Search PubMed⌕ Search

Biomedical subjects

A C Young

Publications and source records attributed to A C Young.

At least 19 recordsLinked to original sources
PubMed2005

Sarcoidosis and HTLV-1 infection.

An asymptomatic, homosexual, white man was found to have an abnormal chest x ray. A presumptive diagnosis of sarcoidosis was made, but pulmonary function tests and a transbronchial biopsy were normal. He then remained asymptomatic for 10 years until he developed a progressive spastic paraparesis. At this point, antibodies to human T cell lymphotropic virus type 1 (HTLV-1) were identified in the serum and cerebrospinal fluid, and the diagnosis of HTLV-1 associated myelopathy was made, the history suggesting sexual exposure to HTLV-1 many years previously. HTLV-1 is associated with a spectrum of immune related disorders, including a pulmonary sarcoid-like syndrome. Infection with this chronic proinflammatory retrovirus should be considered in the differential diagnosis of all immune disorders in at risk individuals.

HTLV-I Infections↗
PubMed2003

Comparative analyses of multi-species sequences from targeted genomic regions.

The systematic comparison of genomic sequences from different organisms represents a central focus of contemporary genome analysis. Comparative analyses of vertebrate sequences can identify coding and conserved non-coding regions, including regulatory elements, and provide insight into the forces that have rendered modern-day genomes. As a complement to whole-genome sequencing efforts, we are sequencing and comparing targeted genomic regions in multiple, evolutionarily diverse vertebrates. Here we report the generation and analysis of over 12 megabases (Mb) of sequence from 12 species, all derived from the genomic region orthologous to a segment of about 1.8 Mb on human chromosome 7 containing ten genes, including the gene mutated in cystic fibrosis. These sequences show conservation reflecting both functional constraints and the neutral mutational events that shaped this genomic region. In particular, we identify substantial numbers of conserved non-coding segments beyond those previously identified experimentally, most of which are not detectable by pair-wise sequence comparisons alone. Analysis of transposable element insertions highlights the variation in genome dynamics among these species and confirms the placement of rodents as a sister group to the primates.

Animals↗
PubMed2001

Case report: Kaposi's sarcoma: an unusual presentation.

Kaposi's sarcoma (KS) is the most common tumor associated with HIV-1 infection, affecting 30% of HIV-infected homosexual men before the advent of highly active antiretroviral therapy (HAART). In the era of HAART, the incidence of KS has markedly declined. KS usually presents with cutaneous lesions, but it may involve other organs, most commonly the pulmonary and gastrointestinal systems. Isolated pulmonary KS without cutaneous involvement is rare, although intrathoracic KS is seen in up to 75% of patients with KS. We describe an unusual case of a patient with AIDS and isolated endobronchial KS despite a normal arterial pO2, normal pulmonary function tests, no cutaneous KS, and normal chest computed tomographic findings.

AIDS-Related Opportunistic Infections↗
PubMed1999

Binding of longer peptides to the H-2Kb heterodimer is restricted to peptides extended at their C terminus: refinement of the inherent MHC class I peptide binding criteria.

MHC class I molecules usually bind short peptides of 8-10 amino acids, and binding is dependent on allele-specific anchor residues. However, in a number of cellular systems, class I molecules have been found containing peptides longer than the canonical size. To understand the structural requirements for MHC binding of longer peptides, we used an in vitro class I MHC folding assay to examine peptide variants of the antigenic VSV 8 mer core peptide containing length extensions at either their N or C terminus. This approach allowed us to determine the ability of each peptide to productively form Kb/beta2-microglobulin/peptide complexes. We found that H-2Kb molecules can accommodate extended peptides, but only if the extension occurs at the C-terminal peptide end, and that hydrophobic flanking regions are preferred. Peptides extended at their N terminus did not promote productive formation of the trimolecular complex. A structural basis for such findings comes from molecular modeling of a H-2Kb/12 mer complex and comparative analysis of MHC class I structures. These analyses revealed that structural constraints in the A pocket of the class I peptide binding groove hinder the binding of N-terminal-extended peptides, whereas structural features at the C-terminal peptide residue pocket allow C-terminal peptide extensions to reach out of the cleft. These findings broaden our understanding of the inherent peptide binding and epitope selection criteria of the MHC class I molecule. Core peptides extended at their N terminus cannot bind, but peptide extensions at the C terminus are tolerated.

Animals↗
PubMed1999

Time-efficiency of nondermatologists compared with dermatologists in the care of skin disease.

