Showing papers by "University of Aberdeen published in 2000"

Interleukin-1 polymorphisms associated with increased risk of gastric cancer

Abstract: Helicobacter pylori infection is associated with a variety of clinical outcomes including gastric cancer and duodenal ulcer disease. The reasons for this variation are not clear, but the gastric physiological response is influenced by the severity and anatomical distribution of gastritis induced by H. pylori. Thus, individuals with gastritis predominantly localized to the antrum retain normal (or even high) acid secretion, whereas individuals with extensive corpus gastritis develop hypochlorhydria and gastric atrophy, which are presumptive precursors of gastric cancer. Here we report that interleukin-1 gene cluster polymorphisms suspected of enhancing production of interleukin-1-beta are associated with an increased risk of both hypochlorhydria induced by H. pylori and gastric cancer. Two of these polymorphism are in near-complete linkage disequilibrium and one is a TATA-box polymorphism that markedly affects DNA-protein interactions in vitro. The association with disease may be explained by the biological properties of interleukin-1-beta, which is an important pro-inflammatory cytokine and a powerful inhibitor of gastric acid secretion. Host genetic factors that affect interleukin-1-beta may determine why some individuals infected with H. pylori develop gastric cancer while others do not.

Building Natural Language Generation Systems

Abstract: This book explains how to build Natural Language Generation (NLG) systems - computer software systems which use techniques from artificial intelligence and computational linguistics to automatically generate understandable texts in English or other human languages, either in isolation or as part of multimedia documents, Web pages, and speech output systems Typically starting from some non-linguistic representation of information as input, NLG systems use knowledge about language and the application domain to automatically produce documents, reports, explanations, help messages, and other kinds of texts The book covers the algorithms and representations needed to perform the core tasks of document planning, microplanning, and surface realization, using a case study to show how these components fit together It also discusses engineering issues such as system architecture, requirements analysis, and the integration of text generation into multimedia and speech output systems

Critique of the Power of Judgment

Abstract: Editor's introduction Part I. The First Draft of the Introduction: 1. The first draft of the introduction Part II. Critique of the Power of Judgment: 2. Preface 3. Introduction Part III. First Part: Critique of the Aesthetic Power of Judgment: 4. First section, first book: analytic of the beautiful 5. First section, second book: analytic of the sublime 6. Deduction of pure aesthetic judgments 7. Second section: the dialectic of the aesthetic power of judgment 8. Appendix: on the methodology of taste Part IV. Second Part: Critique of the Teleological Power of Judgment: 9. First division: analytic of the teleological power of judgment 10. Second division: dialectic of the teleological power of judgment 11. Appendix: methodology of the teleological power of judgment.

Cellular and molecular mechanisms of action of bisphosphonates

Abstract: BACKGROUND Bisphosphonates currently are the most important class of antiresorptive agents used in the treatment of metabolic bone diseases, including tumor-associated osteolysis and hypercalcemia, Paget's disease, and osteoporosis. These compounds have high affinity for calcium and therefore target to bone mineral, where they appear to be internalized selectively by bone-resorbing osteoclasts and inhibit osteoclast function. METHODS This article reviews the pharmacology of bisphosphonates and the relation between the chemical structure of bisphosphonates and antiresorptive potency, and describes recent new discoveries of their molecular mechanisms of action in osteoclasts. RESULTS Bisphosphonates can be grouped into two pharmacologic classes with distinct molecular mechanisms of action. Nitrogen-containing bisphosphonates (the most potent class) act by inhibiting the mevalonate pathway in osteoclasts, thereby preventing prenylation of small GTPase signaling proteins required for osteoclast function. Bisphosphonates that lack a nitrogen in the chemical structure do not inhibit protein prenylation and have a different mode of action that may involve the formation of cytotoxic metabolites in osteoclasts or inhibition of protein tyrosine phosphatases. CONCLUSIONS Bisphosphonates are highly effective inhibitors of bone resorption that selectively affect osteoclasts. After more than 30 years of clinical use, their molecular mechanisms of action are only just becoming clear. Cancer 2000;88:2961–78. © 2000 American Cancer Society.

