bluuebunny/crossref_metadata_2025 huggingface dataset:
q‐space analysis of lung morphometry in vivo with hyperpolarized3He spectroscopy
Authors: Shanbhag Dattesh D. , Altes Talissa A. , Miller G.Wilson , Mata Jaime F. , Knight‐Scott Jack
Published: June 2006

Purpose

To examine the utility of a3He spectroscopic q‐space technique for detecting changes in lung morphometry in vivo.

Materials and Methods

A diffusion‐weighted spectroscopy sequence was used to collect global diffusion data from healthy adults (N= 11), healthy children (N= 5), and chronic obstructive pulmonary disease (COPD) patients (N= 2) using 40 cc of hyperpolarized3He gas within a two second breathhold. Displacement probability profiles (DPP) were obtained by Fourier transformation of diffusion data with respect to q. A bi‐Gaussian model was used to decompose the DPPs into narrow and broad components, characterized by root‐mean‐square displacements Xrms1and Xrms2, respectively.

Results

In healthy adults, the narrow component (Xrms,1) of the DPP had a mean displacement of 188 ± 10 μm, slightly less than the reported average size of the alveoli. The broad component (Xrms,2) had a mean value of 474 ± 44 μm, comparable to the diameter of the respiratory bronchioles in the acinus. In children, both Xrms1(167 ± 4 μm) and Xrms2(382 ± 22 μm) compared to healthy adults (P< 0.01). In COPD patients, the mean displacements were elevated (Xrms1: 265 ± 71 μm; Xrms2: 530 ± 109 μm) compared to healthy adults. Excellent correlation was found between rms displacements and age (age vs. Xrms,1: r = 0.78,P< 0.001; age vs. Xrms,2: r = 0.90,P< 0.001).

Conclusion

The q‐space parameters agreed remarkably well with published alveolar morphometry data. The results suggest that the technique may be sensitive to disease, as evident from the elevated mean displacements in COPD patients compared to healthy volunteers. Detailed lung microstructural information can be obtained using a very low volume of inhaled3He. J. Magn. Reson. Imaging 2006. © 2006 Wiley‐Liss, Inc.
Structural conformation and vibrational spectroscopic studies of 2,6‐bis(p‐N,N‐dimethyl benzylidene)cyclohexanone using density functional theory
Authors: James C. , Raj A. Amal , Reghunathan R. , Jayakumar V. S. , Joe I. Hubert
Published: June 2006

NIR‐FT Raman and FT‐IR spectra of the crystallized 2,6‐bis (p‐N,N‐dimethyl benzylidene)cyclohexanone (C24H28N2O) have been recorded in the region 3200–500 and 4000–400 cm−1, respectively. The spectral interpretation has been done following full structure optimization and vibrational wavenumber calculations based on the density functional theory (DFT) using the standard B3LYP/6‐31G* basis set. The predicted vibrational spectra are in excellent agreement with the experiment, permitting an unambiguous assignment for the unusual downshifting of νCO caused by expanded conjugation effects in the dienone system. The optimized geometry clearly demonstrates the ‘half‐chair’ conformation of the central nonheterocyclic ring. The ring CH stretching vibrational modes involving aromatic hydrogen atoms participating in steric interaction have been observed with low intensities. There are valid structural and spectral bases for the enhancement of its bioactivity due to full charge transfer reaction by the substitution of the electron‐donating 4‐dimethylamino group into the aryl rings. The existence of intramolecular, CH…O, improper, blue‐shifted hydrogen bond was investigated by means of the natural bonding orbitals (NBO) analysis. There are also slight dissimilarities in the bond lengths and endocyclic bond angles of both phenyl rings due to the effect of the heavy substitution. The characteristic ring modes have also been assigned in detail. Copyright © 2006 John Wiley & Sons, Ltd.
Allergen‐specific IgE testing in the diagnosis of food allergy and the event of a positive match in the bioinformatics search
Authors: van Ree Ronald , Vieths Stefan , Poulsen Lars K.
Published: June 2006

Current documents on risk assessment of genetically modified foods recommend including IgE‐binding tests on sera from allergic patients. However, there is no generally accepted recommendation on technical aspects of the testing procedures or on the interpretation of the results, despite that fact that both false positive and false‐negative results may be caused by variability of the test procedures. The present article discusses the state‐of‐the‐art of serological test procedures for qualitative and quantitative determination of specific IgE and interpretation of test results. It is emphasized that the use of sera from clinically well‐characterized subjects is of high importance. In the case of a positive test result, the biological activity of the detected IgE antibodies, i. e., the potential to trigger mediator release from basophils or mast cells in an allergen‐specific manner, should be taken into account. However, present data also indicate that validation of such mediator release tests is required, both in terms of experimental protocols and with respect to correlation of the test results with the clinical situation. Further studies are also required to prove the usefulness of targeted serum screening, i. e., the testing of gene products from organisms not known to be allergenic with sera from subjects allergic to related species.
Allergen sequence databases
Authors: Gendel Steven M. , Jenkins John A.
Published: June 2006

A number of specialized databases have been developed to facilitate studies of human allergens. These include molecular databases focused on protein sequences and structures, informational databases focused on clinical, biochemical and epidemiological data related to protein allergens, a database on allergen nomenclature, and other knowledge bases or informational websites that are peripherally‐related to research on allergens. Examples of each type of databases are listed and described briefly in this review. Database construction and maintenance and their impact on database quality and usefulness are also discussed.
Structural bioinformatic approaches to understand cross‐reactivity
Authors: Breiteneder Heimo , Mills Clare
Published: June 2006

