Biomedical subjects

A Wilson

Publications and source records attributed to A Wilson.

At least 163 records · Page 9Linked to original sources

PubMed1997

Elf-1 contributes to the function of the complex interleukin (IL)-2-responsive enhancer in the mouse IL-2 receptor alpha gene.

Lymphocytes regulate their responsiveness to IL-2 through the transcriptional control of the IL-2R alpha gene, which encodes a component of the high affinity IL-2 receptor. In the mouse IL-2R alpha gene this control is exerted via two regulatable elements, a promoter proximal region, and an IL-2-responsive enhancer (IL-2rE) 1.3 kb upstream. In vitro and in vivo functional analysis of the IL-2rE in the rodent thymic lymphoma-derived, CD4- CD8- cell line PC60 demonstrated that three separate elements, sites I, II, and III, were necessary for IL-2 responsiveness; these three sites demonstrate functional cooperation. Site III contains a consensus binding motif for members of the Ets family of transcription factors. Here we demonstrate that Elf-1, an Ets-like protein, binds to site III and participates in IL-2 responsiveness. In vitro site III forms a complex with a protein constitutively present in nuclear extracts from PC60 cells as well as from normal CD4- CD8- thymocytes. We have identified this molecule as Elf-1 according to a number of criteria. The complex possesses an identical electrophoretic mobility to that formed by recombinant Elf-1 protein and is super-shifted by anti-Elf-1 antibodies. Biotinylated IL-2rE probes precipitate Elf-1 from PC60 extracts provided site III is intact and both recombinant and PC60-derived proteins bind with the same relative affinities to different mutants of site III. In addition, by introducing mutations into the core of the site III Ets-like motif and comparing the corresponding effects on the in vitro binding of Elf-1 and the in vivo IL-2rE activity, we provide strong evidence that Elf-1 is directly involved in IL-2 responsiveness. The nature of the functional cooperativity observed between Elf-1 and the factors binding sites I and II remains unresolved; experiments presented here however suggest that this effect may not require direct interactions between the proteins binding these three elements.

Animals↗

PubMed1997

Antithrombotic efficacy in the guinea pig of a derivative of human protein C with enhanced activation by thrombin.

Conversion by alpha-thrombin of the zymogen human protein C (HPC) to activated protein C (aPC) is an important physiologic feedback control mechanism for the coagulation cascade. Although activation of HPC by thrombomodulin-bound thrombin is relatively rapid, activation by free thrombin occurs at a significantly slower rate. Previously, we generated a "hyper-activatable" derivative of HPC (FLIN-Q3) with an increased activation rate by free alpha-thrombin in vitro. In this study, the antithrombotic efficacy of FLIN-Q3 was compared with both native zymogen and aPC in an arteriovenous shunt model of thrombosis in the guinea pig. Recombinant proteins were infused 15 minutes before and throughout a 15-minute period while blood was circulated from carotid to jugular through tubing that enclosed a thread on which fibrin was deposited. Parallel dose-dependent antithrombotic responses were observed. Under these non-steady-state conditions, the calculated infusion doses associated with a 50% reduction of thrombus mass were 2.7, 24, and 250 mg/kg/h for aPC, FLIN-Q3, and HPC, respectively. Thrombus weight correlated inversely with plasma concentration of aPC, measured amidolytically, from either direct infusion of aPC or that generated from the zymogens in the animal, and similarly correlated inversely with anticoagulant activity measured by whole blood aPTT. Neither zymogen form showed significant aPC activity before shunt circulation, suggesting a requirement for exposure to thrombin. After the infusion was discontinued for 15 minutes, a second period of thrombus formation in the shunt demonstrated the ability of zymogen forms of PC, unlike aPC, to provide "on-demand" anticoagulant responses to repeated thrombotic stimuli. Thus, a "hyper-activatable" PC molecule such as FLIN-Q3 may represent a superior form of anticoagulant therapy than either the native zymogen or aPC.

Animals↗

PubMed1997

T cell receptor alpha gene rearrangement and transcription in adult thymic gamma delta cells.

T cells belong to two separate lineages based on surface expression of alpha beta or gamma delta T cell receptors (TCR). Since during thymus development TCR beta, gamma, and delta genes rearrange before alpha genes, and gamma delta cells appear earlier than alpha beta cells, it has been assumed that gamma delta cells are devoid of TCR alpha rearrangements. We show here that this is not the case, since mature adult, but not fetal, thymic gamma delta cells undergo VJ alpha rearrangements more frequently than immature alpha beta lineage thymic precursors. Sequence analysis shows VJ alpha rearrangements in gamma delta cells to be mostly (70%) nonproductive. Furthermore, VJ alpha rearrangements in gamma delta cells are transcribed normally and, as shown by analysis of TCR beta-/- mice, occur independently of productive VDJ beta rearrangements. These data are interpreted in the context of a model in which precursors of alpha beta and gamma delta cells differ in their ability to express a functional pre-TCR complex.

