Corinna Wicke

Fetuin-A Induces Cytokine Expression and Suppresses Adiponectin Production

Background The secreted liver protein fetuin-A (AHSG) is up-regulated in hepatic steatosis and the metabolic syndrome. These states are strongly associated with low-grade inflammation and hypoadiponectinemia. We, therefore, hypothesized that fetuin-A may play a role in the regulation of cytokine expression, the modulation of adipose tissue expression and plasma concentration of the insulin-sensitizing and atheroprotective adipokine adiponectin. Methodology and Principal Findings Human monocytic THP1 cells and human in vitro differenttiated adipocytes as well as C57BL/6 mice were treated with fetuin-A. mRNA expression of the genes encoding inflammatory cytokines and the adipokine adiponectin (ADIPOQ) was assessed by real-time RT-PCR. In 122 subjects, plasma levels of fetuin-A, adiponectin and, in a subgroup, the multimeric forms of adiponectin were determined. Fetuin-A treatment induced TNF and IL1B mRNA expression in THP1 cells (p<0.05). Treatment of mice with fetuin-A, analogously, resulted in a marked increase in adipose tissue Tnf mRNA as well as Il6 expression (27- and 174-fold, respectively). These effects were accompanied by a decrease in adipose tissue Adipoq mRNA expression and lower circulating adiponectin levels (p<0.05, both). Furthermore, fetuin-A repressed ADIPOQ mRNA expression of human in vitro differentiated adipocytes (p<0.02) and induced inflammatory cytokine expression. In humans in plasma, fetuin-A correlated positively with high-sensitivity C-reactive protein, a marker of subclinical inflammation (r = 0.26, p = 0.01), and negatively with total- (r = −0.28, p = 0.02) and, particularly, high molecular weight adiponectin (r = −0.36, p = 0.01). Conclusions and Significance We provide novel evidence that the secreted liver protein fetuin-A induces low-grade inflammation and represses adiponectin production in animals and in humans. These data suggest an important role of fatty liver in the pathophysiology of insulin resistance and atherosclerosis.

Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing

For many years, lactate has been known to accelerate collagen deposition in cultured fibroblasts and, without detailed explanation, has been presumed to stimulate angiogenesis. Similarly, hypoxia has been linked to angiogenic effects and collagen deposition from cultured cells. Paradoxically, however, wound angiogenesis and collagen deposition are increased by breathing oxygen and decreased by hypoxia. Lactate accumulates to 4–12 mM in wounds for several reasons, only one of which is the result of hypoxia. Oxygen in wounds is usually low but can be increased by breathing oxygen (without change in lactate). We have reported that lactate elicits vascular endothelial growth factor (VECF) from macrophages, as well as collagen, some heat shock proteins, and VECF from endothelial cells, and collagen from fibroblasts, even in the presence of normal amounts of oxygen. Hypoxia exerts many of these same effects in cultured cells. In this study, we elevated extracellular lactate in wounds by implanting purified solid‐state, hydrolysable polyglycolide. A steady‐state 2–3 mM additional elevation of lactate resulted. With it, there was a significant short‐term elevation of interleukin‐1β, a long‐term elevation of VECF (2×) and transforming growth factor‐β1 (2–3×), a 50% elevation in collagen deposition, and a large reduction of insulin‐like growth factor‐1 (− 90%). We propose that lactate induces a biochemical “perception” of hypoxia and instigates several signals that activate growth factor/cytokine signals while the continued presence of molecular oxygen allows endothelial cells and fibroblasts to reproduce and deposit collagen. The data are consistent with ADP‐ribosylation effects and oxidant signaling. (WOUND REP REG 2003;11:504–509)

A new wound-based severity score for diabetic foot ulcers: A prospective analysis of 1,000 patients.

OBJECTIVE—Several well-accepted classification systems are available for diabetic foot ulcers. However, there are only a few and scientifically not validated severity scores. The aim of this study was to establish a new wound-based clinical scoring system for diabetic foot ulcers suitable for daily clinical practice anticipating chances for healing and risk of amputation. RESEARCH DESIGN AND METHODS—Four clinically defined parameters, namely palpable pedal pulses, probing to bone, ulcer location, and presence of multiple ulcerations, were prospectively assessed in 1,000 consecutive patients. In the next step, a new diabetic ulcer severity score (DUSS) was created from these parameters. Palpable pedal pulses were categorized by the absence (scored as 1) or presence (scored as 0) of pedal pulses, while probing to bone was defined as yes (scored as 1) or no (scored as 0). The site of ulceration was defined as toe (scored as 0) or foot (scored as 1) ulcer. Patients with multiple ulcerations were graded as 1 compared with those with single ulcers (scored as 0). The DUSS was calculated by adding these separate gradings to a theoretical maximum of 4. Wounds were followed-up for 365 days or until healing or amputation if earlier. Probability of healing and risk of amputation were calculated by the Kaplan-Meier method. RESULTS—Uni- and multivariate analyses showed a significantly higher probability of healing for patients with palpable pulses, no probing to bone, toe ulcers, and absence of multiple ulcerations. When patients were divided into subgroups with the same DUSS, we found significantly different probabilities for healing. We showed a decreasing probability of healing for ulcers with a high DUSS, concurrent with increasing amputation rates. An increase in the DUSS by one score point reduced the chance for healing by 35%. Similarly, the higher the ulcer score, the larger the initial wound area, the longer the wound history, and the more likely the need for surgery or hospitalization. CONCLUSIONS—The DUSS categorizes different ulcers into subgroups with specific severity and similar clinical outcome. Using this score, the probabilities for healing, amputation, need for surgery, and hospitalization are predictable with high accuracy. This might be useful for the anticipation of health care costs and for comparison of subgroups of patients in clinical studies.

