Mechanical restitution curves: a possible load independent assessment of contractile function.

OBJECTIVE: The time constant of mechanical restitution (T((MRC))), proposed to reflect changes in calcium release and uptake, has been shown to increase in left ventricular (LV) failure, and might have a potential as an index of contractile function. However, in vivo studies of the effect on T((MRC)) of changing loading conditions in the normal and failing heart have not been reported. Consequently, in this study, we tested the hypothesis that the increase in T((MRC)) in vivo is independent of preload and afterload. METHODS: Left ventricular pressure-volume loops were assessed at baseline in eight open chest pigs using the combined pressure-volume conductance catheter technique during right atrial pacing at 120b/min. Mechanical restitution curves (MRC) were constructed during four different loading conditions in all eight animals: uninfluenced load, reduced preload (balloon catheter in v. cava inferior), increased afterload (balloon catheter in descending aorta), and increased preload combined with reduced afterload (aortocaval shunting). Acute LV failure was then induced by microembolization through the left main coronary artery, and the experimental protocol was repeated. Contractile response was defined as the maximal first derivative of pressure (dP/dt(max)), and T((MRC)) was calculated using a least square approximation algorithm. RESULTS: Hemodynamic data 30min after microembolization showed decreased mean arterial pressure (98+/-14-67+/-10mmHg, (mean+/-SD) P<0.0001) and dP/dt(max) (1482+/-193-1001+/-125mmHg/s, P=0.001). Stroke volume decreased from 30+/-5 to 20+/-5ml (P<0.0001) compared to baseline, and preload recruitable stroke work decreased from 52+/-7 to 31+/-10mmHg (P=0.002). T((MRC)) increased in all eight animals after induction of LV failure at all loading conditions. There was no difference between the different loading conditions at baseline, nor at LV heart failure, but T((MRC)) increased significantly after the induction of heart failure (ANOVA, two ways). CONCLUSIONS: We have shown that the left ventricular T((MRC)) increases after developed heart failure. The increase in T((MRC)) was independent on loading conditions and thus have a potential for a contractility index.     

Adrenergic Receptor Genotype but Not Perioperative Bisoprolol Therapy May Determine Cardiovascular Outcome in At-risk Patients Undergoing Surgery with Spinal Block: The Swiss Beta Blocker in Spinal Anesthesia (BBSA) Study: A Double-blinded, Placebo-controlled, Multicenter Trial with 1-Year Follow-up

Background: Neuraxial blockade is used as primary anesthetic technique in one third of surgical procedures. The authors tested whether bisoprolol would protect patients at risk for cardiovascular complications undergoing surgery with spinal block.

Methods: The authors performed a double-blinded, placebo-controlled, multicenter trial to compare the effect of bisoprolol with that of placebo on 1-yr composite outcome including cardiovascular mortality, nonfatal myocardial infarction, unstable angina, congestive heart failure, and cerebrovascular insult. Bisoprolol was given orally before and after surgery for a maximum of 10 days. Adrenergic receptor polymorphisms and safety outcome measures of bisoprolol therapy were also determined.

Results: A total of 224 patients were enrolled. Spinal block could not be established in 5 patients. One hundred ten patients were assigned to the bisoprolol group, and 109 patients were assigned to the placebo group. The mean duration of treatment was 4.9 days in the bisoprolol group and 5.1 days in the placebo group. Bisoprolol therapy reduced mean heart rate by 10 beats/min. The primary outcome was identical between treatment groups and occurred in 25 patients (22.7%) in the bisoprolol group and 24 patients (22.0%) in the placebo group during the 1-yr follow-up (hazard ratio, 0.97; 95% confidence interval, 0.55-1.69; P = 0.90). However, carriers of at least one Gly allele of the [beta]1-adrenergic receptor polymorphism Arg389Gly showed a higher number of adverse events than Arg homozygous (32.4% vs. 18.7%; hazard ratio, 1.87; 95% confidence interval, 1.04-3.35; P = 0.04).     

Effect of selected fluorinated drugs in a "ringing" gel on rheological behaviour and skin permeation.

The purpose of the present study was to investigate the influence of different drugs exhibiting different solubility on the viscoelastic properties and on the skin diffusion profile of a ringing gel. In a preliminary rheology study with the placebo gel predominating elastic properties were confirmed and a temperature influence was indicated. Fluconazole, fludrocortisone-acetate, flumethasone-pivalate, flutamide and flufenamic-acid each 1% (w/w) were incorporated into the preparation and oscillatory measurements were performed at temperatures of 25, 28, 32 and 37 degrees C. In all drug containing formulations a high elastic G' value predominated the viscous G' value. The highest G' value could be obtained with the incorporated flumethasone-pivalate. Additionally in almost all cases the G' values decreased with increasing temperature compared to the placebo gel. Additionally in vitro standard diffusion experiments using Franz-type cells and porcine skin were performed. Following rank order of the cumulative drug release after 48 h was obtained: fluconazole>flufenamic-acid>flumethasone-pivalate>flutamide>fludrocortisone-acetate. Furthermore an excellent chemical stability of all incorporated drugs was confirmed over 10 weeks.     

