Elevated levels of matrix metalloproteinases and chronic wound healing: an updated review of clinical evidence.

OBJECTIVE: In the past 20 years, research and clinical trials on the healing process of chronic wounds have highlighted the key role of the family of enzymes called matrix metalloproteinases (MMPs). If a strong correlation between the course of healing of chronic wounds and the levels of a biological marker can be demonstrated, then it may be possible to: i) identify the best marker threshold to predict the clinical evolution of the pathology; and ii) if causality has been found between the marker and pathology, to improve the healing outcome, to change the marker level. METHOD: The databases Medline and Embase were searched to identify clinical trials pertaining to the assessment of MMPs in chronic wounds with the following keywords 'metalloproteinase' or 'metalloprotease' and 'wound healing'. Clinical trials were considered for inclusion if they enrolled patients with cutaneous chronic wounds and were published in English. More than 50 clinical trials, consensus documents and guidelines were assessed for this review. RESULTS: MMPs play key roles in the wound healing process, and excessive expression and activation of some of these enzymes is seen in chronic cutaneous wounds where healing is delayed. Levels of MMPs are affected by a number of factors, including patient and wound characteristics. CONCLUSION: Levels of MMPs can be used to indicate the prognosis of chronic wounds and protease modulating treatments used to improve healing rates. DECLARATION OF INTEREST: The authors report no conflicts of interest in this work.

[Neuropathy and diabetic foot ulcers]. / Neuropathie und diabetisches Fußsyndrom.

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. Polyneuropathy plays an important role in the pathophysiology of diabetic foot ulceration. Proper adherence to standard treatment strategies and interdisciplinary cooperation can reduce the high rates of major amputations.

[The 'ideal therapy process': testing a new approach for assessing process quality in inpatient parent-child facilities]. / Der "ideale Behandlungsprozess": Erprobung eines neuen Ansatzes zur Prüfung der Prozessqualität in Mutter-/Vater-Kind-Einrichtungen.

Instruments for external quality assurance in inpatient parent-child rehabilitation and prevention facilities were developed in 2 projects. For the assessment of process quality, we sought an alternative test to the peer review procedure which also places a stronger emphasis on patient perspectives. The aim was to define an "ideal process" as a standard, to develop quantifiable criteria, and to test a multimethod approach which involves different data levels. On the basis of different sources, the "ideal process" for parent-child rehabilitation and prevention and associated criteria were defined by involving an accompanying expert group during a consensus process. Criteria were assessed on different levels: on the rehabilitation/prevention centre level, a questionnaire of process-relevant structural features was used; on the patient level, a case-related routine documentation filled in by clinic staff and an incident-related patient questionnaire were applied. Data were collected in 37 centres (prevention: 19; rehabilitation: 11; 7 offering both types of programmes). Analysis of patient-related data is based on a sample of 1 513 prevention patients and 286 rehabilitation patients. The resulting "ideal process" consists of the stages "preparation", "arrival", "treatment planning", "treatment", "completion of treatment", and "organisation", each containing specific criteria. Exemplarily, the outcomes for the stages "treatment planning" and "treatment" are presented. There is variability both between features and between clinics. The majority of the patients report that the criteria are fulfilled while there are medium to high levels of fulfillment regarding the routine documentation. The criteria of the questionnaire of process-relevant structural features are mostly fulfilled according to the clinics. Agreement between the 3 data levels can be observed. On the basis of the defined "ideal process", the methods that were tested seem to be appropriate to illustrate process-relevant features from different perspectives. The exemplary measured process quality of the pilot clinics can be judged as predominantly good. Individual deficits of process quality and limitations of the chosen methods are discussed.

[External quality assurance in inpatient medical rehabilitation and prevention centers for mothers, fathers and children: comparative outcome quality analyses across rehabilitation/prevention centers]. / Externe Qualitätssicherung in Einrichtungen der stationären Vorsorge und Rehabilitation für Mütter und Väter einschließlich Mutter-/Vater-Kind-Einrichtungen: Einrichtungsvergleichende Analysen im Bereich Ergebnisqualität.

