bluuebunny/crossref_metadata_2025 huggingface dataset:
parkin mutation analysis in clinic patients with early‐onset Parkinson's disease
Authors: Poorkaj P. , Nutt J. G. , James D. , Gancher S. , Bird T. D. , Steinbart E. , Schellenberg G. D. , Payami Haydeh
Published: June 2004

parkin mutations are the most common identified cause of Parkinson's disease (PD). It has been suggested that patients with young‐onset PD be screened for parkin mutations as a part of their clinical work‐up. The aim of this study was to assess parkin mutation frequency in a clinical setting, correlate genotype with phenotype, and evaluate the current justification for clinical parkin testing. Patients were selected from a movement disorder clinic based on diagnosis of PD and onset age ≤40 years. parkin was genotyped by sequence and dosage analysis for all 12 exons. Key relatives and controls were screened for identified mutations. Mutations were found in 7/39 patients. Two patients were compound heterozygous; five were heterozygous. Mutations included deletions in exons 2, 3, and 8, duplications in exons 2–4, and 9, and P437L substitution. Seventy‐eight percent of mutations were deletions/multiplications. A novel substitution (R402W) was found in one patient and in one control. None of the point mutations found in patients were detected in 96 controls. parkin phenotypes were consistent with idiopathic PD. In conclusion, parkin mutations are common in the clinic setting: 10% of PD patients had early‐onset and 18% of them had parkin mutations. However, if parkin is recessive, only 5% of early‐onset cases who had compound mutations could be attributed to this locus. Mutation frequency was 0.12 (95% CI 0.04–0.19). parkin cases can present as typical idiopathic PD, distinguishable only by molecular testing. Seventy percent of parkin cases were heterozygous. It is unclear whether heterozygous mutations are pathogenic. parkin‐based diagnosis and counseling require a better understanding of the mode of inheritance, penetrance, and carrier frequencies. © 2004 Wiley‐Liss, Inc.
Association of the dopamine transporter gene (DAT1) core promoter polymorphism −67T variant with schizophrenia
Authors: Khodayari N. , Garshasbi M. , Fadai F. , Rahimi A. , Hafizi L. , Ebrahimi A. , Najmabadi H. , Ohadi Mina
Published: June 2004

Dysfunction of the central dopaminergic neurotransmission has been suggested to play an important role in the etiology of schizophrenia. The dopamine transporter (DAT1) mediates the active reuptake of dopamine from the synapses and thereby plays a key role in the regulation of the dopaminergic neurotransmission. In this study, we sought to determine the possible association of the DAT1 gene core promoter polymorphism −67A/T with schizophrenia in a case/control study. The allele and genotype frequencies of the polymorphism were studied in 100 patients and 100 controls, which were matched on the basis of sex, age, and ethnicity. The genotype frequencies in the patients group were as follows: AA 29%; AT 59%; TT 12% versus the genotype frequencies in the control group: AA 57%; AT 38%; TT 5% [χ2 = 16.54, df = 2, OR = 2.25 (95% CI 1.46–3.45, P ≤ 0.0003]. For the first time, these findings provide tentative evidence for the contribution of the DAT1 gene core promoter polymorphism to the etiopathophysiology of schizophrenia at least in the Iranian male population that we studied. Replication studies of independent samples and family‐based association studies are necessary to further evaluate the significance of our findings. © 2004 Wiley‐Liss, Inc.
Mutation screening of X‐chromosomal neuroligin genes: No mutations in 196 autism probands
Authors: Vincent John B. , Kolozsvari Debbie , Roberts Wendy S. , Bolton Patrick F. , Gurling Hugh M.D. , Scherer Stephen W.
Published: June 2004

Autism, a childhood neuropsychiatric disorder with a strong genetic component, is currently the focus of considerable attention within the field of human genetics as well many other medical‐related disciplines. A recent study has implicated two X‐chromosomal neuroligin genes, NLGN3 and NLGN4, as having an etiological role in autism, having identified a frameshift mutation in one gene and a substitution mutation in the other, segregating in multiplex autism spectrum families (Jamain et al. [2003: Nat Genet 34:27–29]). The function of neuroligin as a trigger for synapse formation would suggest that such mutations would likely result in some form of pathological manifestation. Our own study, screening a larger sample of 196 autism probands, failed to identify any mutations that would affect the coding regions of these genes. Our findings suggest that mutations in these two genes are infrequent in autism. © 2004 Wiley‐Liss, Inc.
Acetylation phenotype status in a Bangladeshi population and its comparison with that of other Asian population data
Authors: Zaid R.B. , Nargis M. , Neelotpol S. , Hannan J.M.A. , Islam S. , Akhter R. , Ali L. , Azad Khan A.K.
Published: June 2004

