Treatment of diabetic polyneuropathy with the neurotrophic peptide ORG 2766

The efficacy of the neurotrophic peptide ORG 2766 in diabetic patients with polyneuropathy was evaluated in a double-blind, placebo-controlled, multicentre trial. One hundred and twenty four patients were randomised in five groups to receive 0.1, 0.4, 2 or 5 mg ORG 2766 or placebo, once daily, administered subcutaneously 52 weeks. Thermal discrimination thresholds (TDT) and vibration perception thresholds (VPT), motor and sensory nerve conduction velocity, Hoffmann reflex, heart rate variation during deep breathing and heart rate response after standing up, neurological examination score and neuropathic symptom score were determined at baseline and after 17, 34 and 52 weeks of treatment. Of the nerve function indices studied, at week 52 the TDT_warmth of the hand in the ORG 2766 0.1, 0.4 and 5 mg groups and the TDT_cold of the foot in the ORG 2766 0.1 and 0.4 mg groups significantly improved compared with placebo. Further significant improvement as compared with placebo was observed in the paraesthesia score at week 34 and week 52 in the ORG 2766 2 mg group. Only at week 34 had both the heartbeat variation during deep breathing and the VPT of the foot in the ORG 2766 0.1 mg group improved significantly, compared with placebo. No further statistically significant differences were observed at time for the other measures. No adverse reactions were observed. The only recorded drug-induced side effect was pain at the injection site. Taking all measures of efficacy into account, the statistically significant results observed did not show consistency within each measure. Therefore, it is concluded that ORG 2766, in contrast to earlier reports, is not effective in treating diabetic polyneuropathy.     

Unusual presentation and clinical variability in Belgian pedigrees with progressive external ophthalmoplegia and multiple deletions of mitochondrial DNA

We studied 14 patients from three unrelated Belgian pedigrees with a familial mitochondrial disorder and multiple deletions of mitochondrial DNA (mtDNA). In one family with an oculopharyngeal presentation there is a clear autosomal dominant inheritance. Progressive external ophthalmoplegia (PEO), “ragged red fibres” (RRF) and multiple deletions of mtDNA are common to all three families. Therefore a diagnosis of autosomal dominant progressive ophthalmoplegia with multiple deletions of mtDNA (adPEO) was made in one family at least. Our data confirm the previous observations that adPEO is a systemic disorder rather than a pure myopathy. In our pedigrees frequently associated features include axonal peripheral neuropathy, dysphagia, psychiatric illness, and sudden death. Mild ataxia, pes cavus and mitral valve prolapse with associated mitral insufficiency also occur. In some cases onset is atypical with neuropathy, adolescent onset myopathy or psychiatric illness. In such cases the common features of PEO and muscle weakness always complete the clinical phenotype later during the course of the disease. Biochemical studies on mitochondrial fractions prepared from one patient's muscle, revealed no abnormalities of respiratory chain enzyme activities.     

Pain-related somatosensory evoked potentials following CO2 laser stimulation in peripheral neuropathies

Pain-related somatosensory evoked potentials (pain SEPs) following CO2 laser stimulation were examined in 30 patients with peripheral neuropathies, and the results were compared with clinical sensory findings. Pain SEP findings showed a significant correlation with the clinical impairment of pain sensation, but not with the impairment of deep sensations. In contrast, conventional electrically-stimulated SEPs (electric SEPs) showed a significant correlation with deep sensations, but not with the impairment of pain sensation. Examinations of both pain SEPs and electric SEPs, therefore, are considered to be very useful to evaluate physiological functions of sensory nerves in patients with peripheral neuropathies.     

Demonstration of dilatation of peripheral airways

Summary. To investigate the ability of various lung-function tests to demonstrate dilatation of peripheral airways, ten asthmatics inhaled increasing doses of a f2-agonist by two different and controlled techniques. Low inspiratory flow with a long post-inspi-ratory pause favoured peripheral deposition, and a high inspiratory flow with a short post-inspiratory pause favoured central deposition of drug in the airways. Ordinary spirometry, maximum expiratory flow rates after breathing air as well as a helium-oxygen mixture, a single breath N₂-test and resistance of the respiratory system were obtained before and after each of five terbutaline doses with both inhalation techniques. By using a double-dummy technique, the study could be performed double blinded. Effects were compared at doses giving equal effects on PEF, assumed to represent equal deposition of bronchodilator and effects on central airways. At such ‘iso A PEF doses’, particularly FVC and the slope of phase III of the N₂-test improved more following the slow inhalation technique. It is concluded that changes in those tests reflect dilatation in peripheral airways in asthmatics.,     

Induction of type II collagen-specific antibody production in blood lymphocyte cultures of rhesus monkeys (Macaca mulatta) with collagen-induced arthritis using the immobilized native antigen.

