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Buvat J.,Center Detudes Et Of Traitement Of La Pathologie Of Lappareil Reproducteur Et Psychosomatique | Maggi M.,University of Florence | Gooren L.,Medical Center | Guay A.T.,Harvard University | And 7 more authors.
Journal of Sexual Medicine | Year: 2010

Introduction. Endocrine disorders may adversely affect men's sexual function. Aim. To provide recommendations based on best evidence for diagnosis and treatment of endocrine-related male sexual dysfunctions. Methods. The Endocrine Aspects of Male Sexual Dysfunctions Committee, including 11 members from eight countries and four continents, collaborated with the Endocrine subcommittee of the Standards Committee of the International Society for Sexual Medicine. Medical literature was reviewed in detail, followed by extensive internal committee discussion over 2 years, then public presentation and discussion with the other experts before finalizing the report. Main Outcome Measure. Recommendations based on grading of evidence-base medical literature and interactive discussion. Results. From animal studies, it is derived that testosterone modulates mechanisms involved in erectile machinery, including expression of enzymes that both initiate and terminate erection. In addition, testosterone is essential for sexual motivation. Whether these findings could be extrapolated to human erections is unclear. Testosterone plays a broad role in men's overall health. Recent studies have established strong associations between low testosterone and metabolic and cardiovascular imbalances. In some studies, low testosterone decreased longevity; however, longitudinal studies do not support the predictive value of low testosterone for further cardiovascular events. The article proposes a standardized process for diagnosis and treatment of endocrine-related male sexual dysfunctions, updating the knowledge on testosterone and prostate safety. There is no compelling evidence that testosterone treatment causes prostate cancer or its progression in men without severe testosterone deficiency (TD). The possible roles of prolactin and thyroid hormones are also examined. Conclusions. Men with erectile dysfunction, hypoactive sexual desire and retarded ejaculation, as well as those with visceral obesity and metabolic diseases, should be screened for TD and treated. Prospective interventional studies are required before screening for TD in more conditions, including cardiovascular diseases, and considering correction as preventive medicine as much data suggests. Buvat J, Maggi M, Gooren L, Guay AT, Kaufman J, Morgentaler A, Schulman C, Tan HM, Torres LO, Yassin A, and Zitzmann M. Endocrine aspects of male sexual dysfunctions. © 2010 International Society for Sexual Medicine.


Floegel A.,German Institute of Human Nutrition | Stefan N.,University of Tübingen | Yu Z.,Helmholtz Center for Environmental Research | Muhlenbruch K.,German Institute of Human Nutrition | And 17 more authors.
Diabetes | Year: 2013

Metabolomic discovery of biomarkers of type 2 diabetes (T2D) risk may reveal etiological pathways and help to identify individuals at risk for disease. We prospectively investigated the association between serum metabolites measured by targeted metabolomics and risk of T2D in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam (27,548 adults) among all incident cases of T2D (n = 800, mean follow-up 7 years) and a randomly drawn subcohort (n = 2,282). Flow injection analysis tandem mass spectrometry was used to quantify 163 metabolites, including acylcarnitines, amino acids, hexose, and phospholipids, in baseline serum samples. Serum hexose; phenylalanine; and diacyl-phosphatidylcholines C32:1, C36:1, C38:3, and C40:5 were independently associated with increased risk of T2D and serum glycine; sphingomyelin C16:1; acyl-alkyl-phosphatidylcholines C34:3, C40:6, C42:5, C44:4, and C44:5; and lysophosphatidylcholine C18:2 with decreased risk. Variance of the metabolites was largely explained by two metabolite factors with opposing risk associations (factor 1 relative risk in extreme quintiles 0.31 [95% CI 0.21- 0.44], factor 2 3.82 [2.64-5.52]). The metabolites significantly improved T2D prediction compared with established risk factors. They were further linked to insulin sensitivity and secretion in the Tübingen Family study and were partly replicated in the independent KORA (Cooperative Health Research in the Region of Augsburg) cohort. The data indicate that metabolic alterations, including sugar metabolites, amino acids, and choline-containing phospholipids, are associated early on with a higher risk of T2D. © 2013 by the American Diabetes Association.


