H. Rübben

Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide

Wilson disease is caused by accumulation of Cu2+ in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu2+ triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu2+-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu2+ induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, events also prevented by inhibition of Asm. Phosphatidylserine exposure resulted in immediate clearance of affected erythrocytes from the blood in mice. Accordingly, individuals with Wilson disease showed elevated plasma levels of Asm, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Our data suggest a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease.

Phase II trial of titanocene dichloride in advanced renal-cell carcinoma

Abstract Titanocene dichloride was capable of inhibiting the growth of different types of human tumors in vitro. A total of 14 patients with metastatic renal-cell carcinoma (RCC) received 270 mg/m2 titanocene dichloride every 3 weeks for 6 weeks. Although the toxicities and side effects encountered were mild to moderate, no partial or complete response was detectable. In conclusion, titanocene dichloride has no advantage in the therapy of RCC.

Male‐to‐female transsexualism: a technique, results and long‐term follow‐up in 66 patients

Objective To report experience of a new surgical technique in male‐to‐female transsexual patients, the complications, and the functional and psychosocial long‐term results.

Comparison of adrenoceptor subtype expression in porcine and human bladder and prostate

We have quantified and characterized α1-, α2-and β-adrenoceptor subtypes in porcine bladder detrusor and bladder neck, human bladder detrusor, and porcine and human prostate. α1-, α2- and β-adrenoceptor were identified in radioligand binding studies using [3H]prazosin, [3H]RX 821002 and [125I]iodocyanopindolol, respectively, as the radioligands. In porcine male and female detrusor and bladder neck and male prostate, adrenoceptors were detected in the order of abundance β > α2 ≫ α1 (not detectable), with no major differences between the sexes or between detrusor and bladder neck. In human detrusor and prostate the order of abundance was β > α2 ≫ α1 (not detectable) and β ≫ α1 > α2. respectively. The α2-adrenoceptors in all tissues were homogeneously of the α2A-subtype as evidenced by competition binding studies with yohimbine, prazosin, ARC 239 and oxymetazoline. The β-adrenoceptors represented a mixed population with a dominance of the β2-subtype in all tissues as demonstrated by competition binding with ICI 118,551 and CGP 20,712A. We conclude that pigs may be a suitable model for studies of detrusor function with respect to adrenoceptor expression. They may be less suitable for studies of bladder neck or prostate function.

Orthotopic implantation of human prostate cancer cell lines: A clinically relevant animal model for metastatic prostate cancer

To study the metastatic behavior of human prostate cancer cell lines, orthotopic injection in nude mice was performed.

DOCETAXEL AND IFOSFAMIDE AS SECOND LINE TREATMENT FOR PATIENTS WITH ADVANCED OR METASTATIC UROTHELIAL CANCER AFTER FAILURE OF PLATINUM CHEMOTHERAPY: A PHASE 2 STUDY

PURPOSE This phase 2 trial was designed to assess the efficacy and safety of combination chemotherapy with docetaxel and ifosfamide in previously treated patients with advanced urothelial cancer. MATERIALS AND METHODS Enrolled in our study were 22 patients with advanced urothelial cancer who failed to respond or had relapse after previous platinum based chemotherapy. Treatment consisted of 60 mg./m.2 docetaxel given during 1 hour and 2.5 gm./m.2 ifosfamide given for 24 hours every 3 weeks with 500 mg. mesna administered intravenously at the start of the ifosfamide infusion, and 4 and 8 hours later. Patients also received premedication with oral dexamethasone. RESULTS The objective response rate in 20 evaluable patients was 25%, including 4 complete responses (20%) associated with lymph node only recurrence. Disease was stable in 5 cases. At followup 16 patients had died 1 to 11 months (median 4) after the initiation of treatment, while 6 remained alive at 4 to 14 months, including 3 who were continuously disease-free. Treatment was well tolerated. Grades 3 and 4 leukopenia developed in 17% and 4% of the cycles, respectively. Neutropenic sepsis and grade 4 thrombocytopenia developed in 1 case each. Nausea and vomiting were mild to moderate. Other nonhematological toxicities included a hypersensitivity reaction in 1 patient and paresthesias in 2. CONCLUSIONS The combination of docetaxel and ifosfamide is active in previously treated patients with urothelial cancer, although it appears to be a reasonable treatment option only in those with lymph node dominant recurrence. The mild toxicity underlines the usefulness of the regimen in this setting. Further investigation of the combination in previously untreated patients seems warranted.

