bluuebunny/crossref_metadata_2025 huggingface dataset:
Magnesium for the prevention and treatment of acute mountain sickness
Authors: DUMONT Lionel , LYSAKOWSKI Christopher , TRAMÈR Martin R. , JUNOD Jean-Daniel , MARDIROSOFF Chahé , TASSONYI Edömer , KAYSER Bengt
Published: February 2004

Magnesium is a physiological N-methyl-D-aspartate (NMDA) antagonist. The NMDA receptor may be involved in the pathogenesis of acute mountain sickness (AMS). In the present study, healthy subjects were randomized to receive either 400 mg of oral magnesium citrate (16 mmol) or matching placebo every 8 h for 5 days (prevention trial). Subjects then climbed to 4559 m in approx. 24 h and stayed there for 48 h. A Lake Louise Score <3 at any time was defined as the absence of AMS, whereas a score >6 (with ataxia, headache and nausea) was defined as a prevention failure. In a subsequent trial (treatment trial), subjects with a Lake Louise Score >6 (with ataxia, headache and/or nausea) were randomized to receive either 4 g of intravenous magnesium sulphate (16 mmol) or matching placebo. A decrease in the score >50% within 60 min was regarded as a treatment success. Dichotomous data were analysed using relative risk (RR) or odds ratio (OR), and continuous data using Student's t test or Wilcoxon's rank-sum test. In the prevention trial, data from 61 subjects (30 receiving magnesium and 31 placebo) were analysed. With oral magnesium, 20% of subjects had no AMS compared with 16.1% in the placebo group [RR (95% CI), 1.2 (0.4–3.6); where CI is confidence interval]. With magnesium, 40% were prevention failures compared with 35.5% in the placebo group [RR (95% CI), 1.13 (0.59–2.15)]. The mean time to failure and severity of AMS was similar between the two groups. With magnesium, 38.2% had loose stools compared with 11.8% in placebo group [RR (95% CI), 3.25 (1.18–8.97)]. In the treatment trial, 12 subjects received magnesium and 13 received the placebo. With intravenous magnesium, 25% were regarded as treatment successes compared with none in the placebo group [OR (95% CI), 9.71 (0.91–103.4)]. With magnesium, mean (±S.D.) scores decreased from 11.6±1.7 before treatment to 9.0±3.5 after treatment (P=0.009); scores remained unchanged in the placebo group. With magnesium, 75% of subjects experienced a transient flushing compared with 7.7% in the placebo group [RR (95% CI), 0.05 (0.01–0.25)]. In conclusion, oral magnesium does not prevent AMS. In subjects with established AMS, intravenous magnesium reduces the severity of symptoms to some extent, but this effect is of no clinical importance.
Optical dynamics of excitons in J aggregates of a carbocyanine dye
Authors: Moll Johannes , Daehne Siegfried , Durrant James R. , Wiersma Douwe A.
Published: February 2004

Results of temperature and wavelength dependent fluorescence lifetime and accumulated photon-echo experiments on the J aggregate of the dye 5,5′,6,6′-tetrachloro-1,1′-diethyl-3,3′-di(4–sulfobutyl) -benzimidazolocarbocyanine (TDBC) in an ethylene glycol/water glass are reported. Additionally, the temperature dependent relative fluorescence quantum yield was determined. Using two-color pump–probe spectroscopy, the intersite correlation of the frequency disorder and the size of the coherence domains were estimated. Both the phase and the population relaxation times are frequency dependent in the echo and the single-photon-counting experiments. The dependence of the fluorescence lifetime on detection wavelength is restricted to temperatures below 80 K, indicating a temperature activated process. From our experiments and by comparison with previously published results we conclude that the dispersive nature of both the dephasing and the depopulation is caused by intraband relaxation processes. At higher temperatures this wavelength dependence vanishes due to thermalization. The temperature dependence of the relative fluorescence quantum yield of TDBC is equal to the one of pseudoisocyanine (PIC). Using a motional narrowing model for disordered molecular aggregates with consideration of intersite correlation, at 1.5 K, the two-color pump–probe experiments indicate a very high correlation in the frequency disorder in TDBC J aggregates with a correlation length of several hundred molecules. From pump–probe experiments the delocalization length of the exciton is determined to be between 30 and 45 molecules at 1.5 K.
Dynamic redistribution of raft domains as an organizing platform for signaling during cell chemotaxis
Authors: Gómez-Moutón Concepción , Lacalle Rosa Ana , Mira Emilia , Jiménez-Baranda Sonia , Barber Domingo F. , Carrera Ana C. , Martínez-A. Carlos , Mañes Santos
Published: February 2004

Spatially restricted activation of signaling molecules governs critical aspects of cell migration; the mechanism by which this is achieved nonetheless remains unknown. Using time-lapse confocal microscopy, we analyzed dynamic redistribution of lipid rafts in chemoattractant-stimulated leukocytes expressing glycosyl phosphatidylinositol–anchored green fluorescent protein (GFP-GPI). Chemoattractants induced persistent GFP-GPI redistribution to the leading edge raft (L raft) and uropod rafts of Jurkat, HL60, and dimethyl sulfoxide–differentiated HL60 cells in a pertussis toxin–sensitive, actin-dependent manner. A transmembrane, nonraft GFP protein was distributed homogeneously in moving cells. A GFP-CCR5 chimera, which partitions in L rafts, accumulated at the leading edge, and CCR5 redistribution coincided with recruitment and activation of phosphatidylinositol-3 kinase γ in L rafts in polarized, moving cells. Membrane cholesterol depletion impeded raft redistribution and asymmetric recruitment of PI3K to the cell side facing the chemoattractant source. This is the first direct evidence that lipid rafts order spatial signaling in moving mammalian cells, by concentrating the gradient sensing machinery at the leading edge.
Regulation of Dendritic Branching and Filopodia Formation in Hippocampal Neurons by Specific Acylated Protein Motifs
Authors: Gauthier-Campbell Catherine , Bredt David S. , Murphy Timothy H. , El-Husseini Alaa El-Din
Published: February 2004

