Accuracy of Distal Femoral Valgus Deformity Correction: Fixator-Assisted Nailing vs Fixator-Assisted Locked Plating.

Fixator-assisted nailing (FAN) and fixator-assisted locked plating (FALP) are 2 techniques that can be used to correct distal femoral valgus deformities. The fixator aids in achieving an accurate adjustable initial reduction, which is then made permanent with either nail or plate insertion. FALP can be performed with the knee held in a neutral extended position, whereas FAN requires 30° to 90° of knee flexion to insert the nail, which may cause some alignment loss. We hypothesized that FAN may yield less accurate correction than FALP. Prospectively collected data of a consecutive cohort of patients who underwent valgus deformity femoral correction with FAN or FALP at a single institution over an 8-year period were retrospectively evaluated. Twenty extremities (18 patients) were treated using FAN (median follow-up, 5 years; range, 1-10 years), and 7 extremities (6 patients) were treated with FALP (median follow-up, 5 years; range, 1-8 years). In the FAN cohort, the mean preoperative and postoperative mechanical lateral distal femoral angles (mLDFAs) were 81° (range, 67°-86°) and 89° (range, 80°-100°), respectively (P = .009). In the FALP cohort, the mean preoperative and postoperative mLDFAs were 80° (range, 71°-87°) and 88° (range, 81°-94°), respectively (P < .001). Although the average mechanical axis deviation correction for the FALP group was greater than for the FAN group (32 mm and 27 mm, respectively), the difference was not significant (P = .66). Both methods of femoral deformity correction can be considered safe and effective. On the basis of our results, FAN and FALP are comparable in accuracy for deformity correction in the distal femur.

Basal elevated serum calcium phosphate product as an independent risk factor for mortality in patients with fractures of the proximal femur-A 20 year observation study.

INTRODUCTION: Fractures of the proximal femur are a significant cause of mortality and morbidity in the elderly population. Yet predictive marker of unfavourable prognosis are still lacking. Calcium phosphate product is a marker of osteo-renal dysregulation. This study investigated the role of serum calcium phosphate product (SCPP) levels as a prognostic parameter for outcome in those patients. PATIENTS AND METHODS: A total of 3577 consecutive patients with diagnosed fractures of the proximal femur were included in our study (72.5% females). SCPP was divided into tertiles: <1.92mmol(2)/l(2), 1.93-2.38mmol(2)/l(2) and >2.39mmol(2)/l(2). Data collection was performed prospectively and statistical evaluation was performed retrospectively. RESULTS: Mean follow up in our study group was 11.0±0.3 months. The mean age of our study group was 79.0 years (SEM ±14 years). To facilitate analysis, patients were divided in two groups: ≤84 years (64.4%) and ≥85 years (35.6%), and mortality <12 months was 12.4% (n=445). In our study population higher SCPP levels ad admission were associated with a markedly elevated mortality. In a multivariate logistic regression model adjusted for age and sex, plasma creatinine and haemoglobin at admission caused a 1.3 (CI: 1.01-1.6) for SCPP 1.93-2.38mmol(2)/l(2), and a 1.6 (CI: 1.2-2.0) for SPP >2.39mmol(2)/l(2) fold increase in overall mortality compared to patients with baseline SCPP levels (<1.92mmol(2)/l(2)) as reference category. CONCLUSION: Those findings in our study population with 3577 patients over a period of 20 years proved to be, that serum Ca levels may be a good predictor for mortality in patients with fracture of the proximal femur. Further studies are required to evaluate whether these high risk patients might benefit from specific therapeutic measurements. This prognostic factor may help to increase the outcome of elderly patients with a fracture of the proximal femur.

Management of bite wounds in children and adults-an analysis of over 5000 cases at a level I trauma centre.

