Evaluation of the effects of anti-thromboxane agents in platelet-vessel wall interaction

We evaluated the capacity of anti-aggregating agents to influence thromboxane A(2) and prostacyclin formation, arachidonic acid-endoperoxide redirection, platelet aggregation and vessel tone, in isolated rabbit aorta incubated with homologous platelets. Picotamide (N,N'bis(3-pyridinylmethyl)-4-methoxy-isophthalamide), the only dual thromboxane A(2)-synthase inhibitor/receptor antagonist in clinical use, inhibited arachidonic acid-induced platelet aggregation with low potency, increased 180-fold by aorta presence. It inhibited thromboxane A(2) formation in platelets and, in aorta presence, increased prostacyclin formation. Ozagrel (OKY-046, (E)-3-(4-(1-imidazolylmethyl)phenyl)-2-propenoic acid), a pure thromboxane A(2)-synthase inhibitor, behaved similarly to picotamide, although the aorta caused a higher (600-fold) shift. The potency of the antagonist SQ 29,548 (1S-(1 alpha,2 beta(5Z),3 beta,4 alpha))-7-(3((2-((phenylamino)carbonyl)hydrazino)methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid) was unaffected by aorta. In coincubation experiments, arachidonic acid-challenge increased thromboxane A(2)-dependent vessel tone; picotamide increased prostacyclin and reduced thromboxane A(2) formation and vasoconstriction. Ozagrel mimicked picotamide; aspirin (acetylsalicylic acid) reduced aorta contractility, thromboxane A(2) and prostacyclin formation. SQ 29,548 reduced vasoconstriction without affecting eicosanoids. We demonstrate the importance of redirection of eicosanoids in the mechanism of action of thromboxane A(2) inhibitors/antagonists within platelet-vascular wall interactions. These findings bear relevance in the development of novel anti-thrombotic drugs.     

Total peripheral vascular resistance in pediatric renal transplant patients

BACKGROUND: Abnormal cardiovascular reactivity at rest and during physical exercise may be a risk factor for left ventricular hypertrophy (LVH) in pediatric renal transplanted (Tx) patients. Data on total peripheral vascular resistance (TPR) are not available. METHODS: Eleven renal Tx patients treated with cyclosporine (7 females and 4 males; mean age 14.6 +/- 3.3 years; mean time since transplantation 43 +/- 35 months) were evaluated for 24-hour blood pressure (BP), TPR and echocardiographic left ventricular mass (LVM). TPR values of patients were compared with data of a group of 11 healthy controls matched for sex and age. RESULTS: Twenty-four-hour ambulatory blood pressure monitoring showed that all but one patient had normal daytime BP values and six patients showed a reduced or inverse nocturnal dip. LVH was found in 72% of the patients. In comparison with healthy controls, patients showed significantly elevated TPR at rest and during exercise suggesting an increased vascular tone. The degree of LVH in these patients is severe and appears disproportionate to the BP values. CONCLUSION: The high incidence of LVH can reflect an augmented cardiovascular reactivity associated with a disturbed circadian pattern. The increase in TPR and the reduction of the nocturnal fall of BP also might contribute to the development of LVH in young renal Tx patients.     

Laparoscopic splenectomy: analysis of 60 consecutive cases

The purpose of the study was to analyze the results of 60 patients who were candidates for laparoscopic splenectomy. Over the period from May 1994 to May 2001, 60 patients were candidates for splenectomy. Laparoscopy was contraindicated in 3 cases because of ASA III and marked splenomegaly (2 cases) and previous gastric resection (1 case). The procedure was indicated for benign disease in 38 cases and for malignant disease in the remainder. Fifty-three procedures were completed laparoscopically (92.9%). Conversion proved necessary in 4 patients (6.7%) due to large incisional hernia, perisplenic abscess, bleeding of major splenic vessels at the hilum and marked splenomegaly (2 cases of lymphoma). The mean operative time was 200 min for the malignancies and 110 min for the benign conditions (P < 0.05). Major morbidity occurred in 5 cases (8.7%). No deaths were registered. The mean postoperative hospital stay was 7.5 days for patients with malignancies and 5.2 days for patients with benign disease (P < 0.05). Laparoscopic splenectomy was safe and effective in patients with benign disease, even in cases of marked splenomegaly. The morbidity rate was significantly higher in lymphoma patients than in patients with benign haematological disorders.     

