交感神经皮肤反应诊断慢性乙醇中毒自主神经病变

目的 :早期发现慢性乙醇 (酒精 )中毒者自主神经病变。方法 :对 48例慢性乙醇中毒患者进行交感神经皮肤反应 (SSR)的检测 ,并与 50例正常人进行对比分析。结果 :慢性乙醇中毒组SSR潜伏期显著延长 (P <0 0 1 ) ,下肢波幅明显减低 (P <0 0 5) ,患者的饮酒年限、饮酒量与SSR呈正相关。结论 :交感神经皮肤反应可作为评价乙醇中毒自主神经功能障碍的客观电生理指标     

Neurotrophins In Diabetic Neuropathy

The recent Genentech/Roche sponsored FDA phase III clinical trial of nerve growth factor (NGF) for the treatment of diabetic neuropathy failed. The aim of this talk is to discuss the reasons for this failure and based upon the lessons learned identify if there remain any other viable avenues for studies on neurotrophins in diabetic neuropathy. The presentation will briefly introduce the basic biology of the neurotrophins and their putative role in the aetiology and/or treatment of diabetic neuropathy. Some details of the NGF clinical trials will be presented and reasons for failure assessed. The main part of the talk will focus on future strategies for neurotrophin work with an emphasis on the possible roles of neurotrophin-3 and brain-derived neurotrophic factor. Alternative approaches based upon regulation of endogenous neurotrophin expression and use of neurotrophin trk receptor agonists will also be discussed. The aim of the talk is to show that lessons learned from the failed NGF trial should lead to a re-invigoration of studies directed at determining alternative methods for optimising neurotrophic support of sensory neurones in diabetes.     

Taurine Replacement Prevents Apoptosis In Experimental Diabetic Neuropathy

The pathophysiology of diabetic neuropathy (DN) is complex involving both metabolic and vascular deficits. Recent data have implicated a potential role for programmed cell death (PCD) in the development of experimental DN (EDN). Oxidative stress has emerged as a leading candidate in the development of nerve blood flow (NBF) and nerve conduction deficits. We have previously shown that replacement of the endogenous antioxidant taurine in the nerve of streptozotocin-diabetic (STZ-D) rats corrects neuro-vascular dysfunction, prevents deficits in Na,K-ATPase activity and attenuates motor and sensory NCV slowing. The aims of this study were to examine the hypothesis that oxidative stress-mediated mitochondrial dysfunction may promote the activation of PCD pathways in STZ-D rats and to determine whether these effects could be attenuated by taurine. Dorsal root ganglion (DRG) neurons were extracted from perfused control (C), STZ-D and STZ-D rats given a 1% taurine supplemented diet for 6 weeks. STZ-D induced a significant decrease in sensory nerve conduction velocity (SNCV) and NBF vs controls and these deficits were corrected by taurine. Lumbar and sacral DRG were sectioned at 10 mm intervals and slides were prepared from two different sampling sites. Apoptosis was detected by TUNEL staining. 150 or more DRG nuclei were counted per animal. In STZ-D rats 21.3 ± 4.9% of DRG nuclei were found to be TUNEL positive as compared with 2.9 ± 2.1% in controls (p < 0.05). Taurine replacement markedly attenuated apoptosis since only 6.5 ± 2.9% neurons were TUNEL positive. In summary, 6 weeks of STZ-D increased apoptosis in DRG neurons of STZ-D rats. This increase in apoptosis could be prevented by replacement of the endogenous antioxidant taurine, implicating a role of taurine depletion in the development of sensory neuron degeneration.     

