bluuebunny/crossref_metadata_2025 huggingface dataset:
Depositional wedge tops: interaction between low basal friction external orogenic wedges and flexural foreland basins
Authors: Ford Mary
Published: August 2004

Growth structures develop mainly across depositional wedge tops where the top of the distal orogenic wedge lies below local base level within the flexural foreland basin. Documented examples indicate that optimum conditions for the development of a depositional wedge top occur when the dip of the upper surface of the outer orogenic wedge (α) is low (0–1°), regardless of the taper angle (α+β), where β is the inclination of the base of the wedge. Low α angles are associated with the presence of low friction décollements, usually salt. Therefore, depositional wedge tops develop most commonly on low basal friction wedges. In natural examples such as the northern Apennines, the South Central Pyrenees and the Zagros, it is shown that whereas α is consistently low, β can vary considerably (1–9°), being principally controlled by flexure of the lower plate. In addition, the distribution of deformation in the wedge is complex. The applicability of the critical wedge model to low basal friction external orogenic zones is examined. Neither taper angles, nor the complex distribution of internal deformation nor the often associated forward slip of the whole wedge, can be satisfactorily explained by the established critical wedge model. As weak detachments such as salt cannot support any significant topography, it follows that low basal friction wedges cannot attain a critical state and, therefore, the critical wedge model cannot be satisfactorily applied to these external orogenic systems. This model, however, explains well the behaviour of external orogenic wedges with high basal friction. In the analysis of orogenic wedges, separate analysis of the angles α and β proves more useful than the critical taper angle α+β.
Role of crustal anisotropy in modifying the structural and sedimentological evolution of extensional basins: the Gamtoos Basin, South Africa
Authors: Paton Douglas A. , Underhill John R.
Published: August 2004

Through the investigation of crustal heterogeneities, sedimentary basin architecture and seismic stratigraphy, we demonstrate how a crust‐scale anisotropy controls the initiation of rifting and the subsequent structural and sedimentological evolution of the Mesozoic Gamtoos Basin, southern South Africa. The results demonstrate that the >90‐km‐long Gamtoos Fault established its length very early in its syn‐rift phase (within ∼5 Ma of rift initiation) before accruing over 6 s (two‐way‐travel time (TWT)), or >12 km, of displacement without any significant subsequent increase in length. In addition, there is no evidence at the resolution of the data of fault segmentation, isolated depocentres nor of intra‐basin faults progressively coalescing during the syn‐rift interval. The early establishment of length resulted in a rapid transition from a terrestrial depositional environment to anoxic, deep marine conditions. The Gamtoos Fault has a 90° bend in the fault trace that we propose is inherited from the underlying structure. Immediately adjacent to the bend the basin‐fill is significantly deformed and a high‐amplitude (>1.7s TWT) monoclinal fold is observed. Previous workers proposed that the fold was a consequence of a complex interplay between compression and extension. Through a restoration of the basin‐fill deformation we produce a model that suggests that the fold is a consequence of the accommodation of extension by the unusual plan‐view trace of the fault. The evolution of the basin does not conform to current fault growth models and it is proposed that its unusual and complex development can be attributed to the underlying crustal‐scale anisotropy, a fact that is likely to be important in other areas in which crustal stretching is superimposed on heterogeneous continental crust.
Detrital thermochronology – a new perspective on hinterland tectonics, an example from the Andean Amazon Basin, Ecuador
Authors: Ruiz G. M. H. , Seward D. , Winkler W.
Published: August 2004

In order to understand the significance of detrital grain ages in sedimentary basins, a new approach is presented. Five characteristic paths, identified by the change in age of detrital grain populations combined with the change in lagtime over time, can be related to different geodynamic settings in the source regions. When lagtime and grain age increase over time, a change in source must be invoked – this is usually a direct response to a geological event. A constant cooling age, a vertical path, associated implicitly with increasing lagtime, implies erosion of materials that had passed through the closure temperature rapidly – exhuming sufficient rock to supply detritus over the time of the path. Constant lagtimes, regardless of the lagtime itself, are indicative of thermochronological stability in the source region. This can involve fast or slow cooling. Finally, decreasing lagtimes support the notion of increasing cooling rates in the source regions over time. A test study is presented from sediments of the northern Ecuadorian Sub‐Andean Zone where geological events had previously been identified using alternative methods. The addition of heavy‐mineral studies increased the precision in the interpretation. At 90 Ma, rapidly decreasing lagtimes point to a phase of tectonic activity. From about 85 Ma until about 60 Ma the lagtimes were approximately zero. This represents a phase of rapid exhumation of the source regions correlating with the previously identified Pallatanga event. An associated increase of metamorphic minerals occurs over this time span, pointing to increased erosion from deeper horizons. At about 70 Ma, the oldest source region, the shield to the east, was switched off. This timing correlates with a change from marine to continental conditions in the basin, a change in palaeocurrent directions from the east to the west, as well as an associated influx of material from the growing Cordillera Real. At about 55 Ma, a change in source is identified by a change in slope of the lagtime curve together with a change in heavy minerals. From 50 to 35 Ma a renewed period of tectonism in the source region is correlated with the docking of the Macuchi terrane which clearly had an effect of increased erosion in the Cordillera Real bringing in higher grade metamorphic minerals. From about 32 Ma onwards the lagtime has been somewhat constant at about 30 Myr. This does not imply, however, a steady‐state environment as it is well known from other geological evidence that there have been other events within this time frame. One must be cautious about over‐interpreting the lagtime as a method to determine steady state in any region. It is a matter of scale.
First‐trimester exposure to amoxycillin/clavulanic acid: a prospective, controlled study
Authors: Berkovitch Matitiahu , Diav‐Citrin Orna , Greenberg Revital , Cohen Michal , Bulkowstein Mordechai , Shechtman Svetlana , Bortnik Oxana , Arnon Judy , Ornoy Asher
Published: August 2004

