A THERMAL PROBE METHOD FOR STAGING DIABETIC NEUROPATHY

糖尿病神经病变是糖尿病的常见并发症。如果要在疾病最容易逆转的时候开始治疗，早期诊断是必不可少的。神经再生的灵敏检测是决定临床治疗试验成功与否的关键。目前的方法缺乏这些任务所需的灵敏度。皮肤神经的形态检查，尤其是表皮神经纤维的检查，与糖尿病患者的神经病变程度密切相关。表皮神经纤维减少可能是糖尿病神经病变的首发形态学征象。通过局部或皮内暴露于辣椒素(辣椒中的有效成分)，可以产生实验性的表皮神经失神经。停用辣椒素后，神经再生会导致恢复。与辣椒素引起的表皮神经丢失一致，受试者失去了对直径3 mm的热探头引起的热痛的感知能力。当治疗停止时，他们恢复了对热痛的敏感。在所研究的前臂部位，表皮神经纤维的密度和检测热痛的能力之间存在着直接的相关性。然而，当使用更大的30x30 mm商用探头时，没有检测到灵敏度变化。这种小型热探头有望成为神经疾病早期诊断的临床工具。辣椒素模型将用于开发临床通用的小探针方法。在正常受试者和糖尿病受试者中，将确定局部使用辣椒素治疗不同身体部位皮肤的最佳探头大小、温度设置和热暴露时间。在糖尿病神经病变期间，通常受表皮神经丢失影响的皮肤部位，如小腿，将受到特别关注。结果将与辣椒素应用期间和停用辣椒素后恢复期间的表皮神经纤维计数相关联。一旦确定了最佳探头大小、温度和曝光量，该探头将在一组正常和糖尿病志愿者身上进行测试，以确定热探头在临床环境中的灵敏度。将用电子显微镜研究辣椒素对表皮神经的影响，以证明免疫组织化学染色方法看到的神经纤维的丢失确实是神经纤维被破坏的结果。这项研究将开发一种用于临床环境中神经病变分期的小型热探头，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患者的神经再生能力。

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.