bluuebunny/crossref_metadata_2025 huggingface dataset:
Peroxisomal disorders: A review
Authors: Fournier B. , Smeitink J. A. M. , Dorland L. , Berger R. , Saudubray J. M. , Poll‐The B. T.
Published: November 2004

Until recently peroxisomal disorders were considered to be extremely rare and the diagnostic procedures available for postanatal and prenatal diagnosis were not widely known. At present, 17 human disorders are linked to peroxisomal dysfunction. The clinical, biochemical and morphological peroxisome heterogeneity described in the different diseases illustrate that only combined analysis of all the different approaches will lead to a correct diagnosis and a coherent pathophysiological model to guide ongoing research. With the study of human peroxisomal diseasese, advances have been gained as to the function of the peroxisome in normal and pathological conditions. Genetic analysis of peroxisome biogenesis and research on peroxisomal targeting signals are now in progress. Peroxisomal disorders are usually classified according to the degree of biochemical impairment. In this paper, a tentative classification of peroxisomal disorders will be proposed, based on the degree of biochemical abnormalities combined with new data obtained on whether or not defective peroxisome assembly is involved: (1) disorders with peroxisome assembly deficiencies; (2) disorders with single enzyme deficiencies.

The clinical onset and the major symptoms of the various disorders, and the recently discovered findings are discussed.
Modifying exogenous glucocerebrosidase for effective replacement therapy in Gaucher disease
Authors: Brady R. O. , Murray G. J. , Barton N. W.
Published: November 2004

Important therapeutic principles were established in developing effective enzyme replacement therapy for patients with Gaucher disease. The background and sequence of the investigations that led to effective delivery of exogenous glucocerebrosidase to the lipid‐storing macrophages in patients with Guacher disease are described. The principle of targeting the intravenously injected enzyme to the mannose lectin on the surface of these cells by engineering the glycoform of the enzyme is a useful model of an essential requirement for effective enzyme therapy. Similar strategies are expected to be effective for the treatment of a number of hereditary metabolic disorders of humans.
Impaired ketogenesis in fructose‐1,6‐bisphosphatase deficiency: a pitfall in the investigation of hypoglycaemia
Authors: Morris A. A. M. , Deshpande S. , Ward‐Platt M. P. , Whitfield A. E. , Aynsley‐Green A. , Leonard J. V. , Pourfarzam M. , Bartlett K.
Published: November 2004

Intermediary metabolite concentrations were measured in blood during fasting in two patients with fructose‐1,6‐bisphosphatase deficiency. Hypoglycaemia was accompanied by markedly raised levels of plasma free fatty acids, without the expected degree of ketosis. This suggests that there is secondary impairment of ketogenesis in this condition, and could lead to diagnostic confusion.
An HPLC assay for detection of elevated urinaryS‐sulphocysteine, a metabolic marker of sulphite oxidase deficiency
Authors: Johnson J. L. , Rajagopalan K. V.
Published: November 2004

Sulphite oxidase deficiency occurs in man in two forms, as the isolated deficiency and as a syndrome of combined molybdoenzyme deficiency. This latter pleiotropic condition has as its underlying cause a defect in the synthesis of the molybdenum cofactor required for the activity of all molybdoenzymes in humans. Difficulties in diagnosis of sulphite oxidase deficiency are often encountered. A new method for detection of a key diagnostic metabolite,S‐sulphocysteine, is outlined. The procedure is based on precolumn derivatization of urinary amino acids with dimethylaminoazobenzene sulphonyl chloride (Dabsyl‐Cl) and resolution of the modifiedS‐sulphocysteine by reversed‐phase HPLC. A number of affected patients and control individuals with similar clinical symptoms have been studied, and a clear demarcation between the two groups has been noted.
Tyrosinaemia type 1 and glutathione synthetase deficiency: two disorders with reduced hepatic thiol group concentrations and a liver 4‐fumarylacetoacetate hydrolase deficiency
Authors: Lloyd A. J. , Gray R. G. F. , Green A.
Published: November 2004

Thiol groups are important components of proteins and their oxidation can lead to a substantial loss of protein function. Patients with two apparently unrelated inborn errors of metabolism, tyrosinaemia type 1 and glutathione synthetase deficiency, have been reported to show reduced cell glutathione concentrations. We have found that not only glutathione but also protein thiol concentrations are reduced in the liver in tyrosinaemia type 1 patients. We also report a case of glutathione synthetase deficiency with a substantial deficiency of liver 4‐fumarylacetoacetate hydrolase and provide evidence that glutathione, or some small‐molecular‐weight thiol, is essential for maintaining stability of this enzymein vitro. Our results suggest that the availability of thiol groups may modify the phenotype of tyrosinaemia type 1 and that liver 4‐fumarylacetoacetate hydrolase deficiency may be a secondary complicating factor in some forms of glutathione synthetase deficiency.
A modified spectrophotometric assay for porphobilinogen deaminase: its application in the detection of both carriers and patients with acute intermittent porphyria
Authors: Vázquez‐Prado J. , Sánchez‐Anzaldo F. J. , Ruiz‐Argüelles G. J. , Marín‐López E. , Lobato‐Mendizábal E.
Published: November 2004

A spectrophotometric method for porphobilinogen deaminase assay in erythrocytes is described. This test is determinant for the definite diagnosis of acute intermittent porphyria. In the method described, δ‐aminolevulinic acid is used as substrate. Mercaptoethanol and zinc ions are introduced to maintain δ‐aminolevulinic acid dehydratase in optimal conditions and to guarantee thein vitro production of porphobilinogen. An incubation temperature of 45°C leads to the production of uroporphyrins, which are measured spectrophotometrically at 405 nm, giving reproducible results. The assay can be performed easily in any clinical laboratory and is valuable for detecting both patients and carriers of acute intermittent porphyria.
Clinical approach to inherited peroxisomal disorders
Authors: Poggi‐Travert F. , Fournier B. , Poll‐The B. T. , Saudubray J. ‐M.
Published: November 2004

At least 21 genetic disorders have now been found that are linked to peroxisomal dysfunction. Whatever the genetic defect might be, peroxisomal disorders should be considered in various clinical conditions, dependent on the age of onset.

