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Biomedical subjects

A C Wilson

Publications and source records attributed to A C Wilson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Carboxy terminus of human herpesvirus 8 latency-associated nuclear antigen mediates dimerization, transcriptional repression, and targeting to nuclear bodies.

Human herpesvirus 8 (HHV-8; also known as Kaposi's sarcoma-associated herpesvirus) is the causative agent of Kaposi's sarcoma and certain B-cell lymphomas. In most infected cells, HHV-8 establishes a latent infection characterized by the expression of latency-associated nuclear antigen (LANA) encoded by open reading frame 73. Although unrelated by sequence, there are functional similarities between LANA and the EBNA-1 protein of Epstein-Barr virus. Both accumulate as subnuclear speckles and are required for maintenance of the viral episome. EBNA-1 also regulates viral gene expression and is required for cell immortalization, suggesting that LANA performs similar functions in the context of HHV-8 infection. Here we show that LANA forms stable dimers, or possibly higher-order multimers, and that this is mediated by a conserved region in the C terminus. By expressing a series of truncations, we show that both the N- and C-terminal regions localize to the nucleus, although only the C terminus accumulates as nuclear speckles characteristic of the intact protein. Lastly, we show that LANA can function as a potent transcriptional repressor when tethered to constitutively active promoters via a heterologous DNA-binding domain. Domains in both the N and C termini mediate repression. This suggests that one function of LANA is to suppress the expression of the viral lytic genes or cellular genes involved in the antiviral response.

Amino Acid Sequence↗
PubMed2000

HCF-1 amino- and carboxy-terminal subunit association through two separate sets of interaction modules: involvement of fibronectin type 3 repeats.

When herpes simplex virus infects permissive cells, the viral regulatory protein VP16 forms a specific complex with HCF-1, a preexisting nuclear protein involved in cell proliferation. The majority of HCF-1 in the cell is a complex of associated amino (HCF-1(N))- and carboxy (HCF-1(C))-terminal subunits that result from an unusual proteolytic processing of a large precursor polypeptide. Here, we have characterized the structure and function of sequences required for HCF-1(N) and HCF-1(C) subunit association. HCF-1 contains two matched pairs of self-association sequences called SAS1 and SAS2. One of these matched association sequences, SAS1, consists of a short 43-amino-acid region of the HCF-1(N) subunit, which associates with a carboxy-terminal region of the HCF-1(C) subunit that is composed of a tandem pair of fibronectin type 3 repeats, a structural motif known to promote protein-protein interactions. Unexpectedly, the related protein HCF-2, which is not proteolyzed, also contains a functional SAS1 association element, suggesting that this element does not function solely to maintain HCF-1(N) and HCF-1(C) subunit association. HCF-1(N) subunits do not possess a nuclear localization signal. We show that, owing to a carboxy-terminal HCF-1 nuclear localization signal, HCF-1(C) subunits can recruit HCF-1(N) subunits to the nucleus.

Amino Acid Sequence↗
PubMed2000

Mutations in host cell factor 1 separate its role in cell proliferation from recruitment of VP16 and LZIP.

Host cell factor 1 (HCF-1) is a nuclear protein required for progression through G(1) phase of the cell cycle and, via its association with VP16, transcriptional activation of the herpes simplex virus immediate-early genes. Both functions require a six-bladed beta-propeller domain encoded by residues 1 to 380 of HCF-1 as well as an additional amino-terminal region. The beta-propeller domain is well conserved in HCF homologues, consistent with a critical cellular function. To date, the only known cellular target of the beta-propeller is a bZIP transcription factor known as LZIP or Luman. Whether the interaction between HCF-1 and LZIP is required for cell proliferation remains to be determined. In this study, we used directed mutations to show that all six blades of the HCF-1 beta-propeller contribute to VP16-induced complex assembly, association with LZIP, and cell cycle progression. Although LZIP and VP16 share a common tetrapeptide HCF-binding motif, our results reveal profound differences in their interaction with HCF-1. Importantly, with several of the mutants we observe a poor correlation between the ability to associate with LZIP and promote cell proliferation in the context of the full HCF-1 amino terminus, arguing that the HCF-1 beta-propeller domain must target other cellular transcription factors in order to contribute to G(1) progression.

Amino Acid Sequence↗
PubMed2000

Late presentation of upper airway obstruction in Pierre Robin sequence.

