bluuebunny/crossref_metadata_2025_split huggingface dataset:
Guidelines for the use of antidepressants in painful rheumatic conditions
Authors: Perrot Serge , Maheu Emmanuel , Javier Rose‐Marie , Eschalier Alain , Coutaux Anne , LeBars Manuela , Bertin Philippe , Bannwarth Bernard , Trèves Richard 
Published: April 2005

AbstractObjectives Antidepressants are widely used to treat painful chronic rheumatic conditions but, contrary to neuropathic conditions, little is known about their true analgesic properties and value in these situations. Our group, which focuses on pain in rheumatology, aimed to develop recommendations for the use of antidepressants in rheumatology, based on evidence‐based review of published data and expert opinion.Method We identified relevant drugs and conditions and searched Medline, Embase and Pascal (1966‐2003) for relevant publications in a number of European languages. We scored each study for quality, and used an expert consensus approach to formulate recommendations.Results We identified 77 studies and 12 meta‐analyses and literature review on the use of antidepressant to treat painful rheumatological conditions. Forty‐nine of these clinical studies were considered valid and were used to develop the recommendations. When evidence was lacking we based recommendations on our clinical experience.Conclusions These recommendations for the treatment of painful rheumatological conditions with antidepressants were developed using evidence‐based and expert consensus approaches and are the first of their kind in this field. Our review of the literature highlights the need for further, well‐designed clinical studies of the use of antidepressants to treat painful rheumatological conditions.
The experience of chronic back pain: Accounts of loss in those seeking help from pain clinics
Authors: Walker Jan , Sofaer Beatrice , Holloway Immy 
Published: April 2005

AbstractBackground This study responded to the need for greater understanding of the experiences that help to shape the worldviews of chronic back patients as they seek help from pain clinics.Aim To elaborate on the lived experience of chronic back pain in those actively seeking help from pain clinics.Methods This was a qualitative study, based on an interpretative phenomenological approach. As part of in‐depth interviews, participants were invited to ‘tell their story’ from the time their pain began. Participants were twelve male and eight female patients, all of whom were diagnosed as having chronic benign back pain and had recently attended one of two pain clinics as new referrals. The data were analysed thematically.Findings Loss was one of five major themes to emerge. The narrative accounts revealed a catalogue of socio‐economic and other material losses including loss of physical and mental abilities, occupational and social activities, job or role. In those of working age, these led to financial hardship and changes in interpersonal relationships, culminating in loss of self‐worth, future and hope.Conclusions The findings suggest that material losses, as well as perceptions of loss, are prominent issues for those of working age seeking help from pain clinics for chronic back pain, and may need to be acknowledged and addressed as part of therapeutic interventions. The possibility of age‐related differences in pain‐related loss may be worthy of further investigation.
Expectation of pain replicates the effect of pain in a hand laterality recognition task: Bias in information processing toward the painful side?
Authors: Hudson Megan L. , McCormick Katherine , Zalucki Nadia , Moseley G. Lorimer 
Published: April 2005

AbstractBackground People in pain, or expecting pain, sometimes bias their attention towards pain‐relevant cues. Perhaps they also bias their attention towards the body part in question.Aim To determine if experimentally induced pain, and the expectation of pain, involve an information processing bias towards the hand in question.Methods Seventeen asymptomatic subjects performed a hand laterality recognition task during three conditions: control, during hand pain induced by intramuscular injection of hypertonic saline (pain), and during expectation of hand pain, induced by isotonic saline injection (expectation). Mean response time (RT) was determined for three 45 s epochs within each condition and RT was compared between hands, conditions and epochs using a 2 × 3 × 3 repeated measures multivariate analysis of variance.Results There was a hand × condition interaction and a hand × condition × epoch interaction (p < 0.05 for both). RT to recognise the opposite hand was ∼600 ms longer during epochs when subjects were in pain or expected pain than during control trials. During those epochs, RT to recognise the opposite hand was ∼600 ms longer than RT to recognise the injected hand, which was consistent across conditions and across epochs.Conclusions Both pain and the expectation of pain increased RT to recognise the opposite hand. The findings are consistent with a bias in information processing toward the painful or impending painful hand.
Disulfide locked variants of factor VIIa with a restricted β‐strand conformation have enhanced enzymatic activity
Authors: Maun Henry R. , Eigenbrot Charles , Raab Helga , Arnott David , Phu Lilian , Bullens Sherron , Lazarus Robert A. 
Published: April 2005

