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Biomedical subjects

B Griffiths

Publications and source records attributed to B Griffiths.

At least 37 records · Page 2Linked to original sources
PubMed2000

Fcgamma receptor type IIIA is associated with rheumatoid arthritis in two distinct ethnic groups.

OBJECTIVE: To investigate a possible association between a functional polymorphism in the intermediate-affinity receptor for IgG called Fc-gamma receptor type IIIA (FcgammaRIIIA [CD16]) and rheumatoid arthritis (RA). METHODS: This was an allelic association study in which a single nucleotide polymorphism in FcgammaRIIIA was examined as a susceptibility and/or severity factor for RA. The FcgammaRIIIA-158V/F polymorphism was genotyped by direct sequencing in 2 well-characterized ethnic groups, UK Caucasians (141 RA patients and 124 controls) and North Indians and Pakistanis (108 RA patients and 113 controls). RESULTS: The FcgammaRIIIA-158V/F polymorphism was associated with RA in both ethnic groups (P = 0.028 for UK Caucasians, P = 0.050 for North Indians and Pakistanis, and P = 0.003 for both groups combined). FcgammaRIIIA-158VF and -158W individuals had an increased risk of developing RA in both populations (UK Caucasians odds ratio [OR] 1.6, P = 0.050; North Indians and Pakistanis OR 1.9, P = 0.023; and combined groups OR 1.7, P = 0.003). In the UK Caucasian group, the highest risk was for nodular RA, a more severe disease subset, associated with homozygosity for the FcgammaRIIIA-158V allele (OR 4.4, P = 0.004). There was also evidence for an interaction between the RA-associated HLA-DRB1 allele and the presence of at least 1 FcgammaRIIIA-158V allele in predicting susceptibility to RA (OR 5.5, P = 0.000). CONCLUSION: We have demonstrated that the FcgammaRIIIA-158V/F polymorphism is a susceptibility and/or severity marker for RA in 2 distinct ethnic groups. This finding may ultimately provide additional insights into the pathogenesis of RA and other autoantibody/immune complex-driven autoimmune diseases.

Alleles↗
PubMed2000

Components of the human spindle checkpoint control mechanism localize specifically to the active centromere on dicentric chromosomes.

The spindle checkpoint control mechanism functions to ensure faithful chromosome segregation by delaying cell division until all chromosomes are correctly oriented on the mitotic spindle. Initially identified in budding yeast, several mammalian spindle checkpoint-associated proteins have recently been identified and partially characterized. These proteins associate with all active human centromeres, including neocentromeres, in the early stages of mitosis prior to the commencement of anaphase. We have examined the status of proteins associated with the checkpoint protein complex (BUB1, BUBR1, BUB3, MAD2), the anaphase-promoting complex (Tsg24, p55CDC), and other proteins associated with mitotic checkpoint control (ERK1, 3F3/2 epitope, hZW10), on a human dicentric chromosome. Each of these proteins was found to specifically associate with only the active centromere, suggesting that only active centromeres participate in the spindle checkpoint. This finding complements previous studies on multicentric chromosomes demonstrating specific association of structural and motor-related centromere proteins with active centromeres, and suggests that centromere inactivation is accompanied by loss of all functionally important centromere proteins.

Anaphase↗
PubMed2000

Uterine expression of alternatively spliced mRNAs of mouse splicing factor SC35 during early pregnancy.

RNA differential display was applied to identify genes critical for the establishment of pregnancy in the mouse. One of the gene fragments identified was homologous to human SC35 splicing factor; the mouse counterpart had not then been cloned. To obtain the full cDNA sequence of the mouse gene, a cDNA library was screened and four positive clones were fully analysed. Sequencing analysis indicated that we had cloned alternatively spliced mRNA species of mouse SC35 splicing factor. A map of splicing structure for this gene's pre-mRNA was then proposed and region-specific mRNA species were tested on Northern blots. This analysis indicated that the overall expression level of SC35 mRNA was much higher in implantation sites than in inter-implantation sites in the mouse uterus during early pregnancy. The expression of alternatively spliced mRNAs for SC35 was differently regulated both during early pregnancy and by steroid hormones. Embryo-derived factors were also implicated in the up-regulation of SC35 mRNA at implantation sites. These results demonstrate, for the first time, that an essential splicing factor is regulated in a complex manner during implantation in the mouse uterus. Hence, its correct regulation could be important for the success of pregnancy.

Alternative Splicing↗
PubMed2000

Racial origin and its effect on disease expression and HLA-DRB1 types in patients with rheumatoid arthritis: a matched cross-sectional study.