The prototype of peroxisomal disorders is represented by ‘classical’ Zellweger syndrome (ZS) which is the most severe disorder combining all the characteristic symptoms. ZS is characterized by the association of errors of morphogenesis, severe neurological dysfunction, neurosensory defects, regressive changes, hepatodigestive involvement with failure to thrive, usually early death, and absence of recognizable liver peroxisomes. Other peroxisomal disorders (pseudo‐Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), pseudo‐neonatal adrenoleukodystrophy, rhizomelic chondrodysplasia punctata (RCDP), and hyperpipecolic acidaemia) share some of these symptoms, but with varying organ involvement, severity of dysfunction, and duration of survival. The diagnosis should not cause difficulty when all the characteristic manifestations are present.

Depending on the main presenting sign, peroxisomal disorders in neonates should be suspected in two categories of circumstances: polymalformative syndrome with craniofacial dysmorphism, and severe neurological dysfunction. During the first 6 months of life, the predominant symptoms may be hepatomegaly, prolonged jaundice, liver failure, anorexia, vomiting and diarrhoea leading to failure to thrive resembling a malabsorption syndrome; severe psychomotor retardation, hearing loss and ocular abnormalities become evident. Beyond 4 years of age, behavioural changes, intellectual deterioration, visual impairment and gait abnormalities may be the presenting symptoms.

Independently of the clinical symptoms and age of onset, most peroxisomal disorders described so far can be clinically screened by recordings of electroretinogram, visual‐evoked responses, and brain auditory‐evoked responses, which are almost always abnormal. Nine of the 17 peroxisomal disorders with neurological involvement are associated with an accumulation of very long‐chain fatty acids (VLCFA), which suggests that assay of plasma VLCFA should be used as a primary test. However, assays of plasma phytanic acid and plasma/urine bile acid intermediates should also be performed in view of the recent reports of atypical chondrodysplasia variants (without rhizomelic shortening) and isolated trihydroxycholestanoic aciduria. The differential diagnoses in various clinical conditions and age periods are discussed.
DNA diagnosis of X‐linked adrenoleukodystrophy
Authors: Seneca S. , Lissens W.
Published: November 2004

The X‐linked adrenoleukodystrophy (ALD) gene was identified recently and is predicted to encode a 745‐amino‐acid peroxisomal membrane protein. Strategies have been designed for the search for mutations in the ALD gene in patients. Several mutations have now been found and it seems that many different mutations are responsible for ALD. There is no straightforward correlation between genotype and phenotype since the same mutation can cause different ALD phenotypes in the same family. However, once a mutation has been found in a family, it can be traced in all at‐risk individuals of that family, both post‐ and prenatally, without the need for very long‐chain fatty acid (VLCFA) analysis. Segregation analysis with extragenic and intragenic polymorphisms may remain useful in families where mutation analysis is not possible for practical reasons; VLCFA analysis and measurement of the peroxisomal β‐oxidation with C26:0 fatty acid as a substrate will remain the alternative. We also briefly discuss the possibilities of DNA diagnosis for other peroxisomal disorders.
Histochemistry of peroxisomal enzyme activities: A tool in the diagnosis of Zellweger syndrome
Authors: Frederiks W. M. , Bosch K. S. , Ankum M. , Wanders R. J. A.
Published: November 2004

The localization of the activity of the peroxisomal enzymesD‐amino acid oxidase and hydroxyacid oxidase was studied at the light‐microscopical level in livers and kidneys of control subjects and patients with Zellweger syndrome, an inherited disease characterized by a lack of intact peroxisomes.D‐Amino acid oxidase and hydroxyacid oxidase activities were demonstrated in unfixed cryostat sections with the cerium‐diaminobenzidine‐cobalt‐hydrogen peroxide procedure, in which cerium ions capture hydrogen peroxide, the product of both enzymes. In a second step reaction decomposition of cerium perhydroxide gives rise to a diaminobenzidine polymer complexed with cobalt ions.D‐Amino acid oxidase and hydroxyacid oxidase activities were found in peroxisomes of liver parenchymal cells, and onlyD‐amino acid oxidase in peroxisomes of proximal tubular cells of kidneys of control humans. The activities of these enzymes were not detectable in livers and kidneys of Zellweger patients. It is concluded that the cerium‐diaminobenzidine‐cobalt‐hydrogen peroxide procedure enables the demonstration of peroxisomal enzyme activities in human tissues at the light‐microscopical level and is an important tool in detecting patients with Zellweger syndrome.
Identification of a new missense mutation in Japanese phenylketonuric patients
Authors: Goebel‐Schreiner B. , Schreiner R.
Published: November 2004

