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Biomedical subjects

C Scott

Publications and source records attributed to C Scott.

At least 37 records · Page 2Linked to original sources
PubMed2001

Contrasting roles of p57(KIP2) and p21(WAF1/CIP1/SDI1) in transplanted human and bovine adrenocortical cells.

Cell transplantation provides a way to compare the regulation of cell proliferation in the same cell type in cell culture and in a vascularized tissue structure in a host animal. The cyclin-dependent kinase inhibitors p57(KIP2), p21(WAF1/CIP1/SDI1) and p27(KIP1) have been extensively studied in cell culture but their role in growth control in tissues is less well understood. In the present experiments we compared the behavior of cell cycle inhibitors in human and bovine adrenocortical cells in culture and following cell transplantation in scid mice. p57 was expressed in the majority of cells in the intact human adrenal cortex. However, double immunofluorescence showed that cells that are in the cell cycle are p57(-) adrenocortical cells, p57 and p27 levels were not affected by inhibition of growth at high cell density, whereas p21 was higher in dividing than growth-inhibited cells. However, p21 was also high in senescent adrenocortical cells. After transplantation of human adrenocortical cells in scid mice, p57 and p27 were observed in most cells in the transplant tissue. Over time the number of p21(+) cells decreased greatly in human adrenocortical cells, but not in bovine adrenocortical cells. This difference correlated with lower levels of cell division (assessed by Ki-67 or incorporation of bromodeoxyuridine) in the human cells in transplant tissues in comparison to bovine cells. The differences between human and bovine cells were observed both when cells were transplanted beneath the kidney capsule and when cells were injected subcutaneously in collagen gel. We conclude that the behavior of p57, but not p21, is consistent with a role as a physiological mediator of proliferative quiescence in the adrenal cortex. The high level of p21 in dividing adrenocortical cells in culture, and in bovine adrenocortical cells in transplant tissues, may be a response to conflicting positive and negative growth influences. Cells may enter the cell cycle under the influence of a strong positive mitogenic signal, but coexisting negative growth stimuli trigger a p21-dependent block to further progression through the cell cycle. This model suggests that bovine adrenocortical cells respond to positive growth stimuli in transplant tissues but human cells lack this response.

Adolescent↗
PubMed2001

Phase I study of topotecan plus cranial radiation for glioblastoma multiforme: results of Radiation Therapy Oncology Group Trial 9507.

PURPOSE: A phase I trial was conducted by the Radiation Therapy Oncology Group (RTOG) to determine the maximum-tolerated dose of topotecan that could be safely combined with standard cranial radiation for glioblastoma multiforme. A secondary objective was to document the acute and late toxicities of this combination of chemotherapy and radiation. PATIENTS AND METHODS: Forty-seven patients with histologically confirmed glioblastoma multiforme were entered onto this phase I trial. Three cycles of topotecan were administered at 21-day intervals commencing at day 1 of cranial radiotherapy (60 Gy/30 fractions). Each cycle consisted of daily 30-minute intravenous (IV) infusions for 5 days. The dose of topotecan was escalated in three-dose increments from 0.5 mg/m(2)/d to 1.0 mg/m(2)/d to 1.5 mg/m(2)/d in different patient groups. RESULTS: The majority of patients were over age 50. Three dose levels of topotecan were tested. Fifteen patients accrued to level 1 (topotecan dose 0.5 mg/m(2)/d). No grade 4 toxicities were seen. Sixteen patients accrued to level 2 (topotecan dose 1.0 mg/m(2)/d), five of whom had brief episodes of grade 4 neutropenia. Seventeen patients accrued to level 3 (1.5 mg/m(2)/d). Six of these patients had brief episodes of grade 4 neutropenia and four developed grade 3 thrombocytopenia. No serious nonhematologic or late toxicities were seen. Median survival for all patients was 9.7 months. There was no apparent difference in survival by topotecan dose schedule. CONCLUSION: Toxicity was acceptable at an IV topotecan dose of 1.5 mg/m(2)/d administered daily for 5 days every 21 days for three cycles. A phase II trial has been performed using this dose of topotecan.

Adolescent↗
PubMed2001

Event-related fMRI with simultaneous and continuous EEG: description of the method and initial case report.

