Vulvodynia/ Vestibulodynia: Anamnestic, clinical and psychosocial findings

Die Vulvodynie und vor allem ihre häufigste Unterform, die Vestibulodynie, ist eine häufige Krankheit der weiblichen Bevölkerung, die bis vor einigen Jahren nur wenig im deutschsprachigen Raum untersucht war. Es handelt sich um chronische Schmerzen, die mehr als 3 Monate dauern, ohne bekannte, klar identifizierbare Ursache. Dabei können mögliche assoziierte Faktoren/ Komorbiditäten vorliegen. Die Vulvodynie kann einen negativen Einfluss auf das körperliche und psychische Wohlbefinden einer Frau haben und ihre Sexualität erheblich beeinträchtigen. Das Ziel der vorliegenden Arbeit ist es, erstmalig (soweit uns bekannt) im deutschsprachigen Raum Daten über die Vulvodynie sowie den Einfluss der Krankheit auf das Sexualleben einer Frau darzustellen. Unsere Arbeit gliedert sich in zwei Teile: eine retrospektive Analyse und eine prospektive Studie von Patientinnen mit Vulvodynie, die im Deutschen Zentrum für Infektionen in Gynäkologie und Geburtshilfe in Wuppertal vorstellig geworden waren. Die retrospektive Analyse umfasst die ausführliche Dokumentation, Bearbeitung und statistische Analyse der epidemiologischen und klinischen Daten von 457 Patientinnen mit Vestibulodynie im Zeitraum vom August 2011 bis Juli 2016. Die prospektive Studie besteht aus 50 Patientinnen mit aktueller Vestibulodynie aus dem Jahr 2016 und 2017. Dabei wird nach schriftlicher Einwilligungserklärung der Einfluss der Vestibulodynie auf das Sexualleben mittels des Fragebogens d-FSFI in deutscher Sprache untersucht. Nach Einleitung einer Therapie erfolgte eine zweite Befragung. Die Antwortsquote dabei ist nur 24,0 %. Die Vestibulodynie trat in jedem Alter auf, mit einem Mittelwert von 34,4 ± 14,3 Jahren. Die häufigste Altersgruppe lag mit 50,8 % zwischen 18 und 30 Jahren. Die Mehrheit unserer Patientinnen ist kaukasischer Herkunft. Sie zeigten einen normalen BMI (59,7 %), waren ledig (59,1 %), berufstätig (94,7 %), hatten eine Berufsausbildung oder einen Hochschullabschluss (90,9 %) und keine Schwangerschaften (69,2 %). 59,7 % der Frauen litt an irgendeiner Allergieform und 44,2 % erhielt zum Zeitpunkt der Vorstellung Hormonsubstitution. Die häufigste Unterform war die sekundäre, provozierte Vestibulodynie. Fast alle Patientinnen unseres Kollektivs gaben als Symptom Schmerzen an, 67,8 % Brennen und 58,4 % Dyspareunie. Komorbiditäten begleiteten die Patientinnen in 43,4 %. Die häufigsten sind craniomandibuläre Dysfunktion (19,9 %) und Reizblase (19,3 %). Die Vestibulodynie hatte einen negativen Einfluss auf die Sexualität einer Frau. Frauen mit Vestibulodynie zeigten eine gestörte Sexualfunktion (d-FSFI: Score 17,0/ 36,0), die nach Einleitung der entsprechenden Therapie positiv beeinflusst wurde. Die Vulvodynie ist eine komplexe, häufig nicht erkannte Krankheit, mit wichtigen Konsequenzen für die körperliche und seelische Gesundheit einer Frau. Um die Zeit zwischen Diagnose und adäquate Behandlung zu minimieren, werden weitere Forschung und Fortbildung dringend benötigt.Vulvodynia, and its most frequent subtype of vestibulodynia, is a relative common illness of the female population, which was until the recent years, especially in the German-speaking areas, only little studied. Vulvodynia is a chronic pain condition, lasting more than three months, without a clear identifiable cause. It may have potential associated factors (e.g., Comorbidities). Vulvodynia may negative influence the physical and mental well-being of a woman and affect the female sexual function. The goal of this study is a profound presentation of our available data over vulvodynia from the German-speaking area and the examination of the influence of the disease on the sexual life of women. Our study is divided in two parts: a retrospective data analysis and a prospective study over patients with vulvodynia from the “German Center of Infections in Gynecology and Obstetrics“ in Wuppertal. The retrospective analysis includes a detailed processing and statistical analysis of the epidemiologic and clinical data from patients with vestibulodynia in the period from August 2011 until July 2016. The retrospective study includes 50 patients with current vestibulodynia. After written consent we use the questionnaire d-FSFI in German to examine the influence of vestibulodynia on the sexual life of a patient. After the beginning of therapy follows a second questioning. The response rate is 24 %. Vestibulodynia occurs in every age, with an average of 34,4 ± 14,3 years. The most common age group is between 18 and 30 years (50,8 %). Most of our patients is of caucasian origin. They have a normal BMI (59,7 %), are unmarried (59,1 %), working (94,7 %), have an academic degree (90,9 %) and no pregnancy (69,2 %). 59,7 % of the patients have some allergy and 44,2 % use a hormonal substitution at the time of the survey. The most common subtype is secondary, provoked vestibulodynia. Almost all our patients have pain as a symptom, 67,8 % have burning and 58,4 % dyspareunia. One or more comorbidities are found in 43,4 %, with the most frequent craniomandibular dysfunction (19,9 %) and irritable bladder (19,3 %). Vestibulodynia can affect the woman’s sexuality. Our patients have disturbed sexual function (d-FSFI: Score 17,0/ 36,0), which can be positive influenced after the beginning of therapy. Vulvodynia is a complex, often unrecognized disease, with potential consequences on physical and mental woman’s health. Further research and advanced training are urgently needed to minimize the time between diagnosis and proper therapy

