Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study.

AIM: Efficacy and safety of benfotiamine in treatment of diabetic polyneuropathy. METHODS: Double blind, placebo-controlled, phase-III-study. 181 patients were screened. 165 patients with symmetrical, distal diabetic polyneuropathy were randomised to one of three treatment groups entering the wash-out phase and 133/124 patients were analysed in the ITT/PP analysis: Benfotiamine 600 mg per day (n=47/43), benfotiamine 300 mg per day (n=45/42) or placebo (n=41/39). RESULTS: After 6 weeks of treatment, the primary outcome parameter NSS (Neuropathy Symptom Score) differed significantly between the treatment groups (p=0.033) in the PP (per protocol) population. In the ITT (intention to treat) population, the improvement of NSS was slightly above significance (p=0.055). The TSS (Total Symptom Score) showed no significant differences after 6 weeks of treatment. The improvement was more pronounced at the higher benfotiamine dose and increased with treatment duration. In the TSS, best results were obtained for the symptom "pain". Treatment was well tolerated in all groups. CONCLUSION: Benfotiamine may extend the treatment option for patients with diabetic polyneuropathy based on causal influence on impaired glucose metabolism. Further studies should confirm the positive experiences.

Comparative biochemical, histochemical and autoradiographic studies of Na+/k+-ATPase in the rectum of dragonfly larvae (Odonata, Aeshnidae).

Na+/K+-ATPase localization in the rectal wall of larval Aeshna cyanea (Insecta, Odonata) was studied with histochemical precipitation techniques and 3H-ouabain autoradiography in conjunction with biochemical measurements of enzyme activities and radiospectrometry of 3H-ouabain binding, respectively. The NPP-strontium and ATP-lead methods led to complete inhibition of Na+/K+-ATPase in this organ and hence to unreliable histochemical results. The 3H-ouabain binding technique revealed sodium pump sites at the basolateral plasma membranes of the absorptive rectal chloride epithelia.

Plasmalemma invaginations, contraction and locomotion in normal and caffeine-treated protoplasmic drops of Physarum.

The de novo formation of plasmalemma invaginations and vacuoles of light microscopic dimension in protoplasmic drops at different age-stages was studied quantitatively by applying morphometric methods and marker techniques. The study includes: i) the normal morphogenetic development to a drop age of 1 hour, ii) the influence of caffeine treatment, and iii) the effects of removal of this drug. In untreated drops, formation of invaginations and vacuoles is accomplished within 10 to 15 min. By application of 5 mM caffeine, the formation of plasmalemma invaginations is inhibited for 20 to 30 min. The onset of oscillating contraction activity is delayed, but not hindered by the drug. Drug removal 20 min after drop generation leads to an immediate initiation of plasmalemma infolding. Although caffeine does not hinder initiation of normal contraction activity, the locomotory ability of the drop is blocked if the drug is not removed from the drop and the substrate. Thus, caffeine uncouples motive force generation from locomotion in all plasmodial stages of Physarum. The cellular sites of drug action are discussed.

Calcium binding sites in plasmodia of Physarum polycephalum as revealed by the pyroantimonate technique.

Plasmodia of the acellular slime mold, Physarum polycephalum, were treated with an osmium tetroxide fixative containing potassium pyroantimonate to precipitate calcium and thereby localize calcium binding sites and sites of increased calcium concentration. Dense calcium pyroantimonate precipitates were detected within the nucleoli. The distribution of these precipitates during interphase and mitosis coincides with the distribution of the unique minichromosomes in Physarum, i.e., the numerous short pieces of extrachromosomal nucleolar chromatin containing segments of amplified DNA coding for ribosomal RNA. Calcium pyroantimonate precipitates were present as frequent dense granules in the mitochondrial matrix and as fine precipitates in the mitochondrial nucleoid. Large calcium-containing precipitates were seen within cytoplasmic vacuoles, confirming reports by others. In addition, we have identified calcium binding sites along the cytoplasmic surface of the plasma membrane. The distribution of calcium within the plasmodium is discussed in relation to the assembly of the mitotic spindle and the regulation of cell motility.

[Controlled-release oxycodone--a therapeutic option for severe neuropathic pain. Two multicenter observational studies]. / Retardiertes Oxycodon--eine Therapieoption bei starken neuropathischen Schmerzen.