AbstractProteolytic processing of zymogen Factor VII to Factor VIIa (FVIIa) is necessary but not sufficient for maximal proteolytic activity, which requires an additional allosteric influence induced upon binding to its cofactor tissue factor (TF). A key conformational change affecting the zymogenicity of FVIIa involves a unique three‐residue shift in the position of β‐strand B2 in their zymogen and protease forms. By selectively introducing new disulfide bonds, we locked the conformation of these strands into an active TF•FVIIa‐like state. FVIIa mutants designated 136:160, 137:159, 138:160, and 139:157, reflecting the position of the new disulfide bond (chymotypsinogen numbering), were expressed and purified by TF affinity chromatography. Mass spectrometric analysis of tryptic peptides from the FVIIa mutants confirmed the new disulfide bond formation. Kinetic analysis of amidolytic activity revealed that all FVIIa variants alone had increased specific activity compared to wild type, the largest being for variants 136:160 and 138:160 with substrate S‐2765, having 670‐ and 330‐fold increases, respectively. Notably, FVIIa disulfide‐locked variants no longer required TF as a cofactor for maximal activity in amidolytic assays. In the presence of soluble TF, activity was enhanced 20‐ and 12‐fold for variants 136:160 and 138:160, respectively, compared to wild type. With relipidated TF, mutants 136:160 and 137:159 also had an approximate threefold increase in their Vmax/Km values for FX activation but no significant improvement in TF‐dependent clotting assays. Thus, while large rate enhancements were obtained for amidolytic substrates binding at the active site, macro‐molecular substrates that bind to FVIIa exosites entail more complex catalytic requirements.
The evolutionary origins and catalytic importance of conserved electrostatic networks within TIM‐barrel proteins
Authors: Livesay Dennis R. , La David 
Published: April 2005

AbstractConservation of function is the basic tenet of protein evolution. Conservation of key electrostatic properties is a frequently employed mechanism that leads to conserved function. In a previous report, we identified several conserved electrostatic properties in four protein families and one functionally diverse enzyme superfamily. In this report, we demonstrate the evolutionary and catalytic importance of electrostatic networks in three ubiquitous metabolic enzymes: triosephosphate isomerase, enolase, and transaldolase. Evolutionary importance is demonstrated using phylogenetic motifs (sequence fragments that parallel the overall familial phylogeny). Phylogenetic motifs frequently correspond to both catalytic residues and conserved interactions that fine‐tune catalytic residue pKa values. Further, in the case of triosephosphate isomerase, quantitative differences in the catalytic Glu169 pKa values parallel subfamily differentiation. Finally, phylogenetic motifs are shown to structurally cluster around the active sites of eight different TIM‐barrel families. Depending upon the mechanistic requisites of each reaction catalyzed, interruptions to the canonical fold may or may not be identified as phylogenetic motifs.
Structural consequences of the familial amyotrophic lateral sclerosis SOD1 mutant His46Arg
Authors: Antonyuk Svetlana , Elam Jennifer Stine , Hough Michael A. , Strange Richard W. , Doucette Peter A. , Rodriguez Jorge A. , Hayward Lawrence J. , Valentine Joan Selverstone , Hart P. John , Hasnain S. Samar 
Published: April 2005

AbstractThe His46Arg (H46R) mutant of human copper‐zinc superoxide dismutase (SOD1) is associated with an unusual, slowly progressing form of familial amyotrophic lateral sclerosis (FALS). Here we describe in detail the crystal structures of pathogenic H46R SOD1 in the Zn‐loaded (Zn‐H46R) and metal‐free (apo‐H46R) forms. The Zn‐H46R structure demonstrates a novel zinc coordination that involves only three of the usual four liganding residues, His 63, His 80, and Asp 83 together with a water molecule. In addition, the Asp 124 “secondary bridge” between the copper‐ and zinc‐binding sites is disrupted, and the “electrostatic loop” and “zinc loop” elements are largely disordered. The apo‐H46R structure exhibits partial disorder in the electrostatic and zinc loop elements in three of the four dimers in the asymmetric unit, while the fourth has ordered loops due to crystal packing interactions. In both structures, nonnative SOD1–SOD1 interactions lead to the formation of higher‐order filamentous arrays. The disordered loop elements may increase the likelihood of protein aggregation in vivo, either with other H46R molecules or with other critical cellular components. Importantly, the binding of zinc is not sufficient to prevent the formation of nonnative interactions between pathogenic H46R molecules. The increased tendency to aggregate, even in the presence of Zn, arising from the loss of the secondary bridge is consistent with the observation of an increased abundance of hyaline inclusions in spinal motor neurons and supporting cells in H46R SOD1 transgenic rats.
Conversion of 5‐aminolevulinate synthase into a more active enzyme by linking the two subunits: Spectroscopic and kinetic properties
Authors: Zhang Junshun , Cheltsov Anton V. , Ferreira Gloria C. 
Published: April 2005

