bluuebunny/crossref_metadata_2025_split huggingface dataset:
Haplotype sharing analysis with SNPs in candidate genes: the genetic analysis workshop 12 example
Authors: Fischer Christine , Beckmann Lars , Majoram Paul , te Meerman Gerard , Chang‐Claude Jenny 
Published: January 2003

AbstractHaplotype sharing analysis was used to investigate the association of affection status with single nucleotide polymorphism (SNP) haplotypes within candidate gene 1 in one sample each from the isolated and the general population of Genetic Analysis Workshop (GAW) 12 simulated data. Gene 1 has direct influence on affection and harbors more than 70 SNPs. Haplotype sharing analysis depends heavily on previous haplotype estimation. Using GENEHUNTER haplotypes, strong evidence was found for most SNPs in the isolated population sample, thus providing evidence for an involvement of this gene, but the maximum −log10(p) values for the haplotype sharing statistics (HSS) test statistic did not correspond to the location of the true variant in either population. In comparison, transmission disequilibrium test (TDT) analysis showed the strongest results at the disease‐causing variant in both populations, and these were outstanding in the general population. In this example, TDT analysis appears to perform better than HSS in identifying the disease‐causing variant, using SNPs within a candidate gene in an outbred population. Simulations showed that the performance of HSS is hampered by closely spaced SNPs in strong linkage disequilibrium with the functional variant and by ambiguous haplotypes. Genet Epidemiol 24:68–73, 2003. © 2003 Wiley‐Liss, Inc.
Detecting genotype combinations that increase risk for disease: Maternal‐Fetal genotype incompatibility test
Authors: Sinsheimer Janet S. , Palmer Christina G.S. , Woodward J. Arthur 
Published: January 2003

AbstractBiological mechanisms that involve gene‐by‐environment interactions have been hypothesized to explain susceptibility to complex familial disorders. Current research provides compelling evidence that one environmental factor, which acts prenatally to increase susceptibility, arises from a maternal‐fetal genotype incompatibility. Because it is genetic in origin, a maternal‐fetal incompatibility is one possible source of an adverse environment that can be detected in genetic analyses and precisely studied, even years after the adverse environment was present. Existing statistical models and tests for gene detection are not optimal or even appropriate for identifying maternal‐fetal genotype incompatibility loci that may increase the risk for complex disorders. We describe a new test, the maternal‐fetal genotype incompatibility (MFG) test, that can be used with case‐parent triad data (affected individuals and their parents) to identify loci for which a maternal‐fetal genotype incompatibility increases the risk for disease. The MFG test adapts a log‐linear approach for case‐parent triads in order to detect maternal‐fetal genotype incompatibility at a candidate locus, and allows the incompatibility effects to be estimated separately from direct effects of either the maternal or the child's genotype. Through simulations of two biologically plausible maternal‐fetal genotype incompatibility scenarios, we show that the type‐I error rate of the MFG test is appropriate, that the estimated parameters are accurate, and that the test is powerful enough to detect a maternal‐fetal genotype incompatibility of moderate effect size. Genet Epidemiol 24:1–13, 2003. © 2003 Wiley‐Liss, Inc.
Association mapping of complex diseases in linked regions: estimation of genetic effects and feasibility of testing rare variants
Authors: Wang William Y.S. , Cordell Heather J. , Todd John A. 
Published: January 2003

AbstractAssociation mapping in linked regions is a current major approach for the identification of genes for complex diseases. Loci contributing to linkage, even with small values of sibling recurrence risk (λs), may be equivalent to substantial underlying genetic effects for association studies. For disease alleles with a frequency as low as 1%, highly reliable association studies (80% power for significance level α=10−6) require only 277, 781, and 1,289 families or cases and controls for loci detected with λs of 1.5, 1.1, and 1.05, respectively, under a multiplicative genetic model. Under alternative models, provided epistatic effects are minor, larger achievable sample sizes will provide sufficient power to map almost any disease gene that may have initially contributed to linkage. Genet Epidemiol 24:36–43, 2003. © 2003 Wiley‐Liss, Inc.
On selecting markers for association studies: Patterns of linkage disequilibrium between two and three diallelic loci
Authors: Garner Chad , Slatkin Montgomery 
Published: January 2003

