Promoting physical activity to older adults: a preliminary evaluation of three general practice-based strategies

The aim of this study was to explore the feasibility of an exercise scientist (ES) working in general practice to promote physical activity (PA) to 55 to 70 year old adults. Participants were randomised into one of three groups: either brief verbal and written advice from a general practitioner (GP) (G1, N=9); or individualised counselling and follow-up telephone calls from an ES, either with (G3, N=8) or without a pedometer (G2, N=11). PA levels were assessed at week 1, after the 12-wk intervention and again at 24 weeks. After the 12-wk intervention, the average increase in PA was 116 (SD=237) min/wk; N=28, p < 0.001. Although there were no statistically significant between-group differences, the average increases in PA among G2 and G3 participants were 195 (SD=207) and 138 (SD=315) min/wk respectively, compared with no change (0.36, SD=157) in G1. After 24 weeks, average PA levels remained 56 (SD=129) min/wk higher than in week 1. The small numbers of participants in this feasibility study limit the power to detect significant differences between groups, but it would appear that individualised counselling and follow-up contact from an ES, with or without a pedometer, can result in substantial changes in PA levels. A larger study is now planned to confirm these findings.

Quality of diabetes care and coronary heart disease absolute risk in patients with type 2 diabetes mellitus in Australian general practice

Objective: To examine the quality of diabetes care and prevention of cardiovascular disease (CVD) in Australian general practice patients with type 2 diabetes and to investigate its relationship with coronary heart disease absolute risk (CHDAR). Methods: A total of 3286 patient records were extracted from registers of patients with type 2 diabetes held by 16 divisions of general practice (250 practices) across Australia for the year 2002. CHDAR was estimated using the United Kingdom Prospective Diabetes Study algorithm with higher CHDAR set at a 10 year risk of >15%. Multivariate multilevel logistic regression investigated the association between CHDAR and diabetes care. Results: 47.9% of diabetic patient records had glycosylated haemoglobin (HbA1c) >7%, 87.6% had total cholesterol >= 4.0 mmol/l, and 73.8% had blood pressure (BP) >= 130/85 mm Hg. 57.6% of patients were at a higher CHDAR, 76.8% of whom were not on lipid modifying medication and 66.2% were not on antihypertensive medication. After adjusting for clustering at the general practice level and age, lipid modifying medication was negatively related to CHDAR (odds ratio (OR) 0.84) and total cholesterol. Antihypertensive medication was positively related to systolic BP but negatively related to CHDAR (OR 0.88). Referral to ophthalmologists/optometrists and attendance at other health professionals were not related to CHDAR. Conclusions: At the time of the study the diabetes and CVD preventive care in Australian general practice was suboptimal, even after a number of national initiatives. The Australian Pharmaceutical Benefits Scheme (PBS) guidelines need to be modified to improve CVD preventive care in patients with type 2 diabetes.

Protein crystallography and examples of its applications in medicinal chemistry

The field of protein crystallography inspires and enthrals, whether it be for the beauty and symmetry of a perfectly formed protein crystal, the unlocked secrets of a novel protein fold, or the precise atomic-level detail yielded from a protein-ligand complex. Since 1958, when the first protein structure was solved, there have been tremendous advances in all aspects of protein crystallography, from protein preparation and crystallisation through to diffraction data measurement and structure refinement. These advances have significantly reduced the time required to solve protein crystal structures, while at the same time substantially improving the quality and resolution of the resulting structures. Moreover, the technological developments have induced researchers to tackle ever more complex systems, including ribosomes and intact membrane-bound proteins, with a reasonable expectation of success. In this review, the steps involved in determining a protein crystal structure are described and the impact of recent methodological advances identified. Protein crystal structures have proved to be extraordinarily useful in medicinal chemistry research, particularly with respect to inhibitor design. The precise interaction between a drug and its receptor can be visualised at the molecular level using protein crystal structures, and this information then used to improve the complementarity and thus increase the potency and selectivity of an inhibitor. The use of protein crystal structures in receptor-based drug design is highlighted by (i) HIV protease, (ii) influenza virus neuraminidase and (iii) prostaglandin H-2-synthetase. These represent, respectively, examples of protein crystal structures that (i) influenced the design of drugs currently approved for use in the treatment of HIV infection, (ii) led to the design of compounds currently in clinical trials for the treatment of influenza infection and (iii) could enable the design of highly specific non-steroidal anti-inflammatory drugs that lack the common side-effects of this drug class.

