Platelet increment is not associated with endothelial damage in haematological patients: a prospective observational study.

The aim of this study was to investigate if thrombocytopenic haematology patients show signs of endothelial damage when transfused with platelets and if that damage correlates with platelet increment measured with corrected count increment (CCI). Endothelial damage secondary to radiation or chemotherapy may lead to consumption of transfused platelets but research in this field is scarce. Patients were divided into four groups: Group 1: Acute leukaemia; Group 2: Autologous stem cell transplantation (SCT); Group 3: Allogenic SCT; and Group 4: patients receiving platelets prior to interventions. Blood was sampled before (baseline) and immediately after (0 h) transfusion and then at 1, 4, 8, 16 and 24 h after transfusion. The biomarkers syndecan-1, soluble thrombomodulin (sTM) and vascular endothelial growth factor (VEGF) were analysed. The plasma concentration differences between baseline and later sampling times were referred to as delta (Δ). Fifty-four platelet transfusion events were studied. All biomarkers were within the normal ranges both before and after the transfusions. The Δsyndecan-1 increased at 0 h (p = .02), but there was no significant correlation between Δsyndecan-1 and CCI. There was no change in any of the other biomarkers after transfusion compared to before. There were no differences between the groups and no correlations were found between CCI and C-reactive protein, Δsyndecan-1, ΔsTM or ΔVEGF. There were no signs of endothelial damage before or after platelet transfusions. A transient significant change in syndecan-1 immediately after platelet transfusion did not influence platelet count or platelet CCI.

Proton pump inhibitor medication is associated with colonisation of gut flora in the oropharynx.

BACKGROUND: The normal body exists in mutualistic balance with a large range of microbiota. The primary goal of this study was to establish whether there is an imbalance in the oropharyngeal flora early after hospital or ICU admittance, and whether flora differs between control, ward and critically ill patients. The secondary goal was to explore whether there are patient characteristics that can be associated with a disturbed oropharyngeal flora. METHODS: Oropharyngeal cultures were obtained from three different study groups: (1) controls from the community, (2) ward patients and (3) critically ill patients, the two latter within 24 h after admittance. RESULTS: Cultures were obtained from 487 individuals: 77 controls, 193 ward patients and 217 critically ill patients. Abnormal pharyngeal flora was more frequent in critically ill and ward patients compared with controls (62.2% and 10.4% vs. 1.3%, P < 0.001 and P = 0.010, respectively). Colonisation of gut flora in the oropharynx was more frequent in critically ill patients compared with ward patients or controls (26.3% vs. 4.7% and 1.3%, P < 0.001 and P < 0.001, respectively). Proton pump inhibitor medication was the strongest independent factor associated with the presence of gut flora in the oropharynx in both ward and critically ill patients (P = 0.030 and P = 0.044, respectively). CONCLUSION: This study indicates that abnormal oropharyngeal flora is an early and frequent event in hospitalised patients and more so in the critically ill, compared to controls. Proton pump inhibitor medication is associated with colonisation of gut flora in the oropharynx.

Bleeding complications after central line insertions: relevance of pre-procedure coagulation tests and institutional transfusion policy.

BACKGROUND: The aim of this study was to map pre-procedural variables for insertion of a central venous catheter, prophylactic blood component use and to investigate whether any independent variable could be identified as an independent risk factor for associated bleeding complications in patients outside the intensive care unit. METHODS: In this retrospective study, we investigated 1737 consecutive insertions of central venous catheters in 1444 patients in a large university hospital during 2009-2010. Pre-procedural coagulation status, blood component use, type of catheter, insertion site and complications during insertion were recorded and compared with bleeding complications documented on electronic charts. RESULTS: No serious bleeding complications were recorded in connection with the insertion of central venous catheters. Sixteen of 1769 (0.9%) insertions caused grade 2 bleeding, defined as bleeding requiring prolonged compression at the insertion site. Insertion of a large bore central dialysis catheter was found to be an independent risk factor for bleeding complications. Neither conventional coagulation tests nor accidental arterial puncture or the number of needle passes could predict bleeding complications in this study. CONCLUSION: This retrospective study, in non-ICU patients, shows that serious bleeding complications in association with central line insertions are uncommon and that insertion of a large bore catheter is likely to be an independent risk factor for mild-bleeding complications in this population.

