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  • 1
    Online Resource
    Online Resource
    35th Annual Meeting of the European Association for the Study of Diabetes : Brussels, Belgium, 28 September–2 October 1999
    Springer Science and Business Media LLC ; 1999
    In:  Diabetologia Vol. 42, No. S1 ( 1999-8), p. A1-A330
    Details
    In: Diabetologia, Springer Science and Business Media LLC, Vol. 42, No. S1 ( 1999-8), p. A1-A330
    Type of Medium: Online Resource
    ISSN: 0012-186X , 1432-0428
    URL: Article
    DOI: 10.1007/BF03375458
    RVK:
    XA 40615
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 1999
    detail.hit.zdb_id: 1458993-X
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  • 2
    Online Resource
    Online Resource
    40th EASD Annual Meeting of the European Association for the Study of Diabetes : Munich, Germany, 5–9 September 2004
    Springer Science and Business Media LLC ; 2004
    In:  Diabetologia Vol. 47, No. S1 ( 2004-8), p. A1-A464
    Details
    In: Diabetologia, Springer Science and Business Media LLC, Vol. 47, No. S1 ( 2004-8), p. A1-A464
    Type of Medium: Online Resource
    ISSN: 0012-186X , 1432-0428
    URL: Article
    DOI: 10.1007/BF03375463
    RVK:
    XA 40615
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2004
    detail.hit.zdb_id: 1458993-X
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  • 3
    Online Resource
    Online Resource
    Structure and promoter activity of an islet-specific glucose-6-phosphatase catalytic subunit-related gene.
    American Diabetes Association ; 1999
    In:  Diabetes Vol. 48, No. 3 ( 1999-03-01), p. 543-551
    Details
    In: Diabetes, American Diabetes Association, Vol. 48, No. 3 ( 1999-03-01), p. 543-551
    Abstract: In liver and kidney, the terminal step in the gluconeogenic pathway is catalyzed by glucose-6-phosphatase (G-6-Pase). This enzyme is actually a multicomponent system, the catalytic subunit of which was recently cloned. Numerous reports have also described the presence of G-6-Pase activity in islets, although the role of G-6-Pase in this tissue is unclear. Arden and associates have described the cloning of a novel cDNA that encodes an islet-specific G-6-Pase catalytic subunit-related protein (IGRP) (Arden SD, Zahn T, Steegers S, Webb S, Bergman B, O'Brien RM, Hutton JC: Molecular cloning of a pancreatic islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP). Diabetes 48:531-542, 1999). We screened a mouse BAC library with this cDNA to isolate the IGRP gene, which spans approximately 8 kbp of genomic DNA. The exon/intron structure of the IGRP gene has been mapped and, as with the gene encoding the liver/kidney G-6-Pase catalytic subunit, it is composed of five exons. The sizes of these exons are 254 (I), 110 (II), 112 (III), 116 (IV), and 1284 (V) bp, similar to those of the G-6-Pase catalytic subunit gene. Two interspecific backcross DNA mapping panels were used to unambiguously localize the IGRP gene (map symbol G6pc-rs) to the proximal portion of mouse chromosome 2. The IGRP gene transcription start site was mapped by primer extension analysis, and the activity of the IGRP gene promoter was analyzed in both the islet-derived HIT cell line and the liver-derived HepG2 cell line. The IGRP and G-6-Pase catalytic subunit gene promoters show a reciprocal pattern of activity, with the IGRP promoter being approximately 150-fold more active than the G-6-Pase promoter in HIT cells.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.48.3.543
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1999
    detail.hit.zdb_id: 1501252-9
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  • 4
    Online Resource
    Online Resource
    P6193Dalcetrapib reduces incident diabetes in patients with recent acute coronary syndrome
    Oxford University Press (OUP) ; 2019
    In:  European Heart Journal Vol. 40, No. Supplement_1 ( 2019-10-01)
    Details
    In: European Heart Journal, Oxford University Press (OUP), Vol. 40, No. Supplement_1 ( 2019-10-01)
