[BCG versus photodynamic therapy (PDT) for nonmuscle invasive bladder cancer-a multicentre clinical phase III study]. / BCG versus Photodynamische Therapie (PDT) beim nicht muskelinvasiven Harnblasenkarzinom--eine multizentrische Phase-III-Studie.

PURPOSE: This multicentre phase III study was designed to compare the efficacy of Bacillus Calmette Guérin (BCG) instillations and photodynamic therapy (PDT) in the treatment of patients with intermediate and high-risk nonmuscle invasive bladder cancer. MATERIAL AND METHODS: Inclusion criteria were multifocal pTaG1-G2 tumours, recurrent pTaG1-2 tumours, pTa / 1G3 tumours, and primary or recurrent carcinoma in situ (CIS). All patients were centrally randomised after transurethral resection (TUR) to receive BCG induction and maintenance therapy or a single PDT with Photofrin. The primary endpoint of the trial was recurrence-free survival. Secondary endpoints were the 2-year recurrence rate, the 2-year progression rate, survival, and quality of life. RESULTS: 124 patients (63 PDT group, 61 BCG group) were enrolled at 7 institutions in Germany and Austria. Each patient had a follow-up for 2 years. Of the 124 enrolled patients 105 were eligible for this analysis. Kaplan-Meier curves demonstrated no statistically significant differences between the two therapy arms with respect to recurrence-free survival after randomisation (p = 0.4598). After intention-to-treat analysis and after as-treated analysis, the estimated median recurrence-free survival periods were 24.9 (BCG) versus 16.6 months (PDT) and 25.8 (BCG) versus 14.7 (PDT) months, respectively. CONCLUSIONS: A single PDT with Photofrin(R) in intermediate and high-risk nonmuscle invasive bladder cancer patients could not be shown to be superior to BCG maintenance therapy. Vice versa, the results of this study cannot exclude a superiority of BCG.

Cardiac magnetic resonance imaging in the evaluation of cardiac sarcoidosis: an Australian single-centre experience.

BACKGROUND: Cardiac involvement in systemic sarcoidosis is common; however, current diagnostic tools are imprecise. Recognition of cardiac sarcoidosis (CS) is important as it has a relatively poor prognosis. Gadolinium-enhanced cardiac magnetic resonance imaging (Gad-CMR) is emerging as an excellent technique in determining the presence of and extent to which cardiac muscle is affected by sarcoidosis. METHODS: A retrospective analysis was performed on all patients with biopsy-proven systemic sarcoidosis referred for Gad-CMR scanning to evaluate potential cardiac involvement. All patients also underwent an electrocardiogram, Holter monitor and echocardiography. Gallium-67 radionuclide investigation, positron emission tomography and cardiac biopsy were ordered at the discretion of the treating physician. RESULTS: Eleven of the 20 patients had Gad-CMR images supportive of the diagnosis of CS. Eight of these 11 patients met the Japanese Ministry of Health and Welfare (JMHW) criteria for the diagnosis of CS; three abnormal Gad-CME scans consistent with diagnosis of CS were seen in patients who did not meet JMHW criteria. No patients with normal Gad-CMR scan met JMHW criteria for CS. CONCLUSION: These findings suggest that Gad-CMR is potentially superior to the JMHW criteria in the diagnosis of cardiac sarcoidosis.

Ion currents and spiking properties of identified subtypes of locust octopaminergic dorsal unpaired median neurons.

