Systemic anti-TNFalpha treatment restores diabetes-impaired skin repair in ob/ob mice by inactivation of macrophages

To date, diabetes-associated skin ulcerations represent a therapeutic problem of clinical importance. The insulin-resistant type II diabetic phenotype is functionally connected to obesity in rodent models of metabolic syndrome through the release of inflammatory mediators from adipose tissue. Here, we used the impaired wound-healing process in obese/obese (ob/ob) mice to investigate the impact of obesity-mediated systemic inflammation on cutaneous wound-healing processes. Systemic administration of neutralizing monoclonal antibodies against tumor necrosis factor (TNF)alpha (V1q) or monocyte/macrophage-expressed EGF-like module-containing mucin-like hormone receptor-like (Emr)-1 (F4/80) into wounded ob/ob mice at the end of acute wound inflammation initiated a rapid and complete neo-epidermal coverage of impaired wound tissue in the presence of a persisting diabetic phenotype. Wound closure in antibody-treated mice was paralleled by a marked attenuation of wound inflammation. Remarkably, anti-TNFalpha- and anti-F4/80-treated mice exhibited a strong reduction in circulating monocytic cells and reduced numbers of viable macrophages at the wound site. Our data provide strong evidence that anti-TNFalpha therapy, widely used in chronic inflammatory diseases in humans, might also exert effects by targeting "activated" TNFalpha-expressing macrophage subsets, and that inactivation or depletion of misbehaving macrophages from impaired wounds might be a novel therapeutic clue to improve healing of skin ulcers.     

A widening perspective regarding the relationship between anti-epiligrin cicatricial pemphigoid and cancer

Anti-epiligrin cicatricial pemphigoid (AECP) is a chronic, autoimmune, subepidermal blistering disease characterized by circulating anti-basement membrane autoantibodies to laminin 5. Recent studies have shown that patients with this form of cicatricial pemphigoid have an increased relative risk for malignant solid tumors. The mechanism underlying this association of AECP and cancer is unknown, but there is accumulating evidence that laminin 5 plays a central role. In this article we report a patient with AECP and co-associated cutaneous T cell lymphoma and summarize all to date reported cases of AECP associated with malignancies. In addition we provide a review of the biology of laminin 5 and its potential role in cancer development.     

Migration of renal carcinoma cells is dependent on protein kinase Cdelta via beta1 integrin and focal adhesion kinase

Migration and adhesion of tumor cells are essential prerequisites for the formation of metastases in malignant diseases. Protein kinase C (PKC) has been shown to regulate cell migration, adhesion and proliferation. In order to identify a connection between PKC isoforms and tumor progression in renal cell carcinoma (RCC), the influence of PKC isoforms on cell migration, adhesion and proliferation and possible influences of the activity of integrins and focal adhesion kinase (FAK) were analyzed in RCC cells. The experiments were performed in the RCC cell line CCF-RC1 after pre-incubation of the cells with the PKC inhibitors GF109203X, GO6976, RO31-8220 and rottlerin. Cell migration and adhesion were assessed through chemotaxis analysis and adhesion to an endothelial monolayer, respectively. Cell proliferation was analysed by a BrdU incorporation assay. The expression and activity of beta1 integrins and FAK were analysed by Western blot analysis. GF109203X reduced cell migration to 69%, the activity of beta1 integrins to 63% and FAK expression to 82% compared to untreated cells. Rottlerin reduced cell migration in a concentration-dependent manner to 36%, cell proliferation to 81%, expression and activity of beta1 integrins to 72 and 79%, and expression and activity of FAK to 56 and 76% of untreated cells, respectively. RO31-8220 also reduced the expression and activity of beta1 integrins as well as the expression of FAK to 84, 66 and 66% of untreated cells, respectively. GO6976 reduced the expression of FAK to 60% of untreated cells. Cell migration was only slightly reduced by GO6976 to 84% of untreated cells, and cell adhesion remained uninfluenced. These findings show a critical role of PKCdelta in the regulation of tumor cell migration, which seems to be caused by affecting the expression and activity of beta1 integrins and FAK. These results can provide a basis for new strategies in preventing metastases of renal cell carcinoma.     

