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On the basis of the recently introduced reduced graph concept of ErG (extending reduced graphs), a straightforward weighting approach to include additional (e.g., structural or SAR) knowledge into similarity searching procedures for virtual screening (wErG) is proposed. This simple procedure is exemplified with three data sets, for which interaction patterns available from X-ray structures of native or peptidomimetic ligands with their target protein are used to significantly improve retrieval rates of known actives from the MDL Drug Report database. The results are compared to those of other virtual screening techniques such as Daylight fingerprints, FTrees, UNITY, and various FlexX docking protocols. Here, it is shown that wErG exhibits a very good and stable performance independent of the target structure. On the basis of this (and the fact that ErG retrieves structurally more dissimilar compounds due to its potential to perform scaffold-hopping), the combination of wErG and FlexX is successfully explored. Overall, wErG is not only an easily applicable weighting procedure that efficiently identifies actives in large data sets but it is also straightforward to understand for both medicinal and computational chemists and can, therefore, be driven by several aspects of project-related knowledge (e.g., X-ray, NMR, SAR, and site-directed mutagenesis) in a very early stage of the hit identification process.

We describe a method for docking of a scaffold-based series and present its advantages over docking of individual ligands, for determining the binding mode of a molecular scaffold in a binding site. The method has been applied to eight different scaffolds of protein kinase inhibitors (PKI). A single analog of each of these eight scaffolds was previously crystallized with different protein kinases. We have used FlexX to dock a set of molecules that share the same scaffold, rather than docking a single molecule. The main mode of binding is determined by the mode of binding of the largest cluster among the docked molecules that share a scaffold. Clustering is based on our 'nearest single neighbor' method [J. Chem. Inf. Comput. Sci., 43 (2003) 208-217]. Additional criteria are applied in those cases in which more than one significant binding mode is found. Using the proposed method, most of the crystallographic binding modes of these scaffolds were reconstructed. Alternative modes, that have not been detected yet by experiments, could also be identified. The method was applied to predict the binding mode of an additional molecular scaffold that was not yet reported and the predicted binding mode has been found to be very similar to experimental results for a closely related scaffold. We suggest that this approach be used as a virtual screening tool for scaffold-based design processes.

Suberoylanilide hydroxamic acid (SAHA) is a hydroxamic acid-containing hybrid polar molecule; SAHA specifically binds to and inhibits the activity of histone deacetylase. Although SAHA, like other inhibitors of histone deacetylase, exhibits antitumor effects by increasing expression of genes regulating tumor survival, we found that SAHA reduces the production of proinflammatory cytokines in vivo and in vitro . A single oral administration of SAHA to mice dose-dependently reduced circulating TNF-α, IL-1-β, IL-6, and IFN-γ induced by lipopolysaccharide (LPS). Administration of SAHA also reduced hepatic cellular injury in mice following i.v. injection of Con A. SAHA inhibited nitric oxide release in mouse macrophages stimulated by the combination of TNF-α plus IFN-γ. Human peripheral blood mononuclear cells stimulated with LPS in the presence of SAHA released less TNF-α, IL-1-β, IL-12, and IFN-γ (50% reduction at 100–200 nM). The production of IFN-γ stimulated by IL-18 plus IL-12 was also inhibited by SAHA (85% at 200 nM). However, SAHA did not affect LPS-induced synthesis of the IL-1-β precursor, the IL-1 receptor antagonist, or the chemokine IL-8. In addition, IFN-γ induced by anti-CD3 was not suppressed by SAHA. Steady-state mRNA levels for LPS-induced TNF-α and IFN-γ in peripheral blood mononuclear cells were markedly decreased, whereas IL-8 and IL-1-β mRNA levels were unaffected. Because SAHA exhibits antiinflammatory properties in vivo and in vitro , inhibitors of histone deacetylase may stimulate the expression of genes that control the synthesis of cytokines and nitric oxide or hyperacetylate other targets.