    Abstract: Among patients with acute coronary syndrome (ACS) who do not have diabetes, incident diabetes is common and associated with an adverse prognosis. Some data suggest that high density lipoprotein (HDL) has favourable effects on beta cell function and that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes in conjunction with increased HDL cholesterol (HDL-C) concentration. Dalcetrapib is a CETP inhibitor under ongoing evaluation as a potential cardiovascular therapy. Purpose We compared the effect of treatment with dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome (ACS). Methods In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg or placebo daily, beginning 4–12 weeks after ACS. Absence of diabetes at baseline was based upon medical history, no use of diabetes medication, haemoglobin A1c 〈 6.5%, and plasma glucose level 〈 7 mmol/L (if measured under fasting conditions) or 〈 11.1 mmol/L (if measured under non-fasting conditions). Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, use of a diabetes medication, HbA1c ≥6.5%, or two measurements of plasma glucose ≥7 mmol/L (fasting) or ≥11.1 mmol/L (non-fasting). The association of incident diabetes with baseline and on-treatment HDL-C was determined. Results At baseline, 10621 patients (67% of the trial cohort) did not have diabetes and formed the analysis cohort. Over median follow-up of 31 months, incident diabetes was identified in 392 of 5314 patients (7.4%) assigned to dalcetrapib and 505 of 5307 (9.5%) assigned to placebo (odds ratio [OR] 0.76; 95% confidence interval [CI] 0.66–0.87; P 〈 0.001). This corresponds to an absolute reduction in incident diabetes of 2.1%, and a need to treat 47 patients (for 31 months) to prevent 1 case of diabetes. Kaplan-Meier estimates of the cumulative incidence of diabetes are shown in the Figure. Across both treatment groups, incident diabetes was inversely associated with baseline HDL-C (OR 0.98 for 1 mg/dL increase in baseline HDL-C; 95% CI 0.97–0.98, P 〈 0.001). In the dalcetrapib group, there was a further inverse association of incident diabetes with the change in HDL-C on assigned treatment (OR 0.98 for 1 mg/dL increase in HDL-C from baseline; 95% CI 0.97–0.99, P=0.002). Dalcetrapib was safe and generally well-tolerated in the trial. Conclusions In patients with recent ACS who do not have diabetes at baseline, incident diabetes is common. Dalcetrapib treatment reduced the relative risk of incident diabetes by 24% and the absolute risk by 2.1% over a median of 31 months. The reduction in incident diabetes with dalcetrapib was associated with increased HDL-C on treatment. Acknowledgement/Funding The dal-OUTCOMES trial was funded by F. Hoffmann LaRoche
    Type of Medium: Online Resource
    ISSN: 0195-668X , 1522-9645
    URL: Article
    DOI: 10.1093/eurheartj/ehz746.0798
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2001908-7
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  • 5
    Online Resource
    Online Resource
    Response durability after cessation of immune checkpoint inhibitors in patients with metastatic Merkel cell carcinoma: a retrospective multicenter DeCOG study
    Springer Science and Business Media LLC ; 2021
    In:  Cancer Immunology, Immunotherapy Vol. 70, No. 11 ( 2021-11), p. 3313-3322
    Details
    In: Cancer Immunology, Immunotherapy, Springer Science and Business Media LLC, Vol. 70, No. 11 ( 2021-11), p. 3313-3322
    Abstract: Immune checkpoint inhibitors (ICI) have led to a prolongation of progression-free and overall survival in patients with metastatic Merkel cell carcinoma (MCC). However, immune-mediated adverse events due to ICI therapy are common and often lead to treatment discontinuation. The response duration after cessation of ICI treatment is unknown. Hence, this study aimed to investigate the time to relapse after discontinuation of ICI in MCC patients. Methods We analyzed 20 patients with metastatic MCC who have been retrospectively enrolled at eleven skin cancer centers in Germany. These patients have received ICI therapy and showed as best overall response (BOR) at least a stable disease (SD) upon ICI therapy. All patients have discontinued ICI therapy for other reasons than disease progression. Data on treatment duration, tumor response, treatment cessation, response durability, and tumor relapse were recorded. Results Overall, 12 of 20 patients (60%) with MCC relapsed after discontinuation of ICI. The median response durability was 10.0 months. Complete response (CR) as BOR to ICI-treatment was observed in six patients, partial response (PR) in eleven, and SD in three