New polyurethanes based on diphenylmethane diisocyanate and 1,4:3,6-dianhydrosorbitol, 1. Model kinetic studies and characterization of the hard segment

1,4:3,6-Dianhydrosorbitol (DAS) seems to be an interesting reagent for the synthesis of polyurethanes. In the present work, the kinetics of the reaction of DAS with a monoisocyanate (p-tolyl isocyanate, p-TI) and with a diisocyanate (4,4′-diphenylmethane diisocyanate, MDI) were studied with the help of a chromatographic method (size exclusion chromatography, SEC). When the condensation reaction is performed in tetrahydrofuran (THF) solution, with dibutyltin dilaurate (SnDBDL) as catalyst, DAS exhibits two equireactive hydroxyl groups. The reaction rate can be well described by a second-order equation modified to include catalysis by the formed urethane functions. MDI and DAS were then condensed using two different experimental procedures (bulk and solution polycondensation in THF, in the presence of SnDBDL), and the characteristics of the resulting polyurethanes were compared. Bulk polycondensation led to an amorphous polymer, whereas the polyurethane prepared in solution was semi-crystalline. In both cases, we obtained a very high glass transition temperature ( ≈ 186°C). The synthesis of samples with various polymerization degrees gave a better understanding of the molecular weight distribution of segmented polyurethanes based on MDI and DAS.     

Transfusion risks of yesterday and of today.

The viral safety of the blood supply provided by serological tests alone decreased the residual risk of viral transmission to less than 1:250,000 for hepatitis C virus (HCV) and 1:1.3 M for HIV in the EU and the USA in 2000. This was further improved to 1:2-4 M by the introduction of nucleic acid testing (NAT) for HCV and HIV RNA that considerably reduced the risk of window period transmission. However, over the past 20 years, the successive introduction of up to 10 direct or surrogate viral markers enormously complicated the screening process and testing errors have become the main residual risk of viral transmission by transfusion. At over $ 2 M per QALY, the very low cost-effectiveness of NAT and some other tests overburdens limited funds that might be better used for other health care priorities. At the same time, haemovigilance programmes have shown that blood transfused to the wrong patient and a range of immunological consequences of transfusion caused two deaths per million transfusions and little is done to prevent them. There are means of limiting these serious hazards of transfusion that should become the priority in blood safety.     

The M2 muscarinic receptor antagonist methoctramine activates mast cells via pertussis toxin-sensitive G proteins

Methoctramine, a selective M₂ muscarinic cholinergic receptor antagonist, has been reported to activate phosphoinositide breakdown at high concentrations. Its polyamine structure suggests a putative activation of guanine nucleotide-binding proteins (G proteins). Incubation of methoctramine with rat peritoneal mast cells resulted in a dose-dependent noncytotoxic histamine release, with an EC₅₀ of 20μM and a maximum effect at 1mM. Atropine, pirenzepine and HHSiD neither inhibited methoctramine-induced histamine release nor stimulated histamine release. Histamine release and inositol phosphates generation induced by methoctramine were both inhibited by pertussis toxin pretreatment. Benzalkonium chloride, a selective inhibitor of histamine secretion induced by basic secretagogues, inhibited the secretory response to methoctramine. [p-Glu⁵, d-Trp^7,9,10]-SP_5–11 (GPAnt-2), a well-characterized antagonist of G proteins, blocked the methoctramine-induced histamine release when the antagonist was allowed to reach its intracellular target by streptolysin O-permeabilization. The response to methoctramine was prevented by the hydrolysis of sialic acid residues of the cell surface by neuraminidase. The response of mast cells was restored by permeabilization of the plasma membrane. These results demonstrate that methoctramine, following its entry into the cell and the involvement of pertussis toxin-sensitive G proteins, activates phosphoinositide hydrolysis leading to mast cell exocytosis. Received: 26 September 1997 / Accepted: 1 December 1997     

Negative Regulation of FcεRI-mediated Degranulation by CD81

Signaling through the high affinity receptor for immunoglobulin E (FcεRI) results in the coordinate activation of tyrosine kinases before calcium mobilization. Receptors capable of interfering with the signaling of antigen receptors, such as FcεRI, recruit tyrosine and inositol phosphatases that results in diminished calcium mobilization. Here, we show that antibodies recognizing CD81 inhibit FcεRI-mediated mast cell degranulation but, surprisingly, without affecting aggregation-dependent tyrosine phosphorylation, calcium mobilization, or leukotriene synthesis. Furthermore, CD81 antibodies also inhibit mast cell degranulation in vivo as measured by reduced passive cutaneous anaphylaxis responses. These results reveal an unsuspected calcium-independent pathway of antigen receptor regulation, which is accessible to engagement by membrane proteins and on which novel therapeutic approaches to allergic diseases could be based.     

Tensioactivity and Supramolecular Organization of the Palmitoyl Prodrug of Timolol

Purpose. To improve the bioavailability of the ocular drug timolol by facilitating its transport through the cornea, an amphiphilic prodrug was synthesized via the addition of a palmitic chain by esterification. The present study was undertaken to investigate the physicochemical and tensioactive properties of the prodrug. Methods. The amphiphilic properties of the prodrug were firstly investigated by the Wilhelmy plate method. The textures generated by the supramolecular organizations of the ester were visualized by optical microscopy. Results. The prodrug clearly decreased the surface tension. Optical microscopy provided excellent evidence for the existence of lyotropic liquid crystalline phases: two isotropic but organized phases and a birefringent lamellar phase. Conclusions. The results from the ensemble of studies undertaken to determine the amphiphilic properties of the prodrug were all in accord with its ability to form liquid crystalline phases. The liquid crystalline state of the prodrug is believed to introduce a delay in the drug pharmacological effect.     

p53 as a therapeutic target

Since the discovery of p53, a vast wealth of knowledge on its function and regulation has been accumulated. It is known that it is a key tumour suppressor and that its function is lost in many types of cancers, either by mutation or by excessive negative regulation. Recently, several discoveries have re-energised P53 as a therapeutic target as it has been shown that reintroduction of functional p53 into tumours has a therapeutic benefit. These encouraging results clearly justify the search for small molecules that diminish negative regulation of P53 in tumour cells, where P53 is not mutated as well as compounds that reactivate mutant P53. Important findings have been made to deal with both situations. Additionally, some of the small molecules identified may also help reduce the side effects of commonly used cancer therapeutics. These studies are still in their infancy and require further therapeutic validation, but the future appears bright for finally harnessing p53's tumour suppressing ability.     

Joint source–channel coding: Secured and progressive transmission of compressed medical images on the Internet

The joint source–channel coding system proposed in this paper has two aims: lossless compression with a progressive mode and the integrity of medical data, which takes into account the priorities of the image and the properties of a network with no guaranteed quality of service. In this context, the use of scalable coding, locally adapted resolution (LAR) and a discrete and exact Radon transform, known as the Mojette transform, meets this twofold requirement. In this paper, details of this joint coding implementation are provided as well as a performance evaluation with respect to the reference CALIC coding and to unequal error protection using Reed–Solomon codes.