To date, there are no programs for external quality assurance for inpatient prevention and rehabilitation programs for mothers, fathers and children. Instruments for outcome quality assessment were evaluated with the goal of determining their ability to document differences between prevention/rehabilitation centers in quality-relevant outcome parameters. Referring to the ICF, relevant outcome variables were specified and operationalized using established questionnaires. Data from 45 inpatient prevention and rehabilitation centers for mothers, fathers and children were analyzed using multilevel modeling with risk adjustment. Intra-class correlations were computed to determine in which parameters differences between institutions could be found. The percentage of variability accounted for by patient vs. institution characteristics was computed while statistically controlling for relevant confounders. For prevention centers, substantial variation on the institutional level was found in 9 out of 15 parameters. Almost all institutions did not deviate significantly from the grand mean of the respective parameter. For rehabilitation centers, significant variability was found in 2 out of 10 parameters. The differences between most institutions remained within a range of expectable variability. The results imply that comparative analyses across hospitals are better suited to identify institutions with low quality rather than establish quality-based rankings of institutions.

[Development of methods and instruments for external quality assurance in inpatient parent-child rehabilitation and prevention]. / Entwicklung von Verfahrensweisen und Instrumenten zur externen Qualitätssicherung in Einrichtungen der stationären Vorsorge und Rehabilitation für Mütter und Väter einschließlich Mutter-/Vater-Kind-Einrichtungen.

OBJECTIVE: There so far is no standardized program for external quality assurance in inpatient parent-child prevention and rehabilitation in Germany. Therefore, instruments and methods of external quality assurance were developed and evaluated on behalf of the federal-level health insurance institutions. METHODS: On the level of structure quality, a modular questionnaire for assessing structural features of rehabilitation/prevention centers, basic and allocation criteria as well as a checklist for visitations were developed. Structural data were collected in a nationwide survey of parent-child prevention and rehabilitation centers. Process and outcome quality data were collected in n=38 centers. Process quality was assessed using multiple methods (process-related structural features, case-related routine documentation, and incident-related patient questionnaires). Outcome quality was measured via patient questionnaires (n=1 799 patients). We used a multi-level modelling approach by adjusting relevant confounders on institutional and patient levels. RESULTS: The methods, instruments and analyzing procedures developed for measuring quality on the level of structure, processes and outcomes were adjusted in cooperation with all relevant stakeholders. Results are exemplarily presented for all quality assurance tools. For most of the risk-adjusted outcome parameters, we found no significant differences between institutions. CONCLUSIONS: For the first time, a comprehensive, standardized and generally applicable set of methods and instruments for routine use in comparative quality measurement of inpatient parent-child prevention and rehabilitation is available. However, it should be considered that the very heterogeneous field of family-oriented measures can not be covered entirely by an external quality assurance program. Therefore, methods and instruments have to be adapted continuously to the specifics of this area of health care and to new developments.

[Diabetic foot syndrome]. / Das diabetische Fußsyndrom.

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.

[Unusual cause of abdominal lymphomas]. / Ungewöhnliche Ursache abdomineller Lymphome.

A 72 year old HIV-negative patient without relevant immunosuppression presented with abdominal lymphomas and inflammatory signs in the colon. Mycobacterium intracellulare was grown from colonic biopsies and stool. There was no sign of malignancy or chronic inflammatory bowel disease. We diagnosed an atypical, gastrointestinal mycobacteriosis und treated the patient accordingly. This led to a good response.

Expression of matrix-metalloproteases in the fluid of chronic diabetic foot wounds treated with a protease absorbent dressing.