BACKGROUND: Bite wounds are among the commonest types of trauma to which man is the subject. They account for 5 % of the total traumatic wounds evaluated in the emergency department (ED) and approximately 1 % of all the ED visits. Early estimation of infection risk, adequate antibiotic therapy and if indicated surgical treatment are the cornerstones of successful cure of bite wounds. METHODS: A total of 5248 consecutive trauma patients were collected prospectively and analysed retrospectively over a period of 15 years in this study at a level I trauma centre, Department of Trauma Surgery, Medical University of Vienna, Austria. RESULTS: The mean age was 33.8 years (range 0-97), 2620 (49.9 %) were male and 2628 (50.1 %) were female individuals. In our study population, a total of 2530 dog bites (48.2 %), 930 cat bites (17.8 %), 357 other animal bites (6.8 %), 426 human bites (8.1 %) and 1005 human self-bites (19.2 %) have been observed. A total of 995 wounds (19.0 %) have been infected. Surgery was done in 132 wounds (2.5 %). CONCLUSION: We could show a six times higher infection rate of cat bites compared to dog bites. Human bites showed a total infection rate of 8.2 %. Observed infection rate of puncture wounds and wounds greater than 3 cm was 1.5 times higher than for all other wounds in the present study. Total infection rates within 24 h to antibiotic administration was 29.3 %, compared to 65.0 % < 48 h and 81.1 % < 72 h. Time interval also influenced the overall outcome showing a 2.6 increase in acceptable and 1.3 increase in poor outcome after 72 h.

Nerve compression and pain in human volunteers with narrow vs wide tourniquets.

AIM: To assess the clinical effects and the morphological grade of nerve compression. METHODS: In a prospective single-center randomized, open study we assessed the clinical effects and the morphological grade of nerve compression during 20 min of either a silicon ring (group A) or pneumatic tourniquet (group B) placement variantly on the upper non-dominant limb in 14 healthy human volunteers. Before and during compression, the median and radial nerves were visualized in both groups by 3 Tesla MR imaging, using high resolutional (2.5 mm slice thickness) axial T2-weighted sequences. RESULTS: In group A, Visual analog pain scale was 5.4 ± 2.2 compared to results of group B, 2.9 ± 2.5, showing a significant difference (P = 0.028). FPS levels in group A were 2.6 ± 0.9 compared to levels in group B 1.6 ± 1, showing a significant difference (P = 0.039). Results related to measureable effect on median and radial nerve function were equal in both groups. No undue pressure signs on the skin, redness or nerve damage occurred in either group. There was no significant difference in the diameters of the nerves without and under compression in either group on T2 weighted images. CONCLUSION: Based on our results, no differences between narrow and wide tourniquets were identified. Silicon ring tourniquets can be regarded as safe for short time application.

Basal haemoglobin levels as prognostic factor for early death in elderly patients with a hip fracture--A twenty year observation study.

INTRODUCTION: Hip fractures are a significant cause of mortality and morbidity in the elderly. This study investigated the relationship between initial haemoglobin (Hb) levels and a prognostic parameter for outcome in those patients. PATIENTS AND METHODS: A total of 3595 consecutive patients with diagnosed hip fractures were included in our study (72.2% females). Anaemia was defined according to WHO criteria, with according subgroups mild, moderate and severe anaemia. Data collection was performed prospectively and statistical evaluation was performed retrospectively. RESULTS: Mean follow up in our study group was 11.2 ± 0.3 months. The mean age of our study group was 78.5 years (SEM ± 0.2 years). To facilitate analysis, patients were divided in two groups: ≤ 84 years (60.1%) and ≥ 85 years (39.9%). Mortality <12 months was 12.2% (n = 439). In our study population lower Hb levels ad admission were associated with a markedly elevated short-term mortality. In a multivariate logistic regression model adjusted for age and sex, mild anaemia at admission caused a 1.5 (CI: 1.1-1.9), moderate anaemia a 2.6 (95 CI: 2.0-3.4), and severe anaemia a 3.6 (CI: 1.8-6.9) fold increase in three months mortality compared to patients without anaemia. Total lymphocyte count (1.2 ± 0) did not show any differences between the subgroups. CONCLUSION: Those findings in our study population with 3595 patients over a period of twenty years have proven that initial Hb levels are a useful and cost effective parameter to predict mortality in elderly patients with a hip fracture. This prognostic factor may help to increase the outcome of elderly patients with a hip fracture.

Primary anterior cruciate ligament reconstruction in athletes: a 5-year follow up comparing patellar tendon versus hamstring tendon autograft.