Efferent dorsal unpaired median (DUM) neurons are key elements of an insect neuromodulatory system. In locusts, subpopulations of DUM neurons mediate octopaminergic modulation at specific targets depending on their activity during different behaviours. This study investigates whether in addition to synaptic inputs, activity in DUM neurons depends on intrinsic membrane properties. Intracellular in situ recordings and whole-cell patch-clamp recordings from freshly isolated somata characterize somatic voltage signals and the underlying ion currents of individual subtypes of DUM neurons identified beforehand by a vital retrograde tracing technique. Na(+), Ca(2+), K(+) currents and a hyperpolarization-activated (I(h)) current are described in detail for their (in-)activation properties and subtype-specific current densities. In addition, a Ca(2+)-dependent K(+) current is demonstrated by its sensitivity to cadmium and charybdotoxin. This complex current composition determines somatic excitability similar in all subtypes of DUM neurons. Both Na(+) and Ca(2+) currents generate overshooting somatic action potentials. Repolarizing K(+) currents, in particular transient, subthreshold-activating A-currents, regulate the firing frequency and cause delayed excitation by shunting depolarizing input. An opposing hyperpolarization-activated (I(h)) current contributes to the resting membrane potential and induces rebound activity after prolonged inhibition phases. A quantitative analysis reveals subtype-specific differences in current densities with more inhibitory I(K) but less depolarizing I(Na) and I(h) - at least in DUM3 neurons promoting a reliable suppression of their activity as observed during behaviour. In contrast, DUM neurons that are easily activated during behaviour (DUM3,4,5 and DUMETi) express less I(K) and a pronounced depolarizing I(h) promoting excitability.

Neuromodulatory octopaminergic neurons and their functions during insect motor behaviour. The Ernst Florey memory lecture.

In this article we describe recent advances in functional studies on the role of octopamine released in the periphery by efferent dorsal or ventral unpaired median neurons. In addition to the previously described modulatory effects on the neuromuscular junction, we describe a metabolic regulatory role for these neurons. Due to their activity glycolytic rates in target tissues, such as muscles, are increased. In flight muscles that use carbohydrate catabolism only at take-off but have to switch to lipid oxidation during prolonged flight, these neurons are only active at rest but are inhibited as soon as flight motor patterns are selected.

Acupuncture in the treatment of psychogenic erectile dysfunction: first results of a prospective randomized placebo-controlled study.

In a prospective study, we investigated the potentially curative effect of acupuncture in patients with psychogenic erectile dysfunction (pED). A total of 22 patients with pED were randomized into two groups. They were either treated with acupuncture specific against ED (treatment group) or acupuncture specific against headache (placebo group). Nonresponders of the placebo group were crossed over to the treatment group. Prior to acupuncture, serum sexual hormone levels, IIEF score, nocturnal penile tumescence testing for three nights (Rigiscan) and the erectile response to 50 mg sildenafil were evaluated. Out of 21 patients, 20 completed the study, including 10 patients after crossover. A satisfactory response was achieved in 68.4% of the treatment group and in 9% of the placebo group (P=0.0017). Another 21.05% of the patients had improved erections, that is, sufficient rigidity under simultaneous treatment with 50 gm sildenafil. The results of our pilot study indicate that acupuncture can be an effective treatment option in more than two-thirds of patients with psychogenic erectile dysfunction.

Pilot study on liposomal recombinant human superoxide dismutase for the treatment of Peyronie's disease.

OBJECTIVE: To assess the efficacy and safety of liposomally encapsulated recombinant human superoxide dismutase (lrhSOD) for the treatment of Peyronie's disease. METHODS: In an uncontrolled phase-2 study, 20 patients with Peyronie's disease were treated with a gel containing lrhSOD (1.5 mg/g). Patients with penile deviation of >45 degrees or plaque calcifications of >5 mm were regarded as candidates for surgical correction and excluded from this study. RESULTS: Elimination of pain was observed in 7/13 patients (in 2 patients after only 3 days of therapy), and an almost complete resolution of pain was reported by the remaining 6/13 patients. Plaque size was reduced in 8/14 patients. Minimal improvement of penile deviation was observed in 3/12 patients. Post-therapeutic improvement of sexual function, mainly due to cessation of pain, was reported by 12/15 patients. No systemic or local side effects were observed. CONCLUSION: In the present study, 100% pain relief as well as a plaque size reduction in 56% of Peyronie's disease patients were observed after a maximum of 6 weeks of lrhSOD therapy. The convenience and safety of lrhSOD gel therapy were superior compared to other current regimens. The present results suggest that lrhSOD gel is a promising treatment for patients with early stage Peyronie's disease. Early institution of lrhSOD therapy may prevent disease progression to penile deviation. The present preliminary results are the basis of a placebo-controlled randomized study.

Long-term followup after laparoscopic nephropexy for symptomatic nephroptosis.

