Diabetisches Fußsyndrom

Die Diabetologie - Das diabetische Fußsyndrom ist eine klassisch interdisziplinär zu behandelnde Erkrankung. Ursächlich spielt die Triopathie von Ischämie, Neuropathie und...     

Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients

AIMS/HYPOTHESIS: The molecular factors that cause an acute wound in diabetic patients to become chronic have not yet been established. Wound healing is known to require a balance between the accumulation of collagenous and non-collagenous extracellular matrix components and their remodelling by matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). Our aim was to assess if the concentrations of MMPs and TIMPs were different between acute and chronic wounds in diabetic patients by analysing biopsy samples. METHODS: A 5 mm punch biopsy was taken from 20 diabetic foot ulcers of patients before initiating treatment and from traumatic wounds of 12 non-diabetic patients 2 days after injury. The concentrations of MMP-1, MMP-2(pro), MMP-2(active), MMP-8, MMP-9 and TIMP-2 were measured in detergent extracts of the biopsy homogenates using ELISAs and gelatin-zymography. RESULTS: The concentration of MMP-1 was increased 65-fold in biopsies of diabetic foot ulcers compared with the concentrations measured in biopsies of traumatic wounds. Similarly, MMP-2(pro) were increased threefold, sixfold for MMP-2(active), twofold for MMP-8 and 14-fold for MMP-9 compared to average concentrations in biopsies of traumatic wounds. Furthermore, the expression of TIMP-2 was reduced twofold in diabetic wounds compared with lesions of non-diabetic patients. CONCLUSION/INTERPRETATION: The combination of increased concentrations of MMPs with decreased concentrations of TIMP-2 in chronic diabetic foot ulcers compared with healing wounds in normal patients suggests that the increased proteolytic environment contributes to the failure of diabetic wounds to heal. New treatment strategies for healing chronic diabetic foot ulcers could be directed towards reducing concentrations of MMPs and increasing levels of TIMPs.     

Das diabetische Fu?syndrom

Diabetic foot ulceration is a serious complication of diabetes mellitus worldwide and the most common cause of hospitalization in diabetic patients. The etiology of diabetic foot ulcerations is complex due to their multifactorial nature. The pathophysiologies of diabetic foot ulceration with polyneuropathy and angiopathy as well as wound-healing impairment in patients with diabetes mellitus are important. Proper adherence to standard treatment strategies and interdisciplinary cooperation can reduce the--compared with European data--noticeably higher rates of major amputations in Germany.     

Differential effects of PDGF-BB on matrix metalloproteases and cytokine release in fibroblasts of Type 2 diabetic patients and normal controls in vitro

AIMS/HYPOTHESIS: The complex process of wound healing is regulated by various growth factors. The systemic character of diabetes mellitus favors the chronification of diabetic wounds. In this study, the in vitro effects of platelet-derived growth factor (PDGF)-BB on the expression of cytokines and matrix metalloproteases (MMPs) in fibroblasts of Type 2 diabetic patients and healthy controls were investigated. METHODS: We studied six Type 2 diabetic patients (mean Hba1(c)=7.5%) and six healthy controls. For proliferation studies, cultivated fibroblasts, prepared from biopsies taken from the thigh, were stimulated with different concentrations of PDGF. After 48 h, the expression of MMPs and cytokines was measured. We analysed the mRNA expression by RT-PCR (TaqMan), tissue protein levels by zymography, and cell supernatant levels by ELISA. RESULTS: Levels of MMP-mRNA were elevated in diabetic fibroblasts compared with healthy controls. At baseline, MMP-2 protein levels were significantly increased in the fibroblast of diabetic patients (P=.019). For MMP-9, a trend towards higher levels (P=.3) was found. After incubation with PDGF, a significant reduction of MMP-9 (P=.01) and MMP-13 (P=.04) was found. Analysis of cytokine release in cell culture supernatant showed elevated levels of interleukin (IL)-8 at baseline conditions. MMP-1 and MMP-2 levels in the supernatant were concentration-dependently reduced. CONCLUSIONS: This study, for the first time, demonstrates elevated MMPs in cultivated fibroblasts (derived from intact skin and not from an open wound) of diabetic patients compared with healthy controls under in vitro conditions. Therefore, our data support the hypothesis of alterations of wound healing in diabetic patients on the cellular level, reflecting the systemic character of the disease.     