OBJECTIVE: There are a significant number of patients with rheumatoid arthritis (RA) of North Indian or Pakistani origin (Asian) now living in the UK. RA has been poorly studied in this racial group. The aim of this study was to compare RA in this Asian group with RA in the indigenous northern European (European) population. It was hypothesized that these two racial groups would have different disease expressions and immunogenetics that could be relevant to pathogenesis, prognosis and therapy. METHODS: One hundred and seven Asian RA patients, who fulfilled the 1987 American College of Rheumatology criteria, were stringently matched for age, sex and disease duration with 107 European RA patients, and were fully assessed. RESULTS: The Asian RA patients had significantly fewer bony erosions [median Larsen score 58.5 (interquartile range 45.5-77.8) vs 68 (52-93) for European patients; P: = 0.0066, Mann-Whitney U:-test] and rarely had nodules (5.7 vs 20%, P: = 0. 0019, Fisher's exact test). The two groups had the same prevalence of rheumatoid factor positivity, number of swollen joints and level of inflammation (C-reactive protein). The Asian RA patients had a reduced prevalence of the conserved third allelic hypervariable region (3AHVR) (45 vs 82%, P: < 0.0001, Fisher's exact test), particularly DRB1*0401 (4.5 vs 55%). However, the prevalence of the conserved 3AHVR was significantly increased in the Asian RA patients compared with Asian controls. By contrast, the Asian patients had more tender joints [13.5 (7-22) vs 5.5 (2-11.8); P: < 0.0001 Mann-Whitney U:-test]. The Health Assessment Questionnaire score was also significantly worse in the Asians compared with the Europeans [median 2.0 (1.13-2.63) vs 1.25 (0.5-2.13), P: = 0.0001). CONCLUSIONS: The Asian patients had similar levels of inflammation and less damage but more pain and disability than the matched European RA patients. Of the known prognostic factors for erosions (rheumatoid factor, conserved 3AHVR, swollen joints and C-reactive protein), only the conserved 3AHVR was reduced in the Asian RA patients, and this was consistent with their less erosive disease. These data also indicate the importance of pain as well as erosive damage in determining disability in Asian patients and stress the importance of adequate pain relief, in addition to disease suppression, when treating Asian RA patients.

Adult↗
PubMed1999

Cyclins D1 and D2 mediate myc-induced proliferation via sequestration of p27(Kip1) and p21(Cip1).

Cyclin E-Cdk2 kinase activation is an essential step in Myc-induced proliferation. It is presumed that this requires sequestration of G(1) cell cycle inhibitors p27(Kip1) and p21(Cip1) (Ckis) via a Myc-induced protein. We provide biochemical and genetic evidence to show that this sequestration is mediated via induction of cyclin D1 and/or cyclin D2 protein synthesis rates. Consistent with this conclusion, primary cells from cyclin D1(-/-) and cyclin D2(-/-) mouse embryos, unlike wild-type controls, do not respond to Myc with increased proliferation, although they undergo accelerated cell death in the absence of serum. Myc sensitivity of cyclin D1(-/-) cells can be restored by retroviruses expressing either cyclins D1, D2 or a cyclin D1 mutant forming kinase-defective, Cki-binding cyclin-cdk complexes. The sequestration function of D cyclins thus appears essential for Myc-induced cell cycle progression but dispensable for apoptosis.

3T3 Cells↗
PubMed1998

The assessment of knowledge in ankylosing spondylitis patients by a self-administered questionnaire.

The aim of the present study was to assess ankylosing spondylitis (AS) patients' level of knowledge, using a self-administered multiple-choice questionnaire. The questionnaire, based on the Arthritis and Rheumatism Council (ARC) leaflet on AS, examined four areas: (A) general knowledge; (B) immunogenetic tests and inheritance; (C) general management; (D) joint protection, pacing and priorities. Statistical analysis was used to validate the questionnaire and to examine correlations with gender, age, disease duration and level of general education. The questionnaire was consistent, reliable and easy to read. The results showed AS patients to have a high level of knowledge (mean = 19.4, maximum possible = 25), although some wrong beliefs about the role of blood tests, the HLA-B27 antigen and inheritance were discovered. No statistical correlation was found between gender, age, duration of the disease, level of general education and the level of knowledge. These data suggest that this questionnaire is a simple way to detect the level of knowledge of patients with AS. The average score achieved by AS patients was outstanding, possibly reflecting the good quality of previous educational programmes. Patients' confusion regarding blood tests, genetics and inheritance was highlighted and should be addressed.

Activities of Daily Living↗
PubMed1998

The role of the T lymphocytic cell cycle and an autogenous lymphocytic factor in clinical medicine.

In this study 315 individuals (25 controls, 290 chemically sensitive immunocompromised patients) were investigated. Each patient had been on a standard therapy of avoidance of pollutants, nutritional supplementation, and injections of antigens for foods, and biological inhalants, but did not attain their immunological competence. Peripheral lymphocytes were collected and DNA histograms were constructed. The flow cytometer was used to evaluate the cell cycle, haematological, and other immunological profiles. From the other portion of the blood specimen, lymphocytes were propagated in vitro, harvested, and a lysate, termed the autogenous lymphocytic factor (ALF), was prepared. When treated with ALF, 88% of these individuals showed a significant (p < 0.001) clinical improvement which correlated with laboratory findings, involving regulation of abnormal cell cycles, increase in total lymphocytes and subsets T4, T8, (p < 0.05) and cell mediated immunity (CMI) response (p < 0.001). The ALF presumably acts as a biological response modifier. The cell cycle and ALF provide clinical tools for diagnosis and regulation of immunological incompetence.