PURPOSE: Symptomatic nephroptosis is a rare disease requiring surgical therapy only in select cases. Laparoscopic nephropexy has been reported as minimally invasive treatment for symptomatic patients. We evaluated our long-term outcome after laparoscopic fixation of the kidney with an alloplastic mesh graft. MATERIALS AND METHODS: Since 1992, 30 patients have undergone laparoscopic transperitoneal nephropexy for symptomatic nephroptosis. All patients were preoperatively investigated by excretory urography (IVP) and split renal scan in the supine and upright positions. For fixing the kidney to the abdominal wall a polyglactin and polypropylene mesh graft was used in 6 and 24 cases, respectively. A total of 17 patients with a minimum followup of 5 years participated in an assessment of long-term outcome. Clinical examination, IVP and split renal function testing were performed with patients lying and standing. Patients were further questioned about postoperative satisfaction and whether they would undergo the procedure again. RESULTS: Of 17 patients 10 completed all investigations, 3 were contacted by telephone and 4 were lost to followup. Median followup was 5.9 years. Improvement in symptoms was reported in all cases with complete relief in 11 and intermittent flank pain requiring no medication in 2. There were no postoperative urinary tract infections or hematuria observed with improved hypertension requiring no postoperative medication in 1 case. Postoperatively IVP showed no recurrence in 8 of 10 patients but there was 5 cm. or greater recurrent ptosis in 2. Recurrence developed after using the polyglactin and polypropylene mesh grafts. Comparing preoperative and postoperative (123)iodine renal scans revealed significant improvement in renal function in 9 cases (p <0.05). There was no postoperative difference in split renal function and only 1 patient did not improve. No complications were noted except 1 symptomatic recurrence 3 months after the initial operation that required open surgical fixation. A total of 11 patients were completely satisfied with the long-term outcome and 2 were moderately satisfied. Of the patients 12 would undergo the procedure again, including 2 with persistent slight flank pain. One patient was inconsistent in regard to whether she would undergo the procedure again. CONCLUSIONS: Symptomatic nephroptosis is a bothersome disease requiring therapy only after thorough evaluation, including IVP and split renal scan with patients supine and upright. The good clinical outcome and highly satisfactory cosmetic result support laparoscopic nephropexy as the treatment of choice. Short-term and long-term results prove the efficacy of renal fixation with alloplastic mesh graft as minimally invasive therapy with a high success rate.

Variations of components of the plasminogen activation system with the cell cycle in benign prostate tissue and prostate cancer.

BACKGROUND: Components of the fibrinolytic system are involved in tumor cell invasion and metastasis. Previous investigations suggested a cell cycle-dependent expression of urokinase-type plasminogen activator (u-PA) in epithelial cells. In order to determine a correlation of cell cycle phases with the fibrinolytic system, we investigated the expression of u-PA, tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor type 1 (PAI-1) in normal and tumor-containing prostate extracts and analyzed a possible relationship with flow cytometry-determined proliferative activity of the samples. Cell cycle phases were correlated with fibrinolytic parameters in prostate tissue. METHODS: Samples were obtained from patients undergoing radical prostatectomy for prostate cancer and separated into two portions for DNA analysis and the detection of u-PA, t-PA, and PAI-1. Flow cytometric analysis was performed according to the Vindelov technique. The concentrations of u-PA, t-PA, and PAI-1 were determined from tissue extracts after homogenization by an enzyme-linked immunosorbent assay (ELISA) technique. RESULTS: Correlations of u-PA and t-PA expression with the frequency of G0/G1, S, G2M, S-phase fraction (SPF), and proliferation index (PI) for normal prostate and prostate cancer revealed no significant correlation. The only significant finding was observed in normal tissue revealing a positive correlation between PAI-1 expression and G0/G1 and a negative correlation with S-phase, SPF, and PI. No dependence of PAI-1 expression on different cell phases was found in prostate cancer. Furthermore, no significant correlation of u-PA, t-PA, and PAI-1 with cell cycles in organ-confined ( or = pT3a) tumors was found. No significant correlation in prostate cancer of components of the fibrinolytic system differentiated according to tumor grade or perineural tumor infiltration and cell cycle analysis was found. Only in highly differentiated G1 (Gleason 2-4) cancer, u-PA had a significant positive correlation with G2M-phase. CONCLUSION: Absence of a correlation between levels of components of the fibrinolytic system and cell cycle phases suggests that the reported association between increases of some of these components and aggressive biological behavior of prostate cancer is secondary to non-cell cycle-related mechanisms.

