bluuebunny/crossref_metadata_2025_split huggingface dataset:
Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?
Authors: Lashuel Hilal A. , Lansbury Peter T. 
Published: September 2006

1. Introduction 22. What is the significance of the shared structural properties of disease-associated protein fibrils? 32.1 Mechanism of amyloid fibril formation in vitro 62.1.1 In vitro fibril formation involves transient population of ordered aggregates of intermediate stability, or protofibrils 63. Toxic properties of protofibrils 73.1 Protofibrils, rather than fibrils, are likely to be pathogenic 73.2 The toxic protofibril may be a mixture of related species 83.3 Morphological similarities of protofibrils suggest a common mechanism of toxicity 93.4 Are the amyloid diseases a subset of a much larger class of previously unrecognized protofibril diseases? 93.5 Fibrils, in the form of aggresomes, may function to sequester toxic protofibrils 94. Amyloid pores, a common structural link among protein aggregation neurodegenerative diseases 104.1 Mechanistic studies of amyloid fibril formation reveal common features, including pore-like protofibrils 104.1.1 Amyloid-β (Aβ) (Alzheimer's disease) 104.1.2 α-Synuclein (PD and diffuse Lewy body disease) 124.1.3 ABri (familial British dementia) 134.1.4 Superoxide dismutase-1 (amyotrophic lateral sclerosis) 134.1.5 Prion protein (Creutzfeldt–Jakob disease, bovine spongiform encephalopathy, etc.) 144.1.6 Huntingtin (Huntington's disease) 144.2 Amyloidogenic proteins that are not linked to disease also from pore-like protofibrils 154.3 Amyloid proteins form non-fibrillar aggregates that have properties of protein channels or pores 154.3.1 Aβ ‘channels’ 154.3.2 α-Synuclein ‘pores’ 164.3.3 PrP ‘channels’ 164.3.4 Polyglutamine ‘channels’ 174.4 Nature uses β-strand-mediated protein oligomerization to construct pore-forming toxins 175. Mechanisms of protofibril induced toxicity in protein aggregation diseases 195.1 The amyloid pore can explain the age-association and cell-type selectivity of the neurodegenerative diseases 195.2 Protofibrils may promote their own accumulation by inhibiting the proteasome 206. Testing the amyloid pore hypothesis by attempting to disprove it 217. Acknowledgments 228. References 22Protein fibrillization is implicated in the pathogenesis of most, if not all, age-associated neurodegenerative diseases, but the mechanism(s) by which it triggers neuronal death is unknown. Reductionist in vitro studies suggest that the amyloid protofibril may be the toxic species and that it may amplify itself by inhibiting proteasome-dependent protein degradation. Although its pathogenic target has not been identified, the properties of the protofibril suggest that neurons could be killed by unregulated membrane permeabilization, possibly by a type of protofibril referred to here as the ‘amyloid pore’. The purpose of this review is to summarize the existing supportive circumstantial evidence and to stimulate further studies designed to test the validity of this hypothesis.
Small molecules with antimicrobial activity against E. coli and P. aeruginosa identified by high‐throughput screening
Authors: De La Fuente R , Sonawane N D , Arumainayagam D , Verkman A S 
Published: September 2006

Background and purpose:New antimicrobials are needed because of the emergence of organisms that are resistant to available antimicrobials. The purpose of this study was to evaluate a high‐throughput screening approach to identify antibacterials against two common disease‐causing bacteria, and to determine the frequency, novelty, and potency of compounds with antibacterial activity.Experimental approach:A high‐throughput, turbidometric assay of bacterial growth in a 96‐well plate format was used to screen a diverse collection of 150,000 small molecules for antibacterial activity against E. coli and P. aeruginosa. The statistical Z′‐factor for the assay was 0.7.Key results:Screening for inhibition of E. coli growth gave a ‘hit’ rate (>60% inhibition at 12.5 μM) of 0.025%, which was more than 5‐fold reduced for P. aeruginosa. The most potent antibacterials (EC50<0.5 μM) were of the nitrofuran class followed by naphthalimide, salicylanilide, bipyridinium and quinoazolinediamine chemical classes. Screening of >250 analogs of the most potent antibacterial classes established structure‐activity data sets.Conclusions and Implications:Our results validate and demonstrate the utility of a growth‐based phenotype screen for rapid identification of small‐molecule antibacterials. The favourable efficacy and structure‐activity data for several of the antibacterial classes suggests their potential development for clinical use.British Journal of Pharmacology (2006) 149, 551–559. doi:10.1038/sj.bjp.0706873
Cholinergic regulation of epithelial ion transport in the mammalian intestine
Authors: Hirota C L , McKay D M 
Published: September 2006

