320 research outputs found
Vergleich unterschiedlicher Definitionen und Determinanten des Belastungshochdrucks anhand einer Stichprobe der populations-basierten Study of Health in Pomerania (SHIP)
Die arterielle Hypertonie (aHT) stellt einen wichtigen kardio- und zerebrovaskulĂ€ren Risikofaktor dar. Durch eine nicht diagnostizierte, unbehandelte aHT kommt es zu einer Reihe von EndorganschĂ€den und damit verbunden zu einem Anstieg der MorbiditĂ€t und MortalitĂ€t. In frĂŒher durchgefĂŒhrten Studien ergab sich der Anhalt dafĂŒr, dass eine ĂŒberschieĂende Blutdruckregulation wĂ€hrend eines Belastungstests als PrĂ€diktor fĂŒr eine sich in Zukunft entwickelnde aHT darstellen könnte. Jedoch existiert fĂŒr den Belastungshypertonus aktuell weder eine einheitliche Definition noch ein standardisiertes Untersuchungsprotokoll.
In der vorliegenden Arbeit wurden erstmalig zwölf unterschiedliche, in der Literatur hĂ€ufig verwendete, Definitionen fĂŒr einen Belastungshypertonus auf eine 662 Probanden (388 Frauen, 274 MĂ€nner) umfassende Stichprobe einer bevölkerungs-basierten Kohorte angewendet, der Study of Health in Pomerania (SHIP). Es wurden die PrĂ€valenzen sowie assoziierte Risikofaktoren und subklinische kardiovaskulĂ€re Risikomarker der unterschiedlichen Definitionen miteinander verglichen. ZusĂ€tzlich konnten mögliche Determinanten eines Belastungshypertonus identifiziert werden.
Durch diese Arbeit konnte ein Beitrag zum weiteren VerstĂ€ndnis der Belastungshypertonie erbracht werden. Es konnte gezeigt werden, dass sich die mit einem Belastungshochdruck assoziierten Risikofaktorenprofile und subklinische kardiovaskulĂ€re Risikomarker abhĂ€ngig von der angewandten Definition stark voneinander unterschieden. Bei der in dieser Arbeit untersuchten Kohorte wiesen insbesondere das Alter, der BMI und eine vergröĂerte IMT signifikante Unterschiede bei den Definitionen auf, die sich auf die Entwicklung des systolischen Blutdrucks bezogen. Die nachgewiesene, vom Geschlecht abhĂ€ngige, ungleiche Blutdruckentwicklung unter Belastung, insbesondere unter einer submaximalen, unterstĂŒtzt die These der Wichtigkeit von geschlechtsspezifischen Referenzwerten und Belastungsstufen.
Damit der Belastungshypertonus einen möglichen Einzug in den praktischen Klinikalltag halten kann, sollte weiter an einer Standardisierung eines Untersuchungsprotokolls und an geschlechtsspezifischen und nach dem Alter abgestuften Referenzwerten gearbeitet werden.Arterial hypertension is an important cardiovascular and cerebrovascular risk factor. An undiagnosed, untreated arterial hypertension causes a series of end organ damages and is associated with an increase in morbidity and mortality. Previous studies suggested that an exceeded exercise blood pressure regulation (exercise hypertension) during a stress test could be a predictor of a developing arterial hypertension in the future. However, there is currently no standard definition or standardized protocol for exercise hypertension.
For the first time, twelve different commonly used definitions of exercise hypertension were applied to a sample of 662 subjects (388 women, 274 men). These were selected out of a population-based cohort, the Study of Health in Pomerania (SHIP). The prevalences, associated risk factors and subclinical cardiovascular risk markers of the different definitions were compared. In addition, possible determinants of an exercise hypertension could be identified.
Through this doctoral thesis, a contribution to the further understanding of exercise hypertension could be provided. It could be shown that the risk factor profiles and subclinical cardiovascular risk markers differed strongly depending on the applied definition of an exercise hypertension. In the examined cohort, in particular, age, BMI and IMT revealed significant differences in definitions those investigated a change of systolic blood pressure under stress testing. The proven gender-dependent, unequal blood pressure development under exercise, especially below submaximal stress, supports the thesis of the importance of gender-specific reference levels and stress levels.
In order for the exercise hypertension to become a possible entry into the daily clinical routine, further work should be carried out to standardize a protocol of examination and gender-specific and age-graded reference values
PKCα Deficiency in Mice Is Associated with Pulmonary Vascular Hyperresponsiveness to Thromboxane A2 and Increased Thromboxane Receptor Expression
Pulmonary vascular hyperresponsiveness is a main characteristic of pulmonary
arterial hypertension (PAH). In PAH patients, elevated levels of the
vasoconstrictors thromboxane A2 (TXA2), endothelin (ET)-1 and serotonin
further contribute to pulmonary hypertension. Protein kinase C (PKC) isozyme
alpha (PKCα) is a known modulator of smooth muscle cell contraction. However,
the effects of PKCα deficiency on pulmonary vasoconstriction have not yet been
investigated. Thus, the role of PKCα in pulmonary vascular responsiveness to
the TXA2 analog U46619, ET-1, serotonin and acute hypoxia was investigated in
isolated lungs of PKCα-/- mice and corresponding wild-type mice, with or
without prior administration of the PKC inhibitor bisindolylmaleimide I or
Gö6976. mRNA was quantified from microdissected intrapulmonary arteries. We
found that broad-spectrum PKC inhibition reduced pulmonary vascular
responsiveness to ET-1 and acute hypoxia and, by trend, to U46619.
