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Objective: Diabetic foot ulcer (DFU) is a severe complication with high mortality. High plantar pressure and poor microcirculation are considered main causes of DFU. The specific aims were to provide a novel technique for real-time measurement of plantar skin blood flow (SBF) under walking-like pressure stimulus and delineate the first plantar metatarsal head dynamic microcirculation characteristics because of life-like loading conditions in healthy individuals., Methods: Twenty young healthy participants (14 male and 6 female) were recruited. The baseline (i.e., unloaded) SBF of soft tissue under the first metatarsal head were measured using laser Doppler flowmetry (LDF). A custom-made machine was utilized to replicate daily walking pressure exertion for 5 min. The exerted plantar force was adjusted from 10 N (127.3 kPa) to 40 N (509.3 kPa) at an increase of 5 N (63.7 kPa). Real-time SBF was acquired using the LDF. After each pressure exertion, postload SBF was measured for comparative purposes. Statistical analysis was performed using the R software., Results: All levels of immediate-load and postload SBF increased significantly compared with baseline values. As the exerted load increased, the postload and immediate-load SBF tended to increase until the exerted load reached 35 N (445.6 kPa). However, in immediate-load data, the increasing trend tended to level off as the exerted pressure increased from 15 N (191.0 kPa) to 25 N (318.3 kPa). For postload and immediate-load SBF, they both peaked at 35 N (445.6 kPa). However, when the exerted force exceeds 35 N (445.6 kPa), both the immediate-load and postload SBF values started to decrease., Conclusions: Our study offered a novel real-time plantar soft tissue microcirculation measurement technique under dynamic conditions. For the first metatarsal head of healthy people, 20 N (254.6 kPa)-plantar pressure has a fair microcirculation stimulus compared with higher pressure. There might be a pressure threshold at 35 N (445.6 kPa) for the first metatarsal head, and soft tissue microcirculation may decrease when local pressure exceeds it., (© 2024 John Wiley & Sons Ltd.)

Background: Xerosis cutis of the feet is one of the most common skin conditions among type 2 diabetics. Whether skin dryness among diabetic patients is different from 'general' skin dryness is unclear. The overall aim was to compare the structure, function and molecular markers of dry and cracked foot skin between diabetics and non-diabetics., Methods: The foot skin of 40 diabetics and 20 non-diabetics was evaluated. A clinical assessment of skin dryness was performed and transepidermal water loss, stratum corneum hydration, skin surface pH, epidermal thickness, skin roughness, elasticity and structural stiffness were measured. Ceramides, natural moisturizing factors, histamines, proteins and molecular markers of oxidative stress were analyzed based on a non-invasive sampling method for collection of surface biomarkers., Results: The mean number of superficial fissures in the diabetic group was nearly three times higher than in the non-diabetic group (11.0 (SD 6.2) vs. 3.9 (SD 4.2)). The skin stiffness was higher in the diabetic group and the values of almost all molecular markers showed considerably higher values compared to non-diabetics. Malondialdehyde and glutathione were lower in the diabetic sample., Conclusions: The high number of superficial fissures may be based on an increased stiffness of dry diabetic foot skin combined with different concentrations of molecular markers in the stratum corneum compared to dry foot skin of non-diabetics., (Copyright © 2019 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.)

According to the literature, the arteriovenous anastomoses in the peripheral parts (ex. hands and feet) respond thermal stimulation susceptibly. Thus, the feet are sensitive to cold stimulation. The aim of the present study was to investigate the effect of menstrual cycle on skin temperature (T sk ) of the foot during menthol application in young women. T sk and partial cutaneous blood flow in the foot, tympanic temperature, blood pressure, heart rate, thermal sensation and pleasantness during the preovulatory (P), luteal (L), and menstrual (M) phases during menthol application in young women using thermography, laser Doppler flowmetry, a digital blood pressure monitor, and VAS scale were examined at 25 °C. After application of the 0.5% menthol solution to the right foot, the measurements were continued for 20 min. The T sk of the second and third right toes in the P phase were lower than that in the L phase. The T sk of the little right toe in the P phase was lower than that in the L and M phases. No significant differences were observed in the T sk of the dorsum of right foot, cutaneous Laser-Doppler flow in the right great toe, tympanic temperature, blood pressure, heart rate, thermal sensation and pleasantness among the phases. The menstrual cycle phase did not affect T sk in the dorsum of the foot, but it affected T sk in some toes during menthol application., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: The addition of skin perfusion pressure (SPP) might enhance the predictive value of the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system. The purpose of the present study was to evaluate the SPP for each WIfI classification stage among patients with foot wounds by cross-referencing the results of prospectively monitored limb outcomes and to derive the SPP criteria that could be combined with other measurements to grade ischemia for the WIfI classification., Methods: From July 2015 to June 2017, patients with foot wounds that met the WIfI classification criteria were prospectively enrolled. We assessed the limbs using the WIfI ischemia grade without measuring the transcutaneous oxygen pressure but measured the SPP. After monitoring for 1 year, the predictability of the WIfI stages was analyzed according to whether the limbs had not healed (unchanged or worsened wounds, minor or major amputation, all-cause death) or had healed (improved or healed wounds) by comparing stages 1 and 2 with stages 3 and 4. We also statistically analyzed the SPP values that could be the boundary values between each ischemia grade and reevaluated the predictability of the WIfI stages with the boundary SPP values., Results: We enrolled a total of 91 limbs for 76 patients (mean age, 70.5 ± 12.0 years). The mean SPP values stratified by ischemia grade 0 to 3 were 52.1, 41.1, 27.1, and 18.8 mm Hg, respectively (an SPP of <30 mm Hg indicates severe ischemia). After monitoring for 1 year, 19 of 48 limbs in stage 1 and 2 and 35 of 43 in stage 3 and 4 were in the nonhealed group and 29 limbs in stage 1 and 2 and 8 limbs in stage 3 and 4 were in the healed group. The SPP boundary values between each ischemia (I) grade were calculated as 45 mm Hg for I-0/I-1, 35 for I-1/I-2, and 25 for I-2/I-3. When jointly using the boundary SPP values, the ischemia grade changed for 23 limbs, altering the distribution of the WIfI stages and limb outcomes: 11 of 38 limbs in stage 1 and 2 and 43 of 53 in stage 3 and 4 were transferred to the nonhealed group. The sensitivity, efficiency, and negative predictive value of WIfI staging improved when staging with SPP: from 65% to 80%, 70% to 77%, and 60% to 71%, respectively., Conclusions: The SPP boundary values that could be used with ischemia grade in the WIfI classification were identified as 45, 35, and 25 mm Hg. The addition of SPP could improve the accuracy of the evaluation., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Improving perfusion under the skin can potentially reduce ulceration and amputation risk in people with diabetic foot. Localized pressure stimulation has been proven capable of improving skin perfusion in the scalp but its effectiveness for the foot has not been tested. In this study, localized pressure stimulation was realized using flexible turf-like structures (TLS) with dense vertical fibers and their ability to increase perfusion was assessed., Methods: The skin in the rearfoot, midfoot, and forefoot of nine healthy volunteers was stimulated using two TLS with different stiffness and one wound filler material that generated a uniform compression. Changes in perfusion were assessed using laser speckle., Results: Mechanical stimulation significantly increased perfusion in the forefoot and midfoot areas with the TLS achieving higher and more long-lasting increase compared to the wound filler. The stiffer of the two TLS appeared to be the most effective for the forefoot achieving a significant increase in perfusion that lasted for 25.5 seconds immediately after stimulation., Conclusion: The results of this study indicate that localized pressure stimulation is more effective compared to uniform compression for improving skin perfusion in the healthy foot. Further research in people with diabetic foot disease is needed to verify the clinical value of the observed effect., (© 2019 John Wiley & Sons Ltd.)

