Search

A weak HTS hit at the CCR2B receptor has been converted into a potent antagonist by array SAR studies. Selectivity over the closely related CCR5 receptor is also achieved.

Transient hyperprolactinaemia has been shown to accompany the procedure of oocyte retrieval under laparoscopic control. This study was concerned with establishing whether transvaginal oocyte retrieval was also associated with hyperprolactinaemia and whether the hyperprolactinaemic response was dependent on the method of anaesthesia/analgesia employed. Two distinct patterns were recorded. Oocyte retrieval under general anaesthesia was accompanied by a rapid rise in prolactin levels, which peaked after 40 min. Oocyte retrieval under intravenous sedation was associated with a slow rise in circulating prolactin concentrations. Significant differences in the prolactin rise between the general anaesthesia and sedation groups appeared within 10 min of the start of the procedure. It is concluded that although the surgical stress of oocyte recovery is associated with mild transient hyperprolactinaemia, most of the hyperprolactinaemic response is due to the anaesthetic.

BACKGROUND—There is an increase in vascularity in the asthmatic airway. Although inhaled corticosteroids (ICS) are an effective anti-inflammatory treatment in asthma, there are few data on any effects on structural changes. METHODS—Endobronchial biopsy specimens from seven asthmatic subjects not receiving ICS and 15 receiving 200-1500 µg/day beclomethasone dipropionate (BDP) were immunohistochemically stained with an anti-collagen type IV antibody to outline the endothelial basement membrane of the vessels. These were compared with biopsy tissue from 11 non-asthmatic controls (four atopic and seven non-atopic). RESULTS—There was a significant increase in the density of vessels (number of vessels/mm2 of lamina propria) in the asthmatic subjects not on ICS compared with non-asthmatic controls (mean 485 (interquartile range (IQR) 390-597) versus 329 (IQR 248-376) vessels/mm2, p

The benefits of measuring patient satisfaction have been increasingly acknowledged in recent years. A range of techniques has been used including analysis of complaints made by patients and/or relatives, focus group interviews following discharge, postal and telephone surveys, face-to-face interviews and critical incident analysis. Both quantitative and qualitative methodologies are often employed in patient-satisfaction research. It is suggested that a two-tier approach of methods can increase validity and reliability (i.e. utilizing qualitative approaches in order to develop a quantitative tool). Surgery will benefit through the identification of quality benchmarks based on this type of research. There must be an emphasis on incorporating the results of patient satisfaction studies into practice and the monitoring of improvements based on the identified benchmarks.

SKF 97426-A is a novel bile acid sequestrant that is threefold more potent than cholestyramine at increasing bile acid excretion in the hamster. SKF 97426-A is a quaternary alkylammonium polymethacrylate that was selected for comparison with cholestyramine in vivo because of its superior in vitro bile acid binding properties. Association, dissociation, affinity, and capacity experiments were performed under physiologically relevant conditions with the most abundant bile acids found in human bile. The bile acids came to equilibrium with SKF 97426-A and cholestyramine within approximately 30 min and 6 min, respectively. SKF 97426-A and cholestyramine had similar capacities for all the bile acids (between 2.5 and 4 mmol/g) and both had similar, very high affinities and slow dissociation rates for the dihydroxy bile acids. However, SKF 97426-A had much higher affinities for the trihydroxy bile acids glycocholic acid and taurocholic acid than did cholestyramine. Dissociation of glycocholic acid and taurocholic acid from SKF 97426-A was also much slower (27 and 25%, respectively, dissociated after 60 min) than from cholestyramine (89 and 84%, respectively, dissociated after 60 min). The higher affinities and slower dissociation rates of the trihydroxy bile acids for and from SKF 97426-A probably account for the increased potency of SKF 97426-A over cholestyramine in vivo.