Oncostatin M expression is functionally connected to neutrophils in the early inflammatory phase of skin repair: implications for normal and diabetes-impaired wounds

In this study, we investigated the role of the cytokine oncostatin M (OSM) for wound biology. OSM and its specific OSM receptor subunit beta (OSMRbeta) were induced upon injury. OSM induction paralleled the early influx of polymorphonuclear neutrophils (PMN) into the wound. OSM protein was localized in PMN in very early wounds, whereas OSMRbeta could be detected on macrophages, keratinocytes, and fibroblasts later in repair. To establish a functional connection between PMN and OSM expression in wounds, we depleted mice from circulating PMN by injecting an anti-PMN monoclonal antibody (Ly-6G). PMN-depleted wounds were characterized by a nearly complete loss of OSM but not OSMRbeta mRNA and protein expression within the initial 16-24 hours after injury. PMN-rich chronic wounds from diabetic ob/ob mice were characterized by a strongly elevated OSM mRNA and protein expression as compared to healthy animals. Moreover, a leptin-mediated improvement of chronic wounds in ob/ob mice was paralleled by a complete inhibition of PMN influx associated again with a dramatic loss of OSM expression at the wound site. These data constitute strong evidence that OSM expression during wound inflammation is functionally connected to PMN infiltration.     

Alternative shift models and the quality of patient care

On 1 January 1996, the German Arbeitszeitgesetz (working-time regulation) came into effect for hospital physicians. It states that working hours must not exceed 8 h per day, even for physician in hospitals. As a consequence, the prevalent two-shift model is legally inadmissible. The intention of this law is to protect the physician and to create better conditions for the patients. However, a systematic evaluation of the postulated benefits is still lacking. AIM: The aim of our study was to analyze the influence of the length of daily working hours on the quality of patient care by measuring the outcome of patients in intensive care units (ICUs), comparing the two-shift model (2-SM)--two 12-h shifts--with the three-shift model (3-SM)--three 8-h shifts. MATERIALS AND METHODS: In a prospective multicenter study, we compared the outcome of patients in six ICUs (organized by surgeons) with different models of working hours. The health status of each patient and the course on ICU [described by hospital mortality, number of complications, readmission to the ICU, reinterventions, duration of the stay in an ICU and hospital, the course of the Acute Physiology and Chronic Health Evaluation (APACHE) II score] were uni- and multivariately analyzed. In addition, the technical and personnel resources of the ICUs and the hospitals were documented. RESULTS: Three hundred and forty seven patients (103 2-SM, 244 3-SM) were included. The epidemiological and the health status on admission to the ICU were comparable. Patients in the 3-SM stayed 1.6 days longer on ICU and 2.3 days longer in the hospital than the 2-SM patients. The frequency of complications, reinterventions, and readmissions to ICU was higher in the 3-SM. The median of the APACHE-II score decreased more for 2-SM than for 3-SM patients. This means a significantly quicker recovery of the patients in 2-SM (P < 0.05). The multivariate analysis with individual outcome measures as dependent variables revealed a significant positive effect of the 2-SM on the physicians' assessment of postoperative course, on the relative frequency of therapeutic procedures, and to a lesser extent on the duration of stay in the ICU.     

Zemententfernung mit Ultraschall bei Revisionen von Hüfttotalprothesen

Bone cement (polymethylmethacrylate, PMMA) removal during revision hip arthroplasty can be a tedious, time-consuming process. The usual methods of removing cement include high-speed drills, chisels, saws, and reamers, which are often associated with fracture or perforation of the femoral shaft. An alternative very promising method is cement removal with ultrasound. We present an ultrasonic device for rapid cement removal with minimum risk of trauma to the fragile femoral bone. The technique of cement removal with ultrasound is described and problems and risks are addressed.     

Transmission of Signals from Rats Receiving High Doses of Microbeam Radiation to Cage Mates: An Inter-Mammal Bystander Effect

Inter-animal signaling from irradiated to non-irradiated organisms has been demonstrated for whole body irradiated mice and also for fish. The aim of the current study was to look at radiotherapy style limited exposure to part of the body using doses relevant in preclinical therapy. High dose homogenous field irradiation and the use of irradiation in the microbeam radiation therapy mode at the European Synchrotron Radiation Facility (ESRF) at Grenoble was tested by giving high doses to the right brain hemisphere of the rat. The right and left cerebral hemispheres and the urinary bladder were later removed to determine whether abscopal effects could be produced in the animals and also whether effects occurred in cage mates housed with them. The results show strong bystander signal production in the contra-lateral brain hemisphere and weaker effects in the distant bladder of the irradiated rats. Signal strength was similar or greater in each tissue in the cage mates housed for 48hrs with the irradiated rats. Our results support the hypothesis that proximity to an irradiated animal induces signalling changes in an unirradiated partner. If similar signaling occurs between humans, the results could have implications for caregivers and hospital staff treating radiotherapy patients.