The objective of the present study was to determine the acetylator status of the Bangladeshi population and to compare the findings with the acetylator status of other Asian populations. The acetylator phenotype was determined in 517 unrelated healthy Bangladeshi subjects. The phenotyping procedure was done according to Price Evans' method using the NAT2 specific probe drug—sulphadimidine. The Bangladeshi population showed a bimodal distribution of fast and slow acetylators. Of a total of 517 healthy Bangladeshi, 79.5% (n=411) were fast acetylators and the rest 20.5% (n=106) were slow acetylators. The high frequency of the fast acetylators in the population of Bangladesh was comparable to other populations in East Asia. When this acetylator status was compared with other Asian data, the Asian population showed a positive correlation between the acetylator status and the geographical longitude (r=0.919; t=7.37; p>0.001; d.f.=10). The regression line of the scatter diagram showed that the frequency of acetylating capacity increasingly occurred in the populations towards eastern Asia (regression coefficient=0.54; constant=52.36). This line was termed as the Asian fast acetylator longitude (AFAL). Thus the AFAL was able to predict the acetylator status of the Asian population by the east–west geographical longitude. The AFAL could be a useful prognosticator in the disposition for the effective and safe use of numerous drugs and xenobiotic compounds in humans. Copyright © 2004 John Wiley & Sons, Ltd.
High rates of neural tube defects in Ukraine
Authors: Yuskiv Nataliya , Andelin Clark O. , Polischuk Svitlana , Shevchuk Oleksandr , Sosynyuk Zoryana , Vihovska Tetyana , Yevtushok Lyubov , Oakley Godfrey P. , Wertelecki Wladimir
Published: June 2004

BACKGROUND

Oral consumption of synthetic folic acid can prevent neural tube defects (NTDs), which are some of the most severe congenital anomalies. The prevalence of NTDs in Ukraine and other countries of the former U.S.S.R. has not been well studied. We determined the prevalence of NTD‐affected pregnancies in Northwestern Ukraine as background for policy decisions related to flour fortification in this country.

METHODS

The Ukrainian‐American Birth Defects Program was established in 1999 and conducts population‐ based surveillance of birth defects in several oblasts (states) of Ukraine. We determined the prevalence of NTDs in the Volyn and Rivne oblasts of Northwestern Ukraine for three years, 2000–2002.

RESULTS

There were 75,928 births in the two oblasts in 2000–2002. There were 159 cases of NTDs among live births, stillbirths, and induced abortions. The prevalence of NTDs in the two oblasts in Northwestern Ukraine is 2.1 per 1000 births.

CONCLUSIONS

The prevalence of NTD‐affected pregnancies we found in Northwestern Ukraine is almost four times what it should be. This prevalence suggests that population folate deficiency is widespread in Ukraine. Universal folic acid fortification of flour milled in Ukraine is urgently needed to end this epidemic of birth defects. Such fortification would be expected to prevent folate deficiency anemia, heart attacks, and strokes. Birth Defects Research (Part A) 2004. © 2004 Wiley‐Liss, Inc.
Maternal autoimmune diseases and immunologically induced embryonic and fetoplacental damage
Authors: Ornoy Asher , Chen Limor , Silver Robert M. , Miller Richard K.
Published: June 2004

BACKGROUND

Autoimmune diseases are a group of illnesses in which autoantibodies are produced against various organs, presenting with a variety of clinical symptoms. In this review, we discuss the different aspects of autoimmune diseases in pregnancy. We also describe experimental models that help to understand the etiology and pathogenesis of the effects of this maternal disease on the developing embryo, fetus and placenta.

METHODS

The possible direct effects of sera or IgG obtained from women with systemic lupus erythematosus/antiphospholipid syndrome (SLE/APS) and recurrent pregnancy loss (RPL) were examined on cultured 10.5‐ and 11.5‐day‐old rat embryos and on cultured human placental explants, as compared to sera from healthy women or synthetic medium that were used as controls. In addition, we examined the effects of the sera obtained from these women after successful treatment that allowed the birth of normal infants.

RESULTS

We observed increased embryonic death and anomalies in embryos cultured on sera and IgG from SLE/APS women. Similarly, when human placental explants were cultured on these sera, trophoblastic cell growth was reduced and apoptotic rate was increased. Successful treatment also reduced the damage caused by the sera from these women in the cultured embryos and placentas.

CONCLUSIONS

Our results, and the cited studies, point to the important role of the placental damage in the etiology of RPL associated with SLE/APS. Animal models, both in vivo and in vitro, as well as cultured early human placental explants can be used successfully to understand some of the pathogenic aspects of SLE/APS and RPL. Birth Defects Research (Part A), 2004. © 2004 Wiley‐Liss, Inc.
Effectiveness of a free folic acid supplement program in family planning clinics
Authors: Watkins Margaret L. , Brustrom Jennifer , Schulman Jane
Published: June 2004

BACKGROUND

Adequate periconceptional folic acid consumption lowers the risk for neural tube defects. We report the results of an evaluation of a folic acid intervention in Georgia family planning clinics that provided free folic acid supplements or fortified breakfast cereal.

METHODS

Six family planning clinics participated in the evaluation. Three clinics provided folic acid pills and educational materials to clients, two provided super‐fortified cereal and educational materials, and one clinic provided educational materials only. Participants between the ages of 18 and 45 who visited the clinics in 2000 completed a brief survey and provided a blood sample. Of the 1093 women who participated, we evaluated the 165 women who had returned to the clinic at least once during the study period. We compared participants' survey and serum folate data from their first and subsequent visits.

RESULTS

Participation in the intervention was associated with increased knowledge about folic acid, (odds ratio, 1.94; 95% confidence interval, 1.37–2.76), but was not directly associated with increased self‐reported folic acid consumption or increased serum folate levels. Reported use of folic acid supplements or cereal within two days of a visit was associated with higher serum folate levels. Knowledge about folic acid was one of the best predictors of self‐reported folic acid consumption.