Using conjoint analysis to elicit preferences for health care.

Abstract: Traditionally the extent of patients' involvement in medical decision making has been minimal. This has been true at both the micro level of the patient consultation with a doctor and the macro level of planning and developing healthcare services. Since 1989, however, greater involvement of patients and the community in these processes has been advocated.1–5 In principle, the elicitation of patients' and the community's values represents a big step forward in terms of enhancing the benefits from the provision of health care. For the exercise to be worth while, however, the information obtained must be useful and scientifically defensible.6 During the 1990s, conjoint analysis was developed to elicit patients' and the community's views on health care. #### Summary points Conjoint analysis is a rigorous method of eliciting preferences It allows estimation of the relative importance of different aspects of care, the trade-offs between these aspects, and the total satisfaction or utility that respondents derive from healthcare services The technique can help with decision making for some of the issues facing the NHS Though further applications of conjoint analysis are encouraged, methodological issues need further consideration This paper explains conjoint analysis, provides examples of applications in health care which were obtained from a systematic review of databases between 1989 and 1999 (Medline, Embase, HealthSTAR, PsychLIT, EconLIT), and uses a study in orthodontic care to show the uses and pitfalls of the technique. The survey method of data collection and analysis known as conjoint analysis was developed in mathematical psychology and has a strong theoretical basis.7–9 It has been successfully used in market research,10 transport economics,11 and environmental economics 12 13 and was recommended to the UK Treasury for valuing quality in the provision of public services.14 Within these areas it has been well received …

Studies of surgical outcome after patellar tendinopathy: clinical significance of methodological deficiencies and guidelines for future studies. Victorian Institute of Sport Tendon Study Group.

Abstract: Patellar tendinopathy is often treated surgically after failure of conservative treatment but clinical experience suggests that results are not uniformly excellent. The aim of this review was to (i) identify the different surgical techniques that have been reported and compare their success rates, and (ii) critically assess the methodology of studies that have reported surgical outcomes. Twenty-three papers and two abstracts were included in the review. Surgical procedures were categorized and outcomes summarized. Using ten criteria, an overall methodology score was derived for each paper. Criteria for which scores were generally low (indicating methodological deficiency) concerned the type of study, subject selection process and outcome measures. We found a negative correlation between papers’ reported success rates and overall methodology scores (r=−0.57, P<0.01). There was a positive correlation between year of publication and overall methodology score (r=0.68, P<0.001). We conclude that study methodology may influence reported surgical outcome. We suggest practical guidelines for improving study design in this area of clinical research, as improved study design would provide clinicians with a more rigorous evidence-base for treating patients who have recalcitrant patellar tendinopathy.

Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients.

Abstract: Purpose: Capecitabine (Xeloda) is a novel fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumors. The purpose of this study was to demonstrate the preferential activation of capecitabine, after oral administration, in tumor in colorectal cancer patients, by the comparison of 5-FU concentrations in tumor tissues, healthy tissues and plasma. Methods: Nineteen patients requiring surgical resection of primary tumor and/or liver metastases received 1,255 mg/m2 of capecitabine twice daily p.o. for 5–7 days prior to surgery. On the day of surgery, samples of tumor tissue, adjacent healthy tissue and blood samples were collected simultaneously from each patient, 2 to 12 h after the last dose of capecitabine had been administered. Concentrations of 5-FU in various tissues and plasma were determined by HPLC. The activities of the enzymes (CD, TP and DPD) involved in the formation and catabolism of 5-FU were measured in tissue homogenates, by catabolic assays. Results: The ratio of 5-FU concentrations in tumor to adjacent healthy tissue (T/H) was used as the primary marker for the preferential activation of capecitabine in tumor. In primary colorectal tumors, the concentration of 5-FU was on average 3.2 times higher than in adjacent healthy tissue (P=0.002). The mean liver metastasis/healthy tissue 5-FU concentration ratio was 1.4 (P=0.49, not statistically different). The mean tissue/plasma 5-FU concentration ratios exceeded 20 for colorectal tumor and ranged from 8 to 10 for other tissues. Conclusions: The results demonstrated the preferential activation of capecitabine to 5-FU in colorectal tumor, after oral administration to patients. This is explained to a great extent by the activity of TP in colorectal tumor tissue, (the enzyme responsible for the conversion of 5′-DFUR to 5-FU), which is approximately four times that in adjacent healthy tissue. In the liver, TP activity is approximately equal in metastatic and healthy tissue, which explains the lack of preferential activation of capecitabine in these tissues.

