hypothermic conditions: an in vitro evaluation of tissue factor initiated whole blood coagulation.

    PubMed

    Whelihan, Matthew F; Kiankhooy, Armin; Brummel-Ziedins, Kathleen E

    2014-02-01

    Despite trauma-induced hypothermic coagulopathy being familiar in the clinical setting, empirical experimentation concerning this phenomenon is lacking. In this study, we investigated the effects of hypothermia on thrombin generation, clot formation, and global hemostatic functions in an in vitro environment using a whole blood model and thromboelastography, which can recapitulate hypothermia. Blood was collected from healthy individuals through venipuncture and treated with corn trypsin inhibitor, to block the contact pathway. Coagulation was initiated with 5pM tissue factor at temperatures 37°C, 32°C, and 27°C. Reactions were quenched over time, with soluble and insoluble components analyzed for thrombin generation, fibrinogen consumption, factor (f)XIII activation, and fibrin deposition. Global coagulation potential was evaluated through thromboelastography. Data showed that thrombin generation in samples at 37°C and 32°C had comparable rates, whereas 27°C had a much lower rate (39.2 ± 1.1 and 43 ± 2.4 nM/min vs 28.6 ± 4.4 nM/min, respectively). Fibrinogen consumption and fXIII activation were highest at 37°C, followed by 32°C and 27°C. Fibrin formation as seen through clot weights also followed this trend. Thromboelastography data showed that clot formation was fastest in samples at 37°C and lowest at 27°C. Maximum clot strength was similar for each temperature. Also, percent lysis of clots was highest at 37°C followed by 32°C and then 27°C. Induced hypothermic conditions directly affect the rate of thrombin generation and clot formation, whereas global clot stability remains intact. © 2013.

  10. Factors affecting the pore space transformation during hydrocarbon generation in source rock (shales): laboratory experiment

    NASA Astrophysics Data System (ADS)

    Giliazetdinova, D. R.; Korost, D. V.

    2014-12-01

    Oil and gas generation is a set of processes which taking place in the interior, the processes can't be observable in nature. In the process of dumping the source rock, organic matter is transformed into a complex of high-molecular compounds - precursors of oil and gas (kerogen). Entering of a source column for specific thermobaric conditions, triggers the formation of low molecular weight hydrocarbon compounds. Generation of sufficient quantities of hydrocarbons leads to the primary fluid migration within the source rock. For the experiment were selected mainly siliceous-carbonate composition rocks from Domanic horizon South-Tatar arch. The main aim of experiment was heating the rocks in the pyrolyzer to temperatures which correspond katagenes stages. For monitoring changes in the morphology of the pore space X-ray microtomography method was used. As a result, when was made a study of the composition of mineral and organic content of the rocks, as well as textural and structural features, have been identified that the majority of the rock samples within the selected collection are identical. However, characteristics such as organic content and texture of rocks are different. Thus, the experiment was divided into two parts: 1) the study of the influence of organic matter content on the morphology of the rock in the process of thermal effects; 2) study the effect of texture on the primary migration processes for the same values of organic matter. Also, an additional experiment was conducted to study the dynamics of changes in the structure of the pore space. At each stage of the experiment morphology of altered rocks characterized by the formation of new pores and channels connecting the primary voids. However, it was noted that the samples with a relatively low content of the organic matter had less changes in pore space morphology, in contrast to rocks with a high organic content. At the second stage of the research also revealed that the conversion of the pore

  11. An integrated transcriptomics-guided genome-wide promoter analysis and next-generation proteomics approach to mine factor(s) regulating cellular differentiation

    PubMed Central

    Mandal, Kamal; Bader, Samuel L.; Kumar, Pankaj; Malakar, Dipankar; Campbell, David S.; Pradhan, Bhola Shankar; Sarkar, Rajesh K.; Wadhwa, Neerja; Sensharma, Souvik; Jain, Vaibhav; Moritz, Robert L.

    2017-01-01

    Abstract Differential next-generation-omics approaches aid in the visualization of biological processes and pave the way for divulging important events and/or interactions leading to a functional output at cellular or systems level. To this end, we undertook an integrated Nextgen transcriptomics and proteomics approach to divulge differential gene expression of infant and pubertal rat Sertoli cells (Sc).Unlike, pubertal Sc, infant Sc are immature and fail to support spermatogenesis. We found exclusive association of 14 and 19 transcription factor binding sites to infantile and pubertal states of Sc, respectively, using differential transcriptomics-guided genome-wide computational analysis of relevant promoters employing 220 Positional Weight Matrices from the TRANSFAC database. Proteomic SWATH-MS analysis provided extensive quantification of nuclear and cytoplasmic protein fractions revealing 1,670 proteins differentially located between the nucleus and cytoplasm of infant Sc and 890 proteins differentially located within those of pubertal Sc. Based on our multi-omics approach, the transcription factor YY1 was identified as one of the lead candidates regulating differentiation of Sc.YY1 was found to have abundant binding sites on promoters of genes upregulated during puberty. To determine its significance, we generated transgenic rats with Sc specific knockdown of YY1 that led to compromised spermatogenesis. PMID:28065881

  12. An integrated transcriptomics-guided genome-wide promoter analysis and next-generation proteomics approach to mine factor(s) regulating cellular differentiation.

    PubMed

    Mandal, Kamal; Bader, Samuel L; Kumar, Pankaj; Malakar, Dipankar; Campbell, David S; Pradhan, Bhola Shankar; Sarkar, Rajesh K; Wadhwa, Neerja; Sensharma, Souvik; Jain, Vaibhav; Moritz, Robert L; Majumdar, Subeer S

    2017-04-01

    Differential next-generation-omics approaches aid in the visualization of biological processes and pave the way for divulging important events and/or interactions leading to a functional output at cellular or systems level. To this end, we undertook an integrated Nextgen transcriptomics and proteomics approach to divulge differential gene expression of infant and pubertal rat Sertoli cells (Sc).Unlike, pubertal Sc, infant Sc are immature and fail to support spermatogenesis. We found exclusive association of 14 and 19 transcription factor binding sites to infantile and pubertal states of Sc, respectively, using differential transcriptomics-guided genome-wide computational analysis of relevant promoters employing 220 Positional Weight Matrices from the TRANSFAC database. Proteomic SWATH-MS analysis provided extensive quantification of nuclear and cytoplasmic protein fractions revealing 1,670 proteins differentially located between the nucleus and cytoplasm of infant Sc and 890 proteins differentially located within those of pubertal Sc. Based on our multi-omics approach, the transcription factor YY1 was identified as one of the lead candidates regulating differentiation of Sc.YY1 was found to have abundant binding sites on promoters of genes upregulated during puberty. To determine its significance, we generated transgenic rats with Sc specific knockdown of YY1 that led to compromised spermatogenesis. © The Author 2017. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.

  13. Factors affecting career choice among the next generation of academic vascular surgeons.

    PubMed

    Danczyk, Rachel C; Sevdalis, Nick; Woo, Karen; Hingorani, Anil P; Landry, Gregory J; Liem, Timothy K; Moneta, Gregory L; Mitchell, Erica L

    2012-05-01

    Few studies have examined factors that influence an individual's decision to enter an academic medical career after residency training. We sought to evaluate whether sex, ethnicity, child care issues, and debt burden influenced residents' choice for a career in academic vascular surgery. A 39-item Web survey, designed to elucidate which factors motivated residents to seek a career in academic vascular surgery, was sent to 295 vascular surgery residents currently enrolled in Accreditation Council on Graduate Medical Education-accredited training programs. A total of 128 responses (43%) were received. Of these, 53% of respondents were white and 47% were nonwhite and 34 (27%) were women and 94 (73%) were men. Fifty-seven percent of minorities anticipate a career in academic vascular surgery. There were no statistical differences between sex and ethnicity for factors influencing career choice, including training paradigm, presence of a life partner or dependents, mentorship role, participation in research, service, and teaching, anticipated salary, and debt burden (P > .05). Seventy-seven percent of respondents carry significant debt; of those with debt, 81% owe >$100,000 and 40% owe >$200,000. Seventy-three percent of 0+5 trainees anticipated choosing an academic practice compared with 42% of 5+2 trainees (P < .01). Respondents planning an academic career cited procedural variation, breadth and depth of practice/tertiary referral experience, and research opportunities as the most important drivers of career choice. Income potential, strength of the job market, and child care needs were deemed less important. This study shows that academic vascular surgery is a popular career option for current vascular surgery trainees, especially those in 0+5 programs. Choosing a career in academic vascular surgery appears not to be influenced by sex, ethnicity, child care concerns, salary expectations, or debt burden, even though most trainees carry enormous debt. The data imply

  14. Geologic factors contributing to landslide generation in a pyroclastic area: August 1998 Nishigo Village, Japan

    NASA Astrophysics Data System (ADS)

    Chigira, Masahiro

    2002-07-01

    Vertical contrasts in permeability, particularly where permeable surface materials overlie impermeable materials that prohibit the downward infiltration of groundwater, concentrate the groundwater and become an important focus of landslides that are triggered by intense rainfall. Just such a hydrogeological structure is present within the pyroclastics in Nishigo Village in Fukushima Prefecture, Japan, where intense rainfall of 1200 mm in 6 days generated more than 1000 landslides in August 1998. Three types of landslides occurred. The first type occurred along the edges of small plateaus, where horizontal beds of permeable ash, scoria, and pumice overlie impermeable mudflow deposits consisting of tuffaceous fines and andesite blocks, and massive, weakly consolidated ignimbrites. The rainfall on the plateaus infiltrated downward first, then laterally within the permeable beds, finally gushing out at the plateau edges and triggering landslides. The second type of landslide occurred where weathered tuff of the same ignimbrite was present with a slip surface at the base of the heavily weathered zone. Within this heavily weathered zone, the tuff exfoliated into thin weak plates running parallel to the slope surface. The third type of landslide involved failure of colluvium or ash that filled hollows. This type occurred as a result of subsurface erosion caused by the groundwater infiltrating the superficial beds above the impermeable tuff.

  15. Understanding the association between teenage pregnancy and inter-generational factors: a comparative and analytical study.

    PubMed

    Whitehead, Elizabeth

    2009-04-01

    (1) to identify the number of teenage pregnant women who also have mothers who became pregnant when they were in their teenage years and (2) to explore the importance of this intergenerational experience on the teenagers themselves, their significant family, friends and society as a whole. semi-structured interviews with the subjects allowed for both breadth and depth exploration. the total research sample was 95 teenage women, which included 48 pregnant (51%) and 47 non-pregnant (49%) women. Stage 1 reports on the findings relating to the intergenerational phenomena and stage 2 focuses on related historical experiences of a further 8 interviews with subjects who had experienced this intergenerational phenomenon. The subjects in both stages of this study came from two contrasting demographic areas of the UK: North West and South East. data were analysed using an appropriate qualitative software package. The specific categories of experience were constructed using a grounded theory approach. the findings of stage 1 of the study showed that the number of teenage women who reported that they had a mother who's first baby was born to her when she was under 20 years of age was 33 (69%) for the pregnant group and 12 (26%) for the non-pregnant group. This was found to be statistically significant (chi(2)=6.51, df=1, p=<0.011). In this study (from a sub-set of 19 themes) three major themes emerged: (a) reflection, (b) peer group pressure and (c) intergenerational factors. reflection, peer group pressure and intergenerational factors were the major thematic findings of this study. Midwives working collaboratively with other health, social and educational colleagues have a pivotal role to work with families in addressing the complexities of intergenerational teenage pregnancy. A national multi-method research study is now required to explore the breadth of intergenerational teenage pregnancy and the experiences of those families where this social construct is prevalent.

  16. Use of vacuum-assisted closure and a dermal regeneration template as an alternative to flap reconstruction in pediatric grade IIIB open lower-extremity injuries.

    PubMed

    Barnett, Ted M; Shilt, Jeffrey S

    2009-06-01

    Severe degloving injuries to the pediatric lower extremity are difficult to treat, traditionally requiring local or free flaps for coverage. Combining vacuum-assisted closure techniques with a dermal regeneration template is proposed as a means for covering these difficult wounds. We retrospectively reviewed the charts of 7 consecutive patients (age range, 2-12 years) who underwent this treatment. All extremities healed without flap reconstruction or amputation. Mean follow-up was 24.4 months, and mean wound size was 196 cm2. There were 2 superficial graft complications, 1 nonunion successfully treated with bone grafting, 2 patients with subsequent bony deformity, and 1 patient who underwent subsequent soft-tissue procedures for equinus contracture. Use of vacuum-assisted closure and a dermal regeneration template has shown good results as a means of successfully managing grade IIIB injuries without performing complicated flap reconstructions.

  17. Identification and characterization of a novel homozygous deletion in the alpha-N-acetylglucosaminidase gene in a patient with Sanfilippo type B syndrome (mucopolysaccharidosis IIIB).

    PubMed

    Champion, Kristen J; Basehore, Monica J; Wood, Tim; Destrée, Anne; Vannuffel, Pascal; Maystadt, Isabelle

    2010-05-01

    Sanfilippo syndrome type B (mucopolysaccharidosis IIIB) is an autosomal recessive disease that is caused by a deficiency of the lysosomal enzyme alpha-N-acetylglucosaminidase (NAGLU). Over 100 different mutations in the NAGLU gene have been identified in Sanfilippo syndrome type B patients; however, no large deletions have been reported. Here we present the first case of a large homozygous intragenic NAGLU gene deletion identified in an affected child of consanguineous parents. Long range and multiplex PCR methods were used to characterize this deletion which encompasses exons 3 and 4 and is 1146 base pairs long. We propose that Alu element-mediated unequal homologous recombination between an Alu-Y in intron 2 and an Alu-Sx in intron 4 is the likely mechanism for this deletion, thereby contributing further insight into the molecular etiology of this disorder and providing additional evidence of its allelic heterogeneity.

  18. Dynamics of Thrombin Generation and Flux from Clots during Whole Human Blood Flow over Collagen/Tissue Factor Surfaces.

    PubMed

    Zhu, Shu; Lu, Yichen; Sinno, Talid; Diamond, Scott L

    2016-10-28

    Coagulation kinetics are well established for purified blood proteases or human plasma clotting isotropically. However, less is known about thrombin generation kinetics and transport within blood clots formed under hemodynamic flow. Using microfluidic perfusion (wall shear rate, 200 s(-1)) of corn trypsin inhibitor-treated whole blood over a 250-μm long patch of type I fibrillar collagen/lipidated tissue factor (TF; ∼1 TF molecule/μm(2)), we measured thrombin released from clots using thrombin-antithrombin immunoassay. The majority (>85%) of generated thrombin was captured by intrathrombus fibrin as thrombin-antithrombin was largely undetectable in the effluent unless Gly-Pro-Arg-Pro (GPRP) was added to block fibrin polymerization. With GPRP present, the flux of thrombin increased to ∼0.5 × 10(-12) nmol/μm(2)-s over the first 500 s of perfusion and then further increased by ∼2-3-fold over the next 300 s. The increased thrombin flux after 500 s was blocked by anti-FXIa antibody (O1A6), consistent with thrombin-feedback activation of FXI. Over the first 500 s, ∼92,000 molecules of thrombin were generated per surface TF molecule for the 250-μm-long coating. A single layer of platelets (obtained with αIIbβ3 antagonism preventing continued platelet deposition) was largely sufficient for thrombin production. Also, the overall thrombin-generating potential of a 1000-μm-long coating became less efficient on a per μm(2) basis, likely due to distal boundary layer depletion of platelets. Overall, thrombin is robustly generated within clots by the extrinsic pathway followed by late-stage FXIa contributions, with fibrin localizing thrombin via its antithrombin-I activity as a potentially self-limiting hemostatic mechanism. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. Generational diversity.

    PubMed

    Kramer, Linda W

    2010-01-01

    Generational diversity has proven challenges for nurse leaders, and generational values may influence ideas about work and career planning. This article discusses generational gaps, influencing factors and support, and the various generational groups present in today's workplace as well as the consequences of need addressing these issues. The article ends with a discussion of possible solutions.

  20. Massively parallel hypercube FFTs: CM-2 implementation and error analysis of a parallel trigonometric factor generation method

    SciTech Connect

    Tong, C.H. ); Swarztrauber, P.N. )

    1991-08-01

    On parallel computers, the way the data elements are mapped to the processors may have a large effect on the timing performance of a given algorithm. In our previous paper, we have examined a few mapping strategies for the ordered radix-2 DIF (decimation-in-frequency) Fast Fourier Transform. In particular, we have shown how reduction of communication can be achieved by combining the order and computational phases through the use of i-cycles. A parallel methods was also presented for computing the trigonometric factors which requires neither trigonometric function evaluation nor interprocessor communication. This paper first reviews some of the experimental results on the Connection Machine to demonstrate the importance of reducing communication in a parallel algorithm. The emphasis of this paper, however, is on analyzing the numerical stability of the proposed method for generating the trigonometric factors and showing how the error can be improved. 16 refs., 12 tabs.

  1. Readability Analysis of SRA Power Builders; An Examination of the Readability Levels of the Power Builder Component of the SRA Reading Laboratory IIIB as Measured by the Dale-Chall Readability Formula.

    ERIC Educational Resources Information Center

    Rosen, Ellen Unell

    This study evaluates the readability levels of frequently used literacy materials, the power builder component of the SRA Reading Laboratory IIIB. A review of the readability literature reveals numerous studies performed on content area textbooks but relatively few studies performed on literacy materials. Three questions are asked: (1) What is the…

  2. Outcomes of anterolateral thigh-free flaps and conversion from external to internal fixation with bone grafting in gustilo type IIIB open tibial fractures.

    PubMed

    Lee, Jae Hoon; Chung, Duke Whan; Han, Chung Soo

    2012-09-01

    The purpose of this study was to analyze the utility and the clinical outcomes of anterolateral thigh (ALT)-free flaps and conversion from external to internal fixation with plating and bone grafting in Gustilo type IIIB open tibial fractures. A total of 21 patients were analyzed retrospectively. The mean follow-up period was 18 months and the mean age was 46.7 years. There were 18 men and three women. The mean time from injury to flap coverage was 11.6 days. The mean size of flaps used was 15.3 × 8.2 cm. The mean size of bone defects was 2.26 cm. Segmental bone defects were observed in 5 five cases, for which bone transport or vascularized fibular graft were performed. When flaps were successful and the fracture sites did not have any evidence of infection, internal fixation with plates and bone grafting were performed. Flaps survived in 20 cases. In the 20 cases with successful flaps, two cases developed osteomyelitis, but the 20 cases achieved solid bone union at a mean of 8.6 months after the injury, salvaging the lower extremity in 100% of the cases. At the last follow-up, 9 nine cases were measured excellent or good; 6, fair; and 6, poor in the functional assessment based on the method developed by Puno et al. ALT- free flaps to cover soft tissue defects in Gustilo type IIIB open tibial fractures are considered as useful option for the treatment of composite defects. In addition, conversion to internal fixation and bone grafting can be an alternative method in order to reduce the risk of complications and inconvenience of external fixators.

  3. The nematode parasite Onchocerca volvulus generates the transforming growth factor-beta (TGF-beta).

    PubMed

    Korten, Simone; Büttner, Dietrich W; Schmetz, Christel; Hoerauf, Achim; Mand, Sabine; Brattig, Norbert

    2009-09-01

    Transforming growth factor-beta (TGF-beta) is a highly conserved cytokine that has a well-known regulatory role in immunity, but also in organ development of most animal species including helminths. Homologous tgf-b genes and mRNA have been detected in the filaria Brugia malayi. The in situ protein expression is unknown for filariae. Therefore, we examined several filariae for the expression and localization of latent (stable) TGF-beta in adult and larval stages. A specific goat anti-human latency associated protein (LAP, TGF-beta 1) antibody, purified by affinity chromatography, was used for light and electron microscopic immunohistochemistry. Adult Onchocerca volvulus, Onchocerca gibsoni, Onchocerca ochengi, Onchocerca armillata, Onchocerca fasciata, Onchocerca flexuosa, Wuchereria bancrofti, Dirofilaria sp., B. malayi, and infective larvae of W. bancrofti reacted with the antibody. Labeling of worm tissues varied between negative and all degrees of positive reactions. Latent TGF-beta was strongly expressed adjacent to the cell membranes of the hypodermis, epithelia, and muscles and adjacent to many nuclei in all organs. TGF-beta was well expressed in worms without Wolbachia endobacteria eliminated by doxycycline treatment. Pleomorphic neoplasms in O. volvulus were also labeled. We conclude that latent TGF-beta protein is expressed by filariae independently of Wolbachia, possibly regulating worm tissue homeostasis.

  4. Glial Tumor Necrosis Factor Alpha (TNFα) Generates Metaplastic Inhibition of Spinal Learning

    PubMed Central

    Huie, J. Russell; Baumbauer, Kyle M.; Lee, Kuan H.; Bresnahan, Jacqueline C.; Beattie, Michael S.; Ferguson, Adam R.; Grau, James W.

    2012-01-01

    Injury-induced overexpression of tumor necrosis factor alpha (TNFα) in the spinal cord can induce chronic neuroinflammation and excitotoxicity that ultimately undermines functional recovery. Here we investigate how TNFα might also act to upset spinal function by modulating spinal plasticity. Using a model of instrumental learning in the injured spinal cord, we have previously shown that peripheral intermittent stimulation can produce a plastic change in spinal plasticity (metaplasticity), resulting in the prolonged inhibition of spinal learning. We hypothesized that spinal metaplasticity may be mediated by TNFα. We found that intermittent stimulation increased protein levels in the spinal cord. Using intrathecal pharmacological manipulations, we showed TNFα to be both necessary and sufficient for the long-term inhibition of a spinal instrumental learning task. These effects were found to be dependent on glial production of TNFα and involved downstream alterations in calcium-permeable AMPA receptors. These findings suggest a crucial role for glial TNFα in undermining spinal learning, and demonstrate the therapeutic potential of inhibiting TNFα activity to rescue and restore adaptive spinal plasticity to the injured spinal cord. TNFα modulation represents a novel therapeutic target for improving rehabilitation after spinal cord injury. PMID:22745823

  5. [Predict factors associated with malnutrition from patient generated subjective global assessment (PG-SGA) in head and neck cancer patients].

    PubMed

    Arribas, L; Hurtós, L; Milà, R; Fort, E; Peiró, I

    2013-01-01

    Patient Generated Subjective Global Assessment (PG-SGA) is a validated tool for nutrition evaluation in patients with cancer. The aim of our study was to estimate the prevalence of malnutrition in head and neck cancer patients at diagnosis and evaluate the independent prognostic factors for malnutrition from PG-SGA. All outpatients attending at the Head and Neck Cancer Multidisciplinary Meeting for primary diagnosis, staging and treatment were evaluated by an oncology dietitian using the patient generated subjective global assessment (PG-SGA). Patients with recurrences or secondary tumours will be excluded. 64 patients were evaluated (55 men and 9 women) with an average age of 63 years and body mass index (BMI) of 25.3 kg/m(2) (SD ± 5.18). After the nutritional assessment we observed that 43.8% of patients were malnourished or at risk of malnutrition. The most frequent symptom at diagnosis was dysphagia (48.4%) and anorexia (26.6%). From PG-SGA, the main prognostic factors (p<0,001) were the percentage of weight loss, serum albumin levels, BMI and the presence of dysphagia or/and anorexia prior diagnosis. Parameters as BMI, weight loss and low albumin levels at the time of diagnosis in head and neck cancer patients are independent predictors for malnutrition as well as the presence of anorexia or dysphagia.reaffirms the need for sustainability of interventions over time. Copyright © AULA MEDICA EDICIONES 2013. Published by AULA MEDICA. All rights reserved.

  6. Analysis of Pre-Analytic Factors Affecting the Success of Clinical Next-Generation Sequencing of Solid Organ Malignancies.

    PubMed

    Chen, Hui; Luthra, Rajyalakshmi; Goswami, Rashmi S; Singh, Rajesh R; Roy-Chowdhuri, Sinchita

    2015-08-28

    Application of next-generation sequencing (NGS) technology to routine clinical practice has enabled characterization of personalized cancer genomes to identify patients likely to have a response to targeted therapy. The proper selection of tumor sample for downstream NGS based mutational analysis is critical to generate accurate results and to guide therapeutic intervention. However, multiple pre-analytic factors come into play in determining the success of NGS testing. In this review, we discuss pre-analytic requirements for AmpliSeq PCR-based sequencing using Ion Torrent Personal Genome Machine (PGM) (Life Technologies), a NGS sequencing platform that is often used by clinical laboratories for sequencing solid tumors because of its low input DNA requirement from formalin fixed and paraffin embedded tissue. The success of NGS mutational analysis is affected not only by the input DNA quantity but also by several other factors, including the specimen type, the DNA quality, and the tumor cellularity. Here, we review tissue requirements for solid tumor NGS based mutational analysis, including procedure types, tissue types, tumor volume and fraction, decalcification, and treatment effects.

  7. Generating induced pluripotent stem cells from common marmoset (Callithrix jacchus) fetal liver cells using defined factors, including Lin28.

    PubMed

    Tomioka, Ikuo; Maeda, Takuji; Shimada, Hiroko; Kawai, Kenji; Okada, Yohei; Igarashi, Hiroshi; Oiwa, Ryo; Iwasaki, Tsuyoshi; Aoki, Mikio; Kimura, Toru; Shiozawa, Seiji; Shinohara, Haruka; Suemizu, Hiroshi; Sasaki, Erika; Okano, Hideyuki

    2010-09-01

    Although embryonic stem (ES) cell-like induced pluripotent stem (iPS) cells have potential therapeutic applications in humans, they are also useful for creating genetically modified human disease models in nonhuman primates. In this study, we generated common marmoset iPS cells from fetal liver cells via the retrovirus-mediated introduction of six human transcription factors: Oct-3/4, Sox2, Klf4, c-Myc, Nanog, and Lin28. Four to five weeks after introduction, several colonies resembling marmoset ES cells were observed and picked for further expansion in ES cell medium. Eight cell lines were established, and validation analyses of the marmoset iPS cells followed. We detected the expression of ES cell-specific surface markers. Reverse transcription-PCR showed that these iPS cells expressed endogenous Oct-3/4, Sox2, Klf4, c-Myc, Nanog and Lin28 genes, whereas all of the transgenes were silenced. Karyotype analysis showed that two of three iPS cell lines retained a normal karyotype after a 2-month culture. Both embryoid body and teratoma formation showed that marmoset iPS cells had the developmental potential to give rise to differentiated derivatives of all three primary germ layers. In summary, we generated marmoset iPS cells via the transduction of six transcription factors; this provides a powerful preclinical model for studies in regenerative medicine.

  8. Factors influencing the study of peroxidase-generated iodine species and implications for thyroglobulin synthesis.

    PubMed

    Kessler, Jack; Obinger, Christian; Eales, Geoff

    2008-07-01

    A key issue in the mechanism of thyroglobulin (Tg) iodination by thyroperoxidase (TPO) is whether a TPO-bound iodine intermediate directly iodinates Tg-incorporated tyrosines (specific iodination) or whether reactive iodine species released from TPO effectuate Tg iodination (nonspecific iodination). We addressed these alternatives by (a) determining the aqueous equilibria of the iodine species potentially involved in the kinetic studies of TPO-mediated iodination, and (b) reviewing the structure of the substrate channel in mammalian peroxidases. Redox-potentiometric analysis of aqueous iodine combined with integrated mathematical modelling demonstrates that I2 reacts with water to form several iodine species including hypoiodious acid (HOI). The HOI/I2 ratio depends on time, iodide concentration, buffering agents, and pH varying dramatically from pH 4 to 7.4. These factors may confound the use of Michaelis-Menten kinetics to determine the mechanism of TPO-catalyzed iodination since both I2 and HOI iodinate tyrosine but with different specificities and reaction rates. Consequently there is as yet no conclusive kinetic evidence that iodination occurs via formation of a TPO-bound iodinated intermediate. Furthermore, knowledge of TPO structure, gained from X-ray crystallographic studies indicates that access of Tg-bound tyrosyl groups to the active site of TPO is not possible. Thus the emerging conclusion is that the mechanism of Tg iodination is nonspecific. This is consistent with the occurrence of thyroid hormone formation in prevertebrate ascidians which exhibit TPO-like activity but lack the Tg gene.

  9. Generation of Potent Anti-Vascular Endothelial Growth Factor Neutralizing Antibodies from Mouse Phage Display Library for Cancer Therapy.

    PubMed

    Lai, Yan-Da; Wu, Yen-Yu; Tsai, Yi-Jiue; Tsai, Yi-San; Lin, Yu-Ying; Lai, Szu-Liang; Huang, Chao-Yang; Lok, Ying-Yung; Hu, Chih-Yung; Lai, Jiann-Shiun

    2016-02-05

    Vascular endothelial growth factor (VEGF) is an important stimulator for angiogenesis in solid tumors. Blocking VEGF activity is an effective therapeutic strategy to inhibit tumor growth and metastasis. Avastin, a humanized monoclonal antibody recognizes VEGF, has been approved by the US Food and Drug Administration. To generate potential VEGF-recognizing antibodies with better tumor regression ability than that of Avastin, we have designed a systematic antibody selection plan. From mice immunized with recombinant human VEGF, we generated three phage display libraries, scFv-M13KO7, Fab-M13KO7, and scFv-Hyperphage, in single-chain Fv (scFv) or Fab format, displayed using either M13KO7 helper phage or Hyperphage. Solid-phase and solution-phase selection strategies were then applied to each library, generating six panning combinations. A total of sixty-four antibodies recognizing VEGF were obtained. Based on the results of epitope mapping, binding affinity, and biological functions in tumor inhibition, eight antibodies were chosen to examine their abilities in tumor regression in a mouse xenograft model using human COLO 205 cancer cells. Three of them showed improvement in the inhibition of tumor growth (328%-347% tumor growth ratio (% of Day 0 tumor volume) on Day 21 vs. 435% with Avastin). This finding suggests a potential use of these three antibodies for VEGF-targeted therapy.

  10. Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in DICER1 syndrome: a unique variant of the two-hit tumor suppression model

    PubMed Central

    Brenneman, Mark; Field, Amanda; Yang, Jiandong; Williams, Gretchen; Doros, Leslie; Rossi, Christopher; Schultz, Kris Ann; Rosenberg, Avi; Ivanovich, Jennifer; Turner, Joyce; Gordish-Dressman, Heather; Stewart, Douglas; Yu, Weiying; Harris, Anne; Schoettler, Peter; Goodfellow, Paul; Dehner, Louis; Messinger, Yoav; Hill, D. Ashley

    2015-01-01

    Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition,  DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of  DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific “hotspot” codons within the RNase IIIb domain of  DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing  DICER1 mutations and sought correlations with clinical phenotypes. Over 70% have inherited or  de novo germline LOF mutations, most of which truncate the  DICER1 open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing  DICER1 mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of  DICER1 syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of patients lack predisposing germline or mosaic mutations and have disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in  DICER1-associated  tumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development. PMID:26925222

  11. Interactions of disulfide-deficient selenocysteine analogs of μ-conotoxin BuIIIB with the α-subunit of the voltage-gated sodium channel subtype 1.3.

    PubMed

    Green, Brad R; Zhang, Min-Min; Chhabra, Sandeep; Robinson, Samuel D; Wilson, Michael J; Redding, Addison; Olivera, Baldomero M; Yoshikami, Doju; Bulaj, Grzegorz; Norton, Raymond S

    2014-07-01

    Inhibitors of the α-subunit of the voltage-gated sodium channel subtype 1.3 (NaV 1.3) are of interest as pharmacological tools for the study of neuropathic pain associated with spinal cord injury and have potential therapeutic applications. The recently described μ-conotoxin BuIIIB (μ-BuIIIB) from Conus bullatus was shown to block NaV 1.3 with submicromolar potency (Kd = 0.2 μm), making it one of the most potent peptidic inhibitors of this subtype described to date. However, oxidative folding of μ-BuIIIB results in numerous folding isoforms, making it difficult to obtain sufficient quantities of the active form of the peptide for detailed structure-activity studies. In the present study, we report the synthesis and characterization of μ-BuIIIB analogs incorporating a disulfide-deficient, diselenide-containing scaffold designed to simplify synthesis and facilitate structure-activity studies directed at identifying amino acid residues involved in NaV 1.3 blockade. Our results indicate that, similar to other μ-conotoxins, the C-terminal residues (Trp16, Arg18 and His20) are most crucial for NaV 1 blockade. At the N-terminus, replacement of Glu3 by Ala resulted in an analog with an increased potency for NaV 1.3 (Kd = 0.07 μm), implicating this position as a potential site for modification for increased potency and/or selectivity. Further examination of this position showed that increased negative charge, through γ-carboxyglutamate replacement, decreased potency (Kd = 0.33 μm), whereas replacement with positively-charged 2,4-diamonobutyric acid increased potency (Kd = 0.036 μm). These results provide a foundation for the design and synthesis of μ-BuIIIB-based analogs with increased potency against NaV 1.3. © 2014 FEBS.

