bluuebunny/crossref_metadata_2025 huggingface dataset:
Electroencephalographic response to transcranial magnetic stimulation in children: Evidence for giant inhibitory potentials
Authors: Bender Stephan , Basseler Kristine , Sebastian Imke , Resch Franz , Kammer Thomas , Oelkers‐Ax Rieke , Weisbrod Matthias
Published: June 2005

The electroencephalographic response to transcranial magnetic stimulation (TMS) recently has been established as a direct parameter of motor cortex excitability. Its N100 component was suggested to reflect an inhibitory response. We investigated influences of cerebral maturation on TMS‐evoked N100 in 6‐ to 10‐year‐old healthy children. We used a forewarned reaction time (contingent negative variation) task to test the effects of response preparation and sensory attention on N100 amplitude. Single‐pulse TMS of motor cortex at 105% motor threshold intensity evoked N100 amplitudes of more than 100μV in resting children (visible in single trials), which correlated negatively with age and positively with absolute stimulation intensity. During late contingent negative variation, which involves preactivation of the cortical structures necessary for a fast response, N100 amplitude was significantly reduced. We conclude that (1) N100 amplitude reduction during late contingent negative variation provides further evidence that TMS‐evoked N100 reflects inhibitory processes, (2) response preparation and attention modulate N100, and (3) TMS‐evoked N100 undergoes maturational changes and could serve to test cortical integrity and inhibitory function in children. Parallels between the inhibitory N100 after TMS (provoking massive synchronous excitation) and the inhibitory wave component of epileptic spike wave complexes are suggested. Ann Neurol 2005
Amyloid‐β oligomers are inefficiently measured by enzyme‐linked immunosorbent assay
Authors: Stenh Charlotte , Englund Hillevi , Lord Anna , Johansson Ann‐Sofi , Almeida Claudia G. , Gellerfors Pär , Greengard Paul , Gouras Gunnar K. , Lannfelt Lars , Nilsson Lars N. G.
Published: June 2005

Amyloid‐β (Aβ) peptide levels are widely measured by enzyme‐linked immunosorbent assay (ELISA) in Alzheimer's disease research. Here, we show that oligomerization of Aβ results in underestimated Aβ ELISA levels. The implications are that comprehensive analysis of soluble Aβ requires either sample pretreatment at denaturing conditions or novel conformation‐dependent immunoassays. Our findings might be of relevance for many neurodegenerative disorders in which soluble protein aggregates are the main neurotoxic species. Ann Neurol 2005;58:147–150
Dopaminergic influences on formation of a motor memory
Authors: Flöel Agnes , Breitenstein Caterina , Hummel Friedhelm , Celnik Pablo , Gingert Christian , Sawaki Lumy , Knecht Stefan , Cohen Leonardo G.
Published: June 2005

The ability of the central nervous system to form motor memories, a process contributing to motor learning and skill acquisition, decreases with age. Dopaminergic activity, one of the mechanisms implicated in memory formation, experiences a similar decline with aging. It is possible that restoring dopaminergic function in elderly adults could lead to improved formation of motor memories with training. We studied the influence of a single oral dose of levodopa (100mg) administered preceding training on the ability to encode an elementary motor memory in the primary motor cortex of elderly and young healthy volunteers in a randomized, double‐blind, placebo‐controlled design. Attention to the task and motor training kinematics were comparable across age groups and sessions. In young subjects, encoding a motor memory under placebo was more prominent than in older subjects, and the encoding process was accelerated by intake of levodopa. In the elderly group, diminished motor memory encoding under placebo was enhanced by intake of levodopa to levels present in younger subjects. Therefore, upregulation of dopaminergic activity accelerated memory formation in young subjects and restored the ability to form a motor memory in elderly subjects; possible mechanisms underlying the beneficial effects of dopaminergic agents on motor learning in neurorehabilitation. Ann Neurol 2005;58:121–130
Renin–angiotensin–aldosterone system in brain infarction and vascular death
Authors: Brenner David , Labreuche Julien , Poirier Odette , Cambien François , Amarenco Pierre ,   GENIC Investigators
Published: June 2005

The renin–angiotensin–aldosterone system has functions that may contribute to brain infarction (BI). In 459 matched pairs of white patients and control subjects, we measured plasma angiotensin‐converting enzyme (ACE) levels, seven polymorphisms (angiotensinogen T174M and M235T, ACE I/D and 4656 2/3CT repeat [rpt], angiotensin II type 1 receptor A1166C and A153G, and aldosterone synthase CYP11B2), and evaluated 5‐year poststroke mortality. Mean plasma ACE levels (±standard error) were significantly greater in patients than control subjects (37.5 ± 0.9 vs 33.9 ± 0.9), in patients with lacunar stroke, and in patients with no previous vascular (cerebrovascular or cardiovascular) history. The risk for BI increased with tertiles of plasma ACE, without an interaction with hypertension. After adjustments, the association disappeared except among patients with cardioembolic BI and those without previous vascular events. Among the polymorphisms, there was a weak association of BI with angiotensin II type 1 receptor 1166C, a weak protective effect with angiotensinogen 174M, and a strong association of angiotensinogen 235T with 5‐year vascular mortality. These results suggest that renin–angiotensin–aldosterone system activity and genes contribute to cerebrovascular disease and poststroke vascular death in white patients. Ann Neurol 2005;58:131–138
A Novel Synthesis and Molluscicidal Activity of some Functionally Substituted Pyridine, Pyrido[3,2‐c]pyridazine, and Pyrido[3,2‐c]pyridazino[2′,3′‐a]quinazoline Derivatives
Authors: Abdelrazek Fathy M. , Fathy Alaa El‐Din M.
Published: June 2005