Aims

The number of published studies on the use of amoxycillin/clavulanic acid during pregnancy is small and so is the number of pregnancies investigated in those studies. In this study we wished to investigate prospectively the safety of intrauterine exposure to amoxycillin/clavulanic acid in a relatively large cohort of women.

Methods

Women treated (n = 191) with amoxycillin/clavulanic acid during the first trimester of pregnancy were recruited from two teratogen information centres in Israel. Exposed women were matched for age, smoking habits and alcohol consumption with 191 controls exposed to amoxycillin only for similar medical indications.

Results

Maternal age, birth weight, gestational age at delivery, rates of live births and abortions were comparable between the two groups. Rates of major malformations in the amoxycillin/clavulanic acid group (3/158, 1.9%) did not differ significantly from controls (5/163, 3%) (P = 0.49, relative risk = 0.62, 95% confidence interval 0.15, 2.55), and were within the expected baseline risk for the general population.

Conclusion

These data suggest that exposure to amoxycillin/clavulanic acid during pregnancy is unlikely to be associated with an increased risk of malformations.
Intravenous indometacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study
Authors: Smyth J. M. , Collier P. S. , Darwish M. , Millership J. S. , Halliday H. L. , Petersen S. , McElnay J. C.
Published: August 2004

Aims

To characterize the population pharmacokinetics of indometacin in preterm infants with symptomatic patent ductus arteriosus and to investigate the influence of various factors on the response to treatment.

Methods

Data were collected from 35 infants (gestational age 25–34 weeks; postnatal age 1–77 days) in neonatal units in Belfast and Copenhagen. Infants received an initial course of up to three doses of intravenous indometacin (0.1–0.2 mg kg−1) as considered appropriate by the treating physician. For those infants who did not respond to therapy or in whom the ductus reopened, a second course was sometimes given. Population analysis of the 185 plasma concentrations obtained was conducted using NONMEM and pharmacokinetic and demographic differences between responders and nonresponders were compared.

Results

The concentration‐time course of indometacin was best described by a one‐compartment model. The final population parameter estimates of clearance (CL) and volume of distribution (V) (standardized to the median weight of 1.17 kg) were 0.00711 l h−1 and 0.266 l, respectively. CL increased from birth by approximately 3.38% per day and V by approximately 1.47% per day. Concomitant digoxin therapy resulted in a 30% decrease in V. Interindividual variability in CL and V was 41% and 21%, respectively. Interoccasion variability for CL was 43%. Residual variability corresponded to a standard deviation of 0.148 mg l−1. Closure occurred in 75% of infants with a plasma concentration ≥ 0.4 mg l−1 24 h after the last dose.

Conclusions

Dosing regimens for indometacin should take into account the weight and postnatal age of the infant and any concomitant digoxin therapy. The population estimates can be used to determine typical values of CL and V allowing the prediction of individualized doses of indometacin that should increase the probability of achieving a 24 h plasma concentration ≥ 0.4 mg l−1. Although the pharmacokinetic estimates will be affected by both interindividual and within‐individual variation, it is anticipated that this approach will decrease the variability of exposure and optimize treatment outcome.
Can coadministration of oxycodone and morphine produce analgesic synergy in humans? An experimental cold pain study
Authors: Grach Michael , Massalha Wattan , Pud Dorit , Adler Rivka , Eisenberg Elon
Published: August 2004

Aims

The coadministration of subantinociceptive doses of oxycodone with morphine has recently been shown to result in a synergistic antinociceptive effect in rats. The present study was aimed to investigate the possibility that coadministration of morphine and oxycodone can produce a similar synergistic effect in humans exposed to an experimental model of cold pressor test (CPT).

Methods

The enriched enrolment design was used to exclude ‘stoic’ and ‘placebo responders’ in a single‐blind fashion. ‘Nonstoic’, placebo ‘nonresponder’ female volunteers (n = 30) were randomly assigned to receive 0.5 mg kg−1 oral morphine sulphate, 0.5 mg kg−1 oral oxycodone hydrochloride, and the combination of 0.25 mg kg−1 morphine sulphate with 0.25 mg kg−1 oxycodone hydrochloride, 1 week apart from each other, in a double‐blind crossover design. Latency to pain onset (threshold), pain intensity (VAS), and pain tolerance (time until removal of the hand from the water) were measured six times over a 3‐h period, subsequent to the administration of each medication, and were used to assess their antinociceptive effect.

