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Biomedical subjects

A Bell

Publications and source records attributed to A Bell.

At least 91 records · Page 5Linked to original sources
PubMed1997

Epstein-Barr virus leader protein enhances EBNA-2-mediated transactivation of latent membrane protein 1 expression: a role for the W1W2 repeat domain.

The Epstein-Barr virus (EBV)-encoded leader protein EBNA-LP is made up of several 66-amino-acid repeats (the W1W2 domains) linked to a unique 45-amino-acid C-terminal sequence (the Y1Y2 domain). This protein is highly expressed along with a second nuclear antigen, EBNA-2, during the initial stages of virus-induced B-cell transformation. While EBNA-2's essential role in transformation as a transcriptional activatory is well documented, very little is known about EBNA-LP function except that recombinant viruses lacking the EBNA-LP Y1Y2 exons show reduced, but still detectable, transforming ability. This was taken as evidence that EBNA-LP plays an auxiliary role but is not essential for transformation. A recent study showed that EBNA-LP could cooperate with EBNA-2 in activating cyclin D2 transcription in resting B cells (A.J. Sinclair, L Palmero, G. Peters, and P.J. Farrell, EMBO J. 13:3321-3328, 1994). Here we report that EBNA-LP can also cooperate with EBNA-2 in up-regulating expression of the major EBV effector protein of B-cell transformation, latent membrane protein 1 (LMP1). In transient-transfection assays, EBNA-LP enhanced the level of EBNA-2-induced LMP1 expression by 5- to 10-fold in one Latency I Burkitt's lymphoma cell line, Eli-BL, and was absolutely required, along with EBNA-2, to induce LMP1 in a second line, Akata-BL. These changes in LMP1 protein expression appeared to be reflected at the transcriptional level. A study of EBNA-LP mutants showed that this cooperative function mapped to the W1W2 repeat domain rather than to Y1Y2. Because a Y1Y2-deleted form of EBNA-LP may therefore retain some aspects of wild-type function, the original data from virus recombinants leave open the possibility that EBNA-LP is actually an essential transforming gene.

Amino Acid Sequence↗
PubMed1997

Physicians' experience with allegations of medical malpractice in the neonatal intensive care unit.

OBJECTIVE: To assess the personal experience of all practitioners of neonatal intensive care unit (NICU) medicine in the United States with the medical malpractice system; in particular, to assess the circumstances of malpractice allegations in which they themselves had personal experience, and to extrapolate from their individual experiences to the field of neonatology in general. DESIGN: Written survey of all MDs practicing NICU medicine in the US. PARTICIPANTS: Two thousand four hundred ninety-eight NICU physicians as determined from three sources: a) the American Board of Medical Specialists; b) the American Academy of Pediatrics Section of Neonatal/Perinatal Medicine; and c) a listing of neonatologists provided by Ross Laboratories. MAIN OUTCOME MEASURES: Responses to survey questions. RESULTS: We received 1813 responses, representing approximately 75% of all physicians practicing NICU medicine in the US. Overall, 43% of respondents had experienced at least one claim of malpractice against them. The probability of a malpractice allegation increased with years in practice, from approximately 20% for NICU physicians in practice </=5 years (65/337), to approximately 60% for NICU physicians in practice >15 years (276/469). Men and women were equally likely to have been sued, accounting for years in practice. Physicians practicing in community NICUs were more likely to be sued than those in university settings. On a scale of 1 to 4 (4 being most reasonable) the median assessment of the reasonableness of malpractice allegations was 1, mean 1.2. On a scale of 1 to 4 (4 being the highest) the median assessment of effectiveness of the current system in identifying true malpractice was 1, mean 1.4. The respondents believed that approximately 80% of malpractice allegations were inappropriate; conversely, they believed that approximately 80% of true medical malpractice escaped detection. On a scale of 1 to 4 (4 being the highest), the median assessment of the detrimental effect of the present malpractice system on health care was 4, mean 3.4. CONCLUSIONS: Most NICU physicians will be sued if they practice long enough. In this context, efforts to use malpractice claims to seek out evildoers (such as underlie the National Practitioners Data Bank) appear ill-conceived. Similarly, exhortations for physicians to become either more educated or more sensitive are unlikely to reduce malpractice claims. Our data suggest that malpractice in the NICU appears to function more like a lottery than like a mechanism for either quality assurance or just retribution.

