A THERMAL PROBE METHOD FOR STAGING DIABETIC NEUROPATHY

糖尿病神经病变是糖尿病常见的并发症。 如果要在疾病最容易逆转时开始治疗，早期诊断至关重要。 神经再生的灵敏检测对于确定临床治疗试验的成功至关重要。 目前的方法缺乏这些任务所需的灵敏度。 皮肤神经的形态学检查，尤其是表皮神经纤维的形态学检查，与糖尿病患者神经病变的程度密切相关。表皮神经纤维减少可能是糖尿病神经病变的首要形态学标志。 表皮神经的实验性去神经支配可以通过局部或皮内暴露于辣椒素（辣椒中的活性成分）来产生。 停止辣椒素后，神经再生导致恢复。 与辣椒素诱导的表皮神经丧失相一致，受试者失去了检测由3 mm直径的热探针诱导的热痛的能力。 停止治疗后，他们恢复了热痛敏感性。表皮神经纤维的密度和检测前臂热痛的能力之间存在直接的相关性。 然而，当使用更大的30x30 mm商业探针时，没有检测到灵敏度的变化。 小型热探头有望用作神经病早期诊断的临床工具。 辣椒素模型将用于开发一般临床使用的小探针方法。 将在正常和糖尿病受试者中确定用局部辣椒素治疗的不同身体位置的皮肤的最佳探针尺寸、温度设置和热暴露时间。 在糖尿病神经病变期间通常受表皮神经丧失影响的皮肤位置，例如小腿，将受到特别关注。 结果将与辣椒素应用期间和辣椒素停药后恢复期间的表皮神经纤维计数相关。 一旦确定了最佳探头尺寸、温度和暴露，将在一组正常和糖尿病志愿者中对探头进行测试，以确定热探头在临床环境中的灵敏度。 将通过电子显微镜研究辣椒素对表皮神经的影响，以证明用免疫组织化学染色方法观察到的神经纤维损失确实是神经纤维破坏的结果。 本研究将开发一种小型热探针，用于在临床环境中对神经病变进行分期，证明神经纤维染色的缺失等同于神经破坏，并证明糖尿病神经病变受试者的神经再生能力。

Diabetic neuropathy is a common complication of diabetes. Early diagnosis is essential if treatment is to be initiated when the disease is most amenable to reversal. Sensitive detection of nerve regeneration is critical for determining the success of a clinical therapeutic trial. Current methods lack the required sensitivity for these tasks. Morphological examination of skin nerves, particularly the nerve fibers in epidermis, relates closely to the degree of neuropathy in diabetic subjects. Reduction of epidermal nerve fibers may be the first morphological sign of diabetic neuropathy. Experimental denervation of epidermal nerves can be produced by topical or intradermal exposure to capsaicin, the active ingredient in hot chili peppers. After discontinuation of capsaicin, nerve regeneration results in recovery. Coincident with capsaicin induced epidermal nerve loss, subjects lost their ability to detect heat pain induced by a 3 mm diameter thermal probe. They recovered hot pain sensitivity when treatment was discontinued. A direct correlation exists between the density of epidermal nerve fibers and ability to detect hot pain in the forearm location studied. However, no change in sensitivity was detected when a larger 30x30 mm commercial probe was used. The small thermal probe holds promise for use as a clinical tool for early diagnosis of neuropathy. The capsaicin model will be used to develop the small probe method for general clinical use. Optimal probe size, temperature setting, and time of heat exposure for skin of different body locations treated with topical capsaicin will be determined in both normal and diabetic subjects. Skin locations that are usually affected by epidermal nerve loss during diabetic neuropathy, e.g. the calf, will receive particular attention. The results will be correlated with counts of epidermal nerve fibers during capsaicin application and during recovery after capsaicin withdrawal. Once the optimal probe size, temperature and exposure are determined the probe will be tested on a cohort of normal and diabetic volunteers to determine the sensitivity of the thermal probe in a clinical setting. The effects of capsaicin on epidermal nerves will be studied by electron microscopy to prove that the loss of nerve fibers seen with immunohistochemical staining methods is indeed the result of destruction of the nerve fibers. This study will develop a small thermal probe for staging neuropathy in a clinical setting, prove that the absence of nerve fibers staining is tantamount to nerve destruction, and demonstrate the capacity for nerve regeneration in subjects with diabetic neuropathy.