Functional aspects of the mitochondrial Hsp90 family member Trap1 in metabolism and in cancer

Molecular chaperones have central role in the maintenance of a functional proteome in the cell. The mitochondrial chaperone Trap1 is a member of the Hsp90 family. Aim of this thesis project is to describe functional aspects of Trap1. We knew that cells lacking Trap1 acquire bigger size. Here we identified that these cells also acquire higher DNA content and we excluded known regulators of cells size, such as mTOR pathway, as the reason of the increased cell size. Interestingly, we were able to observe that ROS is a potential candidate of cell size regulation. Additionally, we described that mice devoid of Trap1 have impaired glucose homeostasis. Moreover, by using a mouse genetic breast cancer model we noticed a delay in tumor onset in the absence of Trap1. Overall, this work proposes new functional aspects of Trap1. Further investigation in order to identify the molecular mechanisms involved is needed

Investigation of mating disruption methods and agronomic techniques as an IPM contribution to control the grapevine moth Lobesia botrana (Denis and Schiffermuller) (Lepidoptera: Tortricidae) in Northern Greece

Lobesia botrana (Denis and Schiffermuller) (Lepidoptera:Tortricidae) is the most serious pest of grape cultivation in Greece. To help develop an integrated pest management (IPM) strategy for L. botrana, research on mating disruption was undertaken, with the following specific objectives: to evaluate the potential role of' mating disruption approaches for the control of L. botrana in commercial vineyards in Northern Greece using the Quant Lb-R pheromone dispenser? (at high and lowmedium pest population densities) and the ExoSex system (at high pest population densities); to evaluate whether these approaches could be integrated, to useful effect, with selective chemical control strategies and non-chemical control strategies, including Bacillus thuringiensis (Bf); to provide data that could be used in assembling a data package for the future registration of com.tllercial mating disruption products in Greece. The results revealed that the efficacy of mating disruption using Quant ~b-R dispensers differed with different pest densities. The method worked most effectively where the initial pest pressure was low-medium. However, in a commercial vineyard where the pest population was high, a combination of the mating disruption method, with the insect growth regulator; f1ufenoxuron, or Bt, was necessary to provide adequate pest control. The efficacy of the ExoSex method was examined at high pest population densities. The results revealed that treatment with ExoSex dispensers together with f1ufenoxuron, provided effective control and performed better than ExoSex alone or f1ufenoxuron alone. A survey of predatory mites, and an evaluation of the effects of crop protection practices on their populations were also carried out. Amongst the predatory mites of the family Phytoseiidae that were recorded on the experimental plots, Typhlodromus Perbibus Wainstein & Arutunjian was by far the most frequently-found species. The results of a field trial indicated that f1ufenoxuron w~s not directly toxic to T. perbibus at recommended rates. In contrast, the acaricide, propargite, had significantly adverse effects on T. perbibus numbers within 24 hours of application. A field experiment was also undertaken to evaluate the effect of vine cultivation practices (levels of nitrogen application; leaf and shoot pruning; growth regulators) on L. botrana incidence. There were highly significant differences recorded amongst the levels of nitrogen applied, amongst the types of pruning, and amongst the growth regulator treatments on L. botrana infestation levels. The contribution that cultural techniques could make to the management of L. botrana populations is discussed.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Unusual Suspects in the Twilight Zone Between the Hsp90 Interactome and Carcinogenesis

The molecular chaperone Hsp90 has attracted a lot of interest in cancer research ever since cancer cells were found to be more sensitive to Hsp90 inhibition than normal cells. Why that is has remained a matter of debate and is still unclear. In addition to increased Hsp90 dependence for some mutant cancer proteins and modifications of the Hsp90 machinery itself, a number of other characteristics of cancer cells probably contribute to this phenomenon; these include aneuploidy and overall increased numbers and levels of defective and mutant proteins, which all contribute to perturbed proteostasis. Work over the last two decades has demonstrated that many cancer-related proteins are Hsp90 clients, and yet only few of them have been extensively investigated, selected either on the basis of their obvious function as cancer drivers or because they proved to be convenient biomarkers for monitoring the effects of Hsp90 inhibitors. The purpose of our review is to go beyond these "usual suspects." We established a workflow to select poorly studied proteins that are related to cancer processes and qualify as Hsp90 clients. By discussing and taking a fresh look at these "unusual suspects," we hope to stimulate others to revisit them as novel therapeutic targets or diagnostic markers