Ethyl benzoylacetate reacts with the malononitrile dimer to afford 4‐amino‐5‐benzoyl‐2‐dicyano methyl‐6‐hydroxypyridine, which undergoes the coupling reaction with aromatic diazonium salts to afford azo derivatives. These azo derivatives could be cyclized into pyrido[3,2‐c]pyridazine and pyrido[3,2‐c]pyridazino[2′,3′‐a]quinazoline derivatives upon reflux in ethanolic NaOH, presumably via their hydrazo tautomers. The molluscicidal activity of these compounds was evaluated.
Pilot study of capillary electrophoresis coupled to mass spectrometry as a tool to define potential prostate cancer biomarkers in urine
Authors: Theodorescu Dan , Fliser Danilo , Wittke Stefan , Mischak Harald , Krebs Ronald , Walden Michael , Ross Mark , Eltze Elke , Bettendorf Olaf , Wulfing Christian , Semjonow Axel
Published: June 2005

We describe the use of capillary eletrophoresis (CE) coupled with mass spectrometry (MS) to identify single polypeptides and patterns of polypeptides specific for prostate cancer (CaP) in human urine. Using improved sample preparation methods that enable enhanced comparability between different samples, we examined samples from 47 patients who underwent prostate biopsy. Of this group, 21 patients had benign pathology and 26 with CaP, and these were used to define potential biomarkers, which allow discrimination between these two states. In addition, CE‐MS data from these 47 urine samples were compared to that of 41 young men (control) without known or suspected clinical CaP to further confirm the polypeptides indicative for CaP. Upon crossvalidation of the same samples, several polypeptides were selected that enabled correct classification of the CaP patients with 92% sensitivity and 96% specificity. We then examined an additional 474 samples from patients with renal disease enrolled in other studies and found that 14 (3%) had polypeptides suggestive of CaP possibly indicating that they harbor clinical CaP. In conclusion, this early pilot study suggests that CE‐MS of urine warrants further investigation as a tool that can identify putative biomarkers for CaP.
Point process methodology for on‐line spatio‐temporal disease surveillance
Authors: Diggle Peter , Rowlingson Barry , Su Ting‐li
Published: June 2005

We formulate the problem of on‐line spatio‐temporal disease surveillance in terms of predicting spatially and temporally localised excursions over a pre‐specified threshold value for the spatially and temporally varying intensity of a point process in which each point represents an individual case of the disease in question. Our point process model is a non‐stationary log‐Gaussian Cox process in which the spatio‐temporal intensity,λ(x,t), has a multiplicative decomposition into two deterministic components, one describing purely spatial and the other purely temporal variation in the normal disease incidence pattern, and an unobserved stochastic component representing spatially and temporally localised departures from the normal pattern. We give methods for estimating the parameters of the model, and for making probabilistic predictions of the current intensity. We describe an application to on‐line spatio‐temporal surveillance of non‐specific gastroenteric disease in the county of Hampshire, UK. The results are presented as maps of exceedance probabilities, P{R(x,t)c|data}, whereR(x,t)is the current realisation of the unobserved stochastic component ofλ(x,t)andcis a pre‐specified threshold. These maps are updated automatically in response to each day's incident data using a web‐based reporting system. Copyright © 2005 John Wiley & Sons, Ltd.
Using a probabilistic model (pCNEM) to estimate personal exposure to air pollution
Authors: Zidek James V. , Shaddick Gavin , White Rick , Meloche Jean , Chatfield Chris
Published: June 2005

This article describes the use of a probabilistic model to estimate personal exposure to airborne pollutants. Such estimates are important when assessing, for example, the potential effects of air pollution on health and in developing related policy. An individual's personal exposure will be determined by local pollution sources which will change throughout the day as the individual's location changes. For this reason, models have been developed that utilize ‘time activity’ patterns to compute the overall exposure to pollutants. The model described here is referred to as ‘pCNEM’ and can be accessed through the WWW. The computational platform is flexible in that it allows users to construct models defining local sources of pollution and emissions in addition to ambient levels. This article demonstrates the construction of such a model, for predicting the exposure to PM10 of random selected individuals from sub‐populations of Greater London. A case study of working females in the spring and summer of 1997 is presented. Copyright © 2005 John Wiley & Sons, Ltd.
A comparison of spatial design methods for correlated observations
Authors: Müller Werner G.
Published: June 2005

Random fields are frequently used to model spatial environmental processes. Optimum design theory for regression experiments is consequently employed to assess and construct monitoring networks for these processes. However, straightforward application of much of this theory is not possible, since the typical assumption of independent errors is violated. In the present article I intend to give an overview on design methods that attempt to cope with the problem, amongst them two recently developed approaches. For a comparison the techniques will be applied to the design of a water‐quality monitoring network in the Südliche Tullnerfeld in Lower Austria. Copyright © 2005 John Wiley & Sons, Ltd.
Dynamic design of ecological monitoring networks for non‐Gaussian spatio‐temporal data
Authors: Wikle Christopher K. , Royle J. Andrew
Published: June 2005