UNLABELLED: It is well known, that wound healing in diabetes is impaired. Persistently high levels of matrix-metalloproteases (MMPs) contribute to wound persistence. The topical use of protease-inhibitors might beneficially affect wound healing. RESEARCH DESIGN AND METHODS: 19 patients with chronic diabetic foot lesions (Wagner/Armstrong 2A) were studied. 6 patients received "good standard wound care", 13 patients were treated with a protease-inhibitor-modulating-matrix (ORC/collagen matrix) that was changed daily. At day 1 and 5 biopsies were taken from the wounds; wound fluids were collected daily. Biopsies were analysed using quantitative real-time-PCR and all samples were analysed using ELISA and zymography for MMPs, TIMPs, IL 1-ß and TNFα levels. RESULTS: No differences in mRNA-expression of MMPs, TNFα and for MMP levels in wound tissue were detected between both groups or between the 2 sampling time points. MMP-2 active was significantly reduced in wound fluids of ORC/collagen treated lesions (p=0.043) after 5 days. MMP-2 pro was also reduced by about 25% when compared to increasing levels in the control group (+27%). We observed a significant reduction of the wound area in the ORC/collagen group (p=0.003). CONCLUSIONS: Local treatment with a protease-inhibitor has a beneficial effect on wound healing. In contrast to unchanged mRNA-levels and protein levels of MMPs there was a clear reduction of MMP-2-levels in wound fluids. Our data support the potential role of ORC/collagen as a wound dressing. Modulation of MMPs appears to be beneficial in the treatment of chronic diabetic wounds.

Mean cell volume of neutrophils and monocytes compared with C-reactive protein, interleukin-6 and white blood cell count for prediction of sepsis and nonsystemic bacterial infections.

Clinicians are in need of better diagnostic markers for rapid diagnosis of severe infections. Therefore, we studied the diagnostic significance of mean cell volume of neutrophils (MNV) and monocytes (MMV) compared with Interleukin-6 (IL-6), C-reactive protein (CRP) and white blood cell count for predicting systemic clinical infection (sepsis). MNV and MMV were obtained by volume conductivity scatter (VCS) technique of the Coulter LH 750 hematology analyzer during automated differential counts, and blood samples from patients with sepsis (n = 37), nonsystemic bacterial infections (n = 39) and controls (n = 48) were studied. We observed a significant increase in MNV and MMV in the sepsis group compared with limited infections and controls. However, at a designated cut-off point of 250 pg/ml, IL-6 seemed to be the best predictor for sepsis with a sensitivity of 93% and a specificity of 76%. Compared with CRP (cut-off point 60 mg/dl), MNV at a cut-off of 150 had a comparable sensitivity and specificity and was the most predictive VCS parameter. Taken together, MNV and MMV seemed to be potential parameters to discriminate between sepsis and nonsystemic infections.

[Differential value of the diagnostic options to determine the level of amputation]. / Aussagekraft der diagnostischen Möglichkeiten zur Bestimmung der Amputationshöhe.

The level of amputation after utilizing all possible options of revascularization is considered one of the substantial criteria for sufficient reconvalescence, recovery of mobility, reduction of perioperative mortality and, finally, social reintegration. In case of vascular genesis, the possibilities to reestablish or improve arterial perfusion need to be proven. According to the data from the literature on the various technical methods, only the ptO2 measurement has become widely accepted to determine efficiently the level of amputation. In addition, study results have given evidence for the distal shifting to the genual and infragenual level of amputation. Furthermore, a good prognostic value has been achieved with measures of radionuclide imaging. An alternative but simple procedure including influencing factors and standards of measurement is the determination of the systolic occlusion pressure. Further technical advances can be achieved by a combination of methods but this requires the systematic verification prior to their use. However, their technical potential and options appear to be not fully utilized yet.

[Specific characteristics of amputations of the lower leg: the physicians view]. / Besonderheiten bei der Amputation der unteren Extremität aus der Sicht des Internisten.

