PubMed Health⌕ Search

Biomedical subjects

I Griffiths

Publications and source records attributed to I Griffiths.

At least 19 recordsLinked to original sources
PubMed2005

The British Society for Rheumatology biologics register.

The British Society for Rheumatology (BSR) established a nationwide register for patients with rheumatological disorders treated with biologic agents. The register is designed as a national prospective study whose primary purpose is to assess long term toxicity from the use of these agents in routine practice. In addition, the data will be capable of addressing the benefits from their use in relation to their toxicity. One specific feature of the BSR register is the recruitment and collection of data from a parallel comparison group, comprising patients with active rheumatoid arthritis treated with conventional disease modifying agents. Both class specific and drug specific analyses of the group treated with biologicals are planned.

Adverse Drug Reaction Reporting Systems↗
PubMed2003

British Society for Rheumatology Biologics Register.

The British Society for Rheumatology (BSR) established a register of patients newly treated with biological agents, the BSR Biologics Register (BSRBR), which became active in January 2002. The goal is to register all patients in the United Kingdom with rheumatic diseases, newly starting treatment with these agents and to follow them up to determine the incidence of any short and long term hazards to health. The Register is also recruiting a comparison cohort of patients with rheumatoid arthritis treated with standard disease modifying antirheumatic drugs to determine the relative contributions of disease factors and other treatments apart from biological agents on any risks observed.

Antirheumatic Agents↗
PubMed1998

Axonal swellings and degeneration in mice lacking the major proteolipid of myelin.

Glial cells produce myelin and contribute to axonal morphology in the nervous system. Two myelin membrane proteolipids, PLP and DM20, were shown to be essential for the integrity of myelinated axons. In the absence of PLP-DM20, mice assembled compact myelin sheaths but subsequently developed widespread axonal swellings and degeneration, associated predominantly with small-caliber nerve fibers. Similar swellings were absent in dysmyelinated shiverer mice, which lack myelin basic protein (MBP), but recurred in MBP*PLP double mutants. Thus, fiber degeneration, which was probably secondary to impaired axonal transport, could indicate that myelinated axons require local oligodendroglial support.

Animals↗
PubMed1998

Current concepts of PLP and its role in the nervous system.

Proteolipid protein (PLP) and its smaller isoform DM20 constitute the major myelin proteins of the CNS. Mutations of the X-linked Plp gene cause the heterogeneous syndromes of Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia (SPG) in man and similar dysmyelinating disorders in a range of animal species. A variety of mutations including missense mutations, deletions, and duplications are responsible. Missense mutations cause a predicted alteration in primary structure of the encoded protein(s) and are generally associated with early onset of signs and generalised dysmyelination. The severity of the phenotype varies according to the particular codon involved and the influence of uncharacterised modifying genes. There is some evidence that the dysmyelination results from the altered protein acquiring a novel function deleterious to the oligodendrocyte's function. Transgenic mice carrying extra copies of the Plp gene provide a valid model of PMD/SPG due to gene duplication. Depending on the gene dosage, the phenotype can vary from early onset of severe and lethal dysmyelination through to a very late onset of a tract-specific demyelination and axonal degeneration. Mice with a null mutation of the Plp gene assemble and maintain normal amounts of myelin but develop a progressive axonopathy, again demonstrating tract specificity. The results indicate that the functions of PLP are far from clear. There is good evidence that it is involved in the formation of the intraperiod line of myelin, and the results from the knockout and transgenic mice suggest a role in the interaction of oligodendrocyte and axon.

Animals↗
PubMed1998

Product recall.

Explore the source record for details and available documents.

Consumer Product Safety↗
PubMed1998

Involvement of products of the nrfEFG genes in the covalent attachment of haem c to a novel cysteine-lysine motif in the cytochrome c552 nitrite reductase from Escherichia coli.