Grzesik P.,Leibniz Institute for Molecular Pharmacology | Teichmann A.,Leibniz Institute for Molecular Pharmacology | Furkert J.,Leibniz Institute for Molecular Pharmacology | Rutz C.,Leibniz Institute for Molecular Pharmacology | And 5 more authors.
FEBS Journal | Year: 2014

The human lutropin/choriogonadotropin receptor (hLHR) for the gonadotropic hormones human luteinizing hormone (hLH; lutropin) and human choriogonadotropin (hCG) is crucial for normal sexual development and fertility. We aimed to unravel differences between the two hLHR hormones in molecular activation mechanisms at hLHR. We utilized a specific hLHR variant that lacks exon 10 (hLHR-delExon10), which maintains full cAMP signaling by hCG, but decreases hLH-induced receptor signaling, resulting in a pathogenic phenotype. Exon 10 encodes 27 amino acids within the hinge region, which is an extracellular segment that is important for signaling and hormone interaction. Initially, we assumed that the lack of exon 10 might disturb intermolecular trans-activation of hLH, a mechanism that has been reported for hCG at hLHR. Coexpression of signaling-deficient hLHR and binding-deficient hLHR can be used to examine the mechanisms of receptor signaling, in particular intermolecular cooperation and intramolecular cis-activation. Therefore, hLHR-delExon10 was combined with the hLHR Lys605→Glu mutant, in which signaling is abolished, and the hLHR mutant Cys131→Arg, in which binding is deficient. We found that hCG signaling was partially rescued, indicating trans-activation. However, the hLH signal could not be restored via forced trans-activation with any construct. Fluorescence cross-correlation spectroscopy detected oligomerization in all combinations, indicating that these functional differences cannot be explained by monomerization of hLHR-delExon10. Thus, our data demonstrate not only that the different behavior of hLH at hLHR-delExon10 is unlikely to be related to modified intermolecular receptor activation, but also that hLH may exclusively stimulate the targeted hLHR by cis-activation, whereas hCG is also capable of inducing trans-activation. Structured digital abstract hLHR and hLHR colocalize by confocal microscopy (View interaction) hLHR and hLHR physically interact by fluorescence correlation spectroscopy (View interaction) Coexpression of signaling-deficient and binding-deficient LHR mutants has been used to examine differences between the two hLHR hormones hLH and hCG in the receptor signaling mechanism. Utilizing a specific LHR deletion mutant (delExon10) our data demonstrates different activation profiles in which hLH may exclusively stimulate the targeted hLHR by cis-activation, while hCG is capable of inducing trans-activation too. © 2014 FEBS.


News Article | November 6, 2015
Site: phys.org

To have an advantage over their neighbours, some plant species release chemicals from their roots (e.g. DIBOA). These compounds can get degraded in the soil and turn into toxic substances, illustrated here by APO. When these toxins enter the roots of neighbouring plants, they prevent them from growing further. Credit: MPI f. Developmental Biology/ C. Becker, S. Petersen and University Hospital Tübingen/M. Burkard Plants are stakeholders in a subtle and complex chemical warfare to secure optimal growth conditions. Although it has been known for decades that plants produce and release chemical substances to fight their neighbors, it has remained unclear how exactly these compounds act on other plants. A team of German and French scientists has been able to show that one particular class of plant toxins slows down the development of competing plants by specifically acting on the structure of their genome. Plants are in a constant competition with their neighbors for limited resources such as light, nutrients and water. Only the fittest survive and reproduce. To defend their territory against invading competitors, plants employ so-called allelochemicals, toxic compounds that can inhibit growth and development of other plants. The existence of this chemical warfare, referred to as 'allelopathy', is widespread among many plant species, and has been known for a long time to scientists and agriculturists. Plants are able to release chemical compounds from their roots into the soil, where the substances decay or are modified by microbes. Some of these products are toxic when the roots of neighboring plants take them up. Work by Sascha Venturelli and colleagues now sheds light on the inner workings of this plant chemical warfare. Claude Becker, one of the leaders of the study, explains the importance of the findings: "The phenomenon has been known for years, and many classes of allelochemicals have been identified over the last decades, but for first time we now understand the molecular mechanism of such a 'territorial behaviour' of plants". The scientists investigated the role a specific class of plant secondary metabolites, the cyclic hydroxamic acids DIBOA and DIMBOA. These are released by several grass species, and their degradation products are well known for their phytotoxicity. Through structural and biochemical analyses, followed by physiological experiments, Venturelli and colleagues could show that these compounds inhibit the activity of so-called histone deacetylases. These enzymes bind to histones, a group of proteins that together with DNA form the genetic material, also known as chromatin. Histone deacetylases remove acetyl side chains from these histones, causing compaction of the DNA and leading to a reduction in gene expression. In the model plant Arabidopsis thaliana, the scientists found that inhibition of histone deacetylases by the plant toxins lead to more histone acetylation and an increase in gene expression, ultimately causing plant growth to slow down. The study thus not only presents the first molecular mechanism for allelopathy, but also illustrates how environmental toxins can alter chromatin structure and gene expression. Allelochemicals are important regulators in natural and agricultural plant communities, and have repeatedly been associated with the success of invasive species in their new habitats. But there is more: "Herbal natural products in general hold great potential for the therapy of human diseases", says Sascha Venturelli from the University Clinics Tübingen, medical scientist and first author of the study, and continues: "We have found that these particular compounds efficiently inhibit the growth of human cancer cells, too." Indeed some inhibitors of histone deacetylases have already been approved as anti-cancer drugs. Michael Bitzer and Ulrich Lauer, initiators and co-advisors of the study explain on-going efforts: "Clinical trials at the University Clinics Tübingen currently assess the efficacy of these plant toxins in cancer patients." Understanding the mode of action of plant toxins could therefore also be of wider significance for medical research. Explore further: Study reveals mechanisms of drought response in plants More information: Plants Release Precursors of Histone Deacetylase Inhibitors to Suppress Growth of Competitors. The Plant Cell, November 2015. doi: dx.doi.org/10.1105/tpc.15.00585