AbstractThe two active sites of dimeric 5‐aminolevulinate synthase (ALAS), a pyridoxal 5′‐phosphate (PLP)‐dependent enzyme, are located on the subunit interface with contribution of essential amino acids from each subunit. Linking the two subunits into a single polypeptide chain dimer (2XALAS) yielded an enzyme with an approximate sevenfold greater turnover number than that of wild‐type ALAS. Spectroscopic and kinetic properties of 2XALAS were investigated to explore the differences in the coenzyme structure and kinetic mechanism relative to those of wild‐type ALAS that confer a more active enzyme. The absorption spectra of both ALAS and 2XALAS had maxima at 410 and 330 nm, with a greater A410/A330 ratio at pH ∼7.5 for 2XALAS. The 330 nm absorption band showed an intense fluorescence at 385 nm but not at 510 nm, indicating that the 330 nm absorption species is the substituted aldamine rather than the enolimine form of the Schiff base. The 385 nm emission intensity increased with increasing pH with a single pK of ∼8.5 for both enzymes, and thus the 410 and 330 nm absorption species were attributed to the ketoenamine and substituted aldamine, respectively. Transient kinetic analysis of the formation and decay of the quinonoid intermediate EQ2 indicated that, although their rates were similar in ALAS and 2XALAS, accumulation of this intermediate was greater in the 2XALAS‐catalyzed reaction. Collectively, these results suggest that ketoenamine is the active form of the coenzyme and forms a more prominent coenzyme structure in 2XALAS than in ALAS at pH ∼7.5.
Fusogenic Alzheimer's peptide fragment Aβ (29–42) in interaction with lipid bilayers: Secondary structure, dynamics, and specific interaction with phosphatidyl ethanolamine polar heads as revealed by solid‐state NMR
Authors: Ravault Stéphanie , Soubias Olivier , Saurel Olivier , Thomas Annick , Brasseur Robert , Milon Alain 
Published: April 2005

AbstractThe interaction of the native Alzheimer's peptide C‐terminal fragment Aβ (29–42), and two mutants (G33A and G37A) with neutral lipid bilayers made of POPC and POPE in a 9:1 molar ratio was investigated by solid‐state NMR. This fragment and the lipid composition were selected because they represent the minimum requirement for the fusogenic activity of the Alzheimer's peptide. The chemical shifts of alanine methyl isotropic carbon were determined by MAS NMR, and they clearly demonstrated that the major form of the peptide equilibrated in membrane is not in a helical conformation. 2H NMR, performed with acyl chain deuterated POPC, demonstrated that there is no perturbation of the acyl chain's dynamics and of the lipid phase transition temperature. 2H NMR, performed with alanine methyl‐deuterated peptide demonstrated that the peptide itself has a limited mobility below and above the lipid phase transition temperature (molecular order parameter equal to 0.94). MAS 31P NMR revealed a specific interaction with POPE polar head as seen by the enhancement of POPE phosphorus nuclei T2 relaxation. All these results are in favor of a β‐sheet oligomeric association of the peptide at the bilayer interface, preferentially recruiting phosphatidyl ethanolamine polar heads.
Laser Doppler imager (LDI) scanner and intradermal injection for in vivo pharmacology in human skin microcirculation: responses to acetylcholine, endothelin‐1 and their repeatability
Authors: Saez Anabelle M. Opazo , Mosel Frank , Nürnberger Jens , Rushentsova U. , Gössl Mario , Mitchell Anna , Schäfers Rafael F. , Philipp Thomas , Wenzel René R. 
Published: April 2005