  12. A deficiency of apoptosis inducing factor (AIF) in Harlequin mouse heart mitochondria paradoxically reduces ROS generation during ischemia-reperfusion

    PubMed Central

    Chen, Qun; Szczepanek, Karol; Hu, Ying; Thompson, Jeremy; Lesnefsky, Edward J.

    2014-01-01

    Background and Aims: AIF (apoptosis inducing factor) is a flavin and NADH containing protein located within mitochondria required for optimal function of the respiratory chain. AIF may function as an antioxidant within mitochondria, yet when released from mitochondria it activates caspase-independent cell death. The Harlequin (Hq) mouse has a markedly reduced content of AIF, providing an experimental model to query if the main role of AIF in the exacerbation of cell death is enhanced mitochondrial generation of reactive oxygen species (ROS) or the activation of cell death programs. We asked if the ROS generation is altered in Hq heart mitochondria at baseline or following ischemia-reperfusion (IR). Methods: Buffer perfused mouse hearts underwent 30 min ischemia and 30 min reperfusion. Mitochondrial function including oxidative phosphorylation and H2O2 generation was measured. Immunoblotting was used to determine the contents of AIF and PAR [poly(ADP-ribose)] in cell fractions. Results: There were no differences in the release of H2O2 between wild type (WT) and Hq heart mitochondria at baseline. IR increased H2O2 generation from WT but not from Hq mitochondria compared to corresponding time controls. The complex I activity was decreased in WT but not in Hq mice following IR. The relocation of AIF from mitochondria to nucleus was increased in WT but not in Hq mice. IR activated PARP-1 only in WT mice. Cell injury was decreased in the Hq mouse heart following in vitro IR. Conclusion: A deficiency of AIF within mitochondria does not increase ROS production during IR, indicating that AIF functions less as an antioxidant within mitochondria. The decreased cardiac injury in Hq mouse heart accompanied by less AIF translocation to the nucleus suggests that AIF relocation, rather than the AIF content within mitochondria, contributes to cardiac injury during IR. PMID:25101006

  13. A deficiency of apoptosis inducing factor (AIF) in Harlequin mouse heart mitochondria paradoxically reduces ROS generation during ischemia-reperfusion.

    PubMed

    Chen, Qun; Szczepanek, Karol; Hu, Ying; Thompson, Jeremy; Lesnefsky, Edward J

    2014-01-01

    AIF (apoptosis inducing factor) is a flavin and NADH containing protein located within mitochondria required for optimal function of the respiratory chain. AIF may function as an antioxidant within mitochondria, yet when released from mitochondria it activates caspase-independent cell death. The Harlequin (Hq) mouse has a markedly reduced content of AIF, providing an experimental model to query if the main role of AIF in the exacerbation of cell death is enhanced mitochondrial generation of reactive oxygen species (ROS) or the activation of cell death programs. We asked if the ROS generation is altered in Hq heart mitochondria at baseline or following ischemia-reperfusion (IR). Buffer perfused mouse hearts underwent 30 min ischemia and 30 min reperfusion. Mitochondrial function including oxidative phosphorylation and H2O2 generation was measured. Immunoblotting was used to determine the contents of AIF and PAR [poly(ADP-ribose)] in cell fractions. There were no differences in the release of H2O2 between wild type (WT) and Hq heart mitochondria at baseline. IR increased H2O2 generation from WT but not from Hq mitochondria compared to corresponding time controls. The complex I activity was decreased in WT but not in Hq mice following IR. The relocation of AIF from mitochondria to nucleus was increased in WT but not in Hq mice. IR activated PARP-1 only in WT mice. Cell injury was decreased in the Hq mouse heart following in vitro IR. A deficiency of AIF within mitochondria does not increase ROS production during IR, indicating that AIF functions less as an antioxidant within mitochondria. The decreased cardiac injury in Hq mouse heart accompanied by less AIF translocation to the nucleus suggests that AIF relocation, rather than the AIF content within mitochondria, contributes to cardiac injury during IR.

  14. Generation and characterization of novel tetracycline-inducible pancreatic transcription factor-expressing murine embryonic stem cell lines.

    PubMed

    Vincent, Robert; Treff, Nathan; Budde, Melisa; Kastenberg, Zachary; Odorico, Jon

    2006-12-01

    Pancreatic development in mammals is controlled in part by the expression and function of numerous genes encoding transcription factors. Yet, how these regulate each other and their target genes is incompletely understood. Embryonic stem (ES) cells have recently been shown to be capable of differentiating into pancreatic progenitor cells and insulin-producing cells, representing a useful in vitro model system for studying pancreatic and islet development. To generate tools to study the relationships of transcription factors in pancreatic development we have established seven unique mouse ES cell lines with tetracycline-inducible expression of either Hnf4alpha, Hnf6, Nkx2.2, Nkx6.1, Pax4, Pdx1, and Ptf1a cDNAs. Each of the cell lines was characterized for induction of transgene expression after exposure to doxycycline (DOX) by quantitative real-time PCR and immunofluorescence microscopy. Transgene expression in the presence of DOX was at least 97-fold that seen in untreated cells. Immunofluorescent staining of DOX-treated cultures showed efficient (>95% of cells) transgene protein expression while showing <5% positive staining in uninduced cells. Each of the ES cell lines maintained their pluripotency as measured by teratoma formation. Furthermore, transgene expression can be efficiently achieved in vivo through DOX administration to mice. The establishment of ES cell lines with temporally controllable induction of critical pancreatic transcription factor genes provides a new set of tools that could be used to interrogate gene regulatory networks in pancreatic development and potentially generate greater numbers of beta cells from ES cells.

  15. Mendelian Factors Underlying Quantitative Traits in Tomato: Comparison across Species, Generations, and Environments

    PubMed Central

    Paterson, A. H.; Damon, S.; Hewitt, J. D.; Zamir, D.; Rabinowitch, H. D.; Lincoln, S. E.; Lander, E. S.; Tanksley, S. D.

    1991-01-01

    of the F(2) parent at QTLs than from the phenotype of the F(2) individual. For a trait with intermediate heritability (fruit pH), QTL genotype and observed phenotype were about equally effective at predicting progeny phenotype. For a trait with high heritability (mass per fruit), knowing the QTL genotype of an individual added little if any predictive value, to simply knowing the phenotype. The QTLs mapped in the L. esculentum X L. cheesmanii F(2) appear to be at similar locations to many of those mapped in a previous cross with a different wild tomato (L. chmielewskii). One possible explanation of this similarity is that genetic factors at some of the same loci may affect the traits in the two distantly-related wild species. Potentially major implications of such similarity across broad genetic distances are discussed, in regard to plant and animal breeding, germplasm introgression, and cloning of QTLs. PMID:1673106

  16. Hot ortho-biologic topics at AAOS 2011†: platelet-rich plasma and related growth factors generate excitement.

    PubMed

    Hoggatt, Julie

    2011-06-01

    Several hot topics relating to ortho-biologics were discussed at the 2011 Annual Meeting of the American Academy of Orthopedic Surgery (AAOS) in San Diego this February. Injecting a patient's own platelet-rich plasma (PRP) prior to orthopedic surgery was an important topic, and had its own forum devoted to debating its uses and merit. PRP use has been promoted by equipment companies such as MTF Sports Medicine, Biomet, and Arteriocyte, but others are likely to take advantage of the trend of increasing PRP use by developing a proprietary injectable that mixes PRP with certain growth factors. One possible addition would be a recombinant platelet-derived growth factor (rhPDGF-BB, becaplermin) being developed by BioMimetic Therapeutics for its bone graft product. On the topic of viscosupplementation, the US's only single-injection product, Genzyme's SynviscOne®, was noticeably missing from the exhibit hall at AAOS, but an abstract comparing the single- and multiple-injection viscosupplementation techniques demonstrated that single-injection acts faster and is longer lasting. New bone morphogenetic protein formulations may improve healing of bone fractures. Molecular diagnostics may be used to predict periprosthetic joint infection, allowing orthopedic medicine to be more personalized. A diagnostic that can be used on a large scale has not yet been identified. † Adapted and reproduced from Hoggatt J. Hot Ortho-Biologic Topics at AAOS 2011: Platelet-Rich Plasma and Related Growth Factors Generate Excitement. inThought Research, 2011 Feb 28.

  17. Generation of leukemia inhibitory factor and basic fibroblast growth factor-dependent induced pluripotent stem cells from canine adult somatic cells.

    PubMed

    Luo, Jiesi; Suhr, Steven T; Chang, Eun Ah; Wang, Kai; Ross, Pablo J; Nelson, Laura L; Venta, Patrick J; Knott, Jason G; Cibelli, Jose B

    2011-10-01

    For more than thirty years, the dog has been used as a model for human diseases. Despite efforts made to develop canine embryonic stem cells, success has been elusive. Here, we report the generation of canine induced pluripotent stem cells (ciPSCs) from canine adult fibroblasts, which we accomplished by introducing human OCT4, SOX2, c-MYC, and KLF4. The ciPSCs expressed critical pluripotency markers and showed evidence of silencing the viral vectors and normal karyotypes. Microsatellite analysis indicated that the ciPSCs showed the same profile as the donor fibroblasts but differed from cells taken from other dogs. Under culture conditions favoring differentiation, the ciPSCs could form cell derivatives from the ectoderm, mesoderm, and endoderm. Further, the ciPSCs required leukemia inhibitory factor and basic fibroblast growth factor to survive, proliferate, and maintain pluripotency. Our results demonstrate an efficient method for deriving canine pluripotent stem cells, providing a powerful platform for the development of new models for regenerative medicine, as well as for the study of the onset, progression, and treatment of human and canine genetic diseases.

  18. Generation of Leukemia Inhibitory Factor and Basic Fibroblast Growth Factor-Dependent Induced Pluripotent Stem Cells from Canine Adult Somatic Cells

    PubMed Central

    Luo, Jiesi; Suhr, Steven T.; Chang, Eun Ah; Wang, Kai; Ross, Pablo J.; Nelson, Laura L.; Venta, Patrick J.; Knott, Jason G.

    2011-01-01

    For more than thirty years, the dog has been used as a model for human diseases. Despite efforts made to develop canine embryonic stem cells, success has been elusive. Here, we report the generation of canine induced pluripotent stem cells (ciPSCs) from canine adult fibroblasts, which we accomplished by introducing human OCT4, SOX2, c-MYC, and KLF4. The ciPSCs expressed critical pluripotency markers and showed evidence of silencing the viral vectors and normal karyotypes. Microsatellite analysis indicated that the ciPSCs showed the same profile as the donor fibroblasts but differed from cells taken from other dogs. Under culture conditions favoring differentiation, the ciPSCs could form cell derivatives from the ectoderm, mesoderm, and endoderm. Further, the ciPSCs required leukemia inhibitory factor and basic fibroblast growth factor to survive, proliferate, and maintain pluripotency. Our results demonstrate an efficient method for deriving canine pluripotent stem cells, providing a powerful platform for the development of new models for regenerative medicine, as well as for the study of the onset, progression, and treatment of human and canine genetic diseases. PMID:21495906

  19. Generating favorable growth factor and protease release profiles to enable extracellular matrix accumulation within an in vitro tissue engineering environment.

    PubMed

    Zhang, Xiaoqing; Battiston, Kyle G; Labow, Rosalind S; Simmons, Craig A; Santerre, J Paul

    2017-05-01

    Tissue engineering (particularly for the case of load-bearing cardiovascular and connective tissues) requires the ability to promote the production and accumulation of extracellular matrix (ECM) components (e.g., collagen, glycosaminoglycan and elastin). Although different approaches have been attempted in order to enhance ECM accumulation in tissue engineered constructs, studies of underlying signalling mechanisms that influence ECM deposition and degradation during tissue remodelling and regeneration in multi-cellular culture systems have been limited. The current study investigated vascular smooth muscle cell (VSMC)-monocyte co-culture systems using different VSMC:monocyte ratios, within a degradable polyurethane scaffold, to assess their influence on ECM generation and degradation processes, and to elucidate relevant signalling molecules involved in this in vitro vascular tissue engineering system. It was found that a desired release profile of growth factors (e.g. insulin growth factor-1 (IGF-1)) and hydrolytic proteases (e.g. matrix-metalloproteinases 2, 9, 13 and 14 (MMP2, MMP9, MMP13 and MMP14)), could be achieved in co-culture systems, yielding an accumulation of ECM (specifically for 2:1 and 4:1 VSMC:monocyte culture systems). This study has significant implications for the tissue engineering field (including vascular tissue engineering), not only because it identified important cytokines and proteases that control ECM accumulation/degradation within synthetic tissue engineering scaffolds, but also because the established culture systems could be applied to improve the development of different types of tissue constructs. Sufficient extracellular matrix accumulation within cardiovascular and connective tissue engineered constructs is a prerequisite for their appropriate function in vivo. This study established co-culture systems with tissue specific cells (vascular smooth muscle cells (VSMCs)) and defined ratios of immune cells (monocytes) to investigate

  20. Decreased atrial natriuretic factor receptors and impaired cGMP generation in glomeruli from the cardiomyopathic hamster.

    PubMed

    Levin, E R; Frank, H J; Chaudhari, A; Kirschenbaum, M A; Bandt, A; Mills, S

    1989-03-15

    To determine a possible basis for the decreased action of atrial natriuretic factors (ANF) in congestive heart failure, we compared the cardiomyopathic hamster (CMH) in frank congestive failure, and the age-matched, normal, F1B strain of Golden Syrian Hamsters. Scatchard analysis of competitive binding studies revealed two classes of glomerular receptors. The CMH exhibited decreased binding overall and a markedly decreased number of high affinity receptors but comparable receptor affinity compared to the F1B. In contrast, the low affinity receptor population in the CMH had a much greater affinity compared to the F1B while receptor number was similar. Plasma ANF levels were substantially elevated in the CMH compared to the F1B and in-vitro generation of cGMP was significantly lower in the CMH. Such abnormalities could contribute to the resistance to ANF in this disease.

  1. Targeted expression of RALT in mouse skin inhibits epidermal growth factor receptor signalling and generates a Waved-like phenotype.

    PubMed

    Ballarò, Costanza; Ceccarelli, Sara; Tiveron, Cecilia; Tatangelo, Laura; Salvatore, Anna Maria; Segatto, Oreste; Alemà, Stefano

    2005-08-01

    Although it has been clearly established that negative feedback loops have a fundamental role in the regulation of epidermal growth factor receptor (EGFR) signalling in flies, their role in the regulation of mammalian EGFR has been inferred only recently from in vitro studies. Here, we report on the forced expression of RALT/MIG-6, a negative feedback regulator of ErbB receptors, in mouse skin. A RALT transgene driven by the K14 promoter generated a dose-dependent phenotype resembling that caused by hypomorphic and antimorphic Egfr alleles-that is, wavy coat, curly whiskers and open eyes at birth. Ex vivo keratinocytes from K14-RALT mice showed reduced biochemical and biological responses when stimulated by ErbB ligands. Conversely, knockdown of RALT by RNA interference enhanced ErbB mitogenic signalling. Thus, RALT behaves as a suppressor of EGFR signalling in mouse skin.

  2. Targeted expression of RALT in mouse skin inhibits epidermal growth factor receptor signalling and generates a Waved-like phenotype

    PubMed Central

    Ballarò, Costanza; Ceccarelli, Sara; Tiveron, Cecilia; Tatangelo, Laura; Salvatore, Anna Maria; Segatto, Oreste; Alemà, Stefano

    2005-01-01

    Although it has been clearly established that negative feedback loops have a fundamental role in the regulation of epidermal growth factor receptor (EGFR) signalling in flies, their role in the regulation of mammalian EGFR has been inferred only recently from in vitro studies. Here, we report on the forced expression of RALT/MIG-6, a negative feedback regulator of ErbB receptors, in mouse skin. A RALT transgene driven by the K14 promoter generated a dose-dependent phenotype resembling that caused by hypomorphic and antimorphic Egfr alleles—that is, wavy coat, curly whiskers and open eyes at birth. Ex vivo keratinocytes from K14-RALT mice showed reduced biochemical and biological responses when stimulated by ErbB ligands. Conversely, knockdown of RALT by RNA interference enhanced ErbB mitogenic signalling. Thus, RALT behaves as a suppressor of EGFR signalling in mouse skin. PMID:16007071

  3. Enrollment Factors that Predict Persistence of At-Risk (Low Income and First Generation) Students' Journey towards Completion of a Baccalaureate Degree at Idaho State University

    ERIC Educational Resources Information Center

    Yizar, James H., Jr.

    2010-01-01

    The purpose of this study was to explore, track, and predict longitudinal differences (over the course of six years beginning fall semester 2001) between and among ISU low income, first generation, or the combination of low income and first generation freshman students; regarding persistence rate, and associated persistence factors, such as ACT…

  4. Transcription factor c-Rel is indispensable for generation of thymic but not of peripheral Foxp3+ regulatory T cells

    PubMed Central

    Luu, Maik; Jenike, Elena; Vachharajani, Niyati; Visekruna, Alexander

    2017-01-01

    The transcription factor c-Rel has been shown to be crucial for development of regulatory T cells (Tregs). Recent studies have reported that the expression of transcription factor Helios in Foxp3+ Tregs correlates with thymic origin of these cells (tTregs). Notably, we found that only the Helios+Foxp3+ Treg cell population was substantially reduced in c-Rel deficient mice. In contrast to a defective tTreg development, we observed an expansion of mucosal Tregs during the induction of acute colitis in rel−/− mice. Furthermore, we found a preferential accumulation of Helios−Foxp3+ Tregs in aged c-Rel deficient mice. This unexpected finding, together with the observation that naïve CD4+ T cells convert into Tregs in vitro in the absence of c-Rel and presence of IL-2, provide an evidence that extra-thymic generation of induced and peripheral Tregs (iTregs and pTregs) is independent of c-Rel. Moreover, the treatment with IL-2/anti-IL-2 mAb (JES6-1) resulted in a widespread increase of Helios+Foxp3+ Tregs in both wild-type (WT) and rel−/− mice. These data suggest that exogenous IL-2 administration compensates for defective IL-2 production and reduced tTreg numbers in c-Rel deficient mice. Our findings reveal that c-Rel is essential for the generation of tTregs but not for that of pTregs and iTregs. PMID:28881761

  5. In vitro comparison of the effect of two factor XI (FXI) concentrates on thrombin generation in major FXI deficiency.

    PubMed

    Pike, G N; Cumming, A M; Hay, C R M; Sempasa, B; Sutherland, M; Thachil, J; Burthem, J; Bolton-Maggs, P H B

    2016-05-01

    Bleeding risk in factor XI (FXI) deficiency following surgery may be reduced by treatment with either of two FXI concentrates, but indications for their use are unclear and treatment has been associated with thrombosis. To quantify and compare the effects of two different FXI concentrates on thrombin generation (TG) in major FXI deficiency (FXI:C < 15 IU dL(-1) ). Thrombin generation was measured in controls (n = 50), FXI-deficient individuals pre and post in vitro spiking with FXI concentrates (n = 10), and in ex vivo samples following treatment with FXI concentrate (n = 3). Thrombin generation was significantly impaired in FXI deficiency but improved following FXI replacement in vitro and in vivo. LFB Hemoleven(®) had greater effect on TG than BPL FXI concentrate in vitro (equivalent in vivo doses 10, 20 and 30 U kg(-1) ): higher endogenous thrombin potential (ETP) (P < 0.0001), peak height (P < 0.01) velocity (P < 0.0002) and shorter lag time and time to peak (both P < 0.003). Some measurements with LFB Hemoleven(®) exceeded the reference range. At lower dose (5 U kg(-1) ), BPL FXI concentrate normalized all TG parameters and LFB Hemoleven(®) normalized the ETP but exceeded the reference range with other parameters. Both FXI concentrates improve TG in vitro in major FXI deficiency but differ in dose response, and for both products, doses lower than previously recommended normalized TG in vitro. Comparison of in vitro spiked and ex vivo samples suggest that in vitro results could be used to estimate an expected in vivo response to FXI replacement. © 2015 John Wiley & Sons Ltd.

  6. Risk Factors and Clinical Impacts of Peri-Stent Contrast Staining After Second-Generation Drug-Eluting Stent Implantation.

    PubMed

    Tokuda, Takahiro; Yamawaki, Masahiro; Mori, Shinsuke; Takimura, Hideyuki; Sakamoto, Yasunari; Kobayashi, Norihiro; Araki, Motoharu; Hirano, Keisuke; Ito, Yoshiaki

    2016-04-01

    Peri-stent contrast staining (PSS) after sirolimus-eluting stent implantation is associated with target lesion revascularization (TLR) and very late stent thrombosis. However, the risk factors and clinical sequelae of PSS after second-generation DES implantation remain unclear. This study comprised 2,090 patients with 2,883 lesions treated with second-generation DES from April 2009 to February 2013. Angiographic findings and clinical outcomes were compared between PSS and non-PSS groups. Follow-up angiography was available for 2,411 lesions. PSS was observed in 23 lesions: 4 in biolimus-eluting stents, 4 in zotarolimus-eluting stents (ZES), and 15 in everolimus-eluting stents (EES). Right coronary artery lesions, chronic total occlusion (CTO), and lesions with severe angulation (>90°) were more frequent in the PSS group compared with the non-PSS group. Lesions were longer and the cumulative TLR incidence at 3 years was higher in the PSS group than those in the non-PSS group (27.9 mm vs. 19.4 mm, P < 0.0001; 27.4% vs. 8.6%, P = 0.0002). There was no significant difference in stent thrombosis between the two groups. Multivariable analysis identified CTO [odds ratio (OR) 3.75, 95%CI 1.52-8.88, P = 0.005] as an independent predictor of PSS. PSS after second-generation DES implantation was associated with an increased risk of subsequent TLR. CTO was the independent predictor of PSS. © 2016, Wiley Periodicals, Inc.

  7. The African Experience. Volume I: Syllabus Lectures; Volume II: Bibliographic References; Volume IIIA: Introductory Essays; Volume IIIB: Introductory Essays.

    ERIC Educational Resources Information Center

    Paden, John N.; Soja, Edward W.

    In response to demands for more and better teaching about Africa in American higher education, the US Office of Education requested that the Program of African Studies at Northwestern University generate a set of teaching materials which could be used in introductory undergraduate courses. Included in these volumes, these materials provide…

  8. Phenotypic features of first-generation transgenic goats for human granulocyte-colony stimulation factor production in milk.

    PubMed

    Batista, Ribrio I T P; Melo, Carlos H S; Souza-Fabjan, Joanna M G; Teixeira, Dárcio I A; Melo, Luciana M; Freitas, Vicente J F

    2014-11-01

    Human granulocyte-colony stimulating factor (hG-CSF) is a hematopoietic growth factor used in neutropenic patients. It is produced in transgenic bacteria or cultured mammalian cells. As an alternative, we now show that hG-CSF can be expressed in the mammary gland of first-generation (F1) transgenic goats during induced lactation. Despite lower milk production, transgenic females presented a similar milk composition (fat, protein and lactose) when compared to non-transgenic (p > 0.05) ones. The mean concentration (±SD) of recombinant hG-CSF in milk during lactation was 360 ± 178 µg ml(-1). All clinical parameters, as well as kidney and liver function, indicated that F1 transgenic goats were healthy. Additionally, no ectopic hG-CSF expression was detected in studied tissues of F1 transgenic males. Thus, F1 hG-CSF-transgenic goats can express the recombinant protein in milk at quantities compatible with their use as bioreactors in a commercial-scale protein-production program.

  9. Tumor necrosis factor-α receptor 1 contributes to ethanol-induced vascular reactive oxygen species generation and hypertension.

    PubMed

    Simplicio, Janaina A; Gonzaga, Natália A; Nakashima, Marcelo A; De Martinis, Bruno S; Cunha, Thiago M; Tirapelli, Luis F; Tirapelli, Carlos R

    2017-07-22

    We evaluated the contribution of tumor necrosis factor-α receptor 1 (TNFR1) to ethanol-induced hypertension and vascular oxidative stress and the possible role of perivascular adipose tissue (PVAT) in such responses. Male C57BL/6 wild-type (WT) or TNFR1-deficient mice (TNFR1(-/-)) were treated with ethanol (20% vol/vol) for 12 weeks. Ethanol induced an increase in blood pressure in WT mice and TNFR1(-/-) at 4 and 5 weeks of treatment, respectively. Treatment with ethanol increased tumor necrosis factor-α and interleukin-6 levels in aortas with or without PVAT (PVAT+ and PVAT-, respectively) from WT mice, but not TNFR1(-/-). Ethanol increased superoxide anion (O2(-)) generation, thiobarbituric acid reactive substance concentration, and the activity of superoxide dismutase and catalase in aortas (PVAT- and PVAT+) from WT mice, but not TNFR1(-/-). Conversely, ethanol consumption decreased the concentration of nitrate/nitrite in aortas (PVAT- and PVAT+) from WT mice, but not TNFR1(-/-). Treatment with ethanol increased myeloperoxidase activity in aortas (PVAT- and PVAT+) from WT mice, but not TNFR1(-/-). The major finding of our study is that TNFR1 contributes to ethanol-induced hypertension and oxidative stress in the vasculature. Additionally, TNFR1 plays a role in ethanol-induced increase in proinflammatory cytokines and neutrophils migration. However, PVAT does not counteract or aggravate the effects induced by ethanol. Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

  10. Generation and Characterization of Leukemia Inhibitory Factor-Dependent Equine Induced Pluripotent Stem Cells from Adult Dermal Fibroblasts

    PubMed Central

    Ovchinnikov, Dmitry A.; Sun, Jane; Fortuna, Patrick R.J.; Wolvetang, Ernst J.

    2014-01-01

    In this study we have reprogrammed dermal fibroblasts from an adult female horse into equine induced pluripotent stem cells (equiPSCs). These equiPSCs are dependent only on leukemia inhibitory factor (LIF), placing them in striking contrast to previously derived equiPSCs that have been shown to be co-dependent on both LIF and basic fibroblast growth factor (bFGF). These equiPSCs have a normal karyotype and have been maintained beyond 60 passages. They possess alkaline phosphatase activity and express eqNANOG, eqOCT4, and eqTERT mRNA. Immunocytochemistry confirmed that they produce NANOG, REX1, SSEA4, TRA1-60, and TRA1-81. While our equiPSCs are LIF dependent, bFGF co-stimulates their proliferation via the PI3K/AKT pathway. EquiPSCs lack expression of eqXIST and immunostaining for H3K27me3, suggesting that during reprogramming the inactive X chromosome has likely been reactivated to generate cells that have two active X chromosomes. EquiPSCs form embryoid bodies and in vitro teratomas that contain derivatives of all three germ layers. These LIF-dependent equiPSCs likely reflect a more naive state of pluripotency than equiPSCs that are co-dependent on both LIF and bFGF and so provide a novel resource for understanding pluripotency in the horse. PMID:24555755

  11. Pathways by which the interplay of organismic and environmental factors lead to phenotypic variation within and across generations.

    PubMed

    Harper, Lawrence V

    2013-01-01

    The range of responses made to environmental exigencies by animals, including humans, may be impacted by the experiences of their progenitors. In mammals, pathways have been documented ranging from transactions between a mother and her developing fetus in the womb through continuity of parenting practices and cultural inheritance. In addition, phenotypic plasticity may be constrained by factors transmitted by the gametes that are involved in the regulation of gene expression rather than modifications to the genome itself. Possible mediators for this kind of inheritance are examined, and the conditions that might have led to the evolution of such transmission are considered. Anticipatory adjustments to possible environmental exigencies are likely to occur when such conditions recur regularly, but intermittently across generations and endure for substantial periods of time, and when adjusting to them after the fact is likely to be biologically costly, even life-threatening. It appears that physical growth and responses to nutrient availability are domains in which anticipatory, epigenetically inherited adjustments occur. In addition, given the fact that humans have oppressed one another repeatedly and for relatively long periods of time, such behavioral tendencies as boldness or innovativeness may be behavioral traits subject to such effects. The implications of these factors for research and policy are discussed.

  12. Changes in the Factors Influencing Public Acceptance of Nuclear Power Generation in Japan Since the 2011 Fukushima Daiichi Nuclear Disaster.

    PubMed

    Tsujikawa, Norifumi; Tsuchida, Shoji; Shiotani, Takamasa

    2016-01-01

    Public support for nuclear power generation has decreased in Japan since the Fukushima Daiichi nuclear accident in March 2011. This study examines how the factors influencing public acceptance of nuclear power changed after this event. The influence factors examined are perceived benefit, perceived risk, trust in the managing bodies, and pro-environmental orientation (i.e., new ecological paradigm). This study is based on cross-sectional data collected from two online nationwide surveys: one conducted in November 2009, before the nuclear accident, and the other in October 2011, after the accident. This study's target respondents were residents of Aomori, Miyagi, and Fukushima prefectures in the Tohoku region of Japan, as these areas were the epicenters of the Great East Japan Earthquake and the locations of nuclear power stations. After the accident, trust in the managing bodies was found to have a stronger influence on perceived risk, and pro-environmental orientation was found to have a stronger influence on trust in the managing bodies; however, perceived benefit had a weaker positive influence on public acceptance. We also discuss the theoretical and practical implications of these findings. © 2015 Society for Risk Analysis.

  13. Thrombin generation by activated factor VII on platelet activated by different agonists. Extending the cell-based model of hemostasis

    PubMed Central

    Altman, Raul; Scazziota, Alejandra Silvia; Herrera, Maria de Lourdes; Gonzalez, Claudio

    2006-01-01

    Background Platelet activation is crucial in normal hemostasis. Using a clotting system free of external tissue factor, we investigated whether activated Factor VII in combination with platelet agonists increased thrombin generation (TG) in vitro. Methods and results TG was quantified by time parameters: lag time (LT) and time to peak (TTP), and by amount of TG: peak of TG (PTG) and area under thrombin formation curve after 35 minutes (AUC→35min) in plasma from 29 healthy volunteers using the calibrated automated thrombography (CAT) technique. TG parameters were measured at basal conditions and after platelet stimulation by sodium arachidonate (AA), ADP, and collagen (Col). In addition, the effects of recombinant activated FVII (rFVIIa) alone or combined with the other platelet agonists on TG parameters were investigated. We found that LT and TTP were significantly decreased (p < 0.05) and PTG and AUC→35min were significantly increased (p < 0.05) in platelet rich plasma activated with AA, ADP, Col, and rFVIIa compared to non-activated platelet rich plasma from normal subjects (p = 0.01). Furthermore platelet rich plasma activated by the combined effects of rFVIIa plus AA, ADP or Col had significantly reduced LT and TTP and increased AUC→35min (but not PTG) when compared to platelet rich plasma activated with agonists in the absence of rFVIIa. Conclusion Platelets activated by AA, ADP, Col or rFVIIa triggered TG. This effect was increased by combining rFVIIa with other agonists. Our intrinsic coagulation system produced a burst in TG independent of external tissue factor activity an apparent hemostatic effect with little thrombotic capacity. Thus we suggest a modification in the cell-based model of hemostasis. PMID:16630353

  14. A nation-wide study of the family aggregation and risk factors in anorexia nervosa over three generations.

    PubMed

    Steinhausen, Hans-Christoph; Jakobsen, Helle; Helenius, Dorte; Munk-Jørgensen, Povl; Strober, Michael

    2015-01-01

    This nation-wide register-based study investigated how often anorexia nervosa (AN) and co-morbid disorders occur in affected families compared with control families. Furthermore, the study addressed the impact of sex, year of birth, and degree of urbanization in terms of risk factors. A total of N = 2,370 child and adolescent psychiatric subjects born between 1951 and 1996 and registered in the Danish Psychiatric Central Research Register (DPCRR) had any mental disorder before the age of 18 and developed AN at some point during their life-time. In addition, N = 7,035 controls without any psychiatric diagnosis before age 18 and matched for age, sex, and residential region were included. Psychiatric diagnoses were also obtained on the first-degree relatives as a part of the Danish Three Generation Study (3GS). A family load component was obtained by using various mixed regression models. AN occurred significantly more often in case than in control families. AN Risk factors included having a sibling with AN, affective disorders in family members, and co-morbid affective, anxiety, obsessive-compulsive, personality, or substance use disorders. Furthermore, female sex, and ascending year of birth were significantly associated with having AN. Urbanization was not related to the family load of AN and case-relatives did not develop AN earlier than control relatives. These findings based on a very large and representative dataset provide evidence for the family aggregation and further risk factors in AN. © 2014 Wiley Periodicals, Inc.

  15. A novel approach to facilitate dopaminergic neuron generation from stem-cells: the combination of genetic modification and signaling factors within a three-dimensional perfusion microbioreactor.

    PubMed

    Song, Lin; Liu, Peng; Han, Chao; Liu, Yang; Zou, Wei; Piao, Hua; Wang, Yachen; Liu, Jing

    2013-04-01

    Recent evidence suggests that cell replacement therapy holds great promise for the treatment of Parkinson's disease. Many efforts have been made to improve current methods for differentiating stem or somatic cells into functional dopaminergic (DA) neurons. Previous studies have demonstrated that lineage-specific factors, extrinsic signaling factors and the cellular microenvironment are important considerations for generating functional DA neurons. We hypothesize that a combination of genetic modification, neurotrophic or extrinsic signaling factors and the construction of dynamic neural networks within a three-dimensional perfusion microbioreactor will produce greater efficiency and effectiveness in DA neuron generation from stem-cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Thrombin generation assay and transmission electron microscopy: a useful combination to study tissue factor-bearing microvesicles.

