Future tech devices. The information chain gets personal.
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Artificial Organs↗
Biomedical subjects
S May
Publications and source records attributed to S May.
Substituted 1,6-naphthyridines as human cytomegalovirus inhibitors: conformational requirements.
Substituted 1,6-naphthyridine derivatives, a new class of human cytomegalovirus inhibitors, were prepared to demonstrate the role of intramolecular hydrogen bonds to maintain the compounds in their active conformation.
Antiviral Agents↗
Design and evaluation of dihydroisoquinolines as potent and orally bioavailable human cytomegalovirus inhibitors.
Following the identification of first pass metabolism issues with our recently described anti-HCMV compounds, the naphthyridines and isoquinolines, we have designed a class of novel metabolically stable and orally bioavailable anti-HCMV agents, the dihydroisoquinolines.
Administration, Oral↗
Effects of backward bending on lumbar intervertebral discs. Relevance to physical therapy treatments for low back pain.
STUDY DESIGN: Mechanical testing of cadaveric motion segments. OBJECTIVES: To test the hypothesis that backward bending of the lumbar spine can reduce compressive stresses within lumbar intervertebral discs. SUMMARY OF BACKGROUND DATA: Lumbar extension affects the distribution of compressive stress inside normal cadaveric discs, but little is known about its effect on mechanically disrupted and degenerated discs. METHODS: Nineteen lumbar motion segments (mean donor age, 48 years) were subjected to complex mechanical loading to simulate the following postures: moderate lumbar flexion, 2 degrees of extension, 4 degrees of extension, and the neutral position (no bending). The distribution of compressive stress within the disc matrix was measured in each posture by pulling a miniature pressure transducer along the midsagittal diameter of the disc. Stress profiles were repeated after a mechanical treatment that was intended to simulate severe disc degeneration in vivo. RESULTS: The "degeneration" treatment reduced pressure in the nucleus pulposus and generated stress concentrations within the anulus, in a manner similar to that found in severely degenerated discs in vivo. When all discs were considered together, 2 degrees of extension increased the maximum compressive stress within the posterior anulus by an average of 16%, compared with the neutral posture. The size of localized stress peaks within the posterior anulus was increased by 43% (P = 0.02). In 4 degrees of extension, changes observed between 0 degree and 2 degrees were usually exaggerated. In contrast, moderate flexion tended to equalize the distribution of compressive stress. In 7 of the 19 discs, 2 degrees of lumbar extension decreased maximum compressive stress in the posterior anulus relative to the neutral posture by up to 40%. Linear regression showed that lumbar extension tended to reduce stresses in the posterior anulus in those discs that exhibited the lowest compressive stresses in the neutral posture (P = 0.003; R2 = 41%). CONCLUSIONS: The posterior anulus can be stress shielded by the neural arch in extended postures, but the effect is variable. This may explain why extension exercises can relieve low back pain in some patients.
Adult↗
UK CropNet: a collection of databases and bioinformatics resources for crop plant genomics.
The UK Crop Plant Bioinformatics Network (UK CropNet) was established in 1996 in order to harness the extensive work in genome mapping in crop plants in the UK. Since this date we have published five databases from our central UK CropNet WWW site (http://synteny.nott.ac.uk/) with a further three to follow shortly. Our resource facilitates the identification and manipulation of agronomically important genes by laying a foundation for comparative analysis among crop plants and model species. In addition, we have developed a number of software tools that facilitate the visualisation and analysis of our data. Many of our tools are made freely available for use with both crop plant data and with data from other species.
Crops, Agricultural↗
Website update: The UK Crop Plant Bioinformatics Network (UK CropNet).
UK CropNet currently provides a range of databases (and database-mining tools) to the plant community that are all freely accessible through our website (http://ukcrop.net/). Recent upgrades have meant that we can now expand the range of available facilities (e.g. addition of new databases) whilst also strengthening and improving access to existing services (e.g. providing a BLAST search facility against sequences in our databases). This article will briefly outline these and other new developments in our service.
Computational Biology↗
Recognition of vertebral fracture in a clinical setting.