patients. Disease progression was less frequent in patients with CR (2/6 patients relapsed) as compared to patients with PR (7/11) and SD (3/3), albeit the effect of initial BOR on the response durability was below statistical significance. The median duration of ICI therapy was 10.0 months. Our results did not show a correlation between treatment duration and the risk of relapse after treatment withdrawal. Major reasons for discontinuation of ICI therapy were CR (20%), adverse events (35%), fatigue (20%), or patient decision (25%). Discontinuation of ICI due to adverse events resulted in progressive disease (PD) in 71% of patients regardless of the initial response. A re-induction of ICI was initiated in 8 patients upon tumor progression. We observed a renewed tumor response in 4 of these 8 patients. Notably, all 4 patients showed an initial BOR of at least PR. Conclusion Our results from this contemporary cohort of patients with metastatic MCC indicate that MCC patients are at higher risk of relapse after discontinuation of ICI as compared to melanoma patients. Notably, the risk of disease progression after discontinuation of ICI treatment is lower in patients with initial CR (33%) as compared to patients with initial PR (66%) or SD (100%). Upon tumor progression, re-induction of ICI is a feasible option. Our data suggest that the BOR to initial ICI therapy might be a potential predictive clinical marker for a successful re-induction.
    Type of Medium: Online Resource
    ISSN: 0340-7004 , 1432-0851
    URL: Article
    DOI: 10.1007/s00262-021-02925-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1458489-X
    detail.hit.zdb_id: 195342-4
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  • 6
    Online Resource
    Online Resource
    Polycythemic responses to hypoxia: molecular and genetic mechanisms of chronic mountain sickness
    American Physiological Society ; 1998
    In:  Journal of Applied Physiology Vol. 84, No. 4 ( 1998-04-01), p. 1242-1251
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 84, No. 4 ( 1998-04-01), p. 1242-1251
    Abstract: We examined erythropoietin (EPO) gene expression and EPO production during hypoxia in two Sprague-Dawley rat strains with divergent polycythemic responses to hypoxia. Hilltop (H) rats develop severe polycythemia, severe hypoxemia, and pulmonary artery hypertension. The H rats often die from a syndrome indistinguishable from chronic mountain sickness (CMS) in humans. Madison (M) rats develop polycythemia and pulmonary artery hypertension that is modest and suffer no excess mortality. We tested the hypothesis that these rat strains have different stimulus-response characteristics governing EPO production. Rats of each strain were exposed to hypoxia (0.5 atm, 73 Torr inspired [Formula: see text]), and renal tissue EPO mRNA and EPO levels, plasma EPO, ventilation, arterial and renal venous blood gases, and indexes of renal function were measured at fixed times during a 30-day hypoxic exposure. During extended hypoxic exposure, H rats had significantly elevated renal EPO mRNA, renal EPO, and plasma EPO levels compared with M rats. Ventilatory responses and indexes of renal function were similar in the strains during the hypoxic exposure. H rats had greater arterial hypoxemia from the onset of hypoxia and more severe renal tissue hypoxemia and greater polycythemia after 14 days of hypoxic exposure. When EPO responses were expressed as functions of renal venous[Formula: see text] , the two strains appeared to lie on the same dose-response curves, but the responses of H rats were shifted along the curve toward more hypoxic values. We conclude that H rats have significantly greater polycythemia secondary to poorer renal tissue oxygenation, but the stimulus-response characteristics governing EPO gene expression and EPO production do not seem to differ between M and H rats. Finally, the regulation of EPO levels during hypoxia occurs primarily at the transcriptional level.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/jappl.1998.84.4.1242
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1998
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 7
    Online Resource
    Online Resource
    Ventilatory and hematopoietic responses to chronic hypoxia in two rat strains
    American Physiological Society ; 1992