INTRODUCTION: ACL reconstruction with quadruple hamstring graft (HT) as well as bone-patellar tendon-bone autograft (PT) is a frequent procedure in athletes after ACL rupture. Both techniques are reported to provide for satisfying results but only few articles compare both techniques. MATERIAL AND METHODS: Prospective evaluation was performed on 96 patients with isolated ACL rupture undergoing reconstruction with a HT or PT autograft by a single surgeon at our institution. Long time follow-up after five years included the IKDC and KOOS evaluation form as well as clinical assessment (ROM, Lachmann testing, KT-2000). RESULTS: Comparing both methods revealed no significant differences regarding IKDC and KOOS. The KT-2000 arthrometer testing showed a slightly increased mean laxity in the HT group. There were no differences regarding harvest side symptoms comparing HT and PT as well as one and two incision technique. Kneeling pain was significantly less common after HT autograft. HT as well as PT autograft achieve equally good clinical results in athletes at five year follow-up with no significant difference regarding knee stability. Although no difference concerning the harvest site was identified, HT seems to be favorable for patients who work in a kneeling position.

The modified Harrington procedure for metastatic peri-acetabular bone destruction.

PURPOSE: We describe the outcome in a series of patients treated for metastatic peri-actetabular and iliac bone destruction using a modified technique of Harrington's procedure. METHODS: Between 2006 and 2012, nine patients with a mean age of 62.2 years (42-75 years) were treated using a modified Harrington technique. Thereby, total hip replacement implants augmented by two to three threaded pins and cement were used to restore bony continuity of the pelvis and to achieve a stable construction allowing immediate full-weight bearing mobilisation. RESULTS: Acetabular destruction was graded according to Harrington's classification of peri-acetabular metastatic destruction, as class IV in one case, class III in six, and class II in two cases. The pre-operative ASA score ranged from II-IV. There were no intra-operative deaths or major complications such as excessive haemorrhage, deep infections, lesions of the femoral nerve, loss of fixation, or dislocations at final follow-up. Eight patients achieved an improvement of their functional status postoperatively. One reconstruction required revision and four patients died due to their underlying disease ten to 36 months after surgery. CONCLUSION: We found this technique an effective, reproducible, and long-lasting method to relieve pain and improve or restore function in patients with destructive metastatic lesions of the peri-acetabular bone and the iliac wing. Although we performed surgery even in severely ill patients with extended, generalised metastatic disease we had no intra- or postoperative death and observed no major complications.

Incidence and analysis of open fractures of the midshaft and distal femur.

BACKGROUND: The purpose of this study was to determine whether different forms of stabilization for open femur fractures can be performed without influencing outcome, in particular infection and delayed unions/nonunions. Although the traditional management of these injuries is external fixation, a trend toward definitive stabilization techniques has evolved in the current literature. METHODS: All open fractures of the femur shaft and the distal femur presenting to our urban Level I trauma center during a 10 year period were reviewed. A total of 40 patients (41 fractures) were initially treated at the above institution within 6 h of injury. All patients underwent emergent wound irrigation, debridement, and antibiothic theraphy. The method of fracture immobilization was left to the discretion of the attending trauma surgent. Study population consited of 12 (29 %) GI, 10 (25 %) GII, and 19 (46 %) GIII fractures. RESULTS: Initially, fracture management was performed with external fixation (EF) 19 (43.2 %), intramedullary nailing (IM) 18 (38.6 %), plating (PL) 3 (6.8 %), screw fixation (SF) 1 (2.3 %) and without treatment 4 (9.1 %). In all, 3 (6.8 %) fractures were complicated by infection, 7 (15.9 %) had implant failure, and 5 (11.4 %) developed delayed union. CONCLUSIONS: Using external fixation in acute fracture treatment for open femur fractures is a safe and effective surgical technique. Based on our results, external fixation might be superior to intramedullary nailing or plating when evaluating outcome parameters and complications.

Incidence and analysis of radial head and neck fractures.

AIM: To investigate several complications like persistent radial head dislocation, forearm deformity, elbow stiffness and nerve palsies, associated with radial head fractures. METHODS: This study reviewed the clinical records and trauma database of this level I Trauma Center and identified all patients with fractures of the radial head and neck who where admitted between 2000 and 2010. An analysis of clinical records revealed 1047 patients suffering from fractures of the radial head or neck classified according to Mason. For clinical examination, range of motion, local pain and overall outcome were assessed. RESULTS: The incidence of one-sided fractures was 99.2% and for simultaneous bilateral fractures 0.8%. Non-operative treatment was performed in 90.4% (n = 947) of the cases, surgery in 9.6% (n = 100). Bony union was achieved in 99.8% (n = 1045) patients. Full satisfaction was achieved in 59% (n = 615) of the patients. A gender related significant difference (P = 0.035) in Mason type distribution-type III fractures were more prominent in male patients vs type IV fractures in female patients-was observed in our study population. CONCLUSION: Mason type I fractures can be treated safe conservatively with good results. In type II to IV surgical intervention is usually considered to be indicated.

