Appropriate body-mass index for Asians.
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Adult↗
Biomedical subjects
E A Hughes
Publications and source records attributed to E A Hughes.
The N-terminal region of tapasin is required to stabilize the MHC class I loading complex.
Tapasin mediates the binding of MHC class I molecules to the transporter associated with antigen processing (TAP). Deletion mutants of tapasin were used to examine the effect of tapasin on interactions within the MHC class I complex. Binding to TAP is mediated by the C-terminal region of tapasin. Michaelis-Menten analysis of peptide transport shows that this interaction is sufficient to increase TAP levels without significantly affecting the intrinsic translocation rate. Weak interactions exist between MHC class I molecules and TAP in the absence of tapasin, and between free heavy chains and TAP-tapasin complexes in the absence of beta2-microglobulin. The N-terminal 50 residues of tapasin constitute the key element which converts the sum of these weak interactions into a stable complex.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
The thiol oxidoreductase ERp57 is a component of the MHC class I peptide-loading complex.
The proper folding and assembly of major histocompatibility complex (MHC) class I molecules in the endoplasmic reticulum (ER) is an intricate process involving a number of components. Nascent heavy chains of MHC class I molecules, translocated into the ER membrane, are rapidly glycosylated and bind the transmembrane chaperone calnexin. In humans, after dissociation from calnexin, fully oxidized MHC class I heavy chains associate with beta 2-microglobulin (beta 2m) and the soluble chaperone calreticulin. This complex interacts with another transmembrane protein, tapasin, which is believed to assist in MHC class I folding as well as in mediating the interaction between assembling MHC class I molecules and the transporter associated with antigen processing (TAP). The TAP heterodimer (TAP1-TAP2) introduces the final component of the MHC class I molecule by translocating peptides, predominately generated by the proteasome, from the cytosol into the ER where they can bind dimers of beta 2M and the MHC class I heavy chain. Recently, the thiol oxidoreductase ERp57--also known as GRP58, ERp61, ER60, Q2, HIP-70, and CPT and first misidentified as phospholipase C-alpha--has been shown to bind in conjunction with calnexin or calreticulin to a number of newly synthesized ER glycoproteins when their N-linked glycans are trimmed by glucosidases I and II. It was speculated that ERp57 is a generic component of the glycan-dependent ER quality control system. Here, we show that ERp57 is a component of the MHC class I peptide-loading complex. ERp57 might influence the folding of MHC class I molecules at a critical step in peptide loading.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Induction of transporter associated with antigen processing by interferon gamma confers endothelial cell cytoprotection against natural killer-mediated lysis.
T lymphocytes react minimally with nonactivated endothelial cells (ECs). However, natural killer (NK) lymphocyte interactions with resting ECs are rapid, avid, and result in endothelial activation and/or cytotoxicity. The molecular basis for these interactions and EC sensitivity to NK-mediated lysis is unclear. To address the EC-specific nature of NK sensitivity, we used syngeneic human umbilical vein ECs, dermal microvascular ECs, dermal fibroblasts, and B lymphoblastoid cell lines in calcein-AM retention NK assays with allogeneic NK effector cells and found the EC lines consistently more NK-sensitive. Because NK inhibitory receptors are engaged by membrane major histocompatibility complex (MHC) I molecules and MHC I-deficient targets are NK-sensitive, we investigated the quantitative levels of membrane MHC I on the panel of syngeneic lines. Highly sensitive ECs expressed similar (or higher) levels of membrane MHC I than their syngeneic NK-resistant counterparts. Pretreatment of ECs with gamma interferon (IFN-gamma) conferred protection against NK-mediated lysis, with much more rapid kinetics (2-6 hr) than those required for membrane MHC I hyperinduction (>8 hr). These kinetics are consistent with induction of transporter associated with antigen processing (TAP) expression and function. As opposed to NK-resistant cell lines, TAP-1 was undetectable in resting ECs. Recombinant expression of the TAP inactivator ICP47 by adenoviral-mediated transduction was used to selectively inhibit IFN-gamma-mediated EC TAP function. ICP47 expression abrogated EC cytoprotection conferred by IFN-gamma. We demonstrate a relationship between both basal and induced TAP-1 expression/function and EC sensitivity to NK-mediated cytotoxicity. We discuss the influence of an induced MHC I-associated peptide repertoire on vascular vulnerability to cytotoxic lymphocytes.