CONCLUSIONS

Participation in the intervention increased clients' knowledge about folic acid but did not directly increase reported folic acid consumption. Because knowledge predicted folic acid consumption, the intervention may be indirectly associated with increased consumption of folic acid. Birth Defects Research (Part A), 2004. Published 2004 Wiley‐Liss, Inc.
Dissociation of double‐headed cytoplasmic dynein into single‐headed species and its motile properties
Authors: Toba Shiori , Toyoshima Yoko Yano
Published: June 2004

Cytoplasmic dynein is a minus‐end directed microtubule motor and plays important roles in the transport of various intracellular cargoes. Cytoplasmic dynein comprises two identical heavy chains and forms a dimer (double‐headed dynein); the total molecular weight of the cytoplasmic dynein complex is about 1.5 million. The dynein motor domain is structurally very different from those of kinesin and myosin, and our understanding of the mechanisms of dynein energy transduction is limited mainly because of the difficulty in obtaining a sufficient quantity of purified and active cytoplasmic dynein. We purified cytoplasmic dynein, which was free from dynactin and other dynein‐associated proteins. The purified cytoplasmic dynein was active in an in vitro motility assay. The controlled dialysis of the purified dynein against 4 M urea resulted in its complete dissociation into monomeric species (single‐headed dynein). The separation of the dynein heads by the treatment was reversible. The MgATPase activities of the single‐headed and reconstituted double‐headed dynein were comparable to that of intact dynein. The double‐headed dynein bundled microtubules in the absence of ATP; the single‐headed dynein did not. The single‐headed dynein produced in vitro microtubule‐gliding motility at velocities very similar to those of double‐headed dynein at various ATP concentrations. These results indicate that a single cytoplasmic dynein heavy chain is sufficient to produce robust microtubule motility. Application of the double‐ and single‐headed dynein molecules in various assay systems will elucidate the mechanism of action of the cytoplasmic dynein. Cell Motil. Cytoskeleton 58:281–289, 2004. © 2004 Wiley‐Liss, Inc.
Reproductive factors and risk of breast carcinoma in a study of white and African‐American women
Authors: Ursin Giske , Bernstein Leslie , Wang Yaping , Lord Sarah J. , Deapen Dennis , Liff Jonathan M. , Norman Sandra A. , Weiss Linda K. , Daling Janet R. , Marchbanks Polly A. , Malone Kathleen E. , Folger Suzanne G. , McDonald Jill A. , Burkman Ronald T. , Simon Michael S. , Strom Brian L. , Spirtas Robert
Published: June 2004

BACKGROUND

Few studies have investigated the association between reproductive factors and the risk of breast carcinoma among African‐American women. The authors assessed whether the number of full‐term pregnancies, age at first full‐term pregnancy, and total duration of breastfeeding were associated with similar relative risk estimates in white and African‐American women in a large multicenter, population‐based case–control study of breast carcinoma.

METHODS

Case patients were 4567 women (2950 white women and 1617 African‐American women) ages 35–64 years with newly diagnosed invasive breast carcinoma between 1994 and 1998. Control patients were 4668 women (3012 white women and 1656 African‐American women) who were identified by random‐digit dialing and were frequency matched to case patients according to study center, race, and age. Adjusted odds ratios and 95% confidence intervals were estimated using unconditional logistic regression.

RESULTS

For white women, the reduction in risk of breast carcinoma per full‐term pregnancy was 13% among younger women (ages 35–49 years) and 10% among older women (ages 50–64 years). The corresponding risk reductions for African‐American women were 10% and 6%, respectively. Risk decreased significantly with increasing number of full‐term pregnancies for both races and both age categories. Duration of lactation was inversely associated with breast carcinoma risk among younger parous white (trend P = 0.0001) and African‐American (trend P = 0.01) women. African‐American women tended to have more children compared with white women, but parity rates were lower in younger women than in older women in both racial groups. However, breastfeeding was substantially more common in young white women than in young African‐American women.

CONCLUSIONS

Overall, parity and lactation had similar effects on breast carcinoma risk in white and African‐American women. If younger African‐American women now are giving birth to fewer children than in the past, without a substantial increase in breastfeeding, breast carcinoma rates may continue to increase at a more rapid rate among these women compared with white women. Cancer 2004. Published 2004 by the American Cancer Society.
Two‐ and Three‐Dimensional Hydrogen‐Bonded Networks Built from 1,3,5‐[(HO)2(O)P]3C6H3 and 4‐(Dimethylamino)pyridine
Authors: Mehring Michael
Published: June 2004

Crystallisation of 3,5‐bis(phosphonophenyl)phosphonic acid, 1,3,5‐[(HO)2(O)P]3C6H3, from MeOH/H2O in the presence of 4‐(dimethylamino)pyridine, 4‐(Me2N)C5H4N, gave [1‐{(HO)2(O)P}‐3,5‐{(HO)(O)2P}2C6H3]2−[{4‐(Me2N)C5H4NH}+]2 (2) and [1,3‐{(HO)2(O)P}2‐5‐{(HO)(O)2P}C6H3]−[4‐(Me2N)C5H4NH]+ (3). Single‐crystal X‐ray diffraction analyses revealed a two‐ and a three‐dimensional hydrogen‐bonded network for compounds 2 and 3, respectively. Compound 2 is composed of layers which are formed by hydrogen‐bonded motifs of the type R2,2(8) and R4,4(16). These motifs are connected within the layer by additional hydrogen bonds and the benzene spacer. The cation [4‐(Me2N)C5H4NH]+ is located between the layers and determines the interlayer separation of approximately 6.5 Å. In compound 3 a layered network of the hydrogen‐bonded building units R2,3(10) was observed. These units are interconnected by four additional hydrogen bonds within the network. The benzene spacer links the adjacent layers to give a three‐dimensional structure. Within this network, channels with internal dimensions of ca. 8.5 × 11.3 Å2 which are occupied by the [4‐(Me2N)C5H4NH]+ cations were observed. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Zwitterionic Phosphorus Ylide Adducts of Boron‐Bridged ansa‐Zirconocene Complexes as Precatalysts for Olefin Polymerization
Authors: Shapiro Pamela J. , Jiang Feilong , Jin Xiaoping , Twamley Brendan , Patton Jasson T. , Rheingold Arnold L.
Published: June 2004