The management of bite wounds in children--a retrospective analysis at a level I trauma centre.

INTRODUCTION: Animal bite wounds are a significant problem, which have caused several preventable child deaths in clinical practice in the past. The majority of bite wounds is caused by dogs and cats, and also humans have to be considered to lead to those extreme complicated diagnosis in the paediatric patient population. Early estimation of infection risk, adequate antibiotic therapy and, if indicated, surgical treatment, are cornerstones of successful cures of bite wounds. However, antibiotic prophylaxis and wound management are discussed controversially in the current literature. In our study, we retrospectively investigated the bite source, infection risk and treatment options of paediatric bite wounds. METHODS: A total of 1592 paediatric trauma patients were analysed over a period of 19 years in this retrospective study at a level I trauma centre, Department of Trauma Surgery, Medical University of Vienna, Austria. Data for this study were obtained from our electronic patient records and follow-up visits. In our database, all paediatric patients triaged to our major urban trauma centre have been entered retrospectively. RESULTS: During the 19-year study period, 1592 paediatric trauma patients met the inclusion criteria. The mean age was 7.7 years (range 0-18.9), 878 (55.2%) were males and 714 (44.8%) were females. In our study population, a total of 698 dog bites (43.8%), 694 human bites (43.6%), 138 other bites (8.7%) and 62 cat bites (3.9%) have been observed. A total of 171 wounds (10.7%) have been infected. Surgical intervention was done in 27 wounds (1.7%). CONCLUSION: Gender-related incidence in bite wounds for dog and cat could be detected. Second, our findings for originator of bite wounds reflect the findings in the published literature. Total infection rate reached 10.7%, primary antibiotic therapy was administered in 221 cases (13.9%) and secondary antibiotic therapy in 20 (1.3%) cases. Observed infection rate of punctured wounds and wounds greater than 3 cm was 3 times higher than for all other wounds. Our findings need to be proven in further prospective clinical trials.

CK/CK-MB ratio as an indirect predictor for survival in polytraumatized patients.

BACKGROUND: Accurate assessment of injury severity is critical for decision making related to the prevention, triage, and treatment of several injured patients. Early estimation of mortality risk of critically injured patients is mandatory for adequate therapeutic strategies. Current risk stratification relies on clinical diagnosis and scoring systems. In our study, we hypothesized whether a simple laboratory test, the CK/CK-MB ratio, could help improving risk prediction in severely traumatized patients. METHODS: In a 9-year period, 328 nonselected trauma patients were included in our retrospective study at a Level I Trauma Center up to September 2002. Data for this study were obtained from our computerized trauma database, established in September 1992. RESULTS: In our study population, we could show a negative correlation between Injury Severity Score (ISS) and leukocytes. A positive correlation was detected for liver enzymes and CK-MB. The correlation between ISS and Na(+) was significant. No correlation between ISS, K(+), and Hb/Ht could be observed. Exitus was associated with ISS, alteration in thrombocytes, CK, CK-MB, CRP, Crea, and Na(+). CONCLUSION: In our study population, CK-MB levels showed a significant correlation with overall surveillance in polytraumatized patients. In our opinion, this might suggest that CK-MB levels could be taken as an indirect predictor for survival. Our findings need to be proven in further prospective clinical trials.

Splenic decapsulation after gastroscopy.

Sanguineous splenic complications in elective treatment procedures remain a potentially life-threatening complication in patients of all age groups. In this case, the patient, as per her past medical history, underwent a laparoscopic appendectomy when she was admitted to the clinic. One of the diagnostic procedures to find the reason for the epigastric pain, a gastroscopy, can retrospectively be held responsible for decapsulation of the spleen.

The ability of fluconazole to penetrate into ventilated, healthy and inflamed lung tissue in a model of severe sepsis in rats.

