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Biomedical subjects

C Scott

Publications and source records attributed to C Scott.

At least 73 records · Page 4Linked to original sources
PubMed2000

Size at birth and cord blood levels of insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and the soluble IGF-II/mannose-6-phosphate receptor in term human infants. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood.

Experimental rodent studies demonstrate that insulin-like growth factor II (IGF-II) promotes fetal growth, whereas the nonsignaling IGF-II receptor (IGF2R) is inhibitory; in humans their influence is as yet unclear. A soluble, circulating form of IGF2R inhibits IGF-II mediated DNA synthesis and may therefore restrain fetal growth. We measured cord blood levels of IGF-II, soluble IGF2R, insulin, IGF-I, IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and examined their relationships to weight, length, head circumference, ponderal index, and placental weight at birth in 199 normal term singletons. IGF-II levels correlated with levels of IGF-I (r = 0.29; P < 0.0005), IGFBP-3 (r = 0.45; P < 0.0005), and soluble IGF2R (r = 0.20; P < 0.005). Insulin and IGF-I were positively related to all parameters of size at birth. IGF-II was weakly related to ponderal index (r = 0.18; P < 0.05) and placental weight (r = 0.18; P < 0.05), and the molar ratio of IGF-II to IGF2R was also related to birth weight (r = 0.15; P < 0.05). Correlations between the IGFs and size at birth were stronger in nonprimiparous pregnancies; in these, IGF-I (r = 0.52; P < 0.0005), IGFBP-3 (r = 0.41; P < 0.0005), and the IGF-II to IGF2R ratio (r = 0.40; P < 0.0005) were most closely related to placental weight, together accounting for 39% of its variance. We demonstrate for the first time relationships between circulating IGF-II and soluble IGF2R levels and size at birth, supporting their putative opposing roles in human fetal growth.

Body Constitution↗
PubMed2000

Identification of a novel C-terminal variant of beta II spectrin: two isoforms of beta II spectrin have distinct intracellular locations and activities.

It is established that variations in the structure and activities of betaI spectrin are mediated by differential mRNA splicing. The two betaI spectrin splice forms so far identified have either long or short C-terminal regions. Are analogous mechanisms likely to mediate regulation of betaII spectrins? Thus far, only a long form of betaII spectrin is reported in the literature. Five human expressed sequence tags indicated the existence of a short splice variant of betaII spectrin. The occurrence and DNA sequence of the short C-terminal variant was confirmed by analysis of human and rat cDNA. The novel variant lacks a pleckstrin homology domain, and has 28 C-terminal residues not present in the previously recognized longer form. Transcripts of the short C-terminal variant (7.5 and 7. 0 kb) were most abundant in tissues originating from muscle and nervous system. Antibodies raised to a unique sequence of short C-terminal variant recognized 240 kDa polypeptides in cardiac and skeletal muscle and in nervous tissue; in cerebellum and forebrain, additional 270 kDa polypeptides were detected. In rat heart and skeletal muscle, both long and short C-terminal forms of betaII spectrin localized in the region of the Z line. The central region of the sarcomere, coincident with the M line, was selectively labeled with antibodies to the short C-terminal form. In cerebellum, the short form was not detectable in parallel fibers, structures in which the long form was readily detected. In cultured cerebellar granule neurons, the long form was dominant in neurites, with the short form being most abundant in cell bodies. In vitro, the short form was found to lack the binding activity for the axonal protein fodaxin, which characterizes the C-terminal region of the long form. Subcellular fractionation of brain revealed that the short form was scarcely detectable in post-synaptic density preparations, in which the long form was readily detected. We conclude that variation in the structure of the C-terminal regions of betaII spectrin isoforms correlates with their differential intracellular targeting.

Alternative Splicing↗
PubMed2000

Accelerated hyperfractionation in patients with non-small cell bronchogenic cancers as a cost-effective and user- and patient-friendly schedule.

