Controlling Healing and Toughness in Polyurethanes by Branch-Mediated Tube Dilation.

In this work, we propose the use of regular branching of polyurethanes as a way to regulate chain dynamics and govern crystallization in highly dense hydrogen-bonded systems. As a result, robust and healable polyurethanes can be obtained. To this end, we synthesized a range of aliphatic propane diol derivatives with alkyl branches ranging from butyl (C4) to octadecanyl (C18). The series of brush polyurethanes was synthesized by polyaddition of the diols and hexamethylene diisocyanate. Polyurethanes with very short (C < 4) and very long (C = 18) brush lengths did not lead to any significant healing due to crystallization. An intermediate amorphous regime appears for polymers with middle branch lengths (C = 4 to 8) showing a fine control of material toughness. For these systems, the side chain length regulates tube dilation, and significant macroscopic healing of cut samples was observed and studied in detail using melt rheology and tensile testing. Despite the high healing degrees observed immediately after repair, it was found that samples with medium to long length brushes lost their interfacial strength at the healed site after being heated to the healing temperature for some time after the optimal time to reach full healing. Dedicated testing suggests that annealed samples, while keeping initial tackiness, are not able to completely heal the cut interface. We attribute such behavior to annealing-induced interfacial crystallization promoted by the aliphatic branches. Interestingly, no such loss of healing due to annealing was observed for samples synthesized with C4 and C7 diols, which is identified as the optimal healing regime. These results point at the positive effect of branching on healing, provided that a critical chain length is not surpassed, as well as the need to study healing behavior long after the optimal healing times.

Influence of psychological factors on risk of temporomandibular disorders.

Psychological characteristics potentially may be a cause or consequence of temporomandibular disorder (TMD). We hypothesized that psychological characteristics associated with pain sensitivity would influence risk of first-onset TMD, but the effect could be attributed to variation in the gene encoding catechol-O-methyltransferase (COMT). We undertook a prospective cohort study of healthy female volunteers aged 18-34 yrs. At baseline, participants were genotyped, they completed psychological questionnaires, and underwent quantitative sensory testing to determine pain sensitivity. We followed 171 participants for up to three years, and 8.8% of them were diagnosed with first-onset TMD. Depression, perceived stress, and mood were associated with pain sensitivity and were predictive of 2- to 3-fold increases in risk of TMD (P < 0.05). However, the magnitude of increased TMD risk due to psychological factors remained unchanged after adjustment for the COMT haplotype. Psychological factors linked to pain sensitivity influenced TMD risk independently of the effects of the COMT haplotype on TMD risk.

Alcoholism is associated with GALR3 but not two other galanin receptor genes.

The neuropeptide galanin is widely expressed in the periphery and the central nervous system and mediates diverse physiological processes and behaviors including alcohol abuse, depression and anxiety. Four genes encoding galanin and its receptors have been identified (GAL, GALR1, GALR2 and GALR3). Recently we found that GAL haplotypes were associated with alcoholism, raising the possibility that genetic variation in GALR1, GALR2 and GALR3 might also alter alcoholism risk. Tag single nucleotide polymorphisms (SNPs) were identified by genotyping SNP panels in controls from five populations. For the association study with alcoholism, six GALR1, four GALR2 and four GALR3 SNPs were genotyped in a large cohort of Finnish alcoholics and non-alcoholics. GALR3 showed a significant association with alcoholism that was driven by one SNP (rs3,091,367). Moreover, the combination of the GALR3 rs3,091,367 risk allele and GAL risk haplotypes led to a modestly increased odds ratio (OR) for alcoholism (2.4) as compared with the effect of either GAL (1.9) or GALR3 alone (1.4). Likewise, the combination of the GALR3 and GAL risk diplotypes led to an increased OR for alcoholism (4.6) as compared with the effect of either GAL (2.0) or GALR3 alone (1.6). There was no effect of GALR1 or GALR2 on alcoholism risk. This evidence suggests that GALR3 mediates the alcoholism-related actions of galanin.

Association of galanin haplotypes with alcoholism and anxiety in two ethnically distinct populations.

