Using Patient-Derived Induced Pluripotent Stem Cells to Identify Parkinson's Disease-Relevant Phenotypes.

PURPOSE OF REVIEW: Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting older individuals. The specific cause underlying dopaminergic (DA) neuron loss in the substantia nigra, a pathological hallmark of PD, remains elusive. Here, we highlight peer-reviewed reports using induced pluripotent stem cells (iPSCs) to model PD in vitro and discuss the potential disease-relevant phenotypes that may lead to a better understanding of PD etiology. Benefits of iPSCs are that they retain the genetic background of the donor individual and can be differentiated into specialized neurons to facilitate disease modeling. RECENT FINDINGS: Mitochondrial dysfunction, oxidative stress, ER stress, and alpha-synuclein accumulation are common phenotypes observed in PD iPSC-derived neurons. New culturing technologies, such as directed reprogramming and midbrain organoids, offer innovative ways of investigating intraneuronal mechanisms of PD pathology. PD patient-derived iPSCs are an evolving resource to understand PD pathology and identify therapeutic targets.

Blood-CSF-barrier dysfunction is a marker for encephalitic involvement in patients with aseptic meningitis/meningoencephalitis.

BACKGROUND: The term "aseptic meningitis" encompasses cases of meningitis with negative bacterial CSF culture, which predominantly are of viral etiology. While the clinical course is usually benign, complications such as encephalitic involvement resulting in a more severe clinical course may occur. Dysfunction of the blood-brain-barrier (BBB), which is a prerequisite for viral entry into the brain parenchyma, can be approximated using the CSF/serum albumin ratio, readily obtainable in routine CSF analysis. OBJECITVES: Analysis of CSF patterns in patients with aseptic meningitis/meningoencephalitis with a focus on BBB dysfunction as a marker for encephalitic involvement. STUDY DESIGN: Retrospective chart review of patients admitted to our hospital between 2004 and 2016 with a diagnosis of aseptic meningitis/meningoencephalitis. RESULTS: Patients with aseptic meningitis displaying clinical, MR-tomographic or electroencephalographic signs of encephalitic involvement were significantly older than patients without these features (47.4 vs. 35.5 yrs., p=0.002). In patients with meningoencephalitis, CSF analysis revealed a more severe disruption of BBB, approximated by the CSF/serum albumin ratio (p=0.002). Compromised BBB function correlated positively with length of hospitalization (p=0.007), indicative of a more severe clinical course. The number of CSF lymphocytes was found to predict the severity of the BBB disruption, which additionally was more frequently observed when herpesviridae were identified as infectious agents. CONCLUSIONS: We suggest that the CSF/serum albumin ratio as an estimate for BBB function should be attended to in the evaluation of patients with aseptic meningitis. Severe BBB dysfunction, older age and infection with herpesviridae appear to raise the risk for encephalitic involvement.

Consensus on Recording Deep Endometriosis Surgery: the CORDES statement.

STUDY QUESTION: Which essential items should be recorded before, during and after endometriosis surgery and in clinical outcome based surgical trials in patients with deep endometriosis (DE)? SUMMARY ANSWER: A DE surgical sheet (DESS) was developed for standardized reporting of the surgical treatment of DE and an international expert consensus proposal on relevant items that should be recorded in surgical outcome trials in women with DE. WHAT IS KNOWN ALREADY: Surgery is an important treatment for symptomatic DE. So far, data have been reported in such a way that comparison of different surgical techniques is impossible. Therefore, we present an international expert proposal for standardized reporting of surgical treatment and surgical outcome trials in women with DE. STUDY DESIGN, SIZE, DURATION: International expert consensus based on a systematic review of literature. PARTICIPANTS/MATERIALS, SETTING, METHODS: Taking into account recommendations from Consolidated Standards of Reporting Trials (CONSORT), the Innovation Development Exploration Assessment and Long-term Study (IDEAL), the Initiative on Methods, Measurement and Pain Assessment in Clinical trials (IMMPACT) and the World Endometriosis Research Foundation Phenome and Biobanking Harmonisation Project (WERF EPHect), a systematic literature review on surgical treatment of DE was performed and resulted in a proposal for standardized reporting, adapted by contributions from eight members of the multidisciplinary Leuven University Hospitals Endometriosis Care Program, from 18 international experts and from audience feedback during three international meetings. MAIN RESULTS AND THE ROLE OF CHANCE: We have developed the DESS to record in detail the surgical procedures for DE, and an international consensus on pre-, intra- and post-operative data that should be recorded in surgical outcome trials on DE. LIMITATIONS, REASONS FOR CAUTION: The recommendations in this paper represent a consensus among international experts based on a systematic review of the literature. For several items and recommendations, high-quality RCTs were not available. Further research is needed to validate and evaluate the recommendations presented here. WIDER IMPLICATIONS OF THE FINDINGS: This international expert consensus for standardized reporting of surgical treatment in women with DE, based on a systematic literature review and international consensus, can be used as a guideline to record and report surgical management of patients with DE and as a guideline to design, execute, interpret and compare clinical trials in this patient population. STUDY FUNDING/COMPETING INTERESTS: None of the authors received funding for the development of this paper. M.A. reports personal fees and non-financial support from Bayer Pharma outside the submitted work; H.T. reports a grant from Pfizer and personal fees for being on the advisory board of Perrigo, Abbvie, Allergan and SPD. TRIAL REGISTRATION NUMBER: N/A.