Although neuronal axons and dendrites with their associated filopodia and spines exhibit a profound cell polarity, the mechanism by which they develop is largely unknown. Here, we demonstrate that specific palmitoylated protein motifs, characterized by two adjacent cysteines and nearby basic residues, are sufficient to induce filopodial extensions in heterologous cells and to increase the number of filopodia and the branching of dendrites and axons in neurons. Such motifs are present at the N-terminus of GAP-43 and the C-terminus of paralemmin, two neuronal proteins implicated in cytoskeletal organization and filopodial outgrowth. Filopodia induction is blocked by mutations of the palmitoylated sites or by treatment with 2-bromopalmitate, an agent that inhibits protein palmitoylation. Moreover, overexpression of a constitutively active form of ARF6, a GTPase that regulates membrane cycling and dendritic branching reversed the effects of the acylated protein motifs. Filopodia induction by the specific palmitoylated motifs was also reduced upon overexpression of a dominant negative form of the GTPase cdc42. These results demonstrate that select dually lipidated protein motifs trigger changes in the development and growth of neuronal processes.
Improvement in cooking quality of soybean (glycine max) by presoaking treatment with enzyme (lipase) solution
Authors: Khetarpaul Neelam , Garg Renu , Goyal Rajni
Published: February 2004

Presoaking treatment of partially defatted soy dhal in water or enzyme (lipase) solution for one, two and four hours decreased the cooking time substantially. When soy dhal was soaked in water for one, two and four hours, it resulted in 0 per cent, 1.24 per cent and 6.17 per cent decrease in cooking time over the unsoaked soy dhals, respectively. Soaking defatted soy dhal in lipase enzyme solution at three different concentrations, i.e. 0.5 per cent, 0.75 per cent and 1.0 per cent reduced the cooking time from 62.96 per cent to 74.69 per cent, over the control (unsoaked soy dhal) depending on the presoaking period. As the soaking period was increased from one to four hours irrespective of the concentration used, decrease in cooking time was observed. Maximum decrease in cooking time was found with soaking in 1 per cent concentration of lipase solution for four hours. There were non‐significant differences between the organoleptic scores of water soaked and enzyme soaked dhal. However, sensory scores of soy dhal were slightly improved by lipase enzyme soaking when compared to water soaked soy dhal.
Efficacy of Zotrim: a herbal weight loss preparation
Authors: Ruxton C.H.S.
Published: February 2004

A consumer survey was undertaken to test the efficacy of Zotrim, a herbal preparation commercially available as an over the counter weight loss aid. A total of 48 subjects completed a 28‐day trial of Zotrim, taken in tablet form just prior to main meals. The results showed a self‐assessed average weight loss of 2.3kg (0.6kg per week). Questionnaire data suggested that subjects ate less at meals and snacked less frequently. The overall findings supported an earlier placebo controlled clinical trial, and provided additional evidence that Zotrim delays gastric emptying and enhances feelings of fullness.
Dynamic sensing
Authors: Braggins Don
Published: February 2004

Describes a novel system that simultaneously measures both force and acceleration, and hence deduces mass. The system has been in use on ships and at fish‐sorting plants in Japan for about 8 years. However, applications are far wider than the fishing industry and the system can be used for “weighing” moving objects. Strictly speaking, the systems deduce mass rather than weight, but for simplicity we talk about “weighing” when we really mean mass determination in order to determine weight due to gravity under static conditions.
Network/multiplayer games and security
Authors: Loo Alfred , Choi Charlie
Published: February 2004

Introduces the special issue on the theme “Network/multiplayer games and security”. Outlines the topics covered by the papers within, with the objective of alerting technical and systems librarians to issues which might concern them and provide them with a wider framework of experience from which they can learn and adapt to their own circumstances.
Folding subdomains of thioredoxin characterized by native‐state hydrogen exchange
Authors: Bhutani Nidhi , Udgaonkar Jayant B.
Published: February 2004

Native‐state hydrogen exchange (HX) studies, used in conjunction with NMR spectroscopy, have been carried out on Escherichia coli thioredoxin (Trx) for characterizing two folding subdomains of the protein. The backbone amide protons of only the slowest‐exchanging 24 amino acid residues, of a total of 108 amino acid residues, could be followed at pH 7. The free energy of the opening event that results in an amide hydrogen exchanging with solvent (ΔGop) was determined at each of the 24 amide hydrogen sites. The values of ΔGop for the amide hydrogens belonging to residues in the helices α1, α2, and α4 are consistent with them exchanging with the solvent only when the fully unfolded state is sampled transiently under native conditions. The denaturant‐dependences of the values of ΔGop provide very little evidence that the protein samples partially unfolded forms, lower in energy than the unfolded state. The amide hydrogens belonging to the residues in the β strands, which form the core of the protein, appear to have higher values of ΔGop than amide hydrogens belonging to residues in the helices, suggesting that they might be more stable to exchange. This apparently higher stability to HX of the β strands might be either because they exchange out their amide hydrogens in a high energy intermediate preceding the globally unfolded state, or, more likely, because they form residual structure in the globally unfolded state. In either case, the central β strands—β3, β2, and β4—would appear to form a cooperatively folding subunit of the protein. The native‐state HX methodology has made it possible to characterize the free energy landscape that Trx can sample under equilibrium native conditions.
Methylation and carbamylation of human γ‐crystallins
Authors: Lapko Veniamin N. , Smith David L. , Smith Jean B.
Published: February 2004