A new missense mutation in the phenylalanine hydroxylase (PAH) gene was identified in 20/30 members of the families of 10 unrelated Japanese phenylketonuria (PKU) patients from Kyushu island. The point mutation was present in 20 of 40 mutant alleles. This was proved by DNA sequence analysis after polymerase chain reaction (PCR) amplification and allele‐specific oligonucleotide (ASO) hybridization. This point mutation, an A to G transition at the first base of codon 276 in exon 7, resulted in an amino acid substitution. Methionine was replaced by valine and the mutation was found to be associated with restriction fragment length polymorphism (RFLP) haplotype 4 in the investigated patients. The mutation was not found in 24 unrelated Caucasian patients from different countries. These findings may indicate a founder effect in the transmission of the mutation.
Diagnosis and prevention of lysosomal storage diseases in Russia
Authors: Krasnopolskaya K. D. , Mirenburg T. V. , Aronovich E. L. , Lebedeva T. V. , Odinokova O. N. , Demina N. A. , Kozlova V. M. , Kuznetsov M. I.
Published: November 2004

A special programme for the diagnosis and prevention of lysosomal storage diseases (LSD) was developed in the former USSR. All the patients from 814 families at risk were investigated using biochemical techniques. In total, 363 patients with mucopolysaccharidoses (MPS), mucolipidoses, glycoproteinoses, sphingolipidoses and other LSD were diagnosed; 55 families at risk sought prenatal diagnosis and 67 fetuses were investigated for MPS (types I, II, IIIA and IIIB, VI), Tay‐Sachs disease, Sandhoff disease, GM1‐gangliosidosis, metachromatic leukodystrophy, mannosidosis, Gaucher disease and multiple sulphatidosis; 17 affected fetuses were diagnosed and aborted. There was an ethnic distribution of different lysosomal storage diseases in the former USSR.
Hereditary tyrosinaemia type I: A long‐term study of the relationship between the urinary excretions of succinylacetone and δ‐aminolevulinic acid
Authors: Schierbeek H. , Beukeveld G. J. J. , van Faassen H. , van Spronsen F. J. , Bijsterveld K. , Venekamp‐Hoolsema E. E. A. , Wolthers B. G. , Smit G. P. A.
Published: November 2004

Patients with hereditary tyrosinaemia type I (HT) excrete large amounts of succinylacetone (SA) in urine. Owing to structural resemblance of SA to δ‐aminolevulinic acid (ALA), SA inhibits the second enzyme in the pathway for haeme biosynthesis, porphobilinogen synthase, resulting in increased urinary ALA excretion. We investigated the relationship between urinary SA and ALA excretions of two patients with different forms of HT (late‐infantile and juvenile). In both patients the urinary SA and ALA excretions showed a more or less inverse correlation. The patient with the early‐infantile form of HT had a relatively greater increase in urinary SA and ALA excretions in comparison to the patient with the juvenile form of HT. A possible explanation for this unexpected inverse correlation between the urinary excretion of SA and ALA might be a lack of intramitochondrial glycine, a substrate for δ‐aminolevulinic acid synthesis. It has been reported previously that high concentrations of SA reversibly and competitively inhibit the transport of glycine through membranes.
NormalN‐oligosaccharyltransferase activity in fibroblasts from patients with carbohydrate‐deficient glycoprotein syndrome
Authors: Knauer R. , Lehle L. , Hanefeld F. , von Figura K.
Published: November 2004

TheN‐oligosaccharyltransferase activity was found to be normal in fibroblasts from five patients with the carbohydrate‐deficient glycoprotein syndrome type I and type III using an assay based on dolichyldiphosphoryl‐N‐N′‐diacetylchitobiose as donor and a hexapeptide as acceptor substrate.
Personality disorder in young women with treated phenylketonuria
Authors: Waisbren S. E. , Zaff J.
Published: November 2004

Twenty‐eight young women with phenylketonuria (PKU) attending a Maternal PKU Summer Camp were interviewed and administered a personality inventory, the Minnesota Multiphasic Personality Inventory (MMPI). The 12 young women who were either late‐treated (treatment initiated after 90 days) or who had terminated the diet for a period of at least 5 years (the extended exposure group) were compared to the 16 women who were early‐treated and had remained continuously on diet (the continuously treated group). Although the mean blood phenylalanine and tyrosine concentrations at the camp for the two groups were comparable (973±344 and 1033±284 µmol/L for phenylalanine and 43±16 and 40±25 µmol/L for tyrosine), the women in the extended exposure group evidenced significantly greater psychopathology as measured by the MMPI and self‐report; thought disorder and mood disturbances were associated with diet termination in PKU.
Severity of mutation in the phenylalanine hydroxylase gene influences phenylalanine metabolism in phenylketonuria and hyperphenylalaninaemia heterozygotes
Authors: Svensson E. , Iselius L. , Hagenfeldt L.
Published: November 2004