In the present work, KTP crystals have been grown by spontaneous nucleation technique in flux medium using K6P4O13 flux. 0.4-1 °C/h cooling rates were applied in the spontaneous nucleation process. The presence and amount of impurities has been determined by using XRF. The optical transmission spectra of impure KTP crystals in the UV–visible region are discussed. The transmission cut-off is clearly shown at the optical absorption edge, as well as the rapidly reduced absorption with increasing wavelength. It is shown that the presence of impurity shifts the absorption edge of KTP towards lower energy region. The wavelength dependence of absorption coefficient is determined in the UV–visible range, and the characteristics of the optical absorption edge are discussed. Results reveal that the absorption edge and the type of optical charge carrier transition can be attributed to indirect transition for these crystals. It is shown that presence of impurity decreases the indirect band gap (Eg) of KTP crystals, causing the indirect transition absorption edge to move towards lower energy.

We construct Schwarz domain decomposition preconditioners for plane wave discontinuous Galerkin methods for Helmholtz boundary value problems. In particular, we consider additive and multiplicative non-overlapping Schwarz methods. Numerical tests show good performance of these preconditioners when solving the linear system of equations with GMRES.

Several descriptors applied to peptide structure−activity and/or structure−property relationships have been developed in recent years. This report describes new descriptors for the natural amino acids which have been derived from the principal component analysis (PCA) applied on the MS-WHIM 3D-description matrices. MS-WHIM indexes are a collection of 36 statistical indexes aimed at extracting and condensing steric and electrostatic 3D-properties of a molecule. These new descriptors have been developed both on extended side-chain conformation and on rotamer library of natural amino acids. The method appeared to be more potent when describing a single conformation (i.e. extended) than when applied collectively on library conformation families. MS-WHIM scores, however, were shown to efficacely describe and correctly classify the natural amino acid features and to provide sound statistical models either predicting activities of two peptide sets taken as a test or correlating amino acid chemicophysical propert...

Using a model of the enzyme structure and the results from a series of free and myristylated peptides, we provide evidence that peptides corresponding to the pseudosubstrate sequence of protein kinase C bind to the enzyme substrate binding site in an essentially extended conformation. This and the nearly symmetrical location of positive charges around the substrate phosphoritable site allow the peptide to bind to the enzyme in either an N-to-C orientation or its C-to-N opposite orientation. The latter is favoured by a change in residue chirality or when the peptide bears a myristoyl chain at its N-terminus. A myristyl binding site was also identified in the enzyme structure and its location in a region proximal to the C-terminal residue of pseudosubstrate bound in the N-to-C direction suggested that C-myristylation of peptide substrates should be more effective than N-myristoylation in antagonizing the enzyme. A peptide (H-RFARKGALRQKN-CONH-Myr) which contains the myristyl chain covalently linked to the C-terminal residue of the pseudosubstrate was thus made and shown to be a potent inhibitor of the histone kinase reaction of protein kinase C and the phosphorylation of p47 in intact cells.

