Treatment with soluble tumor necrosis factor receptor (sTNFR):Fc/p80 fusion protein ameliorates relapsing-remitting experimental autoimmune encephalomyelitis and decreases chemokine expression

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease with pathological and clinical similarities to the major human demyelinating disease multiple sclerosis (MS). Multiple lines of evidence in recent years implicate the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of both EAE and MS. TNF-alpha cellular responses are mediated by signaling through receptors, which are expressed in two functional forms, designated according to molecular weight p55/60 and p75/80. We report a treatment trial using the extracellular domain of the p80 TNFR in a bivalent fusion construct designated soluble tumor necrosis factor receptor (sTNFR):Fc to treat EAE. sTNFR:Fc/p80, given after the onset of clinical signs, reduced the clinical deficit of the first attack of relapsing-remitting EAE (RR-EAE) and the exacerbation rate for subsequent attacks. The effect was reversible as mice treated with sTNFR:Fc/p80 reverted to an exacerbation rate and disease severity typical of placebo-treated animals after treatment was discontinued. Treatment of RR-EAE with sTNFR:Fc/p80 decreased expression of chemokines MIP-1alpha (Monocyte Inflammatory Protein)/CCL3, MIP-1beta/CCL4 and MIP-2/CXCL1-2 in the central nervous system. This treatment trial reveals an important function of TNF in the pathogenesis of RR-EAE and propose the mechanism of beneficial action of sTNFR:Fc/p80 in this disease.     

Effect of experimental diabetes on pharmacokinetic parameters of lidocaine and MEGX in rats

The aim of the study was to evaluate the effect of experimental diabetes on pharmacokinetic parameters of lidocaine and its metabolite monoethyl-glycylxylidide (MEGX) after a single intravenous administration in rats. The study was performed on male Wistar rats, randomized into 2 groups: group I--control animals and group II--animals with experimental diabetes induced by streptozotocin. Evaluation of lidocaine pharmacokinetics was performed 10 days after streptozotocin administration. Lidocaine concentrations were lower in rats with experimental diabetes compared with the values in the control group. In rats with diabetes, the shorter phase of distribution and faster drug elimination has been observed. During the pharmacokinetic study, the dynamic reduction of lidocaine concentration was accompanied by the increase in MEGX concentration in blood. Drug elimination rate constant (gammaz) increased by 68% in rats with experimental diabetes which had an effect on the shortening of lidocaine half-life in those animals (t1/2 by 39%) and on the increase in absolute clearance (CL) to 1.46 l/h comparing to control group (0.95 l/h), i.e. by 54%. The distribution rate constant of lidocaine (gamma1) was significantly greater in the animals with experimental diabetes (by 138%). The volume of distribution (Vd) in those animals decreased by 30% in comparison with the control group. The area under the plasma concentration-time curve (AUC) decreased by 48% in rats with experimental diabetes. The MEGX half-life (t1/2) increased from 0.34 h in the control group to 0.89 h in the rats with diabetes, i.e. by 165%. It reflects the impaired MEGX elimination in experimental diabetes. The results suggest that experimental diabetes can have an effect on lidocaine pharmacokinetics towards enhanced lidocaine elimination with accompanied increase in its metabolite (MEGX) concentration.     

The effect of plant phenolics on the formation of 7,12-dimethylbenz[a]anthracene-DNA adducts and TPA-stimulated polymorphonuclear neutrophils chemiluminescence in vitro

Phenolics, common plant constituents, form up an important part of human diet and are considered potential chemopreventive agents. In the present study, structurally diverse phenolics, such as tannic acid, protocatechuic acid, chlorogenic acid and resveratrol, were investigated for their inhibitory effects on covalent binding of 7,12-dimethylbenz[a]anthracene (DMBA) to DNA in vitro and the suppression of oxidative burst in 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated human polymorphonuclear neutrophils (PMNs). 32P-postlabeling analysis of DNA incubated with DMBA in the presence of 3-methylcholanthrene (3-MC)-induced microsomes produced three major adducts derived from anti-, syn- and anti-dihydrodiol epoxides through reactions with dGuo and dAdo, respectively. Phenolic compounds at the concentration of 150 microM reduced the levels of all DMBA-DNA adducts by 55-98%. The most dramatic effect was observed in case of tannic acid, which completely inhibited the formation of DMBA-dAdo adducts. Chlorogenic acid was the least effective inhibitor of DMBA-DNA adducts formation particularly syn-DMBADE-dAdo (20%). Human neutrophils showed a significant dose-related decrease of TPA-induced chemiluminescence after pretreatment with phenolic compounds. The most effective inhibitors were tannic acid and resveratrol with IC(50)=5.19 and 5.76 microM, respectively. These results suggest that the suppression of reactive oxygen species (ROS) and carcinogen-DNA adducts formation may be important for anticarcinogenic activity of the examined phenolics.     