Mechanisms of apoptosis induced by purine nucleosides in astrocytes

Astrocytes release adenine-based and guanine-based purines under physiological and, particularly, pathological conditions. Thus, the aim of this study was to determine if adenosine induced apoptosis in cultured rat astrocytes. Further, if guanosine, which increases the extracellular concentration of adenosine, also induced apoptosis determined using the TUNEL and Annexin V assays. Adenosine induced apoptosis in a concentration-dependent manner up to 100 microM. Inosine, hypoxanthine, guanine, and guanosine did not. Guanosine or adenosine (100 microM) added to the culture medium was metabolized, with 35% or 15%, respectively, remaining after 2-3 h. Guanosine evoked the extracellular accumulation of adenosine, and particularly of adenine-based nucleotides. Cotreatment with EHNA and guanosine increased the extracellular accumulation of adenosine and induced apoptosis. Inhibition of the nucleoside transporters using NBTI (100 microM) or propentophylline (100 microM) significantly decreased but did not abolish the apoptosis induced by guanosine + EHNA or adenosine + EHNA, respectively. Apoptosis produced by either guanosine + EHNA or adenosine + EHNA was unaffected by A(1) or A(2) adenosine receptor antagonists, but was significantly reduced by MRS 1523, a selective A(3) adenosine receptor antagonist. Adenosine + EHNA, not guanosine + EHNA, significantly increased the intracellular concentration of S-adenosyl-L-homocysteine (SAH) and greatly reduced the ratio of S-adenosyl-L-methioine to SAH, which is associated with apoptosis. These data demonstrate that adenosine mediates apoptosis of astrocytes both, via activation of A(3) adenosine receptors and by modulating SAH hydrolase activity. Guanosine induces apoptosis by accumulating extracellular adenosine, which then acts solely via A(3) adenosine receptors.     

Epidemiologic evidence of cancer risk in textile industry workers: a review and update

A meta-analysis of epidemiologic studies for textile industry workers was undertaken in an attempt to evaluate whether the cancer risk varies within the textile industry in relation to the job held or the textile fiber used. We combined studies published up until 1990, when an ad hoc IARC Monograph was issued, and those published after 1990 with the aim of appreciating evidence of reversing trends in cancer risk. Observed and expected cases reported in the original studies were summed up and the totals were divided to obtain a pooled relative risk (PRR) with a 95% confidence interval (CI) estimated with a fixed-effect model. We calculated a chi-square test (chi2) of heterogeneity among studies. When PRR and chi2 were both significant, PRR and CI were calculated with a random-effect model and the source of heterogeneity was investigated. Lung cancer risk was around 0.4 in the first study on cotton workers published in 1936, around 0.7 in subsequent studies, mostly published in the 1970s and 1980s, and around 1.0 in the last studies published in the 1990s. Papers published in the 1970s and 1980s produced consistent risk estimates for lung cancer risk, which was significantly lower than 1.0 in workers exposed to cotton (PRR = 0.77; CI = 0.69-0.86) and wool dust (0.71; 0.50-0.92), as well as in carders and fiber preparers (0.73; 0.54-0.91), weavers (0.71; 0.56-0.85), and spinners and weavers (0.78; 0.66-0.91). Lung cancer PRRs did not significantly deviate from 1.0 in textile workers using synthetic fibers or silk, and in dyers. Increased PRRs were found for sinonasal cancer in workers exposed to cotton dust, and in workers involved in spinning or weaving (4.14; 1.80-6.49). PRR was 1.46 (1.10-1.82) for cancer of the digestive system in textile workers using synthetic fibers or silk, and 1.34 (1.10-1.59) for colorectal cancer in spinners and weavers. The increased bladder cancer PRR in dyers (1.39; 1.07-1.71) is generally attributed to textile dye exposure. In studies published after 1990, there is a general tendency to move toward unity for all the cancer risk estimates, leading to an increasing heterogeneity among studies. Since adjustment for smoking made little difference to the findings, the latter could be attributed to the exposure to textile dusts. The recent findings could be due to a lowering of dust concentration in the workplaces. The reduction of cases of upper respiratory tract cancer parallels with a corresponding increase of lung cancer cases. So, preventive measures have paradoxically increased the lung cancer burden to the textile workers.     

