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Biomedical subjects

N Cook

Publications and source records attributed to N Cook.

At least 37 records · Page 2Linked to original sources
PubMed1997

Noninvasive, real-time method for the examination of thymidine uptake events--application of the method to V-79 cell synchrony studies.

[14C]Thymidine uptake into V-79 hamster lung fibroblasts has been successfully demonstrated using a noninvasive, real-time method utilizing Cytostar-T scintillating microplates. These plates are standard format, tissue culture-treated, 96-well microplates with an integral scintillating base. The microplates permit the culture and observation of adherent cell monolayers. Biological activities of the cells can be studied by the provision of specific radiolabeled compounds. The biological activities of the adherent monolayer bring the specific radiolabel into proximity with the scintillating base and a scintillation signal is thereby generated. [14C]Thymidine incorporation on the microplates can be used to examine cell proliferation and cell cycle events. Using a combined mitotic shake-off/aphidicolin treatment to achieve synchronization, the thymidine incorporation activities of V-79 cells have been examined on Cytostar-T plates and correlated to traditional methods of determining incorporation. The method was further used to examine the effects of colcemid and olomoucine, both chemical inhibitors of cell proliferation, on synchronous populations of cells. The homogeneous detection format and the microplate nature of the method suggest a role for scintillating microplates in cell biology research and drug discovery.

Animals↗
PubMed1997

Macaques infected with live attenuated SIVmac are protected against superinfection via the rectal mucosa.

Good protection against systemic challenge in the SIVmac model of AIDS has been provided by prior infection with attenuated virus. To determine if such protection extends to intrarectal mucosal challenge two molecular clones, SIVmacC8 and SIVmacJ5, were used in this study. SIVmacC8 has an attenuated phenotype in vivo, due to a 12-bp deletion in the nef/ 3'-LTR, whereas SIVmacJ5 has a full size nef open reading frame and induces AIDS in infected macaques. The J5 molecular clone was shown to infect rhesus macaques following atraumatic intrarectal inoculation. The dynamics were similar to those following intravenous inoculation resulting in early, high, cell-associated viremia and seroconversion. Four macaques previously infected with the attenuated SIVmacC8 resisted superinfection with SIVmacJ5, following intrarectal inoculation. These animals also resisted intrarectal infection with an HIV/SIV chimeric virus (SHIV) composed of SIVmac239 expressing the HXBc2 env, tat, and rev genes, suggesting that immunity to the envelope proteins was unlikely to be involved in the superinfection resistance. Infection with the attenuated SIVmac generated cytotoxic T lymphocytes (CTL) detectable in the peripheral circulation, serum neutralizing antibodies, and SIV-binding antibodies in rectal fluids. SIVmacC8 proviral DNA was found in lymph nodes removed at necropsy but there was no evidence for local sequestration of challenge virus. SIV-specific CTL, were detected in gut-associated lymph nodes and may have a role in limiting superinfection following mucosal exposure.

Animals↗
PubMed1997

An institutional experience with second- and third-stage palliative procedures for hypoplastic left heart syndrome: the impact of the bidirectional cavopulmonary shunt.

OBJECTIVES: The aim of this study was to perform a retrospective analysis of an institutional experience with a consecutive series of patients with post-stage I palliation for hypoplastic left heart syndrome (HLHS). BACKGROUND: In a recent review of 212 consecutive patients who underwent stage I operations for HLHS at our institution between 1983 and 1993, we identified risk factors related to stage I mortality. We sought to examine the outcome for these patients at subsequent palliative procedures. METHODS: All patients who underwent stage I reconstruction between January 1983 and June 1993 and also underwent subsequent palliation at our institution were included. Seventy patients underwent palliative procedures and two underwent heart transplantation. Patient-specific factors and features of the stage II operation were analyzed for impact on stage II mortality and actuarial survival. RESULTS: The only independent risk factor for stage II mortality was the performance of a nonfenestrated Fontan operation (p < 0.001). There were nine in-hospital deaths (69%) in the 13 patients undergoing the nonfenestrated Fontan procedure at stage II. Fifty patients underwent intermediate superior vena cava to pulmonary artery anastomosis at stage II, with 4 (8%) early deaths. Pulmonary artery augmentation was performed in 19 patients (38%) at stage II, without increased operative risk. Hypoplastic left heart syndrome anatomic subtype did not influence stage II mortality. The modified fenestrated Fontan procedure has been performed as a third stage in 32 patients whose median age was 28.7 months, with one early death at a median follow-up of 24.5 months. CONCLUSIONS: A second-stage bidirectional cavopulmonary anastomosis for HLHS reduces second-stage mortality and improves intermediate survival. The modified fenestrated Fontan operation may then be performed as a final palliative stage with low operative risk.