BACKGROUND: It has been suggested that using an established primary care doctor potentially could be a more efficient use of physician time than a new visit to a dermatologist for patients seeking care for skin diseases. OBJECTIVE: We test the hypothesis that seeing an established primary care doctor for a skin problem is a more efficient use of physician-time resources than a new visit to a dermatologist. METHODS: The duration (in minutes) of outpatient visits for dermatologic conditions was obtained from the National Ambulatory Medical Care Survey from 1990 to 1994. To control for the complexity of visits, the analysis was limited to the 62% of these visits in which a single dermatologic condition was the only condition being treated. RESULTS: For all outpatient dermatologic visits combined, dermatologist visits for patients 18 years old or younger were 1.5 minutes (12%) shorter than nondermatologist visits, and dermatologist visits for patients older than 18 years were 3.1 minutes (20%) shorter than nondermatologist visits. Compared with nondermatologists, dermatologists have a shorter average visit duration for new, first-time patient encounters and for encounters with established patients. A significant difference in outpatient visit duration does not exist when comparing new, first-time visits for dermatologists to established visits for nondermatologists (P = .3). CONCLUSION: A visit to an established primary care provider for treatment of a skin problem is not a more efficient use of physician resources than a new or return visit to a dermatologist.

Adult↗
PubMed1998

Point mutations in the beta chain CDR3 can alter the T cell receptor recognition pattern on an MHC class I/peptide complex over a broad interface area.

To study how the T cell receptor interacts with its cognate ligand, the MHC/peptide complex, we used site directed mutagenesis to generate single point mutants that alter amino acids in the CDR3beta loop of a H-2Kb restricted TCR (N30.7) specific for an immunodominant peptide N52-N59 (VSV8) derived from the vesicular stomatitis virus nucleocapsid. The effect of each mutation on antigen recognition was analyzed using wild type H-2Kb and VSV8 peptide, as well as H-2Kb and VSV8 variants carrying single replacements at residues known to be exposed to the TCR. These analyses revealed that point mutations at some positions in the CDR3beta loop abrogated recognition entirely, while mutations at other CDR3beta positions caused an altered pattern of antigen recognition over a broad area on the MHC/peptide surface. This area included the N-terminus of the peptide, as well as residues of the MHC alpha1 and alpha2 helices flanking this region. Assuming that the N30 TCR docks on the MHC/peptide with an orientation similar to that recently observed in two different TCR-MHC/peptide crystal structures, our findings would suggest that single amino acid alterations within CDR3beta can affect the interaction of the TCR with an MHC surface region distal from the predicted CDR3beta-Kb/VSV8 interface. Such unique recognition capabilities are generated with minimal alterations in the CDR3 loops of the TCR. These observations suggest the hypothesis that extensive changes in the recognition pattern due to small perturbations in the CDR3 structure appears to be a structural strategy for generating a highly diversified TCR repertoire with specificity for a wide variety of antigens.

Amino Acid Sequence↗
PubMed1997

The three-dimensional structures of a polysaccharide binding antibody to Cryptococcus neoformans and its complex with a peptide from a phage display library: implications for the identification of peptide mimotopes.

The three-dimensional structure of 2H1, a protective monoclonal antibody to Cryptococcus neoformans, has been solved at 2.4 A resolution, in both its unbound form and in complex with the 12 amino acid residue peptide PA1 (GLQYTPSWMLVG). PA1 was previously identified as a potential mimotope of the cryptococcal capsular polysaccharide by screening of a phage display peptide library. Peptide binding is associated with only minor rearrangements of some side-chains and a small shift in the H2 loop of the antibody. The peptide assumes a tightly coiled conformation consisting of one inverse gamma-turn and one type II beta-turn that serves to place the entire peptide motif, consisting of ThrP5, ProP6, TrpP8, MetP9 and LeuP10, into a depression in the antibody combining site. A small number of H-bonds between peptide and antibody contribute to the affinity and specificity. Poor steric complementarity between PA1 and the antibody heavy chain along with the fact that the majority of the interactions between 2H1 and PA1 involve van der Waals interactions with the light chain may explain why this peptide acts as only a partial mimotope of the capsular polysaccharide epitope.

Amino Acid Sequence↗
PubMed1997

The three-dimensional structure of an H-2Ld-peptide complex explains the unique interaction of Ld with beta-2 microglobulin and peptide.

Solution at 2.5-A resolution of the three-dimensional structure of H-2Ld with a single nine-residue peptide provides a structural basis for understanding its unique interaction with beta-2 microglobulin (beta2m) and peptide. Consistent with the biological data that show an unusually weak association of Ld with beta2m, a novel orientation of the alpha1/alpha2 domains of Ld relative to beta2m results in a dearth of productive contacts compared with other class I proteins. Characteristics of the Ld antigen-binding cleft determine the unique motif of peptides that it binds. Ld has no central anchor residue due to the presence of several bulky side chains in its mid-cleft region. Also, its cleft is significantly more hydrophobic than that of the other class I molecules for which structures are known, resulting in many fewer H-bonds between peptide and cleft residues. The choice of Pro as a consensus anchor at peptide position 2 appears to be related to the hydrophobicity of the B pocket, and to the unique occurrence of Ile (which mirrors Pro in its inability to form H-bonds) at position 63 on the edge of this pocket. Thus, the paucity of stabilizing H-bonds combined with poor complementarity between peptide postion 2 Pro and the B pocket contribute to the weak association between Ld and its peptide antigen. The unique structural interactions of Ld with beta2m and peptide could make Ld more suited than other classical class I molecules to play a role in alternative pathways of antigen presentation.