We developed an accelerated hyperfractionation schedule with acceptable effect and toxicity in non-small cell bronchogenic carcinomas. An evolutionary institutional pilot was initiated in March 1995 as a modification of Radiation Therapy Oncology Group (RTOG) 9205, thrice-daily fractionation schedule. Twenty-nine patients with bronchogenic and 7 with head and neck cancers had treatment initiated and completed. A dose of 1.2 Gy was delivered to a mediastinal plus tumor field concomitantly with synchronous boost of 0.6 Gy to a limited volume of gross tumor (twice daily for 21 treatments days in 4 weeks) with a total dose being 75.60 Gy to the primary gross tumor and 50.4 Gy to the elective volume. The bronchogenic cancers were stages IB (medically unresectable, n = 3), IIB (n = 4), IIIA (n = 4), or IIIB (n = 18). Eleven patients had squamous cell cancers, 13 adenocarcinomas, 1 large cell, and 2 carcinomas not specified. With 12 months median follow-up, tolerance has been excellent without any patient complaining of at least Oncology Nursing Society (ONS) grade 3 esophagitis; treatment interruptions occurred in only one patient after 8 days. Weight loss occurred in 12 patients, averaging 4.8% for these patients and 2% overall. Seven patients had a complete response and 20 a partial response. Median survival was 12 months, 1-year survival 58%, 2-year 21%, and 3-year 18%. Seven patients with bronchogenic cancer are still alive. Seven head and neck cancer patients were treated, in which five had base of tongue tumors stage T2 to 4, N0 to N1. Pharyngitis and mucositis were problematic in at least four patients. The outcomes are comparable with other RTOG experience. Hyperfractionated synchronous concomitant boost of total tumor dose to 75.6 Gy in 4 weeks for bronchogenic patients was well tolerated and acceptable to physicians and patients.

Aged↗
PubMed2000

Automated cover testing for binocular misalignment in awake monkeys using spectacle- mounted liquid crystal shutters.

PURPOSE: In humans, pathologic misalignment of the eyes (strabismus, or hetero-tropia) is readily detected using a clinical technique in which the visual axis of each eye is blocked briefly by a hand held occluder (i.e., the cover test, AKA the single cover test, or unilateral cover test). This manual technique is impractical for use in non-human primates. This paper reports the electronic hardware and computer software we have devised and adapted to perform an automated cover test in awake macaque monkeys (Macaca mulatta or rhesus, and Macaca nemistrina or pigtail) to facilitate the study of strabismus in this species. METHODS: Liquid crystal shutters (Displaytech LV2500OP-OEM) are mounted in aluminum spectacle frames which are positioned in front of the monkey's eyes by attaching the frame holder to an acrylic skull cap. The shutters are electrically actuated alternately to an "open" (transparent) or "closed" (opaque) state, occluding each eye in turn. The actuation signal (+/-5 volts) is generated by a single logic chip. The chip is driven by commercial data control and acquisition software (Spike 2, Cambridge Electronic Design) running on a Macintosh computer. Eye position and movement during this cover tests is monitored and recorded by the computer using surgically implanted scleral coils. Monkeys are rewarded for fixating small, moveable targets so that binocular misalignment can be measured with high precision at different or cardinal positions of horizontal and vertical gaze. RESULTS: The shutters produced occlusion of each eye as effective as that of an opaque plastic occluder used in previous experiments that required monocular viewing. Heterotropias were detected and recorded in monkeys and closely resembled those observed in human patients. It was also possible to detect heterophorias by actuating the shutters alternately. CONCLUSIONS: The shutters operated reliably, with negligible delay and transition times, providing automated, repeatable cover tests that are, in fact, in many respects superior to the standard clinical manual technique. In addition, their application to humans, using infrared electro-oculography instead of scleral coils to monitor eye position and movement, holds promise for future applications.

Animals↗
PubMed2000

Knowledge of display rules in prelingually deaf and hearing children.

Deaf children of elementary and secondary school age participated in a study designed to examine their understanding of display rules, the principles governing the expression and concealment of emotion in social situations. The results showed that deaf children's knowledge of display rules, as measured by their reported concealment of emotion, was comparable to that of hearing children of the same age. However, deaf children were less likely to report that they would conceal happiness and anger. They were also less likely to produce reasons for concealing emotion and a smaller proportion of their reasons were prosocial, that is, relating to the feelings of others. The results suggest that the understanding of display rules (which function to protect the feelings of other people) may develop more gradually in deaf children raised in a spoken language environment than it does in hearing children.

Affect↗
PubMed2000

Nursing in the public sphere: breaching the boundary between research and policy.

Nurses and nursing are associated traditionally with activities in a private sphere. This paper argues that, if clinical care is to be improved, nurses need to take a more active public role in making and implementing health policy at both local and national levels. In the current climate, empirical evidence is one of the most important tools for influencing health policy. This paper discusses contemporary models of the policy-making process before outlining a number of strategies that could be used to increase the policy impact of nursing research. Finally, while the current climate in the United Kingdom health-care arena presents opportunities for researchers to have an impact on policy, the growth of health policy research as a distinct field of scholarship also poses a number of challenges and dangers.

