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Biomedical subjects

J Neil

Publications and source records attributed to J Neil.

At least 19 recordsLinked to original sources
PubMed2000

Clinical associations and characterisation of antineutrophil cytoplasmic antibodies directed against bactericidal/permeability-increasing protein and azurocidin.

Bactericidal/permeability-increasing protein (BPI) and azurocidin (AZ) are recently described target antigens of antineutrophil cytoplasmic antibodies (ANCA). In this study, BPI-ANCA were demonstrated most often in patients with ulcerative colitis (36/92, 39%), Crohn's disease (17/66, 26%) and cystic fibrosis (11/14, 79%), but also in patients with rheumatoid arthritis (8/40, 20%), systemic lupus erythematosus (SLE) (111/65, 17%) and mixed connective tissue disease (4/18, 22%). BPI-ANCA were also common in sera containing antinuclear (ANA) (9/43, 21%) or antidouble-stranded (ds) DNA (7/28, 25%) antibodies. There was no increased frequency of abnormal alpha1-antitrypsin (alphal1AT) phenotypes in patients with BPI-ANCA, and BPI-ANCA were not more common in individuals with an abnormal phenotype. The predominant IgG subclasses were IgG1 and IgG3; IgA but not IgM was present. Both IgG and IgA BPI-ANCA were high affinity antibodies, and the affinity of IgG antibodies did not change with time in the sera tested. Four of the five sera (80%) containing BPI-ANCA did not bind to denatured, reduced BPI, suggesting that most BPI-ANCA recognised conformational epitopes. AZ-ANCA were demonstrated in 2/11 patients (18%) with Wegener's granulomatosis, 3/12 (25%) with cystic fibrosis and 3/14 (21%) with chronic active hepatitis. AZ-ANCA were present in 5/25 sera (25%) with ANA, but the levels were only marginally elevated. AZ-ANCA were uncommon in patients with inflammatory bowel and rheumatological diseases, and in sera containing other autoantibodies. Again, there was no association with abnormal alpha1-AT phenotypes. BPI represents a major ANCA target antigen in patients with rheumatological as well as inflammatory bowel disease and cystic fibrosis, but AZ-ANCA are uncommon.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1999

A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with myc.

The Cbfa1/PEBP2 alpha A/AML3 gene plays an essential role in osteogenesis but is also expressed in the T-cell lineage where it has been implicated in lymphoma development as a target for retroviral insertional mutagenesis. As lymphoma cells with til-1 insertion express at least five distinct Cbfa1 isoforms, it is important to establish which, if any, have intrinsic oncogenic potential. We have generated transgenic mice in which the most abundant lymphoma isoform (G1/p57) is expressed under the control of the CD2 locus control region. Co-precipitation analysis of transgenic thymus revealed high levels of Cbfa1 protein in an abundant complex containing the binding cofactor Cbfb. CD2-Cbfa1-G1 mice displayed abnormal T-cell development, with a pronounced skew towards CD8 SP cells in the thymus and developed a low incidence of spontaneous lymphomas (6% at 12 months) with cells of similar phenotype. Strongly synergistic tumour development was seen when CD2-Cbfa1-G1 mice were crossed with lines carrying myc transgenes (CD2-myc or tamoxifen-regulatable CD2-mycER) and Cbfa1 was found to rescue expression of the CD2-myc transgene in pre-leukaemic mice. However, synergy did not appear to be due to a dominant block of myc-induced apoptosis by Cbfa1 as explanted primary tumours and cell lines from CD2-Cbfa1-G1/CD2-mycER mice showed accelerated death on induction with tamoxifen at similar rates to CD2-mycER controls. Moreover, thymocytes from preleukaemic CD2-Cbfa1-G1 mice showed reduced survival in vitro and increased sensitivity to the inhibitory effects of TGF-beta. This study demonstrates that a full-length Cbf alpha-chain gene can act as an oncogene without fusion to a heterologous protein.

Animals↗
PubMed1999

Positive and negative regulation of chondrogenesis by splice variants of PEBP2alphaA/CBFalpha1 in clonal mouse EC cells, ATDC5.