Many ecological processes exhibit spatial structure that changes over time in a coherent, dynamical fashion. This dynamical component is often ignored in the design of spatial monitoring networks. Furthermore, ecological variables related to processes such as habitat are often non‐Gaussian (e.g. Poisson or log‐normal). We demonstrate that a simulation‐based design approach can be used in settings where the data distribution is from a spatio‐temporal exponential family. The key random component in the conditional mean function from this distribution is then a spatio‐temporal dynamic process. Given the computational burden of estimating the expected utility of various designs in this setting, we utilize an extended Kalman filter approximation to facilitate implementation. The approach is motivated by, and demonstrated on, the problem of selecting sampling locations to estimate July brood counts in the prairie pothole region of the U.S. Copyright © 2005 John Wiley & Sons, Ltd.
Composition‐controlled nanocomposites of apatite and collagen incorporating silicon as an osseopromotive agent
Authors: Lynn A. K. , Nakamura T. , Patel N. , Porter A. E. , Renouf A. C. , Laity P. R. , Best S. M. , Cameron R. E. , Shimizu Y. , Bonfield W.
Published: June 2005

The development of a novel biocomposite of apatite (Ap) and collagen incorporating low‐level additions of silicon (Si) as an osseopromotive agent is detailed. Designed to mimic the structural and compositional characteristics of developing bone, this composite is produced via a coprecipitation method, through which the weight percentage of Ap (i.e., the Ap/collagen ratio) can be varied. Coprecipitates produced at Ap contents of 80 wt % (Ap/collagen = 4:1), 60 wt % (Ap/collagen = 3:2), and 40 wt % (Ap/collagen = 2:3) Ap showed markedly different morphologies, ranging from ceramic‐like particulates to rope‐like macro‐fibrils; at all three Ap contents, however, the nanostructural features of the composites remained qualitatively indistinguishable, with equiaxed Ap nanocrystals distributed randomly throughout a matrix of amorphous collagen. Si incorporation was observed to occur preferentially in the collagenous phase—a result with potential impact on local controlled release of Si. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res, 2005
Synthesis of (R)‐ and (S)‐[O‐methyl‐11C]N‐[2‐[3‐(2‐cyano‐phenoxy)‐2‐hydroxy‐propylamino]‐ethyl]‐N′‐(4‐methoxy‐phenyl)‐urea as candidate high affinity β1‐adrenoceptor PET radioligands
Authors: Wagner Stefan , Law Marilyn P. , Riemann Burkhard , Pike Victor W. , Breyholz Hans‐Jörg , Höltke Carsten , Faust Andreas , Schober Otmar , Schäfers Michael , Kopka Klaus
Published: June 2005

Molecular imaging and quantification of myocardial β1‐adrenoceptor (AR) rather than total β‐AR density is of great clinical interest since cardiac biopsy studies suggest that myocardial β1‐AR density is reduced in patients with chronic heart failure whereas cardiac β2‐AR density may vary. Positron emission tomography (PET), with appropriate radioligands, offers the possibility to assess β‐AR density non‐invasively in humans. However, no PET radioligand for the selective imaging of cardiac β1‐ARs is clinically available. Here some derivatives of the well characterized β1‐AR selective antagonist, ICI 89,406, namely the enantiomers of N‐[2‐[3‐(2‐cyano‐phenoxy)‐2‐hydroxy‐propylamino]‐ethyl]‐N′‐(4‐hydroxy‐phenyl)‐urea (5a and 5b) were synthesized and evaluated in vitro. The (R)‐isomer 5a was more β1‐selective but has lower affinity than its (S)‐enantiomer 5b (β1‐AR selectivity: 6100 vs 1240; β1‐affinity: K1 = 0.288 nM vs K1 = 0.067 nM). Etherification of the analogous desmethyl precursors, 5e and 5f, respectively, with [11C]iodomethane gave 11C‐labelled versions of 5a and 5b, namely 5g and 5h, in 44 ± 5% radiochemical yield (decay‐corrected) and 97.4 ± 1.3% radiochemical purity with specific radioactivities of 26.4 ± 9.4 GBq/µmol within 41.2 ± 3.4 min from the end of bombardment (n = 14). 5g and 5h are now being evaluated as candidate radioligands for myocardial β1‐ARs. Copyright © 2005 John Wiley & Sons, Ltd.
On the decay of solutions for a class of quasilinear hyperbolic equations with non‐linear damping and source terms
Authors: Messaoudi Salim A.
Published: June 2005

In this paper, we consider the non‐linear wave equation

a,b>0, associated with initial and Dirichlet boundary conditions. Under suitable conditions on α, m, and p, we give precise decay rates for the solution. In particular, we show that for m=0, the decay is exponential. This work improves the result by Yang (Math. Meth. Appl. Sci. 2002; 25:795–814). Copyright © 2005 John Wiley & Sons, Ltd.
Rheological, mechanical and morphological properties of thermoplastic vulcanizates based on NR‐g‐PMMA/PMMA blends
Authors: Nakason C. , Pechurai W. , Sahakaro K. , Kaesaman A.
Published: June 2005

