We describe methods to quantify epidermal nerve fibers (ENFs) in skin biopsy specimens from diabetic candidates for pancreas transplantation and control subjects. ENFs and the dermal-epidermal basement membrane were stained by immunohistochemical methods, imaged with a confocal microscope, and quantified using a neuron tracing system. The number of ENFs per surface of epidermis was diminished in diabetic subjects. ENF number and summed length of all ENFs per volume of epidermis examined were also decreased. Length and number of branch points of single surviving ENFs were similar in skin of control and diabetic subjects. The methods and results constitute a basis for continued study of the effects of the euglycemia that attends successful pancreas transplantation and the effects of therapy in patients with various types of polyneuropathy.

Capsaicin applied topically to human skin produces itching, pricking and burning sensations due to excitation of nociceptors. With repeated application, these positive sensory responses are followed by a prolonged period of hypalgesia that is usually referred to as desensitization, or nociceptor inactivation. Consequently, capsaicin has been recommended as a treatment for a variety of painful syndromes. The precise mechanisms that account for nociceptor desensitization and hypalgesia are unclear. The present study was performed to determine if morphological changes of intracutaneous nerve fibers contribute to desensitization and hypalgesia. Capsaicin (0.075%) was applied topically to the volar forearm four times daily for 3 weeks. At various time intervals tactile, cold, mechanical and heat pain sensations were assessed in the treated and in contralateral untreated areas. Skin blisters and skin biopsies were collected and immunostained for protein gene product (PGP) 9.5 to assess the morphology of cutaneous nerves and to quantify the number of epidermal nerve fibers (ENFs). Capsaicin resulted in reduced sensitivity to all cutaneous stimuli, particularly to noxious heat and mechanical stimuli. This hypalgesia was accompanied by degeneration of epidermal nerve fibers as evidenced by loss of PGP 9.5 immunoreactivity. As early as 3 days following capsaicin application, there was a 74% decrease in the number of nerve fibers in blister specimens. After 3 weeks of capsaicin treatment, the reduction was 79% in blisters and 82% in biopsies. Discontinuation of capsaicin was followed by reinnervation of the epidermis over a 6-week period with a return of all sensations, except cold, to normal levels. We conclude that degeneration of epidermal nerve fibers contributes to the analgesia accredited to capsaicin. Furthermore, our data demonstrate that ENFs contribute to the painful sensations evoked by noxious thermal and mechanical stimuli.

The ability of capsaicin to excite and subsequently to desensitize a select group of small sensory neurons has made it a useful tool to study their function. For this reason, application of capsaicin to the skin has been used for a variety of painful syndromes. We examined whether intradermal injection of capsaicin produced morphological changes in cutaneous nerve fibers that would account for its analgesic properties by comparing cutaneous innervation in capsaicin-treated skin with psychophysical measures of sensation. At various times after capsaicin injection, nerve fibers were visualized immunohistochemically in skin biopsies and were quantified. In normal skin the epidermis is heavily innervated by nerve fibers immunoreactive for protein gene product (PGP) 9.5, whereas fibers immunoreactive for substance P (SP) and calcitonin gene-related peptide (CGRP) are typically associated with blood vessels. There was nearly complete degeneration of epidermal nerve fibers and the subepidermal neural plexus in capsaicin-treated skin, as indicated by the loss of immunoreactivity for PGP 9.5 and CGRP. The effect of capsaicin on dermal nerve fibers immunoreactive for SP was less obvious. Capsaicin decreased sensitivity to pain produced by sharp mechanical stimuli and nearly eliminated heat-evoked pain within the injected area. Limited reinnervation of the epidermis and partial return of sensation occurred 3 weeks after treatment; reinnervation of the epidermis was ϳ25% of normal, and sensation improved to 50-75% of normal. These data show that sensory dysfunction after capsaicin application to the skin results from rapid degeneration of intracutaneous nerve fibers.

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Improvements in main memory speeds have not kept pace with increasing processor clock frequency and improved exploitation of instruction-level parallelism. Consequently, the gap between processor and main memory performance is expected to grow, increasing the number of execution cycles spent waiting for memory accesses to complete. One solution to this growing problem is to reduce the number of cache misses by increasing the effectiveness of the cache hierarchy. In this paper we present a technique for dynamic analysis of program data access behavior, which is then used to proactively guide the placement of data within the cache hierarchy in a location-sensitive manner. We introduce the concept of a macroblock, which allows us to feasibly characterize the memory locations accessed by a program, and a Memory Address Table, which performs the dynamic reference analysis. Our technique is fully compatible with existing Instruction Set Architectures. Results from detailed simulations of several integer programs show significant speedups.

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