B-Lymphocytes↗
Cushing's disease and tuberculosis.
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Adult↗
Protein degradation: the ins and outs of the matter.
In eukaryotic cells, nascent membrane or secretory proteins are translocated into the endoplasmic reticulum through the Sec61p translocation channel; recent evidence suggests that, if they fail to achieve a native conformation, they are translocated back into the cytosol by the same route and degraded by the proteasome.
Animals↗
Misfolded major histocompatibility complex class I heavy chains are translocated into the cytoplasm and degraded by the proteasome.
N-acetyl-L-leucyl-L-leucyl-L-norleucinal (LLnL), which reversibly inhibits the proteasome in addition to other proteases, and a more specific irreversible inhibitor of the proteasome, lactacystin, were found to cause the accumulation of major histocompatibility complex (MHC) class I heavy chains in the cytosol of the beta2-microglobulin-deficient cell line Daudi and the TAP-deficient cell line .174. These cell lines, which are severely impaired in their ability to fold MHC class I heavy chain, showed an accumulation of soluble class I heavy chains at different rates over a period of hours in the presence of LLnL. The accumulation of soluble class I heavy chains in the presence of either LLnL or lactacystin was easily revealed in Daudi and .174 but almost undetectable in a Daudi transfectant expressing beta2-microglobulin and in 45.1, the wild-type parent of .174. The soluble class I heavy chain was also found to be devoid of its N-linked glycan and to be located in the cytosol. When the gene for ICP47, a herpes simplex virus protein that blocks the translocation of peptides into the endoplasmic reticulum, was transfected into 45.1, a similar accumulation of soluble MHC class I heavy chain was detectable. These data suggest that in cells where the MHC class I molecule is unable to assemble properly, the misfolded heavy chain is removed from the endoplasmic reticulum to the cytosol, deglycosylated, and degraded by the proteasome.
Acetylcysteine↗
Development of an instrument to measure knowledge in individuals with rheumatoid arthritis: the ACREU rheumatoid arthritis knowledge questionnaire.
OBJECTIVE: Education is an important component of community based rehabilitation programs for people with rheumatoid arthritis (RA). This study describes the development of a questionnaire to measure knowledge in this context. METHODS: Items were generated using focus group methodology and covered the domains of prognosis, pain management, medications, joint protection, energy conservation, exercise, and coping strategies. RESULTS: After extensive pretesting, the questionnaire was administered to 252 people with RA. The final 31 item questionnaire had acceptable internal consistency (Cronbach's alpha: 0.76, n = 185), test-retest reliability (r = 0.91, p < or = 0.001), content and construct validity. Sensitivity to change was confirmed in the context of a 6 week home based physiotherapy educational intervention. CONCLUSION: The RA knowledge questionnaire is a reliable, valid, and sensitive instrument for measuring the effect of a RA educational intervention.
Adult↗
The protease inhibitor, N-acetyl-L-leucyl-L-leucyl-leucyl-L-norleucinal, decreases the pool of major histocompatibility complex class I-binding peptides and inhibits peptide trimming in the endoplasmic reticulum.
N-acetyl-L-leucyl-L-leucyl-L-norleucinal, (LLnL), which inhibits proteasomes in addition to other proteases, was found to prolong the association of major histocompatibility complex class I molecules with the transporters associated with antigen processing (TAP), and to slow their transport out of the endoplasmic reticulum (ER). LLnL induced a reversible accumulation of ubiquitinated proteins and changed the spectrum of peptides bound by class I molecules. These effects can probably be attributed to proteasome inhibition. Unexpectedly, in the TAP-deficient cell line .174, the rate of intracellular transport of human histocompatibility leukocyte antigen (HLA) A2 was also reduced by LLnL, and the generation of most HLA-A2-associated signal sequence peptides was inhibited. The inhibition of HLA-A2 transport in .174 cells was found to be less sensitive to LLnL than in wild-type cells, and a similar difference was found for a second protease inhibitor, benzyloxycarbonyl-L-leucyl-L-leucyl-L-phenylalanilal. These data suggest that under some conditions such inhibitors can block trimming of peptides by an ER peptidase in addition to inhibiting cytosolic peptide generation.