Rupture of the Achilles Tendon

Abstract: Achilles, the warrior and hero of Homer's Iliad, lends his name to the Achilles tendon, the thickest and strongest tendon in the human body138. Thetis, Achilles's mother, made him invulnerable to physical harm by immersing him in the river Styx after learning of a prophecy that Achilles would die in battle. However, the heel by which he was held remained untouched by the water and thus Achilles had a vulnerable point. Achilles led the Greek military forces, which captured and destroyed Troy after killing the Trojan prince Hector. However, Hector's brother Paris killed Achilles by firing a poisoned arrow into his heel164. Hippocrates, in the first recorded description of an injury to the Achilles tendon, stated that “this tendon, if bruised or cut, causes the most acute fevers, induces choking, deranges the mind and at length brings death.”26 Ambroise Pare, in 1575, recommended that a ruptured Achilles tendon be strapped with bandages dipped in wine and spices, but advised that the result was dubious27. Operative repair of a ruptured Achilles tendon was advocated in 1888 by another Frenchman, Gustave Polaillon27, although an Arabian physician performed such procedures as early as the tenth century A.D. In the twelfth century, an Italian surgeon, Guglielmo di Faliceto, believed that nature was unable to unite divided tendons and that operative treatment was necessary27. Much research has been performed to elucidate the etiology of a rupture of the Achilles tendon, but its true nature still remains unclear190. Also, the best method of treatment is still fiercely debated. Some physicians advocate operative repair, whereas others insist that an operation is unnecessary and poses an unacceptable risk. The tendinous portions of the gastrocnemius and soleus muscles merge to form the Achilles tendon. The plantaris …

Protein docking using spherical polar Fourier correlations

Abstract: We present a new computational method of docking pairs of proteins by using spherical polar Fourier correlations to accelerate the search for candidate low-energy conformations. Interaction energies are estimated using a hydrophobic excluded volume model derived from the notion of "overlapping surface skins," augmented by a rigorous but "soft" model of electrostatic complementarity. This approach has several advantages over former three-dimensional grid-based fast Fourier transform (FFT) docking correlation methods even though there is no analogue to the FFT in a spherical polar representation. For example, a complete search over all six rigid-body degrees of freedom can be performed by rotating and translating only the initial expansion coefficients, many unfeasible orientations may be eliminated rapidly using only low-resolution terms, and the correlations are easily localized around known binding epitopes when this knowledge is available. Typical execution times on a single processor workstation range from 2 hours for a global search (5 x 10(8) trial orientations) to a few minutes for a local search (over 6 x 10(7) orientations). The method is illustrated with several domain dimer and enzyme-inhibitor complexes and 20 large antibody-antigen complexes, using both the bound and (when available) unbound subunits. The correct conformation of the complex is frequently identified when docking bound subunits, and a good docking orientation is ranked within the top 20 in 11 out of 18 cases when starting from unbound subunits. Proteins 2000;39:178-194.