Results

The combination produced a significantly higher effect on latency to pain onset than that of morphine alone [difference in mean postbaseline value 2.2; 95% confidence interval (CI) 0.48, 3.9; P = 0.01] but the effect was nonsignificantly smaller that that of oxycodone alone. Similarly, the effect of the combination on pain tolerance was significantly larger than that of morphine alone (combination difference 8.4; 95% CI 2.5, 14.3; P = 0.007), whereas oxycodone alone caused a nonsignificantly larger effect than that of the combination treatment. Comparisons of pain magnitude failed to show any significant differences between the three treatments.

Conclusions

These results indicate that at the doses tested, morphine and oxycodone do not produce synergistic antinociceptive effects in healthy humans exposed to the CPT.
Venetian treacle and the foundation of medicines regulation
Authors: Griffin J. P.
Published: August 2004

Mithridatium and the related product Theriac were both regarded from the time of their original formulations in the 2nd Century BC and the 1st Century AD respectively, until the mid 18th Century as universal panaceas. Any failure of these products to achieve the desired therapeutic result was attributed to defective composition or manufacture. As a result measures were introduced to ensure the quality of ingredients used in these products composition, the establishment of standard formulations and assurance of the competence of the manufacturer. Manufacture frequently was required to take place in public.

Doubts about the efficacy of these panaceas arose in the mid 18th century and concerns of the adverse nature of interactions between the numerous ingredients surfaced in Heberden's treatise of 1745, as result of which these products disappeared from Editions of The London Pharmacopoeia after 1746. Subsequently, arising from these concerns for safety and efficacy, a call was made in 1799 for the establishment of a Public Committee of eminent physicians to scrutinise all new products prior to their launch to an gullible public. The concepts developed in the history of Mithridatium form the basis of modern medicines regulation.
Characterization of human cytochrome P450 enzymes catalyzing domperidone N‐dealkylation and hydroxylation in vitro
Authors: Ward Bryan A. , Morocho Alan , Kandil Abdullah , Galinsky Raymond E. , Flockhart David A. , Desta Zeruesenay
Published: August 2004

Aims

To confirm the identity of the major metabolites of domperidone and to characterize the cytochrome P450s (CYPs) involved in their formation.

Methods

Human liver microsomes (HLMs) were used to characterize the kinetics of domperidone metabolism and liquid chromatography‐mass spectrometry to identify the products. Isoform‐specific chemical inhibitors, correlation analysis and expressed human CYP genes were used to identify the CYPs involved in domperidone oxidation.

Results

In HLMs, domperidone underwent hydroxylation to form 5‐hydroxydomperidone (MIII) and N‐dealkylation to form 2,3‐dihydro‐2‐oxo‐1H‐benzimidazole‐1‐propionic acid (MI) and 5‐chloro‐4‐piperidinyl‐1,3‐dihydro‐benzimidazol‐2‐one (MII). The formation of all three metabolites (n = 4 HLMs) followed apparent Michaelis‐Menten kinetics. The mean Km values for MI, MII and MIII formation were 12.4, 11.9, and 12.6 µm, respectively. In a panel of HLMs (n = 10), the rate of domperidone (5 µm and 50 µm) metabolism correlated with the activity of CYP3A (r > 0.94; P < 0.0001). Only ketoconazole (1 µm) (by 87%) and troleandomycin (50 µm) (by 64%) inhibited domperidone (5 µm) metabolism in HLMs. Domperidone (5 and 50 µm) hydroxylation and N‐dealkylation was catalyzed by expressed CYP3A4 at a higher rate than the other CYPs. CYP1A2, 2B6, 2C8 and 2D6 also hydroxylated domperidone

Conclusions

CYP3A‐catalyzed N‐dealkylation and aromatic hydroxylation are the major routes for domperidone metabolism. The drug would be expected to demonstrate highly variable bioavailability due to hepatic, and possibly intestinal first‐pass metabolism after oral administration. Increased risk of adverse effects might be anticipated during concomitant administration with CYP3A inhibitors, as well as decreased efficacy with inducers of this enzyme.
Stress levels experienced by the parents of enterally fed children
Authors: Pedersen S. D. , Parsons H. G. , Dewey D.
Published: August 2004

Background  The stress levels of parents of children with chronic illness/disability who were also involved in an enteral feeding programme were examined and compared to the stress levels of parents of healthy children and parents of children with other chronic illnesses reported in previous research.

Methods  Sixty‐four parents who had a child with an enteral feeding tube completed the Parenting Stress Index (PSI).

Results  Based on criteria developed by Abidin (1995), 42.18% (n = 29) of these parents displayed high stress levels. T‐tests revealed that Total Stress scores on the PSI of the parents of children involved in the enteral feeding programme were significantly higher than those reported in the sample of parents used to norm the PSI (P < 0.001), and comparison samples of parents of children with growth deficiencies (P < 0.001) and parents of children with insulin‐dependent diabetes mellitus (P < 0.01). Compared to a sample of parents of children with Rett syndrome, the parents of children involved in the enteral feeding programme reported similar levels of stress on the Parent Domain of the PSI and significantly less stress on the Child Domain (P < 0.001).