Graft copolymer of natural rubber and poly(methyl methacrylate) (NR‐g‐PMMA) was prepared using semi‐batch emulsion polymerization technique via bipolar redox initiation system. It was found that the grafted PMMA increased with the increase of methyl methacrylate (MMA) concentration used in the graft copolymerization. The NR‐g‐PMMA was later used to prepare thermoplastic vulcanizates (TPVs) by blending with PMMA through dynamic vulcanization technique. Conventional vulcanization (CV) and efficient sulphur vulcanization (EV) systems were studied. It was found that the CV system provided polymer melt with lower shear stress and viscosity at a given shear rate. This causes ease of processability of the TPVs via extrusion and injection molding processes. Furthermore, the TPVs with the CV system showed higher ultimate tensile strength and elongation. The results correspond to the morphological properties of the TPVs. That is, finer dispersion of the small vulcanized rubber particles were observed in the PMMA matrix. Various blend ratios of the NR‐g‐PMMA/PMMA blends using various types of NR‐g‐PMMA (i.e. prepared using various percentage molar ratios of NR and MMA) were later studied via dynamic vulcanization by a conventional sulphur vulcanization system. It was found that increasing the level of PMMA caused increasing trend of the tensile strength and hardness properties but decreasing level of elongation properties. Increasing level of the grafted PMMA in NR molecules showed the same trend of mechanical properties as in the case of increasing concentration of PMMA used as a blend component. From morphological studies, two phase morphologies were observed with a continuous PMMA phase and dispersed elastomeric phase. It was also found that more finely dispersed elastomeric phase was obtained with increasing the grafted PMMA in the NR molecules. Copyright © 2005 John Wiley & Sons, Ltd.
Reciprocal changes in trefoil 1 and 2 expression in stomachs of mice with gastric unit hypertrophy and inflammation
Authors: Franic TV , van Driel IR , Gleeson PA , Giraud AS , Judd LM
Published: June 2005

H+/K+‐ATPase β‐subunit‐deficient mice (129/Sv background) display numerous pathologies in the stomach. Expression of the mutation in BALB/cCrSlc mice results in the development of an aberrant ‘mucus‐rich’ cell population. ‘Mucus‐rich’ cells have been described in stomachs of mice with autoimmune gastritis, a disease mediated by CD4+ T cells. Other pathological features of autoimmune gastritis are similar to those in H+/K+ β‐deficient mice and include a mononuclear cell infiltrate in the gastric mucosa, non‐functional or absent parietal cells, depletion of zymogenic cells, hypergastrinaemia, and gastric unit hypertrophy caused by immature cell hyperplasia. The present study investigates further the aberrant gastric ‘mucus‐rich’ cell lineage and analyses the mRNA expression of mucus cell products TFF1 and TFF2. ‘Mucus‐rich’ cells stained for both acidic and neutral mucins, and with a TFF2‐specific antibody. Stomachs from both models expressed decreased TFF1 mRNA and reciprocally increased TFF2 mRNA. The involvement of gastrin in regulating trefoil mRNA expression was also investigated using gastrin‐deficient mice. In contrast to previous findings, gastrin did not positively regulate TFF1 mRNA expression, but there was possible augmentation of TFF2. Additionally, a clear role for inflammation was established involving both polymorphonuclear and mononuclear cells in these models, and a link was found between mucosal hypertrophy and increased interleukin‐11 (IL‐11) expression. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Electron paramagnetic resonance spin probe study of carbon dioxide‐induced polymer plasticization
Authors: Harbron Elizabeth J. , Bunyard W. Clayton , Forbes Malcolm D. E.
Published: June 2005

Steady‐state electron paramagnetic resonance (EPR) spectroscopy using nitroxide spin probes has been used to investigate the plasticization of poly(vinyl acetate) and poly(ethyl methacrylate) by carbon dioxide. By varying the CO2 pressure at constant ambient temperature, the glass transition for each polymer could be depressed to 25 °C. This effect has been quantified by a parameter P50G, obtained by plotting the EPR spectral width as a function of CO2 pressure. Certain spin probes showed free volume distribution effects, manifested in the EPR spectra as “double peaks.” Possible reasons for this phenomenon are presented and discussed, and the efficacy of CO2 as a plasticizer is clearly demonstrated by direct comparison with di‐n‐butyl phthalate. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 2097–2108, 2005
Molecular structure development of metallocene‐catalyzed linear low density polyethylene under ultrasonic irradiation
Authors: Wu Hong , Guo Shaoyun , Li Zhen
Published: June 2005

In this work, the effect of ultrasonic irradiation on molecular structure development of metallocene‐catalyzed linear low density polyethylene (mLLDPE) was studied. GPC results show that ultrasonic irradiation have influence on molecular weight and molecular weight distribution of mLLDPE. Molecular weight of mLLDPE decreases slightly at the initial 30 s of ultrasonic irradiation and then increases obviously; its distribution becomes wider with the increase of ultrasonic irradiation time. The power and frequency of ultrasonic irradiation have the distinct influence on molecular weight and its distribution of mLLDPE. DSC results show that ultrasonic irradiation has distinct influence on multiple step crystallizing behaviors of mLLDPE because of the change of branched chain in mLLDPE molecules. Thermal stability of mLLDPE is improved greatly because of micro‐crosslinking structure in mLLDPE molecule, which is formed in the presence of ultrasonic irradiation. A possible mechanism for molecular structure development of mLLDPE in the presence of ultrasonic irradiation is also proposed in this paper. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 2121–2129, 2005
Gain scheduled control for discrete‐time systems depending on bounded rate parameters
Authors: Amato Francesco , Mattei Massimiliano , Pironti Alfredo
Published: June 2005

In this paper we consider a linear, discrete‐time system depending multi‐affinely on uncertain, real time‐varying parameters. A new sufficient condition for the stability of this class of systems, in terms of a feasibility problem involving linear matrix inequalities (LMIs), is obtained under the hypothesis that a bound on the rate of variation of the parameters is known. This condition, obtained by the aid of parameter dependent Lyapunov functions, obviously turns out to be less restrictive than that one obtained via the classical quadratic stability (QS) approach, which guarantees stability in presence of arbitrary time‐varying parameters. An important point is that the methodology proposed in this paper may result in being less conservative than the classical QS approachevenin the absence of an explicit bound on the parameters rate of variation. Concerning the synthesis context, the design of a gain scheduled compensator based on the above approach is also proposed. It is shown that, if a suitable LMI problem is feasible, the solution of such problem allows to design an output feedback gain scheduled dynamic compensator in a controller‐observer form stabilizing the class of systems which is dealt with. The stability conditions are then extended to take into accountL2performance requirements. Some numerical examples are carried out to show the effectiveness and to investigate the computational burden required by the proposed approach. Copyright © 2005 John Wiley & Sons, Ltd.
Individual growth curve models for assessing evidence‐based referral criteria in growth monitoring
Authors: van Dommelen P. , van Buuren S. , Zandwijken G. R. J. , Verkerk P. H.
Published: June 2005