Complement activation products in liquid stored plasma and C3a kinetics after transfusion of autologous plasma.

BACKGROUND AND OBJECTIVES: Keeping a small stock of liquid plasma readily available for transfusion is common practise in Sweden. We report data on complement activation markers in plasma components during storage in the liquid state and the kinetics of C3a-(desArg) after transfusion of autologous plasma with high content of C3a-(desArg). MATERIAL AND METHODS: Plasma components were prepared by apheresis or from whole blood. C3 fragments (C3a-(desArg), C3d,g, iC3), and soluble terminal complement complex (sC5b-9) were investigated. C3a-(desArg) kinetics was investigated in regular apheresis donors. RESULTS: Apheresis plasma prepared by membrane centrifugation had significantly higher level of C3a-(desArg), C3d,g and sC5b-9 from day 0 and low iC3, than plasma prepared by other methods. By storage day 7, C3a-(desArg)-levels were above the reference value in 88% of all components. After re-infusion of autologous plasma with high C3a-(desArg) content, there were rapid a(1) and a(2)-distribution followed by a slower b-elimination phase. CONCLUSION: Plasma components prepared by different methods and stored in the liquid phase differ significantly in the amount and timing of complement activation. C3a-(desArg) present in plasma is rapidly eliminated after transfusion. Autologous plasma could be used to study complement kinetics in different clinical situations.

An evaluation of monitoring possibilities of argatroban using rotational thromboelastometry and activated partial thromboplastin time.

BACKGROUND: Rotational thrombelastometry/thrombelastography with ROTEM and TEG is becoming available bedside in an increasing number of intensive care units, where many patients with heparin-induced thrombocytopenia (HIT) are treated. The study has been performed in an effort to find out whether ROTEM could be an alternative to activated partial thromboplastin time (aPTT) when argatroban is used for anticoagulation. METHODS: Argatroban was added in vitro to a series of citrated whole-blood samples from 10 healthy volunteers to obtain whole-blood concentrations of 0, 0.125, 0.25, 0.5, 1.0, 2.0, 4.0 and 8.0 mg/l. ROTEM and whole-blood aPTT analyses were performed at each argatroban concentration. Correlation analyses were performed using the Spearman correlation analysis. RESULTS: There was a significant and strong correlation between argatroban concentrations and clotting time (CT in ROTEM analysis with INTEM) (P<0.0001 and r=0.98). Also, the ROTEM time to maximum clot formation velocity (MAXV-t) appeared to have a very strong and highly significant correlation to argatroban concentrations (P<0.0001 and r=0.95). When we studied the correlation between aPTT and CT, we found a highly significant and strong correlation between these two analyses (P<0.0001 and r=0.97), especially so in the clinically relevant therapeutic range up to 100 s aPTT prolongation for HIT patients. CONCLUSION: A significant and strong correlation was found between argatroban concentrations and several ROTEM parameters. Rotational thrombelastometry/thrombelastography has a potential role in increasing the safety of argatroban anticoagulation in critically ill patients.

Comparison of citrated and fresh whole blood for viscoelastic coagulation testing during elective neurosurgery.

BACKGROUND: Previous viscoelastic haemostatic tests studies have often indicated a hypercoagulative test signal with citrated blood, which could influence clinical decision makings. PURPOSE: The aim of this study was to compare fresh and citrated whole blood using two non-automated viscoelastic ROTEM and Sonoclot tests. Our hypothesis was that citrated blood would demonstrate a hypercoagulative response in this setting, not tested before. METHODS: Perioperative viscoelastic coagulation changes were evaluated with a ROTEM and Sonoclot in 38 patients undergoing elective brain tumor surgery. The citrated samples were recalcified with CaCl2. Wilcoxon nonparametric-paired tests and Bland-Altman plots were performed to compare the fresh and citrated blood analyses. RESULTS: The citrated blood showed a hypercoagulative response in ROTEM NATEM-clot formation time and α-angle, Sonoclot-clot rate and platelet function, as compared to fresh blood (p<0.0001). CONCLUSIONS: Fresh whole blood may theoretically reflect in vivo haemostasis more closely than citrated analyses, which indicated a hypercoagulative response as compared to the fresh whole blood analyses Bland-Altman plots also indicated that ROTEM reference ranges in patients undergoing brain surgery should be redefined. Future studies must establish the correlation between viscoelastic test results using fresh or citrate anticoagulated blood and clinical outcomes, such as bleeding, transfusion or reoperation for postoperative haematoma.