Conclusions  Factors associated with the stress reported by parents of children with an enteral feeding tube were severity of their child's illness/disability, the constant caretaking demands placed on the parent, and the level of support provided by the parents’ social network.
Screening for language delay in the United Arab Emirates
Authors: Eapen V. , Zoubeidi T. , Yunis F.
Published: August 2004

Background  Developmental language delay (DLD) is frequent among two‐ and three‐year‐olds but little is known about this condition in the Arabian Peninsula. This paper forms part of a multipurpose community psychiatric survey conducted in the United Arab Emirates (UAE). The findings regarding the prevalence and psychosocial correlates of DLD are reported here.

Methods  A total of 694 children, representative of the UAE 3‐year‐old population were screened using the Denver Developmental Screening Test (DDST) and the language screening procedure as used by Westerlund and Sundelin.

Results  Of the 694 children screened for DLD at 3 years of age, 69 children (9.9%; CI 7.8–12.4) were found to have delays in the language sector of DDST. A total of 45 (6.5%; CI 4.3–8.7) were identified as having general language disability, both in comprehension and expression as per the language screening procedure. Language delay was found to be associated with rural living, mother being from a different nationality, non‐involvement of domestic help in child care, family history of language delay, obstetric and perinatal problems and presence of behavioural problems in the child. Using stepwise multiple logistic regression analysis, two factors emerged as important with regard to general language delay, which were previous non‐UAE nationality of the mother and total monthly income of the family.

Conclusion  The pattern and correlates of DLD found in this survey are in line with those reported by other surveys, but some unique socio‐cultural risk factors specific to this community were identified. The implications of these findings to screening and referral for further evaluation and intervention are discussed.
Quality of motor performance in preterm and full‐term 3‐year‐old children
Authors: Hemgren E. , Persson K.
Published: August 2004

Background  A combined assessment of motor performance and behaviour (CAMPB) was introduced previously for use in a longitudinal study of children who needed neonatal intensive care (NIC) and were born very preterm (n = 68), moderately preterm (n = 81) and full‐term (n = 77) and in a reference group of neonatally healthy full‐term children (n = 72).

Aim  To follow up the quality of motor performance at 3 years of age in the above groups of children.

Method  A detailed assessment of motor performance and an assessment of co‐ordination were performed according to the CAMPB protocol. The results were compared between the different groups of children, and the relation between the two ways of assessing quality of motor performance was examined.

Results  The detailed assessment showed that the very preterm children had a significantly higher total score of deviations than any of the other gestational age groups of children. Also, some types of deviations were much more frequently observed in the very preterm children than in the other three groups. Some types of deviations were more often seen in children with pronounced incoordination than in children with no incoordination. The results from the two ways of assessing motor performance were strongly correlated.

Conclusion  At 3 years of age, NIC children born very preterm have a lower quality of motor performance than NIC children born at a higher gestational age and healthy children born at term. The two ways of assessing quality of motor performance proved useful in identifying children with deviations indicating minor motor impairments.
Good practices that address continuity during transition from child to adult care: synthesis of the evidence
Authors: While A. , Forbes A. , Ullman R. , Lewis S. , Mathes L. , Griffiths P.
Published: August 2004

Background  Effective transition to adult services is required by an increasing number of children with ongoing needs.

Aim  To identify practices that promote continuity at transition between child and adult services.

Methods  Systematic examination of the evidence from two search strategies yielding 5319 items.

Results  Only three of the 126 appraised items had strong external validity. A large range of different practices, which focused on the service, the young person and the family, were identified. Practices within the service addressed structural, process and outcome components.

Conclusion  Four transition models are proposed for testing.
Evaluating children's rehabilitation services: an application of a programme logic model
Authors: Stewart D. , Law M. , Russell D. , Hanna S.
Published: August 2004

Objectives  To apply a programme logic model to evaluate the effectiveness of a new therapy service for children with special needs who were in transition from pre‐school to kindergarten.

Setting  A children's outpatient rehabilitation centre in Ontario, Canada.

Main outcomes  The short‐term outcomes included parents’ perceptions of the transition process itself and the information they required, the children's skill development for the transition to kindergarten, and parents’ perceptions of services and satisfaction with resources.

Methods  A combination of quantitative methods [Goal Attainment Scaling (GAS), Measure of Processes of Care (MPOC), Client Satisfaction Questionnaire (CSQ)] and qualitative interviews were used to evaluate both the process (‘Outputs’) and outcomes (‘Short‐term objectives’) of the new therapy service.

Results  The children involved in the evaluation met or exceeded goals that were set by therapists and parents. Parents’ perceptions of, and satisfaction with, the new service were higher than the provincial average. Qualitative data from interviews with parents and service providers supported the findings from standardized measures, and provided suggestions for future service delivery.

Conclusions  The programme logic model provided researchers and service providers a collaborative and systematic approach to conducting programme evaluation in a relatively short‐time frame. It appears to be a useful option for evaluation of other children's services.
Provision for children with developmental co‐ordination disorder (DCD): audit of the service provider
Authors: Peters J. M. , Henderson S. E. , Dookun D.
Published: August 2004

Background  The aim of this study was to conduct an audit of parent/carer satisfaction with the service provided for children presenting with movement difficulties [developmental co‐ordination disorder (DCD)/dyspraxia] at the out‐patient physiotherapy clinic of a specialist tertiary referral paediatric hospital.