Acetylcholine (ACh) is critical in controlling epithelial ion transport and hence water movements for gut hydration. Here we review the mechanism of cholinergic control of epithelial ion transport across the mammalian intestine. The cholinergic nervous system affects basal ion flux and can evoke increased active ion transport events. Most studies rely on measuring increases in short‐circuit current (ISC= active ion transport) evoked by adding ACh or cholinomimetics to intestinal tissue mounted in Ussing chambers. Despite subtle species and gut regional differences, most data indicate that, under normal circumstances, the effect of ACh on intestinal ion transport is mainly an increase in Cl‐secretion due to interaction with epithelial M3muscarinic ACh receptors (mAChRs) and, to a lesser extent, neuronal M1mAChRs; however, AChR pharmacology has been plagued by a lack of good receptor subtype‐selective compounds. Mice lacking M3mAChRs display intact cholinergically‐mediated intestinal ion transport, suggesting a possible compensatory mechanism. Inflamed tissues often display perturbations in the enteric cholinergic system and reduced intestinal ion transport responses to cholinomimetics. The mechanism(s) underlying this hyporesponsiveness are not fully defined. Inflammation‐evoked loss of mAChR‐mediated control of epithelial ion transport in the mouse reveals a role for neuronal nicotinic AChRs, representing a hitherto unappreciated braking system to limit ACh‐evoked Cl‐secretion. We suggest that: i) pharmacological analyses should be supported by the use of more selective compounds and supplemented with molecular biology techniques targeting specific ACh receptors and signalling molecules, and ii) assessment of ion transport in normal tissue must be complemented with investigations of tissues from patients or animals with intestinal disease to reveal control mechanisms that may go undetected by focusing on healthy tissue only.British Journal of Pharmacology(2006)149, 463–479. doi:10.1038/sj.bjp.0706889
Regional vascular responses to ATP and ATP analogues in the rabbit kidneyin vivo: roles for adenosine receptors and prostanoids
Authors: Eppel G A , Ventura S , Evans R G 
Published: September 2006

Background and purpose:Our knowledge of the effects of P2‐receptor activation on renal vascular tone comes mostly fromin vitromodels. We aimed to characterise the pharmacology of ATP in the renal circulationin vivo.Experimental approach:In pentobarbitone anaesthetized rabbits, we examined total renal and medullary vascular responses to ATP (0.2 and 0.8 mg kg‐1), β,γ‐methylene ATP (β,γ‐mATP, 7 and 170 μg kg‐1), α,β‐mATP (0.2 and 2 μg kg‐1) and adenosine (2 and 6 μg kg‐1) using transit‐time ultrasound and laser Doppler flowmetry, respectively. We also determined whether adenosine receptors, NO or prostanoids contribute to the actions of the purinoceptor agonists.Key results:Renal arterial boluses of ATP, β,γ‐mATP, and adenosine produced biphasic changes; ischaemia followed by hyperaemia, in total renal and medullary blood flow. α,β‐mATP induced only ischaemia. The adenosine receptor antagonist 8‐(p‐sulphophenyl)theophylline reduced the responses to adenosine and the hyperaemic responses to ATP and β,γ‐mATP only. NO synthase inhibition (Nω‐nitro‐L‐arginine) did not significantly alter responses to the P2 receptor agonists. Subsequent cyclooxygenase inhibition (ibuprofen) reduced the ATP‐ and β,γ‐mATP‐induced increases in renal blood flow. All other responses remained unchanged.Conclusions and implications:In the rabbit kidneyin vivo, α,β‐mATP sensitive receptors mediate vasoconstriction. β,γ‐mATP and ATP induce vasodilation at least partly through adenosine receptors. ATP induced renal vasodilatation is independent of NO and partly dependent on prostanoids in the bulk of the kidney, but not in the vasculature controlling medullary blood flow.British Journal of Pharmacology(2006)149, 523–531. doi:10.1038/sj.bjp.0706901
Repeated supratherapeutic doses of paracetamol in children—a literature review and suggested clinical approach
Authors: Kozer Eran , Greenberg Revital , Zimmerman Deena R. , Berkovitch Matitiahu 
Published: September 2006