    PubMed

    Gheldof, Damien; Hardij, Julie; Cecchet, Francesca; Chatelain, Bernard; Dogné, Jean-Michel; Mullier, François

    2013-01-01

    Patients with cancer have a 7- to 10-fold increased risk of developing venous thromboembolism. Circulating microvesicles could be a useful predictive biomarker for venous thromboembolism in cancer. Validated and standardised techniques that could be used to determine the complete microvesicle phenotype are required. These were two-fold: a) to characterise tissue factor (TF)-bearing microvesicles released by cultured breast cancer cells MDA-MB-231 by flow cytometry (FCM), transmission electron microscopy (TEM) and thrombin generation assay (TGA); and b) to validate the sensitivity and variability intra/inter-assay of TGA as a useful method to study the procoagulant activity (PCA) of microvesicles. Cultured breast cancer cells MDA-MB-231 were incubated for 45 minutes at 37°C. Samples were then centrifuged or not at 4,500 g for 15 minutes, and cells and MVs or MV-containing supernatants were used for TEM, FCM and TGA. In activity assays, microvesicles (i.e. cell-depleted supernatants) were incubated with anti-TF antibodies or with annexin V to assess the contribution of TF and phospholipids to the PCA. Alternatively, supernatants were filtered through 0.1, 0.22, 0.45 or 0.65 µm membranes and subjected to TGA. The majority of the PCA was associated with microvesicles smaller than 0.1 µm, and the mean microvesicle size estimated by TEM after 10,000 g centrifugation was 121±54 nm with a majority of vesicles between 100 and 200 nm. Microvesicles derived from 5,000 MDA-MB-231cells/ml were sufficient to significantly increase the thrombin generation of normal pooled plasma. TEM, FCM and filtration coupled to TGA represent a useful combination to study the PCA of TF-bearing microvesicles, whatever their size. And it will be interesting to implement these techniques in patients.

  17. Generation rates and emission factors of particulate matter and particle-bound polycyclic aromatic hydrocarbons of incense sticks.

    PubMed

    Lung, Shih-Chun Candice; Hu, Shu-Chuan

    2003-02-01

    The generation rates and emission factors of particulate matter and associated polycyclic aromatic hydrocarbons (PAHs) from incense burning were assessed in a laboratory setting. The differences among different segments of the same stick, among different sticks of the same kind of incense, and between two kinds of manually made Chih-Chen incense sticks (A and B) were evaluated. Joss sticks were burned inside a 44 cm long elutriator; personal environmental monitors fitted into the top of the elutriator were used to take PM2.5 and PM10 samples of incense smoke. Samples were analyzed for PAHs by gas chromatography-flame ionization Detector. It was found that particle and associated PAHs were generated approximately at 561 microg/min (geometric standard deviation (GSD) = 1.1) and 0.56 microg/min (GSD = 1.1) from Incense A, and at 661 microg/min (GSD = 1.7) and 0.46 microg/min (GSD = 1.3) from Incense B, respectively. One gram of Incense A emitted about 19.8 mg (GSD = 1.1) particulate matter and 17.1 microg (GSD = 1.2) particulate-phase PAHs, while one gram of Incense B produced around 43.6 mg (GSD = 1.1) of particles and 25.2 microg (GSD = 1.2) of particle-bound PAHs. There were significant differences in emissions between Incenses A and B, although they belong to the same class of incense. A 10-20% variability in emissions was observed in the main part of the manually produced stick, and a larger variation was found at both tips of the combustible part.

  18. A Neuron-Benign Microfluidic Gradient Generator for Studying the Response of Mammalian Neurons towards Axon Guidance Factors

    PubMed Central

    Bhattacharjee, Nirveek; Li, Nianzhen; Keenan, Thomas M.; Folch, Albert

    2013-01-01

    Investigation of biochemical cues in isolation or in combinations in cell culture systems is crucial for unraveling the mechanisms that govern neural development and repair. The most widely used experimental paradigms that elicit axon guidance in vitro utilize as the source of the gradient a pulsatile pipette, transfected cells, or a loaded gel, producing time-varying gradients of poor reproducibility which are not well suited for studying slow-growing mammalian cells. Although microfluidic device design have allowed for generating stable, complex gradients of diffusible molecules, the flow-induced shear forces in a microchannel has made it impossible to maintain viable mammalian neuronal cultures for sufficiently long times. In this paper, we describe axonal responses of mouse cortical neurons in a “neuron-benign” gradient-generator device based on an open chamber that can establish highly stable gradients of diffusible molecules for at least 6 hours with negligible shear stress, and also allows the neurons to thrive for at least 2 weeks. Except for the period when the gradient is on, the cells in the gradient are under the same conditions as the cells on the control surfaces, which ensure a consistent set of micro-environmental variables. The gradient stability and uniformity over the cell culture surface achieved by the device, together with our software platform for acquiring, post-processing and quantitatively analyzing the large number of images allowed us to extract valuable information even from small datasets. We report a directed response of primary mammalian neurons (from E14 embryonic mice cortex) to a diffusible gradient of netrin in vitro. We infer from our studies that a large majority (~73%) of the neurons that extend axons during the gradient application grow towards the netrin source, and our data analysis also indicates that netrin acts as a growth factor for this same population of neurons. PMID:20957287

  19. Generation and characterization of a panel of monoclonal antibodies specific for human fibroblast growth factor receptor 4 (FGFR4).

    PubMed

    Chen, Chaoyuan; Patel, Sima; Corisdeo, Susanne; Liu, Xiangdong; Micolochick, Holly; Xue, Jiyang; Yang, Qifeng; Lei, Ying; Wang, Baiyang; Soltis, Daniel

    2005-06-01

    Fibroblast growth factor receptor 4 (FGFR4) is a member of the FGFR family of receptor tyrosine kinases, and plays important roles in a variety of biological functions such as cell proliferation, differentiation, migration, angiogenesis, tissue repair, and tumorigenesis. The human FGFRs share a high degree of sequence homology between themselves, as well as with their murine homologs. Consequently, it has been suggested that it may be difficult to prepare monoclonal antibodies (MAbs) that are specific for the individual receptor types. In this communication, we report on the development and characterization of a panel of anti-human FGFR4 MAbs that were generated in mice using a rapid immunization protocol. Using a modified rapid immunization at multiple sites (RIMMS) protocol with the soluble extracellular domain of human FGFR4 (FGFR4-ECD), the immunized mice developed high levels of polyclonal IgG to the immunogen within 13 days of the first immunization. The lymph node cells isolated from the immunized animals were then fused with mouse myeloma cells for hybridoma generation. Use of an efficient hybridoma cloning protocol in combination with an ELISA screening procedure allowed for early identification of stable hybridomas secreting antihuman FGFR4 IgG. Several identified MAbs specifically reacted with the FGFR4 protein without binding to the other human isoforms (FGFR1, FGFR2, and FGFR3). As evaluated by BIAcore analysis, most anti-FGFR4 MAbs displayed high affinities (8.6 x 10(8) approximately 3.9 x 10(10) M) to FGFR4. Furthermore, these MAbs were able to bind to FGFR4 expressed on human breast tumor cell lines MDA-MB-361 and MDA-MB-453. Taken together, the results demonstrate that the RIMMS strategy is an effective approach for generating class-switched, high-affinity MAbs in mice to evolutionarily conserved proteins such as human FGFR4. These MAbs may be useful tools for further investigation of the biological functions and pathological roles of human FGFR4.

  20. Control of Moderate-to-Severe Plaque Psoriasis with Efalizumab: 24-Week, Open-Label, Phase IIIb/IV Latin American Study Results

    PubMed Central

    Stengel, Fernando M; Petri, Valeria; Campbell, Gladys AM; Dorantes, Gladys Leon; López, Magdalina; Galimberti, Ricardo L; Valdez, Raúl P; de Arruda, Lucia F; Guerra, Mario Amaya; Chouela, Edgardo N; Licu, Daiana

    2009-01-01

    Introduction Psoriasis is a debilitating, chronic inflammatory systemic disease affecting around 2% of the South American population. Biological therapies offer the possibility of long-term therapy with improved safety and efficacy. Methods We conducted a multicentre, open-label, single-arm, Phase IIIb/IV study of adult patients (18–75 years) with moderate-to-severe plaque psoriasis who were candidates for systemic therapy or phototherapy. Patients received efalizumab subcutaneously (1.0 mg/kg/wk). The primary endpoint was the proportion of patients achieving a Physician Global Assessment (PGA) rating of “excellent” or “cleared” at Week 24. Safety outcomes were adverse events (AEs), serious AEs (SAEs) and abnormalities on laboratory tests. Results Of 189 patients included in the intent-to-treat and safety populations, 104 (55.0%) were of Hispanic or Latino ethnicity. At Week 24, 92/189 (48.7%) patients achieved or maintained a PGA rating of “excellent” or “cleared”. AEs were reported by 161/189 (85.2%) patients, SAEs by 21/189 (11.1%). One patient died during the study (meningoencephalitis). Laboratory findings were consistent with previous experience. Conclusions Efalizumab demonstrated sustained control of psoriasis up to 24 weeks in patients from Latin America, confirming results seen in Phase III studies conducted in North America and Europe. PMID:20098510

  1. Is it possible to predict limb viability in complex Gustilo IIIB and IIIC tibial fractures? A comparison of two predictive indices.

    PubMed

    O'Sullivan, S T; O'Sullivan, M; Pasha, N; O'Shaughnessy, M; O'Connor, T P

    1997-01-01

    The patient with severe lower limb trauma presents a management dilemma; whether to amputate primarily or to attempt limb salvage. In recent years, many predictive indices have been published which purport to identify limbs which are non-viable. We retrospectively applied two recently described indices, the Mangled Extremity Severity Score (MESS) and the Limb Salvage Index (LSI), to 54 limbs in 50 patients with either Gustilo IIIB or IIIC complex tibial fractures. There were 22 amputations (40.7 per cent) in the series. The mean MESS score in the limb salvage group was 3.8 (range 2-10), and the mean MESS score in the amputation group was 7.7 (range 4-13) (P < 0.0001). The mean LSI score in the limb salvage group was 3.6 (range 3-8), and the mean LSI score in the amputation group was 6.9 (P < 0.01). However, in the group with MESS scores > 7 (which recommends amputation), there were three limbs which were salvaged with acceptable functional outcome. Similarly, in those with LSI scores > 6 (which recommends amputation), there were seven limbs successfully salvaged. A MESS > 7 offered a greater relative risk of amputation (9.2) than a LSI score > 6 (5.3). We found both indices of use in predicting limb salvage and functional outcome. However, neither is sufficiently accurate to be considered absolutely reliable in clinical practice.

  2. 1E10 anti-idiotype vaccine in non-small cell lung cancer: experience in stage IIIb/IV patients.

    PubMed

    Alfonso, Saily; Diaz, Rosa M; de la Torre, Ana; Santiesteban, Eduardo; Aguirre, Frank; Pérez, Kirenia; Rodríguez, José L; Barroso, María del Carmen; Hernández, Ana M; Toledo, Darien; Gabri, Mariano R; Alonso, Daniel F; Viada, Carmen; Gómez, Roberto E; Suárez, Eduardo; Vazquez, Ana M; Perez, Rolando; Macias, Amparo E

    2007-12-01

    Conventional treatment of non-small cell lung cancer (NSCLC) has apparently reached a plateau of effectiveness in improving the survival of the patients. For that reason the search for new therapeutic strategies in this type of tumor is justified. 1E10 is an anti-idiotype murine monoclonal antibody (Ab2 MAb) specific to P3 Ab1 MAb, which reacts with NeuGc-containing gangliosides, sulfatides and with antigens expressed in some tumors, including those from the lung. We report the treatment with aluminum hydroxide-precipitated 1E10 MAb of 34 stage IIIb and 37 stage IV NSCLC patients. These patients were treated with the anti-idiotype vaccine, after received standard chemotherapy and radiotherapy, in a compassionate-use basis study. Patients received five bi-weekly injections of 1 mg of 1E10/Alum, other 10 doses at 28-day intervals and later the patients who maintained a good performance status continued to be immunized at this same time interval. No evidence of unexpected or serious adverse effects was reported. The median survival time of the 56 patients who entered the study with partial response or disease stabilization and with a PS 1 after the first line of chemo/radiotherapy, was 11.50 months from starting vaccination. In contrast, the median survival time calculated for patients who started vaccination with progressive disease and/or a PS2 was 6.50 months.

  3. Radiation Therapy and Cisplatin With or Without Triapine in Treating Patients With Newly Diagnosed Stage IB2, II, or IIIB-IVA Cervical Cancer or Stage II-IVA Vaginal Cancer

    ClinicalTrials.gov

    2017-10-09

    Cervical Adenocarcinoma; Cervical Adenosquamous Carcinoma; Cervical Squamous Cell Carcinoma, Not Otherwise Specified; Stage IB2 Cervical Cancer; Stage II Cervical Cancer; Stage II Vaginal Cancer; Stage IIA Cervical Cancer; Stage IIB Cervical Cancer; Stage III Vaginal Cancer; Stage IIIB Cervical Cancer; Stage IVA Cervical Cancer; Stage IVA Vaginal Cancer; Stage IVB Vaginal Cancer; Vaginal Adenocarcinoma; Vaginal Adenosquamous Carcinoma; Vaginal Squamous Cell Carcinoma, Not Otherwise Specified

  4. Landscape genetics of California mule deer (Odocoileus hemionus): the roles of ecological and historical factors in generating differentiation.

    PubMed

    Pease, Katherine M; Freedman, Adam H; Pollinger, John P; McCormack, John E; Buermann, Wolfgang; Rodzen, Jeff; Banks, Jim; Meredith, Erin; Bleich, Vernon C; Schaefer, Robert J; Jones, Ken; Wayne, Robert K

    2009-05-01

    Landscape genetics is an emerging discipline that utilizes environmental and historical data to understand geographic patterns of genetic diversity. Niche modelling has added a new dimension to such efforts by allowing species-environmental associations to be projected into the past so that hypotheses about historical vicariance can be generated and tested independently with genetic data. However, previous approaches have primarily utilized DNA sequence data to test inferences about historical isolation and may have missed very recent episodes of environmentally mediated divergence. We type 15 microsatellite loci in California mule deer and identify five genetic groupings through a Structure analysis that are also well predicted by environmental data. We project the niches of these five deer ecotypes to the last glacial maximum (LGM) and show they overlap to a much greater extent than today, suggesting that vicariance associated with the LGM cannot explain the present-day genetic patterns. Further, we analyse mitochondrial DNA (mtDNA) sequence trees to search for evidence of historical vicariance and find only two well-supported clades. A coalescence-based analysis of mtDNA data shows that the genetic divergence of the mule deer genetic clusters in California is recent and appears to be mediated by ecological factors. The importance of environmental factors in explaining the genetic diversity of California mule deer is unexpected given that they are highly mobile species and have a broad habitat distribution. Geographic differences in the timing of reproduction and peak vegetation as well as habitat choice reflecting natal origin may explain the persistence of genetic subdivision.

  5. Intellectual function evaluation of first generation immigrant children with sickle cell disease: the role of language and sociodemographic factors

    PubMed Central

    2013-01-01

    Background Sickle Cell Disease (SCD) is the most common genetic disease worldwide. Neurological events are among the most worrisome clinical complications of SCD and are frequently accompanied by cognitive impairment. Intellectual function in SCD may vary according to genetic and environmental factors. Immigrant children with SCD are increasing at a global level and display specific health care needs. The aim of our multicenter study was to describe the intellectual function of first generation African immigrants with SCD and the influence of sociodemographic factors on its characteristics. Methods The Wechsler Intelligence Scales were administered to evaluate broad intellectual functions in children with SCD and in age-matched healthy siblings. Patients’ clinical, socio-demographic, Magnetic Resonance Imaging (MRI) and Angiography (MRA) data were correlated to intellectual function scores. Results 68 children, mean age 8.95 years were evaluated. 72% spoke three languages, 21% two. FSIQ was <75 in 25% of the children. Mean VIQ was lower than PIQ in 75%. Mean verbal subtest scores were lower than performance scores. Female gender, number of languages spoken at home and mother’s employment were associated with single subtest performances (p < 0.05). MRA was abnormal in 73.4% and MRI in 35.9%. No significant correlation was established between silent lesions and intellectual function, even if patients with lesions performed worse. Fifteen siblings performed better than patients on cognitive domains, including language (p < 0.05). Conclusions Immigrant bilingual children with SCD seem to display a rate of cognitive impairment similar to their monolingual counterparts but a more pronounced and precocious onset of language difficulties. Adjunctive tests need to be considered in this group of patients to better define their specific deficits. PMID:23735165

  6. Dysregulation of the Transforming Growth Factor β Pathway in Induced Pluripotent Stem Cells Generated from Patients with Diamond Blackfan Anemia.

    PubMed

    Ge, Jingping; Apicella, Marisa; Mills, Jason A; Garçon, Loïc; French, Deborah L; Weiss, Mitchell J; Bessler, Monica; Mason, Philip J

    2015-01-01

    Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome with clinical features of red cell aplasia and variable developmental abnormalities. Most affected patients have heterozygous loss of function mutations in ribosomal protein genes but the pathogenic mechanism is still unknown. We generated induced pluripotent stem cells from DBA patients carrying RPS19 or RPL5 mutations. Transcriptome analysis revealed the striking dysregulation of the transforming growth factor β (TGFβ) signaling pathway in DBA lines. Expression of TGFβ target genes, such as TGFBI, BAMBI, COL3A1 and SERPINE1 was significantly increased in the DBA iPSCs. We quantified intermediates in canonical and non-canonical TGFβ pathways and observed a significant increase in the levels of the non-canonical pathway mediator p-JNK in the DBA iPSCs. Moreover, when the mutant cells were corrected by ectopic expression of WT RPS19 or RPL5, levels of p-JNK returned to normal. Surprisingly, nuclear levels of SMAD4, a mediator of canonical TGFβ signaling, were decreased in DBA cells due to increased proteolytic turnover. We also observed the up-regulation of TGFβ1R, TGFβ2, CDKN1A and SERPINE1 mRNA, and the significant decrease of GATA1 mRNA in the primitive multilineage progenitors. In summary our observations identify for the first time a dysregulation of the TGFβ pathway in the pathobiology of DBA.

  7. A chimeric repressor of petunia PH4 R2R3-MYB family transcription factor generates margined flowers in torenia

    PubMed Central

    Kasajima, Ichiro; Sasaki, Katsutomo

    2016-01-01

    ABSTRACT The development of new phenotypes is key to the commercial development of the main floricultural species and cultivars. Important new phenotypes include features such as multiple-flowers, color variations, increased flower size, new petal shapes, variegation and distinctive petal margin colourations. Although their commercial use is not yet common, the transgenic technologies provide a potentially rapid means of generating interesting new phenotypes. In this report, we construct 5 vectors which we expected to change the color of the flower anthocyanins, from purple to blue, regulating vacuolar pH. When these constructs were transformed into purple torenia, we unexpectedly recovered some genotypes having slightly margined petals. These transgenic lines expressed a chimeric repressor of the petunia PhPH4 gene under the control of Cauliflower mosaic virus 35 S RNA promoter. PhPH4 is an R2R3-type MYB transcription factor. The transgenic lines lacked pigmentation in the petal margin cells both on the adaxial and abaxial surfaces. Expressions of Flavanone 3-hydroxylase (F3H), Flavonoid 3′-hydroxylase (F3′H) and Flavonoid 3′5′-hydroxylase (F3′5′H) genes were reduced in the margins of these transgenic lines, suggesting an inhibitory effect of PhPH4 repressor on anthocyanin synthesis. PMID:27089475

  8. Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation

    PubMed Central

    Reinhardt, Christoph; von Brühl, Marie-Luise; Manukyan, Davit; Grahl, Lenka; Lorenz, Michael; Altmann, Berid; Dlugai, Silke; Hess, Sonja; Konrad, Ildiko; Orschiedt, Lena; Mackman, Nigel; Ruddock, Lloyd; Massberg, Steffen; Engelmann, Bernd

    2008-01-01

    The activation of initiator protein tissue factor (TF) is likely to be a crucial step in the blood coagulation process, which leads to fibrin formation. The stimuli responsible for inducing TF activation are largely undefined. Here we show that the oxidoreductase protein disulfide isomerase (PDI) directly promotes TF-dependent fibrin production during thrombus formation in vivo. After endothelial denudation of mouse carotid arteries, PDI was released at the injury site from adherent platelets and disrupted vessel wall cells. Inhibition of PDI decreased TF-triggered fibrin formation in different in vivo murine models of thrombus formation, as determined by intravital fluorescence microscopy. PDI infusion increased — and, under conditions of decreased platelet adhesion, PDI inhibition reduced — fibrin generation at the injury site, indicating that PDI can directly initiate blood coagulation. In vitro, human platelet–secreted PDI contributed to the activation of cryptic TF on microvesicles (microparticles). Mass spectrometry analyses indicated that part of the extracellular cysteine 209 of TF was constitutively glutathionylated. Mixed disulfide formation contributed to maintaining TF in a state of low functionality. We propose that reduced PDI activates TF by isomerization of a mixed disulfide and a free thiol to an intramolecular disulfide. Our findings suggest that disulfide isomerases can act as injury response signals that trigger the activation of fibrin formation following vessel injury. PMID:18274674

  9. A highly sensitive thrombin generation assay for assessment of recombinant activated factor VII therapy in haemophilia patients with an inhibitor.

    PubMed

    Livnat, Tami; Martinowitz, Uri; Zivelin, Ariella; Rima, Dardik; Kenet, Gili

    2011-04-01

    Bypass agents are the common treatment for haemophilia patients who develop inhibitory antibodies. Laboratory assessment of the efficacy of bypassing agent therapy is a challenge. In the present work we modified the conditions triggering thrombin generation (TG) assay in order to find the most sensitive assay for detection of rFVIIa and its analogue NN1731 in haemophilic plasma. TG was measured in samples of normal plasma, plasma of haemophilia patient with inhibitors, as well as haemophilia induced plasma. Recalcification-induced TG was compared to tissue factor (TF) -induced TG in the presence and absence of rFVIIa and NN1731. Recalcification-induced TG (without TF) in haemophilic plasma yielded baseline flat curves, with increased TG as a consequence of spiking the plasma rFVIIa. Using our system, we observed both dose-dependence and time-dependence of rFVIIa effect on TG. Elevated concentrations of TF mask the difference between rFVIIa-treated and non-treated haemophilic plasma. NN1731 yielded normalisation of recalcification-induced TG curves (without TF) which may reflect high potency. In conclusion, we suggest that triggering TG by recalcification-only may be the most sensitive assay for determining the impact of bypassing agents in haemophilic plasma, and may serve as a caution surrogate safety marker in future studies.

  10. Analysis and comparison of the wolf microbiome under different environmental factors using three different data of Next Generation Sequencing.

    PubMed

    Wu, Xiaoyang; Zhang, Huanxin; Chen, Jun; Shang, Shuai; Yan, Jiakuo; Chen, Yao; Tang, Xuexi; Zhang, Honghai

    2017-09-12

    Next Generation Sequencing has been widely used to characterize the prevalence of fecal bacteria in many different species. In this study, we attempted to employ a low-cost and high-throughput sequencing model to discern information pertaining to the wolf microbiota. It is hoped that this model will allow researchers to elucidate potential protective factors in relation to endangered wolf species. We propose three high-throughput sequencing models to reveal information pertaining to the micro-ecology of the wolf. Our analyses advised that, among the three models, more than 100,000 sequences are more appropriate to retrieve the communities' richness and diversity of micro-ecology. In addition, the top five wolf microbiome OTUs (99%) were members of the following five phyla: Bacteroidetes, Fusobacteria, Firmicutes, Proteobacteria, and Actinobacteria. While Alloprevotella, Clostridium_sensu_stricto_1, Anaerobiospirillum, Faecalibactreium and Streptococcus were shared by all samples, their relative abundances were differentially represented between domestic dogs and other wolves. Our findings suggest that altitude, human interference, age, and climate all contribute towards the micro-ecology of the wolf. Specifically, we observed that genera Succinivibrio and Turicibacter are significantly related to altitude and human interference (including hunting practices).

  11. Family Aggregation and Risk Factors in Phobic Disorders over Three-Generations in a Nation-Wide Study

    PubMed Central

    Steinhausen, Hans-Christoph; Jakobsen, Helle; Meyer, Andrea; Jørgensen, Povl Munk; Lieb, Roselind

    2016-01-01

    Objective This nation-wide register-based study investigated how often phobic disorders (PHO) and co-morbid disorders occur in affected families compared to control families. Furthermore, the study addressed the impact of sex, year of birth, and degree of urbanization in terms of risk factors. Method A total of N = 746 child and adolescent psychiatric participants born between 1969 and 1986 and registered in the Danish Psychiatric Central Research Register (DPCRR) with a diagnosis of a mental disorder before the age of 18, and developed PHO at some point during their life-time until a maximum age of 40 years were included. In addition, N = 2229 controls without any diagnosis of mental disorders before age 18 and that were matched for age, sex, and residential region were included. Diagnoses of mental disorders were also obtained from the first- degree relatives as a part of the Danish Three Generation Study (3GS). A family load component was obtained by using various mixed regression models. Results PHO occurred significantly more often in case than in control families, in particular, in mothers and siblings. Substance use disorders (SUD), Depressive disorders (DEP), anxiety disorders (ANX) and personality disorders (PERS) in the family were significantly associated with specific phobia in the case-probands. After controlling for various mental disorders comorbid to PHO it was found that some of the family transmission could be caused by various other mental disorders in family members rather than the PHO itself. Female sex and more recent year of birth were further risk factors while region of residence was not related to the manifestation of PHO. Case-relatives did not develop PHO earlier than control relatives. After adjusting for various additional explanatory variables, the family load explained only 0.0013% of the variance in the manifestation of PHO in the case-probands Discussion These findings, based on a very large and representative dataset, provide

  12. Family Aggregation and Risk Factors in Phobic Disorders over Three-Generations in a Nation-Wide Study.

    PubMed

    Steinhausen, Hans-Christoph; Jakobsen, Helle; Meyer, Andrea; Jørgensen, Povl Munk; Lieb, Roselind

    2016-01-01

    This nation-wide register-based study investigated how often phobic disorders (PHO) and co-morbid disorders occur in affected families compared to control families. Furthermore, the study addressed the impact of sex, year of birth, and degree of urbanization in terms of risk factors. A total of N = 746 child and adolescent psychiatric participants born between 1969 and 1986 and registered in the Danish Psychiatric Central Research Register (DPCRR) with a diagnosis of a mental disorder before the age of 18, and developed PHO at some point during their life-time until a maximum age of 40 years were included. In addition, N = 2229 controls without any diagnosis of mental disorders before age 18 and that were matched for age, sex, and residential region were included. Diagnoses of mental disorders were also obtained from the first- degree relatives as a part of the Danish Three Generation Study (3GS). A family load component was obtained by using various mixed regression models. PHO occurred significantly more often in case than in control families, in particular, in mothers and siblings. Substance use disorders (SUD), Depressive disorders (DEP), anxiety disorders (ANX) and personality disorders (PERS) in the family were significantly associated with specific phobia in the case-probands. After controlling for various mental disorders comorbid to PHO it was found that some of the family transmission could be caused by various other mental disorders in family members rather than the PHO itself. Female sex and more recent year of birth were further risk factors while region of residence was not related to the manifestation of PHO. Case-relatives did not develop PHO earlier than control relatives. After adjusting for various additional explanatory variables, the family load explained only 0.0013% of the variance in the manifestation of PHO in the case-probands. These findings, based on a very large and representative dataset, provide evidence for the family aggregation and

  13. A novel intronic cis element, ISE/ISS-3, regulates rat fibroblast growth factor receptor 2 splicing through activation of an upstream exon and repression of a downstream exon containing a noncanonical branch point sequence.

    PubMed

    Hovhannisyan, Ruben H; Carstens, Russ P

    2005-01-01

    Mutually exclusive splicing of fibroblast growth factor receptor 2 (FGFR2) exons IIIb and IIIc yields two receptor isoforms, FGFR2-IIIb and -IIIc, with distinctly different ligand binding properties. Several RNA cis elements in the intron (intron 8) separating these exons have been described that are required for splicing regulation. Using a heterologous splicing reporter, we have identified a new regulatory element in this intron that confers cell-type-specific inclusion of an unrelated exon that mirrors its ability to promote cell-type-specific inclusion of exon IIIb. This element promoted inclusion of exon IIIb while at the same time silencing exon IIIc inclusion in cells expressing FGFR2-IIIb; hence, we have termed this element ISE/ISS-3 (for "intronic splicing enhancer-intronic splicing silencer 3"). Silencing of exon IIIc splicing by ISE/ISS-3 was shown to require a branch point sequence (BPS) using G as the primary branch nucleotide. Replacing a consensus BPS with A as the primary branch nucleotide resulted in constitutive splicing of exon IIIc. Our results suggest that the branch point sequence constitutes an important component that can contribute to the efficiency of exon definition of alternatively spliced cassette exons. Noncanonical branch points may thus facilitate cell-type-specific silencing of regulated exons by flanking cis elements.

  14. Generation of recombinant single-chain antibodies neutralizing the cytolytic activity of vaginolysin, the main virulence factor of Gardnerella vaginalis.

    PubMed

    Pleckaityte, Milda; Mistiniene, Edita; Lasickiene, Rita; Zvirblis, Gintautas; Zvirbliene, Aurelija

    2011-11-03

    Gardnerella vaginalis is identified as the predominant colonist of the vaginal tract in women with bacterial vaginosis. Vaginolysin (VLY) is a protein toxin released by G. vaginalis. VLY possesses cytolytic activity and is considered as a main virulence factor of G. vaginalis. Inhibition of VLY-mediated cell lysis by antibodies may have important physiological relevance. Single-chain variable fragments of immunoglobulins (scFvs) were cloned from two hybridoma cell lines producing neutralizing antibodies against VLY and expressed as active proteins in E. coli. For each hybridoma, two variants of anti-VLY scFv consisting of either VL-VH or VH-VL linked with a 20 aa-long linker sequence (G₄S)₄ were constructed. Recovery of scFvs from inclusion bodies with subsequent purification by metal-chelate chromatography resulted in VLY-binding proteins that were predominantly monomeric. The antigen-binding activity of purified scFvs was verified by an indirect ELISA. The neutralizing activity was investigated by in vitro hemolytic assay and cytolytic assay using HeLa cell line. Calculated apparent Kd values and neutralizing potency of scFvs were in agreement with those of parental full-length antibodies. VH-VL and VL-VH variants of scFvs showed similar affinity and neutralizing potency. The anti-VLY scFvs derived from hybridoma clone 9B4 exhibited high VLY-neutralizing activity both on human erythrocytes and cervical epithelial HeLa cells. Hybridoma-derived scFvs with VLY-binding activity were expressed in E. coli. Recombinant anti-VLY scFvs inhibited VLY-mediated cell lysis. The monovalent scFvs showed reduced affinity and neutralizing potency as compared to the respective full-length antibodies. The loss of avidity could be restored by generating scFv constructs with multivalent binding properties. Generated scFvs is the first example of recombinant single-chain antibodies with VLY-neutralizing activity produced in prokaryote expression system. G. vaginalis caused

  15. Mature results of a pilot study of pelvic radiotherapy with concurrent continuous infusion intra-arterial 5-FU for stage IIIB-IVA squamous cell carcinoma of the cervix.

    PubMed

    Chaney, A W; Eifel, P J; Logsdon, M D; Morris, M; Wharton, J T

    1999-08-01

    To evaluate the long-term results of continuous infusion intra-arterial 5-fluorouracil (CI IA 5-FU) given with concurrent pelvic radiotherapy (RT) for FIGO stage IIIB-IVA carcinoma of the cervix. Between 1965 and 1974, 27 patients with extensive FIGO Stage IIIB (22 patients) or Stage IVA (5 patients) squamous cell carcinoma of the cervix were treated with CI IA 5-FU and RT. Twenty-one patients (78%) had bilateral pelvic wall involvement, 25 (93%) had massive tumors (> or =8 cm in diameter), 7 (27%) had involvement of the lower one-third of the vagina, and 15 (56%) presented with hydronephrosis. All patients underwent routine clinical staging, transperitoneal para-aortic lymph node dissection, and bilateral hypogastric artery catheter placement. 5-FU was continuously infused at a dose rate of 10 mg/kg/day on Days 1-15 of RT. The median dose of 5-FU was 376 mg/m2/day (range 270-692). All patients received concurrent pelvic RT to a median dose of 50 Gy at 2.0 Gy per fraction. Only 4 patients received intracavitary RT. The median follow-up of surviving patients was 190 months. The overall 5-year survival rate was 37%. For the 22 patients with FIGO Stage IIIB disease, the 5-year survival rate was 41%. The survival rate for 18 patients treated with only external beam radiation and chemotherapy for Stage IIIB disease was 33%. Four of 10 patients treated with only 50 Gy of external beam radiation and CI IA 5-FU were long-term survivors. Acute complications, including hematologic toxicity and skin reactions, were severe, with 1 death from neutropenic sepsis. Severe late complications were only observed in patients treated with > or =60 Gy of external beam radiation. While this series is small, the fact that 4 patients with massive Stage IIIB tumors survived after a total radiation dose of only 50 Gy suggests that RT with CI IA 5-FU deserves further study. Modifications in dose, technique, and route of administration should reduce toxicity, and the addition of intracavitary

  16. Acute childhood leukemias and exposure to magnetic fields generated by high voltage overhead power lines - a risk factor in Iran.

