Therapeutic potential of choline magnesium trisalicylate as an alternative to aspirin for patients with bleeding tendencies

We have compared the effects of acetyl salicylic acid (ASA, aspirin) and choline magnesium trisalicylate (CMT), a non-acetylated salicylate product, on platelet aggregation in human whole blood ex-vivo. Using a whole blood platelet counter, platelet aggregation was quantified by measuring the fall in the number of single platelets at peak aggregation in response to collagen, arachidonic acid (AA), as well as spontaneous aggregation. In double blind and random order, 12 healthy volunteers received, on two separate occasions 10 days apart, a single oral dose of 652 mg ASA or 655 mg CMT. Despite a comparable absorption of salicylic acid from the two drugs, ingestion of ASA resulted in a marked inhibition of platelet aggregation induced by collagen (p less than 0.005), AA (p less than 0.01) and spontaneous aggregation (p less than 0.01), whereas such effects were not observed after CMT ingestion. We suggest that CMT may have therapeutic potential as an alternative to aspirin when inhibition of platelet aggregation can induce bleeding complications.     

Angiotensin II stimulates alpha3(IV) collagen production in mouse podocytes via TGF-beta and VEGF signalling: implications for diabetic glomerulopathy.

BACKGROUND: The podocyte is bathed in an angiotensin II (AngII)-rich ultrafiltrate, but the impact of AngII on podocyte pathobiology is not well known. Because podocytes play a direct role in the glomerular basement membrane (GBM) thickening of diabetes, the alpha3(IV) collagen chain was examined. Podocyte expression of alpha3(IV) collagen may involve the transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) systems. METHODS: Cultured mouse podocytes were treated with various doses of AngII for selected periods of time, with or without inhibitors of TGF-beta and VEGF signalling, SB-431542 and SU5416, respectively. TGF-beta1 and VEGF were assayed by enzyme-linked immunosorbent assay (ELISA); alpha3(IV) collagen, TGF-beta type II receptor and phospho-Smad2 were assayed by immunoblotting. RESULTS: AngII >or=10(-10) M was found to stimulate the production of alpha3(IV) collagen significantly in as short a time as 3 h. The expression of alpha3(IV) collagen was influenced by the TGF-beta system, but AngII did not increase the podocyte's production of TGF-beta1 ligand; rather, it increased the expression of the TGF-beta type II receptor and activated the TGF-beta signalling system through Smad2. Despite the TGF-beta receptor upregulation, synergy between AngII and TGF-beta1 to boost alpha3(IV) collagen production was not observed. However, blockade of TGF-beta signalling with SB-431542 prevented AngII from stimulating alpha3(IV) collagen production. Podocyte expression of alpha3(IV) collagen was also increased by the autocrine activity of VEGF. Podocytes were stimulated to secrete VEGF by 10(-10) M or higher AngII after 48 h. Blockade of the endogenous VEGF activity by SU5416 prevented AngII-stimulated alpha3(IV) collagen production. CONCLUSIONS: AngII stimulates the podocyte to produce alpha3(IV) collagen protein via mechanisms involving TGF-beta and VEGF signalling. Alterations in alpha3(IV) collagen production may contribute to GBM thickening and perhaps proteinuria in diabetes.     

Sagittal back contour and craniofacial morphology in preadolescents

The aim of this study was to analyze the correlation ratios between the sagittal back contour (flèche cervicale and lombaire, trunk inclination) and selected parameters of craniofacial morphology in children. The patient sample consisted of 66 healthy children with a mean age of 11.2 years (SD 1.6 years), of which 34 were male (mean age 11.5 years, SD 1.3 years) and 32 were females (mean age 10.9 years, SD 1.9 years). The children were recruited during the preparation of the initial orthodontic treatment records. Craniofacial morphology was analyzed by six angular measurements: facial axis, mandibular plane angle, inner gonial angle, lower facial height, facial depth and maxilla position. Rasterstereography was used for reconstruction of the spinal back sagittal profile. From the profile flèche cervicale, flèche lombaire and trunk inclination were determined and the correlations with the craniofacial morphology were calculated (Pearson and Mann–Whitney U test). Significant correlations were found with respect to the inner gonial angle and the flèche cervicale, the mandibular plane angle and the flèche lombaire, the inner gonial angle and the flèche lombaire, and the angular lower facial height and the flèche lombaire, as well as the inner gonial angle and the trunk inclination. The craniofacial vertical growth pattern, presented by mandibular plane angle, inner gonial angle and the angular lower facial height, and the correlation to flèche cervicale and lombaire as well as trunk inclination reveal correlations between growth pattern and sagittal back contour.     