Accessible sulfhydryls of cysteine residues are likely sites of reaction in long‐lived proteins such as human lens crystallins. Disulfide bonding between cysteines is a major contributor to intermolecular cross‐linking and aggregation of crystallins. A recently reported modification of γS‐crystallins, S‐methylation of cysteine residues, can prevent disulfide formation. The aim of this study was to determine whether cysteines in γC‐, γD‐, and γB‐crystallins are also S‐methylated. Our data show that all the γ‐crystallins are S‐methylated, but only at specific cysteines. In γD‐crystallin, methylation is exclusively at Cys 110, whereas in γC‐ and γB‐crystallins, the principal methylation site is Cys 22 with minor methylation at Cys 79. γD‐crystallin is the most heavily methylated γ‐crystallin. γD‐Crystallins from adult lenses are 37%–70% methylated, whereas γC and γB are ∼12% methylated. The specificity of γ‐crystallin methylation and its occurrence in young clear lenses supports the idea that inhibition of disulfide bonding by S‐methylation may play a protective role against cataract. Another modification, not reported previously, is carbamylation of the N termini of γB‐, γC‐, γD‐crystallins. N‐terminal carbamylation is likely a developmentally related modification that does not negatively impact crystallin function.
Determination of membrane protein stability via thermodynamic coupling of folding to thiol–disulfide interchange
Authors: Cristian Lidia , Lear James D. , DeGrado William F.
Published: February 2004

Although progress has been made in understanding the thermodynamic stability of water‐soluble proteins, our understanding of the folding of membrane proteins is at a relatively primitive level. A major obstacle to understanding the folding of membrane proteins is the discovery of systems in which the folding is in thermodynamic equilibrium, and the development of methods to quantitatively assess this equilibrium in micelles and bilayers. Here, we describe the application of disulfide cross‐linking to quantitatively measure the thermodynamics of membrane protein association in detergent micelles. The method involves initiating disulfide cross‐linking of a protein under reversible redox conditions in a thiol–disulfide buffer and quantitative assessment of the extent of cross‐linking at equilibrium. The 19–46 α‐helical transmembrane segment of the M2 protein from the influenza A virus was used as a model membrane protein system for this study. Previously it has been shown that transmembrane peptides from this protein specifically self‐assemble into tetramers that retain the ability to bind to the drug amantadine. We used thiol–disulfide exchange to quantitatively measure the tetramerization equilibrium of this transmembrane protein in dodecylphosphocholine (DPC) detergent micelles. The association constants obtained agree remarkably well with those derived from analytical ultracentrifugation studies. The experimental method established herein should provide a broadly applicable tool for thermodynamic studies of folding, oligomerization and protein–protein interactions of membrane proteins.
Customising Microsoft Office to develop a tutorial learning environment
Authors: Deacon Andrew , Jaftha Jacob , Horwitz David
Published: March 2004

Powerful applications such as Microsoft Office's Excel and Word are widely used to perform common tasks in the workplace and in education. Scripting within these applications allows unanticipated user requirements to be addressed. We show that such extensibility, intended to support office automation‐type applications, is well suited to the creation of learning activities and learning environments. We have developed a range of tutorial activities using Excel and Word in introductory mathematics, writing and economics courses. These tutorials have the dual purpose of teaching academic concepts and practical computer literacy skills. The software architecture of our learning environment includes a database‐supported back‐end to automatically record students’ responses, which allows for greater control over what students do. Additionally, this allows one to automate common procedures to improve usability and feedback automation to support learning. We have been applying our ideas for the last six years and currently 1,500 students are using the environment. We suggest that this pragmatic solution can provide a high degree of interactivity and flexibility in a range of learning contexts that represents a cost‐effective alternative for use alongside traditional approaches.
Intestinal nematode infection affects host life history and offspring susceptibility to parasitism
Authors: Kristan Deborah M.
Published: March 2004

The effects of experimental infection with a naturally occurring intestinal nematode (Heligmosomoides polygyrus, Dujardin 1845) on reproduction and on offspring growth, morphology and susceptibility to parasitism for wild‐derived house mice (Mus musculus, Linnaeus 1758) that were two to three generations captive‐born were examined.

Parasitized females averaged 2·8 more pups per litter at weaning and, after adjusting for the effects of litter size on offspring mass, parasitized females had slightly larger offspring than unparasitized females (by 1–2%).

Heligmosomoides polygyrus did not affect mean values of other measures of host reproductive output (time to first litter production, interlitter intervals, sex ratio, offspring loss from birth to weaning) but parasitized mice were more variable than unparasitized mice in the number of days to first litter production and for numbers of pups that died between birth and weaning.

Offspring growth was not affected by either maternal parasite infection or direct parasite infection. Body mass of all pups at sexual maturity was equivalent but there were differences in body composition (fat mass, organ masses) between parasitized and unparasitized pups and between males and females.