AbstractThe safety of paracetamol when given in the recommended dosage is well documented. However, in recent years there have been many reports of liver failure associated with repeated exposure to supratherapeutic doses of paracetamol. This paper reviews the literature on chronic supratherapeutic paracetamol exposure in children and the different dosing guidelines. Based on which, we suggest the following approach: liver injury secondary to repeated dosing of paracetamol should be considered when a child has received more than 75 mg/kg/d for at least 2 d, or if risk factors for paracetamol toxicity have been identified. Liver transaminases, coagulation factors, and paracetamol serum concentrations should be measured in these children and in symptomatic children with vomiting, right upper quadrant abdominal pain, and jaundice who have taken paracetamol. Treatment with N‐acetyl cysteine should be started regardless of paracetamol concentrations if transaminases or INR are elevated. Conclusion: Liver injury secondary to repeated dosing of paracetamol is rare but may result in severe morbidity and mortality. The cumulative dose of paracetamol should not exceed 75 mg/kg/d. Children treated with higher doses for more than 2 d should be evaluated for possible liver injury and treated with N‐acetyl cysteine if evidence of liver injury is found.
Effect of a six‐month training programme on the physical capacities of Romanian schoolchildren
Authors: Serbescu Carmen , Flora Dorina , Hantiu Iacob , Greene David , Benhamou Claude Laurent , Courteix Daniel 
Published: September 2006

Abstract Aim: To analyse the effects of a training programme on the motor performance of Romanian schoolchildren. Methods: A total of 178 boys (9.5±0.8 y, 34±9 kg, 137.6±8 cm) and 192 girls (9.6±0.4 y, 32.7±7.6 kg, 136.9±7.5 cm) were randomly selected for the training group (TG) (n=198, 109 girls, 89 boys) and control group (CG) (n=172, 83 girls, 89 boys). The TG completed a 6‐mo extracurricular training programme (two 50‐min sessions per week) involving moderate‐intensity impact exercises. At baseline and at follow‐up, the EUROFIT tests were administered, and body composition, skeletal maturation and BMI were calculated. Results: At baseline there were no differences in physical characteristics between TG and CG. With the exception of cardiorespiratory endurance, both groups improved motor performances at follow‐up. However, for TG boys the improvement was greater than for CG boys in the plate‐tapping (+37.2%), sit‐up (+20.4%), standing broad‐jump (+13%) and shuttle‐run tests (+3.8%). TG girls improved more than CG girls only in the standing broad‐jump (+18.8%) and shuttle‐run (+8.5%) tests. Conclusion: Boys and girls in trained groups demonstrated greater increases in some tests of motor performance compared to their untrained peers. Two extra sessions of physical education per week were sufficient to elicit improvements in a number of components of motor fitness.
Impact of grazing around a watering point on soil status of a semi‐arid rangeland in Ethiopia
Authors: Gebremeskel Kidane , Pieterse P. J. 
Published: September 2006

AbstractThe influence of long‐term livestock grazing on the soil status of a semi‐arid rangeland was studied along a grazing gradient from a watering point in southern Afar Region of Ethiopia for two seasons. The soil samples were analysed for organic carbon (OC), total nitrogen (N), available phosphorus (P), exchangeable cations (Ca2+, Mg2+, K+ and Na+), acidity (pH), cation exchange capacity, and particle size distribution (clay, silt and sand). No significant differences (P > 0.05) were observed for particle size distribution, OC, N, P and K contents along the grazing gradient further than 1500 m from the watering point. Ca2+ and Mg2+ were found to be dominant cations particularly in the severely degraded area contributing about 74% to the exchangeable cations. The study has also recognized high concentrations of Na+ and more than 11% exchangeable sodium percentage. Total exchangeable bases significantly declined (P < 0.05) along the grazing gradient and were indicative of the exchange complex of the soil being saturated with Ca2+ and Mg2+ ions. Thus this study concluded that there are soil differences in the grazing gradient caused by impact of grazing, particularly in the severely degraded area.
Marker‐assisted selection based on a multi‐trait economic index in chicken: experimental results and simulation
Authors: Lahav T. , Atzmon G. , Blum S. , Ben‐Ari G. , Weigend S. , Cahaner A. , Lavi U. , Hillel J. 
Published: September 2006