Prospective and retrospective memory in normal ageing and dementia: A questionnaire study

Abstract: Frequency of prospective memory and retrospective memory failures was rated on a 16-item questionnaire by 862 volunteers, from five groups: patients with Alzheimer Disease (rated by carers), carers of Alzheimer Disease patients, elderly, young, and a group of married couples. Reported memory failures were highest for Alzheimer Disease patients, and lowest for carers, with elderly and young controls in between. More prospective memory than retrospective memory failures were reported in all groups, although the difference was small for Alzheimer Disease patients who were rated near ceiling for both. Prospective memory failures of Alzheimer Disease patients were reported as more frustrating for carers than retrospective memory failures; prospective memory and retrospective memory failures frustrated Alzheimer Disease patients equally. Data from the couples indicated that there were no biases resulting from rating on behalf of someone else. These results suggest that: (1) normal ageing has no greater effect on self-reported retrospective memory than prospective memory failures, (2) the relatively small number of memory failures reported by carers may result from comparing themselves with the Alzheimer Disease patients in their care, and (3) prospective memory failures have a greater impact on the lives of the carers and are therefore more likely to be reported as early indicants of the disease.

Efficacy and Safety of Daily Risedronate in the Treatment of Corticosteroid-Induced Osteoporosis in Men and Women: A Randomized Trial*

Abstract: Long-term use of high-dose corticosteroids often results in bone loss, which may lead to osteoporosis-related fractures. This was a multicenter, double-blind study in which 290 ambulatory men and women receiving high-dose oral corticosteroid therapy (prednisone greater than or equal to 7.5 mg/day or equivalent) for 6 or more months were randomized to receive placebo, risedronate 2.5 mg/day, or risedronate 5 mg/day for 12 months. All patients received calcium 1 g and vitamin D 400 IU daily. The primary endpoint was lumbar spine bone mineral density (BMD) at month 12, Additional measurements included BMD at the femoral neck and trochanter and the incidence of vertebral fractures, Overall, there were statistically significant treatment effects on BMD at 12 months at the lumbar spine (p < 0.001), femoral neck (p = 0.004), and trochanter (p = 0.010), Risedronate 5 mg increased BMD at 12 months by a mean (SEM) of 2.9% (0.49%) at the lumbar spine, 1.8% (0.46%) at the femoral neck, and 2.4% (0.54%) at the trochanter, whereas BMD was maintained only in the control group, Although not powered to show fracture efficacy, we observed a reduction in the incidence of vertebral fractures of 70% in the combined risedronate treatment groups, relative to placebo (p = 0.042), Risedronate was well tolerated, had a good safety profile, and was not associated with gastrointestinal adverse events. We conclude that risedronate increases BMD and potentially reduces the incidence of vertebral fractures in patients,vith corticosteroid-induced osteoporosis.

Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats.

Abstract: Insulin and leptin receptors are present in hypothalamic regions that control energy homeostasis, and these hormones reduce food intake and body weight in lean, but not obese, Zucker rats. Here we demonstrate that insulin, like leptin, hyperpolarizes lean rat hypothalamic glucose-responsive (GR) neurons by opening KATP channels. These findings suggest hypothalamic K ATP channel function is crucial to physiological regulation of food intake and body weight.

Recent developments of induction motor drives fault diagnosis using AI techniques

Abstract: This paper presents a review of the developments in the field of diagnosis of electrical machines and drives based on artificial intelligence (AI). It covers the application of expert systems, artificial neural networks (ANNs), and fuzzy logic systems that can be integrated into each other and also with more traditional techniques. The application of genetic algorithms is considered as well. In general, a diagnostic procedure starts from a fault tree developed on the basis of the physical behavior of the electrical system under consideration. In this phase, the knowledge of well-tested models able to simulate the electrical machine in different fault conditions is fundamental to obtain the patterns characterizing the faults. The fault tree navigation performed by an expert system inference engine leads to the choice of suitable diagnostic indexes, referred to a particular fault, and relevant to build an input data set for specific AI (NNs, fuzzy logic, or neuro-fuzzy) systems. The discussed methodologies, that play a general role in the diagnostic field, are applied to an induction machine, utilizing as input signals the instantaneous voltages and currents. In addition, the supply converter is also considered to incorporate in the diagnostic procedure the most typical failures of power electronic components. A brief description of the various AI techniques is also given; this highlights the advantages and the limitations of using AI techniques. Some applications examples are also discussed and areas for future research are also indicated.