The neuropeptide galanin (GAL) is widely expressed in the central nervous system. Animal studies have implicated GAL in alcohol abuse and anxiety: chronic ethanol intake increases hypothalamic GAL mRNA; high levels of stress increase GAL release in the central amygdala. The coding sequence of the galanin gene, GAL, is highly conserved and a functional polymorphism has not yet been found. The aim of our study was, for the first time, to identify GAL haplotypes and investigate associations with alcoholism and anxiety. Seven single-nucleotide polymorphisms (SNPs) spanning GAL were genotyped in 65 controls from five populations: US and Finnish Caucasians, African Americans, Plains and Southwestern Indians. A single haplotype block with little evidence of historical recombination was observed for each population. Four tag SNPs were then genotyped in DSM-III-R lifetime alcoholics and nonalcoholics from two population isolates: 514 Finnish Caucasian men and 331 Plains Indian men and women. Tridimensional Personality Questionnaire harm avoidance (HA) scores, a dimensional measure of anxiety, were obtained. There was a haplotype association with alcoholism in both the Finnish (P=0.001) and Plains Indian (P=0.004) men. The SNPs were also significantly associated. Alcoholics were divided into high and low HA groups (>or= and

Haplotype block and superblock structures of the alpha1-adrenergic receptor genes reveal echoes from the chromosomal past.

A significant proportion of the human genome is contained within haplotype blocks across which pairwise linkage disequilibrium (LD) is very high. However, LD is also often high between markers at more remote distances, and within different haplotype blocks. Here, we evaluate the origins of haplotype block structure in the three genes for alpha1 adrenergic receptors (alpha1-AR) in the human genome ( ADRA1A, ADRA1B and ADRA1D) by genotyping dense single-nucleotide polymorphism (SNP) marker maps, and show that LD signals between distant markers are due to the presence of extended haplotype superblocks in individuals with ancient chromosomes which have escaped historic recombination. ARs mediate the physiological effects of epinephrine and norepinephrine, and are targets of many therapeutic drugs. This work has identified haplotype backgrounds of alpha1-AR missense variants, haplotype block structures in US Caucasians and African Americans, and haplotype tag SNPs for each block, and we present strong evidence for ancient haplotype block superstructure at these genes which has been partially disrupted by recombination, and evidence for reinstatement of linkage disequilibrium by subsequent recombination events. ADRA1A is comprised of four haplotype blocks in US Caucasians, while in African Americans Block 1 is split. ADRA1B has four blocks in US Caucasians, but in African Americans only the first two blocks are present. ADRA1D has two blocks in US Caucasians, and the first block is replaced by two smaller blocks in African Americans. For both ADRA1A and ADRA1B, haplotype superstructures may represent a novel, higher-level hierarchy in the human genome, which may reduce redundancy of testing by further aggregation of genotype data.

Haplotype structure of inflammatory cytokines genes (IL1B, IL6 and TNF/LTA) in US Caucasians and African Americans.

The major inflammatory cytokines interleukin(IL)1beta, IL6 and tumor necrosis factor alpha (TNFalpha) play a crucial role in infection, inflammation and stress responses. Previously, three coding genes were resequenced, identifying promoter polymorphisms that were used in association studies of neurodegenerative diseases, metabolic disorders and cancer. These studies have produced intriguing but inconsistent results, potentially because the known functional variants: IL1B-511 C>T, IL6-174 G>C and TNF-308 G>A provided an incomplete picture of the total functional diversity at these genes. Therefore, we created marker panels for IL1B, IL6 and TNF/LTA that included the known functional marker but also other markers evenly spaced and with sufficient density to identify haplotype block structure and to maximize haplotype diversity. A total of 26 markers were genotyped in 96 US Caucasians and 96 African Americans. In both populations, a single block with little evidence of historical recombination was observed in IL1B, IL6 and TNF/LTA. For each gene, haplotypes captured the information content of each functional locus, even if that locus was not genotyped, and presumably haplotypes would capture the signal from unknown functional loci whose alleles are of moderate abundance. This study demonstrates the utility of using gene haplotype maps and marker panels as tools for linkage studies on related phenotypes.

Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial.