Metabolic vs. Vascular Abnormalities In Diabetic Neuropathy

The DCCT clearly implicates hyperglycemia as an important contributory factor in the pathogenesis of diabetic polyneuropathy, a multifaceted set of clinical syndromes reflective of widespread damage to peripheral nerve fibers. The biochemical cascade stemming from hyperglycemia and responsible for this disorder remains controversial. Recently published clinical trials in diabetic neuropathy with aldose reductase inhibitors implicate the aldose reductase pathway as an important component in this process. Activation of the aldose reductase pathway by hyperglycemia produces secondary derangements in NAD(P)⁺:NAD(P)H ratios, depletion of alternative intracellular osmolytes such as taurine and myo‐inositol, and accelerated protein glycation. These biochemical alterations in turn can lead to the formation of reactive oxygen species (ROS), as can glucose‐related aldose‐reductase‐independent pathways such as auto‐oxidation and protein glycation. Aldose reductase‐dependent and aldose‐reductase‐independent ROS generation may directly damage end‐organ tissues or their vascular support, producing ischemia. Mitochondria are damaged by ROS, mitochondrial ROS generation is increased by imbalances in substrate and oxygen availability, and mitochondrial defense against ROS‐induced damage requires adequate energy supply. Hence metabolic oxidative stress from glucose and ischemic injury both target the mitochondria. Mitochondrial damage is an important initiator of programmed cell death, or apoptosis, through the release of mitochondrial cytochromes, and activation of caspase enzymes. This cascade of events, stemming from hyperglycemia, operating through aldose‐reductase‐dependent and aldose‐reductase‐independent generation of ROS, involving mitochondrial damage and impaired vascular support and tissue ischemia, and resulting in apoptosis, appears to play a potentially important role in the pathogenesis of chronic diabetic complications such as peripheral neuropathy.     

High Dose Therapy With Alpha-Lipoic Acid Improves Cutaneous Vasomotor Response In Patients With Diabetic Neuropathy

The saposin C-derived peptide TX14(A) prevents onset of functional and structural disorders in the peripheral nerve of diabetic rats. We have now investigated the ability of TX14(A) to alleviate behavioral indices of abnormal pain perception in adult female rats 4-6 weeks after onset of STZ-induced diabetes. Untreated diabetic rats exhibited tactile allodynia (response threshold = 3 ± 1 g) compared to age-matched controls (10 ± 1g). A single ip injection of TX14(A) transiently alleviated tactile allodynia, with an effect that was maximal 6 hours (11 ± 1g) after injection and diminished within 48 hours. Maximal efficacy was seen with a 1 mg/kg dose while no effects were noted in control rats. Control rats exhibited a transient thermal hyperalgesia (77 ± 5% of baseline paw withdrawal latency) 15 minutes after intrathecal delivery of substance P (30 nmol) that resolved within 30 minutes. Untreated diabetic rats exhibited substance P evoked thermal hyperalgesia of similar magnitude (82 ± 5% at 15 minutes) but of greater duration (83 ± 4% at 1 hour). Intrathecal delivery of TX14(A) 30 minutes before intrathecal substance P was without effect on the transient thermal hyperalgesia in control rats (74 ± 9% at 15 minutes). In diabetic rats, the prolonged thermal hyperalgesia was abolished by prior intrathecal delivery of TX14(A), although the transient thermal hyperalgesia (72 ± 8% at 15 minutes) remained. These studies show that TX14(A) can rapidly allevate diabetes-induced allodynia and hyperalgesia for up to 48 hours.     

Evidence Of Spinal Cord Atrophy In Diabetic Peripheral Neuropathy

Hypertension has recently been shown to be an important determinant of diabetic retinopathy and nephropathy. The relationship between cardiovascular risk factors and the incidence of peripheral neuropathy (PN) was examined in type 1 diabetic subjects from 27 centres participating in the EURODIAB Prospective Complications Study. PN was assessed at baseline and follow-up using a standardised protocol involving combinations of neuropathic symptoms, tendon reflexes, age related vibration perception thresholds and autonomic function tests. Serum lipids/lipoproteins, HbA_1c and albumin excretion rate (AER) were measured in a central laboratory. Of 986 subjects with no PN at baseline (mean age 31 years; mean duration 13 years), 24.6% developed PN over the follow up period (average 7.3 years). The incidence of PN was significantly positively associated with age, duration of diabetes and HbA_1c at baseline. After statistical adjustment for these three factors the following baseline variables were significantly predictive of the development of PN; BMI, AER, triglyceride (p < 0.001), cholesterol and systolic BP (p < 0.01). This prospective study shows that over a 7-year period, about one quarter of type 1 diabetic patients will develop peripheral neuropathy; age, duration of diabetes and poor glycaemic control being major determinants. The development of PN is also associated with potentially modifiable cardiovascular risk factors such as serum lipids, BP, BMI and AER supporting risk reduction strategies in its prevention. Furthermore, these findings support the role of vascular factors in pathogenesis of PN.     

