Electrophysiological changes in the acute “axonal” form of Guillain–Barre syndrome

The acute “axonal” form of Guillain—Barre syndrome is characterized by rapid progression to severe widespread paralysis and respiratory dependence within 2–5 days of the onset of weakness with very poor and delayed recovery. In 3 cases studied within the first 7 days, the maximum thenar, hypothenar, tibialis anterior, and extensor digitorum bervis “M” potentials were either very reduced in size or absent in response to stimulation at the usual most distal sites of stimulation at the wrist, fibular head, and/or ankle. In the latter instances, advancing the site of stimulation closer to the motor point often evoked an M response. Furthermore, continued distal advance of the site of stimulation evoked progressively larger sized M potentials. Over succeeding days even these very distally evoked M potentials. Maximum conduction velocities in motor nerve fibers just prior to total loss of excitability were often very reduced. The pattern in these cases is most consistent with progressive loss of excitability and conduction in nerve fibers undergoing axonal degeneration, although coexisting primary demyelination in the terminal segment could not be excluded as the basis for the sometimes very slowed conduction velocities. © 1993 John Wiley & Sons, Inc.     

Phase I trial of the polyelectrolyte carbetimer administered i.v. once every four weeks

Summary Carbetimer, a new synthetic low molecular weight polyelectrolyte with a novel structure displayed antitumor activiy in a number of animal tumor model systems and in vitro investigations. Based on these findings it was brought to a phase I clinical trial in patients with advanced malignant disease after failure of conventional treatment or with no conventional treatment available. Forty-eight patients received 98 courses. The schedule was a one hour i.v. infusion every four weeks. The starting dose was 180 mg/m² and dose escalation was performed according to a modified Fibonacci formula up to 16,690 mg/m². At least three patients were treated at each dose level and each patient was eligible to receive repeat courses at the same dose, until progressive disease or dose-limiting toxicity intervened. No hematological toxicity was encountered. Some adverse effects such as reversible proteinuria, hypercalcaemia, pain at infusion site, nausea and vomiting and fatigue were seen partly in a dose-related manner but did not represent the maximum tolerated dose (MTD). The limiting toxicity at the highest dose level of 16,690 mg/m² consisted of ocular symptoms (light flashes) accompanied by a modest decrease of blood pressure and nausea or vomiting during a one hour infusion. 16,690 mg/m²/1 hour was considered the MTD. There were four deaths on study, all considered diseaserelated. Fourteen patients had stable disease for more than two courses, which, however, could also be explained by the natural course of disease. No clear-cut antitumor responses were noted in our study center.The recommended dose for phase II trials derived from our results is 12,550 mg/m²/2 hours. However, with regard to experiences in other phase I studies, the subsequent phase II studies will be performed with a dose of 6,500 mg/m².     

Ultrasound enhanced drug toxicity on Chinese hamster ovary cells in vitro

Chinese hamster ovary cells (HA1) were exposed to therapeutic ultrasound (F = 2.025 MHz) in the presence of various drugs at temperatures of 37-43 degrees C. The space averaged intensities used were 0.5-2 W/cm2. The survival of these cells was subsequently tested using the clonogenic assay. Marked enhancement by ultrasound of the cytotoxicity of Adriamycin and amphotericin B was observed. For Adriamycin, the potentiation was dependent upon the intensity of sonication (exposure duration being 30 min). At 0.5 W/cm2, there was enhancement of cytotoxicity above 41 degrees C. At 1 W/cm2, there was a 3-order increase in cytotoxicity at 37 degrees C. Thus an increase in intensity resulted in a decrease in "threshold" temperature. The effect with Adriamycin could be explained in part by an increase in net uptake of drug into the cells. Further, ultrasound was observed to increase the sensitivity of cells to Adriamycin. For amphotericin B, the enhancement was observed only at exposure durations greater than 30 min and at 43 degrees C. There was no enhancement observed for cisplatin and etoposide. From these results, it appears that ultrasound potentiates the cytotoxicity of drugs the mode of action of which (at least in part) involves the plasma membrane.     

Time-dependent morphological alterations of cold-stored small bowel in Euro-Collins and Ringer's lactate solutions

Small bowel is one of the organs that can in principle be transplanted. Optimum preservation of the organ is essential for the success of transplantation. The aim of the present study is the investigation of time-related morphological changes of rat small bowel during preservation in hypothermic Euro-Collins (EC) and Ringer's lactate (RL) solution using light microscopy and transmission electron microscopy to evaluate the integrity of intercellular complexes of mucosal epithelium, one of the tissues of the intestine that is most susceptible to ischemia. Small bowels were perfused with either EC, RL solution or physiological saline solution and were placed in the different preservation solutions at 4 degrees C for 0, 3, 6 and 12 h. The results of our study suggest that both preservation solutions are suitable for short-term preservation of the small bowel although RL solution is more effective than EC solution. However, we conclude that further improvement of preservation solutions and/or techniques are needed to perform long-term preservation.     

