bluuebunny/crossref_metadata_2025 huggingface dataset:
Firsthand Learning Through Intent Participation
Authors: Rogoff Barbara , Paradise Ruth , Arauz Rebeca Mejía , Correa-Chávez Maricela , Angelillo Cathy
Published: December 2002

This article examines how people learn by actively observing and “listening-in” on ongoing activities as they participate in shared endeavors. Keen observation and listening-in are especially valued and used in some cultural communities in which children are part of mature community activities. This intent participation also occurs in some settings (such as early language learning in the family) in communities that routinely segregate children from the full range of adult activities. However, in the past century some industrial societies have relied on a specialized form of instruction that seems to accompany segregation of children from adult settings, in which adults “transmit” information to children. We contrast these two traditions of organizing learning in terms of their participation structure, the roles of more- and less-experienced people, distinctions in motivation and purpose, sources of learning (observation in ongoing activity versus lessons), forms of communication, and the role of assessment.
Using DFT methods for the prediction of the structure and energetics of metal‐binding sites in metalloproteins
Authors: Rulíšek Lubomír , Havlas Zdeněk
Published: December 2002

In recent years, density functional theory (DFT) methods have been successfully applied in the area of quantum bioinorganic chemistry. Often, they are the only methods of choice for the calculations of the accurate molecular properties of model systems containing transition metal(s) (TMs) and up to additional 50 atoms. In our contribution, we present an example of the application of DFT methods for the quantitative estimates of complexation energies of several TM ions (Co2+, Ni2+, Cu2+, Zn2+, Cd2+, and Hg2+) in general metal‐binding sites in metalloproteins. Our approach is based on the calculations of the interaction energies of model functional groups with the TM ions, defined as the substitution energy of single water molecule from the coordination sphere of a metal ion, and the evaluation of the cooperative effect, defined as the nonadditive part of the substitution of the second water molecule. It is demonstrated that it is possible to derive complexation energy of the given TM ion in “per‐substituted” [MXn]2+ site by combining the above two contributions with 5‐ to 15‐kcal/mol accuracy and thus a number of metal‐binding sites in metalloproteins can be readily scanned for their specificity toward the studied TM ions. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem, 2003
Density functional theory and Hartree–Fock studies of the geometric and electronic structure of neutral and doped ethylenedioxythiophene (EDOT) oligomers
Authors: Dkhissi A. , Beljonne D. , Lazzaroni R. , Louwet F. , Groenendaal L. , Brédas J. L.
Published: December 2002

The geometric and electronic structure of 3,4‐ethylenedioxythiophene oligomers, ranging in size up to the decamer, have been calculated with density functional theory according to Becke's three‐parameter exchange functional and the gradient‐corrected functional of Lee, Yang, and Paar (DFT/B3LYP/6‐31G) and ab initio Hartree–Fock (HF/6‐31G) methods. A comparison between the energetics of the aromatic and quinoid forms in the neutral state shows as expected that the former is more stable. For both the singly and doubly positively charged compounds, HF is found to localize the excess charge around the center of the molecule, whereas DFT leads to delocalization of the charge all along the conjugated path. The optical properties calculated at the semiempirical level (intermediate neglect of differential overlap/single configuration, (INDO/SCI) on the basis of the geometries provided by DFT and HF are also analyzed. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem, 2002
The Role of Referent and Expert Power in Mutual Help
Authors: Salem Deborah A. , Reischl Thomas M. , Gallacher Fiona , Randall Katie Weaver
Published: December 2002

This study explored the roles of referent power (i.e., influence based on sense of identification) and expert power (i.e., influence based on knowledge and expertise) in Schizophrenics Anonymous (SA), a mutual‐help group for persons experiencing a schizophrenia‐related illness. The study describes SA participants' experience of referent and expert power with SA members, SA leaders, and with mental health professionals. It also examines whether or not referent and expert power ascribed to fellow SA participants predicts the perceived helpfulness of the group. One hundred fifty‐six SA participants were surveyed. Participants reported experiencing higher levels of referent power with fellow SA members and leaders than with mental health professionals. They reported higher levels of expert power for mental health professionals and SA leaders than for SA members. The respondents' ratings of their SA group's helpfulness was significantly correlated with ratings of referent and expert power. Although expert power was the best independent predictor of helpfulness, a significant interaction between referent and expert power indicated that when members reported high referent power, expert power was not related to helpfulness. These results are interpreted to suggest that there are multiple forms of social influence at work in mutual help.
Where the Girls (and Women) Are
Authors: Bertram Corrine , Hall Julia , Fine Michelle , Weis Lois
Published: December 2002

This paper takes up a theoretical and empirical investigation of how two community‐based projects for young women both create safety from community and domestic violence but how, in the process, discourses of multicultural inclusion define one site, and racist discourses of exclusion float through the other site. By relying on two intensive qualitative case studies of community‐based organizations for girls, one exclusively White and working class and the other expressly multicultural and antiracist, we try to identify those structures and practices that support feminist, but inadvertently racist, work and those structures and practices that enable, at once, feminist and antiracist consciousness and praxis.
Searching for Feminism: An Analysis of Community Psychology Literature Relevant to Women's Concerns
Authors: Angelique Holly L. , Culley Marci R.
Published: December 2002