Cross‐reactivity of allergens results from the presence of antibody‐accessible conserved surface structures. These can best be studied when allergens have been structurally defined by X‐ray crystallography or another structure determination method. When this is not the case, mimotope technology provides a useful alternative for elucidating antibody‐binding sites on allergens. Structural bioinformatic approaches have been used to study the cross‐reactivity of inhalant allergens with labile food allergens (Bet v 1 family) as well as the cross‐reactivity between stable food allergens such as members of the nonspecific lipid transfer protein family. It was found that the degree of similarity of the structures correlated with the observed IgE cross‐reactivities. However, IgE cross‐reactivity between structurally unrelated allergens has not been demonstrated to date.
Regional variations in intramyocellular lipid concentration correlate with muscle fiber type distribution in rat tibialis anterior muscle
Authors: De Feyter Henk M.M.L. , Schaart Gert , Hesselink Matthijs K. , Schrauwen Patrick , Nicolay Klaas , Prompers Jeanine J.
Published: June 2006

1H MR spectroscopy (MRS) has proved to be a valuable noninvasive tool to measure intramyocellular lipids (IMCL) in research focused on insulin resistance and type II diabetes in both humans and rodents. An important determinant of IMCL is the muscle fiber type, since oxidative type I fibers can contain up to three times more IMCL than glycolytic type II muscle fibers. Because these different muscle fiber types are inhomogeneously distributed in rodent muscle, in the present study we investigated the distribution of IMCL within the rat tibialis anterior muscle (TA) in vivo using single‐voxel 1H MRS along with the muscle fiber distribution in the TA ex vivo determined from immunohistological assays. IMCL levels in the TA differed by up to a factor of 3 depending on the position of the voxel. The distribution of IMCL over the TA cross section was not random, but emerged in a pattern similar to the distribution of the predominantly oxidative muscle fiber types. Dietary interventions, such as high‐fat feeding and 15 hr of fasting, did not significantly change this typical fiber type‐dependent pattern of IMCL content. These results stress the importance of voxel positioning when single‐voxel 1H MRS is used to study IMCL in rodent muscle. Magn Reson Med, 2006. © 2006 Wiley‐Liss, Inc.
Chromium(VI) as a novel MRI contrast agent for cerebral white matter: Preliminary results in mouse brain in vivo
Authors: Watanabe Takashi , Tammer Roland , Boretius Susann , Frahm Jens , Michaelis Thomas
Published: June 2006

This work demonstrates that intraventricular microinjections of a low dose of potassium dichromate (0.4 μL of 10 mM solution) yield a specific contrast enhancement of white matter (WM) tracts in T1‐weighted 3D MRI of mouse brain in vivo. Pronounced and persistent signal increases (40–100% at 24 hr after injection) were observed in the corpus callosum, anterior commissure, fornix, and stria medullaris, as well as in the mammillothalamic tract and fasciculus retroflexus. These results suggest that the extracellular diffusion of diamagnetic chromium(VI) (Cr(VI)) after injection is followed by a tissue‐specific reduction to paramagnetic Cr(V) and (III), which relies predominantly on the oxidation of myelin lipids. Because Cr(VI)‐induced contrast leads to only a mild unspecific enhancement (10–20%) of gray matter (GM) structures, such as the hippocampal formation, the method reveals novel information that differs from that obtainable using other paramagnetic ions, such as manganese. Magn Reson Med, 2006. © 2006 Wiley‐Liss, Inc.
Task‐modulation of functional synchrony between spontaneous low‐frequency oscillations in the human brain detected by fMRI
Authors: Xu Guofan , Xu Yin , Wu Gaohong , Antuono Piero G. , Hammeke Thomas A. , Li Shi‐Jiang
Published: June 2006

Recent developments in functional MRI (fMRI) technology with high spatial and temporal resolution have made it possible to noninvasively detect spontaneous low‐frequency oscillations (SLOs) and quantify their functional synchrony in the human brain. In the present fMRI study the dynamic characteristics of the functional synchrony between SLOs were quantitatively determined by the phase shift index (PSI). With the use of an fMRI‐guided voxel‐selection method, the SLOs and their functional synchrony were found to be modulated by different memory tasks. The results demonstrate that SLOs in episodic memory‐related circuitry have significantly higher synchrony during the performance of declarative memory‐encoding activities compared to nondeclarative memory‐encoding activities. It is suggested that the dynamic property of SLOs and the quantitative assessment of their functional synchrony could be utilized as a biomarker to noninvasively characterize localized pathophysiological functions in the human brain. Magn Reson Med, 2006. © 2006 Wiley‐Liss, Inc.
General algorithm for automated off‐center MRI
Authors: Magland J. , Wehrli F.W.
Published: June 2006

A general formula was derived that automatically modifies any MRI pulse sequence to realize arbitrary field‐of‐view (FOV) shifts. Unlike conventional techniques for implementing off‐center MRI, the new method is completely automatic and can therefore be incorporated into the scanner hardware or software, thereby simplifying the development of MRI pulse sequences. The algorithm was incorporated into a visual pulse sequence programming environment, and several pulse sequences were programmed and tested at various off‐center locations using the new technique. Unless there is significant background field inhomogeneity or gradient nonlinearity, research sequences employing the automatic technique need only be programmed and tested at the gradient isocenter, whereas with conventional methods, artifacts can sometimes depend on the position of the FOV. Magn Reson Med, 2006. © 2006 Wiley‐Liss, Inc.
Application of parallel imaging to fMRI at 7 Tesla utilizing a high 1D reduction factor
Authors: Moeller Steen , Van de Moortele Pierre‐Francois , Goerke Ute , Adriany Gregor , Uǧurbil Kâmil
Published: June 2006

