The importance of amino and ester functions for the curarizing activity of quaternary ammonium salts

The technique of counterimmunoelectrophoresis was evaluated for its usefulness in the detection of precipitating antibodies to Histoplasma capsulatum, designated h and m precipitin bands. Forty-four patients with active histoplasmosis had either m bands or both h and m bands. The h precipitin band occurred primarily in patients with disseminated disease, chronic pulmonary disease, or mediastinal lymphadenopathy of several months' duration; with resolution of the infection, this antibody disappeared. The m band appeared earlier in the course of histoplasmosis and persisted for months to years after resolution of the infection. Antibodies detected by counterimmunoeelectrophoresis were in the immunoglobin G class and were more specific for histoplasmosis than those detected by the complement fixation test. Only one false positive h band occurred in a total of 81 sera tested (specimens from 24 healthy control subjects and 57 patients with other diseases). Counterimmunoelectrophoresis was both more sensitive and quicker than immunodiffusion at detecting h and m antibodies. Combining this assay with standard complement fixation tests and fungal culture methods should lead to the accurate, rapid diagnosis of histoplasmosis.     

Kinetics of active center formation in dog plasminogin by streptokinase and activity of a modified streptokinase

The rate of activation of dog plasminogen by excess streptokinase showed a significant delay as compared to the rate of activation with catalytic amounts of streptokinase. Studies of the reaction at high streptokinase levels with the active center reagent, p-nitrophenyl-p-guanidinobenzoate showed that only a fraction (13%) of the potential active centers were developed in a equimolar mixture of streptokinase and dog plasminogen in 15s and more than 10 min were required for the formation of 1 mol of active sites. In the first 15s, the yield of active sites could not be increased by increasing streptokinase 10-fold over the molar concentration of plasminogen, suggesting that active center development rather than complex formation was the rate-limiting step. The delayed reactivity seen in this system provides an interesting model for the study of conformationally induced active center formation. With catalytic amounts of streptokinase, the activation proceeded rapidly but reached a plateau, indicating the loss of activator activity in the reaction mixture. With successive additions of fresh streptokinase, complete activation was achieved. Polyacrylamide gel electorphoresis showed that a stable streptokinase-plasmin complex formed. However, in contrast to the human plasmin-steptokinase complex, a potent plasminogen activator in which streptokinase is found as a residue of 37,000 daltons, dog plasmin-streptokinase complex contained a residue of 25,700 daltons and the complex was inactive against canine and human plasminogen. The 25,700 fragment along, however, showed considerable activator activity when tested with human and dog plasminogens.     

Synthesis and antimicrobial activity of a dihydroampicillin and a dihydrocephalexin

A dihydroampicillin (3) and a dihydrocephalexin (4) have been synthesized by condensing alpha-(cyclohexa-1, 3-dienyl)glycyl chloride with 6-aminopenicillanic acid (1) and 7-deacetoxycephalosporanic acid (2) respectively. The two antibiotics obtained show enhanced antimicrobial activity towards certain bacterial strains compared with ampicillin and cephalexin.     

New orally active enkephalinase inhibitors: their synthesis, biological activity, and analgesic properties

A series of (4S)-4-[(2S)-benzyl-3-mercaptopropionylamino]-4-(N-phenylcarbamoyl )-butyric acids has been identified as potent systemically active enkephalinase inhibitors. Structure-activity relationships (SAR) are discussed. Further chemical modification of the inhibitors was carried out in order to identify the inhibitors which are orally active in an animal model. Compounds of particular interest are the prodrug-like analogues, including 5b (ONO-9902). Their analgesic effects after oral administration were evaluated.     