Articles published in both the American Journal of Community Psychology and Journal of Community Psychology, from their inception in 1973 through 1997, were content analyzed for women relevance, diversity, feminism, and historical change. Overall, 9.8% of the articles reviewed ($of1$N = 2,178) were considered women relevant, 4% recognized diversity among women, and 3% were considered feminist. There was an average yearly increase in women‐relevant and feminist articles from 7.3 pre‐1990 to 11.2 post‐1990, and 1.6 pre‐1990 to 4.6 post‐1990, respectively. Overall, mental health and motherhood were the most addressed content areas. Among feminist articles, gender roles and violence against women were most salient. Race and SES were the most noted issues of diversity in both women‐relevant and feminist articles. While an increase in feminist publications by both journals is promising, stereotypes of women and other oppressed groups continue to be perpetuated.
Stories of Relative Privilege: Power and Social Change in Feminist Community Psychology
Authors: Mulvey Anne , Terenzio Marion , Hill Jean , Bond Meg A. , Huygens Ingrid , Hamerton Heather R. , Cahill Sharon
Published: December 2002

Stories about community work in New Zealand and Scotland are presented to describe and reflect on issues central to feminist community psychology. Organizing a lesbian festival, Ingrid Huygens describes feminist processes used to equalize resources across Maori (indigenous) and Pakeha (white) groups. Heather Hamerton presents her experiences as a researcher using collective memory work to reflect on adolescent experiences related to gender, ethnicity, and class. Sharon Cahill chronicles dilemmas and insights from focus groups about anger with women living in public housing in Scotland. Each story chronicles experiences related to oppression and privilege, and describes the author's emotions and reflections. Individually and collectively, the stories illustrate the potential offered by narrative methods and participatory processes for challenging inequalities and encouraging social justice.
Coping, Conflictual Social Interactions, Social Support, and Mood Among HIV‐Infected Persons
Authors: Fleishman John A. , Sherbourne Cathy Donald , Crystal Stephen , Collins Rebecca L. , Marshall Grant N. , Kelly Mark , Bozzette Samuel A. , Shapiro Martin F. , Hays Ron D.
Published: December 2002

This study considers the interrelationships among coping, conflictual social interactions, and social support, as well as their combined associations with positive and negative mood. Research has shown that each of these variables affects adjustment to stressful circumstances. Few studies, however, examine this full set of variables simultaneously. One hundred forty HIV‐infected persons completed a questionnaire containing measures of coping, social support, conflictual social interactions, and positive and negative mood. Factor analyses showed that perceived social support and conflictual social interactions formed separate factors and were not strongly related. Compared to perceived social support, social conflict was more strongly related to coping behaviors, especially to social isolation, anger, and wishful thinking. Conflictual social interactions were more strongly related to negative mood than was perceived social support. Coping by withdrawing socially was significantly related to less positive and greater negative mood. The findings point to the importance of simultaneously considering coping, supportive relationships, and conflictual relationships in studies of adjustment to chronic illness. In particular, a dynamic may occur in which conflictual social interactions and social isolation aggravate each other and result in escalating psychological distress.
Moving Beyond the Illness: Factors Contributing to Gaining and Maintaining Employment
Authors: Cunningham Kiran , Wolbert Randall , Brockmeier Mary Beth
Published: December 2002

The work presented here, exploratory in nature, uses a comparative and qualitative approach to understand the factors associated with the ability of individuals with severe and persistent mental illness to successfully gain and maintain employment. Based on open‐ended interviews with individuals in an Assertive Community Treatment (ACT) program, we compare the experiences of those who have been successful gaining and maintaining employment, with those who have been successful gaining but not maintaining work, and those who have been unsuccessful gaining employment. The three groups seemed to differ in three significant ways: (1) in the ways the individuals talked about their illness, (2) in the ways the individuals talked about work, and (3) in the strategies they described for coping with bad days. In each of these areas individuals' awareness of and attitude toward their illness was significant. The findings have clear implications for agencies working to help people with severe and persistent mental illness obtain and maintain employment.
Neighborhood Disorder, Fear, and Mistrust: The Buffering Role of Social Ties with Neighbors
Authors: Ross Catherine E. , Jang Sung Joon
Published: December 2002

This paper proposes that individuals who report that they live in neighborhoods characterized by disorder—by crime, vandalism, graffiti, danger, noise, dirt, and drugs—have high levels of fear and mistrust. It further proposes that an individual's alliances and connections with neighbors can buffer the negative effects of living in a neighborhood characterized by disorder on fear and mistrust. Results from a representative sample of 2482 Illinois residents collected by telephone in 1995 support the propositions. Living in a neighborhood with a lot of perceived disorder significantly affects mistrust and the fear of victimization, adjusting for sociodemographic characteristics. Perceived neighborhood disorder and social ties significantly interact: informal social ties with neighbors reduce the fear‐ and mistrust‐producing effects of disorder. However, formal participation in neighborhood organizations shows little buffering effect.
Feminist Approaches to Social Science: Epistemological and Methodological Tenets
Authors: Campbell Rebecca , Wasco Sharon M.
Published: December 2002