Gradient‐echo EPI, blood oxygenation level‐dependent (BOLD) functional MRI (fMRI) using parallel imaging (PI) is demonstrated at 7 Tesla with 16 channels, a fourfold 1D reduction factor (R), and fourfold maximal aliasing. The resultant activation detection in finger‐tapping fMRI studies was robust, in full agreement with expected activation patterns based on prior knowledge, and with functional maps generated from full field of view (FOV) coverage of k‐space using segmented acquisition. In all aspects the functional maps acquired with PI outperformed segmented coverage of full k‐space. With a 1D R of 4, fMRI activation based on PI had higher statistical significance, up to 1.6‐fold in an individual case and 1.25 ± .25 (SD) fold when averaged over six studies, compared to four‐segment/full‐FOV data in which the

reduction in the image signal‐to‐noise ratio (SNR) due to k‐space undersampling was compensated for by acquiring additional repetitions of the undersampled k‐space. When this compensation for
loss in SNR was not performed, the effect of PI was determined by the ratio of physiologically induced vs. intrinsic (thermal) noise in the fMRI time series and the extent to which physiological “noise” was amplified by the use of segmentation in the full‐FOV data. The results demonstrate that PI is particularly beneficial at this ultrahigh field strength, where both the intrinsic image SNR and temporal signal fluctuations due to physiological processes are large. Magn Reson Med, 2006. © 2006 Wiley‐Liss, Inc.
Cardiac fat navigator‐gated steady‐state free precession 3D magnetic resonance angiography of coronary arteries
Authors: Nguyen Thanh D. , Spincemaille Pascal , Prince Martin R. , Wang Yi
Published: June 2006

Motion artifacts and the lack of accurate detection of cardiac motion present a major challenge for high‐resolution cardiac MRI. Recently a multidimensional cardiac fat navigator was proposed to provide a fast and direct measurement of bulk cardiac motion. The objective of this study was to demonstrate the feasibility of employing the cardiac fat navigator in balanced steady‐state free precession (SSFP) free‐breathing 3D coronary MRA (CMRA). The cardiac fat navigator echo is optimized to provide both motion monitoring and epicardial fat suppression. Steady‐state magnetization preparation, which is needed for SSFP CMRA, is optimized by comparing three preparation schemes: α/2, linear ramp with 20 RF pulses (20LR), and Kaiser ramp with six RF pulses (6KR). The present preliminary human study shows that the 6KR preparation provides better image quality than both the α/2 (P < 0.0025) and the 20LR preparations (P < 0.025) for free‐breathing SSFP 3D CMRA (N = 11). Magn Reson Med, 2006. © 2006 Wiley‐Liss, Inc.
Improved deconvolution of perfusion MRI data in the presence of bolus delay and dispersion
Authors: Willats Lisa , Connelly Alan , Calamante Fernando
Published: June 2006

Cerebral blood flow (CBF) is commonly estimated from the maximum of the residue function deconvolved from bolus‐tracking data. The bolus may become delayed and/or dispersed in the vessels feeding the tissue, resulting in the calculation of an effective residue function,Reff(t), whose shape reflects the distortion of the bolus as well as the hemodynamic tissue status. Consequently the CBF is often underestimated. Since regularizing the deconvolution introduces additional distortions toReff(t), it is impossible to distinguish a true decrease in the CBF from bias introduced by abnormal vasculature. This may result in misidentification of tissue regions at risk of infarction, which could have serious clinical consequences. We propose a modified maximum‐likelihood expectation‐maximization (mML‐EM) method, which is shown by way of simulations to improve the characterization ofReff(t) across a wide range of shapes. Apointwisetermination approach for the iteration minimizes the effects of noise, and appropriate integral approximations minimize discretization errors. mML‐EM was applied to data from a patient with left internal carotid artery (ICA) occlusion. The shape of each calculatedReff(t) was used to create a map indicating voxels affected by bolus delay and/or dispersion, where CBF estimates are inherently unreliable. Such maps would be a useful adjunct for interpreting bolus‐tracking data. Magn Reson Med, 2006. © 2006 Wiley‐Liss, Inc.
Optimizing the efficiency of high‐field multivoxel spectroscopic imaging by multiplexing in space and time
Authors: Goelman Gadi , Liu Songtao , Hess David , Gonen Oded
Published: June 2006

A new strategy to yield information from the maximum number of voxels, each at the optimum signal‐to‐noise ratio (SNR) per unit time, in MR spectroscopic imaging (MRSI) is introduced. In the past, maximum acquisition duty‐cycle was obtained by multiplexing in time several single slices each repetition time (TR), while optimal SNR was achieved by encoding the entire volume of interest (VOI) each TR. We show that optimal SNR and acquisition efficiency can both be achieved simultaneously by multiplexing in space and time several slabs of several slices, each. Since coverage of common VOIs in 3D proton MRSI in the human brain typically requires eight or more slices, at 3 T or higher magnetic fields, two or more slabs can fit into the optimum TR (∼1.6 s). Since typically four or less slices would then fit into each slab, Hadamard encoding is favored in that direction for slice profile reasons. It is demonstrated that per fixed examination length, the new method gives, at 3 T, twice as many voxels, each of the same SNR and size, compared with current 3D chemical shift imaging techniques. It is shown that this gain will increase for more extensive spatial coverage or higher fields. Magn Reson Med, 2006. © 2006 Wiley‐Liss, Inc.
Large granular lymphocyte leukemia (LGL) in a child with hyper IgM syndrome and autoimmune hemolytic anemia
Authors: Kitchen Brenda J. , Boxer Laurence A.
Published: June 2006