Effects of different colloid infusions on ROTEM and Multiplate during elective brain tumour neurosurgery.

BACKGROUND: The European Medicines Agency does not recommend the use of hydroxyethyl starch-based volume replacement solutions in critically ill patients due to an increased risk of renal failure. However, this recommendation is questionable for its perioperative use. Several recent randomised controlled studies do not indicate a risk for renal failure-not even after high-risk surgery. Human albumin is used in our neurointensive care unit as a part of the "Lund concept" of brain injury resuscitation, and albumin has been introduced in elective neurosurgery instead of starch. The aim of our prospective unblinded observational cohort study was to compare the degree of dilutive coagulopathy after albumin and starch intra-operative fluid therapy. METHODS: Thirty-nine patients undergoing elective brain tumour surgery with craniotomy received either 130/0.42 hydroxyethyl starch or 5 % albumin infusions. The first 18 patients received starch, whereas the rest received albumin. Rotational thromboelastometry with ROTEM and platelet aggregometry with Multiplate were performed before surgery, after the first and second consecutive colloid infusions (250/500 ml albumin or 500/1000 ml starch) and at the end of surgery. RESULTS: Both intra- and inter-group comparisons showed more deranged ROTEM parameters after the higher doses of starch. Multiplate detected changes only in the albumin group after 500-ml infusion. Blood los did not differ between groups, nor did haemoglobin preoperatively or at end of surgery. Lower volumes of albumin were required to maintain stable intra-operative haemodynamic parameters; 250/500 ml albumin corresponded to 500/1000 ml starch. CONCLUSIONS: Hydroxyethyl starch affected coagulation at lower volumes, with a more prominent effect on clot structure at the end of surgery, corroborating previous research. Only albumin decreased platelet aggregation, and 5 % albumin had a more potential volume effect than 130/0.42 hydroxyethyl starch.

Comparison of point-of-care hemostatic assays, routine coagulation tests, and outcome scores in critically ill patients.

PURPOSE: The purposes of the study are to compare point-of-care (POC) hemostatic devices in critically ill patients with routine laboratory tests and intensive care unit (ICU) outcome scoring assessments and to describe the time course of these variables in relation to mortality rate. MATERIALS AND METHODS: Patients admitted to the ICU with a prognosis of more than 3 days of stay were included. The POC devices, Multiplate platelet aggregometry, rotational thromboelastometry, and ReoRox viscoelastic tests, were used. All variables were compared between survivors and nonsurvivors. Point-of-care results were compared to prothrombin time, activated partial thromboplastin time, platelet count, fibrinogen concentration, and Sequential Organ Failure Assessment score and Simplified Acute Physiology Score 3. RESULTS: Blood was sampled on days 0 to 1, 2 to 3, and 4 to 10 from 114 patients with mixed diagnoses during 237 sampling events. Nonsurvivors showed POC and laboratory signs of hypocoagulation and decreased fibrinolysis over time compared to survivors. ReoRox detected differences between survivors and nonsurvivors better than ROTEM and Multiplate. CONCLUSIONS: All POC and routine laboratory tests showed a hypocoagulative response in nonsurvivors compared to survivors. ReoRox was better than ROTEM and Multiplate at detecting differences between surviving and nonsurviving ICU patients. However, Simplified Acute Physiology Score 3 showed the best association to mortality outcome.

Covered stents for prevention of restenosis. Experimental and clinical results with different stent designs.