Child, Preschool↗
PubMed1997

Human papillomavirus (HPV) in head and neck cancer. An association of HPV 16 with squamous cell carcinoma of Waldeyer's tonsillar ring.

BACKGROUND: Certain strains of human papillomavirus (HPV) have been shown to be etiologically related to the development of uterine cervical and other genital cancers, but their role in the development of malignancies at other sites is less well established. Previous studies have shown HPV DNA in tumors of the head and neck, but its prevalence has varied depending on the detection methods and the types of tumor and/or tissue examined. This study was undertaken to estimate the frequency of HPV DNA in squamous cell carcinoma (SCC) at different sites of the esophagus, head and neck and to compare the clinical behavior of HPV positive and negative tumors. METHODS: DNA was extracted from frozen tissue of 167 SCCs of the esophagus, head and neck. The DNA was screened for HPV sequences by polymerase chain reaction with two sets of consensus primers, one to a conserved region in the L1 gene (MY09/ MY11) and the other to a conserved region in the E1 open reading frame (IU/IWDO). The products were run on agarose gels, detected by ethidium bromide staining, and then the gels were subjected to Southern blot analysis and hybridized with probes specific to HPV 6, 16, and 18. All tumors found to be HPV positive with the consensus primers were amplified with type specific primers, and in selected cases the presence of HPV DNA was confirmed by restriction enzyme digestion of the tumor DNA with conventional Southern blot analysis. RESULTS: Overall, HPV sequences were found in 25 of 167 tumors (15%), but HPV was detected most frequently in tumors in Waldeyer's tonsillar ring. In that area, 9 of 15 (60%) were HPV positive. No HPV DNA was detected in 11 esophageal SCCs, 7 tumors of the pharynx/hypopharynx, or 6 pyriform sinus carcinomas. HPV DNA was detected in the following tumor sites: 1 of 28 (3.6%) in the larynx, 1 of 10 (10%) in the oral cavity, 5 of 39 (12.8%) in the tongue, 2 of 15 (13.5%) in the floor of the mouth, 3 of 21 (14.3%) supraglottic, and 1 of 7 (14.3%) in the lip. A high incidence of HPV DNA was also found in metastatic tumors located in cervical lymph nodes for which no primary site was clinically identified (3 of 8, 37.5%). With respect to age, gender, and tobacco and alcohol consumption, analysis of clinical data obtained by retrospective review showed no difference between patients with HPV DNA in their tumors and those in which no HPV was detected. However, HPV positive patients had larger tumors (P = 0.09) and a higher incidence of lymph node metastasis (P = 0.003). In spite of the higher stage of disease at presentation in HPV positive patients, there was no significant difference in 3-year survival rates between HPV positive patients and HPV negative patients (43.1% vs. 48.8%, respectively). Median follow-up was 27 months. CONCLUSIONS: In the head and neck, HPV-associated SCC had site specificity with the viral DNA frequently found in tumors in Waldeyer's tonsillar ring. Patients with HPV positive tumors presented with a higher stage of disease than patients with HPV negative tumors, but there was no significant difference in the 3-year survival rates between these two groups of patients.