Animals↗

PubMed1997

Alpha beta lineage-committed thymocytes can be rescued by the gamma delta T cell receptor (TCR) in the absence of TCR beta chain.

Commitment of the alpha beta and gamma delta T cell lineages within the thymus has been studied in T cell receptor (TCR)-transgenic and TCR mutant murine strains. TCR gamma delta-transgenic or TCR beta knockout mice, both of which are unable to generate TCR alpha beta-positive T cells, develop phenotypically alpha beta-like thymocytes in significant proportions. We provide evidence that in the absence of functional TCR beta protein, the gamma delta TCR can promote the development of alpha beta-like thymocytes, which, however, do not expand significantly and do not mature into gamma delta T cells. These results show that commitment to the alpha beta lineage can be determined independently of the isotype of the TCR, and suggest that alpha beta versus gamma delta T cell lineage commitment is principally regulated by mechanisms distinct from TCR-mediated selection. To accommodate our data and those reported previously on the effect of TCR gamma and delta gene rearrangements on alpha beta T cell development, we propose a model in which lineage commitment occurs independently of TCR gene rearrangement.

Animals↗

PubMed1997

Freeze drying of cardiac valves in preparation for cellular repopulation.

When freeze-dried cardiac valves have been implanted they remained acellular. This study is the initial step in the development of a method designed to repopulate the substance of the freeze-dried valve with fibroblasts and the lumenal surface with endothelial cells. In this scheme, the freeze-drying process performs three functions; it provides a porous matrix, it kills the donor cells, and it preserves the collagen structure and hence the mechanical strength of the valve. This paper describes the production of appropriate porosity in freeze-dried porcine pulmonary valve leaflets. We found that Tg' for this material is -83 degrees C, which made it impracticable to freeze-dry exclusively from the glassy state. Uncontrolled freeze-drying produced a variable structure with most of the pores considerably smaller than the desired size and a dense layer, apparently devoid of perforations, on the surface. Compacted layers also occurred within the substance of the leaflets. These appearances suggested that extensive collapse had occurred during the drying process. Variation of the cooling rate, the primary drying temperature, and the warming rate during secondary drying enabled us to identify the following conditions that provided satisfactory internal porosity: cooling at 5 degrees C/min, vacuum drying for 6 h at -20 degrees C, and secondary drying for 10 h during rewarming at 0.06-0.08 degrees C/min. The internal cavities measured 100-350 microns2 by ca. 400 microns2, which is adequate to provide access for the fibroblasts (cross-sectional area ca. 150-200 microns2 when rounded but fusiform when attached. However, the internal porous structure rarely communicated with the surface and mechanical perforation was required to provide continuity between the surface and the internal sponge. The resulting method provides a basis for studies of cell colonization.

Animals↗

PubMed1997

Nicotine discrimination and self-administration in humans as a function of smoking status.

Nicotine's discriminative stimulus effects may be critical to understanding reinforcement of tobacco smoking. It is not known whether regular nicotine exposure produces tolerance or sensitivity to these effects. In this study, male and female smokers (n = 11) and never-smokers (n = 10) were trained to discriminate 20 micrograms/kg nicotine by nasal spray from placebo (0) on day 1. On day 2, both groups were tested on generalization of this discrimination across intermittent presentations of 0, 3, 6, 12, and 20 micrograms/kg nicotine in random order. Quantitative and quantal behavioral discrimination tasks, used in previous research, were employed. On day 3, subjects were instructed to self-administer sprays from the 20 micrograms/kg nicotine versus 0 bottles in a concurrent-choice procedure. All but one subject (female smoker) learned reliably to discriminate 20 micrograms/kg nicotine from placebo (> or = 80% correct) on day 1. Nicotine-appropriate responding on day 2 was attenuated in smokers versus never-smokers at 20 micrograms/kg on the quantitative task and at 12 micrograms/kg on the quantal task, suggesting tolerance. There was no difference in responding at other doses. Smokers also showed attenuated responses on the subjective measure of "head rush", which was associated with discrimination responding in both groups. Nicotine self-administration was significantly greater in smokers versus never-smokers, who self-administered nicotine below chance levels, and was inversely related to discrimination behavior in never-smokers but unrelated in smokers. Women smokers showed less change in nicotine-appropriate responding across generalization doses, reported less confidence in discriminating training doses during acquisition on day 1, and tended to self-administer less nicotine on day 3. These results indicate that smokers may become tolerant to the discriminative stimulus effects of nicotine, perhaps promoting increased use.