Background The development of a systematised advanced care planning process in Catholic faith based institutions has presented challenges that have seen unsustainable unsupported programme. Increasing clinician need, a changing understanding of the role of advanced care planning in routine health care, changing community expectations of the use of advanced care plans and reform in health care quality standards have necessitated a recommitment to develop a sustainable, workable process. Aim To present a narrative of the factors, internal and external to the hospital, that have had to be considered and worked through, to develop a programme in care planning for advanced care at St. Vincent9s Hospital Melbourne that has gained acceptance and led to implementation to be embarked upon. Methods Review of the Advanced care planning working group9s meeting minutes actions and document developments taken over 8 month period June 1 to December 2. Results The process demonstrates the key steps in the 18 month timeline that has brought significant points of development to create a workable and viable policy and guidelines, acceptable within a Catholic hospital9s ethical and clinical framework Discussion Sharing the learning9s will be helpful for others developing programmes in comparable institutions to see how important the linking together of key people and committees in an organisation is to develop the acceptable shared understanding and language within the institutions ethical and clinical framework. Conclusion Setting aside historical challenges, it has been possible to develop a system of advanced care planning processes within a Catholic, faith base, tertiary hospital.

The development of a broadly tunable waveguide laser offers important advantages in the application of integrated optics to fields such as sensing and spectroscopy. A waveguide laser based on the well known Ti:sapphire laser system, where the gain bandwidth extends over 400nm in the near infra-red, presents an attractive candidate. The realisation of such a device in low cost, high quality sapphire substrates, requires the development of both optical waveguides and the introduction of the active ion. In this paper we report the demonstration of optical waveguides in sapphire, fabricated by the thermal diffusion of titanium, and identify conditions appropriate for the development of a Ti:sapphire waveguide laser.

We have shown previously that the majority of RNA polymerase II complexes initiated at the c-myc gene are paused in the promoter-proximal region, similar to observations in the Drosophila hsp70 gene. Our analyses define the TATA box or initiator sequences in the c-myc gene as necessary components for the establishment of paused RNA polymerase II. Deletion of upstream sequences or even the TATA box does not influence significantly the degree of transcriptional initiation or pausing. Deletion of both the TATA box and sequences at the transcription initiation site, however, abolishes transcriptional pausing of transcription complexes but still allows synthesis of full-length RNA. Further analyses with synthetic promoter constructs reveal that the simple combination of upstream activator with TATA consensus sequences or initiator sequences act synergistically to recruit high levels of RNA polymerase II complexes. Only a minor fraction of these complexes escapes into regions further downstream. Several different trans-activation domains fused to GAL4-DNA-binding domains, including strong activators such as VP16, do not eliminate promoter-proximal pausing of RNA polymerase. Thus, we conclude that pausing of RNA polymerase II is a common phenomenon in eukaryotic transcription and does not require complex promoter structures. Further analyses reveal that enhancers have a modest influence on transcription initiation and on release of transcription complexes out of the pause site but may function primarily to increase the elongation competence of transcription complexes.

A form of bumetanide potassium trihydrate that is structurally similar to bumetanide sodium trihydrate was identified. Structural analysis indicated however that the change from sodium to potassium salt resulted in meaningful changes in the packing arrangement and even greater changes on physicochemical properties. The potassium trihydrate salt was five times more soluble in water relative to the sodium trihydrate salt (27 mg mL−1vs. 5.6 mg mL−1). Both salts underwent complete dehydration to their corresponding anhydrate forms following exposure to low humidity or elevated temperature. Arrhenius plots for the dehydration between 20–30 °C yielded a lower activation barrier for the potassium trihydrate compared to the sodium trihydrate (14.9 kcal mol−1vs. 19.9 kcal mol−1), translating into a 15–20-fold difference in the rate of dehydration. Such a 5.0 kcal mol−1 gap suggests that the H2O molecules are more tightly bound in the sodium trihydrate compared to potassium trihydrate. These differences in solubility and rate of dehydration further illustrate that changes to chemical composition can have a meaningful and unpredictable impact on the physicochemical properties of closely related pharmaceutical salt forms.

Clarity around the intended definitions of isostructurality in solid forms is highlighted with respect to the pharmaceutical industry and the patenting of crystalline forms. The analysis of structural similarity is a difficult problem and especially so when additional components are included such as counterions in salt forms. In this study we investigate the structural similarity of sodium and potassium salts using a range of methods. It is clear that for this type of multi-component system, where one or more components change between forms, PXRD similarity is not sufficient to determine isostructurality, and careful examination of the 3D crystal structure coordinates is needed. Substantial and unpredictable changes in physical properties have been observed for even small deviations away from isostructurality. Finally, it is noted that sodium salt hydrates tend to exhibit a greater hydration level than potassium salt hydrates, and this trend is hypothesised to be due to the differing solution behaviour of the two cations.