We describe a female with a history of autosomal recessive hyper‐IgM (HIGM) syndrome along with a history of autoimmune hemolytic anemia and intermittent lymphadenopathy. She subsequently developed neutropenia, lymphocyostosis and mild thrombocytopenia. Flow cytometry of the peripheral blood revealed the presence of a marked predominance of cytotoxic T lymphocytes, shown to be clonal, with concomitant natural killer (NK) antigen expression. She responded to weekly methotrexate therapy. Pediatr Blood Cancer 2008;50:142–145. © 2006 Wiley‐Liss, Inc.
Risk of a second malignant neoplasm among 5‐year survivors of cancer in childhood and adolescence in British Columbia, Canada
Authors: MacArthur Amy C. , Spinelli John J. , Rogers Paul C. , Goddard Karen J. , Phillips Norm , McBride Mary L.
Published: June 2006

Background

We examined second malignancies, a recognized late effect of therapy among survivors of childhood and adolescent cancer, among a recent, population‐based cohort of 2,322 5‐year survivors diagnosed before 20 years of age in British Columbia (BC), Canada between 1970 and 1995.

Procedure

Survivors and second malignancies were identified from the BC Cancer Registry. Risk of second malignancy was evaluated using standardized incidence ratios (SIRs), absolute excess risk (AER), and cumulative risk. The effect of demographic, temporal, and disease‐related characteristics on risk was assessed.

Results

Fifty‐five second malignancies were observed after 26,071 person‐years of follow‐up. Relative rate of developing a second malignancy among survivors was 5 times higher than expected (SIR = 5.0, 95% CI, 3.8–6.5), and absolute excess risk was 1.7 deaths per 1,000 person‐years. Cumulative incidence of a second malignancy was 5.1% at 25 years after diagnosis of the first cancer. SIRs and absolute excess risk of subsequent cancer was higher among females (SIR = 5.9, 95% CI, 4.5–8.3 and AER = 2.66). While relative risk of second cancer was higher for those diagnosed before 10 years of age (SIR = 10.6, 95% CI, 7.1–16.0), absolute excess risk was slightly higher for those diagnosed after 10 years of age. SIRs were significantly elevated for all follow‐up periods, but absolute excess risk of a second cancer was highest among patients surviving more than 15 years.

Conclusions

Increased risk of a subsequent neoplasm is evident among childhood cancer survivors diagnosed in more recent periods than has been previously reported, continues years after diagnosis, and varies according to several risk factors. Continued surveillance is essential to quantify and characterize long‐term and changing risks for appropriate follow‐up. Pediatr Blood Cancer © 2006 Wiley‐Liss, Inc.
Elevated maternal serum alpha‐fetoprotein, umbilical vein varix, and mesenchymal dysplasia: are they related?
Authors: Mulch Amanda D. , Stallings Shawn P. , Salafia Carolyn M.
Published: June 2006

Objectives and Methods

Variceal dilatation of the umbilical vein is a rare vascular anomaly of the umbilical cord. We present a patient case where dilatation of the umbilical vein was associated with an elevated maternal serum alpha‐fetoprotein on prenatal testing and mesenchymal dysplasia on pathological evaluation of the placenta.

Results

Alterations in the villous structure of the placenta as in mesenchymal dysplasia may lead to increased placental permeability causing an elevated maternal serum alpha‐fetoprotein on antenatal testing.

Conclusion

Abnormal testing should be an indication for close evaluation of the placenta and placental structures, as well as the fetus. Copyright © 2006 John Wiley & Sons, Ltd.
Fetal abdomino‐perineal lymphangioma: differential diagnosis and management
Authors: York Douglas G. , Wolfe Honor , von Allmen Daniel
Published: June 2006

Fetal lymphangiomas are rare congenital anomalies of the lymphatic system most commonly presenting in the head and neck. Cystic abdominal lymphangiomas are more rare with only a few cases reported prenatally. We report a case of a prenatally detected abdomino‐perineal lymphangioma that mimicked the more fatal prenatally detected sacrococcygeal teratoma (SCT), which resulted in one caregiver suggesting termination of the pregnancy. This case demonstrates the importance of carefully considering the differential diagnosis of fetal abdomino‐perineal masses when counseling parents. Copyright © 2006 John Wiley & Sons, Ltd.
Improved electrical, optical, and structural properties of undoped ZnO thin films grown by water‐mist‐assisted spray pyrolysis
Authors: Pérez L. Martínez , Aguilar‐Frutis M. , Zelaya‐Angel O. , Muñoz Aguirre N.
Published: June 2006