RATIONALE AND OBJECTIVES: Metallic stents in small vessels go along with a significant risk of restenosis and reocclusion. Different models of stents and covering materials have been purported to prevent intraluminal neointimal proliferation by cover-based closure of the spaces in the wire mesh. METHODS: Tantalum stents covered with polyethylacrylate/polymethylmethacrylate (PEM) were implanted in the infrarenal aorta of six New Zealand white rabbits by aortotomy and compared with eight rabbits treated with uncovered tantalum stents. For deployment, covered and uncovered stents necessitated a 7-French (F) and 5-F sheath, respectively. In addition, nine human patients with arteriosclerotic lesions of the superficial femoral arteries (stenosis > 5 cm or total occlusion) were treated percutaneously with a Dacron-covered nitinol vascular stent via a 9-F sheath. Patients were followed for a mean of 13.5 months, and control angiography was performed after 6 months. RESULTS: Experimental placement of the tantalum Wiktor stent was feasible technically in all cases. Five of six stents covered with PEM were occluded 3 days after placement despite the intravenous use of heparin and aspirin. In the group with uncovered stents, no area of stenosis greater than 10% was observed. There was a neointimal layer of 89 +/- 68 microns around the stent wires. Stent placement was successful in all patients. In four patients, a hyperergic reaction occurred, resulting in noninfectious periarteriitis. This complication was treated successfully with nonsteroidal antiinflammatory drugs. The primary patency was 50%, and the secondary patency (after application of a second covered stent in two patients) was 63%. CONCLUSIONS: The uncovered stent induces little neointimal proliferation around the stent wires. The insertion of stents covered with PEM into the rabbit aorta was accompanied by a strong thrombotic reaction, despite sufficient anticoagulation. Dacron-covered nitinol stents showed a surprisingly high restenosis rate after 9 months of follow-up. Further research concerning the in vivo properties of new covering materials is mandatory before routine vascular clinical application.

Expression of hepatitis B virus core gene products with specific immunoreactivity for e antigen (HBeAg) in Saccharomyces cerevisiae.

The e antigen of the hepatitis B virus (HBeAg) was expressed in S. cerevisiae. Yeast-derived HBeAg exhibits high HBe antigenicity while lacking any HBc antigenicity. The production yield of HBeAg expressed in yeast is dependent on the host strains and the nature of the leader sequences used in the plasmid constructions. The recombinant antigen is not secreted into the medium, independent from the leader sequences which are used. A simple extraction procedure was developed, enabling the isolation of HBeAg from the cells without killing them. Recombinant HBeAg derived from yeast can replace plasma-derived antigen in ELISA for determining antibodies to HBeAg.

Value of positron emission tomography for lung cancer staging.

OBJECTIVE: The therapeutic strategy in non-small-cell lung cancer (NSCLC) requires exact staging of tumour invasion (T) as well as differentiation between ipsi- and contralateral lymph node invasion (N1/2 vs N3). [18F]FDG-positron emission tomography (FDG-PET) has been shown to detect invaded N with high accuracy while correct determination of T appears to be unclear. The purpose of this prospective study was to evaluate benefit and necessity of 18FDG-PET as an additive to conventional staging modalities. METHODS: Forty patients with suspected non-small-cell lung cancer (NSCLC) were staged by means of computed tomography (CT), bronchoscopy, mediastinoscopy and bone scintigraphy. Additionally, attenuation corrected FDG-PET of the thorax was performed pre-operatively for analysis of T and N topography. After surgical resection with radical lymphadenectomy T and N staging results of CT and PET were compared with the pathological diagnoses. Specificity, sensitivity, positive predictive value and accuracy of CT and PET were calculated. RESULTS: Twenty three squamous cell carcinomas, 14 adenocarcinomas, and three non-malignant tumours were found. Accuracy of CT-T was 0.75 and of PET-T 0.78; accuracy of CT-N was 0.78 and of PET-N 0.80. By combination of CT-T and PET-T accuracy was 0.88. Combination of CT-N and PET-N yielded an accuracy of 0.90. In two out of three cases, PET correctly determined T0. In two cases non-malignant inflammatory lymph nodes were falsely staged as malignant by PET. CONCLUSIONS: Adequate pre-operative T- and N-staging is possible with both CT and FDG-PET. Accuracy can be improved by combination of CT and FDG-PET. FDG-PET is superior to CT in order to differentiate between malignant and benign tumours. However, acute inflammation can mimic malignant lymph node invasion. FDG-PET is justified as a supporting staging measure in cases presenting unclear differentiation between N2 and N3 after conventional staging and is helpful in cases with unclear cell type of the primary tumour.

[Evacuation proctography: physiological variability and clinical relevance of the anorectal angle and the position of the pelvic floor]. / Evakuationsproktographie: Physiologische Streubreite und klinische Relevanz des Anorektalwinkels und der Beckenbodenlage.