The detection of inter-turn short circuits in the stator windings of operating motors

Abstract: This paper develops a winding-function-based method for modeling polyphase cage induction motors with inter-turn short circuits in the machine stator winding. Analytical consideration which sheds light on some components of the stator current spectra of both healthy and faulty machines is developed. It is shown that, as a result of the nature of the cage rotor, no new frequency components of the line current spectra can appear as a consequence of the fault. Only a rise in some of the frequency components which already exist in the line current spectra of a healthy machine can be observed. An experimental setup comprising a 3 kW delta-connected motor loaded by a generator was used to validate this approach. The experimental results obtained clearly validate the analytical and simulation results.

Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis.

Abstract: Familial expansile osteolysis (FEO, MIM 174810) is a rare, autosomal dominant bone disorder characterized by focal areas of increased bone remodelling. The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity. Our previous linkage studies mapped the gene responsible for FEO to an interval of less than 5 cM between D18S64 and D18S51 on chromosome 18q21.2-21.3 in a large Northern Irish family. The gene encoding receptor activator of nuclear factor-kappa B (RANK; ref. 5), TNFRSF11A, maps to this region. RANK is essential in osteoclast formation. We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB). One was a duplication of 18 bases and the other a duplication of 27 bases, both of which affected the signal peptide region of the RANK molecule. Expression of recombinant forms of the mutant RANK proteins revealed perturbations in expression levels and lack of normal cleavage of the signal peptide. Both mutations caused an increase in RANK-mediated nuclear factor-kappaB (NF-kappaB) signalling in vitro, consistent with the presence of an activating mutation.

Azadirachtin from the neem tree Azadirachta indica: its action against insects

Abstract: The neem tree has long been recognized for its unique properties both against insects and in improving human health. It is grown in most tropical and sub-tropical areas of the world for shade, reforestation and for the production of row material for natural insecticides and medicines. Azadirachtin, a complex tetranortriterpenoid limonoid from the neem seeds, is the main component responsible for the toxic effects in insects. Six international conferences on neem and a vast scientific literature report both the antifeedant and physiological effects of neem. This article reviews the behavioral and physiological properties of azadirachtin, including effects on insect reproduction, direct and "secondary" antifeedancy, and the physiological effects measured as growth reduction, increased mortality and abnormal and delayed moults. These effects are here categorized in two ways: direct effects on cells and tissues and indirect effects exerted via the endocrine system. It also describes the work carried out to date to identify the mode of action of azadirachtin at the cellular level. The differential effects between animal phyla and over non-target organisms are discussed and point to its potential success as a safe insecticide.

Induction, regulation, degradation, and biological significance of mammalian metallothioneins.

Abstract: MTs are small cysteine-rich metal-binding proteins found in many species and, although there are differences between them, it is of note that they have a great deal of sequence and structural homology. Mammalian MTs are 61 or 62 amino acid polypeptides containing 20 conserved cysteine residues that underpin the binding of metals. The existence of MT across species is indicative of its biological demand, while the conservation of cysteines indicates that these are undoubtedly central to the function of this protein. Four MT isoforms have been found so far, MT-1, MT-2, MT-3, and MT-4, but these also have subtypes with 17 MT genes identified in man, of which 10 are known to be functional. Different cells express different MT isoforms with varying levels of expression perhaps as a result of the different function of each isoform. Even different metals induce and bind to MTs to different extents. Over 40 years of research into MT have yielded much information on this protein, but have failed to assign to it a definitive biological role. The fact that multiple MT isoforms exist, and the great variety of substances and agents that act as inducers, further complicates the search for the biological role of MTs. This article reviews the current knowledge on the biochemistry, induction, regulation, and degradation of this protein in mammals, with a particular emphasis on human MTs. It also considers the possible biological roles of this protein, which include participation in cell proliferation and apoptosis, homeostasis of essential metals, cellular free radical scavenging, and metal detoxification.

Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia.