Method  A postal questionnaire was used to obtain objective and subjective data on the service offered. Factual information on aspects such as waiting time for first appointment, type of intervention offered, etc. was checked against clinical records. Satisfaction with the service was assessed using ratings and open‐ended comment.

Results  Forty‐five families completed the questionnaire. The results showed that the service was generally rated highly. The opportunity to discuss the child's problems and its implications was considered valuable. Among families offered 1 : 1 intervention, a statistically significant correlation emerged between the number of sessions attended and perceived effectiveness. Among families offered a home programme, perceived effectiveness was related to the number of times per week the child practised the programme.

Conclusions  This study showed that many children from mainstream schools with co‐ordination problems continued to find it difficult to obtain a clear diagnosis. Once a referral and assessment had been achieved, however, parents/carers were shown to be satisfied with the package offered by this service provider.
Gender in discourse behaviour in parent–child dyads: a literature review
Authors: Lanvers U.
Published: August 2004

Background  This literature review on gender differences in child–parent interaction links two types of research bodies gathered over the last decades, on the one hand early between‐child and within‐child differences, and, on the other hand, parental discourse differences with children.

Method  Relevant individual studies, as well as two meta‐analyses investigating gender in child–parent dyadic interaction, are evaluated, addressing differences in parental gender and child gender, early evidence of child gender differences in discourse, and child adaptations to interlocutors in general. Methodological problems of data gathering of both child and parental language are discussed, as well as the logical caveats of linking input to acquisition patterns.

Result  The findings allow no final conclusion regarding the issue of early gender socialization through language but indicate two contrasting hypotheses concerning the importance of early gendered linguistic interaction.

Conclusion  The paper concludes with a discussion of research designs which might allow further differentiation between existing theoretical accounts of early gender socialization through language.
National survey of Patient Advice and Liaison Services (PALS) in England: children, young people and parents’ access to and use of PALS
Authors: Heaton J. , Sloper P.
Published: August 2004

Background  Patient Advice and Liaison Services (PALS) have been set up in the National Health Service (NHS) in England to enable patients and the public to access information and raise issues they are concerned about their health care. The aim of this study was to examine to what extent, and how, PALS have promoted children’s, young people's and parents’ access to and use of the service.

Methods  A postal questionnaire was sent to PALS in 553 NHS Trusts and Primary Care Trusts (PCTs). PALS in Ambulance Trusts, and Specialist Trusts that were known not to provide services for children and young people, were excluded.

Results  Questionnaires were returned by 320 respondents representing 369 trusts – a response rate of 67%. Seventy‐seven responses were not valid, giving a final sample of 243 PALS. This included 122 PALS serving PCTs, 101 serving NHS Trusts, 15 serving a mix of both PCTs and NHS Trusts, and five serving children's hospitals. The responses suggest that, to date, most PALS have been developed as a generic service, with some making special efforts to target specific groups of patients and sections of the public. However, where such efforts have been made, they have tended to focus most of all on older people and least of all on children.

Conclusions  PALS are intended to serve all sections of the community and accordingly need to be developed in ways that ensure the service is accessible to hard‐to‐reach groups such as children and young people. The remainder of the research will examine children, young people and parents’ perspectives on how PALS can involve them, and will provide associated guidelines for trusts.
Primary care clinicians’ use of standardized psychiatric diagnoses
Authors: Gardner W. , Kelleher K. J. , Pajer K. A. , Campo J. V.
Published: August 2004

Objective  Treatment of child mental health (MH) problems should be informed by psychiatric diagnosis. Whether primary care clinicians (PCCs) use standardized psychiatric diagnostic criteria to direct the treatment of child MH problems is unknown. This study investigated PCCs’ use of Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria during office visits.

Methods  The data were obtained from 3674 children ages 4–15 years who were recognized as having one or more MH problems during office visits by clinicians participating in the Child Behaviour Study. Parents completed questionnaires before seeing the clinician. Clinicians completed a survey after the visit. The primary outcome was whether PCCs used standardized criteria to generate a diagnosis for children with recognized MH problems.

Results  Clinicians used DSM criteria in 23% of visits in which a psychosocial problem was recognized, and 57% of PCCs reported no use of DSM. DSM criteria were used most frequently (38% of visits) when PCCs reported attention problems. Medications were much more likely to be prescribed during visits when PCCs diagnosed using DSM criteria (63% of visits vs. 19% when criteria were not used). However, only 51% of psychotropic medication prescriptions were based on a DSM diagnosis.

Conclusions  Clinicians used standardized criteria infrequently, and primarily to diagnose attention problems.
Learning and behavioural difficulties but not microcephaly in three brothers resulting from undiagnosed maternal phenylketonuria
Authors: Shaw‐Smith C. , Hogg S. L. , Reading R. , Calvin J. , Trump D.
Published: August 2004

Universal screening introduced in the 1960s has reduced the incidence of learning disability resulting from phenylketonuria (PKU), which is a treatable condition. Nonetheless, PKU may still be having an impact on the paediatric‐age population. We report a woman with previously undiagnosed PKU who was born before the onset of universal screening. She is of normal intelligence, and so the diagnosis was not suspected until after the birth of her three children. Her serum phenylalanine concentration was found to be in excess of 1 mmol/L, well into the toxic range. She has had three sons, all of whom have a significant degree of learning disability resulting from intrauterine exposure to toxic levels of phenylalanine. None of the sons had microcephaly, a physical sign that, if present, might have helped to point towards the correct diagnosis. We suggest that maternal PKU should be suspected where there is sibling recurrence of cognitive impairment, particularly where the mother was born before the initiation of the neonatal screening programme for PKU.
A national evaluation of school breakfast clubs: evidence from a cluster randomized controlled trial and an observational analysis
Authors: Shemilt I. , Harvey I. , Shepstone L. , Swift L. , Reading R. , Mugford M. , Belderson P. , Norris N. , Thoburn J. , Robinson J.
Published: August 2004

Study objective  To measure the health, educational and social impacts of breakfast club provision in schools serving deprived areas across England.