AimsThe purpose of this study was to evaluate the repeatability of forearm skin blood flow responses to intradermal injections of acetylcholine (ACh) and endothelin‐1 (ET‐1) using a double injection technique (DIT) and a laser Doppler imager (LDI) scanner in the human skin microcirculation.MethodsWe used a laser Doppler imager (Moor LDI V3.01) to continuously monitor the change in skin blood flow during intradermal administration of physiological saline (0.9% NaCl), acetylcholine (ACh 10−7, 10−8, 10−9 M) and endothelin‐1 (ET‐1 10−14, 10−16, 10−18 M) in 10 healthy male subjects. Subjects were examined on 3 different days for assessment of interday and interobserver repeatability. Injections of either drug were randomly placed on different sites of the forearm. Laser Doppler images were collected before and after injection at 2.5 min intervals for 30 min. Data were analysed after the completion of each experiment using Moor Software V.3.01. Results are expressed as changes from baseline in arbitrary perfusion units (PU).ResultsACh caused a significant vasodilation (P < 0.0001 anova, mean ± SE: 766 ± 152 PU, ACh 10−9 M; 1868 ± 360 PU, ACh 10−8 M; 4188 ± 848 PU, ACh 10−7 M; mean of days 1 and 2, n = 10), and ET‐1 induced a significant vasoconstrictive response (P < 0.0001 anova, −421 ± 83 PU, ET‐1 10−18 M; −553 ± 66 PU, ET‐1 10−16 M; −936 ± 90 PU, ET‐1 10−14 M; mean of days 1 and 2, n = 10). There was no difference on the response to either drug on repeated days. Bland‐Altman analyses showed a close agreement of responses between days with repeatability coefficients of 1625.4 PU for ACh, and 386.0 PU for ET‐1 (95% CI: ACh, −1438 to 1747 PU, ET‐1, −399 to 358 PU) and between observers with repeatability coefficients of 1057.2 PU for ACh and 255.8 PU for ET‐1 (95% CI: ACh, −1024 to 1048 PU, ET‐1, −252 to 249 PU). The variability between these responses was independent of average flux values for both ACh and ET‐1. There was a significant correlation between responses measured in the same site, in the same individual on two different days by the same observer (ACh, r = 0.94, P < 0.0001; ET‐1, r = 0.90, P < 0.0006), and between responses measured by two different observers (ACh, r = 0.94, P < 0.0001; ET‐1, r = 0.91, P < 0.0003).ConclusionWe have shown that interday and intraobserver responses to intradermal injections of ET‐1 and ACh, assessed using the DIT in combination with an LDI scanner, exhibited good reproducibility and may be a useful tool for studying the skin microcirculation in vivo.
Pharmacokinetic interaction on valproic acid and recurrence of epileptic seizures during chemotherapy in an epileptic patient
Authors: Ikeda Hiroaki , Murakami Teruo , Takano Mikihisa , Usui Tsuguru , Kihira Kenji 
Published: April 2005

AimsTo report a pharmacokinetic interaction between valproic acid (VPA) and anticancer agents observed in an epileptic patient.MethodsA 34‐year old male epileptic patient receiving VPA underwent cisplatin‐based chemotherapy for the treatment of a testicular tumour. The first chemotherapeutic cycle decreased the serum VPA concentration and caused severe generalized tonic‐clonic seizures. Thus, thereafter, the serum VPA concentration was monitored along with the chemotherapy.ResultsIn a patient receiving VPA daily, severe seizures were observed 7 weeks after the first chemotherapeutic cycle, at which the serum VPA concentration was found to be reduced by approximately 50% of the initial level (90–100 µg ml−1). The following cycles (six cycles over a 7‐month period) also caused seizures in association with decreased serum VPA concentrations. In contrast, the serum concentration of phenytoin, which was given daily after the second chemotherapeutic cycle, remained at a therapeutic concentration (10–20 µg ml−1). After the completion of chemotherapy, the serum concentration of a tumour marker, hCGβ, decreased to 1.2 ng ml−1 from more than 120 ng ml−1 prior to the chemotherapy in this patient.ConclusionsCareful monitoring of VPA concentrations are necessary during cisplatin‐based chemotherapy because anticancer agents can reduce the serum concentration and antiepileptic activity of VPA.
Khat chewing is a risk factor for acute myocardial infarction: a case‐control study
Authors: Al‐Motarreb A. , Briancon S. , Al‐Jaber N. , Al‐Adhi B. , Al‐Jailani F. , Salek M S. , Broadley K J. 
Published: April 2005