Community Health Services↗
PubMed1997

Enhanced monocyte generation of reactive oxygen species in primary systemic vasculitis.

OBJECTIVE: Little is known about the role of mononuclear phagocytes in systemic vasculitis. We examined the hypothesis that monocytes from patients with primary systemic vasculitis have increased capacity to generate reactive oxygen species. METHODS: We studied patients with primary systemic vasculitis (n = 24) and compared them with patients with autoimmune related vasculitis (20), peripheral vascular disease (12), and postrenal transplantation (8). Healthy controls were also studied (56). Peripheral blood monocytes were stimulated using phorbol myristate acetate (PMA). We measured the generation of superoxide by cytochrome c reduction and myeloperoxidase (MPO) dependent products using peak luminol chemiluminescence. RESULTS: Patients with primary systemic vasculitis generated significantly more superoxide than all 3 non-vasculitis groups. Superoxide generation in the autoimmune vasculitis group was also higher than other groups but failed to reach significance versus controls (p = 0.07). Generation of MPO dependent products was also significantly higher in patients with primary vasculitis compared to all other groups. Subgroup analysis within the primary vasculitis group showed no correlation of these findings with disease activity, antineutrophil cytoplasmic antibodies, or American College of Rheumatology classification. CONCLUSION: Mononuclear phagocytes act as a source of reactive oxygen species in primary systemic vasculitis. Further study is required to determine if the reactive oxygen species generated act as a mechanism to promote vessel wall injury, or healing in this condition.

Adult↗
PubMed1996

Alveolar hydatid cyst (AHC): inflammation-induced reactive gastrointestinal (GL) amyloidosis in AHC-infected mice and chemical characterization of the GL amyloid.

A high incidence of GI amyloidosis has been described in patients with various forms of systemic amyloidosis but its evolution and progression in different subregions of the GI tract are not well documented. These aspects including the chemical nature of GI amyloid were examined in the AHC mouse model of inflammation-associated reactive amyloidosis. C57BL/6 mice were infected intraperitoneally with 250 AHC. Paraffin sections from the stomach and the small and large intestines of AHC mice were stained at different time intervals with Congo red or immunocytochemically with monospecific RAA. The submucosal blood vessels at 1 week postinfection were found to be the first target of amyloid deposition. With time the amyloid deposits extended to the mucosa and the Peyer's patches and immunoreacted with RAA; ileum was the most severely affected region. Amyloid was extracted from the GI tract and purified by size exclusion chromatography using 5 M guanidine-formic acid, pH 3. The purified amyloid was identified by Western blotting using RAA and by partial N-terminal microsequencing up to 10 cycles. The GI amyloid showed homology with murine SAA2, although SAA2 mRNA is not expressed in murine GI tract. These results shows that (a) the GI amyloid is derived, similar to that of splenic/hepatic amyloid, from circulating SAA2 and (b) the GI tract submucosal blood vessels are the first target of AA deposition. The data also suggest that AA-mediated damage to the submucosal blood capillaries may lead to SAA leakage followed by cascading of AA deposition in other layers of the GI tract.

Amino Acid Sequence↗
PubMed1996

Flow cytometric crossmatching in renal transplantation--outcome after five years.

The association of a positive flow cytometric crossmatch between recipient IgG directed against donor T lymphocytes and poor outcome is well described in renal transplantation. Until now, no long-term follow-up on such patients has been available. A total of 117 renal transplant patients were followed up for a period of 5 years. Of these, 21 were known to have donor T cell-directed IgG and 5 had B lymphocyte-directed IgG. Both groups of patients with these antibodies had a significantly poorer outcome at 5 years than did the group of patients without IgG (P < 0.0001 Handel Maenzel test). Patients with antibody detected preoperatively were tested again, either at the time of graft failure or at 5 years posttransplantation. The sera were tested against stored donor cells and the intensity of surface IgG compared with the preoperative levels. In those recipients who lost their grafts, the levels increased in 60% of cases but those that retained their grafts also had an increase in levels of donor-directed antibody in 50% of cases. The changing levels of antibody therefore appeared to have little relevance to outcome. However, when IgG isotypes were considered, for those who experienced graft failure and also had a gamma 3 isotype, a rise in IgG was demonstrated in all cases. Conversely, successful grafts with gamma 3 had a decline in levels between preoperative and 5-year samples in three of the four cases (p not significant).