Electrodeposition of manganese metal: role of quaternary ammonium salts on current efficiency,morphology and polarisation behaviour

The electrodeposition of manganese metal from aqueous solutions is problematic due to its high electroreduction potential demanding unique process challenges. In the present work, electrolytic manganese metals (EMMs) of high quality are deposited from sulphate solutions in the presence of quaternary amines: tetra ethyl ammonium bromide (TEABr), tetra propyl ammonium bromide and tetra butyl ammonium bromide. The concentrations of these additives were varied over a relatively broad range to evaluate their effect on current efficiency (CE), specific energy consumption, polarisation behaviour of the cathode and deposit morphology of the electrodeposited manganese metal. A maximum CE of more than 68% was achieved in the presence of 100?mg.L^?1 TEABr in the electrolytic bath at a current density of 500?A.m^?2. X-ray diffraction studies revealed that (330, 411) planes were the most preferred planes of crystal growth during manganese electrodeposition resembling alpha-manganese regardless of the type of quaternary amines used. A smooth and compact deposit was obtained with TEABr that was also supported by the scanning electron micrographs showing uniform deposit morphologies. The presence of these quaternary amines in the electrolyte causes polarisation of the cathode during electrodeposition. The degree of polarisation increases with an increase in the bulkiness of the alkyl group on the quaternary nitrogen atom of the additive. The quaternary amine TEABr was found to be the most suitable additive for producing the desired quality of EMM with better current yield.     

Automated chemical synthesis of biologically active tRNA having a sequence corresponding to Ascaris suum mitochondrial tRNA(Met) toward NMR measurements

RNA samples corresponding to Ascaris suum mitochondrial tRNA(Met) were chemically and automatically synthesized in amounts sufficient for NMR measurement. Conventional and rapid deprotection methods gave tRNA samples with the same amino acid-accepting activity as those prepared by other method; enzymatic synthesis, and enzymatic ligation of chemically synthesized fragments. The synthetic tRNA showed the same 1H-NMR spectrum in the iminoproton region as the ligated tRNA. This rapid and reliable preparation method thus provides biologically active tRNA for NMR measurement, and further, it is applicable for synthesis of other large synthetic RNAs, by combining the site-specific isotopic labeling method.     

Solution structure by NMR of circulin A: a macrocyclic knotted peptide having anti-HIV activity

The three-dimensional solution structure of circulin A, a 30 residue polypeptide from the African plant Chassalia parvifolia, has been determined using two-dimensional 1H-NMR spectroscopy. Circulin A was originally identified based upon its inhibition of the cytopathic effects and replication of the human immunodeficiency virus. Structural restraints consisting of 369 interproton distances inferred from nuclear Overhauser effects, and 21 backbone dihedral and nine chi1 angle restraints from spin-spin coupling constants were used as input for simulated annealing calculations and energy minimisation in the program X-PLOR. The final set of 12 structures had mean pairwise rms differences over the whole molecule of 0.91 A for the backbone atom, and 1.68 A for all heavy atoms. For the well-defined region encompassing residues 2-12 and 18-27, the corresponding values were 0.71 and 1.66 A, respectively. Circulin A adopts a compact structure consisting of beta-turns and a distorted segment of triple-stranded beta-sheet. Fluorescence spectroscopy provided additional evidence for a solvent-exposed Trp residue. The molecule is stabilised by three disulfide bonds, two of which form an embedded loop completed by the backbone fragments connecting the cysteine residues. A third disulfide bond threads through the centre of this loop to form a "cystine-knot" motif. This motif is present in a range of other biologically active proteins, including omega-contoxin GVIA and Cucurbita maxima trypsin inhibitor. Circulin A belongs to a novel class of macrocyclic peptides which have been isolated from plants in the Rubiaceae family. The global fold of circulin A is similar to kalata B1, the only member of this class for which a structure has previously been determined.     

Diagnosis-related groups: a comparative analysis of hospital activity in different countries

Comparative study of hospital activities in the Novgorod district and nine countries of the European Community, carried out within the framework of the International Project CAMISE (Case Mix and Severity) of the European Community on the basis of the classification system for diagnosis-related groups, showed a lower Case Mix Index, a longer hospital stay for all major disease, and a lower surgical activity in the hospitals of the Novgorod district in comparison with other European countries. The detected differences are largely due to specific features in the organization of hospital service in Russia (no special hospitals for acute and chronic patients, no nursing homes) and insufficiently intensive therapeutic and diagnostic process.     