Decision Making, Organizational↗
PubMed1999

A phase 3 randomized study of radiotherapy plus procarbazine, CCNU, and vincristine (PCV) with or without BUdR for the treatment of anaplastic astrocytoma: a preliminary report of RTOG 9404.

PURPOSE: This study was an open label, randomized Phase 3 trial in newly diagnosed patients with anaplastic glioma comparing radiotherapy plus adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy with or without bromodeoxyuridine (BUdR) given as a 96-hour infusion each week of radiotherapy. METHODS AND MATERIALS: Only patients 18 years or older with newly diagnosed anaplastic glioma were eligible; central pathology review was accomplished, but was not mandated prior to registration. The study had initially opened as a Northern California Oncology Group (NCOG) trial in 1991, becoming an Intergroup RTOG, SWOG, and NCCTG study in July 1994. Total accrual of 293 patients was planned as the sample size, using survival and time to tumor progression as the primary endpoints. The experiment arm (RT/BUdR plus PCV) was to be compared to the control arm (RT plus PCV) using an alpha = 0.05, one-tailed, with a power of 85% for detecting an increase in median survival from 160 to 240 weeks, assuming a 3-year follow-up after completion of enrollment. RESULTS: As of July 1996, 281 patients had been randomized; 53 (20%) were ineligible, primarily based upon central pathology review, and another 39 cases were canceled. In total, 30% of cases were excluded from analysis. The treatment arms were well balanced despite this rate of exclusion. The RTOG Data Monitoring Committee recommended suspension of enrollment in July 1996 based upon a stochastic curtailment analysis which strongly suggested that the addition of BUdR would not be associated with increased survival. In February 1997, the study was closed prior to full enrollment. At that time, the 1-year survival estimates were 82% versus 68% for RT plus PCV and RT/BUdR plus PCV respectively (one-sided, p = 0.96). The conditional power analysis indicated that even with an additional 12 months of additional accrual and follow-up the probability of detecting the prespecified difference was less than 0.01%. The differences in the two arms seem to be due to early deaths in the BUdR arm, not related to toxicity of the treatment. CONCLUSIONS: Despite encouraging Phase 2 results with BUdR, it is unlikely that a survival benefit will be seen. A final study analysis will not be done for at least 3 more years.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

The benefit of treatment intensification is age and histology-dependent in patients with locally advanced non-small cell lung cancer (NSCLC): a quality-adjusted survival analysis of radiation therapy oncology group (RTOG) chemoradiation studies.

PURPOSE: Currently, chemoradiation treatment strategies in locally advanced NSCLC are essentially the same irrespective of tumor histology or patient age. The purpose of this study is to analyze the impact of age, histology, Karnofsky performance status (KPS), and specific toxicities on the median survival time (MST) and quality-adjusted survival (QTime) for each treatment strategy. METHODS AND MATERIALS: Nine hundred seventy-nine patients with Stage II-IIIB inoperable NSCLC were enrolled on 6 prospective Phase II and III studies from 1983 to 1995. Treatment regimens ranged from standard RT (SRT) to 60 Gy, hyperfractionated RT (HRT) to 69.6 Gy, induction chemotherapy (ICT) of cisplatin (CIS) and vinblastine (VBL) followed by SRT, ICT + concurrent CT (CCT) + SRT, and CCT + HRT; CCT consisted of etoposide or VBL + CIS. Toxicities assessed were skin, mucous membrane, lung, esophagus, neurologic, hematologic, and upper GI. QTime was calculated by weighting the time spent with a specific toxicity, as well as local or distant tumor progression. Each toxicity was weighted with increasing severity as the toxicity increased in grade. RESULTS: As expected, patients with the worst KPS (50-70) had the lowest MST (7.8 months) and QTime (6.7 months). Patients <70 years had improved survival with more aggressive therapy (i.e., ICT + SRT or CCT + HRT), while patients > 70 years achieved the best QTime with standard RT (SRT) alone. In patients with squamous cell carcinoma, those treated with ICT + CCT + SRT had dramatically improved MST (25.7 months) and QTime (21.8 months) compared to the other treatment regimens (11.7-12.8 and 10.7-12 months, respectively). Patients with adenocarcinoma, however, generally manifested incrementally better MST and QTime as the therapies intensified. Within the concurrent chemoradiation arms, the upper GI and lung toxicities had the greatest impact on QTime. CONCLUSION: This quality-adjusted survival analysis suggests that there is a critical relationship between the type of histology and its optimal treatment, age and the ability to tolerate intensive therapy, and the need to reduce lung and upper GI toxicities.

