Native GABA(B) receptors are heteromultimers with a family of auxiliary subunits.

GABA(B) receptors are the G-protein-coupled receptors for gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. They are expressed in almost all neurons of the brain, where they regulate synaptic transmission and signal propagation by controlling the activity of voltage-gated calcium (Ca(v)) and inward-rectifier potassium (K(ir)) channels. Molecular cloning revealed that functional GABA(B) receptors are formed by the heteromeric assembly of GABA(B1) with GABA(B2) subunits. However, cloned GABA(B(1,2)) receptors failed to reproduce the functional diversity observed with native GABA(B) receptors. Here we show by functional proteomics that GABA(B) receptors in the brain are high-molecular-mass complexes of GABA(B1), GABA(B2) and members of a subfamily of the KCTD (potassium channel tetramerization domain-containing) proteins. KCTD proteins 8, 12, 12b and 16 show distinct expression profiles in the brain and associate tightly with the carboxy terminus of GABA(B2) as tetramers. This co-assembly changes the properties of the GABA(B(1,2)) core receptor: the KCTD proteins increase agonist potency and markedly alter the G-protein signalling of the receptors by accelerating onset and promoting desensitization in a KCTD-subtype-specific manner. Taken together, our results establish the KCTD proteins as auxiliary subunits of GABA(B) receptors that determine the pharmacology and kinetics of the receptor response.

The ProCaSP study: quality of life outcomes of prostate cancer patients after radiotherapy or radical prostatectomy in a cohort study.

BACKGROUND: This study describes and compares health-related quality of life (HRQOL) of prostate cancer patients who received either radical prostatectomy (nerve-sparing, nsRP, or non-nerve-sparing, nnsRP) or radiotherapy (external RT, brachytherapy, or both combined) for treatment of localised prostate cancer. METHODS: The prospective, multicenter cohort study included 529 patients. Questionnaires included the IIEF, QLQ-C30, and PORPUS-P. Data were collected before (baseline), three, six, twelve, and twenty-four months after treatment. Differences between groups' baseline characteristics were assessed; changes over time were analysed with generalised estimating equations (GEE). Missing values were treated with multiple imputation. Further, scores at baseline and end of follow-up were compared to German reference data. RESULTS: The typical time trend was a decrease of average HRQOL three months after treatment followed by (partial) recovery. RP patients experienced considerable impairment in sexual functioning. The covariate-adjusted GEE identified a significant - but not clinically relevant - treatment effect for diarrhoea (b = 7.0 for RT, p = 0.006) and PORPUS-P (b = 2.3 for nsRP, b = 2.2 for RT, p = 0.045) compared to the reference nnsRP. Most of the HRQOL scores were comparable to German norm values. CONCLUSIONS: Findings from previous research were reproduced in a specific setting of a patient cohort in the German health care system. According to the principle of evidence-based medicine, this strengthens the messages regarding treatment in prostate cancer and its impacts on patients' health-related quality of life. After adjustment for baseline HRQOL and other covariates, RT patients reported increased symptoms of diarrhoea, and nnsRP patients decreased prostate-specific HRQOL. RP patients experienced considerable impairment in sexual functioning. These differences should be taken into account by physicians when choosing the best therapy for a patient.

Quality of life in partners of patients with localised prostate cancer.

PURPOSE: The diagnosis of prostate cancer and the following treatment does not only affect the patient, but also his partner. Partners often suffer even more severely from psychological distress than the patients themselves. This analysis aims to describe the quality of life (QoL) after the cancer diagnosis over time and to identify the effects of possible predictors of partners' quality of life in a German study population. DATA AND METHODS: Patients with localised prostate cancer and their partners were recruited from a prospective multicenter study in Germany, the Prostate Cancer, Sexuality, and Partnership (ProCaSP) Study. At five observation times during the follow-up period of 2 years after diagnosis, QoL (EORTC QLQ-C30) and personal, social, and cancer-related health factors as well as adaptation and coping factors of 293 couples were observed and analysed with mixed effects analysis. RESULTS: The men's prostate cancer diagnosis had a small, but significant impact on their partner's QoL. However, QoL of partners was most affected by the partners' own physical health and psychological condition, time, and their relationship quality. CONCLUSION: The finding that average QoL increased again 3 months after diagnosis and later should give partners faith and hope for the future. The identified most important predictors of partners' QoL are potentially susceptible to intervention, and further research on target groups in special need of support and on adequate interventions is needed.