We report on the initial imaging findings with a new technique for the simultaneous and continuous acquisition of functional MRI data and EEG recording. Thirty-seven stereotyped interictal epileptiform discharges (spikes) were identified on EEG recorded continuously during the fMRI acquisition on a patient with epilepsy. Localization of the BOLD activation associated with the EEG events was consistent with previous findings and EEG source modeling. The time course of activation was comparable with the physiological hemodynamic response function (HRF). The new methodology could lead to novel and important applications in many areas of neuroscience.

Cerebrovascular Circulation↗
PubMed2001

Functional versatility in the CRP-FNR superfamily of transcription factors: FNR and FLP.

The cAMP receptor protein (CRP; sometimes known as CAP, the catabolite gene activator protein) and the fumarate and nitrate reduction regulator (FNR) of Escherichia coli are founder members of an expanding superfamily of structurally related transcription factors. The archetypal CRP structural fold provides a very versatile mechanism for transducing environmental and metabolic signals to the transcription machinery. It allows different functional specificities at the sensory, DNA-recognition and RNA-polymerase-interaction levels to be 'mixed and matched' in order to create a diverse range of transcription factors tailored to respond to particular physiological conditions. This versatility is clearly illustrated by comparing the properties of the CRP, FNR and FLP (FNR-like protein) regulators. At the sensory level, the basic structural fold has been adapted in FNR and FLP by the acquisition in the N-terminal region of different combinations of cysteine or other residues; which bestow oxygen/redox sensing mechanisms that are poised according to the oxidative stress thresholds affecting the metabolism of specific bacteria. At the DNA-recognition level, discrimination between distinct but related DNA targets is mediated by amino acid sequence modifications in the conserved core contact between the DNA-recognition helix and target DNA. And, at the level of RNA-polymerase-interaction, different combinations of three discrete regions contacting the polymerase (the activating regions) are used for polymerase recruitment and promoting transcription.

Amino Acid Sequence↗
PubMed2001

SB-272183, a selective 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptor antagonist in native tissue.

A novel compound, SB-272183 (5-Chloro-2, 3-dihydro-6-[4-methylpiperazin-1-yl]-1[4-pyridin-4-yl]napth-1-ylaminocarbonyl]-1H-indole), has been shown to have high affinity for human 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors with pK(i) values of 8.0, 8.1 and 8.7 respectively and is at least 30 fold selective over a range of other receptors. [(35)S]-GTPgammaS binding studies showed that SB-272183 acts as a partial agonist at human recombinant 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors with intrinsic activities of 0.4, 0.4 and 0.8 respectively, compared to 5-HT. SB-272183 inhibited 5-HT-induced stimulation of [(35)S]-GTPgammaS binding at human 5-HT(1A) and 5-HT(1B) receptors to give pA(2) values of 8.2 and 8.5 respectively. However, from [(35)S]-GTPgammaS autoradiographic studies in rat and human dorsal raphe nucleus, SB-272183 did not display intrinsic activity up to 10 microM but did block 5-HT-induced stimulation of [(35)S]-GTPgammaS binding. From electrophysiological studies in rat raphe slices in vitro, SB-272183 did not effect cell firing rate up to 1 microM but was able to attenuate (+)8-OH-DPAT-induced inhibition of cell firing to give an apparent pK(b) of 7.1. SB-272183 potentiated electrically-stimulated [(3)H]-5-HT release from rat and guinea-pig cortical slices at 100 and 1000 nM, similar to results previously obtained with the 5-HT(1B) and 5-HT(1D) receptor antagonist, GR127935. Fast cyclic voltammetry studies in rat dorsal raphe nucleus showed that SB-272183 could block sumatriptan-induced inhibition of 5-HT efflux, with an apparent pK(b) of 7.2, but did not effect basal efflux up to 1 microM. These studies show that, in vitro, SB-272183 acts as an antagonist at native tissue 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

Nursing in the public sphere: health policy research in a changing world.