The alphaA type of the alpha subunit of the polyomavirus enhancer binding protein 2 (PEBP2alphaA), also called the core binding factor alpha1 (CBFalpha1) or til-1, plays crucial roles in osteogenesis. Little is known, however, about the function of PEBP2alphaA in chondrogenesis. Here, we examined the role of PEBP2alphaA in chondrogenesis of clonal mouse embryonal carcinoma cells, ATDC5, which are committed as chondroprogenitors. We found that as ATDC5 cells condensed and formed cartilaginous nodules, PEBP2alphaA increased, and the level was maintained throughout the process of chondrocytic maturation. When an established dominant negative form of PEBP2alphaA was introduced in undifferentiated ATDC5 cells, the cellular condensation and the subsequent processes were inhibited. This inhibition was overcome with BMP-4 treatment, which increased the endogenous expression of PEBP2alphaA. Thus, the process of chondrogenesis is regulated by the level of PEBP2alphaA activity. Along with the wild-type PEBP2alphaA, a splice variant form, til-1 G2, is naturally expressed in ATDC5 cells. In luciferase reporter assays, til-1 G2 not only exhibited a limited ability to transactivate the osteocalcin promoter but also inhibited the activity achieved by the wild-type PEBP2alphaA. When til-1 G2 was overexpressed by stable transfection in undifferentiated ATDC5 cells, it inhibited the progression of chondrogenesis. Therefore, we conclude that PEBP2alphaA acts as a positive regulator of chondrogenesis, and that this positive effect may be finely tuned by the opposing effect of the til-1 G2 isoform.

Alternative Splicing↗
PubMed1998

Rationing organs using psychosocial and lifestyle criteria.

The role of patient psychosocial and lifestyle characteristics in decisions about the allocation of scarce health care resources has not been examined. In this national survey using the Criteria for Selection of Transplant Recipient (CSTR) Scale, organ transplant coordinators (N = 559) identified the psychosocial and lifestyle criteria they believe should be considered in patient selection/rejection for organ transplant. Using factor analysis to reduce the data, six factors were identified: current lifestyle/psychiatric problems, family/socioeconomic issues, habits, controlled lifestyle/psychiatric issues, cost, and stigmatized conditions. Patients who were in prison for a serious crime, used cocaine, had AIDS, or were HIV positive (criteria making up the Stigma factor), were more likely to be labeled for exclusion from transplant than those with other psychosocial/lifestyle characteristics. When transplant coordinators perceived that patients' psychosocial and lifestyle problems were under control or corrected, they were more likely to consider them for a transplant. For all but the cost factor, criteria were most stringent for heart transplants. Although over 90% of the coordinators assessed patients and participated in patient selection for transplant, master's prepared nurses were more likely than nurses with other educational preparation to be involved in organ recipient selection. These findings can serve as a prototype for how decisions are made for allocating other scarce health care resources.

Adult↗
PubMed1998

Ease of placement of the laryngeal mask during manual in-line neck stabilization.

We studied 20 patients, in a randomized, cross-over study, to determine if manual in-line stabilization of the head and neck altered the ease of insertion of the laryngeal mask and its correct positioning. After induction of anaesthesia and neuromuscular block, the laryngeal mask was inserted and adequacy of ventilation assessed while the patient's head and neck were placed in the Magill and manual in-line positions, in turn. Ease of insertion of the mask was assessed using a 10-cm visual analogue scale (VAS) and position using a fibreoptic bronchoscope. Time for insertion of the mask was measured. The laryngeal mask was inserted and adequate ventilation obtained at the first attempt in all 20 patients in the Magill position and in 19 of 20 patients in the manual in-line position. Insertion was always more difficult (P << 0.001; 95% CI for difference in VAS 20-55 mm) and time for insertion longer (P << 0.001; 95% CI for difference 4.9-11.9 s) in the manual in-line position compared with the Magill position. The incidence of a suboptimal position was significantly higher for the manual in-line position (seven patients) than for the Magill position (15 patients) (P < 0.005). We conclude that in paralysed patients, manual in-line stabilization of the head and neck made insertion of the laryngeal mask and its correct positioning more difficult.

Anesthesia, General↗
PubMed1998

A review of immunofluorescent patterns associated with antineutrophil cytoplasmic antibodies (ANCA) and their differentiation from other antibodies.

