Thomas Luebke

Caspase‐1‐inhibitor ac‐YVAD‐cmk reduces LPS‐lethality in rats without affecting haematology or cytokine responses

The effect of acetyl–tyrosyl‐valyl‐alanyl‐aspartyl–chloromethylketone (ac‐YVAD‐cmk), an irreversible caspase‐1 (IL‐1β converting enzyme, ICE) inhibitor on mortality, leukocyte and platelet counts and cytokine levels was investigated in a double‐blind rat model of endotoxaemia. Intravenous (i.v.) bolus administration of lipopolysaccharide (LPS) (25–75 mg kg−1, n=12 per group) to anaesthetized rats induced a dose dependent increase in mortality over 8 h (LD50=48 mg kg−1). During this period, animals became leukopenic and thrombocytopenic. Serum levels of IL‐β, IL‐6, and TNF‐α were highly elevated. Pretreatment of rats with ac‐YVAD‐cmk at a dose of 12.5 μmol kg−1 significantly reduced mortality from 83 to 33% using Log Rank analysis. However, ac‐YVAD‐cmk did not modify blood cell counts or cytokine profiles as compared with the LPS‐drug vehicle group. These data lay credence to the potential importance of caspase‐1‐inhibition in modifying the inflammatory response to endotoxin. Further investigations are warranted in understanding the relationship between caspase‐1 inhibition, cytokine production and animal survival in different experimental paradigms of sepsis.

Meta-analysis of endovenous radiofrequency obliteration of the great saphenous vein in primary varicosis.

Purpose: To compare radiofrequency obliteration (RFO) and conventional surgery with respect to postoperative complications, effectiveness of treatment, and quality of life (QoL). Methods: Several healthcare databases were interrogated to identify all studies published between 1994 and 2007 comparing RFO in primary varicosis to conventional therapy with vein ligation and stripping. Of 65 articles identified, 8 studies representing 428 patients [224 (52%) endovenous RFO and 204 (48%) stripping] were eligible for the meta-analysis. Adverse events, effectiveness, and QoL outcomes were assessed at several time points up to 2 years. Results: There were significant reductions in tenderness and ecchymosis at 1 week and significantly fewer hematomas at 72 hours, 1 week, and 3 weeks associated with RFO. There was no significant difference between the RFO and surgery in immediate or complete great saphenous vein (GSV) occlusion, incomplete GSV closure, freedom from reflux, recurrent varicose veins, recanalization, or neovascularization. QoL results significantly favoring RFO over surgery included return to normal activity and return to work. Conclusion: It seems that RFO benefits most patients in the short term, but rates of recanalization, re-treatment, occlusion, and reflux may alter with longer follow-up. The lack of such data demonstrates the need for further randomized clinical trials of RFO versus conventional surgery.

Endovascular Therapy of a Symptomatic Mobile Thrombus of the Thoracic Aorta

INTRODUCTION The therapeutic strategies of a mobile luminal thrombus of the descending thoracic aorta with peripheral arterial embolization remain a matter of debate. REPORT We report the case of recurrent peripheral arterial embolism caused by a mobile thrombus of the descending aorta, which was successfully treated by implanting an endovascular stent graft. DISCUSSION Our case demonstrates, that endovascular stent graft placement is feasible and can be performed as an effective and minimally invasive treatment option for mobile thoracic aortic thrombi.

Splenic rupture: an unusual complication of colonoscopy: case report and review of the literature.

Splenic rupture after colonoscopy is rare. Only 44 cases previously have been reported in the English literature. Partial capsular avulsion is the proposed mechanism of injury. Any condition causing increased splenocolic adhesions may be a predisposing factor to splenic injury. One case of splenic injury after colonoscopy is reported in addition to a complete review of the literature.

Chemokines and interleukin-18 are up-regulated in bronchoalveolar lavage fluid but not in serum of septic surgical ICU patients.

