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Biomedical subjects

A Singer

Publications and source records attributed to A Singer.

At least 91 records · Page 5Linked to original sources
PubMed1996

Regular audit of colposcopic biopsies from women with a mildly dyskaryotic or borderline cervical smear results in fewer cases of CINIII.

Two years after introducing mandatory review of cases in which the cervical smear was discrepant with subsequent colposcopic or histological finding, the predictive accuracy of a first abnormal smear and the need for treatment were analysed. The results were compared with performance figures prior to this form of audit policy. Over 12 months 415 women referred for colposcopy were studied. Three per cent of patients with a single borderline smear and 6% with mild dyskaryosis had cervical intraepithelial neoplasia grade III (CINIII) revealed in histopathological examinations after colposcopy. Only 25% with a borderline smear and 33% with mild dyskaryosis required treatment. Of women with moderate dyskaryosis, 18% had a biopsy showing CINIII and 46% were treated. Of women with severe dyskaryosis in their cervical smear, 61% were shown to have CINIII or invasive cancer on biopsy and 90% were treated. Regular audit improved cytological prediction of grade of epithelial abnormality found on biopsy, allowing accurate, safe surveillance for minor smear abnormalities.

Adult↗
PubMed1996

Timing of parenchymal enhancement on dual-phase dynamic helical CT of the liver: how long does the hepatic arterial phase predominate?

OBJECTIVE: Dual-phase dynamic helical CT is now being used to detect and characterize benign and malignant hypervascular lesions in the liver. The purpose of this study is to define the timing and degree of parenchymal enhancement of normal liver during the hepatic arterial phase. SUBJECTS AND METHODS: This prospective study included 102 patients with known or suspected hypervascular hepatic lesions who underwent dual-phase helical CT. After unenhanced CT scanning, we injected iopamidol (Isovue 300; Bracco Diagnostics, Princeton, NJ) at 3 ml/sec for 120 ml, then at 2 ml/sec for 55-60 ml. Scan delay for the hepatic arterial phase was 25 sec and for the portal venous phase was 76 sec. Section thickness was 7 mm and pitch was 1:1. Operator-defined regions of interest were obtained from all three phases. RESULTS: Mean unenhanced attenuation of the liver was 51 +/- 12 H. The liver revealed progressive enhancement during the hepatic arterial phase as follows: an increase of 10 H occurred at a mean time of 33 +/- 4 sec, 20 H at 39 +/- 6 sec, 30 H at 44 +/- 8 sec, 40 H at 46 +/- 6 sec, and 50 H at 48 +/- 5 sec. At 20 H and 30 H of enhancement, we found a statistically significant difference (p < .01) for the mean times of men and women. Mean peak enhancement during the portal venous phase was 89 +/- 23 H. CONCLUSIONS: Because the hepatic arterial contribution to liver perfusion is approximately 30%, parenchymal enhancement greater than approximately 30% of peak might indicate portal venous predominance. In our study, this percentage corresponded to an increase of approximately 30 H. Therefore, detection of hypervascular lesions in the hepatic arterial phase may be compromised when imaging lasts longer than approximately 44 sec after the initiation of contrast material injection because 44 sec was the mean time for 30 H of enhancement in our series. However, variability between patients was marked, particularly between men and women. Furthermore, the data suggests that the hepatic arterial phase may be relatively brief and that it may be difficult to image properly using current helical CT technology.

Adult↗
PubMed1996

The mildly abnormal cervical smear: patient anxiety and choice of management.

Argument continues over the best management of women with a first mildly dyskaryotic cervical smear: should they be referred for prompt colposcopy, or should they be kept under cytological review, with recourse to colposcopy if the abnormality persists? One consideration is the amount of anxiety generated. We measured anxiety, retrospectively, in two groups of women who had been managed by one or other method. Colposcopy caused more anxiety than cytological surveillance. When told that their smear was mildly abnormal, 47% of the immediate-colposcopy group (n = 182), compared with 33% of the surveillance group (n = 163), thought they had cancer. None the less, there was a general preference for immediate colposcopy. Whatever the relative merits of these two strategies for clinical management, it is clear that both forms of screening, and especially colposcopy, demand better information for patients.

Adult↗
PubMed1995

The molecular chaperone calnexin is expressed on the surface of immature thymocytes in association with clonotype-independent CD3 complexes.