Regulatory effects of biophysical strain on rat TMJ discs

Recent studies have revealed that dynamic biomechanical forces can exert antiinflammatory and antiproteolytic effects on fibrocartitage. Whether the effects of mechanical strain also involve stimulation of the insulin-like growth factor (IGF) system and, therefore, of growth and repair of fibrocartilage has yet to be determined. The objective of this in vitro study was to determine if continuous biophysical strain regulates the gene expression of IGF1, IGF2, IGF1 receptor (IGF1R), insulin receptor substrate (IRS1), and IGF-binding proteins (IGFBP) 3 and 5 in cells from the fibrocartilaginous disc of the temporomandibular joint (TMJ). Rat TMJ disc cells were subjected to continuous biophysical strain (3% and 20%) for 4 and 24 h. Subsequently, RNA was extracted and real-time PCR was performed using an iCycler iQ detection system to analyze the gene expression of the IGF system. The gene expression of IGF1, IGF2, IGF1R, IRS1, IGFBP3, and IGFBP5 was significantly (p < 0.05) inhibited when cells were subjected to continuous biophysical strain, as compared to control at both time points. High strain induced a stronger inhibition of these molecules as compared to strain of Low magnitude. In conclusion, continuous biophysical strain seems to downregulate the expression of the IGF system and may, therefore, reduce the potential of fibrocartilage for growth and repair.     

The effect of Dextransulfate 500 on the pathogenesis of herpes simplex virus infections in weanling mice

Summary Intraperitoneal (i.p.) injection of Dextran Sulfate (D.S.) 500 during a limited period of time influences the course of herpes simplex-virus-infections. D.S.500 was found to reduce the resistance of mice for some herpes simplex-virus strains (Len, L3-2s, Haase) if given between 16 hours before and 2 hours after i.p. infection. The decrease of resistance could be correlated with an increase of the virus content of liver, spleen, brain and spinal cord. Injection of herpes simplex-virus-specific immune serum counteracted the effect of D.S.500 on the course of infections. Conversely, D.S.500 increased the resistance of mice to another group of herpes simplex-viruses (strains D-316, Thea, DD), if given 3 to 8 hours before infection.These effects are ascribed to a special interaction of D.S.500 with macrophages and probably other virus-susceptible cells of the peritoneal cavity and elsewhere with a resulting counteraction to the virus infection.With 2 FiguresIn part presented at the 76th Ordinary meeting of the Society for General Microbiology at the University of Cambridge, April 5–8, 1976.In partial fulfilment of the requirements for the MD degree.     

Associations between total serum IgE levels and the 6 potentially functional variants within the genes IL4, IL13, and IL4RA in German children: the German Multicenter Atopy Study

BACKGROUND: Increased total serum IgE levels are a common characteristic of atopic disorders. Six potentially functional variants, including C-590T in the IL4 gene, C-1055T and Arg130Gln in the IL13 gene, and Ile50Val, Ser478Pro, and Gln551Arg in the IL4RA gene, have been evaluated for their involvement in the control of total serum IgE levels and related atopic disorders, but the results of these studies have been inconsistent. OBJECTIVE: We examined whether these 6 variants had genotypic effects on total serum IgE levels in 823 unrelated German children from a large infant cohort, the German Multicenter Atopy Study. METHODS: Marginal effect models were used for the analyses of the repeated IgE measurements. Weighted linear regression and family-based tests of association were performed to minimize the possibility of spurious effects caused by selection bias or confounding on the basis of ethnic background. RESULTS: There are significant associations between increased total serum IgE levels and 2 variants in the IL13 gene (P <.005 and.0002 for Arg130Gln and C-1055T, respectively). These genetic effects are unlikely to be due to solely linkage disequilibrium between 2 polymorphisms, population stratification, or nonrepresentative samples. In addition, exposure to maternal smoking appears to modify the above effects on total serum IgE levels. However, no statistical association was observed between this quantitative phenotype and the other 4 variants examined. CONCLUSION: These findings suggest that variants C-1055T and Arg130Gln of the IL13 gene might play an important role on total serum IgE production in this study population.