Adenocarcinoma↗
PubMed1999

Transient exposure to HIV-1 Tat protein results in cytokine production in macrophages and astrocytes. A hit and run phenomenon.

The pathological correlates of dementia due to human immunodeficiency virus (HIV) infection are glial cell activation and cytokine dysregulation. These findings occur in the setting of small numbers of productively infected cells within the brain. We determined whether exposure of susceptible cells to Tat protein of HIV could result in the production of select proinflammatory cytokines. In a dose-responsive manner, Tat induced interleukin (IL)-1beta production in monocytic cells, while astrocytic cells showed an increase in mRNA for IL-1beta, but had a translation block for IL-1beta protein production. Conversely, IL-6 protein and mRNA productions were strongly induced in astrocytic cells and minimally in monocytic cells. IL-1beta and IL-6 production were independent of tumor necrosis factor-alpha production. An exposure to Tat for a few minutes was sufficient for sustained releases of cytokines for several hours. This prolonged cytokine production is likely maintained by a positive feed back loop of Tat-induced nuclear factor kappaB activation and cytokine production that is independent of extracellular calcium. Thus a transient exposure may be sufficient to initiate a cascade of events resulting in cerebral dysfunction and a "hit and run" approach may be in effect. Hence cross-sectional measurement of viral load in the brain may not be a useful indicator of the role of viral products in the neuropathogenesis of HIV dementia.

Astrocytes↗
PubMed1999

Interfraction interval does not affect survival of patients with non-small cell lung cancer treated with chemotherapy and/or hyperfractionated radiotherapy: a multivariate analysis of 1076 RTOG patients.

PURPOSE: It was observed by Jeremic et al. that a shorter interfraction interval (IFI) was associated with an improved survival in patients (pts) with locally advanced non-small cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (HFX-RT), with or without chemotherapy (CT). Our analysis was undertaken to verify this hypothesis. METHODS AND MATERIALS: Records of patients treated on 5 Radiation Therapy Oncology Group (RTOG) studies were reviewed, and an actual IFI, defined as a mean of all daily IFIs, was calculated. RT dose was 1.2 Gy BID to 69.6 Gy. The relationship between the length of IFI and the median survival time and incidence of esophagitis was investigated. RESULTS: In 682 pts eligible for this analysis, a full dose of RT was delivered and at least 90% of all daily IFIs were available. The actual mean IFI was as follows: 4-4.9 h in 51% of pts; 5-5.9 h in 17%; 6-6.9 h in 28% and 7-8 h in 4%. In multivariate analysis, only lack of weight loss, use of CT, low nodal stage and good KPS, but not IFI (4-6 h vs. 6-8 h) were associated with an improved survival for all pts (p values: <0.0001; <0.0001; 0.006; 0.006, and 0.73, respectively), as well as for HFX-RT only pts. For the CT-HFX-RT pts, not enough data points are available for a meaningful analysis. Length of IFI did not influence the incidence of Grade 3 or higher esophagitis (p = 0.82), but use of CT was associated with a 12-fold greater risk of developing severe esophagitis (p < 0.0001). CONCLUSION: Length of IFI (4-6 h vs. 6-8 h) did not influence survival and acute complications incidence in pts with NSCLC treated in RTOG studies with HFX-RT to 69.6 Gy. Previously identified factors, such as use of CT, minimal weight loss, good KPS and low nodal stage, were confirmed again to be associated with a favorable prognosis in a multivariate analysis. Use of CT was associated with a 12-fold greater risk of developing severe esophagitis than HFX-RT alone. It appears that an IFI of 4-8 hr is acceptable in clinical practice for pts with NSCLC, treated with HFX-RT.

Adenocarcinoma↗
PubMed1999

Prevention of exercise-induced bronchospasm in pediatric asthma patients: a comparison of salmeterol powder with albuterol.