Only offspring from parasitized mothers cleared their own infection but for offspring that retained their infection there were no effects of either offspring sex or maternal parasite infection on infection intensity.

These results clearly demonstrate that infection with an intestinal nematode affects host life history, primarily litter size but also offspring mass at weaning, and susceptibility of offspring to infection with the same parasite.
Significant developments in sustainable development law and governance: A proposal
Authors: Segger Marie‐Claire Cordonier
Published: February 2004

This article develops a practical proposal for progress on sustainable development law. It examines the prospects for an international sustainable development law to provide a framework for more effective, coherent governance. Sustainable development law is briefly defined and an analytical framework is provided. Different degrees of integration between economic, social and environmental law are described. Certain principles of international law related to sustainable development are also highlighted. It is argued that these principles may serve to guide law‐makers and jurists where social, economic and environmental law and policy conflict or overlap. Continuing, underlying questions of sustainable development governance are addressed and its global frameworks analysed. The article also focuses on the 2002 World Summit on Sustainable Development, held in Johannesburg in August‐September 2002, and its specific mandate for the United Nations Commission on Sustainable Development (UNCSD) to take related legal developments into account. The article advances a proposal: that governments, economic, social and environmental intergovernmental organizations and other actors establish a ‘network of inquiry’ with members from relevant groups, including legal and academic organizations, and other expert groups, in order to follow, research, analyse and debate legal developments in a balanced way.
Prescriptions for contraindicated category X drugs in pregnancy among women enrolled in TennCare
Authors: Cooper William O. , Hickson Gerald B. , Ray Wayne A.
Published: March 2004

Filling of prescriptions for medications labelled as category X by the United States Food and Drug Administration (considered to be contraindicated for use in pregnancy) was identified among 95 284 women enrolled in TennCare, Tennessee's programme for Medicaid enrollees and individuals without health insurance. Using administrative claims data, 391 women (4.10/1000) were identified as having filled category X prescriptions during pregnancy. This included 118 women (1.24/1000) who filled prescriptions for non‐contraceptive oestrogens, 81 (0.85/1000) for sedatives, and 71 (0.75/1000) for statins. While many women had physician visits with a diagnosis consistent with a possible indication for an individual drug outside of pregnancy, none of these indications is included for use during pregnancy. Older women and disabled women were more likely than younger women (P < 0.0001) and women enrolled for other reasons (P < 0.0001) to fill category X prescriptions. Nearly two‐thirds of the 391 women filled prescriptions after clinical signs or pregnancy tests would indicate pregnancy; nearly 40% filled a category X prescription after a pregnancy‐related physician visit. Although the absolute rate of category X medication use in pregnancy is low, substantial numbers of women and their fetuses are exposed during pregnancy. Women above the age of 35 years and women enrolled in TennCare because of disabilities were more likely to fill prescriptions for category X medications during pregnancy than others, implying that risk communication to practitioners and women should focus on identification of these women to reduce their risk of exposure.
High‐resolution FISH on super‐stretched flow‐sorted plant chromosomes
Authors: Valárik M. , Bartoš J. , Kovářová P. , Kubaláková M. , De Jong J. H. , Doležel J.
Published: March 2004

A novel high‐resolution fluorescence in situ hybridisation (FISH) strategy, using super‐stretched flow‐sorted plant chromosomes as targets, is described. The technique that allows longitudinal extension of chromosomes of more than 100 times their original metaphase size is especially attractive for plant species with large chromosomes, whose pachytene chromosomes are generally too long and heterochromatin patterns too complex for FISH analysis. The protocol involves flow cytometric sorting of metaphase chromosomes, mild proteinase‐K digestion of air‐dried chromosomes on microscopic slides, followed by stretching with ethanol:acetic acid (3 : 1). Stretching ratios were assessed in a number of FISH experiments with super‐stretched chromosomes from barley, wheat, rye and chickpea, hybridised with 45S and 5S ribosomal DNAs and the [GAA]n microsatellite, the [TTTAGGG]n telomeric repeat and a bacterial artificial chromosome (BAC) clone as probes. FISH signals on stretched chromosomes were brighter than those on the untreated control, resulting from better accessibility of the stretched chromatin and maximum observed sensitivity of 1 kbp. Spatial resolution of neighbouring loci was improved down to 70 kbp as compared to 5–10 Mbp after FISH on mitotic chromosomes, revealing details of adjacent DNA sequences hitherto not obtained with any other method. Stretched chromosomes are advantageous over extended DNA fibres from interphase nuclei as targets for FISH studies because they still retain chromosomal integrity. Although the method is confined to species for which chromosome flow sorting has been developed, it provides a unique system for controlling stretching degree of mitotic chromosomes and high‐resolution bar‐code FISH.
Airways obstruction in survivors of thoracoplasty: Reversibility is greater in non‐smokers
Authors: O'Connor Terence M. , O'Riordan Deirdre M. , Stack Maria , Bredin Charles P.
Published: February 2004

Objective:  Before the advent of antituberculous chemotherapy, thoracoplasty (TPL) was the definitive form of therapy for cavitary pulmonary tuberculosis. This study aimed to characterize the late functional sequelae of TPL, and to establish the degree of reversibility of any consequent airway obstruction.

Methodology:  Pulmonary function was studied in 21 long‐term (mean 35 years) survivors of TPL between the years 1990–2001.