BACKGROUND: Tricyclic antidepressants (TCA) provide less than satisfactory pain relief for postherpetic neuralgia (PHN), and the role of opioids is controversial. OBJECTIVE: To compare the analgesic and cognitive effects of opioids with those of TCA and placebo in the treatment of PHN. METHODS: Seventy-six patients with PHN were randomized in a double-blind, placebo-controlled, crossover trial. Each subject was scheduled to undergo three treatment periods (opioid, TCA, and placebo), approximately 8 weeks' duration each. Doses were titrated to maximal relief or intolerable side effects. The primary outcome measures were pain intensity (0 to 10 scale), pain relief (0 to 100%), and cognitive function. Analyses included patients who provided any pain ratings after having received at least a single dose of a study medication. RESULTS: Fifty patients completed two periods, and 44 patients completed all three. Mean daily maintenance doses were morphine 91 mg or methadone 15 mg and nortriptyline 89 mg or desipramine 63 mg. Opioids and TCA reduced pain (1.9 and 1.4) more than placebo (0.2; p < 0.001), with no appreciable effect on any cognitive measure. The trend favoring opioids over TCA fell short of significance (p = 0.06), and reduction in pain with opioids did not correlate with that following TCA. Treatment with opioids and TCA resulted in greater pain relief (38 and 32%) compared with placebo (11%; p < 0.001). More patients completing all three treatments preferred opioids (54%) than TCA (30%; p = 0.02). CONCLUSIONS: Opioids effectively treat PHN without impairing cognition. Opioids and TCA act via independent mechanisms and with varied individual effect.

Topiramate in trigeminal neuralgia: a randomized, placebo-controlled multiple crossover pilot study.

We conducted a pilot study to evaluate the efficacy of topiramate in trigeminal neuralgia using a randomized, double-blind, placebo-controlled, two-period crossover design. Three patients were enrolled in and completed the study. All three patients responded to topiramate in this main study and entered a subsequent confirmatory study consisting of three topiramate-placebo crossovers. In the main study, topiramate reduced pain by 31%, 42%, and 64% in the three patients (p = 0.04). However, topiramate showed no effect in the confirmatory study. Given that trials of less common pain conditions are fraught with low patient recruitment rates, a multiple crossover design provides more information, which is important in conditions associated with considerable pain fluctuation. Larger trials are needed to more precisely estimate the effect of topiramate in trigeminal neuralgia.

A randomized, controlled trial of high-dose dextromethorphan in facial neuralgias.

BACKGROUND: NMDA glutamate receptor antagonists such as ketamine and dextromethorphan reduce pain in certain neuropathic pain conditions. However, there have been no controlled trials of NMDA antagonists in facial neuralgias. METHODS: A randomized, double-blind, crossover trial compared 6 weeks of oral dextromethorphan with active placebo (low-dose lorazepam) in 19 patients, stratified into three groups: 11 with facial pain and possible trigeminal neuropathy, five with anesthesia dolorosa, and three with idiopathic trigeminal neuralgia. Dosage was titrated in each patient to the highest level reached without disrupting normal activities. RESULTS: Patients completing the trial included 10 with possible trigeminal neuropathy, four with anesthesia dolorosa, and two with trigeminal neuralgia. In patients with possible trigeminal neuropathy and anesthesia dolorosa, dextromethorphan decreased pain by a mean of only 2 to 4%, and these estimates were not significant. Both patients with trigeminal neuralgia had more pain during dextromethorphan treatment than during placebo treatment. Of three patients who demonstrated an analgesic response to dextromethorphan during the main trial, only one repeatedly responded in four subsequent confirmatory drug-placebo crossovers. CONCLUSIONS: Dextromethorphan shows little or no analgesic efficacy in pain due to possible trigeminal neuropathy and anesthesia dolorosa. Additional trials are necessary to conclusively evaluate the efficacy of NMDA-receptor antagonists in trigeminal neuralgia.

Effects of the 2-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid/kainate antagonist LY293558 on spontaneous and evoked postoperative pain.