We examined whether the degree of residual activity from the mutant phenylalanine hydroxylase (PAH) allele affected phenylalanine metabolism in heterozygotes for phenylketonuria (PKU) or non‐PKU hyperphenylalaninaemia (HPA). Discriminant analysis was carried out to find the function of fasting plasma concentrations of phenylalanine (PHE) and tyrosine (TYR) that best separated carriers from non‐carriers. This function (0.103TYR −0.214PHECORR −4.499) was subsequently used as the dependent variable, with thein vitro activity of the expressed mutant PAH as the independent variable, in a regression analysis performed on heterozygotes for mutations that had been studied in a eukaryotic cell expression system. This analysis showed a significant correlation (r=0.40,n=140,p<0.001), although there was a wide spread of values within each of the two major groups of carriers and a considerable overlap between the groups. We conclude that the severity of the mutation, as determined byin vitro expression analysis, in the mutant PAH gene is reflected in the biochemical phenotype of heterozygotes. This result emphasizes the relevance of the cell expression system used for establishing the relative severities of most mutations at the PAH locus. Differences in the activities from the carried mutant PAH allele on phenylalanine metabolism in heterozygotes are, however, small compared to the activity from the normal PAH allele and are easily obscured by other factors leading to inter‐ or intra‐individual variation in phenylalanine metabolism. Fasting plasma concentrations of phenylalanine and tyrosine thus can not be used to predict the severity of the carried PAH mutation in individual PKU or HPA heterozygotes.
Inborn errors of amino acid metabolism in North India
Authors: Kaur Manjeet , Das Prasad Ganesh , Verma Ishwar Chander
Published: November 2004

We screened 2560 referred cases for inborn errors of amino acid metabolism by chemical tests and thin‐layer chromatography of urine/plasma. In 62(2.4%) cases, eleven inherited Mendelian disorders of amino acids were identified. The four commonest disorders were homocystinuria, alcaptonuria, maple syrup urine disease and nonketotic hyperglycinaemia. Ornithinaemia was detected in two cases (0.08%), and phenylketonuria and cystinuria in two cases each (0.08%). Generalized hyperaminoacidurias were found in 90 (3.52%) subjects. The frequency pattern of the various amino acid disorders in North India was found to be remarkably different from that observed in the West.
Biochemical evidence for the requirement of continuous glucose therapy in young adults with type 1 glycogen storage disease
Authors: Wolfsdorf J. I. , Crigler J. F.
Published: November 2004

To determine whether patients with GSD‐1 need nocturnal glucose therapy after completing physical growth and development, studies were performed on two consecutive nights. On the first night uncooked cornstarch (UCS) was given at the calculated glucose production rate at 21:00 h and 02:00 h. On the second night UCS was given at 21:00 h but omitted at 02:00 h. Six GSD‐1 patients, aged 17.2–20.9 years, previously treated with continuous glucose therapy were studied. Measurements were made of plasma glucose (PG), serum insulin, growth hormone, cortisol, plasma glucagon (n=4), and blood lactate at 30–60‐min intervals. Serum uric acid, cholesterol, and triglycerides were measured at 21:00 h and 07:00 h, and serum FFA at 21:00 h, 02:00 h and 07:00 h on the first night and immediately before treatment for hypoglycaemia on the second night.

For five hours after UCS at 21:00 h, mean PG, serum insulin and blood lactate concentrations were similar on the two nights. With UCS at 02:00 h, mean PG concentrations were ≥4.1 mmol/L from 02:00 to 07:00 h. Without UCS at 02:00 h, in all subjects PG concentrations fell to <2.5 mmol/L after 6.5–8.5 h and mean blood lactate concentration increased to 7.4±3.0 mmol/L.

Young adults with GSD‐1 developed hypoglycaemia and hyperlactataemia after a relatively brief period without exogenous glucose and, therefore, need to continue nocturnal glucose therapy to prevent fasting hypoglycaemia.
Molecular basis for the phenotypical diversity of phenylketonuria and related hyperphenylalaninaemias
Authors: Güttler F. , Guldberg P. , Henriksen K. F. , Mikkelsen I. , Olsen B. , Lou H.
Published: November 2004

Conclusion

Phenylalanine hydroxylase deficiency results in a fairly continuous spectrum of metabolic phenotypes, which can now be predicted by means of molecular analysis. Methods for direct detection of previously identified mutations and mutation scanning techniques (SSCP and DGGE) have facilitated genotyping of the hyperphenylalaninaemic neonate. Genotyping will confirm that the hyperphenylalaninaemic neonate has PAH deficiency and not a BH4‐deficient form of hyperphenylalaninaemia or acquired hyperphenylalaninaemia. Genotyping will also distinguish between non‐PKU HPA neonates and PKU patients. Finally, genotyping predicts the metabolic phenotype, facilitating optimal dietary therapy from the neonatal period.

A possible relationship between mutation genotype and the ultimate prognosis of PKU (MRI changes, cognitive development), and the question of whether the maternal genotype and the mutant allele of her offspring may influence pregnancy outcome are challenges for future studies.
Extracellular and cerebrospinal fluids
Authors: Segal M. B.
Published: November 2004

The mechanism of formation of extracellular fluid is first described, followed by an explanation of the relation between osmotic force, reflection coefficient and molecular size. The possible mechanism of brain extracellular fluid formation is then proposed in relation to the restriction offered by the blood‐brain barrier.

The functions and compositions of cerebrospinal fluid (CSF) are then described followed by sections on the process of formation of CSF, the nonelectrolytes and proteins in CSF, the drainage mechanisms and protein synthesis by the choroid plexus.
Physiology and pathophysiology of organic acids in cerebrospinal fluid
Authors: Hoffmann G. F. , Meier‐Augenstein W. , Stöckler S. , Surtees R. , Rating D. , Nyhan W. L.
Published: November 2004

Concentrations of organic acids in cerebrospinal fluid (CSF) appear to be directly dependent upon their rate of production in the brain. There is evidence that the net release of short‐chain monocarboxylic acids from the brain is a major route for removing these products of cerebral metabolism. Concentrations of organic acids in blood and CSF are largely independent of each other. Quantitative reference values for the concentrations of organic acids in CSF and plasma as well as ratios of individual organic acids between CSF and plasma were determined in 35 pairs of samples from paediatric patients. Over 25 organic acids were quantifiable in all or in the majority of CSF and/or plasma specimens (limit of detection 1 µmol/L). There were substantial differences in the CSF/plasma ratios between subgroups of organic acids. Metabolites related to fatty‐acid oxidation were present in CSF in substantially less amounts than in plasma. Organic acids related to carbohydrate and energy metabolism and to amino acid degradation were present in CSF in the same amounts as or slightly smaller amounts than in plasma. Finally, some organic acids were found in substantially higher amounts in CSF than in plasma, e.g. glycolate, glycerate, 2,4‐dihydroxybutyrate, citrate and isocitrate.

