Ralf Lobmann

Autologous human keratinocytes cultured on membranes composed of benzyl ester of hyaluronic acid for grafting in nonhealing diabetic foot lesions: a pilot study.

Diabetic foot complications are the most common cause of nontraumatic lower extremity amputations in the industrialised world. Unsatisfactory healing requires advanced therapeutic strategies, such as the use of skin grafts, which may represent a helpful option for wound coverage. Alternatively, a method using autologous keratinocytes grown to thin sheet grafts is available. The purpose of this pilot study was to investigate the application of autologous human keratinocytes cultured on membranes composed of benzyl ester of hyaluronic acid (Laserskin autograft) to diabetic foot ulcers. We studied 14 patients with type 2 diabetes mellitus and a nonhealing diabetic foot lesion, defined as existing longer than 6 months or with no wound healing apparent for 12 weeks. Between 7 and 64 days after the transplantation (depending on the size of the ulceration), 11/14 of the lesions were completely healed. The transplantation of autologous keratinocytes may allow faster closure of diabetic foot lesions and subsequently reduce length of hospitalization. This method can easily be planned with regard to logistics and time, and furthermore, this therapy option can be carried out by the diabetologist.

Interleukin-6 concentrations in wound fluids rather than serological markers are useful in assessing bacterial triggers of ulcer inflammation.

Bacterial pathogenicity, microbial load and diversity are decisive for outcome and therapy of non healing ulcers. However, until now, no routine laboratory parameter is available to assess the inflammatory level caused by chronic wound infections. We thus investigated the usefulness of levels of interleukin (IL)‐6 and tumour necrosis factor alpha (TNFα) in wound fluids for assessing ulcer inflammation in the presence or absence of microbial triggers. In addition, the predictive values of local cytokine analyses were compared with those of C‐reactive protein (CRP) and lipopolysaccharide‐binding protein (LBP) because serological markers are normally used to underline the suspicion of wound infections.

Endogenous ACTH, not only α-melanocyte-stimulating hormone, reduces food intake mediated by hypothalamic mechanisms

ACTH and alpha-melanocyte-stimulating hormone (alpha-MSH) are both consecutively processed from proopiomelanocortin (POMC), which is synthesized in hypothalamic arcuate neurons innervating the paraventricular nuclei (PVN). POMC secretion/synthesis is regulated by energy availability. ACTH and alpha-MSH bind with equal affinity to melanocortin-4 receptors and elicit similar effects on signal transduction in-vitro. Endogenous alpha-MSH thus far is believed to be the major physiological agonist and to act in an anorexigenic manner. Until now, it was fully unknown whether endogenous ACTH is also involved in the regulation of appetite and food intake. In this study in rats, we now show that icv ACTH as well as alpha-MSH possess anorexigenic effects in the PVN or areas in close proximity in vivo and that the effect of ACTH is direct and not mediated via alpha-MSH. We investigated the roles of endogenous ACTH and alpha-MSH by PVN application of the respective antibodies under different physiological conditions. In satiated rats with high levels of ACTH and alpha-MSH in the PVN, antibody administration increased food intake and body weight gain; hungry animals were unaffected. Finally, repeated injections of ACTH antibodies into PVN resulted in persistently increased food intake during the light period. These data now provide robust evidence that endogenous ACTH without further processing acts in the PVN or areas in close proximity to reduce food intake under conditions of feeding-induced satiety.

Diabetic foot infections: microbiological aspects, current and future antibiotic therapy focusing on methicillin-resistant Staphylococcus aureus.

Diabetic patients are at increased risk of complicated skin, skin structure and bone infections including infections of diabetic foot ulcerations (DFU). Analyses of epidemiology and microbial pathogenicity show that staphylococci seem to be predestined to induce such infections. In addition, multidrug resistance particularly due to an increasing prevalence of methicillin‐resistant Staphylococcus aureus (MRSA) seems to be the challenge for effective antibiotic therapy. With regard to infections with MRSA, classical agents like vancomycin, linezolid, fosfomycin or trimethroprim–sulphametoxazol might be agents of choice in DFU. New‐generation drugs including broad‐spectrum tetracyclines like tigecycline, first and second generation of cyclic lipopeptides, anti‐MRSA β‐lactams including ceftobiprole and anti‐MRSA antibodies are developed or in progress and the hope for the future.