Osteoporosis-related vertebral fractures have important health consequences for older individuals, including disability and increased mortality. Because these fractures can be prevented with appropriate medications, recognition and treatment of high-risk patients is warranted. A cross-sectional survey was carried out in a large, regional hospital in New England to examine the frequency with which vertebral fractures are identified and treated by clinicians in a population of hospitalized older women who have radiographic evidence of fractures. The study population consisted of 934 women aged 60 years and older who were hospitalized between October 1, 1995 and March 31, 1997, and who had a chest radiograph obtained. Vertebral fractures in the thoracic region were identified by two radiologists. Discharge diagnoses, medical record notes and radiology reports were compared with the results of the radiologists' readings to determine the frequency with which fractures were identified and appropriate, osteoporosis-preventing medications prescribed. Moderate or severe vertebral fractures were identified for 132 (14.1%) study subjects, but only 17 (1.8%) of the 934 participants had a discharge diagnosis of vertebral fracture. Of these 132, only 17% had fracture noted in the medical record or discharge summary; 50% of contemporaneous radiology reports identified a fracture as present; and 23% of the time it was found in the radiologist's summary impression. Only 18% of medical records indicated that fracture patients had been prescribed calcium, vitamin D, estrogen replacement or an antiresorptive agent. Relatively few hospitalized older women with radiographically demonstrated vertebral fractures were thus identified or treated by clinicians, suggesting a need for improved recognition.
Aged↗
A comparison of the abuse liability and dependence potential of nicotine patch, gum, spray and inhaler.
RATIONALE: Nicotine replacement therapy (NRT) in varying forms is becoming widely used. Clinicians, therapists and regulatory authorities are interested in the abuse liability and dependence potential of the different forms. OBJECTIVES: To compare the abuse liability and dependence potential of nicotine gum, transdermal patch, spray and inhaler. METHODS: 504 male and female smokers seeking help with stopping smoking were randomly allocated to the four products. Measures were taken at the designated quit date, then 1 week, 4 weeks, 12 weeks and 15 weeks later. Smokers were advised to use the product for up to 12 weeks. Those still using the product at the 12-week visit were advised to cease use by week 14. Measures included: pleasantness and satisfaction ratings at weeks 1 and 4 (used as a marker of abuse liability); ratings of feeling dependent on NRT at weeks 1, 4, 12 and 15 (used as a marker of subjective dependence); mood and physical symptoms ratings at weeks 12 and 15 (the change being used to assess physical dependence on NRT), continued usage of NRT at week 15 (used as an marker of behavioural dependence). RESULTS: Average ratings of pleasantness were low. The nicotine patch was rated as less unpleasant to use than all other products. There were no significant differences between the products in terms of satisfaction or subjective dependence except at week 15 when no patch users rated themselves as dependent. Continued use of NRT at week 15 was related to rate of delivery of nicotine from the products - 2% for patch, 7% for gum and inhaler, 10% for spray (P<0.05 for linear association). Among those
Adult↗
Protein-induced bilayer deformations: the lipid tilt degree of freedom.
The theory of hydrophobic interaction between a transmembrane protein and a lipid bilayer is reinvestigated. The protein is modeled as a cylindrically symmetric rigid inclusion, residing in a symmetric, tension-free lipid bilayer. The hydrophobic coupling between the inclusion and the lipids may induce an elastic bilayer deformation, which is commonly described in terms of stretching (or compressing) the hydrocarbon chains of the lipids. In the present work, we additionally include the possibility of the average lipid director to tilt with respect to the normal direction of the hydrocarbon-water interface. The corresponding membrane deformation energy is expressed using both a phenomenological description of elastic lipid layer perturbations and employing a specific molecular lipid model. The molecular lipid model accounts for head group repulsions, interfacial tension, and the chain conformational free energy. Assuming incompressibility of the hydrocarbon chains, we estimate and compare typical membrane deformation energies induced by single gramicidin A channels, with and without the lipid tilt degree of freedom taken into account. The membrane deformation energies are conveniently expressed using a spring constant. We argue that the consideration of the lipid tilt degree of freedom leads to a severalfold reduction of the spring constant and should thus not be excluded from the description of protein-induced membrane deformations. Possible limits of membrane elasticity-based theories for lipid-protein interactions are discussed. Finally, we calculate inclusion-induced deformations of electrostatically charged bilayers, illuminating the coupling between electrostatic and elastic energies in charged membranes.