Muller-Hulsbeck S.,Academic Hospitals | Libicher M.,University Clinics | Atar E.,Hasharon Hospital | Trentmann J.,University of Kiel | And 5 more authors.
CardioVascular and Interventional Radiology | Year: 2011

Purpose: Vascular closure devices are routinely used after many vascular interventional radiology procedures. However, there have been no major multicenter studies to assess the safety and effectiveness of the routine use of closure devices in interventional radiology. Methods: The CIRSE registry of closure devices with an anchor and a plug started in January 2009 and ended in August 2009. A total of 1,107 patients were included in the registry. Results: Deployment success was 97.2%. Deployment failure specified to access type was 8.8% [95% confidence interval (95% CI) 5.0-14.5] for antegrade access and 1.8% (95% CI 1.1-2.9) for retrograde access (P = 0.001). There was no difference in deployment failure related to local PVD at the access site. Calcification was a reason for deployment failure in only <0.5% of patients. Postdeployment bleeding occurred in 6.4%, and most these (51.5%) could be managed with light manual compression. During follow-up, other device-related complications were reported in 1.3%: seven false aneurysms, three hematoma >5.9 cm, and two vessel occlusions. Conclusion: The conclusion of this registry of closure devices with an anchor and a plug is that the use of this device in interventional radiology procedures is safe, with a low incidence of serious access site complications. There seems to be no difference in complications between antegrade and retrograde access and other parameters. © The Author(s) 2010. This article is published with open access at Springerlink.com.


Bocklet T.,University Clinics | Bocklet T.,Friedrich - Alexander - University, Erlangen - Nuremberg | Noth E.,Friedrich - Alexander - University, Erlangen - Nuremberg | Stemmer G.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 3 more authors.
2011 IEEE Workshop on Automatic Speech Recognition and Understanding, ASRU 2011, Proceedings | Year: 2011

70% to 90% of patients with Parkinson's disease (PD) show an affected voice. Various studies revealed, that voice and prosody is one of the earliest indicators of PD. The issue of this study is to automatically detect whether the speech/voice of a person is affected by PD. We employ acoustic features, prosodic features and features derived from a two-mass model of the vocal folds on different kinds of speech tests: sustained phonations, syllable repetitions, read texts and monologues. Classification is performed in either case by SVMs. A correlation-based feature selection was performed, in order to identify the most important features for each of these systems. We report recognition results of 91% when trying to differentiate between normal speaking persons and speakers with PD in early stages with prosodic modeling. With acoustic modeling we achieved a recognition rate of 88% and with vocal modeling we achieved 79%. After feature selection these results could greatly be improved. But we expect those results to be too optimistic. We show that read texts and monologues are the most meaningful texts when it comes to the automatic detection of PD based on articulation, voice, and prosodic evaluations. The most important prosodic features were based on energy, pauses and F0. The masses and the compliances of spring were found to be the most important parameters of the two-mass vocal fold model. © 2011 IEEE.


Morgentaler A.,Beth Israel Deaconess Medical Center | Khera M.,Baylor College of Medicine | Maggi M.,University of Florence | Zitzmann M.,University Clinics
Journal of Sexual Medicine | Year: 2014