Amputations are relevant problems not only for the surgeon. Physicians and dialectologists are also involved into the wound treatment, the coordination of the attending problems which leads to impaired wound healing (e.g. hyperglycaemia, infection, arterial occlusive disease). Internists should be part of the interdisciplinary setting and also of the decision for the necessary amputation. A well coordinated and interdisciplinary procedure allows to control appearing wound healing disturbances and to receive a functionally optimal result by employing minimal surgical interventions.

[Microalbuminuria in diabetes: setting the points for treatment]. / Mikroalbuminurie bei Diabetes: Nicht nur den Nieren droht Gefahr.

Both type 1 and type 2 diabetes mellitus have a cumulative risk of 25-40% for the development of microalbuminuria 25 years into the disease. In type 2 diabetes micro- and macroangiopathic complications, and frequently hypertension, may also develop. This means that the risk of a type 2 diabetic with microalbuminuria of developing cardiovascular disease is three times greater than that of a diabetic with no renal involvement. Annual screening for microalbuminuria should therefore be obligatory. An increasing albumin excretion rate (AER) is considered an indication for an elevated cardiovascular risk. Studies have shown that the rate of cardiovascular events in diabetics with microalbuminuria and hypertension can be reduced only by the combined treatment of hypertension, hyperglycemia, hyperlipidemia and microalbuminuria.

[Hypoglycemia despite hyperglycemia. Is a cerebral glucose deficiency possible even with raised blood sugar levels?]. / Hypoglykämie trotz Hyperglykämie. Ist eine zerebrale Minderversorgung mit Glukose auch bei erhöhtem Blutzuckerspiegel möglich?

Hypoglycemia represents the most frequent endocrinologic emergency situation in prehospital patient care. As the patients are usually unconscious on arrival of emergency medical personnel, often the only way to establish a diagnosis is by determination of the blood glucose concentration. However, even normoglycemic or hyperglycemic levels cannot definitively exclude the diagnosis of a previous hypoglycemia as the cause of the acute cerebral deficiency. Therefore, and especially in the case of insulin-dependent diabetes mellitus, a differential diagnosis should be considered. We report a case of emergency treatment of a hypoglycemic episode in a female patient with prolonged neuroglycopenia together with cerebrovascular dementia and Alzheimer's disease.

Expression of cell surface antigens in diabetic patients and healthy controls after injury.

AIMS: Due to the systemic character of Type 2 diabetes, cellular disturbances paralleled by an altered expression of various growth factors constitute the basis for impaired wound healing. Cell-surface antigens are altered in chronic wounds and may also have an effect on the persistance of diabetic foot lesions. METHODS: We investigated blood samples of diabetic patients with diabetic foot ulcers (n=21) in comparison with those from healthy control patients subsequent to an injury (n=9). A blood sample (EDTA) was taken from each participant (in the trauma control group on the third day after injury) and examined by flow cytometry [fluorescence-activated cell sorter (FACS)]. Typical cell surface antigens involved in wound healing were studied [cluster of differentiation (CD)2, CD3, CD4, CD25 and human leukocyte antigen (HLA)-diabetic retinopathy (DR)]. RESULTS: known to adversely affect wound healing were elevated in diabetic patients (CD2 p<0.001; CD3 p=0.016, CD4 p=0.22, CD25 p<0.001). HLA-DR expression was also decreased in diabetic foot patients (p=0.023). CONCLUSIONS: Cell-surface antigens appear to be altered in diabetic patients when compared to healthy controls. Thus, due to the systemic character of Type 2 diabetes, cellular disturbances may well constitute the basis for impaired wound healing in diabetes.

Antibiotic therapy for diabetic foot infections: comparison of cephalosporines with chinolones.