Mikrobiologische Aspekte und rationelle antibiotische Therapie des diabetischen Fußsyndroms

Zusammenfassung.q Immunologische und mikrobiologische Aspekte des diabetischen Fußulkus: Diabetische Patienten sind einem erhöhten Risiko für schwere Weichteil- und Knocheninfektionen ausgesetzt. Einerseits spielt hier die veränderte patientenabhängige Immunkompetenz eine Rolle, die von einer eingeschränkten spezifischen und unspezifischen zellulären Immunität herrührt. Andererseits zeigen die Epidemiologie des Erregerspektrums und die erregerspezifische Pathogenität, dass insbesondere Staphylokokken für dieses Krankheitsbild prädestiniert zu sein scheinen: Staphylococcus aureus und koagulasenegative Staphylokokken besitzen Eigenschaften, die ihnen die Adhärenz auf Wundoberflächen ermöglichen. Hierzu zählen zunächst unspezifische Mechanismen wie Ionenwechselwirkungen und Hydrophobizität zwischen bakterieller und Wirtszelloberfläche wie auch spezifische Interaktionen zwischen bakteriellen Adhäsinen und zellulären Rezeptoren. Darüber hinaus sezernieren Staphylokokken Polysaccharide, die gemeinsam mit den phänotypischen Veränderungen der Infektionserreger und der Ausbildung von Mikrokolonien zur Bildung eines Biofilms führen können. Dieses strukturierte Konglomerat aus Bakterien, Polysacchariden und Wirtsproteinen zeigt eine ausgesprochene Resistenz gegenüber immunologischen Effektoren und antimikrobiellen Substanzen und neigt deshalb zur chronischen Persistenz.q Aspekte der antibiotischen Therapie: Vor Beginn einer Therapie ist der Schweregrad der Infektion abzuschätzen, da hiervon sowohl die Auswahl und Darreichungsform des Antibiotikums als auch die Dauer der Therapie abhängen. Die initiale Therapie bei schweren und länger bestehenden Infektionen sollte mit einem Breitspektrumantibiotikum in parenteraler Applikation zum Erreichen schneller Wirkspiegel durchgeführt werden. Bei bestehender Osteomyelitis muss die Therapie aufgrund der hohen Rückfallquote häufig über > 4 Wochen durchgeführt werden, bei oberflächlichen Infektionen der Weichteile reichen im Regelfall 1–2 Wochen aus.q Schlussfolgerung und Ausblick: Aufgrund der erheblichen Fortschritte auf dem Gebiet der Diagnostik und Therapie des diabetischen Fußsyndroms besteht allgemeiner Konsens, dass mit einer optimalen Wundversorgung, einer metabolischen Kontrolle und einer frühen aggressiven chirurgischen und antibiotischen Intervention Infektionen kontrolliert werden können. Die Problematik der Biofilmbildung bei chronischen Infektionen ist bislang noch wenig in das Bewusstsein des Therapeuten gedrungen, erklärt aber im Einzelfall die geringe Effektivität einer antimikrobiellen Therapie. Abseits der Anwendung der klassischen Antibiotika gibt es hier erfolgversprechende Ansätze einer enzymatischen Behandlung bzw. einer Inhibition der bakteriellen “Kommunikation” (“quorum sensing”), die für eine effizientere Therapie zukünftig von Bedeutung sein können.Abstract.q Immunological and Microbiological Aspects of Diabetic Foot Infections: Diabetic patients are at increased risk of severe skin and bone infections. Immunological disturbances are reasonable and due to altered specific and unspecific cellular immune responses. Analysis of epidemiology and microbial pathogenicity shows that staphylococci seem to be predestined to induce such infections. Staphylococcus aureus and coagulase-negative staphylococci are able to adhere to the wound ground by a sequela of mechanisms. Initial bacterial adherence is due to hydrophobicity, ion exchanges, and specific binding of bacterial adhesion molecules to cellular receptors. Moreover, staphylococci secrete polysaccharides which form a biofilm together with multilayer cell clusters. The highly structured communities within a biofilm are resistant to distinct immunoeffectors and have a decreased susceptibiliy to antibiotics in vivo.q Aspects of Antibiotic Therapy: Assessing the severity of an infection is essential to selecting an antibiotic regimen, the mode of drug administration, and the duration of therapy. Regimens for severe and chronic infections are broader spectrum and often intravenously to obtain high drug concentrations immediately. Infections of the bone often require an antibiotic therapy for > 4 weeks, while a 1- to 2-week therapy for mild to moderate infections has been found to be effective.q Conclusions: Because of the tremendous progress in diagnostics and therapy of diabetic foot infections, infectious complications can be successfully treated by appropriate wound care, metabolic control, and early surgical and antibiotic intervention. Bacterial biofilms involved into chronic infections are new aspects currently not visualized by clinical therapy. Besides the classic antimicrobial therapy, new concepts of an enzymatic therapy or the inhibition of bacterial “communication” (quorum sensing) are in progress and the hope for the future.