Pott's disease (spinal tuberculosis), a condition characterized by massive resorption of the spinal vertebrae, is one of the most striking pathologies resulting from local infection with Mycobacterium tuberculosis (Mt; Boachie-Adjei, O., and R.G. Squillante. 1996. Orthop. Clin. North Am. 27:95–103). The pathogenesis of Pott's disease is not established. Here we report for the first time that a protein, identified by a monoclonal antibody to be the Mt heat shock protein (Baird, P.N., L.M. Hall, and A.R.M. Coates. 1989. J. Gen. Microbiol. 135:931–939) chaperonin (cpn) 10, is responsible for the osteolytic activity of this bacterium. Recombinant Mt cpn10 is a potent stimulator of bone resorption in bone explant cultures and induces osteoclast recruitment, while inhibiting the proliferation of an osteoblast bone–forming cell line. Furthermore, we have found that synthetic peptides corresponding to sequences within the flexible loop and sequence 65–70 of Mt cpn10 may comprise a single conformational unit which encompasses its potent bone-resorbing activity. Our findings suggest that Mt cpn10 may be a valuable pharmacological target for the clinical therapy of vertebral tuberculosis and possibly other bone diseases.\ud \ud Tuberculosis is epidemic, accounting for 7% of the annual worldwide death toll (1). Tuberculous infections of bone, particularly of the spinal vertebrae (Pott's disease), are still common in the third world (2). It is not known how Mycobacterium tuberculosis (Mt)1 infections of bone cause bone breakdown. Healthy bone is maintained by a dynamic equilibrium between the mesenchymal bone matrix–forming osteoblast cell lineage and the myeloid bone– resorbing osteoclast cell lineage (3). Mt infection of the spine obviously alters this dynamic equilibrium, resulting in the net loss of the extracellular matrix of vertebral bone and collapse of the vertebrae. Whether this loss of bone matrix is the result of the direct action of components of Mt, for example, the LPS-like cell surface molecule lipoarabinomannan (LAM) (4), on bone cells, or an indirect activation of inflammatory cells leading to bone cell activation, is not established. Evidence is appearing to suggest that molecular chaperones have biological actions in addition to their intracellular protein–folding activity (5). For example, chaperonin (cpn)10 has been found to be an essential growth and immunosuppressive factor in early pregnancy (6), and cpn60 induces cytokine synthesis (7) and resorption of bone (8).\ud \ud In this study we have established that the bone resorbing activity of Mt is due to cpn10 which is as active as the most potent osteolytic cytokine, IL-1 (9, 10). Mt cpn10 also appears to induce the recruitment of osteoclasts in calvaria, and it is notable that calvarial bone resorption induced by this cpn can be completely blocked by the osteoclast-inhibiting hormone, calcitonin (11). Mt cpn10 was also found to inhibit the proliferation of cultured osteoblasts.\ud \ud Using a series of NH2- and COOH-terminal truncated peptides, we have identified sites in Mt cpn10 responsible for the osteolytic activity of this molecular chaperone. We have identified the flexible loop of Mt cpn10 and the sequence 65–70 as regions most probably responsible for the bone-modulating bioactivity of this molecule.

We describe a new clustering program, SONHICA (Simple Optimized Non-HIerarchical Cluster Analysis), developed to analyze large data sets of molecular conformations. Unlike traditional clustering methods, SONHICA does not make use of an overall index, like a distance, to evaluate similarity between objects. Each descriptor variable is compared individually on the basis of a preset threshold value. This assures high control and sensitivity over the input variables. In addition, periodic and nonperiodic descriptors, such as dihedral angles and interatomic distances, can easily be used together. SONHICA generates clusters with the highest possible density and all pairs of objects within a cluster are similar. These features make SONHICA particularly suitable for the analysis of data sets which tend to form globular clusters. This method was applied to the analysis of a modified linear tetrapeptide, ITF1697, under investigation for its anti-ischemic properties, and a cyclic pentapeptide, BQ123, a potent antagonist of endothelin A. On the basis of the results presented here, SONHICA appears to be an interesting new tool in the field of the clustering methods applied to the analysis of molecular conformations. © 1997 John Wiley & Sons, Inc. J Comput Chem18: 1295–1311, 1997

Leflunomide is one of the most promising disease-modifying antirheumatic drug now in clinical trials for the treatment of rheumatoid arthritis. Metabolic studies have indicated that leflunomide is rapidly processed in vivo to an active metabolite, A771726 (2). To identify the chemical characteristics necessary for the immunosuppressive activity of 2, configurational and conformational studies were carried out on the latter and its inactive analogues (ethyl 3-hydroxy-2-((4-(trifluoromethyl)phenyl)carbamoyl)but-2-enoate, 3a, and 3-hydroxy-2-nitro-N-(4-(trifluoromethyl)phenyl)but-2-enamide, 3b). These studies suggested that the pharmacophore responsible for the immunosuppressive activity of 2 is a beta-keto amide with the enolic hydroxy group cis to the amidic moiety. To verify this hypothesis, a new class of immunosuppressive agents was designed and synthesized. Their testing in vitro and in vivo identified compounds which were more potent than both leflunomide and 2 and above all confirmed our hypothesis as to the key structural and chemical determinants for the immunosuppressive properties of 2 and our compounds.