Treatment of periprosthetic soft tissue infection of the groin following vascular surgical procedures by means of a polyvinyl alcohol-vacuum sponge system

Deep groin infections after prosthetic vascular surgical procedures represent a serious complication of surgical practice. Septicemia and/or erosive hemorrhage can both be consequences. In this situation, removal of the graft appears to be the only option. However, if the infection is detected early (type Szilagyi III), local treatment to eradicate the infection could serve as an alternative. Twenty‐four patients with confirmed infection of the soft tissue adjacent to the prosthetic material in the groin were treated locally by implantation of a vacuum sponge system. Duration of this treatment was 2 weeks. All patients showed excellent tissue granulation of the wound area and the microbial stains were negative at the end of therapy. In 21 patients the wound could be primarily closed after explantation of the sponge. Three patients underwent open treatment because of a skin defect. After 12 months, the wounds had healed well in all patients. Histologic evaluation revealed a physiological healing process. Deep soft tissue infections of the groin adjacent to prosthetic vascular material (type Szilagyi III) can be treated effectively and safely with the vacuum sponge system. The treatment is inexpensive, easy to perform, and the initial vascular reconstruction can be preserved. (WOUND REP REG 2003;11:104–109)

Examination of expanded polytetrafluoroethylene wound healing models.

The object of this animal study was to examine and further develop the expanded polytetrafluoroethylene wound healing model. The goal was to increase its potential for assessing wound healing by increasing yield, reducing variability, establishing the elements of a standard technique, and further testing its ability to detect variations of healing which have clinical significance. Expanded polytetrafluoroethylene implants of various dimensions and fabrications and several implantation and sterilization techniques were compared in rats. Hydroxyproline, DNA, and protein deposition into the expanded polytetrafluoroethylene implants as parameters for wound healing were assessed. Additionally, a 4 cm skin incision for tensile strength assessment was created. Wound healing was assessed under normal and corticosteroid‐impaired healing conditions. The highest yield of collagen was found in the stiffer fabrication of expanded polytetrafluoroethylene with the larger pore size and after the more traumatic implantation technique of incisional placement. Variability was unaffected by fabrication, implantation technique, indexing by various geometric dimensions of the implant, sterilization, or sampling techniques. Variability was the same in the individual animals as in groups of animals. The expanded polytetrafluoroethylene method also detects the influence of antiinflammatory corticosteroids and reflects the tensile strength of incisional wounds made in other sites in the same animal.

M.A.I.D.: a prognostic score estimating probability of healing in chronic lower extremity wounds.

Objective:To evaluate a wound-based prognostic score for chronic lower extremity wounds suitable for daily routine use capable of predicting long-term healing. Summary Background Data:The main obstacle in the treatment of chronic wounds is to estimate long-term clinical outcome. For diabetic foot ulcers, several ulcer, and nonulcer-related risk factors associated with impaired healing have been described in the past. Methods:A new chronic lower extremity ulcer score (M.A.I.D.) was created out of 4 clinically defined parameters, namely palpable pedal pulses (I), wound area (A), ulcer duration (D), and presence of multiple ulcerations (M). Palpable pedal pulses were categorized by the absence (scored as 1) or presence (scored as 0) of pedal pulses, while wounds >4 cm2 were scored as 1 and wounds ≤4 cm2 as 0. Ulcers lasting more than 130 days were categorized as 1 and wounds with a duration of <130 days as 0. Patients with multiple ulcerations were graded as 1 (=1) compared with those with single ulcers (=0). M.A.I.D. was calculated by adding these separate scores to a theoretical maximum of 4. Results:Two thousand nineteen consecutive patients with 4004 wounds were included. When patients were divided into subgroups with the same M.A.I.D., we showed a decreasing probability of healing for ulcers with higher M.A.I.D. scores. An increase in the M.A.I.D. by 1 score-point reduced the chance for healing by 37%. Similarly, the higher the ulcer score, the larger the initial wound area, the longer the wound history, and the more likely the occurrence of soft-tissue infection during follow-up. Conclusions:This new chronic lower extremity ulcer score is capable of anticipating long-term probability of healing by combining 4 clinically assessable parameters. However, adequate and standardized wound care is an indispensable prerequisite for M.A.I.D. to be a valid diagnostic tool in daily clinical routine.

Age‐dependency of insulin‐like growth factors, insulin‐like growth factor–binding proteins, and acid labile subunit in plasma and wounds of surgical patients

Wound problems are common in the elderly. We hypothesized that age‐related decrements in blood levels of components of the insulin‐like growth factor (IGF) system are reflected in the wound environment. In this prospective, observational study IGF‐I, IGF‐II, IGF‐binding protein‐2, IGF‐binding protein‐3, and acid labile subunit were measured by immunoassays in the wound fluid and plasma of young (23.5 ± 3.3 years) and elderly (78.9 ± 6.2 years) patients before and daily for 4 days after elective surgery. IGFs, IGFBP‐3, and acid labile subunit in plasma were significantly lower in the elderly group (p < 0.0001). The decrements of these proteins in plasma were reflected in corresponding decrements of 25–70% in the wound fluid of elderly patients (p < 0.0001). Additionally, bioavailability of IGF‐I was less in the aged. The IGF parameters in the wound displayed a constant ratio with those of blood, suggesting that blood contributes a major share of the IGF that enters the wound during the initial phase of healing. The current data adds to accumulating evidence that a decline in the IGF system in aged patients contributes to the healing deficits observed in the elderly. (WOUND REP REG 2002;10:360–365)