Accidental release of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at Sèveso,Italy: III. Monitoring of residual TCDD levels in reclaimed buildings

The uneven distribution of TCDD in soil and on internal and external building surfaces of Subzones A6 and A7 was a main problem when assessing the effectiveness of decontamination operations. Consequently, Subzones A6 and A7 were broken down into smaller sections to identify building clusters with more homogeneous TCDD levels and distribution patterns. Three clusters were the basic units for stratified samplings. After all decontamination operations had been completed, a minimum of 113 randomly selected samples for each cluster were taken from building inside surfaces and analyzed. All the values were within the maximum tolerated level of TCDD. Similar results were also obtained from outside walls and from soil.     

Are immunological mechanisms involved in colon cancer and are they possible markers for biotherapy improvement?

This paper focuses on our data on colon cancer patients. Our overall results lead us to believe that the suppressive effect of specific cytokines in colon cancer patients alters the functionality of TH1 and TH2 subsets of CD4+ T-cells, with an expansion of TH2 cells and a malfunctioning of TH1 cells. This immunological disregulation appears to increase with stage progression, suggesting a direct role in the mechanisms that allow the tumour to locate and expand within the host. It is also clear that in order to identify disease markers and generate an in vivo immune response that corrects the imbalance between TH1 and TH2 cells, we need to understand how tumour mechanisms cause this imbalance to begin with.     

Differential processing of antitumour-active and antitumour-inactive trans platinum compounds by SKOV-3 ovarian cancer cells

In order to compare the mechanistic properties of the antitumour-active trans platinum complex trans-[PtCl(2){Z-HN=C(OMe)Me}(NH(3))] (trans-Z) and of the antitumour-inactive isomer of cisplatin trans-[PtCl(2)(NH(3))(2)] (trans-DDP), the differential processing of the two compounds by SKOV-3 ovarian cancer cells has been investigated. trans-Z and trans-DDP enter cells with the same efficacy, but trans-Z shows a two-fold higher affinity for cellular DNA. The treatment with trans-DDP IC(50) determines an initial and transient cytostatic effect, paralleled by a moderate increase of apoptosis and by sequential and reversible arrests in S and G(2)/M phases of cell-cycle. In contrast, trans-Z IC(50) determines an initial cytotoxic effect, a more persistent and marked increase of apoptosis, and a more marked and prolonged arrest in S and G(2)/M phases of the cell-cycle. Treatment-induced gene expression modifications indicate that phenotypic effects of trans-DDP are driven by an initial and transient up-regulation of some genes related to cell-cycle checkpoint and arrest networks, whereas the more dramatic phenotypic effects of trans-Z are driven by a persistent up-regulation of more numerous genes involved in cell-cycle checkpoint and arrest networks, and in genome stability and DNA repair. Therefore, molecular and cellular events have been identified which are produced by trans-Z but not by trans-DDP, and which likely represent the mechanistic basis of antitumour activity of trans-Z in the SKOV-3 system.     

In vitro and in vivo pharmacological characterization of the novel UT receptor ligand [Pen5,DTrp7,Dab8]urotensin II(4-11) (UFP-803)

The novel urotensin-II (U-II) receptor (UT) ligand, [Pen(5),DTrp(7),Dab(8)]U-II(4-11) (UFP-803), was pharmacologically evaluated and compared with urantide in in vitro and in vivo assays. In the rat isolated aorta, UFP-803 was inactive alone but, concentration dependently, displaced the contractile response to U-II to the right, revealing a competitive type of antagonism and a pA(2) value of 7.46. In the FLIPR [Ca(2+)](i) assay, performed at room temperature in HEK293(hUT) and HEK293(rUT) cells, U-II increased [Ca(2+)](i) with pEC(50) values of 8.11 and 8.48. Urantide and UFP-803 were inactive as agonists, but antagonized the actions of U-II by reducing, in a concentration-dependent manner, the agonist maximal effects with apparent pK(B) values in the range of 8.45-9.05. In a separate series of experiments performed at 37 degrees C using a cuvette-based [Ca(2+)](i) assay and CHO(hUT) cells, urantide mimicked the [Ca(2+)](i) stimulatory effect of U-II with an intrinsic activity (alpha) of 0.80, while UFP-803 displayed a small (alpha=0.21) but consistent residual agonist activity. When the same experiments were repeated at 22 degrees C (a temperature similar to that in FLIPR experiments), urantide displayed a very small intrinsic activity (alpha=0.11) and UFP-803 was completely inactive as an agonist. In vivo in mice, UFP-803 (10 nmol kg(-1)) antagonized U-II (1 nmol kg(-1))-induced increase in plasma extravasation in various vascular beds, while being inactive alone. In conclusion, UFP-803 is a potent UT receptor ligand which displays competitive/noncompetitive antagonist behavior depending on the assay. While UFP-803 is less potent than urantide, it displayed reduced residual agonist activity and as such may be a useful pharmacological tool.     