脑梗死患者交感神经皮肤反应分析

交感神经皮肤反应（sympathetic skin response,SSR）是由内源或外源性刺激所诱发的皮肤 瞬时电位变化,属于脑和脊髓参与的交感催汗运动。本文主要概述近年来SSR在脑梗死患者中应用 价值,阐述其对脑梗死患者自主神经功能紊乱的临床诊断作用,与脑梗死患者运动功能的相关性, 以及SSR在推断交感神经可能的中枢传导通路中的价值。     

C-Peptide Deficiency: An Important Pathogenetic Factor In Type 1 Diabetic Neuropathy

12 diabetic patients aged 47.5 ± 9.4 yr., duration of diabetes (14.6 ± 10.3 yr.) and 15 control subjects were studied. In diabetic patients neuropathy symptom score =0, neuropathy deficit score = 4.5 + 0.7/30, vibration = 12.0 + 1.8 V, thermal perception (2.0 + 0.8°C), heart rate variation during deep breathing (17.8 + 2.3), 30:15 ratio (1.31 + 0.07) was normal. Baseline (n=12) and repeat neurophysiology (n=10) performed 8.7 + 0.6 years after sural nerve biopsy demonstrated normal values at baseline, with progression of neuropathy (peroneal motor nerve conduction velocity (ms⁻¹) (42.3 + 2.9 v 39.4 +2.0), sural nerve conduction velocity (45.4 + 3.7 v 43.6 + 1.7). Myelinated fibre density, fibre and axonal area and g-ratio were not significantly reduced. Teased fibre studies showed paranodal abnormalities (p < 0.001), segmental demyelination (P < 0.01) with remyelination (P < 0.01) without axonal degeneration. Unassociated Schwann cell profile density (p < 0.04) and axon density (P < 0.001) were increased and axon diameter was decreased (P < 0.007) with a shift of the size frequency distribution to the left (skewness- 0.89 v 0.64, P < 0.03) suggestive of unmyelinated axonal atrophy/regeneration. Endoneurial capillary basement membrane thickening (P < 0.006), endothelial cell hyperplasia (P < 0.004) and luminal narrowing (P < 0.007) occurred. Current measures of neuropathy are too insensitive to detect significant nerve fibre pathology. The presence of microangiopathy provides support for a microvascular basis of diabetic neuropathy.     

Elevation Of Electric Gustatory Threshold In Type 2 Diabetic Patients With Neuropathy

To specify the diabetic complications related to taste function in type 2 diabetes mellitus, electrogustometry was performed in 49 patients and 48 normal subjects. The results showed that the electric gustatory threshold (EGT) rose with aging. The EGT in normal subjects was, on average, not changed compared to the diabetics without complications (6.29 dB vs 6.3 dB), but the EGT was significantly higher in diabetic patients with neuropathy compared to the normal (13.3 dB vs 6.29 dB p < 0.05). The EGT was significantly higher in diabetic patients with both neuropathy and retinopathy (18.1 dB vs 6.29 p < 0.05). In the patients with chronic renal failure due to chronic glomerulonephritis treated with hemodialysis, the EGT was not changed compared to the normal (3.8 dB vs 6.29 dB), but the EGT in the diabetic renal failure treated with hemodialysis was much higher compared to the CGN patients (19.1 dB vs 3.0 dB). Thus, the electric gustatory threshold is a sensitive indicator of diabetic complications.     

探讨皮肤交感反应测定以及在神经传导正常患者中的应用

目的:探讨皮肤交感反应(SSR)测定在小纤维感觉神经病诊断中的应用价值。方法:选取20例神经传导速度(NCV)正常但具有典型小纤维损害症状的患者(NCV正常组)和26名健康对照者(对照组),取刺激强度为20 mA,脉宽为0.2ms,刺激右侧正中神经,记录波形(P/N)、潜伏期、波幅和曲线下面积测定SSR值。分析SSR的波形特征,评价受试者的交感节后C类小纤维功能,探讨具有典型小纤维损害症状但肌电图和NCV正常患者是否有小纤维损害的证据。结果:NCV正常组与对照组比较,手部SSR无明显差异;而足部潜伏期(P<0.01)和曲线下面积两组间比较,差异有统计学意义(P=0.03)。结论:NCV正常组患者足部SSR有长度依赖性损害表现,提示有早期罹患交感节后C类小纤维损害的可能。     

Therapeutic Strategies for Diabetic Neuropathy

Diabetes is the leading cause of peripheral neuropathy globally. Duration of diabetes, glycemic control, and preexisting cardiovascular risk factors independently correlate with the development and progression of diabetic peripheral neuropathy as well as cardiovascular autonomic neuropathy. The pathogenesis of diabetic neuropathy remains unclear, although insulin resistance, oxidative stress, mitochondrial dysfunction, abnormal glucose metabolism, advanced glycation end products, neurotrophic factors, and protein kinase C activation all may play a role. Strict glycemic control remains the only available treatment option, although other treatments are in development. Multiple options are available for symptom management. In this article, we review factors associated with development and progression of diabetic neuropathy and discuss available treatment options.     