Objectives: Laser speckle flowgraphy is a new method that enables the rapid evaluation of foot blood flow without contact with the skin. We used laser speckle flowgraphy to evaluate foot blood flow in peripheral arterial disease patients before and after surgical revascularization., Materials and Methods: A prospective single-center study. Thirty-one patients with 33 limbs that underwent surgical revascularization for peripheral arterial disease were included. Pre- and postoperative foot blood flows were measured on the plantar surface via laser speckle flowgraphy and skin perfusion pressure. The laser speckle flowgraphy device was used to visualize the blood flow distribution of the target skin and processed the pulse wave velocity of synchronized heart beats. The mean blood flow, which was expressed as the area of the pulse wave as the beat strength of skin perfusion on laser speckle flowgraphy converted into a numerical value, was assessed as dynamic changes following surgery. Beat strength of skin perfusion was also investigated in non-peripheral arterial disease controls (23 patients/46 limbs)., Results: The suitability of beat strength of skin perfusion in non-peripheral arterial disease controls was achieved; the beat strength of skin perfusion value was significantly higher in every area of interest in non-peripheral arterial disease controls compared to that in peripheral arterial disease limbs at the preoperative stage (105.8 ± 8.2 vs. 26.3 ± 8.2; P < 0.01). Although the pulse wave before surgery was visually flat in peripheral arterial disease patients, the pulse wave was remarkably and immediately improved through surgical revascularization. Beat strength of skin perfusion showed a dynamic change in foot blood flow (26.3 ± 8.2 at preoperation, 98.5 ± 6.7 immediately after surgery, 107.6 ± 5.7 at seven days after surgery, P < 0.01 for each compared to preoperation) that correlated with an improvement in skin perfusion pressure., Conclusions: Laser speckle flowgraphy is a noninvasive, contact-free modality that is easy to implement, and beat strength of skin perfusion is a useful indicator of foot circulation during the perioperative period. Further analysis with a larger number of cases is necessary to establish appropriate clinical use.

The improvement of peripheral circulation is crucial for the care of vasculopathic diabetic foot ulcer (DFU). Near-infrared spectroscopy (NIRS) was used to investigate the effects of Buerger's exercise on dorsal foot skin circulation with novel technique of measuring the absorption difference in wavelength of light between oxy-hemoglobin (HbO 2 ) and deoxy-hemoglobin (HbR). Patients with vasculopathic DFU who could tolerate Buerger's exercise three times a day at home for at least 8 weeks were enrolled (group A). They were divided into two subgroups: without previous percutaneous transluminal angioplasty (PTA) (group A1) vs. with previous PTA (group A2). Wireless NIRS were applied on patients' dorsal foot to assess the peripheral circulation in follow-up clinics. The patients' wound condition, follow-up time, and concentration of HbO 2 and total hemoglobin (HbT) before and after exercise rehabilitation program were documented. From May 2015 to February 2016, 14 patients with average age of 70.2 ± 11.2 were enrolled in this study (group A), including eight without previous PTA (group A1), and six with previous PTA (group A2). The concentration of HbO2 and HbT were significantly increased after exercise rehabilitation program training in group A (p = 0.024 in HbO 2 , p = 0.02 in HbT, n = 14) and group A2 (p = 0.021 in HbO 2 , p = 0.028 in HbT, n = 6), while the concentration in group A1 were improved with borderline significance after exercise (p = 0.055 in HbO 2 , p = 0.058 in HbT, n = 8). The majority of the ulcers were either completely healed (11/14 = 78.57%) or improving (3/14 = 21.43%). Buerger's exercise improved the peripheral circulation and wound condition in patients with vasculopathic DFU. The wireless apparatus is a novel and efficient tool to monitor rehabilitation program.

Background: Diabetic foot disease carries a high morbidity and is a leading cause of lower limb amputation. This may in part be due to the effect diabetes mellitus (DM) has on the microcirculation including in the skin., Method: We conducted a review of studies that have examined the relationship between microcirculatory function and wound healing in patients with DM. A search of the Medline, Embase, and Web of Science databases was performed coupled with a review of references for the period 1946 to March 2015., Results: Nineteen studies of diverse methodology and cohort selection were identified. Poor function of the microcirculation was related to poor outcome. Transcutaneous oxygen pressure (TcPO 2 ) was the most commonly used method to measure the microcirculation and thresholds for poor outcome proposed ranged from 10 mmHg to <34 mmHg. Two studies reexamined microcirculatory function following revascularization. Both found an increase in TcPO 2 , however only 1 reached statistical significance. No significant difference in the results of microcirculation tests was found between diabetic and nondiabetic patients., Conclusions: While it is not possible to draw firm conclusions from the evidence currently available there are clear areas that warrant research. Good microcirculation unsurprisingly appears to associate with better wound healing. The influence of DM is not clear, and neither is the degree of improvement required to achieve healing. Studies that examine a clearly defined cohort both with and without DM are urgently required. Accurate quantitative assessment of microcirculation will aid prediction of wound healing identifying those at greatest risk of amputation.

Objective: In recent years, a controversial discussion about the clinical relevance of the angiosome concept during tibial angioplasty has developed. Therefore, we conducted a prospective study to evaluate the angiosome concept on the level of microcirculation during tibial vascular interventions., Methods: Thirty patients with isolated tibial angioplasty were examined prospectively. Macrocirculation was evaluated by measurement of the ankle-brachial index (ABI). For the assessment of microcirculation, a combined method of laser Doppler flowmetry and tissue spectrometry (O2C; LEA Medizintechnik GmbH, Giessen, Germany) was applied. Microcirculatory parameters were measured continuously during the procedures. Measuring points were located over different angiosomes of the index foot; a control probe was placed on the contralateral leg., Results: Cumulated microcirculation parameters (sO 2 , flow) as well as the ABI showed a significant improvement postinterventionally (ABI, P < .001; sO 2 , P < .001; flow, P < .001). Assessment of the separate angiosomes of the index leg and the comparison of the directly revascularized (DR) and indirectly revascularized (IR) angiosomes showed no significant difference concerning the microperfusion postinterventionally (DR - IR: sO 2 , P = .399; flow, P = .909) as well as during angioplasty. Even a further subdivision of the collective into patients with diabetes (sO 2 , P = .445; flow, P =.758) and renal insufficiency (sO 2 , P = .246; flow, P = .691) could not demonstrate a superiority of the direct revascularization at the level of microcirculation in these patients (comparison DR - IR)., Conclusions: There is a significant overall improvement in tissue perfusion of the foot immediately after tibial angioplasty. The effect shown in this study, however, was found to be global and was not restricted to certain borders, such as defined by angiosomes., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Sympathetic denervation and impaired angiogenesis cause skin diseases. However, the relationship between the sympathetic nervous system and vascular cell turnover in normal skin remains unclear., Objective: To determine the effects of sympathetic denervation on vascular cell turnover in normal skin., Methods: Rats underwent bilateral L2-4 sympathetic trunk resection (sympathectomy group) or sham operation (control). Hindfoot plantar skin was analyzed 2 weeks and 3 months postoperatively., Results: Mural cell marker (α-smooth muscle actin; p < 0.001, and desmin; p = 0.047) expression decreased 2 weeks after sympathectomy, but recovered 3 months after sympathectomy (p > 0.05). CD31 levels were lower in the experimental group than in the control group at 2 weeks (p = 0.009), but not at 3 months. Von Willebrand factor, vascular endothelial growth factor, and angiopoietin-2 expression were not significantly different between the groups (p > 0.05). Angiopoietin-1 expression levels were higher in the experimental group than in the control group at 2 weeks (p = 0.035), but not at 3 months., Conclusions: Lumbar sympathectomy regulates vascular cell turnover in rat hindfoot plantar skin by inhibiting mural cell proliferation and increasing angiopoietin-1 expression. Sympathetic nerves therefore play an important role in plantar skin vascular cell turnover.

