ISSN:0042-1138    

DOI:10.1159/000282683

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

The androgen receptor, a ligand-activated nuclear transcription factor belonging to the large superfamily of nuclear receptors, mediates the intracellular action of androgens. It plays a central role in male sexual development and in prostatic carcinoma as a target of endocrine therapy. We have looked for androgen receptor mutations as a cause of male sexual ambiguity and as a possible reason for failure of androgen ablation therapy on prostatic carcinoma. In 5 patients of 2 families with perineoscrotal hypospadia and undescended testes, we have identified a mutation ala596 → thr in the DNA-binding domain of the androgen receptor. This mutation interferes with DNA binding of the receptor. Reactivation of this mutant receptor by binding of an antibody or by interaction with other proteins and by exchange of the amino acid thr602 → ala indicates that the dimerization step is affected. A point mutation ser703 → gly was detected in a newborn male child with perineoscrotal hypospadias. This mutation decreased receptor-hormone affinity. As a consequence its transactivation activity was dependent on the androgen concentration. Although the molecular mechanisms of these two mutations are completely different, both resulted in partial androgen insensitivity and interfered with virilization in the affected patients. A different kind of mutation was present in a tumor specimen derived from an advanced therapy-resistant prostatic carcinoma. This point mutation resulted in exchange of valine → methionine at amino acid position 715 in the receptor protein. In contrast to the former two mutations this receptor showed a gain in function. In transactivation assays it was activated not only by testicular androgens but also by the adrenal androgens, androstenedione and dehydroepiandrosterone, and by progesterone. This aberrant transactivation spectrum may contribute to progressive tumor

ISSN:0042-1138    

DOI:10.1159/000282684

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

The increased sympathetic neurotransmission in benign prostatic hyperplasia (BPH) results in a α1C-adrenoceptor-mediated increase in prostatic smooth muscle tone which seems to be responsible for the dynamic infravesical obstruction occurring in BPH. The prostatic smooth muscle contractions evoked by norepinephrine can be efficiently blocked by α1-adrenoceptor blockers. Moreover, an impressive number of clinical trials illustrated the beneficial results of α1-adrenoceptor blockers in the treatment of BPH. However, despite knowledge of α1-adrenergic neurotransmission and the clinical application of its blockade by selective α1-adrenoceptor antagonists, very little is known about the intracellular pathways involved in the regulation of prostatic smooth muscle contractility. To study the intracellular mechanism of the α1c-adrenoceptor-induced prostatic smooth muscle contraction, the patch-clamp technique in the whole-cell configuration mode combined with the Fura-II fluorescence technique was used in human, enzymatically isolated smooth muscle cells obtained from patients undergoing transurethral resection of the prostate because of symptomatic BPH. Furthermore changes in prostatic smooth muscle contractility were registered in organ bath experiments. Application of the selective α1-adrenoceptor agonist phenylephrine (PE) increased the L-type Ca2+-channel current (ICa) dose dependently from 8 up to 18.5 µA/cm2, simultaneously elevating the free cytoplasmic Ca2+ concentration ([Ca2+]i) up to 1.9 µM. Pretreating the myocytes with pertussis toxin, an exotoxin of Bordetella pertussis which inactivates GTP-binding proteins (G proteins) of the Gi and Go family by ADP ribosylation, reduced the PE-induced lea stimulation by 71.5 ± 5.6% (n = 21). Dialysis of the cytosol with the second messenger inositol-1,4,5-trisphosphate (IP3), which releases Ca2+ from intracellular non-mitochondrial, IP3-sensitive Ca2+ pools, imitated the PE-evoked responses. Pretreating the myocytes with the Ca2+-release blockers ryanodine (10–100 µM, n = 8), thapsigargin (0.1 µM, n = 11) or low-molecular weight heparin (n = 14) largely attenuated the PE-evoked responses. The experimental results suggest a coupling of α1-adrenoceptors to phospholipase C-converting phosphoinositol-4,5-bisphosphate into diacylglycerol, an endogenous activator of the protein kinase C and IP3 which releases Ca2+ from intracellular stores stimulating ICa via Ca2+-calmodulin-dependent protein kinase induced phosphorylation of voltage-dependent Ca2+ channels. This knowledge could be of interest for conservative treatment in s