Carcinoma, Squamous Cell↗
PubMed1996

HPV6 variants from malignant tumors with sequence alterations in the regulatory region do not reveal differences in the activities of the oncogene promoters but do contain amino acid exchanges in the E6 and E7 proteins.

Human papillomavirus type 6 (HPV6) causes benign epithelial proliferations of the anogenital and aerodigestive tract, which usually tend to regress spontaneously. The low incidence of HPV6 in carcinomas and the rare progression of the benign tumors has led to the classification of HPV6 as "low-risk" virus. A series of reports, however, described the isolation of HPV6 variants from malignant tumors characterized by sequence rearrangements in the noncoding regulatory region (NCR). It was speculated that these sequence alterations play a role in tumor progression by enhancing the promoter activity and thereby increasing the expression of the viral oncogenes E6 and E7. To elucidate if HPV6 isolates from malignancies do regularly exhibit sequence alterations in the regulatory region we first determined and complied the sequences of the NCRs of a number of isolates from benign and malignant lesions. This analysis revealed in general a high degree of sequence conservation between the individual isolates. Most of the isolates, however, differed, independently of origin, by a major and one or two minor insertions from the prototype HPV6b sequence. When tested in a functional assay these altered NCR sequences did not result in significantly different activities of the promoters responsible for the expression of the E6 and E7 genes. Further analysis of the E6 and E7 coding region revealed a surprisingly high sequence variability within the E6 ORF and allowed the detection of amino acid exchanges unique for isolates from carcinomas.

Base Sequence↗
PubMed1996

Protective mucosal immunity elicited by targeted iliac lymph node immunization with a subunit SIV envelope and core vaccine in macaques.

Prevention of sexually transmitted HIV infection was investigated in macaques by immunization with a recombinant SIV (simian immunodeficiency virus) envelope gp 120 and core p27 vaccine. In two independent series of experiments, we used the novel targeted iliac lymph node (TILN) route of immunization, aiming close to the iliac lymph nodes draining the genitorectal mucosa. Rectal challenge with the SIVmac 32H J5 molecular clone in two series induced total protection in four out of seven macaques immunized by TILN, compared with infection in 13 of 14 unimmunized macaques or immunized by other routes (P = 0.025). The remaining three macaques showed either a decrease in viral load ( > 90%) or transient viremia, indicating that all seven TILN-immunized macaques showed total or partial protection (P = 0.001). Protection was associated with significant increase in the iliac lymph nodes of IgA antibody-secreting cells to p27 (P < 0.02), CD8-suppressor factor (P < 0.01), and the chemokines RANTES and MIP-1 beta (P < 0.01).

Animals↗
PubMed1995

Ten-year institutional experience with palliative surgery for hypoplastic left heart syndrome. Risk factors related to stage I mortality.

BACKGROUND: We reviewed 212 consecutive patients who underwent stage I palliative surgery for hypoplastic left heart syndrome (HLHS) at our institution between January 1983 and June 1993. METHODS AND RESULTS: Six surgeons participated in the care of these patients. Follow-up is 97% complete. Preoperative anatomic and physiological factors and procedural features of the stage I operation were analyzed for impact on stage I mortality, survival to stage II palliation, and actuarial survival. Hospital mortality was not significantly lower during the second half of the study period (P = .242). Operative mortality was 46.2%. Multivariate analysis revealed improved stage I operative survival in patients with mitral stenosis (MS) and aortic stenosis (AS; P = .006). Additional risk factors for stage I mortality were a lower immediately pre-stage I pH (P = .034) and weight < 3 kg (P = .015). Overall first-year actuarial survival for MS/AS was 59%, and it was 33% for all others (P = .001). Among stage I survivors, patients with MS/AS were more likely to survive to stage II palliation (P = .031). Analysis of actuarial survival of stage I survivors showed that a smaller ascending aorta (P < .001), aortic atresia (P < .001), and mitral atresia (P = .002) were all risk factors for intermediate death. CONCLUSIONS: Preoperative anatomic and physiological state are predictors of stage I mortality. HLHS anatomic subtype also influences intermediate outcome, most notably pre-stage II attrition. These data may be useful in choosing initial management for patients with HLHS.