Results:  A mixed obstructive/restrictive defect was found in this patient cohort. After inhalation of bronchodilator, marginal increases in FEV1 and FVC and marginal decreases in FRC, RV and TLC were observed. Maximum mid‐expiratory flow rate was severely reduced (28.8% of predicted), but reversibility after inhaled β2‐agonist was highest for this parameter of pulmonary function (mean 11%). Smokers had a higher RV (P = 0.04), suggesting hyperinflation, while non‐smokers had a larger increase in FEV1/FVC ratio postbronchodilator (P = 0.004), suggesting more marked reversibility of airways obstruction in this group.

Conclusions:  Long‐term survivors of TPL have an obstructive as well as a restrictive ventilatory defect. These patients have partial reversibility of the obstructive defect. The degree of reversibility found suggests that bronchodilator therapy may help these patients.
Increased lung water without hypocapnia does not cause central sleep apnoea in a lamb model
Authors: Burgess Keith R. , Berend Norbert
Published: February 2004

Objective:  Central sleep apnoea (CSA) in patients with heart failure is associated with an extremely poor prognosis. It is unclear as to whether pulmonary congestion contributes to CSA.

Methodology:  We developed a sheep model of congestive cardiac failure (CCF) to address the question of whether pulmonary congestion without hypocapnia could cause CSA. Fourteen lambs were given CCF by overdrive pacing for 3 weeks. CCF was defined by a pulmonary artery occlusion pressure (PAOP) ≥ 15 mmHg. There were 11 controls. Extravascular lung water (EVLW) was measured by the double indicator dilution method.

Results:  The CCF lambs had a PAOP = 18 ± 3 mmHg and controls had a PAOP = 10 ± 2 mmHg (P < 0.01). EVLW was 12.6 ± 1.8 (CCF) compared to 8.9 ± 2 mL/kg (controls) (P < 0.01). The respiratory rate was 74 ± 21 b.p.m. (CCF) compared to 47 ± 6 b.p.m. (controls) (P < 0.05). Acute volume loading with saline raised PAOP without changing respiration. pH and PaCO2 were the same in both groups (PaCO2−37 mmHg).

Conclusions:  These results support the view that hypocapnia is essential for CSA, and demonstrated that increased EVLW causes tachypnoea but not CSA.
Role of first‐order consumers in ecosystem carbon flow
Authors: Cebrian Just
Published: February 2004

Herbivores and detritus consumers (i.e. microbial decomposers and invertebrate and vertebrate detritivores) are pivotal components of trophic food webs and thus play a paramount role in the trophic transference and turnover of producer‐fixed carbon. Hence, elucidating patterns in carbon flux through these first‐order consumers is important to understand the nature and controls of carbon flow in ecosystems. Here, using the largest literature compilation to date, I show that, in contrast with the current belief, aquatic herbivores accumulate on average three times as much biomass as do terrestrial herbivores for a given level of primary production and, as a consequence, turn over the ingested carbon only slightly faster than do terrestrial herbivores. Conversely, aquatic detritus consumers generally accumulate a much lower biomass (i.e. over ten times lower) than their terrestrial counterparts for a given level of primary production and, thus, they turn over the ingested carbon much more quickly (i.e. over ten times faster). Because the detrital pathway generally dominates the trophic flow of carbon in both aquatic and terrestrial ecosystems, carbon also tends to flow through the total compartment of first order‐consumers (both herbivores and detritus consumers) at a much faster rate in aquatic than in terrestrial ecosystems. Thus, aquatic systems, because of faster carbon recycling rates through their basal and first‐order levels of the food chain, appear to have a lower capacity than do terrestrial systems for retaining carbon under natural or anthropogenic increases in photosynthetic fixation.
Framing the doctor‐patient relationship in chronic illness: a comparative study of general practitioners’ accounts
Authors: May Carl , Allison Gayle , Chapple Alison , Chew‐Graham Carolyn , Dixon Clare , Gask Linda , Graham Ruth , Rogers Anne , Roland Martin
Published: March 2004

Abstract  How family doctors conceptualise chronic illness in the consultation has important implications for both the delivery of medical care, and its experience by patients. In this paper, we present the results of a re‐analysis of qualitative data collected in a series of studies of British family doctors between 1995 and 2001, to explore the ways in which the legitimacy and authority of medical knowledge and practice are organised and worked out in relation to three kinds of chronic illness (menorrhagia; depression; and chronic low back pain/medically unexplained symptoms). We present a comparative analysis of (a) the moral evaluation of the patient (and judgements about the legitimacy of symptom presentation); (b) the possibilities of disposal; and (c) doctors’ empathic responses to the patient, in each of these clinical cases. Our analysis defines some of the fundamental conditions through which general practitioners frame their relationships with patients presenting complex but sometimes diffuse combinations of ‘social’, ‘psychological’ and ‘medical’ symptoms. These are fundamental to, yet barely touched by, the increasingly voluminous literature on how doctors should interact with patients. Moving beyond the individual studies from which our data are drawn, we have outlined some of the highly complex and demanding features of what is often seen as routine and unrewarding medical work, and some of the key requirements for the local negotiation of patients’ problems and their meanings (for both patients and doctors) in everyday general practice.
Human growth hormone and the temptations of biomedical enhancement
Authors: Conrad Peter , Potter Deborah
Published: March 2004