Cloricromene, a coumarine derivative, reduced the development of periodontitis in rats

Recent studies have demonstrated that cloricromene, a coumarin derivative, exerts protective effects in models of inflammation and shock. Tumour necrosis factor plays a pivotal role in the induction of genes involved in physiological processes, as well as in the response to inflammation. We investigated the effect of cloricromene in a rat model of periodontitis. Periodontitis was induced in rats by placing a 2/0 braided silk ligature around the lower left first molar. At day 8 the gingivomucosal tissue encircling the mandibular first molar was removed for evaluation of tumour necrosis factor production, neutrophil infiltration, tissue permeability, nitrotyrosine formation, poly (ADP-ribose) polymerase activation, radiography and histology. Ligation significantly induced an increased tumour necrosis factor production, neutrophil infiltration and a positive staining for nitrotyrosine formation and poly (ADP-ribose) polymerase activation. Ligation significantly increased Evans blue extravasation in gingivomucosal tissue and alveolar bone erosion as evaluated by radiography analysis. Intraperitonal injection of cloricromene (10 mg/kg daily for 8 days) significantly decreased all of the parameters of inflammation as described above. This suggests that cloricromene treatment, which reduced tumour necrosis factor production, may be of benefit in the treatment of periodontitis.     

Gastro-intestinal problems and concomitant medication in NSAID users: additional findings from a questionnaire-based survey in Italy

Background In a previous questionnaire-based survey, we found extensive use of nonsteroidal anti-inflammatory drugs (NSAIDs) in subjects with risk factors for serious gastrointestinal complications. Aim This study focused on the use of NSAIDs in subjects who reported either (a) pre-existing disorders which would have required caution in using NSAIDs (e.g. dyspepsia/heartburn or peptic ulcer) or (b) co-medication with drugs having a high risk of interacting with NSAIDs. Methods Between March and September 2002, 65 general practitioners (GPs) submitted a validated self-administered questionnaire on health status and drug use to 3,250 subjects (age ≥18 years, stratified by sex and age). The questionnaire was divided into three parts: (1) sociodemographic information, (2) symptoms/illnesses (in the previous 6 months) and (3) drugs taken during the previous week. Results Of the 2,738 subjects who filled in the questionnaire (84% of responders), 633 (23%) used NSAIDs and, among them, 114 (18%) were chronic users. Among the subjects reporting dyspepsia/heartburn or ulcer (n=909 of 2,738), 24% were occasional NSAID users and 6% chronic users. Of the chronic NSAID users reporting gastrointestinal symptoms, 35% also used a drug for acid-related disorders, but only 14% used daily a proton pump inhibitor (PPI). One hundred six subjects used concomitantly more than one NSAID. Eighteen percent of the subjects using corticosteroids also reported NSAID use; similar proportions were seen in subjects using selective serotonin reuptake inhibitor (SSRI) antidepressants or calcium channel blockers, whereas 6% of the subjects with oral anticoagulants used NSAIDs. Conclusions Our study shows that NSAIDs are frequently used in patients with upper gastrointestinal complaints or in combination with potentially interacting medications. Adverse effects and untoward drug interactions should be monitored in patients treated with NSAIDs in order to minimise their occurrence.     

Intracameral administration of α-MSH increases intraocular pressure in rabbits

A growing body of evidence suggests that neural peptides may induce important modulations on vegative and motor functions of the eye. The present study was designed to evaluate the effect of intracameral (I.C.) administration of α-melanocyte-stimulating hormone (α-MSH) and several other ocular peptides on intraocular pressure (IOP) in rabbits. α-MSH (5 μg) produced a significant and prolonged unilateral increase of IOP. This efeect of I.C. α-MSH was dose-dependent (ED₅₀ = 2.5 μg). Structure-activity studies revealed that equimolar doses of β-MSH and γ-MSH, unlike α-MSH, were totally ineffective. In addition, the structurally unrelated peptides β-endorphin, thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (Gn-RH) did not affect IOP, when tested in a dose equimolar to 5 μg of α-MSH.These results confirm and extend previous observations, suggesting that α-MSH may be an important factor involved in regulation of IOP.