Expression of CD154 on renal cell carcinomas and effect on cell proliferation,motility and platelet-activating factor synthesis

CD40 activation by CD154 may trigger diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death, in normal and malignant cells. However, the pathophysiologic role of CD154 expressed by tumor cells remains unclear. We have investigated the expression of the CD40-CD154 system in 24 primary cultures derived from renal cell carcinomas, its correlation with tumor stage and its potential functional significance. We found coexpression of CD40 and CD154 in most of the renal carcinoma cell lines. CD154, but not CD40 expression, significantly correlated with tumor stage. Moreover, renal carcinoma cell lines also released the soluble form of CD154 into the supernatant. CD40 engagement by CD154 did not affect apoptosis or survival. On the contrary, CD154 stimulated cell proliferation, motility and production of PAF, a phospholipid mediator of inflammation with angiogenic properties. Furthermore, the renal carcinoma cell lines expressed PAF-R. Blockade of PAF-R by WEB-2170, a PAF-R antagonist, abolished the CD154-dependent motility, indicating a role for PAF synthesized after CD154 stimulation in renal carcinoma cell motility. In conclusion, this study identifies new functional properties for CD154, which are potentially relevant for the growth and dissemination of renal carcinoma cells.     

Effect of thalidomide on the skeletal muscle in experimental heart failure

BACKGROUND: Tumour Necrosis Factor alpha (TNFalpha) has been shown to contribute to heart failure (CHF) progression. AIMS: We have tried to antagonise the detrimental effects of TNFalpha on skeletal muscle apoptosis, by using thalidomide, a drug that inhibits its biosynthesis. METHODS: CHF was induced in 20 rats by injecting monocrotaline, which determines right ventricle (RV) failure. After 2 weeks, when CHF developed, 12 rats were treated with thalidomide 3.5.mg/kg per day for 2 weeks. Eight had saline and served as CHF controls. RESULTS: Thalidomide failed to decrease TNFalpha and its second messenger sphingosine (SPH), but was able to prevent the shift toward the fast myosin heavy chains. In the Tibialis Anterior muscle of the thalidomide group, the degree of atrophy, the number of apoptotic nuclei and the levels of caspases, were similar to those of the CHF controls. CONCLUSIONS: Thalidomide, at the doses used in this study, which are the same employed for the treatment of tubercolosis, leprosy, AIDS and cancer in humans, did not lower either TNFalpha or SPH and only marginally influenced the apoptosis-induced muscle atrophy. Since other TNFalpha blockers are under investigation for improving the clinical status of patients with CHF, the present data could be relevant in the design of randomised clinical trials in humans.     

Traumatic injuries: imaging of facial injuries

Facial injuries are common and require radiologic evaluation to plan treatment. The role of imaging is to detect fractures, describe their morphology and topography, and evaluate adjacent soft tissue damage. Computed tomography is the imaging method of choice for an accurate diagnosis and for depicting the complex anatomic structures of the maxillo-facial region. Magnetic resonance imaging plays a limited role, mainly in the assessment of lesions of orbital soft tissues. This paper reviews the most common traumatic injuries of facial bones, paranasal sinuses, orbits and mandible.