The recently proposed WHIM (Weighted Holistic Invariant Molecular) approach [Todeschini,R., Lasagni, M. and Marengo, E., J. Chemometrics, 8 (1994) 263] has been applied tomolecular surfaces to derive new 3D theoretical descriptors, called MS-WHIM. To test theirreliability, a 3D QSAR study has been performed on a series of steroids, comparing the MS-WHIM description to both the original WHIM indices and CoMFA fields. The analysis of thestatistical models obtained shows that MS-WHIM descriptors provide meaningful quantitativestructure–activity correlations. Thus, the results obtained agree well with thoseachieved using CoMFA fields. The concise number of indices, the ease of their calculationand their invariance to the coordinate system make MS-WHIM an attractive tool for 3DQSAR studies.

The first synthetic pathway to synthesize 6-unsubstituted-2,3-dihydro-1,3-oxazin-4-ones is described. The α-formylation of the starting amide and the cyclization of the α-formylamide with a desired aldehyde under acidic conditions gave compounds 5a−h (R = nPr, iPr, cPr, cHex, Ph, CH2Ph, nHex, and R1 = H, Me). This strategy was used with little modification for the preparation of new monocyclic organic nitrates such as 2a−c (2a (R = Ph, R1 = H, and R2 = H), 2b (R = Ph, R1 = H, and R2 = Me), and 2c (R = H, R1 = Ph, and R2 = H).

The chaperonin activity of sequence-related chaperonin 10 proteins requires their aggregation into heptameric structures. We describe size-exclusion chromatography and ultracentrifugation studies that reveal that while Escherichia coli chaperonin 10 exists as a heptamer, the Mycobacterium tuberculosis chaperonin 10 is tetrameric in dilute solutions and in whole M. tuberculosis lysate. At high protein concentration and in the presence of saturating amounts of divalent ions, the protein is heptameric. Human chaperonin 10 is predominantly heptameric, although smaller oligomers were detected. These differences in structural assembly between species may explain differences in biological activity such as antigenicity. Using C-terminal and N-terminal fragments, sequence 1-25 was identified as indispensable for aggregation. CD spectroscopy studies revealed that (i) a minimum at 202-204 nm correlates with aggregation and characterizes not only the spectrum of the mycobacterial protein, but also those of E. coli and human chaperonin 10 proteins; (ii) the interactions between subunits are of the hydrophobic type; and (iii) the anti-parallel β-pleated sheet is the main secondary structure element of subunits in both tetrameric and heptameric proteins.

Conformationally constrained peptidomimetics of the Lys-Pro sequence have been obtained using a new polycyclic structure. Bicyclic compounds containing a dioxopiperazine-thiazolidine fused ring have been synthesised starting from N-lysyl-4-ethoxycarbonylthiazolidine-2-carboxylic acid. The carboxyl group in either position 2 or 4 of the thiazolidine ring was reacted with the N-terminal amino group, giving different regioisomers. NMR and computer modelling were used to study the configuration of isomers and the lysine side-chain orientation with respect to the pseudoproline ring.

Persistent hiccup rarely occurs during rehabilitation, but its management can prove to be very difficult, particularly in presence of associated dysphagia, requiring longer hospitalization and higher risk of severe clinical complications. We present a case of persistent hiccup after surgical resection of a brainstem arteriovenous malformation successfully treated with gabapentin during rehabilitation.

Inducible arginine oxidation and subsequent NO production by correspondent synthase (iNOS) are important cellular answers to proinflammatory signals. Prolonged NO production has been proved in higher organisms to cause stroke or septic shock. Several classes of potent NOS inhibitors have been reported, most of them targeting the arginine binding site of the oxygenase domain. Here we disclose the SAR and the rational design of potent and selective iNOS inhibitors which may be useful as anti-inflammatory drugs.