Methylenetriphenylphosphorane was coordinated to the boron of phenylborylidene‐bridged bis(cyclopentadienyl)‐ and bis(2‐Me,4‐Ph‐indenyl)zirconium dichloride to form zwitterionic ansa‐zirconocene complexes. The cyclopentadienyl complex 2, when activated with MAO, exhibits remarkable polymerization activity that is more than an order of magnitude greater than that of a related amidoborylidene‐bridged complex as well as the commercially important precatalyst [Cp′−SiMe2−N−tBu]TiCl2 (Cp′ = C5Me4). The zwitterionic bis(2‐Me,4‐Ph‐indenyl)zirconium dichloride species is isolated as a mixture of rac and meso isomers 4−6. The propylene polymerization efficiency of the isomer mixture activated by MAO is greater than that of a related silylene bridged system at 70 and 85 °C; however, the activity of the zwitterionic system decreased with further increase in temperature. The high level of isotactic triads (63.6%) and pentads (52.4%) in the polypropylene formed by 4−6 indicates that the rac isomer is the most active precatalyst of the mixture. The molecular structures of 2 and the rac bis‐indenylzirconium isomer 4 and one of the meso isomers 5 are described. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
RuII Complexes of Bis(1,10‐phenanthrolin‐2‐yl)diazines
Authors: Brown Darren , Zong Ruifa , Thummel Randolph P.
Published: June 2004

A series of three bis‐tridentate bridging ligands has been prepared in which two 1,10‐phenanthroline units have been symmetrically appended to a central pyridazine, pyrimidine, or pyrazine ring. These ligands have been treated with [Ru(tpy‐d11)Cl3] to afford both mono‐ and dinuclear complexes whose photo‐ and electrochemical properties have been evaluated (tpy = 2,2′:6′,2′′‐terpyridine). A structural comparison is made between [(tpy)Ru(3)Ru(tpy)](PF6)4 and a previously reported complex involving 2,2′‐bipyridines in place of phenanthrolines on the bridging ligand and surprisingly little difference is found. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Studies with the azoxymethane–rat preclinical model for assessing colon tumor development and chemoprevention
Authors: Reddy Bandaru S.
Published: June 2004

During recent years, multidisciplinary studies in epidemiology and molecular biology have contributed to our understanding of the etiology of colorectal cancer; more importantly they have enabled us to approach its prevention. An impressive body of epidemiological data suggests an inverse relationship between colorectal cancer risk and consumption of diets rich in omega (ω)‐3 fatty acids (n‐3 PUFAs) or the regular use of nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin. The development of strategies for the chemoprevention of colorectal cancer have been facilitated by the use of relevant animal models mimicking the neoplastic processes that occur in humans, including similarities in histopathology and molecular and genetic lesions during both the early and promotion/progression stages of carcinogenesis. Studies with the azoxymethane‐F344 rat model indicate that diets rich in n‐3 PUFAs, NSAIDs, selective cyclooxygenase‐2 (COX‐2), inducible nitric oxide synthase (iNOS) inhibitors, and curcumin can reduce the incidence of colon cancer. Advances in the knowledge of the mechanisms by which chemopreventive agents act offer opportunities to use combinations of specific chemopreventive agents, having clinically beneficial aggregate activity with minimal toxicity. This approach is extremely important when a promising chemopreventive agent demonstrates apparent efficacy but may produce toxic effects at high doses. Our studies show that a combination of very low doses of piroxicam (NSAID) and difluoromethylornithine, a specific inhibitor of ornithine decarboxylase, or very low doses of COX‐2 and HMG‐CoA reductase inhibitors are more effective in inhibiting colon carcinogenesis than administration of these compounds as single agents even at higher levels. The natural history of colorectal cancer, from dysplastic aberrant crypts to adenomas and adenocarcinomas, offers multiple opportunities for assessment and intervention. Of further importance is to identify whether the molecular targets that are critical in the growth and survival of the malignant colorectal cell are modulated by n‐3 PUFAs, NSAIDs, or COX‐2 and iNOS inhibitors. Environ. Mol. Mutagen. 44:26–35, 2004. © 2004 Wiley‐Liss, Inc.
Genotoxicity of field‐collected inter‐tidal sediments from Cork Harbor, Ireland, to juvenile turbot (Scophthalmus maximus L.) as measured by the Comet assay
Authors: Kilemade M.F. , Hartl M.G.J. , Sheehan D. , Mothersill C. , van Pelt F.N.A.M. , O'Halloran J. , O'Brien N.M.
Published: June 2004