Cholinergic transmission via central synapses in the locust nervous system.

In this study we examine the nature of chemical synaptic transmission between identified filiform hair receptors on the prothoracic segment of a locust and the identified postsynaptic projection interneuron (A4I1). The effects of pressure ejected acetylcholine, and various ligands of acetylcholine receptors on the activity of the postsynaptic neuron A4I1, or on wind-elicited responses in A4I1 are reported. It is suggested that the transmitter of the afferent fibers is acetylcholine, and that fast transmission is mediated by nicotinic acetylcholine-receptors. Both nicotine and carbachol act as agonists, whereas d-tubocurarine and alpha-bungarotoxin act as antagonists. The presence of muscarinic acetylcholine receptors was also evident from the modulatory effects of muscarine, oxotremorine and pilocarpine, which were blocked by bath application of atropine. GABA, and its agonists muscimol and cis-4-amino-crotonic-acid lead to inhibition of A4I1 responses. This inhibition was prevented by the additional application of picrotoxin. This suggests involvement of a ligand-gated GABA receptor which, most likely, increases chloride conductance. Metabotropic GABA-receptors do not seem to be involved, since baclofene, diazepam and bicuculline ejections had no effects. Glutamate also inhibits wind elicited A4I1 responses. Although attempts were made to further characterize the receptor involved, tested substances such as kainic acid, glycine, CNQX or GDEE had no effect.

[Evidence based medicine with reference to the aging man]. / Evidence Based Medicine beim alternden Mann.

There is increasing public and medical interest in the physiological changes of the ageing male. The intention for prolongation of life in combination with maintenance of physical and mental fitness are a great challenge for modern medicine. There are known alterations in the hormonal profiles of ageing males supporting the hypothesis of hormonal substitution to increase quality of life and even to prolong life. These therapies must be faced with the performance of evidence-based medicine defined by the combination of clinical experience with available scientific results including experimental and clinical investigations. There are several systems involved in the ageing process but the pathophysiological background for these changes is not completely understood. Some controlled, randomised studies reported positive effects of hormonal therapy in the ageing male but only a few investigated sufficient patients over a longer period. Due to the lack of long-term data, analysis of the literature for the application of evidence based medicine cannot be sufficiently done yet. It is necessary to perform experimental studies and clinical investigations on clearly defined questions concerning the ageing male including high number of patients over long term treatment periods to get sufficient data to evaluate the value of hormonal substitution in the ageing male according to evidence-based medicine criteria for the performance of best patient's care.

[CVID (common variable immunodeficiency): heterogeneous clinical manifestation of the commonest symptomatic primary immunodeficiency disease]. / CVID (common variable immunodeficiency): heterogene Krankheitsmanifestation dieses häufigsten symptomatischen primären Immundefekts.

Common variable immunodeficiency is the most common symptomatic primary immunodeficiency disease. The patients typically present with a long history of respiratory tract infections, sometimes sarcoid-like lesions and in rare cases boils. Heterogeneity of initial clinical manifestations as well as insufficient knowledge of the syndrome often delay the diagnosis. However, early therapy is important to reduce infections and in particular the development of bronchiectasis. Documenting 19 cases, we discuss initial clinical manifestations, some clinical complications, diagnostic procedures and therapeutic management.

Electromotive administration of intravesical bethanechol and the clinical impact on acontractile detrusor management: introduction of a new test.