AIM: To describe the neutrophil fluorescent patterns produced by antineutrophil cytoplasmic antibodies (ANCA) with different antigen specificities, and by other auto- and alloantibodies. BACKGROUND: Most sera from patients with active generalised Wegener's granulomatosis result in diffusely granular cytoplasmic neutrophil fluorescence with internuclear accentuation (cANCA) and proteinase 3 (PR3) specificity. About 80% of the sera from patients with microscopic polyangiitis result in perinuclear neutrophil fluorescence with nuclear extension (pANCA) and myeloperoxidase (MPO) specificity, or a cANCA pattern with PR3 specificity. However, many different neutrophil fluorescence patterns are noted on testing for ANCA in routine immunodiagnostic laboratories. METHODS: Sera sent for ANCA testing, or containing a variety of auto- and alloantibodies, were studied. They were examined by indirect immunofluorescence according to the recommendations of the first international ANCA workshop, and for PR3 and MPO specificity in commercial and in-house enzyme linked immunosorbent assays (ELISA). RESULTS: Sera with typical cANCA accounted for only half of all neutrophil cytoplasmic fluorescence. Other sera had "flatter" fluorescence without internuclear accentuation, and the corresponding antigens included MPO and bactericidal/permeability increasing protein (BPI), but were usually unknown. Peripheral nuclear fluorescence without nuclear extension occurred typically when the antigens were BPI, lactoferrin, lysozyme, elastase, or cathepsin G. Most types of ANA were evident on ethanol fixed neutrophil nuclei. AntidsDNA, antiRo, and antilamin antibodies resembled pANCA. Antimicrobial and antiribosomal antibodies produced cytoplasmic fluorescence, and antiGolgi antibodies, a pANCA. Sera from patients with anti-smooth muscle antibodies were associated with cytoplasmic fluorescence. There was no neutrophil fluorescence with anti-skeletal muscle and anti-heart muscle antibodies, anti-liver/kidney microsomal, antithyroid microsomal, or antiadrenal antibodies. Alloantibodies such as antiNB1 typically resulted in cytoplasmic fluorescence of only a subpopulation of the neutrophils. CONCLUSIONS: The ability to distinguish between different neutrophil fluorescence patterns, and the patterns seen with other auto- and alloantibodies is helpful diagnostically. However, the demonstration of MPO or PR3 specificity by ELISA will indicate that the neutrophil fluorescence is probably clinically significant, and that the diagnosis is likely to be Wegener's granulomatosis or microscopic polyangiitis.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1997

Inhibition of feline immunodeficiency virus infection by CD9 antibody operates after virus entry and is independent of virus tropism.

A monoclonal antibody which blocks infection with feline immunodeficiency virus (FIV) was found previously to react with the cell surface molecule CD9, implicating CD9 in the process of virus entry. We report here that inhibition by anti-CD9 antibody does not operate at the level of virus entry but at a subsequent stage in the virus life-cycle. Moreover, inhibition of infection is independent of the passage history of the virus or the virus subtype. Inhibition of FIV infection by anti-CD9 antibody does not operate in 3201 cells, which do not express this surface antigen. However, ectopic expression of CD9 on 3201 cells enhances infection with FIV, suggesting that the role of CD9 may be direct rather than via cellular signalling pathways. These results suggest a novel control point in the lentivirus life-cycle which might be susceptible to modulation by natural antagonists.

Animals↗
PubMed1995

On the use of 133Cs as an NMR active probe of intracellular space in vivo.

Data are presented from 133Cs NMR studies on both excised and in situ tissues from rats fed a regular diet and administered i.p. CsCI in aqueous solution for 6 to 14 days. Cesium is an NMR-active potassium analog which accumulates in the intracellular spaces of tissues [Davies et al., Biochemistry 27, 3547 (1988); Shehan, B.P. et al., Magn. Reson. Med. 30,573 (1993)]. Chemical shifts, relaxation properties, sensitivity and detectability of cesium in tissues were investigated. Consistent with previous reports, two resonances (representing intra- and extracellular cesium) were detected in blood. Only one resonance was detected in brain, kidney, and muscle tissue. Efforts to resolve intra- and extracellular components by T1 and T2 relaxation discrimination were not successful. Following i.p. administration, cesium accumulates intracellularly with a brain-to-cerebrospinal fluid concentration (mumol/g) ratio of 9:1 and a thigh muscle-to-plasma concentration ratio of 40:1. Considering the small extracellular volume in these tissues (ca 18% and 10%, respectively), the net content differences between intra- and extracellular cesium are approximately 40-fold in brain and 360-fold in muscle. The concentration ratio of cesium in brain to cesium in cerebrosinal fluid decreased to 3:1 1 h after death, indicating a relatively slow rate of leakage of cesium from the intra- to extracellular space in the face of bioenergetic failure. These data suggest that the cesium signal is dominated by the intracellularly located cesium and, thus, cesium may be useful as a probe of the intracellular environment despite an inability to resolve and directly observe distinct resonances from intra- and extracellular spaces.