Studies of organic acids in CSF and plasma samples are presented from patients with ‘cerebral’ lactic acidosis, disorders of propionate and methylmalonate metabolism, glutaryl‐CoA dehydrogenase deficiency andl‐2‐hydroxyglutaric acidura. It became apparent that derangements of organic acids in the CSF may occur independently of the systemic metabolism. Quantitative organic acid analysis in CSF will yield new information on the pathophysiology in the central nervous system (CNS) of these disorders and may prove necessary for successful monitoring of treatment of organoacidopathies, which present mainly with neurological disease. For example, in glutaryl‐CoA dehydrogenase deficiency the urinary excretion of glutarate appears to be an inadequate parameter for monitoring the effect of dietary therapy, without plasma and CSF determinations. Inl‐2‐hydroxyglutaric aciduria the elevation ofl‐2‐hydroxyglutarate was found to be greater in CSF than in plasma. In addition, some other organic acids, glycolate, glycerate, 2,4‐dihydroxybutyrate, citrate and isocitrate, were also elevated in the CSF of the patients out of proportion to normal levels in plasma and urine. High concentrations of an unknown compound, which was tentatively identified as 2,4‐dihydroxyglutarate, were found in the CSF of patients withl‐2‐hydroxyglutaric aciduria. Quantitative determination of organic acids in CSF and plasma should aid the monitoring of treatment of patients with organic acid disorders, allow investigations of metabolites in known disorders, and detect neurometabolic diseases in which the diagnostic metabolites accumulate preferentially in CSF.
Non‐ketotic hyperglycinaemia: Molecular lesion, diagnosis and pathophysiology
Authors: Tada K. , Kure S.
Published: November 2004

Non‐ketotic hyperglycinaemia (NKH) is a well‐recognized metabolic cause of life‐threatening illness in the neonate. The fundamental defect is in the glycine cleavage system, which consists of four protein components. Our study revealed that the majority of NKH patients had a specific defect in P‐protein (glycine decarboxylase). The primary lesion of NKH at gene level was investigated, using cDNA encoding human glycine decarboxylase. A three‐base deletion resulting in deletion of Phe756 was found in a Japanese patient with NKH. The majority of NKH patients in Finland, where there is a high incidence of NKH, were found to be due to a common mutation, a point mutation resulting in the amino acid substitution of Ile564 for Ser564. Prenatal diagnosis is feasible by determining the activity of the glycine cleavage system and is also possible by DNA analysis. Recent findings suggest that a high concentration of glycine in the brain may contribute to the pathophysiology of NKH by overactivatingN‐methyl‐d‐aspartate receptors allosterically, which may result in intracellular calcium accumulation, DNA fragmentation and neuronal death. These provide the possibility that early treatment withN‐methyl‐d‐aspartate receptor antagonist may prevent brain damage in NKH.
Inherited disorders of GABA metabolism
Authors: Jakobs C. , Jaeken J. , Gibson K. M.
Published: November 2004

Gamma‐aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian central nervous system, is produced from glutamic acid in a reaction catalysed by glutamic acid decarboxylase. The sequential actions of GABA‐transaminase (converting GABA to succinic semialdehyde) and succinic semialdehyde dehydrogenase (oxidizing succinic semialdehyde to succinic acid) allow oxidative metabolism of GABA through the tricarboxylic acid cycle. The inherited disorders of GABA metabolism include: (1) pyridoxine‐dependent seizures (?glutamic acid decarboxylase deficiency) (>50 patients); (2) GABA‐transaminase deficiency (2 patients/1 family); (3) succinic semialdehyde dehydrogenase deficiency (32 patients/21 families); and (4) homocarnosinosis associated with serum carnosinase deficiency (3 patients/1 family). Homocarnosine is a brain‐specific dipeptide of GABA andl‐histidine. Of these four defects, definitive enzymatic diagnoses have been made only for GABA‐transaminase and succinic semialdehyde dehydrogenase deficiencies. The presumptive mode of inheritance for all disorders is autosomal recessive, and all are associated with central nervous system dysfunction. Only succinic semialdehyde dehydrogenase deficiency manifests organic aciduria, which may account for the higher number of patients identified with this disorder; identification of additional patients with some of the other disorders will require increased request for analysis of cerebrospinal fluid metabolites by paediatricians and neurometabolic specialists.
Recent developments in Menkes disease
Authors: Kodama H.
Published: November 2004

