Biomedical subjects

Thomas A Griffin

Publications and source records attributed to Thomas A Griffin.

6 recordsLinked to original sources

PubMed2006

T cells lacking immunoproteasome subunits MECL-1 and LMP7 hyperproliferate in response to polyclonal mitogens.

Immunoproteasomes comprise a specialized subset of proteasomes that is defined by the presence of three catalytic immunosubunits: LMP2, MECL-1 (LMP10), and LMP7. Proteasomes in general serve many cellular functions through protein degradation, whereas the specific function of immunoproteasomes has been thought to be largely, if not exclusively, optimization of MHC class I Ag processing. In this report, we demonstrate that T cells from double knockout mice lacking two of the immunosubunits, MECL-1 and LMP7, hyperproliferate in vitro in response to various polyclonal mitogens. We observe hyperproliferation of both CD4(+) and CD8(+) T cell subsets and demonstrate accelerated cell cycling. We do not observe hyperproliferation of T cells lacking only one of these subunits, and thus hyperproliferation is independent of either reduced MHC class I expression in LMP7(-/-) mice or reduced CD8(+) T cell numbers in MECL-1(-/-) mice. We observe both of these latter two phenotypes in MECL-1/LMP7(-/-) mice, which indicates that they also are independent of each other. Finally, we provide evidence of in vivo T cell dysfunction by demonstrating increased numbers of central memory phenotype CD8(+) T cells in MECL-1/LMP7(-/-) mice. In summary, this novel phenotype of hyperproliferation of T cells lacking both MECL-1 and LMP7 implicates a specific role for immunoproteasomes in T cell proliferation that is not obviously connected to MHC class I Ag processing.

Animals↗

PubMed2005

Gastrointestinal symptoms and their association with health-related quality of life of children with juvenile rheumatoid arthritis: validation of a gastrointestinal symptom questionnaire.

OBJECTIVES: The objectives of this study were to perform an initial validation of the Gastrointestinal Symptom Scale for Kids (GISSK) in children with juvenile rheumatoid arthritis (JRA); and too evaluate the relationship between gastrointestinal (GI) symptoms and health-related quality of life (HRQOL) in JRA. METHODS: A convenience sample of 77 children (median age, 10 years; range, 2-18 years) with JRA requiring second-line agents and one of their parents were interviewed. GI symptoms during the preceding 1 week were measured using the GISSK, which consists of 2 components, a visual analog scale of GI symptom severity (GISSK-VAS) and an 8-item questionnaire (GISSK-Q; score 0-8; 0= no GI symptoms). Information on medications, joint involvement with arthritis, and a physician rating of disease activity were obtained. Patient-centered outcomes included the Childhood Health Assessment Questionnaire (CHAQ) to assess disability and discomfort. HRQOL was measured by the Pediatric Quality of Life Generic Core Scale (PedsQL-GC) and the Rheumatology Module (PedsQL-RM), as well as a visual analog scale (VAS-health). To determine test-retest reliability, the GISSK was completed by 40 parents twice within a 1- to 2-week period. To determine the quality of parent proxy-reporting, parent ratings were compared with those of their children aged 8 years or older. RESULTS: GI symptoms were present in the majority of the patients with JRA (58%). Compared with other patients with JRA, those with a GISSK-Q score of > or =2 had significantly lower HRQOL (PedsQL-GC: P < 0.04; PedsQL-RM: P < 0.05; VAS-health: P < 0.02) and more disability (CHAQ: P < 0.002), despite similar disease activity and joint findings. Similar relationships were observed for the GISSK-VAS with traditional outcomes and HRQOL. The test-retest reliability of the GISSK was good (ICCGISSK-Q = 0.60; ICCGISSK-VAS = 0.67). The quality of parent proxy-reporting was fair to good (ICCGISSK-Q = 0.47; ICCGISSK-VAS = 0.66). CONCLUSION: GI symptoms are frequent among children with JRA requiring advanced therapies and, if moderate or severe, are associated with significantly lower HRQOL. The GISSK is a reliable and valid measure of GI symptoms and their severity in JRA. This self-administered measure can be used to screen for GI symptoms in clinical practice and may be useful to assess the effects of medication changes on the perceived GI side effects in children with JRA.

Adolescent↗

PubMed2004

Feasibility and construct validity of the parent willingness-to-pay technique for children with juvenile idiopathic arthritis.