The goal of this study is to assess whether a growth curve model approach will lead to a more precise detection of Turner sydnrome (TS) than conventional referral criteria for growth monitoring. The Jenss–Bayley growth curve model was used to describe the process of growth over time. A new screening rule is defined on the parameters of this growth curve model, parental height and gestational age. The rule is applied to longitudinal growth data of a group of children with TS (n=777) and a reference (n=487) group. The outcome measures are sensitivity, specificity and median referral age. Growth curve parameters for TS children were different from reference children and can therefore be used for screening. The Jenss–Bayley growth model, which uses all longitudinal measurements from birth to a maximum age of 5 years with at least one measurement after the age of 2, together with parental height and gestational age can achieve a sensitivity of 85.2 per cent with a specificity of 99.5 per cent and a median referral age of 4.2 (the last measurement between the age of 2 and 5 of each child is considered to be the moment of referral). Sensitivity increases by 2 percentage points when decreasing the specificity to 99 per cent. The Jenss–Bayley growth model from birth to a maximum age of 8 years with at least one measurement after the age of 2, together with parental height results in a sensitivity of 89.0 per cent with a specificity of 99.5 per cent and a median referral age of 6.1. For a specificity of 98 per cent, we obtain a sensitivity of 92.3 per cent. In comparison to conventional rules applied to the same data, sensitivity is about 11–30 percentage points higher at the same level of specificity for the Jenss–Bayley growth rule. We conclude that from the age of 4, growth curve models can improve the screening on TS to conventional screening rules. Copyright © 2005 John Wiley & Sons, Ltd.
Disorders of the electron transport chain
Authors: Adams P. L. , Turnbull D. M.
Published: June 2005

Defects in a pathway as complex as the electron transport chain cause a variety of clinical abnormalities, which vary from fatal lactic acidosis in infancy to mild muscle disease in adults. The primary defect may reside in the nucleus or the mitochondrial genome. Until relatively recently, biochemical assays were the definitive means of establishing a defect of the electron transport chain. However, identification of mtDNA abnormalities allows defects to be defined more precisely and in a number of cases provides an easier (more reliable) means of investigation. Despite advances in this field, disorders of the electron transport chain still remain underdiagnosed. This review attempts to provide a general outline of the biochemistry and molecular genetics associated with these disorders and some of the factors involved in establishing a diagnosis in those patients with a suspected defect of the electron transport chain.
Metabolic intermediates in lactic acidosis: compounds, samples and interpretation
Authors: Poggi‐Travert F. , Martin D. , Billette de Villemeur T. , Bonnefont J. P. , Vassault A. , Rabier D. , Charpentier C. , Kamoun P. , Munnich A. , Saudubray J. M.
Published: June 2005

A number of acquired conditions including infections, severe catabolic states, tissue anoxia, severe dehydration and poisoning can give rise to hyperlactacidaemia. All these causes should be ruled out before considering inborn errors of metabolism. Carefully collected samples are necessary if artefacts that results in spuriously increased lactate/pyruvate (L/P) and 3‐hydroxybutyrate/acetoacetate (B/A) ratios are to be avoided. When properly performed, 24‐h studies of L/P and B/A ratios provide a useful tool in making a diagnosis. A few metabolic profiles when present are specific or highly suggestive of a given disorder. When the L/P ratio is normal or low, pyruvate dehydrogenase (PDH) deficiency is highly probable whatever the lactate concentration, which is often only moderately elevated after meal, may be. When the L/P ratio is very high in association with post‐prandial hyperketonaemia and in contrast to a normal or low B/A ratio, pyruvate carboxylase (PC) deficiency andα‐ketoglutarate dehydrogenase (KGDH) deficiency are the most likely diagnoses. The distinction between the two disorders relies upon amino acid and organic acid profiles (glutamate andα‐ketoglutarate accumulations in KGDH deficiency and hyperammonaemia and hypercitrullinaemia in PC deficiency). When both L/P and B/A ratios are elevated and associated with significant post‐prandial hyperketonaemia, respiratory‐chain disorders should first be suspected. All other profiles, especially a high L/P ratio without hyperketonaemia, are compatible with respiratory‐chain disorders but are not specific; all acquired anoxic conditions should also be ruled out. Clearly, the clinical utility of these profiles needs to be interpreted cautiously in very ill patients in relation to the cardiocirculatory condition and to therapy. Finally, a normal profile, even after stress and loading, does not rule out an inborn error of lactate/pyruvate oxidation.
Mitochondrial encephalomyopathies: what next?
Authors: DiMauro S.
Published: June 2005

In few areas of medicine has progress been more spectacular than in the field of mitochondrial diseases, especially those related to mtDNA mutations. Much remains to be done, however, and this brief review discusses the following areas of research where progress has been more limited or data are still controversial: (1) the molecular basis of respiratory‐chain defects due to nuclear DNA mutations; (2) defects of mitochondrial protein importation; (3) defects of intergenomic signalling; (4) pathophysiology of mtDNA‐related disorders; (5) ageing and age‐related neuro‐degenerative diseases; (6) therapy; and (7) genetic counselling.
Morphological studies of skeletal muscle in lactic acidosis
Authors: Romero N. B. , Lombès A. , Touati G. , Rigal O. , Frachon P. , Cheval M. A. , Giraud M. , Possekel S. , Fardeau M. , Ogier de Baulny H.
Published: June 2005