Animals↗
PubMed1997

Organization and expression of human telomere repeat binding factor genes.

The ends of mammalian chromosomes terminate in structures called telomeres. Recently a human telomere repeat binding factor (TRF1) that binds the vertebrate TTAGGG telomeric repeat in situ was isolated by Chong et al. (1). TRF1 regulates telomere length (2), which is often altered in cancer cells. To understand their genetic organization, TRF1 genes were localized to human chromosomes 13cen, 21cen, and Xq13 by analysis of human monochromosomal hybrids, and by fluorescent in situ hybridization. We also confirmed the recent localization of a human TRF1 gene to chromosome 8, and provide evidence that this locus is alternatively spliced. In contrast to the TRF1 genes on chromosomes 8 and X, the chromosomes 13 and 21 TRF1 genes contained a 60 bp deletion in the coding region. The results suggest that two distinct forms of TRF1 are expressed and that the TRF1 gene family includes at least three pseudogenes whose dispersal in the human genome may have occurred via cDNA intermediates.

Alternative Splicing↗
PubMed1997

The use of percutaneous endoscopic gastrostomy (PEG) feeding tubes in patients with neurological disease.

Percutaneous endoscopic gastrostomy (PEG) is being used increasingly in the treatment of patients with neurogenic dysphagia to improve nutrition and prevent choking and aspiration pneumonia. PEG is used in a wide range of general medical conditions, but its role in clinical neurology is sometimes controversial. This paper reviews the place of PEG in the management of 32 patients with a variety of chronic and progressive neurological disorders. All the patients found it to be an effective and acceptable method of feeding that prevented weight loss, reduced chest infections, facilitated nursing care and improved their quality of life. PEG has an important role in neurological rehabilitation.

Adolescent↗
PubMed1996

Molecular mapping of the 8.12 SLE-associated idiotype specificity at the single amino acid level.

The 8.12 idiotype is expressed in elevated titer in the serum of patients with systemic lupus erythematosus and is a marker for a subpopulation of anti-DNA antibodies that possess a V(lambda)II encoded light chain. This study utilized a eukaryotic expression system to identify the structural basis for expression of this idiotype. Reversion of the 8.12+ DSC light chain to the hslv215.23/DPL11 germline gene reveals that the 8.12 idiotype is encoded in the germline. The 8.12+ DSC and the 8.12 AS17 light chains, both belonging to the V(lambda)II family, were subjected to site directed mutagenesis, to localize amino acids important for expression of the 8.12 idiotype. Point mutations were performed in CDR1, CDR2, FR3 and CDR3, in positions where the 8.12+ DSC differs from the 8.12-AS17. Amino acids in CDR1 and the CDR2 proximal region of FR3, but not the J proximal region of CDR3, play a crucial role in 8.12 reactivity. The 3-D structure of Mcg, a human IgG1, with which DSC shares a sequence homology of 92.3% has been examined to visualize the effect of each of the mutations and to identify the surface on DSC that comprises the idiotype.

Amino Acid Sequence↗
PubMed1995

Structural studies of class I major histocompatibility complex proteins: insights into antigen presentation.

The three-dimensional structures of three human and two murine class I molecules, in complex with single peptides and with mixtures of endogenous peptides, have now been determined to high resolution. These structures have afforded important insights into the way in which antigenic peptides are bound by an MHC class I molecule, and how a given MHC molecule can bind a large number and variety of peptides, for presentation to a T cell receptor. Peptides are bound in a cleft located in the alpha 1/alpha 2 domain of a class I molecule. They are tethered by an array of hydrogen bonding interactions many of which are conserved among the different structures. Binding is also accomplished through van der Waals interactions between two or three peptide residues and complementary pockets in the cleft. The location and the characteristics of its pockets are unique to a given MHC class I molecule, and so determine the identity of the anchor residues of the set of peptides that bind. The antigenic epitope recognized by the TCR consists of residues on the MHC as well as the side chains of those peptide residues that point out from the cleft. The various strategies used to expand the repertoire of peptides bound and presented are discussed.

Amino Acid Sequence↗
PubMed1995

MHC class I-peptide interactions and TCR recognition.

The recent crystal structure determinations of MHC class I molecules with single bound peptides have allowed us to understand the guidelines that govern peptide binding in a given MHC allele. Evolution has provided for MHC class I molecules whose antigen binding clefts possess distinct physical and chemical properties as a result of the particular arrangement of variable residues lining the binding cleft. As a result, a given molecule binds a unique set of peptides, the position and identity of whose anchor residues are dictated by the features of the cleft. In addition to the interactions between the anchor residues and the cleft, the peptide is held in the groove by a highly conserved array of hydrogen bonds. A tantalizing application of our newfound understanding of peptide binding will be in the design of model peptides that either block or enhance immune response, in order to achieve effective treatments for a variety of disorders of the immune system.

Alleles↗