    In:  Journal of Applied Physiology Vol. 72, No. 6 ( 1992-06-01), p. 2354-2363
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 72, No. 6 ( 1992-06-01), p. 2354-2363
    Abstract: Hilltop (H) and Madison (M) strains of Sprague-Dawley rats exhibit strikingly different susceptibilities to the effects of chronic altitude exposure. The H rats develop greater polycythemia, hypoxemia, and pulmonary hypertension. We studied ventilation, pulmonary gas exchange, tissue oxygenation, and hematologic adaptations in the two rat strains during a 50-day exposure to a simulated altitude (HA) of 5,500 m (18,000 ft). There were no strain differences among the variables we studied under sea level (SL) conditions. Within the first 14 days of hypoxic exposure, the only significant strain differences were that erythropoietin (EPO) rose much higher and erythroid activity was greater in the H rats, even though arterial Po2 and PCo2 (Pao2 and PaCo2, respectively), renal venous PO2 (Prvo2), and ventilation (VE) were equivalent in the two strains during this time. By day 14 at HA, the H rats had significantly higher erythroid activity, hematocrit (Hct), and EPO levels, significantly lower PaO2 and PrvO2, but equivalent VE and PaCO2. These changes persisted for the remainder of the exposure, except that the Hct continued to rise and the increase was greater in H rats. Despite the greater O2-carrying capacity of H rats in the later stages of hypoxic exposure, PaO2 and PrvO2 were significantly lower in H rats. There were no strain differences at either SL or HA in ventilatory responses to hypercapnia or hypoxia, in blood O2 affinity or 2,3-diphosphoglycerate, in extrarenal production of EPO, or in EPO clearance. We conclude that early in the hypoxic exposure the H rats produce more EPO at apparently equivalent levels of hypoxia, and this is the first step in the pathogenesis of the maladaptation to HA manifest by H rats. We find no consistent evidence that differences in VE contribute to the variable susceptibility to hypoxia in the two rat strains.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/jappl.1992.72.6.2354
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1992
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 8
    Online Resource
    Online Resource
    Identification of respiratory vagal feedback in awake normal subjects using pseudorandom unloading
    American Physiological Society ; 2001
    In:  Journal of Applied Physiology Vol. 90, No. 6 ( 2001-06-01), p. 2330-2340
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 90, No. 6 ( 2001-06-01), p. 2330-2340
    Abstract: Evidence of the Hering-Breuer reflex has been found in humans during anesthesia and sleep but not during wakefulness. Cortical influences, present during wakefulness, may mask the effects of this reflex in awake humans. We hypothesized that, if lung volume were increased in awake subjects unaware of the stimulus, vagal feedback would modulate breathing on a breath-to-breath basis. To test this hypothesis, we employed proportional assist ventilation in a pseudorandom sequence to unload the respiratory system above and below the perceptual threshold in 17 normal subjects. Tidal volume, integrated respiratory muscle pressure per breath, and inspiratory time were recorded. Both sub- and suprathreshold stimulation evoked a significant increase in tidal volume and inspiratory flow rate, but a significant decrease in inspiratory time was present only during the application of a subthreshold stimulus. We conclude that vagal feedback modulates respiratory timing on a breath-by-breath basis in awake humans, as long as there is no awareness of the stimulus.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/jappl.2001.90.6.2330
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2001
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 9
    Online Resource
    Online Resource
    Temozolomide (TMZ) in combination with pegylated interferon alfa-2b for stage IV metastatic melanoma: A multicenter phase II trial of the Dermatologic Cooperative Oncology Group (DeCOG)
    American Society of Clinical Oncology (ASCO) ; 2006
    In:  Journal of Clinical Oncology Vol. 24, No. 18_suppl ( 2006-06-20), p. 8017-8017
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 24, No. 18_suppl ( 2006-06-20), p. 8017-8017