Cell Cycle↗
PubMed1996

The 5' end of the BRCA1 gene lies within a duplicated region of human chromosome 17q21.

To begin to address the hypothesis that abnormal regulation of the breast/ovarian cancer susceptibility gene BRCA1 is a critical step in sporadic breast/ovarian tumorigenesis, we have determined the detailed structure of the BRCA1 genomic region. We show that this region of the genome contains a tandem duplication of approximately 30 kilobases, which results in two copies of BRCA1 exons 1 and 2, of exons 1 and 3 of the adjacent 1A1-3B gene and of the previously reported 295 base pair intergenic region. Sequence analysis of the duplicated exons of BRCA1 and 1A1-3B and flanking genomic DNA reveals maintenance of the intron-exon structure and a high degree of nucleotide sequence identity, suggesting that these are non-processed pseudogenes and that the duplication is a recent event in evolutionary terms. We also show that a processed pseudogene of the acidic ribosomal phosphoprotein P1 (ARPP1) is inserted directly upstream of pseudo-BRCA1 exon 1A. We believe that these findings could not only confound BRCA1 mutation analysis, but could have implications for the normal and abnormal regulation of BRCA1 transcription, translation and function.

BRCA1 Protein↗
PubMed1995

Distinct transcription start sites generate two forms of BRCA1 mRNA.

Using primer extension and 5' RACE, we have mapped the 5' end of the BRCA1 gene and identified a new 5' exon. Two distinct BRCA1 transcripts differing by the first exons were found; these transcripts were generated by the alternative use of dual promoters and alternative splicing. The expression of the distinct transcripts was examined in four primary tissues (placenta, mammary gland, testis and thymus), six normal or cancer cell lines, four primary breast tumor tissues and four primary ovary tumour tissues. Both transcripts were detected in all the samples studied, with the exon 1a transcript being the major expressed form in mammary gland and the exon 1b transcript in placenta. This suggests that the two transcripts may be expressed in a tissue-specific fashion. The 5' flanking regions of both BRCA1 transcripts were analysed, neither contains a TATA box. Initiator elements, which have been proposed to mediate transcription in TATA-less promoters, were found at the transcription initiation sites. Transcription factor binding sites such as Sp1, PEA3, C/EBP, CREB, E4F1 and Pu boxes were identified in the 5' flanking regions of the exon 1a transcript, and Sp1, NF-kB and PEA3 binding sites in the 5' flanking region of the exon 1b transcript. The interactions of these DNA elements with trans-acting factors are likely to modulate the alternative use of the distinct transcription start sites and the expression of the BRCA1 gene.

Alternative Splicing↗
PubMed1993

Physical mapping within the tuberous sclerosis linkage group in region 9q32-q34.

Pulsed-field gel electrophoresis and flow dot-blot analysis have been used to construct a physical map of the q32-q34 region of chromosome 9, where one of the loci responsible for tuberous sclerosis (TSC1) has been mapped by genetic linkage. Five linked groups of markers have been defined by pulsed-field gel electrophoresis. The orientation of these groups and the order of markers within them were determined by hybridization to flow-sorted dot blots derived from a panel of cell lines of chromosome 9 translocations to place probes proximal or distal to each breakpoint. The local map order in 9q32-q34 derived by application of this combination of techniques is as follows: centromere-ALAD-1.3 Mb-ORM/20 kbD9S16-GSN-250 kb-C5-HXB-1.9 Mb-D9S21-AK1-1.4 Mb-SPTAN1-ASS-800 kb-ABL-2 Mb-D9S10/350 Kb/DBH-telomere.

Cell Line↗
PubMed1992

Alternative strategies to the scaleup of animal cells.

The use of porous microcarriers has given manufacturers the option of having a high cell density/medium volume (10-100 L)/high specific productivity/long-term process. The advantages of the system are listed in Table 7 and many of the criteria listed in Table 1 are met. The question of being able to license products from continuous processes has been addressed and guidelines are being prepared. Methods are available to compare the master and end-of-process (extended) cell banks to ensure that no change has occurred to the cell or product. Rigid attention to process definition and validation, as well as to the definition of production lots, overcomes many of the other reservations. In conclusion, the method has been demonstrated as technically feasible, economically advantageous, and licensable and the many advantages of a high density perfusion process (listed in Table 8) make porous microcarrier technology an ideal scaleup process because it is a simple, reliable, and scalable system.

Animal Population Groups↗