Flow Cytometry↗
PubMed1996

Influence of minor groove binders on the eukaryotic topoisomerase II cleavage reaction with 41 base pair model oligonucleotides.

This report deals with the cleavage reaction of calf thymus (CT) topoisomerase II with oligonucleotides containing one main cleavage site and adjacent binding sites for minor groove binders. The sequences of the oligonucleotides were derived from a pBR 322 sequence, which contains one main topoisomerase II cleavage site. The cleavage reaction was performed under increasing concentrations of minor groove binders and it showed characteristic inhibition dependences of topoisomerase II to the binding sites and to the binding length of the minor groove binders. The extension of the minor groove binder length on DNA from 4 to 10 base pairs (bp) by netropsin and bis-netropsin, respectively, causes a strong increase of the topoisomerase II cleavage inhibition. The same is observed by the introduction of a second minor groove binder sequence symmetrically positioned around the topoisomerase II main cleavage site. The combination of two different minor groove binders can lead to an increased topoisomerase II inhibition but also to a prevention of total inhibition as shown with chromomycin A3 and distamycin A at concentrations of 0.1 and 0.25 microM, respectively.

Animals↗
PubMed1996

The antiparasite effects of cyclosporin A: possible drug targets and clinical applications.

1. The immunosuppressive drug cyclosporin A, and some of its nonimmunosuppressive derivatives, are potent inhibitors of a range of parasites of humans. 2. Cyclosporin A and the structurally unrelated immunosuppressant FK506 are known to act on T-lymphocytes as complexes with their binding proteins, cyclophilins and FKBPs, respectively. 3. Cyclophilins and FKBPs have been structurally identified in a number of parasites and, in some instances, are believed to play roles in the antiparasitic actions of these drugs. 4. Nonimmunosuppressive cyclosporins and FK506 derivatives may have clinical potential in certain parasitic diseases, especially malaria and schistosomiasis, and identification of the targets of these drugs in parasites may lead to development of novel chemotherapeutic agents.

Amino Acid Isomerases↗
PubMed1996

Effects of brief counselling among male heavy drinkers identified on general hospital wards.

Although the prevalence of heavy alcohol consumption among patients of general hospitals is well documented, no study has yet reported an effect of counselling on the ward in reducing the level of consumption among such patients after discharge. This study was designed to evaluate brief counselling to reduce alcohol consumption among male heavy drinkers identified on general hospital wards. Male patients were screened on wards of four teaching hospitals in Sydney, Australia. Identified heavy drinkers (n = 174) showing predominantly low levels of alcohol dependence were allocated to one of two forms of brief counselling (skills-based counselling or brief motivational interviewing) or to a non-intervention control group. Blind follow-up for 123 patients (71%) was carried out approximately 6 months after discharge from hospital and self-reports of alcohol consumption were compared with collateral sources of information. Patients who received counselling showed a significantly greater mean reduction in a quantity-frequency measure of weekly alcohol consumption than controls but there were no significant differences in reduced consumption between the two intervention groups. However, patients who were deemed "not ready to change" showed greater reductions if they had received brief motivational interviewing than if they had received skills-based counselling. The implications of these findings for counselling male in-patients to reduce alcohol consumption are discussed.

Journal Article↗
PubMed1996

Inhibition of restriction endonucleases by DNA sequence-reading ligands.

DNA sequence-reading bisquaternary ammonium heterocycles SN 6570, SN 6999, SN 6053, SN 6132, SN 6131, SN 18071 and the non-specific binders SN 6113, SN 5754, SN 6324, and SN 4094 influence the enzymatic activity of restriction endonucleases in different manners. A prerequisite for sequence-specific ligand interaction is a dAdT run of at least four base pairs. The sequence-specific binders inhibit the cleavage activity of restriction endonucleases EcoRI, SspI, and Dral with four and six dAdT base pairs in their restriction sites, while the activity of SalI and BamHI with less than four dAdT base pairs in their recognition motifs remains unaffected. On the contrary, the non-specific binding DNA ligands are incapable of suppressing the digestion for restriction nucleases under research. These results are in line with our footprint data. The inhibitory effect is independent of the number of cleavage sites in DNA and of whether the macromolecule exists in the ccc or lds conformation. Sequence specific binding of the ligand SN 6053 in close vicinity to the cleavage sites of restriction endonuclease Dral also interferes with enzyme inhibition.