Abstract  It is likely that humans have sought enhancements for themselves or their children for as long as they have recognised that improvements in individuals are a possibility. One genre of self‐improvement in modern society can be called ‘biomedical enhancements’. These include drugs, surgery and other medical interventions aimed at improving the mind, body or performance. This paper uses the case of human growth hormone (hGH) to examine the social nature of enhancements. Synthetic hGH was developed in 1985 by the pharmaceutical industry and was approved by the FDA for very specific uses, particularly treatment of growth hormone deficiency. However, it has also been promoted for a number of ‘off label’ uses, most of which can be deemed enhancements. Drugs approved for one treatment pave the way for use as enhancements for other problems. Claims have been made for hGH as a treatment for idiopathic shortness, as an anti‐ageing agent and to improve athletic performance. Using the hGH case, we are able to distinguish three faces of biomedical enhancement: normalisation, repair and performance edge. Given deeply ingrained social and individual goals in American society, the temptations of biomedical enhancements provide inducement for individuals and groups to modify their situation. We examine the temptations of enhancement in terms of issues such as unnaturalness, fairness, risk and permanence, and shifting social meanings. In our conclusions, we outline the potentials and pitfalls of biomedical enhancement.
Results of Arthroscopic Versus Open Arthrotomy for Surgical Management of Cranial Cruciate Ligament Deficiency in Dogs
Authors: Hoelzler Michael G. , Millis Darryl L. , Francis David A. , Weigel Joseph P.
Published: February 2004

Objective—To evaluate postoperative morbidity in dogs after experimental cranial cruciate ligament transection and immediate stifle stabilization using an arthroscopically assisted or open arthrotomy technique.

Study Design—Experimental, prospective study.

Animals—Thirteen mature, healthy dogs.

Methods—Dogs were randomly assigned to 1 of 2 groups. Seven underwent open arthrotomy while 6 underwent arthroscopy of 1 stifle joint. Cranial cruciate ligaments were transected and debrided and all stifles were stabilized using 2 lateral extracapsular fabellar‐tibial sutures. Minimally invasive suture placement was employed in the arthroscopy group. All animals were evaluated for 9 weeks using kinetic gait assessments, comfortable stifle range of motion measurements, thigh girth measurements, differential cell counts of synovial fluid, and subjective scores of behavior, limb use, and lameness.

Results—Significant differences in postoperative morbidity were observed during the 9‐week postoperative period. Greater peak vertical force for 8 weeks (P=.015), vertical impulse for 6 weeks (P=.044), comfortable stifle range of motion for 9 weeks (P=.017), comfortable stifle flexion for 4 weeks (P=.005), and operative limb thigh circumference (P=.020) for 9 weeks were observed for the arthroscopy group. A trend towards a lower differential mean synovial polymorphonuclear cell count in the arthroscopy group was seen at 4 and 8 weeks postoperatively. No differences in subjective evaluation scores were noted.

Conclusions—In this study population, significant differences were seen between the arthroscopy and arthrotomy groups for peak vertical force, vertical impulse, comfortable stifle range of motion, comfortable stifle flexion, and thigh circumference data.

Clinical Relevance—The results of this study suggest that short‐term postoperative morbidity may be reduced in dogs receiving arthroscopic joint surgery with a limited approach for stifle stabilization as compared with a traditional open arthrotomy technique.
Pre‐ and Postoperative Force Plate Analysis of Dogs with Experimentally Transected Cranial Cruciate Ligaments Treated Using Tibial Plateau Leveling Osteotomy
Authors: Ballagas Antonio J. , Montgomery Ronald D. , Henderson Ralph A. , Gillette Robert
Published: February 2004

Objective—Quantitative and objective assessment of hindlimb kinetics after cranial cruciate ligament (CrCL) transection and subsequent stifle stabilization using the tibial plateau leveling osteotomy (TPLO) in normal dogs.

Study Design—In vivo experimental biomechanical evaluation.

Animals—Six healthy adult foxhounds.

Methods—Dogs were screened by orthopedic and radiographic examination before study entry. Force plate analysis of gait was measured before extirpation of the right CrCL and TPLO and again at 8 and 18 weeks after surgery.

Results—There was a significant decrease in peak vertical forces (PVFs) and vertical impulse (VI) of the treated hindlimb at 8 weeks when compared with preoperative and 18‐week measurements. When compared with preoperative values, there was no significant difference in 18 week PVF and VI in dogs that had TPLO.

Conclusion—TPLO can restore kinetic measures of limb function at 18‐weeks after surgery when compared with preoperative values after experimental transection of the CrCL in dogs.

Clinical Relevance—TPLO induces lameness that returns to near normal at 18 weeks. The severity and duration of lameness was similar to that reported for other experimental models of stifle instability repaired by different techniques.
Staphylococcus aureus
Isolates with Reduced Susceptibility to Glycopeptides Belong to Accessory Gene Regulator Group I or II
Authors: Verdier Isabelle , Reverdy Marie-Elisabeth , Etienne Jerome , Lina Gérard , Bes Michèle , Vandenesch François
Published: February 2004

We used multiplex PCR to determine the
agr
group membership of 18 European glycopeptide heterointermediate and intermediate-resistant
Staphylococcus aureus
strains. Of the 15
agr
group I strains, 13 were resistant and 2 were susceptible to methicillin. The remaining three strains, like the United States and Japanese control strains, belonged to
agr
group II.
Role of
attP
in Integrase-Mediated Integration of the
Shigella
Resistance Locus Pathogenicity Island of
Shigella flexneri
Authors: Turner Sally A. , Luck Shelley N. , Sakellaris Harry , Rajakumar Kumar , Adler Ben
Published: February 2004