Systematic review of surgical treatments for benign prostatic hyperplasia and presentation of an approach to investigate therapeutic equivalence (non-inferiority).

OBJECTIVE: • To assess the potential additional benefit of non-standard vs standard surgical treatments for benign prostatic hyperplasia (BPH) and to present a new methodological approach to investigate therapeutic equivalence (non-inferiority) regarding symptom reduction. PATIENTS AND METHODS: • We conducted a systematic review and searched MEDLINE, Embase and the Cochrane Library (last search: 10/2009) for randomized controlled trials (RCTs) and non-randomized controlled clinical trials (CCTs). • Eligible studies were those that included patients with symptomatic BPH requiring surgical treatment and which compared non-standard procedures (e.g. minimally invasive technologies) with standard ones (e.g. transurethral resection of the prostate, TURP). In addition, only studies analysing patient-relevant outcomes were considered (e.g. irritative and obstructive symptoms, length of hospital stay, quality of life and adverse events). • The main outcome of interest for the present analysis was superiority or non-inferiority for symptom reduction. • As no trial investigated non-inferiority, we defined a non-inferiority threshold (0.25 standard deviation) on the basis of published literature. If a non-standard procedure showed non-inferiority for symptom reduction, additional outcomes were assessed. Meta-analyses were conducted if feasible and meaningful. RESULTS: • In all, 43 mainly low-quality trials (RCTs only) compared nine non-standard surgical treatments with standard ones. • Mean follow-up ranged from 6 to 84 months. • No non-standard procedure was superior for symptom reduction. Non-inferiority for symptom reduction was shown in patients who had undergone holmium laser resection of the prostate (HoLRP) or thulium laser resection of the prostate (TmLRP). • As procedural advantages (e.g. no occurrence of transurethral resection syndrome) and other advantages (e.g. shortened hospital stay) were found, an indication of an additional benefit of HoLRP and TmLRP was determined. CONCLUSIONS: • No proof of superiority for symptom reduction has been shown for non-standard surgical treatments in patients with BPH. • There is a lack of high-quality RCTs and trials designed to investigate non-inferiority. • Future studies should define a non-inferiority threshold (ideally, uniform) a priori, so that results of individual studies are interpretable and comparable, and future systematic reviews should consider this issue.

[Post-corona fatigue-a familiar picture in a new guise?] / Post-Corona-Fatigue ­ das bekannte Bild in neuem Gewand?

BACKGROUND: Myalgic encephalitis or chronic fatigue syndrome (ME/CFS) has again come into focus as a result of coronavirus disease 2019 (COVID-19). Fundamentally problematic is the fact that ME/CFS is considered a separate entity; however, extreme fatigue is also a common symptom of an underlying disease. Our article aims to increase the acceptance of ME/CFS and extreme fatigue facing a symptomatology that is not fully understood, and to highlight the need for research, orientation for physicians, and counselling services for patients. MATERIALS AND METHODS: Orientative research by focused information gathering. RESULTS: In various research projects, the hypothesis of post-infectious ME/CFS as an autoimmune disease could be confirmed. In general, the heterogeneity of diagnostic criteria as well as the variety of formulations to describe the symptomatology and different coding options make it difficult to clearly assign symptoms to a clinical picture. Exertion intolerance has been identified as a severe symptom of post-COVID-19 disorder. For this reason, recommendations in international guidelines are currently being revised, especially with regard to pacing. The implications for recommendations in tumor-related fatigue or due to multiple sclerosis are unclear. CONCLUSION: Against the background of a decreasing burden of disease due to increasing vaccination rates, research on fatigue should not only include viral diseases.