The chemistry of 5-oxodihydroisoxazoles .16. A new synthesis of pyrroles, furans, thiophens and their benzo analogues

Ethyl 5-oxo-2-phenyl-2,5-dihydroisoxazole-4-carboxylate (2) was photolysed at 300 mn in the presence of phenols, enols, anilines, enamines, aryl thiols and thioenols affording enamines. Treatment of these enamines with Lewis or protic acids gives the respective benzo and five-membered ring systems.

Biologically active conformer of the effector region of human C5a and modulatory effects of N-terminal receptor binding determinants on activity

A conformationally biased decapeptide agonist of human C5a (C5a(65-74)Y65,F67,P69,P71,D-Ala73 or YSFKPMPLaR) was used as a functional probe of the C5a receptor (C5aR) in order to understand the conformational features in the C-terminal effector region of C5a that are important for C5aR binding and signal transduction. YSFKPMPLaR was a potent, full agonist of C5a, but at higher concentrations had a superefficacious effect compared to the natural factor. The maximal efficacy of this analogue was 216 +/- 56% that of C5a in stimulating the release of beta-glucuronidase from human neutrophils. C5aR activation and binding curves both occurred in the same concentration range with YSFKPMPLaR, characteristics not observed with natural C5a or more conformationally flexible C-terminal agonists. YSFKPMPLaR was then used as a C-terminal effector template onto which was synthesized various C5aR binding determinants from the N-terminal core domain of the natural factor. In general, the presence of N-terminal binding determinants had little effect on either potency or binding affinity when the C-terminal effector region was presented to the C5aR in this biologically active conformation. However, one peptide, C5a(12-20)-Ahx-YSFKPMPLaR, expressed a 100-fold increase in affinity for the neutrophil C5aR and a 6-fold increase in potency relative to YSFKPMPLaR. These analyses showed that the peptides used in this study have up to 25% of the potency of C5a in human fetal artery and up to 5% of the activity of C5a in the PMN enzyme release assay.

Pore structure characterisation of pillared clays using a modified MP method

The data of nitrogen adsorption on pillared clays (PILC) are converted to comparison plots (t-plots) to derive their pore size distribution (PSD). As in the MP method, the surface area of a group of pores having similar pore sizes is calculated from the slopes of tangent lines at two succeeding points on a comparison plot. By the modified MP method in this work, the tangent line is extrapolated to the adsorption axis on the t-plot, and the difference between intercepts is used to obtain the volume of the group of pores. From the information of surface area and pore volume, the average width of the pore group can be calculated and hence the PSDs of PILCs are obtained by carrying out such calculation procedures from high to low t. With this method, PSDs of several pillared clays are calculated over a wide pore size range, from micropores to mesopores. It is found that the modified MP method could result in the underestimation of the width of ultramicropores due to the enhancement in adsorption energy in these pores. Nevertheless, the method can be very useful in calculating the surface area and pore volume, as well as a mean width of these pores. For super-micropores and mesopores, pore size can also be underestimated, due to deviation of the pore shape from a slit. The principles of the improved MP method, as well as problems associated with it are thoroughly discussed in this paper. In general, this modified method provides practically meaningful results which are consistent with the pore dimension obtained from powder X-ray diffraction measurements, but involves no complicated theoretical treatment or assumptions.