BACKGROUND: Previous studies suggest that 2-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA)/kainate antagonists reduce experimentally induced pain. There have been no studies of AMPA/kainate antagonists in clinical pain. METHODS: Analgesic efficacy of intravenous LY293558 (0.4 or 1.2 mg/kg) was compared with that of intravenous ketorolac tromethamine (INN, ketorolac; 30 mg) and placebo in a randomized, double-blind, parallel-group study after oral surgery (n = 70). Study drugs were administered at the onset of moderate pain; pain intensity and relief were measured for 240 minutes. RESULTS: High-dose LY293558 and ketorolac tromethamine were superior to placebo (P < .05) for pain evoked by mouth opening and one of several measures of spontaneous pain: SPID240 +/- SEM for pain evoked by mouth opening was highest for ketorolac tromethamine (151 +/- 58), intermediate for high-dose LY293558 (-45 +/- 35), and least for low-dose LY293558 (-151 +/- 39) and placebo (-162 +/- 50). High-dose LY293558 was superior to placebo at individual time points (45 to 240 minutes) for pain evoked by mouth opening but not for spontaneous pain. The spontaneous summed pain intensity difference over 240 minutes (SPID240 +/- SEM) was highest for ketorolac tromethamine (303 +/- 84), intermediate for high-dose LY293558 (-51 +/- 40) and low-dose LY293558 (-96 +/- 45), and least for placebo (-180 +/- 24). LY293558 was well tolerated, with dose-dependent and reversible side effects including hazy vision in 20% of patients and sedation in 15%. CONCLUSIONS: This is the first evidence that an AMPA/kainate antagonist reduces clinical pain. Tests of evoked pain may be more sensitive to certain analgesics than those of spontaneous pain. The evaluation of evoked pain as an outcome measure in analgesic trials may identify potentially useful compounds otherwise missed if only spontaneous pain is evaluated.

Is mechanism-based pain treatment attainable? Clinical trial issues.

Woolf et al have recently called for the development of a mechanism-based pain taxonomy to guide the individualization of treatment based on each patient's pain mechanisms. Although any scientific physician could endorse this ideal, small academic clinical trials so far have failed to identify obvious differences in the response of different pain symptoms in the same condition to various drugs. In contrast, there are clear differences in the analgesic responses of patient groups distinguished on the basis of etiology or tissue origin of pain, factors which tend to be associated with groups of mechanisms. The few tests to diagnose pain mechanisms remain too delicate, time-consuming, or uncomfortable for general clinical use. To understand how best to exploit new mechanistic insights to assign treatments, one must scrutinize the relative value of diagnostic classifications based on etiology, tissue, and individual patients' pain characteristics in large clinical trials. Research priorities should include developing simple methods for assessing pain mechanisms in the clinic and increasing the efficiency of pain assessment methods in clinical trials. I describe a collaborative research agenda for academic pain researchers and funding agencies, the pharmaceutical industry, and regulatory bodies.

Tourniquet constriction exacerbates hyperalgesia-related pain induced by intradermal capsaicin injection.

BACKGROUND: When capsaicin is injected intradermally, hyperalgesia develops around the injection site. The authors observed that volunteers report painful sensations in the skin remote from the injection site during tourniquet constriction of the affected extremity. METHODS: Each volunteer received an intradermal injection of capsaicin on the volar forearm, followed by intermittent tourniquet constriction of the extremity. In some participants, the tourniquet position was rotated between different sites on the upper extremities. Laser Doppler measurements were made in the skin to measure capillary blood flow during pain magnification. RESULTS: Hyperalgesia developed in the volunteers who were tested after the capsaicin injection. Blood flow increased three times in the dermal capillaries remote from the injection site after capsaicin injection. The tourniquet-induced pain reached peak intensity soon after tourniquet inflation. Tourniquet constriction of the arm on the affected side reliably induced painful exacerbation in each person tested. The quality of the sensation was described as burning and extended across the arm in most volunteers. Only when pinprick hyperalgesia was detectable did the volunteers experience the diffuse, immediate pain sensation. The pain initiated by the tourniquet constriction likely is related to changes in skin capillary blood flow. CONCLUSIONS: Low cutaneous blood perfusion is related to the intensity of ongoing, spontaneous pain when secondary hyperalgesia is present. The specific trigger(s) have yet to be identified.

The substance P receptor antagonist CP-99,994 reduces acute postoperative pain.