Gestational and Non-gestational Trophoblastic Disease. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry No. 032/049, December 2015).

Purpose: The aim was to establish an official interdisciplinary guideline, published and coordinated by the German Society of Gynecology and Obstetrics (DGGG). The guideline was developed for use in German-speaking countries. In addition to the Germany Society of Gynecology and Obstetrics, the guideline has also been approved by the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). The aim was to standardize diagnostic procedures and the management of gestational and non-gestational trophoblastic disease in accordance with the principles of evidence-based medicine, drawing on the current literature and the experience of the colleagues involved in compiling the guideline. Methods: This s2k guideline represents the consensus of a representative panel of experts with a range of different professional backgrounds commissioned by the DGGG. Following a review of the international literature and international guidelines on trophoblastic tumors, a structural consensus was achieved in a formalized, multi-step procedure. This was done using uniform definitions, objective assessments, and standardized management protocols. Recommendations: The recommendations of the guideline cover the epidemiology, classification and staging of trophoblastic tumors; the measurement of human chorionic gonadotropin (hCG) levels in serum, and the diagnosis, management, and follow-up of villous trophoblastic tumors (e.g., partial mole, hydatidiform mole, invasive mole) and non-villous trophoblastic tumors (placental site nodule, exaggerated placental site, placental site tumor, epitheloid trophoblastic tumor, and choriocarcinoma).

Implementation of certified endometriosis centers: 5-year experience in German-speaking Europe.

The idea of quality improvement in the management of endometriosis has been brought to attention throughout Europe. This - first and foremost - includes the implementation of centers specialized in treating endometriosis. This leads to qualification of both physicians and other medical staff, enforcement of research efforts, and informing the patients, the public, politicians, healthcare providers, and industry. Given limited budgets, focusing on the existing national commitment may be the first step.

Endoscopic resection of a vaginal septum in a bitch and observation of septa in two related bitches.

CASE HISTORY: In 2008, a 3-year-old female Labrador Retriever was presented for routine breeding soundness evaluation. CLINICAL FINDINGS: Vaginal endoscopy revealed an 8-cm long and 1-cm thick vaginal septum. Surgical resection of the septum was performed under general anaesthesia using a bipolar high-frequency resectoscope. Three months later the bitch was naturally mated and subsequently delivered five male and two female puppies without complications. Both female puppies were examined at the age of 12 and 15 months and showed a vaginal septum with a diameter of 0.3 and 0.5 cm, respectively. DIAGNOSIS: Vaginal septa in three related bitches. CLINICAL RELEVANCE: This is the first report describing the use of a bipolar high-frequency resectoscope for vaginal surgery in dogs. The septum could be resected quickly, with preservation of surrounding structures. Furthermore, it is the first report collecting information about familial presentation of vaginal septa in female dogs. Based on this case, we suggest that consideration should be given to the possible risk of inheritance of vaginal septa before considering surgical resection and breeding of female dogs.

First evaluation of the Joint Clinical Registries of the Coordinating Tumor Center of Berlin.