The alkaline single cell gel electrophoresis (SCGE) or Comet assay was employed to test the potential of surficial sediment collected from Cork Harbor, Ireland, to induce DNA damage in turbot (Scophthalmus maximus L.) in a laboratory exposure experiment. Turbot were exposed for 21 days to field‐collected sediment from Cork Harbor and from a relatively clean reference site at Ballymacoda and sampled at 0, 7, 14, and 21 days. As a positive control for the sediment exposure experiment, a subsample of the turbot was exposed to cadmium chloride‐spiked seawater. DNA damage analysis was performed on epidermal, gill, spleen, liver, and whole blood cell preparations. Liver, gill, and blood were the most sensitive tissues while a lower level of damage was detected in the epidermis and spleen. The blood was determined to be a suitable predictor of DNA damage in the whole organism. Chemical analysis of the sediment indicated that polycyclic aromatic hydrocarbons formed the bulk of the contaminants, with the harbor sites having almost double the levels of those from the reference site. The data indicated that turbot exposed to sediments from Cork Harbor elicited a significant increase in DNA damage in comparison with those exposed to sediment from the reference site and that exposure to the contaminated sediments caused a multi‐organ genotoxic response. Results from the study indicate a relationship between the presence of genotoxicants in sediment and DNA damage. This finding was encouraging with regard to the potential use of the Comet assay as part of a marine biomonitoring strategy. Environ. Mol. Mutagen. 44:56–64, 2004. © 2004 Wiley‐Liss, Inc.
Epigenetic events and protection from colon cancer in New Zealand
Authors: Ferguson Lynnette R. , Karunasinghe Nishi , Philpott Martin
Published: June 2004

The incidence of colon cancer is high in many developed nations, especially New Zealand. Molecular understanding of the nature of colon cancer shows a disease whose well‐characterized morphological progression is paralleled at the cellular level by increased numbers of gene or chromosome mutations, loss of heterozygosity, changed methylation patterns, and genomic instability. In the present study, we consider whether an imbalance of factors that affect DNA methylation patterns might explain at least part of the high colon cancer incidence in New Zealand. Folate is the major micronutrient whose intake impacts methylation, particularly through interaction with choline and methionine. Folate is generally somewhat deficient in the New Zealand diet, with the voluntary addition of folate to white flour not producing desired levels. Selenium affects methylation status in several ways and is recognized as being low in New Zealand soils and, therefore, diet. Zinc is also low in the diets of some New Zealand population groups, which can lead to hypomethylation. Several of the components of fruits and vegetables affect methylation patterns, and the average New Zealand intake, at two to three servings per day, is considerably below recommended amounts. Low dietary fiber, high tobacco use, and increasing rates of obesity are also likely New Zealand risk factors that may impact on methylation status. Dietary supplementation is not as common in New Zealand as in countries such as the United States, but may provide a way to raise the levels of nutrients and phytochemicals affecting methylation status, thereby enhancing colon cancer protection. Environ. Mol. Mutagen. 44:36–43, 2004. © 2004 Wiley‐Liss, Inc.
The oldest ape
Authors: Maclatchy Laura
Published: June 2004

This paper recounts the history and significance of Morotopithecus bishopi, an early Miocene East African ape. Morotopithecus differs in intriguing ways from its contemporary Proconsul. While craniodental differences are slight, the known elements of its postcranium suggest that Morotopithecus was capable of modern ape–like positional behaviors, including vertical postures, deliberate climbing, and arm hanging. In contrast, Proconsul and other early and middle Miocene hominoids have been reconstructed as above–branch quadrupeds. Paleoanthropologists are currently divided over whether and which of the anatomical features associated with upright posture and suspension in the modern apes are due to inheritance or independent evolution. This debate has important implications for interpreting the phylogenetic positions of both Morotopithecus and Proconsul, as well as for reconstructing the pattern and timing of the emergence of modern ape adaptations.
Ponce de Leon and the telomere of youth
Authors: Weiss Kenneth
Published: June 2004

The explorer went to the ends of the earth looking for immortality. Did he only have to go to the ends of his chromosomes?
The canopy conductance of a boreal aspen forest, Prince Albert National Park, Canada
Authors: Blanken P. D. , Black T. A.
Published: June 2004

Annual fluxes of canopy‐level heat, water vapour and carbon dioxide were measured using eddy covariance both above the aspen overstory (Populus tremuloides Michx.) and hazelnut understory (Corylus cornuta Marsh.) of a boreal aspen forest (53·629 °N 106·200 °W). Partitioning of the fluxes between overstory and understory components allowed the calculation of canopy conductance to water vapour for both species. On a seasonal basis, the canopy conductance of the aspen accounted for 70% of the surface conductance, with the latter a strong function of the forest's leaf area index. On a half‐hour basis, the canopy conductance of both species decreased non‐linearly as the leaf‐surface saturation deficits increased, and was best parameterized and showed similar sensitivities to a modified form of the Ball–Berry–Woodrow index, where relative humidity was replaced with the reciprocal of the saturation deficit. The negative feedback between the forest evaporation and the saturation deficit in the convective boundary layer varied from weak when the forest was at full leaf to strong when the forest was developing or loosing leaves. The coupling between the air at the leaf surface and the convective boundary layer also varied seasonally, with coupling decreasing with increasing leaf area. Compared with coniferous boreal forests, the seasonal changes in leaf area had a unique impact on vegetation–atmosphere interactions. Copyright © 2004 John Wiley & Sons, Ltd.
Involvement of the FGFR4 Arg388 allele in head and neck squamous cell carcinoma
Authors: Streit Sylvia , Bange Johannes , Fichtner Alexander , Ihrler Stephan , Issing Wolfgang , Ullrich Axel
Published: June 2004