PURPOSE: It is often difficult to determine the functional status of the detrusor muscle in patients with detrusor areflexia. We performed a clinical study to establish a test defining residual detrusor capacity in such patients. MATERIALS AND METHODS: In phase 1, 5 controls with detrusor areflexia were tested with an intravesical instillation of 20 mg. bethanechol in 150 cc of sodium chloride 0.3% with and without 20 mA. of pulsed current applied via an electrode catheter through the saline. Cystometry simultaneously recorded intravesical pressure changes. In phase 2, 45 patients with detrusor areflexia were tested with electromotive administration of intravesical bethanechol. In phase 3, 25 mg. bethanechol given orally once daily were prescribed for 15 patients and voiding control was assessed after 6 weeks of therapy. RESULTS: Neither bethanechol without current nor current through saline only led to increased intravesical pressure. However, we noted a mean pressure increase of 34 cm. water during the electromotive administration of bethanechol in 24 of 26 patients with areflexia and neurological disease compared to only 3 cm. water in 3 of 11 with a history of chronic bladder dilatation. Oral bethanechol restored spontaneous voiding in 9 of 11 patients who had had a positive response to the electromotive administration of bethanechol, whereas all 4 without a pressure increase during the electromotive administration of bethanechol did not void spontaneously. CONCLUSIONS: Electromotive administration of intravesical bethanechol identifies patients with an atonic bladder and adequate residual detrusor muscle function who are candidates for restorative measures, such as oral bethanechol and intravesical electrostimulation. Those who do not respond to the electromotive administration of bethanechol do not benefit from oral bethanechol and are candidates for catheterization.

The functional role of octopaminergic neurons in insect motor behavior.

The role of efferent, octopaminergic dorsal unpaired median (DUM) neurons in insects is examined by recording from them during motor behaviour. This population of neuromodulatory neurons is divided into sub-populations which are specifically activated or inhibited during ongoing motor behavior. These neurons are always activated in parallel to the respective motor circuits, and in addition to their modulatory effects on synaptic transmission may also cause metabolic changes in their target tissues.

Correction methods for three-dimensional reconstructions from confocal images: I. Tissue shrinking and axial scaling.

We show here, using locust wholemount ganglia as an example, that scaling artifacts in three-dimensional reconstructions from confocal microscopic images due to refractive index mismatch in the light path and tissue shrinking, can account for dramatic errors in measurements of morphometric values. Refractive index mismatch leads to considerable alteration of the axial dimension, and true dimensions must be restored by rescaling the Z-axis of the image stack. The appropriate scaling factor depends on the refractive indices of the media in the light path and the numerical aperture of the objective used and can be determined by numerical simulations, as we show here. In addition, different histochemical procedures were tested in regard to their effect on tissue dimensions. Reconstructions of scans at different stages of these protocols show that shrinking can be avoided prior to clearing when dehydrating ethanol series are carefully applied. Fixation and mismatching buffer osmolarity have no effect. We demonstrate procedures to reduce artifacts during mounting and clearing in methyl salicylate, such that only isometric shrinkage occurs, which can easily be corrected by rescaling the image dimensions. Glycerol-based clearing agents produced severe anisometric and nonlinear shrinkage and we could not find a way to overcome this.

Directional sensitivity of an identified wind-sensitive interneuron during the postembryonic development of the locust.

Simultaneous extracellular recordings from both locust abdominal connectives show a differential activation of both bilateral homologues of an identified long projection interneuron (A4I1) in response to wind stimuli from different directions. Despite the previously shown extensive structural dynamics of sensory afferents and synaptic rearrangement of the direct afferent-to-interneuron connections during postembryonic development, a directional sensitivity is already present in first instar nymphs. Only quantitative changes in the strength of the directional response can be detected. Intracellular stainings of the A4I1 interneuron in first instar nymphs and adults show that general morphological features do not change during postembryonic development, in contrast to the presynaptic sensory afferents. This also holds for general morphological features of pleuroaxillary flight motoneurons. The output connections of A4I1 to these motoneurons and an unidentified intersegmental interneuron are already present in flightless nymphs.

Effects of aging on male fertility?

The increase in male life expectancy has raised issues concerning the impact of aging on the endocrine system and male fertility. This review focuses on the relationship of spermatogenesis to changes with age in androgen production and testicular morphology, the influence of age on semen parameters and chromosomal quality, and the impact of paternal age and pregnancy outcome. While age-related endocrine changes are well documented, those concerning semen parameters and consequent fertility are based on cross-sectional studies alone. Nevertheless, characteristic age-related morphological testicular alternations have been described, such as decreased numbers of Leydig cells paralleling decreased testosterone production, arteriosclerotic lesions, thickening and hernia-like protrusions of the basal membrane of the seminiferi tubules, and fibrotic thickening of the tunica albuginea. Surprisingly, these alterations do not lead to significant differences in sperm-morphology, time of spermatozoa development or sperm function between young and elderly males. Reports on decreased sperm motility, semen volume and changes in sperm count are contradictory. Although numerical chromosomal abnormalities of spermatozoa are not higher in aging males, an increase in structural aberrations can be observed. Consequently, children of elderly fathers show a 20% higher risk for autosomal dominant diseases, presumably due to increasing numbers of germ cell meioses and mitoses. Thus, the American Fertility Society recommends an age limit for semen donors of 50 years or less.