Several descriptors applied to peptide structure−activity and/or structure−property relationships have been developed in recent years. This report describes new descriptors for the natural amino acids which have been derived from the principal component analysis (PCA) applied on the MS-WHIM 3D-description matrices. MS-WHIM indexes are a collection of 36 statistical indexes aimed at extracting and condensing steric and electrostatic 3D-properties of a molecule. These new descriptors have been developed both on extended side-chain conformation and on rotamer library of natural amino acids. The method appeared to be more potent when describing a single conformation (i.e. extended) than when applied collectively on library conformation families. MS-WHIM scores, however, were shown to efficacely describe and correctly classify the natural amino acid features and to provide sound statistical models either predicting activities of two peptide sets taken as a test or correlating amino acid chemicophysical propert...

Interleukin-2 inducible T-cell kinase (ITK) is one of five kinases that belong to the Tec kinase family that plays an important role in T-cell and mast cell signaling. Various reports point to a role of ITK in the treatment of allergic asthma. For example, it was shown that mice lacking ITK have reduced airway hyperresponsiveness, inflammation and tracheal responses in an allergic asthma model. In this article, we disclose novel ITK inhibitors based on (4 or 5-aryl)pyrazolyl-indole scaffold that were also found to be selective for ITK over other kinases like IRK, CDK2, GSK3ss and PKA.

For computational de novo design, a general retrospective validation work is a very challenging task. Here we propose a comprehensive workflow to de novo design driven by the needs of computational and medicinal chemists and, at the same time, we propose a general validation scheme for this technique. The study was conducted combining a suite of already published programs developed within the framework of the NovoBench project, which involved three different pharmaceutical companies and four groups of developers. Based on 188 PDB protein-ligand complexes with diverse functions, the study involved the ligand reconstruction by means of a fragment-based de-novo design approach. The structure-based de novo search engine FlexNovo showed in five out of eight total cases the ability to reconstruct native ligands and to rank them in four cases out of five within the first five candidates. The generated structures were ranked according to their synthetic accessibilities evaluated by the program SYLVIA. This investigation showed that the final candidate molecules have about the same synthetic complexity as the respective reference ligands. Furthermore, the plausibility of being true actives was assessed through literature searches.

In latest years, there has been an increasing attention to chemoinformatic and modeling methods enabling selectivity predictions for small molecules in case of same mechanism of action. Selectivity profiling of small molecules is emerging as one of the most expensive, though yet unmissable, task in drug discovery and cross-reactivity prediction as one of the most challenging chemoinformatic field, accordingly. Following the widely accepted similarity principle [1] for which structurally similar compounds should act similarly, we have to expect also that similar proteins cavities recognize similar compounds. For historical reasons, kinase inhibition is one of the most attractive field to test new predictive methodologies as ATP antagonism is probably the most inherently problematic mechanism of action from a cross-reactivity standpoint. In the present work, we thus focus on kinases, approaching the problem with the use of PKSIM, a novel software tool for protein active site comparison. PKSIM is based on finding interaction spots developed for docking calculations [2] and the maximal overlap thereof. The pairwise PKSIM spots score has been used to rationalize a published cross-reactivity panel of a series of Kinase inhibitors [3]. We also performed a new classification of 584 kinases on the basis of the similarity score which allowed us to build a “classification tree” of the currently known kinases ATP cavities. This tree, as expected, showed marked differences from the known kinome tree based on sequence alignment [4]. Moreover, from this training set panel a simple empirical rule has been found to predict the extent of selectivity for a general ligand active on a given kinase ATP binding site. Extending the similarity concept further to the family of crystallized protein targets, we can now apply and optimize the present tool to different and important tasks: 1) to check easily if, and at which extent, old drugs with their selectivity profiles, are worth to be tested on new target proteins according to their target similarities; 2) to predict risks of possible off-target toxic effects on the basis of unprecedented cavity similarities of targets and finally, 3) through the similarity assessment of every newly crystallized cavity, try to infer its recognition potential towards known chemical space.