Two postmarketing studies (PMS) involving 603 patients with neuropathic pain treated with controlled-release oxycodone were performed. Pain intensity and impairment of performance were evaluated using a numeric rating scale (NRS) ranging from 0 to 10 (0 = no pain/impairment, 10 = most severe pain/impairment) measured at the start of the study, and at one week and some three weeks into the study. Mean pain intensity decreased from more than 6 at the start of the PMS to about 4 after one week, and under 3 after three weeks, of treatment. The mean dose of oxycodone after three weeks was slightly more than 40 mg per day. Impairment, quality of life and performance (daily activities, mood, sleep quality and joie de vivre) improved substantially.

Oscillating contractions in protoplasmic strands of Physarum: effects of externally applied ouabain, sodium-, potassium- and calcium-ions.

1. Concentrations of 0.1-10 mM Ouabain do not affect oscillating contractions, when applied externally in physiological solutions. 2. Ouabain has no effect, when applied in solutions of increased sodium- (100 mM) and lowered potassium-concentration (0.1 or zero mM). 3. De novo generation of oscillating contractions in protoplasmic drops is not suppressed in Ouabain-solutions. 4. Biochemical studies of Na-K-ATPase did not show any Ouabain sensitive ATPase-activity. 5. Reaction of veins on high concentrations (300 mosm) is discussed as to be a physical effect. 6. It is concluded that no Na-K-ATPase is engaged in triggering oscillating contraction automaticity.

Synchronization and signal transmission in protoplasmic strands ofPhysarum : Reaction to varying temperature gradients.

Isolated protoplasmic strands ofPhysarum polycephalum, mounted as a trapeze, show synchronous contraction activities when the isometric tension development of both arms of the trapeze is measured independently of each other. This phase regulation can be experimentally disturbed by temperature changes. Within a permanent gradient, however, the phases become resynchronized. The maximal temperature gradient between both arms allowing a phase resynchronization was approximately 9° C along a distance of 25 mm. The transmission of the signal along the middle piece of the trapeze (which, as the connecting part of both arms, is responsible for signal transmission in phase synchronization) can be influenced by temperature changes. The minimal temperature allowing a signal transmission is 15° C, the maximal temperature approximately 29° C. A morphological investigation of protoplasmic strands mounted as trapezes revealed that the normal architecture of the objects is not influenced by the experimental trapeze arrangement. Permanent thermal gradients induce thermotactic reactions, i.e., a preferred protoplasmic mass transport into one arm of the trapeze. This leads, after several hours, to a morphological asymmetry of the trapeze. In spite of the fact that this reaction limits the temporal use of trapezes within thermal gradients to 2-3 h, the capacity of such strands for phase regulation is not hindered. Thermal gradients are suitable methods for studying the unknown phase-regulating factor and its transmission. As criteria for an intact pathway of signal transmission, the capacity of the trapeze arms to resynchronize as well as to maintain synchronization within a thermal gradient can be used.

Synchronization and signal transmission in protoplasmic strands of Physarum : Effects of externally applied substances and mechanical influences.

The phenomenon of synchronization of contraction rhythms was investigated on isolated protoplasmic strands of Physarum polycephalum. The strands were mounted as (gymnastic) trapezes; the contraction activities of the arms were measured independently under isometric conditions; and the connecting middle part of the arms was treated in different ways to block the signal transmission between the arms. Experiments for testing the influence of different chemicals on signal transmission demonstrated that whenever a substance blocked signal transmission it also disturbed the normal oscillatory contraction activity of a single strand, the endoplasmic streaming, and the normal architecture of the strand. No substance inhibited the transmission of the synchronizing factor specifically. As a depolarizing medium, 70 mM KCl solution did not hinder phase synchronization. On the other hand, compression of the middle part with a glass needle immediately led to dissynchronization as soon as the endoplasmic flow could not pass the point of constriction. Gelation of the endoplasm by a vibrating glass needle placed at the surface of the middle part had the same effect. It is concluded that a bioelectric continuance of the plasmalemma is not sufficient for signal transmission. In contrast, an intact endoplasmic flow appears to be obligatory. According to the experimental data presented, an electrical coupling responsible for phase synchronization between the two arms seems to be unlikely. The unknown synchronizing factor is transported via endoplasmic flow, i.e., the endoplasmic stream seems to present the pacemaker of the oscillatory contraction activity.