Elasticity↗
Lipid demixing and protein-protein interactions in the adsorption of charged proteins on mixed membranes.
The adsorption free energy of charged proteins on mixed membranes, containing varying amounts of (oppositely) charged lipids, is calculated based on a mean-field free energy expression that accounts explicitly for the ability of the lipids to demix locally, and for lateral interactions between the adsorbed proteins. Minimization of this free energy functional yields the familiar nonlinear Poisson-Boltzmann equation and the boundary condition at the membrane surface that allows for lipid charge rearrangement. These two self-consistent equations are solved simultaneously. The proteins are modeled as uniformly charged spheres and the (bare) membrane as an ideal two-dimensional binary mixture of charged and neutral lipids. Substantial variations in the lipid charge density profiles are found when highly charged proteins adsorb on weakly charged membranes; the lipids, at a certain demixing entropy penalty, adjust their concentration in the vicinity of the adsorbed protein to achieve optimal charge matching. Lateral repulsive interactions between the adsorbed proteins affect the lipid modulation profile and, at high densities, result in substantial lowering of the binding energy. Adsorption isotherms demonstrating the importance of lipid mobility and protein-protein interactions are calculated using an adsorption equation with a coverage-dependent binding constant. Typically, at bulk-surface equilibrium (i.e., when the membrane surface is "saturated" by adsorbed proteins), the membrane charges are "overcompensated" by the protein charges, because only about half of the protein charges (those on the hemispheres facing the membrane) are involved in charge neutralization. Finally, it is argued that the formation of lipid-protein domains may be enhanced by electrostatic adsorption of proteins, but its origin (e.g., elastic deformations associated with lipid demixing) is not purely electrostatic.
Adsorption↗
The phase behavior of cationic lipid-DNA complexes.
We present a theoretical analysis of the phase behavior of solutions containing DNA, cationic lipids, and nonionic (helper) lipids. Our model allows for five possible structures, treated as incompressible macroscopic phases: two lipid-DNA composite (lipoplex) phases, namely, the lamellar (L(alpha)(C)) and hexagonal (H(II)(C)) complexes; two binary (cationic/neutral) lipid phases, that is, the bilayer (L(alpha)) and inverse-hexagonal (H(II)) structures, and uncomplexed DNA. The free energy of the four lipid-containing phases is expressed as a sum of composition-dependent electrostatic, elastic, and mixing terms. The electrostatic free energies of all phases are calculated based on Poisson-Boltzmann theory. The phase diagram of the system is evaluated by minimizing the total free energy of the three-component mixture with respect to all the compositional degrees of freedom. We show that the phase behavior, in particular the preferred lipid-DNA complex geometry, is governed by a subtle interplay between the electrostatic, elastic, and mixing terms, which depend, in turn, on the lipid composition and lipid/DNA ratio. Detailed calculations are presented for three prototypical systems, exhibiting markedly different phase behaviors. The simplest mixture corresponds to a rigid planar membrane as the lipid source, in which case, only lamellar complexes appear in solution. When the membranes are "soft" (i.e., low bending modulus) the system exhibits the formation of both lamellar and hexagonal complexes, sometimes coexisting with each other, and with pure lipid or DNA phases. The last system corresponds to a lipid mixture involving helper lipids with strong propensity toward the inverse-hexagonal phase. Here, again, the phase diagram is rather complex, revealing a multitude of phase transitions and coexistences. Lamellar and hexagonal complexes appear, sometimes together, in different regions of the phase diagram.
Biophysical Phenomena↗
Differences in the concentration of various synovial fluid constituents between the distal interphalangeal joint, the metacarpophalangeal joint and the navicular bursa in normal horses.