Abstract: Thiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurines, including 6-mercaptopurine and 6-thioguanine. TPMT activity exhibits genetic polymorphism, with about 1/300 inheriting TPMT deficiency as an autosomal recessive trait. If treated with standard doses of thiopurines, TPMT-deficient patients accumulate excessive thioguanine nucleotides in hematopoietic tissues, leading to severe hematological toxicity that can be fatal. However, TPMT-deficient patients can be successfully treated with a 10- to 15-fold lower dosage of these medications. The molecular basis for altered TPMT activity has been defined, with rapid and inexpensive assays available for the three signature mutations which account for the majority of mutant alleles. TPMT genotype correlates well with in vivo enzyme activity within erythrocytes and leukemic blast cells and is clearly associated with risk of toxicity. The impact of 6-mercaptopurine dose intensity is also being clarified as an important determinate of event-free survival in childhood leukemia. In addition, there are emerging data that TPMT genotype may influence the risk of secondary malignancies, including brain tumors and acute myelogenous leukemia. Ongoing studies aim to clarify the influence of TPMT on thiopurine efficacy, acute toxicity, and risk for delayed toxicity. Together, these advances hold the promise of improving the safety and efficacy of thiopurine therapy.

Endogenous Development, Social Capital and Social Inclusion: perspectives from leader in the UK

Abstract: There is a danger of subscribing too readily to the rhetoric of participative development. The communitarian assumptions of the endogenous approach privilege a ‘territory’ as potentially homogenous and gloss over internal socio-economic and cultural inequality. The insights of Bourdieu are particularly instructive here. This paper argues that leader-type programmes need to include pro-active action targeted at raising the social and cultural capital of individuals and of disadvantaged groups (either of which happen to be in the area, but not innately defined by the area).The ideas are illustrated in relation to leader in the United Kingdom.

Fatty acid composition of lipids in immature cattle, pig and sheep oocytes with intact zona pellucida.

Abstract: Cattle, pig and sheep oocytes isolated from healthy cumulus‐oocyte complexes were pooled, within species, to provide samples of immature denuded oocytes with intact zona pellucida (n = 1000 per sample) for determination of fatty acid mass and composition in total lipid, constituent phospholipid and triglyceride. Acyl-containing lipid extracts, transmethylated in the presence of a reference penta-decaenoic acid (15:0), yielded fatty acid methyl esters which were analysed by gas chromatography. Mean (± SEM) fatty acid content in samples of pig oocytes (161 ± 18 µg per 1000 oocytes) was greater than that in cattle (6 3±6µ g; P < 0.01) and sheep oocytes (8 9±7µ g; P < 0.05). Of 24 fatty acids detected, palmitic (16:0; 25‐35%, w/w), stearic (18:0; 14‐16%) and oleic (18:1n-9; 22‐26%) acids were most prominent in all three species. Saturated fatty acids (mean = 45‐55%, w/w) were more abundant than mono- (27‐34%) or polyunsaturates (11‐21%). Fatty acids of the n-6 series, notably linoleic (18:2n-6; 5‐8%, w/w) and arachidonic acid (20:4n-6; 1‐3%), were the most abundant polyunsaturates. Phospholipid consistently accounted for a quarter of all fatty acids in the three species, but ruminant oocytes had a lower complement of polyunsaturates (14‐19%, w/w) in this fraction than pig oocytes (34%, w/w) which, for example, had a three- to fourfold greater linoleic acid content. An estimated 74 ng of fatty acid was sequestered in the triglyceride fraction of individual pig oocytes compared with 23‐25 ng in ruminant oocytes (P < 0.01). It is concluded that the greater fatty acid content of pig oocytes is primarily due to more abundant triglyceride reserves. Furthermore, this speciesspecific difference, and that in respect of polyunsaturated fatty acid reserves, may underlie the contrasting chilling, culture and cryopreservation sensitivities of embryos derived from pig and ruminant (cattle, sheep) oocytes.

Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298.