Iontophoresis for treatment of Peyronie's disease.

PURPOSE: We evaluate the efficacy of iontophoresis of dexamethasone, lidocaine and verapamil to treat Peyronie's disease. MATERIALS AND METHODS: In an uncontrolled prospective study 100 unselected patients with Peyronie's disease were treated with 3 weekly courses of iontophoresis. The drug mixture was administered by an electrical current of 5 mA. and a self-adhesive receptacle fixed to the penile skin overlying the plaque. RESULTS: Resolution of pain was observed in 96% of patients, plaque diminution in 53% and improvement of penile deviation in 37%. Impaired sexual function was improved in 19 of 43 patients (44%). The benefit of iontophoresis therapy was more pronounced in patients with a short history of disease. Because of lack of side effects and painless administration iontophoresis was well tolerated and accepted by all patients. CONCLUSIONS: Iontophoresis of dexamethasone, lidocaine and verapamil may be regarded as first line nonsurgical treatment for Peyronie's disease.

Neuromodulation during motor development and behavior.

Important recent advances have been made in understanding the role of aminergic modulation during the maturation of Xenopus larvae swimming rhythms, including effects on particular ion channel types of component neurons, and the role of peptidergic modulation during development of adult central patterns generators in the stomatogastric ganglion of crustaceans. By recording from octopaminergic neuromodulatory neurons during ongoing motor behavior in the locust, new insights into the role of this peripheral neuromodulatory mechanism have been gained. In particular, it is now clear that the octopaminergic neuromodulatory system is automatically activated in parallel to the motor systems, and that both excitation and inhibition play important functional roles.

Unilateral or bilateral testicular biopsy in the era of intracytoplasmic sperm injection.

PURPOSE: Intracytoplasmic sperm injection has significantly improved the treatment of male infertility. Since only single vital spermatozoa are required for successful fertilization, the value of unilateral or bilateral diagnostic testicular biopsies in patients with azoospermia is controversial. We evaluated differences in bilateral testicular biopsies in azoospermic patients with regard to testicular histology and focal spermatogenesis. MATERIALS AND METHODS: Histopathological results of 100 testicular biopsies from 50 patients (mean age 33.3 years) were reviewed. In all cases azoospermia was the indication for diagnostic testicular biopsy. Intra-individual differences of bilateral testicular biopsies were retrospectively reviewed by determining the latest stage of spermatogenesis. RESULTS: After bilateral biopsy a difference in testicular histology was found in 28% and identical histopathology was noted in 70% of patients. An unsuspected burned out seminoma with maturation arrest in the contralateral testis was seen in 2% of cases. Testicular symmetry determined by a Prader orchidometer was noted in 54.8% of patients whereas 45.2% had asymmetrical testis. The frequency of divergent histopathologies in relation to testicular symmetry was 21.7 and 26.3%, respectively. Spermatozoa were found in 42% of right and 44% of left testes (p >0.05), and spermatids as the latest stage of differentiation were detected in 14 and 16%, respectively (p >0.05). Differentiation of testicular histologies according to the side of biopsy revealed spermatozoa and/or spermatids in 56% of right and 58% of left testes (p >0.05). Bilateral biopsies increased the detection of focal spermatogenesis to 68%. If only unilateral diagnostic testicular biopsies had been performed, in 20% of patients focal spermatogenesis in the contralateral testis would have been missed. CONCLUSIONS: Bilateral testicular biopsies are superior to unilateral biopsies in the evaluation of patients with azoospermia. A 28% intra-individual difference in testicular pathology was seen after bilateral biopsies, and in 20% of patients focal spermatogenesis would have been missed after unilateral biopsy only. Due to the prognostic relevance of testicular biopsies for successful sperm retrieval before assisted reproduction, bilateral diagnostic testicular biopsies are recommended in the evaluation of patients with azoospermia.