Amino Acid Sequence↗
Short side chain sterols from the tunicate Polizoa opuntia.
The sterol composition of the Patagonian tunicate Polizoa opuntia was examined, and twenty-four compounds were identified as having either a delta 5, delta 7, or delta 0 nucleus. Two of them, the rare 20-methylpregn-5-en-3 beta-ol and 20-ethylpregn-5-en-3 beta-ol, were previously unreported as natural products from tunicates. These compounds were present only as trace components; therefore, their structures were confirmed by synthesis from suitable precursors and by comparison of the spectral and chromatographic constants of the synthetic and natural compounds.
Animals↗
Fine specificity analysis indicates that the primary and secondary fluorescein-specific cytotoxic T cell receptor repertoires are indistinguishable.
Previous data from this laboratory have shown that fluorescein-specific cytotoxic T cells derived from naive mice are capable of distinguishing between different isomeric forms of the fluorescein hapten, as well as between the iodoacetamido-, isothiocyanate- and dichlorotriazinyl amino-fluorescein derivatives. In this report, we show that T cells derived from previously immunized animals, while demonstrating a stronger and more cross-reactive response overall, display identical fine specificity patterns to those of primary T cells for a panel of fluorescein homologues. We interpret this finding to indicate that the antigen receptor repertoires utilized by primary and secondary cytotoxic T cells are indistinguishable and that the enhanced response of memory as compared with naive CTL results from factors such as a higher density of cell surface receptors or receptor-associated molecules and/or a higher frequency of antigen-responsive T cells.
Animals↗
Are elderly Asians in Britain at a high risk of vitamin D deficiency and osteomalacia?
Many studies have shown the indigenous elderly population and Asian immigrants to be groups at particular risk of vitamin D deficiency and osteomalacia, but there are no data on the risks in elderly Asians. In this community-based study a group of elderly Asians was compared with control groups of elderly and young whites and young Asians. Levels of 25-hydroxyvitamin D3 (25-OHD3) were significantly lower (p < 0.0001) in elderly Asians (21/37) and young Asians (7/17) compared with white controls. The difference in parathyroid hormone (PTH) between Asians and whites was also significant (p < 0.0007) as was that between young and old (p < 0.0002). Abnormal PTH and 25-OHD3 (high PTH and low 25-OHD3), indicative of a high risk of osteomalacia, occurred in 22% of elderly Asians compared with 6% of elderly whites. The calcium, phosphate and alkaline phosphatase were normal in all individuals. Among the Asians, vegetarianism was not related to lower 25-OHD3 levels. Symptoms suggestive of osteomalacia were more common (p < 0.05) in elderly Asians than in their white counterparts. This first study of 25-OHD3 levels in community-resident elderly Asians suggests that more than half were low, placing them at a significantly higher risk of osteomalacia.
Adult↗
Hospitalizations for respiratory syncytial virus infection in Alaska Native children.
To characterize the epidemiology of Alaska Native children hospitalized for respiratory syncytial virus infections, we reviewed records of hospitalizations during the winter seasons of 1991 to 1992 and 1992 to 1993 at a hospital in Anchorage and a rural hospital in the Yukon Kuskokwim Delta (YKD) region of southwestern Alaska. The median age of hospitalization for respiratory syncytial virus infection was 2 months of age for YKD residents and 4.5 months for Anchorage residents. Sixteen percent of the hospitalized YKD children were less than 1 month of age, whereas the same was true for only 3% of the Anchorage children. Eight percent of the YKD patients required mechanical ventilation, whereas none of the Anchorage patients required ventilation. The median hospital stay was 4.8 days for YKD patients and 3.2 days for Anchorage patients. Hospitalization rates for infants less than 1 year of age were 33/1000 for Alaska Natives in Anchorage and 100/1000 for those in the YKD region. The extremely high hospitalization rate, especially among very young infants in the rural YKD region, points to a need for early preventive efforts.