Buerger exercise can improve the peripheral circulation of lower extremities. However, the evidence and a quantitative assessment of skin perfusion immediately after this exercise in patients with diabetes feet are still rare.We recruited 30 patients with unilateral or bilateral diabetic ulcerated feet in Chang Gung Memorial Hospital, Chia-Yi Branch, from October 2012 to December 2013. Real-time dorsal foot skin perfusion pressures (SPPs) before and after Buerger exercise were measured and analyzed. In addition, the severity of ischemia and the presence of ulcers before exercise were also stratified.A total of 30 patients with a mean age of 63.4 ± 13.7 years old were enrolled in this study. Their mean duration of diabetes was 13.6 ± 8.2 years. Among them, 26 patients had unilateral and 4 patients had bilateral diabetes foot ulcers. Of the 34 wounded feet, 23 (68%) and 9 (27%) feet were classified as Wagner class II and III, respectively. The real-time SPP measurement indicated that Buerger exercise significantly increased the level of SPP by more than 10 mm Hg (n = 46, 58.3 vs 70.0 mm Hg, P < 0.001). In terms of pre-exercise dorsal foot circulation condition, the results showed that Buerger exercise increased the level of SPP in severe ischemia (n = 5, 22.1 vs 37.3 mm Hg, P = 0.043), moderate ischemia (n = 14, 42.2 vs 64.4 mm Hg, P = 0.001), and borderline-normal (n = 7, 52.9 vs 65.4 mm Hg, P = 0.028) groups, respectively. However, the 20 feet with SPP levels more than 60 mm Hg were not improved significantly after exercise (n = 20, 58.3 vs 71.5 mm Hg, P = 0.239). As to the presence of ulcers, Buerger exercise increased the level of SPP in either unwounded feet (n = 12, 58.5 vs 66.0 mm Hg, P = 0.012) or wounded feet (n = 34, 58.3 vs 71.5 mm Hg, P < 0.001). The majority of the ulcers was either completely healed (9/34 = 27%) or still improving (14/34 = 41%).This study quantitatively demonstrates the evidence of dorsal foot peripheral circulation improvement after Buerger exercise in patients with diabetes., Competing Interests: The authors have no funding and conflicts of interest to disclose.

Introduction: The purpose of the study was to reveal the effect of blood flow supply to the foot by analyzing the skin perfusion pressure values and the pedal arch connection after bypass surgery., Patients and Methods: We selected 48 operated limbs whose skin perfusion pressure was measured pre- and post-operatively on the opposite site of distal anastomosis. We also assigned the ischemic limbs to three groups according to the patency of the pedal arch: good, intermediate, and poor., Results: The mean value of skin perfusion pressure increased significantly from 27.0 ± 14.9 to 52.8 ± 16.0 (p < 0.001) post-operatively. Skin perfusion pressure improved in most of the limbs post-operatively and decreased or unchanged in only four limbs, all of which showed improved tissue loss. Three amputated limbs were due to infection, and all showed an increase in skin perfusion pressure., Conclusion: It was difficult to correlate limb prognosis to skin perfusion pressure and the pedal arch connection., (© The Author(s) 2015.)

Introduction: Cutaneous arterio-venous malformations (AVM) are high-flow vascular malformations made up of a direct link between arteries and veins without intermediary capillary space. 'Distal limb's AVM', which mean involving hands or feet, are rare and their functional prognosis is often poor. Little is known about their early clinical symptoms. The objectives of this study were to identify early clinical symptoms of distal limb's cutaneous AVMs and to determine their long-term clinical outcome., Methods: A retrospective study was carried out including adult patients who had distal limb's AVM, who were followed up between January 2000 and November 2013 in two regional tertiary care centres. The information was collected from patients' clinical records and completed by a structured telephone questionnaire., Results: Nineteen patients were included in the study: four (21%) with foot AVM and 15 (79%) with hand AVM. The first clinical symptoms were as follows: swelling (47%), pain (47%), one or several venous dilatations (37%) and rarely abnormal skin colour, hyperthermia and pulsating sensation. The median diagnosis delay was 9 years after the onset of first manifestations. Amongst the 17 patients who underwent a treatment, 53% had embolotherapy session(s), 12% surgery and 35% had both. After an average follow-up of 57.6 months, 31% of the 13 patients contacted who were receiving treatment were in complete remission; 31% had partial remission; 15% had relapse after initial improvement and 23% had treatment failure. Overall, 74% of patients had a serious development of the AVM: 37% had digital or hand amputation, and 42% remained symptomatic and/or unstable., Conclusion: This study suggests that initial manifestations of distal limb's AVMs are discreet and non-specific, leading to a diagnosis delay of about 10 years, with poor prognosis. Doctors should evoke the diagnosis earlier, when these symptoms are shown: pain and/or swelling, sometimes with a large vein., (© 2015 European Academy of Dermatology and Venereology.)

Aims: To identify differences in the characteristics of patients with diabetic foot ulcers (DFUs) according to their etiological classification and to compare their healing time., Methods: Over a 4.5-year period, 73 patients with DFUs were recruited. DFUs were etiologically classified as being of neuropathic, ischemic, or neuro-ischemic origin. Descriptive analyses were performed to characterize study subjects, foot-related factors, and healing outcome and time. Duration of healing was assessed using the Kaplan-Meier method. Healing time among the three types was compared using the log rank test., Results: The number of patients manifesting neuropathic, ischemic, and neuro-ischemic ulcers was 30, 20, and 14, respectively. Differences were identified for age, diabetes duration, body mass index, hypertension, and estimated glomerular filtration rate. Patients with neuro-ischemic ulcers had better ankle-brachial index, skin perfusion pressure (SPP), and transcutaneous oxygen pressure values compared to those with ischemic ulcers. The average time in which 50% of patients had healed wounds was 70, 113, and 233 days for neuropathic, neuro-ischemic, and ischemic ulcers, respectively. Main factors associated with healing were age and SPP values., Conclusions: Based on the etiological ulcer type, DFU healing course and several patient factors differed. Failure to consider the differences in DFU etiology may have led to heterogeneity of results in previous studies on DFUs., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Because of its outstanding texture, bulkiness, pliability and sensory recovery, the medialis pedis is an excellent alternative in the reconstruction of complex volar skin defects of the digits in selected patients. However, the surgical flap anatomy related with the medial plantar artery is still somewhat confusing to the point that the different journal articles and anatomy textbooks and atlases use different terminology and are, to some extent, misleading and/or incomplete. The authors report a clinical series of 15 medialis pedis free flaps in the reconstruction of skin defects of the fingers and evaluate their indications in free flap reconstruction of the skin defects of the digits. A review is made of the most relevant journal articles, anatomy textbooks, and atlases that describe the anatomy of the medial plantar artery with a special emphasis on the cutaneous branches that nourish the medialis pedis flap.

Background: High-variable-frequency ultrasound is used as an imaging tool for various cutaneous disorders. We utilized this tool in pachyonychia congenita (PC) patients, who typically present with plantar hyperkeratosis and often severely debilitating pain, compared to patients with epidermolytic palmoplantar keratoderma (EPPK) and mal de Meleda (MDM)., Objective: To ascertain the feasibility of ultrasound technology for the diagnosis of PC., Methods: The study included a total of 16 patients, 7 with PC, 5 with EPPK and 4 with MDM, who underwent ultrasound examination of the plantar skin with high-resolution multifrequency ultrasound equipment., Results: Ultrasound scans performed over the proximal and distal plantar foot calluses in PC patients demonstrated hyperechoic dots and lines within the epidermis compatible with hyperkeratosis, engorged varicose veins in the dermis and an anechoic layer interposed between the epidermis and the dermis, corresponding to blister fluid below the calluses. In contrast to PC patients, patients with MDM and EPPK demonstrated no blisters., Conclusion: PC patients, as opposed to a group of patients with MDM and EPPK, displayed subepidermal blistering beneath their calluses. This finding may help in the diagnosis of PC and in partially explaining plantar pain as part of PC symptomatology.

The present study tests the hypothesis that skin on the plantar surface of the foot absorbs oxygen (O(2)) when immersed in water that has a high dissolved O(2) content. Healthy male and female subjects (24.2 ± 1.4 years) soaked each foot in tap water (1.7 ± 0.1 mg O(2)·L(-1); 30.7 ± 0.3 °C) or O(2)-infused water (50.2 ± 1.7 mg O(2)·L(-1); 32.1 ± 0.5 °C) for up to 30 min in 50 different experiments. Transcutaneous oximetry and near infrared spectroscopy were used to evaluate changes in skin PO(2), oxygenated haemoglobin, and cytochrome oxidase aa(3) that resulted from treatment. Compared with the tap water condition, tissue oxygenation index was 3.5% ± 1.3% higher in feet treated for 30 min with O(2)-infused water. This effect persisted after treatment, as skin PO(2) was higher in feet treated with O(2)-infused water at 2 min (237 ± 9 vs. 112 ± 5 mm HG) and 15 min (131 ± 1 vs. 87 ± 4 mm HG) post-treatment. When blood flow to the foot was occluded for 5 min, feet resting in O(2)-infused water maintained a 3-fold higher O(2) consumption rate than feet treated with tap water (9.1 ± 1.4 vs. 3.0 ± 1.0 µL·100 g(-1)·min(-1)). We estimate that skin absorbs 4.5 mL of O(2)·m(-2)·min(-1) from O(2)-infused water. Thus, skin absorbs appreciable amounts of O(2) from O(2)-infused water. This finding may prove useful and assist development of treatments targeting skin diseases with ischemic origin.