AbstractAssociation studies depend on linkage disequilibrium (LD) between a causative mutation and linked marker loci. Selecting markers that give the best chance of showing useful levels of LD with the causative mutation will increase the chances of successfully detecting an association. This report examines the variation in the extent of LD between a disease locus and one or two diallelic marker loci (termed single nucleotide polymorphisms or SNPs). We use a simulation method based on the neutral coalescent in a population of variable size to find the distribution of LD as a function of allele frequencies, the recombination rate, and the population history. Given that LD exists, the allele frequencies determine if a site will be useful for detecting an association with the disease mutation. We show that there is extensive variation in LD even for closely linked loci, implying that several markers may be needed to detect a disease locus. The distribution of LD between common variants is strongly influenced by ancestral population size. We show that in general, best results will be obtained if the frequencies of marker alleles are at least as large as the frequency of the causative mutation. Haplotypes of two or more SNPs generally have a higher probability than individual SNPs of showing useful LD with a disease mutation, although exceptions are described. Genet Epidemiol 24:57–67, 2003. © 2003 Wiley‐Liss, Inc.
Astrocytes selectively enhance N‐type calcium current in hippocampal neurons
Authors: Mazzanti Mary , Haydon Philip G. 
Published: January 2003

AbstractAstrocytes influence neuronal development, synapse formation, and synaptic transmission, partly through affecting neuronal calcium signals. In order to elucidate the extent to which astrocytes modulate neuronal voltage‐gated calcium currents, we performed a whole‐cell patch clamp analysis of neurons in astrocyte‐deplete and astrocyte‐enriched conditions. We demonstrate that hippocampal neurons in an astrocyte‐enriched environment show augmentation of voltage‐gated calcium current at 1–3 days in vitro. Further study in pairs of adjacent neurons showed that the augmentation in calcium current was dependent on direct contact with the astrocyte. Pharmacological analysis demonstrated the augmentation is selective for the N‐type calcium current, although immunochemical labeling of the α1B subunit of the N‐type calcium channel was unchanged. These findings show that astrocytes regulate neuronal voltage‐gated calcium currents in a contact‐dependent manner. The specificity of the effect for the N‐type calcium current at early days in culture has special significance regarding the role of astrocytes in hippocampal synaptogenesis. GLIA 41:128–136, 2003. © 2003 Wiley‐Liss, Inc.
Peroxynitrite‐induced oligodendrocyte toxicity is not dependent on poly(ADP‐ribose) polymerase activation
Authors: Scott Gwen S. , Virág Laszlo , Szabó Csaba , Hooper D. Craig 
Published: January 2003

AbstractOligodendrocyte loss is a characteristic feature of several CNS disorders, including multiple sclerosis (MS) and spinal cord injury. However, the mechanisms responsible for oligodendrocyte destruction remain undefined. As recent studies have implicated peroxynitrite in the pathogenesis of both spinal cord injury and MS, we have examined whether peroxynitrite may mediate at least some of the oligodendrocyte damage and demyelination observed in these conditions. Primary rat oligodendrocytes were exposed to authentic peroxynitrite in vitro and assessed for cytotoxicity. Mitochondrial function, measured by the reduction of MTT to formazan, and mitochondrial membrane potential were used as indicators of cell viability. Cell death was quantitated by measuring either the release of lactate dehydrogenase from, or the uptake of propidium iodide into, damaged and dying cells. Peroxynitrite dose‐dependently reduced the viability of primary oligodendrocytes and induced cell death. Furthermore, peroxynitrite significantly increased DNA strand breakage and the activity of poly(ADP‐ribose) polymerase (PARP) in oligodendrocyte cultures. To identify whether PARP activation plays a role in peroxynitrite‐induced oligodendrocyte toxicity, we examined the effects of the PARP inhibitors 3‐aminobenzamide (3AB) and 5‐iodo‐6‐amino‐1,2‐benzopyrone (INH2BP) on mitochondrial function and cell death in oligodendrocytes. The presence of 3AB and INH2BP did not protect oligodendrocytes from peroxynitrite‐induced cytotoxicity. However, both compounds significantly reduced PARP activity in these cells. Primary oligodendrocytes generated from PARP‐deficient mice were also highly susceptible to peroxynitrite‐induced cell death. Therefore, our results show that peroxynitrite exerts cytotoxic effects on oligodendrocytes in vitro independently of PARP activation. GLIA 41:105–116, 2003. © 2003 Wiley‐Liss, Inc.
Gabaergic signaling mediates the morphological organization of astrocytes in the adult rat forebrain
Authors: Runquist Martin , Alonso Gérard 
Published: January 2003

