PERIPHERAL VASCULAR AND NERVE FUNCTION ASSOCIATED WITH LOWER LIMB AMPUTATION IN PEOPLE WITH AND WITHOUT DIABETES

Multiple factors, including peripheral vascular disease and neuropathy, contribute to the development and perpetuation of complications of the lower extremities in diabetes. The main aim of the present study was to assess the peripheral vascular and nerve status of diabetic and non‐diabetic subjects that had undergone lower limb amputation. Various non‐invasive tests of peripheral vascular and nerve function were carried out on subjects who had undergone unilateral lower limb amputation and were now attending a Rehabilitation Centre. The control group (n = 23), the diabetic amputee group (n = 64) and the non‐diabetic amputee group (n = 32) were age‐matched. Only the diabetic amputee group had evidence of medial arterial calcification. Transcutaneous oxygen levels were significantly lower in the diabetic amputee group (median 43 mmHg; interquartile range 33–49 mmHg) than in the control (59; 56–74 mmHg) and non‐diabetic amputee (57; 43–65 mmHg) groups (control compared with diabetic amputee group, P < 0.001; diabetic amputee compared with non‐diabetic amputee group, P < 0.01). The same trend was found for carbon dioxide levels in the skin [mmHg: diabetic amputees, 25 (21–37); controls, 38 (32–42); non‐diabetic amputee, 34 (31–39)] (control compared with diabetic amputee, P < 0.01; diabetic amputee compared with non‐diabetic amputee, P < 0.05). Vibration and pressure perception measurements (which assess A beta nerve fibre function) showed that both the diabetic amputee and non‐diabetic amputee subjects had significantly greater impairment than the controls. However, measures of A alpha and C nerve fibre function were abnormal only in the diabetic amputee group. Thus the peripheral vascular and nerve functions of age‐matched diabetic and non‐diabetic subjects having undergone lower limb amputation show specific differences, with non‐diabetic amputees exhibiting signs of neuropathy. This indicates that factors characteristic of diabetes (such as hyperglycaemia and non‐enzymic glycation) are associated with calcification, lower oxygen and carbon dioxide levels in the skin, and abnormal A alpha and C nerve fibre function.     

FUNCTIONAL ASPECTS AND PATHOGENETIC CONSIDERATIONS OF THE NEUROPATHY IN THE SPONTANEOUSLY DIABETIC BB-WISTAR RAT

Sima A.A.F. & Hay K. (1981) Neuropathology and Applied Neurobiology 7, 341–350
Functional aspects and pathogenetic considerations of the neuropathy in the spontaneously diabetic BB-Wistar rat
Electrophysiological features were studied longitudinally in the spontaneously diabetic insulin-dependent, BB-Wistar rat. These were correlated in time with the state of the patency of the protective barriers in peripheral nerves. Motor nerve conduction velocity was significantly slowed only 3 weeks after the onset of the diabetes. When ultrastructural changes began, the maximal conduction velocity was further diminished. The amplitudes of evoked muscle potentials and distal latencies were significantly altered in diabetic rats. No change in the permeability of the blood-nerve barrier could be demonstrated before, during or after the onset of the nerve conduction defect. The possible pathogenetic mechanisms are discussed and a possible mechanism is suggested, namely a reduced availability of energy to axons in diabetes.     

THE EXTRACELLULAR MATRIX OF PERIPHERAL NERVE IN DIABETIC POLYNEUROPATHY

The pattern of collagenisation in peripheral nerve in diabetic polyneuropathy was examined in nerve biopsy specimens from patients with diabetic polyneuropathy in comparison with organ donor control nerves and disease controls (other neuropathies). There was increased endoneurial collagenisation both in the diabetic polyneuropathy cases and the disease controls, this predominantly involving types I and III. Type II collagen was not detected in organ donor control nerves or in the diabetic and the disease control nerves. There was a relative increase in type VI collagen in the endoneurium in the diabetic nerves immediately surrounding groups of Schwann cells. This was not a feature in the other neuropathies. The quantity of types IV, V and VI collagen was increased around the endoneurial microvessels in the diabetic patients and, to a lesser extent, in those with hereditary motor and sensory neuropathy (HMSN). Increased deposition of types IV and V collagen was observed in the perineurium in the diabetic nerves, the latter being most evident in the innermost lamellae where the amount of laminin was possibly also increased. The diameter of the general endoneurial collagen fibrils was greater in the diabetic nerves, although this was not more than in a disease control (HMSN). The collagen fibrils that were present within the basal laminal tubes that had surrounded degenerated myelinated fibres in the diabetic nerves, and those within the onion bulbs of the HMSN cases, were of the normal endoneurial calibre. The expression of laminin by Bungner bands in diabetic neuropathy did not differ from that in disease control nerves, nor were any differences detected for fibronectin. Whether the changes observed are important for the impaired regenerative capacity in diabetic neuropathy requires further investigation.     