Undoped ZnO thin films were prepared using the ultrasonic spray pyrolysis deposition technique with zinc acetylacetonate dissolved in N,N‐dimethylformamide as the source materials solution. The addition of water mist in a parallel flux to the spray solution stream was also used during deposition of the films. The addition of water mist improved the electrical characteristics of the ZnO films. Fresh ZnO samples were then thermally annealed in a H2 reducing atmosphere. X‐ray diffraction patterns show mainly the wurzite crystalline ZnO phase in the films. An electrical resistivity (ρ ) of around 2.7 × 10−2 Ω cm was measured at room temperature for the best undoped ZnO film. ρ is approximately one order of magnitude lower than the resistivities found in undoped ZnO films obtained by means of similar non‐vacuum deposition techniques. (© 2006 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Mimicking the atmospheric OH‐radical‐mediated photooxidation of isoprene: formation of cloud‐condensation nuclei polyols monitored by electrospray ionization mass spectrometry
Authors: Silva Santos Leonardo , Dalmázio Ilza , Eberlin Marcos N. , Claeys Magda , Augusti Rodinei
Published: June 2006

Recently, it has been proposed (M. Claeys et al., Science 2004; 303: 1173) that the atmospheric OH‐radical‐mediated photooxidation of isoprene is a source of two major secondary organic aerosol (SOA) components, that is, 2‐methylthreitol and 2‐methylerythritol. These diastereoisomeric tetrols, which were characterized for the first time in the fine size fraction (<2.5 µm aerodynamic diameter) of aerosols collected in the Amazon rain forest during the wet season, were proposed to enhance the capability of the aerosols to act as cloud‐condensation nuclei. In the present study, we performed the oxidation of isoprene in aqueous solution under conditions that attempted to mimic atmospheric OH‐radical‐induced photooxidization, and monitored and characterized on‐line the reaction products via electrospray ionization mass (and tandem mass) spectrometry in the negative ion mode. The results show that the reaction of isoprene with photo‐ or chemically generated hydroxyl radicals indeed yields 2‐methyltetrols. Other polyols were also detected, and they may therefore be considered as plausible SOA components eventually formed in normal or more extreme OH‐radical‐mediated photooxidation of biogenic isoprene. Copyright © 2006 John Wiley & Sons, Ltd.
Mini‐Symposium: Newborn screening for inborn errors of metabolism—Clinical effectiveness
Authors: Wilcken Bridget
Published: June 2006

With the application of tandem mass spectrometry, newborn screening has become an important topic in inborn metabolic disease. The aim of newborn screening is to produce an improved clinical outcome by early detection of disease, but it has been difficult to measure clinical effectiveness. Good evidence of clinical effectiveness has been hard to obtain because of the rarity of individual disorders, often precluding randomized controlled trials, the increase in diagnosis of individual disorders by screening, compared with clinical diagnosis, variable definitions of what constitutes a case, uncertainty about completeness of ascertainment, and differences in treatment in different geographical areas or at different times. Multiplex testing has introduced some new problems. There have been recent attempts to standardize screening in several countries, which have taken different approaches. Public pressure has driven the introduction of screening for inborn errors in some areas. Since it seems inevitable that screening may often be implemented ahead of hard evidence of benefit, ongoing evaluation of clinical effectiveness is a necessary part of any screening programme.
Breast feeding in organic acidaemias
Authors: Gokcay G. , Baykal T. , Gokdemir Y. , Demirkol M.
Published: June 2006

Breast feeding has been recommended for the dietary treatment of infants with organic acidaemias, but studies documenting clinical experience are still very few. Nine infants, diagnosed with methylmalonic acidaemia (n = 4), propionic acidaemia (n = 1), isovaleric acidaemia (n = 2) and glutaric acidaemia type I (n = 2) were breast fed after diagnosis. The age of the patients was 28.9± 13.4 months (mean ± SD) (range 10–57 months). Eight patients were diagnosed with clinical symptoms and one because of an affected sibling. After the control of acute metabolic problems, an initial period with a measured volume of expressed breast milk was continued with on‐demand breast feeding with the addition of a special essential amino acid mixture and energy supplements. Breast feeding was well tolerated in seven infants with good growth, metabolic control and neurological outcome. The duration of breast feeding was 12.3± 7.4 months (mean ± SD) (range 4–24 months) in these patients. Breast feeding was terminated in the patient with propionic acidaemia because of two acute metabolic episodes requiring hospitalization, and could not be continued in one of the patients with isovaleric acidaemia owing to shortage of breast milk. A decrease in the frequency of infections, acute metabolic episodes and hospital admissions was observed in breast‐fed infants. Breast feeding of infants with organic acidaemias is feasible with close monitoring of clinical parameters such as growth, development and biochemistry, including amino acids, organic acids and ammonia.
Limitations of enzyme replacement therapy: Current and future
Authors: Wraith J. E.
Published: June 2006

Orphan drug legislation passed in the USA in 1983 and in Europe in 1999 has encouraged biotechnology companies to develop treatments for diseases that the industry previously ignored because they affect only small numbers of people and promised only limited profitability. Incentives, exclusivity and the freedom to charge sufficient to cover development costs has led to a niche market, and patients with lysosomal storage disorders have been one of the main beneficiaries of these developments. The recombinant production of highly purified enzymes that are modified to improve tissue targeting has been a direct result of this legislation. The spectacular clinical and financial success of Cerezyme (and previously Ceredase, Genzyme) for the treatment of Gaucher disease has led to the development of enzyme replacement treatment(s) for Fabry disease and mucopolysaccharidoses types I and VI. A number of other enzyme replacement therapies are at an earlier stage in development and the next 12 months could see the launch of therapies for mucopolysaccharidosis type II and Pompe disease. Like all medical treatments, this approach has some limitations. Not all patients are suitable for treatment, some organs and tissues are corrected more readily than others, and there are problems with gauging efficacy in these highly variable disorders. Finally, the therapies are expensive, limiting access to patients from those countries that are able to afford expensive health care.
Hepatocyte transplantation for liver‐based metabolic disorders
Authors: Dhawan Anil , Mitry Ragai R. , Hughes Robin D.
Published: June 2006