Our objective was to investigate the levels of chemokines (MIP1-alpha, MCP-1, and Gro-alpha), Interleukin-18 (IL-18), and Interleukin (IL-6) in bronchoalveolar lavage (BAL) fluid and serum at the onset and ongoing states of sepsis as defined by the American College of Chest Physicians/Society of Critical Care Medicine in septic surgical ICU patients. Our summary background data was to understand the significance of compartmentalized inflammatory mediator production in an immunologically active organ (lung) in comparison with levels in the systemic circulation. The study group consisted of 20 septic patients and 10 non-septic patients on surgical ICU. At the onset of sepsis, both BAL fluid and serum samples were taken and levels of MIP-1alpha, MCP-1, GRO-alpha, IL-18, and IL-6 were measured by ELISA. Furthermore, over a subsequent 8-day period, levels of these mediators were determined in serum. In some experiments, IL-18 mRNA levels were determined in peripheral blood lymphocytes (PBL) of septic and non-septic patients. At the onset of sepsis, MIP-1alpha, MCP-1, GRO-alpha, IL-18, and IL-6 levels were significantly up-regulated in BAL fluid as compared with non-septic controls. In marked contrast, with the exception of IL-18 mRNA and IL-6 peptide, there was no increase in serum levels of inflammatory mediators determined both at the onset and during the ongoing states of sepsis. Based on the present data, monitoring levels of serum chemokines and IL-18 protein as markers of sepsis might be misleading since despite their non-detection in serum, they were highly up-regulated in the lung tissue compartment. These data might underscore the role of MIP-1alpha, MCP-1, GRO-alpha, and IL-18 in the mediation of local tissue damage. Furthermore, these findings raise the notion that mediator measurement in immunologically active organs might serve as pivotal indicators of sepsis prior to the actual fulfillment of specific clinical criteria that defines the patient as being septic.

Type B Aortic Dissection: A Review of Prognostic Factors and Meta-analysis of Treatment Options

According to international guidelines, stable patients with uncomplicated Type B aortic dissection (TBAD) should receive optimal medical treatment. Despite adequate antihypertensive therapy, the long-term prognosis of these patients is characterized by a significant aortic aneurysm formation in 25-30% within four years, and survival rates from 50 to 80% at five years and 30 to 60% at 10 years. In a prospective randomized trial, preemptive thoracic endovascular aortic repair (TEVAR) in patients with chronic uncomplicated TBAD was associated with an excess early mortality (due to periprocedural hazards), but the procedure showed its benefit in prevention of aortic-specific mortality at five years of follow-up. However, preemptive TEVAR may not be the treatment of choice in all patients with uncomplicated TBAD because of the inherent periprocedural complications like stroke, paraparesis, and death, as well as stent graft-induced complications (i.e., retrograde dissection or endoleaks). Thus, the TEVAR-related deaths and complications (especially paraplegia and stroke) raise concerns that moderate the better survival with TEVAR at five years. By timely identification of those patients prone for developing complications, early intervention, preferably in the subacute or early chronic phase, may improve the overall long-term outcome for these patients. Therefore, early detectable and reliable prognostic factors for adverse events are essential to stratify patients who can be treated medically and those who will benefit from rigorous follow-up and, in the long-term, from timely, or even prophylactic, TEVAR. Several studies have identified prognostic factors in TBAD such as aortic diameter, partial false lumen thrombosis, false lumen thickness, and location of the primary entry tear. Combining these clinical and radiological predictors may be essential to implement a patient-specific approach designed to intervene only in those patients who are at high risk of developing complications to improve the long-term outcomes of patients with uncomplicated Type B aortic dissection.

Cost-effectiveness of endovascular versus open repair of acute complicated type B aortic dissections

OBJECTIVE This study weighed the cost and benefit of thoracic endovascular aortic repair (TEVAR) vs open repair (OR) in the treatment of an acute complicated type B aortic dissection by (TBAD) estimating the cost-effectiveness to determine an optimal treatment strategy based on the best currently available evidence. METHODS A cost-utility analysis from the perspective of the health system payer was performed using a decision analytic model. Within this model, the 1-year survival, quality-adjusted life-years (QALYs), and costs for a hypothetical cohort of patients with an acute complicated TBAD managed with TEVAR or OR were evaluated. Clinical effectiveness data, cost data, and transitional probabilities of different health states were derived from previously published high-quality studies or meta-analyses. Probabilistic sensitivity analyses were performed on uncertain model parameters. RESULTS The base-case analysis showed, in terms of QALYs, that OR appeared to be more expensive (incremental cost of €17,252.60) and less effective (-0.19 QALYs) compared with TEVAR; hence, in terms of the incremental cost-effectiveness ratio, OR was dominated by TEVAR. As a result, the incremental cost-effectiveness ratio (ie, the cost per life-year saved) was not calculated. The average cost-effectiveness ratio of TEVAR and OR per QALY gained was €56,316.79 and €108,421.91, respectively. In probabilistic sensitivity analyses, TEVAR was economically dominant in 100% of cases. The probability that TEVAR was economically attractive at a willingness-to-pay threshold of €50,000/QALY gained was 100%. CONCLUSIONS The present results suggest that TEVAR yielded more QALYs and was associated with lower 1-year costs compared with OR in patients with an acute complicated TBAD. As a result, from the cost-effectiveness point of view, TEVAR is the dominant therapy over OR for this disease under the predefined conditions.