A retrospective review was carried out of 11 consecutive patients with the Pierre Robin sequence referred to a tertiary paediatric referral centre over a five year period from 1993 to 1998. Ten patients were diagnosed with significant upper airway obstruction; seven of these presented late at between 24 and 51 days of age. Failure to thrive occurred in six of these seven infants at the time of presentation, and was a strong indicator of the severity of upper airway obstruction. Growth normalised on treatment of the upper airway obstruction with nasopharyngeal tube placement. All children had been reviewed by either an experienced general paediatrician or a neonatologist in the first week of life, suggesting that clinical signs alone are insufficient to alert the physician to the degree of upper airway obstruction or that obstruction developed gradually after discharge home. The use of polysomnography greatly improved the diagnostic accuracy in assessing the severity of upper airway obstruction and monitoring the response to treatment. This report highlights the prevalence of late presentation of upper airway obstruction in the Pierre Robin sequence and emphasises the need for close prospective respiratory monitoring in this condition. Objective measures such as polysomnography should be used, as clinical signs alone may be an inadequate guide to the degree of upper airway obstruction.

Age of Onset↗
PubMed1999

Impact of availability of hospital-based invasive cardiac services on racial differences in the use of these services.

BACKGROUND: Reports indicate that black patients are less likely than white patients to receive invasive cardiac services after hospitalization for acute myocardial infarction (AMI). There is still uncertainty as to why racial differences exist and how they affect patient outcomes. This is the first study to focus on the availability of invasive cardiac services and racial differences in procedure use. Study objectives were to (1) document whether racial differences existed in the use of invasive cardiac procedures, (2) study whether these racial differences were related to availability of hospital-based invasive cardiac services at first admission for AMI, and (3) determine whether there were racial differences in long-term mortality rates. METHODS: A historical cohort study was conducted with discharge records from all acute care hospitals in New Jersey for 1993 linked to death certificate records for 1993 and 1994. There were 13,690 black and white New Jersey residents hospitalized with primary diagnosis of AMI. Use of cardiac catheterization within 90 days, revascularization within 90 days (percutaneous transluminal coronary angioplasty [PTCA] or coronary artery bypass graft surgery [CABG]), and death within 1 year after admission for AMI were the main outcome measures. Patterns for PTCA and CABG as separate outcomes were also studied. Hospital-based cardiac services available were described as no invasive cardiac services, catheterization only, or PTCA/CABG. To account for payer status and comorbidity differences, patients 65 years and older with Medicare coverage were analyzed separately from those younger than 65 years. RESULTS: Black patients aged 65 and older were generally less likely to receive catheterization and revascularization than white patients, regardless of facilities available at first admission. For patients younger than 65 years, the greatest differences between black and white patients in catheterization and PTCA/CABG use within 90 days after AMI occurred when no hospital-based invasive cardiac services were available. However, use of invasive cardiac procedures within 90 days after AMI was substantially increased if the first hospital offered catheterization only or PTCA/CABG services, among all patients, especially among blacks younger than age 65. No significant racial differences or interactions with available services were found in 1-year mortality rates. CONCLUSIONS: Availability of invasive cardiac services at first hospitalization for AMI was associated with increased procedure use for both races. However, use of invasive cardiac procedures was generally lower for black patients than for white patients, regardless of services available. Long-term mortality rates after hospitalization for AMI did not differ between blacks and whites.

Black or African American↗
PubMed1999

Mass mailing and staff experience in a total recruitment program for a clinical trial: the SHEP experience. Systolic Hypertension in the Elderly Program. Cooperative Research Group.

The Systolic Hypertension in the Elderly Program (SHEP) staff contacted 447,921 screenees, of whom 11,919 (2.7%) were originally eligible and 4,736 (1.1%) maintained eligibility and were randomized. The total number of participants enrolled at the 16 clinical centers ranged from 133 to 559. The low yield of screenees to randomizations resulted from the study design, not from low levels of agreement to participate, and required the employment of a variety of recruitment strategies in a prudent overall plan. SHEP was one of the first clinical trials to use mass mailing as a primary strategy of recruitment. The study used mailing lists from seven generic sources. More than 3.4 million letters of invitation were mailed; they yielded an overall response rate of 4.3%. Motor vehicle and voter registration lists provided the greatest numbers of names. Mailings to members of health maintenance organizations (HMOs) and registrants of the Health Care Finance Administration (HCFA) provided the greatest response rates. Considerable variability in response rates existed among clinical centers using generically similar mailing lists. Generally, the number of hours spent on recruitment showed a positive, but not statistically significant, association with randomization yields. The recruitment yield was statistically significantly higher in clinics with experienced recruitment coordinators than in clinics with inexperienced ones (p = 0.0008). From these findings we conclude that mass mailing is an important strategy in an overall recruitment program, that the involvement of experienced recruitment staff is important, and that although the total time spent by staff on recruitment may also improve results, it matters less than the staff's level of recruiting experience.