Peripheral blood mononuclear cells (PBMC) from Rhesus monkeys previously immunized with bovine type II collagen to induce arthritis were cultured with the same antigen. Because the native protein is poorly soluble in culture medium a heating step is often used. The antigen in this form induced PBMC proliferation, but epitopes for the induction of antibody production and arthritis were lost. To keep the native protein intact it was coated on affigel beads. With the immobilized antigen specific antibody production could be induced.     

SCHWANN CELLS AND THE REGROWTH OF AXONS IN THE MAMMALIAN CNS: A REVIEW OF TRANSPLANTATION STUDIES IN THE RAT VISUAL SYSTEM

1. We have used peripheral nerve transplants or cultured Schwann cells grafted in association with different types of polymer to study axonal regrowth in the rat visual system. In some instances the glia were co-grafted with fetal tectal tissue. 2. The studies have two main aims: (i) to determine whether retinal axons can be induced to regrow at a site distant from their cell soma, that is, after damage to the brachial region of the optic tract; (ii) to determine whether retinal axons exposed to Schwann cells retain the ability to recognize their appropriate target neurons in CNS tissue. 3. In brachial lesion studies, Schwann cells were placed in the lesion site in association with nitrocellulose papers, within polycarbonate tubes in the presence or absence of a supporting extracellular matrix (ECM), or within polymer hydrogel scaffolds. Autologous sciatic nerve grafts were also used. Immuno-histochemical studies revealed the presence of regenerating axons within all polymer bridges. Regrowth of retinal axons was also seen, however, growth was not extensive and was limited to the proximal 1–1.5 mm of the implants. 4. In target innervation experiments, two surgical paradigms were developed. In one experiment, a segment of sciatic nerve was autografted onto the transected optic nerve in adult rats and the distal end of each graft was placed adjacent to fetal tectal (target) tissue implanted into the frontal cortex. To date, we have not been able to demonstrate selective recognition of target regions within tectal transplants by retinal axons exiting the sciatic nerve implants. 5. In the second experiment, Schwann cells were mixed with fetal tectal cells and co-grafted to the midbrain of newborn host rats. Schwann cells altered the characteristic pattern of host retinal growth into tectal grafts; in some cases axons were induced to grow away from appropriate target areas by nearby co-grafted Schwann cells. 6. In summary, Schwann cell/polymer scaffolds may provide a useful way of promoting the regrowth of damaged axons in the CNS, however: (i) in adults, at least, their effectiveness is reduced if they are located at a distance from the cell bodies giving rise to regenerating axons; (ii) in some circumstances exposure to a peripheral glial environment may affect the capacity of regenerating axons to recognize appropriate target cells in the CNS neuropil.     

4℃保存外周血造血干细胞动态观察

本文对4℃条件下不同时间保存后的外周血造血干细胞(peripheral bloodhematopoietic stem cells,PBHSC)数进行了动态观察。在本实验中以定向造血祖细胞(CFU-GM)作为观察PBHSC的指标。结果表明:随着保存时间的延长,PBHSC集落数逐渐下降;0小时与24小时保存后的干细胞数无显著差异;24小时与48、72、96、120小时保存后的干细胞数有高度显著差异;48小时与72、96、120小时保存后的干细胞数无显著差异。同时发现,红细胞的存在有利于PBHSC的4℃保存。     

Aldose reductase inhibition with imirestat — effects on impulse conduction and insulin-stimulation of Na+/K+-adenosine triphosphatase activity in sciatic nerves of streptozotocin-diabetic rats

Summary This study describes reduced motor nerve conduction velocity and increased resistance to hypoxia-induced conduction failure in sciatic nerves of rats after four weeks of streptozotocin-induced diabetes (both effects were significant at p <0.05). These changes occurred in the absence of any deficit in the steady-state ouabain-sensitive adenosine triphosphatase (ATPase) activity of sciatic nerve endoneurial homogenates. The addition of 10 nmol/l insulin to endoneurial homogenates from control animals resulted in a 34% increase in ouabain-sensitive ATPase activity and a 19% reduction in ouabain-insensitive ATPase activity (both p <0.01). This stimulation of ouabain-sensitive ATPase activity by insulin did not occur in homogenates from diabetic rats. Treating diabetic rats daily with the aldose reductase inhibitor, imirestat (1 mg/kg) improved nerve conduction velocity (p <0.05) but was without effect upon the resistance to hypoxic conduction blockade or the deficit in insulin-stimulated oubain-sensitive ATPase activity. These data suggest that in streptozotocin-diabetic rats the functional disorders of reduced motor nerve conduction velocity and increased resistance to hypoxic conduction blockade do not share a common aetiology and that impaired nerve conduction is not related to reduced maximal potential oubain-sensitive ATPase activity.