Peripheral Osteopenia in Adult Patients with Insulin-dependent Diabetes Mellitus

Alterations in bone metabolism in diabetes mellitus is a topic of special interest. Bone blood flow is increased in the distal limb of diabetic patients, which is believed to increase osteoclastic activity. We measured bone mineral density using dual-photon absorptiometry in the distal lower limb, the femoral neck, and the lumbar spine in 41 IDDM patients and in 30 control persons, In the diabetic group there was a 10 % reduction of bone mineral density in the femoral neck (p < 0.01) and a 12 % reduction in the distal limb (p < 0.001) compared with the control group. No significant difference was found in the lumbar spine (p = 0.22). Our data yield incidence for peripheral osteopenia in IDDM-patients, independent of any systemic bone diseases such as osteoporosis. A link between decreased bone mineral density and diabetic neuropathy has been observed for the femoral neck (p < 0.001), but not for the distal limb or axial skeleton. Whether there is a common aetiological link or a causal connection between diabetic neuropathy and bone mineral density has still to be determined.     

Recombinants of influenza virus type B as potential live vaccine candidates: RNA characterization and evaluation in man.

Two recombinants (R22 and R75) of the attenuated B/USSR/69 strain Bright and the virulent B/Hong Kong/5/72 and one recombinant (R5) of Bright and the virulent B/Hong Kong /8/73 were selected for genotypic and phenotypic caracterization. All three recombinants had the growth property of the attenuated parent Brigit. Analysis of their RNA''s by polyacrylamide gel electrophoresis revealed that, the strains R22 and R75 had derived all their genes from Brigit, those coding for haemagglutinin excepted. These recombinants were clinically evaluated and found to be attenuated and immunogenic. The recombinant R5 which derived, besides the bene coding for the haemagglutinin, several other genes from B/Hong Kong/8/73 was only partly attenuated since it induced influenza-like symptoms in one out of three volunteers. It is concluded that the strain Brigit can be used as a donor of genes for the attenuation of the B/Hong Kong/5/72 virus and that recombinants of influenza type B can be identified, like influenza type A recombinants, by their RNA pattern.     

Laboratory characteristics of an attenuated influenza type A (H3N2) virus ('Alice' strain).

The Alice strain of live attenuated influenza virus was obtained by selection of a gamma inhibitor-resistant strain from a virus recombinant between A/PR/8/34 (HON1) and A/England/42/72 (H3N2). Its behaviour in vitro and in vivo was studied. Three marker systems were investigated: resistance to serum inhibitors, growth capacity at high temperature and low sensitivity to amantadine hydrochloride. In ferrets the strain was found to be attenuated and immunogenic. Passages in man, animals and eggs have not affected its resistance to gamma inhibitors.     

The influence of polymorbidity, revascularization, and wound therapy on the healing of arterial ulceration

Objective

An ulcer categorized as Fontaine’s stage IV represents a chronic wound, risk factor of arteriosclerosis, and co-morbidities which disturb wound healing. Our objective was to analyze wound healing and to assess potential factors affecting the healing process.

Methods

199 patients were included in this 5-year study. The significance levels were determined by chi-squared and log-rank tests. The calculation of patency rate followed the Kaplan-Meier method.

Results

Mean age and co-morbidities did not differ from those in current epidemiological studies. Of the patients with ulcer latency of more than 13 weeks (up to one year), 40% required vascular surgery. Vascular surgery was not possible for 53 patients and they were treated conservatively. The amputation rate in the conservatively treated group was 37%, whereas in the revascularizated group it was only 16%. Ulcers in patients with revascularization healed in 92% of cases after 24 weeks. In contrast, we found a healing rate of only 40% in the conservatively treated group (p < 0.001). Revascularization appeared more often in diabetic patients (n = 110; p < 0.01) and the wound size and number of infections were elevated (p = 0.03). Among those treated conservatively, wound healing was decelerated (p = 0.01/0.02; χ² test).

Conclusions

The success of revascularization, presence of diabetes mellitus, and wound treatment proved to be prognostic factors for wound healing in arterial ulcers.