Hepatocyte transplantation is being investigated as an alternative to orthotopic liver transplantation in patients with liver‐based metabolic disorders. The progress made in this field to date is reviewed. Protocols have been developed using collagenase perfusion to isolate human hepatocytes from unused donor liver tissue. Hepatocytes with a high viability can often be obtained and can be cryopreserved for later use, though with loss of function on thawing. For clinical use, hepatocytes must be prepared in clean GMP conditions with cells meeting criteria of function and lack of microbial contamination before patient use. Hepatocytes are infused intraportally into the patient's liver, where a proportion of cells will engraft and replace the deficient metabolic function without the need for major surgery. Twenty patients have now received hepatocyte transplantation, including eight children at King's College Hospital. There was a range of aetiologies of liver disease: familial hypercholesterolaemia, Crigler–Najjar syndrome type 1, urea cycle defects, infantile Refsum disease, glycogen storage disease type Ia, inherited factor VII deficiency and progressive familial intrahepatic cholestasis type 2. Clinical improvement and partial correction of the metabolic abnormality was observed in most cases. Considerable progress has been made in developing the technique, but hepatocyte transplantation is limited by the available supply of liver tissue. Hepatocytes derived from stem cells could provide alternative sources of cells in the future.
Inborn error of amino acid synthesis: Human glutamine synthetase deficiency
Authors: Häberle Johannes , Görg Boris , Toutain Annick , Rutsch Frank , Benoist Jean‐François , Gelot Antoinette , Suc Annie‐Laure , Koch Hans Georg , Schliess Freimut , Häussinger Dieter
Published: June 2006

Glutamine synthetase (GS) is ubiquitously expressed in human tissues, being involved in ammonia detoxification and interorgan nitrogen flux. Inherited systemic deficiency of glutamine based on a defect of glutamine synthetase was recently described in two newborns with an early fatal course of disease. Glutamine was largely absent in their serum, urine and cerebrospinal fluid. Each of the patients had a homozygous mutation in the glutamine synthetase gene and enzymatic investigations confirmed that these mutations lead to a severely reduced glutamine synthetase activity. From the observation in the first patients with congenital glutamine synthetase deficiency, brain malformation can be expected as one of the leading signs. In addition, other organ systems are probably involved as observed in one of the index patients who suffered from severe enteropathy and necrolytic erythema of the skin. Deficiency of GS has to be added to the list of inherited metabolic disorders as a rare example of a defect in the biosynthesis of an amino acid.
Potential of fibrates in the treatment of fatty acid oxidation disorders: Revival of classical drugs?
Authors: Djouadi F. , Aubey F. , Schlemmer D. , Gobin S. , Laforet P. , Wanders R. J. A. , Strauss A. W. , Bonnefont J. P. , Bastin J.
Published: June 2006

Exposure to fibrates leads to normalization of fatty acid oxidation (FAO) in fibroblasts from patients with myopathic forms of CPT2 deficiency or VLCAD deficiency. Correction of FAO is related to a drug‐induced increase of residual enzyme activity, and this could provide a new treatment strategy for these disorders.
Treatment with amino acids in serine deficiency disorders
Authors: de Koning T. J.
Published: June 2006

Serine deficiency disorders are rare defects in the biosynthesis of the amino acid L‐serine. At present two disorders have been reported: 3‐phosphoglycerate dehydrogenase deficiency and 3‐phosphoserine phosphatase deficiency. These enzyme defects lead to severe neurological symptoms such as congenital microcephaly and severe psychomotor retardation and in addition in patients with 3‐phosphoglycerate dehydrogenase deficiency to intractable seizures. These symptoms respond to a variable degree to treatment with L‐serine, sometimes combined with glycine. In this paper the current practice of amino acid treatment with L‐serine and glycine in serine deficiency is reviewed.
Gene therapy of metabolic diseases
Authors: Fischer Alain , Hacein‐Bey‐Abina Salima , Cavazzana‐Calvo Marina
Published: June 2006

This review surveys the potential application of gene therapy to metabolic diseases. Proof of principle has been achieved in the treatment of two inherited immunodeficiency conditions. A significant safety issue has also been observed. Several strategies are being experimentally tested for a number of metabolic diseases (more than 20) and may provide a rationale for the future development of clinical trials.
Overexpression of wild‐type creatine transporter (SLC6A8) restores creatine uptake in primary SLC6A8‐deficient fibroblasts
Authors: Rosenberg Efraim H. , Muñoz Cristina Martínez , Degrauw Ton J. , Jakobs Cornelis , Salomons Gajja S.
Published: June 2006

In the study reported, we prove that mutations in the SLC6A8 gene are responsible for SLC6A8 deficiency, a cerebral creatine deficiency syndrome (CCDS), since overexpression of the wild‐type SLC6A8 open reading frame (ORF) restores the creatine uptake profile in SLC6A8‐deficient fibroblasts.
‘Classical’ organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria: Long‐term outcome and effects of expanded newborn screening using tandem mass spectrometry
Authors: Dionisi‐Vici Carlo , Deodato Federica , Röschinger Wulf , Rhead William , Wilcken Bridget
Published: June 2006