Adult↗

PubMed1997

The winged-helix transcription factor Trident is expressed in actively dividing lymphocytes.

We recently identified the winged-helix transcription factor Trident and described its expression pattern in synchronized fibroblasts. We have now studied Trident expression in cell lines, differentiating thymocytes and in lymphocytes derived from peripheral blood. During T cell differentiation, expression peaked in the actively dividing immature single positive cells. In peripheral blood lymphocytes, expression of Trident mRNA was absent, but could be induced upon stimulation with mitogens in vitro. These observations imply a function for Trident in dividing lymphocytes.

Cell Cycle↗

PubMed1997

The effect of tramadol on dento-alveolar surgical pain.

The aim of the study was to assess the analgesic effect of tramadol in the relief of pain after dentoalveolar operations that involve the removal of bone and suturing. Four-hundred and fifty-two patients over the age of 18 years who were to undergo removal of impacted teeth (n = 362), removal of root (n = 79), or alveolectomy, enucleation of cysts, or removal of soft tissue (n = 11) under local anesthesia were studied. Patients were randomly allocated to receive tramadol 100 mg or 50 mg four times daily, or 50 mg twice daily, or placebo. Median pain scores on the day of operation in the three tramadol groups were similar (2 in each group, ranges 1-5, 1-4.8, and 1-5 respectively) and were all significantly lower than that in the placebo group (2.3 range 1-4.2). The median number of Paracetamol tablets taken by patients in the three tramadol groups was 2 (ranges 0-8, 0-12 and 0-8 respectively), and were all significantly less than in the placebo group (4, range 0-12). More patients given tramadol reported complete pain relief than the placebo group. The advantages of tramadol continued over the next 2 days. There were no serious or unexpected adverse effects. It is concluded that tramadol is an effective analgesic after dentoalveolar operations.

Acetaminophen↗

PubMed1997

Hospital pharmacy decisions, cost containment, and the use of cost-effectiveness analysis.

The key hypothesis of the study was that hospital pharmacies under the pressure of managed care would be more likely to adopt process innovations to assure less costly and more cost-effective provision of care. We conducted a survey of 103 hospitals and analyzed secondary data on cost and staffing. Compared to the size of the reduction in length of stay, changes in the way that a day of care is delivered appear to be minor, even in areas with substantial managed care share. The vast majority of hospitals surveyed had implemented some form of therapeutic interchange and generic substitution. Most hospitals used some drug utilization guidelines, but as of mid 1995 these were not yet important management tools for hospital pharmacies. To our knowledge, ours was the first survey to investigate the link between hospital formularies and use of cost-effectiveness analysis. At most cost-effectiveness was a minor tool in pharmaceutical decision making in hospitals at present. We could determine no differences in use of such analyses by managed care market share in the hospital's market share. One impediment to the use of cost-effectiveness studies was the lack of timeliness of studies. Other stated reasons for not using cost-effectiveness analysis more often were: lack of information on hospitalized patients and hence on the potential cost offsets accruing to the hospital: lack of independent sponsorship, and inadequate expertise in economic evaluation.

Cost Control↗

PubMed1997

Facial palsy in Kawasaki syndrome.

Facial nerve palsy, a very rare complication of Kawasaki syndrome, has been reported in only 25 patients. We treated a 12-week-old boy with bilateral coronary artery aneurysms due to Kawasaki syndrome who developed marked unilateral peripheral facial nerve palsy on day 36 of illness. None of the 25 previously reported patients with this complication were treated with immunoglobulin; they required 7 to 90 days to recover. In our patient, treatment with this agent was associated with complete resolution of facial nerve palsy within 36 hours. Review of prior cases demonstrates that children with Kawasaki-associated facial nerve palsy have more than twice the risk for coronary artery aneurysm (52% vs <25%) as that of children who do not develop this neurological complication. Unexplained facial nerve paralysis in young children with a prolonged febrile illness should provoke consideration of Kawasaki syndrome and of echocardiography to exclude coronary artery aneurysms. Although facial palsy appears likely to resolve in all patients that survive the acute phase of Kawasaki syndrome, treatment with intravenous immunoglobulin appears to considerably shorten the time to full recovery and provides an important clue to the mechanisms of neurological injury in this illness.