Recent studies on Menkes disease are reviewed, focusing especially on copper transport in the cells. A large amount of copper accumulated in the organelle‐free cytoplasm, whereas mitochondria were in a state of copper deficiency, indicating that Menkes mutation probably affects copper transport from the cytosol to the organelles in the cells. Microscopic observation of the brain of the macular mouse showed that copper accumulates in the blood vessels. Observation of the brain tissue of the macular mouse after intraventricular administration of copper revealed that copper accumulates in the glia as well as the blood vessels. Copper accumulation was also observed in cultured astrocytes, a type of glial cell, indicating that the affected astrocytes accumulate blood‐borne copper and release little of it in the patients with Menkes disease. Thus the effective treatment of Menkes disease could possibly be to release trapped copper from the blood vessels and glia into the neurons.
Global and hemispheric climate variations affecting the Southern Ocean
Authors: SIMMONDS IAN , KING JOHN C.
Published: November 2004

The hemispheric and regional atmospheric circulation influences the Southern Ocean in many and profound ways, including intense air-sea fluxes of momentum, energy, fresh water and dissolved gases. The Southern Ocean ventilates a large fraction of the world ocean and hence these influences are spread globally. We use the NCEP-2 reanalysis data set to diagnose aspects of the large-scale atmospheric structure and variability and explore how these impact on the Southern Ocean. We discuss how the ‘Southern Annular Mode’ and the ‘Pacific-South American’ pattern influence the Southern Ocean, particularly in the eastern Pacific. We review the importance of atmospheric eddies in Southern Ocean climate, and the role they play in the transport of mechanical energy into the ocean. The fluxes of fresh water across the air-sea boundary influence strongly the processes of water mass formation. It is shown that climatological precipitation exceeds evaporation over most of the Southern Ocean. When averaged over the ocean from 50°S to the Antarctic coast the annual mean excess is 0.80 mm day−1. The magnitude of the flux displays only a small measure of seasonality, and its largest value of 0.92 mm day−1 occurs in summer.
Advection, krill, and Antarctic marine ecosystems
Authors: HOFMANN EILEEN E. , MURPHY EUGENE J.
Published: November 2004

Advective processes are recognized as being important in structuring and maintaining marine ecosystems. In the Southern Ocean advective effects are perhaps most clearly observed because the Antarctic Circumpolar Current (ACC) provides a connection between most parts of the system, including open ocean and continental shelf regions. The ACC also provides a mechanism for large-scale transport of plankton, such as Antarctic krill (Euphausia superba Dana), which is an important component of the Southern Ocean food web. This overview provides a summary of recent observational and modelling results that consider the importance of advection to the Southern Ocean ecosystem and, in particular, the role of advection in structuring the large-scale distribution of Antarctic krill. The results of these studies show that advection is a dominant process controlling Antarctic krill distribution and by inference an important process affecting overall structure and production of the Southern Ocean food web. The overview shows that quantifying the roles of advective and retentive physical processes, and population dynamic and behavioural biological processes in determining the regional and local distribution of krill and abundance will be an important research focus. Strategies for future Antarctic multidisciplinary research programmes that are focused on understanding advective processes at a circumpolar scale are suggested.
Variability of atmospheric winds and waves in the Arctic polar mesosphere during a stratospheric sudden warming
Authors: Bhattacharya Yajnavalkya , Shepherd G. G. , Brown S.
Published: November 2004

A ground‐based wide angle Michelson Interferometer was used to monitor the temporal variation of winds and waves in the mesopause region at Resolute Bay, Canada (74.9°N, 94.9°W) during a stratospheric warming event of February 2001. Observed variability of zonal and meridional winds is compared to the daily mean temperature fields at 3.16 hPa from assimilated stratospheric data. Reversal of eastward zonal winds is seen to occur during maximum mean temperatures in the stratospheric polar cap. Spectral analysis of the wind‐velocity time series shows the evolution of different periodicities and their amplitudes. A cool period between two warming events shows a decrease in the amplitude of the semi‐diurnal tide and an increase in the power of waves shorter than 12 hours before peak stratospheric temperatures are reached.
Environmental and biological controls on the seasonal variations in latent heat fluxes derived from flux data for three forest sites
Authors: Schulz K. , Jarvis A. J.
Published: November 2004

One difficulty that arises when predicting canopy‐scale energy fluxes is that the parameterization of complex (bio)physical soil vegetation atmosphere transfer schemes is often only partially conditioned by the information content of the eddy covariance data commonly used for calibration, rendering subsequent predictions and extrapolations somewhat uncertain. Here we derive a functional description for daily evaporative fluxes directly from observations at the canopy scale using a nonstationary regression framework. This method is applied to 3 year blocks of eddy covariance and micrometeorological data from three different FLUXNET forest sites: Harvard Forest, USA, University of Michigan Biological Station, USA, and Hyytiälä, Finland, covering a variety of climate and vegetation conditions. The approach yields a simple three‐parameter model which is based on partitioning latent heat between equilibrium latent heat fluxes and fluxes that are under strong stomatal control and hence are related to CO2 fluxes. Despite being well defined and able to account for much of the observed variations in latent heat, predictive validation of the model emphasizes the need to account for surface and subsurface water balance in such descriptions.
Substrate specificity and functional characterisation of the H+/amino acid transporter rat PAT2 (Slc36a2)
Authors: Kennedy David J , Gatfield Kelly M , Winpenny John P , Ganapathy Vadivel , Thwaites David T
Published: November 2004

Functional characteristics and substrate specificity of the rat proton‐coupled amino acid transporter 2 (rat PAT2 (rPAT2)) were determined following expression in Xenopus laevis oocytes using radiolabelled uptake measurements, competition experiments and measurements of substrate‐evoked current using the two‐electrode voltage‐clamp technique. The aim of the investigation was to determine the structural requirements and structural limitations of potential substrates for rPAT2.