Objective: The purpose of this study was to evaluate the influence of monochromatic infrared energy (MIRE) on the microcirculation of the skin surface of the feet in healthy subjects., Background Data: Near-infrared energy was shown to increase microcirculation in an animal study. In humans, only one case study demonstrated that MIRE increases microcirculation in the skin of the lower limbs., Methods: Thirty healthy volunteers were recruited and randomly allocated into three groups to receive either: (1) active MIRE; (2) sham MIRE (placebo group); or (3) warm packs (control group) on the feet. The MIRE device comprised an array of 60 x 890 nm LEDs attached to flexible pads (3×7.5 cm). Each diode spot size was 0.2 cm(2), and each LED power was 12 mW with a power density of 60 mW/cm(2). The arrays were placed in direct contact with the skin for 30 min delivering a total fluence of 108 J/cm(2) over an area of 22.5 cm(2). Capillary blood cell velocity (CBV) and superficial skin blood flow (flux) were recorded before and after intervention., Results: Significant differences among the three groups were recorded in both CBV and flux (both p<0.05). Post-hoc comparisons indicated that a significantly greater increase in both CBV and flux occurred in the active MIRE group than in the placebo group and control group (all p<0.05)., Conclusions: A 30-min MIRE produced a significantly greater increase in the CBV and flux of the feet in the active MIRE group than in the placebo and control groups.

Background: Skin perfusion pressure (SPP) has been shown to be useful in the assessment of the severity of peripheral arterial disease (PAD), and ulcers can be cured when the SPP is ≥30-40 mmHg. The purpose of this study was to determine the best body position for measuring SPP in patients with severe PAD., Methods and Results: We studied 24 limbs of 18 patients with PAD whose SPP was ≤40 mmHg. After patients had been resting supine for 10 min (Position I), their SPP was measured at the dorsum of the foot with a laser Doppler probe. Following measurement in the supine position, SPP was measured in the sitting position after the foot had been extended horizontally for 10 min (Position II), and in the sitting position after the foot had been lowered vertically for 10 min (Position III). SPP increased significantly from Position I to Positions II and III (25.3±10.9 mmHg, 40.6±12.7 mmHg, and 73.4±17.7 mmHg, respectively; P<0.0001). In all patients, SPP values exceeding 30 mmHg were obtained in Position III., Conclusions: The best SPP values were obtained in Position III, which is the ideal position for peripheral arterial circulation in patients with severe PAD.

Neuropathy, peripheral arterial occlusive disease and microvascular disturbances are important factors contributing to foot problems in diabetic patients. In the diabetic foot with ischemia, the alterations in skin microvascular function are pronounced including severely reduced capillary circulation and abolished hyperaemic responses. These microvascular disturbances, which are superimposed on the already existing structural diabetic microangiopathy, are compatible with a state of "chronic capillary ischemia" and an increased shunting of blood through arteriovenous channels. This maldistribution of blood in skin microcirculation is not detected by measurement of peripheral blood pressure (systolic ankle blood pressure, systolic toe blood pressure). As indicated in several studies toe blood pressure is a poor predictor of local tissue perfusion, tissue survival and healing of chronic foot ulcers. Consequently, the disturbances in peripheral tissue perfusion of the diabetic foot may be underestimated leading to delayed vascular interventions and/or medical treatment. Thus, measurements of peripheral blood pressure, e.g. toe blood pressure, should be combined with investigations of local tissue perfusion in order to get an adequate estimation of peripheral tissue perfusion in diabetic patients. For this purpose local skin microcirculation can be investigated by transcutaneous oxygen tension of the forefoot. Also, due to these reasons, the threshold for revascularization should be lower in diabetic patients with foot ulcer.

Objectives: A paucity of data exists regarding manifestations of macro- and microcirculation in contemporary critical limb ischemia (CLI). The aim of this study was (1) to evaluate the differences in foot circulation based on angiographic findings, (2) to clarify the relationship between macro- and microcirculation, and (3) to investigate the effects of postural changes on micro as well as macrocirculation between the supine position to the dependent position., Methods: A total of 40 critically ischemic limbs in 29 patients were included in this study. Noninvasive evaluation of macrocirculation, based on the ankle brachial index (ABI) and ankle pressure, and microcirculation, using skin perfusion pressure (SPP), was performed in both the supine and dependent positions., Results: There was no significant difference in macro- and microcirculations between any angiographical involvements. In the supine position, dorsal SPP correlated significantly with ABI (P = 0.021, r = 0.363) and ankle-pressure (P = 0.001, r = 0.495), whereas plantar SPP failed to correlate with ABI (P = 0.198, r = 0.208) or ankle-pressure (P = 0.185, r = 0.214). In the dependent position, however, SPP showed no significant correlation with ABI and ankle pressure. Postural change from the supine to dependent position yielded a significant increase in SPP (dorsal: 37.2 ± 16.2 to 77.9 ± 17.7 mm Hg, P < 0.001; plantar: 33.6 ± 17.3 to 75.7 ± 18.3 mm Hg, P < 0.001) as well as ABI and ankle-pressure (ABI: 0.70 ± 0.35 to 0.78 ± 0.42, P = 0.003; ankle-pressure; 108 ± 61 to 111 ± 60 mm Hg, P = 0.038). The effect of postural change on SPP showed no difference between patients with and without any clinical and angiographical complications., Conclusions: Of microcirculation assessed, only dorsal SPP correlated significantly with macrocirculation in the supine position. Furthermore, postural change from the supine to dependent position produced a dramatic improvement in microcirculation due to the effects of gravity., (Copyright © 2011 Wiley Periodicals, Inc.)

The aim of this study was to analyze and compare the deterministic nonlinear structure of cutaneous laser Doppler flowmetry signals obtained from the forearm and foot of normal subjects and diabetic patients without neuropathy (D), with peripheral neuropathy (DPN) and with combined autonomic and peripheral neuropathy (DAN). Flow oscillations were evaluated under baseline conditions, after local warming of the skin to 44 °C and after warming plus iontophoresis of phenylephrine. The presence of nonlinearity was investigated by three complementary approaches: (i) attractor reconstruction, (ii) calculation of largest Lyapunov exponents (LLEs), and (iii) correlation dimension analysis. Conclusions were validated against surrogate stochastic time series generated by randomizing the Fourier phase of the raw data. In the control and D groups, the combination of phenylephrine and warming unmasked flowmotion with a prominent component at 0.1 Hz. Attractor reconstruction revealed toroidal structure and estimated LLEs were positive. LLEs decreased to zero and dimension estimates increased for surrogate data, consistent with loss of determinism. In diabetic subjects with neuropathy estimates of LLE were not significantly different from zero and dimensions were unaffected by phase randomization. Evidence for nonlinear structure was also obtained under baseline conditions in normal and D subjects, but was lost on warming alone. We conclude that deterministic control mechanisms contribute to cutaneous flowmotion, particularly when pseudo-quasiperiodic behavior is enhanced by phenylephrine. Nonlinear analysis of laser Doppler signals may provide previously unrecognized insights into the effects of diabetic neuropathy on perfusion because it can identify loss of complexity independently of the amplitude of the signals recorded., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: Difficulty healing wounds and skin defects is a frequent problem in patients on chronic hemodialysis (HD) because of malnutrition, inflammation, and atherosclerosis (MIA) syndrome. The aim of the present study was to estimate the influence of peripheral blood flow changes during HD on the development of foot defects and its relationship to plasma albumin levels., Methods: Peripheral skin blood flow was measured using a laser Doppler line scanner in 10 different areas of the dorsal part of the instep and the toes of each foot before and during HD with ultrafiltration (897 +/- 465 mL/procedure) in 31 HD patients (10 female, 21 male; age 36-79 y, body mass index = 28 +/- 5.0). No skin defects or apparent acute disease or infection were detected in any patient at the time of laser Doppler line scanner measurement. The feet of the patients were clinically re-examined carefully over the next 18 mo., Results: We found a significant and constant decrease of skin blood flow during the HD procedure (P < 0.001). Skin blood flow was significantly correlated with serum albumin level both before HD (r = 0.36, P = 0.05) and during HD (r = 0.47, P = 0.007). Skin defects developed in 11 patients, with significantly lower skin blood flow during the 18-mo follow-up period. A significantly larger number of patients who had normal perfusion remained defect-free in comparison to patients with critical perfusion (93% versus 38%, P = 0.002, Kaplan-Meier analysis)., Conclusion: Skin blood flow may be impaired in HD patients. The apparent malnutrition and inflammation in HD patients are likely responsible for the decreased skin blood flow and the development of the difficulty to heal skin defects and wounds., ((c) 2010 Elsevier Inc. All rights reserved.)

