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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.

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.

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.

Floegel A.,German Institute of Human Nutrition | Stefan N.,University of Tubingen | 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.

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.

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