As a prerequisite for the identification of navicular disease markers, the concentrations of cartilage oligomeric matrix protein (COMP), total glycosaminoglycans (GAG), hyaluronan, metalloproteinases (MMP) 2 and 9 and total protein were measured in synovial fluid samples obtained from the distal interphalangeal joint (DIP), the metacarpophalangeal joint (MCP) and the navicular bursa of 24 horses. Mean GAG, COMP and total protein levels were significantly higher in the DIP joint and in the navicular bursa compared to the MCP joint. Hyaluronan content was lower. MMP -2 activity was present in all fluids measured and had similar levels in different joints. MMP -9 was present in 42 per cent of MCP joint samples and 58 per cent of DIP joint samples and of navicular bursal samples. In relation to the constituents measured, the composition of navicular bursal fluid was similar to the articular synovial fluids, in particular that obtained from the DIP joint. Correlation between the constituents of DIP joint fluid and navicular bursal fluid obtained from the same legs was statistically significant for all the parameters measured.
Animals↗
Antiviral properties of a series of 1,6-naphthyridine and 7, 8-dihydroisoquinoline derivatives exhibiting potent activity against human cytomegalovirus.
A series of 1,6-naphthyridine (L. Chan, H. Jin, T. Stefanac, J. F. Lavallee, G. Falardeau, W. Wang, J. Bedard, S. May, and L. Yuen, J. Med. Chem. 42:3023-3025, 1999) and isoquinoline (L. Chan, H. Jin, T. Stefanac, W. Wang, J. F. Lavallee, J. Bedard, and S. May, Bioorg. Med. Chem. Lett. 9:2583-2586, 1999) analogues exhibiting a high level of anti-human cytomegalovirus (HCMV) activity were investigated in a series of studies aimed at better understanding the mechanism of action of some representatives of this class of compounds. In vitro antiviral profiling revealed that these compounds were active against a narrow spectrum of viruses, essentially the human herpesviruses and type 2 rhinovirus. In HCMV assays, a 39- to 223-fold lower 50% inhibitory concentration was obtained for compound A1 than for ganciclovir against strains AD 169 and Towne. In addition, ganciclovir, foscarnet, cidofovir, and BDCRB (2-bromo-5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole)-resistant HCMV strains remained susceptible to 1,6-naphthyridines and 7, 8-dihydroisoquinolines tested in this study, supporting the view that a novel mechanism of action could be involved. Drug combination studies showed a small but significant synergistic antiviral effect between compound B2 and ganciclovir. Cytotoxicity profiling of representative compounds under various cell growth conditions indicated a generally similar cytotoxic effect, relative to ganciclovir, in log-phase growing cells. However, in stationary cells, a relatively higher level of toxicity was observed than that for control compound. Effect of time of drug addition showed that the anti-HCMV activity of compound A1, ganciclovir, and cidofovir was lost at approximately the same time (72 h postinfection), indicating that the compound was affecting events at the early and late stage of virus replication. This interpretation is also supported by reduction of de novo synthesis of pp65 tegument protein and lack of any effect of the compound on viral adsorption. A reduction of the HCMV enhancer-promoter-directed luciferase expression was also observed in a stably transfected cell line when compound A1 was present at relatively high concentrations.
Antiviral Agents↗
Do social support interventions ("buddy systems") aid smoking cessation? A review.
OBJECTIVE: To provide an overview of the role of social support in smoking cessation and to critically review evidence regarding the use of "buddy systems" (where smokers are specifically provided with someone to support them) to aid smoking cessation. DATA SOURCES: Studies were located by searching Medline and Psyclit using the key words "smoking", "smoking cessation", "social support", and "buddy". Additional studies were identified through reference lists. Only studies reported in English and published since 1980 were included. STUDY SELECTION: Studies were selected on four criteria: publication in a peer reviewed journal; randomised controlled trial using smokers who wanted to stop; the use of a social support intervention, including a "buddy"; dependent variable of smoking abstinence. Most research in this area does not use a randomised design so only a small proportion of the originally identified studies were included. DATA SYNTHESIS: In view of the diverse nature of the studies, a meta-analysis was not attempted. Ten studies were identified: nine were clinic based smoking trials, eight used a group format, and nine used buddies from among smokers' existing relationships. Support training varied from role play and rehearsal to a simple instruction to call each other regularly. Intervention and follow up periods varied between studies. Two studies showed a significant benefit of the intervention in the short term. CONCLUSIONS: Research methodology in many cases was poor. The evidence would suggest that in the context of a smokers clinic the use of buddies may be of some benefit. There is a lack of evidence regarding the efficacy of the use of buddies in community interventions. This is an important area for future research.