Fibroblast growth factor receptors (FGFRs) have been implicated in various forms of human hyperproliferative disorders such as cancers of the cervix and bladder. We investigated the expression pattern of FGFR4 and the clinical significance of the recently identified Gly/Arg polymorphism (388) in head and neck squamous cell carcinomas (HNSCCs) of the oral cavity and the oropharynx. Sections from 104 paraffin‐embedded tumors were analyzed by a restriction fragment length polymorphism‐based method to determine the FGFR4 genotypes. Protein expression was investigated immunohistochemically and graded into a low, intermediate, or high degree of staining. FGFR4 expression was scored as high in 17, as intermediate in 59 and as low in 28 cases. The FGFR4 Arg388 allele was found in 59 tumors, 46 of them having heterozygous and 13 homozygous genotypes. High expression of the FGFR4 Arg388 allele was significantly associated with reduced overall survival (p = 0.032) and with an advanced tumor stage (p = 0.023), whereas expression of the FGFR4 Gly388 had no impact on disease progression. Our findings indicate that high expression of FGFR4 in connection with the Arg388 allele is associated with poor clinical outcome and support the significance of FGFR4 as a diagnostic marker and a target for therapeutic intervention in human HNSCC. © 2004 Wiley‐Liss, Inc.
Immunodetection and quantification of vascular endothelial growth factor receptor‐3 in human malignant tumor tissues
Authors: Bando Hiroko , Brokelmann Maren , Toi Masakazu , Alitalo Kari , Sleeman Jonathan P. , Sipos Bence , Gröne Hermann‐Josef , Weich Herbert A.
Published: June 2004

Vascular endothelial growth factor recpetor‐3 (VEGFR‐3) and its ligands, vascular endothelial growth factor‐C (VEGF‐C) and –D (VEGF‐D), are the major molecules involved in developmental and pathological lymphangiogenesis. Here we describe for the first time the development of a specific indirect enzyme‐linked immunosorbent assay (ELISA) for the quantification of VEGFR‐3 in different human cell and tissue lysates. A combination of the goat polyclonal anti‐VEGFR‐3 antibody and the mouse monoclonal anti‐human VEGFR‐3 antibody was used. The assay was highly sensitive and reproducible with a detection range of 0.2–25 ng/ml. The assay was specific for VEGFR‐3, with no cross‐reactivity to VEGFR‐1 or VEGFR‐2. Complex formation with VEGF‐C and VEGF‐D had no effect on the sensitivity of the assay. The VEGFR‐3 concentration in the lysates of cultured human dermal microvascular endothelial cells was 14‐fold higher than in the lysates from human umbilical vein endothelial cells. In human kidney, breast, colon, gastric and lung cancer tissues the protein levels of VEGFR‐3 were in the range of 0.6–16.7 ng/mg protein. Importantly, the level of VEGFR‐3 protein detected in the ELISA correlated significantly with the number of VEGFR‐3 positive vessels observed in histochemical sections, suggesting that the ELISA assay may be a reliable surrogate of measuring VEGFR‐3‐positive vessel density. The protein levels of VEGFR‐3 in 27 renal cell carcinoma samples had a significant correlation with the levels of VEGF‐C (p<0.001), or biological active, free VEGF‐A (p<0.0001), but not with VEGFR‐1 or total VEGF‐A. This assay provides a useful tool for the investigations of the expression levels of VEGFR‐3 in physiological and pathological processes, particular in cancer and in lymphangiogenesis‐related disease. © 2004 Wiley‐Liss, Inc.
Suppression of tumor growth and metastasis by a VEGFR‐1 antagonizing peptide identified from a phage display library
Authors: An Ping , Lei Hetian , Zhang Jianzhi , Song Shumei , He Luowen , Jin Genglin , Liu Xiaoying , Wu Jian , Meng Lin , Liu Meisheng , Shou Chengchao
Published: June 2004

Although the VEGF‐Flk‐1‐pathway has been known as the major driving force of angiogenesis, new evidence has shown that VEGFR‐1/Flt‐1 plays important roles during the neovascularization under pathological conditions including tumor, atherosclerosis and arthritis. In search of Flt‐1 receptor antagonizing peptides, we screened a phage display 12‐mer‐peptide library with recombinant Flt‐1 protein. Seven candidate peptides were identified that specifically bound to VEGF receptor Flt‐1, of which peptide F56 (WHSDMEWWYLLG) almost abolished VEGF binding to receptor Flt‐1 in vitro. In vivo, F56 fused with DHFR (DHFR‐F56) inhibited angiogenesis in a CAM assay. Moreover, DHFR‐F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC‐803 in BALB/c nude mice. Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with DHFR‐F56. In the severe combined immunodeficiency disease (SCID) mouse model for studying metastasis of the human breast cancer cell line BICR‐H1, synthetic peptide F56 significantly inhibited tumor growth and lung metastases. Taken together, our results have demonstrated that peptide F56, as a Flt‐1 receptor antagonist, fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between VEGF and receptor Flt‐1. Thus, short peptide F56 may have clinical potential in tumor therapy. © 2004 Wiley‐Liss, Inc.
Expression of the tyrosine kinase c‐kit is an independent prognostic factor in patients with small cell lung cancer
Authors: Rohr Ulrich‐Peter , Rehfeld Nina , Pflugfelder Lucy , Geddert Helene , Müller Wolfram , Steidl Ulrich , Fenk Roland , Gräf Thorsten , Schott Matthias , Thiele Klaus‐Peter , Gabbert Helmut Erich , Germing Ulrich , Kronenwett Ralf , Haas Rainer
Published: June 2004