Amino (and imino) acid transport via rPAT2 was pH‐dependent, Na+‐independent and electrogenic. At extracellular pH 5.5 (in Na+‐free conditions) proline uptake was saturable (Km 172±41 μM), demonstrating that rPAT2 is, relative to PAT1, a high‐affinity transporter.

PAT2 preferred substrates are L‐α‐amino acids with small aliphatic side chains (e.g. the methyl group in alanine) and 4‐ or 5‐membered heterocyclic amino and imino acids such as 2‐azetidine‐carboxylate, proline and cycloserine, where both D‐ and L‐enantiomers are transported.

The major restrictions on transport are side chain size (the ethyl group of α‐aminobutyric acid is too large) and backbone length, where the separation of the carboxyl and amino groups by only two CH2 groups, as in β‐alanine, is enough to reduce transport. Methylation of the amino group is tolerated (e.g. sarcosine) but increasing methylation, as in betaine, decreases transport. A free carboxyl group is preferred as O‐methyl esters show either reduced transport (alanine‐O‐methyl ester) or are excluded.

The structural characteristics that determine the substrate specificity of rPAT2 have been identified. This information should prove valuable in the design of selective substrates/inhibitors for PAT1 and PAT2.

British Journal of Pharmacology (2005) 144, 28–41. doi:10.1038/sj.bjp.0706029
Information Flow Structure in Large-Scale Product Development Organizational Networks
Authors: Braha Dan , Bar-Yam Yaneer
Published: November 2004

This paper analyzes the statistical properties of real-world networks of people engaged in product development (PD) activities. We show that complex PD networks display similar statistical patterns to other real-world complex social, information, biological and technological networks. The paper lays out the foundations for understanding the properties of other intra- and inter-organizational networks that are realized by specific network architectures. The paper also provides a general framework towards characterizing the functionality, dynamics, robustness, and fragility of smart business networks.
Anchoring the potential energy surface of the cyclic water trimer
Authors: Anderson Julie A. , Crager Kelly , Fedoroff Lisa , Tschumper Gregory S.
Published: November 2004

Six cyclic stationary points on the water trimer potential energy surface have been fully optimized at the MP2 level with the aug-cc-pVQZ basis set. In agreement with previous work, harmonic vibrational frequencies indicate that two structures are minima, three are transition states connecting minima on the surface while the remaining stationary point is a higher-order saddle point. The 1- and n-particle limits of the electronic energies of each of these six structures were estimated by systematically varying both the basis sets and theoretical methods. The former limit was approached with the cc-pVXZ and aug-cc-pVXZ families of basis sets (X=2–7) while MP2, CCSD(T), and BD(TQ) calculations helped examine the latter. Core correlation effects have also been assessed at the MP2 level with the cc-pCVXZ series of basis sets (X=2–5). These data have been combined to provide highly accurate relative energies and dissociation energies for these stationary points.
Thermodynamic integration at constant pressure from the nonlocal Einstein crystal
Authors: Lusk Mark T.
Published: November 2004

The Gibbs free energy of a periodic, d-dimensional crystalline assembly can be estimated using thermodynamic integration at constant pressure from a nonlocal Einstein crystal. The method is demonstrated using a two-dimensional, harmonic crystal with hexagonal symmetry for which the isobaric Gibbs function can be derived analytically.
Resonance Raman analysis of nonlinear solvent dynamics: Betaine-30 in ethanol
Authors: Zhao Xihua , Burt Jim A. , McHale Jeanne L.
Published: November 2004

Resonance Raman profiles for 14 vibrational modes of betaine-30 in ethanol at room temperature were measured at wavelengths within the first charge-transfer absorption band. The absorption spectrum and resonance Raman profiles were analyzed using time-dependent theory and a Brownian oscillator model modified to account for nonlinear solvent response; i.e., dependence of the solvent reorganization energy on the electronic state of the solute. As in our previous study of betaine-30 in acetonitrile, the solvent reorganization energy for the excited electronic state, determined from resonance Raman spectroscopy, was found to be smaller than that for the ground electronic state, determined from the absorption spectrum. The mode-dependent internal reorganization energies of betaine-30 in ethanol were found to be slightly larger than those of betaine-30 in acetonitrile. Temperature-dependent solvent reorganization energies for the ground electronic state were determined from analysis of the absorption line shape from 279 to 332 K and were found to decrease with increasing temperature. The influence of hydrogen bonding on the solvent and internal reorganization energy of betaine-30 is considered, and the physical basis for nonlinear solvent response is discussed.
Investigating the M*He exciplexes, M={Li,Na,K,Rb,Cs,Fr}: Density functional approach
Authors: Zbiri Mohamed , Daul Claude
Published: November 2004

Potential curves for the ground and the first lowest excited states of the MHe (where M={Li,Na,K,Rb,Cs,Fr}) exciplexes are calculated using the density functional theory (DFT) formalism. Relativistic calculations are carried out with and without spin-orbit (SO) coupling effect, using a zeroth order regular approximation (ZORA) approach. The depth De and position Re parameters of the potential curves for the case without spin-orbit effect are presented and compared with other works. Potential curves for Li-He, Cs-He, and Fr-He without spin-orbit effect and Cs-He with the spin-orbit effect are shown. A bond analysis is presented too, since the central interest of the study of the exciplexes is the nature and the existence of the bonding states that are the origin of emission spectra observed experimentally for these systems.
First-order semidefinite programming for the direct determination of two-electron reduced density matrices with application to many-electron atoms and molecules
Authors: Mazziotti David A.
Published: November 2004