This paper is a primer for community psychologists on feminist research. Much like the field of community psychology, feminist scholarship is defined by its values and process. Informed by the political ideologies of the 1970s women's movement (liberal, radical, socialist feminism, and womanism), feminist scholars reinterpreted classic concepts in philosophy of science to create feminist epistemologies and methodologies. Feminist epistemologies, such as feminist empiricism, standpoint theory, and postmodernism, recognize women's lived experiences as legitimate sources of knowledge. Feminist methodologies attempt to eradicate sexist bias in research and find ways to capture women's voices that are consistent with feminist ideals. Practically, the process of feminist research is characterized by four primary features: (1) expanding methodologies to include both quantitative and qualitative methods, (2) connecting women for group‐level data collection, (3) reducing the hierarchical relationship between researchers and their participants to facilitate trust and disclosure, and (4) recognizing and reflecting upon the emotionality of women's lives. Recommendations for how community psychologists can integrate feminist scholarship into their practice are discussed.
Mutation prevalence among 47 unrelated Japanese patients with Gaucher disease: identification of four novel mutations
Authors: Ida H. , Rennert O. M. , Kawame H. , Maekawa K. , Eto Y.
Published: December 2002

Utilizing PCR and PCR‐SSCP analysis we investigated the prevalence of glucocerebrosidase gene mutations in 47 unrelated Japanese patients with Gaucher disease. Sixty alleles (63.8%) and 20 alleles (21.3%) were identified by analysis for common mutations and PCR‐SSCP analysis, respectively. The L444P and F213I mutations were common, accounting for 41 alleles (43.6%) and 14 alleles (14.9%). R496C, D409H, S366G and 1447‐1466 del ins TG mutations were identified in 5, 3, 3 and 3 alleles, respectively. The other mutations were unique. In spite of vigorous screening, 14 alleles (14.9%) could not be identified. Four novel mutations were identified by PCR‐SSCP analysis: G189V, S366G, K413Q and R433G. These data indicate that besides the L444P mutation no other frequent mutation is present and there is broad heterogeneity of the glucocerebrosidase gene mutations in Japanese patients with Gaucher disease.
Essential fatty acids in clinically stable children with propionic acidaemia
Authors: Decsi T. , Sperl W. , Koletzko B.
Published: December 2002

Disturbances of fatty acid metabolism with accumulation of odd‐chain fatty acids have been reported in propionic acidaemia (PA). It is not known whether the synthesis of long‐chain polyunsaturated fatty acids (LCPUFA) is also affected. In five clinically stable children with PA (median age 8 years, range 3.5‐9.5 years; median percentage fibroblast propionyl‐CoA carboxylase activity 0.8, range 0.8‐1.5), we determined the fatty acid composition of plasma phospholipids, triglycerides and sterol esters and compared the results with those of 18 age‐matched healthy controls. Odd‐numbered fatty acids were found in all samples of PA patients but in controls median values were zero. Percentage contributions of substrate (linoleic acid, C18:2 ω‐6) and principal product (arachidonic acid, C20:4 ω‐6) of ω‐6 LCPUFA synthesis did not differ between patients and controls. Similarly, there were no differences between both groups in the substrate (α‐linolenic acid, C18:3 ω‐3) and principal product (docosahexaenoic acid, C22:6 ω‐3) of ω‐3 LCPUFA formation. We conclude that disturbances of fatty acid metabolism in clinically stable children with PA do not affect LCPUFA synthesis.
Cardiac mitochondrial dysfunction and DNA depletion in children with hypertrophic cardiomyopathy
Authors: Marin‐Garcia J. , Ananthakrishnan R. , Goldenthal M. J. , Filiano J. J. , Perez‐Atayde A.
Published: December 2002

Abnormalities in specific mitochondrial respiratory enzymes and DNA (mtDNA) have been reported in cardiomyopathy. In this study, we report 4 cases of severe hypertrophic cardiomyopathy (HCM) in which specific cardiac mitochondrial enzyme activity defects were found, including complex I (n = 2), complex III (n = 2), complex IV (n = 2) and complex V (n = 1). Other abnormalities were also noted including a marked depletion of mtDNA (n = 1) and decreased content of subunit 2 of cytochrome c oxidase (n = 1). None of the mtDNA point mutations and common deletions previously found in association with cardiomyopathy were detected in these patients. These data indicate that specific respiratory enzyme activity defects are frequently present in HCM. Also, our finding of a marked depletion of mtDNA in 1 patient suggests that cardiac mtDNA depletion, previously unreported in HCM, needs further examination in order to establish whether it plays a primary role in its pathogenesis.
The role of vitamins in the pathogenesis and treatment of hyperhomocyst(e)inaemia
Authors: Ubbink J. B.
Published: December 2002

The relation between vitamin nutritional status and circulating plasma homocyst(e)ine concentrations is reviewed. Several studies have shown that plasma concentrations of folate, vitamin B12 and pyridoxal 5′‐phosphate are inversely associated with plasma total homocyst(e)ine concentrations. Of the three vitamins mentioned above, folate is the most powerful homocyst(e)ine lowering agent and a daily supplement of 0.65 mg/day is sufficient to normalize moderate hyperhomocyst(e)inaemia in most individuals with normal renal function. In patients with severe renal failure, high doses of folate are required to treat hyperhomocyst(e)inaemia. Folic acid is ineffective in reducing plasma total homocyst(e)ine concentrations in patients with a vitamin B12 deficiency. Vitamin B6 supplementation has no effect on fasting plasma total homocyst(e)ine concentrations, but attenuates the post‐methionine load plasma homocyst(e)ine peak.

