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Biomedical subjects

G Chapman

Publications and source records attributed to G Chapman.

At least 19 recordsLinked to original sources
PubMed2005

Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype.

The spondylocostal dysostoses (SCDs) are a heterogeneous group of vertebral malsegmentation disorders that arise during embryonic development by a disruption of somitogenesis. Previously, we had identified two genes that cause a subset of autosomal recessive forms of this disease: DLL3 (SCD1) and MESP2 (SCD2). These genes are important components of the Notch signaling pathway, which has multiple roles in development and disease. Here, we have used a candidate-gene approach to identify a mutation in a third Notch pathway gene, LUNATIC FRINGE (LFNG), in a family with autosomal recessive SCD. LFNG encodes a glycosyltransferase that modifies the Notch family of cell-surface receptors, a key step in the regulation of this signaling pathway. A missense mutation was identified in a highly conserved phenylalanine close to the active site of the enzyme. Functional analysis revealed that the mutant LFNG was not localized to the correct compartment of the cell, was unable to modulate Notch signaling in a cell-based assay, and was enzymatically inactive. This represents the first known mutation in the human LFNG gene and reinforces the hypothesis that proper regulation of the Notch signaling pathway is an absolute requirement for the correct patterning of the axial skeleton.

Base Sequence↗
PubMed2004

New HLA-B alleles detected by polymerase chain reaction-sequence-specific oligonucleotide typing: HLA-B*0725, B*0728, and B*3808.

Three novel alleles, human leukocyte antigen (HLA)-B*0725, B*0728, and B*3808, were discovered during routine genotyping of samples for the Australian Bone Marrow Donor Registry and Australian Cord Blood Bank. The new alleles contain amino acid changes in the antigen-binding site of the expressed HLA protein, which may alter the antigen-binding properties of the functional protein.

Base Sequence↗
PubMed2004

Detection of a novel HLA-A allele by polymerase chain reaction-sequence-specific oligonucleotide typing: HLA-A*0252.

Anew human leukocyte antigen (HLA) class I allele, HLA-A*0252, has been found during routine typing of samples for the Australian Bone Marrow Donor Registry. A*0252 differs from A*020101 at four codon positions, with all the new polymorphisms resulting in an amino acid change. The amino acids involved are located in the antigen-binding region of the HLA protein.

Base Sequence↗
PubMed2004

Identification of new HLA-C alleles by polymerase chain reaction-sequence specific oligonucleotide typing: Cw*0314 and Cw*1511*.

In this article, we report two new human leukocyte antigen-C (HLA-C) alleles, HLA-Cw*0314 and Cw*1511, which were identified during routine tissue typing of donors for the Australian Bone Marrow Donor Registry and Australian Cord Blood Bank. HLA-Cw*0314 shows six codon changes in exon 3 compared to Cw*030401 and shares some sequence homology with Cw*07 alleles. Cw*1511 has two nucleotide changes compared with Cw*150201 in exon 2, both resulting in amino acid changes in the protein sequence.

Alleles↗
PubMed2004

Identification of two novel HLA class II alleles, DQB1*0311 and DQB1*0620.

Two novel HLA class II alleles have been identified in routine typing of a kidney transplant patient and a cord blood unit from the Australian Cord Blood Bank in Sydney. Sequence analysis of exon 2 of the DQB1 genes revealed the novel polymorphism. A substitution of A to C at nucleotide position 136 has been identified for the DQB1*0311 allele when compared to the closest-matched allele, DQB1*030201. An identical substitution has also been identified for the DQB1*0620 allele when compared to the closest-matched allele, DQB1*0602. The substitution results in an amino acid change from methionine to leucine at position 46 implicating different specificity and affinity of antigen binding.

Alleles↗
PubMed2004

Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats.

Recent evidence suggests that spinal cord glia can contribute to enhanced nociceptive responses. However, the signals that cause glial activation are unknown. Fractalkine (CX3C ligand-1; CX3CL1) is a unique chemokine expressed on the extracellular surface of spinal neurons and spinal sensory afferents. In the dorsal spinal cord, fractalkine receptors are primarily expressed by microglia. As fractalkine can be released from neurons upon strong activation, it has previously been suggested to be a neuron-to-glial signal that induces glial activation. The present series of experiments provide an initial investigation of the spinal pain modulatory effects of fractalkine. Intrathecal fractalkine produced dose-dependent mechanical allodynia and thermal hyperalgesia. In addition, a single injection of fractalkine receptor antagonist (neutralizing antibody against rat CX3C receptor-1; CX3CR1) delayed the development of mechanical allodynia and/or thermal hyperalgesia in two neuropathic pain models: chronic constriction injury (CCI) and sciatic inflammatory neuropathy. Intriguingly, anti-CX3CR1 reduced nociceptive responses when administered 5-7 days after CCI, suggesting that prolonged release of fractalkine may contribute to the maintenance of neuropathic pain. Taken together, these initial investigations of spinal fractalkine effects suggest that exogenous and endogenous fractalkine are involved in spinal sensitization, including that induced by peripheral neuropathy.