Analysis of Variance↗
PubMed1995

Migraine and subsequent risk of stroke in the Physicians' Health Study.

OBJECTIVE: To evaluate, in a prospective design, whether migraine is an independent risk factor for subsequent stroke. DESIGN: Evaluated as part of the Physicians' Health Study, a randomized, double-blind, placebo-controlled trial of aspirin and beta-carotene in the primary prevention of cardiovascular disease and cancer begun in 1982. The aspirin component of the study was terminated in 1988, with average follow-up of 60.2 months. SETTING: Conducted by mail among male physicians throughout the United States. PARTICIPANTS: A total of 22,071 US male physicians aged 40 to 84 years in 1982 with no prior history of cancer or cardiovascular diseases who were enrolled in the Physicians' Health Study. INTERVENTIONS: Participants were randomized to receive 325 mg of aspirin or aspirin placebo every other day and to receive 50 mg of beta-carotene or placebo on alternate days. MAIN OUTCOME MEASURES: The primary outcomes of the Physicians' Health Study were cardiovascular disease and cancer. Because stroke was a main outcome, this provided the opportunity to evaluate the association between migraine headaches and stroke. RESULTS: Physicians reporting migraine (n = 1479) had significantly increased risks of subsequent total stroke and ischemic stroke compared with those not reporting migraine. After adjustment for age, aspirin and beta-carotene treatment assignment, and a number of cardiovascular risk factors, the relative risks were 1.84 (95% confidence interval, 1.06 to 3.20) for total stroke and 2.00 (95% confidence interval, 1.10 to 3.64) for ischemic stroke. There were too few hemorrhagic strokes in the study to evaluate this end point. No associations were seen between ordinary nonmigraine headache and subsequent stroke or between migraine and subsequent myocardial infarction or cardiovascular death. CONCLUSION: These data raise the possibility that vascular events associated with migraine may also have causative importance in stroke but require confirmation in other studies specifically designed to evaluate this question.

Adult↗
PubMed1995

The effect of potassium supplementation in persons with a high-normal blood pressure. Results from phase I of the Trials of Hypertension Prevention (TOHP). Trials of Hypertension Prevention (TOHP) Collaborative Research Group.

We conducted a randomized, double-blind, placebo-controlled trial of oral potassium chloride supplementation (60 mmol/d) in 353 men and women with an initial average diastolic blood pressure between 80 and 89 mm Hg. In the active (n = 178) compared to the placebo (n = 175) treatment group, the urinary potassium level was significantly (p < 0.001) increased by an average of 44.0 and 42.3 mmol/24 h following 3 and 6 months of therapy, respectively. Compared to placebo, active treatment was associated with a small (mean = 1.8 mm Hg) but significant (p = 0.04) reduction in diastolic blood pressure following 3 months of therapy. Following 6 months, however, this apparent treatment effect had virtually disappeared (mean reduction in diastolic blood pressure = 0.3 mm Hg). There was no significant effect of potassium supplementation on systolic blood pressure at either follow-up visit. There was a significant, independent, dose-response relationship between change in both 24-hour urinary potassium excretion and urinary sodium-potassium ratio and the corresponding change in diastolic blood pressure (-1.49 mm Hg for the highest versus the lowest quartile of change in urinary potassium excretion.

Administration, Oral↗
PubMed1995

Early suppression of SIV replication by CD8+ nef-specific cytotoxic T cells in vaccinated macaques.