Diabetic foot complications are the most common cause of non-traumatic lower extremity amputations and uncontrolled infections represent a major risk factor. This open prospective, multicenter trial compared the efficacy of two antibiotic regimens for treatment of foot infections Wagner stage II or III in diabetic adults. Three hundred diabetic patients with severe, limb-threatening foot infection were consecutively enrolled in a prospective, observational, matched pairs controlled study to test two different antibiotic regimes (ceftriaxone vs chinolones) in addition to standard treatment of foot infection. After matching, 90 patients--each receiving ceftriaxone or chinolones--were analyzed. Our study demonstrated that treatment with a third generation cephalosporine is as effective as a treatment with chinolones. Response (reaching Wagner I or 0) was achieved in 58.0% in the ceftriaxone group and in 51.1% in the chinolone group (NS.). Fourteen days after initiation of treatment, the number of patients with microbiological isolates decreased in both groups (52 to 5 in the ceftriaxone group and 60 to 12 in the chinolone group). At hospital discharge, 66.0% of ceftriaxone and 64.4 of chinolone-treated diabetic ulcers were cured or improved. In summary, both substances proved to be effective in the primary antibiotic treatment of the diabetic foot; an early broad spectrum antibiotic treatment, that covers both gram-positive and gram negative bacteria as well as anerobes is undisputedly an imperative therapeutic intervention for the treatment of diabetic foot infection.

[Hypoglycemia, classification, therapy and preventable errors]. / Hypoglykämie. Klassifikation, Therapie und vermeidbare Fehler.

Hypoglycemia is a multifactorial problem that is caused by the interaction of numerous variables such as a individual pathophysiological response, treatment aspects and self control. In particular, the increasing use of intensified insulin therapy and thus the goal of normoglycemia has made hypoglycaemia to become a major hazard among the acute complications of diabetes mellitus. Early diagnosis and treatment is thus mandatory to reduce the increased morbidity and mortality of hypoglycaemia. Among the acute therapy of hypoglycaemia treatment includes a modification of diabetes therapy, patient education and a special training of hypoglycaemia awareness.

[Strategies for control of diabetic foot syndrome. Amputation rate can be reduced!]. / Strategien gegen das diabetische Fusssyndrom. Die Amputationsrate lässt sich senken!

In two-thirds of the cases, wound healing can be achieved by good wound care, namely structured and stage-related management. Some 30% of the cases require extended and innovative therapeutic measures. In these complicated, poorly healing wounds, the supplementary use of special wound dressings or wound medication in the granulation phase can be considered. The application of such substances promoting wound healing (growth factors, cytokinin modulators, e.g. hyaluronic acid or protease inhibitors) may help to activate chronic lesions and thus initiate, and in particular abbreviate, healing. This aspect of reduced healing duration is of particular importance in the diabetic lesion, since it prevents or reduces secondary infection, the most common cause of major amputation.

Association of increased plantar pressures with peripheral sensorimotor and peripheral autonomic neuropathy in Type 2 diabetic patients.

AIM: Diabetic polyneuropathy plays a highly significant role in the pathogenesis of the diabetic foot syndrome. It was the objective of this study to investigate the association of different forms of neuropathy (cardiac autonomic, sensorimotor and peripheral autonomic) with elevated plantar pressures in diabetic patients. METHODS: A total of 103 Type 2 diabetic patients was investigated. High plantar pressure was diagnosed when the total peak pressure was greater than 500 N/m2. Thirty-three participants were identified as patients with high-risk pressure and 70 patients had a mean peak pressure lower than 500 N/m2. All patients underwent a complete medical examination including determination of neuropathy, vascular status and foot pressures. RESULTS: Peripheral sensomotoric (p<0.012) and peripheral autonomic neuropathy (p<0.05) were significantly found more often in patients with high plantar pressures. There was no apparent association between autonomic cardial neuropathy and enhanced foot pressure (p=0.175). CONCLUSIONS: Our data clearly point to a correlation of diabetic neuropathy and higher plantar pressures. Interestingly, while there was a strong association between peripheral measures of neuropathy, no higher incidence of cardiac neuropathy in patients with increased foot pressure profiles was found. We strongly recommend that patients with clinical signs and indices of peripheral neuropathy be monitored by pedobarography for early detection and prophylactic shoe care for preventing the development of a diabetic foot ulcer.