AIMS OF THE PAPER: To identify recent trends in the academic field of health policy, setting them in the context of wider changes in the socio-political and research environments and considering their implications for nursing research. BACKGROUND: Health policy is a well-established field of academic study and research in the United Kingdom (UK). The 1990s have seen some important intellectual developments in this field, as well as some major changes in the context of health-related research. DESIGN: A selective review of the relevant literature. CONCLUSIONS: The Department of Health's new Research & Development strategy can be understood as part of a wider trend, moving away from the traditional, university-based model of knowledge production towards a new one which involves other groups, such as employers, practitioners and patients. This may increase the opportunities for health care professionals in general - and nurses in particular - to influence the research agenda and to participate as researchers in the critical evaluation of health policy.

Health Policy↗
PubMed2001

Protein 4.1 in forebrain postsynaptic density preparations: enrichment of 4.1 gene products and detection of 4.1R binding proteins.

4.1 Proteins are a family of multifunctional cytoskeletal components (4.1R, 4.1G, 4.1N and 4.1B) derived from four related genes, each of which is expressed in the nervous system. Using subcellular fractionation, we have investigated the possibility that 4.1 proteins are components of forebrain postsynaptic densities, cellular compartments enriched in spectrin and actin, whose interaction is regulated by 4.1R. Antibodies to each of 4.1R, 4.1G, 4.1N and 4.1B recognize polypeptides in postsynaptic density preparations. Of these, an 80-kDa 4.1R polypeptide is enriched 11-fold in postsynaptic density preparations relative to brain homogenate. Polypeptides of 150 and 125 kDa represent 4.1B; of these, only the 125 kDa species is enriched (threefold). Antibodies to 4.1N recognize polypeptides of approximately 115, 100, 90 and 65 kDa, each enriched in postsynaptic density preparations relative to brain homogenate. Minor 225 and 200 kDa polypeptides are recognized selectively by specific anti-4.1G antibodies; the 200 kDa species is enriched 2.5-fold. These data indicate that specific isoforms of all four 4.1 proteins are components of postsynaptic densities. Blot overlay analyses indicate that, in addition to spectrin and actin, postsynaptic density polypeptides of 140, 115, 72 and 66 kDa are likely to be 4.1R-interactive. Of these, 72 kDa and 66 kDa polypeptides were identified as neurofilament L and alpha-internexin, respectively. A complex containing 80 kDa 4.1R, alpha-internexin and neurofilament L was immunoprecipitated with anti-4.1R antibodies from brain extract. We conclude that 4.1R interacts with the characteristic intermediate filament proteins of postsynaptic densities, and that the 4.1 proteins have the potential to mediate the interactions of diverse components of postsynaptic densities.

Actins↗
PubMed2001

Properties of the C-terminal domain of 4.1 proteins.

At the C-terminus of all known 4.1 proteins is a sequence domain unique to these proteins, known as the C-terminal domain (CTD). Mammalian CTDs are associated with a growing number of protein-protein interactions, although such activities have yet to be associated with invertebrate CTDs. Mammalian CTDs are generally defined by sequence alignment as encoded by exons 18-21. Comparison of known vertebrate 4.1 proteins with invertebrate (Caenorhabditis elegans and Drosophila melanogaster) 4.1 proteins indicates that mammalian 4.1 exon 19 represents a vertebrate adaptation that extends the sequence of the CTD with a Ser/Thr-rich sequence. The CTD was first described as a 22/24-kDa domain by chymotryptic digestion of erythrocyte 4.1 (4.1R) [Leto, T.L. & Marchesi, V.T. (1984) J. Biol. Chem. 259, 4603-4608]. Here we show that in 4.1R the 22/24-kDa fragment is not stable but rapidly processed to a 15-kDa fragment by chymotrypsin. The 15-kDa fragment is extremely stable, being resistant to overnight digestion in chymotrypsin on ice. Analysis of this fragment indicates that it is derived from residues 709-858 (SwissProt accession no. P48193), and represents the CTD of 4.1R. The fragment behaves as a globular monomer in solution. Secondary-structure predictions indicate that this domain is composed of five or six beta strands with an alpha helix before the most C-terminal of these. Together these data indicate that the CTD probably represents an independent folding structure which has gained function since the divergence of vertebrates from invertebrates.

Amino Acid Sequence↗
PubMed2001

A follow-up study of the characteristics of dean's letters.