Immature thymocytes express clonotype-independent CD3 complexes that, when engaged by anti-CD3 antibodies, can signal CD4-CD8- thymocytes to differentiate into CD4+CD8+ cells. Clonotype-independent CD3 complexes consist of CD3 components associated with an unknown 90 kDa surface protein. We now report the surprising finding that this 90 kDa surface protein is the molecular chaperone calnexin, an integral membrane protein previously thought to reside only in the endoplasmic reticulum (ER). We found that calnexin-CD3 complexes escaping to the cell surface utilize interchain associations distinct from those utilized by calnexin-CD3 complexes remaining within the ER. Specifically, we demonstrate that carbohydrate-mediated luminal domain interactions that are necessary for formation of most internal calnexin-CD3 complexes destined to be expressed on the cell surface, and we provide evidence that cytoplasmic domain interactions between calnexin and CD3 epsilon chains mask calnexin's ER retention signal, permitting calnexin and associated proteins to escape ER retention. Thus, the present study demonstrates that partial T cell antigen receptor complexes can escape the ER of immature thymocytes in association with their molecular chaperone to be expressed at low levels on the cell surface where they may function as a signaling complex to regulate thymocyte maturation.

Amino Acid Sequence↗
PubMed1995

Early molecular events induced by T cell receptor (TCR) signaling in immature CD4+ CD8+ thymocytes: increased synthesis of TCR-alpha protein is an early response to TCR signaling that compensates for TCR-alpha instability, improves TCR assembly, and parallels other indicators of positive selection.

Differentiation of immature CD4+ CD8+ thymocytes into mature CD4+ or CD8+ T cells occurs within the thymus and is dependent upon expression of antigen receptor complexes (T cell receptor [TCR]) containing clonotypic alpha/beta proteins. We have recently found that CD4+ CD8+ thymocytes express low levels of surface TCR because of limitations placed on TCR assembly by the instability of nascent TCR-alpha proteins within the endoplasmic reticulum (ER) of immature thymocytes. Because TCR-alpha/beta expression increases during development, a molecular mechanism must exist for increasing the number of assembled TCR complexes present in immature CD4+ CD8+ thymocytes that have been signaled to differentiate into mature T cells, although no such mechanism has yet been described. In the current report we have examined the molecular consequences of intracellular signals generated by engagement of surface TCR complexes on immature CD4+ CD8+ thymocytes. Isolated TCR engagement generated signals that increased TCR-alpha RNA levels and increased synthesis of TCR-alpha proteins, which, in turn, significantly increased assembly of complete TCR-alpha/beta complexes in CD4+ CD8+ thymocytes. Increased TCR-alpha protein levels in TCR-signaled CD4+ CD8+ thymocytes was the result of increased synthesis and not increased stability of TCR-alpha proteins, indicating that TCR engagement compensates for, but does not correct, the inherent instability of TCR-alpha proteins in the ER of immature thymocytes. Consistent with the delivery by TCR engagement of a positive selection signal, TCR engagement also increased CD5 expression, decreased RAG-1 expression, and decreased CD4/CD8 coreceptor expression in immature CD4+ CD8+ thymocytes. These data identify amplified TCR-alpha expression as an initial response of immature CD4+ CD8+ thymocytes to TCR-mediated positive selection signals and provide a molecular basis for increased surface TCR density on developing thymocytes undergoing selection events within the thymus.

Animals↗
PubMed1995

Developmental regulation of alpha beta T cell antigen receptor assembly in immature CD4+CD8+ thymocytes.

Most lymphocytes of the T cell lineage develop along the CD4/CD8 pathway and express antigen receptors on their surfaces consisting of clonotypic alpha beta chains associated with invariant CD3- gamma delta epsilon components and sigma chains, collectively referred to as the T cell antigen receptor complex (TCR). Expression of the TCR complex is dynamically regulated during T cell development, with immature CD4+CD8+ thymocytes expressing only 10% of the number of alpha beta TCR complexes on their surfaces expressed by mature CD4+ and CD8+ T cells. Recent evidence demonstrates that low surface TCR density on CD4+CD8+ thymocytes results from the limited survival of a single TCR component within the ER, the TCR alpha chain, which as a half life of only 15 minutes in immature thymocytes, compared to >75 minutes in mature T cells. Instability of TCR alpha proteins in immature CD4+CD8+ thymocytes represents a novel mechanism by which expression of the multisubunit TCR complex is quantitatively regulated during T cell development. In the current review we discuss our recent findings concerning the assembly, intracellular transport, and expression of alpha beta TCR complexes in CD4+CD8+ thymocytes and comment on the functional significance of TCR alpha instability during T cell development.

Animals↗
PubMed1995

Disruption of intrathymic CD4-Ia interactions on immature CD4+CD8+ thymocytes results in diminished TCR expression on mature CD8+ T cell progeny.