BACKGROUND/AIMS: We measured the extracellular concentrations of fluconazole in lung tissue of septic and healthy rats. METHODS: A single intravenous dose of 6 mg/kg total body weight of fluconazole was administered intravenously to rats following insertion of microdialysis probes into lung tissue. Another probe was inserted into skeletal muscle and served as control. RESULTS: The mean peak concentration (C(max)), time to C(max), area under the concentration-versus-time curve from 0 to 6 h (fAUC(0-6)) and area under the concentration-versus-time curve from 0 to ∞ of unbound fluconazole for healthy lung were 11.0 ± 2.3 mg/l, 1.9 ± 1.5 h, 47.4 ± 8.6 mg·h/l and 233.7 ± 121.1 mg·h/l, respectively. The corresponding values for inflamed lung were 11.8 ± 1.7 mg/l, 1.5 ± 0.0 h, 52.9 ± 6.2 mg·h/l and 212.6 ± 79.7 mg·h/l, respectively. The mean apparent terminal elimination half-lives of fluconazole ranged from 12.3 to 22.4 h between compartments. The ratios of the fAUC(0-6) for lung to the fAUC(0-6) for plasma were 1.38 ± 0.39 and 1.32 ± 0.04 for healthy and inflamed lung, respectively. CONCLUSION: We provide evidence that free fluconazole levels in plasma, the extracellular space fluid of lung tissue and skeletal muscle are almost superimposable during inflammatory and normal conditions.

Bone graft harvesting using the RIA (reaming irrigation aspirator) system - a quantitative assessment.

INTRODUCTION: Autologous bone graft is still considered to be the gold standard for treating non-unions in trauma and orthopedic surgery. Intramedullary bone graft harvest appears to be an alternative to other bone graft options such as iliac crest bone graft and synthetic bone substitutes. A one-step reamer-irrigator-aspirator (RIA) system has been developed to reduce the intramedullary pressure and, as a consequence, minimize the risk of fat embolization. The purpose of this study was to determine whether the quantity of harvested intramedullary bone graft is comparable to the quantity of graft that was harvested from the iliac crest in other studies. The aim of the present study was to quantify harvested bone marrow and to compare our results to already published data. METHODS: Eight human cadavers (7 males, 1 female, and 16 limbs) with an average age of 68 years (range, 49-79 years) were obtained for this study. Intramedullary reaming was performed in the tibiae and femora of each cadaver. Two different sizes (12- and 14-mm diameter) of the RIA system were used. After a medial parapatellar incision was made at the knee, antegrade and retrograde reaming were performed in the tibiae and femur to harvest bone graft. RESULTS: A significantly greater quantity of bone graft was harvested from the femora (27 ± 12 g) than the tibiae (17 ± 9 g) (p = 0.007). CONCLUSIONS: On the basis of our present results, harvesting intramedullary bone graft with the RIA system appears to be an innovative technique for bone grafting in limb reconstruction. A significantly greater quantity of bone graft was harvested from the femora than the tibiae (p = 0.007). No significant differences among age, sex, body weight, bone length, or BMI were observed. Our results showed that a sufficient quantity in weight of autogenous bone graft could be obtained using the RIA system.

Coagulation factor VIII levels are associated with long-term survival - interactions with gender in a large hospital-based cohort.

INTRODUCTION: Elevated coagulation factor VIII activity has been associated with increased risk for both venous and arterial thrombosis. The current study evaluated the influence of Factor VIII levels and interactions with gender on all cause mortality in a large Austrian cohort. PATIENTS AND METHODS: During 1991 and 2003, 11203 individuals, first ever request for laboratory analyses of FVIII: C, age > or =18 years, were included in this study. The median observation period was 5 years covering a total of 46000 person-years. The death rate was 17.1%. RESULTS: Compared to individuals within the reference category (FVIII: C <94%) hazard ratios gradually increased from 1.4 (95% CI: 1.1-1.8) in the 152-170% category (5th decile) to finally 4.4 (95% CI: 3.5-5.5) in the >313% category (highest decile, all p < 0.05). The association between FVIII: C levels and mortality remained essentially unchanged when considering non-cancer mortality, all cause vascular mortality or mortality due to ischemic heart disease. Compared to males females with elevated FVIII: C had a worse outcome resulting in higher hazard ratios reaching 6.8 (95% CI: 4.6-9.9) within the highest decile compared to males (HR: 3.4 (95% CI: 2.6-4.5)). CONCLUSIONS: In our large patient cohort we might be able to demonstrate for the first time that FVIII: C plasma activity is strongly associated with all cause mortality. Additionally, FVIII: C appears to interact with gender. Especially in women FVIII: C might help identifying high-risk cohorts, which might benefit from individualized prevention strategies.