AbstractPrevious studies have provided evidence that the morphological organization of immature astrocytes is influenced by the inhibitory neuronal transmitter gamma amino‐butyric acid (GABA). The present study was designed to determine whether the occurrence of differential organization of mature astrocytes throughout various regions of the adult brain is related to differential GABAergic signaling. For this we first used Western blotting and high‐performance liquid chromatography to quantify the levels of the astrocytic protein glial fibrillary acidic protein (GFAP) and GABA, respectively, within the same tissue punches taken from different forebrain regions of the adult rat, as well as immunocytochemistry for GFAP, GABA, or glutamate decarboxylase to visualize the morphological organization of astrocytes and of GABAergic axons in these regions. These data indicate that GFAP and GABA contents are correlated throughout the different forebrain regions analyzed, and that the regions containing the highest densities in GABAergic terminals are those that contain astrocytes exhibiting the highest degree of stellation. Secondly, we chronically increased GABAergic signaling in vivo by the systemic administration of an inhibitor of GABA transaminase or by the intracerebroventricular infusion of muscimol, a potent agonist of GABAA receptors. Our data show that in both cases, the GFAP content of the different forebrain regions is significantly augmented, in close association with a marked increase in the number of astrocytic processes and with their degree of branching. Taken together, these data strongly suggest that GABAergic signaling mediates the morphological organization of astrocytes and their expression of GFAP in the adult brain. GLIA 41:137–151, 2003. © 2003 Wiley‐Liss, Inc.
Cytokine‐stimulated inducible nitric oxide synthase expression in astroglia: Role of Erk mitogen‐activated protein kinase and NF‐κB
Authors: Marcus Joshua S. , Karackattu Sharon L. , Fleegal Melissa A. , Sumners Colin 
Published: January 2003

AbstractExpression of inducible nitric oxide synthase (iNOS), which leads to the production of nitric oxide (NO), is stimulated by proinflammatory cytokines such as interleukin‐1β (IL‐1β) and tumor necrosis factor‐α (TNF‐α). Here we report on the roles of nuclear factor‐κB (NF‐κB) and mitogen‐activated protein (MAP) kinases in IL‐1β/TNF‐α–induced iNOS expression in adult rat astroglia. Cytokine‐induced increases in nitrite accumulation (an index of NO production) and iNOS expression were attenuated by inhibition of NF‐κB with pyrrolidine dithiocarbamate (PDTC). Similar attenuation of these cytokine‐induced responses was produced by inhibition of MAP kinase (MEK), the immediate upstream activator of Erk, using PD098,059. Combined treatment of astroglia with PDTC and PD098,059 completely abolished the cytokine‐induced increases in iNOS expression and nitrite accumulation. By contrast, the selective p38 kinase inhibitor SB203,580 amplified the effects of IL‐1β/TNF‐α on nitrite accumulation. In accordance with these findings, IL‐1β– and TNF‐α–induced a time‐dependent increase in Erk1/Erk2 activation. This cytokine action was completely abolished by PD098,059 but was not altered by PDTC. Finally, IL‐1β and TNF‐α induced degradation of NF‐κB's bound inhibitory protein, IκB‐α, leading to translocation of NF‐κB into the nucleus. IκB‐α expression was not restored to control levels by inhibition of MEK. Furthermore, inhibition of MEK with PD098,059 did not alter IL‐1β– and TNF‐α–induced expression of active NF‐κB. The results demonstrate that autonomous Erk and NF‐κB pathways mediate cytokine‐induced increases in iNOS expression in astroglia. GLIA 41:152–160, 2003. © 2003 Wiley‐Liss, Inc.
Suppression of activated microglia promotes survival and function of transplanted oligodendroglial progenitors
Authors: Zhang Su‐Chun , Goetz Brian D. , Duncan Ian D. 
Published: January 2003