BACKGROUND: Animal studies suggest that substance P, a peptide that preferentially activates the neurokinin-1 (NK1) receptor, is involved in pain transmission, with particular importance in pain after inflammation. METHODS: The analgesic efficacy of CP-99,994, a NK1 receptor antagonist, was compared with ibuprofen and placebo in 78 subjects undergoing third molar extraction. The initial 60 subjects randomly received 1 of 3 possible treatments in a double-blind fashion before oral surgery: 750 microg/kg CP-99,994 infused intravenously over 5 hours on a tapering regimen starting 2 hours before surgery, 600 mg oral ibuprofen 30 minutes before surgery, or placebo. In a second study, 18 subjects were randomized to the same regimens starting 30 minutes before surgery to maximize the amount of CP-99,994 circulating during pain onset. RESULTS: In the first study, ibuprofen significantly reduced pain, as measured by visual analog scale, from 90 to 240 minutes postoperatively compared with placebo. CP-99,994 produced analgesia that was significant at 90 minutes (P < 0.01 compared with placebo), but not at subsequent time points. In the second study, ibuprofen and, to a lesser extent, CP-99,994 significantly suppressed pain in comparison to placebo at 60, 90, and 120 minutes (P < 0.05). The incidence of side effects was similar across groups. CONCLUSIONS: This replicate demonstration that a NK1 receptor blocker relieves clinical pain supports the hypothesis that substance P contributes to the generation of pain in humans. The reduction in postoperative pain at doses not producing side effects suggests that NK1 antagonists may be clinically useful.

A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team.

BACKGROUND: Painful sensory neuropathy is a common complication of HIV infection. Based on prior uncontrolled observations, we hypothesized that amitriptyline or mexiletine would improve the pain symptoms. METHOD: A randomized, double-blind, 10-week trial of 145 patients assigned equally to amitriptyline, mexiletine, or matching placebo. The primary outcome measure was the change in pain intensity between baseline and the final visit. RESULTS: The improvement in amitriptyline group (0.31+/-0.31 units [mean+/-SD]) and mexiletine group (0.23+/-0.41) was not significantly different from placebo (0.20+/-0.30). Both interventions were generally well tolerated. CONCLUSIONS: Neither amitriptyline nor mexiletine provide significant pain relief in patients with HIV-associated painful sensory neuropathy.

Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: a randomized controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS.

CONTEXT: Peripheral neuropathy is common in persons infected with the human immunodeficiency virus (HIV) but few data on symptomatic treatment are available. OBJECTIVE: To evaluate the efficacy of a standardized acupuncture regimen (SAR) and amitriptyline hydrochloride for the relief of pain due to HIV-related peripheral neuropathy in HIV-infected patients. DESIGN: Randomized, placebo-controlled, multicenter clinical trial. Each site enrolled patients into 1 of the following 3 options: (1) a modified double-blind 2 x 2 factorial design of SAR, amitriptyline, or the combination compared with placebo, (2) a modified double-blind design of an SAR vs control points, or (3) a double-blind design of amitriptyline vs placebo. SETTING: Terry Beirn Community Programs for Clinical Research on AIDS (HIV primary care providers) in 10 US cities. PATIENTS: Patients with HIV-associated, symptomatic, lower-extremity peripheral neuropathy. Of 250 patients enrolled, 239 were in the acupuncture comparison (125 in the factorial option and 114 in the SAR option vs control points option), and 136 patients were in the amitriptyline comparison (125 in the factorial option and 11 in amitriptyline option vs placebo option). INTERVENTIONS: Standardized acupuncture regimen vs control points, amitriptyline (75 mg/d) vs placebo, or both for 14 weeks. MAIN OUTCOME MEASURE: Changes in mean pain scores at 6 and 14 weeks, using a pain scale ranging from 0.0 (no pain) to 1.75 (extremely intense), recorded daily. RESULTS: Patients in all 4 groups showed reduction in mean pain scores at 6 and 14 weeks compared with baseline values. For both the acupuncture and amitriptyline comparisons, changes in pain score were not significantly different between the 2 groups. At 6 weeks, the estimated difference in pain reduction for patients in the SAR group compared with those in the control points group (a negative value indicates a greater reduction for the "active" treatment) was 0.01 (95% confidence interval [CI], -0.11 to 0.12; P=.88) and for patients in the amitriptyline group vs those in the placebo group was -0.07 (95% CI, -0.22 to 0.08; P=.38). At 14 weeks, the difference for those in the SAR group compared with those in the control points group was -0.08 (95% CI, -0.21 to 0.06; P=.26) and for amitriptyline compared with placebo was 0.00 (95% CI, -0.18 to 0.19; P=.99). CONCLUSIONS: In this study, neither acupuncture nor amitriptyline was more effective than placebo in relieving pain caused by HIV-related peripheral neuropathy.