This paper underscores the contribution of routine morphological examination of skeletal muscle in patients with lactic acidosis. Mitochondrial disorders are by far the most common causes of primary lactic acidosis, in which muscle biopsy analysis helps in diagnosis and in the search for the molecular anomalies. Thus, we focus our attention on one particular point: the contribution of the morphological study of muscle biopsy in primary lactic acidosis due to mitochondrial disorders, especially mitochondrial respiratory‐chain diseases.
Magnetic resonance imaging in lactic acidosis
Authors: van der Knaap M. S. , Jakobs C. , Valk J.
Published: June 2005

Mitochondrial defects, defects in gluconeogenesis, and biotin‐responsive multiple carboxylase deficiency are disorders characterized by primary lactic acidosis. In this review, characteristic findings in magnetic resonance imaging (MRI) of the brain, as related to histopathological abnormalities, are described for the different disorders and the diagnostic value of the MRI findings is discussed. Inborn errors of metabolism with primary lactic acidosis should be considered in particular when MRI shows lesions similar to or reminiscent of effects of focal or generalized hypoxia‐ischaemia, or when MRI shows signs of chronic neurodegeneration, but rarely in cases with predominantly white‐matter changes.
Riboflavin‐responsive ethylmalonic—adipic aciduria
Authors: Green A. , Marshall T. G. , Bennett M. J. , Gray R. G. F. , Pollitt R. J.
Published: June 2005

A patient presenting with a condition resembling Reye's syndrome was found to have a urinary organic acid excretion pattern similar to those previously described in a single patient with ethylmalonic‐adipic aciduria. The present patient responded clinically to riboflavin supplementation and his fibroblasts, when cultured in riboflavin‐depleted medium, showed an abnormal reduction in the rate of butyrate oxidation.
Heterogeneity and complementation analysis of fibroblasts from vitamin B6 responsive and non‐responsive patients with gyrate atrophy of the choroid and retina
Authors: Wirtz M. K. , Kennaway N. G. , Weleber R. G.
Published: June 2005

Fibroblasts from four pyridoxine responsive and three non‐responsive patients with gyrate atrophy of the choroid and retina have been examined. Responsive patients had higher activity of ornithine ketoacid transaminase (OKT) in cell homogenates and greater incorporation of radioactivity from14C‐ornithine into protein in cultured cellsin situ compared to non‐responsive patients. Complementation analysis of the cells from these seven patients was performed, based on the ratio of incorporation of14C/3H into protein in fused cells incubated in14C‐ornithine and3H‐leucine. Lack of positive complementation in these crosses suggests that pyridoxine responsive and non‐responsive patients with gyrate atrophy represent different allelic mutations of the same genetic locus coding for OKT.
Hypercholesterolaemia type II: Changes in plasma insulin and glucagon levels after portacaval shunt
Authors: Farriaux J. P. , Luyckx A. S. , Ribet M.
Published: June 2005

Insulinaemia and glucagonaemia were measured in two cases of hypercholesterolaemia type II, before and after portacaval shunt. The results show an increase of both hormones although these variations are not concomitant with the decrease in cholesterolaemia. The data still do not explain the mechanism of the decrease.
Results of screening for phenylalanine and other amino acid disturbances among pregnant women
Authors: Hyánek J. , Homolka J. , Trnka J. , Seemanová E. , Červenka J. , Třesohlavá Z. , Kapras J. , Doležal A. , Šráček J. , Vácha V. , Hoza J. , Lošan F. , Nevšímalová S. , Malá M. , Viletová H.
Published: June 2005

Blood specimens were collected from 15000 pregnant women during the first 3 months of their pregnancy and screened for amino acid disturbances by means of paper chromatography. A high incidence of disturbances in the phenylalanine metabolism was discovered: three cases of mild hyperphenylalaninaemia without phenylpyruvicaciduria (incidence 1:5000); two cases of mild hyperphenylalaninaemia with phenylpyruvicaciduria (incidence 1:7550); four cases of mild phenylketonuria (incidence 1:3750). Disturbances in the metabolism of other amino acids were found to be rare. Metabolic and genealogical findings in some detected families are briefly described.
Phenylketonuria in Indian children
Authors: Joshua Gertrude E. , Chandy S. , Radhakrishnan A. N. , Mammen D. , Mathai K. V.
Published: June 2005

Three untreated phenylketonuric Indian children aged respectively 3 1/2 years, 1 1/2 years and 1 year showed rapid neurological deterioration. Plasma, cerebrospinal fluid and urine phenylalanine concentrations were significantly raised and the phenylalanine‐tyrosine ratio was high. Analysis of a biopsy of the right frontal lobe of the brain in one case showed the myeline lipids—cerebroside and sulphatide—to be decreased. The total cerebroside in white matter was low. Light microscopy showed marked pallor of the white matter of the brain and extensive spongy degeneration. Ultrastructurally these spongy vesicles are located between the lamellae of the myelin sheath.
Anderson‐fabry disease: Rapid detection of carriers by hair bulb analysis
Authors: Ejiofor A. , Robinson D. , Wise D. , Hamers M. , Tager J. M.
Published: June 2005