Background: To protect against ischemia, pressure-induced vasodilation (PIV) causes an increase in skin blood flow. Endothelial dysfunction, which is commonly found in older patients and those with diabetes, and global temperatures can affect the resting blood flow in skin, which may reduce the blood flow during and after the application of local pressure. The present study investigated the PIV of the skin with exposure to three global temperatures in younger and older populations and those with diabetes., Materials and Methods: Older subjects (n = 15, mean age 64.2 +/- 14.0 years), subjects with diabetes (n = 15, mean age 62 +/- 5.9 years, mean duration 13.2 +/- 9.1 years), or younger subjects (n = 15, mean age 25.7 +/- 2.9 years) participated. An infrared laser Dopler flow meter was used to measure skin blood flow on the bottom of the foot, lower back, and hand during and after applications of pressure at 7.5, 15, 30, 45, and 60 kPa at 16 degrees C, 24 degrees C, and 32 degrees C global temperatures., Results: The resting blood flow for all subjects was significantly lower in the 16 degrees C environment (P < 0.05). Blood flow in the group with diabetes was significantly lower at rest, during the application of all pressure, and after the release of pressure in all global temperatures (P < 0.05). The younger group showed a significant increase in blood flow after every pressure application, except 7.5 kPa, in all global conditions (P < 0.001). Older subjects and patients with diabetes did not have a significant reactive hyperemia, especially in the 16 degrees C environment., Conclusion: The protective mechanism of PIV is severely reduced in older populations and those with diabetes, especially in colder environments where skin blood flow is already diminished.

Objectives: To investigate the impact of lipid lowering therapy by different means on skin microvascular function in patients with dysglycaemia and coronary artery disease (CAD)., Design and Setting: Thirty-six patients were randomized to simvastatin 80 mg daily (S80, n = 19) or ezetimibe 10 mg and simvastatin 10 mg daily (E10/S10, n = 17) for 6 weeks. Skin microvascular function was assessed by laser Doppler fluxmetry (LDF) at rest, following arterial occlusion (peak postocclusive LDF) and following local heating on the forearm (heat arm LDF) and foot (heat foot LDF). LDF parameters and serum lipids were evaluated at baseline and follow-up., Results: At follow-up, LDL cholesterol had decreased from 3.1 (2.7-3.5) to 1.6 (1.5-1.8) (mmol L(-1)) and 3.0 (2.4-3.9) to 1.3 (1.1-1.8) (mmol L(-1)) in the E10/S10 and S80 groups respectively. In the entire study group (n = 32), LDF parameters increased significantly; postocclusive LDF from 22 (17-27) to 26 (21-32) perfusion units (PU) (P < 0.001), heat foot LDF from 61 (44-82) to 66 (45-83) PU (P < 0.001) and heat arm LDF from 60 (48-121) to 75 (54-125) PU (P < 0.01). The changes in LDF parameters did not differ between the E10/S10 and S80 groups., Conclusions: Lipid lowering improves microvascular function in patients with dysglycaemia and CAD. The data suggest that lipid lowering per se is more important than pleiotropic effects of statins for this effect.

Objectives: Treatment of cutaneous wounds is one of the many applications of hyperbaric oxygen therapy (HBO). However, the complex regulation of skin microcirculation during different phases of HBO is not completely understood. We therefore investigated skin microcirculation and oxygenation during HBO and normobaric oxygen (NBO) exposure., Methods: Seven healthy volunteers were investigated using measurements of transcutaneous oxygen pressure (PtcO2), tissue spectrophotometry and laser Doppler flowmetry recorded simultaneously in the hand and foot during HBO and NBO in 2- and 4-mm depths. We defined tissue hypoxia as a PtcO2 below 30 mmHg., Results: At the hand, in 2 mm depth, NBO induced a mild vasoconstriction (-37%, p=0.07), but a significant increase in PtcO2 (+380%, p<0.001). HBO induced a mild vasoconstriction (-45%, p=0.08), significantly increasing PtcO2 (+1430%, p<0.001). Hand changes in 2 and 4 mm were comparable. Foot changes were smaller than at the hand and more pronounced in 4 mm than in 2 mm depth during NBO and compression. No episodes of tissue hypoxia occurred at any time., Conclusions: In healthy subjects, NBO and especially HBO significantly improve tissue oxygenation, despite vasoconstriction. Differences in vascular regulation between hand and foot and especially at the latter site between 2 and 4 mm depth exist.

The Pennes model predicts the ability of the skin to dissipate heat as a function of conductive heat transfer and blood flow. Conductive heat exchange may be affected by skin moisture and subcutaneous fat thickness, factors not considered by Pennes. In the present investigation, we sought to expand the Pennes model by examining subcutaneous fat and skin moisture as factors of heat dissipation and their effects on heat exchange and blood flow. Subjects who were older (O) (mean age 64.2+/-5.9 years, n=15), had diabetes (D) (mean age 62+/-5.9 years, mean duration 13.2+/-9.1 years, n=15), and were younger (Y) (mean age 25.7+/-2.9 years, n=15) participated. Thermisters were placed in an iron heat probe and on the skin to measure the change in skin temperature to create a thermal change index to demonstrate the ability of the skin to dissipate heat. The lower back had the thickest subcutaneous fat layer for all subjects, which contributed to higher skin temperatures than the foot and hand in response to local and global heat. There was a significant inverse correlation between skin moisture and skin temperature after 5s of heat application (r=-0.73, p<0.001) with O and D having significantly less skin moisture than Y (p<0.05). O and D had significantly increased skin temperatures in response to local heat, as compared to Y, in all global temperatures (p<0.05). Thus, the Pennes model may need to be adjusted to take into consideration aging, diabetes, skin moisture, and subcutaneous fat thickness.

Objective: To determine if videodermatoscopy (VD), by evaluation of superficial vascular patterns, may be helpful in the diagnosis of psoriasis in a series of subjects affected by palmar and/or plantar dermatoses with no readily apparent diagnostic features., Method: Thirty-two subjects (12 male/20 female, mean age 50 years, range 20-72 years) were sequentially enrolled in an open-label study involving a single visit. Inclusion criteria were the presence of clinically nonspecific, active, and untreated palmar and/or plantar erythematous scaly lesions with no other skin involvement. Exclusion criteria were the presence of co-morbid disorders, excessive hyperkeratosis and/or pustular lesions, and the use of systemic and/or topical drugs within 4 and 2 weeks of study entry, respectively. A videodermatoscope equipped with a zoom lens that allowed magnifications from x50 to x200 was used for vascular pattern evaluation. A skin biopsy for hematoxylin and eosin staining was taken from each patient., Results: In 15 subjects, VD examination at magnification x50 showed the presence of pinpoint-like capillaries linearly arranged along the furrows of dermatoglyphics; at magnification x200, the same capillaries appeared to be dilated and tortuous, with a 'bushy' homogeneous aspect in all examined fields, suggesting a diagnosis of psoriasis, as confirmed by histologic examination. In the remaining 17 subjects, no evidence of 'bushy' capillaries was present at magnification x200 VD examination; in these patients, a diagnosis of eczema was established by histology., Conclusion: Although further investigations in larger series are necessary to confirm these findings, and to provide further information about the specificity and sensitivity of the method, our study has indicated that analysis of superficial vascular patterns by VD may represent a promising, non-invasive diagnostic tool in palmar and/or plantar psoriasis.