The
Shigella
resistance locus (SRL) pathogenicity island (PAI) in
Shigella
spp. mediates resistance to streptomycin, ampicillin, chloramphenicol, and tetracycline. It can be excised from the chromosome via site-specific recombination mediated by the P4-related
int
gene. Here, we show that SRL PAI
attP
is capable of RecA-independent, site-specific,
int
-mediated integration into two bacterial tRNA
attB
sites.
Comparative Efficacies of Four Amphotericin B Formulations—Fungizone, Amphotec (Amphocil), AmBisome, and Abelcet—against Systemic Murine Aspergillosis
Authors: Clemons Karl V. , Stevens David A.
Published: February 2004

We compared various amphotericin B formulations (no treatment or 0.8 mg of Fungizone [conventional deoxycholate amphotericin B] per kg of body weight, or 0.8, 4, or 8 mg of Amphocil, AmBisome, or Abelcet per kg of body weight) for treatment of systemic murine aspergillosis. In two studies, all formulations prolonged survival, with the results for AmBisome nearly equivalent to those for Fungizone; Amphocil and Abelcet were less effective or equivalent depending on the severity of infection. No survivors were cured in both kidneys and brain, but each formulation showed efficacy, especially in the kidneys. Although higher doses could be given, no lipid-based formulation showed consistent superiority over Fungizone or over each other.
Antibiotic Susceptibility of
Tropheryma whipplei
in MRC5 Cells
Authors: Boulos Areen , Rolain Jean-Marc , Raoult Didier
Published: February 2004

Whipple's disease is considered a rare chronic disease with a broad spectrum of clinical manifestations. Several antibiotics have been used for the treatment of this disease, and the current reference treatment was determined empirically on the basis of only a few clinical observations. Patients should be treated for months, and many relapse after antibiotic withdrawal. We report here the first extensive study on the susceptibilities of three reference strains of
Tropheryma whipplei
to antibiotic in cell culture by using a real-time PCR assay as previously described. We found that doxycycline, macrolides, ketolides, aminoglygosides, penicillin, rifampin, teicoplanin, chloramphenicol, and trimethoprim-sulfamethoxazole were active, with MICs ranging from 0.25 to 2 μg/ml. Vancomycin was somewhat active at an MIC of 10 μg/ml. We found heterogeneity in the susceptibility to imipenem, with one strain being susceptible and the two other strains being resistant. Cephalosporins, colimycine, aztreonam, and fluoroquinolones were not active. We also demonstrated that a combination of doxycycline and hydroxychloroquine was bactericidal. This combination has been shown to be active in the treatment of patients suffering from chronic infections with
Coxiella burnetii
, a bacterium that is also found intracellularly in acidic vacuoles. We believe, then, that this combination therapy should be further evaluated in clinical trials for the treatment of Whipple's disease.
Pharmacokinetics of Indinavir and Nelfinavir in Treatment-Naive, Human Immunodeficiency Virus-Infected Subjects
Authors: DiCenzo Robert , Forrest Alan , Fischl Margaret A. , Collier Ann , Feinberg Judith , Ribaudo Heather , DiFrancecso Robin , Morse Gene D.
Published: February 2004

AIDS Clinical Trials Group protocol 388 was designed to compare a three-drug regimen (indinavir with dual nucleosides) to a four-drug regimen (indinavir plus nelfinavir or indinavir plus efavirenz with dual nucleosides). Blood samples from patients taking indinavir and nelfinavir were collected over 8 to 12 h following a specified dose and were analyzed with high-performance liquid chromatography. Pharmacokinetic data were derived by using noncompartmental analysis. Following administration of indinavir every 8 h in the absence of nelfinavir (
n
= 8), the median predose indinavir concentration (
C
0
) was 369 ng/ml (range, <10 to 949 ng/ml; one subject had a concentration of <10 ng/ml), and the concentration 8 h after administration of the study dose was 159 ng/ml (range, 85 to 506 ng/ml). In the group receiving 1,000 mg of indinavir every 12 h with nelfinavir (
n
= 10), the median indinavir
C
0
was <10 ng/ml (range, <10 to 3,740 ng/ml; six subjects had a value of <10 ng/ml), and the
C
12 h
was 44 ng/ml (range, <10 to 4,236 ng/ml; five subjects had a value of <10 ng/ml), while the subjects who received 1,200 mg of indinavir every 12 h with nelfinavir (
n
= 7) had a
C
0
of 146 ng/ml (range, 58 to 5,215 ng/ml) and a
C
12 h
of 95 ng/ml (range, 12 to 954 ng/ml). Indinavir clearance was significantly lower in the presence of nelfinavir (median [interquartile range], 34.1 liters/h [range, 22.6 to 45.8 liters/h] versus 47.9 liters/h [range, 42.7 to 70.3 liters/h];
P
< 0.017). For subjects receiving 1,000 mg of indinavir every 12 h, the median
C
0
value for nelfinavir (
n
= 9) was 1,779 ng/ml (range, <187.5 to 4,579 ng/ml), and the
C
12 h
was 1,554 ng/ml (range, <187.5 to 5,540 ng/ml). Due to the unacceptable number of undetectable indinavir trough concentrations, 1,200 mg of indinavir appears to be the preferred dose in a twice-daily regimen that includes nelfinavir.
Plasmodium falciparum-Based Bioassay for Measurement of Artemisinin Derivatives in Plasma or Serum
Authors: Teja-Isavadharm Paktiya , Peggins James O. , Brewer Thomas G. , White Nicholas J. , Webster H. Kyle , Kyle Dennis E.
Published: February 2004