Synchronization and signal transmission in protoplasmic strands of Physarum : The endoplasmic streaming as a pacemaker and the importance of phase deviations for the control of streaming reversal.

The importance of endoplasmic streaming in the synchronization of contraction activites in plasmodial strands of Physarum was investigated under experimental conditions allowing simultaneous observation of the endoplasmic flow in the middle part of a strand mounted as a trapeze and the measurement of isometric contraction activities of the arms of the trapeze, as well as of the activities of the strand portion connecting the arms. The correlation of longitudinal and radial contraction activities in different regions of a trapeze was examined. Whereas the arms and the middle part of a trapeze contract synchronously in a longitudinal direction (in-phase behaviour), an antiphase correlation appeared when comparing the longitudinal contraction activity of the arms and the radial activity of the middle part. This result is interpreted to mean that the middle part is able to perform isotonic contractions which induce radial dilatation of the strands. No clear-cut correlation between longitudinal and radial activities could be found when measuring simultaneously both activities in one and the same arm of a trapeze by combining tensiometry and cinematography. Protoplasmic shuttle streaming within a strand mounted as a trapeze is found to run regularly out of one arm through the middle part into the other arm, and vice versa. There is no correlation between the time points of streaming reversal and a certain stage of contraction cycles as presented by the contraction curves of the arms. However, there is a good correlation between the points of streaming reversal and the phase deviations of the longitudinal contraction activities of the arms. The importance of these phase deviations for the control of streaming reversal, i.e., for the generation of hydrostatic pressure differences in a system working with phase synchrony, is discussed. The role of endoplasmic streaming as a pacemaker for synchronization phenomena of contraction activities is stressed. The possibility is discussed that shuttle streaming of endoplasm acts as a mechanical coupling within the regulation phenomena resulting in spatial monorhythmicity.

Prematurity and maternal bronchial hyperresponsiveness.

Bronchial reactivity was compared among mothers of neonates with unexplained premature delivery and mothers of preterm neonates with known etiology of prematurity as well as mothers who delivered their children at term. Bronchial reactivity was measured by unspecific bronchial provocation testing with histamine. A significantly higher incidence of bronchial hyperreactivity was found among mothers with unexplained prematurity as compared to the control groups. An imbalance in the autonomic nerve system leading to prematurity as well as bronchial hyperresponsiveness is suggested.

Oral budesonide significantly improves water absorption in patients with ileostomy for Crohn disease.

BACKGROUND: In addition to their anti-inflammatory effects, steroids influence electrolyte and water transport systems in the intestinal mucosa. This study analysed the effect of the topically acting glucocorticoid budesonide on ileostomy output in patients with Crohn disease. METHODS: Oral budesonide (3 mg/three times daily for 8 days; n = 20) was compared to placebo (n = 20) in a double-blind design using matched-pair randomization according to ileal resection length in patients without detectable inflammatory activity. Under controlled hospital conditions, absolute output volumes were measured and response was defined as a reduction in intestinal output of > 25% compared to pretreatment conditions. RESULTS: In the treatment group, we observed an absolute decrease in median intestinal output from 1,240 ml to 865 ml (30.2%), compared to 0.3% under placebo (from 950 ml to 947.5 ml). Response was documented in 60% (12/20 patients) in the treatment group compared to no response under placebo (P < 0.0001). While both treatment groups showed similar absolute median reductions (400 ml with ileal resection < or = 20 cm and 405 ml with ileal resection > 20 cm), the relative reduction (response rate) was lower in the subgroup of an ileal resection > 20 cm (36%) due to the greater increase in output secondary to the loss of ileum. CONCLUSIONS: These data support the assumption that the absorptive capacity of the intestinal mucosa for water may be improved by topically acting steroids and suggest that this occurs independently of their anti-inflammatory effect.

An inexpensive "silicone photo device" for transmicroscopic registration of rhythmical movement phenomena.

A highly sensitive electronic unit (called "silicon photo probe") is described, which enables registration of cellular motion phenomena simultaneous with their light microscopic observation. Changes in light intensity caused by movements of the living object are registered by means of a silicon photo diode (silicon blue cell), which can be mounted within the binocular tube of any type of light microscope replacing one of the oculars. Its application during investigations of oscillating contraction activity in Physarum is reported. Advantages and short-comings are discussed with respect to established photometric, tensiometric and infrared registration techniques.