Age Factors↗
Digoxin measurements following plasma ultrafiltration in two patients with digoxin toxicity treated with specific Fab fragments.
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Aged↗
Inattention and the perception of visual features.
Subjects selectively attended to one of two interleaved, novel figures while ignoring the other figure. In subsequent tests administered to determine the extent to which the ignored figure was perceived, recognition of shape and the location of contour gaps was at the chance level. Moreover, recognition of the presence of contour gaps was significantly below the chance level. These results indicate that preattentive visual processing of unattended objects is too crude to encode global shape and local features such as contour gaps. It is suggested that preattentive processing creates visual representations of unattended objects that contain very limited information about features.
Adult↗
Thyroxine replacement therapy and circulating lipid concentrations.
OBJECTIVE: Hypothyroidism is a common disorder and while the association of overt hypothyroidism with hypercholesterolaemia is clear, the effect upon lipids of the minor abnormalities of thyroid function often found in those receiving T4 replacement therapy is unclear. The aim of the present studies was to define in those with hypothyroidism the effect upon circulating lipids of subtle changes in thyroid status, indicated by serum TSH values below or above the normal range. DESIGN: (i) Prospective study of short-term T4 treatment of those with subclinical hypothyroidism. (ii) Cross-sectional study of long-term T4 treatment, comparing non-T4 treated controls and T4 treated patients with serum TSH values either below or within the normal range. PATIENTS: Short-term T4 therapy was examined in 11 post-menopausal females with subclinical hypothyroidism (high TSH, normal free T4) studied before therapy and 6 weeks after T4 at incremental doses (50, 100, 150 micrograms/day). Long-term T4 treatment for hypothyroidism was investigated in 105 females on therapy for at least 1 year compared with 105 controls matched for age and menopausal status. MEASUREMENTS: Fasting levels of total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and HDL subfractions were determined in patients and controls. RESULTS: (i) T4 treatment of subjects with subclinical hypothyroidism resulted in reductions in total and LDL cholesterol with increasing T4 dose (P < 0.001). Comparison of lipid results pretreatment with those when TSH was restored to normal revealed no significant difference in lipids; in contrast, comparison of lipids in those with normal TSH compared with the same subjects when TSH was suppressed revealed reductions in total and LDL cholesterol. (ii) Long-term T4 treatment was associated with a reduction in total and LDL cholesterol measurements in those over 55 years receiving suppressive doses of T4 but no significant difference in lipids in those with normal serum TSH compared with non-T4 treated controls. CONCLUSION: Effects of T4 upon lipid measurements suggest that patients with subclinical hypothyroidism should receive replacement therapy. Doses of T4 which suppress TSH to below normal may have a more significant influence upon lipids than doses of T4 which restore TSH to the normal range.
Aged↗
Management of hyperlipidaemia: guidelines of the British Hyperlipidaemia Association.
There is considerable evidence to suggest that the identification and treatment of dyslipidaemia will reduce the risk of premature CHD, i.e. before the age of 65. Diagnosis of the cause of raised plasma lipid levels will enable appropriate decisions to be taken with regard to management. The cornerstone of treatment is nutritional counselling and attention to other major risk factors for CHD, particularly smoking and hypertension. For a small percentage of patients with severe hyperlipidaemia drug therapy is indicated. Appropriate drug choices need to be made based on the particular lipid abnormality to be treated. In general those patients with clinical vascular disease are treated more aggressively than those where the aim is primary prevention. More research is needed to determine individual risk more precisely and to allow proper targeting of therapy. Genetic factors, qualitative changes in lipoproteins, lipoprotein (a), fibrinogen, and other coagulation and thrombotic factors are likely to be important in individual risk assessment. There is no doubt that more information is needed from prospective studies of lipid-lowering therapy in terms of risk benefit for affected individuals. Hopefully the major studies currently underway will fill some of the gaps in our knowledge. Until then aggressive therapy with drugs should be reserved for those at highest risk where the benefit is likely to be greatest.
Cholesterol, Dietary↗
The incidence of asymptomatic hypothyroidism in new referrals to a hospital lipid clinic.
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Female↗