The EGF 61A/G polymorphism - a predictive marker for recurrence of liver metastases from colorectal cancer.

BACKGROUND: Epidermal growth factor (EGF) plays an important role in tumorigenesis. Variations in the DNA sequence of the gene EGF can lead to alterations in EGF activity, which is suspected to influence tumor progression. This retrospective study aimed to investigate the influence of EGF 61A/G polymorphism on the recurrence of liver metastases after hepatic surgery in patients with colorectal cancer. METHODS: EGF 61A/G polymorphism was determined in 268 consecutive patients (175 [65%] men and 93 [35%] women, mean age 62 +/- 10.3 years) who had liver metastases at primary diagnosis and were treated by surgery with curative intent (R0) for liver metastases from colorectal cancer. RESULTS: Overall, 81 of 268 (30%) patients exhibited wild-type EGF 61 A/A, 137 (51%) were heterozygous EGF 61 A/G and 50 (19%) were homozygous EGF 61 G/G. After adjusting for age, sex, UICC stage and tumor location, we observed a trend-wise 1.6-fold increased risk for hepatic recurrence (HR 1.6; 95% CI 1.0-2.5, P = 0.06) in individuals with the G/G genotype compared with carriers of the A-allele. The effect was much more pronounced in younger patients (or= 65 years). Interestingly, male patients with EGF G/G had a 1.6-fold higher risk of recurrence (HR 1.6; 95% CI 1.0-2.5, P = 0.07). A significant correlation (P = 0.033) was detected between Dukes classification and the homozygous 61 G/G genotype. CONCLUSION: Despite the limitations of our study, the retrospective results indicate that carriers of the EGF polymorphism might be at higher risk of developing liver recurrences. If confirmed in subsequent studies, genotyping for the EGF A/G variant might help in identification of patients at high risk of recurrence of liver metastases.

The inflammatory response is influenced by FXIII VAL 34 LEU polymorphism in a human LPS model.

BACKGROUND: In sepsis, activation of coagulation and inhibition of fibrinolysis lead to microvascular thrombosis. The Val34Leu polymorphism affects the function of FXIII by increasing the rate of FXIII activation by thrombin, which results in an increased and faster rate of fibrin stabilization. Sepsis and multi-organ failure cause disturbance of the normal balance of inflammation and coagulation, one of the most frequent causes of death in ICU patients. Research in polymorphism has shown the possible influence of FXIII in coagulation and inflammation. METHODS: We analyzed the influence of the common FXIII Val34Leu polymorphism on inflammatory and coagulation parameters in human experimental endotoxinemia. Healthy volunteers (n = 62) received 2 ng endotoxin (LPS) per kg body weight as a bolus infusion over 2 min. We developed a new mutagenic separated PCR assay for determination of the FXIII promoter polymorphism. RESULTS: FXIII levels were higher for homozygous carriers of the FXIII polymorphism in comparison with wild-type 34 Val/Val and heterozygous 34 Val/Leu. Interestingly, persons homozygous for the FXIII Val34Leu polymorphism had lower monocyte and neutrophil counts throughout the observation period, yet prothrombin fragment 1+2 and D-dimer levels did not differ after LPS challenge. CONCLUSION: Our findings indicate that the common FXIII Val34Leu polymorphism is associated with differences in monocyte and neutrophil cell counts in response to systemic LPS infusion in humans.

Comparison of a treatment strategy combining CCI-779 plus DTIC versus DTIC monotreatment in human melanoma in SCID mice.