Artemisinin and its derivatives, artesunate and artemether, are rapidly acting antimalarials that are used for the treatment of severe and uncomplicated multidrug-resistant falciparum malaria. To optimize treatment regimens that use this new class of antimalarials, there is a need for readily available and reproducible assays to monitor drug levels closely in patients. A sensitive and reproducible bioassay for the measurement of the concentrations of artemisinin derivatives in plasma and serum is described. By modifying the in vitro drug susceptibility test, it was found that antimalarial activity in plasma or serum containing an unknown concentration of drug could be equated to the known concentrations of dihydroartemisinin (DHA) required to inhibit parasite growth. Dose-response curves for aPlasmodium falciparumclone (clone W2) and DHA were used as a standard for each assay. Assays with plasma or serum spiked with DHA proved to be reproducible (coefficient of variation, ≤10.9%), with a lower limit of quantitation equivalent to 2.5 ng of DHA per ml. For plasma spiked with artesunate or artemether, there was good agreement of the results obtained by the bioassay and the concentrations measured by high-performance liquid chromatography (HPLC) with electrochemical detection. The bioassay for measurement of the antimalarial activities of artemisinin derivatives in body fluids requires a smaller volume of plasma or serum and is more sensitive than the presently available HPLC methods, can provide pharmacodynamic parameters for determination of activity against the parasite, and should enhance the design of more appropriate dosage regimens for artemisinin drugs.
Intrapatient Variability of Efavirenz Concentrations as a Predictor of Virologic Response to Antiretroviral Therapy
Authors: Brundage Richard C. , Yong Florence H. , Fenton Terence , Spector Stephen A. , Starr Stuart E. , Fletcher Courtney V.
Published: February 2004

Intrapatient variability of drug concentrations over time has not been evaluated as a predictor of drug response but may provide information on the onset and maintenance of response and a patient's adherence to therapy. Our objective was to develop a pharmacologically based measure of intrapatient variability of concentrations and investigate its association with a patient's response to antiretroviral therapy. Efavirenz concentrations were obtained for 50 children enrolled in Pediatric AIDS Clinical Trials Group study 382, a concentration-controlled trial of efavirenz plus nelfinavir and at least one nucleoside reverse transcriptase inhibitor. Efavirenz pharmacokinetic parameters were determined from 24-h concentration-time profiles at weeks 2 and 6 and used to predict trough concentrations obtained during 1 year of therapy. A concentration predictability score, defined as the fraction of measured trough concentrations that fell within a ±50% range of the predicted concentration, was used to place subjects into high and low concentration predictability groups. Relationships between this score and human immunodeficiency virus RNA levels in plasma were investigated. Eight of 33 children (24%) in the high-predictability group experienced viral rebound, compared with 9 of 17 children (53%) in the low-predictability group (P= 0.042). Children with low predictability scores exhibited a significantly shorter time to their first viral rebounds and were significantly more likely to experience viral rebound; the latter finding persisted after adjustment for baseline viral load and efavirenz exposure at week 6. This novel method for the quantitation of intrapatient concentration variability was independently predictive of virologic rebound. This measure may allow interventions to minimize therapeutic failure and is applicable to other drugs.
Molecular Mechanisms of Tenofovir Resistance Conferred by Human Immunodeficiency Virus Type 1 Reverse Transcriptase Containing a Diserine Insertion after Residue 69 and Multiple Thymidine Analog-Associated Mutations
Authors: White Kirsten L. , Chen James M. , Margot Nicolas A. , Wrin Terri , Petropoulos Christos J. , Naeger Lisa K. , Swaminathan S. , Miller Michael D.
Published: February 2004

Two amino acids inserted between residues 69 and 70 of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) are rare mutations that may develop in viruses containing multiple thymidine analog (zidovudine [AZT], stavudine)-associated mutations and that confer high-level resistance to all currently approved chain-terminating nucleoside and nucleotide RT inhibitors (NRTIs). The two known mechanisms of resistance to NRTIs are decreased incorporation and increased excision. The mechanism used by RT insertion mutants has not been described for tenofovir (TFV), a recently approved agent in this class. A patient-derived HIV-1 strain (strain FS-SSS) that contained an insertion mutation in a background of additional resistance mutations M41L, L74V, L210W, and T215Y was obtained. A second virus (strain FS) was derived from FS-SSS. In strain FS the insertion and T69S were reverted but the other resistance mutations were retained. The FS virus showed strong resistance to AZT but low-level changes in susceptibilities to other NRTIs and TFV. The FS-SSS virus showed reduced susceptibilities to all NRTIs including TFV. Steady-state kinetics demonstrated that the relative binding or incorporation of TFV was slightly decreased for FS-SSS RT compared to those for wild-type RT. However, significant ATP-mediated excision of TFV was detected for both mutant RT enzymes and followed the order FS-SSS RT > FS RT > wild-type RT. The presence of physiological concentrations of the +1 nucleotide inhibited TFV excision by the wild-type RT and slightly inhibited excision by the FS RT, whereas the level of excision by the FS-SSS RT remained high. Computer modeling suggests that the increased mobility of the β3-β4 loop may contribute to the high-level and broad NRTI resistance caused by the T69 insertion mutation.