The glucose-sensing enzyme glucokinase (GK) plays a key role in glucose metabolism. We report here the effects of a novel glucokinase activator, LY2121260. The activator enhanced GK activity via binding to the allosteric site located in the hinge region of the enzyme. LY2121260 stimulated insulin secretion in a glucose-dependent manner in pancreatic beta-cells and increased glucose use in rat hepatocytes. In addition, incubation of beta-cells with the GK activator resulted in increased GK protein levels, suggesting that enhanced insulin secretion on chronic treatment with a GK activator may be due to not only changed enzyme kinetics but also elevated enzyme levels. Animals treated with LY2121260 showed an improved glucose tolerance after oral glucose challenge. These results support the concept that GK activators represent a new class of compounds that increase both insulin secretion and hepatic glucose use and in doing so may prove to be effective agents for the control of blood glucose levels in patients with type 2 diabetes.

patent submitter:Eli Lilly and Company According to the present invention there is provided a compound of formula (I) wherein Z isR3 is lower alkyl or halo lower alkyl having from 2 to 6 carbon atoms or arylalkyl or -(CH2)s-V where V is a 3 to 8-membered ring which is cycloalkyl, cycloalkenyl, or heterocycloalkyl having one heteroatom selected from oxygen and sulfur ; s is independently 0, 1 or 2; M is hydrogen or halo or lower alkyl or perfluoro-lower alkyl;A is or where Y is oxygen or sulfur, and its pharmaceutically acceptable salts thereof. These compounds are considered to be useful for the treatment of type II Diabetes.

patent submitter:Eli Lilly and Company

The aim of this work was to correlate the in vitro human skin permeability, expressed as the permeability coefficient ( K p ), and some physicochemical parameters of a new series of benzoxazinones. The in vitro human skin permeability of 14 substances, including regioisomers with CH 3 , OH, OCH 3 , and Cl groups in different positions on the aromatic ring, was determined. The modified Franz diffusion cell method was used. The K p values were in the range 0.14–8.24 cm/h, showing a strong dependence on the position and type of substituent. Physicochemical descriptors usually referred in literature, such as log P , molecular weight and volume (MV), hydrogen bond donor ( H d ) and acceptor activity ( H a ), and molecular refractivity were considered, with the addition of solvation enthalpy (ΔΔ H solv ). ΔΔ H solv is defined as the difference between formation enthalpies in water and octanol. The algorithm with the best correlation between K p and physicochemical descriptors was calculated, taking into account the differences observed among the regioisomers. The algorithm obtained with ΔΔ H solv had a good correlation ( r 2 =0.749, F =16.43, P =0.0005), comparable with the equation, proposed by Potts and Guy, based on MV, H d and H a ( r 2 =0.830, F =16.3, P =0.0004).

The recently proposed MS-WHIM indices, a set of theoretical descriptors containing information about size, shape and electrostatic distribution of a molecule, have been further investigated. The main objectives of this work were: (i) to confirm the descriptive power of MS-WHIM in modelling specific biological interactions, (ii) to analyse the dependence of MS-WHIM on the type of atomic charges used for computing electrostatic potential and (iii) to compare the performances of MS-WHIM with those provided by other global 3D molecular descriptors. The spatial autocorrelation of atomic and molecular surface properties were selected for comparison purposes. WHIM-based and autocorrelation-based vectors were calculated for two molecular sets from the literature, namely a series of 18 HIV-1 reverse transcriptase inhibitors and a set of 36 sulphonamide endothelin inhibitors. PLS was adopted to derive statistical predictive models that were validated by means of cross-validation. The reported results confirmed that MS-WHIM indices are able to provide meaningful statistical correlations with biological activity. MS-WHIM descriptors are sensitive to the type of partial atomic charges applied and improved models were obtained using more accurate charges. Moreover for both the datasets, MS-WHIM results, in terms of fitting and predictive power of PLS models, were superior to those from autocorrelation. Finally, the strengths/weaknesses of global 3D-QSAR descriptors over local CoMFA-like methods, as well as the main differences between WHIM-based and autocorrelation-based vectors, are discussed.