Is the urokinase-type plasminogen activator system a reliable prognostic factor in gastric cancer?

AIM The aim of this prospective study was to evaluate the clinical and prognostic impact of immunohistochemically assessed uPA and PAI-1 in patients with gastric cancer. METHODS This prospective study analyzed specimens obtained from 105 gastric cancer patients who underwent gastrectomy with extended lymphadenectomy. The immunohistochemical expression of uPA and PAI-1 was studied semiquantitatively in the tumor epithelium and was correlated with the clinicopathological features of each patient. RESULTS Univariate analysis revealed no statistically significant association of uPA levels with pT and pN category (p=0.655 and 0.053, respectively), grading (p=0.374), depth of tumor invasion (p=0.665), UICC classification (p=0.21) and the Laurén classification (p=0.578). PAI-1 expression showed no statistically significant correlation with pT, pN and M category (p=0.589, 0.414, and 0.167, respectively), grading (p=0.273), and the Laurén classification (p=0.368). Only the UICC classification was significantly correlated with PAI-1 (p=0.016). Kaplan-Meier analysis revealed no significant association of uPA and PAI-1 with overall survival (p=0.0929 and 0.0870, respectively). CONCLUSIONS Our results could not verify any prognostic value of uPA and PAI-1 levels in patients with gastric carcinoma. Therefore, the uPA-system as a biologically defined prognostic marker to identify high-risk gastric cancers should be applied with caution. However, considering the number of patients involved and the borderline level of significance observed in this study, a larger number of events may have resulted in significant differences.

Implementation of an artificial neuronal network to predict shunt necessity in carotid surgery.

In carotid surgery, it could be useful to know which patient will tolerate carotid cross-clamping in order to minimize the risks of perioperative strokes. In this clinical study, an artificial neuronal network (ANN) was applied and compared with conventional statistical methods to assess the value of various parameters to predict shunt necessity. Eight hundred and fifty patients undergoing carotid endarterectomy for a high-grade internal carotid artery stenosis under local anesthesia were analyzed regarding shunt necessity using a standard feed-forward, backpropagation ANN (NeuroSolutions); NeuroDimensions, Gainesville, FL) with three layers (one input layer, one hidden layer, one output layer). Among the input neurons, preoperative clinical (n = 9) and intraoperative hemodynamic (n = 3) parameters were examined separately. The accuracy of prediction was compared to the results of a regression analysis using the same variables. In 173 patients (20%) a shunt was used because hemispheric deficits or unconsciousness occurred during cross-clamping. With the ANN, not needing a shunt was predicted by preoperative and intraoperative parameters with an accuracy of 96% and 91%, respectively, where the regression analysis showed an accuracy of 98% and 96%, respectively. Those patients who needed a shunt were identified by preoperative parameters in 9% and by intraoperative parameters in 56% when the ANN was used. Regression analysis predicted shunt use correctly in 10% using preoperative parameters and 41% using intraoperative parameters. Intraoperative hemodynamic parameters are more suitable than preoperative parameters to indicate shunt necessity where the application of an ANN provides slightly better results compared to regression analysis. However, the overall accuracy is too low to renounce perioperative neuromonitoring methods like local anesthesia.

Superficial Femoral Artery Aneurysm: A Rare Complication of Wegener Granulomatosis

Wegener granulomatosis (WG) is a systemic disease of unknown etiology characterized by necrotizing granulomatous inflammation, tissue necrosis, and variable degrees of vasculitis, typically in small and medium-sized blood vessels. The classic clinical pattern is a triad involving the upper airways, lungs, and kidneys. However, large vessel aneurysm is an extremely rare finding in WG. We describe a 67-year-old Caucasian male with formerly proven WG who presented with a progressively growing superficial femoral artery aneurysm. Histologic findings revealed necrotizing granulomatous vasculitis involving this artery.