Aged↗
PubMed1999

Herpes simplex virus transactivator VP16 discriminates between HCF-1 and a novel family member, HCF-2.

Herpes simplex virus infection is initiated by VP16, a viral transcription factor that activates the viral immediate-early (IE) genes. VP16 does not recognize the IE gene promoters directly but instead forms a multiprotein complex with Oct-1 and HCF-1, a ubiquitous nuclear protein required for progression through the G1 phase of the cell cycle. The functional significance of recruiting HCF-1 to the VP16-induced complex is not understood. Here we describe the identification of a second HCF-like protein, designated HCF-2. HCF-2 is smaller than HCF-1 but shares three regions of strong amino acid sequence homology, including the beta-propeller domain required for association with VP16. HCF-2 is expressed in many tissues, especially the testis, and shows a more dynamic pattern of subcellular localization than HCF-1. Although HCF-2 associates with VP16 and can support complex assembly with Oct-1 and DNA, it is significantly less efficient than HCF-1. A similar preference is shown by LZIP, a cellular counterpart of VP16. Analysis of chimeric proteins showed that differences between the fifth and sixth kelch repeats of the beta-propeller domains from HCF-1 and HCF-2 dictate this selectivity. These results reveal an unexpected level of specificity in the recruitment of HCF-1 to the VP16-induced complex, paralleling the preferential selection of Oct-1 rather than the closely related POU domain protein Oct-2. Implications for regulation of the viral life cycle are discussed.

Amino Acid Sequence↗
PubMed1998

Angiotensin-converting enzyme gene polymorphism in systemic hypertension.

We determined the angiotensin-converting enzyme (ACE) insertion/deletion genotype in 209 hypertensive individuals and in 100 matched normotensive controls. A significant association was detected between hypertension and the deletion/deletion (D/D) genotype of the ACE gene when the relation was adjusted for age, sex, and body mass index.

Aged↗
PubMed1998

Relation of infant diet to childhood health: seven year follow up of cohort of children in Dundee infant feeding study.

OBJECTIVE: To investigate the relation of infant feeding practice to childhood respiratory illness, growth, body composition, and blood pressure. DESIGN: Follow up study of a cohort of children (mean age 7.3 years) who had detailed infant feeding and demographic data collected prospectively during the first two years of life. SETTING: Dundee. SUBJECTS: 674 infants, of whom 545 (81%) were available for study. Data on respiratory illness were available for 545 children (mean age 7.3 (range 6.1-9.9) years); height for 410 children; weight and body mass index for 412 children; body composition for 405 children; blood pressure for 301 children (mean age 7.2 (range 6.9-10.0) years). MAIN OUTCOME MEASURES: Respiratory illness, weight, height, body mass index, percentage body fat, and blood pressure in relation to duration of breast feeding and timing of introduction of solids. RESULTS: After adjustment for the significant confounding variables the estimated probability of ever having respiratory illness in children who received breast milk exclusively for at least 15 weeks was consistently lower (17.0% (95% confidence interval 15.9% to 18.1%) for exclusive breast feeding, 31.0% (26.8% to 35.2%) for partial breast feeding, and 32.2% (30.7% to 33.7%) for bottle feeding. Solid feeding before 15 weeks was associated with an increased probability of wheeze during childhood (21.0% (19.9% to 22.1%) v 9.7% (8.6% to 10.8%)). It was also associated with increased percentage body fat and weight in childhood (mean body fat 18.5% (18.2% to 18.8%) v 16.5% (16.0% to 17.0%); weight standard deviation score 0.02 (-0.02 to 0.06) v -0.09 (-0.16 to 0.02). Systolic blood pressure was raised significantly in children who were exclusively bottle fed compared with children who received breast milk (mean 94.2 (93.5 to 94.9) mm Hg v 90.7 (89.9 to 91.7) mm Hg). CONCLUSIONS: The probability of respiratory illness occurring at any time during childhood is significantly reduced if the child is fed exclusively breast milk for 15 weeks and no solid foods are introduced during this time. Breast feeding and the late introduction of solids may have a beneficial effect on childhood health and subsequent adult disease.

Blood Pressure↗
PubMed1998

Factors associated with atrial fibrillation in patients with mitral stenosis: a cardiac catheterization study.