Base Sequence↗
PubMed1996

Analysis of meningococcal serogroup C-specific antibody levels in British Columbian children and adolescents.

The effects of age, sex, and possible prior exposure to serogroup C meningococci on group C-specific antibody levels (total and functional) were examined in 2- to 19-year-olds just before and 1 and 12 months after immunization with divalent (groups A + C) meningococcal capsular polysaccharide vaccine. Only age was found to have a significant effect on antibody levels. At 1 month, only 50% of 2- to 6-year-olds had detectable serum bactericidal antibody, in contrast to 84.1% and 96.3% of 9- to 12- and 13- to 19-year-olds respectively. By 12 months, only 20%, 40.9%, and 53.8% of subjects in these age groups had serum bactericidal antibody, suggesting that current meningococcal C polysaccharide vaccines provide only short-term protection. However, the drop in total specific antibody levels (by EIA) was less pronounced. Persistence of antibodies detectable by EIA (but not serum bactericidal antibodies) suggests that this vaccine may also give rise to antibodies of low affinity or directed to nonfunctional (nonprotective) epitopes (or both).

Adolescent↗
PubMed1996

Transcription start sites downstream of the Epstein-Barr virus (EBV) Fp promoter in early-passage Burkitt lymphoma cells define a fourth promoter for expression of the EBV EBNA-1 protein.

In Epstein-Barr virus (EBV)-transformed B lymphoblastoid and many Burkitt lymphoma cell lines, the EBV EBNA-1 protein is one of six viral nuclear antigens expressed from a common transcription unit under the control of one of two promoters, Wp or Cp. In contrast, EBNA-1 is the only EBV nuclear antigen expressed in Burkitt and other EBV-positive tumors. We previously identified a promoter of EBNA-1 transcription, designated Fp, in early-passage Mutu Burkitt tumor cells, and this promoter is also active in long-term Mutu and Akata Burkitt cell lines which maintain the exclusive expression of EBNA-1 characteristic of the tumor. However, transcription initiation within Fp reporter gene plasmids in EBV-negative cells occurs at positions 100 to 200 bases downstream of the Fp start site in the BamHI-Q restriction fragment. Here we demonstrate that transcription initiation within newly established Burkitt lymphoma cell lines is consistent with the transcription initiation we observed in reporter plasmids. Furthermore, previous observations of transcription from Fp to generate EBNA-1 transcripts can be attributed to lytic-cycle gene expression. These data, in conjunction with our previous characterization of promoter regulatory elements, define a fourth EBNA-1 promoter, Qp, that is active in latently infected Burkitt tumor cells.

Antigens, Viral↗
PubMed1996

Group B streptococcal sepsis impairs cerebral vascular reactivity to acute hypercarbia in piglets.

