Modeling and biological evaluation of 3,3'-(1,2-ethanediyl)bis[2-(4-methoxyphenyl)-thiazolidin-4-one], a new synthetic cyclooxygenase-2 inhibitor

Within the series of chiral 3,3'-(1,2-ethanediyl)bis[2-arylthiazolidin-4-ones], the 3,4-dimethoxyphenyl substituted derivative was found in the primary anti-inflammatory screening to be endowed with superior in vivo properties and good safety profile. Such a lead compound was modified by eliminating 3-methoxy group while retaining 4-methoxy group on the aryl rings at 2 and 2' stereogenic carbons. The 2R,2'S-meso isomer (VIG3b) of the resulting bisthiazolidinone has been widely investigated. The inhibitory effects on cyclo-oxygenase-1 and cyclo-oxygenase-2 isoenzymes were measured in a human whole blood assay. VIG3b was almost 50 times more selective on the inducible isoform. The cyclo-oxygenase-2 preferential selectivity has been confirmed by modeling VIG3b into the cyclo-oxygenase-1 and cyclo-oxygenase-2 active sites. Furthermore, VIG3b was assayed in the experimental model of carrageenan-induced lung injury by evaluating its ability to inhibit: (1) fluid accumulation in the pleural cavity, (2) neutrophil infiltration, (3) prostaglandin E(2) production and (4) lung injury. VIG3b exhibited interesting activity in all these tests.     

Guess what! Multiple pilomatricomas and Steiner disease

An 18-year-old male adolescent was referred to our department for the presence of multiple skin nodules since the age of 9 years. At the age of 22 months the patient was diagnosed as having myotonic dystrophy (Steinert's disease). So far, nine lesions like these have been excised and histologically analysed, two located on the left arm, one on the neck and one on the scalp. A skin examination revealed three nodular lesions, two localised on the scalp (Fig. 1) and one on the trunk (Fig. 2); the lesions ranged from 0.5 to 3.5 cm, and were hard on palpation and asymptomatic, with elevated, smooth and teleangiectatic borders and a central invagination filled with whitish, firm, granular material. The lesions were all excised. The histological examination of all the biopsy specimens revealed basophilic cells at the periphery, and islets of shadow cells with an unstained central area at the site of lost nucleus (Fig. 3). The shadow cells were surrounded by a granulomatous infiltration composed mainly of giant cells.     

Radiological Investigations in Vertical Banded Gastroplasty Patients

In our Institute we have performed 124 vertical banded gastroplasties. Patients with a follow-up beyond 3 months were studied with a barium meal, in order to evaluate the efficiency of surgery and the eventual complications. Seventy-nine patients have had one or more X-ray investigations at various times after surgery (for a total of 136 studies). The first 20 patients were routinely studied at 1, 2 and 3 years after the operation; the next 32 patients were studied for features such as vomiting, poor weight loss or low food intake; the last 27 patients were studied with an early overlook beginning 3 months after surgery. We noted gastroesophageal reflux in eight (10.1%) cases, outlet dilatation in four (5%) cases, outlet substenosis (diameter 6-8 mm) in 13 (16.4%) cases, outlet stenosis (diameter ≤5 mm) in four (5%) cases, peanut-type deformation in three (3.7%) cases, and staple-line disruption in 17 (21.5%) cases. The staple-line disruption was correlated in the first part of the series with a reinforcement of such a suture, while the last 27 patients, with vertical stapling carried out with a 4-row stapler without reinforcement, did not present any disruption. The radiographic examination gives information about weight loss and side effects.     

Urban air pollution and respiratory emergency visits at pediatric unit, Reggio Emilia, Italy

Short-term effects of air pollution on daily mortality and hospital admissions for respiratory causes are well documented. Few studies, however, explore the association between exposure to air pollution and daily emergency room visits for respiratory disorders, particularly in Italy and particularly among children as a susceptible population. A time-series analysis was conducted to explore the short-term association between air pollutants (PM10, total suspended particulates [TSP], NO2, SO2, CO, O3) and pediatric emergency room (ER) visits in a small city of northern Italy, Reggio Emilia, during the period 03/01/2001-03/31/2002. There were 1051 ER visits included in the study. Data were analyzed using generalized additive models (GAM), adjusting for various confounding variables, including temperature, humidity, and pollens (Graminaceae). The analyses were also stratified according to the nationality of children (Italians and foreigners). In single-pollutant models, the strongest associations were observed at lag 3 for a 10-microg/m3 increase of TSP (2.7% increase in ER, 95% CI 0.7-4.6) and PM10 (3.0% increase, 95% CI 0.4-5.7), and at lag 4 for a 10-microg/m3 increase of NO2 (11.0% increase in ER, 95% CI 3.6-18.8). At lag 3, the percentage increase in ER visits is similar for the 2 groups of children (Italians and foreigners) for TSP and PM10. The results of the study support the findings that air pollution is a relevant determinant of deterioration of respiratory health among children.     