    Abstract: 8017 Background: Modifying the pharmacokinetic profile of IFN alfa-2b (PegIFN) may improve its activity and tolerability. Specifically, the conjugation of recombinant IFN alfa-2b with a 12 kDa polyethylene glycol (Peg) chain results in a prolonged half-life and has been previously demonstrated to increase efficacy in hepatitis C patients compared to nonpegylated IFNs. We therefore evaluated the combination of TMZ with PegIFN in stage IV metastatic melanoma. Methods: This open-label, phase II study was conducted by the DeCOG at 10 study sites. Eligible pts were between 18 and 75 yrs, had a histologically confirmed diagnosis of metastatic melanoma (stage IV AJCC), no brain metastases and no prior chemotherapy. Pts were required to have a Karnofsky score of 〉 60% as well as adequate renal, liver and bone marrow function. Informed consent from all participants and approval from the corresponding ethic committees was provided. The regimen (28 d cycles) consisted of TMZ (200 mg/m 2 d 1–5) in combination with PegIFN (100 μg sc d 1, 8, 15 and 21). Patients received 2 cycles before reevaluation (WHO response criteria). OR and OS were primary and TTP and toxicity were secondary endpoints of the trial. Results: 124 pts were accrued between 10/02 and 7/04, 8 pts were ineligible or withdrew consent, and thus 116 pts were treated per protocol. At the time of data analysis, 81.0% of pts had died from melanoma and median follow up time was 9.4 months. OR was 18.1% (2 CR, 1.7%; 16 PR; 16.4%); 25.0% of pts presented with SD and 54.3 % progressed (2.6% not evaluable). Median TTP was 2.8 months, median OS 9.0 months (95% CI 7,4;10,6). Grade (gr) 3/4 leucopenia occurred in 22.8% and gr 3/4 thrombocytopenia in 20.3%. Gr 1/2 nausea and emesis experienced 37.5% of the pts; severe nausea (gr 3/4) was rare (1.7%). Liver enzyme elevation occurred in 30.5 % (26.3% gr 1/2; 4.2% gr 3). Conclusions: Combination therapy with TMZ and pegylated interferon alfa-2b constitutes a manageable treatment option in the outpatient setting for advanced metastatic melanoma. Its primary advantage is an increased patient convenience as a result of oral intake of TMZ and once weekly application of PegIFN. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2006.24.18_suppl.8017
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2006
    detail.hit.zdb_id: 2005181-5
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  • 10
    Online Resource
    Online Resource
    A Proof-of-Concept Study of Transcutaneous Magnetic Spinal Cord Stimulation for Neurogenic Bladder
    Springer Science and Business Media LLC ; 2018
    In:  Scientific Reports Vol. 8, No. 1 ( 2018-08-22)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2018-08-22)
    Abstract: Patients with chronic spinal cord injury (SCI) cannot urinate at will and must empty the bladder by self-catheterization. We tested the hypothesis that non-invasive, transcutaneous magnetic spinal cord stimulation (TMSCS) would improve bladder function in individuals with SCI. Five individuals with American Spinal Injury Association Impairment Scale A/B, chronic SCI and detrusor sphincter dyssynergia enrolled in this prospective, interventional study. After a two-week assessment to determine effective stimulation characteristics, each patient received sixteen weekly TMSCS treatments and then received “sham” weekly stimulation for six weeks while bladder function was monitored. Bladder function improved in all five subjects, but only during and after repeated weekly sessions of 1 Hz TMSCS. All subjects achieved volitional urination. The volume of urine produced voluntarily increased from 0 cc/day to 1120 cc/day (p = 0.03); self-catheterization frequency decreased from 6.6/day to 2.4/day (p = 0.04); the capacity of the bladder increased from 244 ml to 404 ml (p = 0.02); and the average quality of life ranking increased significantly (p = 0.007). Volitional bladder function was re-enabled in five individuals with SCI following intermittent, non-invasive TMSCS. We conclude that neuromodulation of spinal micturition circuitry by TMSCS may be used to ameliorate bladder function.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-018-30232-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2615211-3
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