Coronary Aneurysm↗

PubMed1997

TRAMP, a novel apoptosis-mediating receptor with sequence homology to tumor necrosis factor receptor 1 and Fas(Apo-1/CD95).

A novel member of the tumor necrosis factor (TNF) receptor family, designated TRAMP, has been identified. The structural organization of the 393 amino acid long human TRAMP is most homologous to TNF receptor 1. TRAMP is abundantly expressed on thymocytes and lymphocytes. Its extracellular domain is composed of four cysteine-rich domains, and the cytoplasmic region contains a death domain known to signal apoptosis. Overexpression of TRAMP leads to two major responses, NF-kappaB activation and apoptosis. TRAMP-induced cell death is inhibited by an inhibitor of ICE-like proteases, but not by Bcl-2. In addition, TRAMP does not appear to interact with any of the known apoptosis-inducing ligands of the TNF family.

Adaptor Proteins, Signal Transducing↗

PubMed1997

The shear behaviour of the rabbit medial collateral ligament.

This study was conducted to determine whether load is transmitted via shear through the matrix between ligament fibres rather than solely as tension in the fibres. Thirty-six rabbit medial collateral ligaments were subjected to uniaxial tension tests. Twenty-four of these ligament complexes were incised laterally to create longitudinal shear planes, while the remaining 12 complexes served as controls. Data were used in conjunction with finite element models to determine how shear transfer, if any, occurred in the ligament. Non-linear, anisotropic, plane stress finite element models were able to simulate the non-linear structural behaviour shown by uncut control ligaments under normal tensile testing. The finite element models were also able to reproduce the ligament load deformation behaviour observed in the shear tests. Results indicated that some load was transferred between the collagen fibres and other constituents in the ground substance of these ligaments and possibly also through fibres missed during the cutting procedure. The exact manner in which the load was transmitted remains unclear and requires further investigation and quantification.

Animals↗

PubMed1997

Extraction and replacement of permanent pacemaker leads through occluded vessels: use of extraction sheaths as conduits--balloon venoplasty as an adjunct.

Patients (pts) may present for lead extraction with symptomatic or asymptomatic subclavian vein or superior vena cava thrombosis. Replacement of permanent pacemaker leads (PPLs) in these pts may be difficult and may require accessing a new site. We examined the utility of replacing PPLs through completely occluded vessels using extraction sheaths as conduits through the total occlusion. Over six years, a total of 210 atrial and/or ventricular PPLs were extracted from 137 pts. Two pts presented with angiographically documented thrombotic occlusion of the subclavian vein. One additional pt. who had presented with a superior vena cava (SVC) syndrome, had a totally occluded innominate vein and SVC occlusion. Balloon venoplasty was used as an adjunct to dilate the SVC. In all pts, after PPLs were removed via a subclavian extraction sheath through the occluded vessel, the retained sheath was used to place a guide wire, then a peel away dilating sheath, to insert new PPLs, in each case on the side of total venous occlusion. Seven PPLs and two lead fragments were extracted, and five new PPLs replaced, ipsilateral to the venous occlusion. These data show that extraction of PPLs through thrombosed veins may be performed successfully and may not require replacing the leads through a new site. This technique spares the pt the need to access the opposite subclavian vein, and it avoids an excessive number of PPLs in the subclavian vein and SVC. The procedure illustrates an efficient means to reintroduce new PPLs with the potential to reduce associated morbidity, since repeat puncture of the subclavian vein is not required. Safety of the procedure as a whole must be considered with regard to the known risks of lead extraction, some complications of which may be substantial using current techniques.

Adult↗

PubMed1997

T-cell epitopes recognized within the 65,000 MW hsp in patients with IgA nephropathy.

IgA nephropathy (IgAN) is the commonest cause of glomerulonephritis and clinical exacerbation of IgAN is frequently associated with mucosal infection. T-cell receptor gamma delta (TCR gamma delta+) cells are increased in both the circulation and in renal biopsies of patients with progressive IgAN. We examined the hypothesis that specific peptides within the 65,000 MW heat-shock protein (hsp) might stimulate TCR gamma delta cells and play a part in the immunopathogenesis of IgAN. We studied T-cell proliferative responses stimulated by overlapping peptides derived from the sequence of mycobacterial 65,000 MW hsp. Three T-cell epitopes have been identified (peptides 51-65, 71-85 and 281-295). The three peptides have a synergistic effect and they stimulate significantly higher proliferation of T cells in patients with IgAN than in disease or healthy controls. This response was inhibited by monoclonal antibodies (mAb) to TCR gamma delta+ and human leucocyte antigen (HLA) class I, but not by mAb to HLA class II. The involvement of TCR gamma delta+ cells was confirmed by up-regulation of the proportion of TCR gamma delta+ cells when stimulated with the three specific peptides. We suggest that IgAN might be associated with mucosal infection by a variety of micro-organisms and that peptides within the microbial hsp cross-react with the homologous human hsp which may stimulate TCR gamma delta+ cells and play a part in the pathogenesis of IgAN.