In a retrospective analysis of 203 patients with small cell lung cancer (SCLC), we examined the prognostic value of c‐kit expression on survival. Expression of c‐kit was examined immunohistochemically in formalin‐fixed, paraffin‐embedded tissue sections. c‐kit was observed in 87.7% of SCLC tumors. Using the Kaplan‐Meier model, we found that lack of c‐kit expression was associated with significantly shorter survival time compared to the presence of c‐kit expression (mean survival 151 ± 27 vs. 358 ± 49 days, p = 0.0084). Moreover, the proportion of c‐kit+ cells within the tumor was also related to survival time. Patients with tumors in which >75% of cells stained positive for c‐kit had a mean overall survival time of 424 (±72) compared to 295 (±67) days for patients with 25–75% c‐kit+ tumor cells. Patients with tumors containing <25% c‐kit+ cells had the worst survival, with 164 (±24) days (p = 0.0033). Further parameters associated with short survival times were low performance status, elevated levels of lactate dehydrogenase and higher stage according to the TNM classification. Multivariate analysis using the Cox regression model showed that the proportion of c‐kit+ cells within the tumor specimen was one of 3 independent prognostic parameters (p = 0.004) for overall survival next to TNM classification (p = 0.001) and performance status (p < 0.001). © 2004 Wiley‐Liss, Inc.
Reduced expression of class II histone deacetylase genes is associated with poor prognosis in lung cancer patients
Authors: Osada Hirotaka , Tatematsu Yoshio , Saito Hiroko , Yatabe Yasushi , Mitsudomi Tetsuya , Takahashi Takashi
Published: June 2004

HDAC genes are thought to be involved in gene expression through the regulation of chromatin structure, alterations of which may cause abnormal gene silencing in cancers. To clarify the possible role of HDAC genes during tumor development and progression, we studied their expression and influence on clinical features. Expression levels of HDAC class I and class II genes in cancer tissues resected from 72 patients with NSCLC were measured with real‐time RT‐PCR. Their association with clinicopathologic features was statistically investigated. Reduced expression of each class II HDAC gene was significantly associated with poor prognosis and an independent predictor of poor prognosis. Of all the genes, HDAC10 was the strongest predictor of poor prognosis. Hierarchical clustering analysis showed that lung cancer tissues could be divided into 3 groups based on the expression level of class I and class II HDAC genes. The group with reduced expression of class II HDACs showed poor prognosis. These results suggest that class II HDACs may repress critical genes and that low expression of these genes may play a role in lung cancer progression. Results of clustering analyses imply that class II HDAC genes may be regulated by a similar mechanism and deregulated during cancer development. © 2004 Wiley‐Liss, Inc.
Long‐run monetary neutrality and long‐horizon regressions
Authors: Coe Patrick J. , Nason James M.
Published: June 2004

A prominent test of long‐run monetary neutrality (LRMN) involves regressing long‐horizon output growth on long‐horizon money growth. We obtain limited support for LRMN with this test in long‐annual Australian, Canadian, UK and US samples. Although empirical confidence intervals yield evidence in favour of LRMN, Monte Carlo experiments reveal the power of this test is near its size. Thus, this test is unlikely to detect important deviations from LRMN. These problems arise because the long‐horizon regression test of LRMN relies on estimates of the covariance of long‐horizon output growth and long‐horizon money growth. Copyright © 2004 John Wiley & Sons, Ltd.
Projection pursuit regression and disaggregate productivity effects: the case of the Indian blast furnaces
Authors: Das Sanghamitra , Sengupta Ramprasad
Published: June 2004

Productivity of blast furnaces in India is studied by disaggregating the production process and the utilization process. A dimension‐reducing nonparametric approach—projection pursuit regression—is used. We find that productivity can be increased significantly by improving the quality of coal. There is no evidence that executives have a positive marginal product. The production workers have a negative marginal product for the production process and a positive one for the utilization process. But the training of executives has a positive effect whereas that of the production workers has a negative effect on productivity. Copyright © 2004 John Wiley & Sons, Ltd.
A microeconometric evaluation of rehabilitation of long‐term sickness in Sweden
Authors: Frölich Markus , Heshmati Almas , Lechner Michael
Published: June 2004

In this study the effects of various types of rehabilitation programmes on labour market outcomes are estimated. A main feature of this study is that it jointly evaluates multiple treatments by nonparametric matching estimators. The study is based on a large sample of persons in western Sweden who are long‐term sick and could participate in rehabilitation programmes. Our results suggest that workplace training is superior to the other rehabilitation programmes with respect to labour market outcomes, but compared to non‐participation no positive effects are found. Copyright © 2004 John Wiley & Sons, Ltd.
Poverty comparisons with dependent samples
Authors: Zheng Buhong
Published: June 2004

Standard inference procedures for poverty comparisons require samples to be independent. For many commonly used income samples, however, this requirement is not fulfilled since samples are rotated. This article introduces an easy‐to‐use method of correction for sample dependency. We also apply the method to test changes in US poverty in the 1990s and to evaluate the marginal effects of public assistance on poverty before and after the recent welfare reform. Copyright © 2004 John Wiley & Sons, Ltd.
Mechanical signals and IGF‐I gene splicing in vitro in relation to development of skeletal muscle
Authors: Cheema Umber , Brown Robert , Mudera Vivek , Yang Shi Yu , McGrouther Gus , Goldspink Geoffrey
Published: June 2004