60Co γ-irradiation of both lithium trans-2-butenoate (11) and lithium trans-2-butenoate·formamide (12) affords the same dimer, dilithium trans-5-methyl-2-heptenedioate (13). However, stereochemical analysis of products 22 and 24 from the analogous trans-2-butenoate-2-d salts 21 and 23 established that C–C and C–H bond formation occur stereospecifically by syn addition to the double bond in lithiumtrans-2-butenoates 11 and 21 and anti addition to the double bond in lithium trans-2-butenoate·formamide complexes 12 and 23. These reactions, which provide an unprecedented, chemospecific one step synthesis of dicarboxylate 13, add significantly to the synthetic scope of the γ-ray induced reactions of crystalline metal trans-2-butenoates that lead to cyclic and acyclic dimers and acyclic trimers by γ-ray initiated radical chain reactions. The stereochemistry of products 22 and 24 is that predicted by analysis of crystal packing, consistent with least-motion principles of the topochemical postulate as shown in Fig. 12 and 13. Analysis of the crystal structures, with respect to nearest neighbors, is consistent with the hypothesis that formation of carbon–carbon bonds in propagation step 1 and hydrogen atom transfer in propagation step 2 are topochemical and controlled by the crystal lattice. Analysis of the packing diagrams provides a pathway for chain propagation throughout the crystal that consumes all the molecules in the unit cell. The dimerization of 12 is much more rapid and proceeds in much higher yield than that of 11, probably as a result of significantly shorter C⋯C contacts and a more robust pathway for hydrogen transfer.

SK&F 97426-A is a novel bile acid sequestrant which was selected for comparison with cholestyramine in vivo because of its superior in vitro bile acid binding properties. The effects of the two sequestrants on faecal bile acid excretion, plasma total cholesterol, VLDL + LDL and HDL cholesterol and triglyceride concentrations and on liver enzymes involved in the synthesis and metabolism of cholesterol were investigated in normocholesterolaemic hamsters. Four studies were conducted to determine the relative potencies of the two resins using a range of doses of the sequestrants over treatment periods of up to 2 weeks. Curves fitted to the resulting data allowed common maximum responses and separate ED 50 s to be calculated for each sequestrant. The maximum response of both sequestrants was to increase bile acid excretion by 352% and lower plasma total cholesterol by 37–58%. LDL + VLDL and HDL cholesterol were reduced by 56–75% and 25–41%, respectively. SK&F 97426-A was 3 times more potent than cholestyramine at increasing the excretion of bile acids in the faeces and 2.1–3.4-fold and 2.3–3.2-fold more potent at lowering total plasma cholesterol and LDL plus VLDL cholesterol, respectively. In some of the experiments SK&F 97426-A was also more potent than cholestyramine at lowering HDL cholesterol. Plasma triglycerides were also lowered by both sequestrants by up to 31 % after 1 week but the relative potency could not be determined. These HDL cholesterol and total triglyceride lowering effects of bile acid sequestrants in the hamster are known not to occur in people treated with cholestyramine. There were minimal differences between hamsters treated for 1 or 2 weeks in the relative potencies or ED 50 s calculated for the total plasma cholesterol, LDL + VLDL and HDL cholesterol. Both sequestrants may have been slightly more efficacious on these parameters after 2 weeks of treatment. Liver weights were reduced by about 15% by both sequestrants at 2% (w/w) in the diet for 1 week. The activities of the liver HMG-CoA reductase and cholesterol 7a-hydroxylase were increased as expected, whilst the activity of the acyl-CoA:cholesterol acyltransferase was reduced by both sequestrants at this dose. SK&F 97426-A was, therefore, 2–3-fold more potent as a bile acid sequestrant and hypocholesterolaemic agent than cholestyramine when tested in the hamster.

