O-(2-[(18)F]Fluoroethyl)- L-tyrosine (FET): a tracer for differentiation of tumour from inflammation in murine lymph nodes

High uptake of [(18)F]fluoro-2-deoxy- D-glucose (FDG) by inflammatory cells is a frequent cause of false positive results in lymph node (LN) staging by positron emission tomography. Previous studies suggest that radiolabelled amino acids may be more specific markers for viable tumour tissue than FDG. The aim of this study was to investigate quantitatively the uptake of FDG, [(3)H]methyl- L-methionine (MET) and O-2-([(18)F]fluoroethyl)- L-tyrosine (FET) in tumour-infiltrated and immunologically stimulated LNs. Popliteal LNs of Balb/c and DBA/2 mice were stimulated by injection into the right posterior foot pad of mice of either streptozotocin (STZ), causing chronic lymphadenitis, or concanavalin A (Con A), resulting in acute lymphadenitis. Tumour-infiltrated popliteal LNs were induced by inoculation of 2x10(5) lacZ-tagged T cell mouse lymphoma cells into the right posterior foot pad of syngeneic mice. Twenty-one days post inoculation of tumour cells or at various time points after STZ or Con A injection, mice were simultaneously injected intravenously with MET and FDG or MET and FET. After 30 min, mice were sacrificed and tracer uptake was determined in popliteal LNs. Contralateral LNs and LNs of untreated mice served as controls. Histopathological and immunohistochemical analysis demonstrated typical signs of chronic inflammation (non-specific sinus hyperplasia with macrophages) in STZ-treated animals and acute inflammatory changes (accumulation of neutrophilic granulocytes, vascular dilation, follicular hyperplasia) in Con A-treated animals. X-Gal staining confirmed the presence of tumour cells in the LNs of the injected side of tumour-inoculated mice. In the chronic lymphadenitis model, FDG uptake increased 3.0+/-0.1 fold [from 2.7+/-0.2 to 8.2+/-1.2 percent of injected dose per gram tissue (%ID/g)] and MET uptake 2.0+/-0.01 fold (from 4.5+/-0.6 to 9.2+/-1.1 %ID/g). In the acute lymphadenitis model, FDG uptake increased 3.9+/-0.3 fold (from 2.7+/-0.2 to 10.6+/-2.4 %ID/g) and MET uptake 1.9+/-0.1 fold (from 4.5+/-0.6 to 8.5+/-1.4 %ID/g). In contrast, FET uptake in both lymphadenitis models (1.0+/-0.03 and 1.2+/-0.04 fold) was not significantly different from that in controls (from 4.2+/-0.3 to 4.7+/-0.7 and to 5.1+/-0.4 %ID/g, respectively). Uptake of all three tracers in tumour-infiltrated LNs was significantly higher than that in control LNs. FDG uptake increased 2.8+/-0.15 fold (from 2.7+/-0.2 to 7.6+/-1.3%ID/g), MET uptake 1.7+/-0.11 fold (from 4.5+/-0.6 to 7.5+/-1.3 %ID/g) and FET uptake 2.4+/-0.15 fold (from 4.2+/-0.3 to 10.0+/-1.8 %ID/g). MET and FDG uptake was similar or higher in inflammatory than in tumour-infiltrated LNs ( P=0.01 and P<0.01, respectively). In contrast, uptake of FET showed no overlap between tumour-infiltrated and inflammatory LNs ( P<0.00001). In conclusion, tumour-infiltrated and inflammatory LNs could not be differentiated by means of FDG and MET uptake. FET, in contrast, proved to be a specific tracer for differentiating between tumour-infiltrated and inflammatory LNs in the murine models studied.     

Osmotic stress, crowding, preferential hydration, and binding: A comparison of perspectives

There has been much confusion recently about the relative merits of different approaches, osmotic stress, preferential interaction, and crowding, to describe the indirect effect of solutes on macromolecular conformations and reactions. To strengthen all interpretations of measurements and to forestall further unnecessary conceptual or linguistic confusion, we show here how the different perspectives all can be reconciled. Our approach is through the Gibbs-Duhem relation, the universal constraint on the number of ways it is possible to change the temperature, pressure, and chemical potentials of the several components in any thermodynamically defined system. From this general Gibbs-Duhem equation, it is possible to see the equivalence of the different perspectives and even to show the precise identity of the more specialized equations that the different approaches use.     

Development of the MEDOS/HIA DeltaStream extracorporeal rotary blood pump

The DeltaStream blood pump has been developed for extracorporeal circulation with one focus on potential integration into simplified bypass systems (SBS). Its small size and an embedded electric motor are the basic pump properties. A variation of the impeller design has been performed to optimize hydraulic and hematologic characteristics. A simple impeller design was developed which allows flow and pressure generation for cardiopulmonary bypass applications. The option of a pulsatile flow mode for ventricular assist device applications also was demonstrated in vitro. Impeller washout holes were implemented to improve nonthrombogenicity. The pump was investigated for potential thermal hazards for blood caused by the integrated electric motor. It could be demonstrated that there is no thermal risk associated with this design. Durability tests were performed to assess the lifetime of the pump especially with regard to the incorporated polymeric seal. Seal lifetimes of up to 28 days were achieved using different blood substitutes. In animal tests using either the pump as a single device or in an SBS setup, biocompatibility, low hemolysis, and nonthrombogenicity were demonstrated. In summary, the DeltaStream pump shows great potential for different extracorporeal perfusion applications. Besides heart-lung machine and SBS applications, ventricular assist and extracorporeal membrane oxygenation up to several days also appear promising as potential applications.     