In order to develop a successful subunit vaccine against infection with the human immunodeficiency virus (HIV), protective immune effector functions must be identified. Until now, there has been only indirect evidence that HIV-specific cytotoxic T lymphocytes (CTLs) fulfill this role. Using the macaque simian immunodeficiency virus (SIV) model, the protective potential of nef-specific CTLs, stimulated by vaccination, was examined in animals challenged with a high intravenous dose of the pathogenic simian immunodeficiency virus, SIVmac251(32H)(pJ5). An inverse correlation was found between the vaccine-induced nef-specific CTL precursor frequency and virus load measured after challenge. In addition, the early decline in viraemia, observed in both vaccinated and unvaccinated control animals was associated with the development of virus-specific CTL activity and not with the presence of virus-specific neutralizing antibodies. The results imply that vaccines that stimulate strong CTL responses could protect against HIV infection.

Animals↗
PubMed1995

Astroviruses.

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Adult↗
PubMed1995

Repair and evolution of nef in vivo modulates simian immunodeficiency virus virulence.

Experimental evidence from the simian immunodeficiency virus (SIV) model of AIDS has shown that the nef gene is critical in the pathogenesis of AIDS. Consequently, nef is of considerable interest in both antiviral drug and vaccine development. Preliminary findings in two rhesus macaques indicated that a deletion of only 12 bp found in the overlapping nef/3' long terminal repeat (LTR) region (9501 to 9512) of the SIVmacC8 molecular clone was associated with reduced virus isolation frequency. We show that this deletion can be repaired in vivo by a sequence duplication event and that sequence evolution continues until the predicted amino acid sequence of the repair is virtually indistinguishable from that of the virulent wild type. These changes occurred concomitantly with reversion to virulence, evidenced by a high virus isolation frequency and load, decline in anti-p27 antibody, substantial reduction in the CD4/CD8 ratio, and development of opportunistic infections associated with AIDS. These findings clearly illustrate the capacity for repair of small attenuating deletions in primate lentiviruses and also strongly suggest that the region from 9501 to 9512 in the SIV nef/3' LTR region is of biological relevance. In addition, the ability of attenuated virus to revert to virulence raises fundamental questions regarding the nature of superinfection immunity.

Amino Acid Sequence↗
PubMed1995

Detection of human papillomavirus types in balanitis xerotica obliterans and other penile conditions.

OBJECTIVES: To determine the prevalence of human papillomavirus (HPV) types 6, 11, 16 and 18 in foreskin biopsies from patients with balanitis xerotica obliterans (BXO) and other penile conditions. MATERIALS AND METHODS: Foreskin biopsy specimens from 24 patients with penile lesions and 5 control patients were analysed by type-specific polymerase chain reaction (PCR). RESULTS: HPV6 or HPV16 were not detected in patients with BXO. HPV6 was detected in 2 controls. CONCLUSIONS: Genital papillomaviruses do not have a strong association with BXO.

Balanitis↗
PubMed1994

The internal clock: electroencephalographic evidence for oscillatory processes underlying time perception.

It has been proposed that temporal perception and performance depend on a biological source of temporal information. A model for a temporal oscillator put forward by Treisman, Faulkner, Naish, and Brogan (1990) predicted that if intense sensory pulses (such as auditory clicks) were presented to subjects at suitable rates they would perturb the frequency at which the resulting pattern of interference between sensory pulse rates and time judgments would depend on the frequency of the temporal oscillator and so might allow the frequency to be estimated. Such interference patterns were found using auditory clicks and visual flicker (Treisman & Brogan, 1992; Treisman et al., 1990). The present study examines time estimation together with the simultaneously recorded electroencephalogram to examine whether evidence of such an interference pattern can be found in the EEG. Alternative models for the organization of a temporal system consisting of an oscillator or multiple oscillators are considered and predictions derived from them relating to the EEG. An experiment was run in which time intervals were presented for estimation, auditory clicks being given during those intervals, and the EEG was recorded concurrently. Analyses of the EEG revealed interactions between auditory click rates and certain EEG components which parallel the interference patterns previously found. The overall pattern of EEG results is interpreted as favouring a model for the organization of the temporal system in which sets of click-sensitive oscillators spaced at intervals of about 12.8 Hz contribute to the EEG spectrum. These are taken to represent a series of harmonically spaced distributions of oscillators involved in time-keeping.

Acoustic Stimulation↗