PERIPHERAL NERVE REGENERATION THROUGH GRAFTS OF LIVING AND FREEZE-DRIED CNS TISSUE

The ability of peripheral nerve fibres to regenerate through the central nervous system (CNS) extracellular matrix in the presence of CNS myelin debris was examined using living and freeze-dried optic nerve grafts. The grafts were placed end-to-end with the proximal stumps of severed common peroneal nerves of inbred mice. Within a 4 week period, regenerating peripheral nervous system fibres were found in only two of 14 living grafts. However axons always grew into freeze-dried grafts within one week, despite the presence of CNS myelin debris. The regenerating axons in freeze-dried grafts were accompanied by Schwann cells and were initially found associated with the inner aspect of the glial basal lamina. Although the extracellular matrix of the freeze-dried CNS tissue was subsequently reorganized by invading cells, it seems likely that neither the nature of the CNS extracellular matrix nor the presence of CNS myelin debris had a major inhibitory influence on peripheral nerve regeneration. It is suggested that the presence of living astrocytes covered by a basal lamina at the proximal end of the living optic nerve grafts may inhibit their penetration by regenerating axons.     

胎脑提取液与桥接物联合应用对脊髓损伤修复的影响

研究胎脑提取液对脊髓损伤修复的影响。用ＳＤ大鼠４０ 只,过半切除长约０５ ｃｍ 的左下胸段（Ｔ８,Ｔ９）脊髓,肌基膜管（ＭＢＬ）桥接脊髓缺损。局部用药组将ＭＢＬ浸泡于胎脑提取液（ＥＦＢ）中,全身用药组腹腔注射ＥＦＢ,生理盐水（ＮＳ）作对照。实验组动物行为学测试指标和斜板试验ＩＰ分数均明显优于对照组;实验组术后６ 周可测到ＳＥＰ波形,而对照组未测到;实验组ＭＢＬ与脊髓融合,ＭＢＬ内有髓神经纤维髓鞘较厚,轴突直径较粗,腰部脊神经节细胞结构完整,均优于对照组;图像分析显示实验组ＭＢＬ内有髓神经纤维数、轴突直径和脊神经节细胞数均优于对照组。局部和全身应用ＥＦＢ对脊髓损伤修复均有明显促进作用     

GLIAL BUNDLES IN SPINAL NERVE ROOTS: A FORM OF ISOMORPHIC GLIOSIS AT THE JUNCTION OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM

A morphologic study of the spinal nerve roots was undertaken in three cases of Werdnig-Hoffmann disease to investigate the phenomenon of glial bundle formation. The glial elements extended along the ventral roots as discrete cylindrical bundles comprising a large number of parallel astrocytic processes and sparsely scattered cell bodies all enclosed by a basal lamina. The bundles tapered off at a variable distance from the root exit zones. The early stage of glial bundle formation was characterized by the protrusion of astrocytes into the neurilemmal tubes containing degenerated myelinated axons. It was concluded that axonal degeneration, evoking a glial reaction, was the initial event in this process. Subsequently, the reactive astrocytes from the vicinity of the root exit zones enter the neurilemmal tubes previously occupied by myelinated axons and migrated into the domain of the peripheral nervous system in an orderly fashion. Thus glial bundle formation might be considered a special form of isomorphic gliosis occurring in Werdnig-Hoffmann disease and also in several other conditions all sharing a common feature, namely, degeneration of axons within the spinal nerve roots.     

EXPERIMENTAL ALLERGIC NEURITIS IN THE SJL/J MOUSE: INDUCTION OF SEVERE AND REPRODUCIBLE DISEASE WITH BOVINE PERIPHERAL NERVE MYELIN AND PERTUSSIS TOXIN WITH OR WITHOUT INTERLEUKIN-12

Charcot-Marie-Tooth disease comprises a group of genetically heterogeneous disorders of the peripheral nervous system. The X-linked form of Charcot-Marie-Tooth (CMTX) is associated with mutations in the gene encoding the gap junction protein connexin 32 (Cx32), which is expressed in Schwann cells. Immunocytochemical evidence suggests that Cx32 is localized to the incisures of Schmidt-Lantermann and the paranodes of myelinating Schwann cells, where it appears to form reflexive gap junctions. It is currently thought that this cytoplasmic continuity provides a much shorter diffusion pathway for the transport of ions, metabolites and second messenger molecules through intracellular channels between the adaxonal and perinuclear regions of Schwann cells, across the myelin sheath. This review summarizes our current understanding of the role of connexins in Schwann cells and focuses on the lessons for channel function and disease pathophysiology derived from the functional analysis of Cx32 mutations. One of the most intriguing aspects emerging from this work is that several mutations retain functional competence, although the mutated channels exhibit altered Sating properties. This suggests that partial and/or selective disruption of the radial communication pathway formed by Cx32 is sufficient to cause a functional deficit and lead to the development of CMTX. The next challenge will be to define, at the molecular level, the sequence of events involved in the disease process. The presence of a group of functional mutations should help understand the cellular basis of CMTX, by allowing the identification of the specific molecules that need to be exchanged through Cx32 channels, but are excluded from the mutated ones.     