Analogously, selective inhibition of conventional PKC isozymes or PKCα
deficiency reduced ET-1-evoked pulmonary vasoconstriction. The pulmonary
vasopressor response to serotonin was unaffected by either broad PKC
inhibition or PKCα deficiency. Surprisingly, PKCα-/- mice showed pulmonary
vascular hyperresponsiveness to U46619 and increased TXA2 receptor (TP
receptor) expression in the intrapulmonary arteries. To conclude, PKCα
regulates ET-1-induced pulmonary vasoconstriction. However, PKCα deficiency
leads to pulmonary vascular hyperresponsiveness to TXA2, possibly via
increased pulmonary arterial TP receptor expression
final results of a noninterventional study
Background Data are limited regarding routine use of everolimus after initial
vascular endothelial growth factor (VEGF)âtargeted therapy. The aim of this
prospective, noninterventional, observational study was to assess efficacy and
safety of everolimus after initial VEGF-targeted treatment in patients with
metastatic renal cell carcinoma (mRCC) in routine clinical settings. Methods
Everolimus was administered per routine clinical practice. Patients with mRCC
of any histology from 116 active sites in Germany were included. The main
objective was to determine everolimus efficacy in time to progression (TTP).
Progression-free survival (PFS), treatment duration, tumor response, adherence
to everolimus regimen, treatment after everolimus, and safety were also
assessed. Results In the total population (Nâ=â334), median follow-up was 5.2
months (range, 0â32 months). Median treatment duration (safety population, nâ=
318) was 6.5 months (95% confidence interval [CI], 5â8 months). Median TTP and
median PFS were similar in populations investigated. In patients who received
everolimus as second-line treatment (nâ=â211), median (95% CI) TTP was 7.1
months (5â9 months) and median PFS was 6.9 months (5â9 months). Commonly
reported adverse events (safety population, nâ=â318) were dyspnea (17%),
anemia (15%), and fatigue (12%). Limitations of the noninterventional design
should be considered. Conclusions This study reflects routine clinical use of
everolimus in a large sample of patients with mRCC. Favorable efficacy and
safety were seen for everolimus after previous therapy with one VEGF-targeted
agent. Results of this study confirm everolimus as one of the standard options
in second-line therapy for patients with mRCC. Novartis study code,
CRAD001LD27: VFA registry for noninterventional studies
(http://www.vfa.de/de/forschung/nisdb/ webcite)
Everolimus in metastatic renal cell carcinoma after failure of initial anti-VEGF therapy: final results of a noninterventional study
Background: Data are limited regarding routine use of everolimus after initial vascular endothelial growth factor (VEGF)-targeted therapy. The aim of this prospective, noninterventional, observational study was to assess efficacy and safety of everolimus after initial VEGF-targeted treatment in patients with metastatic renal cell carcinoma (mRCC) in routine clinical settings. Methods: Everolimus was administered per routine clinical practice. Patients with mRCC of any histology from 116 active sites in Germany were included. The main objective was to determine everolimus efficacy in time to progression (TTP). Progression-free survival (PFS), treatment duration, tumor response, adherence to everolimus regimen, treatment after everolimus, and safety were also assessed. Results: In the total population (N = 334),median follow-up was 5.2 months (range, 0-32 months). Median treatment duration (safety population, n = 318) was 6.5 months (95% confidence interval [CI], 5-8 months). Median TTP and median PFS were similar in populations investigated. In patients who received everolimus as second-line treatment (n = 211),median (95% CI) TTP was 7.1 months (5-9 months) and median PFS was 6.9 months (5-9 months). Commonly reported adverse events (safety population, n = 318) were dyspnea (17%),anemia (15%), and fatigue (12%). Limitations of the noninterventional design should be considered. Conclusions: This study reflects routine clinical use of everolimus in a large sample of patients with mRCC. Favorable efficacy and safety were seen for everolimus after previous therapy with one VEGF-targeted agent. Results of this study confirm everolimus as one of the standard options in second-line therapy for patients with mRCC
Acute Moraxella catarrhalis Airway Infection of Chronically Smoke-Exposed Mice Increases Mechanisms of Emphysema Development : A Pilot Study
In chronic obstructive pulmonary disease (COPD), acute exacerbations and emphysema development are characteristics for disease pathology. COPD is complicated by infectious exacerbations with acute worsening of respiratory
symptoms with Moraxella catarrhalis as one of the most frequent pathogens. Although cigarette smoke (CS) is the
primary risk factor, additional molecular mechanisms for emphysema development induced by bacterial infections
are incompletely understood. We investigated the impact of M. catarrhalis on emphysema development in CS exposed mice and asked whether an additional infection would induce a solubilization of pro-apoptotic and proinflammatory endothelial monocyte-activating-protein-2 (EMAPII) to exert its activities in the pulmonary microvasculature and other parts of the lungs not exposed directly to CS.