    PubMed

    Feizi, Abbas Ali H Pour; Arabi, M A Ahmad

    2007-01-01

    Many investigators have studied the effects of Extremely Low Frequency-Magnetic Fields generated by ordinary and domestic power lines, as a risk factor in acute leukaemias of children, but there are limited information available regarding very high voltage overhead power lines. Children in developing countries sometimes live very close to such structures and we have registered several patients with acute leukaemias appearing in clusters. In the present study we have analyzed 60 consecutively diagnosed patients with acute leukaemias, and 59 matched controls in a provincial capital city in North-Western Iran. After provision of consent, a detailed form was filled in, and a visit to the present (or previous) residential areas of both groups was arranged. The locations of the very high voltage power lines (123, 230, 400 kilo volts), were noted in each area, if present, and their distances from the houses under study were detected. The expected intensities of the Magnetic Fields (B) were calculated having the mean intensity of the electrical current and other line characteristics, by means of relevant equations. Fourteen patients in the case group (23.5%) were living near the high voltage power lines in distances < or = 500 meters. (Mean B = 0.6 microTeslas, microT). In the control group at the same distance, the figure was 2 children (3.3%) (Mean B = 0.35 microT). Statistically, the likelihood of leukaemia was increased considerably in this distance (Odds ratio (OR) = 8.67, 95% Confidence Interval (CI) = 1.74- 58.4, P value= 0.001). On the other hand 15 pts (25 %) in the leukaemia group were experiencing Magnetic fields above 0.45 microT in comparison to 5 in the control group ( 8.5% )(OR = 3.60, 95% CI = 1.11-12.39, P = 0.01). More children in developing countries like Iran live close to very high voltage lines, and they experience relatively more harmful effects from the Magnetic Fields, in comparison with children in developed countries. Residence near very high

  17. Second Generation Reusable Launch Vehicle Development and Global Competitiveness of US Space Transportation Industry: Critical Success Factors Assessment

    NASA Technical Reports Server (NTRS)

    Enyinda, Chris I.

    2002-01-01

    In response to the unrelenting call in both public and private sectors fora to reduce the high cost associated with space transportation, many innovative partially or fully RLV (Reusable Launch Vehicles) designs (X-34-37) were initiated. This call is directed at all levels of space missions including scientific, military, and commercial and all aspects of the missions such as nonrecurring development, manufacture, launch, and operations. According to Wertz, tbr over thirty years, the cost of space access has remained exceedingly high. The consensus in the popular press is that to decrease the current astronomical cost of access to space, more safer, reliable, and economically viable second generation RLVs (SGRLV) must be developed. Countries such as Brazil, India, Japan, and Israel are now gearing up to enter the global launch market with their own commercial space launch vehicles. NASA and the US space launch industry cannot afford to lag behind. Developing SGRLVs will immeasurably improve the US's space transportation capabilities by helping the US to regain the global commercial space markets while supporting the transportation capabilities of NASA's space missions, Developing the SGRLVs will provide affordable commercial space transportation that will assure the competitiveness of the US commercial space transportation industry in the 21st century. Commercial space launch systems are having difficulty obtaining financing because of the high cost and risk involved. Access to key financial markets is necessary for commercial space ventures. However, public sector programs in the form of tax incentives and credits, as well as loan guarantees are not yet available. The purpose of this paper is to stimulate discussion and assess the critical success factors germane for RLVs development and US global competitiveness.

  18. Second Generation Reusable Launch Vehicle Development and Global Competitiveness of US Space Transportation Industry: Critical Success Factors Assessment

    NASA Technical Reports Server (NTRS)

    Enyinda, Chris I.

    2002-01-01

    In response to the unrelenting call in both public and private sectors fora to reduce the high cost associated with space transportation, many innovative partially or fully RLV (Reusable Launch Vehicles) designs (X-34-37) were initiated. This call is directed at all levels of space missions including scientific, military, and commercial and all aspects of the missions such as nonrecurring development, manufacture, launch, and operations. According to Wertz, tbr over thirty years, the cost of space access has remained exceedingly high. The consensus in the popular press is that to decrease the current astronomical cost of access to space, more safer, reliable, and economically viable second generation RLVs (SGRLV) must be developed. Countries such as Brazil, India, Japan, and Israel are now gearing up to enter the global launch market with their own commercial space launch vehicles. NASA and the US space launch industry cannot afford to lag behind. Developing SGRLVs will immeasurably improve the US's space transportation capabilities by helping the US to regain the global commercial space markets while supporting the transportation capabilities of NASA's space missions, Developing the SGRLVs will provide affordable commercial space transportation that will assure the competitiveness of the US commercial space transportation industry in the 21st century. Commercial space launch systems are having difficulty obtaining financing because of the high cost and risk involved. Access to key financial markets is necessary for commercial space ventures. However, public sector programs in the form of tax incentives and credits, as well as loan guarantees are not yet available. The purpose of this paper is to stimulate discussion and assess the critical success factors germane for RLVs development and US global competitiveness.

  19. Severe wind/hail storms over Bulgaria in 1999-2001 period: synoptic- and meso-scale factors for generation

    NASA Astrophysics Data System (ADS)

    Simeonov, Petio; Georgiev, Christo G.

    A brief overview of severe wind/hail storms over Bulgaria in the last 5 years (1997-2001) is presented. Synoptic and thermodynamic analyses of 27 cases during 1999-2001 (April-September) were performed. Among others, two events during this period produced extremely damaging winds. The first of them was associated with a tornado close to the Mediterranean coast on 15 May 1999 and has been already described in the literature. This paper illustrates the role of synoptic scale factors for generation of a second severe windstorm (that occurred near the Bulgarian capital Sofia on 22 May 2001) by using numerical model analysis fields. On the large scale, the circulation pattern was associated with a deformation middle-tropospheric field over the North Atlantic, Western Europe and Mediterranean. A zone of convergence in temperature and mass fields was formed over the Balkans, where there was an interleaving of warm, moist Mediterranean air advected in association with a warm front and cold dry air coming from the northwest in the eastern flank of an upper-level ridge. This synoptic circulation pattern produced deep convection along the boundary between the polar and subtropical high-level frontal systems. It is shown that synoptic- and meso-scale elements of the development may be revealed or confirmed by radiosounding data as well as by satellite and radar imagery. Data from the upper-air sounding of Sofia at 1200 UTC (available up to 650 hPa level) and other proximity soundings were processed and analysed. The obtained results show very high values of atmospheric instability indices (the energy of instability Ei=3785 J/kg, TT=59 °C, Z(ULC)=12.6 km). The updraft was up to 21.9 m/s and the difference of the wind velocity between 300- and 700-hPa levels was up to 12 m/s. Cloud water content reached up to 12.9 g/kg.

  20. Generation of Wheat Transcription Factor FOX Rice Lines and Systematic Screening for Salt and Osmotic Stress Tolerance.

    PubMed

    Wu, Jinxia; Zhang, Zhiguo; Zhang, Qian; Liu, Yayun; Zhu, Butuo; Cao, Jian; Li, Zhanpeng; Han, Longzhi; Jia, Jizeng; Zhao, Guangyao; Sun, Xuehui

    2015-01-01

    Transcription factors (TFs) play important roles in plant growth, development, and responses to environmental stress. In this study, we collected 1,455 full-length (FL) cDNAs of TFs, representing 45 families, from wheat and its relatives Triticum urartu, Aegilops speltoides, Aegilops tauschii, Triticum carthlicum, and Triticum aestivum. More than 15,000 T0 TF FOX (Full-length cDNA Over-eXpressing) rice lines were generated; of these, 10,496 lines set seeds. About 14.88% of the T0 plants showed obvious phenotypic changes. T1 lines (5,232 lines) were screened for salt and osmotic stress tolerance using 150 mM NaCl and 20% (v/v) PEG-4000, respectively. Among them, five lines (591, 746, 1647, 1812, and J4065) showed enhanced salt stress tolerance, five lines (591, 746, 898, 1078, and 1647) showed enhanced osmotic stress tolerance, and three lines (591, 746, and 1647) showed both salt and osmotic stress tolerance. Further analysis of the T-DNA flanking sequences showed that line 746 over-expressed TaEREB1, line 898 over-expressed TabZIPD, and lines 1812 and J4065 over-expressed TaOBF1a and TaOBF1b, respectively. The enhanced salt and osmotic stress tolerance of lines 898 and 1812 was confirmed by retransformation of the respective genes. Our results demonstrate that a heterologous FOX system may be used as an alternative genetic resource for the systematic functional analysis of the wheat genome.

  1. Generation of tumour-necrosis-factor-alpha-specific affibody molecules capable of blocking receptor binding in vitro.

    PubMed

    Jonsson, Andreas; Wållberg, Helena; Herne, Nina; Ståhl, Stefan; Frejd, Fredrik Y

    2009-08-17

    Affibody molecules specific for human TNF-alpha (tumour necrosis factor-alpha) were selected by phage-display technology from a library based on the 58-residue Protein A-derived Z domain. TNF-alpha is a proinflammatory cytokine involved in several inflammatory diseases and, to this day, four TNF-alpha-blocking protein pharmaceuticals have been approved for clinical use. The phage selection generated 18 unique cysteine-free affibody sequences of which 12 were chosen, after sequence cluster analysis, for characterization as proteins. Biosensor binding studies of the 12 Escherichia coli-produced and IMAC (immobilized-metal-ion affinity chromatography)-purified affibody molecules revealed three variants that demonstrated the strongest binding to human TNF-alpha. These three affibody molecules were subjected to kinetic binding analysis and also tested for their binding to mouse, rat and pig TNF-alpha. For ZTNF-alpha:185, subnanomolar affinity (KD=0.1-0.5 nM) for human TNF-alpha was demonstrated, as well as significant binding to TNF-alpha from the other species. Furthermore, the binding site was found to overlap with the binding site for the TNF-alpha receptor, since this interaction could be efficiently blocked by the ZTNF-alpha:185 affibody. When investigating six dimeric affibody constructs with different linker lengths, and one trimeric construct, it was found that the inhibition of the TNF-alpha binding to its receptor could be further improved by using dimers with extended linkers and/or a trimeric affibody construct. The potential implication of the results for the future design of affibody-based reagents for the diagnosis of inflammation is discussed.

  2. New Role for Kruppel-like Factor 14 as a Transcriptional Activator Involved in the Generation of Signaling Lipids*

    PubMed Central

    de Assuncao, Thiago M.; Lomberk, Gwen; Cao, Sheng; Yaqoob, Usman; Mathison, Angela; Simonetto, Douglas A.; Huebert, Robert C.; Urrutia, Raul A.; Shah, Vijay H.

    2014-01-01

    Sphingosine kinase 1 (SK1) is an FGF-inducible gene responsible for generation of sphingosine-1-phosphate, a critical lipid signaling molecule implicated in diverse endothelial cell functions. In this study, we identified SK1 as a target of the canonical FGF2/FGF receptor 1 activation pathway in endothelial cells and sought to identify novel transcriptional pathways that mediate lipid signaling. Studies using the 1.9-kb SK1 promoter and deletion mutants revealed that basal and FGF2-stimulated promoter activity occurred through two GC-rich regions located within 633 bp of the transcription start site. Screening for GC-rich binding transcription factors that could activate this site demonstrated that KLF14, a gene implicated in obesity and the metabolic syndrome, binds to this region. Congruently, overexpression of KLF14 increased basal and FGF2-stimulated SK1 promoter activity by 3-fold, and this effect was abrogated after mutation of the GC-rich sites. In addition, KLF14 siRNA transfection decreased SK1 mRNA and protein levels by 3-fold. Congruently, SK1 mRNA and protein levels were decreased in livers from KLF14 knock-out mice. Combined, luciferase, gel shift, and chromatin immunoprecipitation assays showed that KLF14 couples to p300 to increase the levels of histone marks associated with transcriptional activation (H4K8ac and H3K14ac), while decreasing repressive marks (H3K9me3 and H3K27me3). Collectively, the results demonstrate a novel mechanism whereby SK1 lipid signaling is regulated by epigenetic modifications conferred by KLF14 and p300. Thus, this is the first description of the activity and mechanisms underlying the function of KLF14 as an activator protein and novel regulator of lipid signaling. PMID:24759103

  3. Comparison of PG-SGA, SGA and body-composition measurement in detecting malnutrition among newly diagnosed lung cancer patients in stage IIIB/IV and benign conditions.

    PubMed

    Li, Rong; Wu, Jing; Ma, Meili; Pei, Jun; Song, Yiyi; Zhang, Xueyan; Han, Baohui

    2011-09-01

    Assessment tools and body-composition measurements are useful in diagnosing malnutrition. Which one is better for lung disease patients is unclear. The objectives of the present study are: to assess relationships between different methods of nutritional measurements in lung diseases patients; to determine which one is better in diagnosing malnutrition for lung disease patients; and to determine whether lung cancer patients can be differentiated from benign lung disease patients using different measurements. A total of 96 newly diagnosed primary lung cancer patients in stage IIIB/IV and 52 benign lung disease patients nutritional status were assessed according to the SGA, the scored PG-SGA, and serum albumin, prealbumin, transferrin, hemoglobin, total lymphocyte count, body mass index (BMI), and weight. A total of 40% of lung cancer patients were severely malnourished, with men or elder having a higher rate of malnutrition. Significantly lower values of weight, BMI, total lymphocyte count, transferrin, prealbumin and serum albumin were found for them. Age, sex, weight, weight half year ago and prealbumin are in the regression equation to predict them. For benign lung disease patients, 21.2% were severely malnourished with significantly lower values of weight and transferrin. Age and prealbumin are in the equation to predict severely malnourished benign lung disease patients. The highest receiver operation characteristic area under the curve was found for the PG-SGA score, BMI and weight. PG-SGA global rating, age and iron-transferring protein are in the equation for predicting disease status. The SGA and PG-SGA are appropriate for identifying malnutrition in lung disease patients. Lung cancer patients can be differentiated from benign conditions by PG-SGA.

  4. Study design and rationale for ELPIS: A phase I/IIb randomized pilot study of allogeneic human mesenchymal stem cell injection in patients with hypoplastic left heart syndrome.

    PubMed

    Kaushal, Sunjay; Wehman, Brody; Pietris, Nicholas; Naughton, Casey; Bentzen, Soren M; Bigham, Grace; Mishra, Rachana; Sharma, Sudhish; Vricella, Luca; Everett, Allen D; Deatrick, Kristopher B; Huang, Sihong; Mehta, Helina; Ravekes, William A; Hibino, Naru; Difede, Darcy L; Khan, Aisha; Hare, Joshua M

    2017-10-01

    Despite advances in surgical technique and postoperative care, long-term survival of children born with hypoplastic left heart syndrome (HLHS) remains limited, with cardiac transplantation as the only alternative for patients with failing single ventricle circulations. Maintenance of systemic right ventricular function is crucial for long-term survival, and interventions that improve ventricular function and avoid or defer transplantation in patients with HLHS are urgently needed. We hypothesize that the young myocardium of the HLHS patient is responsive to the biological cues delivered by bone marrow-derived mesenchymal stem cells (MSCs) to improve and preserve right ventricle function. The ELPIS trial (Allogeneic Human MEsenchymal Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome: An Open Label Pilot Study) is a phase I/IIb trial designed to test whether MSC injection will be both safe and feasible by monitoring the first 10 HLHS patients for new major adverse cardiac events. If our toxicity stopping rule is not activated, we will proceed to the phase IIb component of our study where we will test our efficacy hypothesis that MSC injection improves cardiac function compared with surgery alone. Twenty patients will be enrolled in a randomized phase II trial with a uniform allocation to MSC injection versus standard surgical care (no injection). The 2 trial arms will be compared with respect to improvement of right ventricular function, tricuspid valve annulus size, and regurgitation determined by cardiac magnetic resonance and reduced mortality, morbidity, and need for transplantation. This study will establish the safety and feasibility of allogeneic mesenchymal stem cell injection in HLHS patients and provide important insights in the emerging field of stem cell-based therapy for congenital heart disease patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Dolutegravir/abacavir/lamivudine versus current ART in virally suppressed patients (STRIIVING): a 48-week, randomized, non-inferiority, open-label, Phase IIIb study.

    PubMed

    Trottier, Benoît; Lake, Jordan E; Logue, Ken; Brinson, Cynthia; Santiago, Lizette; Brennan, Clare; Koteff, Justin A; Wynne, Brian; Hopking, Judy; Granier, Catherine; Aboud, Michael

    2017-04-12

    Simplified dosing regimens are important for patients who face challenges in adhering to HIV-1 therapy. We investigated the safety and virological efficacy of switching to once-daily abacavir/dolutegravir/lamivudine (ABC/DTG/3TC). The STRIIVING study was a randomized, open-label, Phase IIIb study in adults with HIV-1 RNA <50 copies/ml on antiretroviral therapy (ART) at enrolment (ClinicalTrials.gov identifier, NCT02105987). Subjects were randomly assigned to switch to ABC/DTG/3TC once daily for 48 weeks (early-switch group) or continue current ART for 24 weeks and then switch to ABC/DTG/3TC (late-switch group). The primary end point was the proportion of subjects with HIV-1 RNA <50 copies/ml at week 24. Of 553 subjects enrolled, 275 were randomly assigned to switch immediately to ABC/DTG/3TC and 278 continued on current ART. At week 24, 85% and 88% of subjects who switched to ABC/DTG/3TC or remained on current ART, respectively, were virologically suppressed, indicating that ABC/DTG/3TC was non-inferior (difference in proportion, -3.4%; 95% CI -9.1, 2.4). At week 48, 83% and 92% were virologically suppressed in the early- and late-switch groups, respectively. Adverse events were reported more frequently with ABC/DTG/3TC (66%) than with current ART (47%) by week 24, and in the late-switch group, 60% of subjects reported adverse events post-switch. Pharmacokinetic data supported immediate switch. HIV Treatment Satisfaction Questionnaire scores improved in participants switching to ABC/DTG/3TC versus current ART. Data demonstrating non-inferiority of switching to ABC/DTG/3TC versus continuing current ART support ABC/DTG/3TC as an option when considering switch regimens in HIV-1-infected adults with stable viral suppression.

  6. A phase II study of sorafenib in patients with platinum-pretreated, advanced (Stage IIIb or IV) non-small cell lung cancer with a KRAS mutation.

    PubMed

    Dingemans, Anne-Marie C; Mellema, Wouter W; Groen, Harry J M; van Wijk, Atie; Burgers, Sjaak A; Kunst, Peter W A; Thunnissen, Erik; Heideman, Danielle A M; Smit, Egbert F

    2013-02-01

    Sorafenib inhibits the Ras/Raf pathway, which is overactive in cancer patients with a KRAS mutation. We hypothesized that patients with non-small cell lung cancer (NSCLC) with KRAS mutation will benefit from treatment with sorafenib. In this phase II study, patients with KRAS-mutated, stage IIIb or IV NSCLC that progressed after at least one platinum-containing regimen were treated with sorafenib. Treatment consisted of sorafenib 400 mg twice daily until disease progression or unacceptable toxicity. Pretreatment serum from each patient was obtained to predict outcome using a proteomic assay (VeriStrat). Primary endpoint was disease control rate (DCR) at 6 weeks. Fifty-nine patients were entered between May 2010 and February 2011. Fifty-seven patients started sorafenib. Mean age was 58.5 (SD = ±8.1) years, 16 male/41 female, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2 24/30/3. At 6 weeks, 5 partial response, 25 stable disease, and 27 progressive disease were observed; DCR was 52.6%. Median duration of treatment was 9 weeks. The median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 5.3 months. Patients with a prediction of good prognosis according to VeriStrat serum proteomics assay showed a significantly superior PFS [HR, 1.4; 95% confidence interval (CI), 1.0-1.9] but not OS (HR, 1.3; 95% CI, 0.9-1.7). Sorafenib-related grade III/IV toxicity was reported in 10 patients (17.5%); all but one patient experienced grade III skin toxicity (14.0%) or grade III gastrointestinal toxicity (8.8%). Treatment with sorafenib has relevant clinical activity in patients with NSCLC harboring KRAS mutations. Further randomized study with this agent is warranted as single-agent or combination therapy.

  7. Mid-Infrared (MIR) and Near-Infrared (NIR) Detection of Rhizoctonia solani AG 2-2 IIIB on Barley-Based Artificial Inoculum.

    PubMed

    Webb, Kimberly M; Calderón, Francisco J

    2015-10-01

    The amount of Rhizoctonia solani in the soil and how much must be present to cause disease in sugar beet (Beta vulgaris L.) is relatively unknown. This is mostly because of the usually low inoculum densities found naturally in soil and the low sensitivity of traditional serial dilution assays. We investigated the usefulness of Fourier transform mid-infrared (MIR) and near-infrared (NIR) spectroscopic properties in identifying the artificial colonization of barley grains with R. solani AG 2-2 IIIB and in detecting R. solani populations in plant tissues and inoculants. The objectives of this study were to compare the ability of traditional plating assays to NIR and MIR spectroscopies to identify R. solani in different-size fractions of colonized ground barley (used as an artificial inoculum) and to differentiate colonized from non-inoculated barley. We found that NIR and MIR spectroscopies were sensitive in resolving different barley particle sizes, with particles that were <0.25 and 0.25-0.5 mm having different spectral properties than coarser particles. Moreover, we found that barley colonized with R. solani had different MIR spectral properties than the non-inoculated samples for the larger fractions (0.5-1.0, 1.0-2.0, and >2.0 mm) of the ground barley. This colonization was confirmed using traditional plating assays. Comparisons with the spectra from pure fungal cultures and non-inoculated barley suggest that the MIR spectrum of colonized barley is different because of the consumption of C substrates by the fungus rather than because of the presence of fungal bands in the spectra of the colonized samples. We found that MIR was better than NIR spectroscopy in differentiating the colonized from the control samples.

  8. Our experiences with erlotinib in second and third line treatment patients with advanced stage IIIB/ IV non-small cell lung cancer.

    PubMed

    Mehić, Bakir; Stanetić, Mirko; Tinjić, Ljuljeta; Smoljanović, Vlatka

    2008-11-01

    HeadHER1/EGFR is known to play a pivotal role in tumorigenesis and is overexpressed in up to 80% of NSCLCs. The study of an Expanded Access Clinical Program of Erlotinib in NSCLC is a phase IV open-label, non-randomized, multicenter trial in patients with advanced (inoperable stage IIIb/IV) NSCLC who were eligible for treatment with erlotinib but had no access to trial participation. Patients for the study from Bosnia and Herzegovina (B&H) were selected from two Clinical centres (Sarajevo and Banja Luka). The aim of study was to evaluated efficacy and tolerability of erlotinib monotherapy in this setting. All patients who received at least one dose of erlotinib and data were entered in the database as of the CRF cut-off date of 14th May 2008 were included in analysis of data (n = 19). This population is defined as the Intent to Treat (ITT) population and includes all patients who had at least one dose of erlotinib regardless of whether major protocol violations were incurred. The findings are consistent with the results of the randomized, placebo-controlled BR.21 study. Indicating that erlotinib is an effective option for patients with advanced NSCLC who are unsuitable for, or who have previously failed standard chemotherapy. In B&H group of patients DCR was almost 84%, and PFS was approximately 24,7 weeks (compared with 44% and 9,7 weeks for erlotinib reported in phase III). Almost three quarter of the patients received erlotinib as their second line of therapy. Overall, erlotinib was well tolerated; there were no patients who withdrew due to a treatment-related AE (mainly rash) and there were few dose reductions. 24% of patients experienced an SAE (most commonly gastrointestinal (GI) disorders).

  9. Application of spatial and non-spatial data analysis in determination of the factors that impact municipal solid waste generation rates in Turkey

    SciTech Connect

    Keser, Saniye; Duzgun, Sebnem; Aksoy, Aysegul

    2012-03-15

    Highlights: Black-Right-Pointing-Pointer Spatial autocorrelation exists in municipal solid waste generation rates for different provinces in Turkey. Black-Right-Pointing-Pointer Traditional non-spatial regression models may not provide sufficient information for better solid waste management. Black-Right-Pointing-Pointer Unemployment rate is a global variable that significantly impacts the waste generation rates in Turkey. Black-Right-Pointing-Pointer Significances of global parameters may diminish at local scale for some provinces. Black-Right-Pointing-Pointer GWR model can be used to create clusters of cities for solid waste management. - Abstract: In studies focusing on the factors that impact solid waste generation habits and rates, the potential spatial dependency in solid waste generation data is not considered in relating the waste generation rates to its determinants. In this study, spatial dependency is taken into account in determination of the significant socio-economic and climatic factors that may be of importance for the municipal solid waste (MSW) generation rates in different provinces of Turkey. Simultaneous spatial autoregression (SAR) and geographically weighted regression (GWR) models are used for the spatial data analyses. Similar to ordinary least squares regression (OLSR), regression coefficients are global in SAR model. In other words, the effect of a given independent variable on a dependent variable is valid for the whole country. Unlike OLSR or SAR, GWR reveals the local impact of a given factor (or independent variable) on the waste generation rates of different provinces. Results show that provinces within closer neighborhoods have similar MSW generation rates. On the other hand, this spatial autocorrelation is not very high for the exploratory variables considered in the study. OLSR and SAR models have similar regression coefficients. GWR is useful to indicate the local determinants of MSW generation rates. GWR model can be utilized to

  10. In vitro effects of recombinant activated factor VII on thrombin generation and coagulation following inhibition of platelet procoagulant activity by prasugrel.

    PubMed

    Mazzeffi, Michael; Szlam, Fania; Jakubowski, Joseph A; Tanaka, Kenichi A; Sugidachi, Atsuhiro; Levy, Jerrold H

    2013-07-01

    Prasugrel is a thienopyridyl P2Y12 antagonist with potent antiplatelet effects. At present, little is known about its effects on thrombin generation or what strategies may emergently reverse its anticoagulant effects. In the current study we evaluated whether recombinant activated factor VII may reverse prasugrel induced effects and increase thrombin generation in an in vitro model. The effect of prasugrel active metabolite, PAM (R-138727), was evaluated on platelet aggregation, thrombin generation, and rotational thromboelastometry parameters using blood from 20 healthy volunteers. Additionally, we evaluated the effects of adenosine diphosphate (ADP) and recombinant activated factor VII on restoring these parameters towards baseline values. PAM reduced maximum platelet aggregation and led to platelet disaggregation. It also decreased peak thrombin, increased lag time, and increased time to peak thrombin. Treatment with recombinant activated factor VII restored all three parameters of thrombin generation towards baseline. ADP decreased lag time and time to peak thrombin, but had no effect on peak thrombin. When recombinant activated factor VII and ADP were combined they had a greater effect on thrombin parameters than either drug alone. PAM also increased thromboelastometric clotting time and clot formation time, but had no effect on maximum clot firmness. Treatment with either recombinant activated factor VII or ADP restored these values towards baseline. Recombinant activated factor VII restores thrombin generation in the presence of PAM. In patients taking prasugrel with life-threatening refractory bleeding it has the potential to be a useful therapeutic approach. Additional clinical studies are needed to validate our findings. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Genetic polymorphism of Fcγ-receptors IIa, IIIa and IIIb in South Indian patients with generalized aggressive periodontitis.

    PubMed

    Hans, Veenu Madaan; Mehta, Dhoom Singh

    2011-12-01

    Recent evidence suggests that polymorphisms in Fcγ receptors are associated with different forms of periodontitis. However, the FcγR genotypes and their allele frequency differ among subjects from different ethnic backgrounds. The aim of the present study was to determine whether specific FcγRIIa, FcγRIIIa, and FcγRIIIb alleles and/or genotypes are associated with susceptibility to generalized aggressive periodontitits (GAgP) in a South Indian population. Buccal scrapings were obtained from 60 subjects with GAgP and 60 periodontally healthy individuals, and DNA was extracted from each of the samples. FcγRIIa and FcγRIIIa genotyping was performed by polymerase chain reaction (PCR) amplification of DNA with allele-specific primers followed by allele-specific restriction digestion of the products, whereas FcγRIIIb genotyping was done by allele-specific PCR. There was no significant difference in the distribution of the FcγRIIa H/R genotype between GAgP patients and healthy subjects, although significant over-representation of the R allele was noted in GAgP patients. With regard to FcγRIIIa F/V genetic polymorphism, the homozygous V/V genotype and V allele were significantly over-represented in the GAgP group, whereas the F/F genotype and F allele were over-represented in the controls. Furthermore, there was significant over-representation of the FcγRIIIb-NA2 allele and NA2/NA2 genotype in GAgP patients, and of the NA1/NA1 genotype and NA1 allele in the controls. These data suggest that the FcγRIIIa V/V genotype and/or V allele, as well as the FcγRIIIb NA2/NA2 and/or NA2 allele, along with the FcγRIIa- R allele, may be risk factors for GAgP in the population of South India.

  12. Thrombin generation induced by tissue factor plus ADP in human platelet rich plasma: A potential new measurement to assess the effect of the concomitant use of an oral factor Xa inhibitor edoxaban and P2Y12 receptor antagonists.

    PubMed

    Honda, Yuko; Morishima, Yoshiyuki

    2015-05-01

    Patients with atrial fibrillation undergoing percutaneous coronary intervention may require combination therapy with anticoagulants and antiplatelet agents. The objectives of this study were to establish an assay which can evaluate the effects of both anticoagulants and P2Y12 receptor antagonists and determine the effects of edoxaban, a direct factor Xa inhibitor, and P2Y12 receptor antagonists (clopidogrel and ticagrelor) alone and when combined. Human platelet-rich plasma (PRP) from healthy subjects was stimulated with adenosine diphosphate (ADP) plus tissue factor. Thrombin generation was measured by means of calibrated automated thrombography. Combination of 10μM ADP and low concentration (0.25 pM) tissue factor induced reproducible thrombin generation in human PRP. Edoxaban (40 and 80ng/mL), active metabolite of clopidogrel (AM-clopidogrel, 10 and 20μg/mL), and ticagrelor (3μg/mL) alone inhibited ADP plus tissue factor-induced thrombin generation. Edoxaban suppressed all 5 parameters (lag time, peak, time to peak, endogenous thrombin potential, and maximum rate), whereas AM-clopidogrel and ticagrelor inhibited 4 and 3 parameters, respectively. Concomitant treatment with edoxaban and AM-clopidogrel or ticagrelor produced an additive inhibition of thrombin generation compared to the single treatments. The thrombin generation assay induced by ADP plus tissue factor can detect the activities of both edoxaban and P2Y12 receptor antagonists. Combination of edoxaban and a P2Y12 receptor antagonist shows additive inhibition. These results suggest that ADP plus tissue factor-induced thrombin generation may be a useful measurement to assess the combination effects of anticoagulants and P2Y12 receptor antagonists in a single assay. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Factors influencing storm-generated suspended-sediment concentrations and loads in four basins of contrasting land use, humid-tropical Puerto Rico

    Treesearch

    A. C. Gellis; NO-VALUE

    2013-01-01

    The significant characteristics controlling the variability in storm-generated suspended-sediment loads and concentrations were analyzed for four basins of differing land use (forest, pasture, cropland, and urbanizing) in humid-tropical Puerto Rico. Statistical analysis involved stepwise regression on factor scores. The explanatory variables were attributes of flow,...

  14. Factor Analysis of the ESL/EFL Strategy Inventory for Language Learning: Generation 1.5 Korean Immigrant College Students' Language Learning Strategies

    ERIC Educational Resources Information Center

    Heo, Misook; Stoffa, Rosa; Kush, Joseph C.

    2012-01-01

    This study explores factors related to the language learning strategies of second language learners, specifically Generation 1.5 Korean immigrant students--the seventh-largest and one of the fastest growing foreign-born groups in the USA. Participants in this study were members of the Korean communities located in Pittsburgh and Philadelphia who…

  15. Factor Analysis of the ESL/EFL Strategy Inventory for Language Learning: Generation 1.5 Korean Immigrant College Students' Language Learning Strategies

    ERIC Educational Resources Information Center

    Heo, Misook; Stoffa, Rosa; Kush, Joseph C.

    2012-01-01

    This study explores factors related to the language learning strategies of second language learners, specifically Generation 1.5 Korean immigrant students--the seventh-largest and one of the fastest growing foreign-born groups in the USA. Participants in this study were members of the Korean communities located in Pittsburgh and Philadelphia who…

  16. Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non-small cell lung cancer.

