Sacral electrical neuromodulation as an alternative treatment option for lower urinary tract dysfunction

Temporary electrical stimulation using anal or vaginal electrodes and an external pulse generator has been a treatment modality for urinary urge incontinence for nearly three decades. In 1981 Tanagho and Schmidt introduced chronic electrical stimulation of the sacral spinal nerves using a permanently implanted sacral foramen electrode and a battery powered pulse generator for treatment of different kinds of lower urinary tract dysfunction, refractory to conservative treatment. At our department chronic unilateral electrical stimulation of the S3 sacral spinal nerve has been used for treatment of vesi-courethral dysfunction in 43 patients with a mean postoperative follow up of 43,6 months. Lasting symptomatic improvement by more than 50 % could be achieved in 13 of 18 patients with motor urge incontinence (72,2 %) and in 18 of the 21 patients with urinary retention (85,7 %). Implants offer a sustained therapeutic effect to treatment responders, which is not achieved by temporary neuromodulation. Chronic neuromodulation should be predominantly considered in patients with urinary retention. Furthermore in patients with motor urge incontinence, refusing temporary techniques or in those requiring too much effort to achieve a sustained clinical effect. Despite high initial costs chronic sacral neuromodulation is an economically reasonable treatment option in the long run, when comparing it to the more invasive remaining therapeutic alternatives.     

Retinal pigment epithelial cells from Royal College of Surgeons dystrophic rats can take up melanin granules

· Background: Many successful pigment epithelium transplantation studies involving pink-eyed Royal College of Surgeons (RCS) dystrophic rats showed highly pigmented transplanted cells forming a double layer with slightly pigmented cells, attached to Bruch’s membrane. Since it is not clear whether transplanted pigmented cells can displace retinal pigment epithelial (RPE) host cells from Bruch’s membrane, we suggested that RPE cells of RCS dystrophic rats can phagocytize melanin granules, possibly derived from perished transplanted cells. · Methods: In a series of three experiments, RPE cells of nine pink-eyed, 2-month-old RCS dystrophic rats were isolated by trypsinization and mechanical dissection and cultivated in Dulbecco’s modified Eagles’ medium. These cells were then fed with melanin granules, isolated from bovine RPE cells, double-trypsinized after phagocytosis and viewed by light and electron microscopy. We also transplanted iris pigment epithelial (IPE) cells of 20-day-old Long-Evans rats into the subretinal space of pink-eyed RCS dystrophic rats of the same age, shown in light-microscopic photography after 42 days. · Results: Living RPE cells were heavily pigmented after feeding with isolated melanin granules in all three experiments as viewed by light microscopy. In addition, we identified melanin granules phagocytized by dystrophic RPE cells in electron microscopy. After transplantation of pigmented IPE cells into the subretinal space of pink-eyed RCS dystrophic rats’ eyes, a layer of slightly pigmented cells was seen on Bruch’s membrane below the transplanted IPE cells, shown in light microscopy. · Conclusion: We have shown by phagocytosis assay that dystrophic RPE cells can take up melanin granules in vitro. Our results assume that pigmented cells in transplantation studies, found as a monolayer, attached to Bruch’s membrane, cannot automatically be identified as transplanted cells. Instead, the possibility of perished transplanted cells serving as melanin donors for RPE host cells must be taken into consideration. Received: 11 March 1998 Revised version received: 5 May 1998 Accepted: 26 May 1998     

Concomitant blockade of P2X-receptors and ecto-nucleotidases by P2-receptor antagonists: functional consequences in rat vas deferens