Direct variational calculation of two-electron reduced density matrices (2-RDMs) for many-electron atoms and molecules in nonminimal basis sets has recently been achieved through the use of first-order semidefinite programming [D. A. Mazziotti, Phys. Rev. Lett. (in press)]. With semidefinite programming, the electronic ground-state energy of a molecule is minimized with respect to the 2-RDM subject to N-representability constraints known as positivity conditions. Here we present a detailed account of the first-order algorithm for semidefinite programming and its comparison with the primal-dual interior-point algorithms employed in earlier variational 2-RDM calculations. The first-order semidefinite-programming algorithm, computations show, offers an orders-of-magnitude reduction in floating-point operations and storage in comparison with previous implementations. We also examine the ability of the positivity conditions to treat strong correlation and multireference effects through an analysis of the Hamiltonians for which the conditions are exact. Calculations are performed in nonminimal basis sets for a variety of atoms and molecules and the potential-energy curves for CO and H2O.
Multireference calculations of the phosphorescence and photodissociation of chlorobenzene
Authors: Liu Ya-Jun , Persson Petter , Lunell Sten
Published: November 2004

Multireference complete active space self-consistent-field (CASSCF) and multireference CASSF second-order perturbation theory (MSCASPT2) calculations were performed on the ground state and a number of low-lying excited singlet and triplet states of chlorobenzene. The dual phosphorescence observed experimentally is clearly explained by the MSCASPT2 potential-energy curves. Experimental findings regarding the dissociation channels of chlorobenzene at 193, 248, and 266 nm are clarified from extensive theoretical information including all low-energy potential-energy curves.
Liquid crystalline behavior of a semifluorinated oligomer
Authors: Escobedo Fernando A. , Chen Zhong
Published: November 2004

Monte Carlo simulations with a coarse-grained model were performed to study the microstructure of a semifluoroalkane C20 diblock oligomer [F(CF2)10(CH2)10H]. The coarse-grained model adopted is based on previously reported united-atom force fields for alkanes and perfluoroalkanes and was first validated by simulating the phase behavior of a mixture of hexane and perfluorohexane. These preliminary simulations established the need of a significant correction factor in the Berthelot mixing rule between alkane and perfluoroalkane groups. Using such a force field, the semifluorinated C20 oligomer liquid was simulated using efficient Monte Carlo moves to sample different molecular arrangements and box dimensions so as to allow different layering structures to form. In qualitative agreement with experimental observations, a smectic-to-isotropic phase transition occurs as temperature is increased but the transition point and the structure of the smectic phase depend on the stiffness of the torsional potential and the model of van der Waals interactions adopted. We identify two smectic phases LC1′ and LC2′, whose structures do not agree with those that have been postulated before to explain x-ray diffraction data, namely, LC1 and LC2. LC1′ has a layer spacing similar to LC1 but the antiparallel packing is not observed with individual chains but with groups of chains producing a checkerboard pattern. LC2′ has fully microsegregated blocks such as LC2 but the alkyl tails are not fully stretched or interdigitated. Despite these inconsistencies, and considering that reported experimental data also reveal the presence of mixed phases, the simulated structures suggest other plausible ways how the semifluorinated chains could pack and microsegregate to best negotiate energetic and entropic constraints.
Response to “Comment on: ‘New phase for one-component hard spheres’ ” [J. Chem. Phys. 120, 11686 (2004)]
Authors: Wu Guang-Wen , Sadus Richard J.
Published: November 2004

The nature of the phases observed in a hard-sphere system is considered. Simulation data, obtained via both Monte Carlo simulation and molecular dynamics support the existence of a new phase for hard spheres. The data include configurational snapshots, compressibility factors, radial distribution functions, order parameters, and self-intermediate scattering functions. To facilitate further investigation of the new phase, the relevant configuration files are available on the internet.
Spatially adaptive lattice coarse-grained Monte Carlo simulations for diffusion of interacting molecules
Authors: Chatterjee Abhijit , Vlachos Dionisios G. , Katsoulakis Markos A.
Published: November 2004

While lattice kinetic Monte Carlo (KMC) methods provide insight into numerous complex physical systems governed by interatomic interactions, they are limited to relatively short length and time scales. Recently introduced coarse-grained Monte Carlo (CGMC) simulations can reach much larger length and time scales at considerably lower computational cost. In this paper we extend the CGMC methods to spatially adaptive meshes for the case of surface diffusion (canonical ensemble). We introduce a systematic methodology to derive the transition probabilities for the coarse-grained diffusion process that ensure the correct dynamics and noise, give the correct continuum mesoscopic equations, and satisfy detailed balance. Substantial savings in CPU time are demonstrated compared to microscopic KMC while retaining high accuracy.
Ar
n
HF
van der Waals clusters revisited. I. New low-energy isomeric structures for n=6–13
Authors: Xu Minzhong , Jiang Hao , Bačić Zlatko
Published: November 2004

New low-lying isomeric structures of ArnHF clusters are reported for n=6–13. They were determined using simulated annealing and evolutionary programing, for pairwise additive intermolecular potential energy surfaces. New global minima were found for the clusters with n=7, 10, 11. The new lowest-energy structure of Ar7HF and several new local minima for n=6, 7 clusters have the HF bound on a threefold surface site, consistent with the recent spectroscopic data for ArnHF clusters in helium nanodroplets. A new type of low-energy local minima were determined for n=9–13 clusters.