Design  A cluster randomized controlled trial and an observational analysis.

Setting  England, the UK. Intervention: funding to establish a school‐based breakfast club vs. control (no funding).

Main results  Intention to treat analysis showed improved concentration (Trail Making Test Part A) amongst the intervention group at 3 months. Fewer pupils within the intervention group reported having skipped classes within the last month and fewer pupils within the intervention group reported having skipped 1 or more days of school within the last month at 1 year. Observational analysis at 1 year showed a higher proportion of primary‐aged breakfast club attendees reported eating fruit for breakfast in comparison to non‐attendees. A higher proportion of breakfast club attendees had borderline or abnormal conduct and total difficulties scores (primary‐aged pupils) and prosocial score (secondary‐aged pupils).

Conclusions  Analyses revealed a mixed picture of benefit and apparent disbenefit. This study illustrated the challenges of evaluating a complex intervention in which the evaluators had less control than is usual in randomized trials over recruitment, eligibility checking and implementation. If the impact of new policy initiatives is to be assessed using the most robust forms of evaluation, social policy needs to be organized so that evaluations can be constructed as experiments. This is likely to prove most difficult where the perceived value of implementing an intervention rapidly is high.
A national evaluation of school breakfast clubs: where does economics fit in?
Authors: Shemilt I. , Mugford M. , Moffatt P. , Harvey I. , Reading R. , Shepstone L. , Belderson P.
Published: August 2004

Study objective  To describe the economics of UK school breakfast clubs, to estimate costs resulting from clubs and to investigate relationships between costs and outcomes.

Design  A postal survey of schools with a 1‐year follow‐up, a cluster randomized controlled trial, case studies, semi‐structured interviews with parents and a secondary econometric analysis.

Setting  England, the UK.

Main results  Key economic differences were identified between clubs based in primary schools and those based in secondary schools in terms of both funding levels and cost structures. However, funding levels were not a significant determinant of the observed outcomes in either type of school.

Conclusions  For formal economic evaluation to succeed during implementation of a new initiative, a clearer understanding of relevant outcomes and the distinction between short‐ and long‐term outcomes and potential individual, institutional and societal benefits are required from an early stage.
CD40–CD154 interactions between macrophages and natural killer cells during sepsis are critical for macrophage activation and are not interferon gamma dependent
Authors: SCOTT M J , HOTH J J , STAGNER M K , GARDNER S A , PEYTON J C , CHEADLE W G
Published: August 2004

Natural killer (NK) cell interactions with macrophages have been shown to be important during bacterial sepsis in activating macrophages to improve bacterial clearance. The mechanism for this increased activation, however, is unclear. This study determines the relative roles of interferon (IFN)-γ and CD40/CD154 direct cell interactions on macrophage and NK cell activation in an experimental model of sepsis. Splenic NK cells and peritoneal macrophages were isolated and cultured alone or in coculture, with and without LPS. CD69 expression on NK cells, phagocytosis ability of macrophages, and cell cytokine production was assessed at 24 and 48 h. Coculture of NK cells and macrophages significantly increased activation levels of both cell types, and through experiments culturing NK cells with supernatants from stimulated macrophages and macrophages with supernatants from stimulated NK cells, this activation was determined to be cell-contact-dependent. Similar experiments were conducted using NK cells from IFN-γ deficient (–/–) mice, as well as anti-IFN-γ neutralizing antibody. These experiments determined that IFN-γ is not required for NK or macrophage activation, although it did augment activation levels. Experiments were again repeated using peritoneal macrophages from CD40-/– mice or splenic NK cells from CD154-/– mice. CD40/CD154 interactions were important in the ingestion of bacteria by macrophages, but did not affect NK cell activation at 24 h. There was, however, a protective effect of CD40/CD154 interactions on NK cell activation-induced cell death that occurred at 48 h. CD40/CD154 interactions between macrophages and NK cells are therefore important in macrophage phagocytosis, and are not dependent on IFN-γ.
Decreased interferon-αproduction and impaired T helper 1 polarization by dendritic cells from patients with chronic hepatitis C
Authors: MURAKAMI H , AKBAR S M F , MATSUI H , HORIIKE N , ONJI M
Published: August 2004