SummaryA method proposed herein allows simultaneous selection for several production traits, taking into consideration their marginal economic values (i.e. the economic value of a trait's additional unit). This economic index‐marker assisted selection (EI‐MAS) method is based on the calculation of the predicted economic breeding value (BV), using information on DNA markers that have previously been found to be associated with relevant quantitative trait loci. Based on the proposed method, results with real birds showed that sire progeny performance was significantly correlated with expected performance (r = 0.61–0.76; P = 0.03–0.01). Simulation analysis using a computer program written specifically for this purpose suggested that the relative advantage of EI‐MAS would be large for traits with low heritability values. As expected, the response to EI‐MAS was higher when the map distance between the marker and the quantitative trait gene was small, and vice versa. A large number of distantly located markers, spread 10 cM apart, yielded higher response to selection than a small number of closely located markers spread 3 cM apart. Additionally, the response to EI‐MAS was higher when a large number (ca.150) of progeny was used for the prediction equation.
Comparison of DNA variants in the PRNP and NF1 regions between bovine spongiform encephalopathy and control cattle
Authors: Geldermann H. , He H. , Bobal P. , Bartenschlager H. , Preuß S. 
Published: September 2006

SummaryDNA from 252 bovine spongiform encephalopathy (BSE) cattle and 376 non‐diseased control cattle were genotyped for nine loci in the prion protein (PRNP) gene region, three loci in the neurofibromin 1 (NF1) region and four control loci on different chromosomes. The allele and genotype frequencies of the control loci were similar in BSE and control cattle. In the analysed 7.4 Mb PRNP region, the largest differences between BSE and control cattle were found for the loci REG2, R16 and R18, which are located between +300 and +5600 bp, spanning PRNP introns 1 to 2. Carriers of the REG2 genotype 128/128 were younger at BSE diagnosis than those with the other genotypes (128/140 or 140/140). The predominant haplotype REG2 128 bp–R18 173 bp occurred more frequently (P < 0.001), and the second‐most frequent haplotype (REG2 140 bp–R18 175 bp) occurred less frequently (P < 0.05) in BSE than in control cattle. The largest frequency differences between BSE and control groups were observed in the Brown Swiss breed. Across all breeds, most of the same alleles and haplotypes of the PRNP region were associated with BSE. In the 23‐cM NF1 region, associations with BSE incidence were found for the RM222 allele and for the DIK4009 genotype frequencies. Cattle carrying RM222 genotypes with the 127‐ or 129‐bp alleles were about half a year older at BSE incidence than those with other genotypes. Across the breeds, different alleles and genotypes of the NF1 region were associated with BSE. The informative DNA markers were used to localize the genetic disposition to BSE and may be useful for the identification of the causative DNA variants.
Do the limits of serum prolactin in disconnection hyperprolactinaemia need re‐definition? A study of 226 patients with histologically verified non‐functioning pituitary macroadenoma
Authors: Karavitaki Niki , Thanabalasingham Gaya , Shore Helena C. A. , Trifanescu Raluca , Ansorge Olaf , Meston Niki , Turner Helen E. , Wass John A. H. 
Published: September 2006