Anatomical Course of the Superficial Branch of the Radial Nerve and Clinical Significance for Surgical Approaches in the Distal Forearm

Abstract 10 embalmed cadaver forearms and wrists were dissected to determine the anatomical course of the superficial branch of the radial nerve in the distal forearm. The superficial radial nerve bifurcated in two branches at a mean of 54,7 mm proximal to the radial styloid. From the styloid process of the radius, the mean distance to the closest dorsal branch of the superficial radial nerve was 3,5 mm and the mean distance to the closest volar branch was 9,8 mm. The mean distance between the closest branch of the superficial radial nerve and Lister?s tubercle was 16,4 mm. The crossing point between the nerve and the cephalic vein was located at a mean of 54,3 mm proximal to the styloid process. At the level of styloid process the mean distance between the closest dorsal branch of the superficial radial nerve and the first dorsal compartment was 15,2 mm and between the closest volar branch and the first dorsal compartment 4,4 mm. Detailed knowledge of anatomic characteristics of the superficial branch of the radial nerve may help prevent injury during operations and treat traumatic lesions of the nerve. Because of great variations in the course of the superficial radial nerve we could not define an absolute safe zone for surgical procedures on the distal forearm. Iatrogenic lesions of the superficial radial nerve are described complications of percutaneous procedures. Therefore open surgical approaches are recommended. Daniela Klitscher and Lars Peter Müller contributed equally to this work.     

Compressed collagen sponges as gastroretentive dosage forms: in vitro and in vivo studies.

The objective of the present investigations was to develop oblong tablets which expand after contact with gastrointestinal fluids within a few minutes to a length of 4-6 cm and which should remain in the stomach for a prolonged period of time due to their size. The tablets were prepared from riboflavin-containing collagen sponges using a computer controlled single punch tablet machine. The collagen material was compressed to oblong tablets with dimensions of 3.5 mm x 9 mm x 18 mm. In vitro investigations were carried out to characterise drug release. The model drug riboflavin was released from the collagen tablets over 12h. The gastrointestinal retention time of the new dosage form was indirectly estimated by determining the duration of riboflavin excretion after oral intake of the tablet. A crossover in vivo study with 12 healthy male and female subjects was performed. The renal excretion of riboflavin was measured after oral administration of collagen tablets and small sustained release hydrocolloid tablets as reference preparation. The amount of riboflavin excreted into the urine was enhanced after administration of the expanding collagen tablets in comparison with the hydrocolloid tablets. The differences were statistically significant after 5, 6, 8, 9, 10 and 12 h.     

The effect of comonomer composition, silane heating, and filler type on aqueous TEGDMA leachability in model resin composites

Experimental composites using either bisGMA/TEGDMA or UEDMA/ TEGDMA matrices, quartz or barium glass fillers, and 2 different filler silanization methods were evaluated regarding monomer leachability in distilled water. The leached amount was detected and quantified using gas chromatography. The results showed that twice as much TEGDMA is leached from a bisGMA/TEGDMA based composite than from an UEDMA/ TEGDMA based composite, when both contain 50 wt% TEGDMA. The hypothesis suggested that the higher degree of cure of UEDMA/TEGDMA based composites would be reflected in a lower monomer leaching value, and this hypothesis was supported by the findings. Whether such a correlation exists within groups of UEDMA/TEGDMA based matrices having different degrees of cure was not determined and needs to be investigated in future studies. Variables such as filler composition and silane treatment did not affect the leaching values of TEGDMA in water. That finding suggests that future studies should target differences in matrices, and that the need for considering effects of filler composition and silane treatment methods should not receive the same priority.     

A path-analytical approach to differentiate between direct and indirect drug effects on negative symptoms in schizophrenic patients

The hypothesis that differences in drug effects of risperidone and haloperidol on negative symptoms in schizophrenia are secondary to effects on positive, extrapyramidal, and depressive symptoms was investigated by means of an analysis of the data from the USA-Canada risperidone double-blind randomized clinical trial of 523 chronic schizophrenic patients. Regression analyses in the total sample and within treatment groups confirmed a strong relationship between changes in negative symptoms and the other variables studied (R²=0.50–0.51,p<0.001). Only depressive symptoms did not contribute significantly to these results (p>0.10). Path analysis showed that the greater mean change (p<0.05) of negative symptoms with risperidone compared to haloperidol could not be fully explained by correlations with favourable effects on positive and extrapyramidal symptoms. The relationship between shift in extrapyramidal symptoms and shift in negative symptoms failed to reach statistical significance; however, there was a clear tendency in the expected direction in both treatment groups.     

Histological and scanning electron microscopic alterations in ileal conduit depending on the time factor

Five ileal conduit biopsies, taken after 1-7 years, were examined by light microscopy and scanning electron microscopy. The total height of the lamina mucosa decreased from 700 to 275 microns. The height of the villi diminished from 550 to 50 microns; the depth of the crypts increased from 130 to 244 microns and the villus-crypt index changed from 4.2 to 0.2. Signs of chronic inflammation could be observed. Scanning electron microscopy shows that the number of microvilli per cell was markedly reduced. There was a varied picture of different stages of atrophy. After 3 years microvilli could no longer be observed. In view of the prolonged urinary contamination time, it appears to be imperative to check neobladders with regard to possible carcinoma induction.