We investigated whether group B streptococcal (STREP) infusion impairs the cerebral blood flow (CBF) response to acute hypercarbia in piglets, and whether STREP-induced prostanoids or hemodynamic alterations could account for this impairment. Piglets, 2-3 wk old, were anesthetized, paralyzed, and mechanically ventilated (50% O2; partial pressure of arterial CO2 (PaCO2) approximately 40 torr). CBF was assessed by internal carotid artery blood flow (ICBF). Group 1 (n = 5) received a continuous infusion of STREP for 4 h (2.0-8.0 x 10(7) org/kg-min). Group 2 (n = 5) was pretreated with indomethacin (5 mg/kg), then received the identical STREP infusion. Group 3 (n = 6) did not receive STREP, but cardiac output (CO) and systemic blood pressure (BP) were reduced to levels equal to that of group 1 by incremental inflation of a left atrial balloon (LAB) catheter. Cerebral vascular reactivity to acute hypercarbia (PaCO2 approximately 70 torr for 7.5 min) was assessed at baseline and after each hour of STREP infusion or LAB inflation. We found that 4 h of STREP infusion caused CO to fall significantly (634 +/- 121 to 324 +/- 172 mL/min, group 1; 600 +/- 68 to 291 +/- 80 mL/min, group 2) and BP to fall significantly (104 +/- 20 to 57 +/- 4 mm Hg, group 1; 91 +/- 11 to 53 +/- 16 mm Hg, group 2) By design, in group 3 LAB inflation caused CO (573 +/- 181 to 375 +/- 159 mL/min) and BP (104 +/- 14 to 60 +/- 9 mm Hg) to fall to values not significantly different from septic groups 1 and 2. At 4 h, unilateral ICBF decreased significantly during STREP infusion in group 1 (32.0 +/- 10.8 to 21.0 +/- 7.3 mL/min) and group 2 (22.9 +/- 9.9 to 13.1 +/- 4.3 mL/min), but not in nonseptic group 3 (23.1 +/- 7.4 to 19.6 +/- 6.3 mL/min). At baseline, hypercarbia induced an increase in ICBF (% delta ICBF = 68.7 +/- 13.0% in group 1, 62.2 +/- 15.6% in group 2, and 87.7 +/- 34.0% in group 3). After 4 h of STREP, this response was completely ablated as ICBF fell during hypercarbia by -7.8 +/- 23.2% (group 1). Indomethacin did not protect cerebral vascular reactivity after 4 h of STREP infusion, as % delta ICBF fell during hypercarbia by -10.9 +/- 17.7% (group 2). In contrast, despite equivalent reductions in CO and BP after 4 h of LAB inflation in nonseptic group 3, ICBF rose during hypercarbia by 61.8 +/- 23.2%, not significantly different from baseline, but significantly different from the decrease in % delta ICBF in groups 1 and 2. We conclude that STREP infusion reduces ICBF and cerebral vascular reactivity to acute hypercarbia in piglets. This phenomenon is not accounted for by STREP-induced reduction in CO or BP, and is not mediated by prostanoids.

Animals↗
PubMed1996

Determination of microscopic binding constants at individual DNA base sequences for the minor groove binders Hoechst 33258, DAPI and pentamidine.

Footprinting titration experiments have been used to estimate microscopic binding constants (KA) for interactions of the ligands Hoechst 33258, DAPI and pentamidine with the 167-mer of the EcoRl-Rsal restriction fragment of the plasmid pBR322. The symmetric base sequence AATTAA yielded the lowest KA values while binding sites which contain an AAA-segment displayed higher binding constants. The accommodation of an adjacent G-C base pair to the ATTT-sequence does not significantly interfere with the stability of the DNA-drug complex. The footprint pattern of the compound Hoechst 33258 shows a peculiarity. Complex formation at low drug concentrations (up to 0.5 mu M) is accompanied by distinct protection sites in the DNA fragment against DNAasel digestion, while at higher drug concentration (up to 5.0 mu M) at the same sites the cleavage activity of the enzyme is enhanced. This is discussed in terms of a conformational change of DNA induced by two concentration-dependent binding modes (AT-specific minor groove binding at low drug concentration and GC-specific interaction at a higher one).

Base Sequence↗
PubMed1995

Assessment of a universal, school-based hepatitis B vaccination program.

OBJECTIVE: To assess a hepatitis B vaccination program offered to all grade 6 students in British Columbia in 1992. DESIGN: Cohort study. SETTING: British Columbia, Canada. PARTICIPANTS: All grade 6 students were offered vaccine. Subsets of 454 and 259 students participated in studies of minor adverse events and seroresponse, respectively. INTERVENTION: The vaccine used was Engerix-B, 20 micrograms, given at intervals of 0, 1, and 6 months. MAIN OUTCOME MEASURES: Province-wide acceptance and series completion rates and reports of severe adverse events. Minor adverse events and immunogenicity in subsamples. RESULTS: A total of 127,922 vaccine doses were administered. Initial enrollment totaled 43,358 students or 95.4% of those eligible. The series was completed by 41,594 students (95.6%). Minor adverse events were infrequent in the cohort assessed: no absenteeism or physician visits resulted from vaccination. Sixty-nine reported severe adverse events met surveillance definitions, the major categories being injection site reactions (23% of reports), fainting (20%), and rashes (17%). There was one instance of anaphylaxis. Only 13 of these events resulted in recommendations to discontinue the series. Of students tested following the series, 98% had levels of antibody to hepatitis B surface antigen considered to be protective (> or = 10 IU/L), the geometric mean titer being 690 IU/L (95% confidence interval, 498 to 957 IU/L). CONCLUSION: Our experience indicates that school-based programs for universal vaccination of preadolescents can be highly acceptable and efficient.

Adolescent↗