Cytochrome c552 is the terminal component of the formate-dependent nitrite reduction pathway of Escherichia coli. In addition to four 'typical' haem-binding motifs, CXXCH-, characteristic of c-type cytochromes, the N-terminal region of NrfA includes a motif, CWSCK. Peptides generated by digesting the cytochrome from wild-type bacteria with cyanogen bromide followed by trypsin were analysed by on-line HPLC MS/MS in parent scanning mode. A strong signal at mass 619, corresponding to haem, was generated by fragmentation of a peptide of mass 1312 that included the sequence CWSCK. Neither this signal nor the haem-containing peptide of mass 1312 was detected in parallel experiments with cytochrome that had been purified from a transformant unable to synthesize NrfE, NrfF and NrfG: this is consistent with our previous report that NrfE and NrfG (but not NrfF) are essential for formate-dependent nitrite reduction. Redox titrations clearly revealed the presence of high and low mid-point potential redox centres. The best fit to the experimental data is for three n=1 components with mid-point redox potentials (pH 7.0) of +45 mV (21% of the total absorbance change), -90 mV (36% of the total) and -210mV (43% of the total). Plasmids in which the lysine codon of the cysteine-lysine motif, AAA, was changed to the histidine codon CAT (to create a fifth 'typical' haem c-binding motif), or to the isoleucine and leucine codons, ATT and CTT, were unable to transform a Nrf deletion mutant to Nrf+ or to restore formate-dependent nitrite reduction to the transformants. The presence of a 50 kDa periplasmic c-type cytochrome was confirmed by staining proteins separated by SDS-PAGE for covalently bound haem, but the methyl-viologen-dependent nitrite reductase activities associated with the mutated proteins, although still detectable, were far lower than that of the native protein. The combined data establish not only that there is a haem group bound covalently to the cysteine-lysine motif of cytochrome c552 but also that one or more products of the last three genes of the nrf operon are essential for the haem ligation to this motif.

Anaerobiosis↗
PubMed1996

A transgenic rat model of Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy in humans and has been associated with a partial duplication of chromosome 17 (CMT type 1A). We have generated a transgenic rat model of this disease and provide experimental evidence that CMT1A is caused by increased expression of the gene for peripheral myelin protein-22 (PMP22, gas-3). PMP22-transgenic rats develop gait abnormalities caused by a peripheral hypomyelination, Schwann cell hypertrophy (onion bulb formation), and muscle weakness. Reduced nerve conduction velocities closely resemble recordings in human patients with CMT1A. When bred to homozygosity, transgenic animals completely fail to elaborate myelin. We anticipate that the CMT rat model will facilitate the identification of a cellular disease mechanism and serve in the evaluation of potential treatment strategies.

Animals↗
PubMed1996

Changing patterns of rheumatology manpower and practice in the UK in the 1990s.

This paper reports the results of two surveys of all UK rheumatologists conducted in 1993 and 1995. Results are presented by regional health authority and by country. During the 2 yr, there has been a rise in the number of consultants, but a fall in the proportion doing rheumatology combined with rehabilitation. Consultants are working harder-doing more clinics and seeing more patients. Regional disparities in service provision persist, but are slowly diminishing. On the whole, the south of the country is better provided with consultants, but has fewer in-patient facilities, while the reverse is true in the north.

Data Collection↗
PubMed1995

Intranasal insulin: the effects of three dose regimens on postprandial glycaemic profiles in type II diabetic subjects.

In both fasting normal and diabetic subjects, nasally administered insulin achieves significant falls in plasma glucose concentrations. Repeated administration before and during a meal has been necessary to lower postprandial glycaemic excursion in subjects with NIDDM. We have studied the use of Novolin Nasal which employs a non-irritant, lecithin-based enhancer as a vehicle for human insulin, on postprandial glucose profiles in NIDDM subjects to determine efficacy, optimal dose frequency, and tolerability. Seventeen NIDDM subjects (15 men, 2 women) participated in a randomized, partially blinded, placebo-controlled, crossover trial of three active treatment regimens (nasal insulin, 120 U at 0 min, 60 U at 0 and +20 min or 120 U at +20 min) in relation to a standardized mixed meal given at 0 min. All active treatments significantly reduced postprandial glucose concentrations compared to placebo. Intranasal insulin given at 0 min at a dose of 60 U or 120 U resulted in a 50% reduction in postprandial incremental glucose compared to placebo over the first 2 h, whereas treatment with 60 U both at 0 and 20 min lead to a 70% reduction over the 240 min postprandial period. Post-prandial intravenous insulin was the least effective. There were no episodes of symptomatic hypoglycaemia. Local tolerability was excellent with only four reports of transient nasal irritation out of a total of 68 doses. The delivery device was accurate with intra-device CV of delivered dose of 4.8%.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intranasal↗
PubMed1995

Defective repair of O6-methylguanine-DNA in primary Sjögren's syndrome patients predisposed to lymphoma.