Fracture, osteosynthesis, union of fractured bones - historical reflections

This article presents the review of the achievement and progress in fracture treatment from ancient ages till XXth century. There was shown the development of the conservative treatment - creating the suitable immobilizing splints, casts and the first surgical procedures, equipment, plates, screws, nails for the osteosynthesis. Besides there were presented the first observations and remarks of former researcher on biology of the fracture healing process.     

Additional pulmonary resections after pneumonectomy: actual long-term survival and functional results

Objective: Pulmonary resections after pneumonectomy due to metastases or metachronous non-small cell lung cancer (NSCLC) are rare because of the high potential risk of the second procedure and uncertain long-term results. On the basis of our series (largest in Europe) we tried to assess the long-term survival of patients treated in stage IV NSCLC. Methods: Retrospective analysis was carried out on 18 patients treated at our department by pneumonectomy followed by additional resection in the years 1981-2002 (15 males and 3 females, 44-69 years, mean 57). Eleven pneumonectomies were performed on the right side and seven on the left. Twelve squamous cell carcinomas and six adenocarcinomas were diagnosed. All patients were staged postoperatively as IIB-IIIA (four were N2). Their WHO status ranged between 0 and 1. The second surgical procedure (16 wedge resections, 2 chest wall resections) was performed 4-106 months later (mean 26). The patients staged N2 were radiated postoperatively. Results: There were no early postoperative deaths. The morbidity rate after second surgery was comparable to that observed after ordinary wedge resection. Histology of the lesions removed during the second operation was the same as after pneumonectomy in all patients. The pulmonary function tests (PFT) results worsened significantly but still reached 56-63% of the predicted values. Sixteen resected tumors of the remaining lung were staged T1 (<3cm), 2 - T3 (<3cm but infiltration of the parietal pleura on an area of 2-4cm(2)). Three patients revealed N2 disease (they were all N0 after pneumonectomy). All patients were considered M1 after second surgery. WHO status after the second procedure remained the same in 8 patients (44%) and worsened in 10 patients (56%). The survival rates were as follows: 11 patients survived 2 years (61%) while 8 patients survived 5 years (44%). The majority of patients died due to lung cancer (70%) but all the rest (30%) due to circulatory or respiratory insufficiency. There was a significant difference (p<0.05) in 5-year survival for N0-N1 vs N2 status (63% vs 14% - 1 patient) and also regarding the time interval between surgeries: less than 12 months vs more than 12 months (0% vs 63%). Conclusions: Pulmonary resections performed after pneumonectomy due to NSCLC are rare procedures but with an acceptable perioperative risk. The second procedure should be limited to wedge resection. The prognosis is poor for patients with N2 status and for those treated by second surgery earlier than 12 months after the first procedure.     

DeltaF508 CFTR Hetero- and Homozygous Paediatric Patients with Cystic Fibrosis Do Not Differ with Regard to Nutritional Status

The purpose of this study was to compare the nutritional status between deltaF508 CFTR hetero- and homozygous paediatric patients with cystic fibrosis. We assessed the percentage profiles of fatty acids measured in erythrocyte membranes and the serum levels of vitamins A, D3, E and K1 in the studied groups. We also measured the weights and heights and calculated the body mass indexes (BMIs). The studied groups consisted of 34 heterozygous and 30 homozygous patients. No statistically significant differences were found in the serum vitamins or erythrocyte membrane fatty acid profiles between the hetero- and homozygous patient groups, except for heptadecanoic acid (p = 0.038). The mean percentiles of height, weight and BMI did not differ significantly between the two groups. The homozygous and heterozygous paediatric patients with cystic fibrosis were similar in terms of their nutritional statuses.