Atrial fibrillation (AF) is frequently found in association with rheumatic mitral valve disease. To study the interrelation of factors contributing to the risk of AF in patients with mitral stenosis, we examined a cardiac catheterization database of a series of 314 patients. Patients with AF were older, 53.4 +/- 6.1 years versus 51.7 +/- 7.2 years (p = 0.03), and had a lower cardiac index, 2.3 +/- 0.6 L/min/m2 versus 2.6 +/- 0.7 L/min/m2 (p = 0.0002), than patients in sinus rhythm at catheterization. The mitral valve area was significantly smaller in patients with AF than in patients in sinus rhythm, 1.2 +/- 0.5 cm2 versus 1.6 +/- 0.7 cm2 (odds ratio 1.40/0.25 cm2 decrease; p = 0.0001) as was mitral valve index. The pressure-AF association with the highest statistical significance was seen with mean right atrial pressure, 10.6 +/- 4.9 mm Hg versus 7.6 +/- 3.8 mm Hg (odds ratio 2.24; p < 0.0001). Other variables with significant positive associations by univariate analysis were pulmonary artery wedge pressure, pulmonary artery mean pressure, and pulmonary resistance. When stepwise logistic multiple regression analysis was performed, the results indicated that both severity of mitral stenosis and increased right atrial pressure were independently associated with AF in this population with mitral stenosis. After adjustment was performed for these variables, age was not independently associated with AF.

Adult↗
PubMed1997

A single-point mutation in HCF causes temperature-sensitive cell-cycle arrest and disrupts VP16 function.

The temperature-sensitive BHK21 hamster cell line tsBN67 ceases to proliferate at the nonpermissive temperature after a lag of one to a few cell divisions, and the arrested cells display a gene expression pattern similar to that of serum-starved cells. The temperature-sensitive phenotype is reversible and results from a single missense mutation--proline to serine at position 134--in HCF, a cellular protein that, together with the viral protein VP16, activates transcription of herpes simplex virus (HSV) immediate-early genes. The tsBN67 HCF mutation also prevents VP16 activation of transcription at the nonpermissive temperature. The finding that the same point mutation in HCF disrupts both VP16 function and the cell cycle suggests that HCF plays a role in cell-cycle progression in addition to VP16-dependent transcription.

Amino Acid Sequence↗
PubMed1997

Association of calcium channel blocker use with increased rate of acute myocardial infarction in patients with left ventricular dysfunction.

The Studies of Left Ventricular Dysfunction (SOLVD) assessed the effect of enalapril in patients with systolic left ventricular dysfunction (LVD). We performed retrospective analyses of the association between calcium channel blocker (CCB) use and fatal and nonfatal myocardial infarction (MI) in these patients. MI occurred in 11.5% of 845 patients receiving CCBs versus 7.5% of 2551 patients not receiving CCBs in the enalapril group and in 14.4% of 874 patients receiving CCBs versus 9.3% of 2527 patients not receiving CCBs in the placebo group. By multivariate Cox regression analysis, adjusting for comorbidity, cause and severity of LVD, heart failure, and concomitant drug use, CCB use was an independent predictor of MI (relative risk [RR] 1.37, confidence interval [CI] 1.14 to 1.63). The increase in MI risk was greater among patients with a higher heart rate (RR 1.46, CI 1.14 to 1.86) and lower blood pressure (RR 1.45, CI 1.14 to 1.86). The adjusted risk ratio for all-cause mortality associated with CCB use was 1.14 (CI 1.00 to 1.28; p = 0.0454). In this analysis of patients with LVD, CCB use was associated with significantly increased risk of fatal or nonfatal MI.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Association of hemostatic factors with peripheral vascular disease.

Hemostatic risk factors have been well established in coronary artery disease but less well studied in peripheral vascular disease. The relationship of coagulation and fibrinolytic proteins to lower limb arterial occlusive disease and other vascular risk factors remains poorly defined. Fibrinogen, factor VII coagulant activity, von Willebrand factor (vWf) antigen, and plasminogen activator inhibitor-1 (PAI-1) activity were measured in 46 adult participants in the Arterial Disease Multiple Intervention Trial (ADMIT) and in 76 control subjects and related to ankle-brachial systolic pressure index (ABI), a measure of lower limb arterial stenosis. The primary inclusion criterion for the ADMIT study population was an average of two ABIs <0.85. Fibrinogen and PAI-1 in ADMIT subjects were significantly higher than in control subjects (331 +/- 52 mg/dl vs 273 +/- 46 mg/dl, p < 0.0001; 18.7 +/- 10 units/ml vs 13.5 +/- 8.9 units/ml, p < 0.04). There were significant correlations of fibrinogen with ABI, factor VII coagulant activity, and systolic and diastolic blood pressures; PAI-1 with body mass index and age; and factor VII coagulant activity with cholesterol levels. Logistic regression analysis, considering hemostatic variables and several known nonhemostatic risk factors of peripheral arterial disease, showed that fibrinogen and systolic blood pressure were independently associated with ABI status in this population. The results demonstrate a strong independent correlation between fibrinogen levels and the presence of lower limb arterial stenosis. PAI-1 levels were elevated in ADMIT participants, but multivariate analysis did not demonstrate an independent relationship between PAI-1 and ABI.