It has been shown that the insulin‐like growth factor (IGF‐I) gene is spliced in response to mechanical signals producing forms of IGF‐I which have different actions. In order to study how mechanical signals influence this gene splicing in developing muscle, C2C12 cells were grown in three‐dimensional (3D) culture and subjected to different regimens of mechanical strain. IGF‐IEa which initiates the fusion of myoblasts to form myotubes was found to be constitutively expressed in myoblasts and myotubes (held under endogenous tension) and its expression upregulated by a single ramp stretch of 1‐h duration but reduced by repeated cyclical stretch. In contrast, mechano growth factor (MGF), which is involved in the proliferation of mononucleated myoblasts that are required for secondary myotube formation and to establish the muscle satellite (stem) cell pool, showed no significant constitutive expression in static cultures, but was upregulated by a single ramp stretch and by cycling loading. The latter types of force simulate those generated in myoblasts by the first contractions of myotubes. These data indicate the importance of seeking to understand the physiological signals that determine the ratios of splice variants of some growth factor/tissue factor genes in the early stages of development of skeletal muscle. © 2005 Wiley‐Liss, Inc.
Increased expression of VEGF in retinal pigmented epithelial cells is not sufficient to cause choroidal neovascularization
Authors: Oshima Yuji , Oshima Sachiko , Nambu Hiroyuki , Kachi Shu , Hackett Sean F. , Melia Michele , Kaleko Michael , Connelly Sheila , Esumi Noriko , Zack Donald J. , Campochiaro Peter A.
Published: June 2004

Increased expression of vascular endothelial cell growth factor (VEGF) in the retina is sufficient to stimulate sprouting of neovascularization from the deep capillary bed of the retina, but not the superficial retinal capillaries or the choriocapillaris. Coexpression of VEGF and angiopoietin 2 (Ang2) results in sprouting of neovascularization from superficial and deep retinal capillaries, but not the choriocapillaris. However, retina‐derived VEGF and Ang2 may not reach the choriocapillaris, because of tight junctions between retinal pigmented epithelial (RPE) cells. To eliminate this possible confounding factor, we used the human vitelliform macular dystrophy 2 (VMD2) promoter, an RPE‐specific promoter, combined with the tetracycline‐inducible promoter system, to generate double transgenic mice with inducible expression of VEGF in RPE cells. Adult mice with increased expression of VEGF in RPE cells had normal retinas and choroids with no choroidal neovascularization (CNV), but when increased expression of VEGF in RPE cells was combined with subretinal injection of a gutless adenoviral vector containing an expression construct for Ang2 (AGVAng2), CNV consistently occurred. In contrast, triple transgenic mice with induced expression of Ang2 and VEGF in RPE cells, did not develop CNV. These data suggest that increased expression of VEGF and/or Ang2 in RPE cells is not sufficient to cause CNV unless it is combined with a subretinal injection of a gutless adenoviral vector, which is likely to perturb RPE cells. These data also suggest that the effects of angiogenic proteins may vary among vascular beds, even those that are closely related, and, therefore, generalizations should be avoided. © 2004 Wiley‐Liss, Inc.
Changes in GABA transporters in the rat hippocampus after kainate‐induced neuronal injury: Decrease in GAT‐1 and GAT‐3 but upregulation of betaine/GABA transporter BGT‐1
Authors: Zhu Xiao‐Ming , Ong Wei‐Yi
Published: June 2004

The γ‐aminobutyric acid (GABA) transporters GAT‐1, GAT‐2, GAT‐3, and BGT‐1 have been cloned and identified according to their differential amino acid sequences and pharmacologic properties. In contrast to GAT‐1, ‐2, or ‐3, BGT‐1 is capable of utilizing both GABA and betaine as substrates. Betaine has been suggested to be a protective osmolyte in the brain. Because changes in expression of GABA transporters/BGT‐1 might result in alterations in levels of GABA/betaine in the extracellular space, with consequent effects on neuronal excitability or osmolarity, the present study was carried out to explore expression of GABA transporters in the rat hippocampus after kainate‐induced neuronal injury. A decrease in GAT‐1 and GAT‐3 immunostaining but no change in GAT‐2 staining was observed in the degenerating CA subfields. In contrast, increased BGT‐1 immunoreactivity was observed in astrocytes after kainate injection. BGT‐1 is a weak transporter of GABA in comparison to other GABA transporters and the increased expression of BGT‐1 in astrocytes might be a protective mechanism against increased osmotic stress known to occur after excitotoxic injury. On the other hand, excessive or prolonged BGT‐1 expression might be a factor contributing to astrocytic swelling after brain injury. © 2004 Wiley‐Liss, Inc.
Factors to consider when entering into a partnership arrangement in Japan
Authors: Lee Yang‐Im
Published: June 2004

Japanese companies have a collectivist culture that reinforces their organizational learning concept. They are highly skilled, communicate openly and are customer focused.

Before entering the Japanese market, managers in overseas companies need to fully understand the political, economic, technological and socio‐cultural environment in order that they understand and accommodate the priorities of Japanese managers.

Copyright © 2004 John Wiley & Sons, Ltd.