    PubMed

    Tan, Chee-Seng; Cho, Byoung-Chul; Soo, Ross A

    2016-03-01

    Since the discovery of sensitizing EGFR mutations as a predictive marker of sensitivity to EGFR tyrosine kinase inhibitors (TKIs), the field of targeted therapy in non-small cell lung cancer (NSCLC) has been revolutionized. Patients harbouring these sensitizing mutations treated with EGFR TKI have derived significant clinical outcome when compared with standard platinum based chemotherapy doublets. However disease progression invariably occurs at a median of about 9-13 months from initiation treatment, if acquired resistance commonly due to the development of EGFR T790M mutation. A novel class of "third generation" EGFR TKIs have been developed that is sensitising and T790M mutant-specific whilst sparing WT EGFR, representing a significant breakthrough in the treatment in NSCLC patients with acquired resistance harboring these genotypes. Early phase clinical data suggest the third generation EGFR TKIs such as osimertinib, rociletinib, and HM61713 are highly efficacious and well tolerated. Another promising class of EGFR TKI such as AZD3759 has been designed to penetrate blood brain barrier to treat brain metastases and leptomeningeal disease and has showed promising responses in patients with brain metastases. Acquired resistance to third generation EGFR TKIs has been reported including EGFR C797S. Given its non-invasive nature, plasma ctDNA is being explored as a possible approach to detect T790M mutation and to also inform on novel molecular mechansims of tertiary resistance to third generation EGFR TKIs. An understanding of the mechanisms of acquired resistance to the third-generation EGFR TKIs will greatly aid in the development of the next generation of EGFR TKIs.

  17. Prediction of household and commercial BMW generation according to socio-economic and other factors for the Dublin region.

    PubMed

    Purcell, M; Magette, W L

    2009-04-01

    Both planning and design of integrated municipal solid waste management systems require accurate prediction of waste generation. This research predicted the quantity and distribution of biodegradable municipal waste (BMW) generation within a diverse 'landscape' of residential areas, as well as from a variety of commercial establishments (restaurants, hotels, hospitals, etc.) in the Dublin (Ireland) region. Socio-economic variables, housing types, and the sizes and main activities of commercial establishments were hypothesized as the key determinants contributing to the spatial variability of BMW generation. A geographical information system (GIS) 'model' of BMW generation was created using ArcMap, a component of ArcGIS 9. Statistical data including socio-economic status and household size were mapped on an electoral district basis. Historical research and data from scientific literature were used to assign BMW generation rates to residential and commercial establishments. These predictions were combined to give overall BMW estimates for the region, which can aid waste planning and policy decisions. This technique will also aid the design of future waste management strategies, leading to policy and practice alterations as a function of demographic changes and development. The household prediction technique gave a more accurate overall estimate of household waste generation than did the social class technique. Both techniques produced estimates that differed from the reported local authority data; however, given that local authority reported figures for the region are below the national average, with some of the waste generated from apartment complexes being reported as commercial waste, predictions arising from this research are believed to be closer to actual waste generation than a comparison to reported data would suggest. By changing the input data, this estimation tool can be adapted for use in other locations. Although focusing on waste in the Dublin region

  18. Human factors engineering control-room-design review/audit report: Palo Verde Nuclear Generating Station, Arizona Public Service Company

    SciTech Connect

    Savage, J.W.; Lappa, D.A.

    1981-10-09

    A human factors engineering design review of the Palo Verde control room simulator was performed at the site on September 15 through September 17, 1981. Observed human factors design discrepancies were given priority ratings. This report summarizes the team's observations of the control room design and layout and of the control room operators' interface with the control room environment. A list of the human factors strengths observed in the Palo Verde control room simulator is given.

  19. Wind Generators

    NASA Technical Reports Server (NTRS)

    1989-01-01

    When Enerpro, Inc. president, Frank J. Bourbeau, attempted to file a patent on a system for synchronizing a wind generator to the electric utility grid, he discovered Marshall Space Flight Center's Frank Nola's power factor controller. Bourbeau advanced the technology and received a NASA license and a patent for his Auto Synchronous Controller (ASC). The ASC reduces generator "inrush current," which occurs when large generators are abruptly brought on line. It controls voltage so the generator is smoothly connected to the utility grid when it reaches its synchronous speed, protecting the components from inrush current damage. Generator efficiency is also increased in light winds by applying lower than rated voltage. Wind energy is utilized to drive turbines to generate electricity for utility companies.

  20. Shared Genetic Aetiology between Cognitive Ability and Cardiovascular Disease Risk Factors: Generation Scotland's Scottish Family Health Study

    ERIC Educational Resources Information Center

    Luciano, Michelle; Batty, G. David; McGilchrist, Mark; Linksted, Pamela; Fitzpatrick, Bridie; Jackson, Cathy; Pattie, Alison; Dominiczak, Anna F.; Morris, Andrew D.; Smith, Blair H.; Porteous, David; Deary, Ian J.

    2010-01-01

    People with higher general cognitive ability in early life have more favourable levels of cardiovascular disease (CVD) risk factors in adulthood and CVD itself. The mechanism of these associations is not known. Here we examine whether general cognitive ability and CVD risk factors share genetic and/or environmental aetiology. In this large,…

  1. Shared Genetic Aetiology between Cognitive Ability and Cardiovascular Disease Risk Factors: Generation Scotland's Scottish Family Health Study

    ERIC Educational Resources Information Center

    Luciano, Michelle; Batty, G. David; McGilchrist, Mark; Linksted, Pamela; Fitzpatrick, Bridie; Jackson, Cathy; Pattie, Alison; Dominiczak, Anna F.; Morris, Andrew D.; Smith, Blair H.; Porteous, David; Deary, Ian J.

    2010-01-01

    People with higher general cognitive ability in early life have more favourable levels of cardiovascular disease (CVD) risk factors in adulthood and CVD itself. The mechanism of these associations is not known. Here we examine whether general cognitive ability and CVD risk factors share genetic and/or environmental aetiology. In this large,…

  2. Consolidative Involved-Node Proton Therapy for Stage IA-IIIB Mediastinal Hodgkin Lymphoma: Preliminary Dosimetric Outcomes From a Phase II Study

    SciTech Connect

    Hoppe, Bradford S.; Flampouri, Stella; Su Zhong; Morris, Christopher G.; Latif, Naeem

    2012-05-01

    Purpose: To compare the dose reduction to organs at risk (OARs) with proton therapy (PT) versus three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) in patients with mediastinal Hodgkin lymphoma (HL) enrolled on a Phase II study of involved-node radiotherapy (INRT). Methods and Materials: Between June 2009 and October 2010, 10 patients were enrolled on a University of Florida institutional review board-approved protocol for de novo 'classical' Stage IA-IIIB HL with mediastinal (bulky or nonbulky) involvement after chemotherapy. INRT was planned per European Organization for Research and Treatment of Cancer guidelines. Three separate optimized plans were developed for each patient: 3D-CRT, IMRT, and PT. The primary end point was a 50% reduction in the body V4 with PT compared with 3D-CRT or IMRT. Results: The median relative reduction with PT in the primary end point, body V4, was 51% compared with 3D-CRT (p = 0.0098) and 59% compared with IMRT (p = 0.0020), thus all patients were offered treatment with PT. PT provided the lowest mean dose to the heart, lungs, and breasts for all 10 patients compared with either 3D-CRT or IMRT. The median difference in the OAR mean dose reduction with PT compared with 3D-CRT were 10.4 Gy/CGE for heart; 5.5 Gy/CGE for lung; 0.9 Gy/CGE for breast; 8.3 Gy/CGE for esophagus; and 4.1 Gy/CGE for thyroid. The median differences for mean OAR dose reduction for PT compared with IMRT were 4.3 Gy/CGE for heart, 3.1 Gy/CGE for lung, 1.4 Gy/CGE for breast, 2.8 Gy/CGE for esophagus, and 2.7 Gy/CGE for thyroid. Conclusions: All 10 patients benefitted from dose reductions to OARs with PT compared with either 3D-CRT or IMRT. It is anticipated that these reductions in dose to OAR will translate into lower rates of late complications, but long-term follow-up on this Phase II INRT study is needed.

  3. Fc gamma receptor IIIb polymorphism and systemic lupus erythematosus: association with disease susceptibility and identification of a novel FCGR3B*01 variant.

    PubMed

    Santos, V C; Grecco, M; Pereira, K M C; Terzian, C C N; Andrade, L E C; Silva, N P

    2016-10-01

    The objective of this study was to evaluate the association between Fc gamma receptor IIIb polymorphism and susceptibility to systemic lupus erythematosus and clinical traits of the disease. Genomic DNA was obtained from 303 consecutive systemic lupus erythematosus patients and 300 healthy blood donors from the southeastern region of Brazil. The polymorphic region of the FCGR3B gene was sequenced and the alleles FCGR3B*01, FCGR3B*02 and FCGR3B*03 were analyzed. The FCGR3B*01 allele was more frequent in systemic lupus erythematosus patients (43.1%) while the FCGR3B*02 allele prevailed among controls (63.7%) (P = 0.001). The FCGR3B*03 allele was found equally in both groups. The FCGR3B*01/*01 (20.7%) and FCGR3B*01/*02 (41.1%) genotypes were more frequent among systemic lupus erythematosus patients (P = 0.028 and P = 0.012, respectively) while the FCGR3B*02/*02 genotype was more frequent in controls (45.5%) (P < 0.001). One variant of the FCGR3B*01 allele previously described in Germany was found in only one control. A new variant of the FCGR3B*01 allele with two substitutions (A227G/G277A) was found in one control. Three variants of the FCGR3B*02 allele previously described in African-Americans, Brazilians, Chinese and Japanese were found in ten 10 patients and two controls. In addition, several single nucleotide polymorphisms at non-polymorphic positions were identified in both patients and controls. Susceptibility to systemic lupus erythematosus was associated with the FCGR3B*01 allele, as well as with the FCGR3B*01/*01 and FCGR3B*01/*02 genotypes. No association was found between FCGR3B genotypes and clinical manifestations, disease severity or the presence of autoantibodies. © The Author(s) 2016.

  4. Ranibizumab 0.5 mg for Diabetic Macular Edema with Bimonthly Monitoring after a Phase of Initial Treatment: 18-Month, Multicenter, Phase IIIB RELIGHT Study.

    PubMed

    Pearce, Ian; Banerjee, Sanjiv; Burton, Ben J L; Chakravarthy, Usha; Downey, Louise; Gale, Richard P; Gibson, Jonathan; Pagliarini, Sergio; Patel, Jignesh; Sivaprasad, Sobha; Andrews, Chris; Brittain, Christopher; Warburton, James

    2015-09-01

    To evaluate ranibizumab 0.5 mg using bimonthly monitoring and individualized re-treatment after monthly follow-up for 6 months in patients with visual impairment due to diabetic macular edema (DME). A phase IIIb, 18-month, prospective, open-label, multicenter, single-arm study in the United Kingdom. Participants (N = 109) with visual impairment due to DME. Participants received 3 initial monthly ranibizumab 0.5 mg injections (day 0 to month 2), followed by individualized best-corrected visual acuity (BCVA) and optical coherence tomography-guided re-treatment with monthly (months 3-5) and subsequent bimonthly follow-up (months 6-18). Laser was allowed after month 6. Mean change in BCVA from baseline to month 12 (primary end point), mean change in BCVA and central retinal thickness (CRT) from baseline to month 18, gain of ≥10 and ≥15 letters, treatment exposure, and incidence of adverse events over 18 months. Of 109 participants, 100 (91.7%) and 99 (90.8%) completed the 12 and 18 months of the study, respectively. The mean age was 63.7 years, the mean duration of DME was 40 months, and 77.1% of the participants had received prior laser treatment (study eye). At baseline, mean BCVA was 62.9 letters, 20% of patients had a baseline BCVA of >73 letters, and mean baseline CRT was 418.1 μm, with 32% of patients having a baseline CRT <300 μm. The mean change in BCVA from baseline to month 6 was +6.6 letters (95% confidence interval [CI], 4.9-8.3), and after institution of bimonthly treatment the mean change in BCVA at month 12 was +4.8 letters (95% CI, 2.9-6.7; P < 0.001) and +6.5 letters (95% CI, 4.2-8.8) at month 18. The proportion of participants gaining ≥10 and ≥15 letters was 24.8% and 13.8% at month 12 and 34.9% and 19.3% at month 18, respectively. Participants received a mean of 6.8 and 8.5 injections over 12 and 18 months, respectively. No new ocular or nonocular safety findings were observed during the study. The BCVA gain achieved in the initial 6-month

  5. Benefits of switching from latanoprost to preservative-free tafluprost eye drops: a meta-analysis of two Phase IIIb clinical trials

    PubMed Central

    Uusitalo, Hannu; Egorov, Evgeniy; Kaarniranta, Kai; Astakhov, Yuri; Ropo, Auli

    2016-01-01

    Introduction Glaucoma patients frequently exhibit ocular surface side effects during treatment with prostaglandin eye drops. The present work investigated whether glaucoma patients suffering from signs and symptoms of ocular surface disease while using preserved latanoprost eye drops benefited from switching to preservative-free tafluprost eye drops. Patients and methods The analysis was based on 339 glaucoma patients enrolled in two Phase IIIb trials. The patients were required to have two symptoms, or one sign and one symptom of ocular surface disease at baseline, and at least 6 months preceding treatment with latanoprost eye drops preserved with benzalkonium chloride. All eligible patients were switched from latanoprost to preservative-free tafluprost for a total of 12 weeks. Ocular symptoms and ocular signs were evaluated at baseline and at 2 weeks, 6 weeks, and 12 weeks after commencing treatment with tafluprost. Intraocular pressure (IOP), drop discomfort, and treatment preference were evaluated to investigate the clinical efficacy and patient-related outcomes. Results After 12 weeks of treatment with preservative-free tafluprost, the incidences of irritation/burning/stinging, foreign body sensation, tearing, itching, and dry eye sensation had diminished to one-third of those reported for preserved latanoprost at baseline. The incidences of blepharitis and corneal/conjunctival fluorescein staining had in turn decreased to one-half of those reported for preserved latanoprost. Severity of conjunctival hyperemia was halved during treatment with preservative-free tafluprost, and there was significant improvement in tear break-up time and tear production. A further reduction in IOP (~1 mmHg) was seen with preservative-free tafluprost compared with preserved latanoprost. Drop discomfort was alleviated during preservative-free tafluprost treatment, and an outstanding majority of patients (72%) preferred preservative-free tafluprost over preserved latanoprost

  6. Differences in problem behaviour among ethnic minority and majority preschoolers in the Netherlands and the role of family functioning and parenting factors as mediators: the Generation R Study.

    PubMed

    Flink, Ilse J E; Jansen, Pauline W; Beirens, Tinneke M J; Tiemeier, Henning; van IJzendoorn, Marinus H; Jaddoe, Vincent W V; Hofman, Albert; Raat, Hein

    2012-12-19

    Studies have shown that, compared to native counterparts, preschoolers from ethnic minorities are at an increased risk of problem behaviour. Socio-economic factors only partly explain this increased risk. This study aimed to further unravel the differences in problem behaviour among ethnic minority and native preschoolers by examining the mediating role of family functioning and parenting factors. We included 4,282 preschoolers participating in the Generation R Study, an ethnically-diverse cohort study with inclusion in early pregnancy. At child age 3 years, parents completed the Child Behavior Checklist (CBCL/1,5-5); information on demographics, socio-economic status and measures of family functioning (maternal psychopathology; general family functioning) and parenting (parenting stress; harsh parenting) were retrieved from questionnaires. CBCL Total Problems scores in each ethnic subgroup were compared with scores in the Dutch reference population. Mediation was evaluated using multivariate regression models. After adjustment for confounders, preschoolers from ethnic minorities were more likely to present problem behaviour than the Dutch subgroup (e.g. CBCL Total Problems Turkish subgroup (OR 7.0 (95% CI 4.9; 10.1)). When considering generational status, children of first generation immigrants were worse off than the second generation (P<0.01). Adjustment for socio-economic factors mediated the association between the ethnic minority status and child problem behaviour (e.g. attenuation in OR by 54.4% (P<0.05) from OR 5.1 (95% CI 2.8; 9.4) to OR 2.9 (95% CI 1.5; 5.6) in Cape Verdean subgroup). However, associations remained significant in most ethnic subgroups. A final adjustment for family functioning and parenting factors further attenuated the association (e.g. attenuation in OR by 55.5% (P<0.05) from OR 2.2 (95% CI 1.3; 4.4) to OR 1.5 (95% CI 1.0; 2.4) in European other subgroup). This study showed that preschoolers from ethnic minorities and particularly

  7. Updated survival analysis in patients with stage IIIB or IV non-small-cell lung cancer receiving BLP25 liposome vaccine (L-BLP25): phase IIB randomized, multicenter, open-label trial.

    PubMed

    Butts, Charles; Maksymiuk, Andrew; Goss, Glenwood; Soulières, Denis; Marshall, Ernie; Cormier, Yvon; Ellis, Peter M; Price, Allan; Sawhney, Ravinder; Beier, Frank; Falk, Martin; Murray, Nevin

    2011-09-01

    To present an updated survival analysis of an open-label, parallel-group, phase IIB trial of BLP25 liposome vaccine (L-BLP25) in patients with stage IIIB or IV non-small-cell lung cancer (NSCLC). Patients were randomized to either L-BLP25 plus best supportive care (BSC) or BSC alone. Patients in the L-BLP25 arm received subcutaneous vaccinations of L-BLP25 930 μg weekly for 8 weeks, followed by maintenance vaccinations at 6-week intervals. Median survival time was 4.2 months longer in patients receiving L-BLP25 plus BSC (n = 88) than in those receiving BSC alone (n = 83; 17.2 months vs. 13.0 months, respectively; hazard ratio [HR] 0.745, 95% confidence interval [CI] 0.533-1.042). The 3-year survival rate was 31% in patients receiving L-BLP25 plus BSC and 17% in those receiving BSC (P = 0.035). In the stratified subset of patients with stage IIIB loco-regional (LR) disease, median survival time was 17.3 months longer in patients receiving L-BLP25 plus BSC (n = 35) than in those receiving BSC (n = 30; 30.6 months vs. 13.3 months, respectively; HR 0.548, 95% CI 0.301-0.999). In this subgroup, 3-year survival was 49% in patients receiving L-BLP25 plus BSC and 27% in those receiving BSC (P = 0.070). Confirming the initial results, further follow-up continues to show that survival time for patients with stage IIIB/IV NSCLC was longer with L-BLP25 plus BSC compared with BSC alone, with the greatest difference seen in patients with stage IIIB LR disease.

  8. Municipal solid waste generation in growing urban areas in Africa: current practices and relation to socioeconomic factors in Jimma, Ethiopia.

    PubMed

    Getahun, T; Mengistie, E; Haddis, A; Wasie, F; Alemayehu, E; Dadi, D; Van Gerven, T; Van der Bruggen, B

    2012-10-01

    As one of cities in the developing countries, a rapid population growth and industrial activities pose many environmental challenges for Jimma city, Ethiopia. One aspect of urban growth posing a threat on sustainable development is poor solid waste management, which results in environmental pollution. The purpose of this study is to evaluate the quantity, composition, sources of waste generated, their current disposal practices, and to recommend appropriate management technologies. The total waste generated daily in Jimma city was ca. 88,000 kg, and the average per capita generation rate was 0.55 ± 0.17 kg/capita/day. Eighty-seven percent of the waste was produced by households and 13% by institutions, and a negligible fraction (0.1%) was generated by street sweepings. During the rainy season, 40% more waste was generated than in the dry season because of the increased availability of agricultural food product. Further analysis showed that biodegradable organic waste constitutes 54% by weight with an average moisture content of 60% that falls within the required limits for composting. The nonbiodegradable components constitute 46% of which 30% of it was nonrecyclable material. Only 25% of the community uses municipal containers for disposal at the selected landfill site. Fifty-one percent of the households disposed their waste in individually chosen spots, whereas 22% burned their waste. Finally 2% of households use private waste collectors. The socioeconomic analysis showed that higher family income and educational status is associated more with private or municipal waste collection and less with the application of backyard or open dumping. These insights into generated waste and management practice in Jimma city allow making suggestions for improved collection, treatment, and disposal methods. A primary conclusion is that the biodegradable waste is a major fraction having suitable properties for recycling. As such an economic benefit can be obtained from

  9. A model for the unique role of factor Va A2 domain extension in the human ternary thrombin-generating complex.

    PubMed

    Shim, Joong-Youn; Lee, Chang Jun; Wu, Sangwook; Pedersen, Lee G

    2015-04-01

    An all-atom human ternary model for the prothrombinase-prothrombin complex, including metal ions and post-translationally modified residues, was constructed from existing X-ray crystal structures. The factor Xa-prothrombin interface was taken from an existing ternary model, which locates the active site of factor Xa in the vicinity of prothrombin cleavage positions. The three sulfotyrosine residues at the C-terminal sequence of factor Va A2 domain are accommodated by modelling rational interactions with positively charged patches on the surface of prothrombin. The entire model is then solvent-equilibrated with molecular dynamics. This ternary model for the thrombin-generating complex provides an estimate as to the role of the C-terminus of the factor Va A2 domain: to establish an interface between FXa and prothrombin and to stabilize the orientation of this interface. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Contributing Factors to Generation 1.5 Students' Successes on the Exit State Assessment for High School

    ERIC Educational Resources Information Center

    Vanderhoef, Deborah E.

    2012-01-01

    This phenomenological narrative study investigated the successes of eight Generation 1.5 high school seniors on the Exit state assessment in English language arts in Texas. These eight participants represented three difficult ethnic cultures, Hispanic, Pakistani and Turkish; within the Hispanic cultures the countries of Mexico and El Salvador were…

  11. Contributing Factors to Generation 1.5 Students' Successes on the Exit State Assessment for High School

    ERIC Educational Resources Information Center

    Vanderhoef, Deborah E.

    2012-01-01

    This phenomenological narrative study investigated the successes of eight Generation 1.5 high school seniors on the Exit state assessment in English language arts in Texas. These eight participants represented three difficult ethnic cultures, Hispanic, Pakistani and Turkish; within the Hispanic cultures the countries of Mexico and El Salvador were…

  12. Human-factors engineering control-room design review/audit report: Byron Generating Station, Commonwealth Edison Company

    SciTech Connect

    Savage, J.W.

    1983-03-10

    A human factors engineering design review/audit of the Byron Unit 1 control room was performed at the site on November 17 through November 19, 1981. This review was accomplished using the Unit 2 control room appropriately mocked-up to reflect design changes already committed to be incorporated in Unit 1. The report was prepared on the basis of the HFEB's audit of the applicant's Preliminary Design Assessment report and the human factors engineering design review performed at the site. This design review was carried out by a team from the Human Factors Engineering Branch, Division of Human Factors Safety. The review team was assisted by consultants from BioTechnology, Inc. (Falls Church, Virginia), and from Lawrence Livermore National Laboratory (University of California), Livermore, California.

  13. A Chimeric Subunit of Yeast Transcription Factor IIIC Forms a Subcomplex with τ95

    PubMed Central

    Manaud, Nathalie; Arrebola, Rosalía; Buffin-Meyer, Bénédicte; Lefebvre, Olivier; Voss, Hartmut; Riva, Michel; Conesa, Christine; Sentenac, André

    1998-01-01

    The multisubunit yeast transcription factor IIIC (TFIIIC) is a multifunctional protein required for promoter recognition, transcription factor IIIB recruitment, and chromatin antirepression. We report the isolation and characterization of TFC7, an essential gene encoding the 55-kDa polypeptide, τ55, present in affinity-purified TFIIIC. τ55 is a chimeric protein generated by an ancient chromosomal rearrangement. Its C-terminal half is essential for cell viability and sufficient to ensure TFIIIC function in DNA binding and transcription assays. The N-terminal half is nonessential and highly similar to a putative yeast protein encoded on another chromosome and to a cyanobacterial protein of unknown function. Partial deletions of the N-terminal domain impaired τ55 function at a high temperature or in media containing glycerol or ethanol, suggesting a link between PolIII transcription and metabolic pathways. Interestingly, τ55 was found, together with TFIIIC subunit τ95, in a protein complex which was distinct from TFIIIC and which may play a role in the regulation of PolIII transcription, possibly in relation to cell metabolism. PMID:9584160

  14. Technique for information retrieval using enhanced latent semantic analysis generating rank approximation matrix by factorizing the weighted morpheme-by-document matrix

    DOEpatents

    Chew, Peter A; Bader, Brett W

    2012-10-16

    A technique for information retrieval includes parsing a corpus to identify a number of wordform instances within each document of the corpus. A weighted morpheme-by-document matrix is generated based at least in part on the number of wordform instances within each document of the corpus and based at least in part on a weighting function. The weighted morpheme-by-document matrix separately enumerates instances of stems and affixes. Additionally or alternatively, a term-by-term alignment matrix may be generated based at least in part on the number of wordform instances within each document of the corpus. At least one lower rank approximation matrix is generated by factorizing the weighted morpheme-by-document matrix and/or the term-by-term alignment matrix.

  15. In Arabidopsis thaliana distinct alleles encoding mitochondrial RNA PROCESSING FACTOR 4 support the generation of additional 5' termini of ccmB transcripts.

    PubMed

    Stoll, Katrin; Jonietz, Christian; Schleicher, Sarah; des Francs-Small, Catherine Colas; Small, Ian; Binder, Stefan

    2017-04-01

    In plant mitochondria, the 5' ends of many transcripts are generated post-transcriptionally. We show that the pentatricopeptide repeat (PPR) protein RNA PROCESSING FACTOR 4 (RPF4) supports the generation of extra 5' ends of ccmB transcripts in Landsberg erecta (Ler) and a number of other Arabidopsis thaliana ecotypes. RPF4 was identified in Ler applying a forward genetic approach supported by complementation studies of ecotype Columbia (Col), which generates the Ler-type extra ccmB 5' termini only after the introduction of the RPF4 allele from Ler. Studies with chimeric RPF4 proteins composed of various parts of the RPF4 proteins from Ler and Col identified differences in the N-terminal and central PPR motifs that explain ecotype-specific variations in ccmB processing. These results fit well with binding site predictions in ccmB transcripts based on the known determinants of nucleotide base recognition by PPR motifs.

  16. In-Plume Emission Test Stand 2: Emission Factors for 10- to 100-kW U.S. Military Generators

    DTIC Science & Technology

    2009-12-01

    benzene and naphthalene) emissions during cold starts were 15 times those for a hot-stabilized 60-kW BUG . Reported here are fuel- based particulate and...dards, local communities near military bases must con- form to the National Ambient Air Quality Standards. Mil- itary diesel generators are widely used...in training. A portable in-plume system was used to measure fuel- based emission factors (EFs) for particulate matter (PM), carbon monoxide (CO

  17. Generation of iPS cells using defined factors linked via the self-cleaving 2A sequences in a single open reading frame

    PubMed Central

    Shao, Lijian; Feng, Wei; Sun, Yan; Bai, Hao; Liu, Jun; Currie, Caroline; Kim, Jaejung; Gama, Rafael; Wang, Zack; Qian, Zhijian; Liaw, Lucy; Wu, Wen-Shu

    2010-01-01

    Generation of induced pluripotent stem (iPS) cells from somatic cells has been achieved successfully by simultaneous viral transduction of defined reprogramming transcription factors (TFs). However, the process requires multiple viral vectors for gene delivery. As a result, generated iPS cells harbor numerous viral integration sites in their genomes. This can increase the probability of gene mutagenesis and genomic instability, and present significant barriers to both research and clinical application studies of iPS cells. In this paper, we present a simple lentivirus reprogramming system in which defined factors are fused in-frame into a single open reading frame (ORF) via self-cleaving 2A sequences. A GFP marker is placed downstream of the transgene to enable tracking of transgene expression. We demonstrate that this polycistronic expression system efficiently generates iPS cells. The generated iPS cells have normal karyotypes and are similar to mouse embryonic stem cells in morphology and gene expression. Moreover, they can differentiate into cell types of the three embryonic germ layers in both in vitro and in vivo assays. Remarkably, most of these iPS cells only harbor a single copy of viral vector. This system provides a valuable tool for generation of iPS cells, and our data suggest that the balance of expression of transduced reprogramming TFs in each cell is essential for the reprogramming process. More importantly, when delivered by non-integrating gene-delivery systems, this re-engineered single ORF will facilitate efficient generation of human iPS cells free of genetic modifications. PMID:19238173

  18. Initiating and potentiating role of platelets in tissue factor-induced thrombin generation in the presence of plasma: subject-dependent variation in thrombogram characteristics.

    PubMed

    Vanschoonbeek, K; Feijge, M A H; Van Kampen, R J W; Kenis, H; Hemker, H C; Giesen, P L A; Heemskerk, J W M

    2004-03-01

    The hemostatic activity of plasma is determined by platelet activation and coagulation, which processes are mutually stimulatory. We studied this interaction by measuring the cleavage of fluorescent thrombin substrate in platelet-rich plasma (PRP), using the calibrated thrombogram method. In freshly isolated human plasma, thrombin formation triggered by tissue factor was fully dependent on the presence of platelets. It was abolished by annexin A5, indicating dependence on phosphatidylserine (PS) exposure at activated platelets. Comparison of plasmas from various subjects showed considerable interindividual variation in total amount of thrombin generation, regardless of whether platelets or PS-containing phospholipids were present. Integrin alphaIIbbeta3 antagonists and ADP receptor blockage, but not aspirin, decreased the rate of thrombin generation (thrombin peak level) and extended the time of onset. Platelet inhibition with cAMP-elevating agents decreased the thrombin-forming rate, but surprisingly shortened the onset time. Stimulation of platelets with agonists of Gi/q-coupled receptors and, to a larger extent, with collagen or Ca2+-ionophore increased the rate of thrombin generation and shortened its onset. In PRP from donors with low and high generation, platelet inhibitors and activators were similarly effective. Taken together, these results indicate that, in tissue factor-triggered PRP, PS exposure on activated platelets regulates both onset and rate of thrombin generation. However, coagulant activity rather than platelet activation determines the total amount of thrombin formed, i.e. the endogenous thrombin potential. Thus, kinetics of thrombin generation in PRP are controlled by platelet inhibitors and agonists, but the process is restricted in amount by the subject-dependent variation in coagulation.

  19. Theoretical exploration of control factors for the high-order harmonic generation (HHG) spectrum in two-color field.

    PubMed

    Huang, Xinting; Yang, Dapeng; Yao, Li

    2014-09-15

    In this work, the laser-parameter effects on the high-order harmonic generation (HHG) spectrum and attosecond trains by mixing two-color laser field, a visible light field of 800 nm and a mid-infrared (mid-IR) laser pulses of 2400 nm, are theoretically demonstrated for the first time. Different schemes are applied to discuss the function of intensity, carrier-envelope phase (CEP) and pulse duration on the generation of an isolated attosecond pulse. As a consequence, an isolated 16as pulse is obtained by Fourier transforming an ultrabroad XUV continuum of 208 eV with the fundamental field of duration of 6 fs, 9×10(14)W/cm2 of intensity, the duration of 12 fs, the CEPs of the two driving pulses of -π and the relative strength ratio √R=0.2.

  20. Three-loop radiative-recoil corrections to hyperfine splitting generated by one-loop fermion factors

    SciTech Connect

    Eides, Michael I.; Grotch, Howard; Shelyuto, Valery A.

    2004-10-01

    We consider three-loop radiative-recoil corrections to hyperfine splitting in muonium generated by diagrams with one-loop radiative photon insertions both in the electron and muon lines. An analytic result for these nonlogarithmic corrections of order {alpha}(Z{sup 2}{alpha})(Z{alpha})(m/M)E{sub F} is obtained. This result constitutes a next step in the implementation of the program of reduction of the theoretical uncertainty of hyperfine splitting below 10 Hz.

  1. Immigrant Parents' Choice of a Bilingual versus Monolingual Kindergarten for Second-Generation Children: Motives, Attitudes, and Factors

    ERIC Educational Resources Information Center

    Schwartz, Mila; Moin, Victor; Leikin, Mark; Breitkopf, Anna

    2010-01-01

    This study investigated how immigrant parents describe and explain their family language policy concerning their child's preschool bilingual development, and also explored the factors linked to the parents' choice of bilingual or monolingual kindergarten for their child. The study design was based on a comparison of 2 groups of parents: those who…

  2. Human factors in the presentation of computer-generated information - Aspects of design and application in automated flight traffic

    NASA Technical Reports Server (NTRS)

    Roske-Hofstrand, Renate J.

    1990-01-01

    The man-machine interface and its influence on the characteristics of computer displays in automated air traffic is discussed. The graphical presentation of spatial relationships and the problems it poses for air traffic control, and the solution of such problems are addressed. Psychological factors involved in the man-machine interface are stressed.