Evacuation proctography is an important imaging method for the investigation of abnormalities of defecation. For this procedure, the most commonly carried out measurements are the ano-rectal angle and the position of the pelvic floor. The given mean values and the physiologically acceptable deviations vary just as much as the perceived clinical value of these measurements. 173 evacuation proctograms were evaluated in a prospective study; the subjective abnormalities were correlated with clinical findings. No significant correlation between the measurements from the proctograms and the clinical findings could be determined. The clinical relevance of these measurements is, therefore, uncertain.

[The adjuvant use of the monoclonal antibody c7E3 Fab in peripheral arterial thrombolysis]. / Adjuvanter Einsatz des monoklonalen Antikörpers c7E3 Fab bei peripherer arterieller Thrombolyse.

Thrombolysis of arterial occlusions has limitations, e.g. it requires extensive time for thrombolysis, occlusions may be resistant to lysis, and the rate of reocclusions may be high. c7E3 Fab inhibits platelet aggregation by binding to the GPIIb/IIIa receptor on platelets. Experimentally, this monoclonal antibody has been shown to decrease, the time required for lysis, and to prevent reocclusion. This is the first report on the adjunctive use of c7E3 Fab in peripheral arterial occlusions in humans. Three patients with occlusion of the iliac or femoropopliteal artery were treated with c7E3 Fab (bolus injection of 0.25 mg/kg KG + i.v.-application 12 micrograms/min for 12 h). In addition, the patients received urokinase (100,000 IU bolus + 100,000 IU/h). Heparin (5,000 IU bolus + 1,000 IU/h) and acetylsalicylate (100 mg/day/p.o.). Occlusion length ranged between 6-40 cm. Therapy was successful in all patients. During the follow-up period (4-6 months) no reocclusion occurred. There were no serious side effects like major bleeding or thrombocytopenia. We conclude that the applied doses appear safe. Even the time required for thrombolysis was short, a conclusion in respect of a significant reduction of the time required for lysis can be drawn only after further controlled studies.

[Echo contrast agents for the color Doppler sonographic diagnosis of deep femoral venous thrombosis]. / Echokontrastmittel für die farbdopplersonographische Diagnostik der tiefen Oberschenkelvenenthrombose.

PURPOSE: Evaluation of an echo contrast medium (Echovist) for color-coded duplex sonography of deep venous thrombosis of the thigh. MATERIAL AND METHODS: In 19 patients with deep vein thrombosis of the thigh, diagnosed by contrast phlebography, 22 color-coded duplex sonography studies were performed for flow analysis at the top of the thrombus. During the studies 8.5 ml echo contrast medium were injected in an ipsilateral vein at the back of the foot. The flow signals of the non-enhanced color coded duplex sonography were compared with those of the echo enhanced study for differentiation between floating thrombi from those adherent to the vein wall. RESULTS: The echo-enhanced color-coded duplex sonography showed a significant increase in detection of perfusion at the top of the thrombus in comparison with non-enhanced color-coded duplex sonography (p < 0.01). 9 thrombi were regarded as wall adherent after the native study, 7 of these could be identified as floating thrombi by echo-enhanced color-coded duplex sonography. CONCLUSION: Echo-enhanced color-coded duplex sonography yields a significant increase of diagnostic information in certain findings of the non-enhanced color-coded duplex sonography differentiating between floating thrombi and wall adherent thrombi in the deep venous system of the thigh.

[Transjugular intrahepatic portosystemic shunt in children. Initial clinical experiences and literature review]. / Der transjuguläre intrahepatische portosystemische Shunt bei Kindern. Erste klinische Erfahrungen und Literaturübersicht.

PURPOSE: To present special methodical and clinical findings of transjugular intrahepatic portosystemic shunts (TIPSS) in children and to discuss potential indications. PATIENTS AND METHODS: Between 1993 and 1996, 6 children aged 2-13 years were treated by TIPSS-insertion. In four cases, the underlying disease was extrahepatic biliary atresia (EHBA) and in two cases liver fibrosis secondary to treatment of neoplasms during early childhood. Indications for TIPSS insertion were variceal bleeding resistant to other treatment modalities in three patients, hypersplenism in one patient and both bleeding and hypersplenism in two. Portal vein punctures were performed using 16-gauge needles, because 19-gauge fine-needles showed insufficient stiffness. The mean follow-up was 24.5 months. RESULTS: Shunt insertion succeeded in all children with a mean procedure time of 5.2 hours. Periportal fibrosis associated with EHBA, atypical course of hepatic veins and small diameters and distances of vessels were conditions making the procedure difficult. Bleeding ceased in all patients, peripheral platelet counts rose by a mean value of 58%. Procedure-related complications were minor extrahepatic bleeding in one child and temporary haemolysis in another child. Restenosis resulted in three patients and were treated successfully by means of transjugular interventions. 5 children remain free of symptoms to this day, one child underwent successful orthotopic liver transplantation 8 months after TIPSS. CONCLUSIONS: TIPSS insertion is technically more difficult in children and has to consider child growth and possible subsequent liver transplantation. Potential indications are recurrent variceal bleeding, also of intestinal origin, resistant to standard treatment and clinically significant hypersplenism.