Abstract: Bisphosphonates are the important class of antiresorptive drugs used in the treatment of metabolic bone diseases. Although their molecular mechanism of action has not been fully elucidated, recent studies have shown that the nitrogen-containing bisphosphonates can inhibit protein prenylation in macrophages in vitro. In this study, we show that the nitrogen-containing bisphosphonates risedronate, zoledronate, ibandronate, alendronate, and pamidronate (but not the non nitrogen-containing bisphosphonates clodronate, etidronate, and tiludronate) prevent the incorporation of [14C]mevalonate into prenylated (farnesylated and geranylgeranylated) proteins in purified rabbit osteoclasts. The inhibitory effect of nitrogen-containing bisphosphonates on bone resorption is likely to result largely from the loss of geranylgeranylated proteins rather than loss of farnesylated proteins in osteoclasts, because concentrations of GGTI-298 (a specific inhibitor of geranylgeranyl transferase I) that inhibited protein geranylgeranylation in purified rabbit osteoclasts prevented osteoclast formation in murine bone marrow cultures, disrupted the osteoclast cytoskeleton, inhibited bone resorption, and induced apoptosis in isolated chick and rabbit osteoclasts in vitro. By contrast, concentrations of FTI-277 (a specific inhibitor of farnesyl transferase) that prevented protein farnesylation in purified rabbit osteoclasts had little effect on osteoclast morphology or apoptosis and did not inhibit bone resorption. These results therefore show the molecular mechanism of action of nitrogen-containing bisphosphonate drugs in osteoclasts and highlight the fundamental importance of geranylgeranylated proteins in osteoclast formation and function.

Experimental and quasi-experimental designs for evaluating guideline implementation strategies.

Abstract: The choice of study design for guideline implementation studies will determine the confidence with which the observed effects can be attributed to the interventions under study. In general, cluster randomized trials, of which there are different types, provide the most robust design. However, the use of these designs has implications for the power, conduct and analysis of studies. Wherever possible, designs allowing head-to-head comparisons, which incorporate baseline measures of performance, should be used.

Job Satisfaction, Comparison Earnings, and Gender

Abstract: This paper examines sex differences in job satisfaction by utilizing data from the 1986 UK Social and Economic Life Initiative (SCELI) household survey. It attempts to ascertain the relationship between actual and comparison pay and job satisfaction. Employees were asked on a 0–10 scale how satisfied or dissatisfied they were with their present job. They were also asked to state whether they were equitably, over or underpaid and to say how much pay they thought they deserved. Uniquely, therefore, we are able to analyse the effects of both actual and objective and subjective comparative pay measures on job satisfaction. The paper rejects the view that the higher expressed job satisfaction of women represents an innate difference rather than the results of self-selection into jobs with highly valued attributes.

Climatic inferences from glacial and palaeoecological evidence at the last glacial termination, southern South America

Abstract: There is uncertainty about the interhemispheric timing of climatic changes during the last glacial-interglacial transition. Different hypotheses, relying on different lines of evidence, point variously to the Northern Hemisphere leading the Southern Hemisphere and vice versa, or to synchrony between the hemispheres. Southern South America is well placed to test the various alternatives using both glacial and palaeoecological evidence. We argue here from a synthesis of key proxy records that there was a sudden rise in temperature that initiated deglaciation sychronously over 16° of latitude at 14 600-14 300 14 C yr BP (17 500-17 150 cal. yr). There was a second step of warming in the Chilean Lake District at 13 000-12 700 14 Cy r BP (15 650-15 350 cal. yr), which saw temperatures rise to close to modern values. A third warming step, particularly clear in the south, occurred at ca. 10 000 14 C yr BP (11 400 cal. yr), the latter achieving Holocene levels of warmth. Following the initial warming, there was a lagged response in precipitation as the westerlies, after a delay of ca. 1600 yr, migrated from their northern glacial location to their present latitude, which was attained by 12 300 14 Cy r BP (14 300 cal. yr). The latitudinal contrasts in the timing of maximum precipitation are reflected in regional contrasts in vegetation change and in glacier behaviour. The large scale of a 80-km glacier advance in the Strait of Magellan at 12 700-10 300 14 C yr BP (15 350-12 250 cal. yr), which spans the Antarctic Cold Reversal and the Younger Dryas, was influenced by the return of the westerlies to southern latitudes. The delay in the migration of the westerlies coincides with the Heinrich 1 iceberg event in the North Atlantic. The suppressed global thermohaline circulation at the time may have affected sea-surface temperatures in the South Pacific, and the return of the westerlies to their present southerly latitude only followed ocean reorganisation to its present interglacial mode. Copyright © 2000 John Wiley & Sons, Ltd.