In order to assess the consequences of a concomitant blockade of P2X-receptors and ecto-nucleotidases, effects of 13 P2-receptor antagonists were investigated on contractions of the rat vas deferens elicited by α,β-methylene ATP (α,β-MeATP) and ATP and on the removal of ATP from the incubation medium by vas deferens tissue. Increasing concentrations of all antagonists reduced and finally abolished contractions elicited by α,β-MeATP (3 μM), with IC₅₀-values ranging from 1.1 to 100 μM. Pyridoxalphosphate-6-azophenyl-2’,4’-disulphonate (PPADS), 6-azophenyl-4-amino-5-hydroxy-naphthalene-1,3-disulphonate (NH02), 4,4’-diisothiocyanatostilbene-2,2’-disulphonate (DIDS) and uniblue A also progressively reduced and finally abolished contractions elicited by ATP (1 mM). 8,8’-[Carbonylbis(imino-3,1-phenylenecarbonyl-imino)]-bis-(1,3,5-naphthalenetrisulphonate) (NF023), sura- min, pyridoxalphosphate-6-azophenyl-2’,5’-disulphonate (iso-PPADS), trypan blue and reactive blue 19, in contrast, caused only partial blockade, by 34–43% maximally; reactive blue 2 and reactive red 2 had no effect; and 6,6’-(1,1’-biphenyl-4,4’-diylbisazo)-bis-4-amino-5-hydroxy-naphtha-lene-1,3-disulphonate (NH01) and Evans blue even enhan- ced the response to ATP. For antagonists causing full or partial inhibition, the IC₅₀-values against ATP were close to those against α,β-MeATP. All antagonists attenuated the removal of ATP, with IC_25%-values ranging from 0.8 μM to >320 μM. The results confirm the frequent combination, in one antagonist molecule, of P2-receptor blockade and blockade of ecto-nucleotidases. This dual action underlies the effect of such compounds on contractions of the vas deferens elicited by ATP which, for certain substances (e.g., suramin, reactive blue 2), can be explained by a simple model in which the antagonist simultaneously blocks the degradation of ATP and a single contraction-mediating receptor (P2X₁). Several observations, however, do not conform with this model, and the existence of multiple contraction-mediating receptors for ATP or multiple, pharmacologically distinct ecto-nucleotidases has to be considered. Received: 23 October 1998 / Accepted: 11 January 1999     

HMR 1883, a cardioselective KATP channel blocker, inhibits ischaemia- and reperfusion-induced ventricular fibrillation in rats

Ventricular fibrillation (VF) is a major cause of sudden cardiac death in which myocardial ischemia plays a leading role. During ischaemia activation of ATP-sensitive potassium channels (K(ATP)) occurs, leading to potassium efflux from cardiomyocytes and shortening of the action potential favoring the genesis of ventricular fibrillation. In confirmation of this concept the sulfonylurea glibenclamide, which stimulates insulin release by inhibition of pancreatic K(ATP) channels, has been shown to inhibit VF in different models of ischaemia by inhibition of myocardial K(ATP) channels. HMR 1883 (1-[15-12-(5-chloro-o-anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-m ethylthiourea) was designed as a cardioselective K(ATP) channel blocker. The aim of this study was to show that with this compound it is possible to separate the antifibrillatory from the insulin-releasing effect for the treatment of patients at risk of ischaemia-induced arrhythmias and sudden death. In the present study HMR 1883 reduced VF in Sprague-Dawley rats during prolonged ischaemia and also diminished mortality and the duration of VF in a separate reperfusion experiment at 3 mg/kg and 10 mg/kg with no effect on blood glucose or insulin. Glibenclamide, which was antifibrillatory at 0.3 mg/kg and 1 mg/kg, increased plasma insulin and lowered blood glucose already at a dose as low as 0.01 mg/kg. In conclusion, based on its antifibrillatory action and the absence of significant pancreatic effects at therapeutic doses, HMR 1883 is of potential clinical utility for the prevention of severe arrhythmias in patients with ischaemic heart disease.     