At least one report has shown that some individuals appear to be unable to maintain plasma total homocyst(e)ine concentrations in the normal reference range by a dietary intake of folic acid only. Long‐term vitamin supplementation may be indicated in these individuals. However, the clinical benefit of vitamin supplementation has not yet been demonstrated and controlled trials are urgently required.
Metabolic control and renal dysfunction in type I glycogen storage disease
Authors: Wolfsdorf J. I. , Laffel L. M. B. , Crigler J. F.
Published: December 2002

This study was undertaken to determine the effect on renal function of continuous glucose therapy from early childhood. Twenty‐three subjects, median age 13.9 years, range 5.9‐26.9 years, with type I glycogen storage disease (GSDI) treated with continuous glucose therapy from a median age of 1.3 years, range 0.1‐12.9 years, had 24 h monitoring of metabolites and glucoregulatory hormones on their home feeding regimen to assess metabolic control at approximately yearly intervals for a median duration of 8 years. During the most recent evaluation, 24 h urinary albumin excretion rate (AER), kidney size, and creatinine clearance (Ccr) were measured.

CCr was unrelated to age and was increased (>2.33 ml/s per 1.73 m2) in 10/23 (43%). Mean kidney length exceeded 2SD in 16/23 (70%). AER was normal in all five subjects < 10 years and was increased (> 10 µg/min) in 8/23 (35%), all > 10 years of age. AER was significantly greater in subject of similar age who started continuous glucose therapy later in childhood and was significantly higher in subjects with lower mean 24 h plasma glucose concentrations and higher mean 24 h blood lactate concentrations, both at the time of assessment of renal function and over the preceding 5 years.

GSDI subjects with persistently elevated concentrations of blood lactate, serum lipids and uric acid are at increased risk of nephropathy. Optimal dietary therapy instituted early in life may delay, prevent, or slow the progression of renal disease.
Pyruvate dehydrogenase complex deficiency and absence of subunit X
Authors: De Meirleir L. , Lissens W. , Benelli C. , Marsac C. , De Klerk J. , Scholte J. , Van Diggelen O. , Kleijer W. , Seneca S. , Liebaers I.
Published: December 2002

The pyruvate dehydrogenase complex (PDHc) is a multienzyme complex consisting of three catalytic and two regulatory enzymes, as well as a less well defined subunit called protein X. PDHc deficiency is a common cause of congenital lactic acidosis. Most patients with PDH deficiency have a mutation in the α chain of the PDH E1 enzyme. Very few patients have been described in whom the basic defect of a PDH deficiency is situated in the X protein. We studied a boy with severe lactic acidosis and developmental delay in whom a deficiency of PDH activity led to further investigations. Immunochemical analysis with anti‐PDHc antibodies demonstrated an absence of the X component. This report is the fourth family in which an abnormal protein X has been found. In cases with PDH deficiency where no mutation of the PDHE1α gene is found, further investigations by means of immunoblotting with specific antibodies against the different subunits should be performed.
Neurological dysfunction in methylmalonic acidaemia is probably related to the inhibitory effect of methylmalonate on brain energy production
Authors: Wajner M. , Coelho J.C.
Published: December 2002

Methylmalonic acidaemia is an inherited metabolic disorder caused by a severe deficiency of the activity of the enzyme L‐methylmalonyl‐CoA mutase or its cofactor 5′‐deoxyadenosylcobalamin, resulting in tissue accumulation of large quantities of methylmalonic acid. Among the various clinical features, neurological symptoms are frequently observed. Patients may present cerebral atrophy and basal ganglia abnormalities are common. In the present report, we update the current knowledge on the influence of methylmalonic acid on brain metabolism in the hope of better understanding the neurological dysfunction characteristic of methylmalonic acidaemia. We present evidence showing that the metabolite inhibits brain energy production by various mechanisms and propose that a fall in cellular ATP generation leading to excitotoxicity is crucial for the occurrence of the neurological damage observed in these patients.
Intragenic complementation at the argininosuccinate lyase locus: Reconstruction of the active site
Authors: Howell P. L. , Turner M. A. , Christodoulou J. , Walker D. C. , Craig H. J. , Simard L. R. , Ploder L. , McInnes R. R.
Published: December 2002

Intragenic complementation has been observed at the argininosuccinate lyase (ASL) locus and the ASL alleles in the ASL‐deficient cell strains of two complementation phenotypes have been identified. The frequent complementers, strains that participate in the majority of the complementation events, were found to be either homozygous or heterozygous for the Q286R allele, while the high‐activity complementers, those strains in which complementation is associated with a high restoration of activity, were found to be either homozygous or heterozygous for the D87G allele. Direct proof of the intragenic complementation observed at the ASL locus has been obtained with the co‐expression of the D87G and Q286R alleles in COS cells. A significant increase in the ASL activity was observed when the two alleles were co‐expressed relative to the expression of each mutant allele alone. The increase in activity was comparable to that observed previously in the fibroblast complementation studies. The structure determinations of ASL and the homologous eye lens protein, duck δII crystallin, have revealed that the active site of ASL is made up of residues from three different monomers. The structural mapping of the Q286 and D87 residues shows that both are located near the active site but that, in any one active site, each is contributed by a different monomer. The molecular symmetry of the ASL protein is such that when mutant monomers combine randomly, one active site will contain both mutations and at least one active site will contain no mutations at all. It is these ‘native’ active sites in the hybrid Q286R/D87G proteins that give rise to the partial recovery of enzymatic activity observed during intragenic complementation.
Mucolipidosis type IV: Abnormal transport of lipids to lysosomes
Authors: Bargal R. , Bach G.
Published: December 2002