  3. Immigrant Parents' Choice of a Bilingual versus Monolingual Kindergarten for Second-Generation Children: Motives, Attitudes, and Factors

    ERIC Educational Resources Information Center

    Schwartz, Mila; Moin, Victor; Leikin, Mark; Breitkopf, Anna

    2010-01-01

    This study investigated how immigrant parents describe and explain their family language policy concerning their child's preschool bilingual development, and also explored the factors linked to the parents' choice of bilingual or monolingual kindergarten for their child. The study design was based on a comparison of 2 groups of parents: those who…

  4. Human factors in the presentation of computer-generated information - Aspects of design and application in automated flight traffic

    NASA Technical Reports Server (NTRS)

    Roske-Hofstrand, Renate J.

    1990-01-01

    The man-machine interface and its influence on the characteristics of computer displays in automated air traffic is discussed. The graphical presentation of spatial relationships and the problems it poses for air traffic control, and the solution of such problems are addressed. Psychological factors involved in the man-machine interface are stressed.

  5. Activation of the endothelium by IL-1 alpha and glucocorticoids results in major increase of complement C3 and factor B production and generation of C3a.

    PubMed Central

    Coulpier, M; Andreev, S; Lemercier, C; Dauchel, H; Lees, O; Fontaine, M; Ripoche, J

    1995-01-01

    Constitutive secretion of complement C3 and factor B by the endothelial cell (EC) is lowered by therapeutic concentrations of glucocorticoids such as hydrocortisone or dexamethasone, whereas regulatory protein factor H production is increased by these hormones. In contrast, the proinflammatory cytokine IL-1 alpha has a stimulatory effect on C3 and factor B secretion by the endothelium and an inhibitory effect on factor H secretion. In this study, we examined the combined effect of IL-1 alpha and glucocorticoids on C3 and factor B expression by the endothelial cell. When dexamethasone or hydrocortisone were added to IL-1 alpha, significant potentialization of IL-1 alpha-induced stimulation of C3 and factor B production was observed, occurring at various concentrations of either stimuli. Dose-response experiments indicate that, in vitro, optimal concentrations are in the range of 10(-7) to 10(-5) M for dexamethasone and 50-200 U for IL-1 alpha. In contrast, dexamethasone counteracts, in an additive way, the inhibitory effect of IL-1 alpha on regulatory complement protein factor H production by EC. Such a potentialization between glucocorticoids and IL-1 alpha was not observed for another marker of endothelial activation, IL-1 alpha-induced stimulation of coagulation tissue factor expression. The association of glucocorticoids and IL-1 alpha therefore appears to be a specific and major stimulus for the secretion of complement C3 and factor B, two acute-phase proteins, by the endothelium. As a result of the in vitro endothelium stimulation by glucocorticoids and IL-1 alpha, C3a is generated in the vicinity of the endothelial cell. This study further suggests that complement activation, with its deleterious consequences, may result from the stimulation of endothelium in situations where high levels of IL-1 alpha and endogenous glucocorticoids coexist, such as in septic shock. Images Fig. 4 Fig. 6 PMID:7621583

  6. Generation of reactive oxygen species (ROS) is a key factor for stimulation of macrophage proliferation by ceramide 1-phosphate

    SciTech Connect

    Arana, Lide; Gangoiti, Patricia; Ouro, Alberto; Rivera, Io-Guane; Ordonez, Marta; Trueba, Miguel; Lankalapalli, Ravi S.; Bittman, Robert; Gomez-Munoz, Antonio

    2012-02-15

    We previously demonstrated that ceramide 1-phosphate (C1P) is mitogenic for fibroblasts and macrophages. However, the mechanisms involved in this action were only partially described. Here, we demonstrate that C1P stimulates reactive oxygen species (ROS) formation in primary bone marrow-derived macrophages, and that ROS are required for the mitogenic effect of C1P. ROS production was dependent upon prior activation of NADPH oxidase by C1P, which was determined by measuring phosphorylation of the p40phox subunit and translocation of p47phox from the cytosol to the plasma membrane. In addition, C1P activated cytosolic calcium-dependent phospholipase A{sub 2} and protein kinase C-{alpha}, and NADPH oxidase activation was blocked by selective inhibitors of these enzymes. These inhibitors, and inhibitors of ROS production, blocked the mitogenic effect of C1P. By using BHNB-C1P (a photolabile caged-C1P analog), we demonstrate that all of these C1P actions are caused by intracellular C1P. It can be concluded that the enzyme responsible for C1P-stimulated ROS generation in bone marrow-derived macrophages is NADPH oxidase, and that this enzyme is downstream of PKC-{alpha} and cPLA{sub 2}-{alpha} in this pathway. -- Highlights: Black-Right-Pointing-Pointer Ceramide 1-phosphate (C1P) stimulates reactive oxygen species (ROS) formation. Black-Right-Pointing-Pointer The enzyme responsible for ROS generation by C1P in macrophages is NADPH oxidase. Black-Right-Pointing-Pointer NADPH oxidase lies downstream of cPLA{sub 2}-{alpha} and PKC-{alpha} in this pathway. Black-Right-Pointing-Pointer ROS generation is essential for the stimulation of macrophage proliferation by C1P.

  7. Lavage of Leukotriene B4 Induces Lung Generation of Tumor Necrosis Factor-A and Neutrophil Diapedesis.

    DTIC Science & Technology

    2007-11-02

    iTlHIMTiTi METHODS Animal Preparation Adult male Sprague-Dawley rats ( Charles River Lab, Wilmington, MA) (n=114) weighing approximately 500 g were...airways. Rabbit Serum: Sterile normal rabbit preimmune serum (IP:001 Genzyme) was diluted and given in the same volume as IP:400. Endotoxin content of IP...interleukin-1, tumor necrosis factor-a of endotoxin versus leukoctye chemoat- tractants. Am J Pathol 1989; 135:227-237. 23. Carlos TM, Harlan JM

  8. Changes in the pattern of distribution of von Willebrand factor in rat aortic endothelial cells following thrombin generation in vivo.

    PubMed

    Senis, Y A; Richardson, M; Tinlin, S; Maurice, D H; Giles, A R

    1996-04-01

    The pattern of distribution of von Willebrand factor (VWF) in relatively large sheets of rat aortic endothelial cells (EC) obtained by the Häutchen technique were analysed by immunocytochemistry and light microscopy. EC were examined pre and post administration of a procoagulant mixture of factor Xa (F.Xa) and phosphotidylcholine/phosphotidylserine (PCPS) vesicles which was demonstrated to result in the selective loss of high molecular weight multimers (HMWM) of plasma VWF in the rat. In placebo animals the pattern was heterogenous both in overall distribution and in individual cells which showed both a diffuse and granular pattern. Groups of intensely stained EC were oriented parallel to the longitudinal axis of the aorta and staining was particularly prominent around the orifices of the intercostal arteries, implicating shear-stress as a possible factor in VWF expression by EC. Changes in the pattern of distribution of staining were observed at various time points post-infusion of F.Xa/PCPS, suggesting the immediate release of VWF from EC stores followed by the recruitment of EC to synthesize and store VWF. These changes are consistent with the decrease in EC Weibel-Palade Body (WPB) content observed by EM in previously reported studies using this model.

  9. Monitoring Low Molecular Weight Heparins at Therapeutic Levels: Dose-Responses of, and Correlations and Differences between aPTT, Anti-Factor Xa and Thrombin Generation Assays

    PubMed Central

    Thomas, Owain; Lybeck, Emanuel; Strandberg, Karin; Tynngård, Nahreen; Schött, Ulf

    2015-01-01

    Background Low molecular weight heparins (LMWH’s) are used to prevent and treat thrombosis. Tests for monitoring LMWH’s include anti-factor Xa (anti-FXa), activated partial thromboplastin time (aPTT) and thrombin generation. Anti-FXa is the current gold standard despite LMWH’s varying affinities for FXa and thrombin. Aim To examine the effects of two different LMWH’s on the results of 4 different aPTT-tests, anti-FXa activity and thrombin generation and to assess the tests’ concordance. Method Enoxaparin and tinzaparin were added ex-vivo in concentrations of 0.0, 0.5, 1.0 and 1.5 anti-FXa international units (IU)/mL, to blood from 10 volunteers. aPTT was measured using two whole blood methods (Free oscillation rheometry (FOR) and Hemochron Jr (HCJ)) and an optical plasma method using two different reagents (ActinFSL and PTT-Automat). Anti-FXa activity was quantified using a chromogenic assay. Thrombin generation (Endogenous Thrombin Potential, ETP) was measured on a Ceveron Alpha instrument using the TGA RB and more tissue-factor rich TGA RC reagents. Results Methods’ mean aPTT at 1.0 IU/mL LMWH varied between 54s (SD 11) and 69s (SD 14) for enoxaparin and between 101s (SD 21) and 140s (SD 28) for tinzaparin. ActinFSL gave significantly shorter aPTT results. aPTT and anti-FXa generally correlated well. ETP as measured with the TGA RC reagent but not the TGA RB reagent showed an inverse exponential relationship to the concentration of LMWH. The HCJ-aPTT results had the weakest correlation to anti-FXa and thrombin generation (Rs0.62–0.87), whereas the other aPTT methods had similar correlation coefficients (Rs0.80–0.92). Conclusions aPTT displays a linear dose-respone to LMWH. There is variation between aPTT assays. Tinzaparin increases aPTT and decreases thrombin generation more than enoxaparin at any given level of anti-FXa activity, casting doubt on anti-FXa’s present gold standard status. Thrombin generation with tissue factor-rich activator is

  10. A Combinatorial Code for Gene Expression Generated by Transcription Factor Bach2 and MAZR (MAZ-Related Factor) through the BTB/POZ Domain

    PubMed Central

    Kobayashi, Akira; Yamagiwa, Hironori; Hoshino, Hideto; Muto, Akihiko; Sato, Kazushige; Morita, Masanobu; Hayashi, Norio; Yamamoto, Masayuki; Igarashi, Kazuhiko

    2000-01-01

    Bach2 is a B-cell- and neuron-specific transcription repressor that forms heterodimers with the Maf-related oncoproteins. We show here that Bach2 activates transcription by interacting with its novel partner MAZR. MAZR was isolated by the yeast two-hybrid screen using the BTB/POZ domain of Bach2 as bait. Besides the BTB/POZ domain, MAZR possesses Zn finger motifs that are closely related to those of the Myc-associated Zn finger (MAZ) protein. MAZR mRNA was coexpressed with Bach2 in B cells among hematopoietic cells and in developing mouse limb buds, suggesting a cooperative role for MAZR and Bach2 in these cells. MAZR forms homo- and hetero-oligomers with Bach2 through the BTB domain, which oligomers bind to guanine-rich sequences. Unlike MAZ, MAZR functioned as a strong activator of the c-myc promoter in transfection assays with B cells. However, it does not possess a typical activation domain, suggesting a role for it as an unusual type of transactivator. The fgf4 gene, which regulates morphogenesis of limb buds, contains both guanine-rich sequences and a Bach2 binding site in its regulatory region. In transfection assays using fibroblast cells, the fgf4 gene was upregulated in the presence of both MAZR and Bach2 in a BTB/POZ domain-dependent manner. The results provide a new perspective on the function of BTB/POZ domain factors and indicate that BTB/POZ domain-mediated oligomers of transcription factors may serve as combinatorial codes for gene expression. PMID:10669750

  11. Hysteresis behavior of Kerr frequency comb generation in a high-quality-factor whispering-gallery-mode microcavity

    NASA Astrophysics Data System (ADS)

    Kato, Takumi; Chen-Jinnai, Akitoshi; Nagano, Takuma; Kobatake, Tomoya; Suzuki, Ryo; Yoshiki, Wataru; Tanabe, Takasumi

    2016-07-01

    A numerical and experimental study of Kerr frequency comb generation in a silica toroid microcavity is presented. We use a generalized mean-field Lugiato-Lefever equation and solve it with the split-step Fourier method. We observe that a stable mode-locked regime can be accessed when we reduce the input power after strong pumping due to the bistable nature of the nonlinear cavity system used. The experimental results agree well with the results of the numerical analysis, where we obtain a low-noise Kerr comb spectrum by gradually reducing the pumping input after strong pumping. This finding complements the results obtained by a previous wavelength scanning method and clarifies the procedure for achieving mode-locked states in such high-Q microcavity systems.

  12. Use of mice tolerant to lipopolysaccharide to demonstrate requirement of cooperation between macrophages and lymphocytes to generate lipopolysaccharide-induced colony-stimulating factor in vivo.

    PubMed Central

    Williams, Z; Hertogs, C F; Pluznik, D H

    1983-01-01

    Injection of lipopolysaccharide (LPS) into mice was followed by a rapid elevation of colony-stimulating factor (CSF) in the serum. A second, challenging injection of LPS given 3 to 4 days later failed to induce elevated levels of CSF in the serum. Such mice tolerant to LPS were used as an experimental tool to identify the CSF-producing cells which respond to LPS. We observed that generation of LPS-induced CSF in mice tolerant to LPS could be restored by an intraperitoneal injection of spleen cells 24 h before the challenging injection of LPS. Depletion of the adherent cells from the spleen cells reduced the ability of the splenic lymphocytes to restore the capacity of the mice tolerant to LPS to generate serum CSF. Reconstitution of the splenic lymphocytes with 5% thioglycolate-elicited peritoneal macrophages, however, reestablished the restorative capacity of these cells, whereas almost no restoration was observed after direct injection of elicited peritoneal macrophages. These data suggest that the spleen cells are active in generating CSF, provided that macrophages are present and can interact with the splenic lymphocytes to generate LPS-induced CSF in the serum. PMID:6602767

  13. Mobilization of Neural Stem Cells and Generation of New Neurons in 6-OHDA–lesioned Rats by Intracerebroventricular Infusion of Liver Growth Factor

    PubMed Central

    Gonzalo-Gobernado, Rafael; Reimers, Diana; Herranz, Antonio S.; Díaz-Gil, Juan José; Osuna, Cristina; Asensio, María José; Baena, Silvia; Rodríguez-Serrano, Macarena; Bazán, Eulalia

    2009-01-01

    Neural stem cells with self-renewal and multilineage potential persist in the subventricular zone of the adult mammalian forebrain. These cells remain relatively quiescent but, under certain conditions, can be stimulated, giving rise to new neurons. Liver growth factor (LGF) is a mitogen for liver cells that shows biological activity in extrahepatic sites and is useful for neuroregenerative therapies. The aim of this study was to investigate the potential neurogenic activity of LGF in the 6-hydroxydopamine rat model of Parkinson's disease. Proliferation was significantly increased in the subventricular zone and denervated striatum of rats receiving ICV LGF infusions, and 25% of the proliferating cells were doublecortin-positive neurons. Doublecortin-positive cells with the morphology of migrating neuroblasts were also observed in the dorsal and ventral regions of the striatum of LGF-infused animals. Moreover, some newly generated cells were neuronal nuclei-positive mature neurons. LGF also stimulated microglia and induced astrogliosis, both phenomena associated with generation and migration of new neurons in the adult brain. In summary, our study shows that LGF stimulates neurogenesis when applied intraventricularly in 6-hydroxydopamine–lesioned rats. Considering that this factor also promotes neuronal migration into damaged tissue, we propose LGF as a novel factor useful for neuronal replacement in neurodegenerative diseases. (J Histochem Cytochem 57:491–502, 2009) PMID:19188487

  14. Targeting Fibroblast Growth Factor Receptor (FGFR) with BGJ398 in a Gastric Cancer Model.

    PubMed

    Schmidt, Katharina; Moser, Christian; Hellerbrand, Claus; Zieker, Derek; Wagner, Christine; Redekopf, Julia; Schlitt, Hans J; Geissler, Edward K; Lang, Sven A

    2015-12-01

    To assess the efficacy of targeting fibroblast growth factor receptor (FGFR) with the pan-FGFR inhibitor BGJ398 in a gastric cancer (GC) model. Expression of FGFRs was determined in GC cell lines (KKLS, MKN-45, TMK-1). Impact of the FGFR inhibitor BGJ398 on growth, motility, signaling, expression of transcription factors and secretion of vascular endothelial growth factor-A (VEGFA) was determined in vitro. Results were validated in subcutaneous tumor models. In vitro, FGFR inhibition was most effective in KKLS cells (high FGFR1, FGFR2IIIc, no FGFR2IIIb expression) with inhibition of growth, motility, signaling, c-MYC expression and VEGFA secretion. BGJ398 showed some activity in MKN-45 cells (intermediate FGFR1, high FGFR2IIIb, low FGFR2IIIc expression), while TMK-1 cells (low FGFR1, no FGFR2IIIb and FGFR2IIIc expression) did not respond. Results were confirmed in vivo with strongest efficacy on growth in KKLS tumors and only minor impairment of TMK-1 lesions. Efficacy of FGFR inhibition is dependent on FGFR1 and FGFR2IIIc expression in GC models. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  15. Generation of a complement-derived chemotactic factor for tumor cells in experimentally induced peritoneal exudates and its effect on the local metastasis of circulating tumor cells.

    PubMed Central

    Orr, F. W.; Mokashi, S.; Delikatny, J.

    1982-01-01

    A chemotactic factor for tumor cells was found in inflammatory exudate fluids induced by giving intraperitoneal injections of glycogen to Sprague-Dawley rats. The quantity of chemotactic activity and the period of time during which it could be detected correlated with the inflammatory reaction, measured by the cellular composition of the exudates and their content of protein and lysosomal enzymes. In gel filtration the chemotactic factor behaved mainly as a molecule having a molecular weight of approximately 6000 daltons. Its biologic activity was blocked by antiserums directed against C5 but not by antiserums against C3 or C4. In these two respects, the factor generated in vivo has the same properties as a previously described chemotactic factor that can be generated in vitro by proteolysis of purified C5 or C5a. Chemotactic activity was not detected in the glycogen-induced peritoneal exudates of rats depleted of serum complement by cobra venom factor. Intravenously injected Walker tumor cells arrested and formed metastases in the mesenteries of rats with peritonitis in greater numbers than in normal controls, animals depleted of complement during the experimental period, or animals given intraperitoneal injections of the vasopermeability agent, histamine. The growth of tumor cells in vitro was not promoted by peritoneal exudate fluids, nor was the number of metastases on vivo greater than in negative controls, in animals in which peritonitis was induced 24 hours after the intravenous injection of tumor cells. It is argued that chemotactic mechanisms can contribute to the formation of metastases at sites of tissue injury. PMID:7091299

  16. Generating elastin-rich small intestinal submucosa-based smooth muscle constructs utilizing exogenous growth factors and cyclic mechanical stimulation.

    PubMed

    Heise, Rebecca Long; Ivanova, Julia; Parekh, Aron; Sacks, Michael S

    2009-12-01

    Successful approaches to tissue engineering smooth muscle tissues utilize biodegradable scaffolds seeded with autologous cells. One common problem in using biological scaffolds specifically is the difficulty of inducing cellular penetration and controlling de novo extracellular matrix deposition/remodeling in vitro. Our hypothesis was that small intestinal submucosa (SIS) exposed to specific mechanical stimulation regimes would modulate the synthesis of de novo collagen and elastin by bladder smooth muscle cells (BSMC) within the SIS matrix. We further hypothesized that the cytokines vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2), two key growth factors involved in epithelial mesenchymal signaling, will promote the cellular penetration into SIS necessary for mechanical stimulation. BSMC were seeded at 0.5 x 10(6) cells/cm(2) onto the luminal side of SIS specimens. VEGF (10 ng/mL) and FGF-2 (5 ng/mL) were added to each insert in the media every other day for up to 7 days in static culture. Following static culture, specimens were stretched strip-biaxially under 15% peak strain at either 0.5 or 0.1 Hz for an additional 7 days. Following the culture period, specimens were assayed histologically and biochemically for cellular penetration, proliferation, elastin, collagen, and protease activity. Histological analyses demonstrated that in standard culture media, BSMC remained on the surface of the SIS while both FGF-2 and VEGF profoundly promoted ingrowth of the BSMC into the SIS. The penetration of the cells in response to these cytokines was confirmed using a Transwell assay. Following cellular penetration, BSMC produced significant amounts of elastic fibers under cyclic mechanical stretching at 0.1 Hz under 15% stretch, as evidenced by colorimetric assay and histology using a Verhoeff-Van Gieson stain. Protease activity was assessed in the media and found to be statistically increased in static culture following FGF-2 treatment. These

  17. Robust Replication Control Is Generated by Temporal Gaps between Licensing and Firing Phases and Depends on Degradation of Firing Factor Sld2.

    PubMed

    Reusswig, Karl-Uwe; Zimmermann, Fabian; Galanti, Lorenzo; Pfander, Boris

    2016-10-04

    Temporal separation of DNA replication initiation into licensing and firing phases ensures the precise duplication of the genome during each cell cycle. Cyclin-dependent kinase (CDK) is known to generate this separation by activating firing factors and at the same time inhibiting licensing factors but may not be sufficient to ensure robust separation at transitions between both phases. Here, we show that a temporal gap separates the inactivation of firing factors from the re-activation of licensing factors during mitosis in budding yeast. We find that gap size critically depends on phosphorylation-dependent degradation of the firing factor Sld2 mediated by CDK, DDK, Mck1, and Cdc5 kinases and the ubiquitin-ligases Dma1/2. Stable mutants of Sld2 minimize the gap and cause increased genome instability in an origin-dependent manner when combined with deregulation of other replication regulators or checkpoint mechanisms. Robust separation of licensing and firing phases therefore appears indispensable to safeguard genome stability.

  18. Factors influencing storm-generated suspended-sediment concentrations and loads in four basins of contrasting land use, humid-tropical Puerto Rico

    USGS Publications Warehouse

    Gellis, Allen C.

    2013-01-01

    The significant characteristics controlling the variability in storm-generated suspended-sediment loads and concentrations were analyzed for four basins of differing land use (forest, pasture, cropland, and urbanizing) in humid-tropical Puerto Rico. Statistical analysis involved stepwise regression on factor scores. The explanatory variables were attributes of flow, hydrograph peaks, and rainfall, categorized into 5 flow periods: (1) the current storm hydrograph, (2) the flow and rainfall since the previous storm event, (3) the previous storm event, (4) 2nd previous storm event, and (5) the 3rd previous storm event. The response variables (storm generated sediment loads and concentrations) were analyzed for three portions of the storm hydrograph: (1) the entire storm, (2) the rising limb, and (3) the recessional limb. Hysteresis differences in sediment concentration between the rising and falling limb were also analyzed using these explanatory variables.

  19. Use of principal factor analysis to generate a corn silage fermentative quality index to rank well- or poorly preserved forages.

    PubMed

    Gallo, Antonio; Giuberti, Gianluca; Bruschi, Sara; Fortunati, Paola; Masoero, Francesco

    2016-03-30

    To investigate corn silage fermentative quality, a principal factor analysis was carried out on a database consisting of 196 corn silages sampled from the core, lateral and apical parts of silo feed-out face and characterised by 36 variables. Eleven principal factor components (PCs) were retained and interpreted. Two PCs were related to chemical and digestibility variables; four PCs were characterised by end-products associated with clostridia, heterolactic, homolactic or aerobic fermentations; two PCs were associated with mycotoxins produced by Penicillium roqueforti or by Aspergillus fumigatus and Fusarium spp., while three PCs explained ensiling procedures adopted to store corn silages. Lower (P < 0.05) yeast or mould counts and greater (P < 0.05) aerobic stability were measured in core than in peripheral samples. Excluding PCs related to ensiling procedures, other PCs were able to predict microbiological counts, aerobic stability or biogenic amine content as verified by multiple linear regression analysis. Based on these results, several corn silage quality index calculations were computed by using a summative equation approach in which different PCs as well as diverse relative weights multiplying each PCs were combined. To compute definitive index calculation, only PCs explaining clostridia, heterolactic and homolactic fermentations were used with relative weights of 30%, 50% and 20%. The new proposed fermentative quality index was highly correlated to parameters related to corn silage fermentative quality, such as microbiological counts, aerobic stability or biogenic amines and it properly discriminated well- and poorly preserved forages. © 2015 Society of Chemical Industry.

  20. SU-E-P-15: Technique Factor Modulation and Reference Plane Air Kerma Rates in Response to Simulated Patient Thickness Variations for a Sample of Current Generation Fluoroscopes

    SciTech Connect

    Wunderle, K; Rakowski, J; Dong, F

    2015-06-15

    Purpose: To evaluate and compare approaches to technique factor modulation and air kerma rates in response to simulated patient thickness variations for four state-of-the-art and one previous-generation interventional fluoroscopes. Methods: A polymethyl methacrylate (PMMA) phantom was used as a tissue surrogate for the purposes of determining fluoroscopic reference plane air kerma rates, kVp, mA, and spectral filtration over a wide range of simulated tissue thicknesses. Data were acquired for each fluoroscopic and acquisition dose curve within a default abdomen or body imaging protocol. Results: The data obtained indicated vendor- and model-specific variations in the approach to technique factor modulation and reference plane air kerma rates across a range of tissue thicknesses. Some vendors have made hardware advances increasing the radiation output capabilities of their fluoroscopes; this was evident in the acquisition air kerma rates. However, in the imaging protocol evaluated, all of the state-of-the-art systems had relatively low air kerma rates in the fluoroscopic low-dose imaging mode as compared to the previous-generation unit. Each of the newest-generation systems also employ copper filtration in the selected protocol in the acquisition mode of imaging; this is a substantial benefit, reducing the skin entrance dose to the patient in the highest dose-rate mode of fluoroscope operation. Conclusion: Understanding how fluoroscopic technique factors are modulated provides insight into the vendor-specific image acquisition approach and provides opportunities to optimize the imaging protocols for clinical practice. The enhanced radiation output capabilities of some of the fluoroscopes may, under specific conditions, may be beneficial; however, these higher output capabilities also have the potential to lead to unnecessarily high dose rates. Therefore, all parties involved in imaging, including the clinical team, medical physicists, and imaging vendors, must work

  1. Targeted next generation sequencing and identification of risk factors in World Health Organization defined atypical chronic myeloid leukemia.

    PubMed

    Patnaik, Mrinal M; Barraco, Daniela; Lasho, Terra L; Finke, Christy M; Reichard, Kaaren; Hoversten, Katherine P; Ketterling, Rhett P; Gangat, Naseema; Tefferi, Ayalew

    2017-03-17

    Atypical chronic myeloid leukemia (aCML) is an aggressive myeloid neoplasm with overlapping features of myelodysplastic syndromes (prominent granulocytic dysplasia) and myeloproliferative neoplasms (neutrophilic leukocytosis). We studied 25 molecularly-annotated and World Health Organization defined aCML patients; median age 70 years, 84% males. Cytogenetic abnormalities were seen in 36% and gene mutations in 100%. Mutational frequencies were, ASXL1 28%, TET2 16%, NRAS 16%, SETBP1 12%, RUNX1 12%, ETNK1 8% and PTPN11 4%. Fifteen patients (60%) had >1 mutation, while 9 (36%) had ≥3. The median overall survival (OS) was 10.8 months and at last follow up (median 11 months), 17 (68%) deaths and 2 (8%) leukemic transformations were documented. On univariate analysis, survival was adversely impacted by advanced age (p=0.02), low hemoglobin (p=0.01), red blood cell transfusion dependence (p=0.03), high white blood cell count (p=0.02), TET2 (p=0.03), NRAS (p=0.04), PTPN11 (p=0.02) mutations and the presence of ≥3 gene mutations (p=0.006); ASXL1, SETBP1, and ETNK1 mutations did not impact OS. In multivariable analysis, advanced age (p=0.003) [age >67: HR 10.1, 95% CI 1.3-119], low hemoglobin (p=0.008) [HB< 10gm/dl: HR 8.2, 95% CI 1.6-23.2] and TET2 mutations (p=0.01) [HR 8.8, 95% CI 1.6-47.7] retained prognostic significance. We then used age >67 years, hemoglobin <10 gm/dl and the presence of TET2 mutations (each counted as one risk factor) to create a hazard ratio weighted prognostic model; effectively stratifying patients into two risk categories, low (0-1 risk factor) and high (≥2 risk factors), with median OS of 18 and 7 months respectively. This article is protected by copyright. All rights reserved.

  2. A novel approach for the generation of human dendritic cells from blood monocytes in the absence of exogenous factors.

    PubMed

    Schanen, Brian C; Drake, Donald R

    2008-06-01

    Human dendritic cells (DCs) for research and clinical applications are typically derived from purified blood monocytes that are cultured in a cocktail of cytokines for a week or more. Because it has been suggested that these cytokine-derived DCs may be deficient in some important immunological functions and might not accurately represent antigen presenting cell (APC) populations found under normal conditions in vivo, there is an interest in developing methods that permit the derivation of DCs in a more physiologically relevant manner in vitro. Here, we describe a simple and reliable technique for generating large numbers of highly purified DCs that is based on a one-way migration of blood monocytes through a layer of human umbilical vein endothelial cells (HUVECs) that are cultured to confluency in the upper chamber of a Transwell device. The resultant APCs, harvested from the lower Transwell chamber, resemble other cultured DC populations in their expression of major histocompatibility (MHC) and costimulatory molecules, ability to phagocytose protein antigens and capacity to trigger primary antigen-specific T cell responses. This technique offers several advantages over the standard method of in vitro cytokine-driven DC development, including: (1) the rapidity of this approach, as DC differentiation occurs in only 2 days, (2) the differentiation process itself, which is more akin to the development of DCs under physiologic conditions and (3) the cost-effectiveness of the system, since no monocyte pre-selection is required and DC development occurs in the absence of expensive recombinant cytokines.

  3. Blood Cell-Derived Induced Pluripotent Stem Cells Free of Reprogramming Factors Generated by Sendai Viral Vectors

    PubMed Central

    Muench, Marcus O.; Fusaki, Noemi; Beyer, Ashley I.; Wang, Jiaming; Qi, Zhongxia; Yu, Jingwei

    2013-01-01

    The discovery of induced pluripotent stem cells (iPSCs) holds great promise for regenerative medicine since it is possible to produce patient-specific pluripotent stem cells from affected individuals for potential autologous treatment. Using nonintegrating cytoplasmic Sendai viral vectors, we generated iPSCs efficiently from adult mobilized CD34+ and peripheral blood mononuclear cells. After 5–8 passages, the Sendai viral genome could not be detected by real-time quantitative reverse transcription-polymerase chain reaction. Using the spin embryoid body method, we showed that these blood cell-derived iPSCs could efficiently be differentiated into hematopoietic stem and progenitor cells without the need of coculture with either mouse or human stromal cells. We obtained up to 40% CD34+ of which ∼25% were CD34+/CD43+ hematopoietic precursors that could readily be differentiated into mature blood cells. Our study demonstrated a reproducible protocol for reprogramming blood cells into transgene-free iPSCs by the Sendai viral vector method. Maintenance of the genomic integrity of iPSCs without integration of exogenous DNA should allow the development of therapeutic-grade stem cells for regenerative medicine. PMID:23847002

  4. Factors Generating Glucose Degradation Products In Sterile Glucose Solutions For Infusion: Statistical Relevance Determination Of Their Impacts.

    PubMed

    Haybrard, J; Simon, N; Danel, C; Pinçon, C; Barthélémy, C; Tessier, F J; Décaudin, B; Boulanger, E; Odou, P

    2017-09-20

    Sterilising glucose solutions by heat promotes the generation of a large number of glucose degradation products (GDPs). It has been shown that high levels of GDPs may result in Advanced Glycation End products that have an impact on cellular homeostasis and health in general. If data is available for peritoneal dialysis solutions, little has been published for glucose infusion fluids. It is essential to identify the parameters causing the formation of GDPs and so limit the risk of exposing patients to them. After quantifying both 5-hydroxymethyl-2-furfural, considered as an important indicator of degradation, and 2-furaldehyde, an ultimate GDP of one degradation pathway, in marketed solutions, the aim of this work is to build a model integrating all the parameters involved in the formation rates of these two GDPs: supplier, glucose amount, container material, oxygen permeability coefficient and time-lapse since manufacture. Our results show a good logarithmic relationship between GDP formation rates and time-lapse since manufacture for both GDPs. The amount of GDPs in the glucose solutions for infusion depends on the initial glucose amount, the polymer of the container, the time elapsed since manufacturing and the supplier.

  5. Fluctuations of the transcription factor ATML1 generate the pattern of giant cells in the Arabidopsis sepal

    PubMed Central

    Meyer, Heather M; Teles, José; Formosa-Jordan, Pau; Refahi, Yassin; San-Bento, Rita; Ingram, Gwyneth; Jönsson, Henrik; Locke, James C W; Roeder, Adrienne H K

    2017-01-01

    Multicellular development produces patterns of specialized cell types. Yet, it is often unclear how individual cells within a field of identical cells initiate the patterning process. Using live imaging, quantitative image analyses and modeling, we show that during Arabidopsis thaliana sepal development, fluctuations in the concentration of the transcription factor ATML1 pattern a field of identical epidermal cells to differentiate into giant cells interspersed between smaller cells. We find that ATML1 is expressed in all epidermal cells. However, its level fluctuates in each of these cells. If ATML1 levels surpass a threshold during the G2 phase of the cell cycle, the cell will likely enter a state of endoreduplication and become giant. Otherwise, the cell divides. Our results demonstrate a fluctuation-driven patterning mechanism for how cell fate decisions can be initiated through a random yet tightly regulated process. DOI: http://dx.doi.org/10.7554/eLife.19131.001 PMID:28145865

  6. A case of pulmonary thromboembolism due to coagulation factor V Leiden in Japan ~ usefulness of next generation sequencing~.