OBJECTIVE: To assess the feasibility and construct validity of the willingness-to-pay (WTP) technique for measuring health care preferences in families of children with juvenile idiopathic arthritis (JIA). METHODS: Parents were asked to estimate the monthly US dollar amount they would be willing to pay to obtain for their child the following hypothetical drugs: ARTHRO, which guarantees complete clinical response; and NO-STOM-ACHE, a drug that eliminates gastrointestinal (GI) symptoms. A yes/no question was used with random assignment of the starting bids. Parents who agreed to pay the starting bid were then asked whether they would be willing to pay 200% and then 400% of this initial bid. Socioeconomic data and information on medications, disease activity, patient physical function, wellbeing, and health-related quality of life (HRQOL) were obtained. RESULTS: Sixty-two families of children with JIA were interviewed. GI symptoms were present in 54%, and 53% of the children had joints with active arthritis or limited range of motion. Four parents (7%) were unwilling to pay anything for any of the studied medications. The mean amount (median; mean percentage of available family income) families were willing to pay was $395 ($300; 15%) for ARTHRO and $109 ($80; 4%) for NO-STOM-ACHE. Correlation and regression analysis supported that, adjusted for the available family income, the WTP for ARTHRO was associated with disease activity, pain, and the HRQOL of the patients. After correction for the starting bids and the available family income, the WTP for NO-STOM-ACHE was associated with the patient's HRQOL, pain, and the amount of GI discomfort. CONCLUSION: The WTP technique is feasible and has construct validity for measuring health care preferences for children with JIA. Relatively large WTP estimates support a possible important negative impact of the disease on families of children with JIA.

Adolescent↗

PubMed2004

Health of children with chronic arthritis: relationship of different measures and the quality of parent proxy reporting.

OBJECTIVE: To examine the strength of the association between different measures of health-related quality of life (HRQOL), disability, pain, and well-being in children with chronic arthritis. To evaluate whether HRQOL scores vary as a function of disability status beyond chance. To assess the quality of the parent proxy report for HRQOL as compared with disability, pain, and well-being. METHODS: Measures of HRQOL (visual analog scale [VAS] of health, Pediatric Quality of Life Inventory [PedsQL], Juvenile Arthritis Quality of Life Questionnaire (JAQQ), and modified standard gamble technique [SG]), disability (Childhood Health Assessment Questionnaire), VAS of pain, and VAS of well-being (VAS-well) were completed by the parents (n = 119) and patients > or =8 years (SG: > or =12 years). RESULTS: HRQOL was highest when measured by the SG, whose utilities were no more than weakly correlated with any of the other outcomes. The values of all other HRQOL measures were at least moderately correlated with each other and with the VAS-well. Irrespective of the measure used, disability was associated with significantly decreased HRQOL. There was fair to good agreement and moderate consistency of the HRQOL ratings (SG: fair consistency) between patients and parents with marked differences between health domains. CONCLUSION: HRQOL measured by the PedsQL, JAQQ, and VAS are moderately to highly correlated with each other in children with chronic arthritis. The children's HRQOL significantly decreases with increasing disability. Despite more pronounced differences for some health domains, parents are moderate to good proxy reporters of HRQOL, disability, and well-being of children with chronic arthritis.

Adolescent↗

PubMed2004

Protein-protein interactions among human 20S proteasome subunits and proteassemblin.

Immunoproteasomes and standard proteasomes assemble by alternative pathways that bias against the formation of certain "mixed" proteasomes. Differences between beta subunit propeptides contribute to assembly specificity and an assembly chaperone, proteassemblin, may be involved via differential propeptide interactions. We investigated possible mechanisms of biased proteasome assembly and the role of proteassemblin by identifying protein-protein interactions among human 20S proteasome subunits and proteassemblin using a yeast two-hybrid interaction assay. Forty-one interactions were detected, including five involving proteassemblin and contiguous beta subunits, which suggests that proteassemblin binds to preproteasomes via a beta subunit surface. Interaction between proteassemblin and beta5, but not beta5i, suggests that proteassemblin may be involved in the propeptide-dependent differential incorporation of these subunits. Interactions between proteassemblin and beta1, beta1i, and beta7 suggest that proteassemblin may regulate preproteasome dimerization via interactions with the C-termini of these subunits, which in the mature 20S structure extend to contact opposing beta subunit rings.

Cysteine Endopeptidases↗

PubMed2002

Beta 2 subunit propeptides influence cooperative proteasome assembly.

Vertebrate proteasomes are structurally heterogeneous, consisting of both "constitutive" (or "standard") proteasomes and "immunoproteasomes." Constitutive proteasomes contain three ubiquitously expressed catalytic subunits, Delta (beta 1), Z (beta 2), and X (beta 5), whereas immunoproteasomes contain three interferon-gamma-inducible catalytic subunits, LMP2 (beta 1i), MECL (beta 2i), and LMP7 (beta 5i). We recently have demonstrated that proteasome assembly is biased to promote immunoproteasome homogeneity when both types of catalytic subunits are expressed in the same cell. This cooperative assembly is due in part to differences between the LMP7 (beta 5i) and X (beta 5) propeptides. In the current study we demonstrate that differences between the MECL (beta 2i) and Z (beta2) propeptides also influence cooperative assembly. Specifically, replacing the MECL propeptide with that of Z enables MECL incorporation into otherwise constitutive (Delta(+)/X(+)) proteasomes and facilitates X incorporation into otherwise immunoproteasomes (MECL(+)/LMP2(+)). We also show, using MECL(-/-) mice, that LMP2 incorporation does not require MECL, in contrast with previous suggestions that their incorporation is mutually codependent. These results enable us to refine our model for cooperative proteasome assembly by determining which combinations of inducible and constitutive subunits are favored over others, and we propose a mechanism for how propeptides mediate cooperative assembly.

Amino Acid Sequence↗