Mucolipidosis type IV (MLIV) is a lysosomal storage disorder in which various phospholipids and gangliosides accumulate. The cause of this storage has not yet been identified. Loading experiments in cultured fibroblasts with radioactive phosphatidylcholine ([14C]PC) labelled either in the acyl groups or in the choline residue, indicated increased retention of this lipid in the lysosomes of these patients. Chase experiments in intact fibroblasts, on the other hand, indicated normal degradation and discharge of the radioactive PC in MLIV lysosomes. This was further supported by measurements of the degradation of [14C]PC by isolated lysosomes which indicated normal breakdown of PC in MLIV. Cultured fibroblasts from Hunter (MPSII) patients, which contain enlarged and numerous lysosomes, did not store [14C]PC when compared to normal controls, indicating that the storage of this lipid in MLIV is not a secondary phenomenon caused by the presence of enlarged and numerous lysosomes in these cells. Incubation of [14C]PC at 18°C limits the endocytosis process only up to early endosomes. This temperature did not yield increased retention of [14C]PC in MLIV, indicating that accumulation occurs only after the PC reached late endosomes or the lysosomes.

The data indicate that PC as well as other phospholipids and gangliosides accumulate in MLIV apparently owing to a defect in the endocytosis process of membranous components. This defect apparently leads to excessive transportation of these macromolecules into lysosomes rather than their recycling to the plasma membrane. The endocytosis of membrane components is different from receptor‐mediated endocytosis which is not affected in MLIV. Once the membrane macromolecules reach the lysosomes in MLIV they are normally catabolized and normally discharged. This may explain the heterogeneity of the stored materials in MLIV. The normal catabolism of macromolecules in the lysosomes is reflected in the minor deterioration in the clinical manifestations of these patients.
Disorders of homocysteine metabolism
Authors: Fowler B.
Published: December 2002

This review of recent advances covers (1) the metabolism of methionine and its regulation, emphasizing interactions with the three important vitamins folate, cobalamin and pyridoxine; (2) present knowledge of enzymological and molecular‐genetic aspects of homozygous deficiencies of the three enzymes which cause elevated homocyst(e)ine; (3) recent clinical findings, post‐methionine loading results related to enzyme and mutation studies in obligate heterozygotes for cystathionine β‐synthase deficiency; (4) important new evidence for disturbed homocysteine metabolism in neural tube defects, particularly based on studies of the thermolabile methylene‐tetrahydrofolate reductase mutation which is also of importance in vascular disease; (5) the suitability and limitations of animal models that have so far been described.
The natural history of vascular disease in homocystinuria and the effects of treatment
Authors: Wilcken D. E. L. , Wilcken B.
Published: December 2002

Among 40 patients with homocystinuria due to cystathionine β‐synthase deficiency diagnosed in the state of New South Wales, Australia (population 6 million) and followed long‐term, there were 10 deaths at ages 2‐30 years. Of these 8 were definite vascular deaths, one was a presumed vascular death, and the other was due to an accident and unrelated to homocystinuria. The vascular deaths were all early cases and only one patient, a pyridoxine‐responsive 30‐year‐old woman, had been prescribed adequate treatment although it was uncertain that she was taking it.

In 32 patients of mean age 30 years (range 9‐66 years) there were 539 patient‐years of treatment with pyridoxine, folic acid and hydroxocobalamin. There were 17 pyridoxine‐responsive patients and all maintained plasma total free homocyst(e)ine levels <200µmol/L over an average treatment period of 16.6 years. The 15 non‐responsive patients received additionally 6‐9 g of betaine daily. This resulted in a further 74% mean decline (±14% SD) in plasma total free homocyst(e)ine, persisting during an average (post‐betaine) treatment period of 11 years; current mean ± SD levels are 33 ± 17 µmol/L (n=15).

There were two vascular events during treatment, one fatal pulmonary embolus (see above) and one myocardial infarction, whereas without treatment, 21 would have been expected, χ2 = 14.22, p = 0.0001, relative risk 0.09 (95% CI 0.02‐0.38). There were no events during 258 patient‐years of treatment in the 15 pyridoxine‐nonresponsive patients (p<0.005 versus expected untreated). Nineteen patients had a total of 19 major and 15 minor operations requiring anaesthetic, and three had successful pregnancies, one whilst receiving betaine. There were no thromboembolic complications.