Intensity dependence of auditory evoked potentials (AEPs) as biological marker for cerebral serotonin levels: effects of tryptophan depletion in healthy subjects

Rationale: The intensity dependence of the auditory evoked potentials (AEP) has been suggested to be a specific biological marker of central serotonergic activity. Objective: While previous studies used circumstantial evidence to support this hypothesis, we manipulated (decreased) cerebral levels of serotonin directly by using tryptophan depletion. Methods: Twelve healthy young subjects were investigated using placebo and two different amino acid mixtures in a double blind cross over design on three different occasions. AEPs recorded during tryptophan depletion were analyzed by dipole analysis and regional sources using methods published in the literature. Results: For none of the mixtures a significant effect of tryptophan depletion was found. There was a trend towards reduced intensity dependency after tryptophan depletion, especially in the right hemisphere. This reduction correlated with the amount of reduced tryptophan in plasma. Conclusions: The results indicate, in contrast to earlier indirect studies, that the intensity dependence of AEPs is not a specific marker of central serotonergic activity. Received: 8 March 1999 / Final version: 25 May 1999     

Exceptional performance in heart preservation with an amino acid—Containing perfusion fluid

This is a report of a study aimed at putting into practice a new theory for hypothermic preservation of viable organs. A perfusion fluid elaborated according to this theory was applied in preservation of the heart, and resulted in storage of the heart for up to 72 hours with preservation of its functions (rhythm, presystolic ventricular pressure, systolic ventricular pressure, cardiac work, coronary blood pressure, sensitivity to drugs) and its morphology. An important finding was that repeated heart storage for 24 hours alternating with functional testing for 5–7 hours could be performed without irreversible alterations of cardiac function and fine structure. Furthermore, during functional testing following storage the hearts consistently demonstrated improvement of function in time, suggesting that the preserved myocardial tissues were able to rapidly achieve metabolic reequilibration. The results of this study provide the possibility of developing a system for efficient ex vivo heart conditioning before transplantation.

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Résumé Nous avons testé la valeur d'une nouvelle théorie sur la préservation d'organes en hypothermie. Un liquide de perfusion conforme à cette théorie a été utilisé pour la préservation cardiaque. Il permet de conserver le coeur pendant 72 heures, sans altérations de ses fonctions (rythme, pression ventriculaire pré-systolique et systolique, travail cardiaque, pression coronaire, sensibilité aux médicaments) ni de sa morphologie. De plus, le coeur peut-être, à plusieurs reprises, conservé pendant 24 heures, avec des intervalles de reprise fonctionnelle de 5–7 heures, sans que sa fonction ni sa structure fine ne soient altérées de façon irréversible. Enfin, l'étude fonctionnelle montre qu'après conservation la fonction cardiaque s'améliore avec le temps, suggérant donc une rééquilibration métabolique rapide du tissu myocardique. Les résultats de cette étude permettront la mise au point d'un système efficace de conservation cardiaque ex-vivo en vue de la transplantation.

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Supported by the German Heart Center, Munich, and the German Academy Department for Foreign Scientific Relationships, Bonn.     

Malignes Histiocytom der Haut mit multivesiculärer Vacuolisierung

Zusammenfassung Bei einem 47 jährigen Patienten entwickelten sich am rechten Bein mehrere rasch wachsende Tumoren von distal nach proximal. Histologisch und elektronenmikroskopisch zeigten die Tumorzellen morphologische Besonderheiten, die für ihre histiocytäre Provenienz sprechen. Auffallend war die große Anzahl polymorpher cytoplasmatischer Membranstrukturen und großer Vacuolen, die massenhaft kleine Vesikel enthielten. Diese Strukturen werden als transformierte multivesiculäre Körper gedeutet; ihre Entstehung vollzieht sich im Rahmen einer bizarr übersteigerten Membranaktivierung einer malignen Zellrasse. Bemerkenswert ist die rasche und völlige Remission durch Radiotherapie.

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Multivesicular vacuolization in malignant histiocytoma of the skin

Summary A 47-year-old patient developed several rapidly growing tumours in his right leg. Histologic and electron microscopic examination revealed morphological characteristics suggesting the histiocytic origin of the tumour cells. An important finding was the striking number of pleomorphic membraneous inclusions and large vacuoles containing numerous small vesicles. These cytoplasmic inclusions are interpreted as transformed multivesicular bodies. Their formation may be an expression of an increased and bizarre membraneous activity of a malignant cell race. Radiotherapy resulted in a remarkably rapid and complete remission.