AbstractTo evaluate the functional consequence of microglial activation in vivo, oligodendroglial progenitors were transplanted into the spinal cord of Long Evans shaker, a myelin mutant rat in which myelin defects are associated with progressive microglial activation. Cells grafted into neonatal rats at the initiation of gliosis successfully myelinated axons. However, cells transplanted during peak microglial activation did not lead to myelination due to death of the grafted cells within 3 days after transplantation. Pretreatment of these animals with minocycline, a tetracycline derivative, resulted in cell survival and myelination by the grafted cells. In culture, minocycline did not affect the survival, proliferation, or differentiation of oligodendroglial progenitors. Hence, minocycline likely modulates the function of reactive glia in vivo to promote the survival and myelination of transplanted oligodendroglial progenitors. GLIA 41:191–198, 2003. © 2003 Wiley‐Liss, Inc.
Sphingosine 1‐phosphate induces the production of glial cell line‐derived neurotrophic factor and cellular proliferation in astrocytes
Authors: Yamagata Kazuo , Tagami Motoki , Torii Yasuyoshi , Takenaga Fumio , Tsumagari Shigehisa , Itoh Shingo , Yamori Yukio , Nara Yasuo 
Published: January 2003

AbstractSphingosine 1‐phosphate (S1P) is a platelet‐derived bioactive sphingolipid that evokes a variety of biological responses. To understand the role of S1P in the central nervous system, we have examined the effect of S1P on the production of glial cell line‐derived neurotrophic factor (GDNF) and growth regulation of cortical astrocytes from rat embryo. Moreover, we examined the possibility that the expression of GDNF is regulated differently in cultured astrocytes from the stroke‐prone spontaneously hypertensive rat (SHRSP) than in those from Wistar kyoto rats (WKY). The mRNA expression was quantitated by RT‐PCR based on the fluorescent TaqMan methodology. A new instrument capable of measuring fluorescence in real time was used to quantify gene amplification in astrocytes. GDNF protein was investigated by enzyme‐linked immunosorbent assay. S1P induced the expression of GDNF mRNA and the production of GDNF protein in a dose‐dependent manner in WKY astrocytes. Moreover, S1P increased cell numbers and induced the proliferation of astrocytes. In addition, the level of mRNA expression and protein production of GDNF was significantly lower in SHRSP than WKY astrocytes following exposure to S1P. These findings revealed that S1P augments GDNF protein production and cellular growth in astrocytes. Also, our results indicate that production in SHRSP astrocytes was attenuated in response to S1P compared with that observed in WKY. We conclude that S1P specifically triggers a cascade of events that regulate the production of GDNF and cell growth in astrocytes. Our results also suggest that the reduced expression of GDNF caused by S1P is a factor in the stroke proneness of SHRSP. GLIA 41:199–206, 2003. © 2003 Wiley‐Liss, Inc.
Annamaria Cimini, Antonietta Bernardo, Maria Grazia Cifone, Luisa Di Marzio, Silvia Di Loreto. TNF downregulates PPAR expression in oligodendrocyte progenitor cells: Implications for demyelinating diseases. GLIA 2003;41(1):3–14.
Authors: Cimini Annamaria , Bernardo Antonietta , Grazia Cifone Maria , Di Marzio Luisa , Di Loreto Silvia 
Published: January 2003

AbstractThe original article to which this Erratum refers was published in GLIA (2003)41:3–14
Psychosocial adjustment in head and neck cancer: The impact of disfigurement, gender and social support
Authors: Katz Mark R. , Irish Jonathan C. , Devins Gerald M. , Rodin Gary M. , Gullane Patrick J. 
Published: January 2003

AbstractBackground.The purpose of this study was to examine the psychosocial impact of disfigurement, gender, and social support after surgical treatment of head and neck cancer.Method.Eighty‐two ambulatory head and neck cancer patients, 6 months or more after treatment and free of active disease were assessed. Ratings of disfigurement were obtained using a valid and reliable 9‐point scale developed for the study. Standardized measures of social support, depressive symptoms, well‐being, and life happiness were used.Results.The sample as a whole displayed high levels of life happiness, low levels of depression, and positive feelings of well‐being. Women demonstrated higher levels of depression and lower life happiness; subjects with greater disfigurement were more depressed. Social support seemed to buffer the impact of greater levels of disfigurement on well‐being for women but not for men.Conclusion.These results suggest that women with head and neck cancer who experience low social support and face disfiguring treatment are at greatest risk for psychosocial dysfunction. © 2003 Wiley Periodicals, Inc. Head Neck 25: 103–112, 2003
Different prognostic indices in 310 patients with tonsillar carcinomas
Authors: Hannisdal Kirsten , Boysen Morten , Evensen Jan F. 
Published: January 2003