We conclude that treatment which effectively lowers circulating homocyst(e)ine, even to suboptimal levels, markedly reduces cardiovascular risk in patients with cystathionine β‐synthase deficiency, and that betaine therapy contributes importantly to this in pyridoxine‐nonresponsive patients. Betaine as additional therapy is safe and effective for at least 16 years.
Intravenous immune globulin in lysinuric protein intolerance
Authors: Dionisi‐Vici C. , De Felice L. , El Hachem M. , Bottero S. , Rizzo C. , Paoloni A. , Goffredo B. , Sabetta G. , Caniglia M.
Published: December 2002

In addition to systemic manifestations with skeletal, pulmonary, renal, and haematological signs, lysinuric protein intolerance (LPI), a membrane transport defect of cationic amino acids, is often complicated by severe life‐threatening immunological manifestations. A 10‐year‐old boy with LPI who exhibited a severe systemic immunohaematological disease is described here. This patient showed cutaneous lesions similar to the subacute form of systemic lupus erythematosus, severe anaemia and dysproteinaemia, and a marked reduction of circulating T lymphocytes, mainly the CD4+ cells. In vitro bone marrow cell culture studies showed that addition of patient's serum induced macrophage proliferation and inhibited erythroid progenitor cell growth. Treatment with high‐dose intravenous immune globulin resolved most of the clinical and laboratory abnormalities.
Abnormal glutathione conjugation in patients with tyrosinaemia type I
Authors: Mulders T. M. T. , Bergman D. J. W. , Poll‐The B.‐T. , Smit G. P. A. , Breimer D. D. , Mulder G. J. , Duran M. , Smeitink J. A. M.
Published: December 2002

Previous studies have suggested that tyrosinaemia type I may be associated with reduced glutathione availability due to conjugation of tyrosinaemia‐associated reactive intermediates with glutathione. In the present study, the glutathione/glutathione S‐transferase system of two tyrosinaemia patients and three healthy controls were characterized by administering the racemic sedative drug bromisoval, a probe drug for assessing glutathione conjugation activity in vivo. Furthermore, concentrations of glutathione and glutathione S‐trasnferase class alpha (GSTA) isoenzymes as well as the glutathione S‐transferase class mu phenotype were assessed in the blood of six tyrosinaemia patients.

The excretion of bromisoval mercapturates in healthy children was comparable to that observed in healthy adults. Tyrosinaemia patients were found to have a very high urinary recovery of bromisoval mercapturates (≥60% of the dose compared to about 30% for healthy, age‐matched children and adults), which could be attributed mainly to a higher urinary excretion of the mercapturate derived from S‐bromisoval. Healthy children and adults predominantly excrete the (R)‐bromisoval mercapturate. The differences in amount excreted as well as in stereoselectivity of the urinary excretion of bromisoval mercapturates in tyrosinaemia patients are possibly related to an increased activity of specific glutathione S‐transferase isoenzymes.

Plasma glutathione and blood cell glutathione disulphide concentrations in tyrosinaemia patients were normal. Low blood cell glutathione concentrations were in general found only in two patients with a poor clinical condition. These results indicate that, in contrast to previous suggestions, reduced glutathione availability is not a generalized problem in (stabilized) tyrosinaemia patients.
A novel mutation found in an adrenoleukodystrophy patient who underwent bone marrow transplantation
Authors: Osaka H. , Sekiguchi H. , Inoue K. , Ikuta K. , Sakakihara Y. , Oka A. , Onishi H. , Miyakawa T. , Suzuki K. , Kosaka K. , Matsuyama S.
Published: December 2002

We identified a novel mutation, L322P, in a patient with X‐linked adrenoleukodystrophy (ALD) who underwent bone marrow transplantation (BMT). An identification of the ALD gene mutation enabled us to employ an approach not dependent on the use of radioisotopes for detecting mixed chimerism. This assay could show more than 99.0% of the patient's peripheral white blood cells were replaced by the donor's cells.
Mouse models of genetic disease: New approaches, new paradigms
Authors: Brown S. D. M.
Published: December 2002

The mouse mutant resource is a valuable tool for gene function studies in the post‐genomics era. However, despite a seemingly large catalogue of mouse mutants, it is recognized that we have access to mutations at only a small fraction of the total number of mouse genes. There is a phenotype gap that needs to be narrowed by the implementation of large‐scale, systematic mutagenesis programmes in the mouse. Both genotype‐driven and phenotype‐driven approaches can be employed to recover new mouse mutations. Genotype‐driven approaches include large‐scale genome‐wide mutagenesis by gene trapping in embryonic stem cells. For genotype‐driven approaches, the initial focus is on the characterization of the mutational change to the genome. Identification of the mutated gene is relatively trivial, but the genotype‐driven route provides little indication of the likely phenotypic outcome of the mutation. In contrast, phenotype‐driven approaches employ mutagenesis procedures that emphasize the recovery of novel phenotypes without prior assumptions about the underlying gene or pathway that has been disrupted – although identifying the underlying gene may not be trivial. One phenotype‐driven approach includes chemical mutagenesis using N‐ethyl‐N‐nitrosourea (ENU). ENU mutagenesis programmes are increasingly being brought to bear on increasing the breadth and depth of the mouse mutant resource, and in so doing narrowing the phenotype gap.
Comparative biochemical studies of ATPases in cells from patients with the T8993G or T8993C mitochondrial DNA mutations
Authors: Vázquez‐Memije M. E. , Shanske S. , Santorelli F. M. , Kranz‐Eble P. , DeVivo D. C. , DiMauro S.
Published: December 2002

We performed comparative biochemical studies in cultured fibroblast mitochondria from patients with the T8993G or the T8993C point mutations in the ATPase 6 gene of mitochondrial DNA. We found that ATP production was much more severely decreased in cells from patients with the T8993G mutation than in those from patients with the T8993C mutation. Kinetic studies suggest that both mutations affect only the F0 sector of the mitochondrial ATPase complex. We conclude that these two mutations, which result in the substitution of different amino acids at the same site of the ATPase, result in an enzyme with different biochemical characteristics.
The role of manganese superoxide dismutase in health and disease
Authors: Robinson B. H.
Published: December 2002