‘Classical organic acidurias’ comprise isovaleric aciduria, propionic aciduria and methylmalonic aciduria. Available data from the literature suggest that the use of ‘new’ therapeutic strategies has improved survival but has not modified neurodevelopment. Progressive neurocognitive deterioration is almost invariably present in propionic and methylmalonic acidurias, while large‐scale studies on the long‐term outcome of patients with isovaleric aciduria are still lacking. In order to answer to some of the questions suggested by Wilson and Jungner in 1968 about the criteria of disease screening, we compared the natural history of patients with ‘classical’ organic acidurias diagnosed on clinical bases to those diagnosed through neonatal mass screening using tandem mass spectrometry. Decreased early mortality, less severe symptoms at diagnosis, and more favourable short‐term neurodevelopmental outcome were recorded in patients identified through expanded newborn screening. The short duration of follow‐up so far does not allow us to draw final conclusions about the effects of newborn screening on long‐term outcome. The evaluation of the effect of neonatal screening on the detection rate of these three diseases showed that the incidence of isovaleric aciduria was significantly higher in the screening population than in clinically detected cases, with no changes for propionic and methylmalonic acidurias. Further multicentre longitudinal studies are needed to assess the usefulness of expanded newborn screening for ‘classical’ organic acidurias and to better understand the clinical spectrum of these diseases. This paper describes the long‐term outcome and the impact of expanded newborn screening on the so‐called ‘classical’ organic acidurias (propionic aciduria, methylmalonic aciduria and isovaleric aciduria).
Methylmalonic and propionic acidurias: Management without or with a few supplements of specific amino acid mixture
Authors: Touati G. , Valayannopoulos V. , Mention K. , de Lonlay P. , Jouvet P. , Depondt E. , Assoun M. , Souberbielle J. C. , Rabier D. , Ogier de Baulny H. , Saudubray J.‐M.
Published: June 2006

In a series of 137 patients with methylmalonic acidaemia (MMA) and propionic acidaemia (PA) diagnosed since the early 1970s, we report in more detail 81 patients (51 MMA and 30 PA) diagnosed between 1988 and 2005. In this series, 14% of patients died at initial access revealing the disease before or despite treatment, 18% died later, and the remainder (68%) are still alive. All patients were treated with the same protocol of enteral feeds with a low‐protein diet adjusted to individual tolerance, carnitine, antibiotics, and only occasional use of an amino acid (AA) mixture. There was intensive follow‐up and monitoring using measurements of urinary urea. Thirty‐nine patients with severe forms, followed for more than 3 years, are analysed in particular detail. Of the 17 PA patients, 6 had moderate disability (all neonatal‐onset forms), whereas 11 were normal or slightly delayed in their mental development. Four presented with cardiomyopathy, of whom 2 died. Of the 22 MMA patients, 13 presented in the neonatal period, of whom 3 died later, 2 are in renal failure and only 5 are still alive and have a normal or slightly delayed mental development. In the 9 patients with late‐onset forms, there were no deaths and all patients but one have normal mental development. Among the 39 patients, only 40% were given an AA supplement at 3 years, and 50% between 6 and 11 years. The actual intake of natural protein was 0.92, 0.78 and 0.77 g/kg per day at 3, 6 and 11 years, respectively, in patients without AA supplementation, whereas it was 0.75, 0.74 and 0.54 g/kg per day in the group who received small quantities of AA (0.4–0.6 g/kg per day). In both groups, feeding disorders were frequent: 55% at 3 years, 35% at 6 years and 12% at 11 years. Many patients were given a food supplement by tube overnight or were even exclusively tube fed: 60% at 3 years, 48% at 6 years and still 27% at 11 years. Growth velocity was near the normal values. Plasma valine and isoleucine were low to very low, as were leucine and phenylalanine but to a lesser extent. Albumin, vitamins, trace elements and markers of bone metabolism were within the normal values. IGF1, 24‐hour urine calcium and body mass density were low. Body composition showed a normal to low lean mass and a normal to high fat mass.
Effectiveness of hyperbaric oxygen therapy in idiopathic sudden hearing loss
Authors: Satar B , Hidir Y , Yetiser S
Published: June 2006

The aim of this study was to investigate the efficacy of hyperbaric oxygen (HBO) therapy in idiopathic sudden sensorineural hearing loss (ISSHL) by comparing hearing gain and improvement rate in patients who have been placed on both HBO and medical treatment (MT) (37 patients), and patients who have received MT only (17 patients). Both groups were compared with reference to pure tone average (PTA) and the number of patients who experienced hearing gain. Of 37 patients (40 ears) who received HBO + MT, 24 (60 per cent) experienced ≥ 10 decibels (dB) improvement in PTA compared to 13 (76.4 per cent) of 17 patients who were placed on MT only. Inter- or intra-group comparison of age stratification (<50 and ≥50 ages) did not produce significant differences in PTA and in the number of patients who experienced hearing gain.