Angiotensin II-dependent chronic hypertension and cardiac hypertrophy are unaffected by gp91phox-containing NADPH oxidase

The gp91phox-containing NADPH oxidase is the major source of reactive oxygen species (ROS) in the cardiovascular system and inactivation of gp91phox has been reported to blunt hypertension and cardiac hypertrophy seen in angiotensin (Ang) II-infused animals. In the current study, we sought to determine the role of gp91phox-derived ROS on cardiovascular outcomes of chronic exposure to Ang II. The gp91phox-deficient mice were crossed with transgenic mice expressing active human renin in the liver (TTRhRen). TTRhRen mice exhibit chronic Ang II-dependent hypertension and frank cardiac hypertrophy by age 10 to 12 weeks. Four genotypes of mice were generated: control, TTRhRen trangenics (TTRhRen), gp91phox-deficient (gp91-), and TTRhRen transgenic gp91phox-deficient (TTRhRen/gp91-). Eight to 10 mice/group were studied. ROS levels were significantly reduced (P<0.05) in the heart and aorta of TTRhRen/gp91- and gp91-mice compared with control counterparts, and this was associated with reduced cardiac, aortic, and renal NADPH oxidase activity (P<0.05). Systolic blood pressure (SBP), cardiac mass, and cardiac fibrosis were increased in TTRhRen versus controls. In contrast to its action on ROS generation, gp91phox inactivation had no effect on development of hypertension or cardiac hypertrophy in TTRhRen mice, although interstitial fibrosis was reduced. Cardiac and renal expression of gp91phox homologues, Nox1 and Nox4, was not different between groups. Thus, although eliminating gp91phox-associated ROS production may be important in cardiovascular consequences in acute insult models, it does not prevent the development of hypertension and cardiac hypertrophy in a model in which the endogenous renin-angiotensin system is chronically upregulated.     

Comparison of the effect of aspirin and choline magnesium trisalicylate on thromboxane biosynthesis in human platelets: role of the acetyl moiety

Parameters of platelet thromboxane biosynthesis were measured 24 h after ingestion of equivalent salicylate doses (500 mg) of aspirin (ASA) and choline magnesium trisalicylate (CMT), a non-acetylated salicylate. In random order, 10 healthy volunteers received these drugs on 2 separate days, 2 weeks apart. While ASA significantly prolonged bleeding time, and decreased plasma thromboxane generation and serum thromboxane B2 levels, CMT failed to produce such effects. Thus CMT, which lacks an acetyl moiety in its structure, has no inhibitory effect on platelet thromboxane biosynthesis, and may therefore be considered safer than ASA for therapeutic use, when inhibition of platelet function can be hazardous.     

Can we rely on public data as a source of information for cancer registry in developing countries?

BACKGROUND/AIMS: Although a "hospital-based cancer registry" is important in improving patient care, a "population-based cancer registry" with emphasis on epidemiology is important in allocating health care resources and prioritizing public health programs. Because of its reliance on retrieved clinical and para-clinical documents, there is some limitation in registering all cancer incidents in this system, especially in developing countries. In this study we examined the possibility of using public data as a complementary source of information for recording cancers in a population-based cancer registry. METHODS: Along with the annual census in rural areas, a survey was performed in Golestan province in March 2004 to identify public awareness about cancer incidents in the community. Individuals were questioned about history of cancer in their close relatives during the last two years. Those who reported cancer in their relatives were also asked to name the main organ of involvement. A similar list was retrieved from the cancer registry at the Ministry of Health in Gorgan, and cases with upper GI (esophagus and gastric) cancer diagnosis from 21 March 2002 through 20 March 2004 were selected for this study. Finally, these two lists were compared for examining accuracy of the collected data. RESULTS: We included 137 cases in our study with rural residence and known addresses. Only 35 (25.5%) cases were reported by the relatives and among them only 20 (57.1%) relatives correctly reported the tumor location. Although we found a difference in accurate reporting of cancer incidents by year of diagnosis (more correct cases reported during the second versus the first year), the difference was not statistically significant between the two years. CONCLUSION: In this study, we examined the possibility of using public awareness about cancer incidents as a complementary source of information for a population-based cancer registry. We found that this approach is not ideal for reducing limitations. Therefore, we recommend a nationwide cancer registry to record all cancer-related information at the time of diagnosis. This strategy will reduce the need for performing retrospective surveys in collecting cancer-related information.