PURPOSE: To assess the content and quality of dean's letters since the publication of guidelines recommended by the Association of American Medical Colleges (AAMC) in 1989. METHOD: In 1998, the dean's letter writers at all 124 U.S. medical schools were surveyed. The questionnaire incorporated items from two previous surveys (1981 and 1992). In addition, samples of dean's letters (n = 451) from all U.S. medical schools for the graduating class of 1998 were rated based on the AAMC's guidelines. RESULTS: The response rate of the 1998 survey (66%) was lower than those of the two previous surveys (87% for 1992 and 85% for 1981). Schools that prepared letters that followed the AAMC's guidelines were somewhat more likely to have responded. According to the letter writers in 1998, close to 300,000 letters (approximately 1,050,000 pages total) were sent to residency directors, at an estimated cost of $26,000 per school. A total of 65% of schools produced adequate dean's letters based on the 1989 AAMC's guidelines, compared with 55% in 1992. Many schools were organizing the dean's letter in more readable formats, and more schools provided information that allowed for a comparison of students within the same school. CONCLUSION: The improvements in dean's letters are encouraging, but ten years after the AAMC's guidelines, 35% of U.S. schools still produce unacceptable letters. With the addition of the electronic submission of information, it is time to review further improvements to the dean's letter.

Academic Medical Centers↗
PubMed2001

Anaerobic acquisition of [4FE 4S] clusters by the inactive FNR(C20S) variant and restoration of activity by second-site amino acid substitutions.

The FNR protein of Escherichia coli controls the transcription of target genes in response to anoxia. The anaerobic incorporation of oxygen-sensitive [4Fe 4S] clusters promotes dimerization, which in turn enhances DNA binding. Four potential iron ligands (C20, C23, C29 and C122) are essential for normal FNR activity in vivo. Three FNR variants (C20S, C23G and C29G) retained the ability to incorporate oxygen-sensitive [4Fe 4S] clusters and to bind target DNA with essentially unimpaired affinity, suggesting that their failure to function normally in vivo resides at a later stage in the signal transduction pathway. The C122 variant failed to assemble iron-sulphur clusters and to bind DNA. Second-site substitutions that partially restore activity to FNR(C20S) were generated by error-prone polymerase chain reaction and were located in the dimer interface, in the activating regions (AR1, 2 or 3) or close to C122. Substitutions at E47, R48, E123, I124, E127 or T128 allowed the extent of the FNR AR2 surface to be defined. Only one revertant, FNR(C20S Y69F G149S), specifically corrected the C20S defect. It was concluded that [4Fe 4S] cluster acquisition, dimerization and DNA binding are not sufficient to confer transcription regulatory activity on FNR: the iron-sulphur cluster must also be correctly liganded in order to establish effective activating contacts between FNR and RNA polymerase.

Amino Acid Substitution↗
PubMed2001

Phenotypes Associated with SHOX Deficiency.

Leri-Weill dyschondrosteosis (LWD) (MIM 127300) is a dominantly inherited skeletal dysplasia characterized phenotypically by Madelung wrist deformity, mesomelia, and short stature. LWD can now be defined genetically by haploinsufficiency of the SHOX (short stature homeobox-containing) gene. We have studied 21 LWD families (43 affected LWD subjects, including 32 females and 11 males, ages 3-56 yr) with confirmed SHOX abnormalities. We investigated the relationship between SHOX mutations, height deficit, and Madelung deformity to determine the contribution of SHOX haploinsufficiency to the LWD and Turner syndrome (TS) phenotypes. Also, we examined the effects of age, gender, and female puberty (estrogen) on the LWD phenotype. SHOX deletions were present in affected individuals from 17 families (81%), and point mutations were detected in 4 families (19%). In the LWD subjects, height deficits ranged from -4.6 to +0.6 SD (mean +/- SD = -2.2 +/- 1.0). There were no statistically significant effects of age, gender, pubertal status, or parental origin of SHOX mutations on height z-score. The height deficit in LWD is approximately two thirds that of TS. Madelung deformity was present in 74% of LWD children and adults and was more frequent and severe in females than males. The prevalence of the Madelung deformity was higher in the LWD vs. a TS population. The prevalence of increased carrying angle, high arched palate, and scoliosis was similar in the two populations. In conclusion, SHOX deletions or mutations accounted for all of our LWD cases. SHOX haploinsufficiency accounts for most, but not all, of the TS height deficit. The LWD phenotype shows some gender- and age-related differences.