AbstractBackground.Several modifications of the TNM system have been reported as better prognostic tools than the original classification in head and neck cancer, but none of these modifications has been tested in a large series of tonsillar carcinomas. These studies did not examine host and treatment factors as predictors in addition to TNM.Methods.Three hundred and ten consecutively untreated patients with squamous cell carcinoma of the tonsillar region admitted to the Norwegian Radium Hospital and/or the National Hospital between 1960 and 1996 were included.Results.The five reported TN‐based stage modifications were all highly significant predictors of survival. Four clinical variables indicating shorter disease‐specific survival were identified: age > 60, male gender, total radiation dose < 70 Gy, and duration of radiotherapy > 50 days.Conclusions.Earlier reported TNM‐based stage modifications are all very useful predictors of survival in tonsillar carcinomas. In addition, age, gender, total radiation dose, and duration of radiotherapy were important prognostic factors. We propose that both host and treatment factors should be tested carefully when building new prognostic indices in tonsillar carcinomas. © 2003 Wiley Periodicals, Inc. Head Neck 25: 123–131, 2003
Phase 1 trial of combined chemotherapy and reirradiation for recurrent unresectable head and neck cancer
Authors: Spencer Sharon , Wheeler Richard , Peters Glenn , Meredith Ruby , Beenken Sam , Nabel Lisle , Wooten Ann , Soong Seng‐jaw , Salter Merle 
Published: January 2003

AbstractBackground.The management of recurrent unresectable head and neck cancer remains a challenging problem. Based on the circadian rhythm concept, we sought to determine the maximum tolerated dose (MTD) of infusional 5‐flourouracil (5‐FU), hydroxyurea (HU), and reirradiation (RT).Method.Bolus 5‐FU was escalated from 300mg/m2/d to a 10‐hour infusion beginning at midnight, increased at 150 mg/m2/d increments. HU, 1.5 g, remained constant. Chemotherapy was given on weeks 1 and 4. RT was given daily, 2.0 Gy per fraction on weeks 1 and 2 followed by a 1‐week break, then hyperfractionated weeks 4 and 5, total dose 50 Gy. The goal was to deliver a continuous course of RT to 60 Gy after the MTD was determined with an additional week of chemotherapy.Results.Six cohorts were treated to establish the 5‐FU MTD of 900 mg/m2/d. The seventh cohort received continuous RT and 5‐FU, 750 mg/m2/d, one dose level below the MTD. Two hematologic, three skin, and six mucosal ≥ grade 3 toxicities were noted in 7 of 16 patients. The median survival was 10.2 months and the 1‐year survival was 41%. The median survival for the entire group was 9.4 months, with a 1‐ and 2‐year survival of 39% and 15%, respectively.Conclusion.RT can be given in a continuous fashion with concurrent 5‐FU and HU. Because radiation sensitization should be achievable at nontoxic doses of 5‐FU, we recommend 600 mg/m2/d in phase a II setting. © 2003 Wiley Periodicals, Inc. Head Neck 25: 118–122, 2003
The usefulness of fluorine 18–labelled deoxyglucose positron emission tomography in the investigation of patients with cervical lymphadenopathy from an unknown primary tumor
Authors: Fogarty Gerald B. , Peters Lester J. , Stewart Josephine , Scott Clare , Rischin Danny , Hicks Rodney J. 
Published: January 2003

AbstractBackground.The usefulness of fluorine 18‐labelled deoxyglucose positron emission tomography (PET) in the detection of unknown primary tumor in patients seen with malignant cervical lymphadenopathy thought to arise from a head and neck primary differs in the published reports to date. To assess the role of PET in this scenario in our institution, an audit was performed.Methods.The records of 21 patients who met the clinical indication were reviewed. End points were the ability of PET to detect an unknown primary tumor and/or distant metastatic disease.Results.In 8 of the 21 patients, PET detected a potential primary site, although none was unequivocally PET positive. One case was pathologically confirmed. In five patients the potential primary site identified on PET could not be confirmed: two had negative biopsies, and three had no clinical evolution in the PET‐suspect area for at least 24 months after the initial study. In the remaining two patients, the potential primary site detected by PET was treated without biopsy. PET detected additional regional and/or distant disease that had not been previously documented in nine cases.Conclusions.PET did not add significantly to the detection of an occult primary tumor in patients who had already been comprehensively evaluated by clinical and radiologic investigations. It was of substantial benefit, however, in detecting unsuspected distant disease in patients with undifferentiated nodal histologic findings and helped in delineating regional disease in patients with N2 disease. © 2003 Wiley Periodicals, Inc. Head Neck 25: 138–145, 2003