Cell surface TCR expression by developing thymocytes is actively regulated during ontogeny. Whereas most immature CD4+CD8+ thymocytes express low levels of TCR alpha beta, mature CD4+ and CD8+ thymocytes express significantly higher levels of surface TCR. Low TCR expression on CD4+CD8+ thymocytes is due, at least in part, to inhibitory signals generated by CD4 interactions with MHC class II ligands in the thymus. In the present study we wished to determine whether levels of TCR expressed on mature thymocytes were also influenced by CD4-Ia interactions that had occurred on their CD4+CD8+ precursors. To do so, we examined TCR expression on mature CD8+ T cells from animals in which CD4-ligand interactions had been disrupted experimentally by in vivo administration of anti-CD4 mAb or by targeted disruption of an MHC class II gene. We found that TCR expression was significantly diminished on all mature CD8+ T cells from both anti-CD4 mAb-treated mice and MHC class II-deficient animals. These results demonstrate that TCR expression by mature CD8+ T cells, as well as that of immature CD4+CD8+ thymocytes, is regulated by CD4-mediated signals acting on CD4+CD8+ thymocytes. Because the effects of disrupting CD4-Ia interactions on TCR expression by CD8+ T cells were independent of TCR specificity, these findings directly support the concept that CD4-CD8+ T cells arise from precursor CD4+CD8+ cells.

Animals↗
PubMed1995

Acute cardiotoxicity of the Anti-HIV dideoxynucleoside, F-ddA, in the rat.

2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA), an acid-stable, purine dideoxynucleoside with in vitro anti-HIV activity, has been selected by the NCI as a clinical trial candidate. A recent report that high, single doses of F-ddA produce cardiotoxicity in rats prompted the present investigation whose objective was to quantitate this effect and establish a relationship between this toxicity and F-ddA plasma concentrations. Microscopic examination of cardiac tissues for degenerative lesions established the effects of F-ddA and ddA on three iv schedules [daily x 1(2.5-250 mg/kg); daily x 5(125, 250 mg/kg), and BID x 1 (250 mg/kg)] as well as one oral schedule [BID x 1 (500 mg/kg) using 8- to 12-week old female Sprague-Dawley rats. For both F-ddA and ddA, the group mean severity of the cardiac lesions was dose-dependent and proportional to the measured plasma concentrations of the undeaminated parent drugs. F-ddI and ddI, were essentially nontoxic in this study (iv, 250 mg/kg, daily x 1 and daily x 5), since plasma concentrations exceeding 2 mM produced only minimal cardiac lesions. The cardiomyopathy of F-ddA was minimal to mild for all iv doses except 250 mg/kg (daily x 1) and usually was greater than that of ddA at any given dose. This is a consequence of the fact that F-ddA is deaminated 20 times more slowly than ddA, resulting in higher plasma concentrations of F-ddA relative to ddA at any given time for any given dose. Neither F-ddA nor ddA was more cardiotoxic on a repeated iv schedule (daily x 5) than when administered only once, suggesting that rat cardiotoxicity is related Cmax rather than total exposure. In this most sensitive species, the formation of cardiac lesions above the background level is associated with i.v. F-ddA administration when the F-ddA plasma concentration approaches 300 microM, 30-50 times the anticipated therapeutic level in humans.

Administration, Oral↗
PubMed1995

TCR alpha-CD3 delta epsilon association is the initial step in alpha beta dimer formation in murine T cells and is limiting in immature CD4+ CD8+ thymocytes.

The present study has examined the molecular events leading to formation of alpha beta dimers in normal murine thymocytes and mature T cells. We demonstrate that TCR assembly proceeds by initial association of TCR alpha with CD3 delta epsilon proteins and by association of TCR beta with CD3 gamma epsilon proteins to form alpha delta epsilon and beta gamma epsilon trimers; these trimers then associate to form alpha delta epsilon-beta gamma epsilon complexes, within which alpha-beta disulfide bond formation occurs. We also show that TCR-associated protein (TRAP) associates uniquely with CD3 gamma epsilon pairs and that formation of beta gamma epsilon trimers occurs subsequent to TRAP dissociation. Importantly, we document that the assembly step that is quantitatively limiting in CD4+ CD8+ thymocytes is the initial association of TCR alpha with CD3 delta epsilon chains, which appears necessary to protect nascent TCR alpha proteins from accelerated degradation within the ER of immature thymocytes.

Animals↗
PubMed1995

Asymmetric signaling requirements for thymocyte commitment to the CD4+ versus CD8+ T cell lineages: a new perspective on thymic commitment and selection.

Differentiation of immature CD4+ CD8+ thymocytes into mature CD4+ CD8- and CD4-CD8+ T cells requires that synthesis of one or the other coreceptor molecule be terminated, a process referred to as lineage commitment. The present study has utilized a novel coreceptor reexpression assay to identify lineage commitment in immature thymocytes and has found that the MHC recognition requirements for CD4 commitment and CD8 commitment fundamentally differ from one another. Remarkably, we found that thymocyte commitment to the CD8+ lineage requires MHC class I-dependent instructional signals, whereas thymocyte commitment to the CD4+ lineage is MHC independent and may occur by default. In addition, an unanticipated relationship between lineage commitment and surface phenotype has been identified. These results are incompatible with current concepts and require a new perspective on lineage commitment and positive selection, which we refer to as asymmetric commitment.