Adolescent↗
PubMed2001

Patient evaluation of the hotel function of hospitals.

BACKGROUND: A means of measuring patient satisfaction is essential in the effort to improve the quality of health care delivered in our nation's hospitals. Accurate feedback allows employers to better meet patients' needs and allows hospital administrators to improve service delivery. Patients are empowered by having a voice in the manner in which their health care is delivered. Moreover, improving the efficiency of the health care delivery system decreases health care costs. Hospital comparisons can be made readily available to a large audience through the Internet, resulting in empowerment of the patient and a universal improvement in hospital care. This is the first multi-institutional analysis of patient satisfaction among New York City and northern New Jersey area tertiary care hospitals. In this study, we evaluated the patient-assessed hotel function of hospitals in a single geographic region to determine whether clinically and statistically significant differences would be revealed that could provide beneficial information to stakeholders in the healthcare system. METHODS: Patients (n = 261) who had spent a night during the past year in one of eleven hospitals within 60 miles of New York City were chosen at random from doctors' waiting rooms. On average, 24 patients from each hospital were surveyed. They were asked to complete a questionnaire that rated the various departments in the hospital on qualities such as courtesy, promptness, and cleanliness. The questionnaire also rated important characteristics of the patient experience, such as the ease of parking and the taste of the food. Each item on the survey was coded on a scale of 1 to 10 with 10 being the most positive response. The 26 specific questions were divided into 14 domains. Averages in each domain were compared by gender, age, and hospital identity, attractiveness, and setting. All statistical calculations were performed using SPSS/PC, and means were compared using t-tests. RESULTS: Analysis designed to evaluate outcomes between each of the possible 54 pairs of hospitals comparisons revealed statistically significant differences as often as 44% of the time in some outcomes measures (logistics), but as rarely as 7% of the time in others (billing function). Clinically significant differences (>2 units per scale) were frequently evident, although the ranges differed dramatically depending on the domains surveyed. Although age, gender, and race/ethnicity were generally not predictive of satisfaction, non-urban setting was correlated with greater patient satisfaction. CONCLUSION: By having access to patient satisfaction comparisons among hospitals, patients are empowered to make better choices, employers can identify and adapt to patient preferences, and administrators can improve the services delivered and decrease health care costs by improving efficiency. Although our study was somewhat limited by patient selection biases, the study's results suggest that Internet-based tools of comparison will enable patients to make free and informed decisions about their health care by comparing local hospitals and voting on their impressions of the facilities from which they receive care.

Data Collection↗
PubMed2001

The postsynaptic spectrin/4.1 membrane protein "accumulation machine".

An important aspect of the function of the membrane-associated cytoskeleton has been suggested to be to trap and retain selected transmembrane proteins at points on the cell surface specified by cell adhesion molecules. In the process, cell adhesion molecules are cross-linked to each other, and so junctional complexes are strengthened. In this short review, we will discuss recent advances in understanding the role of this "accumulation machine" in postsynaptic structures. Function in the brain depends on correct ordering of synaptic intercellular junctions, and in particular the recruitment of receptors and other apparatus of the signalling system to postsynaptic membranes. Spectrin has long been known to be a component of postsynaptic densities, and recent advances in molecular cloning indicate that beta spectrins at PSDs are all "long" C-terminal isoforms characterised by pleckstrin homology domains. Isoforms of protein 4.1 are also present at synapses. All four 4.1 proteins are represented in PSD preparations, but it is 4.1R that is most enriched in PSDs. 4.1R binds to several proteins enriched in PSDs, including the characteristic PSD intermediate filament, alpha-internexin. Both 4.1 and spectrin interact with ionotropic glutamate receptors (AMPA and NMDA receptors, respectively): 4.1 stabilises AMPA receptors on the cell surface. By linking these receptors to the cytoskeletal and cell adhesion molecules that specify glutamatergic synapses, the membrane protein accumulation machine is suggested to direct the formation of postsynaptic signalling complexes.

Animals↗