Manganese superoxide dismutase (MnSOD) is the mitochondrial enzyme that disposes of superoxide generated by respiratory chain activity. Of all electrons passing down the mitochondrial respiratory chain, 1–2% are diverted to form superoxide; thus production of hydrogen peroxide occurs at a constant rate due to MnSOD activity. Mice lacking MnSOD develop cardiomyopathy and basal ganglia lesions, have no lipid peroxidation products, but show destruction of enzymes with 4Fe–4S centres. Patients with complex I (NADH‐CoQ oxidoreductase) deficiency show variable hyperinduction of MnSOD that is at least partially dependent on the extent of disturbance of redox state. This in turn appears to result in production of excess hydroxyl radicals, which are damaging to proteins, lipids and DNA. An alternative method of protection from oxygen radicals is employed by complex I‐deficient cell types that do not induce MnSOD in that they show induction of the bcl‐2 protein.
Molecular heterogeneity of Krabbe disease
Authors: Fu L. , Inui K. , Nishigaki T. , Tatsumi N. , Tsukamoto H. , Kokubu C. , Muramatsu T. , Okada S.
Published: December 2002

Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive neurodegenerative disorder that affects both the central and peripheral nervous system due to an enzymatic defect of galactocerebrosidase (GALC). Following its cloning, many mutations in the galactocerebrosidase gene have been reported, but the correlation between phenotype and genotype was not clear in many cases. In this study we further investigated the molecular defects in another 10 patients (6 Japanese and 4 non‐Japanese), using cultured skin fibroblasts, and found 10 mutations, of which 8 were novel, including a nonsense mutation (W647X) and 7 missense mutations (G43R, S52F, T262I, Y319C, W410G, R515H, T652R) in the coding region. Some phenotype‐specific mutations were found but the other mutations were private. Mutations reported so far have been distributed over the whole GALC gene and it is difficult to speculate on functional domains of the GALC protein and phenotypically specific regions.
Sphingolipids and cell signalling
Authors: Fredman P.
Published: December 2002

The sphingolipid storage disorders constitute a group of inherited metabolic disorders in which the structure of the stored sphingolipid and the corresponding genetic defect have been established. However, the pathological mechanism(s) behind the disorders has not been fully elucidated. Sphingolipids are known to be recognition molecules involved in intercell communication and altered expression might lead to dyscommunication. The impaired degradation and lysosomal accumulation of specific sphingolipids might influence the metabolism of other molecules and/or intracellular transport, which in turn might alter the distribution of these molecules. However, the progress of these diseases indicates that additional factors, besides the stored sphingolipid itself, might be involved. During the last decade, several sphingolipids have emerged as active participants in intracellular signalling processes such as growth control and apoptosis. Particular interest focused on the sphingolipid metabolites, ceramide and sphingosine, as potential mediators in intracellular events and an altered presence of these metabolites in sphingolipidoses cannot be ruled out. Some sphingolipids have been found to influence cytokine release and thereby might induce immunological processes, which are known to exist in at least one of the sphingolipidoses – Gaucher disease. These processes might already have a pathogenic effect during early development, before significant storage has occurred.
Variable clinical presentation in three patients with 3‐methylglutaconyl‐coenzyme A hydratase deficiency
Authors: Gibson K. M. , Wappner R. S. , Jooste S. , Erasmus E. , Mienie L. J. , Gerlo E. , Desprechins B. , De Meirleir L.
Published: December 2002

3‐Methylglutaconyl‐coenzyme A (3‐MG‐CoA) hydratase deficiency (type I 3‐methylglutaconic aciduria), a rare defect of L‐leucine catabolism, has previously been identified in 5 patients (four families). Clinical findings in 3 were mild, with delayed speech development in 2 siblings, and bronchiolitis, mild hyperchloraemic acidosis, and gastro‐oesophageal reflux in a third patient (Narisawa et al 1986; Gibson et al 1992). In two recently described patients, a more severe presentation was observed. The presentation included vomiting, seizures, coma, speech retardation, hepatomegaly, and decerebrate posture in one patient in whom the provisional diagnosis was Reye syndrome (Hou and Wang 1995). In another patient, the clinical picture encompassed psychomotor retardation, failure to thrive, spastic quadriplegia, dystonic involuntary movements in the upper limbs, and bilateral atrophic changes of the basal ganglia (Shoji et al 1996). We present 3 patients with 3‐MG‐CoA hydratase deficiency who also manifested widely differing clinical presentations, bringing to eight the total number of patients with documented 3‐MG‐CoA hydratase deficiency.
The molecular basis of transferase galactosaemia in South African negroids
Authors: Manga N. , Jenkins T. , Jackson H. , Whittaker D. A. , Lane A. B.
Published: December 2002