In an investigation of novel potential bile acid sequestrants, the affinities of the sodium salts of the glycine and taurine conjugates of naturally occurring bile acids (cholate, deoxycholate, chenodeoxycholate and lithocholate) for several cationic ammonium bile acid derivatives have been investigated by measurements of the extent to which the derivatives are able to precipitate the bile acids. This is roughly proportional to the lipophilicity of the interacting species. Thus, amino and ammonium derivatives of cholic acid do not precipitate taurocholate or glycocholate to any great extent, whereas ammonium derivatives of deoxycholate and lithocholate are much more effective. To complement the precipitation measurements, high resolution 13C-NMR has been applied to investigate the weaker interactions between the ammonium cholate derivative and glycocholate, glycodeoxycholate and glycochenodeoxycholate. Addition of either of the latter two bile acids to the cationic ammonium compound results in considerable broadening of the 13C resonances of both species, indicating the formation of relatively rigid structures. In addition, we have used T2 relaxation enhancement induced by spin-labelled fatty acids to examine the mechanism of interaction with bile acids of amphiphilic anions, which might compete with bile acids for sites on bile acid sequestrants. Low concentrations of 16-DOXY L-Stearate dramatically broaden the 13C-NMR resonances of deoxycholate carbons 19, 18 and 7 in particular, while 5-DOXY L-Stearate exerts much less specific effects. These results have been incorporated into a snapshot model of bile acid-fatty acid interactions.

1. Octimibate, 8-[(1,4,5-triphenyl-1H-imidazol-2-yl)oxy]octanoic acid, is reported to have antithrombotic properties. This is in addition to its antihyperlipidaemic effects which are due to inhibition of acylCoA:cholesterol acyltransferase (ACAT). The aim of this study was to investigate the mechanism of the antithrombotic effect of octimibate, and to determine whether the effects of octimibate are mediated through prostacyclin receptors. 2. In suspensions of washed (plasma-free) human platelets, octimibate is a potent inhibitor of aggregation; its IC50 is approx. 10 nM for inhibition of aggregation stimulated by several different agonists, including U46619 and ADP. The inhibitory effects of octimibate on aggregation are not competitive with the stimulatory agonist; the maximal response is suppressed but there is no obvious shift in potency of the agonist. In platelet-rich plasma, octimibate inhibits agonist-stimulated aggregation with an IC50 of approx. 200 nM. 3. Octimibate also inhibits agonist-stimulated rises in the cytosolic free calcium concentration, [Ca2+]i, in platelets. Both Ca2+ influx and release from intracellular stores are inhibited. The effects of octimibate on aggregation and [Ca2+]i are typical of agents that act via elevation of adenosine 3':5'-cyclic monophosphate (cyclic AMP). Similar effects are seen with forskolin, prostacyclin (PGl2) and iloprost (a stable PGl2 mimetic). 4. Octimibate increases cyclic AMP concentrations in platelets and increases the cyclic AMP-dependent protein kinase activity ratio. Octimibate stimulates adenylyl cyclase activity in human platelet membranes, with an EC50 of 200 nM. The maximal achievable activation of adenylyl cyclase by octimibate is 60% of that obtainable with iloprost. Octimibate has no effect on the cyclic GMP-inhibited phosphodiesterase (phosphodiesterase-ITI), which is the major cyclic AMP-degrading enzyme in human platelets.5. Octimibate inhibits, apparently competitively, the binding of [3H]-iloprost (a stable PGl2 mimetic) to platelet membranes; the estimated Ki is 150 nm. 6. The platelets of different species show considerable differences in the apparent potency of their inhibition of aggregation by octimibate; platelets from cynomolgus monkeys are 3 fold more sensitive than those from humans, while rat, cat and cow platelets are 50, 100, and 250 fold less sensitive than human platelets. The sensitivity of these different species to iloprost, however, varies over a range of only 10 fold with no obvious difference between primates and non-primates. 7. Octimibate appears to be a potent agonist (aggregation), or partial agonist (adenylyl cyclase), at prostacyclin receptors and is the first non-prostanoid agent of this type to be identified. The species differences in relative potency of octimibate and iloprost may reflect the existence of receptor subtypes.