Patients with chronic hepatitis C (CHC) are unable to prime and maintain vigorous T cell responses that are initiated during the acute phase of hepatitis C virus (HCV) infection. As dendritic cells (DCs) induce and regulate both innate and adaptive immune responses, the aim of this study was to analyse two critical functions of DCs: firstly, production of interferon (IFN)-α and, secondly, polarization of T helper 1 lymphocytes. The frequencies of plasmacytoid DC (PDC) and myeloid DC (MDC) were estimated in 63 patients with CHC and 34 normal controls using four-colour flow cytometry. Circulating DCs were isolated from peripheral blood of CHC patients (n = 10) and normal controls (n = 10). These DCs were cultured with herpes simplex virus-1 to evaluate their capacity to produce IFN-α. The capacity of DCs to induce polarization of autologous naive CD4+ T lymphocytes to IFN-γ-producing effector T lymphocytes was also assessed. The frequencies of PDCs producing intracellular IFN-α (P < 0·01) and the levels of IFN-α in culture supernatant of PDCs (P < 0·01) were significantly lower in patients with CHC compared to those of normal controls. The numbers of MDC were significantly lower in patients with CHC (8·2 (6·0)/µl, median (interquartile range), n = 63) compared to normal control (11·7 (7·8)/µl, n = 34) (P < 0·01). Moreover, DCs from patients with CHC induced significantly lower numbers of IFN-γ-producing effector T lymphocytes compared to that of controls (P < 0·01). This study indicates that the low IFN-α-producing capacity and impaired T helper 1 polarization ability of DCs from patients with CHC might be responsible for the typical low anti-HCV immune responses in these patients.
Correlation of virulence, lung pathology, bacterial load and delayed type hypersensitivity responses after infection with different Mycobacterium tuberculosis genotypes in a BALB/c mouse model
Authors: DORMANS J , BURGER M , AGUILAR D , HERNANDEZ-PANDO R , KREMER K , ROHOLL P , AREND S M , VAN SOOLINGEN D
Published: August 2004

One of the most intriguing aspects of tuberculosis is that the outcome of an infection with M. tuberculosis (TB) is highly variable between individuals. The possibility of differences in virulence between M. tuberculosis strains or genotypes has only recently been studied. There is evidence of multifactorial genetic predisposition in humans that influences the susceptibility to tuberculosis. A better understanding of differences in virulence between M. tuberculosis genotypes could be important with regard to the efforts at TB control and the development of improved antituberculosis vaccines. Survival, lung pathology, bacterial load and delayed type hypersensitivity (DTH) responses of BALB/c mice after intratracheal infection with any of 19 different M. tuberculosis complex strains of 11 major genotype families were studied. The results indicate that among genetically different M. tuberculosis strains a very broad response was present with respect to virulence, pathology, bacterial load and DTH. ‘Low’-responders were the H37Rv, Canetti, Beijing-1 strains, while Beijing-2,3, Africa-2 and Somalia-2 strains were ‘high’-responders. A severe pathological response correlates with a high mortality and a high CFU counts in lungs, but poorly with the degree of the DTH response.
Diagnostic and prognostic values of anti glucose-6-phosphate isomerase antibodies in community-recruited patients with very early arthritis
Authors: JOUEN F , VITTECOQ O , LEGUILLOU F , TABTI-TITON I , MENARD J F , MEJJAD O , POUPLIN S , BOUMIER P , FARDELLONE P , GAYET A , GILBERT D , TRON F , LE LOËT X
Published: August 2004

The objective of this study was to determine the diagnostic and prognostic values of antiglucose-6-phosphate isomerase (GPI) antibodies in patients with very early arthritis. Anti-GPI antibodies were measured by ELISA using purified GPI from rabbit muscle in: (i) 383 sera from healthy blood donors (n = 120), well-established rheumatoid arthritis (RA) (n = 99) and non-RA differentiated arthritis (NRADA) (n = 164) patients; (ii) 195 sera obtained from community-recruited patients with very early inflammatory arthritis (VErA cohort) that were studied for 1 year and classified as having RA (n = 116), NRADA (n = 41), and undifferentiated arthritis (UA) (n = 38) after the follow-up period. The criterion for severity was the progression of radiographic damage. Prevalence of anti-GPI antibodies was significantly higher in well-established RA patients (45·4%) compared to healthy subjects (2·5%). Anti-GPI antibodies were also present in sera from NRADA: systemic lupus erythematosus 53%, polymyositis 45·4%, adult-onset Still's disease 44%, systemic sclerosis 42·8%, spondylarthropathies 25% and primary Sjögren’s syndrome 5·8%. No significant association was found between the presence of anti-GPI antibodies and the 3 diagnostic groups from the VErA cohort. No correlation was observed between anti-GPI and autoantibodies usually associated with RA. Anti-GPI antibodies were not predictive of radiological progression in patients with very early arthritis. Thus, anti-GPI antibodies are not useful for discriminating RA from non-RA rheumatic diseases and do not constitute a predictive factor of structural damage.
Superiority of thyroid peroxidase DNA over protein immunization in replicating human thyroid autoimmunity in HLA-DRB1*0301 (DR3) transgenic mice
Authors: FLYNN J C , GARDAS A , WAN Q , GORA M , ALSHARABI G , WEI W Z , GIRALDO A A , DAVID C S , KONG Y M , BANGA J P
Published: August 2004