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Auszugsweise vorgetragen beim 4th European Meeting on Electron Microscopy Applied on Cutaneous Pathology, Heidelberg, 6. und 7. Mai 1977: Multivesicular Vacuolization in Malignant Histiocytoma.     

Influence of selected pesticides on the microbial degradation of14C-triallate and14C-diallate in soil

Degradation in soil of [allyl-2-¹⁴Ctriallate and [carbonyl-¹⁴ Cdiallate herbicides, as affected by other selected pesticides, was studied in an incubation system that allowed recovery of 95 to 100% of added¹⁴C. The amount and sequence of pesticide additions simulated field use in the protection of wheat (triallate) and sugar beets (diallate).Neither the rate nor the pattern of triallate degradation in soil was influenced by the following sequence of formulated pesticides: dinoseb acetate, (bentazon + dichlorprop + 2,4,5-T), 2,4-D, (chlorcholinchloride + cholinchloride), tridemorph, and thiophanate. Similarly, diallate degradation was unaffected by pyrazon, dimethoate, and thiophanate. The effect of azinphosmethyl was unclear. In contrast, chlorpyrifos reduced diallate degradation by approximately 14% relative to that occurring in the insecticide's absence. This effect was caused by chlorpyrifos and not its formulation components. Chlorpyrifos was also found to partially inhibit degradation of triallate in soil. Inhibition of neither herbicide was considered to be of ecological significance. Triallate, diallate, and thiophanate were applied at 1g/g; all others were at 2g/g.     

“Real time” measurement of endogenous dopamine release during short trains of pulses in slices of rat neostriatum and nucleus accumbens : role of autoinhibition

Summary Release of endogenous dopamine elicited in slices of rat neostriatum or nucleus accumbens by a single electric pulse or by trains of 4 or 10 pulses was examined using fast cyclic voltammetry.Single electric pulses gave rise to a marked and transient increase in the extracellular concentration of dopamine in the neostriatum (by 0.43 mol/l) and nucleus accumbens (by 0.39 mol/l). The overflow elicited by subsequent pulses delivered at a frequency of 0.2 Hz caused separate but much smaller peaks of dopamine concentration, whereas the overflow elicited by subsequent pulses delivered at 1 Hz caused only a shoulder in the descending limb of the peak due to pulse 1. Four pulses at 5 Hz produced a monophasic response that was higher than the single pulse-evoked peak. Nomifensine 1 mol/l greatly increased and prolonged the evoked overflow of dopamine. In the absence of nomifensine, metoclopramide 0.3 mol/l did not change the response to a single pulse or 4 pulses delivered at 0.2 Hz but increased the response to 4 or 10 pulses at 1 Hz and to 4 pulses at 5 Hz. In the presence of nomifensine, metoclopramide increased the response to a single pulse as well as, to a greater extent, the response to 4 pulses at 0.2 Hz and 4 pulses at 1 Hz. Sulpiride 1 mol/l produced effects similar to those of metoclopramide in the neostriatum in the presence of nomifensine. During trains of pulses at 0.2 or 1 Hz, metoclopramide and sulpiride did not increase (or increased only slightly in the presence of nomifensine) the initial peak that reflected dopamine overflow elicited by pulse 1, but increased greatly the subsequent peaks (0.2 Hz) or the sholder (1 Hz) that reflected the overflow due to the subsequent pulses.The study demonstrates the release of dopamine in the neostriatum and nucleus accumbens with high temporal resolution so that, at least at low frequency, the release elicited by each pulse in a train can be recognized. As previously concluded from experiments with ³H-dopamine, single pulses elicit a large release whereas subsequent pulses delivered at 0.2 to 5 Hz elicit much smaller release. Presynaptic autoinhibition develops immediately after pulse 1 in trains of appropriately spaced pulses. However, it is only partly responsible for the marked fall in release after pulse 1; other, unknown factors contribute to the decline.The experiments were carried out at the Department of Pharmacology, Queen Mary and Westfield College, London, UK, while N.L. was a visiting scientist Send offprint requests to N. Limberger at the above address