Thalidomide treatment reduces the alteration of paracellular barrier function in mice ileum during experimental colitis

Small intestine permeability is frequently altered in inflammatory bowel diseases and may be caused by the translocation of intestinal toxins through leaky small intestine tight junctions (TJs) and adherence. Thus, the aim of the present study was to examine the effects of thalidomide treatment on the permeability and structure of small intestine TJs in an animal model of experimental colitis induced by dinitrobenzene sulfonic acid (DNBS). Four days after colitis induction with DNBS, the ileal TJs were studied by means of transmission electron microscopy using lanthanum nitrate and immunohistochemistry of occludin and zonula occludens 1. When compared with DNBS-treated mice, thalidomide-treated (200 mg/kg orally starting 30 min after the administration of DNBS) mice subjected to DNBS-induced colitis experienced a significantly reduced rate of the extent and severity of the histological signs of colon injury associated with a significant reduction of plasma and colon tumor necrosis factor alpha levels. After administration of DNBS to the mice induced a significant increase of ileal permeability was observed. Distal colitis in mice induced an increase of TJ permeability throughout the entire small intestine, and the extent of alterations correlates with colonic damage. In particular, we have observed that thalidomide treatment resulted in a significant reduction of the following: (1) the degree of colon injury, (2) the alteration of zonula occludens 1 and occludin localization (immunohistochemistry), and (3) intestinal permeability caused by DNBS in the colon. Taken together, our results clearly show that thalidomide treatment reduced small intestinal permeability in experimental colitis through the regulation of TJ protein.     

Effectiveness of activated charcoal and equilibrium dialysis in removing Asian, American, Siberian and Indian ginseng from human serum

BACKGROUND: Ginsengs are used by the general population worldwide and toxicity of various ginsengs has been reported. We studied the effectiveness of activated charcoal and in vitro equilibrium dialysis for removal of Asian, American, Siberian and Indian ginseng from human serum by measuring digoxin-like immunoreactivity using the fluorescence polarization immunoassay. METHODS: 1xPBS (phosphate buffered saline) or drug free serum pool was supplemented with Asian, American, Siberian or Indian ginseng extract in amount expected in overdose. The aliquots of supplemented buffer or serum pool were treated with activated charcoal (15 or 50 mg of activated charcoal/ml of buffer/serum) for 5, 10, 20 and 30 min and digoxin-like immunoreactivities were compared with the original specimens. Other drug free serum pools were also supplemented with various ginsengs and then passed through a small column packed with activated charcoal or subjected to in vitro equilibrium dialysis against phosphate buffer at pH 7.4. RESULTS: Complete removal of digoxin-like immunoreactivity from buffer solution or serum pool supplemented with various ginsengs can be achieved by treatment with activated charcoal. Moreover, when serum pools supplemented with various ginsengs were passed through columns packed with activated charcoal, we observed complete removal of digoxin-like immunoreactivity. In addition, significant removal of digoxin-like immunoreactivity was observed when serum pools supplemented with ginsengs were subjected to equilibrium dialysis for 24 h. CONCLUSIONS: Removal of digoxin-like immunoreactivity from buffer solution or serum due to the presence of ginsengs can be achieved by treatment with activated charcoal in vitro but complete removal of digoxin-like activity from serum is not possible even after 24 h of equilibrium dialysis.     

De novo synthesis of cyclooxygenase-1 counteracts the suppression of platelet thromboxane biosynthesis by aspirin

Aspirin affords cardioprotection through the acetylation of serine529 in human cyclooxygenase-1 (COX-1) of anucleated platelets, inducing a permanent defect in thromboxane A2 (TXA2)-dependent platelet function. However, heterogeneity of COX-1 suppression by aspirin has been detected in cardiovascular disease and may contribute to failure to prevent clinical events. The recent recognized capacity of platelets to make proteins de novo paves the way to identify new mechanisms involved in the variable response to aspirin. We found that in washed human platelets, the complete suppression of TXA2 biosynthesis by aspirin, in vitro, recovered in response to thrombin and fibrinogen in a time-dependent fashion (at 0.5 and 24 hours, TXB2 averaged 0.1+/-0.03 and 3+/-0.8 ng/mL; in the presence of arachidonic acid [10 micromol/L], it was 2+/-0.7 and 25+/-7 ng/mL, respectively), and it was blocked by translational inhibitors, by rapamycin, and by inhibitors of phosphatidylinositol 3-kinase. The results that COX-1 mRNA was readily detected in resting platelets and that [35S]-methionine was incorporated into COX-1 protein after stimulation strongly support the occurrence of de novo COX-1 synthesis in platelets. This process may interfere with the complete and persistent suppression of TXA2 biosynthesis by aspirin necessary for cardioprotection.     

First-trimester screening for trisomy-21 using a simplified method to assess the presence or absence of the fetal nasal bone

OBJECTIVE: To determine the benefit of including nasal bone assessment in addition to standard first-trimester markers (nuchal translucency, free beta human chorionic gonadotropin and pregnancy-associated plasma protein A) as a screening test for Down syndrome, using a strict criterion for classification of nasal bone absence. STUDY DESIGN: Nasal bone assessment was conducted in 2411 patients with crown-rump length between 45 and 84 mm, including 15 patients with Down syndrome. A patient was considered to have an absent nasal bone only if there was no evidence of present nasal bone. Unlike other studies, nasal bone was classified as present when there was evidence of a thin echogenic line under the skin. Simulation studies were conducted to assess the detection rate and false-positive rate of a combined first-trimester screening protocol including nasal bone assessment. RESULTS: There were 9 of 2396 (0.4%) unaffected cases with absent nasal bone (95% confidence interval 0.2%, 0.7%) and 8 of 15 (53.3%) Down syndrome cases (95% confidence interval 26.6%, 78.7%). Using a 1 in 250 risk cut-off, the detection rate of standard first-trimester screening was 87%, with a false-positive rate of 4.3%. Incorporating nasal bone measurement improved the detection rate of Down syndrome to 90% and reduced the false-positive rate to 2.5%. CONCLUSION: The use of a strict criterion to determine nasal bone absence leads to fewer cases classified as absent and may simplify the implementation of nasal bone as a marker for first-trimester screening, resulting in lower false-positives and higher detection, compared with other current screening protocols.