Measuring prostate-specific quality of life in prostate cancer patients scheduled for radiotherapy or radical prostatectomy and reference men in Germany and Canada using the Patient Oriented Prostate Utility Scale-Psychometric (PORPUS-P).

BACKGROUND: The PORPUS-P is a short questionnaire for measuring prostate-specific quality of life (QoL), which was designed in Canada for use in prostate cancer (PC) patients. We aimed to generate a German version and compare PORPUS-P scores of German reference men from the general population, and German and Canadian patients with newly diagnosed PC who were scheduled to receive radical prostatectomy (RP) or radiotherapy (RT). METHODS: The study sample consisted of 988 reference men, 121 German and 66 Canadian PC patients scheduled for RT, and 371 German and 68 Canadian PC patients scheduled for RP. All men completed the PORPUS-P (German postal questionnaire, Canada personal interview). Data were gathered from PC patients before the start of therapy. RESULTS: Canadian patients were better educated than the German patients, and fewer were retired. Patients scheduled to receive RT were older and more were retired. German RT patients had lower D'Amico risk scores and pre-treatment Gleason scores than RP patients, and Canadian RT patients had higher pre-treatment PSA than RP patients. Urinary and sexual dysfunction were seen in PC patients (especially RT patients), but were also common in the German reference men. Crude mean PORPUS-P scores differed statistically significant between German RT and RP and Canadian RP and RT patients, with RT patients having higher QoL scores. The differences in age-adjusted mean PORPUS-P scores between reference men and RP patients were not clinically significant, while RT patients had (clinically) significantly lower scores than the reference men. CONCLUSION: The German translation of the PORPUS-P appears to be a short and feasible tool for assessing prostate-specific QoL. Although we found a similar response pattern, Canadian and German PC patients scheduled to receive RT or RP rated their pre-treatment quality of life on different levels, which reveals the need for national reference data. Problems in several QoL domains exist before treatment, and differ between PC patients scheduled for RT and RP.

Economical data and advanced prostate carcinoma: do we need new guidelines for decision making?

Based on epidemiological data of incidence, estimated prevalence of advanced prostate carcinoma in Germany, and the cost of androgen deprivation of different regimens were determined in a study model. We analyzed data, published by the Tumor Registry of Munich, which indicate that from 3,838 patients with carcinomas of the prostate, 38% has been treated exclusively with hormone suppression therapy, 14% of patients had undergone a combined radiation therapy and hormone suppression therapy and 9% underwent combined surgical therapy and hormone suppression therapy. The mean survival time of patients treated with medical therapy alone, for patients treated with combined radiation therapy and medical therapy were 60, 24, and 120 months, respectively. The cost for orchiectomy was estimated as $1,072, and for LH-RH therapy as $224/month. We estimated an incidence of 17,700 (per year) and a prevalence of 115,000 patients with advanced prostate cancer for Germany. Provided all patients received LH-RH treatment a total cost of $308,000,000/year would arise. Provided, all patients underwent surgery a total cost of $19,000.000/year would arise. If all patients received LH-RH agonists, the treatment would amount to $16,944 per patient, independently of the prognostic group; and for surgery $1,072 per patient would arise. Limited health care budgets mandate critical determination and evaluation of costs to provide a component for the complex decision making process. However, they must be complimented by validated data of quality of life, which can than be a basis for new guidelines of decision making.

Analysis of microdissected prostate tissue with ProteinChip arrays--a way to new insights into carcinogenesis and to diagnostic tools.