Animals↗
PubMed1995

Cervical cancer screening: state of the art.

Screening for cervical cancer, the most common form of cancer in women in most developing countries and the second commonest in women in the world as a whole, presents many challenges. Cervical cancer is preventable and it should be a high priority in all national cancer control programmes. It would seem as though, to be highly effective, various methods warrant joint usage, i.e. cytology with virological studies. Their use in both the developed and developing world offer much hope, as does the recent arrival of a physical method for detection.

Adult↗
PubMed1995

Evaluation of renal masses detected by excretory urography: cost-effectiveness of sonography versus CT.

OBJECTIVE: The purpose of this study was to compare the cost-effectiveness of sonography and CT for the evaluation of renal masses discovered at excretory urography. MATERIALS AND METHODS: The records of 225 patients with a renal mass shown by urography who then had either sonography or CT within 3 months were reviewed retrospectively. The number, location, and size of lesions; initial and subsequent imaging tests; and final diagnoses were determined. Using the current Medicare reimbursements for sonography and CT, we calculated the economic implications of using sonography or CT as the initial examination. Any effect of the location or size of the lesion on the most cost-effective examination was also determined. RESULTS: Twenty-one percent of patients had both initial sonography and follow-up CT because of indeterminate findings or detection of a solid mass that required further staging. When CT was done first, CT findings were equivocal in 12%, necessitating follow-up sonography. At the prevailing charges, CT would have to be needed in 70% of patients initially imaged with sonography to justify the use of CT as the initial examination. The location and size of the lesion did not affect the need for CT at a rate (greater than 70%) that would economically justify use of CT as the first imaging test. Eighty-six percent of patients with a mass detected by urography had either a simple cyst or no evidence of a mass on sonography or CT. CONCLUSION: Sonography is the most cost-effective imaging method for the workup of a renal mass detected at urography. The number of sonographic examinations in which findings are indeterminate or positive (for a solid mass) is not sufficiently high to warrant replacement of sonography by CT, regardless of the size and location of the lesion. CT should be reserved for a limited number of specific indications.

Aged↗
PubMed1995

New estimates of undocumented Mexican migration and the probability of apprehension.

Using a new source of data, we estimate the probability of apprehension among Mexican migrants attempting to cross into the United States without documents. Over the period 1965-1989 we found an average apprehension probability of .35, confirming earlier estimates. We then applied annual probabilities to estimate the gross volume of undocumented Mexican migration and adjusted these figures to derive estimates of the net undocumented inflow.

Adult↗
PubMed1994

Developmental regulation of alpha beta T cell antigen receptor expression results from differential stability of nascent TCR alpha proteins within the endoplasmic reticulum of immature and mature T cells.

The alpha beta T cell antigen receptor (TCR) that is expressed on most T lymphocytes is a multisubunit transmembrane complex composed of at least six different proteins (alpha, beta, gamma, delta, epsilon and zeta) that are assembled in the endoplasmic reticulum (ER) and then transported to the plasma membrane. Expression of the TCR complex is quantitatively regulated during T cell development, with immature CD4+CD8+ thymocytes expressing only 10% of the number of surface alpha beta TCR complexes that are expressed on mature T cells. However, the molecular basis for low TCR expression in developing alpha beta T cells is unknown. In the present study we report the unexpected finding that assembly of nascent component chains into complete TCR alpha beta complexes is severely impaired in immature CD4+CD8+ thymocytes relative to their mature T cell progeny. In particular, the initial association of TCR alpha with TCR beta proteins, which occurs relatively efficiently in mature T cells, is markedly inefficient in immature CD4+CD8+ thymocytes, even for a matched pair of transgenic TCR alpha and TCR beta proteins. Inefficient formation of TCR alpha beta heterodimers in immature CD4+CD8+ thymocytes was found to result from the unique instability of nascent TCR alpha proteins within the ER of immature CD4+CD8+ thymocytes, with nascent TCR alpha proteins having a median survival time of only 15 min in CD4+CD8+ thymocytes, but > 75 min in mature T cells. Thus, these data demonstrate that stability of TCR alpha proteins within the ER is developmentally regulated and provide a molecular basis for quantitative differences in alpha beta TCR expression on immature and mature T cells. In addition, these results provide the first example of a receptor complex whose expression is quantitatively regulated during development by post-translational limitations on receptor assembly.

Animals↗