Aged↗
PubMed1997

Mivacurium or vecuronium for muscular relaxation in day-case surgery.

Anaesthetic agents for day-case surgery ideally should have a short duration of action. This study was designed to compare the efficacy and safety of mivacurium and vecuronium for healthy adults undergoing dental day-case surgery. Thirty fit healthy adult patients (ASA I or II) randomly received either mivacurium 0.15 mg kg-1 (n = 15) or vecuronium 0.1 mg kg-1 (n = 15). Anaesthesia included propofol, fentanyl, nitrous oxide and isoflurane. Maximum depression of T1 was greater in the vecuronium group (99.8%) than in the mivacurium group (98.3%). There was no difference between grade of intubation at 2 min between the two groups, although patients receiving vecuronium had a more profound block at the time of intubation than those who received mivacurium (89.2% vs. 78.9%). Recovery to 10% T1 was faster in the mivacurium group (11.2 min vs. 33.1 min). All patients in the vecuronium group received neostigmine at the termination of surgery. The neostigmine evoked recovery index in the vecuronium group (4.39 min) was less than the spontaneous recovery index in the mivacurium group (6.78 min). One patient in the mivacurium group had a low plasma cholinesterase concentration (0.43 ku L-1); recovery times however, fell within the 95% confidence intervals (CI) for the group. There was no correlation between cholinesterase levels and recovery time. Mivacurium may be the more appropriate agent for dental day-case surgery because it has a shorter duration of action and does not generally require antagonism with an anticholinesterase.

Adolescent↗
PubMed1997

Recruitment in the Trial of Nonpharmacologic Intervention in the Elderly (TONE).

OBJECTIVE: To compare the effectiveness of different approaches to participant enrollment in a behavior modification trial. DESIGN: Concurrent, prospective evaluation performed in context of recruitment for a randomized, controlled trial. SETTING: Four study centers located in Baltimore, Maryland, Memphis, Tennessee New Brunswick, New Jersey, and Winston-Salem, North Carolina. PARTICIPANTS: Men and women aged 60 to 80 years who were being treated with a prescription medication for control of hypertension. MAIN OUTCOME MEASURES: Visit counts and percent yields were assessed at each stage of the screening and randomization process. Logistic regression was used to contrast the randomization yields for different recruitment strategies and to explore the impact of sociodemographic characteristics and geographic location on recruitment yields. RESULTS: The overall randomization yields from a prescreen contact and a first screening visit to enrollment in the trial were 11% and 31%, respectively. Randomization yields varied significantly by participant age, education, and marital status. CONCLUSIONS: Our results demonstrate the feasibility of recruitment for trials of nonpharmacologic interventions in older people and suggest that mass mailing and mass media advertising campaigns provide an effective means of enrolling in such studies participants with a broad range of personal characteristics.

Advertising↗
PubMed1997

VP16 targets an amino-terminal domain of HCF involved in cell cycle progression.

The herpes simplex virus (HSV) regulatory protein VP16 activates HSV immediate-early gene transcription through formation of a multiprotein-DNA complex on viral promoters that includes the preexisting nuclear proteins HCF and Oct-1. The HCF protein is a complex of amino- and carboxy-terminal polypeptides derived from a large (approximately 2,000-amino-acid) precursor by proteolytic processing. Here we show that a 361-residue amino-terminal region of HCF is sufficient to bind VP16, stabilize VP16-induced complex assembly with Oct-1 and DNA, and activate transcription in vivo. This VP16 interaction region contains six kelch-like repeats, a degenerate repeat motif that is likely to fold as a distinctive beta-propeller structure. The third HCF kelch repeat includes a proline residue (P134) that is mutated to serine in hamster tsBN67 cells, resulting in a temperature-sensitive defect in cell proliferation. This missense mutation also prevents direct association between HCF and VP16, suggesting that VP16 mimics a cellular factor required for cell proliferation. Rescue of the tsBN67 cell proliferation defect by HCF, however, requires both the VP16 interaction domain and an adjacent basic region, indicating that HCF utilizes multiple regions to promote cell cycle progression.

Amino Acid Sequence↗