Prostate carcinomas are one of the most common malignancies in western societies. The pathogenesis of this tumor is still poorly understood. These tumors present with two characteristic features: epithelial-mesenchymal interactions, which play a pivotal role for tumor development and most of clinically manifest cancers arise in prostate proper compared to a minority of tumors which develop in the transitional zone. Deciphering the epithelial-mesenchymal cross talk and identification of molecular pecularities of the sub-populations of cells in different zones can therefore help understanding carcinogenesis and development of new, non-invasive tools for the diagnosis and prognosis of prostate carcinomas which has remained a challenge until today. A ProteinChip array technology (SELDI = surface enhanced laser desorption ionization) has been developed recently by Ciphergen Biosystems enabling analysis and profiling of complex protein mixtures from a few cells. This study describes the analysis of approximately 500-1000 freshly obtained prostate cells by SELDI-TOF-MS (surface enhanced laser desorption ionization time-of-flight mass spectrometry). Pure cell populations of stroma, epithelium and tumor cells were selected by laser assisted microdissection. Multiple specific protein patterns were reproducibly detected in the range from 1.5 to 30 kDa in 28 sub-populations of 4 tumorous prostates and 1 control. A specific 4.3 kDa peak was increased in the prostate tumor stroma compared to normal prostate proper and transitional zone stroma and increased in prostate tumor glands compared to normal prostate proper and transitional zone glands. Coupling laser assisted microdissection with SELDI provides tremendous opportunities to identify cell and tumor specific proteins to understand molecular events underlying prostate carcinoma development. It underlines the vast potential of this technology to better understand pathogenesis and identify potential candidates for new specific biomarkers in general which could help to screen for and distinguish disease entities, i.e. between clinically significant and insignificant carcinomas of the prostate.

Giant urethral diverticulum: unusual complication following ventral buccal mucosa onlay graft urethroplasty.

During the past 10 years, buccal mucosa grafting for urethroplasty has gained widespread acceptance. In general the reported success rates are 80% and higher. Typical complications are recurrent strictures, fistula, and, especially when the technique of ventral onlay urethroplasty has been used, sacculations that are of little clinical significance in most cases. The development of large diverticula has not been described yet. We report on the case of a 63-year-old man who developed a giant diverticulum of the urethra 1 year after a ventral buccal mucosa onlay graft urethroplasty for recurrent bulbar urethral strictures had been worked out.

Orchiectomy versus medical therapy with LH-RH analogues for the treatment of advanced prostatic carcinoma.

BACKGROUND: In Germany prostatic cancer is the most frequent cancer in men. The therapy of advanced prostatic cancer has changed significantly from the sub capsulate and / or total orchiectomy to the medical LH-RH analogues therapy during the last ten years, which has considerable effects on results and on costs. Both treatment procedures are based on a slowing down regulation of the growth of the hormone sensitive, neoplastic prostatic cells by the withdrawal of testosterone, which is clinically accompanied by a slowed tumor progression. OBJECTIVES: This health technology assessment depicts and evaluates international data of medical effectiveness and efficiency of orchiectomy and medical therapy with LH-RH-analogues in patients with advanced prostate cancer. METHODS: A systematic, diversified literature analysis in the common medical, economic and HTA data bases and further media was conducted. RESULTS: Five identified, randomized and controlled studies concerning the application of LH-RH analogues showed the same medical effectiveness of orchiectomy and treatment with LH-RH analogues. Four different studies regarding the quality of life revealed no significant difference between the treatment with LH-RH analogues and the therapy with orchiectomy. Dealing with health economic aspects seven cost-minimizing studies and one cost effectiveness study could be identified. All cost-minimizing studies show methodological restrictions. In general all studies draw the conclusion that the treatment of advanced prostatic cancer with orchiectomy is the most cost effective method, if one assumes a remaining life expectancy of more than one year. CONCLUSIONS: According to available studies, there is clear evidence for the equivalent effectiveness of LH-RH analogues and orchiectomy. Until now the studies - due to immense methodological restrictions - could not supply sufficient scientific evidence concerning the aspects of quality of life. In cases of a remaining life expectancy of more than one year, the orchiectomy is the more cost-effective alternative of therapy.

Validation of the German prostate-specific module.