Background: It is well known that venous drainage of the medial plantar flap is performed by two venous systems: cutaneous veins visible through the skin that drain into the great saphenous vein; and deep veins, namely, accompanying veins of the medial plantar artery. However, there are only a few illustrations of the cutaneous veins of the sole in anatomical textbooks. Further clarification of the cutaneous veins of the sole was considered to be useful information in elevating the medial plantar flap., Methods: Whole-body or local injection with contrast medium was performed in 10 fresh cadavers. The skin and subcutaneous tissue were elevated and radiographed with a soft x-ray system. In an embalmed cadaver, macroscopic observation was performed., Results: In the sole, an intimate venous network was formed by branches of the great saphenous vein, small saphenous vein, and dorsal venous arch. Vascular arrangement of the venous network was not random but characteristic in each region of the sole. In the medial plantar, vessels were arranged toward the anterior margin of the medial malleolus., Conclusion: In planning the medial plantar flap, taking the vascular arrangement into consideration is considered to help the flap to avoid venous congestion and to extend the skin portion.

Aims: Although skin oxygenation is an important factor in the development and healing of foot ulcers, its regulation was not fully understood. We studied changes in foot skin oxygenation and blood flow during postural changes in patients with type 2 diabetes mellitus., Methods: Skin oxygenation was measured using transcutaneous oxygen pressure (TcPO(2)) and skin blood flow by laser Doppler flowmetry in 40 patients with type 2 diabetes mellitus without evidence of peripheral arterial disease and 13 healthy control subjects., Results: TcPO(2) in the supine position was significantly lower in patients with type 2 diabetes mellitus compared with control, although skin blood flow was not different. In the sitting position, TcPO(2) significantly increased in control and diabetic patients. The postural change-related increase in TcPO(2) was significantly enhanced in diabetic patients. On the other hand, skin blood blow significantly decreased in the sitting position from the supine position in control subjects but remained stable in diabetic patients. Orthostatic drop in systolic blood pressure correlated negatively with TcPO(2) in the supine position while correlated positively with %change in TcPO(2) and blood flow by postural changes., Conclusions: The present study demonstrated the dissociated regulation of skin oxygenation and blood flow in response to leg dependency. Impaired postural vasoconstriction was associated with altered regulation of skin oxygenation probably due to sympathetic vascular dysfunction in diabetic patients.

Contrast baths have been used for therapy for over 2,000 years. The basic concept is to alternate warm and cool water baths during a treatment session. It is believed that this will increase circulation better than just placing the limb in a warm water bath. However, there is little supportive evidence for this assertion. Further, for subjects with diabetes, with underlying impairments in their circulation, this may not work at all. Fourteen people with type 2 diabetes were compared to 14 age-matched controls. Skin blood flow of the foot (BF) was measured during 16 minutes of contrast baths at two different intervals: 3 minutes warm and 1 minute cold and 6 minutes warm and 2 minutes cold. In control subjects, warm and cold contrast baths with the ratio 3 minutes warm to 1 minute cold elicited significantly (p < 0.01) greater BF than placing the limb continuously in warm water or using a 6:2 ratio of warm to cold bath time. In control subjects, there was also a greater plantar than dorsal BF. For subjects with diabetes, there was no statistical difference between BF with contrast baths versus warm whirlpool; but in both cases BF was significantly less than that seen in control subjects under similar circumstances. There was also very little difference between BF on the plantar and dorsal aspects of the foot in the subjects with diabetes. Patients with diabetes do not show a vascular response to contrast bath therapy. The BF response to contrast temperatures may be a good diagnostic test for diabetic vascular impairment.

Objectives: To report normal values of skin perfusion in healthy subjects in three age groups using a laser Doppler imager; to determine differences attributable to gender, age, site, and use of red or near-infrared lasers; and to correlate transcutaneous oxygen with laser flux values., Design: Flux and transcutaneous oxygen were measured at ten sites in the lower extremity in 60 subjects from three age groups. Heated and unheated sites were scanned with red and near-infrared lasers., Results: Heat hyperemia was prominent at all sites. Small, statistically significant mean +/- SD differences were found between heated and nonheated sites for the red and near-infrared lasers (P = 0.02). All flux ratios were independent of gender but were higher in the oldest group. Plantar sites demonstrated higher flux in unheated areas and lower flux ratios compared with leg sites. Transcutaneous oxygen did not correlate significantly with flux for either laser type., Conclusions: Scanning laser-Doppler imaging flux values provide a reference for identifying patients at risk for tissue ischemia and poor healing potential caused by impaired circulatory reserve in the legs and distal feet. The lack of correlation between flux and transcutaneous oxygen in healthy individuals suggests that they measure different physiologic processes.

Objective: The pathogenesis of painful diabetic neuropathy (PDN) is not clear. Following our in vivo observations of increased sural nerve epineurial blood flow in patients with PDN, we investigated the cutaneous microcirculation of the foot by laser Doppler flowmetry to determine if the epineurial findings were just confined to the nerve or more widespread in other vascular beds., Research Design and Methods: We measured foot skin vasodilator responses to acetylcholine (Ach) and sodium nitroprusside (SNP) and vasoconstrictor responses to sympathetic (deepest possible gasp) stimulation in 5 healthy control subjects, 10 non-neuropathic diabetic (NND) patients, 10 diabetic patients with painless neuropathy (PLDN), and 8 diabetic patients with PDN., Results: In PDN, there were significantly reduced responses to Ach (ANOVA P = 0.003) and vasoconstrictor inspiratory gasp (ANOVA P < 0.001) but not to SNP (NS). Post hoc analysis showed significant differences in Ach-induced vasodilation between PDN and nondiabetic control subjects (P < 0.05) as well as between PDN and NND (P < 0.05) but not PDN and PLDN (NS). There were no significant differences for SNP-induced vasodilation. However, there were significant differences in the vasoconstrictor response between PDN and control, NND, and PLDN (P < 0.01)., Conclusions: We found an impairment of cutaneous endothelium-related vasodilation and C-fiber-mediated vasoconstriction in PDN. Inappropriate local blood flow regulation may have a role in the pathogenesis of pain in diabetic neuropathy. Prospective studies are required to determine the temporal relationship of these changes in relation to the emergence of neuropathic pain.

Objective: Peripheral arterial occlusive disease and peripheral neuropathy are major risk factors in diabetic foot disease. We evaluated the relative influences of noncritical lower limb arterial disease and peripheral neuropathy on cutaneous foot perfusion in diabetes., Method: Toe-brachial pressure indices, transcutaneous oxygen, and carbon dioxide tensions at foot and chest sites were measured in individuals with diabetes, with or without detectable peripheral neuropathy and with or without significant arterial disease on color duplex imaging. Subjects without diabetes, with and without arterial disease, were used as controls., Results: A total of 130 limbs were studied during an 8-month period. Toe-brachial pressure indices reflected the presence of arterial disease in all groups. Foot transcutaneous oxygen values were reduced in diabetes and correlated with chest transcutaneous oxygen values. Low foot transcutaneous oxygen with elevated transcutaneous carbon dioxide values were only demonstrated in individuals with diabetes, arterial disease, and peripheral neuropathy. Toe-brachial pressure indices demonstrated a positive correlation with foot transcutaneous oxygen values, but values >1.2 demonstrated a negative correlation., Conclusions: We demonstrated two influences on cutaneous foot perfusion in diabetes: (1) a global microcirculatory dysfunction, reflected in low chest and foot transcutaneous oxygen values, and (2) macrovascular disease as indicated by reduced toe-brachial pressure indices and foot transcutaneous oxygen values. Further, the results demonstrated that in diabetic individuals without critical limb ischemia, impaired foot perfusion secondary to arterial disease is amplified significantly by coexisting microcirculatory disease.

The concept of microcirculation being implicated in the pathogenesis of diabetic foot disease is being challenged by evidence that fails to confirm it. However, there is evidence of structural changes with capillary and in the basement membrane that do not permit the concept to be denied either. The lack of evidence should not be a reason to argue against surgery in the diabetic foot.