AimKhat chewing is a common habit in Yemen and east African countries. Millions of people chew khat leaves daily for its euphoric and energetic effects and to increase alertness. Cathinone, the main active substance in fresh khat leaves, has sympathomimetic effects which increase heart rate and blood pressure. The aim was to examine the hypothesis that khat chewing is a risk factor for acute myocardial infarction (AMI) using a hospital‐based matched case‐control study.MethodBetween 1997 and 1999, we selected 100 patients admitted to the Al‐Thawra teaching hospital Sana’a ICU, Yemen with acute myocardial infarction. 100 control subjects, matched to cases for sex and age, were recruited from the outpatients clinics of the same hospital. A questionnaire was completed for case and control groups covering personal history of khat chewing, smoking, hypertension, diabetes and any family history of myocardial infarction. A blood sample was collected for performing lipid profiles. Cases and controls were compared by analysis conducted using conditional logistic regression which corrected for baseline imbalances leading to less biased estimations of odds ratio (OR). The risk associated with each classical factor and khat chewing habits was then investigated. OR values greater than 2.5 indicated a significant risk factor.ResultsKhat chewing was significantly higher among the AMI case group than control group (OR = 5.0, 95% CI 1.9–13.1). A dose–response relationship was observed, the heavy khat chewers having a 39‐fold increased risk of AMI.ConclusionThis study indicates that khat chewing is associated with AMI and is an independent dose‐related risk factor for the development of myocardial infarction.
Influence of acute upper respiratory tract infection on the absorption of inhaled insulin using the AERx® insulin Diabetes Management System
Authors: McElduff Aidan , Mather Laurence E. , Kam Peter C. , Clauson Per 
Published: April 2005

AimsTo assess the effects due to an uncomplicated acute upper respiratory tract infection (URTI) on the pharmacokinetics and glucose response of insulin when delivered by oral pulmonary absorption.MethodsNormally healthy adult men (n = 11) and women (n = 9) received a single dose of inhaled human insulin, equivalent to ∼ 6 IU subcutaneous, using the AERx® insulin Diabetes Management System (iDMS), during and following recovery from an URTI. The first dose was administered with ongoing symptoms of < 3 days’ duration, the second dose following recovery, and within 3 weeks of the first. Blood sampling for determination of insulin pharmacokinetics (serum AUC(0−6 h), AUC(0−8), Cmax,tmax, t1/2, MRT) and glucose response (plasma AOC(0−6 h)) was performed from 15 min predose to 6 h postdose.ResultsInsulin pharmacokinetics were not different for subjects during and following recovery from URTI [e.g. URTI: no URTI ratio in serum AUC(0−6 h) = 0.92 (95% confidence interval 0.81, 1.05)]; this was reflected by a similar glucose response. Inhaled insulin delivered by AERx® iDMS was well tolerated by all subjects; no significant changes were observed in pulmonary function tests. No safety concerns arising from the mode of insulin administration were raised by either dose.ConclusionsThe results suggest that insulin can be administered via AERx® iDMS to nondiabetic subjects experiencing a URTI without any statistically significant changes in insulin pharmacokinetics or pharmacodynamics, and that the necessity for dose adjustments will not differ from subjects with an acute URTI who are receiving subcutaneous insulin.
Ventilatory responses of healthy subjects to intravenous combinations of morphine and oxycodone under imposed hypercapnic and hypoxaemic conditions
Authors: Ladd L. A. , Kam P. C. , Williams D. B. , Wright A. W. E. , Smith M. T. , Mather L. E. 
Published: April 2005

AimsPrevious isobolographic analysis revealed that coadministration of morphine and oxycodone produces synergistic antinociception in laboratory rodents. As both opioids can produce ventilatory depression, this study was designed to determine whether their ventilatory effects were synergistic when coadministered to healthy human subjects.MethodsA placebo‐controlled, randomized, crossover study was performed in 12 male volunteers. Ventilatory responses to hypoxaemia and hypercapnia were determined from 1‐h intravenous infusions of saline (‘placebo’), 15 mg morphine sulphate (M), 15 mg oxycodone hydrochloride (O), and their combination in the dose ratios of 1 : 2, 1 : 1, 2 : 1. Drug and metabolite concentrations in serial peripheral venous blood samples were measured by high‐performance liquid chromatography–MS/MS.Results‘Placebo’ treatment was without significant ventilatory effects. There were no systematic differences between active drug treatments on either the slopes or intercepts of the hypoxaemic and hypercapnia ventilation responses. During drug treatment, the mean minute ventilation at PetCO2 = 55 mmHg (VE55) decreased to 74% of the subjects’ before treatment values (95% confidence interval 62, 87), 68% (57, 80), 69% (59, 79), 68% (63, 73), and 61% (52, 69) for M15, M10/O5, M7.5/O7.5, M5/O10 and O15, respectively. Recovery was more prolonged with increasing oxycodone doses, corresponding to its greater potency and lower clearance compared with morphine.ConclusionsAlthough adverse ventilatory effects of these drugs were found as expected, no unexpected or disproportionate effects of any of the morphine and oxycodone treatments were found that might impede their use in combination for pain management.