GCPII (NAALADase) Inhibition Prevents Long-Term Diabetic Neuropathy In Type 1 Diabetic BB/WOR Rats

We describe an algorithm that permits representative fascicle selection for sample acquisition from the entire cross-section of a nerve. We calculate the number of fascicles necessary for the acquisition of a given sample volume of nerve fibres from the image magnification, determine the scheme of intrafascicular sampling, and measure the (estimated) nerve fibre density. We start by storing the positions of all fascicles as coordinates of the microscope motor stage. We then recruit the needed fascicles from the file by calling them up out of the storage order with a constant interval, using the quotient of the total number of fascicles and the number of fascicles necessary to obtain the sample size for this purpose. The results obtained on the analysis of 40 specimens of sural and tibial nerves by means of the image analysis system IBAS are reported.     

Current Evidence For Treating Diabetic Neuropathy

Instead of nerve biopsy which is most reliable method for diagnosing diabetic neuropathy but rather harmful, we have examined the usefulness of skin biopsy to evaluate the grade of diabetic neuropathy and therapeutic effects of given compounds. Nerve fibers immunostained by antibodies against protein gene product (PGP)9.5 and labeled with streptavidin fluorescein isothiocyanate and measured under confocal laser scanning microscopy were significantly shorter in the epidermis and dermis and around sweat glands in diabetic patients than in healthy subjects. Sural nerve conduction velocity was significantly correlated with dermal nerve fiber length (NFL) (p < 0.05) in diabetic patients. Patients with higher aldose reductase (AR) level of erythrocytes (>10.8 ng/Hg) showed shorter dermal NFL than those with lower AR level (<10.8)(p < 0.05). Using this technique, we evaluated the therapeutic effect of AR inhibitor (ARI) epalrestat during approximately 13 months in diabetic patients with neuropathy (19, epalrestat-treated; 12, control). The number of patients whose percent change of dermal NFL exceeded its mean ± 2SD in the control group was significantly higher in the ARI group than in the control group (p < 0.05, 8/9 vs 1/12). These results suggest that quantitation of cutaneous nerves using biopsied skin samples may provide important information about the severity of diabetic neuropathy and that epalrestat can elongate dermal unmyelinated nerve fibers in at least part of diabetic patients.     

Arterial Rigidity And Cardiovascular Sympathetic Tone In Hypertensive Obese And Type 2 Diabetic Patients

An increase of arterial rigidity and sympathetic activity has been suggested to contribute to essential hypertension. We have shown that vagal control of heart rate (HR) variations during standardized tests is similarly impaired in normotensive obese and type 2 diabetic patients. The aim was to compare cardiovascular vagosympathetic balance and the link between pulse pressure, an index of arterial rigidity, and sympathetic activity in normotensive and hypertensive obese and type 2 diabetic patients. Groups 1 and 2 consisted of 70 normotensive and 32 hypertensive obese patients, groups 3 and 4 of 18 normotensive and 14 hypertensive diabetic patients respectively. HR and blood pressure (BP) variations were studied with a plethysmographic system and spectral analysis (Finapres). During a 5 min-period at a controlled breathing rate, in the 4 groups, the high frequency peak of HR variations (vagal control) was significantly lower than in controls (19 healthy subjects), and the mid/high frequency peak ratio of HR variations was significantly increased. During a standing test, the mid-frequency peak of systolic BP variations (sympathetic activity) did not differ significantly in obese or diabetic patients, either normotensive or hypertensive, and in controls. This peak correlated significantly with pulse pressure in groups 2 and 4 and in the control group but not in groups 1 and 3. In conclusion, 1) spectral analysis confirms that in obese and diabetic patients vagal control of HR variations is similarly reduced and suggests that sympathetic activity is relatively increased ; 2) in hypertensive patients sympathetic tone is not higher than in normotensive ones, but may contribute to arterial rigidity.