1. This study investigated a local effect of cooling on the plantar skin blood flow (PSBF) of tetrodotoxin-treated rats by laser-Doppler flowmetry. 2. When the air temperature around the left foot was locally cooled from 25 to 10 degrees C, the PSBF of the left foot decreased. 3. The response was inhibited by the alpha-adrenoceptor antagonist phentolamine, the alpha1-adrenoceptor antagonist bunazosin, the alpha2-adrenoceptor antagonist RS79948, and bretylium and guanethidine that inhibit noradrenaline release from sympathetic nerves. Adrenalectomy of the rats did not affect the cooling-induced response. 4. The P2 purinoceptor antagonists suramin and PPADS also significantly suppressed the cooling-induced reduction of PSBF. However, the inhibitory effect of PPADS on the cooling-induced response was abolished after the treatment with phentolamine. Intra-arterial injections of ATPgammaS, a stable P2 purinoceptor agonist, at 25 degrees C caused a transient decrease in PSBF in a dose-dependent manner, which was significantly inhibited by phentolamine and guanethidine. 5. These results suggest a novel mechanism for local cooling-induced reduction of skin blood flow in vivo; moderate cooling of the skin induces the release of ATP, which stimulates presynaptic P2 purinoceptors on sympathetic nerve terminals and facilitates the release of noradrenaline, thereby causing contractions of skin blood vessels via the activation of alpha1-and alpha2-adrenoceptors.

A positive association has previously been demonstrated between chronic aerobic exercise and prior maximal exercise and enhanced dorsal foot skin perfusion in physically active individuals with type 2 diabetes. The current study examined whether an 8-week resistance training program would also positively affect cutaneous perfusion in type 2 diabetic individuals. Ten individuals with type 2 diabetes and nine similar nondiabetic controls participated in 8 weeks of moderate-intensity resistance training. Prior to training, dorsal foot cutaneous perfusion was measured noninvasively by continuous laser Doppler assessment at baseline and during localized heating to 44 degrees C. These measurements were repeated exactly 48-72 h following 8 weeks of resistance training performed 3 days per week. Interstitial nitric oxide (NO) levels were measured concurrently in the contralateral foot dorsum. Neither subject group experienced significant increases in dorsal foot perfusion responsiveness during local heating to 44 degrees C following moderate resistance training, nor did the training significantly enhance baseline skin perfusion. Interstitial NO levels were not significantly different under any condition. At baseline, groups differed only on fasting serum glucose and overall glycemic control. In conclusion, the responsiveness of cutaneous perfusion in response to heating to 44 degrees C is not significantly enhanced by 8 weeks of moderate resistance training in diabetic individuals or their matched controls, independent of interstitial NO levels.

Unlabelled: Plasma extravasation (PE) can be triggered by neurotransmitters as part of a neuroinflammatory response. We present a technique based on video digital image processing that provides a simple, noninvasive, reliable, and quantitative method for measuring the time course and extent of PE in the skin. After intravenous infusion of Evans Blue dye, stimulation of the saphenous nerve caused the skin on the dorsomedial region of the hind paw to become dark blue. The change in reflectance of the skin was recorded with a monochrome video camera. Images were digitized and analyzed with inexpensive or public domain software. The change in pixel intensity was determined in a selected region. Stimulation at 4 Hz caused greater darkening of the skin than at 1 Hz, and this was confirmed with spectrophotometric measurements of Evans Blue content. The NK1 receptor antagonist CP-99, 994 blocked saphenous nerve and substance P-induced darkening of the skin. The results indicate that our measurement gives results similar to those obtained with classic methods that are widely accepted as an indication of PE. This simple and quick method reveals the extent, time course, and location of PE, is cheap to implement and easy to learn, and thus represents a useful and alternative tool for studies of PE and its modulation., Perspective: This article presents a simple technique with which to evaluate the time course and extent of plasma extravasation in the skin of animal models of neuroinflammation. The technique is well suited to answer questions about basic physiologic mechanisms of neuroinflammation and should also be useful in drug testing studies.

The aim of this study was to investigate patients with non-insulin dependent diabetes by laser Doppler flowmetry in order to assess changes in the peripheral flow regulation during hemodynamic tests as evidence of the impaired auto-regulation of the microcirculation. Two groups of subjects were included in the study. The first group included 12 diabetic patients with electromyographical signs of neuropathy and without peripheral arterial occlusive disease, while the second (control) group included 12 healthy subjects. Microcirculation investigations were carried out at rest and after hemodynamic tests. Blood flow was measured using a laser Doppler flowmetry. Changes in the flow minus the "biological zero" value were measured after 3 minutes of artificial arterial occlusion, after deep inspiration and by experimental venous hypertension (40 and 70 mm Hg), which was used to provoke the venoarteriolar reflex. The resting flow was significantly higher in diabetic patients compared to the healthy subjects (p < 0.01). The vasoconstrictor response to the deep inspiration and experimental venous hypertension, cuff pressure 40 mm Hg, was significantly impaired in diabetic patients as compared to the healthy subjects (p < 0.001 vs. p < 0.05). The maximal hyperemia after artificial arterial occlusion was significantly reduced in diabetic patients in comparison with the healthy controls (p < 0.01). Laser Doppler flowmetry provides a non-invasive means for evaluating microcirculating disturbances in diabetes, long before the initial clinical presentation of peripheral arterial occlusive disease or diabetic foot.

Background: While wounds heal more quickly when electrical stimulation (ES) is applied, few studies have examined blood flow (BF) in and around wounds during ES in controls with no wounds compared to wounds in diabetic and non diabetic subjects., Material/methods: Ten subjects with stage III and IV wounds and 8 controls were subjected to 5 minutes of biphasic ES (20 milliamps, pulse width 250 usec). Before, during, and after, BF were measured by a Laser Doppler Imager., Results: For the control subjects, in the fingers, BF increased from 307 flux to 687 after 5 min of ES to one finger but BF also increased to other fingers indicating a reflex increase in flow mediated by the sympathetic nervous system. For hairy skin, there was a 12% increase in BF with ES and only in the line directly between the stimulating electrodes. For the patients (either with or without Type 2 diabetes), stimulation in the hand, leg and foot all caused a large increase in BF during and for 5 minutes after stimulation. In patients, BF was high in the wound area before ES and increased by 53% during, and remained high after stimulation was over., Conclusions: The results show that in wounds, where BF is high due to bradykinin and cytokine release, the vasoconstrictor tone is not present and electrical stimulation causes a large increase in circulation which lasts after stimulation is over.

Objective: Tissue oxygen supply is crucial for wound healing. Especially in diabetic foot lesions, the chances for healing are mainly dependent on the presence or absence of ischemia. This study investigates the impact of the tissue O2 analysis system "O2C" for noninvasive quantification of tissue oxygenation in diabetic foot ulcer patients., Research Design and Methods: O2C assessed relative blood flow (flow), flow velocity (velo), and hemoglobin concentration (rHb) and hemoglobin oxygenation (SO2) at 2 and 6 mm depth (means +/- SE). 1) Measurements were performed on intact skin of the forefoot and forearm of 20 healthy volunteers on 2 consecutive days. 2) Parameters were assessed on intact skin of the forefoot of diabetic foot ulcer patients (n=14). 3) Measurements were performed directly at the wound site in diabetic patients (n = 14)., Results: 1) Flow, velo, rHb, and SO2 at 2 and 6 mm depth were not significantly different when measured at 2 consecutive days. 2) There were no significant differences between diabetic subjects and healthy volunteers. Only flow in 6 mm depth was significantly higher in diabetic subjects (75 +/- 13 vs. 51 +/- 0.4 arbitrary units [AU], P <0.05). When diabetic foot ulcer patients were split into healers and nonhealers, initial readings of SO2 at 2 mm (32 +/- 6 vs. 44 +/- 3%, P <0.05) and flow in 6 mm (28 +/- 1 vs. 51 +/- 0.6 AU, P <0.05) were significantly reduced in nonhealers compared with control subjects, whereas in healers flow in 6 mm (70 +/- 0.6 vs. 51 +/- 0.6 AU, P <0.05) was significantly higher than that in control subjects. 3) Initial SO2, rHb, flow, and velo were significantly lower in nonhealing compared with healing wounds., Conclusions: O2C is a new reliable and valid method for noninvasive measurement of tissue oxygenation and microvascular blood flow in patients with diabetic foot ulcers.