ISSN:0042-1138    

DOI:10.1159/000282685

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Over the last few years cytological investigations of bladder lavage have gained ever-increasing importance in the diagnosis and follow-up of bladder tumors. Flow cytometric DNA analysis is searching for more objective ways to characterize tumor tissue beyond its morphological differentiation. Since the end of 1987 more than 400 bladder lavages have been analyzed both cytologically and by multiparameter flow cytometry. DNA/cytokeratin-8,18 antibody labelling of methanol-fixed single cells provides a standardized method which is not liable to disturbances and enables use in a routine laboratory. Aneuploidy was divided in several subgroups according to the DNA index. Proliferation of the urothelial population as a diagnostic parameter was investigated. Multiparameter flow cytometric measurement can identify and assess all subpopulations of bladder lavage such as inflammatory cells, squamous cells and squamous cell metaplasia. Cytokeratins enable a selective examination of the urothelial population after gating; the diagnostic accuracy for aneuploid tumor stem lines is markedly increased when compared to single-parameter DNA analysis. Higher specificity is reached by excluding falsely positive ‘aneuploid’ squamous cells; higher sensitivity is made possible by lowering the limit of detection for actual aneuploidy within a specimen, especially for near-diploid and tetraploid carcinomas. When compared to cytological malignancy grading, the aneuploidy rate is 26% in G1/2 tumors, 42% in G2 and 78% in G3 tumors (p < 0.005). More than half of the aneuploid bladder lavages with a negative or suspect cytology were diagnosed as tumor recurrences either histologically or cytologically in the following year. Moderately differentiated carcinomas with an aneuploid DNA distribution had a higher rate of recurrence than tumors with euploid distributions when treated curatively by organ-conserving therapy. DNA/cytokeratin analysis of bladder lavage enables an artefact-free measurement of tumor criterium aneuploidy; this is more specific and less sensitive than cytology. Due to the lack of separability of urothelial proliferation in euploid specimens, the aim to make flow cytometry a method equaling cytology cannot be reached. Therefore, the greatest value of flow cytometry is not in tumor screening, but in reliable detection of highly malignant aneuploid tumors at initial diagnosis, during therapy and recognition of recurrence of superficial bladder carcinomas. Reviewing the literature, flow cytometrically proven aneuploidy, especially triploid tumor stemlines, can be used to predict possible invasive growth. DNA/cytokeratin measurements are hence indicated when an exact assessment of prognosis can influence the therapeutic procedu

ISSN:0042-1138    

DOI:10.1159/000282686

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Extracorporeal shock-wave lithotripsy (ESWL) has rapidly become established worldwide as a routine method for treatment of nephro- and ureterolithiasis. Although initial studies showed no tissue-damaging effect by the shock waves, we found, in an animal experiment using canine kidneys, that the ESWL-induced damage to the renal parenchyma is more marked than originally assumed. The damage is limited to the area that was focused on, and heals relatively rapidly by connective tissue encapsulation with final cicatrisation without any further residual effects being observed up to the present. This parenchymal damage is probably also the cause of the macrohematuria that is always observed during therapy. The resulting tissue damage is not extensive enough to cause a demonstrable reduction of function as measured by the usual methods (serum creatinine, creatinine clearance, isotopy renography, i.v. urography). In serum we observed a transient decrease of calcium, an immediate increase of lactate-dehydrogenase, transaminases (SGOT and SGPT) and a delayed increase of alkaline phosphates. Creatinine, blood urea nitrogen, sodium, potassium and amylase remained within normal limits. In urine, a decrease of creatinine and an increase of glucose excretion were noted. We believe that these changes represent a relatively mild and transient damage of renal cells and do not reflect the occasionally heavy morphological changes observed after shock-wave exposure. The main clinical complication is the large subcapsular hematoma which, according to the present knowledge, could well result from a lesion of the larger peripheral vessels. Damage to other organs such as subserous colonic and small bowel hematomata are to be expected although they do not lead to clinical symptoms.

ISSN:0042-1138    

DOI:10.1159/000282687

出版商:S. Karger AG    

年代:1995

数据来源: Karger

摘要:

Cerebral metastases of testicular malignant lymphomas have been reported. In this case a testicular metastasis secondary to a primary cerebral malignant lymphoma is presented. This unusual case does not correspond to the known metastatic pattern of malignant lymphoma.

ISSN:0042-1138    

DOI:10.1159/000282688

出版商:S. Karger AG    

年代:1995

数据来源: Karger

ISSN:0042-1138    

DOI:10.1159/000282689

出版商:S. Karger AG    

年代:1995

数据来源: Karger