    PubMed

    Sueta, Daisuke; Ito, Miwa; Uchiba, Mitsuhiro; Sakamoto, Kenji; Yamamoto, Eiichiro; Izumiya, Yasuhiro; Kojima, Sunao; Kaikita, Koichi; Shinriki, Satoru; Hokimoto, Seiji; Matsui, Hirotaka; Tsujita, Kenichi

    2017-01-01

    Because the venous thromboembolisms (VTEs) due to the coagulation factor V R506Q (FV Leiden) mutation is often seen in Caucasians, the VTE onset in Japan has not been reported. A 34-year-old man from north Africa experiencing sudden dyspnea went to a hospital for advice. The patient had pain in his right leg and a high plasma D-dimer level. A contrast-enhanced computed tomography scan revealed a contrast deficit in the bilateral pulmonary artery and in the right lower extremity. The patient was diagnosed with VTE, and anticoagulation therapy was initiated. Our targeted gene panel sequencing revealed that the occurrence of VTE was attributed to a presence of the FV Leiden mutation. This is the first report demonstrating VTE caused by the FV Leiden mutation in Japan.

  7. Transforming growth factor-beta1 inhibits tissue engineering cartilage absorption via inducing the generation of regulatory T cells.

    PubMed

    Li, Chichi; Bi, Wei; Gong, Yiming; Ding, Xiaojun; Guo, Xuehua; Sun, Jian; Cui, Lei; Yu, Youcheng

    2016-02-01

    The objective of the present study was to explore the mechanisms of transforming growth factor (TGF)-β1 inhibiting the absorption of tissue engineering cartilage. We transfected TGF-β1 gene into bone marrow mesenchymal stem cells (BMMSCs) and co-cultured with interferon (IFN)-γ and tumour necrosis factor (TNF)-α and CD4(+) CD25(-) T lymphocytes. We then characterized the morphological changes, apoptosis and characterization of chondrogenic-committed cells from TGF-β1(+) BMMSCs and explored their mechanisms. Results showed that BMMSCs apoptosis and tissue engineering cartilage absorption in the group with added IFN-γ and TNF-α were greater than in the control group. In contrast, there was little BMMSC apoptosis and absorption by tissue engineering cartilage in the group with added CD4(+) CD25(-) T lymphocytes; Foxp3(+) T cells and CD25(+) CD39(+) T cells were found. In contrast, no type II collagen or Foxp3(+) T cells or CD25(+) CD39(+) T cells was found in the TGF-β1(-) BMMSC group. The data suggest that IFN-γ and TNF-α induced BMMSCs apoptosis and absorption of tissue engineering cartilage, but the newborn regulatory T (Treg) cells inhibited the function of IFN-γ and TNF-α and protected BMMSCs and tissue engineering cartilage. TGF-β1not only played a cartilage inductive role, but also inhibited the absorption of tissue engineering cartilage. The pathway proposed in our study may simulate the actual reaction procedure after implantation of BMMSCs and tissue engineering cartilage in vivo. Copyright © 2013 John Wiley & Sons, Ltd.

  8. Generation of an optimized lentiviral vector encoding a high-expression factor VIII transgene for gene therapy of hemophilia A.

    PubMed

    Johnston, J M; Denning, G; Doering, C B; Spencer, H T

    2013-06-01

    We previously compared the expression of several human factor VIII (fVIII) transgene variants and demonstrated the superior expression properties of B domain-deleted porcine fVIII. Subsequently, a hybrid human/porcine fVIII molecule (HP-fVIII) comprising 91% human amino-acid sequence was engineered to maintain the high-expression characteristics of porcine fVIII. The bioengineered construct then was used effectively to treat knockout mice with hemophilia A. In the current study, we focused on optimizing self-inactivating (SIN) lentiviral vector systems by analyzing the efficacy of various lentiviral components in terms of virus production, transduction efficiency and transgene expression. Specifically, three parameters were evaluated: (1) the woodchuck hepatitis post-transcriptional regulatory element (WPRE), (2) HIV versus SIV viral vector systems and (3) various internal promoters. The inclusion of a WPRE sequence had negligible effects on viral production and HP-fVIII expression. HIV and SIV vectors were compared and found to be similar with respect to transduction efficiency in both K562s and HEK-293T cells. However, there was an enhanced expression of HP-fVIII by the SIV system, which was evident in both K562 and BHK-M cell lines. To further compare expression of HP-fVIII from an SIV-based lentiviral system, we constructed expression vectors containing the high expression transgene and a human elongation factor-1 alpha, cytomegalovirus (CMV) or phosphoglycerate kinase promoter. Expression was significantly greater from the CMV promoter, which also yielded therapeutic levels of HP-fVIII in hemophilia A mice. Based on these studies, an optimized vector contains the HP-fVIII transgene driven by a CMV internal promoter within a SIV-based lentiviral backbone lacking a WPRE.

  9. Generation of an Optimized Lentiviral Vector Encoding a High-Expression Factor VIII Transgene for Gene Therapy of Hemophilia A

    PubMed Central

    Johnston, Jennifer M.; Denning, Gabriela; Doering, Christopher B.; Spencer, H. Trent

    2012-01-01

    We previously compared the expression of several human factor VIII (fVIII) transgene variants and demonstrated the superior expression properties of B domain deleted porcine fVIII. Subsequently, a hybrid human/porcine fVIII molecule (HP-fVIII) comprising 91% human amino acid sequence was engineered to maintain the high-expression characteristics of porcine fVIII. The bioengineered construct then was used effectively to treat knockout mice with hemophilia A. In the current study, we focused on optimizing self-inactivating (SIN) lentiviral vector systems by analyzing the efficacy of various lentiviral components in terms of virus production, transduction efficiency and transgene expression. Specifically, three parameters were evaluated: 1) the woodchuck hepatitis post-transcriptional regulatory element (WPRE), 2) HIV versus SIV viral vector systems, and 3) various internal promoters. The inclusion of a WPRE sequence had negligible effects on viral production and HP-fVIII expression. HIV and SIV vectors were compared and found to be similar with respect to transduction efficiency in both K562s and HEK-293T cells. However, there was an enhanced expression of HP-fVIII by the SIV system, which was evident in both K562 and BHK-M cell lines. To further compare expression of HP-fVIII from an SIV-based lentiviral system, we constructed expression vectors containing the high expression transgene and a human elongation factor-1 alpha (EF1α), cytomegalovirus (CMV) or phosphoglycerate kinase (PGK) promoter. Expression was significantly greater from the CMV promoter, which also yielded therapeutic levels of HP-fVIII in hemophilia A mice. Based on these studies, an optimized vector contains the HP-fVIII transgene driven by a CMV internal promoter within a SIV-based lentiviral backbone lacking a WPRE. PMID:22996197

  10. Generation of Rhesus Macaque-Tropic HIV-1 Clones That Are Resistant to Major Anti-HIV-1 Restriction Factors

    PubMed Central

    Nomaguchi, Masako; Yokoyama, Masaru; Kono, Ken; Nakayama, Emi E.; Shioda, Tatsuo; Doi, Naoya; Fujiwara, Sachi; Saito, Akatsuki; Akari, Hirofumi; Miyakawa, Kei; Ryo, Akihide; Ode, Hirotaka; Iwatani, Yasumasa; Miura, Tomoyuki; Igarashi, Tatsuhiko

    2013-01-01

    Human immunodeficiency virus type 1 (HIV-1) replication in macaque cells is restricted mainly by antiviral cellular APOBEC3, TRIM5α/TRIM5CypA, and tetherin proteins. For basic and clinical HIV-1/AIDS studies, efforts to construct macaque-tropic HIV-1 (HIV-1mt) have been made by us and others. Although rhesus macaques are commonly and successfully used as infection models, no HIV-1 derivatives suitable for in vivo rhesus research are available to date. In this study, to obtain novel HIV-1mt clones that are resistant to major restriction factors, we altered Gag and Vpu of our best HIV-1mt clone described previously. First, by sequence- and structure-guided mutagenesis, three amino acid residues in Gag-capsid (CA) (M94L/R98S/G114Q) were found to be responsible for viral growth enhancement in a macaque cell line. Results of in vitro TRIM5α susceptibility testing of HIV-1mt carrying these substitutions correlated well with the increased viral replication potential in macaque peripheral blood mononuclear cells (PBMCs) with different TRIM5 alleles, suggesting that the three amino acids in HIV-1mt CA are involved in the interaction with TRIM5α. Second, we replaced the transmembrane domain of Vpu of this clone with the corresponding region of simian immunodeficiency virus SIVgsn166 Vpu. The resultant clone, MN4/LSDQgtu, was able to antagonize macaque but not human tetherin, and its Vpu effectively functioned during viral replication in a macaque cell line. Notably, MN4/LSDQgtu grew comparably to SIVmac239 and much better than any of our other HIV-1mt clones in rhesus macaque PBMCs. In sum, MN4/LSDQgtu is the first HIV-1 derivative that exhibits resistance to the major restriction factors in rhesus macaque cells. PMID:23966385

  11. Computational protein design to reengineer stromal cell-derived factor-1α generates an effective and translatable angiogenic polypeptide analog.

    PubMed

    Hiesinger, William; Perez-Aguilar, Jose Manuel; Atluri, Pavan; Marotta, Nicole A; Frederick, John R; Fitzpatrick, J Raymond; McCormick, Ryan C; Muenzer, Jeffrey R; Yang, Elaine C; Levit, Rebecca D; Yuan, Li-Jun; Macarthur, John W; Saven, Jeffery G; Woo, Y Joseph

    2011-09-13

    Experimentally, exogenous administration of recombinant stromal cell-derived factor-1α (SDF) enhances neovasculogenesis and cardiac function after myocardial infarction. Smaller analogs of SDF may provide translational advantages including enhanced stability and function, ease of synthesis, lower cost, and potential modulated delivery via engineered biomaterials. In this study, computational protein design was used to create a more efficient evolution of the native SDF protein. Protein structure modeling was used to engineer an SDF polypeptide analog (engineered SDF analog [ESA]) that splices the N-terminus (activation and binding) and C-terminus (extracellular stabilization) with a diproline segment designed to limit the conformational flexibility of the peptide backbone and retain the relative orientation of these segments observed in the native structure of SDF. Endothelial progenitor cells (EPCs) in ESA gradient, assayed by Boyden chamber, showed significantly increased migration compared with both SDF and control gradients. EPC receptor activation was evaluated by quantification of phosphorylated AKT, and cells treated with ESA yielded significantly greater phosphorylated AKT levels than SDF and control cells. Angiogenic growth factor assays revealed a distinct increase in angiopoietin-1 expression in the ESA- and SDF-treated hearts. In addition, CD-1 mice (n=30) underwent ligation of the left anterior descending coronary artery and peri-infarct intramyocardial injection of ESA, SDF-1α, or saline. At 2 weeks, echocardiography demonstrated a significant gain in ejection fraction, cardiac output, stroke volume, and fractional area change in mice treated with ESA compared with controls. Compared with native SDF, a novel engineered SDF polypeptide analog (ESA) more efficiently induces EPC migration and improves post-myocardial infarction cardiac function and thus offers a more clinically translatable neovasculogenic therapy.

  12. The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling

    PubMed Central

    Iwasaki, Yasuno; Thomsen, Gerald H.

    2014-01-01

    Alternative splicing of pre-mRNAs is an important means of regulating developmental processes, yet the molecular mechanisms governing alternative splicing in embryonic contexts are just beginning to emerge. Polyglutamine-binding protein 1 (PQBP1) is an RNA-splicing factor that, when mutated, in humans causes Renpenning syndrome, an X-linked intellectual disability disease characterized by severe cognitive impairment, but also by physical defects that suggest PQBP1 has broader functions in embryonic development. Here, we reveal essential roles for PQBP1 and a binding partner, WBP11, in early development of Xenopus embryos. Both genes are expressed in the nascent mesoderm and neurectoderm, and morpholino knockdown of either causes defects in differentiation and morphogenesis of the mesoderm and neural plate. At the molecular level, knockdown of PQBP1 in Xenopus animal cap explants inhibits target gene induction by FGF but not by BMP, Nodal or Wnt ligands, and knockdown of either PQBP1 or WBP11 in embryos inhibits expression of fgf4 and FGF4-responsive cdx4 genes. Furthermore, PQBP1 knockdown changes the alternative splicing of FGF receptor-2 (FGFR2) transcripts, altering the incorporation of cassette exons that generate receptor variants (FGFR2 IIIb or IIIc) with different ligand specificities. Our findings may inform studies into the mechanisms underlying Renpenning syndrome. PMID:25209246

  13. Assessment of Parametrial Response by Growth Pattern in Patients With International Federation of Gynecology and Obstetrics Stage IIB and IIIB Cervical Cancer: Analysis of Patients From a Prospective, Multicenter Trial (EMBRACE).

    PubMed

    Yoshida, Kenji; Jastaniyah, Noha; Sturdza, Alina; Lindegaard, Jacob; Segedin, Barbara; Mahantshetty, Umesh; Rai, Bhavana; Jürgenliemk-Schulz, Ina; Haie-Meder, Christine; Sasaki, Ryohei; Pötter, Richard

    2015-11-15

    To assess disease response along the parametrial space according to tumor morphology in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIB and IIIB cervical cancer at the time of image-guided adaptive brachytherapy. Patients with FIGO stage IIB and IIIB cervical cancer registered as of November 2013 in the EMBRACE study were evaluated. Tumors were stratified according to morphologic subtype on magnetic resonance imaging (expansive and infiltrative), and the characteristics of those subtypes were analyzed. Parametrial involvement at diagnosis and at brachytherapy was evaluated, and the response to chemo-radiotherapy was classified as good, moderate, or poor. The response grade was compared between the 2 groups and analyzed with regard to tumor volumes, and dosimetric parameters. A total of 452 patients were evaluated, of whom 186 had expansive growth type and 266 had infiltrative morphology. Patients with infiltrative tumors had more extensive disease, as indicated by a higher rate of FIGO stage IIIB disease, as well as radiologic evidence of extension into the distal parametrial space and to the pelvic side wall on magnetic resonance imaging. Cervical necrosis was more common in the infiltrative group. Good response was more common in the expansive group (34% vs 24%; P=.02), and poor response was more common in the infiltrative group (11% and 19%; P=.02). Mean gross tumor volume at diagnosis was equal in both groups (51.7 cm(3)). The high-risk clinical target volume was larger in infiltrative tumors (37.9 cm(3) vs 33.3 cm(3), P=.005). The mean high-risk clinical target volume D90 was slightly higher in expansive tumors (92.7 Gy and 89.4 Gy, P<.001). Infiltrative tumors are more advanced at presentation and respond less favorably to chemo-radiotherapy when compared with expansive tumors that are more or less equivalent in size. The use of image-guided adaptive brachytherapy allows achieving reasonably high doses in both groups

  14. The effectiveness of power-generating complexes constructed on the basis of nuclear power plants combined with additional sources of energy determined taking risk factors into account

    NASA Astrophysics Data System (ADS)

    Aminov, R. Z.; Khrustalev, V. A.; Portyankin, A. V.

    2015-02-01

    The effectiveness of combining nuclear power plants equipped with water-cooled water-moderated power-generating reactors (VVER) with other sources of energy within unified power-generating complexes is analyzed. The use of such power-generating complexes makes it possible to achieve the necessary load pickup capability and flexibility in performing the mandatory selective primary and emergency control of load, as well as participation in passing the night minimums of electric load curves while retaining high values of the capacity utilization factor of the entire power-generating complex at higher levels of the steam-turbine part efficiency. Versions involving combined use of nuclear power plants with hydrogen toppings and gas turbine units for generating electricity are considered. In view of the fact that hydrogen is an unsafe energy carrier, the use of which introduces additional elements of risk, a procedure for evaluating these risks under different conditions of implementing the fuel-and-hydrogen cycle at nuclear power plants is proposed. Risk accounting technique with the use of statistical data is considered, including the characteristics of hydrogen and gas pipelines, and the process pipelines equipment tightness loss occurrence rate. The expected intensities of fires and explosions at nuclear power plants fitted with hydrogen toppings and gas turbine units are calculated. In estimating the damage inflicted by events (fires and explosions) occurred in nuclear power plant turbine buildings, the US statistical data were used. Conservative scenarios of fires and explosions of hydrogen-air mixtures in nuclear power plant turbine buildings are presented. Results from calculations of the introduced annual risk to the attained net annual profit ratio in commensurable versions are given. This ratio can be used in selecting projects characterized by the most technically attainable and socially acceptable safety.

  15. The immunosuppressives FK 506 and cyclosporin A inhibit the generation of protein factors binding to the two purine boxes of the interleukin 2 enhancer.

    PubMed Central

    Brabletz, T; Pietrowski, I; Serfling, E

    1991-01-01

    Like Cyclosporin A (CsA), the macrolide FK 506 is a potent immunosuppressive that inhibits early steps of T cell activation, including the synthesis of Interleukin 2 (II-2) and numerous other lymphokines. The block of II-2 synthesis occurs at the transcriptional level. At concentrations that block T cell activation, FK 506 and CsA inhibit the proto-enhancer activity of Purine boxes of the II-2 promoter and the generation of lymphocyte-specific factors binding to the Purine boxes. Under the same conditions, the DNA binding of other II-2 enhancer factors remains unaffected by both compounds. These results support the view that FK 506 and CsA, which both inhibit the activity of peptidylprolyl cis/trans isomerases, suppress T cell activation by a similar, if not identical mechanism. Images PMID:1707162

  16. Dissipation pattern, safety evaluation, and generation of processing factor (PF) for pyraclostrobin and metiram residues in grapes during raisin preparation.

    PubMed

    Shabeer T P, Ahammed; Girame, Rushali; Hingmire, Sandip; Banerjee, Kaushik; Sharma, Ajay Kumar; Oulkar, Dasharath; Utture, Sagar; Jadhav, Manjusha

    2015-02-01

    A residue analysis method was validated for trace level estimation of pyraclostrobin by liquid chromatography-mass spectrometry and metiram (analyzed as CS2) by gas chromatography mass spectrometry in grapes and raisin matrix. Dissipation of their residues and processing factors (PFs) during raisin making were evaluated through field studies with applications at single dose (SD) and double dose (DD). Residue data during drying process were best fitted to first + first-order kinetics model giving half-life ranging between 6 and 7 days for pyroclostrobin and 4 days for metiram. PFs for metiram and pyraclostrobin related to washing and oil dipping were 0.47 and 0.41, and 0.78 and 0.63 at single dose (SD) and double dose (DD), respectively. PF value of >1 for drying (1.01 and 1.31 for metiram and 1.34 and 1.10 for pyraclostrobin) indicates concentration of the residues during the drying process. The dietary exposure corresponding to average daily consumption of 0.0043 kg raisin per day on each sampling day was less than the respective maximum permissible intake at both the doses.

  17. Evaluation of field-generated accumulation factors for predicting the bioaccumulation potential of sediment-associated PAH compounds. Final report

    SciTech Connect

    McFarland, V.A.

    1995-07-01

    Equilibrium partitioning of neutral organic chemicals between the organic carbon fraction of bedded sediments and the lipids of resident organisms provides the theoretical basis for one of the most popular approaches to the development of sediment quality criteria (SQC) by the U.S. Environmental Protection Agency (EPA). The proposed equilibrium partitioning-based SQC seek to relate estimated doses of sediment-associated chemicals to toxicity in exposed biota. Criteria documents for several polynuclear aromatic hydrocarbon (PAH) compounds, endrin, and dieldrin have been released by the EPA for public review, and may soon be promulgated. A procedure recommended in the Implementation Manual (the Green Book) for public law regulating ocean disposal of dredged sediments (Section 103, Public Law 92-532, Marine Protection, Research, and Sanctuaries Act, the Ocean Dumping Act) has used equilibrium partitioning-based estimations to screen sediments for bioaccumulation potential for several years. The screening test, termed theoretical bioaccumulation potential, TBP, is also included in the draft manual for inland waters to implement dredged material testing requirements of the Clean Water Act. TBP employs an accumulation factor (AF), defined as the ratio at equilibrium of the organic carbon-normalized concentration of a neutral organic chemical in a sediment and the lipid-normalized concentration of the chemical in an exposed organism. The Green Book currently recommends using a universal AF =4 for all neutral chemicals, the rationale being that this value is suitably protective of all neutral chemicals, provided certain caveats are recognized. This study compared the predictive capability of PAH AFs derived from field data with that of the universal AF=4 in making TBP estimations.

  18. Regulation of Na(+)/K(+)-ATPase by nuclear respiratory factor 1: implication in the tight coupling of neuronal activity, energy generation, and energy consumption.

    PubMed

    Johar, Kaid; Priya, Anusha; Wong-Riley, Margaret T T

    2012-11-23

    NRF-1 regulates mediators of neuronal activity and energy generation. NRF-1 transcriptionally regulates Na(+)/K(+)-ATPase subunits α1 and β1. NRF-1 functionally regulates mediators of energy consumption in neurons. NRF-1 mediates the tight coupling of neuronal activity, energy generation, and energy consumption at the molecular level. Energy generation and energy consumption are tightly coupled to neuronal activity at the cellular level. Na(+)/K(+)-ATPase, a major energy-consuming enzyme, is well expressed in neurons rich in cytochrome c oxidase, an important enzyme of the energy-generating machinery, and glutamatergic receptors that are mediators of neuronal activity. The present study sought to test our hypothesis that the coupling extends to the molecular level, whereby Na(+)/K(+)-ATPase subunits are regulated by the same transcription factor, nuclear respiratory factor 1 (NRF-1), found recently by our laboratory to regulate all cytochrome c oxidase subunit genes and some NMDA and AMPA receptor subunit genes. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, in vivo chromatin immunoprecipitation, promoter mutational analysis, and real-time quantitative PCR, NRF-1 was found to functionally bind to the promoters of Atp1a1 and Atp1b1 genes but not of the Atp1a3 gene in neurons. The transcripts of Atp1a1 and Atp1b1 subunit genes were up-regulated by KCl and down-regulated by tetrodotoxin. Atp1b1 is positively regulated by NRF-1, and silencing of NRF-1 with small interference RNA blocked the up-regulation of Atp1b1 induced by KCl, whereas overexpression of NRF-1 rescued these transcripts from being suppressed by tetrodotoxin. On the other hand, Atp1a1 is negatively regulated by NRF-1. The binding sites of NRF-1 on Atp1a1 and Atp1b1 are conserved among mice, rats, and humans. Thus, NRF-1 regulates key Na(+)/K(+)-ATPase subunits and plays an important role in mediating the tight coupling between

  19. Major controlling factors on hydrocarbon generation and leakage in South Atlantic conjugate margins: A comparative study of Colorado, Orange, Campos and Lower Congo basins

    NASA Astrophysics Data System (ADS)

    Marcano, Gabriela; Anka, Zahie; di Primio, Rolando

    2013-09-01

    We present a supra-regional comparative study of the major internal and external factors controlling source rock (SR) maturation and hydrocarbon (HC) generation and leakage in two pairs of conjugate margins across the South Atlantic: the Brazil (Campos Basin)-Angola (Lower Congo Basin) margins located in the "central segment", and the Argentina (Colorado Basin)-South Africa (Orange Basin) in the "southern segment". Our approach is based on the analysis and integration of borehole data, 1D numerical modeling, 2D seismic reflection data, and published reports. Coupling of modeling results, sedimentation rate calculation and seal-bypass system analysis reveal that: (1) oil window is reached by syn-rift SRs in the southern segment during the Early to Late Cretaceous when thermal subsidence is still active, while in the central segment they reach it in Late-Cretaceous-Neogene during a salt remobilization phase, and (2) early HC generation from post-rift SRs in the southern segment and from all SRs in the central segment appears to be controlled mainly by episodes of increased sedimentation rates. The latter seems to be associated with the Andes uplift history for the western South Atlantic basins (Campos and Colorado) and to a possibly climate-driven response for the eastern South Atlantic basins (Orange and Lower Congo). Additionally, we observe that the effect of volcanism on SR maturation in the southern segment is very local. The comparison of Cretaceous mass transport deposit (MTD) episodes with HC peak of generation and paleo-leakage indicators in the southern segment revealed the possible causal effect that HC generation and leakage have over MTD development. Interestingly, Paleogene leakage indicators, which were identified in the Argentina-South Africa conjugate margins, occur contemporaneously to low sedimentation rate periods. Nonetheless, present-day leakage indicators which were also identified in both pairs of conjugate margins might be related to seal

  20. Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor.

    PubMed Central

    MacPhee, C H; Moores, K E; Boyd, H F; Dhanak, D; Ife, R J; Leach, C A; Leake, D S; Milliner, K J; Patterson, R A; Suckling, K E; Tew, D G; Hickey, D M

    1999-01-01

    A novel and potent azetidinone inhibitor of the lipoprotein-associated phospholipase A2 (Lp-PLA2), i.e. platelet-activating factor acetylhydrolase, is described for the first time. This inhibitor, SB-222657 (Ki=40+/-3 nM, kobs/[I]=6. 6x10(5) M-1.s-1), is inactive against paraoxonase, is a poor inhibitor of lecithin:cholesterol acyltransferase and has been used to investigate the role of Lp-PLA2 in the oxidative modification of lipoproteins. Although pretreatment with SB-222657 did not affect the kinetics of low-density lipoprotein (LDL) oxidation by Cu2+ or an azo free-radical generator as determined by assay of lipid hydroperoxides (LOOHs), conjugated dienes and thiobarbituric acid-reacting substances, in both cases it inhibited the elevation in lysophosphatidylcholine content. Moreover, the significantly increased monocyte chemoattractant activity found in a non-esterified fatty acid fraction from LDL oxidized by Cu2+ was also prevented by pretreatment with SB-222657, with an IC50 value of 5.0+/-0.4 nM. The less potent diastereoisomer of SB-222657, SB-223777 (Ki=6.3+/-0.5 microM, kobs/[I]=1.6x10(4) M-1.s-1), was found to be significantly less active in both assays. Thus, in addition to generating lysophosphatidylcholine, a known biologically active lipid, these results demonstrate that Lp-PLA2 is capable of generating oxidized non-esterified fatty acid moieties that are also bioactive. These findings are consistent with our proposal that Lp-PLA2 has a predominantly pro-inflammatory role in atherogenesis. Finally, similar studies have demonstrated that a different situation exists during the oxidation of high-density lipoprotein, with enzyme(s) other than Lp-PLA2 apparently being responsible for generating lysophosphatidylcholine. PMID:10024526

  1. Generation of a conditionally immortalized myeloid progenitor cell line requiring the presence of both interleukin-3 and stem cell factor to survive and proliferate.

    PubMed

    Lee, Candy; Evans, Caroline A; Spooncer, Elaine; Pierce, Andrew; Mottram, Rachel; Whetton, Anthony D

    2003-09-01

    The H-2Kappab temperature-sensitive (ts) A58 transgenic (Immorto) mouse has been used previously to generate conditionally immortalized cells from a number of tissues. The present study aimed to investigate characteristics of primitive myeloid precursor cells derived from H-2Kappab-tsA58 bone marrow. Cell populations were enriched for granulocyte/macrophage progenitors by centrifugal elutriation, and were cultured in the presence and absence of cytokines at the permissive and restrictive temperatures for the A58 oncogene. Cells derived from H-2Kappab-tsA58 mice required both A58 activation and the growth factors, stem cell factor (SCF) and interleukin-3 (IL-3), for long-term cell survival and growth; cells were maintained for > 300 d in culture under these conditions. IL-3- and SCF-dependent clonal cell lines were derived with a phenotype (lin-, Sca-1+, CD34+, ER-MP 58+, ER-MP 12+, ER-MP 20-) characteristic of primitive myeloid progenitors. These cells differentiated on addition of granulocyte/macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF) and acquired mature cell morphology with some upregulation of differentiation markers. In conclusion, the A58 oncogene can immortalize haemopoietic progenitor cells. These cells require two cytokines for growth, IL-3 and SCF; as such, they constitute a useful resource for the study of synergistic interactions between growth factors. The ability to develop monocytic cell characteristics also permits the investigation of cytokine-mediated early haemopoietic progenitor cell development.

  2. Diagnostic throughput factor analysis for en-route airspace and optimal aircraft trajectory generation based on capacity prediction and controller workload

    NASA Astrophysics Data System (ADS)

    Shin, Sanghyun

    Today's National Airspace System (NAS) is approaching its limit to efficiently cope with the increasing air traffic demand. Next Generation Air Transportation System (NextGen) with its ambitious goals aims to make the air travel more predictable with fewer delays, less time sitting on the ground and holding in the air to improve the performance of the NAS. However, currently the performance of the NAS is mostly measured using delay-based metrics which do not capture a whole range of important factors that determine the quality and level of utilization of the NAS. The factors affecting the performance of the NAS are themselves not well defined to begin with. To address these issues, motivated by the use of throughput-based metrics in many areas such as ground transportation, wireless communication and manufacturing, this thesis identifies the different factors which majorly affect the performance of the NAS as demand (split into flight cancellation and flight rerouting), safe separation (split into conflict and metering) and weather (studied as convective weather) through careful comparison with other applications and performing empirical sensitivity analysis. Additionally, the effects of different factors on the NAS's performance are quantitatively studied using real traffic data with the Future ATM Concepts Evaluation Tool (FACET) for various sectors and centers of the NAS on different days. In this thesis we propose a diagnostic tool which can analyze the factors that have greater responsibility for regions of poor and better performances of the NAS. Based on the throughput factor analysis for en-route airspace, it was found that weather and controller workload are the major factors that decrease the efficiency of the airspace. Also, since resources such as air traffic controllers, infrastructure and airspace are limited, it is becoming increasingly important to use the available resources efficiently. To alleviate the impact of the weather and controller

  3. Mitigating environmental impacts through the energetic use of wood: Regional displacement factors generated by means of substituting non-wood heating systems.

    PubMed

    Wolf, Christian; Klein, Daniel; Richter, Klaus; Weber-Blaschke, Gabriele

    2016-11-01

    Wood biomass, especially when applied for heating, plays an important role for mitigating environmental impacts such as climate change and the transition towards higher shares of renewable energy in today's energy mix. However, the magnitude of mitigation benefits and burdens associated with wood use can vary greatly depending on regional parameters such as the displaced fossil reference or heating mix. Therefore, regionalized displacement factors, considering region-specific production conditions and substituted products are required when assessing the precise contribution of wood biomass towards the mitigation of environmental impacts. We carried out Life Cycle Assessments of wood heating systems for typical Bavarian conditions and substitute energy carriers with a focus on climate change and particulate matter emissions. In order to showcase regional effects, we created weighted displacement factors for the region of Bavaria, based on installed capacities of individual wood heating systems and the harvested tree species distribution. The study reveals that GHG displacements between -57gCO2-eq.∗MJ(-1) of useful energy through the substitution of natural gas with a 15kW spruce pellets heating system and -165gCO2-eq.∗MJ(-1) through the substitution of power utilized for heating with a modern 6kW beech split log heating system can be achieved. It was shown that the GHG mitigation potentials of wood utilization are overestimated through the common use of light fuel oil as the only reference system. We further propose a methodology for the calculation of displacement factors which is adaptable to other regions worldwide. Based on our approach it is possible to generate displacement factors for wood heating systems which enable accurate decision-making for project planning in households, heating plants, communities and also for entire regions. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Overcoming resistance to first/second generation epidermal growth factor receptor tyrosine kinase inhibitors and ALK inhibitors in oncogene-addicted advanced non-small cell lung cancer

    PubMed Central

    Romanidou, Ourania; Landi, Lorenza; Cappuzzo, Federico; Califano, Raffaele

    2016-01-01

    Epidermal growth factor receptor (EGFR) activating mutations and anaplastic lymphoma kinase (ALK) gene rearrangement in advanced non-small cell lung cancer (NSCLC) represent the two oncogenic events with an impact on current clinical practice. EGFR tyrosine kinase inhibitors (TKIs) and crizotinib are the standard of care for the treatment of EGFR mutant and ALK gene rearranged advanced NSCLC patients. Unfortunately, despite initial clinical benefit, acquired resistance to EGFR-TKIs or crizotinib usually develops after an average of 10–12 months of treatment. The aim of this review is to describe the mechanisms of resistance to first/second generation EGFR-TKIs and crizotinib. In particular, we focus on strategies to overcome resistance due to secondary EGFR T790M mutation and mutations of the ALK domain. PMID:27239236

  5. Science versus the stars: a double-blind test of the validity of the NEO Five-Factor Inventory and computer-generated astrological natal charts.