Theoretically, all patients newly diagnosed with prostate cancer are faced with a choice of treatment options: radical prostatectomy or radio therapy. Although these different treatments may have no differences in terms of survival, they may have very different consequences on the subsequent quality of life (QoL). Prerequisite to analyze QoL is a reliable and valid instrument to assess these differences not only in terms of general QoL (EORTC QLQ-C30) but prostate specific symptoms with a prostate specific module as well. Therefore, the aim of this study was a psychometric evaluation (validation) of the prostate-specific module (PSM). Five historical cohort studies were put together for an empirical meta-analysis. The main objective was to analyze the module's psychometric properties. The total sample consisted of 1,185 patients, of whom 950 completed the QoL questionnaires (EORTC QLQ-C30 and a prostate specific module developed by Kuechler et al.). First step of analysis was a principal component analysis that revealed the following scales: urinary problems, incontinence, erectile dysfunction, sexual problems, problems with partner, pain, heat, nutrition, and psychic strain. The module showed good reliability and concurrent validity and very good construct validity, since the module is able to discriminate between different treatment regimes, tumor stages and age. The German PSM is a reliable, valid and applicable tool for QoL in patients with prostate cancer.

Prescription practice for LH-RH analogs and androgen receptor antagonists in the treatment of advanced prostate cancer in Germany (1993-2003).

INTRODUCTION: Nearly 80% of the patients suffering from advanced stages of prostate cancer in Germany are treated currently with luteinizing hormone-releasing hormone (LH-RH) analogs alone or in combination with androgen receptor antagonists. The aim of this study was to assess whether the prescription practice for LH-RH analogs and direct antiandrogens between 1993 and 2003 parallels the rise in the incidence rates for prostate cancer associated with the proportional rise in daily doses. METHODS: Between 1993 and 2000 a yearly randomly selected number of receipts has been evaluated from official pharmacies in Germany which have been billed to public health insurance companies. Data concerning drug use, number of daily doses, and total cost of the respective drugs have been calculated by the Research Institute of the AOK (Wissenschaftliches Institut der AOK, WIdO). These prescription data have been related to incidence and mortality rates of patients with prostate cancer. RESULTS: Between 1993 and 2003 the age-standardized incidence rate of carcinomas of the prostate has risen by 180%, while the disease-specific mortality practically has remained nearly at the same level. The daily prescribed doses of LH-RH analogs have risen by a factor of 8.5 from 3.9 to 33.5 million daily doses during this time. In contrast, the daily doses of androgen receptor antagonists have remained unchanged between 1997 and 2001, followed by a rise of 50% between 2001 and 2003. CONCLUSIONS: The first analysis of the prescription practice of antiandrogens in the treatment of prostate cancer with respect to the incidence rates in Germany could only be facilitated by the fact that these medications are in exclusive use for this indication in Germany. The rise in prescriptions may be explained by the therapy shift from surgery to LH-RH application until the year 2000; the reasons for a further rise since 2000 remain speculative. In conclusion, only prevalence data would allow the exact calculation of medication needs among prostate cancer patients.

BKCa-Cav channel complexes mediate rapid and localized Ca2+-activated K+ signaling.

Large-conductance calcium- and voltage-activated potassium channels (BKCa) are dually activated by membrane depolarization and elevation of cytosolic calcium ions (Ca2+). Under normal cellular conditions, BKCa channel activation requires Ca2+ concentrations that typically occur in close proximity to Ca2+ sources. We show that BKCa channels affinity-purified from rat brain are assembled into macromolecular complexes with the voltage-gated calcium channels Cav1.2 (L-type), Cav2.1 (P/Q-type), and Cav2.2 (N-type). Heterologously expressed BKCa-Cav complexes reconstitute a functional "Ca2+ nanodomain" where Ca2+ influx through the Cav channel activates BKCa in the physiological voltage range with submillisecond kinetics. Complex formation with distinct Cav channels enables BKCa-mediated membrane hyperpolarization that controls neuronal firing pattern and release of hormones and transmitters in the central nervous system.

Gender differences in quality of life of patients with rectal cancer. A five-year prospective study.