Although there are numerous studies showing efficacy of HBO therapy; this study did not reveal a trend in favour of HBO therapy.
PROJECTIVE DUALITY OF TORIC MANIFOLDS AND DEFECT POLYTOPES
Authors: DI ROCCO SANDRA
Published: June 2006

Non-singular toric embeddings with dual defect are classified. The associated polytopes, called defect polytopes, are proven to be the class of Delzant integral polytopes for which a combinatorial invariant vanishes. The structure of a defect polytope is described.
HOMOLOGICAL TRANSCENDENCE DEGREE
Authors: YEKUTIELI AMNON , ZHANG JAMES J.
Published: June 2006

Let $D$ be a division algebra over a base field $k$. The homological transcendence degree of $D$, denoted by $\text{Htr}\; D$, is defined to be the injective dimension of the algebra $D \otimes_k D^{\circ}$. We show that $\text{Htr}$ has several useful properties which the classical transcendence degree has. We extend some results of Resco, Rosenberg, Schofield and Stafford, and compute $\text{Htr}$ for several classes of division algebras. The main tool for the computation is Van den Bergh's rigid dualizing complex.
TORSIONAL RIGIDITY OF MINIMAL SUBMANIFOLDS
Authors: MARKVORSEN STEEN , PALMER VICENTE
Published: June 2006

We prove explicit upper bounds for the torsional rigidity of extrinsic domains of minimal submanifolds $P^m$ in ambient Riemannian manifolds $N^n$ with a pole $p$. The upper bounds are given in terms of the torsional rigidities of corresponding Schwarz symmetrizations of the domains in warped product model spaces. Our main results are obtained via previously established isoperimetric inequalities, which are here extended to hold for this more general setting based on warped product comparison spaces. We also characterize the geometry of those situations in which the upper bounds for the torsional rigidity are actually attained and give conditions under which the geometric average of the stochastic mean exit time for Brownian motion at infinity is finite.
FAMILIES OF $D$-MINIMAL MODELS AND APPLICATIONS TO 3-FOLD DIVISORIAL CONTRACTIONS (Proc. London Math. Soc. (3) 90 (2005) 345–370)
Authors: TZIOLAS NIKOLAOS
Published: June 2006

A gap in the proofs of Lemma 2.3 and Theorem 2.4 in the above paper is corrected.
ON THE NON-VANISHING OF ELLIPTIC CURVE $L$-FUNCTIONS AT THE CENTRAL POINT
Authors: YOUNG MATTHEW P.
Published: June 2006

We show that a large number of elliptic curve L-functions do not vanish at the central point, conditionally on the Generalized Riemann Hypothesis and on an assumption on the regular distribution of the root number.
The early drug selection of nematodes to anthelmintics: stochastic transmission and population in refuge
Authors: GABA S. , CABARET J. , GINOT V. , SILVESTRE A.
Published: June 2006

We have developed an individual-based model to reflect the complexity of the early phase of drug resistance selection in a nematode/sheep model. The infection process consists of the stochastic ingestion of infective larvae spatially aggregated in clumps. Each clump corresponds to infective larvae, which are the offspring of the mature nematodes from a given sheep. We studied the dynamics of the parasitic population and the frequency of the recessive resistance alleles during selection by anthelmintic treatments. The interaction between genetic and demographic processes illustrated the trade-off between the control of the infection and the delay of resistance selection. We confirmed the importance of the number of treatments and their timing. The same treatment frequency may result in different outcomes on resistance selection in relation to the size of the refuge (infective larvae on pasture). Treatment applied during the summer (when the mortality of infective larvae on pasture was high), may lead to a rapid selection of drug resistance and a lack of control of sheep and pasture contamination. We showed that higher stocking rates were also a force in promoting the resistance allele selection.
Using shallow linguistic analysis to improve search on Danish compounds
Authors: PEDERSEN BOLETTE SANDFORD
Published: June 2006

In this paper we focus on a specific search-related query expansion topic, namely search on Danish compounds and expansion to some of their synonymous phrases. Compounds constitute a specific issue in search, in particular in languages where they are written in one word, as is the case for Danish and the other Scandinavian languages. For such languages, expansion of the query compound into separate lemmas is a way of finding the often frequent alternative synonymous phrases in which the content of a compound can also be expressed. However, it is crucial to note that the number of irrelevant hits is generally very high when using this expansion strategy. The aim of this paper is therefore to examine how we can obtain better search results on split compounds, partly by looking at the internal structure of the original compound, partly by analyzing the context in which the split compound occurs. In this context, we pursue two hypotheses: (1) that some categories of compounds are more likely to have synonymous ‘split’ counterparts than others; and (2) that search results where both the search words (obtained by splitting the compound) occur in the same noun phrase, are more likely to contain a synonymous phrase to the original compound query. The search results from 410 enhanced compound queries are used as a test bed for our experiments. On these search results, we perform a shallow linguistic analysis and introduce a new, linguistically based threshold for retrieved hits. The results obtained by using this strategy demonstrate that compound splitting combined with a shallow linguistic analysis focusing on the argument structure of the compound head as well as on the recognition of NPs, can improve search by substantially bringing down the number of irrelevant hits.
Mechanism of fibre assembly through the chaperone–usher pathway
Authors: Vetsch Michael , Erilov Denis , Molière Noël , Nishiyama Mireille , Ignatov Oleksandr , Glockshuber Rudi
Published: June 2006

The chaperone–usher pathway directs the formation of adhesive surface fibres in numerous pathogenic Gram‐negative bacteria. The fibres or pili consist exclusively of protein subunits that, before assembly, form transient complexes with a chaperone in the periplasm. In these chaperone:subunit complexes, the chaperone donates one β‐strand to complete the imperfect immunoglobulin‐like fold of the subunit. During pilus assembly, the chaperone is replaced by a polypeptide extension of another subunit in a process termed ‘donor strand exchange’ (DSE). Here we show that DSE occurs in a concerted reaction in which a chaperone‐bound acceptor subunit is attacked by another chaperone‐bound donor subunit. We provide evidence that efficient DSE requires interactions between the reacting subunits in addition to those involving the attacking donor strand. Our results indicate that the pilus assembly platforms in the outer membrane, referred to as ushers, catalyse fibre formation by increasing the effective concentrations of donor and acceptor subunits.