SummaryBackground  The differentiation of a pituitary non‐functioning macroadenoma from a macroprolactinoma is important for planning appropriate therapy. Serum PRL levels have been suggested as a useful diagnostic indicator. However, values between 2500 and 8000 mU/l are a grey area and are currently associated with diagnostic uncertainty.Objective  We wished therefore, to investigate the serum PRL values in a large series of patients presenting with apparently non‐functioning pituitary macroadenomas.Patients and methods  All patients presenting to the Department of Endocrinology in Oxford with clinically non‐functioning pituitary macroadenomas (later histologically verified) between 1990 and 2005 were studied. Information documented in the notes on the medications and on the presence of conditions capable of affecting the serum PRL levels at the time of blood sampling was also collected.Results  Two hundred and twenty‐six patients were identified (median age at diagnosis 55 years, range 18–88 years; 146 males/80 females; 143 gonadotroph, 46 null cell, 25 plurihormonal and 12 silent ACTH adenomas). All tumours had suprasellar extension. At the time of blood sampling 41 subjects were taking medications capable of increasing serum PRL. Hyperprolactinaemia was found in 38·5% (87/226) of the patients. The median serum PRL values in the total group were 386 mU/l (range 16–3257) (males: median 299 mU/l, range 16–1560; females: median 572 mU/l, range 20–3257) and in those not taking drugs capable of increasing serum PRL 363 mU/l (range 16–2565) (males: median 299 mU/l, range 16–1560; females: median 572 mU/l, range 20–2565). Serum PRL < 2000 mU/l was found in 98·7% (223/226) of the total group and in 99·5% (184/185) of those not taking drugs. Among the three subjects with serum PRL > 2000 mU/l, two were taking oestrogen preparations.Conclusions  Based on a large series of histologically confirmed cases, serum PRL > 2000 mU/l is almost never encountered in nonfunctioning pituitary macroadenomas. Values above this limit in the presence of a macroadenoma should not be surrounded by diagnostic uncertainty (after acromegaly or Cushing's disease have been excluded); a prolactinoma is the most likely diagnosis and a dopamine agonist should be considered as the treatment of choice.
Drug dosing in children – special considerations
Authors: PENCHARZ P. B. 
Published: September 2006

Summary.  During growth the body composition, protein and energy metabolism of children changes. This paper aims to assess these changes as they relate to factors which might affect the metabolism of factor concentrates, through a review of body composition, protein and energy metabolism literature in childhood.Key findings were that protein metabolism is four times higher in neonates and twice as high in infants as compared with adults. In addition the interstitial fluid space in infants and younger children is approximately double that in adults. On the basis that protein metabolism relates most closely to lean body mass, which in turn relates to body weight one can conclude that factor concentrate doses should be based on body weight.We concluded that clearance of protein factor concentrates might be faster in infants and young children due to their higher protein turnover rate.
Work‐related fatigue and recovery: the contribution of age, domestic responsibilities and shiftwork
Authors: Winwood Peter C. , Winefield Antony H. , Lushington Kurt 
Published: September 2006

Aim.  This paper reports a study of the relationship between age, domestic responsibilities (being partnered and having dependents), recovery from shiftwork‐related fatigue and the evolution of maladaptive health outcomes among full‐time working female nurses.Background.  Several studies have suggested that full‐time working women with family responsibilities are at greater risk of developing work‐related fatigue problems than single women without these responsibilities.Method.  A questionnaire was distributed in 2004 to 2400 nurses at two hospitals in Australia, and 1280 responses were obtained (response rate 54%). The data from a purposive sample of 846 full‐time working nurses are reported here.Findings.  Domestic responsibilities were not related to differences in fatigue and recovery. Our results suggested that for full‐time shiftworking nurses, being part of a family structure, may actually be protective against the development of maladaptive fatigue. The most important factor determining maladaptive fatigue outcome was shift pattern worked, particularly rotation including night duty. The effect of age was equivocal. The youngest age group reported the highest fatigue and poorest recovery compared to the oldest group, who reported the best characteristics. However, this latter group may represent a particularly well‐adapted ‘survivor cohort’. The relationship between age and fatigue was partly confounded by older, experienced, nurses with greater job responsibilities, working fewer multiple shifts including night duty. In general, increasing age was not associated with poorer recovery or higher maladaptive fatigue.Conclusions.  Unpredictable internal shift rotations, including night duty, which are traditional and typical in nursing, are inimical to maintaining nurses’ health. More creative approaches to rostering for nurses working multiple shifts are a necessary step towards reducing wastage from the profession due to chronic work‐related fatigue. Younger nurses in particular, may need more support than is currently recognized if they are to be retained within the profession.