A rapid and simple method is described for the identification of the carrier state in angiokeratoma corporis diffusum. The α‐galactosidase (α‐D‐galactoside galactohydrolase, E.C.3.2.1.22) activities in individual hair roots are measured and compared with those ofN‐acetyl‐β‐hexosaminidase (E.C.3.2.1.30), another lysosomal enzyme that is not affected. The cellular mosaicism typical of females heterozygous for X‐linked disorders is revealed by the presence of normal, affected and partially affected hair roots. Normal individuals show no affected roots, while males hemizygous for the trait have no hair roots with enzyme activities in the normal range.
Hypoxanthine‐guanine phosphoribosyltransferase deficiency in three brothers with gout: Characterization of a variant, HPRTEdinburgh, having altered isoelectric point, increased thermal lability and normal levels of messenger RNA
Authors: Snyder F. F. , Joyce J. E. , Carter‐Edwards T. , Joshi R. , Rylance H. L. , Wallace R. C. , Nuki G.
Published: June 2005

Three brothers who developed acute gouty arthritis at ages 16, 20 and 26 years were found to have increased plasma urate. Erythrocyte hypoxanthine phosphoribosyltransferase (HPRT) activity was less than 1% of normal and adenine phosphoribosyltransferase (APRT) activity was increased 2–3‐fold. This variant, HPRTEdinburgh, was further studied using lymphoblast lines established from these patients and the following observations are consistent with a mutation involving a single amino acid substitution. Lymphoblasts from these patients had 0.9–1.6% of control HPRT activity which was 8‐fold more labile than control activity at 75°C. Isoelectric focusing of the variant protein in polyacrylamide gels indicated a pI of 6.5–6.7 which is more basic than normal HPRT, pI 6.0–6.3. The Michaelis constants were increased: 10‐fold for hypoxanthine from 1.3 to 13 µmol/L, and 5‐fold for PP‐ribose‐P from 6 to 30 µmol/L, for control and variant respectively. TheKi for product inhibition by GMP was marginally increased in the variant. Northern blot analysis of variant lymphoblast RNA indicated normal amounts of the expected 1.6 kilobase messenger RNA.
Further analysis of the disturbed adrenocortical function in the cerebro‐hepato‐renal syndrome of zellweger
Authors: Govaerts L. , Sippell W. G. , Monnens L.
Published: June 2005

Plasma aldosterone, corticosterone, 11‐deoxycorticosterone, progesterone, 17‐hydroxyprogesterone, 11‐desoxycortisol, cortisol and cortisone were determined simultaneously in small plasma samples obtained during an i.v. ACTH (Synacthen) stimulation test in five patients (age 4–7 years) with Zellweger syndrome. The response of all ACTH‐dependent steroids to Synacthen was severely impaired in all patients, despite normal basal levels. It can be concluded that the biochemical defect in adrenal steroidogenesis causing the inadequate response to ACTH injection is located proximal to progesterone.

We propose that the lack of responsiveness to ACTH is secondary to an abnormality of ACTH receptors on the adrenocortical cell. The extremely low levels of non‐specific lipid transfer protein may be a contributing factor.
Myoclonic epilepsy of lafora and arylsulphatase a deficiency in the same patient
Authors: Bertagnolio B. , Girotti F. , Pelucchetti D. , Pandolfo M.
Published: June 2005

Very low levels of arylsulphatase A were found in a young patient with the clinical features of Lafora disease, confirmed by muscle biopsy. The deficiency was shown both in leukocytes and cultured fibroblasts. A cerebroside sulphate loading showed that 93% of [14C]cerebroside sulphate taken up by skin fibroblasts from the patient remained unmetabolized after a 24 h pulse, ruling out pseudo‐arylsulphatase A deficiency. In the healthy parents and siblings of the patient, biochemical data suggested heterozygosity for arylsulphatase A deficiency. The apparent co‐inheritance of arylsulphatase A deficiency and Lafora disease in this family might be the consequence of genetic linkage between the two genes.
Sanfilippo B disease: a re‐examination of a particular sibship after 12 years
Authors: Di Natale P.
Published: June 2005

A particular sibship, with mild and severe types of Sanfilippo B disease within the same family, was re‐examined after 12 years. The phenotypes of the mild and of the severe patients were maintained, specifically the mental retardation. Cultures of lymphoblasts from the mild patient were established and proteins were electrophoresed in native conditions and then immunoblotted with specific antibody. Two bands of 182000 and 131000 Da were found, comigrating with the enzyme from normal lymphoblasts and the enzyme from normal urine. The data are discussed in relationship to the molecular defect underlyingα‐N‐acetylglucosaminidase deficiency and to the ability of the antiserum to react with normal, mutant, monomeric and multimeric forms of the enzyme.
Successful treatment of dihydropteridine reductase deficiency, with an interesting effect of 5‐hydroxytryptophan deficiency on sleep patterns
Authors: Lipson A. H. , Earl J. W. , Wilcken B. , Yu J. S. , O'Halloran M. , Cotton R. G. H.
Published: June 2005

We report a child in whom dihydropteridine reductase deficiency was diagnosed prenatally because of an affected sibling and who was treated from birth with apparent good response.

