Evidence for the involvement of the nitric oxide–cGMP pathway in the antinociception of morphine in the formalin test

The effect of inhibition of nitric oxide synthesis and guanylate cyclase on the peripheral antinociceptive effect of morphine was assessed by using the formalin test in the rat. Saline, N^G-monomethyl-

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-arginine, a nitric oxide synthesis inhibitor (50 μg) and methylene blue, a guanylate cyclase inhibitor (500 μg), did not exhibit any antinociceptive activity. However, morphine (10 μg) produced a significant antinociceptive effect in phases 2a and 2b, which was reduced by pretreatment with either N^G-monomethyl-

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-arginine or methylene blue. These results suggest that the local administration of morphine induces antinociception by the activation of the

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-arginine–nitric oxide–cGMP pathway.     

Synergistic antinociceptive interaction between acetaminophen or metamizol and B vitamins in the formalin test

There is evidence that B vitamins produce antinociception in animals. However, potentiation of NSAID‐induced antinociception by B vitamins is unclear. The current study was designed to investigate the antinociceptive interaction between a mixture of B vitamins and either acetaminophen or metamizol. Acetaminophen (56–316 mg/kg), metamizol (32–178 mg/kg), and the mixture of B vitamins (32–178 mg/kg of thiamine, pyridoxine, and cyanocobalamin in a 100:100:1 proportion, respectively) or a combination of each drug with the B vitamins mixture was administered orally to female Wistar rats, and the antinociceptive effect determined in the formalin test. Isobolographic analyses were used to define the nature of the interaction between NSAIDs and B vitamins. Oral administration of either drug produced a dose‐related antinociceptive effect. Isobolographic analyses revealed that both acetaminophen or metamizol and the B vitamins mixture interacted synergistically in the formalin test, suggesting that these two combinations could be useful in treating inflammatory pain states. Drug Dev. Res. 66:286–294, 2006. © 2006 Wiley‐Liss, Inc.     

Hepatic stellate cells and extracellular matrix in hepatocellular carcinoma: more complicated than ever

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer death. Recent epidemiological data indicate that the mortality rate of HCC will double over the next decades in the USA and Europe. Liver cancer progresses in a large percentage of cases during the clinical course of chronic fibro‐inflammatory liver diseases leading to cirrhosis. Therefore, HCC development is regarded as the result of different environmental risk factors each involving different genetic, epigenetic‐ and chromosomal alterations and gene mutations. During tumour progression, the malignant hepatocytes and the activated hepatic stellate cells are accompanied by cancer‐associated fibroblasts, myofibroblasts and immune cells generally called tumour stromal cells. This new and dynamic milieu further enhances the responsiveness of tumour cells towards soluble mediators secreted by tumour stromal cells, thus directly affecting the malignant hepatocytes. This results in altered molecular pathways with cell proliferation as the most important mechanism of liver cancer progression. Given this contextual complexity, it is of utmost importance to characterize the molecular pathogenesis of HCC, and to identify the dominant pathways/drivers and aberrant signalling pathways. This will allow an effective therapy for HCC that should combine strategies affecting both cancer and the tumour stromal cells. This review provides an overview of the recent challenges and issues regarding hepatic stellate cells, extracellular matrix dynamics, liver fibrosis/cirrhosis and therapy, tumour microenvironment and HCC.     

Prothrombin antigen levels in symptomatic and asymptomatic carriers of the 20210A prothrombin variant

A recently discovered variant in the prothrombin gene (20210A) has been found in approximately 5–10% of patients with venous thromboembolism. It has been shown that patients with this variant present with high levels of prothrombin in plasma and this is maintained to be the most likely mechanism by which the risk of thrombosis is increased. We have evaluated prothrombin antigen levels in 50 carriers of the 20210A allele and compared with non-carriers. 327 subjects were subdivided according to deficiency status and previous thrombosis. 30 symptomatic and 20 asymptomatic carriers had increased mean prothrombin levels as compared to symptomatic ( n  = 178) or asymptomatic ( n  = 99) non-carriers. The percentage of subjects with prothrombin levels above cut-off values of 1.15 u/ml or 1.30 u/ml was significantly higher in carriers of the prothrombin variant as compared to non-carriers, regardless of a previous thrombosis. However, among non-carriers the percentage of those with prothrombin levels above cut-off values was significantly higher in the group of symptomatic as compared to asymptomatic individuals. In conclusion, increased prothrombin antigen levels, as detected by a specific ELISA, were found among 50 symptomatic and asymptomatic carriers of the 20210A prothrombin variant as well as among a large group of symptomatic non-carriers. The data are in agreement with those found by using functional tests for the determination of prothrombin levels in these patients.     

Competitive sports activity in subjects undergoing the surgical correction of an ostium-secundum type of interatrial defect: the experience of 9 cases]

Patients who have undergone surgical repair of congenital heart diseases are usually not allowed to participate in competitive sports. In the present study we report our long-term experience with 9 male athletes aged 17 to 23 years who participate in competitive sports after undergoing surgical repair of ostium secundum atrial septal defect at a median age of 9 years; six of them play football and three of them volleyball. Competitive sport activities began 1 to 5 years after surgical repair. The mean duration of follow-up is 88 +/- 26 months. Sport fitness was granted on the basis of the following criteria: 1) a normal physical examination; 2) a normal working capacity on exercise test; 3) no arrhythmias on exercise test and Holter monitoring, recorded also during sport activities; 4) a normal M-mode and two-dimensional echocardiography, including the normalization of right ventricular size; the persistence of an abnormal ventricular septal motion did not exclude sport fitness. Recently we also performed Doppler and color Doppler echocardiography and gated equilibrium radionuclide angiography at rest and during exercise. We studied left ventricular diastolic filling through the pulsed wave Doppler evaluation of transmitral flow and measured cardiac output by continuous wave Doppler echocardiography during exercise test in the supine position. We also performed exercise test and M-mode, two-dimensional, Doppler and color Doppler echocardiography in a control group made up of 15 athletes (10 football players and 5 volleyball players). The exercise duration at graded treadmill exercise test (according to the Carù protocol), the maximal heart rate and the maximal systolic blood pressure were, respectively, 12.9 +/- 0.8 min, 192 +/- 10 beats/min and 198 +/- 12 mmHg. Left ventricular end-diastolic dimension, mass and ejection fraction (single-plane area-length method) were 50.3 +/- 2.8 mm, 210 +/- 38 g and 65 +/- 6%. M-mode right ventricular diastolic dimension was 23.4 +/- 1.6 mm; the right ventricular maximal diastolic diameter and area obtained on two-dimensional echocardiography from the apical four chamber view were 44.1 +/- 3.6 mm and 25 +/- 3.8 cm2 respectively. The evaluation of transmitral flow showed the following data: E velocity 77 +/- 12 cm/sec, A velocity 45 +/- 6 cm/sec, E/A ratio 1.7 +/- 0.3, the isovolumic-relaxation period 72 +/- 8 m/sec and the deceleration half-time of the early rapid filling 71 +/- 10 m/sec. A trivial tricuspid regurgitation was detected in 6 subjects; the peak velocity of the regurgitant jet was less than 2.1 m/sec.(ABSTRACT TRUNCATED AT 400 WORDS)