AMPA/kainate antagonist LY293558 reduces capsaicin-evoked hyperalgesia but not pain in normal skin in humans.

BACKGROUND: Animal studies suggest that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-kainate (AMPA-KA) receptors are involved in pain processing. The effects of the competitive AMPA-KA antagonist LY293558 in two types of experimental pain in human volunteers, brief pain sensations in normal skin, and mechanical allodynia-pinprick hyperalgesia were studied after the injection of intradermal capsaicin. METHODS: Brief intravenous infusions of the competitive AMPA-KA antagonist LY293558 were given to 25 healthy volunteers to examine acute toxicity and analgesic effects. Fifteen volunteers then entered a double-blinded, three-period crossover study. In a Phase II study, LY293558 infusions (100% maximally tolerated dose vs. 33% maximally tolerated dose vs. placebo) began 10 min after intradermal injection of 250 microg capsaicin in volar forearm. Spontaneous pain, areas of mechanical allodynia and pinprick hyperalgesia, and side effects were determined every 5 min for 60 min. RESULTS: The median maximally tolerated dose was 1.3 +/- 0.4 (range, 0.9-2.0) mg/kg. Tests of cognitive and neurological function were unchanged. Dose-limiting side effects were hazy vision in 95% of volunteers and sedation in 40%. There were no significant changes in electrical or warm-cool detection and pain thresholds or heat pain thresholds. LY293558 had little effect on brief pain sensations in normal skin. Both high and low doses of LY293558 significantly reduced pain intensity, pain unpleasantness, and the area in which light brush evoked pain after intradermal capsaicin. There was a trend toward a dose-response effect of LY293558 on the area in which pinprick evoked pain after intradermal capsaicin, which did not reach statistical significance. CONCLUSIONS: The authors infer that AMPA-KA receptor blockade reduces the spinal neuron sensitization that mediates capsaicin-evoked pain and allodynia. The low incidence of side effects at effective doses of LY293558 suggests that this class of drugs may prove to be useful in clinical pain states.

The human capsaicin model of allodynia and hyperalgesia: sources of variability and methods for reduction.

Intradermal and topical application of capsaicin have been used to study mechanisms of mechanical allodynia (MA) and pinprick hyperalgesia (PPH) and the efficacy of drugs in relieving these symptoms. However, it is associated with significant inter- and intra-subject variability. In order to improve the model's sensitivity, we examined several potential sources of variability of capsaicin-evoked MA and PPH in healthy volunteers, including skin temperature fluctuations, method (intradermal vs. topical) and site (volar forearm vs. foot dorsum) of administration. In study I, 12 subjects received, in a 6-session, randomized, crossover trial, 1) 250 micrograms of intradermal (ID) CAP to the volar forearm with skin temperature fixed at 36 degrees C (36 ID). 2) 250 micrograms ID CAP with varying skin temperature (VT ID), or 3) 250 microliters of l% CAP patch placed on the skin at 36 degrees C. The resulting MA and PPH areas observed with each method were measured. In study II, a 4-session, randomized crossover trial, 12 subjects were given 100 micrograms ID CAP in the volar forearm or foot dorsum and subsequent areas of MA and PPH recorded. In study I, 5/12 subjects had small MA areas (< or = 5 cm2) and one subject had small PPH areas in at least 4/6 sessions. The most consistent intra-subject responses were seen with the 36 ID method. Correlation coefficients for the two sessions using the same method of administration were: MA; 36 ID r = 0.83, VT ID = 0.19. Topical r = 0.81; PPH: 36 ID r = 0.93; VT ID r = 0.38, Topical r = 0.78. In study II, 4/12 subjects had little MA for both forearm and foot though all subjects developed PPH. However, greater intra-subject consistency (MA: foot: r = 0.84; arm: r = 0.49; PPH: r = 0.87; r = 0.39) and significantly larger areas of MA (15.8 +/- 4.2 vs 9.1 +/- 2.5, p < 0.05) were seen with the foot. (PPH: foot: 28.9 +/- 6.7; arm: 21.6 +/- 4.2, NS). Large variability exists among subjects receiving CAP, with some developing minimal MA. However, these subjects may be screened out prior to entry, increasing the sensitivity of the model, which may be further improved by clamping the skin temperature.