In the present study, we report the first analysis of the clinical management [corrected] of patients with primary ovarian cancer following the summarized data of the Joint Clinical Registries of the Coordinating Tumor Center of Berlin (Dachverband Tumorzentrum Berlin e.V.). All data were summarized for the period of 2005 to 2008 regarding age, histopathology, time of surgical intervention, follow-up and survival, based on 1124 provided data sets of patients with suspected ovarian tumours. We identified 946 patients with a diagnosis of primary ovarian cancer, mostly of advanced T3 tumour stage (63.7%), FIGO III and IV stage (40.6%) or grade II and III (91%) histology. The median age at time of diagnosis was 61 years (range 15 to 94 years). Most patients (n=414, 69.8%) underwent cytoreductive surgery within one month of diagnosis. The median follow-up period was 26 months; 241 patients died in the analyzed period. The calculated 3-year survival rate was 63.3%, although the median overall survival has not yet been reached. We detected positive correlation of tumour stage (p<0.001) and of FIGO stage (p<0.001) with survival, and these were evaluated as being prognostically significant. The implementation of institutional based clinical registries as part of the modern clinical management of patients with ovarian cancer is feasible and well accepted inside the gynaecological departments of Berlin.

[Relevance of MRI for endometriosis diagnosis]. / Stellenwert der Magnetresonanztomografie in der Diagnostik der Endometriose.

Endometriosis is a disease of the uterus with displacement of endometrium-like tissue outside the endometrium. Endometriosis is a common benign chronic often debilitating disease that primarily affects young woman. The estimated prevalence is about 10 %. In addition to the uterus and ovaries, clinically important localisations are the rectovaginal space, rectum, sigmoid colon, urinary bladder, ureter and peritoneum. The most common localisation outside the pelvis is the abdominal wall. Today, MRI is one of the most important tools in the diagnosis of endometriosis. The detection of peritoneal manifestations and the exact definition of the depth of infiltration in the rectum, sigmoid colon and bladder walls are limitations of MRI.

Response of aged parkinsonian monkeys to in vivo gene transfer of GDNF.

This study assessed the potential for functional and anatomical recovery of the diseased aged primate nigrostriatal system, in response to trophic factor gene transfer. Aged rhesus monkeys received a single intracarotid infusion of MPTP, followed one week later by MRI-guided stereotaxic intrastriatal and intranigral injections of lentiviral vectors encoding for glial derived neurotrophic factor (lenti-GDNF) or beta-galactosidase (lenti-LacZ). Functional analysis revealed that the lenti-GDNF, but not lenti-LacZ treated monkeys displayed behavioral improvements that were associated with increased fluorodopa uptake in the striatum ipsilateral to lenti-GDNF treatment. GDNF ELISA of striatal brain samples confirmed increased GDNF expression in lenti-GDNF treated aged animals that correlated with functional improvements and preserved nigrostriatal dopaminergic markers. Our results indicate that the aged primate brain challenged by MPTP administration has the potential to respond to trophic factor delivery and that the degree of neuroprotection depends on GDNF levels.

[Informant report of cognitive changes in the elderly. A first evaluation of the German version of the IQCODE]. / Fremdbeurteilung kognitiver Veränderungen im Alter. Erste Vergleichswerte für den deutschen IQCODE.

BACKGROUND: Cognitive deficits occurring with dementia are frequently not reported by the affected subject. Therefore, informant reports from close relatives are especially important for the early diagnosis of dementia. Internationally, the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) has been evaluated with positive results and is a widely used informant-rated instrument for the diagnosis of cognitive decline. For the German speaking countries, norms and evaluation of the psychometric properties of the instrument are lacking. METHODS: Norms for the German long version of the IQCODE were established with 46 healthy elderly married couples. These were compared with respect to their concurrent and discriminative validity with groups of patients suffering from mild cognitive impairment (MCI, n=25), Alzheimer's or mixed dementia (AD, n=59) and frontotemporal lobe degeneration (FTLD, n=15). RESULTS: The German version of the IQCODE exhibited good psychometric properties and was able to best discriminate between cognitively intact and demented subjects with AD. Receiver-operating characteristic analyses indicated a cut-off score of 3.38 which corresponds well with the value given in international literature. Patients with MCI and with FTLD were also reliably distinguished from cognitively intact subjects. However, the instrument did not distinguish AD from FTLD with any significant degree of confidence. DISCUSSION: The German version of the IQCODE reliably discriminates cognitively intact persons from those suffering from MCI or cortical dementia, but not between different types of cortical dementia, such as AD and FTLD. The IQCODE is an efficient informant-rated screening instrument for the early diagnosis of cognitive decline and dementia.

[Suspected Alzheimer's disease. Selection of outpatients for neuropsychological assessment]. / Verdachtsdiagnose Alzheimer-Demenz : Bei welchen Patienten erfolgt eine neuropsychologische Abklärung?