One stable form (Form I) and two metastable forms (Forms II and IV) of p-methylchalcone have been obtained, with Form II having previously been reported to be a disappearing polymorph. To prevent t...

The industrially important compound methacrylamide crystallizes as concomitant conformational polymorphs; the monoclinic form contains only the s-cis conformer, while the orthorhombic form contains only the s-trans conformer.

Note on Environment: The sort of systems discussed here are primarily central databases accessed through a client-server architecture offering information obtained primarily from scientific societies and commercial publishers.

OCLC has developed a CD‐ROM‐based system for the storage, distribution, and retrieval of documents. The system stores an ASCII copy of the text of the original document. It also stores page make‐up and font definition codes. These codes are used to control an inexpensive laser printer in the production of copies that closely resemble the original document. The authors discuss trends in the information equipment and printing industries that will govern the future application of this technology.

SynopsisWe describe the structure of regular semigroups in which each element is dominated, in the Nambooripad order, by a unique maximal element that is ℋ-equivalent to a mididentity. These are precisely direct products of a rectangular band and a uniquely unit regular semigroup.

For any element a of a semigroup (S,·), we may define a “sandwich” operation ∘ on the set S by x ∘ y = xay (x, y ∈ S). Under this operation the set S is again a semigroup; we denote this semigroup by (S, a) and call it a variant of S. Variants of semigroups of binary relations have been studied by Chase [6, 7]. In this paper we consider variants of arbitrary semigroups.

Photolysis of azidocinnamates (1a–e) at 300 nm in light petroleum gives exclusively the triazatricyclononenes (7a–e) in a highly stereospecific trimerisation of the corresponding azirine (2). A mechanism is proposed involving the sequence: azide (1)→ azirine (2)→ nitrile ylide (8)→ dimer (9)→ azomethine ylide (10)→ trimer (7)(Scheme 2). This mechanism not only rationalizes the formation of the trimers (7), rather than dimers or oligomers, but also their stereochemistry. Further evidence for it is provided by photolyses of the azidocinnamates (1f–h) which give the ‘dimer’(13), the cyclopropaisoquinoline (16), and the imidazopyridine (20), respectively; these three products result from intramolecular interception of the azomethine ylide or nitrile ylide intermediates.

A synthesis of L-3,5-dibromo-3′-[(6-oxo-l,6-dihydropyridazin-3-yl)methyl]thyronine-SK&F L-94901 (1), a novel, selective and potent thyromimetic – is described. The key step in this synthesis involves the formation of a hindered diaryl ether moiety. This paper describes an approach via oxidative coupling of the hindered phenols (2) and (3). Some by-products and impurities generated during the synthesis are discussed briefly.

IfSis a (multiplicative) Semigroup anda∈S, the binary operation ∘ defined on the setSbyx∘y=x a yis associative and the resulting semigroup is called a variant ofS. We study the congruenceadefined onSby saying that two elements are α-related if and only if they determine the same variant ofS. Certain quotients of variants are used to provide an arbitrary semigroup with a generalised local structure. The variant formulation of Nambooripad's partial order on a regular semigroup is used to show that the order possesses a certain property (involvingD-equivalence).

Cochcrane, G. M., Prieto, F., Hickey, B., Benatar, S. R., and Clark, T. J. H. Thorax , 29 , 389-393. Early diagnosis of airways obstruction. Three simple tests, maximum expiratory flow volume curve, maximum expiratory volume time curve and `closing volume9, were used to detect early airways obstruction in 21 smokers. A high proportion had abnormal values for MEF 75% , MEF 50% , and FET (86%, 71%, and 62% respectively) with a relatively normal FEV 1 . There was a good correlation between tests of small airways obstruction obtained from the forced expiratory manoeuvre. The measurement of `closing volume9 (phase 4/VC%) was less satisfactory as there were difficulties with interpretation of the records in half of the studies. We conclude that the forced expiratory manoeuvre can be used to detect early airways obstruction as well as providing FEV 1 and vital capacity. The importance of early diagnosis of airways obstruction is not yet clear and further information is required about its natural history, and its relation to smoking habits and to the more advanced and less reversible stages of airways obstruction. It may be possible to use early detection to prevent the development of disabling chronic obstructive bronchitis.