Enhanced fMLP‐stimulated chemotaxis in human neutrophils from individuals carrying the G protein β3 subunit 825 T‐allele

We have recently described a C825T polymorphism in the gene encoding for the Gβ3 subunit of heterotrimeric G proteins. The 825T allele is associated with a novel splice variant (Gβ3‐s) and enhanced signal transduction via pertussis toxin (PTX)‐sensitive G proteins. fMLP‐induced chemotaxis, but not O2− generation, was increased in neutrophils with the TC/TT (EC50=1.5±1.3 nM) genotypes compared to the CC genotype (EC50=5.9±1.5 nM). Maximal fMLP‐induced increase in [Ca2+]i was significantly reduced in neutrophils from individuals with TC/TT genotype vs. CC genotype (212.9±10.1 nM vs. 146.4±24.2 nM). Gβ3‐s appears to be associated with enhanced immune cell function in humans.

Prevalence and Physician Awareness of Symptoms of Urinary Bladder Dysfunction

PURPOSE To determine awareness of bladder dysfunction and attitudes towards its management among office-based physicians. MATERIALS AND METHODS A total of 211,648 patients consulting office-based primary care physicians (PCPs), gynaecologists (OBGs) or urologists (UROs) for any reason were given a questionnaire of four questions related to symptoms of bladder dysfunction. The physicians were asked to discuss the answers with their patients and to choose from a list of suspected diagnoses. They were also asked whether medical therapy would be initiated and/or the patient referred to a specialist. RESULTS Patients (57%) had a least one symptom of bladder dysfunction, with increased frequency being most common (41.9%), and symptoms of stress incontinence (30.6%), urgency (24.3%) and urge incontinence (20.2%) less frequent. However, patients with symptoms of overactive bladder (OAB), mixed incontinence or stress incontinence according to the questionnaire remained undiagnosed by their physician in 57.5, 47.5 and 38.1% of cases, respectively. When a diagnosis was suspected by the physician, it often did not match what would be expected based on the questionnaire, and in half of all cases did not result in medical treatment. CONCLUSIONS Bladder dysfunction is highly prevalent among patients consulting an office-based physician for any reason, but remains undiagnosed in many cases and untreated despite diagnosis in many others. Since various effective treatment options are available for bladder dysfunction, educational programs for patients and physicians appear necessary to improve the quality of diagnosis and treatment for this wide-spread condition.

Saw palmetto extracts potently and noncompetitively inhibit human α1-adrenoceptors in vitro

We wanted to test whether phytotherapeutic agents used in the treatment of lower urinary tract symptoms have α1‐adrenoceptor antagonistic properties in vitro.

The T393C polymorphism of the Gαs gene (GNAS1) is a novel prognostic marker in bladder cancer

The G protein Gαs pathway is linked to proapoptotic signaling in cancer cell lines. To assess the role of the GNAS1 locus encoding Gαs as a genetic factor for disease progression of transitional cell carcinoma (TCC) of the bladder, we genotyped the synonymous T393C polymorphism in 254 patients with TCC (minor allele frequency: 0.43) to examine a potential association between genotypes and disease progression. Using Kaplan-Meier estimates to calculate 5-year probabilities of follow-up, we could show that progression-free survival, metastasis-free survival, and cancer-specific survival was significantly increased in TT genotypes (56%, 84%, 82%) compared with CC genotypes (35%, 53%, 58%). In multivariate Cox proportional hazard analysis, the T393C polymorphism was an independent prognostic factor for clinical outcome. Homozygous CC patients were at highest risk for progression [odds ratio (OR), 1.94; P = 0.020], metastasis (OR, 3.49; P = 0.005), and tumor-related death (OR, 2.49; P = 0.031) compared with TT genotypes. Heterozygous patients had an intermediate risk compatible with a gene-dose effect. Real-time PCR analysis of urothelial tumor tissue as well as adipose and heart tissue revealed that Gαs mRNA expression was highest in TT genotypes, indicating a proapoptotic effect in these genotypes. In conclusion, the GNAS1 T393C status associated with differential Gαs mRNA expression is a novel independent prognostic marker for clinical outcome supporting a functional role of Gαs in bladder cancer progression.