The aim of the present work is to study the Oligocene Scaphopoda and Archaeogastropoda of the Tertiary Piedmont Basin (T.P.B.), aiming towards an overall revision of the Oligocene mollusc fauna of this Basin. Five taxa of Scaphopoda and twenty-eight taxa of Archaeogastropoda have been analysed; among these a new species of Nerita (Theliostyla) is proposed., Rivista italiana di Paleontologia e Stratigrafia, Vol 106, No 2

A 3D model of the catalytic domain of PKC was built based on the X-ray structure of the homologous PKA enzyme. The two enzymes were found to have similar general architecture although differing for the number of negatively charged clusters and their location near the phosphorylation site. These differences were consistent with the charge requirements deduced from the consensus sequence of PKC and PKA substrates. A Myristyl Binding Site (MBS) was found in the PKC model between helix C and sheets 8 and 9. The identification of this MBS allowed the rationalization of the results obtained with N-myristoylated peptide inhibitors and, above all, the design of ITF1671 (H-RFARKGALRQKN-CONH-Myr), a new C-myristylamido peptide, which exerted one of the most potent inhibitory activity against PKC and PKM known to-date.

The peptide corresponding to the C-terminal half of M.tuberculosis hsp10 was synthesised based on the prediction that it might represent an independent structural region of the protein. This hypothesis was confirmed by aggregation and CD studies using this peptide and longer sequences of the protein. The peptide shares about 40-50% sequence homology with alpha 2 and beta 1 chains of MHC class I and II antigens. This and the CD results which indicated that the peptide at acidic pHs folds into an anti-parallel beta-sheet were used to generate a 3D model which has the same "W" fold contained in the MHC peptide binding groove. These data suggest that the hypothesis of molecular mimicry proposed to be one of the mechanisms which triggers autoimmune diseases may be extended to hsp10 proteins. Furthermore the suggested evolutionary relationship between hsp's and MHC antigens may find support from these data.

Nursing personnel and physical therapists refer to the lifting and moving of patients as the most important determinant of occupationally related low-back pain. This study was conducted in 12 nurses and 12 patients, to compare three methods of transferring patients from bed to wheelchair; (I) manual lifting, (II) an assistive device-a walking belt (with both one- and two-person transfers) and (III) a mechanical hoist. After completion of a given transfer, nurses were asked to rate the physical stress and how secure they felt the method was. Patients were asked to rate how secure and comfortable they felt. We also recorded the time required to make each transfer. The walking belt two persons had the most favourable ratings (the least stressful and most secure and comfortable), however transfers with this method took longer than those with the manual methods (although less than transfers with the hoist). Both nurses and patients rated one-person manual lifting as most stressful and least secure. Two-person transfer methods were preferred to the corresponding one-person methods. The hoist was the least suitable transfer method in view of the corresponding one-person methods. The hoist was the least suitable transfer method in view of the considerable physical stresses to the nurses, perceived lack of safety, discomfort for the patients and time involved.

A study was made on a group of workers occupationally exposed to tools producing medium-to-low frequency vibrations, and on a comparable control group. The subjects underwent a plethysmographic examination with the cold test, which revealed a greater number of sphygmic alterations in the exposed group; at the same time spontaneous platelet aggregation, blood levels of 6-K-PGF-1 alpha and TXB2 and urinary levels of BTGU were determined in basal conditions and after the cold test. Except for the slight, and not statistically significant, increase in TXB2, the results did not reveal any alterations in the constituents of the prostaglandin balance after the cold test. This therefore indicates that biohumoral changes of this type were not involved in producing cold-induced vasomotor alterations in the group under study. However, further investigations are recommended which will take account of the age and working history of the subjects, and particularly of the physical characteristics of the vibrations produced by the tools used, especially the Hz number.