BACKGROUND: Incipient Alzheimer's disease (AD) is frequently suspected by neurologists and psychiatrists, but diagnosis is difficult to establish. The aim of this report was to analyse to what extent suspicion is confirmed by a comprehensive neuropsychological examination intended to distinguish different types of dementia. METHODS: Descriptive data analysis was used for investigating the differential diagnoses of 47 outpatients with suspected AD referred to a department of neuropsychology by physicians in private practice. Data analysis was based upon the NINCDS-ADRDA diagnostic criteria of AD. RESULTS: Only 38% of the outpatients examined with suspected AD met the NINCDS-ADRDA diagnostic criteria for AD or mixed dementia from a neuropsychological point of view, whereas 22% met criteria for other types of dementia. The remaining patients met criteria for distinct differential diagnoses (23%) or lacked pathological findings in neuropsychological functions (17%). CONCLUSIONS: Neuropsychology is an essential part in the differential diagnosis of mild to moderate dementias. It can aid in differential therapeutic considerations concerning the treatment of dementia, for example in selecting appropriate treatments or avoiding expensive but inappropriate ones.

Development of leiomyosarcoma of the uterus in MMTV-CR-1 transgenic mice.

Overexpression of Cripto-1 (CR-1) in FVB/N mice using the MMTV-LTR promoter results in increased mammary tumourigenesis in these female transgenic mice (MMTV-CR-1). Here, we characterize uterine tumours that developed in 15/76 (19.7%) of MMTV-CR-1 female nulliparous or multiparous mice during 24 months of observation compared with 0/33 (0%) of FVB/N normal control mice observed during the same time period (p < 0.01). The uterine tumours collected from the MMTV-CR-1 mice were classified as leiomyosarcomas and found to express the CR-1 transgene by polymerase chain reaction analysis and immunohistochemistry. Detection by western blot analysis showed higher levels of phosphorylated (P) forms of c-src, Akt, GSK-3beta, and dephosphorylated (DP)-beta-catenin in lysates from MMTV-CR-1 uterine leiomyosarcomas in comparison with lysates from normal control FVB/N uteri. Immunostaining showed increased nuclear localization of beta-catenin in the MMTV-CR-1 uterine leiomyosarcomas. Increased immunostaining for CR-1 was detected in 9/13 (69.2%) cases of human leiomyosarcoma compared with staining in 3/15 (20%) human leiomyoma sections. Stronger immunostaining for P-src, P-Akt, P-GSK-3beta and increased nuclear localization of beta-catenin was also seen in human leiomyosarcomas in comparison with leiomyomas. Normal human uterine smooth muscle (UtSM) cells treated with exogenous soluble rhCR-1 showed increased levels of P-src, P-Akt, P-GSK-3beta and dephosphorylated (DP)-beta-catenin and increased proliferation (p < 0.05) and migration (p < 0.01) in comparison with untreated control UtSM cells. Inhibitors against c-src, Akt or beta-catenin, individually or in combination, significantly reduced CR-1-induced migration. These results suggest a role for CR-1 during uterine tumourigenesis either directly by activating c-src and Akt and/or via cross-talk with the canonical Wnt signalling pathway, as suggested by the increased expression of P-GSK-3beta, DP-beta-catenin, and increased nuclear localization of beta-catenin in human and MMTV-CR-1 mice leiomyosarcomas.

[Unanswered questions in the management of cervical cancer]. / Grenzen in der Therapie des Zervixkarzinoms.

The Task Force Group "Uterus of the Association of Gynecologic Oncology" has recently published the interdisciplinary S2 guidelines on diagnostics and therapy of cervical cancer. In view of quality development strategies of the German Cancer Society and the German Society for Obstetrics and Gynecology, a practicable concept with clear algorithms for gynecologists has been presented. Nevertheless, both development of oncologic sciences and daily practice, lead to new questions which should be answered by prospective studies. In this respect, women with cervical cancer should be treated on the same level of quality as patients with breast cancer. As discussed both nationally and internationally, laparoscopic staging, the development of laparoscopic surgical techniques (i. e., laparoscopic-assisted radical vaginal hysterectomy), the safety and efficacy of the sentinel concept, and TMMR, and finally, the indication for trachelectomy are main scientific questions. Also, innovative vaccination studies that might increase hope of a breakthrough even in cervical cancer prevention, the implementation of nerve-sparing surgical techniques, the radical parametrectomy or current strategies on exenteration are main focuses of clinical gynecologic oncology.

Treatment of uterine fibroids by embolization--advantages, disadvantages, and pitfalls.