α-Gluthathione S-Transferase as an Early Marker of Hepatic Ischemia/Reperfusion Injury after Liver Resection

Organ dysfunction following liver resection is one of the major postoperative complications of liver surgery. The Pringle maneuver is often applied during liver resection to minimize bleeding, which in turn complicates the postoperative course owing to liver ischemia and reperfusion. Routinely, hepatocellular damage is diagnosed by, for example, abnormal aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and the prothrombin time (PT). The cytosolic liver enzyme α-glutathione S-transferase (α-GST) has recently been shown to have good sensitivity for detecting hepatic injury after acetaminophen poisoning or liver transplantation, but its role in non-transplantation liver surgery has not been assessed. In this prospective randomized clinical study, the diagnostic role of plasma α-GST following warm ischemia and reperfusion is reported. A total of 75 patients who underwent liver resection were randomly assigned to three groups: (1) without Pringle (NPR); (2) with Pringle (PR); (3) with ischemic preconditioning by 10 minutes of ischemia and reperfusion each prior to the Pringle manuever (IPC). The major findings are as follows: (1) ALT, AST, and α-GST increased upon liver manipulation as early as prior to resection, with a rapid return of α-GST values to preoperative levels, whereas ALT and AST further increased on the first postoperative day. (2) In the PR group, α-GST, but not ALT and AST, was significantly elevated compared with that in the NPR group at 15 and 30 minutes and 2 hours after resection/reperfusion. In addition, only levels of α-GST significantly correlated with the Pringle duration. (3) The ischemia/reperfusion-induced early rise in α-GST was completely prevented by ischemic preconditioning. Moreover, only α-GST concentrations (>490 μg L⁻¹) determined early after resection (2 hours) predicted postoperative liver dysfunction (24 hours PT < 60%) with a positive predictive value of 74% and a negative predictive value of 76%. Thus α-GST seems to be a sensitive, predictive marker of ischemia/reperfusion-induced hepatocellular injury and postoperative liver dysfunction.     

Beneficial effects of ischemic preconditioning in patients undergoing hepatectomy: the role of neutrophils

HYPOTHESES: Temporary vascular clampage (Pringle maneuver) during liver surgery can cause ischemia-reperfusion injury. In this process, activation of polymorphonuclear leukocytes (PMNLs) might play a major role. Thus, we investigated the effects of hepatic ischemic preconditioning on PMNL functions. DESIGN: Prospective randomized study. Patients who underwent partial liver resection were randomly assigned to 3 groups: group 1 without Pringle maneuver; group 2 with Pringle maneuver, and group 3 with ischemic preconditioning using 10 minutes of ischemia and 10 minutes of reperfusion prior to Pringle maneuver for resection. SETTING: University hospital, Munich, Germany. PATIENTS: Seventy-five patients underwent hepatic surgery mostly owing to metastasis. MAIN OUTCOME MEASURES: Perioperative factors for PMNL activation, inflammation, and postoperative hepatocellular integrity. RESULTS: Ischemia-reperfusion of the human liver (mean +/- SD time to perform the Pringle maneuver, 35.5 +/- 2.6 minutes) caused (1) a decrease in the number of circulating PMNLs, (2) their intrahepatic sequestration, (3) their systemic activation, and (4) a significant correlation between the degree of their postischemic activation and the postoperative rise in liver enzyme serum levels. In parallel, cytokines with proinflammatory and chemotactic properties were released reaching the highest values when stimulation of PMNLs was most pronounced. When ischemic preconditioning preceded the Pringle maneuver, activation of PMNLs and cytokine plasma levels was reduced as evidenced by the attenuation of superoxide anion production, beta(2)-integrin up-regulation, and interleukin 8 serum concentrations, followed by a significant reduction in serum alanine aminotransferase levels on the first and second postoperative days. CONCLUSIONS: These results demonstrate in humans that ischemic preconditioning reduces activation of PMNLs elicited by the Pringle maneuver. The down-regulation of potentially cytotoxic functions of PMNLs might be one of yet unknown important pathways that altogether mediate protection by ischemic preconditioning.     

Radiosynoviorthesis in osteoarthritis and other disorders with concomitant synovitis in comparison to rheumatoid arthritis

AIM: The aim of this study was to evaluate the effectiveness of radiosynoviorthesis (RSO) in osteoarthritis and other disorders with concomitant synovitis versus rheumatoid arthritis by means of a standardized questionnaire. METHODS: Eight-hundred and three RSO treatments were monitored in 691 patients by seven centers in three countries, using standardized questionnaires. Patients were assigned to three groups according to their age (20-40, 41-60, and 61-80 years). Additionally, the data was analyzed separately for patients with rheumatoid arthritis (group A) and those with osteoarthritis, psoriasis arthritis, pigmental villonodular synovitis, or persistent effusions after joint replacement (group B). RESULTS: Quality of life improved in 78% of group A and 59% of group B (p < 0.01). Ameliorations of joint pain, swelling/effusion, or flexibility were found in 80% of group A and 56% of group B (p < 0.01). The response rate was similar for small- and large-sized joints in group A, but was significantly higher for large-sized joints in group B (p < 0.01). The positive effects on joint pain, swelling/effusion, or flexibility lasted longer in group A (p < 0.01). Repeated RSOs were as effective as initial RSOs. The clinical outcome was not influenced by age, gender, or transient immobilization for 48 hours after RSO. CONCLUSION: Although slightly more efficient in rheumatoid arthritis, RSO represents an effective treatment option also in osteoarthritis and other disorders with concomitant synovitis.