Animals↗
PubMed2002

Description of a novel HLA-DRB1 allele, DRB1*1207.

A new DRB1 allele has been identified during routine HLA-DRB1 generic typing with sequence specific oligonucleotides. The new allele was confirmed by PCR-restriction fragment length polymorphism analysis and subsequently sequenced. This showed the novel allele, named HLA-DRB1*1207, was similar in sequence to DRB1*12011, except for codon 69 of exon 2.

Alleles↗
PubMed2002

Six new HLA class I alleles detected by PCR-SSO genotyping.

This paper describes six new alleles; A*0240, A*2614, B*3924, B*4425, Cw*0807 and Cw*12023, which were discovered during routine genotyping with sequence specific oligonucleotides (SSO's). Five of the new alleles have changes in residues which belong to the antigen binding site of the HLA protein. These new variants may have altered antigen binding properties and may cause differential immunological responses that could affect transplantation outcome1.

Base Sequence↗
PubMed2002

Novel HLA-DRB1 alleles revealed by sequencing based typing, DRB1*04053 and DRB1*1143.

We report the discovery of two HLA-DRB1 alleles by sequencing based typing (SBT). DRB1*04053 differs from previously reported DRB1 alleles by a single synonymous nucleotide substitution, resulting in a unique polymorphism at codon 93. DRB1*1143 differs from previously identified DRB1 alleles by a single non-synonymous nucleotide substitution, resulting in a polymorphism observed in other DRB1 and DRB3 alleles1.

Alleles↗
PubMed2000

CRTR-1, a developmentally regulated transcriptional repressor related to the CP2 family of transcription factors.

CP2-related proteins comprise a family of DNA-binding transcription factors that are generally activators of transcription and expressed ubiquitously. We reported a differential display polymerase chain reaction fragment, Psc2, which was expressed in a regulated fashion in mouse pluripotent cells in vitro and in vivo. Here, we report further characterization of the Psc2 cDNA and function. The Psc2 cDNA contained an open reading frame homologous to CP2 family proteins. Regions implicated in DNA binding and oligomeric complex formation, but not transcription activation, were conserved. Psc2 expression in vivo during embryogenesis and in the adult mouse demonstrated tight spatial and temporal regulation, with the highest levels of expression in the epithelial lining of distal convoluted tubules in embryonic and adult kidneys. Functional analysis demonstrated that PSC2 repressed transcription 2.5-15-fold when bound to a heterologous promoter in ES, 293T, and COS-1 cells. The N-terminal 52 amino acids of PSC2 were shown to be necessary and sufficient for this activity and did not share obvious homology with reported repressor motifs. These results represent the first report of a CP2 family member that is expressed in a developmentally regulated fashion in vivo and that acts as a direct repressor of transcription. Accordingly, the protein has been named CP2-Related Transcriptional Repressor-1 (CRTR-1).

Amino Acid Sequence↗
PubMed2000

The costs of HIV/AIDS care at government hospitals in Zimbabwe.

According to official figures, HIV infection in Zimbabwe stood at 700 000-1 000 000 in 1995, representing 7-10% of the population, with even higher expected numbers in 2000. Such high numbers will have far reaching effects on the economy and the health care sector. Information on costs of treatment and care of HIV/AIDS patients in health facilities is necessary in order to have an idea of the likely costs of the increasing number of HIV/AIDS patients. Therefore, the present study estimated the costs per in-patient day as well as per in-patient stay for patients in government health facilities in Zimbabwe with special emphasis on HIV/AIDS patients. Data collection and costing was done in seven hospitals representing various levels of the referral system. The costs per in-patient day and per in-patient stay were estimated through a combination of two methods: bottom-up costing methodology (through an in-patient note review) to identify the direct treatment and diagnostic costs such as medication, laboratory tests and X-rays, and the standard step-down costing methodology to capture all the remaining resources used such as hospital administration, meals, housekeeping, laundry, etc. The findings of the study indicate that hospital care for HIV/AIDS patients was considerably higher than for non-HIV/AIDS patients. In five of the seven hospitals visited, the average costs of an in-patient stay for an HIV/AIDS patient were found to be as much as twice as high as a non-HIV/AIDS patient. This difference could be attributed to higher direct costs per in-patient day (medication, laboratory tests and X-rays) as well as longer average lengths of stay in hospital for HIV/AIDS patients compared with non-infected patients. Therefore, the impact on hospital services of increasing number of HIV/AIDS patients will be enormous.