Uterine fibroids are the most common benign tumors of the female genital tract. Apart from vaginal or abdominal hysterectomy, which has been in use for more than 100 years, the more recently established techniques of laparoscopy and hysteroscopy provide two additional treatment approaches. In cases of symptomatic uterine fibroids, the most widely accepted alternative to surgery is the catheter-supported embolization of uterine arteries (uterine artery embolization, UAE). All patients who wish to be treated by UAE because of symptomatic fibroids should be presented to both gynecologists and radiologists. To the best of our knowledge, there are no interdisciplinary guidelines for UAE. Therefore, it would be very helpful if gynecologists and radiologists could reach an agreement for both indications and treatment strategies. However, there is no defined "gold standard" for fibroid therapy at all. In this respect, the therapeutic approach should be influenced less by the preference of the (potential) surgeon, and more by factors like size, localization, and number of fibroids. In addition, symptoms, ethnicity, and the wish to have children should be considered. Cooperation between radiologists and gynecologists is absolutely necessary, not only for the choice of the optimal treatment and care of patients, but also for the development of useful guidelines and future studies. UAE may be a therapeutic approach for selected patients. In these special cases, embolization is a safe and practical alternative to the established treatment options.

[Angiogenesis and endometriose]. / Angiogenese und Endometriose.

Endometriosis is considered a chronic disease of women during their reproductive phase, which resembles many signs of malignancy. So far, therapeutic options for endometriosis-associated pain and infertility are unsatisfactory and often lead to recurrence of disease after termination of treatment. Angiogenesis seems to play an important role in the pathogenesis of endometriosis. The use of angiogenesis inhibitors may add an important new tool to well-established treatment schedules. Therefore, it is very important to thoroughly investigate the role of angiogenesis in endometriosis with respect to the female reproductive system.

[COX-2-expression in extragenital endometriosis lesions as a novel therapeutical approach?]. / COX-2-Expression in extragenitalen Endometrioseläsionen als neuer Therapieansatz?

OBJECTIVE: Extragenital endometriosis is a rare form of endometriosis. Due to its invasive and metastatic properties it resembles some features of malignant tumours. Cyclooxygenase (COX)-2 is a rate-limiting enzyme in the biosynthesis of prostaglandins and is mainly expressed in inflammatory and malignant processes. In this study we investigated the COX-2 expression in extragenital endometriosis. MATERIAL AND METHODS: Tissue was obtained of 13 women with rectal and vaginal endometriosis, scar endometriosis and endometriosis of the omentum majus. The COX-2 expression was investigated by immunohistochemistry. RESULTS: In the glandular epithelium a COX-2 overexpression was found in all cases and in the stroma a weak to moderate COX-2 expression was found in half of the cases. A hormonal therapy at the time of surgery had no influence on the COX-2 expression in extragenital endometriosis. CONCLUSION: The high COX-2 expression in extragenital endometriosis is believed to be strongly correlated with the pathological abnormalities this of disease.

[Aromatase inhibitors--theoretical concept and present experiences in the treatment of endometriosis]. / Aromatasehemmer--theoretisches Konzept und bisherige Erfahrungen in der Endometriosetherapie.

The medical treatment of endometriosis needs to be optimized. Therapeutic management strategies of endometriosis-associated pain or recurrent disease is primarily aimed at downregulating the ovarian function or at antagonizing the effect of estrogen in ectopic endometrial implants. In this context, basic research is delivering powerful tools for the possible development of new, specific treatment modalities. Recently, aromatase overexpression has been detected in endometriotic tissue. Aromatase (p450arom) is responsible for conversion of C19 androgens to estrogen in several human tissues. Aromatase activity gives rise to local estrogen biosynthesis, which, in turn, stimulates prostaglandin E(2) production by upregulation of cyclooxygenase-2 (COX-2), thus establishing a positive feedback cycle. Another abnormality in endometriosis, i. e. the deficiency in 17 beta-hydroxysteroiddehydrogenase type-II (17 beta-HSD-Type-II) expression, impairs the inactivation of estradiol to estrone. In contrast to the eutopic endometrium, these molecular aberrations collectively favour accumulation of increasing amounts of local estradiol and prostaglandin E(2) in endometriosis. In several human cell lines, prostaglandin and estrogen concentrations are associated with proliferation, migration, angiogenesis, apoptosis resistance, and even invasiveness. Consequently, aromatase and COX-2 are promising new therapeutic targets. In summary, specific aromatase inhibitors (such as Letrozole, Anastrozol or Exemestan) or selective COX-2 inhibitors (e.g. Celecoxib, Rofecoxib) are of great interest to be studied in clinical trials in premenopausal woman with endometriosis to extend the spectrum of currently available treatment options.