Introduction: Despite increasing use of testosterone therapy (TTh) for men with testosterone deficiency (TD), there remains uncertainty determining who is a candidate for treatment. Aim: The aim if this study was to report the opinions of international experts on TTh, as initially presented at the meeting of the World Meeting on Sexual Medicine in Chicago, United States in August 2012. Methods: Expert responses to questions regarding the diagnosis of TD based on their own clinical and research experience. Results: All experts emphasized the primacy of symptoms for the diagnosis of TD. Total testosterone (T) thresholds used to identify TD ranged from 350ng/dL to 400ng/dL (12-14nmol/L); however, experts emphasized the diagnostic limitations of this test. Free T was obtained by all, with some valuing this test more than total T for clinical decision making. Only one expert routinely used a screening questionnaire. None used age-adjusted values. Bioavailable T and the free androgen index were not used. Luteinizing hormone (LH) and sex hormone-binding globulin levels were routinely obtained at evaluation. Additional supportive evidence for TD diagnosis included small testicular volume, high androgen receptor CAG repeats, elevated LH, and presence of diabetes or metabolic syndrome. Two T tests were generally obtained but not always required. Some experts did not require morning testing in men 50 years and older. All monitored prostate-specific antigen and hematocrit after initiation of TTh. All but one expert would consider a trial of TTh to a symptomatic man with total T within the normal range. Recent studies suggesting increased cardiovascular risk with T therapy were not found to be credible. Conclusions: Determining who is a candidate for TTh requires clinical assessment based on symptoms and signs, with confirmatory laboratory evaluation. These expert opinions differed from some published guidelines by the emphasis on symptoms as paramount, recognition of the limitations of total T as a diagnostic test, and the potential utility of a therapeutic trial in symptomatic cases with normal total T concentrations. © 2014 International Society for Sexual Medicine.


Sedlacik J.,St Jude Childrens Research Hospital | Sedlacik J.,University Clinics | Reichenbach J.R.,University Clinics
Magnetic Resonance in Medicine | Year: 2010

The blood oxygenation level dependent signal of cerebral tissue can be theoretically derived using a network model formed by randomly oriented infinitely long cylinders. The validation of this model by phantom and in vivo experiments is still an object of research. A network phantom was constructed of solid polypropylene strings immersed in silicone oil, which essentially eliminated the effect of spin diffusion. The volume fraction and magnetic property of the string network was predetermined by independent methods. Ten healthy volunteers were measured for in vivo demonstration. The gradient echo sampled spin echo signal was evaluated with the cylinder network model. We found a strong interdependency between the two network characterizing parameters deoxygenated blood volume and oxygen extraction fraction. Here, different sets of deoxygenated blood volume/ oxygen extraction fraction values were able to describe the measured signal equally well. However, by setting one parameter constant to a predetermined value, reasonable estimates of the other parameter were obtained. The same behavior was found for the in vivo demonstration. The signal theory of the cylinder network was validated by a well-characterized phantom. However, the found interdependency that was found between deoxygenated blood volume and oxygen extraction fraction requires an independent estimation of one variable to determine reliable values of the other parameter. © 2010 Wiley-Liss, Inc.


Traish A.M.,Boston University | Traish A.M.,Brown University | Miner M.M.,Brown University | Miner M.M.,The Miriam Hospital | And 4 more authors.
American Journal of Medicine | Year: 2011

Testosterone deficiency (TD) afflicts approximately 30% of men aged 40-79 years, with an increase in prevalence strongly associated with aging and common medical conditions including obesity, diabetes, and hypertension. A strong relationship is noted between TD and metabolic syndrome, although the relationship is not certain to be causal. Repletion of testosterone (T) in T-deficient men with these comorbidities may indeed reverse or delay their progression. While T repletion has been largely thought of in a sexual realm, we discuss its potential role in general men's health concerns: metabolic, body composition, and all-cause mortality through the use of a single clinical vignette. This review examines a host of studies, with practical recommendations for diagnosis of TD and T repletion in middle-aged and older men, including an analysis of treatment modalities and areas of concerns and uncertainty. © 2011 Elsevier Inc.


Werler S.,University Clinics | Poplinski A.,University Clinics | Gromoll J.,University Clinics | Wistuba J.,University Clinics
Acta Paediatrica, International Journal of Paediatrics | Year: 2011

Aim: We hypothesized that patients with Klinefelter's syndrome (KS) not only undergo X inactivation, but also that genes escape from inactivation. Their transcripts would constitute a significant difference, as male metabolism is not adapted to a 'female-like' gene dosage. We evaluated the expression of selected X-linked genes in our 41, XX Y* male mice to determine whether these genes escape inactivation and whether tissue-specific differences occur. Methods: Correct X inactivation was identified by Xist expression. Relative expression of X-linked genes was examined in liver, kidney and brain tissue by real-time PCR in adult XX Y* and XY* males and XX females. Results: Expression of genes known to escape X inactivation was analysed. Relative mRNA levels of Pgk1 (control, X inactivated), and the genes Eif2s3x, Kdm5c, Ddx3x and Kdm6a escaping from X inactivation were quantified from liver, kidney and brain. Pgk1 mRNA expression showed no difference, confirming correct X inactivation. In kidney and liver, XX Y* males resembled the female expression pattern in all four candidate genes and were distinguishable from XY* males. Contrastingly, in brain tissue XX Y* males expressed all four genes higher than male and female controls. Conclusion: Altered expression of genes escaping X inactivation probably contributes directly to the XX Y* phenotype. © 2011 The Author(s)/Acta Pædiatrica © 2011 Foundation Acta Pædiatrica.

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