Comprehensive study of surface chemistry of MCM-41 using Si-29 CP/MAS NMR, FTIR, pyridine-TPD, and TGA

A comprehensive study was conducted on mesoporous MCM-41. Spectroscopic examinations demonstrated that three types of silanol groups, i.e., single, (SiO)(3)Si-OH, hydrogen-bonded, (SiO)(3)Si-OH-OH-Si(SiO)(3), and geminal, (SiO)(2)Si(OH)(2), can be observed. The number of silanol groups/nm(2), alpha(OH), as determined by NMR, varies between 2.5 and 3.0 depending on the template-removal methods. All these silanol groups were found to be the active sites for adsorption of pyridine with desorption energies of 91.4 and 52.2 kJ mol(-1), respectively. However, only free silanol groups (involving single and geminal silanols) are highly accessible to the silylating agent, chlorotrimethylsilane. Silylation can modify both the physical and chemical properties of MCM-41.

Structure optimization combining soft-core interaction functions, the diffusion equation method, and molecular dynamics

Smoothing the potential energy surface for structure optimization is a general and commonly applied strategy. We propose a combination of soft-core potential energy functions and a variation of the diffusion equation method to smooth potential energy surfaces, which is applicable to complex systems such as protein structures; The performance of the method was demonstrated by comparison with simulated annealing using the refinement of the undecapeptide Cyclosporin A as a test case. Simulations were repeated many times using different initial conditions and structures since the methods are heuristic and results are only meaningful in a statistical sense.

Chemistry of 5-oxodihydroisoxazoles .17. Acylation of 5-oxodihydroisoxazoles

2-Unsubstituted isoxazol-5(4H)-ones and -5(2N)-ones may be acylated by acid chlorides, anhydrides or carboxylic acids in the presence of carbodiimides, to give O- and N-acylated products, The solvent, the presence of base and the temperature are found to alter the product ratios dramatically, but the substituents present at C-3 have the greatest effect, Aliphatic acid anhydrides and chlorides generally react at nitrogen, but aroyl halides give significant proportions of O-acylated products, Limited success in converting O-aroyl to N-aroyl isoxazolones is reported.

Chemistry of 5-oxodihydroisoxazoles .18. Synthesis of oxazoles by the photolysis and pyrolysis of 2-acyl-5-oxo-2,5-dihydroisoxazoles

N-Acylisoxazol-5-ones lose carbon dioxide under photochemical and thermal conditions affording iminocarbenes which undergo intramolecular cyclisation through the oxygen of the acyl group to give oxazoles. Under photochemical conditions those acylisoxazolones with electron withdrawing groups at C-4 usually give high yields of oxazoles, while those with electron donating groups at C-4 give only poor yields: the reverse is observed under thermal conditions.

The chemistry of 5-oxodihydroisoxazoles .19. The synthesis and photolysis of N-thioacylisoxazol-5(2H)-ones

5-Oxodihydroisoxazoles react with thiocarbonyl chlorides to afford N-thioacylisoxazol-5(2H)-ones which lose carbon dioxide under photochemical conditions and undergo intramolecular cyclisation of the iminocarbene to afford thiazoles, However, in some cases loss of carbon dioxide is accompanied by loss of sulfur, giving 1,3-oxazin-6-ones.

The chemistry of novolac resins .3. C-13 and N-15 nmr studies of curing with hexamethylenetetramine

The reactions between novolac resins and hexamethylenetetramine (HMTA) which occur on curing have been studied by C-13 and N-15 high-resolution n.m.r. in both solution and the solid state. Strong evidence for the existence of many curing intermediates is obtained. New curing intermediates are reported along with experimental data to support previously postulated intermediates. The initial curing reactions between novolac and HMTA produce various substituted benzoxazines and benzylamines. Thermal decomposition/oxidation and further reactions of these initial intermediates generate methylene linkages between phenolic rings for chain extension and cross-linking. Among the three kinds of methylene linkages, the para-para methylene linkages are formed at relatively lower temperatures. Various imine, amide and imide side-products also concurrently appear during the process. The initial amount of HMTA plays a critical role in the curing reactivity and chemical structures of the cured resins. The lower the amount of HMTA, the lower the temperature at which curing occurs, and the lower the amount of the nitrogen-containing side-products in the finally cured resins. The ortho-linked intermediates are relatively stable, and can remain in the cured resins up to higher temperatures. The study provides an extensive description of the curing reactions of novolac resins. (C) 1997 Elsevier Science Ltd.