This family has been reported before (Firgairaet al., 1980, 1981, 1983; Lipsonet al., 1984; Cottonet al., 1986; Dahlet al., 1988). The parents are Lebanese Muslims who are first cousins, and their first and third children, both male, are well. The third child was diagnosed as normalin utero (Firgairaet al., 1983). The second child, the subject of an early report (Lipsonet al., 1984), has dihydropteridine reductase deficiency. The dihydropteridine reductase is non‐functional due to an amino acid insertion (Howellset al., 1990).
Urinary excretion of 2‐methylacetoacetate, 2‐methyl‐3‐hydroxybutyrate and tiglylglycine after isoleucine loading in the diagnosis of 2‐methylacetoacetyl‐CoA thiolase deficiency
Authors: Aramaki S. , Lehotay D. , Sweetman L. , Nyhan W. L. , Winter S. C. , Middleton B.
Published: June 2005

The concentrations of 2‐methylacetoacetate, 2‐methyl‐3‐hydroxybutyrate and tiglylglycine were determined by gas chromatography‐mass spectrometry in urine collected before and for 8 h after loading with 100mg of isoleucine per kg of body weight. The sum of 2‐methylacetoacetate and 2‐butanone, a decarboxylation product, was determined as the 2‐butanone dinitrophenylhydrazone derivative. Substantial increases in each compound were encountered in a patient with a documented defect of 2‐methylacetoacetyl‐CoA thiolase. Increased quantities of 2‐methyl‐3‐hydroxybutyrate and tiglylglycine were also found in four children with clinical symptoms similar to those associated with 2‐methylacetoacetyl‐CoA thiolase deficiency but in whom the activity of the enzyme was found to be normal. The concentration of 2‐methylacetoacetate plus 2‐butanone in the urine increased after an isoleucine load only in the patient with 2‐methylacetoacetyl‐CoA thiolase deficiency.
Biochemical observations on a case of hepatic fructose‐1,6‐diphosphatase deficiency
Authors: Hommes F. A. , Campbell R. , Steinhart C. , Roesel R. A. , Bowyer F.
Published: June 2005

A case of hepatic fructose‐1,6‐diphosphatase deficiency is described. She presented with congenital bilateral cataracts, failure to thrive, hypoglycaemia and hyperlactacidaemia. A liver biopsy revealed normal levels of gluconeogenic enzymes except fructose‐1,6‐diphosphatase which was present at 30% of the level of the lower control values. The residual activity had a normal affinity for fructose‐1,6‐diphosphate, a decreased sensitivity for inhibition by fructose‐2,6‐diphosphate and an increased resistance toward conversion to the AMP‐insensitive form of the enzyme. As a result of this mutation, the residual FDPase will always be maintained in the AMP‐inhibited form.
Dolichol and phosphorylated dolichol content of tissues in ceroid‐lipofuscinosis
Authors: Hall N. A. , Patrick A. D.
Published: June 2005

Concentrations of free dolichol, total non‐phosphorylated dolichol, and total phosphorylated dolichol were measured in autopsy specimens of brain and liver from ceroid‐lipofuscinosis (CL) and control cases. Levels of non‐phosphorylated dolichol, mainly as free dolichol, were increased approximately two‐fold in late‐infantile CL brain. No increase was observed for CL liver. In late‐infantile and juvenile CL brain, the increase in phosphorylated dolichol was at least ten‐fold, but no significant difference was found for CL liver. A substantial part of the increase in phosphorylated dolichol in CL brain appeared to be due to lipid‐linked oligosaccharides. The results suggest that CL might involve a defect in the metabolism of dolichol‐linked oligosaccharides.
Intracellular activity of HPRTCape Town: Purine uptake and growth of cultured cells in selective media
Authors: Steyn L. M. , Harley E. H.
Published: June 2005

The low activity of the human variant HPRTCape Town is associated with substrate inhibition by hypoxanthine and guaninein vitro. The intracellular activity of this variant was investigated by studying the relative uptake or radiolabelled purine nucleotide precursors and the growth in selective media of EBvirus‐transformed lymphoblasts prepared from the proband (TK). These cells incorporated less than 10% of the [14C]hypoxanthine and [14C]guanine of the control cells; while their purinede novo synthesis was accelerated 8‐fold. In selective media the HPRTCapeTown cells grew in a similar manner to HPRT‐ve cells. These results indicate that if substrate inhibition is responsible for the low intracellular activity of HPRTCape Town, the concentration of either hypoxanthine or guanine in the vicinity of the active site of the enzyme must be greater than theKi(app) for these substrates, 118 and 28 µmol L−1 respectively. Evidence is presented that the intracellular concentration of guanine, but not hypoxanthine, is well in excess of theKi(app) in cultured lymphoblasts.
Successful adjustment to society by adults with phenylketonuria
Authors: Koch R. , Yusin M. , Fishler K.
Published: June 2005

The study shows that most individuals between 16 and 25 years of age with PKU appear to function in a productive manner in society. Although they have not become professional men and women, they can acquire jobs of a skilled or semiskilled nature and perform them satisfactorily. The majority seemed content with their jobs and happy with the way their lives were progressing, although only 23% were financially independent. Of the patients interviewed, the majority had made friendships and appeared to keep them without much trouble. The majority of the patients would not tell their friends that they had PKU. The reason for this was that they felt uncomfortable acknowledging that they had this disorder.
Cystinosis in the Federal Republic of Germany. Coordination and analysis of the data
Authors: Manz F. , Gretz N.
Published: June 2005

In our survey, 101 infants and children with cystinosis were registered in the Federal Republic of Germany. Ninety‐five patients showed the infantile type of cystinosis, five the adolescent type and one possibly the adult type. The minimum incidence rate of infantile and adolescent cystinosis in the FRG was 1 patient per 179 000 live‐births. In contrast to other countries, cystinotic patients were evenly distributed in the FRG. Patients with cystinosis originated more frequently from rural communities than from large cities. Before 1968 most patients died before reaching terminal renal failure, usually due to uncontrolled disturbances of water and electrolyte metabolism. Since 1976 the causes of death other than uraemia have been rare and most patients with terminal renal failure have entered a renal replacement program.