Murine experimental autoimmune thyroiditis (EAT), characterized by thyroid destruction after immunization with thyroglobulin (Tg), has long been a useful model of organ-specific autoimmune disease. More recently, porcine thyroid peroxidase (pTPO) has also been shown to induce thyroiditis, but these results have not been confirmed. When (C57BL/6 × CBA)F1 mice, recently shown to be susceptible to mouse TPO-induced EAT, were immunized with plasmid DNA to human TPO (hTPO) and cytokines IL-12 or GM-CSF, significant antibody (Ab) titres were generated, but minimal thyroiditis was detected in one mouse only from the TPO + GM-CSF immunized group. However, after TPO DNA immunization of HLA-DR3 transgenic class II-deficient NOD mice, thyroiditis was present in 23% of mice injected with TPO + IL-12 or GM-CSF. We also used another marker for assessing the closeness of the model to human thyroid autoimmunity by examining the epitope profile of the anti-TPO Abs to immunodominant determinants on TPO. Remarkably, the majority of the anti-TPO Abs was directed to immunodominant regions A and B, demonstrating the close replication of the model to human autoimmunity. TPO protein immunizations of HLA-DR3 transgenic mice with recombinant hTPO did not result in thyroiditis, nor did immunization of other mice expressing HLA class II transgenes HLA-DR4 or HLA-DQ8, with differential susceptibility to Tg-induced EAT. Moreover, our efforts to duplicate exactly the experimental procedures used with pTPO also failed to induce thyroiditis. The success of hTPO plasmid DNA immunization of DR3+ mice, similar to our reports on Tg-induced thyroiditis and thyrotropin receptor DNA-induced Graves’ hyperthyroidism, underscores the importance of DR3 genes for all three major thyroid antigens, and provides another humanized model to study autoimmune thyroid disease.
Faster activation of polymorphonuclear neutrophils in resistant mice during early innate response toPseudomonas aeruginosalung infection
Authors: JENSEN P Ø , MOSER C , KOBAYASHI O , HOUGEN H P , KHARAZMI A , HØIBY N
Published: August 2004

Polymorphonuclear neutrophils (PMNs) are crucial for the outcome of Pseudomonas aeruginosa lung infection in patients with cystic fibrosis. We compared PMNs and inflammatory cytokines in the lungs and blood from susceptible BALB/c and resistant C3H/HeN mice 1 and 2 days after intratracheal challenge with alginate embedded P. aeruginosa. These parameters were correlated with the quantitative bacteriology and histopathology of the lungs. After challenge, the content of granulocyte colony-stimulating factor (G-CSF) and macrophage inflammatory protein-2 (MIP-2) was increased in the lungs and the sera and the percentage of PMNs was increased in the blood. However, 2 days after challenge the concentration of G-CSF and MIP-2 was higher in the lungs and sera of BALB/c mice. CD11b expression was higher on the PMNs of the C3H/HeN mice. The expression of CD62L on PMNs of both strains of mice was decreased 1 day after bacterial challenge, whereas the expression was increased after 2 days of challenge on PMNs of C3H/HeN mice only. These changes were accompanied by a more severe lung inflammation in BALB/c mice and faster clearance of the bacteria in C3H/HeN mice. In conclusion, the rapid early bacterial clearance in the lungs of C3H/HeN mice could be explained by faster activation of the PMNs, as indicated by the higher up-regulation of CD11b. The severe lung inflammation in BALB/c mice may be caused by the early higher content of G-CSF in the sera mobilizing PMNs from the bone marrow and the persistent chemotactic gradient provided by MIP-2 in the lungs.
Suppressive effect of leflunomide metabolite (A77 1726) on metalloproteinase production in IL-1β stimulated rheumatoid synovial fibroblasts
Authors: MIGITA K , MIYASHITA T , ISHIBASHI H , MAEDA Y , NAKAMURA M , YATSUHASHI H , IDA H , KAWAKAMI A , AOYAGI T , KAWABE Y , EGUCHI K
Published: August 2004

Leflunomide, an isoxazol derivative structurally unrelated to other immunomodulatory drugs, has proven to be efficacious in the treatment of rheumatoid arthritis (RA). This study was conducted to elucidate the mechanism by which leflunomide mediated antirheumatic effects. We investigated the effects of A77 1726, leflunomide's active metabolite, on mitogen-activated protein kinase (MAPK) activation in IL-1β-stimulated rheumatoid synovial fibroblasts. The effects of A77 1726 on the secretion of matrix metalloproteinases (MMPs) from rheumatoid synovial fibroblasts were also examined. A77 1726 partially suppressed IL-1β-induced ERK1/2 and p38 kinase activation. In contrast, A77 1726 efficiently suppressed IL-1β-stimulated JNK1/2 kinase activation. Although no suppressive effect was demonstrated on MMP-2, A77 1726 markedly inhibited MMP-1, 3, and 13 secretions from IL-1β-stimulated rheumatoid synovial fibroblasts. Tissue inhibitor of metalloproteinases-1 (TIMP-1) was constitutively produced from rheumatoid synovial fibroblasts and the suppressive effects of A77 1726 on TIMP-1 production were minimal. Our results suggest that the suppression of the MAPK signalling pathway and MMP synthesis in rheumatoid synovial fibroblasts is a possible mechanism for the inhibitory activity of leflunomide against rheumatoid arthritis.