Mice were exposed to smoke (6 or 9 months) and/or infected with M. catarrhalis. Lungs, bronchoalveolar lavage
fluid (BALF), and plasma were analyzed.
CS exposure reduced ciliated area, caused rarefaction of the lungs, and induced apoptosis. EMAPII was increased
independent of prior smoke exposure in BALF of infected mice. Importantly, acute M. catarrhalis infection increased release of matrixmetalloproteases-9 and -12, which are involved in emphysema development and comprise
a mechanism of EMAPII release.
Our data suggest that acute M. catarrhalis infection represents an independent risk factor for emphysema development in smoke-exposed mice
Extensive arterial and venous thrombo-embolism with chemotherapy for testicular cancer: a case report
Germ cell tumours tend to affect young adults and with advanced treatments achieve more than 90% cure rates. Over the years cisplatin has significantly improved the relapse free survival in these patients, hence forming an essential component of chemotherapy regimes. But, the thrombo-embolic complications suffered with cisplatin significantly affect the quality of life in these young patients
Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment
Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1 . In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene ( OPA1 ), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1 . Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1 , p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1 . Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome. © 2011 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/84383/1/33970_ftp.pd
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p90 ribosomal S6 kinases play a significant role in early gene regulation in the cardiomyocyte response to Gq protein-coupled receptor stimuli, endothelin-1 and α1-adrenergic receptor agonists
Extracellular signal-regulated kinases 1/2 (ERK1/2) and their substrates, p90 ribosomal S6 kinases (RSKs), phosphorylate different transcription factors, contributing differentially to transcriptomic profiles. In cardiomyocytes, ERK1/2 are required for >70% of the transcriptomic response to endothelin-1. Here, we investigated the role of RSKs in the transcriptomic responses to Gq protein-coupled receptor agonists, endothelin-1, phenylephrine (generic α1-adrenergic receptor agonist) and A61603 (α1A-adrenergic receptor selective). Phospho-ERK1/2 and phospho-RSKs appeared in cardiomyocyte nuclei within 2-3 min of stimulation (endothelin-1>a61603âphenylephrine). All agonists increased nuclear RSK2, but only endothelin-1 increased nuclear RSK1 content. PD184352 (inhibits ERK1/2 activation) and BI-D1870 (inhibits RSKs) were used to dissect the contribution of RSKs to the endothelin-1-responsive transcriptome. Of 213 RNAs upregulated at 1 h, 51% required RSKs for upregulation whereas 29% required ERK1/2 but not RSKs. The transcriptomic response to phenylephrine overlapped with, but was not identical to, endothelin-1. As with endothelin-1, PD184352 inhibited upregulation of most phenylephrine-responsive transcripts, but the greater variation in effects of BI-D1870 suggests that differential RSK signalling influences global gene expression. A61603 induced similar changes in RNA expression in cardiomyocytes as phenylephrine, indicating that the signal was mediated largely through α1A-adrenergic receptors. A61603 also increased expression of immediate early genes in perfused adult rat hearts and, as in cardiomyocytes, upregulation of the majority of genes was inhibited by PD184352. PD184352 or BI-D1870 prevented the increased surface area induced by endothelin-1 in cardiomyocytes. Thus, RSKs play a significant role in regulating cardiomyocyte gene expression and hypertrophy in response to Gq protein-coupled receptor stimulation
Integrin alpha V beta 3 targeted dendrimerârapamycin conjugate reduces fibroblastâmediated prostate tumor progression and metastasis
Therapeutic strategies targeting both cancer cells and associated cells in the tumor microenvironment offer significant promise in cancer therapy. We previously reported that generation 5 (G5) dendrimers conjugated with cyclicâRGD peptides target cells expressing integrin alpha V beta 3. In this study, we report a novel dendrimer conjugate modified to deliver the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. In vitro analyses demonstrated that this drug conjugate, G5âFIâRGDârapamycin, binds to prostate cancer (PCa) cells and fibroblasts to inhibit mTOR signaling and VEGF expression. In addition, G5âFIâRGDârapamycin inhibits mTOR signaling in cancer cells more efficiently under proinflammatory conditions compared to free rapamycin. In vivo studies established that G5âFIâRGDârapamycin significantly inhibits fibroblastâmediated PCa progression and metastasis. Thus, our results suggest the potential of new rapamycinâconjugated multifunctional nanoparticles for PCa therapy.Here, we synthesized and characterized a novel dendrimer conjugate, G5âFIâRGDârapamycin. Multifunctional G5âFIâRGDârapamycin binds to PCa and fibroblasts via alpha V beta 3 integrin and significantly inhibits mTOR signaling and VEGF expression. These in vitro data were confirmed by in vivo data that G5âFIâRGDârapamycin inhibits fibroblastâmediated PCa progression and metastasis.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146470/1/jcb26727.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146470/2/jcb26727_am.pd
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