While moderate caloric restriction has beneficial effects on animal health state, fasting may be harmful. The present investigation was designed to test how fasting affects oxidative stress, and to find out whether the effects are opposite to those previously found in caloric restriction studies. We have focused on one of the main determinants of aging rate: the rate of mitochondrial free radical generation. Different parameters related to lipid and protein oxidative damage were also analyzed. Liver mitochondria from rats subjected to 72 h of fasting leaked more electrons per unit of O(2) consumed at complex III, than mitochondria from ad libitum fed rats. This increased leak led to a higher free radical generation under state 3 respiration using succinate as substrate. Regarding lipids, fasting altered fatty acid composition of hepatic membranes, increasing the double bond and the peroxidizability indexes. In accordance with this, we observed that hepatic membranes from the fasted animals were more sensitive to lipid peroxidation. Hepatic protein oxidative damage was also increased in fasted rats. Thus, the levels of oxidative modifications, produced either indirectly by reactive carbonyl compounds (N(epsilon)-malondialdehyde-lysine), or directly through amino acid oxidation (glutamic and aminoadipic semialdehydes) were elevated due to the fasting treatment in both liver tissue and liver mitochondria. The current study shows that severe food deprivation increases oxidative stress in rat liver, at least in part, by increasing mitochondrial free radical generation during state 3 respiration and by increasing the sensitivity of hepatic membranes to oxidative damage, suggesting that fasting and caloric restriction have different effects on liver mitochondrial oxidative stress.

The effects of zinc, magnesium and calcium in seminal plasma on time-to-pregnancy (TTP) in healthy couples, on conventional semen parameters and computer-assisted semen analysis (CASA) parameters were evaluated. The localization of chelatable zinc ions in seminal plasma and spermatozoa were assessed by autometallography (AMG). Differences in chelatable zinc localization in samples with high and low total zinc were evaluated. Semen samples from 25 couples with short TTP and 25 couples with long TTP were subjected to conventional semen analysis, CASA, zinc and magnesium measurements by inductively coupled plasma mass spectrometry, and calcium by flame atomic absorption spectrometry. The cations were strongly inter-correlated, but no correlation with TTP or conventional semen parameters was found. Semen samples with high zinc concentrations exhibited statistically significant poorer motility assessed by the CASA parameters straight line velocity and linearity than samples with low zinc content. Calcium concentration also showed statistically significant differences for the same parameters, but the effect was removed by entering zinc concentration into a multiple regression model. Semen samples with high total zinc exhibited stronger staining of the seminal plasma at AMG. It is suggested that high seminal zinc concentrations have a suppressing effect on progressive motility of the spermatozoa ('quality of movement'), but not on percentage of motile spermatozoa ('quantity of movement').

BACKGROUND The prostate contains high amounts of free zinc ions which are excreted into the seminal fluid. The extra‐ and intracellular distribution of zinc ions using the highly specific autometallographical (AMG) method is described. METHODS Prostates from sulfide‐perfused rats were excised, and the ZnS crystals were silver‐enhanced to sizes detectable by the electron and light microscope. RESULTS AMGZnS grains were found primarily in the acinic lumen of the lateral lobes. The dorsal lobe stained only faintly, while the ventral lobe was void of grains. At ultrastructural levels, the presence of zinc ions was confined to apical secretory vesicles and lysosome‐like structure of the epithelium of mainly the lateral lobes. CONCLUSIONS We suggest a constant secretion of zinc ions from the epithelial cells into both the acinar lumen and the intercellular canaliculi, and that the zinc enriched secretory cells in the prostate belong to a system of glandular cells that uses zinc ions to aggregate macromolecules to be excreted. Prostate 31:125–130, 1997. © 1997 Wiley‐Liss, Inc.

Sacral nerve stimulation in fecal incontinence shows promising results. Patients with idiopathic, spinal etiology, or persisting incontinence after sphincter repair may benefit from this minimally invasive treatment.