Effect of Daptomycin on Local Interleukin-6, Matrix Metalloproteinase-9, and Metallopeptidase Inhibitor 1 in Patients With MRSA-Infected Diabetic Foot

Infection is a major cause of the diabetic foot syndrome that is promoted by the increased burden of multiresistant germs like methicillin-resistant Staphylococcus aureus (MRSA). Maximizing positive outcome for serious MRSA infections requires an aggressive treatment approach and careful monitoring of the healing process. Therefore, we examined 8 patients with MRSA-infected diabetic foot syndrome of Wagner classification grade 2 or 3 (corresponding to the Texas classification stage 2 or 3) during antibiotic treatment with daptomycin. We documented the wound size and obtained samples of wound secretion for analyses of proinflammatory interleukin-6 (IL-6), protease (matrix metalloproteinase-9 [MMP-9]), and antiprotease (metallopeptidase inhibitor 1 [TIMP-1]) activity. During the course of anti-MRSA therapy, we observed a decrease in the concentration of local IL-6 within the first 3 days followed by a decrease of MMP-9 and an increase of TIMP-1. Finally, a reduction of wound size was documented. The present data show that efficient antimicrobial treatment with daptomycin has a number of beneficial effects on wound healing at the molecular level in MRSA-infected diabetic foot ulcers.

Molekulare Grundlagen der Wundheilung bei diabetischem Fußsyndrom

Zusammenfassung.q Hintergrund: Das diabetische Fußsyndrom ist ein außerordentlich bedeutendes sozioökonomisches Gesundheitsproblem. Aufgrund des Systemcharakters des Diabetes mellitus wird von einer bereits auf molekularer Ebene beginnenden Störung der Wundheilung ausgegangen.q Pathogenese: Wachstumsfaktoren und Proteasen beeinflussen die geordnete normale Wundheilung, Veränderungen ihrer Expressionsmuster sind von Bedeutung für die Pathophysiologie der chronischen Wunde. Erste Studien beschreiben auf molekularer und zellulärer Ebene die Entwicklung der Läsion beim Patienten mit Diabetes mellitus zu einer nicht heilenden chronischen Wunde.q Aktuelle Forschung: Diese Übersicht informiert über den gegenwärtigen Stand der Forschung und deren Auswirkungen auf die Therapie des diabetischen Fußsyndroms.Abstract.q Background: The diabetic foot syndrome represents a considerable problem of health care. Due to the systemic character of diabetes mellitus, disturbances on the molecular level of wound healing are assumed.q Pathogenesis: Growth factors and proteases affect the process of normal wound healing, and changes of their activity are relevant to the pathogenesis of the chronic wound. First studies describe the transition of a diabetic foot lesion to a nonhealing chronic wound on the molecular and cellular level.q Current Research: This review reports on the current status of research and new implications for the treatment of diabetic foot syndrome.

Analysis of the Gly40Ser polymorphism in the glucagon receptor gene in a German non-insulin-dependent diabetes mellitus population

Abstract A heterozygous polymorphism changing GGT40 (Gly) to AGT40 (Ser) in the glucagon receptor gene (GCG-R) was reported to be associated with non-insulin-dependent diabetes mellitus (NIDDM). A possible involvement of this polymorphism in impaired glucose tolerance was also suggested in a French population. However, the prevalence of this polymorphism differs markedly among different ethnic groups, whereby the results in German populations were found to be contradictory. We thus investigated the association of this mutation with NIDDM and healthy subjects in 508 German subjects (196 NIDDM, and 312 controls). None of the control subjects, but one of the NIDDM patients demonstrated the Gly40Ser polymorphism. Since no first-degree relative of the index patient had this genetic variance, a de novo mutation is suggested. Although the frequency of the Gly40Ser polymorphism in NIDDM observed in France is not confirmed in our population, this genetic variance is also evident in Germany.

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.