Agronomic techniques to control Lobesia botrana

The grapevine moth Lobesia botrana (Denis & Schiffermuller) (Lepidoptera: Tortricidae) is a key pest of grapevines in Greece. As part of a broader study on integrated pest management, the effects were investigated of different cultural methods on the establishment and survival of L. botrana, specifically: application of different nitrogen levels (30 and 100 units of ammonium sulfate or 70 units of Agrobiosol); summer leaf and shoot pruning; application of growth regulators (Regalis, probexadione-calcium; or Falgro, gibberellic acid). There were significant differences among the three levels of N application. The lowest L. botrana infestation rates were found in plots treated with 30 units of (NH4)(2)SO4 and plots that received some summer pruning. Following the application of plant growth regulators, the lowest L. botrana infestation levels occurred in the plots treated with Regalis or Falgro at the manufacturers' recommended concentrations. On vines where growth regulators had been applied, the clusters had fewer berries than those not treated with growth regulators

Mitochondrial RNA granules are fluid condensates positioned by membrane dynamics

Phase separation concentrates mitochondrial RNA granules. Here Rey et al., show that mitochondrial RNA granules (MRGs) behaviour is consistent with liquid-liquid phase separation (LLPS) and their fusion coincides with mitochondrial remodelling.Mitochondria contain the genetic information and expression machinery to produce essential respiratory chain proteins. Within the mitochondrial matrix, newly synthesized RNA, RNA processing proteins and mitoribosome assembly factors form punctate sub-compartments referred to as mitochondrial RNA granules (MRGs)(1-3). Despite their proposed importance in regulating gene expression, the structural and dynamic properties of MRGs remain largely unknown. We investigated the internal architecture of MRGs using fluorescence super-resolution localization microscopy and correlative electron microscopy, and found that the MRG ultrastructure consists of compacted RNA embedded within a protein cloud. Using live-cell super-resolution structured illumination microscopy and fluorescence recovery after photobleaching, we reveal that MRGs rapidly exchange components and can undergo fusion, characteristic properties of fluid condensates(4). Furthermore, MRGs associate with the inner mitochondrial membrane and their fusion coincides with mitochondrial remodelling. Inhibition of mitochondrial fission or fusion leads to an aberrant accumulation of MRGs into concentrated pockets, where they remain as distinct individual units despite their close apposition. Together, our findings reveal that MRGs are nanoscale fluid compartments, which are dispersed along mitochondria via membrane dynamics

Mechanism of ribosome-associated mRNA degradation during tubulin autoregulation

Microtubules play crucial roles in cellular architecture, intracellular transport, and mitosis. The availability of free tubulin subunits affects polymerization dynamics and microtubule function. When cells sense excess free tubulin, they trigger degradation of the encoding mRNAs, which requires recognition of the nascent polypeptide by the tubulin-specific ribosome-binding factor TTC5. How TTC5 initiates the decay of tubulin mRNAs is unknown. Here, our biochemical and structural analysis reveals that TTC5 recruits the poorly studied protein SCAPER to the ribosome. SCAPER, in turn, engages the CCR4-NOT deadenylase complex through its CNOT11 subunit to trigger tubulin mRNA decay. SCAPER mutants that cause intellectual disability and retinitis pigmentosa in humans are impaired in CCR4-NOT recruitment, tubulin mRNA degradation, and microtubule-dependent chromosome segregation. Our findings demonstrate how recognition of a nascent polypeptide on the ribosome is physically linked to mRNA decay factors via a relay of protein-protein interactions, providing a paradigm for specificity in cytoplasmic gene regulation

Cytosolic Hsp90α and its mitochondrial isoform Trap1 are differentially required in a breast cancer model

The Hsp90 family of molecular chaperones includes the cytosolic isoforms Hsp90α and Hsp90β, and the mitochondrial isoform Trap1. Hsp90α/β support a large number of client proteins in the cytoplasm and the nucleus whereas Trap1 regulates oxidative phosphorylation in mitochondria. Many of the associated proteins and cellular processes are relevant to cancer, and there is ample pharmacological and genetic evidence to support the idea that Hsp90α/β and Trap1 are required for tumorigenesis. However, a direct and comparative genetic test in a mouse cancer model has not been done. Here we report the effects of deleting the Hsp90α or Trap1 genes in a mouse model of breast cancer. Neither Hsp90α nor Trap1 are absolutely required for mammary tumor initiation, growth and metastasis induced by the polyoma middle T-antigen as oncogene. However, they do modulate growth and lung metastasis in vivo and cell proliferation, migration and invasion of isolated primary carcinoma cells in vitro. Without Hsp90α, tumor burden and metastasis are reduced, correlating with impaired proliferation, migration and invasion of cells in culture. Without Trap1, the appearance of tumors is initially delayed, and isolated cells are affected similarly to those without Hsp90α. Analysis of expression data of human breast cancers supports the conclusion that this is a valid mouse model highlighting the importance of these molecular chaperones