Tenocytes from Ruptured and Tendinopathic Achilles Tendons Produce Greater Quantities of Type III Collagen than Tenocytes from Normal Achilles Tendons An In Vitro Model of Human Tendon Healing

Abstract: Type I collagen is the main collagen in tendons; type III collagen is present in small amounts. Ruptured Achilles tendons contain a significantly greater proportion of type III collagen, which predisposes them to rupture. We used an in vitro model to determine whether tenocytes from Achilles tendons that were ruptured (N 22), nonruptured (N 7), tendinopathic (N 12), and fetal (N 8) show different behavior. Samples of Achilles tendon were digested with collagenase and the released tenocytes were collected. Primary tenocyte cultures were established and subsequently cultured onto glass coverslips. Once a confluent monolayer was obtained, the cell populations were “wounded” by scraping a pipette tip along the surface. The cultures were further incubated for either 1, 4, 8, 12, 16, or 24 hours, and production of types I and II collagen was assessed by immunostaining. In cultures from ruptured and tendinopathic tendons, there was increased production of type III collagen. Athletic participation places excess s...

Expanding the roles of outpatient pharmacists: effects on health services utilisation, costs, and patient outcomes

Abstract: Background In recent years pharmacists' roles have expanded from packaging and dispensing medications to working with other health care professionals and the public. Objectives To examine the effect of expanding outpatient pharmacists' roles on health services utilisation, costs, and patient outcomes. Search strategy We searched the Cochrane Effective Practice and Organisation of Care Group specialised register, MEDLINE, EMBASE, Pharmline, and International Pharmaceutical Abstracts (January 1966 to March 1999), the published abstracts of three meetings, hand searched five journals and two bibliographies, and reference lists of articles. Selection criteria Randomised trials, controlled clinical trials, controlled before and after studies and interrupted time series analyses comparing 1. Pharmacist services targeted at patients versus services delivered by other health professionals; 2. Pharmacist services targeted at patients versus the delivery of no comparable service; 3. Pharmacist services targeted at health professionals versus services delivered by other health professionals; 4. Pharmacist services targeted at health professionals versus the delivery of no comparable service. Data collection and analysis Two reviewers independently extracted data and assessed study quality. Main results Twenty-five studies were included involving more than 40 pharmacists and 16,000 patients. For comparison 1 (one study), scheduled service utilisation was slightly increased, whereas hospital admissions and emergency room admissions were decreased. For comparison 2, pharmacist services decreased the use of non-scheduled health services, the number of specialty physician visits or the number and costs of drugs, compared to control patients (six studies). Improvements in the targeted patient condition were reported in 10 of 13 studies that measured patient outcomes but patients' quality of life did not seem to change. For comparison 3 (one study), the intervention delivered by the pharmacist was less successful than that delivered by physician counsellors in decreasing inappropriate prescribing. For comparison 4, all studies demonstrated that pharmacist interventions produced the intended effects on physicians prescribing practices. The one study measuring patient outcomes was unable to show a difference in patients' quality of life. Authors' conclusions Only two studies compared pharmacist services with other health professional services. Both had some bias and did not allow us to draw conclusions about comparisons 1 and 3. The other studies supported the expanded roles of pharmacists in patient counselling and physician education. However, doubts about the generalisability of the studies, the poorly defined interventions, and the lack of cost assessments and patient outcome data, indicate that more rigorous research is needed to document the effects of outpatient pharmacist interventions.