This study compares the antineoplastic potential of a novel treatment strategy combining cell cycle inhibitor-779 (CCI-779) plus dacarbazine (DTIC) versus DTIC monotreatment, the current chemotherapeutic mainstay in combating metastatic melanoma. A controlled four-group parallel study design comprising 24-40 mice per tumor cell line was used in a severe combined immunodeficiency (SCID)-mouse xenotransplantation model. SCID mice were injected with 518A2, Mel-JUSO, or 607B human melanoma cells. After they developed tumors, mice received daily CCI-779 or solvent over 14 days. From treatment day 4-8 mice were additionally injected with DTIC or saline. Treatment with CCI-779 plus DTIC was superior to single agent DTIC in two out of three cell lines (P<0.05). The tumor weight reduction was 44+/-17 and 61+/-6% compared with DTIC monotreatment in Mel-JUSO and 607B melanomas, respectively (P<0.05). In contrast, in 518A2 xenotransplants, CCI-779 plus DTIC treatment was as effective as DTIC monotreatment. CCI-779 monotherapy exerted no statistically significant antitumor effect. Collectively, these data indicate that CCI-779 has the potential to increase the chemotherapeutic efficacy, as the combination of CCI-779 plus DTIC proved to be more efficacious compared to DTIC monotherapy in two out of three melanoma cell lines in vivo.

The fibrinogen -148 C/T polymorphism influences inflammatory response in experimental endotoxemia in vivo.

INTRODUCTION: The acute phase reactant fibrinogen plays a critical role in the coagulation system and inflammation. Recently several polymorphisms have been described regulating basal and peak fibrinogen expression. We evaluated the role of a frequent promoter polymorphism in the beta chain of the fibrinogen gene (-148 C/T) in a human in vivo model of experimental endotoxemia. MATERIAL AND METHODS: Healthy volunteers received 2 ng/kg endotoxin (LPS, n=73) as a bolus infusion over 2 min. Blood samples were collected by venipunctures into EDTA anticoagulated vacutainer tubes before LPS infusion. For determination of the fibrinogen promoter polymorphism, we developed a new mutagenic separated polymerase chain reaction assay. RESULTS: Carriers of the -148 T allele had significantly lower TNFalpha expression throughout the whole time course of LPS stimulation and Interleukin-6 levels were trendwise lower, however only basal levels reached statistical significance. No effects were observed on markers of coagulation activation (D-Dimer, Prothrombin F(1+2)). CONCLUSION: Our findings indicate, that the common -148 C/T polymorphism is associated with differences in the TNFalpha release in response to systemic LPS infusion in humans, and add to current evidence that gene-sequence changes in beta-fibrinogen locus can alter the ability of the host to respond to endotoxin.

The tumor necrosis factor alpha -308 G/A polymorphism does not influence inflammation and coagulation response in human endotoxemia.

Tumor necrosis factor (TNF)-alpha plays a major role in the immune system. Release of proinflammatory cytokines, such as TNF-alpha and interleukin 6, by macrophages and other cells occurs in response to bacterial products. It has been reported that the TNF-alpha -308 G/A polymorphism in the TNF-alpha gene determines basal TNF-alpha levels. We hypothesized that it may also be associated with the degree of inflammatory response in a well-standardized model of systemic inflammation. Eighty-seven young men (age range, 19-35 years) received 2 ng/kg i.v. endotoxin (lipopolysaccharide [LPS]). The TNF-alpha promoter genotype was analyzed on a TaqMan genomic analyzer. Inflammation markers (interleukin 6, TNF-alpha), temperature, and coagulation markers (prothrombin fragment F1+2, D-dimer) were measured at 0, 2, 6, and 24 h after LPS infusion. Tumor necrosis factor-alpha plasma concentrations increased from a baseline 1.3 ng/L (range, 0.8-3.1 ng/L) before LPS infusion to a peak of 57.5 ng/L (range, 10.8-131.4 ng/L) at 2 h after LPS and then decreased continually to 10.8 ng/L (range, 4.7-16.5 ng/L) after 6 h and returned to baseline values after 24 h (1.9 ng/L [range, 1.1-3.9 ng/L]). We observed no significant differences in TNF-alpha baseline levels or in response to LPS after stratification of the data according to TNF-alpha genotype. Basal and peak values of selected inflammatory and coagulation markers were not different between wild-type TNF-alpha -308 individuals (GG) and carriers of the TNF-alpha -308 mutant allele (GA and AA). The TNF-alpha -308 G/A polymorphism does not contribute significantly to the individual variability of systemic TNF-alpha plasma concentrations after endotoxin challenge. Thus, if any, the impact of the TNF-alpha -308 G/A polymorphism on systemic endotoxin-triggered inflammation seems to be limited.