[Intra-arterial calcium stimulation for preoperative localization of insuloma]. / Intraarterieller Kalzium-Stimulationstest zur präoperativen Lokalisationsdiagnostik des Insulinoms.

PURPOSE: Objective is to evaluate the efficacy of the intraarterial calcium test in the preoperative localisation of insulinomas. MATERIAL AND METHOD: To stimulate the pathological release of insulin, calcium gluconate (0.015 meq Ca++/kg) was selectively injected into the arteries supplying the pancreas. Prior to calcium injection and 30, 60, 90 and 120 seconds later, 5 ml samples of blood were obtained from the right or from both right and left hepatic veins. Insulin levels were then determined by mean of immunoassays. A twofold increase in insulin level in the venous sample after 30 or 60 seconds localised the insulinoma to the region of the pancreas supplied by the selectively injected artery. Results of the calcium test were prospectively analysed in 6 patients and compared with operative findings. RESULTS: All 6 patients had a surgically proved solitary and benign insulinoma. Calcium stimulation with venous sampling provided true-positive localisation of insulinomas in all patients without suspicion of liver metastasis. All 6 patients currently have normal insulin levels after a mean period of 16 months (range 4-24 months) with no evidence of hypoglycaemia on fasting. CONCLUSION: Intraarterial stimulation with calcium and hepatic vein samplings for insulin gradients is a very sensitive minimally invasive functional method and may replace transhepatic portal venous samplings for the preoperative detection of insulinomas.

Intravascular ultrasound diagnosis of aortic graft infection.

BACKGROUND: To assess the value of intra-aortic ultrasound (US) for diagnosing intraprosthetic vegetations in atypical aortic graft infection. METHODS: A 66-year-old man presented with fever 12 months after emergency insertion of a straight infrarenal aortic graft because of rupture of an inflammatory abdominal aneurysm. Blood cultures, leukocyte scan, transabdominal US study, and digital angiography were negative. Spiral CT was equivocal. The patient was imaged with a mechanically rotating US transducer at 12.5-MHz from inside the graft. RESULTS: Intravascular catheter ultrasound showed mobile lesions at the graft wall in the absence of periprosthetic fluid. Immediately after the procedure the patient developed several small cutaneous septic infarctions on both feet. At operation the presence of graft infection was confirmed. CONCLUSIONS: This case report suggests that intra-aortic US may constitute a helpful adjunctive modality in suspected atypical infection of prosthetic aortic grafts.

[The wound care center in surgery: an interdisciplinary concept for diagnostic and treatment of chronic wounds]. / Die chirurgische Wundsprechstunde. Ein interdisziplinäres, diagnostisches und therapeutisches Konzept für chronische Wunden.

In Germany there is no standardized wound care for patients with chronic wounds in specialized centers. We have established a wound care unit for the past 6 years. The principal concept of therapy was characterized by standardized local surgery, moist wound dressings and concomitant treatment of the underlying disease. We performed local therapy, coordinated the interdisciplinary treatment and developed a new wound documentation system for quality control. We established a close network, integrating general practitioners and home care organizations to realize a mainly outpatient treatment supported by short hospital therapy. Exclusive outpatient treatment was performed in 42% of all patients. According to our prospective data, we achieved an improvement in wound care: 69% of the wounds resistant to therapy for a mean of 30 months healed within 12 months after therapy according to our protocol. Our data strongly supported the importance of local surgery: neither wound depth nor wound infection had any influence on the healing rate, presumably due to radical excisional debridement of necrotic tissue. The presented data justify on medical and economic grounds the establishment of such wound care centers in Germany.