To determine how quality of life changes over time and to assess gender-related differences in quality of life of rectal cancer patients we conducted a 5-year study. Little is known about how quality of life (QoL) changes over time in patients after surgery for rectal cancer, and whether gender of the patients is associated with a different perception of QoL. The aim of this study was to assess prospectively, changes in quality of life after surgery for rectal cancer, with a focus on gender related differences. Over a 5-year period, the EORTC-QLQ-C-30 and a tumor-specific module were prospectively administered to patients before surgery, at discharge, 3, 6, 12, and 24 months postoperatively. Comparisons were made between female and male patients. A total of 519 patients participated in the study, 264 men and 255 women. The two groups were comparable in terms of surgical procedures, adjuvant treatment, tumor stage, and histology. Most QoL scores dropped significantly below baseline in the early postoperative period. From the third month onward, global health, emotional and physical functioning, improved. Female gender was associated with significantly worse global health and physical functioning and with higher scores on treatment strain and fatigue. Men reported difficulties with sexual enjoyment; furthermore, over time, sexual problems created high levels of strain in men, worse than baseline levels in the early postoperative period. These problems tended to continue over the course of time. The findings in this study confirm that QoL changes after surgery and differs between men and women. Women appear to be affected by impaired physical functioning and global health. Female gender is associated with significantly higher fatigue levels and increased strain values after surgery. Through impaired sexual enjoyment, men are put more under strain than woman.

Evidence of chromosomal integration of AAV DNA in human testis tissue.

Persistent infection with adeno-associated virus (AAV) has been demonstrated in human tissues, most frequently in the female and male genital tract. The clinical significance of latent AAV infection remains, however, uncertain to date. The mode of latency of AAV is not known, i.e., it is unclear whether the viral genome is integrated in the cellular genome, and if integration occurs site-specifically in chromosome 19 as has been observed in cell culture. Therefore we investigated if viral DNA in AAV DNA-positive human testis samples from two patients, is integrated in the cellular genome. Using two different molecular approaches, uni-directional PCR and Walking Primer PCR, we could demonstrate that AAV DNA is present in an integrated form in testis tissue. Virus-cell DNA junction fragments were cloned and sequenced. A detailed analysis revealed integration within sequences of the so-called AAVS1 region on chromosome 19. These data demonstrate that AAV DNA can integrate also after natural infection, and that integration occurs within the AAVS1 region, at least in some cases.

Telomerase activity and telomerase subunit gene expression levels are not related in prostate cancer: a real-time quantification and in situ hybridization study.

Because the mechanisms of telomerase activation in prostate cancer are mainly unknown, we investigated the relationships between telomerase activity and expression levels of human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) mRNA in benign and malignant alterations of the human prostate gland. Using the LightCycler technology, hTERT mRNA expression was quantified in 46 radical prostatectomy and 10 benign prostatic hyperplasia (BPH) cases; hTR expression was quantified in a subset of these tissue samples. Telomerase activity was measured using a quantitative telomeric repeat amplification protocol ELISA assay. Similar to hTR, which was expressed in all tissue samples tested, hTERT mRNA was detected in 98% of the prostate cancer samples and in 30% of the BPH samples. Regarding clinicopathologic variables, telomerase activity was significantly correlated with Gleason score (<7 vs > or =7, p = 0.02). No relationships emerged between normalized hTR or hTERT expression levels and tumor stage, Gleason score, lymph node status, or preoperative serum prostate-specific antigen. Remarkably, one third of all cancer and BPH tissue samples with hTR and hTERT expression lack telomerase activity. Quantitative analyses contradict the assumption that a certain threshold level of hTR or hTERT mRNA is required for telomerase activation, thus indicating that telomerase regulation in prostate cancer occurs more likely on a posttranscriptional level. Nevertheless, the observation that hTR and hTERT mRNA levels are significantly (p < 0.002) correlated suggests some common mechanisms in the up-regulation of hTR and hTERT expression. Because in situ hybridization revealed strong hTERT expression in all cells of the tumor glands but also in high-grade prostatic intraepithelial neoplasia foci, this up-regulation seems to occur early in prostate carcinogenesis.