Telomerase activity and metastasis: expansion of cells having higher telomerase activity within culture lines and tumor tissues

Tumor cells with metastatic potential may have a high telomerase activity that augments telomeric DNA repeats, allowing the cells to escape from the inhibition of cell proliferation due to shortened telomeres. We examined the expression level of telomerase activity using the telomeric repeat amplification protocol among a series of cell lines obtained by repeated transplantation of a mouse fibrosarcoma. The lines could be grouped into three; one has no metastatic potential, and the other two show metastatic abilities after intravenous or subcutaneous injection. Comparison of their telomerase activity indicated that more malignant lines had higher activity. A similar relation was seen in metastatic nodules formed through clonal expansion from the heterogeneous population of inoculated cells; clonality was monitored in terms of variable patterns of subtelomeric repeats. The results suggest that a high level of telomerase activity may not be requisite for metastasis, but may confer a propensity to dominate in a tumor tissue.     

Conjugation of trypsin by temperature-sensitive polymers containing a carbohydrate moiety: thermal modulation of enzyme activity

Given the substantial increase in the numbers of community psychiatric nurses (CPNs) in England in the last 15 years this paper asks the question: is CPN activity where it should be? In-other words is activity distributed around the country according to need? Various indicators of need are suggested including population age structure, deprivation indices and suicide rates. We find no evidence -- based on information from scatterplots, Spearman correlations and more innovative measures of inequality -- that CPNs are distributed according to need. If this is confirmed by further research it is cause for alarm -- CPNs should be where they are most needed.     

Stereoselective synthesis and thromboxane A2 (TXA2) receptor antagonistic activity of optically active phenol derivatives

At the present time monotherapy is preferable to polytherapy if the epilepsy can be controlled with a single drug. However, persons with intractable epilepsy may need more than one antiepileptic drug to attain the best seizure control with the fewest side-effects. Although clinical studies have not been performed to identify the best combinations, rational polytherapy would imply combining antiepileptic drugs with different mechanisms of action.     

The effect of N-duopropenide (a new disinfectant with quaternary ammonium iodides) and formaldehyde on survival of organisms of sanitary interest in pig slurry

The counts of different groups of organisms (mesophilic total aerobic and anaerobic bacteria, enterobacteriaceae, faecal coliform bacteria and faecal streptococci type D), as well as the presence or absence of Pseudomonas spp. and Salmonella spp., were recorded in both unfiltered and filtered pig slurry samples at 1, 8 and 29 days of storage, before and after applying N-duopropenide (a new disinfectant with a quaternary ammonium structure) at 1, 2 x 1, 5 and 2 x 5% concentrations of the commercial product (equivalent to 0.11, 2 x 0.11, 0.55 and 2 x 0.55%, respectively, of active ingredient) for 1 h, or 0.5% commercial formaldehyde for 6 days. Before disinfection, anaerobic and aerobic organisms resulted in the highest counts (between 6 and 7 log units/ml), followed by enterobacteriaceae, faecal coliforms and streptococci (4-5 log units/ml). The unfiltered slurry showed higher bacterial counts than the filtered slurry. The variation in counts was similar for all the groups studied, with the highest count on day 1 of storage with a continuous decrease over the 3 days studied. N-duopropenide efficacy depended on the dose used, but a 2 x 5% concentration resulted in total inactivation (100% reduction) of all the bacteria studied, except for the total aerobic and anaerobic organisms present in unfiltered slurry. Formaldehyde efficacy was much lower. In respect of Pseudomonas spp., more isolates were obtained after using N-duopropenide at lower concentrations (1 and 2 x 1%) than before treatment, thus suggesting its suitability for selective isolation of this genus. Finally, no Salmonella spp. strains were isolated in any of the cases considered in this study.     

Halohydrin analogues of cryptophycin 1: synthesis and biological activity

The chloro-, bromo-, and iodo-derivatives 2-4 of the antimitotic drug cryptophycin 1 were synthesized by opening the epoxide ring. The biological activities of the compounds were tested in an in vitro microtubule assembly and a cell proliferation assay. The chloro-derivative 2 showed lower activity in the tubulin assay compared to 3 and 4, but they all showed similar inhibition in the proliferation assay.