Animals↗
PubMed1995

Determination of intracellular calcium in vivo via fluorine-19 nuclear magnetic resonance spectroscopy.

Fluorine-19-nuclear magnetic resonance (19F-NMR) spectroscopic detection of the NMR-active Ca2+ indicator 5-fluoro-1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (5F-BAPTA) is one method for measuring cytosolic free Ca2+ concentration ([Ca2+]i) and has been used previously to measure [Ca2+]i in isolated cells and perfused organs. The aim of the present investigation was to demonstrate the feasibility of determining [Ca2+]i in vivo and in situ using 19F-NMR and 5F-BAPTA. Experiments were performed on male Sprague-Dawley rats with a surface-coil antenna employed for NMR interrogation. The Ca2+ indicator, 5F-BAPTA, was infused either intravenously (kidney, spleen) or intraventricularly (brain) as a 100 mg/ml solution of the cell-permeant acetoxymethyl ester (5F-BAPTA-AM) in dimethyl sulfoxide. Rats tolerated intravenous infusion without evident change in mean arterial blood pressure. In all tissues examined, kidney, spleen, and brain, [Ca2+]i was approximately 200 nM. To our knowledge, these results represent the first in vivo and in situ determinations of [Ca2+]i employing 19F-NMR.

Animals↗
PubMed1994

Chondromyxoid fibroma of a metatarsal and cuneiform.

The occurrence of chondromyxoid fibroma in the foot is relatively rare, and it is highly unusual for the lesion to involve the epiphysis. The authors report a case of a highly aggressive tumor occurring in the first metatarsal bone, crossing the epiphysis and invading the medial cuneiform bone. A literature search did not reveal previous cases of chondromyxoid fibroma in this unusual location.

Adult↗
PubMed1992

Anti-RNA polymerase I antibodies in the sera of MRL lupus mice at the initial stages of disease are directed primarily against phosphorylation-dependent epitopes.

Anti-RNA polymerase I (RPI) antibodies in the sera of MRL/Mp-lpr/lpr and MRL/Mp(-)+/+ mice, which develop an autoimmune disease similar to human systemic lupus erythematosus, were screened for reactivity with purified RPI or RPI which had been dephosphorylated. In every case (n = 10), dephosphorylation of RPI resulted in a significant decrease (33-95%) in antibody binding. The anti-RPI antibodies in the sera of the same mice approximately 6 weeks later also reacted better with untreated as compared to dephosphorylated RPI but, in every case, the decrease in antibody (0-30%) caused by dephosphorylation was substantially diminished. That the proportion of anti-RPI antibodies in the sera of MRL mice decreased with progression of lupus-like disease was confirmed by closely monitoring the antibodies over the course of disease. Anti-RPI antibodies produced at the earliest stages appeared to be directed almost exclusively against phosphorylation-dependent determinants since dephosphorylation of RPI essentially abolished antibody binding. Subsequently, the percentage of the total anti-RPI antibodies in the sera of these mice directed towards phosphorylation-independent epitopes increased linearly with time. The importance of phosphorylation-dependent epitopes on RPI for the development of the anti-RPI autoimmune response was supported by the observation that treatment of mice with alkaline phosphatase partially attenuated anti-RPI antibody production.

Animals↗
PubMed1987

Recombinant feline viruses containing the myc gene rapidly produce clonal tumours expressing T-cell antigen receptor gene transcripts.

We, and others, have recently shown that recombinant feline leukaemia viruses (FeLV) containing the myc gene (FeLV-myc) occur in up to 30% of naturally occurring cases of T-cell lymphosarcoma. Investigation of the disease spectrum of two FeLV-myc isolates showed that they induced clonal or oligoclonal T-cell tumours after a short latent period. The phenotypic pattern of the thymic tumours was restricted in that they all expressed the alpha and beta chains of the T-cell antigen receptor and could readily be established in culture in vitro without the addition of exogenous interleukin-2. Although helper FeLV was transmitted from infected cats to uninfected tracer cats, there was no evidence of horizontal transmission of FeLV-myc viruses, suggesting that these viruses arise de novo in individual cases of thymic lymphosarcoma.

Animals↗