Adult↗

PubMed1997

The effect of attention on phenomenal length.

The effect of attention of the perceived length of briefly presented peripheral lines was investigated. Attention was manipulated by engaging observers in a second concurrent task (letter identification). Observers used the method of adjustment to indicate the length of the stimulus lines. In two experiments it was found that the primary effect of attention was to reduce the variability of line length adjustments. Previously investigators had reported that attention reduces perceived line length. A third experiment suggested that these previously reported results might have been the outcome of a spatial interaction with the cue used to manipulate attention, but not the result of visual attention.

Adult↗

PubMed1997

Development and implementation of outreach strategies for breast and cervical cancer prevention among African American women. FoCaS Project. Forsyth County Cancer Screening.

BACKGROUND: The purpose of the FoCaS (Forsyth County Cancer Screening) Project was to develop and implement strategies that would improve the beliefs, attitudes, and preventive health habits of populations typically considered hard to reach. Conventional health education methods have not produced substantial results; thus, innovative and unusual strategies are needed. METHODS: The FoCaS project implemented specific methods to reach the targeted population of African American women aged 40 and older that resides in public housing communities. Five outreach strategies were used: 1) educational classes (group setting and one-on-one sessions) on various topics that relate not to breast and cervical cancer but to women's issues in general; 2) media campaigns strategically scheduled throughout the year; 3) the inclusion of religion in educational classes and community outreach; 4) the use of information centers to distribute materials; and 5) a community-wide cancer-awareness event. RESULTS: These strategies reached women in nonthreatening environments that permitted heavy involvement and easy understanding of the importance of breast and cervical cancer screening. CONCLUSION: The effects of these strategies on promoting screening will be evaluated using data from the follow-up survey conducted during the spring of 1996.

Adult↗

PubMed1997

Evidence for a type 1 diabetes susceptibility locus (IDDM10) on human chromosome 10p11-q11.

A region of linkage to type 1 diabetes has been defined on human chromosome 10p11-q11 (IDDM10; P = 0.0007) using 236 UK and 76 US affected sibpairs and a 1 cM resolution microsatellite marker map. Analysis by the transmission disequilibrium test (TDT) in 1159 families with at least one diabetic child, from the UK, the US, Norway, Sardinia and Italy provided additional support for linkage at D10S193 (P = 0.006, Pc = 0.17). Notably, 5.1 cM distal to D10S193, marker D10S588 also provided positive TDT results (P = 0.009, Pc = 0.25) but the allele under analysis was also preferentially transmitted to nonaffected siblings (P = 0.0008, Pc = 0.02). This allele was positively associated in an independent UK case control study and, importantly, was neutrally transmitted in control CEPH families. These results suggest a type 1 diabetes susceptibility locus on chromosome 10p11-q11 (provisionally designated IDDM10) and demonstrate the necessity of analysis of non affected siblings in disease families, as well as analysis of control families.

Adolescent↗

PubMed1997

Pre-AIDS deaths in HIV infection related to intravenous drug use.

We prospectively collected data on deaths in the Edinburgh City Hospital HIV cohort of patients (60-70% acquired via injection drug use) from October 1986 to September 1994. Sixty-four patients (25% of all HIV deaths or 2.5/100 person-years) had died without an AIDS diagnosis, and 42 (66%) of these had autopsy data available. Some pre-AIDS deaths (20% or 0.5/100 person-years) were the expected consequence of underlying medical conditions diagnosed during life: the remainder (80% or 1.98/100 person-years) were sudden or unexpected. Examining the underlying conditions, drug overdoses accounted for 45% or 1.1/100 person-years; bacterial sepsis, 25% or 0.6/100 person-years; liver disease, 26% or 0.6/100 person-years; and an undiagnosed AIDS condition, 9% or 0.2/100 person-years. Drug overdoses were the commonest cause of pre-AIDS death in this cohort of patients predominantly infected via IDU, but many of the sudden deaths had significant underlying pathology, which may have increased their susceptibility to an overdose of drugs. In future, death before an AIDS diagnosis should be classified into Medical or Expected Non-AIDS (MNA or ENA) and Sudden Non-AIDS (SNA).

Bacterial Infections↗