Two types of linear on‐line search have been implemented on a data base of 100,000 INSPEC records, and compared with an inverted search program on the same file. It was found that the linear search which does a character‐by‐character scan of the whole file was too slow to be useful as an on‐line search, but that the second linear search, which uses a linear file of keys to select records for full scanning, was useable on‐line. An algorithm suitable for the on‐line searching of the linear file of keys is presented with run time nearly independent of the number of terms in the search query. Neither of the linear searches can compete with an inverted search in terms of user convenience, but they do not require as complex file‐maintenance software, they use less processing time to build indexes, and they have lower storage requirements than inverted files.

The key step in the synthesis of L-3,5-dibromo-3′-[6-oxo-1,6-dihydropyridazin-3-yl)methyl]-thyronine, SK&F L-94901 (1), a novel, selective, and potent thyromimetic, is the formation of the hindered diaryl ether moiety. This paper describes an investigation into the formation of the required diaryl ether by copper-catalysed reaction both of symmetrical iodonium salts (2a) and (10) and mixed iodonium salts (2b–e) with protected dibromotyrosine (5). The importance of the counter-ion of the iodonium salt is discussed. This work is extended to a large-scale synthesis of SK&F L-94901 (1).

Summary— A pericaliceal haemangioma associated with papillary necrosis caused haematuria which led to nephrectomy. Seven similar vascular lesions were found on review of the surgical histopathology records from the last 25 years at the St Peter's Hospitals, Institute of Urology, London. In 4 of these there was histological evidence of damage to the renal papilla adjacent to the vascular abnormality; a possible mechanism for these changes is discussed. In all 8 cases the patients presented with haematuria and, in 5, abnormalities were seen on renal radiological investigation. Nephrectomy was performed in 5 instances and the remaining 3 patients were treated by partial nephrectomy. The presence of a vascular malformation was considered pre-operatively in 2 patients and in the remainder the diagnosis was first made on laboratory examination. In all patients haematuria ceased post-operatively and in 5 cases where follow-up information was available there has been no evidence of bilateral involvement.

Direct computer experiments are conducted on electron diffusion in a simple cubic lattice where the disorder corresponds to the Anderson model. Results for the onset of total localisation are in good agreement with other numerical estimates and it is found that the critical value of the parameterW/ZV is (17.7/6). A random structurally disordered system is also investigated with hopping integrals given by V(r) = -V0 exp (-r/a) and found that localisation occurs at the critical value a = 3 ± 0.3. Thisis in agreement with the only other numerical estimate but is substantiallydifferent from theoretical calculations. Es werden direkte Computerexperimente der Elektronendiffusion im primitiven kubischen Gitter durchgefuhrt, wo die Fehlordnung dem Andersonmodell entspricht. Ergebnisse fur das Einsetzen der Gesamtlokalisierung befinden sich in guter Ubereinstimmung mit anderen numerischen Berechnungen, und es wird ein kritischer Wert des Parameters W/ZV von 17,7/6 gefunden. Ein strukturell statistisch fehlgeordnetes System wird ebenfalls untersucht, wobei die Hoppingintegrale durch V(r) = -V0 exp (-r/a) gegeben sind, und es wird gefunden, das Lokalisierung beim kritischen Wert a = 3 ± 0,3 auftritt. Dies befindet sich in Ubereinstimmung mit der einzigen anderen numerischen Berechnung, ist jedoch wesentlich verschieden von theoretischen Berechnungen.

Summary A method of simultaneous bilateral ureterocolic anastomosis based on that devised by Davalos is described, and a short account is given of four patients on whom it was employed satisfactorily.

Uniform semilattices can be characterized as the semilattices of bisimple inverse semigroups [4,5]. This motivates the study of such semilattices. In particular, we may consider ways of forming uniform semilattices by combining together known ones. In this paper, we give a construction which, given two suitable semilattices, produces another semilattice, their so-called link product. The construction may be used to obtain uniform semilattices and, in particular, yields a family of pairwise non-isomorphic uniform semilattices M(r), indexed by the non-negative integer r.