Transferase galactosaemia is an autosomal recessively inherited disorder caused by a deficiency of galactose‐1‐phosphate uridyltransferase (GALT). Manifestations include jaundice, vomiting, cataracts, mental retardation, speech abnormalities and poor growth. The GALT gene has been mapped and sequenced. The S135L mutation accounts for approximately 48% of galactosaemia alleles in African Americans and has been found to account for about 91% of galactosaemia alleles in negroid South African patients which suggested that the mutation had an African origin. We have calculated the S135L allele frequency (±1SE) in a sample of healthy unrelated negroid South Africans to be 0.0067 (±0.0024). The S135L mutation was also detected in negroid populations from other regions of Africa confirming its African origin.
Mutations in the glucose‐6‐phosphatase gene of 53 Italian patients with glycogen storage disease type Ia
Authors: Stroppiano M. , Regis S. , DiRocco M. , Caroli F. , Gandullia P. , Gatti R.
Published: December 2002

Type Ia glycogen storage disease (GSD1a) is an autosomal recessive metabolic disorder caused by a deficiency in glucose‐6‐phosphatase (G6Pase). Recent cloning of the G6Pase gene and the subsequent identification of several disease‐causing mutations have shown an ethnic molecular heterogeneity. Using SSCP analysis and DNA sequencing, we characterized the G6Pase gene of 53 unrelated Italian patients. The two most common mutations, R83C and Q347X, accounted for 66.9% of the mutant alleles. Eight novel mutations and three rare mutations were identified in 15.7% of disease alleles. These results suggest that a DNA‐based method can be used as an initial screening in Italian patients clinically suspected of having GSD1a, avoiding liver biopsy for enzymatic diagnosis. In particular, a noninvasive diagnosis is a suitable method for the Italian subpopulation coming from Sicily, where the R83C mutation is present in 80% of mutant alleles. Molecular carrier detection and prenatal diagnosis can be provided to GSD1a families with identified mutation in the propositus.
Influence of Aerobic Oxidation of Mouse Erythrocytes on their Recognition by Macrophages
Authors: Olmos Gemma , Lotero L. Alfredo , Herráez Angel , Alvarez F. Javier , Murciano Juan C. , Tejedor M. Cristina , Díez José C.
Published: December 2002

Membrane protein modification can change cell surface properties which canbe correlated with altered macrophage-erythrocyte interactions. Mouseerythrocytes were incubated in phosphate buffer for different times toinduce protein modification. Mouse erythrocyte membrane changes wereanalyzed by infrared analyses and gel electrophoresis. Proteolyticdigestion of membrane proteins was observed. After 22 hours preliminaryincubation, the number of erythrocytes adhering to a monolayer ofmacrophages reached a maximum, the majority of which had not beenphagocytosed. Most of the erythrocytes incubated for 40 hours underwentphagocytosis after adhesion to the macrophages.
Fasting, postprandial, and post‐methionine‐load homocysteinaemia and methylenetetrahydrofolate reductase polymorphism in vascular disease
Authors: Candito M. , Bedoucha P. , Gibelin P. , Jambou D. , de Franchis R. , Sadoul J.‐L. , Chatel M. , Van Obberghen E.
Published: December 2002

Hyperhomocysteinaemia is an independent risk factor for cardiovascular disease. The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) is a common genetic cause of increased homocysteine (HCY) levels. Post‐methionine‐load HCY concentrations allow identification of certain cases of hyperhomocysteinaemia not demonstrated by fasting levels. This study investigated the relationship between MTHFR polymorphism and (1) fasting HCY levels (77 patients); (2) post‐methionine HCY levels (54 patients); and (3) postprandial HCY concentrations (36 patients) in cardiovascular disease. As expected, mean fasting HCY value was higher in the +/+ patients. Moreover, patients who were homozygous for the mutation exhibited significantly increased mean post‐methionine‐load HCY; in contrast, literature results are conflicting. Mean postprandial HCY, which is not known to be increased in controls, was also increased in the (+/+) patients, although the difference did not reach statistical significance, probably owing to the small size of the sample. MTFHR polymorphism is known to be aggravated by a drop in circulating folate. Additional risk factors may be more prevalent in patients with cardiovascular disease.
UV-Induced Apoptosis in Resistant HeLa Cells
Authors: Kamarajan P. , Chao Chuck C.-K.
Published: December 2002

Recently, apoptosis (genetically programmed cell death) induced by UV hasbeen documented in some cell culture models. However, the significance ofapoptosis in UV-induced cytotoxicity and resistance is uncertain. In thisstudy, we investigated the induction of apoptosis in HeLa cells and itsrole in acquired UV-resistance. The membrane receptor Fas was induced toassembly, and its immediate downstream target, caspase-8, was induced byUV in a dose- and time-dependent manner. Caspase-10, another possiblecandidate for forming the death-inducing signaling complex with Fas, wasalso activated in a dose- and time-dependent manner. There was significantactivation of caspase 9, 3 and 2 by UV. The apoptotic pathways appeared tobe normal in acquired UV-resistant HeLa cells. In addition, there was a UVdose-dependent induction of chromatin condensation in both parental andUV-resistant cells. However, resistant cells displayed significant reductionin chromatin condensation at lower doses. Inhibition of caspase-3 activation byspecific inhibitor significantly reduced the chromatin condensation in bothcell types, and unexpectedly, the difference between the two cell lines wascompletely eradicated, suggesting that the caspase-3 pathway plays asignificant role in reducing apoptosis in resistant cells. The resultsindicate that UV induces apoptosis by direct activation of apoptoticproteins in HeLa and resistant cells. Although resistant cells displayedpartial inhibition of UV-induced apoptosis through the caspase-3 pathway,there was no consistent difference in the activation of this and relatedcaspase-9 caspases compared to parental HeLa cells.