THE INFLUENCE OF FOOD ON SIDE EFFECTS AND ABSORPTION OF LITHIUM

In a cross-over study, 24 mmol of lithium sulphate was given as a single dose in slow release tablets to 30 healthy volunteers fasting and after a standardised meal. Comparisons were also made with lithium citrate in slow release tablets and placebo. Postprandial administration of lithium gave practically no side effects, while lithium on an empty stomach gave diarrhoea in about 20 % of the subjects. The absorption was measured by determination of the amount of lithium excreted in the urine in a group of ten subjects. Lithium was completely absorbed when given after food, but when given on an empty stomach the absorption was lower in some subjects, apparently due to rapid gastrointestinal passage in connection with diarrhoea. Lithium should therefore preferably be administered after meals.     

EFFECTS OF BETA-ADRENOCEPTOR BLOCKADE ON THE PHENOTYPIC CHARACTERISTICS OF THYMOCYTES AND PERIPHERAL BLOOD LYMPHOCYTES

The study revealed that β-adrenoceptor blockade with propranolol (0.40 mg/100 g/day, s.c.) in adult male DA rats: (i) increased the thymocyte proliferation and apoptosis, (ii) caused disturbances in kinetics of T cell differentiation leading to distinguishable changes in relative proportion of thymocytes at distinct maturational steps and to an expansion of the most mature single positive (CD4+, CD8+) thymocyte pool, (iii) affected the relative proportion of neither CD4+ nor CD8+ peripheral blood lymphocytes (PBL), and (iv) augmented the relative number of CD8+CD25+ cells. Thus, the results suggest the role of β-adrenoceptors in fine-tuning of T cell maturation, and, possibly, distribution and activation of distinct PBL subsets     

NEURAL TISSUE GRAFTS AND REPAIR OF THE INJURED SPINAL CORD

Neural tissue grafting presently stands as one of the more intriguing experimental strategies being applied to the problem of spinal cord regeneration. The following annotation presents an overview of recent investigations which have shown: that peripheral nerve grafts can stimulate axonal outgrowth in many descending and ascending fibre populations of the injured spinal cord and that central nervous system (CNS) implants, derived from segmental and supraspinal levels of the embryonic neuraxis, may likewise have the potential for promoting repair of damaged intraspinal neural circuitries in adult and neonatal recipients.     

THE EFFECTS OF EXTRACELLULAR MATRIX AND OSTEOGENIC PROTEIN-1 ON THE MORPHOLOGICAL DIFFERENTIATION OF RAT SYMPATHETIC NEURONS

The growth patterns of axons and dendrites differ with respect to their number, length, branching, and spatial orientation; therefore, it is likely that these processes differ in their growth requirements. To examine this hypothesis, we have been analyzing the responses of cultured rat sympathetic neurons to three types of stimuli: large structural proteins of the extracellular matrix, matrix-associated growth factors, and neurotrophins. Purified structural proteins such as laminin and collagen IV have been found to promote only axonal growth; whereas the matrix associated growth factor, osteogenic protein-1, selectively stimulates dendritic growth. In contrast, nerve growth factor modulates the growth of both types of processes. These data suggest that process-specific interactions with the extracellular environment may be critical determinants of cell shape in neurons. Perinatal rat sympathetic neurons grown in culture in the absence of serum or glial cells extend a single process which is axonal in nature. Exposure to osteogenic protein-1 causes the formation of additional processes which express the morphological, cytoskeletal, and ultrastructural characteristics of dendrites. Consistent with observations on the regulation of dendritic growth in sympathetic neurons in situ, the dendrite-promoting activity of osteogenic protein-1 is independent of synaptic or electrical activity, but is modulated by nerve growth factor. In the presence of optimal concentrations of osteogenic protein-1 and nerve growth factor, the size of the dendritic arbor extended by cultured sympathetic neurons approximates that seen in situ at comparable developmental stages. Osteogenic protein-1 does not promote dendritic growth in cultured neurons obtained from embryonic ciliary, dorsal root, trigeminal or nodose ganglia, suggesting that its morphogenetic effects are cell selective. Since mRNA for osteogenic protein-1 is expressed in mature as well as embryonic target tissues of the sympathetic nervous system, we also examined the effects of osteogenic protein-1 on cultures of sympathetic neurons derived from adult rats. Consistent with results obtained with perinatal neurons, osteogenic protein-1 selectively promoted dendritic growth in adult neurons. These data suggest that this matrix-associated growth factor could play a role not only in the morphogenesis of the developing nervous system, but also in the maintenance and remodeling of dendritic structures in the mature animal. Copyright © 1996 ISDN. Published by Elsevier Science Ltd.