Humans↗
Nitric oxide inhibits aggrecan degradation in explant cultures of equine articular cartilage.
Arthroses are debilitating diseases of articular joints which result in erosion of the cartilage extracellular matrix. Nitric oxide (NO) is a major component of the inflammatory response, and has been implicated as a mediator of some of the effects of the proinflammatory cytokine, interleukin-1 (IL-1). In this study, we investigated the role of NO in the regulation of proteoglycan degradation in equine articular cartilage. NO fully mediated the suppressive effect of IL-1 on proteoglycan synthesis. However, NO was also antagonistic to proteoglycan degradation, irrespective of whether degradation was initiated by 10 ng/ml IL-1 or 1 micromol/l all-trans retinoic acid (RA) which (unlike IL-1) does not elevate NO production. This was confirmed using the NO donor 2,2'-(hydroxynitrosohydrazono) bis-ethanamine (DETA-NONOate) and the iNOS inhibitor L-N5-iminoethyl ornithine (dihydrochloride) (L-NIO). The G1 fragments of aggrecan were detected in the media and extracts of cartilage explant cultures treated with all-trans RA, DETA-NONOate and L-NIO. The presence of exogenous NO in culture resulted in a decrease in the appearance of the 'aggrecanase' cleavage epitope. Therefore, changes in the appearance of the G1 fragment expressing the 'aggrecanase' cleavage epitope in the media emulated the glycosaminoglycan loss from the tissue. These results lend further support to the hypothesis that NO has an anticatabolic role in equine cartilage proteoglycan degradation, and suggest that this may be mediated by the regulation of 'aggrecanase' activity. Therefore, any pharmacological intervention using NO as a target must take into account both its catabolic and anticatabolic roles in joint tissue turnover.
Aggrecans↗
Hypofibrinogenaemia with compound heterozygosity for two gamma chain mutations - gamma 82 Ala-->Gly and an intron two GT-->AT splice site mutation.
We investigated the molecular basis of hypofibrinogenaemia in a woman with a history of recurrent, pregnancy-associated bleeding, and miscarriage. She had a Clauss fibrinogen of 0.9 mg/ml and SDS PAGE of purified fibrinogen showed a normal pattern of chains. However careful inspection of reverse phase chain separation profiles showed apparent homozygosity for a more hydrophilic form of the gamma chain. DNA Sequencing showed only heterozygosity for a CGT-->GGT (Ala-->Gly) mutation at codon gamma82, but further sequencing showed an additional GT splice sequence mutation at the 5' end of intron 2 of the gamma gene. Translation of mRNA containing this intron would result in premature truncation explaining the phenotypic homozygosity of the gamma82 Ala-->Gly substitution. The patient's sister had a mild bleeding disorder with hypofibrinogenaemia and she too was a compound heterozygote for the y mutations. Her nephew had only the novel splice site mutation, while her mother and daughter inherited only the gamma82 Ala-->Gly substitution.
Adult↗
Isoquinoline-6-carboxamides as potent and selective anti-human cytomegalovirus (HCMV) inhibitors.
Structure-activity relationship studies on our newly identified anti-HCMV compounds, the 1,6-naphthyridines led to the identification of isoquinoline-6-carboxamides as potent and selective anti-HCMV agents.
Antiviral Agents↗
Discovery of 1,6-naphthyridines as a novel class of potent and selective human cytomegalovirus inhibitors.
Explore the source record for details and available documents.
Antiviral Agents↗