Vascular and neurological mechanisms are both likely to be involved in foot ulcer. We recently reported a pressure-induced vasodilation (PIV), relying on unmyelinated afferent excitation. We previously found that cutaneous blood flow in response to locally applied pressure might be impaired in diabetic patients because of the combined effects of low cutaneous temperature and alterations in microcirculatory function. Therefore, we aimed to analyze whether, at a relatively high cutaneous temperature, PIV is present in type 1 diabetes and to assess endothelial-dependent vasodilation and endothelium-independent vasodilation. We measured cutaneous blood flow using laser Doppler flowmetry on the head of the first metatarsus in response to applied pressure at 5.0 mmHg/min in warm conditions (29.5 +/- 0.2 degrees C). Responses to iontophoresis of acetylcholine (endothelium dependent) and sodium nitroprusside (endothelium independent) were measured using laser Doppler flowmetry in the forearm. The data indicate that PIV exists at the foot level in normal subjects, whereas it was not found in diabetic patients. In diabetic patients, the nonendothelial-mediated response to sodium nitroprusside was preserved, whereas the endothelial-mediated response to acetylcholine was impaired. These findings might be relevant to the high prevalence of foot ulcer that occurs in diabetic patients.

A pressure-induced vasodilation (PIV) was recently reported as a putative protective response in human skin. Therefore, we examined the influence of skin temperatures on cutaneous blood flow responses to local progressive pressure strain. Ten healthy volunteers were studied at different ambient temperatures leading to low (29.0 +/- 0.3 degrees C), intermediate (32.6 +/- 0.1 degrees C), high (33.9 +/- 0.1 degrees C) and very high (36.0 +/- 0.1 degrees C) skin temperatures. We measured cutaneous blood flow using laser Doppler flowmetry on the foot in response to a local progressive pressure increase of 5.0 mm Hg min(-1). Progressive pressure strain led to an almost linear cutaneous laser Doppler flow decrease at both low and intermediate skin temperatures (-40.1 +/- 6.6% and -31.2 +/- 6.5% from baseline at 30 +/- 1.25 mm Hg), whereas at both high and very high skin temperatures, subjects responded with a transient cutaneous vasodilation (+33.6 +/- 10.6% and +50.6 +/- 15.4% from baseline at 30 +/- 1.25 mm Hg). These findings suggest that high skin temperatures are required for the PIV to develop.

In a recent study, we have demonstrated that the dorsal root reflex (DRR)-mediated acute cutaneous neurogenic inflammation following intradermal injection of capsaicin (CAP) is sympathetically dependent and subject to modulation by peripheral alpha(1)-adrenoceptors. Postganglionic sympathetic neurons contain not only adrenergic neurotransmitters, but also non-adrenergic substances, including neuropeptide Y (NPY). In this study, we examined if peripheral NPY receptors participate in the flare following CAP injection. Different NPY receptor subtypes were studied by using relatively specific agonists and antagonists for the Y(1) and Y(2) subtypes. Changes in cutaneous blood flow on the plantar surface of the foot were measured using a laser Doppler flowmeter. Following CAP injection, cutaneous flare spread more than 20 mm away from the site of CAP injection. Removal of the postganglionic sympathetic nerves by surgical sympathectomy reduced dramatically the CAP-evoked flare. If the foot of sympathectomized rats was pretreated with either NPY or Y(2) receptor agonists by intra-arterial injection, the spread of flare induced by CAP injection could be restored and prolonged. However, if the spinal cord was pretreated with a GABA(A) receptor antagonist, bicuculline, to prevent DRRs, NPY or an Y(2) receptor agonist no longer restored the CAP-evoked flare. A Y(1) receptor agonist did not affect the CAP-evoked flare in sympathectomized rats. In sympathetically intact rats, blockade of either peripheral NPY or Y(2) receptors with [D-Trp(32)]-NPY or BIIE0246 markedly reduced the flare induced by CAP injection, whereas blockade of peripheral Y(1) receptors by BIBP3226 did not obviously affect the flare. It is suggested that NPY is co-released with NE from the postganglionic sympathetic terminals to activate NPY Y(2) and alpha(1) receptors following CAP injection. Both substances are involved, at least in part, in modulation of the responses of CAP sensitive afferents thereby affecting their ability to evoke the release of inflammatory agents from primary afferents.

Aim: Vasogen's immune modulation therapy (IMT)* involves the ex vivo exposure of a sample of autologous blood to 3 oxidative stress factors (heat, an oxidative environment, and ultraviolet light), followed by intramuscular re-injection. The primary objective of this study was to assess the effect of Vasogen's IMT on skin blood flow in patients with symptomatic peripheral arterial occlusive disease (PAOD)., Methods: In a double-blind, placebo-controlled pilot study, 18 patients with moderately advanced PAOD were randomized to receive 2 courses each of 6 intramuscular injections of either saline or Vasogen's IMT over a 9-week period. Dorsal foot skin blood flow was assessed directly using laser Doppler fluxmetry (LDF) and indirectly using measurement of transcutaneous pO(2) (tcpO(2)). Key outcome measures of skin blood flow were, for LDF: resting values, peak postischemic values, and the total time to reach peak values following release from 4 min of total foot ischemia and, for tcpO(2): resting values and the time for tcpO(2) to reach 50% of the pre-ischemia value. Measurements were carried out at baseline, at weeks 3, 6, and 9, and at 2 months post-therapy., Results: No significant differences were detected between groups for resting or peak postischemic LDF values for dorsal foot skin blood flow. Patients randomised to IMT experienced a progressive decrease in the time to peak postischemic skin blood flow, reaching statistical significance at 2 months. Treated patients experienced a 26.1 s decrease in time to peak blood flow (p=0.026) vs a 7.9 s decrease in the placebo group (p=ns). Similar but less striking results were achieved for tcpO(2) recovery time to 50% of pre-ischemia values (treated group, p=0.035; placebo group, p=ns)., Conclusion: Vasogen's IMT improved recovery rates of postischemic dorsal foot skin blood flow in a group of patients with moderately advanced PAOD, probably due to improved endothelial function.

The sensitive and autonomic innervation of foot pads in the ostrich was studied employing an usual histological technique as hematoxylin-eosin or different gold chloride impregnations. The autonomic innervation is represented by isolated or grouped ganglion cells located along the course of nerve bundles. The sensitive somatic innervation is composed by free and capsulated nerve endings usually distributed in the thickness of the connective arrangement of the foot pads, in the most superficial part the first one, while the latter was generally located close to the blood vessels. The capsulated nerve endings, morphologically classified as Pacini, Pacini-like and Herbst corpuscles, show the typical structure. They are not uniformly distributed throughout the considered districts and their number are always higher in the plantar pad compared with digital pads. These corpuscles could be found isolated or assembled to organize simple flower-sprays and to constitute opposito-polar corpuscles. The Authors have put forward a hypothesis on the possible functional role of the above-mentioned nerve components.

Low-intensity laser irradiation has been shown to induce wound healing in conditions of reduced microcirculation, which is in part explained by systemic effects. We therefore investigated such a potential systemic effect of low-intensity laser irradiation on skin blood circulation in patients with diabetic microangiopathy. Patients with diabetic microangiopathy were randomized to receive either a single helium-neon (HeNe, 632.8 nm) low-intensity laser irradiation with a dose of 30 J/cm(2) or a sham irradiation over the forefoot region in a double-blind, placebo-controlled clinical study. Skin blood circulation by means of temperature recordings over forefoot regions was detected by infrared thermography. Following a single transcutaneous low-intensity laser irradiation, a rise in skin temperature in both feet of the subjects in the laser group was noted, whereas in both feet of the subjects in the placebo group a drop in skin temperature occurred. The baseline-adjusted skin temperature 15 min after the end of the irradiation was significantly higher in the laser-treated forefeet compared to the placebo-"treated" forefeet (p < 0.0001); the baseline-adjusted difference in the temperature was 1.94 +/- 0.35 degrees C. Simultaneously, the baseline-adjusted skin temperature was significantly higher in the laser-untreated forefeet compared to the placebo-"untreated" forefeet (P < 0.0001); the baseline-adjusted difference was 1.70 +/- 0.33 degrees C. Our data show a significant increase in skin circulation due to athermic laser irradiation in patients with diabetic microangiopathy and point to the possibility of inducing systemic effects.