BACKGROUND: Exercise-induced bronchospasm (EIB) is a common problem in children with asthma. Pretreatment with the beta2 (beta 2)-adrenoreceptor agonist albuterol is effective for preventing EIB, but is recognized as providing only short-term (2 to 3 hour) protection. OBJECTIVE: To evaluate the 12-hour efficacy and safety of single doses of 25 micrograms and 50 micrograms of salmeterol powder administered via Diskus inhaler versus albuterol aerosol via pressurized metered-dose inhaler and placebo in preventing EIB in asthmatic children. METHODS: A randomized, double-blind, placebo-controlled, double-dummy, single-dose, four-way crossover study was conducted in pediatric patients (4 to 11 years of age) demonstrating EIB and mild-to-moderate asthma. Serial forced expiratory volume in 1 second (FEV1) was measured before and after standard treadmill exercise at hour 1, hour 6, and hour 12 after administration of 25 micrograms or 50 micrograms salmeterol powder, 180 micrograms albuterol aerosol, or placebo. Adverse events were recorded. RESULTS: After completion of the hour 1 exercise challenge, mean minimum % predicted FEV1 was significantly higher following albuterol (91.3%) than for placebo (75.3%) and for both dosages of salmeterol (86.9% and 85.8% for salmeterol 25 micrograms and 50 micrograms, respectively; P < or = .026). After completion of both the hour 6 and hour 12 exercise challenges, the 50-microgram salmeterol treatment produced a significantly higher mean minimum percent of predicted FEV1 (90.6% and 87.3% predicted, respectively) than the mean minimum percent of predicted FEV1 for placebo or albuterol (73.8% to 78.4% of predicted; P < or = .041). At hour 6, the 25-microgram salmeterol treatment was not significantly different from albuterol or placebo. At hour 12, the 25-microgram salmeterol treatment mean minimum percent of predicted was significantly higher than albuterol (87.9% versus 73.8% of predicted; P = .006) and there was also a trend toward significance over placebo (76.9% predicted; P = .056). At all exercise periods, no statistically significant differences in spirometry values were observed between the two salmeterol treatment groups. Safety profiles were similar among treatments, including placebo. No drug-related adverse events or withdrawals due to adverse events occurred. Changes in laboratory values, vital signs, 12-lead ECGs, and physical examinations were unremarkable. CONCLUSIONS: A single 50-microgram dose of salmeterol powder provided effective and safe protection against EIB for at least 12 hours in asthmatic children and provided a significantly more prolonged effect than albuterol aerosol (180 micrograms).

Administration, Inhalation↗
PubMed1999

Participation of the melanocortin-1 receptor in the UV control of pigmentation.

The cloning of the melanocortin-1 receptor (MC1R) gene from human melanocytes and the demonstration that these cells respond to the melanocortins alpha-melanocyte stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH) with increased proliferation and melanogenesis have renewed the interest in investigation the physiological role of these hormones in regulating human pigmentation. Alpha-melanocyte stimulating hormone and ACTH are both synthesized in the human epidermis, and their synthesis is upregulated by exposure to ultraviolet radiation (UVR). Activation of the MC1R by ligand binding results in stimulation of cAMP formation, which is a principal mechanism for inducing melanogenesis. The increase in cAMP is required for the pigmentary response of human melanocytes to UVR, and for allowing them to overcome the UVR-induced G1 arrest. Treatment of human melanocytes with alpha-MSH increases eumelanin synthesis, an effect that is expected to enhance photoprotection of the skin. Population studies have revealed more than 20 allelic variants of the MC1R gene. Some of these variants are overexpressed in individuals with skin type I or II, red hair, and poor tanning ability. Future studies will aim at further exploration of the role of these variants in MC1R function, and in determining constitutive human pigmentation, the response to sun exposure, and possibly the susceptibility to skin cancer.

Alleles↗
PubMed1999

Two operons that encode FNR-like proteins in Lactococcus lactis.

Global regulatory circuits of the type mediated by CRP and FNR in Escherichia coli were sought in Lactococcus lactis to provide a basis for redirecting carbon metabolism to specific fermentation products. Using a polymerase chain reaction (PCR) approach, two genes (flpA and flpB) encoding FNR-like proteins (FlpA and FlpB) with the potential for mediating a dithiol-disulphide-dependent regulatory switch, were identified. Transcript analysis indicated that they are distal genes of two paralogous operons, orfX-orfY-flp, in which the orfX and orfY genes were predicted to encode binding domain components of cation ATPases and storage proteins respectively. The corresponding promoters were each associated with a potential FNR site (TTGAT----ATCAA) at positions +4.5 (flpA operon) and -42.5 (flpB operon), suggesting that the respective operons might be negatively and positively autoregulated. The incomplete open reading frames (orfWA/B) located upstream of each operon were predicted to encode additional components of paralogous cation ATPases. No phenotypic effects were detected in flpA and flpB single mutants, but the double mutant had a lower intracellular zinc content, an increased sensitivity to hydrogen peroxide and an altered polypeptide profile (as determined by two-dimensional gel electrophoresis): formate production was not affected. It was concluded tentatively that FlpA and FlpB regulate overlapping modulons, including systems concerned with zinc uptake, in response to metal ion or oxidative stress.

Amino Acid Sequence↗