Cost Allocation↗
PubMed2000

The North Staffordshire Maternity Hospital prospective study of pregnancy-associated depression.

The objective of the study was to establish the frequency of depression during pregnancy and the puerperium, and its relationship to marital disharmony and sociodemographic variables. A prospective longitudinal study was carried out in a district general hospital in the West Midlands, UK. The cohort consisted of 417 women booked for confinement at the hospital. Depression was measured as a proportion of high scores (> 14) on the Edinburgh Postnatal Depression Scale (EPDS) and marital disharmony was determined by the Spanier Dyadic Adjustment Scale. Using recommended cut-offs, 41/417 (9.8%) of the women were depressed during pregnancy and 31/417 (7.4%) were depressed at 3 months postpartum. There was a significant association between antenatal and postnatal depression, seven of the 31 women who were depressed postpartum had also been depressed in the antenatal period. Only five of the 41 women with antenatal depression and eight of the 31 women with postnatal depression were identified by their general practitioners as depressed. Marital disharmony was sequentially associated with depression before and after delivery. We conclude that antenatal depression is more common than generally thought, and that both antenatal and postnatal depression are frequently missed during routine consultation. Pregnancy-associated depression is more common where marital disharmony exists. More widespread use of the EPDS during pregnancy may help to highlight these often unidentified mental health problems.

Adolescent↗
PubMed1999

Site-specific splice variation of the human P2X4 receptor.

P2X4 receptors are expressed in specific brain areas. We now describe site-specific splice variations of the human P2X4 receptor subunit, occurring at residue [YVIG / WVFV(W)] near the end of the first predicted transmembrane domain. p2X4(b) is formed by the insertion of an additional 16 amino acids. p2X4(C) is formed by deleting a cassette of 130 amino acids, including six of the 10 conserved extracellular cysteine residues. Transfection of P2X4(a), but not p2x4(c), formed functional channels in Xenopus oocytes and human 1321N1 cells. After transfection of p2X4(b) small, inconsistent ATP-evoked responses were detected only in the human cells, but when co-expressed, p2x4(b) may alter the function of P2X4(a) in oocytes. The distribution of splice variant RNA within human brain suggests regionally-dependent expression. These data indicate that the functions of the human P2X4 receptor may be altered by alternative splicing.

Adenosine Triphosphate↗
PubMed1999

Formation of a primitive ectoderm like cell population, EPL cells, from ES cells in response to biologically derived factors.

The primitive ectoderm of the mouse embryo arises from the inner cell mass between 4.75 and 5.25 days post coitum, around the time of implantation. Positioned at a pivotal time in development, just prior to formation of the three germ layers of the embryo proper, the primitive ectoderm responds directly to the signals generated during gastrulation. We have identified a conditioned medium, MEDII, which caused the homogeneous conversion of ES cells to a morphologically distinct cell population, termed early primitive ectoderm-like (EPL) cells. EPL cells expressed the pluripotent cell markers Oct4, SSEA1 and alkaline phosphatase. However, the formation of EPL cells was accompanied by alterations in Fgf5, Gbx2 and Rex1 expression, a loss in chimaera forming ability, changes in factor responsiveness and modified differentiation capabilities, all consistent with the identification of EPL cells as equivalent to the primitive ectoderm population of the 5.5 to 6.0 days post coitum embryo. EPL cell formation could be reversed in the presence of LIF and withdrawal of MEDII, which suggested that EPL cell formation was not a terminal differentiation event but reflected the ability of pluripotent cells to adopt distinct cell states in response to specific factors. Partial purification of MEDII revealed the presence of two separable biological activities, both of which were required for the induction and maintenance of EPL cells. We show here the first demonstration of uniform differentiation of ES cells in response to biological factors. The formation of primitive ectoderm, both in vivo and in vitro, appears to be an obligatory step in the differentiation of the inner cell mass or ES cells into cell lineages of the embryonic germ layers. EPL cells potentially represent a model for the development of lineage specific differentiation protocols and analysis of gastrulation at a molecular level. An understanding of the active components of MEDII may provide a route for the identification of factors which induce primitive ectoderm formation in vivo.

Animals↗