OBJECTIVE: To investigate a role for mutation in the aetiogenesis of autoimmune disease by examining levels of repairing enzyme for the promutagenic DNA base lesion, O6-methylguanine, in lymphocyte extracts from patients with autoimmune diseases. We included primary Sjögrens syndrome (PSS) patients because of the additional relevance of their being at increased risk (> 40-fold) of developing lymphoma. METHODS: Lymphocytes were prepared from patients with PSS (n = 22) (12 with parotid gland enlargement, an indicator of extensive lymphoproliferation), rheumatoid arthritis (n = 12), primary biliary cirrhosis (n = 11), osteoarthritis (n = 12), and healthy individuals (n = 11). MGMT amounts were determined in lymphocyte extracts by direct enzyme assay and expressed in relation to total extract DNA, protein, or cell number. RESULTS: We found no defect in the repairing methyltransferase enzyme between any of the groups, except in PSS patients at increased risk of developing lymphoma (those with enlarged parotid glands): p < 0.0001 and p = 0.0056, compared with healthy controls and PSS patients without parotid gland swelling, respectively. CONCLUSIONS: Our findings implicate persistence of O6-methylguanine-DNA in the aetiology of lymphoma associated with PSS, and raise the possibility that an alternative repair process for O6-methylguanine-DNA, nucleotide excision repair, might be defective in autoimmune disease.

Aged↗
PubMed1994

Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage.

Proteolipid protein (PLP) is an integral membrane protein of CNS myelin. Mutations of the X chromosome-linked PLP gene cause glial cell death and myelin deficiency in jimpy mice and other neurological mutants. As part of an attempt to rescue these mutants by transgenic complementation, we generated normal mouse lines expressing autosomal copies of the entire wild-type PLP gene. Surprisingly, increase of the PLP gene dosage in nonmutant mice with only 2-fold transcriptional overexpression results in a novel phenotype characterized by severe hypomyelination and astrocytosis, seizures, and premature death. This demonstrates that precise control of the PLP gene is a critical determinant of terminal oligodendrocyte differentiation. Dysmyelination of PLP transgenic mice provides experimental evidence that Pelizaeus-Merzbacher disease, previously associated with a partial duplication of the human X chromosome, can be caused by doubling of the PLP gene dosage.

Animals↗
PubMed1993

Linkage studies of HLA and primary Sjögren's syndrome in multicase families.

OBJECTIVE: To define the role of HLA-DR phenotype in the expression of primary Sjögren's syndrome (SS). METHODS: A family study of Caucasian probands with definite primary SS was conducted. Relatives with features of primary SS were classified according to the Fox criteria. Several types of linkage analysis between primary SS and HLA haplotype (HLA-A, B, and DR) were performed. RESULTS: A trend toward haplotype sharing between affected siblings was evident for definite/probable primary SS when analyzed by the Green and Woodrow method. This reached statistical significance when data from other published family studies were included. LOD scores and analyses using the Penrose method showed little evidence of linkage. CONCLUSION: In view of the strong association with HLA-DR3, these results suggest that the HLA-DR3 allele is an important susceptibility factor for expression of primary SS in Caucasians. The apparent haplotype sharing may be a consequence of this association. The potential influence of other genetic factors (major histocompatibility complex [MHC] and non-MHC) is discussed.

Adolescent↗
PubMed1993

Thyroid disease and other autoimmune phenomena in a family study of primary Sjögren's syndrome.

Autoimmune diseases and autoantibodies have been documented in 42 index cases with definite primary Sjögren's syndrome (1 degree SS), 207 relatives and 39 spouses. The results were compared with control data from a local population survey. Thyroid disease, 1 degree SS and their associated autoantibodies were the commonest autoimmune abnormalities observed and found predominantly in older female relatives. The HLA-DR3 phenotype associated with 1 degree SS, antinuclear factor, hypothyroidism, and thyroid microsomal antibody. Rheumatoid arthritis and systemic lupus erythematosus were not found in excess in the families. Primary Sjögren's syndrome is frequently associated with thyroid disease and we suggest that there is a common genetic predisposition between these diseases which differs from 2 degrees SS associated with rheumatoid arthritis and systemic lupus erythematosus. This includes MHC and non-MHC genes.

Adolescent↗
PubMed1992

Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene.

Proteolipid protein (PLP; M(r) 30,000) is a highly conserved major polytopic membrane protein in myelin but its cellular function remains obscure. Neurological mutant mice can often provide model systems for human genetic disorders. Mutations of the X-chromosome-linked PLP gene are lethal, identified first in the jimpy mouse and subsequently in patients with Pelizaeus-Merzbacher disease. The unexplained phenotype of these mutations includes degeneration and premature cell death of oligodendrocytes with associated hypomyelination. Here we show that a new mouse mutant rumpshaker is defined by the amino-acid substitution Ile-to-Thr at residue 186 in a membrane-embedded domain of PLP. Surprisingly, rumpshaker mice, although myelin-deficient, have normal longevity and a full complement of morphologically normal oligodendrocytes. Hypomyelination can thus be genetically separated from the PLP-dependent oligodendrocyte degeneration. We suggest that PLP has a vital function in glial cell development, distinct from its later role in myelin assembly, and that this dichotomy of action may explain the clinical spectrum of Pelizaeus-Merzbacher disease.

Amino Acid Sequence↗