    PubMed

    Wyman, Alyssa Jayne; Vyse, Stuart

    2008-07-01

    The authors asked 52 college students (38 women, 14 men, M age = 19.3 years, SD = 1.3 years) to identify their personality summaries by using a computer-generated astrological natal chart when presented with 1 true summary and 1 bogus one. Similarly, the authors asked participants to identify their true personality profile from real and bogus summaries that the authors derived from the NEO Five-Factor Inventory (NEO-FFI; P. T. Costa Jr. & R. R. McCrae, 1985). Participants identified their real NEO-FFI profiles at a greater-than-chance level but were unable to identify their real astrological summaries. The authors observed a P. T. Barnum effect in the accuracy ratings of both psychological and astrological measures but did not find differences between the odd-numbered (i.e., favorable) signs and the even-numbered (i.e., unfavorable) signs.

  6. Ethanol Influences on Bax Translocation, Mitochondrial Membrane Potential, and Reactive Oxygen Species Generation are Modulated by Vitamin E and Brain-Derived Neurotrophic Factor

    PubMed Central

    Heaton, Marieta Barrow; Paiva, Michael; Siler-Marsiglio, Kendra

    2011-01-01

    Background This study investigated ethanol influences on intracellular events which predispose developing neurons toward apoptosis, and the capacity of the antioxidant α-tocopherol (vitamin E) and the neurotrophin brain-derived neurotrophic factor (BDNF) to modulate these effects. Assessments were made of the following: (1) ethanol-induced translocation of the pro-apoptotic Bax protein to the mitochondrial membrane, a key upstream event in the initiation of apoptotic cell death; (2) disruption of the mitochondrial membrane potential (MMP) as a result of ethanol exposure, an important process in triggering the apoptotic cascade; and (3) generation of damaging reactive oxygen species (ROS) as a function of ethanol exposure. Methods These interactions were investigated in cultured postnatal day 8 neonatal rat cerebellar granule cells, a population vulnerable to developmental ethanol exposure in vivo and in vitro. Bax mitochondrial translocation was analyzed via subcellular fractionation followed by Western blot, and mitochondrial membrane integrity was determined using the lipophilic dye, JC-1, which exhibits potential-dependent accumulation in the mitochondrial membrane as a function of the MMP. Results Brief ethanol exposure in these preparations precipitated Bax translocation, but both vitamin E and BDNF reduced this effect to control levels. Ethanol treatment also resulted in a disturbance of the MMP, and this effect was blunted by the antioxidant and the neurotrophin. ROS generation was enhanced by a short ethanol exposure in these cells, but the production of these harmful free radicals was diminished to control levels by co-treatment with either vitamin E or BDNF. Conclusions These results indicate that both antioxidants and neurotrophic factors have the potential to ameliorate ethanol neurotoxicity, and suggest possible interventions which could be implemented in preventing or lessening the severity of the damaging effects of ethanol in the developing central

  7. Hypercoagulability in patients with Cushing disease detected by thrombin generation assay is associated with increased levels of neutrophil extracellular trap-related factors.

    PubMed

    Tripodi, Armando; Ammollo, Concetta T; Semeraro, Fabrizio; Colucci, Mario; Malchiodi, Elena; Verrua, Elisa; Ferrante, Emanuele; Arnaldi, Giorgio; Trementino, Laura; Padovan, Lidia; Chantarangkul, Veena; Peyvandi, Flora; Mantovani, Giovanna

    2017-05-01

    Patients with Cushing disease (CD) are at increased risk of venous thromboembolism (VTE). It was surmised, but not conclusively shown that the risk is related to plasma hypercoagulability secondary to the glucocorticoids effect. This study is aimed at detecting hypercoagulability in patients with CD. Case-control study of 48 CD patients and controls enrolled at two Italian clinics for whom we assessed the thrombin-forming-potential in the presence of optimal activation of protein C obtained by adding into the assay system its main endothelial activator, thrombomodulin. These experimental conditions mimic more closely than any other test the in vivo situation. We observed enhanced thrombin-generation in CD patients, as shown by the modification of thrombin-generation parameters [i.e., shortened lag-time and time-to-peak, increased thrombin peak and endogenous thrombin potential (ETP)]. Moreover, the ETP ratio (with/without thrombomodulin), recognized as an index of hypercoagulability, was increased in patients as compared to controls. We attempted to explain such hypercoagulability by measuring both procoagulant and anticoagulant factors, and some other non-coagulation parameters (i.e., neutrophil extracellular traps (NET), recently associated with the VTE risk and/or increased hypercoagulability. We showed that the hypercoagulability in patients with CD is associated with increased levels of factor VIII and NET-related variables. We detected plasma hypercoagulability in patients with CD and found experimental explanation for its occurrence. Whether this hypercoagulability can entirely explain the occurrence of VTE in patients with CD should be investigated by ad-hoc clinical trials. However, until these studies will be available the evidence supports the concept that patients with CD are candidates for antithrombotic prophylaxis.

  8. GIPC mediates the generation of reactive oxygen species and the regulation of cancer cell proliferation by insulin-like growth factor-1/IGF-1R signaling.

    PubMed

    Choi, Ji Seung; Paek, A Rome; Kim, Soo Youl; You, Hye Jin

    2010-08-28

    Insulin-like growth factor-1 (IGF-1)/IGF-1 receptor signaling participates in a variety of cellular processes, including cell survival, growth, and proliferation. Increased expression of IGF-1R and activation of its downstream signaling components have been implicated in human cancers. Although a regulatory role for IGF-1R has been established, the relationship between IGF-1R and its binding partner, GAIP-interacting protein C-terminus (GIPC), in terms of promoting cell proliferation, remains unclear. We found that siRNA-mediated silencing of GIPC expression decreased IGF-1-mediated IGF-1R phosphorylation and cellular proliferation in breast cancer models. IGF-1-mediated cellular proliferation was also inhibited by N-acetylcysteine, which implicates reactive oxygen species generation. siRNA-mediated silencing of GIPC expression also decreased IGF-1-mediated reactive oxygen species generation. Taken together, these data suggest that GIPC contributes to IGF-1-induced cancer cell proliferation via the regulation of reactive oxygen species production. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  9. Quantification of factors influencing fluorescent protein expression using RMCE to generate an allelic series in the ROSA26 locus in mice.

    PubMed

    Chen, Sara X; Osipovich, Anna B; Ustione, Alessandro; Potter, Leah A; Hipkens, Susan; Gangula, Rama; Yuan, Weiping; Piston, David W; Magnuson, Mark A

    2011-07-01

    Fluorescent proteins (FPs) have great utility in identifying specific cell populations and in studying cellular dynamics in the mouse. To quantify the factors that determine both the expression and relative brightness of FPs in mouse embryonic stem cells (mESCs) and in mice, we generated eight different FP-expressing ROSA26 alleles using recombinase-mediated cassette exchange (RMCE). These alleles enabled us to analyze the effects on FP expression of a translational enhancer and different 3'-intronic and/or polyadenylation sequences, as well as the relative brightness of five different FPs, without the confounding position and copy number effects that are typically associated with randomly inserted transgenes. We found that the expression of a given FP can vary threefold or more depending on the genetic features present in the allele. The optimal FP expression cassette contained both a translational enhancer sequence in the 5'-untranslated region (UTR) and an intron-containing rabbit β-globin sequence within the 3'-UTR. The relative expressed brightness of individual FPs varied up to tenfold. Of the five different monomeric FPs tested, Citrine (YFP) was the brightest, followed by Apple, eGFP, Cerulean (CFP) and Cherry. Generation of a line of Cherry-expressing mice showed that there was a 30-fold variation of Cherry expression among different tissues and that there was a punctate expression pattern within cells of all tissues examined. This study should help investigators make better-informed design choices when expressing FPs in mESCs and mice.

  10. The human fibroblast growth factor receptor genes: a common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain.

    PubMed Central

    Johnson, D E; Lu, J; Chen, H; Werner, S; Williams, L T

    1991-01-01

    To determine the mechanisms by which multiple forms of fibroblast growth factor (FGF) receptors are generated, we have mapped the arrangement of exons and introns in the human FGF receptor 1 (FGFR 1) gene (flg). We found three alternative exons encoding a portion of the third immunoglobulin (Ig)-like domain of the receptor. One of these alternatives encodes a sequence that is part of a secreted form of FGFR 1. The other two encode sequences that are likely part of transmembrane forms of FGFR 1. One of these forms has not been previously reported in published cDNAs. Also, we have determined the structural organization of a portion of the human FGFR 2 gene (bek) and found a similar arrangement of alternative exons for the third Ig-like domain. The arrangement of these genes suggests that there are conserved mechanisms governing the expression of secreted FGF receptors as well as the expression of at least two distinct membrane-spanning forms of the FGF receptors. The diverse forms appear to be generated by alternative splicing of mRNA and selective use of polyadenylation signals. Images PMID:1652059

  11. Generation of Naïve Bovine Induced Pluripotent Stem Cells Using PiggyBac Transposition of Doxycycline-Inducible Transcription Factors.

    PubMed

    Kawaguchi, Takamasa; Tsukiyama, Tomoyuki; Kimura, Koji; Matsuyama, Shuichi; Minami, Naojiro; Yamada, Masayasu; Imai, Hiroshi

    2015-01-01

    Generation of pluripotent stem cells (PSCs) in large domestic animals has achieved only limited success; most of the PSCs obtained to date have been classified as primed PSCs, which possess very little capacity to produce chimeric offspring. By contrast, mouse PSCs have been classified as naïve PSCs that can contribute to most of the tissues of chimeras, including germ cells. Here, we describe the generation of two different types of bovine induced pluripotent stem cells (biPSCs) from amnion cells, achieved through introduction of piggyBac vectors containing doxycycline-inducible transcription factors (Oct3/4, Sox2, Klf4, and c-Myc). One type of biPSCs, cultured in medium supplemented with knockout serum replacement (KSR), FGF2, and bovine leukemia inhibitory factor (bLIF), had a flattened morphology like human PSCs; these were classified as primed-type. The other type biPSCs, cultured in KSR, bLIF, Mek/Erk inhibitor, GSK3 inhibitor and forskolin, had a compact morphology like mouse PSCs; these were classified as naïve-type. Cells could easily be switched between these two types of biPSCs by changing the culture conditions. Both types of biPSCs had strong alkaline phosphatase activity, expressed pluripotent markers (OCT3/4, NANOG, REX1, ESRRβ, STELLA, and SOCS3), and formed embryoid bodies that gave rise to differentiated cells from all three embryonic germ layers. However, only naïve-type biPSCs showed the hallmarks of naïve mouse PSCs, such as LIF-dependent proliferation, lack of FGF5 expression, and active XIST expression with two active X chromosomes. Furthermore, naïve-type biPSCs could contribute to the inner cell mass (ICM) of host blastocysts and most tissues within chimeric embryos. This is the first report of generation of biPSCs with several characteristics similar to those of naïve mouse PSCs and a demonstrated potential to contribute to chimeras.

  12. Generation of Naïve Bovine Induced Pluripotent Stem Cells Using PiggyBac Transposition of Doxycycline-Inducible Transcription Factors

    PubMed Central

    Kawaguchi, Takamasa; Tsukiyama, Tomoyuki; Kimura, Koji; Matsuyama, Shuichi; Minami, Naojiro; Yamada, Masayasu; Imai, Hiroshi

    2015-01-01

    Generation of pluripotent stem cells (PSCs) in large domestic animals has achieved only limited success; most of the PSCs obtained to date have been classified as primed PSCs, which possess very little capacity to produce chimeric offspring. By contrast, mouse PSCs have been classified as naïve PSCs that can contribute to most of the tissues of chimeras, including germ cells. Here, we describe the generation of two different types of bovine induced pluripotent stem cells (biPSCs) from amnion cells, achieved through introduction of piggyBac vectors containing doxycycline-inducible transcription factors (Oct3/4, Sox2, Klf4, and c-Myc). One type of biPSCs, cultured in medium supplemented with knockout serum replacement (KSR), FGF2, and bovine leukemia inhibitory factor (bLIF), had a flattened morphology like human PSCs; these were classified as primed-type. The other type biPSCs, cultured in KSR, bLIF, Mek/Erk inhibitor, GSK3 inhibitor and forskolin, had a compact morphology like mouse PSCs; these were classified as naïve-type. Cells could easily be switched between these two types of biPSCs by changing the culture conditions. Both types of biPSCs had strong alkaline phosphatase activity, expressed pluripotent markers (OCT3/4, NANOG, REX1, ESRRβ, STELLA, and SOCS3), and formed embryoid bodies that gave rise to differentiated cells from all three embryonic germ layers. However, only naïve-type biPSCs showed the hallmarks of naïve mouse PSCs, such as LIF-dependent proliferation, lack of FGF5 expression, and active XIST expression with two active X chromosomes. Furthermore, naïve-type biPSCs could contribute to the inner cell mass (ICM) of host blastocysts and most tissues within chimeric embryos. This is the first report of generation of biPSCs with several characteristics similar to those of naïve mouse PSCs and a demonstrated potential to contribute to chimeras. PMID:26287611

  13. Stretching human mesenchymal stromal cells on stiffness-customized collagen type I generates a smooth muscle marker profile without growth factor addition

    NASA Astrophysics Data System (ADS)

    Rothdiener, Miriam; Hegemann, Miriam; Uynuk-Ool, Tatiana; Walters, Brandan; Papugy, Piruntha; Nguyen, Phong; Claus, Valentin; Seeger, Tanja; Stoeckle, Ulrich; Boehme, Karen A.; Aicher, Wilhelm K.; Stegemann, Jan P.; Hart, Melanie L.; Kurz, Bodo; Klein, Gerd; Rolauffs, Bernd

    2016-10-01

    Using matrix elasticity and cyclic stretch have been investigated for inducing mesenchymal stromal cell (MSC) differentiation towards the smooth muscle cell (SMC) lineage but not in combination. We hypothesized that combining lineage-specific stiffness with cyclic stretch would result in a significantly increased expression of SMC markers, compared to non-stretched controls. First, we generated dense collagen type I sheets by mechanically compressing collagen hydrogels. Atomic force microscopy revealed a nanoscale stiffness range known to support myogenic differentiation. Further characterization revealed viscoelasticity and stable biomechanical properties under cyclic stretch with >99% viable adherent human MSC. MSCs on collagen sheets demonstrated a significantly increased mRNA but not protein expression of SMC markers, compared to on culture flasks. However, cyclic stretch of MSCs on collagen sheets significantly increased both mRNA and protein expression of α-smooth muscle actin, transgelin, and calponin versus plastic and non-stretched sheets. Thus, lineage-specific stiffness and cyclic stretch can be applied together for inducing MSC differentiation towards SMCs without the addition of recombinant growth factors or other soluble factors. This represents a novel stimulation method for modulating the phenotype of MSCs towards SMCs that could easily be incorporated into currently available methodologies to obtain a more targeted control of MSC phenotype.

  14. Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice.

    PubMed

    Peng, Baowei; Ye, Peiqing; Blazar, Bruce R; Freeman, Gordon J; Rawlings, David J; Ochs, Hans D; Miao, Carol H

    2008-09-01

    Formation of inhibitory antibodies is a common problem encountered in clinical treatment for hemophilia. Human factor VIII (hFVIII) plasmid gene therapy in hemophilia A mice also leads to strong humoral responses. We demonstrate that short-term therapy with an anti-ICOS monoclonal antibody to transiently block the inducible costimulator/inducible costimulator ligand (ICOS/ICOSL) signaling pathway led to sustained tolerance to hFVIII in hFVIII plasmid-treated hemophilia A mice and allowed persistent, high-level FVIII functional activity (100%-300% of normal). Anti-ICOS treatment resulted in depletion of ICOS(+)CD4(+) T cells and activation of CD25(+)Foxp3(+) Tregs in the peripheral blood, spleen, and lymph nodes. CD4(+) T cells from anti-ICOS-treated mice did not proliferate in response to hFVIII stimulation and produced high levels of regulatory cytokines, including interleukin-10 and transforming growth factor-beta. Moreover, CD4(+)CD25(+) Tregs from tolerized mice adoptively transferred dominant tolerance in syngeneic hFVIII plasmid-treated hemophilia A mice and reduced the production of antibodies against FVIII. Anti-ICOS-treated mice tolerized to hFVIII generated normal primary and secondary antibody responses after immunization with the T-dependent antigen, bacteriophage Phix 174, indicating maintenance of immune competency. Our data indicate that transient anti-ICOS monoclonal antibody treatment represents a novel single-agent immunomodulatory strategy to overcome the immune responses against transgene product after gene therapy.

  15. Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study.

    PubMed

    Hawi, Z; Cummins, T D R; Tong, J; Arcos-Burgos, M; Zhao, Q; Matthews, N; Newman, D P; Johnson, B; Vance, A; Heussler, H S; Levy, F; Easteal, S; Wray, N R; Kenny, E; Morris, D; Kent, L; Gill, M; Bellgrove, M A

    2017-04-01

    Attention-deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome-wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we believe we performed the first large-scale next-generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene-level analysis of rare (<1% frequency) single-nucleotide variants (SNVs) revealed that the gene encoding brain-derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity.

  16. A Hox Transcription Factor Collective Binds a Highly Conserved Distal-less cis-Regulatory Module to Generate Robust Transcriptional Outcomes.

    PubMed

    Uhl, Juli D; Zandvakili, Arya; Gebelein, Brian

    2016-04-01

    cis-regulatory modules (CRMs) generate precise expression patterns by integrating numerous transcription factors (TFs). Surprisingly, CRMs that control essential gene patterns can differ greatly in conservation, suggesting distinct constraints on TF binding sites. Here, we show that a highly conserved Distal-less regulatory element (DCRE) that controls gene expression in leg precursor cells recruits multiple Hox, Extradenticle (Exd) and Homothorax (Hth) complexes to mediate dual outputs: thoracic activation and abdominal repression. Using reporter assays, we found that abdominal repression is particularly robust, as neither individual binding site mutations nor a DNA binding deficient Hth protein abolished cooperative DNA binding and in vivo repression. Moreover, a re-engineered DCRE containing a distinct configuration of Hox, Exd, and Hth sites also mediated abdominal Hox repression. However, the re-engineered DCRE failed to perform additional segment-specific functions such as thoracic activation. These findings are consistent with two emerging concepts in gene regulation: First, the abdominal Hox/Exd/Hth factors utilize protein-protein and protein-DNA interactions to form repression complexes on flexible combinations of sites, consistent with the TF collective model of CRM organization. Second, the conserved DCRE mediates multiple cell-type specific outputs, consistent with recent findings that pleiotropic CRMs are associated with conserved TF binding and added evolutionary constraints.

  17. A Hox Transcription Factor Collective Binds a Highly Conserved Distal-less cis-Regulatory Module to Generate Robust Transcriptional Outcomes

    PubMed Central

    Uhl, Juli D.; Zandvakili, Arya; Gebelein, Brian

    2016-01-01

    cis-regulatory modules (CRMs) generate precise expression patterns by integrating numerous transcription factors (TFs). Surprisingly, CRMs that control essential gene patterns can differ greatly in conservation, suggesting distinct constraints on TF binding sites. Here, we show that a highly conserved Distal-less regulatory element (DCRE) that controls gene expression in leg precursor cells recruits multiple Hox, Extradenticle (Exd) and Homothorax (Hth) complexes to mediate dual outputs: thoracic activation and abdominal repression. Using reporter assays, we found that abdominal repression is particularly robust, as neither individual binding site mutations nor a DNA binding deficient Hth protein abolished cooperative DNA binding and in vivo repression. Moreover, a re-engineered DCRE containing a distinct configuration of Hox, Exd, and Hth sites also mediated abdominal Hox repression. However, the re-engineered DCRE failed to perform additional segment-specific functions such as thoracic activation. These findings are consistent with two emerging concepts in gene regulation: First, the abdominal Hox/Exd/Hth factors utilize protein-protein and protein-DNA interactions to form repression complexes on flexible combinations of sites, consistent with the TF collective model of CRM organization. Second, the conserved DCRE mediates multiple cell-type specific outputs, consistent with recent findings that pleiotropic CRMs are associated with conserved TF binding and added evolutionary constraints. PMID:27058369

  18. Generation and characterization of tabalumab, a human monoclonal antibody that neutralizes both soluble and membrane-bound B-cell activating factor

    PubMed Central

    Manetta, Joseph; Bina, Holly; Ryan, Paul; Fox, Niles; Witcher, Derrick R; Kikly, Kristine

    2014-01-01

    B-cell activating factor (BAFF) is a B-cell survival factor with a key role in B-cell homeostasis and tolerance. Dysregulated BAFF expression may contribute to autoimmune diseases or B-cell malignancies via effects on abnormal B-lymphocyte activation, proliferation, survival, and immunoglobulin secretion. Monoclonal antibodies were generated against human BAFF, characterized for species specificity and affinity, and screened for the ability to neutralize both membrane-bound and soluble BAFF. In addition, studies were undertaken to determine the relative potency of membrane-bound and soluble BAFF. Tabalumab has a high affinity for human, cynomolgus monkey, and rabbit BAFF. No binding to mouse BAFF was detected. Tabalumab was able to neutralize soluble human, cynomolgus monkey, or rabbit BAFF with equal potency. Our data demonstrate that membrane-bound BAFF can be a more potent stimulus for B-cells than soluble BAFF, and tabalumab also neutralized membrane-bound BAFF. Tabalumab prevented BAFF from binding to BAFF receptors and demonstrated pharmacodynamic effects in human BAFF transgenic mice. Tabalumab is a high-affinity human antibody with neutralizing activity against membrane-bound and soluble BAFF. Given our findings that membrane-bound BAFF can have greater in vitro potency than soluble BAFF, neutralization of both forms of BAFF is likely to be important for optimal therapeutic effect. PMID:25258549

  19. Stretching human mesenchymal stromal cells on stiffness-customized collagen type I generates a smooth muscle marker profile without growth factor addition

    PubMed Central

    Rothdiener, Miriam; Hegemann, Miriam; Uynuk-Ool, Tatiana; Walters, Brandan; Papugy, Piruntha; Nguyen, Phong; Claus, Valentin; Seeger, Tanja; Stoeckle, Ulrich; Boehme, Karen A.; Aicher, Wilhelm K.; Stegemann, Jan P.; Hart, Melanie L.; Kurz, Bodo; Klein, Gerd; Rolauffs, Bernd

    2016-01-01

    Using matrix elasticity and cyclic stretch have been investigated for inducing mesenchymal stromal cell (MSC) differentiation towards the smooth muscle cell (SMC) lineage but not in combination. We hypothesized that combining lineage-specific stiffness with cyclic stretch would result in a significantly increased expression of SMC markers, compared to non-stretched controls. First, we generated dense collagen type I sheets by mechanically compressing collagen hydrogels. Atomic force microscopy revealed a nanoscale stiffness range known to support myogenic differentiation. Further characterization revealed viscoelasticity and stable biomechanical properties under cyclic stretch with >99% viable adherent human MSC. MSCs on collagen sheets demonstrated a significantly increased mRNA but not protein expression of SMC markers, compared to on culture flasks. However, cyclic stretch of MSCs on collagen sheets significantly increased both mRNA and protein expression of α-smooth muscle actin, transgelin, and calponin versus plastic and non-stretched sheets. Thus, lineage-specific stiffness and cyclic stretch can be applied together for inducing MSC differentiation towards SMCs without the addition of recombinant growth factors or other soluble factors. This represents a novel stimulation method for modulating the phenotype of MSCs towards SMCs that could easily be incorporated into currently available methodologies to obtain a more targeted control of MSC phenotype. PMID:27775041

  20. Control of fibroblast growth factor (FGF) 7- and FGF1-induced mitogenesis and downstream signaling by distinct heparin octasaccharide motifs.

    PubMed

    Luo, Yongde; Ye, Sheng; Kan, Mikio; McKeehan, Wallace L

    2006-07-28

    Variation in length, disaccharide composition, and sulfation of heparan sulfate (HS) affects fibroblast growth factor (FGF) signaling. However, it is unclear whether the specific distribution of groups within oligosaccharides or random variations in charge density underlies the effects. Recently we showed that a mixture of undersulfated octasaccharides exhibiting 7 and 8 sulfates (7,8-S-OctaF7) generated from heparin had the highest affinity for FGF7 monitored by salt resistance (>0.60 M salt) of octasaccharide-FGF7 complexes. 7,8-S-OctaF7 also had the highest specific activity for formation of a complex with dimeric FGFR2IIIb competent to bind FGF7. Here we show that when endogenous HS was inhibited by chlorate treatment, 7,8-S-OctaF7 specifically supported FGF7-stimulated DNA synthesis and downstream signaling in FGFR2IIIb-expressing mouse keratinocytes. It failed to support FGF1 signaling in both HS-deficient mouse keratinocytes and 3T3 fibroblasts. In contrast, abundant, more highly sulfated and heterogenous mixtures of octasaccharides with lower affinity (0.30-0.60 M salt) for FGF7 supported FGF1-induced signaling in both cell types. In contrast to the two-component 7,8-S-OctaF7 mixture from FGF7, the high affinity octasaccharide fraction from FGF1 was a heterogeneous mixture with components ranging from 8 to 12 sulfates with 11-S-octasaccharides the most abundant. The high affinity fraction exhibited similar properties to the lower affinity fractions from both FGF1 and FGF7. Octasaccharide mixtures eluting from FGF1 between 0.30 and 0.60 M and above 0.60 M salt were nearly equal in support of FGF1 signaling in fibroblasts and keratinocytes. Both were deficient in support of FGF7-induced signaling in keratinocytes. The results show that both variations in overall charge density and specific distribution of charged groups within HS motifs exhibit FGF-specific control over formation of FGF-HS-FGFR complexes and downstream signaling.

  1. Isolated rat stomach ECL cells generate prostaglandin E(2) in response to interleukin-1 beta, tumor necrosis factor-alpha and bradykinin.

    PubMed

    Lindström, E; Lerner, U H; Håkanson, R

    2001-03-30

    The ECL cells control parietal cells by releasing histamine in their immediate vicinity. Gastrin and pituitary adenylate cyclase-activating peptide (PACAP) stimulate histamine secretion from isolated ECL cells, while somatostatin and galanin inhibit stimulated secretion. Prostaglandin E2 and related prostaglandins likewise suppress ECL-cell histamine secretion. Conceivably, that is how they inhibit acid secretion. In the present study, we examined if prostaglandin E2 can be generated by isolated ECL cells. Rat stomach ECL cells were purified (>90% purity) by counterflow elutriation and gradient centrifugation and cultured for 48 h. ECL cell stimulants (gastrin and PACAP) and inflammatory agents (interleukin-1 beta, tumor necrosis factor-alpha and bradykinin) were tested for their ability to induce prostaglandin E2 accumulation (24-h incubation), measured by radioimmunoassay. Gastrin and PACAP did not affect prostaglandin E2 accumulation but interleukin-1 beta (300 pg/ml), tumor necrosis factor-alpha (10 ng/ml) and bradykinin (1 microM) induced a 2- to 3-fold increase in the amount of prostaglandin E2 accumulated. While the combination of interleukin-1 beta and bradykinin induced a 9-fold increase, the combination interleukin-1 beta+tumor necrosis factor-alpha and bradykinin + tumor necrosis factor-alpha induced additive effects only. The combination of interleukin-1 beta + tumor necrosis factor-alpha + bradykinin did not induce a greater effect than interleukin-1 beta + bradykinin. The effect of interleukin-1 beta + bradykinin was abolished by adding 10 nM hydrocortisone (suppressing phospholipase A2 and cyclooxygenase) or 1 microM indomethacin (inhibiting cyclooxygenase). Incubating ECL cells in the presence of interleukin-1 beta+bradykinin for 24 h reduced their ability to secrete histamine in response to gastrin. The inhibitory effect was reversed by 1 microM indomethacin. Also, increasing the concentrations of hydrocortisone in the medium resulted in an

  2. Tissue-factor-bearing microparticles (MPs-TF) in patients with acute ischaemic stroke: the influence of stroke treatment on MPs-TF generation.

    PubMed

    Świtońska, M; Słomka, A; Sinkiewicz, W; Żekanowska, E

    2015-02-01

    Stroke is an important cause of death and disability throughout the world. Microparticles play a cardinal role in vascular hemostasis. The primary aim of this study was to evaluate the procoagulant activity of microparticles and levels of tissue-factor-bearing microparticles (MPs-TF), tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with acute ischaemic stroke. Seventy-three patients with a diagnosis of acute ischaemic stroke were included. Venous blood samples were drawn on the first day and the seventh day after stroke onset. Plasma microparticles, MPs-TF, TF and TFPI were determined by enzyme-linked immunosorbent assay. Assessment variables were timing of blood collection, type of stroke treatment, presence or absence of diabetes mellitus and hypertension, and scores on the National Institutes of Health Stroke Scale together with scores on the modified Rankin Scale. Whilst MPs-TF and TFPI levels of stroke subjects were significantly higher (median, 1.63 vs. 0.73 pg/ml; median, 114.26 vs. 78.60 ng/ml, respectively), TF levels in the plasma of stroke patients were significantly lower (median, 82.27 vs. 97.80 pg/ml) than those of healthy individuals. Lower levels of TF were detected in patients with severe stroke in comparison with patients with mild stroke. Moreover, the data also showed that in stroke patients not treated with alteplase the activity of microparticles was significantly higher 1 week after diagnosis in comparison with the activity at the time of diagnosis. Our findings suggest that patients with acute ischaemic stroke have increased generation of MPs-TF. Nevertheless, further studies are needed in order to confirm such inference. © 2014 EAN.

  3. Value of anti-modified citrullinated vimentin and third-generation anti-cyclic citrullinated peptide compared with second-generation anti-cyclic citrullinated peptide and rheumatoid factor in predicting disease outcome in undifferentiated arthritis and rheumatoid arthritis.

    PubMed

    van der Linden, Michael P M; van der Woude, Diane; Ioan-Facsinay, Andreea; Levarht, E W Nivine; Stoeken-Rijsbergen, Gerrie; Huizinga, Tom W J; Toes, René E M; van der Helm-van Mil, Annette H M

    2009-08-01

    Autoantibodies such as rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPAs) determined by testing with second-generation anti-cyclic citrullinated peptide (anti-CCP-2) are frequently measured in clinical practice because of their association with disease outcome in undifferentiated arthritis (UA) and rheumatoid arthritis (RA). Recently, 2 new ACPA tests were developed: third-generation anti-CCP (anti-CCP-3) and anti-modified citrullinated vimentin (anti-MCV) autoantibody tests. To facilitate the decision on which autoantibody to test in daily practice, this study evaluated the capability of these autoantibodies and combinations of them to predict 3 outcome measures: progression from UA to RA, the rate of joint destruction in RA, and the chance of achieving sustained disease-modifying antirheumatic drug (DMARD)-free remission in RA. Patients with UA (n=625) were studied for whether UA progressed to RA after 1 year. Patients with RA (n=687) were studied for whether sustained DMARD-free remission was achieved and for the rate of joint destruction during a median followup of 5 years. Positive predictive values (PPVs) for RA development and for associations with the disease course in RA were compared between single tests (anti-CCP-2, anti-CCP-3, anti-MCV, and RF) and between combinations of these tests. Among the single tests performed in patients with UA, anti-CCP-2 tended to have the highest PPV for RA development (67.1%), but the 95% confidence intervals of the other tests overlapped. Among the single tests in patients with RA, all 4 tests showed comparable associations with the rate of joint destruction and with the achievement of remission. In both ACPA-positive and ACPA-negative RA, the presence of RF was not associated with more joint destruction. For all outcome measures, performing combinations of 2 or 3 autoantibody tests did not increase the predictive accuracy compared with performing a single test. For clinical practice, a single

  4. A combined supplementation of vitamin B12 and n-3 polyunsaturated fatty acids across two generations improves nerve growth factor and vascular endothelial growth factor levels in the rat hippocampus.

    PubMed

    Rathod, Richa; Khaire, Amrita; Kale, Anvita; Joshi, Sadhana

    2016-12-17

    Vitamin B12 and n-3 polyunsaturated fatty acid (n-3 PUFA) are known to influence cognition. This study aims to examine if these nutrients affect the protein levels and gene expression of nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) in the cortex and hippocampus in the second-generation offspring at 3 mo of age. Wistar rats were fed the following diets for two generations: Control (CON), vitamin B12 deficient (VBD), vitamin B12 deficient supplemented with n-3 PUFA (VBDO), vitamin B12 supplemented (VBS), vitamin B12 supplemented with n-3 PUFA (VBSO). The VEGF and NGF gene expression and protein levels in the hippocampus were lower (P⩽0.01) in the VBD group as compared to the CON group while the VBDO group restored the VEGF and NGF gene expression (P⩽0.01). The VBS group showed similar levels of NGF and VEGF to that of the CON group. However, the VBSO group demonstrated higher (P⩽0.05) NGF gene expression and protein levels in the hippocampus and higher cortex NGF protein levels as compared to the CON group. In addition, VEGF (in hippocampus) and NGF (in cortex and hippocampus) protein levels were also higher (P⩽0.05) in the VBSO group as compared to the VBS group. Our results indicate that the combined supplementation of vitamin B12 and n-3 PUFA improves NGF and maintains VEGF levels in the brain which may improve neurovascular function. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Efficacy and safety of a new generation von Willebrand factor/factor VIII concentrate (Wilate®) in the management of perioperative haemostasis in von Willebrand disease patients undergoing surgery.