On behalf of the European SNM Expert Group Background: In sacral neuromodulation (SNM), stimulation programming plays a key role to achieve success of the therapy. However to date, little attention has been given to the best ways to set and optimize SNM programming during the test and chronic stimulation phases of the procedure. Objective: Standardize and make SNM programming easier and more efficient for the several conditions for which SNM is proposed. Methods: Systematic literature review and collective clinical experience report. Results: The basic principles of SNM programming are described. It covers choice of electrode configuration, stimulation amplitude, pulse frequency and pulse widths, while use of cycling is also briefly discussed. Step-by-step practical flow charts developed by a group of 13 European experts are presented. Conclusions: Programming of SNM therapy is not complex. There are few programming settings that seem beneficial or significantly impact patient outcomes. Only four basic electrode configurations could be identified according to four different options to define the cathode. In a majority of patients, the proposed stimulation parameters will allow a satisfactory improvement for long periods of time. A regular follow-up is, however, necessary to assess and eventually optimize results, as well as to reassure patients.

SummaryFigdor et al.' demonstrated in 1957 that a series of structurally related pregnanes, without notable endocrine action, were anaesthetically active when administered to mice. The most active of these pregnanes was pregnanolone (3a-hydroxy-5/l-pregnane-20-one), which is a naturally occurring metabolite of progesterone, first isolated from urine of pregnant women in 1937.' The anaesthetic effect of pregnanolone has been demonstrated in several animal speciesZ3 but its lack of water solubility prevented its development in clinical practice. Pregnanolone is now prepared in a stable emulsion which may prove to be suitable for clinical use. It is solubilised in soya bean oil and emulsified in a similar way to diazepam in the form of Diazemuls.A wide species variation in toxicity and tolerance of pregnanolone emulsion was observed in preclinical studies. Administration of a single bolus injection of 40 mg/kg did not cause any (or only marginal) mortality in the mouse and the rat. No organ toxicity was noted after repeated daily intravenous injections in several species: rat 16 mglkg for 4 days and 7 mg/kg for 28 days; dog 12 mg/kg for 4 days and 3 mg/kg for 28 days; monkey 28 mg/kg for 14 days and 21 mg/kg for 28 days. Hepatic lesions restricted to the biliary system, manifested as morphological changes and increased serum enzymes, occurred after daily administration of 40-64 mg/kg for 4 days and after 14 mg/kg for 28 days in the rat. In the dog the threshold dose for hepatobiliary changes at repeated doses was about 7 mg/kg. The liver damage was clearly related to the dose, but also to the duration of the treatment, and was reversible at least in its initial state (toxicological report, not published). The anaesthetic and anticonvulsive properties of pregnanolone in animals are encouraging and very similar to those of Althesin.-This study reports the findings of a preliminary and limited clinical investigation with pregnanolone emulsion in male volunteers.

Objectives: In some patients treated for urinary or fecal incontinence with sacral neuromodulation (SNM) persistence of symptoms, a reduction in efficacy or adverse effects of stimulation can occur. In such situations, further programming of the SNM device can help resolve problems. Infrequently hardware failure is detected. This article aims to provide practical guidance to solve sub-optimal outcomes (troubleshooting) occurring in the course of SNM therapy. Materials and Methods:A systematic literature review was performed. Collective clinical experience from an expert multidisciplinary group was used to form opinion where evidence was lacking.Results: Circumstances in which reprogramming is required are described. Actions to undertake include changes of electrode configuration, stimulation amplitude, pulse frequency, and pulse width. Guidance in case of loss of efficacy and adverse effects of stimulation, developed by a group of European experts, is presented. In addition, various hardware failure scenarios and their management are described.Conclusions: Reprogramming aims to further improve patient symptoms or ensure a comfortable delivery of the therapy. Initial changes of electrode configuration and adjustment of stimulation parameters can be performed at home to avoid unnecessary hospital visits. A logical and stepwise approach to reprogramming can improve the outcome of therapy and restore patient satisfaction.

The effects of two different zinc chelators, diethyldithiocarbamate (DEDTC) and calcium ethylenediaminetetraacetic acid (EDTA), in full semen samples and 'swim-up' samples were investigated. DEDTC, which crosses cell membranes, and EDTA, which does not cross cell membranes, were added to semen samples in different concentrations. Sperm cell motility parameters were assessed by computer-assisted semen analysis (CASA). It was found that very small concentrations (0.01 mM) of DEDTC immobilized the sperm cells within 80 min, while EDTA had no depressing effect at the concentrations used. In full semen samples EDTA enhanced straight line velocity (VSL) at concentrations of 1.0 and 0.5 mM; this effect was not found at higher concentrations. It is suggested that intracellular mitochondrial zinc ions play a crucial role for sperm cell motility, while loosely bound or free zinc ions in the seminal plasma exert a secondary role on human sperm cell motility.